ECOMBINANT DNA RESEARCH Volume 1 1 QH 443 N278 v.ll 1990 Documents Relating to "NIH Guidelines for Research Involving Recombinant DNA Molecules" January 1 986— April 1987 December 1 990 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Services National Institutes of Health LIBRARY JUL ? ^ National Institutes o f ffogC O MBINANT DNA RES E A R C H Volume 1 1 Documents Relating to "NIH Guidelines for Research Involving Recombinant DNA Molecules" January 1986-April 1987 December 1 990 Prepared by the Office of Recombinant DNA Activities NIH Publication No. 91-3203 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health (US. ) Recombinant DNA Research, Volume 1 1 PREFACE This is the eleventh in a series constituting a "public record" of activities in regard to the National Institutes of Health (NIH) Guidelines for recombinant DNA research. The first ten volumes cover events from February 1 975 through December 1 985. This eleventh volume covers events from January 1 986 through April 1 987. Volumes 1 through 5 in this series and the Environmental Impact Statement may be purchased from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402 or GPO bookstores in selected cities throughout the United States. They may also be viewed in some 600 public libraries of the GPO depository system. The GPO stock numbers are: Volume 1, 017-004-00398-6; Volume 2, 017-040-00422-2; Volume 2 Supplement (Environmental Impact Statement), 017-040- 00413-3; Volume 3, 017-040-00429-0; Volume 3 Appendices, 017-040-0043-3; Volume 4, 01 7-040-00443-5; Volume 4 Appendices 01 7-040-00422-7; and Volume 5, 01 7-040-00470- 2. Volumes 6 through 1 1 are available from the Office of Recombinant DNA Activities, Building 31, Room 4B11, National Institutes of Health, Bethesda, MD 20892 USA. Recombinant DNA Research, Volume 1 1 [iii] Recombinant DNA Research, Volume 1 1 CONTENTS Federal Register of May 7, 1 986, promulgating Guidelines for Research Involving Recombinant DNA Molecules 1 Federal Register of June 25, 1986, announcing a meeting of the Recomninant DNA Advisory Committee (RAC) Working Group on Human Gene Therapy, August 8, 1986 30 Federal Register of June 25, 1 986, announcing a meeting of the RAC, September 29, 1 986 32 Federal Register of June 25, 1986, seeking comments on Proposed Actions Under the Guidelines for a meeting of the RAC Working Group on Human Gene Therapy, August 8, 1986, and a meeting of the RAC, September 29, 1 986 32 Federal Register of August 7, 1 986, announcing a meeting of the RAC Working Group on Definitions, September 5, 1986 34 Minutes of the Human Gene Therapy Subcommittee, August 8, 1986 36 Federal Register of August 1 5, 1 986, seeking comments on Proposed Actions Under the Guidelines to be considered at the RAC meeting, September 29, 1 986 72 Minutes of the RAC Working Group on Definitions, September 5, 1986 73 Minutes of the RAC meeting, September 29, 1986 81 Federal Register of October 29, 1 986, announcing a meeting of the RAC Working Group on Definitions, December 5, 1986 140 Minutes of the RAC Working Group on Definitions, December 5, 1986 141 Federal Register of December 1 9, 1 986, announcing a meeting of the RAC, February 2, 1987 155 Federal Register of December 19, 1986, seeking comments on Proposed Actions Under the Guidelines for the RAC meeting, February 2, 1987 155 Recombinant DNA Research, Volume 1 1 M CONTENTS (continued) Minutes of the RAC Lay Summary Working Group of the Human Gene Therapy Subcommittee, January 9, 1987 158 Minutes of the RAC meeting, February 2, 1987 163 Federal Register of March 11,1 987, seeking comments on Proposed Actions Under Guidelines to be considered at the RAC meeting, June 15, 1987 198 Federal Register of March 30, 1 987, announcing a meeting of the RAC Working Group on Human Gene Therapy, April 24, 1987 199 Minutes of the RAC Human Gene Therapy Subcommittee meeting, April 24, 1987 200 Selected letters and documents in the period January 1 986 through April 1987 209 Author index of letters and documents 295 Institution index of letters and documents 297 Recombinant DNA Research, Publication History 299 [vi] Recombinant DNA Research, Volume 1 1 V/ednesday Mav 7, 1986 Part III Department of Health and Human Services National Institutes of Health Guidelines for Research Involving Recombinant DNA Molecules; Notice ERRA1UM p. 16969 - Appendix C-I, insert word viral after line 3, eukaryotic Recombinant DNA Research, Volume 1 1 [ 1 ] 6958 Federal Register / Vol. 51, No. 88 / Wednesday, May 7, 1936 / Notices DEPARTMENT OF HEALTH AND HUMAN SERVICES Guidelines for Research Involving Recombinant DNA Molecules Way 1S86. These N1H Guidelines supersede earlier versions and will be in effect until further notice. Table of Contents I. Scope of Guidelines I-A — Purpose I-B — Definition of Recombinant DMA Molecules 1-C — General Applicability I-D — General Definitions II. Containment III. Guidelines for Covered Experiments III— A — Experiments that Require RAC Review and NIH and IDC Approval Before Initiation III— B — Experiments that Require IBC Approval Before Initiation M-B-l — Experiments Using Human or Animal Pathogens (Class 2, Class 3. Class 4. or Class 5 Agents) as Host- Vector S> stems III-B-2 — Experiments in Which DMA from Human or Animal Pathogens (Class 2, Class 3, Class 4, or Class 5 Agents) is Cloned in Nonpathoger.ic Prokaryotic or Lower Eukaryotic Host-Vector Systems III— 3— 3 — Experiments Involving the Use of Infectious Animal or Plant DNA or RMA Viruses or Defective Animal or Plant DNA or RNA Viruses in the Presence of Helper Vims in Tissue Culture Systems III— B— 4 — Recombinant DNA Experiments Involving Whole Animals or Plants III-B-5 — Experiments Involving More than 10 Liters of Culture III— C — Experiments that Require IBC Notice Simultaneously with Initiation of Experiments UI-D— Exempt Experiments IV. Roles and Responsibilities IV- A — Policy IV-B — Responsibilities cf the Institution IV-B-1 — General Information IV-B-2 — Membership and Procedures of the IBC IV-B-3 — Functions of the IBC IV-E-4 — Biological Safety Officer IV-B-5 — Principal Investigator (PI) IV-B-5-a — PI — General IV-B-S-b — Submission by tha PI to NIH IV-B-5-c — Submissions by the PI to the IBC IV-B-5-d — PI Responsibilities Prior to Initiating Research IV-B-5-e — PI Responsibilities During the Conduct of the Research IV-C — Responsibilities of NIH IV-C-1 — Director IV— C— l—a — General Responsibilities of the Director. NIH FV-C-l-b — Specific Responsibilities of the Director. NIH IV-C-2 — Recombinant DNA Advisory Committee IV-C-3 — Office of Recombinant DNA Activities IV-C— 4 — Other NIH Components [ 2 ] IV-D — Compliance V. Footnotes and References of Sections I— IV VL Voluntary Compliance VT-A — Basic Policy VI-B — !BC Approval VI-C — Certification of Host-Vector Systems VI-D — Requests for Exemptions and Approvals Vl-E — Protection of Proprietary Data Appendix A. Exemptions Under UI-D— 1 Appendix B. Classification of Microorganisms on the Basis of Hazard Appendix B-I — Classification of Etiologic Agents Appendix B-I-A — Class 1 Agents Appendix B-i-B— Class 2 Agents Appendix B-I-B-l — Bacterial Agents Appendix B-l-B-2 — Fungal Agents Appendix 3-I-B-3 — Parasitic Agents Appendix 3-I-B-4 — Viral. Rickettsial, and Chlamydial Agents Appendix B-I-C — Class 3 Agents Appendix B-I-C-l — Bacterial Agents Appendix E-I-C-2 — Fungal Agents Appendix B-I-C- 3 — Parasitic Agents Appendix B-I-C-4 — Viral. Rickettsial, and Chlamydial Agents Appendix B-I-D — Class 4 Agenls Appendix B-i-D-1 — Bacterial Agents Appendix 3-I-D-2 — Fungal Age.nt3 Appendix B-I-D-3 — Parasitic Agents Appendix E-I-D-4 — Viral. Rickettsial, and Chlamydia! Agents Appendix B— n — - Classification of Onccgenic Viruses on the Basis of Potential I Isz3rd Appendix B-il-A — Low-Risk Oncogenic Viruses Appendix B— II— B — Moderate-Risk Oncogenic Viruses Appendix B— III. — Class 5 Agents Appendix B— III— A — Animal Disease Organisms Which are Forbidden Entry into the United States by Law Appendix B— III— B — Animal Disease Organisms and Vectors Which are Forbidden Entry into the United States by USDA Policy Appendix B— III— C — Organisms Which may not be Studied in the United States Except at Specified Facilities Appendix B -IV — Footnotes and References of Appendix B Appendix C. Exemptions Under III— D— 5 Appendix C-I — Recombinant DNAs in Tissue Culture Appendix C-II — Experiments Involving E. coli K-12 Host-Vector Systems Appendix C— III — Experiments Involving Saccharomyces Host-Vector Systems Appendix C-!V — Experiments Involving Bacillus subtilis Host-Vector Systems Appendix C-V — Extrachromosomal Elements of Gram Positive Organisms Appendix C-VI — Footnotes and References of Appendix C Appendix D. Actions Taken Under the Guidelines Appendix E. Certified Host-Vector Systems Appendix F. Containment Conditions for Cloning of Genes Coding for the Biosynthesis of Molecules Toxic for Vertebrates Appendix F-! — General Information Appendix F-II — Containment Conditions for Cloning of Toxic Molecule Genes in E. coli K-12 Appendix F— III — Containment Conditions for Cloning of Toxic Molecule Genes ip Organisms Other than E. coli K-12 Appendix F-IV — Specific Approvals Appendix C. Physical Containment Appendix C-I — Standard Practices and Training Appendix G — II — Physical Containment Levels Appendix G-II-A — Biosafety Level 1 (BLi j Appendix G-II-A-1 — Standard Microbiological Practices Appendix C-Il-A-2 — Special Practices Appendix G-II-A-3 — Containment Equipment Appendix C-II-A— 4 — Laboratory Facilities .Appendix C— I!— B — Biosafety Level 2 (BL2) Appendix G-II-B-1 — Standard Microbiological Practices Appendix G-II-B-2 — Special Practices Appendix G-II-3-3 — Containment Equipment Appendix G — II— B — 4 — Laboratory Facilities Appendix G-Il-C — Biosafety Level 3 (BL3) Appendix G-II-C-l — Standard Microbiological Practices Appendix G-II-C-2 — Special Practices Appendix G-II-C-3 — Containment Equipment Appendix C-II-C— 4 — Laboratory Faciliti es Appendix G-II-D — Biosafety Level 4 (EL-5) Appendix C-II-D-1— Standard Microbiological Practices Appendix G-II-D-2 — Special Practices A.ppendix C-II-D-3 — Containment Equipment Appendix G-II-D— 1 — Laboratory Facilities Appendix C— III — Footnotes and References of Appendix G Appendix H. Shipment Appendix I. Biological Containment Appendix I-I — Levels of Biological Containment Appendix I-I-A — HV1 Appendix I-I-A-l — EKl Appendix I-I-A.-2 — Other HVl Appendix I-I-B — HV2 Appendix I— II — Certification of Host- Vector Systems Appendix I— II— A — Responsibility Appendix I— II— B — Data to be Submitted for Certification Appendix I— II— 3—1 — HVl Systems Other than E. ccii K-12 Appendix I— II— 3— 2 — HV2 Systems Appendix I— III — Footnotes and References of Appendix I Appendix J. Biotechnology Science Coordinating Committee Appendix K. Physical Containment for Large- Scale Uses of Organisms Containing Recombinant DNA Molecules Appendix K-I — Selection of Physical Containment Levels Appendix K-II — BL1-LS Level Appendix K— III — BL2-LS Level Appendix K-IV — BL3-LS Level Appendix L. Release into the Environment of Certain Plants Appendix L-I — General Information Appendix L-II — Criteria Allowing Review by the RAC Plant Working Group Recombinant DNA Research, Volume 1 1 Federal Register / Vol. 51, No. 88 / Wednesday, May 7, 1986 / Notices 16959 Without the Requirement for Full RAC Review Appendix L-I1I — Specific Approvals L Scope of the Guidelines I- A — Purpose The purpose of these Guidelines is to specify practices for constructing and handling (i) recombinant DN'A molecules and (ii) organisms and viruses containing recombinant DNA molecules. I-B — Definition of Recombinant DNA Molecules In the context of these Guidelines, recombinant DNA molecules are defined as either (i) molecules which are constructed outside living cells by joining natural or synthetic DNA segments to DNA molecules that can replicate in a living cell, or (ii) DNA molecules that result from the replication of those described in (i) above. Synthetic DNA segments likely to yield a potentially harmful polynucleotide or polypeptide (e.g.. a toxin or a pharmocologically active agent) shall be considered as equivalent to their natural DNA counterpart. If the synthetic DNA segment is not expressed in vivo as a biologically active polynucleotide or polypeptide product, it is exempt from the Guidelines. l-C— General Applicability The Guidelines are applicable to all recombinant DNA research within the United States or its territories which is conducted at or sponsored by an institution that receives any support for recombinant DNA research from the National Institutes of Health (NIH). This includes research performed by NIH directly. An individual receiving support for research involving recombinant DNA must be associated with or sponsored by an institution that can and does assume the responsibilities assigned in these Guidelines. The Guidelines are also applicable to projects done abroad if they are supported by NIH funds. If the host country, however, has established rules for the conduct of recombinant DNA projects, then a certificate of compliance with those rules may be submitted to NIH in lieu of compliance with the NIH Guidelines. The NIH reserves the right to withhold funding if the safety practices to be employed abroad are not reasonably consistent with the NIH Guidelines. l-D— General Definitions The following terms, which are used throughout the Guidelines, are defined as follows: I-D-l. "Institution" means any public or private entity (including Federal. State, and local government agencies). l-D-2. “Institutional Biosafety Committee" or "IBC" means a committee that (i) meets the requirements for membership specified in Section IV-B-2, and (ii) reviews, approves, and oversees projects in accordance with the responsibilities defined in Sections IV-B-2 and IV-B-3. I-D-3. "NIH Office of Recombinant DNA Activities" or "ORDA” means the office within NIH with responsibility for (i) reviewing and coordinating all activities of NIH related to the Guidelines, and (ii) performing other duties as defined in Section IV-C-3. l-D—i. "Recombinant DNA Advisory Committee" of "RAC" means the public advisory committee that advises the Secretary, the Assistant Secretary for Health, and the Director. NIH. concerning recombinant DNA research. The RAC shall be constituted as specified in Section FV-C-2. I-D-5. "Director. NIH" or "Director" means the Director, NIH. or any other officer or employee of NIH to whom authority has been delegated. II. Containment Effective biological safety programs have been operative in a variety of laboratories for many years. Considerable information, therefore, already exists for the design of physical containment facilities and the selection of laboratory procedures applicable to organisms carrying recombinant DNAs (3-16J. The existing programs rely upon mechanisms that, for convenience, can be divided into two categories: (i) A set of standard practices that are generally used in microbiological laboratories: and (ii) special procedures, equipment, and laboratory installations that provide physical barriers which are applied in varying degrees according to the estimated biohazard. Four biosafety levels (BL) are described in Appendix G. These biosafety levels consist of combinations of laboratory practices and techniques, safety equipment, and laboratory facilities appropriate for the operations performed and the hazard posed by agents and for the laboratory function and activity. Biosafety level 4 (BL4) provides the most stringent containment conditions. BLl the least stringent. Experiments on recombinant DNAs by their very nature lend themselves to a third containment mechanism — namely, the application of highly specific biological barriers. In fact natural barriers do exist which limit either (i) the infectivity of a vector or vehicle (plasmid or virus) for specific hosts, or (ii) its dissemination and survival in the environment. The vectors that provide the means for replication of the recombinant DNAs and/or the host cells in which they replicate can be genetically designed to decrease by many orders of magnitude the probability of dissemination of recombinant DNAs outside the laboratory. Further details on biological containment may be found in Appendix L As these three means of containment are complementary, different levels of containment appropriate for experiments with different recombinants can be established by applying various combinations of the physical and biological barriers along with a constant use of the standard practices. We consider these categories of containment separately in order that such combinations can be conveniently expressed in the Guidelines. In constructing these Guidelines, it was necessary to define boundary conditions for the different levels of physical and biological containment and for the classes of experiments to which they apply. We recognize that these definitions do not take into account all existing and anticipated information on special procedures that will allow particular experiments to be carried out under different conditions than indicated here without affecting risk. Indeed, we urge that individual investigators devise simple and more effective containment procedures, and that investigators and IBCs recommend changes in the Guidelines to permit their use. ID. Guidelines for Covered Experiments Part III discusses experiments involving recombinant DNA. These experiments have been divided into four classes: III-A. Experiments which require specific RAC review and HIH and IBC approval before initiation of the experiment; I1I-B. Experiments which require IBC approval before initiation of the experiment; I1I-C. Experiments which require IBC notification at the time of initiation of the experiment; UI-D. Experiments which are exempt from the procedures of the Guidelines. IF AN EXPERIMENT FALLS INTO BOTH CLASS III-A AND ONE OF THE OTHER CLASSES. THE RULES PERTAINING TO CLASS III-A MUST BE FOLLOWED. If an experiment falls into Class III— D and into either Class HI— B or III— C as well, it can be considered Recombinant DNA Research, Volume 1 1 [3] 16960 Federal Register / Vol. 51. No. 88 / Wednesday. May 7, 1986 / Notices exempt from the requirements of the Guidelines. Changes in containment levels from those specified here may not be instituted without the express approval of the Director, N1H (see Sections IV-C- l-b-(l), IV — C— 1— b— (2). and subsections). Ill- A — Experiments That Require RAC Review and NIH and IDC Approval Before Initiation Experiments in this category cannot be initiated without submission of relevant information on the proposed experiment to NIH. the publication of the proposal in the Federal Register for thirty days of comment, review by the RAC, and specific approval by NIH. The containment conditions for such experiments will be recommended by RAC and set by NIH at the time of approval. Such experiments also require the approval of the IBC before initiation. Specific experiments already approved in this section and the appropriate containment conditions are listed in Appendices D and F. If an experiment is similar to those listed in Appendices D and F. ORDA may determine appropriate containment conditions according to case precedents under Section IV-C-l-b-(3)-(g). If the experiments in this category are suomitted for review to another Federal agency, the submitter shall notify CEDA; ORDA may then determine that such review serves the same purpose, and based on that determination, notify the submitter that no RAC review will take place, no NIH approval is necessary, and the experiment may proceed upon approval from the other Federal agency. I1I-A-1. Deliberate formation of recombinant DNAs containing genes for the biosynthesis of toxic molecules lethal for vertebrates at an LD 5 o of less than 100 nanograms per kilogram body weight (e.g., microbial toxins such as the botulinum toxins, tetanus toxin, diphtheria toxin, Shigella dysenteriae neurotoxin). Specific approval has been given for the cloning in E. coli K-12 of DNAs containing genes coding for the biosynthesis of toxic molecules which are lethal to vertebrates at ICO nar.ograms to 100 micrograms per kilogram body weight. Containment levels for these experiments are specified in Appendix F. III-A-2. Deliberate release into the environment of any organism containing recombinant DNA, except certain plants as described in Appendix L. I1I-A-3. Deliberate transfer of a drug resistance trait to microorganisms that are not known to acquire it naturally [2], if such acquisition could compromise the use of the drug to control disease agents in human or veterinary medicine or agriculture. III-A-4. Deliberate transfer of recombinant DNA or DNA or RNA derived from recombinant DNA into human subjects [21]. The requirement for RAC review should not be considered to preempt any other required review of experiments with human subjects. Institutional Review Board (IRB) review of the proposal should be completed before submissin to NIH. III-B — Experiments That Require IBC Approval Before Initiation Investigators performing experiments in this category must submit to their IBC. prior to initiation of the experiments, a registration document that contains a description of: (i) The source(s) of DNA: (ii) the nature of the inserted DNA sequences: (iii) the hosts and vectors to be used: (iv) whether a deliberate attempt will be made to obtain expression of a foreign gene, and, if so, what protein will be produced; and (v) the containment conditions specified in these Guidelines. This registration document must be dated and signed by the investigator and filed only with the local IBC. The IBC shall review all such proposals prior to initiation of the experiments. Requests for lowering of containment for experiments in this category will be considered by NIH (see Section IV-C-l-b-(3)). III-B-1 — Experiments Using Human or Animal Pathogens (Class 2, Class 3, Class 4, or Class 5 A.gents [ 1 ]) as Host- Vector Systems lll-B-l-a. Experiments involving the introduction of recombinant DNA into Class 2 agents can be carried out at BL2 containment. III-B-l-b. Experiments invoking the introduction of recombinant DNA into Class 3 agent3 can be carried out at BL3 containment. lll-B-l-c. Experiments involving the introduction of recombinant DNA into Class 4 agents can be carried out at BL4 containment. 111-B-l-d. Containment conditions for experiments involving the introduction of recombinant DNA into Class 5 agents wili be set on a case-by-case basis following ORDA review. A U.S. Department of Agriculture (USDA) permit is required for work with Class 5 agents ri8, 20]. III-B-2 — Experiments in Which DNA From Human or Animal Pathogens (Class 2. Class 3, Class 4, or Class 5 Agents [1]) is Cloned in Nonpathogenic Prokaryotic or Lower Eukaryotic Host- Vector Systems III-B-2-a. Recombinant DNA experiments in which DNA from Class 2 or Class 3 agents [1] is transferred into nonpathogenic prokaryotes or lower eukaryotes may be performed under BL2 containment. Recombinant DNA experiments in which DNA from Class 4 agents is transferred into nonpathogenic prokaryotes or lower eukaryotes can be performed at BL2 containment after demonstration that only a totally and irreversibly defective fraction of the agent's genome is present in a given recombinant. In the absence of such a demonstration. BL4 containment should be used. Specific lowering of containment of BLl for particular experiments can be approved by the IBC. Many experiments in this category will be exempt from the Guidelines (see Sections III— D — 4 and III— D— 5). Experiments involving the formation of recombinant DNAs for certain genes coding for molecules toxic for vertebrates require RAC review and NIH approval (see Section III— A— 1) or must be carried out under NIH specified conditions as described in Appendix F. III-B-2-b. Containment conditions for experiments in which DNA from Class 5 agents is transferred into nonpathogenic prokaryotes or lower eukaryotes will be determined by ORDA following a case- by-case review. A USDA permit is required for work with Class 5 agents [13. 20 J. III-B-3 — Experiments Involving the Use of Infectious Animal or Plant DNA or RNA Viruses or Defective Animal or Plant DNA or RNA Viruses in the ■Presence of Helper Virus in Tissue Culture Systems Caution: Special care should be used in the evaluation of containment levels for experiments which are likely to either enhance the pathogenicity (e.g.. insertion of a host oncogene) or to extend the host range (e.g.. introduction of novel control elements) of viral vectors under conditions which permit a productive infection. In such cases, serious consideration should be given to raising the physical containment by at least one level. Note. — Recombinant DNA molecules or RNA molecules derived therefrom, which contain less than two-thirds of the genome of any eukaryotic virus (all virus from a single Family (17] being considered identical [19]). may be considered defective and can be used [ 4 ] Recombinant DNA Research, Volume 1 1 Federal Register / Vol. 51, No. 88 / Wednesday. May 7, 1986 / Notices 16961 in the absence of helper under the conditions specified in Section lit— O. I/I-B-3-a. Experiments involving the use of infectious Class 2 animal viruses [1] or defective Class 2 animal viruses in the presence of helper virus can be performed at BL2 containment. III-B-3-b. Experiments involving the use of infectious Class 3 animal viruses [lj or defective Class 3 animal viruses in the presence of helper virus can be carried out at BL3 containment. III-B-3-c. Experiments involving the use of infectious Class 4 viruses [1] or defective Class 4 viruses in the presence of helper virus may be carried out under BL4 containment. HI-B-3-d. Experiments involving the .use of infectious Class 5 [1] viruses or defective Class 5 viruses in the presence of helper virus will be determined on a case-by-case basis following ORDA review. A USDA permit is required for work with Class 5 pathogens (18. 20). HI-B-3-e. Experiments involving the use of infectious animal or plant viruses or defective animal or plant viruses in the presence of helper virus not covered by Sections III— B— 3— a. U!-B-3-b. DI-B- 3— c. or III-B-3-d may be carried out under BLl containment. Ill-B— t — Recombinant DNA Experiments Involving Whole Animals or Plants Hl-B-4-a. Recombinant DNA. or RNA molecules derived therefrom, from any source except for greater than two- thirds of a eukaryotic viral genome may be transferred to any non-human vertebrate organism and propagated under conditions of physical containment comparable to BLl and appropriate to the organism under study [2] . It is important that the investigator demonstrate that the fraction of the viral genome being utilized does not lead to productive infection. A USDA permit is required for work with Class 5 agents (18. 20]. III-B—4-b. For all experiments involving whole animals and plants and not covered by Section III-B-4-a. the appropriate containment will be determined by the EC [22]. I/l-B-5 — Experiments Involving More Than 10 Liters of Culture The appropriate containment will be decided by the IBC. Where appropriate. Appendix K. Physical Containment for Large-Scale Uses of Organisms Containing Recombinant DNA Molecults. should be used. Ill-C. Experiments That Require IBC Notice Simultaneously With Initiation of Experiments Experiments not included in Secticns Ili-A. UI-B. III-D. and subsections of these sections are to be considered in Section III-C. All such experiments can be carried out at BLl containment. For experiments in this category, a registration document as described in Section III— B must be dated and signed by the investigator and filed with the local IBC at the time of initiation of the experiment The EC shall review all such proposals, but EC review prior to initiation of the experiment is not required. (The reader should refer to the policy statement in the first two paragraphs of Section TV— A.) For example, experiments in which all components derive from non-pathogenic prokaryotes and non-pathogenic lower eukaryotes fall under Section E-C and can be carried out at BLl containment. CAUTION: Experiments Involving Formation of Recombinant DNA Moiecules Containing no more than Two-Thirds of the Genome of any Eukaryotic Virus. Recombinant DNA molecules containing no more than two- thirds of the genome of any eukaryotic virus (all viruses from a single Family (17] being considered identical [19]). may be propagated and maintained in cells in tissue culture using BLl containment. For such experiments, it must be shown that the cells lack helper virus for the specific Families of defective viruses being used. If helper virus is present, procedures specified under Section III- B-3 should be used. The DNA may contain fragments of the genome of viruses from more than one Family but each fragment must be less than two- thirds of a genome. III-D — Exempt Experiments The following recombinant DNA molecules are exempt from these Guidelines and no registration with the EC is necessary: III-D-1. Those that are not in organisms or viruses. III-D-2. Those that consist entirely of DNA segments from a single nonchromosomal or viral DNA source though one or more of the segments may be a synthetic equivalent III-D-3. Those that consist entirely of DNA from a prokaryotic host including its indigenous plasmids or viruses when propagated only in that host (or a closely related strain of the same species) or when transferred to another host by well established physiological means: also, those that consist entirely of DNA rrom an eukaryotic host including its chloroplasts, mitochondria. or plasmids (but excluding viruses) when propagated only in that host (or a closely related strain of the same species). III-D— 1. Certain specified recombinant DNA molecules that consist entirely of DNA segments from different species that exchange DNA by known physiological processes though one or more of the segments may be a synthetic equivalent. A list of such exchangers will be prepared and periodically revised by the Director. NIH. with advice of the RAC after appropriate notice and opportunity for public comment (see Section IV-C-l-b- (lHc)). Certain classes are exempt as of publication of these revised Guidelines. This list is in Appendix A. An updated list may be obtained from the Office of Recombinant DNA Activities, National Institutes of Health, Building 31. Room 3B10. Bethesda, Maryland 20892. III-D-5. Other classes of recombinant DNA molecules — if the Director. NIH. with advice of the RAC. after appropriate notice and opportunity for public comment, finds that they do not present a significant risk to health or the environment (see Section IV-C-l-b-(l)- (c)). Certain classes are exempt as of publication of these revised Guidelines. The list is in Appendix C. An updated list may be obtained from the Office of Recombinant DNA Activities. National Institutes of Health, Building 31. Room 3B10, Bethesda. Maryland 20892. IV. Roles and Responsibilities TV- A — Policy Safety in activities involving recombinant DNA depends on the individual conducting them. The Guidelines cannot anticipate every possible situation. Motivation and goed judgment are the key essentials to protection of health and the environment The Guidelines are intended to help the institution. Institutional Biosafety Committee (IBC), Biological Safety Officer (BSO), and Principal Investigator (PI) determine the safeguards that should be implemented. These Guidelines will never be complete or final, since all conceivable experiments involving recombinant DNA cannot be foreseen. Therefore, it is the responsibility of the institution and those associated with it to adhere to the intent of the Guidelines as well as to their specifics. Each institution (and the EC acting on its behalf) is responsible for ensuring that recombinant DNA activities comply with the Guidelines. General recognition of institutional authority and Recombinant DNA Research, Volume 1 1 [5] 16982 Federal Register / Vol. 51, No. 88 / Wednesday, May 7, 198G / Notices responsibility properly establishes accountability for safe conduct of the research at the local level. The following roles and responsibilities constitute an administrative framework in which safety is an essential and integral part of research involving recombinant DNA molecules. Further clarifications and interpretations of roles and responsibilities will be issued by NIH as necessary. IV-B — Responsibility of the Institution IV-B-1. General Information. Each institution conducting or sponsoring recombinant DNA research covered by these Guidelines is responsible for ensuring that the research is carried out in full conformity with the provisions of the Guidelines. In order to fulfill this responsibility, the institution shall: TV-B-l-a. Establish and implement policies that provide for the safe conduct of recombinant DNA research and that ensure compliance with the Guidelines. The institution as part of its general responsibilities for implementing the Guidelines may establish additional procedures as deemed necessary to govern the institution and its components in the discharge of its responsibilities under the Guidelines. This may include: (i) Statements formulated by the institution for general implementation of the Guidelines, and (ii) whatever additional precautionary steps the institution may deem appropriate. IV-B-l-b. Establish an IBC that meets the requirements set forth in Section IV- B-2 and carries out the functions detailed in Section IV-B-3. TV-B-l-c. If the institution is engaged in recombinant DNA research at the BL3 or BL4 containment level, appoint a BSO, who shall be a member of the IBC and carry out the duties specified in Section IV-B— 1. IV-B-l-d. Require that investigators responsible for research covered by these Guidelines comply with the provisions of Section IV-B-5 and assist investigators to do so. rV-B-l-e. Ensure appropriate training for the IBC chairperson and members, the BSO, PI 3 , and laboratory staff regarding the Guidelines, their implementation, and laboratory safety. Responsibility for training IBC members may be carried out through the IBC chairperson. Responsibility for training laboratory staff may be carried out through the PI. The institution is responsible for seeing that the PI has sufficient training but may delegate this responsibility to the IBC. IV-B-l-f Determine the necessity in connectior with each project for health surveillance of recombinant DNA research personnel, and conduct, if found appropriate, a health surveillance program for the project. [The “Laboratory Safety Monograph" (LSM) discusses various possible components of such a program — for example, records of agents handled, active investigation of relevant illnesses, and the maintenance of serial serum samples for monitoring serologic changes that may result from the employees’ work experience. Certain medical conditions may place a laboratory worker at increased risk in any endeavor where infectious agents are handled. Examples given in the LSM include gastrointestinal disorders and treatment with steroids, immunosuppressive drugs, or antibiotics. Workers with such disorders or treatment should be evaluated to determine whether they should be engaged in research with potentially hazardous organisms during their treatment or illness. Copies of the LSM are available from ORDA.J IV-B-l-g. Report within 30 days to ORDA any significant problems with and violations of the Guildelines and significant research-related accidents and illnesses, unless the institution determines that the PI or IBC has done so. IV-3-2. Membership and Procedures of the IBC. The institution shall establish an IBC whose responsibilities need not be restricted to recombinant DNA. The committee shall meet the following requirements: IV-B-2-a. The IEC shall comprise no fewer than five members so selected that they collectively have experience and expertise in recombinant DNA technology and the capability to assess the safety of recombinant DNA research experiments and any potential risk to public health or the environment. At least two members shall not be affiliated with the institution [apart from their membership on the IBC) and shall represent the interest of the surrounding community with respect to health and protection of the environment. Members meet this requirement if, for example, they are officials of State or local public health or environmental protection agencies, members of other local governmental bodies, or persons active in medical, occupational health, or environmental concerns in the community. The BSO, mandatory when research is being conducted at the BL3 and BL4 levels, shall be a member (see Section IV-B— 4). IV-B-2-b. In order to ensure the competence necessary to review recombinant DNA activities, it is recommended that: (i) The IBC include persons with expertise in recombinant DNA technology, biological safety, and physical containment; (ii) the IBC include, or have available as consultants, persons knowledgeable in institutional commitments and policies, applicable law, standards of professional conduct and practice, community attitudes, and the environment; and (iii) at least one member be from the laboratory technical staff. 1V-B-2-C. The institution shall identify the committee members by name in a report to ORDA and shall include relevant background information on each member in such form and at such times as ORDA may require. IV-B-2-d. No member of an IBC may be involved (except to provide information requested by the IBC) in the review or approval of a project in which he or she has been or expects to be engaged or has a direct financial interest. IV-B-2-e. The institution, who is ultimately responsible for the effectiveness of the IBC, may establish procedures that the IBC will follow in its initial and continuing review of applications, proposals, and activities. (IBC review procedures are specified in Section IV-B-3-a.) IV-B-2-f. Institutions are encouraged to open IBC meetings to public whenever possible, consistent with protection of privacy and proprietary interests. IV-B-2-g. Upon request, the institution shall make available to the public all minutes of IBC meetings and any documents submitted to or received from funding agencies which the latter are required to make available to the public. If comments are made by members of the public on IBC actions, the institution shall forward to NIH both the comments and the ICB's response. IV-B-3. Functions of the IBC. On behalf of the institution, the IBC is responsible for: IV-B-3-a. Reviewing for compliance with the NIH Guidelines recombinant DNA research as specified in Part III conducted at or sponsored by the institution, and approving those research projects tfiat it finds are in conformity with the Guidelines. This review shall include: I\'-B-3-a-(l). An independent assessment of the containment levels required by these Guidelines for the proposed research, and TV-B-3-a-(2). An assessment of the facilities, procedures, and practices, anu of the training and expertise of recombinant DNA personnel. [ 6 ] Recombinant DNA Research, Volume 1 1 Federal Register / Vol. 51, No. 83 / Wednesday. May 7, 1986 / Notices 16963 [V-B-3-b. Notifying the PI of the results of their review. IV-B-3-C. Lowering containment levels for certain experiments as specified in Sections IU-B-2. IV-B-3-d. Setting containment levels as specified in Section III— B — t-b and III— B-5. r\/-B-3-e. Reviewing periodically recombinant DNA research being conducted at the institution to ensure that the requirements of the Guidelines are being fulfilled. lV-B-3-f. Adopting emergency plans covering accidental spills and personnel contamination resulting from such research. Note. — Basic elements in developing specific procedures for dealing with major spills of potentially hazardous materials in the laboratory are detailed in the LSM. Included are information and references on decontamination and emergency plans. The N!H and the Centers for Disease Control are available to provide consultation and direct assistance, if necessary, as posted in the LSM. The institution shall cooperate with the State and local public health departments reporting any significant research-related illness or accident that appears to be a hazard to the public health. IV-B-3-g. Reporting within 30 days to the appropriate institutional official and to ORDA any significant problems with or violations of the Guidelines and any significant research-related accidents or illnesses unless the IBC determines that the PI has done so. IV-B-3-h. The IBC may not authorize initiation of experiments not explicitly covered by the Guidelines until NIH (with the advice of the RAC when required) establishes the containment requirement. tV-B-3-i. Performing such other functions as may be delegated to the IBC under Section IV-B-1. IV-B-i. Biological Safety Officer. The institution shall appoint a BSO if it engages in recombinant DNA research at the BL3 or BL4 containment level. The officer shall be a member of the IBC. and his or her duties shall include (but need not be limited to): TV-B—4-a. Ensuring through periodic inspections that laboratory standards are rigorously followed; IV-B—t-b. Reporting to the IBC and the institution all significant problems with and violations of the Guidelines and all significant research-related accidents and illnesses of which the BSO becomes aware unless the BSO determines that the PI has done so; fV-B-4-c. Developing emergency plans for dealing with accidental spills and personnel contamination and investigating recombinant DNA research laboratory accidents, rV-B-4-d. Providing advice on laboratory security: IV-B—t-e. Providing technical advice to the PI and the IBC on research safety procedures. Note. — See the LSM for additional information on the duties of the BSO. IV-B-o. Principal Investigator (PI). On behalf of the institution, the PI is responsible for complying fully with the Guidelines in conducting any recombinant DNA research. rV-B-5. PI — General. As part of this general responsibility, the PI shall: rV-BS-a-(l). Initiate or modify no recombinant DNA research requiring approval by the IBC prior to initiation (see Sections III-A and III— B) until that research or the proposed modification thereof has been approved by the IBC and has met all other requirements of the Guidelines; IV-B-5-a-(2). Determine whether experiments are covered by Section III— C and follow the appropriate procedures: [V-B-5-a-(3j. Report within 30 days to the IBC and NIH (ORDA) all significant problems with and violations of the Guidelines and all significant research-related accidents and illnesses: IV-B-5-o-(4). Report to the IBC and to NTH (ORDA) new information bearing on the Guidelines: lV-B-5-a-(5). Be adequately trained in good microbiological techniques: rV-BS~a-(6). Adhere to IBC- approved emergency plans for dealing with accidental spills and personnel contamination: and IV-B-5-a-(7). Comply with shipping requirements for recombinant DNA molecules. (See Appendix H for shipping requirements and the LSM for technical recommendations.) rV-BS-b. Submissions by the PI to NIH. The PI shall: rV-B-S-b-(l). Submit information to' NIH (ORDA) in order to have new host- vector systems certified; IV-B-5-b-(2). Petition NIH with notice to the IBC for exemptions to these Guidelines; IV-B~5-b-{3). Petition NIH with concurrence of the IBC for approval to conduct experiments specified in Section III-A of the Guidelines; IV-B-5-b-(4). Petition NIH for determination of containment for experiments requiring case-bv-case review; IV-B—5-b~{5). Petition NIH for determination of containment for experiments not covered by the Guidelines. IV-B-5-c. Submissions by the PI to the IBC. The PI shall: IV-B-5-c-(l). Make the initial determination of the required levels of physical and biological containment in accordance with the Guidelines; IV-B-5-c-{2). Select appropriate microbiological practices and laboratory techniques to be used in the research; IV-B-5-c-(3). Submit the initial research protocol if covered under Guidelines Section III-A. Ill— B. or III— C (and also subsequent changes — ex- changes in the source of DNA or host- vector system) to the IBC for review and approval or disapproval; and IV-B-5-c-(4). Remain in communication with the IBC throughout the conduct of the project. IV-B-5-d. PI Responsibilities Prior to Initiating Research. The PI is responsible for IV-B-5-d-{l). Making available to the laboratory staff copies of the protocols that describe the potential biohazards and the precautions to be taken: lV-B-5-d-(2). Instructing and training staff in the practices and techniques required to ensure safety and in the procedures for dealing with accidents; and IV-B-5~d-(3). Informing the staff of the reasons and provisions for any precautionary medical practices advised or requested, such as vaccinations or serum collection. lV-B-5-e. PI Responsibilities During the Conduct of the Research. The PI is responsible for: IV-B-5-e-(l). Supervising the safety performance of the staff to ensure that the required safety practices and techniques are employed: IV-B-5-e-(2 ). Investigating and reporting in writing to ORDA, the BSO (where applicable), and the IBC any significant problems pertaining to the operation and implementation of containment practices and procedures; IV-B-5—e-(3). Correcting work errors and conditions that may result in the release of recombinant DNA materials; rV-B-5~e-(4). Ensuring the integrity of the physical containment (e.g., biological safety cabinets) and the biological containment (e g., purity and genotypic and phenotypic characteristics). IV -C — Responsibilities of NIH IV-C-1. Director. The Director, NIH, is responsible for (i) establishing the NIH Guidelines for Research Involving Recombinant DNA Molecules, (ii) overseeing their implementation, and (iii) their final interpretation. The Director has responsibilities under the Guidelines that involve ORDA and RAC. The ORDA’s responsibilities under the Guidelines are administrative. Advice from the RAC is primarily Recombinant DNA Research, Volume 1 1 [7] 16964 Federal Register / Vol. 51, No. 88 / Wednesday, May 7. 1986 / Notices scientific and technical. In certain circumstances, there is specific opportunity for public comment with published response before final action. IV-C-l-a. General Responsibilities of the Director, NIH. The responsibilities of the director shall include the following: IV-C-l-a-(l). Promulgating requirements as necessary to implement the Guidelines: IV-C-l-a-(2J. Establishing and maintaining the RAC to carry out the responsibilities set forth in Section IV- C-2. The RAC’s membership is specified in its charter and in Section IV-C-2: IV-C-l-a-{3). Establishing and maintaining ORDA to carry out the responsibilities defined in Section IV-C- 3. IV-C-l-b. Specific Responsibilities of the Director, NIH. In carrying out the responsibilities set forth in this section, the director or a designee shall weigh each proposed action through appropriate analysis and consultation to determine that it complies with the Guidelines and presents no significant risk to health or the environment. IV-C-l-b-ll). Major Actions. To execute major actions the director must seek the advice of the RAC and provide an opportunity for public and Federal agency comment. Specifically, the agenda of the RAC meeting citing the major actions will be published in the Tederal Register at least 30 days before the meeting, and the director will also publish the proposed actions in the Federal Register for comment as least 30 days before the meeting. In addition, the director's proposed decision, at his discretion, may be published in the Federal Register for 30 days of comment before final action is taken. The director’s final decision, along with response to the comments, will be published in the Federal Register and the Reco;nbir.ant DNA Technical Bulletin. The RAC and IBC chairpersons will be notified of this decision: IV-C-l-b-(l]-(a). Changing containment levels for types of experiments that are specified in the Guidelines when a major action is involved; IV-C-l-b-( 1 )-( b ). Assigning containment levels for types of experiments that are not explicitly considered in the Guidelines when a major action is involved: IV-C-l-b-(l)-(c). Promulgating and amending a list of classes of recombinant DNA molecules to be exempt from these Guidelines because they consist entirely of DNA segments from species that exchange DNA by known physiological processes or otherwise do not present a significant risk to health or the environment: IV-C-l-b-(l)-(d]. Permitting experiments specified by Section III— A of the Guidelines: IV-C-l-b-(l)-(e). Certifying new host- vector systems with the exception of minor modifications of already certified systems (the standards and procedures for certification are described in Appendix I-II-A. Minor modifications constitute, for example, those of minimal or no consequence to the properties relevant to containment); and IV-C-l-b-(l)-(f). Adopting other changes in the Guidelines. IV-C-l-b-(2J. Lesser Actions. To execute lesser actions, the director must seek the advice of the RAC. The director’s decision will be transmitted to the RAC and IBC chairpersons and publiched in the Recombinant DNA Technical Bulletin: IV-C-l-b-(2)-(a). Interpreting and determining containment levels upon request by ORDA; IV-C-l-b-(2)-(b). Changing containment levels for experiments that are specified in the Guidelines (see Section III); lV-C-l-b-(2j-(c). Assigning containment levels for experiments not explicitly considered in the Guidelines: IV-C-l-b-(2)-(d). Revising the “Classification of Eticlogic Agents" for the purpose of these Guidelines (1). IV-C-l-b-(3). Other Actions. The director's decision will be transmittede to the RAC and IBC chairpersons and published in the Recombinant DNA Technical Bulletin: IV-C-l-b-(3)-(a). Interpreting the Guidelines for experiments to which the Guidelines specifically assign containment levels; lV-C-2-b-(3)-(b). Setting containment under Section III-B-l-d and Section III— B-3-d; IV-C-l-b-(3)-(c). Approving minor modifications of already certified host- vector systems (the standards and procedures for such modifications are described in Appendix I— II); IV-C~l-b-[3)-(d). Decertifying already certified host-vector systems: IV-C-l-b-(3)-(e). Adding new entries to the list of molecules toxic for vertebrates (see Appendix F); IV-C-l-b-(3)~(f). Approving the cloning of toxin genes in host-vector systems ether than E. coli K-12 (see Appendix F); and IV-C-l-b-(3 )-(g /Determining appropriate containment conditions for experiments according to case precedents developed under Section IV- C -l-b-(2)-(c). IV-C-l-b-(4). The director shall conduct, support, and assist training programs in laboratory safety for IBC members. BSOs. Pis, and laboratory staff. IV-C-2. Recombinant DNA Advisor}- Committee. The Recombinant DNA Advisory Committee (RAC) is responsible for carrying out specified functions cited below as well as others assigned under its charter or by the Secretary. HHS, the Assistant Secretary for Health, and the Director. NTH. The committee shall consist of 25 members including the chair, appointed by the Secretary or his or her designee, at least fourteen of whom shall be selected from authorities knowledgeable in the fields of molecular biology or recombinant DNA research or in scientific fields other than molecular biology or recombinant DNA research, and at least six of whom shall be persons knowledgeable in applicable law, standards of professional conduct and practice, public attitudes, the environment, public health, occupational health, or related fields. Representatives from Federal agencies shall serve as non-voting members. Nominations for the RAC may be submitted to the Office of Recombinant DNA Activities. National Institutes of Health. Building 31. Room 3B10, Bethesda. MD 20892. All meetings of the RAC will be announced in 'the Federal Register, including tentative agenda items, 30 days in advance of the meeting with final agendas (if modified) available at least 72 hours before the meeting. No item defined as a major action under Section IV-C-l-b-(l) may be added to an agenda after it appears in the Federal Register. The PvAC shall be responsible for advising the Director. NIH, on the actions listed in Section IV-C-l-b-(l) and IV-C-l-b-(2). IV-C-3. The Office of Recombinant DNA Activities. The ORDA shall serve as a focal point for information on recombinant DNA activities and provide advice to all within and outside NIH including Institutions, BSOs, Pis, Federal agencies, State and local governments and institutions in the private sector. The ORDA shall carry out such other functions as may be delegated to it by the Director, NIH, including those authorities described in Section IV-C-1- b-(3). In addition. ORDA shall be responsible for the following: IV-C-3-a. Reviewing and approving IBC membership; IV-C-3-b. Publishing in the Federal Register: lV-C-3-b-fl). Announcements of RAC meetings and agendas at least 30 days in advance: Recombinant DNA Research, Volume 1 1 [ 8 ] Federal Register / Vol. 51. No. 88 / Wednesday. May 7, 1986 / Notices 16S65 Note. — If the agenda for an RAC meeting is modified, ORDA shall make the revised agenda available to anyone upon request at least 72 hours in advance of the meeting. IV-C-3-b-(2). Proposed major actions of the type falling under Section IV-C- 1— b — (1) at least 30 days prior to the RAC meeting at which they will be considered: and rV-C-3-b~(3). The N1H director’s final decision on recommendations made by the RAC. rV-C-3-c. Publishing the Recombinant DNA Technical Bulletin; and IV-C-3-d. Serving as executive secretary of the RAC. IV-C-4. Other N1H Components. Other NIH components shall be responsible for certifying maximum containment (BL4) facilities, inspecting them periodically, and inspecting other recombinant DNA facilities as deemed necessary. TV-D — Compliance As a condition for NIH funding of recombinant DNA -esearch, institutions must ensure that such research conducted at or sponsored by the institution, irrespective of the source of funding, shall comply with these Guidelines. The policies on noncompliance are as follows: rV-D- 1 . All NIH-funded projects involving recombinant DNA techniques must comply with the NIH Guidelines. Noncompliance may result in (i) suspension, limitation, or termination of financial assistance for such projects and of NIH funds for other recombinant DNA research at the institution, or (ii) a requirement for prior NIH approval of any or all recombinant DNA projects at the Institution. TV-D-2. All non-NIH funded projects involving recombinant DNA techniques conducted at or sponsored by an institution that receives NIH funds for projects involving such techniques must comply with the NIH Guidelines. Noncompliance may result in: (i) Suspension, limitation, or termination of NIH funds for recombinant DNA research at the institution, or (ii) a requirement for prior NIH approval of any or all recombinant DNA projects at the institution. IV-D-3. Information concerning noncompliar ~e with the Guidelines may be brought forward by any person. It should be delivered to both NIH (ORDA) and the relevant Institution. The institute n. generally through the IBC, shall take appropriate action. The institution shall forward a complete report of the incident to ORDA, recommending any further action. TV-D-4. In cases where NIH proposes to suspend, limit, or terminate financial assistance because of noncompliance with the Guidelines, applicable DHHS and Public Health Service procedures shall govern. TV-D-S. Voluntary Compliance. Any individual, corporation, or institution that is not otherwise covered by the Guidelines is encouraged to conduct recombinant DNA research activities in accordance with the Guidelines through the procedures set forth in Part VI. V. Footnotes and References of Sections I-IV 1. The original reference to organisms as Class 1. 2. 3, 4. or S refers to the classification in the publication Classification of Etiologic Agents on the Basis of Hazard. 4th Edition, July 1974: U.S. Department of Health. Education, and Welfare. Public Health Service. Centers for Disease Control. Office of Biosafety. Atlanta. Georgia 30333. The Director. NIH. with advice of the Recombinant DNA Advisory Committee, may revise the classification for the purposes of these Guidelines (see Section IV-C-l-b-{2)- (d]J. The revised list of organisms in each class is reprinted in Appendix B to these Guidelines. 2. In Part III of the Guidelines, there are a number of places where judgments are to be made. In all these cases the principal investigator is to make the judgment on these matters as part of his responsibility to "make the initial determination of the required levels of physical and biological containment In accordance with the Guidelines" (Section IV-B-5-C— (1)). In the cases falling under Sections ID-A. -B or -C. this judgment is to be reviewed and approved by the IBC as part of its responsibility to make "an independent assessment of the containment levels required by these Guidelines for the proposed research" (Section IV-B-3-a-{l)). If the IBC wishes, any specific cases may be referred to ORDA as part of ORDA's functions to "provide advice to all within and outside NIH" (Section IV-C-3), and ORDA may request advice from the RAC as part of the RAC's responsibility for "interpreting and determining containment levels upon request by ORDA" (Section IV-C-l-b-{2)-(a)). 3. Laboratory Safety at the Center for Disease Control (Sept. 1974). U.S. Department of Health. Education and Welfare Publication No. CDC 75-8118. 4. Classification of Etiologic Agents on the Basis of Hazard (4th Edition. July 1974). U.S. Department of Health. Education and Welfare. Public Health Service. Centers for Disease Control. Office of Biosafety. Atlanta. Georgia 30333. 5. National Cancer Institute Safety Standards for Research Involving Oncogenic Viruses (Oct. 1974). U.S. Department of Health. Education and Welfare Publication No. (NIH) 75-790. 8. National Institutes of Health Biohazards Safety Guide (1974). U.S. Department of Health, Education and Welfare. Public Health Service. National Institutes of Health. U.S. Government Printing Office. Stock No. 1740- 00383. 7. Biohazards in Biological Research (1973). A. Heilman. M.N. Oxman, and R. Pollack (ed.) Cold Spring Harbor Laboratory. 8. Handbook of Laboratory Sa fety (1971). 2nd Edition. N.V. Steere (ed.). The Chemical Rubber Co.. Cleveland. 9. Bodily. J.L (1970). General Administration of the Laboratory, H.L Bodily. E.L Updyke. and J.O. Mason (eds.). Diagnostic Procedures for Bacterial. Mycotic and Parasitic Infections. American Public Health Association. New York. pp. 11-28. 10. Darlow. H.M. (1969). Safety in the Microbiological Laboratory. In j.R. Norris and D.W. Robbins (ed.). Methods in Microbiology. Academic Press. Inc.. New York. pp. 169-204. 11. The Prevention of Laboratory Acquired Infection (1974). C.H. Collins. E.G. Hartley, and R. Pilsworth. Public Health Laboratory Service. Monograph Series No. 8. 12. Chatigny. M_A. (1961). Protection Against Infection in the Microbiological Laboratory: Devices and Procedures. In W.W. Umbreit (ed.). Advances in Applied Microbiology. Academic Press. New York. N.Y. 3:131-192. 13. Design Criteria for Virol Oncology Research Facilities (1975). U.S. Department of Health. Education and Welfare, Public Health Service. National Institutes of Health, DHEW Publication No. (NIH) 75-891. 14. Kuehne, R.W. (1973). Biological Containment Facility for Studying Infectious Disease. Appl. Microbiol. 28-239-243. 15. Runkle. R.S.. and G.B. Phillips (1969). Microbial Containment Control Facilities. Van Nostrand Reinhold. New York. 16. Chatigny. M.A., and D.I. Clinger (1969). Contamination Control in Aerobiology. In R.L Dimmick and A.B. Akers (eds.). An Introduction to Experimental Aerobiology. John Wiley & Sons. New York. pp. 194-263. 17. As classified in the Third Report of the International Committee on Taxonomy of Viruses: Classification and Nomenclature of Viruses, R.E.F. Matthews, Ed. Intervirology 12 (129-296) 1979. 18. A USDA permit, required for import and Interstate transport of pathogens, may be obtained from the Animal and Plant Health Inspection Service. USDA Federal Building. Hyattsville. MD 20782. 19. i.e.. the total of all genomes within a Family shall not exceed two-thirds of the genome. 20. All activities, including storage of variola and whitepox, are restricted to the single national facility (World Health Organization (WHO) Collaborating Center for Smallpox Research, Centers for Disease Control, in Atlanta). 21. Section III— A— 4 covers only those experiments in which the intent is to modify stably the genome of cells of a human subject. Other experiments involving recombinant DNA in human subjects such 83 feeding of bacteria containing recombinant DNA or the administration of vaccines containing recombinant DNA are not covered In Section III-A-4 of the Guidelines. 22. For recombinant DNA experiments in which the intent is to modify stably the genome of cells of a human subject, see Section III-A-4. Recombinant DNA Research, Volume 1 1 [9] 16966 Federal Register / Vol. 51, No. 88 / Wednesday, May 7, 1986 / Notices VI. Voluntary Compliance VI-A. — Basic Policy Individuals, corporations, and institutions not otherwise covered by the Guidelines are encouraged to do so by following the standards and procedures set forth in Parts I-IV of the Guidelines. In order to simplify discussion, references hereafter to “institutions” are intended to encompass corporations, and individuals who have no organizational affiliation. For purposes of complying with the Guidelines, an individual intending to carry out research involving recombinant DNA is encouraged to affiliate with an institution that has an IBC approved under the Guidelines. Since commercial organizations have special concerns, such as protection of proprietary data, some modifications and explanations of the procedures in Parts I-IV are provided below, in order to address these concerns. VI-B — IBC Approval The ORDA will review the membership of an institution's IBC, and where it finds the IBC meets the requirements set forth in Section IV-B-2 will give its approval to the IBC membership. It should be emphasized that employment of an IBC member solely for purposes of membership on the IBC does not itself make the member an institutionally affiliated member for purposes of Section IV-B-2-a. Except for the unaffiliated members, a member of an IBC for an institution not otherwise covered by the Guidelines may participate in the review and approval of a project in which the member has a direct financial interest so long as the member has not been, and does not expect to be, engaged in the project. Section IV-B-2-d is modified to that extent for purposes of these institutions. VI-C — Certification of Host- Vector Systems A host-vector system may be proposed for certification by the Director, NIH, in accordance with the procedures set forth in Appendix I-II-A. In order to ensure protection for proprietary data, any public notice regarding a host-vector system which is designated by the institution as proprietary under Section VI-E-1 will be issued only after consultation with the institution as to the content of the notice. VI-D — Requests for Exemptions and Approvals Requests for exemptions or other approvals required by the Guidelines should be requested by following the procedures set forth in the appropriate sections in Parts I-IV of the Guidelines. In order t'o ensure protection for proprietary data, any public notice regarding a request for an exemption or other approval which is designated by the institution as proprietary under Section VI-E-1 will be issued only after consultation with the institution as to the content of the notice. VI-E — Protection of Proprietary Data In general, the Freedom of Information Act requires Federal agencies to make their records available to the public upon request. However, this requirement does not apply to, among other things, "trade secrets and commercial and financial information obtained from a person and privileged or confidential." 18 U.S.C. 1905, in tum makes it a crime for an officer or employee of the United States or any Federal department or agency to publish, divulge, disclose, or make known "in any manner or to any extent not authorized by law any information coming to him in the course of his employment or official duties or by reason of any examination or investigation made by, or return, report or record made to or filed with, such department or agency or officer or employee thereof, which information concerns or relates to the trade secrets, [or] processes ... of any person, firm, partnership, corporation, or association." This provision applies to all employees of the Federal Government, including special Government employees. Members of the Recombinant DNA Advisory Committee are “special Government employees.” VI-E-1. In submitting to NIH for purposes of complying voluntarily with the Guidelines, an institution may designate those items of information which the institution believes constitute trade secrets, privileged, confidential commercial, or financial information. VI-E-2. If NIH receives a request under the Freedom of Information Act for information so designated, NIH will promptly contact the institution to secure its views as to whether the information (or some portion] should be released. VI-E-3. If the NIH decides to release this information (or some portion) in response to a Freedom of Information request or otherwise, the institution will be advised: and the actual release will not be made until the expiration of 15 days after the institution is so advised except to the extent that earlier release in the judgment of the Director, NIH, is necessary to protect against an imminent hazard to the public or the environment. VI-E-4. Presukmission Review. VI-E-4-a. Any institution not otherwise covered by the Guidelines, which is considering submission of data or information voluntarily to NIH, may request presubmission review of the records involved to determine whether if the records are submitted NIH will or will not make part or all of the records available upon request under the Freedom of Information Act. VI-E—l-b. A request for presubmission review should be submitted to ORDA along with the records involved. These records must be clearly marked as being the property of the institution on loan to NIH solely for the purpose of making a determination under the Freedom of Information Act. The ORDA will then seek a. determination from the HHS Freedom of Information Officer, the responsible official under HHS regulations (45 CFR Part 5) as to whether the records involved (or some portion) are or are not available to members of the Public under the Freedom of Information Act. Pending such a determination the records will be kept separate from ORDA files, will be considered records of the institution and not ORDA, and will not be received as part of ORDA files. No copies will be made of the records. VI-E-4-c. The ORDA will inform the institution of the HHS Freedom of Information Officer’s determination and follow the institution's instructions as to whether some or all of the records involved are to be returned to the institution or to become a part of ORDA files. If the institution instructs ORDA to return the records, no copies or summaries of the records will be made or retained by HHS, NIH, or ORDA. VI-E-4-d. The HHS Freedom of Information Officer’s determination will represent that official’s judgement at the time of the determination as to whether the records involved (or some portion) would be exempt from disclosure under the Freedom of Information Act if at the time of the determination the records were in ORDA files at a request were received for them under the Act. Appendix A — Exemptions Under Section III— D — 4 Section III— D— 4 states that exempt from these Guidelines are “certain specified recombinant DNA molecules that consist entirely of DNA segments from different species that exchange [ 10 ] Recombinant DNA Research, Volume 1 1 Federal Register / Vol. 51,. No. 88 / Wednesday, May 7, 1986 / Notices 16967 DNA by known physiological processes though one or more of the segments may be a synthetic equivalent. A list of such exchangers will be prepared and periodically revised by the Director. NIH. with advice of the RAC after appropriate notice and opportunity for public comment (see Section IV-C-l-b- (iHc))- Certain classes are exempt as of publication of these revised Guidelines. The list is in Appendix A." Under Section III-D-1 of these Guidelines are recombinant DNA molecules that are: (1) Composed entirely of DNA segments from one or more of the organisms within a sublist and (2) to be propagated in any of the organisms within a sublist. (Classification of Bergey's Manual of Determinative Bacteriology. 8th edition. R. E. Buchanan and N. E. Gibbons, editors. Williams and W'ilkins Company: Baltimore. 1974.) Although these experiments are exempt, it is recommended that they be performed at the appropriate biosafety level for the host or recombinant organism (for biosafety levels see Biosafety in Microbiological and Biomedical Laboratories. 1st Edition (March 1984). U.S. Department of Health and Human Services. Public Health Service, Centers for Disease Control Atlanta. Georgia 30333. and National Institutes of Health, pethesda. Maryland 20892). Sublist -4 1. Genus Escherichia 2. Genus Shigella 3. Genus Sclmonella (including Arizona) 4 . Genus Enterobac'.er 5. Cenus Citrobacter (including Levinea) 8. Cenus Klebsiella 7. Genus Er.vinia 8. Pseudomonas aeruginosa. Pseudomonas Pulida and Pseudomonas fluorescens 9. Serratia morcescens 10. Yersinia enterocolitica Sublist B 1. Bacillus subtilis 2. Bacillus licheniformis 3. Bacillus pumilus 4 . Bacillus globigii 5. Bacillus niger 8. Bacillus nato 7. Bacillus amyloliquefaciens 8. Bacillus aterrimus Sublist C 1. Streptomycss aureofaciens 2. Streptomyces rimosus 3. Streptomyces coelicolor Snblist D 1. Streptomyces griseus 2. Streptomyces cyar.eus 3. Streptomyces venezuelae Recombinant DNA Research, Sublist E 1. One way transfer of Streptococcus mutans or Streptococcus lactis DNA into Streptococcus sanguis. Sublist F 1. Streptococcus sanguis 2. Streptococcus pneumoniae 3. Streptococcus faecalis 4 . Streptococcus pyogenes 5. Streptococcus mutans APPENDIX B — CLASIFICATION OF MICROORGANISMS ON THE BASIS OF HAZARD Appendix B-I — Classification of Etio logic Agents The original reference for this classification was the publication Classification of Etiological Agents on the Basis of Hazard. 4th edition. July 1974, U.S. Department of Health. Education, and Welfare. Public Heslth Service. Center for Disease Control. Office of Biosafety. Atlanta. Georgia 30333. For the purposes of these Guidelines, this list has been revised by the NIH (1). Appendix B-I-A. Class 1 Agents. All bacterial, parasitic, fungal, viral, rickettsial, and chlamydial agents not included in higher classes. Appendix B-l-B. Class 2 Agents. Appendix B-l-B-1. Bacteria! Agents. Acinetobacter calcoaceticus Actinobacillus-a)) species Aeromonas hydrophila Arizona hinshawii-aW serotypes Bacillus anthracis Bordetella - all species Borrelia recurrentis. B. vincenti Campylobacter fetus Campylobacter jejdni Chlamydia psittaci Chlamydia trachomatis Clostridium botulinum. Cl. chauvoei. CL haemolyticum. Cl. histolyticum. Cl. novyi. Cl. septicum. Cl. letani Corynebacterium diphtheriae. C. equi, C. haemolyticum. C. pseudotuberculosis. C. pyogenes. C. renale Edwardsiella tarda Erysipelothrix insidioso Escherichia coli - all enteropathogenic. enterotoxigenic, enteroir.vasive and strains bearing Kl antigen Haemophilus ducreyi. H. influenzce Klebsiellas.)) species and all serotypes Legionella pneumophila Leptospira interrogans-a)) serotypes Listeria - all species Moraxella-a)) species Mycobacteria - all species except those listed in Class 3 Mycoplasma-a)) species except Mycoplasma mycoides and Mycoplasma agolactioe. which are in Class 5 Neisseria gonorrhoeae. N. meningitidis Posteurella - all species except those listed in Class 3 Salmonello-a)) species and all serotypes Volume 1 1 Shigella-a)) species and all serotypes Sphcerophorus necrophorus Staphylococcus aureus Slreptobacillus moniliformis Streptococcus pneumoniae Streptococcus pyogenes Treponema carateum. T. pallidum, end T. pertenue Vibrio cholerae Vibrio parahemolyticus Yersinia enterocolitica Appendix B-I-B-2. Fungal Agents. Actinomycetes (including Nocardio species. Actinomyces species, and Arachnia prcpionica) (2) Blastomyces dermatitidis Cryptococcus neoformans Paracoccidioides brazihensis Appendix B-I-B-3. Parcsitic Agents. Entlamoeba histolytica Leishmania sp. Kaegleria gruberi Schistosoma mansoni Toxoplasma gondii Toxocara cams Trichine/la spiralis Trypanosoma cruzi Appendix B-l-B-1. Viral. Rickettsial, and Chlamydia! Agents. Adenoviruses — human — all types Cache Valley virus Coxsackie A end B viruses Cytomegaloviruses Echoviruses — all types Encephalomyocarditis virus (EMC) Flanders virus Hart Park virus Hepatitus — associated antigen material Herpes viruses-ex cept Herpesvirus simice (Monkey B virus) which is in Class 4 Corona viruses Influenza viruses — all types except A/PR8 / 34. which is in Class 1 Langat virus Lymphogranuloma venereum agent Measles virus Mumps virus Parainfluenza virus — all types except Parainfluenza virus 3, SF4 strain, which is in Class 1 Polioviruses — all types, wild and attenuated Poxviruses — all types except Alostrim. Smallpox, and Whitepox which are Class 5 and Monkey pox which depending on experiments is in Class 3 or Class 4 Babies virus — all strains except Rabies street virus which should be classified in Class 3 Reoviruses — all types Respiratory syncytia / virus Rhinoviruses — all types Rubella virus Simian viruses — all types except Herpesvirus simiae (Monkey B virus) and Marburg virus which are in Class 4 Sindbis virus Tensaiv virus Turlock virus Vaccinia virus Varicella virus Vesicular stomatitis virus [3| [ 11 ] 16S68 Federal Register / Vol. 51, No. 88 / Wednesday, May 7, 1980 / Notices Vole rickettsia Yellow fever virus, 17D vaccine strain Appendix B-I-C. Class 3 Agents. Appendix B-I-C-l. Bacterial Agents. Bartonella — all species Brucella — all species Francisella tularensis Mycobacterium avium, M. bovis, M. tuberculosis Pasteurella multocide type B ("buffalo" ar.d other foreign virulent strains) [3] Pseudomonas mallei [3] Pseudomonas pseudomallei [3) Yersinia pestis Appendix B-I-C-2. Fungal Agents. Coccidioides immitis Histoplcsma capsulatum Histoplasrr.a capsulatum var. duboisii A.ppendix B-I-C-3. Parasitic Agents. None. Appendix B-l-C-t. Viral, Rickettsial, and Chlamydial Agents. Monkey pox. when used in vitro [4] Arboviruses- all strains except these in Class 2 and 4 [Arboviruses indigenous to the United States are in Class 3 except those listed in Class 2. West Nile and Semliki Fcrest viruses may be classified up or down depending on the conditions of use and geographical location of the laboratory.) Dengue virus, when used for transmfssion or animal inoculation experiments Lymphocytic choriomeningitis virjs (LCM) Rickettsia — all species except Vole rickettsia when used for transmission or animal inoculation experiments Yellow fever virus — wild, when used in vitro Appendix B-l-D. Class 4 Agents. Appendix B-I-D-l. Bcctericl Agents. None. Appendix B-I-D-2. Fungal Agents. None. Appendix B-I-D-3. Parasitic Agents. No ns. Appendix B-I-D-4. Viral. Rickettsial, and Chlamydial Agents. Ebola fever virus Monkey pox. when used for transmission or animal inoculation experiments [4] Hemorrhagic fever agents, including Crimean hemorrhagic fever. (Congo), funin. and Machupo viruses, and others as yet undefined Herpesvirus simiae (Monkey B virus ) Lassa virus Marburg virus Tick-borne encephalitis virus complex. including Russian spring-summer encephalitis. Kyasanur forest disease. Omsk hemorrhagic fever, and Central European encephalitis viruses Venezuelan equine encephalitis virus. epidemic strains, when used for transmission or animal inoculation experiments Yellow fever virus — wild, when used for transmission or animal inoculation experiments Appendix B-1I — Classification of Oncogenic Viruses on the Basis of Potential Hazard [5] Appendix B-II-A. Low-Risk Oncogenic Viruses. Rous sarcoma SV— 40 CELO Ad7-SV40 Polyoma Bovine papilloma Rat mammary tumor Avian leukosis Murine lpuksmia Murine sarcoma Mouse mammary tumor Rat leukemia Hamster leukemia Bovine leukemia Dog sarcoma Mason-Pfizer monkey virus Marek's Guinea pig herpes Lucke (Frog) Adenovirus Shope fibroma Shope papilloma A.ppendix B-1I-B. Moderate-Risk Oncogenic Viruses. Ad2-SV40 FeLV HV Saimiri EEV SSY-1 GaLV HV ateles Yaba FeSV Appendix 3-111 — Class 5 Agents Appendix B-III-A. Animal Disease Organisms Which are Forbidden Entry into the United States by Law. Foot and mouth disease virus. Appendix B-III-B. Animal Disease Organisms and Vectors Which are Forbidden Entry into the United States by USD A Policy. African horse sickness virus African swine fever virus Besnoitia bssnoiti Boma disease virus Bovine infectious petechial fever Camel pox virus -Ephemeral fever virus Fowl plague virus Goat pcx virus Hog cholera virus Louping ill virus Lumpy skin disease virus Nairobi sheep disease virus Newcastle disease virus (Asiatic strains) Mycoplasma mycoides (contagious bovine pleuropneumonia) Mycoplasma agalactiae (contagious agalactia of sheep) Rickettsia ruminatium (heart water) Rift valley fever virus Rhinderpest virus Sheep pox virus Swine vesicular disease virus Teschen disease virus Trypanosoma vivex (Nagana) Trypanosoma evansi Theileria pan'a (East Coast fever) Theileria annulata Theileria lawrencei Theileria bovis Theileria hirci Vesicular exanthema virus Wesselsbron disease virus Zyonerna Appendix B-III-C. Organisms Which may not be Studied in the United States Except at Specified Facilities. Small pox [4] Alastrim [4] White pox [4] Appendix B-IV— Footnotes and References of Appendix B. 1. The original reference for this classification was the publication Classification of Etiologic Agents on the Basis of Hazard, 4th edition. July 1974, U.S. Department of Health. Education, and Welfare, Public Health Service, Center for Disease Control. Office of Biosafety, Atlanta, Georgia 30333. For the purposes of these Guidelines, this list has been revised by the NIH. 2. Since the publication of the classification in 1974 [1], the Actinomycetes have been reclassified as bacterial rather than fungal agents. 3. A USDA permit, required for import and interstate transport of pathogens, may be obtained from the Animal and Plant Health Inspection Service, USDA, Federal Building, Hyattsville. MD 207e2. 4. All activities, including storage of variola and whitepox, are restricted to the single national facility [World Health Organization (WHO) Collaborating Center for Smallpox Research, Centers for Disease Control, in Atlanta]. 5. National Cancer Institute Scfety Standards for Research Involving Oncogenic Viruses (October 1974). U.S. Department of Health, Education, and Welfare Publication No. (NIH) 75-790. 6. U.S. Department of Agriculture, Animal and Plant Health Inspection Service. Appendix C — Exemptions Under Section III-D-5 Section III-D-5 states that exempt from these Guidelines are “Other classes of recombinant DNA molecules if the Director, NIH, with advice of the RAC, after appropriate notice and opportunity for public comment finds that they do not present a significant risk to health or the environment (see Section IV-C-l-b-(l}-(c)). Certain classes are exempt as of publication of these revised Guidelines.” The following classes of experiments are exempt under Section III-D-5 of the Guidelines: [12] Recombinant DNA Research, Volume 1 1 Federal Register / Vol. 51. No. 88 / Wednesday, May 7, 1986 / Notices 16969 Appendix C-I — Recombinant DMAs in Tissue Culture. Recombinant DNA molecules containing less than one-half of any eukaryotic genome (all viruses from a single Family (4) being considered identical (5)) that are propagated and maintained in cells in tissue culture are exempt from these Guidelines with the exceptions listed below. Exceptions. Experiments described in Section III— A which require specific RAC review and NIH approval before initiation of the experiment. Experiments involving DN’A from Class 3. 4. or S organisms [1] or cells known to be infected with these agents. Experiments involving the deliberate introduction of genes coding for (he biosynthesis of molecules toxic for vertebrates (see Appendix F). Appendix C-II — Experiments Involving E. coli K-12 Host - Vector Systems Experiments which use E. coli K-12 host-vector systems, with the exception of those experiments listed below, are exempt from these Guidelines provided that: (i) the E coli host shall not contain conjugation proficient plasmids or generalized transducing phages: and (ii) lambda or lambdoid or Ff bacteriophages or nonconjugative plasmids (2] shall be used as vectors. However, experiments involving the insertion into E. coli K-12 of DNA from prokaryotes that exchange genetic information (3) with E. coli may be performed with any E coli K-12 vector (e g . conjugative plasmid). When a nonconjugative vector is used, the E. coli K-12 host may contain conjugation- proficient plasmids either autonomous or integrated, or generalized transducing phages. For these exempt laboratory experiments. BLl physical containment conditions are recommended. For large-scale (LS) fermentation experiments BLl-LS physical containment conditions are recommended. However, following review by the IBC of appropriate data for a particular host-vector system, some latitude in the application of BLl-LS requirements as outlined in Appendix K-II-A through K-1I-F is permitted. Exceptions. Experiments described in Section L1I-A which require specific RAC review and NIH approval before initiation of the experiment. Experiments involving DNA from Class 3. 4. or 5 organisms (1) or from cells known to be infected with these agents may be conducted under containment conditions specified in Section III— B— 2 with prior IBC review and approval. Recombinant DNA Research, Large-scale experiments (e g., more than 10 liters of culture) require prior IBC review and approval (see Section III— B— 5). Experiments involving the deliberate cloning of genes coding for the biosynthesis of molecules toxic for vertebrates (see Appendix F). Appendix C-Ill — Experiments Involving Saccbaromyces Host-Vector Systems Experiments which use Saccbaromyces cerevisiae host-vector systems, with the exception of experiments listed below, are exempt from these Guidelines. Experiments which use Saccbaromyces uvarum host-vector systems, with the exception of experiments listed below, are exempt from these Guidelines. For these exempt laboratory experiments. BLl physical containment conditions are recommended. For large-scale fermentation experiments BLl-LS physical containment conditions are recommended. However, following review by the IBC of appropriate data for a particular host-vector system some latitude in the application of BLl-LS requirements as outlined in Appendix K-II-A through K— II— F is permitted. Exceptions. Experiments described in Section III— A which require specific RAC review and NIH approval before initiation of the experiment. Experiments involving Class 3, 4. or 5 organisms (1) or cells knowns to be infected with these agents may be conducted under containment conditions specified in Section III— B— 2 with prior IBC review and approval. Large-scale experiments (e.g.. more than 10 liters of culture) require prior IBC review and approval (see Section III— B— 5). Experiments involving the deliberate cloning of genes coding for the biosynthesis of molecules toxic for vertebrates (see Appendix F). Appendix C-TV— Experiments Involving Bacillus subtilis Host- Vector Systems Any asporogenic Bacillus subtilis strain which does not revert to a sporefermer with a frequency greater than 10" 7 can be used for cloning DNA with the exception of those experiments listed below. For these exempt laboratory experiments. BLl physical containment conditions are recommended. For large-scale fermentation experiments BLl-LS physical containment conditions are recommended. However, following review by the IBC of appropriate data for a particular host-vector system, some Volume 1 1 latitude in the application of BLl-LS requirements as outlined in Appendix K-II-A through K-II-F is permitted. Exceptions. Experiments described in Section III— A which require specific RAC review and approval before initiation of the experiment. Experiments involving Class 3. 4. or 5 organisms (1) or cells known to be infected with these agents may be conducted under containment conditions specified by Section III— B— 2 with prior IBC review and approval. Large-scale experiments (e g., more than 10 liters of culture) Require prior IBC review and approval (see Section III— B— 5). Experiments involving the deliberate cloning of genes coding for the biosynthesis of molecules toxic for vertebrates (see Appendix F). Appendix C-V — Extrccbromosomal Elements of Cram Positive Organisms Recombinant DN’A molecules derived entirely from extrachromosomal elements of the organisms listed below (including shuttle vectors constructed from vectors described in Appendix C). propagated and maintained in organisms listed below are exempt from these Guidelines. Bacillus subtilis Bacillus pumilus Bacillus licheniformis Bacillus thuringiensis Bacillus cereus Bacillus amyloliquefaciens Bacillus brevis Bacillus natto Bacillus niger Bacillus atem'mus Bacillus amylosacchariticus Bacillus anthracis Bacillus globigii Bacillus megaterium Staphylococcus aureus Staphylococcus epidermidis Staphylococcus camosus Clostridium acetobutylicum Pediococcus damnosus Pediococcus pentosaceus Pediococcus acidilactici Lactobacillus casei Listeria grayi Listeria murrayi Listeria monocytogenes Streptococcus pyogenes Streptococcus agalactiae Streptococcus sanguis Streptococcus salivarious Streptococcus cremoris Streptococcus pneumoniae Streptococcus avium Streptococcus faecalis Streptococcus anginosus Streptococcus sobrinus Streptococcus lactis Streptococcus mutans Streptococcus equisimilis Streptococcus thermophylus [13] 16970 Federal Register / Vol. 51, No. 88 / Wednesday, May 7, 1986 / Notices Streptococcus milled Streptococcus durans Streptococcus mitior Streptococcus Ferus Exceptions. Experiments described in Section III— A which require specific RAC review and NIH approval before initiation of the experiment. Large-scale experiments (e.g.. more than 10 liters of culture) require prior IBC review and approval (see Section III- B-5). Experiments involving the deliberate cloning of genes coding for the biosynthesis of molecules toxic for vertebrates (see* Appendix F). Appendix C-VI — Footnotes end References of Appendix C 1. The original reference to organisms as Class 1. 2, 3, 4, or 5 refers to the classification in the publication Classification of Etiologic Agents on the Basis of Hazard. 4th Edition, July 1974; U.S. Department of Health, Education and Welfare, Public Health Service, Centers for Disease Control. Office of 3iosafety, Atlanta, Georgia 30333. The Director. NIH, with advice of the Recombinant DNA Advisory Committee, may revise the classification for the purposes of these Guidelines (see Section IV-C-l-b-(2)- (d)). The revised list of organisms in each class is reprinted'in Appendix 3 to these Guidelines. 2. A subset cf non-conjugative plasmid vectors are also poorly mobilizable (e.g., pBR322. pBR313). Where practical, these vectors should be employed. 3. Defined as observable under optimal laboratory conditions by transformation, transduction, phage infection, and/or conjugation with transfer of phage, plasmid, and/or chromosomal genetic information. Note that this definition of exchange may be less stringent than that applied to exempt organisms under Section III— D— 4. 4. As classified in the Third Report of the International Committee on Taxonomy of Viruses: Classification and Nomenclature of Viruses, R.E.F. Matthews. Ed. Interviro'ogy 12 (129-296) 1979. 5. i.e.. the total of ell genomes within a Family shall not exceed one-half of the genome. Appendix D — Actions Taken Under the Guidelines As noted in the subsections of Section IV- C-l-b-(l), the Director, NTH, may take certain actions with regard to the Guidelines after the issues have been considered by the RAC. Some of the actions taken to date include the following: Appendix D-I Permission is granted to clone foot and mouth disease virus in the EK1 host- vector system consisting of E. coli K-12 and the vector pBR322. all work to be done at the Plum Island Animal Disease Center. Appendix D-I I Certain specified clones derived from segments of the foot and mouth disease virus may be transferred from Plum Island Animal Disease Center to. the facilities of Genentech. Inc., of South San Francisco, California. Further development of the clones at Genentech has been approved under BLl + EKl conditions. Appendix D-III The Rd strain of Hemophilus influenzae can be used as a host for the propagation of the cloned Tn 10 tet R gene derived from E. coli K-12 employing the non-conjugative Hemophilus plasmid, pRSF0885. under BLl conditions. Appendix D-IV Permission is granted to clone certain subgenomic segments of foot and mouth disease virus in HVl Bacillus subtilis and Sacchcromyces cerevisiae host- vector systems under ELI conditions at Genentech, Inc., South San Francisco, California. Appendix D-V Permission is granted to Dr. Ronald Davis of Stanford University to field test corn plants modified by recombinant DNA techniques under specified containment conditions. Appendix D-VI Permission is granted to clone in E. coli K-12 under BLl physical containment conditions subgenomic segments of rift valley fever virus subject to conditions which have been set forth by the RAC. Appendix D-V II Attenuated laboratory strains of Sclmonella typhimurium may be used under BLl physical containment conditions to screen for the Saccharomyces cerevisiae pseudouridine synthetase gene. The plasmid YEpl3 will be employed as the vector. Appendix D-VHI Permission is granted to transfer certain clones of subgenomic segments of foot and mouth disease virus from Plum Island Animal Disease Center to the laboratories of Molecular Genetics. Inc.. Minnetonka, Minnesota, and to work with these clones under BLl containment conditions. Approval is contingent upon review of data on infectivity testing of the clones by a working group of the RAC. Appendix D-IX Permission is granted to Dr. John Sanford cf Cornell University to field test tomato and tobacco plants transformed with bacterial [E. ccli K-12) and yeast DNA using pollen as a vector. Appendix D-X Permission is granted to Drs. Steven Lindow and Nicholas Panopouios of the University of California, Berkeley, to release under specified conditions Pseudomoncs syringee pv. syringae and Erwinia herbicola carrying in vitro generated deletions of all or part of the genes involved in ice nucleation. Appendix D-Xl Agracetus of Middleton, Wisconsin, may field test under specified conditions disease resistant tobacco plants prepared by recombinant DNA techniques. Appendix E — Certified Host-Vector Systems (See also Appendix I) While many experiments using E. coli K-12, Saccharomyces cerevisiae and Bacillus subtilis are currently exempt from the Guidelines under Section III-D- 5, some derivatives of these host-vector systems were previously classified as HVl. or HV2. A listing of those systems follows: Appendix E-I — Bccillus subtilis HVl. The following plasmids are accepted as the vector components of certified B. subtilis HVl systems: pUBllO, pCl94, pS!94, pSA2100, pEl94, pTl27, pUBll2, pC221, pC223, and pABl24. B. subtilis strains RUB 331 and BGSC 1S53 have been certified as the host component of HVl systems based on these plasmids. HV2. The asporogenic mutant derivative of Bacillus subtilis, ASB 298, with the following plasmids as the vector component: pUBllO, pCl34, pSl94, pSA2100, pEl94, pT127. pUBl12, pC221, pC223, and pABl24. Appendix E-Il — Saccharomyces cerevisiae HV2. The following sterile strains of Saccharomyces cerevisiae, all of which have the ste-VC9 mutation, SHYl, SHY2, SHY3, and 3HY4. The following plasmids are certified for use: YIpl, YEp2, YEp4, YIp5, YEp0, YRp7, YEp20. YEp21. YEp24, YIp25, YIp26, YIp27, YIp28, YIp29, YIp30, YIp31, YIp32, and YIp33. Appendix E-III — Escherichia coli EX2 Plasmid Systems. The E. coli K- 12 strain chi-1776. The followinn Recombinant DNA Research, Volume 11 [14] 16971 Federal Register / Vol. 51, No. 88 / Wednesday. May plasmids are certified for use: pSClOl. pMB9. pBR313. pBR322. pDH24. pBR325. pBR327, pGLlOl. and pHBl. The following E. coli/S. cerevisiae hybrid plasmids are certified as EK2 vectors when used in £. coli chi-1776 or in the sterile yeast strains. SHYl. SHY2. SHY3, and SHY4: YIpl. YEp2. YEp4. YIp5, YEp6. YRp7. YEp20. YEp21. YEp24. YIp25. YIp26, Ylp27. Yip28. YIp29, Ylp30. YIp31. Ylp32. and Ylp33. EK2 Bacteriophage Systems. The following are certified EK2 systems based on bacteriophage lambda: Vector Xgt A*t USSXB* Xgt Z| AgtALO XB Cturon 3A Charon 4 A Charon ISA Charon 71 A Chiron 23 A Chiron 24A Host DPSOftpF DPSOiupF £ colt K-IZ OPSCUupF DPSO or DPSO supf DP50 or OPSOjjpF DPSO or DPSOjupF DPSOaupF DPSO or DPIOiupF DPSO or DPSOrupF E. coli K-12 strains chi-2447 and chi- 2281 are certified for use with lambda vectors that are certified for use with strain DPSO or DPSOsopF provided that the su * strain not be used as a propagation host. Appendix E-IV — Neurospora crassa HVl. The following specified strains of Neurospora crassc which have been modified to prevent aerial dispersion: Ini (inositolless) strains 37102. 37401. 46316. 64001. and 896G1. Csp-1 strain UCLA37 and csp-2 strains FS 590. UCLA101 (these are conidial separation mutants). Eas strain UCLA191 (an "easily wettable" mutant). Appendix E-V — Streptomyces HVl. The following Streptomyces species: Streptomyces coelicolor. S. lividans, S. parvulus. and S. griseus. The following are accepted as vector components of certified Streptomyces HVl systems: Streptomyces plasmids SCP2. SLPl.2. plJlOl. actinophage phi C31. and their derivatives. Appendix E- V ! — Pseudomonas putida HVl. Pseudomonas putida strains KT2440 with plasmid vectors pKT282. pKT283. and pKT264. Appendix F — Containment Conditions for Cloning of Genes Coding for the Biosynthesis of Molecules Toxic for Vertebrates Appendix F-l— General Information. Appendix F specifies the containment to be used for the deliberate cloning of genes coding for the biosynthesis of molecules toxic for vertebrates. The cloning of genes coding for molecules toxic for vertebrates that have an LDio of less than 100 nanograms per killogram body weight (e g., microbial toxins such as the botulinum toxins, tetanus toxin, diphtheria toxin. Shigella dysenteriae neurotoxin) is covered under Section III— A— 1 of the Guidelines and requires RAC review and NTH and 1BC approval before initiation. No specific restrictions shall apply to the cloning of genes if the protein specified by the gene has an LDio of 100 micrograms or more per kilogram of body weight. Experiments involving genes coding for toxic molecules with an LD*) of 100 micrograms or less per kilogram body weight shall be registered with ORDA prior to initiating the experiments. A list of toxic molecules classified as to LD»> is available from ORDA. Testing procedures for determining toxicity of toxic molecules not on the list are available from ORDA. The results of such tests shall be forwarded to ORDA which will consult with the RAC Working Group on Toxins prior to inclusion of the molecules on the list (see Section IV-C-l-b-(2H e ))- Appendix F-ll — Containment Conditions for Cloning of Toxic Molecule Genes in E coli K-12 Appendix F-ll-A. Cloning of genes coding for molecules toxic for vertebrates that have an LD»o in the range of 100 nanograms to 1000 nanograms per kilogram body weight (e g., abrin. Clostridium perfringens epsilon toxin) may proceed under BL2 + EK2 or BL3 + EXl containment conditions.. Appendix F-ll-B. Cloning of genes for the biosynthesis of molecules toxic for vertebrates with an LD W in the range of 1 microgram to 100 micrcgrams per kilogram body weight may proceed under BLl + EKl containment conditions (e g.. Staphylococcus aureus alpha toxin. Staphylococcus aureus beta toxin, ricin. Pseudomonas aeruginosa exotoxin A, Bordatella pertussis toxin, the lethal factor of Bacillus anthracis, the Pasteurella pestis murine toxins, the oxygen-labile hemolysins such as streptolysin O. and certain neurotoxins present in snake venoms and other venoms). Appendix F-II-C. Some enterotoxins are substantially more toxic when administered enterally than parenterally. The following enterotoxins shall be subject to BLl -t-EKl containment conditions: cholera toxin, the heat labile toxins of E. coli, Klebsiella, and other related proteins that may be identified by neutralization with an antiserum monospecific for cholera toxin, and the heat stable toxins of E. coli and of Yersinia enterocolitica. 7, 1586 / Notices Appendix F-III — Containment Conditions for Cloning of Toxic Molecule Genes in Organisms Other Than E. coli K-12 Requests involving the cloning of genes coding for molecules toxic for vertebrates in host-vector systems other than E. coli K-12 will be evaluated by ORDA which will consult with the Working Group on Toxins (see Section IV-C-l-b-(3;-(f)). Appendix F-IV — Specific Approvals Appendix F-IV-A. Permission is granted to clone the Exotoxin A gene of Pseudomonas aeruginosa under BLl conditions in Pseudomonas aeruginosa and in Pseudomonas putida. Appendix F-IV-B. The pyrogenic exotoxin type A (Tox A) gene of Staphylococcus aureus may be cloned in an HV2 Bacillus suktilis host-vector system under BL3 containment conditions. Appendix F-IV-C. Restriction fragments of Corynephage Beta carrying the structural gene for diphtheria toxin may be safely cloned in e. coli K-12 in high containment Building 550 at the Frederick Cancer Research Facility. Laboratory practices and containment equipment are to be specified by the IBC. If the investigators wish to proceed with the experiments, a prior review will be conducted to advise NIH whether the proposal has sufficient scientific merit to justify the use of the NIH BL4 facility. Appendix F-TV-D. The genes coding for the Staphylococcus aureus determinants. A. B. and F. which may be implicated in toxic shock syndrome may be cloned in E. coli K-12 under BL2 + EK1 conditions. The Staphylococcus aureus strain used as the donor is to be alpha toxin minus. It is suggested that, if possible, the donor Staphylococcus aureus strain should lack other toxins with LDj 0 s in the range of one microgram per kilogram body weight such as the exfoliative toxin. Appendix F-TV-E. Fragments F-l, F-2, and F-3 of the diphtheria toxin gene (tox) may be cloned in £". coli K-12 under BLl + EK1 containment conditions and may be cloned in Bacillus subtilis host-vector systems under BLl containment conditions. Fragment F-l and fragment F-2 both contain: (i) Some or all of the transcriptional control elements of tox: (ii) the signal peptide; and (iii) fragment A (the center responsible for ADP-ribosylation of elongation factor 2). Fragment F-3 codes for most of the non-toxic fragment B of the toxin and contains no sequences coding for any portion of the enzymatically active fragment A moiety. Recombinant DNA Research, Volume 1 1 [15] 16972 Federal Register / Vol. 51. No. 88 / Wednesday. May 7. 1S86 / Notices Appendix F-IV-F. The gene(s) coding for a toxin (designated LT-like) isolated from E. coli which is similar to the E. coli beat labile enterotoxin (LT) with respect to its activities and mode of action but is not neutralized by antibodies against cholera enterotoxin or against LT from human cr porcine E. coli strains, and sequences homologous to the E. coli LT-like toxin ger.e may be cloned under BLl+EXl conditions. Appendix F-IV-G. Genes from Vibrio fluvialis. Vibrio mimicus. and non 0-1 Vibrio chclerae. specifying virulence factors for animals, may be cloned under ELl + EKl conditions. The virulence factors to be cloned will be selected by testing fluid induction in suckling mice and Y-l mouse adrenal cells. Appendix F-I\'-H. The intact structural gene(s) of the Shiga-like toxin from bacterial species classified in the families Enterobcctericceae or Vibrionaceae including Campylobacter species may be cloned in E. coli K-12 under BL3+EK1 containment conditions. E. coli host-vector systems expressing the Shiga-like toxin gene product may be moved from BL3+EK1 to BL2 + EK1 containment conditions provided that: (1) The amount of toxin produced by the modified host-vector systems be no greater than that produced by the positive control strain Shigella dysenteriae 6GR. grown and measured under optimal conditions: and (2) the cloning vehicle is to be an EXl vector preferably belonging to the class of poorly mobilizable plasmids such as pER322, pBk328, and pBR325. Nontoxinogenic fragments of the Shiga-like toxin structural gene(s) may be moved from BL3 + EK1 to BL2-j-EKl containment conditions or such nontoxic fragments may be directly cloned in E. coli K-12 under BL2 + EK1 conditions provided that the E. coli host-vector systems containing the fragments do not contain overlapping fragments which together would encompass the Shigalike toxin structural gene(s). Appendix F-IV-l. A hybrid gene in which the gene coding for the melanocyte stimulating hormone (MSH) is joined to a segment of the gene encoding diphtheria toxin may be safely propagated in E. coli K-12 under BL4 containment in high containment building 550 at the Frederick Cancer Research Facility. If the investigators wish to proceed with the experiment, a prior review will be conducted to advise NTH whether the proposal has sufficient scientific merit to justify the use of the NTH BL4 facility. Before any of the strains may be removed from the BL4 facility, data on their safety shall be [ 16 ] evaluated by the Working Group in Toxins and the working group recommendation shall be acted upon by NIH. Appendix F-IV-J. The gene segment encoding the A subunit of chlolera toxin of Vibrio cholerae may be joined to the transposons Tn5 and Tn5-131 and the A-subunit::Tn5-131 hybrid gene cloned in E. coli K-12 and V. cholerae under BLl containment Conditions. Appendix F-IV-K. A hybrid gene in which the gene coding for interleukin 2 (1L-2) is joined to a specific segment of the gene encoding diphtheria toxin may be propagated in E. coli K-12 host- vector systems under BL2 containment plus BL3 practices, with the use of poorly mobilizable plasmid vectors such as EK2 certified plasmids. Appendix G — Physical Containment Appendix G-l — Standard Practices and Training The first principle of containment is a strict adherence to good microbiological practices [1-10]. Consequently, all personnel directly or indirectly involved ir. experiments on recombinant DMAs must receive adequate instruction (see Sections IV-B-l-e and IV-B-5-d). This shall, as a minimum, include instructions in aseptic techniques and in the biology of the organisms used in the experiments so that the potential biohazards can be understood and appreciated. Any research group working with agents with a known or potential biohazard shall have an emergency plan which describes the procedures to be followed if an accident contaminates personnel or the environment. The PI must ensure that everyone in the laboratory is familiar with both the potential hazards of the work and the emergency plan (see Sections IV-B-3-d and IV-B-5-e). If a research group is working with a known pathogen for which there is an effective vaccine, the vaccine should be made available to all workers. Where serological monitoring is clearly appropriate, it shall be provided (see Section IV-B-l-f). The “Laboratory’ Safety Monograph" and Biosafety in Microbiological and Biomedical Laboratories [2] booklets describe practices, equipment, and facilities in detail. Appendix G-Il — Physical Containment Levels The objective of physical containment is to confine organisms containing recombinant DMA molecules and thus to reduce the potential for exposure of the laboratory worker, persons outside of the laboratory, and the environment to organisms containing recombinant DNA molecules. Physical containment is achieved through the use of laboratory practices, containment equipment, and special laboratory design. Emphasis is placed on primary means of physical containment which are provided by laboratory practices and containment equipment. Special laboratory design provides a secondary means of protection against the accidental release of organisms outside the laboratory or to the environment. Special laboratory design is used primarily in facilities in which experiments of moderate ic high potential hazards are performed. Combinations of laboratory’ practices, containment equipment, and special laboratory design can be made to achieve different levels of physical containment. Four levels of physical containment, which are designated as BLl. BL2, BL3, and BLl. are described. It should be emphasized that the descriptions and assignments of physical containment detailed below are based on existing approaches to containment of pathogenic organisms [2]. The National Cancer Institute describes three levels for research on oncogenic viruses which roughly correspond to our BI.2, BL3. and BLl level [3]. It is recognized that several different combinations of laboratory’ practices, containment equipment, and special laboratory design may be appropriate for containment of specific research activities. The Guidelines, therefore, allow alternative selections of primary containment equipment within facilities that have been designed to provide EL3 and BLl levels of physical containment. The selection of alternative methods of primary’ containment is dependent, however, on the level of biological containment provided by the host-vector system used in the experiment. Consideration will also be given by the Director, NIH, with tha advice of the RA.C to other combinations which achieve an equivalent level of containment (see Section IV-C-l-b-{2)- (bJJ. Appendix C-II-A — Biosafety Level 1 (BLl) [13] Appendix G-II-A-1. Standard Micro biological Practices. Appendix G-II-A-l-a. Access to the laboratory is limited or restricted at the discretion of the laboratory director when experiments are in progress. Appendix C-II-A-l-b. Work surfaces are decontaminated once a day and after any spill of viable material. Recombinant DNA Research, Volume 1 1 Federal Register / Vol. 51. No. 88 / Wednesday, May 7. 1986 / Notices 16973 Appendix C-II-A-l-c. All contaminated liquid or solid wastes are decontaminated before disposal. Appendix G-fl-A-l-d. Mechanical pipetting devices are used: mouth pipetting is prohibited. Appendix G-U-A-l-e. Eating, drinking, smoking, and applying cosmetics are not permitted in the work area. Food may be stored in cabinets or refrigerators designated and used for this purpose only. Appendix G-ll-A-l-f. Persons wash their hands after they handle materials Involving organisms containing recombinant DNA molecules, and animals, and before leaving the laboratory. Appendix G-II-A-l-g All procedures are performed carefully to minimize the creation of aerosols. Appendix C-U-A-l-h. It is recommended that laboratory coats, gowns, or uniforms be worn to prevent contamination or soiling of street clothes. Appendix C-II-A-2 — Special Practices Appendix C-II-A-2-a. Contaminated materials that are to be decontaminated at a site away from the laboratory arc placed in a durable leakproof container which is closed before being removed from the laboratory. Appendix G-lI-A-2-b. An insect and rodent control program is in effect. Appendix C-Il-A-3 — Containment Equipment Appendix C-lI-A-3-c. Special containment equipment is generally not required for manipulations of agents assigned to Biosafety Level 1. Appendix G-lI-A-4 — Laboratory Facilities Appendix G-U-A-4-a. The laboratory is designed so that it can be easily- cleaned. Appendix G-tl-A—t-b. Bench tops are impervious to water and resistant to acids, alkalis, organic solvents, and moderate heat Appendix G-ll-A-4-c. Laboratory- furniture is sturdy. Spaces between benches, cabinets, and equipment are accessible for cleaning. Appendix C-lI-A-4-d. Each laboratory contains a sink for hand- washing. Appendix C-ll-A-4-e. If the laboratory has windows that open, they are fitted with fly screens. Appendix G-II-B — Biosa r ety Level 2 (BL2) [14 J Appendix G-lI-B-1. Standard Microbiological Practices. Appendix G-II-B-l-a. Access to the laboratory is limited or restricted by the laboratory director when work with organisms containing recombinant DNA molecules is in progress. Appendix G-II-B-l-b. Work surfaces are decontaminated at least once a day and after any spill of viable material. Appendix C-ll-B-l-c. All contaminated liquid or solid wastes are decontaminated before disposal. Appendix G-II-B-l-d. Mechanical p-petting devices are used: mouth pipetting is prohibited. Appendix G-II-B-l-e. Eating, drinking, smoking, and applying cosmetics are not permitted in the work area. Food may be stored in cabinets or refrigerators designated and used for this purpose only. Appendix G-U-B-l-f. Persons wash their hands after handling materials involving organisms containing recombinant DNA molecules, and animals, and when they leave the laboratory. Appendix G-Il-B-l-g All procedures are performed carefully to minimize the creation of aerosols. Appendix C-II-B-l-h. Experiments of lesser biohazard potential can be carried out concurrently in carefully demarcated areas of the same laboratory - . Appendix C-ll-B-2 — Special Practices Appendix C-II-B-2-c. Contaminated materials that are to be decontaminated at a site away from the laboratory are placed in a durable leakproof container which is closed before being removed from the laboratory. Appendix C-II-B-2-b. The laboratory- director limits access to the laboratory. The director has the final responsibility for assessing each circumstance and determining who may enter or work in the laboratory. Appendix C-II-B-2-c. The laboratory- director establishes policies and procedures whereby only persons who have been advised of the potential hazard anj meet any specific entry requirements (e g., immunization) enter the laboratory or animal rooms. Appendix G-Il-B-2-d. When the organisms containing recombinant DNA molecules in use in the laboratory require special provisions for entry (e.3.. vaccination), a hazard warning sign incorporating the universal biohazard symbol is posted on the access door to the laboratory work area. The hazard warning sign identifies the agent, lists the name and telephone number of the laboratory director or other responsible person(s), and indicates the special requiremcnt(s) for entering the laboratory. Appendix G-lI-B-2-e. An insect and rodent control program is in effect. Appendix G-lI-B-2-f. Laboratory- coats. gowns, smocks, or uniforms are wem while in the laboratory. Before leaving the laboratory for nonlaboratory areas (e.g.. cafeteria, library, administrative offices), this protective clothing is removed and left in the laboratory or covered with a clean coat not used in the laboratory. Appendix G-Il-B-2-g. Animals not involved in the work being performed are not permitted in the laboratory. Appendix G-II-B-2-h. Special care is taken to avoid skin contamination with organisms containing recombinant DNA molecules: gloves should be worn when handling experimental animals and when skin contact with the agent is unavoidable. Appendix G-ll-B-2-i. All wastes from laboratories and animal rooms are appropriately decontaminated before disposal. Appendix G-lI-B-2-j. Hypodermic needles and syringes are used only for parenteral injection and aspiration of fluids from laboratory animals and diaphragm bottles. Only needle-locking syringes or disposable syringe-needle units (i.e.. needle is integral to the syringe) are used for the injection or aspiration of fluids containing organisms that contain recombinant DNA molecules. Extreme caution should be used when handling needles and syringes to avoid autoinoculation and the generation of aerosols during use and disposal. Needles should not be bent, sheared, replaced in the needle sheath or guard, or removed from the syringe following use. The needle and syringe should be promptly placed in a puncture-resistant container and decontaminated, preferably by autoclaving, before discard or reuse. Appendix G-l!-B-2-k. Spills and accidents which result in overt exposures to organisms containing recombinant DNA molecules are immediately reported to the laboratory- director. Medical evaluation, surveillance, and treatment are provided as appropriate and written records are maintained. Appendix C-II-B-2-1. When appropriate, considering the agent(s) handled, baseline serum samples for laboratory and other at-risk personnel are collected and stored. Additional serum specimens may be collected periodically depending on the agents handled or the function of the facility. Appendix G-ll-B-2-m. A biosafety manual is prepared or adopted. Personnel are advised of special hazards and are required to read Recombinant DNA Research, Volume 1 1 [17] 16974 Federal Register / Vol. 51, No. 88 / Wednesday, May 7, 1986 / Notices instructions on practices and procedures and to follow them. Appendix G-II-B-3 — Containment Equipment Appendix C-II-B-3-a. Biological safety cabinets (Class I or II) (see Appendix G — III— 12) or other appropriate personal protective or physical containment devices are used whenever: Appendix G-II-B-3-a-(lJ. Procedures with a high potential for creating aerosols are conducted (15). These may include centrifuging, grinding, blending, vigorous shaking or mixing, sonic disruption, opening containers of materials whose internal pressures may be different from ambient pressures, inoculating animals intranasally, and harvesting infected tissues from animals or eggs. Appendix G-II-B-3-a-(2J. High concentrations or large volumes of organisms containing recombinant DNA molecules are used. Such materials may be centrifuged in the open laboratory if sealed heads or centrifuge safety cups are used and if they are opened only in a biological safety cabinet. Appendix G-II-B-4 Laboratory Facilities Appendix G-II-B—L-a. The laboratory is designed so that it can be easily cleaned. Appendix G-II-B—4-b. Bench tops are impervious to water and resistant to acids, alkalis, organic solvents, and moderate heat. Appendix G-II-B-4-c. Laboratory furniture is sturdy and spaces between benches, cabinets, and equipment are accessible for cleaning. Appendix G-II-B-4-d. Each laboratory contains a sink for hand- washing. Appendix G-II-B-4-e. If the laboratory has windows that open, they are fitted with fly screens. Appendix G-II-B-4-f. An autoclave for decontaminating laboratory wastes is available. Appendix G-Il-C — Biosafety Level 3 (BL3) [16] Appendix G-II-C-1. Standard Microbiological Practices. Appendix G-II-C-l-a. Work surfaces are decontaminated at least once a day and after any spill of viable material. Appendix G-II-C-l-b. All contaminated liquid or solid wastes are decontaminated before disposal. Appendix G-ll-C-l-c. Mechanical pipetting devices are used; mouth pipetting is prohibited. Appendix G-II-C-l-d. Eating, drinking, smoking, storing food, and applying cosmetics are not permitted in the work area. Appendix G-U-C-l-e. Persons wash their hands after handling materials involving organisms containing recombinant DNA molecules, and animals, and when they leave the laboratory. Appendix G-II-C-l-f. All procedures are performed carefully to minimize the creation of aerosols. Appendix G-ll-C-l-g. Persons under 16 years of age shall not enter the laboratory. Appendix G-II-C-l-h. If experiments involving other organisms which require lower levels of containment are to be conducted in the same laboratory concurrently with experiments requiring BL3 level physical containment, they shall be conducted in accordance with all BL3 level laboratory practices. Appendix G-II-C-2 — Special Practices Appendix G-II-C-2-a. Laboratory doors are kept closed when experiments are in progress. Appendix G-II-C-2-b. Contaminated materials that are to be decontaminated at a site away from the laboratory are placed in a durable leakproof container which is closed before being removed from the laboratory. Appendix G-Il-C-2-c. The laboratory director controls access to the laboratory and restricts access to persons whose presence is required for program or support purposes. The director has the final responsibility for assessing each circumstance and determining who may enter or work in the laboratory. Appendix G-II-C-2-d. The laboratory director establishes policies and procedures whereby only persons who have been advised of the potential biohazard, who meet any specific entry requirements (e.g., immunization), and who comply with all entry and exit procedures enter the laboratory or animal rooms. Appendix G-Il-C-2-e. When organisms containing recombinant DNA molecules or experimental animals are present in the laboratory or containment module, a hazard warning sign incorporating the universal biohazard symbol is posted on all laboratory and animal room access doors. The hazard warning sign identifies the agent, lists the name and telephone number of the laboratory director or other responsible person(s), and indicates any special requirements for entering the laboratory, such as the need for immunizations, respirators, or other personal protective measures. Appendix G-II-C-2-f. All activities involving organisms containing recombinant DNA molecules are conducted in biological safety cabinets or other physical containment devices within the containment module. No work in open vessels is conducted on the open bench. Appendix G-II-C-2-g. The work surfaces of biological safety cabinets and other containment equipment are decontaminated when work with organisms containing recombinant DNA molecules is finished. Plastic-backed paper toweling used on nonperforated work surfaces within biological safety cabinets facilitates clean-up. Appendix G-U-C-2-h. An insect and rodent program is in effect. Appendix G-II-C-2-i. Laboratory clothing that protects street clothing (e.g., solid front or wTap-around gowns, scrub suits, coveralls) is worn in the laboratory. Laboratory clothing is not worn outside the laboratory, and it is decontaminated before being laundered. Appendix G-II-C-2-j. Special care is taken to avoid skin contamination with contaminated materials: gloves should be worn when handling infected animals and when skin contact with infectious materials is unavoidable. Appendix G-II-C-2-k. Molded surgical masks or respirators are worn in rooms containing experimental animals. Appendix G-II-C-2-1. Animals and plants not related to the work being conducted are not permitted in the laboratory. Appendix G-Il-C-2-m. Laboratory animals held in a BL3 area shall be housed in partial-containment caging systems, such as Horsfall units [11], open cages placed in ventilated enclosures, solid-wall and -bottom cages covered by filter bonnets, or solid-wall and -bottom cages placed on holding racks equipped with ultraviolet in radiation lamps and reflectors. Note. — Conventional caging systems may be used provided that all personnel wear appropriate personal protective devices. These shall include at a minimum wrap- around gowns, head covers, gloves, shoe covers, and respirators. All personnel shall shower on exit from areas where these devices are required. Appendix G-II-C-2-n. All wastes from laboratories and animal rooms are appropriately decontaminated before disposal. Appendix G-II-C-2-o. Vacuum lines are protected with high efficiency particulate air (HEPA) filters and liquid disinfectant traps. Appendix G-lI-C-2-p. Hypodermic needles and syringes are used only for parenteral injection and aspiration of fluids from laboratory animals and [ 18 ] Recombinant DNA Research, Volume 1 1 Federal Register / Vol. 51. No. 68 / Wednesday. May 7, 1986 / Notices 18975 diaphragm bottles. Only needle-locking syringes or disposable s> rir.ge-r.eedle units {i.e.. needle is integral to the syringe) are used for the injection or aspiration of fluids containing organisms that contain recombinant DNA molecules. Extreme caution should be used when handling needles and syringes to avoid autoinoculation and the generation of aerosols during use and disposal. Needles should not be bent, sheared, replaced in the needle sheath or guard or removed from the syringe following use. The needle and syringe should be promptly placed in a puncture-resistant container and decontaminated, preferably by autoclaving, before discard or reuse. Appendix C-II-C-2-q. Spills end accidents which result in evert or potential exposures to organisms containing recombinant DN'A molecules are immediately reported to the laboratory director. Appropriate medical evaluation, surveillance, and treatment are provided and written records are maintained. Appendix G-II-C-2-r. Baseline serum samples for all laboratory and other at- risk personnel should be collected and stored. Additional serum specimens may be collected periodically drpendir.g on the agents handled or the function of the laboratory. Appendix C-Il-C-2-s. A biosafety manual is prepared or adopted. Personnel are advised of special hazards and are required to read instructions on practices and procedures and to follow them. Appendix G-lI-C-2-t. Alternative Selection of Containment Equipment. Experimental procedures involving a host-vector system that provides a one- step higher level of biological containment than that specified can be conducted in the BL3 laboratory using containment equipment specified for the BL2 level of physical containment. Experimental procedures involving a host-vector system that provides a one- step lower level of biological containment than that specified can be conducted in the BL3 laboratory using containment equipment specified for the BU level of physical containment. Alternative combination of containment safeguards are shown in Table 1. Appendix C-/I-C-3 — Containment Equipment Appendix G-II-C-3-a. Biological safety cabinets (Class 1. 11. or 111) (see Appendix G— 111—12) or other appropriate combinations of personal protective or physical containment devices (e g . special protective clothing, masks, gloves, respirators, centrifuge safety cups, sealed centrifuge rotors, and containment caging for animals) are used for all activities with organisms containing recombinant DNA molecules which pose a threat of aerosol exposure. These Include: manipulation of cultures and of those clinical or environmental materials which may be a source of aerosols: the aerosol challenge of experimental animals: and harvesting infected tissues or fluids from experimental animals and embryonate eggs; and necropsy of experimental animals. Appendix G-lI-C—f — Laboratory Facilities .Appendix G-II-C—t-a. The laboratory is separated from areas which are open to unrestricted traffic Row within the building. Passage through two sets of doors is the basic requirement for entry' into the laboratory from access corridors or other contiguous areas. Physical separation of the high containment laboratory from access corridors or other laboratories or activities may also be provided by a double-docred clothes change room (showers may be included), airlock, or other access facility which requires passage through two sets of doors before entering the laboratory. Appendix G-lI-C-4-b The interior surfaces of walls, fioors. and ceilings are water resistant so that they can be easily cleaned. Penetrations in these surfaces are sealed or capable of being sealed to facilitate decontaminating the area. Appendix G-H-C—t-c. Bench tops are impervious to water and resistant to acids, alkalis, organic solvents, and moderate heat. Appendix G-lI-C-4-d. Laboratory furniture is sturdy and spaces between benches, cabinets, and equipment are accessible for cleaning. Appendix C-II-C-4-e. Each laboratory contains a sink for hand- washing. The sink is foot, elbow, or automatically operated and is located near the laboratory exit door. Appendix G-Il-C-4~f. Windows in the laboratory are closed and sealed. Appendix G-U-C^t-g. Access doors to the laboratory or containment module are self-closing. Appendix G-II-C-4-h. An autoclave for decontaminating laboratory wastes is available preferably within the laboratory. Appendix C-lI-C-t~i. A ducted exhaust air ventilation system is provided. This system creates directional airflow that draws air into the laboratory through the entry area. The exhaust air is not recirculated to any other area of the building, is discharged to the outside, and is dispersed away from the occupied areas and air intakes. Personnel must verify that the direction of the airflow (into the laboratory) is proper. The exhaust air from the laboratory room can be discharged to the outside without being filtered or otherwise treated. Appendix C-II-C-t-j. The HEPA- filtered exhaust air from Class l or Class II biological safety cabinets is discharged directly to the outside or through the building exhaust system. Exhaust air from Class I or II biological safety cabinets may be recirculated within the laboratory if the cabinet is tested and certified at least every twelve months. If the HEPA-filtersd exhaust air from Class I or 11 biological safety cabinets is to be discharged to the outside through the building exhaust air system, it is connected to this system in a manner (e g., thimble unit connection (12)) that avoids any interference with the air balance of the cabinets or building exhaust system. Appendix C-1I-D — Bioso r ety Level V (BL4). Appendix C-1I-D-1. Standard Microbiological Practices. Appendix G-Il-D-l-a. Work surfaces are decontaminated at least once a day and immediately after any spill of viable material. Appendix G-11-D-l-b. Only mechanical pipetting devices are used. Appendix G-II-D-l-c. Eating, drinking, smoking, storing food, and applying cosmetics are not permitted in the laboratory. Appendix G-H-D-l-d. Ail procedures are performed carefully to minimize the creation of aerosols. Appendix G-ll-D-2 — Special Practices Appendix G-II-D-2-a. Biological materials to be removed from the Class III cabinets or from the maximum containment laboratory in a viable or intact state are transferred to a nonbreakabie. sealed primary container and then enclosed in a nonbreakabie. sealed secondary container which is removed from the facility through a disinfectant dunk tank, fumigation chamber, or an airlock designed for this purpose. Appendix G-ll-D-2-b. No materials, except for biological materials that are to remain in a viable or intact state, are removed from the maximum containment laboratory unless they have been autoclaved or decontaminated before they leave the facility. Equipment or material which might be damaged by high temperatures or steam is decontaminated by gaseous Recombinant DNA Research, Volume 1 1 [ 19 ] 16976 Federal Register / Vol. 51, No. 88 / Wednesday, May 7, 1986 / Notices or vapor methods in an airlock or chamber designed for this purpose. Appendix G-II-D-2-c. Only persons whose presence in the facility or individual laboratory rooms is required for program or support purposes are authorized to enter. The supervisor has the final responsibility for assessing each circumstance and determining who may enter or work in the laboratory. Access to the facility is limited by means of secure, locked doors; accessibility is managed by the laboratory director, biohazards control officer, or other person responsible for the physical security of the facility. Before entering, persons are advised of the potential biohazards and instructed as to appropriate safeguards for ensuring their safety. Authorized persons comply with the instructions and all other applicable entry and exit procedures. A logbook signed by all personnel indicates the date and time of each entry and exit. Practical and effective protocols for emergency situations are established. Appendix G-II-D-2-d. Personnel enter and leave the facility only through the clothing change and shower rooms. Personnel shower each time they leave the facility. Personnel use the airlocks to enter or leave the laboratory only in an emergency. Appendix G-II-D-2-e. Street clothing is removed in the outer clothing change room and kept there. Complete laboratory clothing, including undergarments, pants and shirts or jumpsuits, shoes, and gloves, is provided and used by all personnel entering the facility. Head covers are provided for personnel who do not wash their hair during the exit shower. When leaving the laboratory and before proceeding into the shower area, personnel remove their laboratory clothing and store it in a locker or hamper in the inner change room. Appendix G-ll-D-2-f. When materials that contain organisms containing recombinant DNA molecules or experimental animals are present in the laboratory or animal rooms, a hazard warning sign incorporating the universal biohazard symbol is posted on all access doors. The sign identifies the agent, lists the name of the laboratory director or other responsible person(s), and indicates any special requirements for entering the area (e.g., the need for immunizations or respirators). Appendix G-II-D-2-g. Supplies and materials needed in the facility are brought in by way of the double-doored autoclave, fumigation chamber, or airlock which is appropriately decontaminated between each use. After securing the outer doors. personnel within the facility retrieve the materials by opening the interior doors or the autoclave, fumigation chamber, or airlock. These doors are secured after materials are brought into the facility. Appendix G-II-D-2-h. An insect and rodent control program is in effect. Appendix G-II-D-2-i. Materials (e.g.. plants, animals, and clothing) net related to the experiment being conducted are not permitted in the facility. Appendix G-U-D-2-j. Hypodermic needles and syringes are used only for parenteral injection and aspiration of fluids from laboratory animals and diaphragm bottles. Only needle-locking syringes or disposable syringe-needle units (i.e., needle is integral part of unit) are used for the injection or aspiration of fluids containing organisms that contain recombinant DNA molecules. Needles should not be bent, sheared, replaced in the needle sheath or guard, or removed from the syringe following use. The needle and syringe should be placed in a puncture-resistant container and decontaminated, preferably by autoclaving before discard or reuse. Whenever possible, cannulas are used instead of sharp needles (e.g., gavage). Appendix G-II-D-2-k. A system is set up for reporting laboratory accidents and exposures and employee absenteeism and for the medical surveillance of potential laboratory- associated illnesses. Written records are prepared and maintained. An essential adjunct to such a reporting-surveillance system is the availability of a facility for quarantine, isolation, and medical care of personnel with potential or known laboratory associated illnesses. Appendix G-II-D-2-I. Laboratory animals involved in experiments requiring BL4 level physical containment shall be housed either in cages contained in Class III cabinets or in partial containment caging systems (such as Horsfall units [11]), open cages placed in ventilated enclosures, or solid- wall and -bottom cages placed on holding racks equipped with ultraviolet irradiation lamps and reflectors that are located in a specially designed area in which all personnel are required to wear one-piece positive pressure suits. Appendix G-II-D-2-m. Alternative Selection of Containment Equipment. Experimental procedures involving a host-vector system that provides a one- step higher level of biological containment than that specified can be conducted in the BL4 facility using containment equipment requirements specified for the BL3 level of physical containment. Alternative combinations of containment safeguards are shown in Table I. Appendix G-II-D-3. — Containment Equipment Appendix G-II-D-3-a. All procedures within the facility with agents assigned to Biosafety Level 4 are conducted in the Class III biological safety cabinet or in Class I or U biological safety cabinets used in conjunction with one-piece positive pressure personnel suits ventilated by a life-support system. Appendix G-lI-D-4. — Laboratory Facilities Appendix G-U-D-^—a. The maximum containment facility consists of either a separate building or a clearly demarcated and isolated zone within a building. Outer and inner change rooms separated by a shower are provided for personnel entering and leaving the facility. A double-doored autoclave, fumigation chamber, cr ventilated airlock is provided for passage of those materials, supplies, or equipment which are not brought into the facility through the change room. Appendix G-II-D—l-b. Walls, floors, and ceilings of the facility are constructed to form a sealed internal shell which facilitates fumigation and is animal and insect proof. The internal surfaces of this shell are resistant to liquids and chemicals, thus facilitating cleaning and decontamination of the area. All penetrations in these structures and surfaces are sealed. Any drains in the floors contain traps filled with a chemical disinfectant of demonstrated efficacy against the target agent, and they are connected directly to the liquid waste decontamination system. Sewer and other ventilation lines contain HEPA filters. Appendix G-II-D-4-c. Internal facility appurtenances, such as light fixtures, air ducts, and utility pipes, are arranged to minimize the horizontal surface area on which dust can settle. Appendix G-I!-D-4-d. Eench tops have seamless surfaces which are impervious to water and resistant to acids, alkalis, organic solvents, and moderate heat. Appendix G-lI-D-4-e. Laboratory furniture is of simple and sturdy construction, and spaces between benches, cabinets, and equipment are accessible for cleaning. Appendix G-II-D-i-f. A foot, elbow, or automatically operated hand-washing sink is provided near the door of each laboratory room in the facility. Appendix G-ll-D-4-g. If there is a central vacuum system, it does not serve areas outside the facility. In-line HEPA filters are placed as near as practicable to each use point or service cock. Filters Recombinant DNA Research, Volume 1 1 [ 20 ] Federal Register / Vol. 51, No. 88 / Wednesday, May 7, 1986 / Notices 16977 are installed to permit in-place decontamination and replacement. Other liquid and gas services to the facility are protected by devices that prevent backflow. Appendix C-Il-D—t-h. If water fountains are provided, they are foot operated and are located in the facility corridors outside the laboratory. The water service to the fountain is not connected to the backfiow-protccted distribution system supplying water to the laboratory areas. Appendix G-II-D-t-i. Access doors to the laboratory are self-closir.g and lockable. Appendix C-ll-D—t-j. Any windows are breakage resistant. Appendix G-II-D—t-k. A double- doored autoclave is provided for decontaminating materials passing out of the facility. The autoclave door which opens to the area external to the facility is sealed to the outer wall and automatically controlled so that the outside door can only be opened after the autoclave "sterilization" cycle has been completed. Appendix G-lI-D-A-l. A pass-through dunk tank, fumigation chamber, or an equivalent decontamination method is provided so that materials and equipment that cannot be decontaminated in the autoclave can be safely removed from the facility. Appendix G-U-D-4-m. Liquid effluents from laboratory sinks, biological safety cabinets, floors, and autoclave chambers are decontaminated by heat treatment before being released from the maximum containment facility. Liquid wastes from shower rooms and toilets may be decontaminated with chemical disinfectants or by heat in the liquid waste decontamination system. The procedure used for heat decontamination of liquid wastes is evaluated mechanically and biologically by using a recording thermometer and an indicator microorganism with a defined heat susceptibility pattern. If liquid wastes from the shower room are decontaminated with chemical disinfectants, the chemical used is of demonstrated efficacy against the target or indicator microorganisms. Appendix G-II-D-4-n. An Individual supply and exhaust air ventilation system is provided. The system maintains pressure differentials and directional airflow as required to assure flows inward from areas outside of the facility toward areas of highest potential risk within the facility. Manometers are used to sense pressure differentials between adjacent areas maintained at different pressure levels. If a system malfunctions, the manometers sound an alarm. The supply and exhaust airflow is interlocked to assure inward (or zero) airflow at all times. Appendix G-lI-D—J~o. The exhaust air from the facility is filtered through HEPA filters and discharged to the outside so that it is dispersed away from occupied buildings and air intakes. Within the facility, the filters are located as near the laboratories as practicable in order to reduce the length of potentially contaminated air ducts. The filter chambers are designed to allow in situ decontamination before filters are removed and to facilitate certification tasting after they are replaced. Coarse filters and HEPA filters are provided to treat air supplied to the facility in order to increase the lifetime of the exhaust HEPA filters and to protect the supply air system should air pressures become unbalanced in the laboratory. Appendix C-lI-D-i-p The treated exhaust air from Class I and II biological safety cabinets can be discharged into the laboratory room environment or the outside through the facility air exhaust system. If exhaust air from Class I or II biological safety cabinets is discharged into the laboratory the cabinets are tested and certified at 6-month intervals. The exhaust air from Class 111 biological safety cabinets is discharged, without recirculation through two sets of HEPA filters in series, via the facility exhaust air system. If the treated exhaust air from ary of these cabinets is discharged to the outside through the facility exhaust air system, it is connected to this system in a manner (e g . thimble unit connection [12]) that avoids any interference with the air balance of the cabinets or the facility exhaust air system. Appendix G-ll-D-f-q. A specially- designed suit area may be provided in the facility. Personnel who enter this area wear a one-piece positive pressure suit that is ventilated by a life-support- system. The life-support system includes alarms and emergency backup breathing air tanks. Entry to this area is through an airlock fitted with airtight doors. A chemical shower is provided to decontaminate the surface of the suit before the worker leaves the area. The exhaust air from the suit area is filtered by two sets of HEPA filters installed in series. A duplicate filtration unit, exhaust fan. and an automatically starting emergency power source are provided. The air pressure within the suit area is lower than that of any adjacent area. Emergency lighting and communication systems are provided. All penetrations into the internal shell of the suit area are sealed. A double- doored autoclave is provided for decontaminating waste materials to be removed from the suit area. Table 1.— Possible Alternate Combina- tions of Physical and Biological Con- tainment Safeguards C'assif*C3t>on of ph^vcai and b«c »og*cal COniamrrmnt A gnate physical containment Alter- nate brc'ogi- cal contain- ment Labora- tory facilities labora- tory prac bees Conta.n- ment equip- ment 813 HV2 813 Bl3 8L3 HV2 0L3 8L3 814 HV1 BL3HV1 . , 813 Bl3 eu HV1 BL3 813 812 HV2 BL4'HV1 6'.4 814 Bl4 HV1 814 814 813 HV2 Appendix G-III — Footnotes and References of Appendix C 1. Laboratory Safety at the Center for Disease Control (Sept. 1974). U.S. Department of Health Education and Welfare Publication No. CDC 75-8118. 2. Biosafety in Microbiological and Biomedical Laboratories. 1st Edition (March 1984). U S. Dapartment of Health and Human Services. Public Health Service. Centers fur Disease Control. Atlanta. Georgia 30333. and National Institutes of Health. Bcthesda. Maryland 20205. 3. National Career Institute Safety- Standards for Research Involving Oncogenic Viruses (Oct. 1974). L'.S. Department of Health. Education and Welfare Publication No. (NIH) 75-790. 4. National Institutes of Health Biohazards Safety Cuide (1974). U.S. Department of Health. Education, and Welfare. Public Health Service. National Institutes of Health. U.S. Government Printing Office. Stock No. 1740-00383. 5 Biohazc rds in Biological Research (1973). A. Heilman. M.N. Oxman. and R Pollack (ed.) Cold Spring Harbor Laboratory. 6 Handbook of Laboratory Safety (1971). 2nd Edition. N.V. Steere (ed.). The Chemical Rubber Co.. Cleveland. 7. Bodily. J.L. (197o). Genera! Administration of the Laboratory. H.L. Bodily. E.L. Ifpdyke. and J.O. Mason (eds.). Diagnostic Procedures for Bacterial. Mycotic and Parasitic Infections. American Public Health Association. New York. pp. 11-28. 8 Darlow. H.M. (1969). Safety in the Microbiological Laboratory. In J.R. Norris and D.W. Robbins (ed.). Methods in Microbiology. Academic Press. Inc.. New York. pp. 169-204. 9. The Prevention of Laboratory Acquired Infection (1974). C.H. Collins. E.G. Hartley, and R. Pilswcrth. Public Health Laboratory- Service. Monograph Series No. 6. 10. Chatigr.y. M.A. (1961). Protection Against Infection in the Microbiological Laboratory: Devices and Procedures. In WAV. Umb.-eit (ed.). Advances in Applied Microbiology. Academic Press. New York N.Y. 3:131-192. 11. Horsfall. F.L.. Jr.. 8nd J.H. Bar.er (1940). Individual Isolation of Infected Animals in c Single Room. J. Bact. 40. 569-580. 12. Biological safety cabinets referred to in this section are classified as Class I. Class II. or Class III cabinets. A Class / is a ventilated cabinet for personnel protection having an Recombinant DNA Research, Volume 1 1 [ 21 ] 16978 Federal Register / Vol. 51, No. 88 / Wednesday, May 7, 1986 / Notices inward flow of air away from the operator. The exhaust air from this cabinet is filtered through a high-efficiency particulate air (HEPA) filter. This cabinet is used in three operational modes: (1) with a full-width open front, (2) with an installed front closure panel (having four 8-mch diameter openings) without gloves, and (3) with an installed front closure panel equipped with arm-length rubber gloves. The face velocity of the inward flow of air through the full-width open front is 75 feet per minute or greater. A Class //cabinet is a ventilated cabinet for personnel and product protection having an open front with inward air flow for personnel protection, and HEPA filtered mass recirculated air flew for product protection. The cabinet exhaust air is filtered through a HEPA filter. The face velocity of the inward flow of air through the full-width open front is 75 feet per minute or greater. Design and performance specifications for Class 11 cabinets have been adopted by the National Sanitation Foundation, Ann Arbor, Michigan. A Class 111 cabinet is a closed-front ventilated cabinet of gas-tight construction which provides the highest level of personnel protection of all biohazard safety cabinets. The interior of the cabinet is protected from contaminants exterior to the cabinet. The cabinet is fitted with arm-length rubber gloves and is operated under a negative pressure of at least 0.5 inches water gauge. All supply air is filtered through HEPA filters. Exhaust air is filtered through two HEPA filters or one HEPA filter and incinerator before being discharged to the outside environment National Sanitation Foundation Standard 49. 1976. Class II (Laminar Flow) Biohazard Cabinetry. Ann Arbor, Michigan. 13. Biosafety Level 1 is suitable for work involving agents of no known or minimal potential hazard to laboratory personnel and the environment. The laboratory is not separated from the general traffic patterns in the building. Work is generally conducted on open bench tops. Special containment equipment is not required or generally used. Laboratory personnel have specific training in the procedures conducted in the laboratory and are supervised by a scientist with general training in microbiology or a related science (see Appendix G-.UI-2). 14. Biosafety Level 2 is similar to Level 1 and is suitable for work involving agents of moderate potential hazard to personnel and the environment. It differs in that: (1) laboratory personnel have specific training in handling pathogenic agents and are directed by competent scientists; (2) access to the laboratory is limited when work is being conducted; and (3) certain procedures in which infectious aerosols are created are conducted in biological safety cabinets or other physical containment equipment (see Appendix G-III-2). 15. Office of Research Safety. National Cancer Institute, and the Special Committee of Safety and Health Experts. 1978. "Laboratory Safety Monograph: A Supplement to the NIH Guidelines for Recombinant DNA Research." Bethesda, Maryland, National Institutes of Health. 16. Biosafety Level 3 i3 applicable to clinical, diagnostic, teaching, research, or production facilities in which work is done with indigenous or exotic agents which may cause serious or potentially lethal disease as a result of exposure by the inhalation route. Laboratory personnel. have specific training in handling pathogenic and potentially lethal agents and are supervised by competent scientists who are experienced in working with these agents. All procedures involving the manipulation of infectious material are conducted within biological safety cabinets or other physical containment devices or by personnel wearing appropriate personal protective clothing and devices. The laboratory has special engineering and design features. It is recognized, however, that many existing facilities may not have all the facility safeguards recommended for Biosafety Level 3 (e.g., access zone, sealed penetrations, and directional airflow, etc.). In these circumstances, acceptable safety may be achieved for routine or repetitive operations (e.g., diagnostic procedures involving the propagation of an agent for identification, typing, and susceptibility testing) in laboratories where facility features satisfy Biosafety Level 2 recommendab'ons provided the recommended "Standard Microbiological Practices." “Special Practices," and "Containment Equipment" for Biosafety Level 3 are rigorously followed. The decision to implement this modification of Biosafety Level 3 recommendations should be made only by the laboratorv director (see Appendix G-III-2). Appendix H — Shipment Recombinant DNA molecules contained in an organism or virus shall be shipped only as an etiologic agent under requirements of Lhe U.S. Public Health Service, and the U.S. Department of Transportation (§ 72.3, Part 72, Title 42, and §§ 173.3e6-.388, Part 173, Title 49, U.S. Code of Federal Regulations (CFR)) as specified below: Appendix H-I Recombinant DNA molecules contained in an organism or virus requiring BLl, BL2, or BL3 physical containment, when offered for transportation or transported, are subject to all requirements of §§ 72.3(a)- (e), Part 72, Title 42 CFR, and §§ 173.386-.388, Part 173, Title 49 CFR Appendix H-ll Recombinant DNA molecules contained in an organism or virus requiring"BL4 physical containment, when offered for transportation or transported, are subject to the requirements listed above under Appendix H-I and are also subject to § 72.3(f), Part 72, Title 42 CFR. Appendix H-I1I Information on packaging and labeling of etiologic agents is shown in Figures 1, 2, and 3. Additional information on packaging and shipment is given in the "Laboratory Safety Monograph — A Supplement to the NIH Guidelines for Recombinant DNA Research,” available from the Office of Recombinant DNA Activities and in Biosafety in Microbiological and Biomedical Laboratories (see Appendix G-III-2). BILLING COCE 4140-01-41 [ 22 ] Recombinant DNA Research, Volume 1 1 FIGURE 1 Federal Register / Vol. 51, No. 88 / Wednesday, May 7, 1986 / Notices 16979 CO H UJ «-yT* cso^ «3 SS CJ3 O £2 ® css: c^a: f— . d.^LJ " o < S * s u o “ Recombinant DNA Research, Volume 1 1 [23] O-IO-OH* 3000 ONITlIfe 18980 Federal Register / Vol. 51, No. 88 / Wednesday, May 7, 1986 [ Notices Appendix I — Biological Containment (See also Appendix E) Appendix l-l — Levels of Biological Containment. In consideration of biological containment, the vector (plasmid, organelle, or virus) for the recombinant DNA and the host (bacterial, plant, or animal cell) in which the vector is propagated in the laboratory will be considered together. Any combination of vector and host which is to provide biological containment must be chosen or constructed so that the following types of “escape" are minimized: (i) Survival of the vector in its host outside the laboratory, and (ii) transmission of the vector from the propagation host to other nonlaboratory hosts. The following levels of biological containment (HV, or //ost- Vector, systems) for prokaryotes will be established; specific criteria will depend on the organisms to be used. Appendix l-I-A. HVl. A host-vector system which provides a moderate level of containment. Specific systems are: Appendix I-I-A-l. EKl. The host is always E. coli K-12 or a derivative thereof, and the vectors include nonconjugative plasmids (e.g., pSClOl, ColEl, or derivatives thereof [1-7] and variants of bacteriophage, such as lambda [8-15]. The E. coli K-12 hosts shall not contain conjugation-proficient plasmids, whether autonomous or integrated, or generalized transducing phages. Appendix I-I-A-2. Other HVl. Hosts and vectors shall be, at a minimum, comparable in containment to E. coli K- 12 with a non conjugative plasmid or bacteriophage vector. The data to be considered and a mechanism for approval of such HVl systems are described below (Appendix I— II). Appendix I-l-B. HV2. These are host- vector systems shown to provide a high level of biological containment as demonstrated by data from suitable tests performed in the laboratory. Escape of the recombinant DNA either via survival of the organisms or via transmission of recombinant DNA to other organisms should be less than 1/ 10 8 under specified conditions. Specific systems are: Appendix I-I-B-l. For EK2 host- vector systems in which the vector is a plasmid, no more than one in 10 8 host cells should be able to perpetuate a cloned DNA fragment under the specified nonpermissive laboratory conditions designed to represent the natural environment, either by survival of the original hos* or as a consequences of transmission of the cloned DNA fragment. Appendix l-l-B-2. For EK2 host- vector systems in which the vector is a phage, no more than one in 10* phage particles should be able to perpetuate a cloned DNA fragment under the specified nonpermissive laboratory conditions designed to represent the natural environment either: (i) as a prophage (in the inserted or plasmid form) in the laboratory host used for phage propagation or (ii) by surviving in natural environments and transferring a cloned DNA fragment to other hosts (or their resident prophages). Appendix /-// — Certification of Host- Vector Systems Appendix I-II-A. Responsibility. HVl systems other than E. coli K-12 and HV2 host-vector systems may not be designated as such until they have been certified by the Director, NIH. Application for certification of a host- vector system is made by written application to the Office of Recombinant DNA Activities, National Institutes of Health, Building 31, Room 3B10, Bethesda, Maryland 20892. Host-vector systems that are proposed for certification will be reviewed by the RAC (see Section IV-C-l-b-(l)-(e)). This will first involve review of the data on construction, properties, and testing of the proposed host-vector system by a working group composed of one or more members of the RAC and other persons chosen because of their expertise in evaluating such data. The committee will then evaluate the report of the working group and any other available information at a regular review meeting. The Director, NIH, is responsible for certification after receiving the advice of the RAC. Minor modifications of existing certified host-vector systems where the modifications are of minimal or no consequence to the properties relevant to containment may be certified by the Director, NIH, without review by the RAC (see Section IV— C— 1— b— (3)— (c)). *Vhen new host-vector systems are certified, notice of the certification will be sent by ORDA to the applicant and to all IBCs and will be published in the Recombinant DNA Technical Bulletin. Copies of a list of all currently certified host-vector systems may be obtained from ORDA at any time. The Director. NIH, may at any time rescind the certification of any host- vector system (see Section IV-C-l-b- (3)-(d)). If certification of a host-vector system is rescinded, NIH will instruct investigators to transfer cloned DNA into a different system or use the clones at a higher physical containment level unless'NIH determines that the already constructed clones incorporate adequate biological containment. Certification of a given system does not extend to modifications of either the host or vector component of that system. Such modified systems must be independently certified by the Director, NIH. If modifications are minor, it may only be necessary for the investigator to submit data showing that the modifications have either improved or not impaired the major phenotypic traits on which the contaiment of the system depends. Substantial modifications of a certified system require the submission of complete testing data. Appendix I-II-B. Data to be Submitted for Certification. Appendix I-lI-B-1. HVl Systems Other than E. coli K-12. The following types of data shall be submitted, modified as appropriate for the particular system under consideration: ,(i) A description of the organism and vector, the strain’s natural habitat and growth requirements: its physiological properties, particularly those related to its reproduction and survival and the mechanisms by which it exchanges genetic information; the range of organisms with which this organism normally exchanges genetic information and what sort of information is exchanged; and any relevant information on its pathogenicity or toxicity; (ii) a description of the history of the particular strains and vectors to be used, including data on any mutations which render this organism less able to survive or transmit genetic information; and (iii) a general, description of the range of experiments contemplated with emphasis on the need for developing such an HVl system. Appendix I-II-B-2. HV2 Systems. Investigators planning to request HV2 certification for host-vector systems can obtain instructions from ORDA concerning data to be submitted [14-15]. In general, the following types of data are required: (i) Description of construction steps with indication of source, properties, and manner of introduction of genetic traits; (ii) quantitative data on the stability of genetic traits that contribute to the containment of the system;. (iii) data on the survival of the host-vector system under nonpermissive laboratory conditions designed to represent the relevant natural environment; (iv) Data on transmissibility of the vector and/or a cloned DNA fragment under both permissive and nonpermissive conditions; (v) data on all other properties of the system which affect containment and utilitv, includir.G Recombinant DNA Research, Volume 1 1 [ 24 ] Federal Register / Vol. 51, No. 88 / Wednesday, May 7, 1986 / Notices 16981 information on yields of phage or plasmid molecules, ease of DMA isolation, and ease of transfection or transformation: and (vi) in some cases, the investigator may be asked to submit data on survival and vector transmissibility from experiments in which the host-vector is fed to laboratory animals and human subjects. Such in vivo data may be required to confirm the validity of predicting in vivo survival on the basis of in vitro experiments. Data must be submitted in writing to ORDA. Ten to twelve weeks are normally required for review and circulation of the data prior to the meeting at which such data can be considered by the RAC. Investigators are encouraged to publish their data on the construction, properties, and testing of proposed HV2 systems prior to consideration of the system by the RAC and its subcommittee. More specific instructions concerning the type of data to be submitted to NIH for proposed EK2 systems involving either plasmids or bacteriophage in E. coli K-12 arc available from ORDA. Apocndix l-IIl — Footnotes and References of Appendix / 1. Hersfield. V., H.W. Boyer. C. Yanofsky. M..Y Lovett, and D.R. Heiinski (1974). Plasmid Co, 'El as a Molecular Vehicle for Cloning and Amplification of DXA. Proc. Nat. Acad. Sci. USA 71. 3455-3459. 2. Wensink. P.C., D.J. Finnegan. J.E. Uonelson. and D.S. Hogness (1974). A System for Mapping DXA Sequences in the Chromosomes of Drosophila Me'.anczaster. Cell 3. 315-335. 3. Tanaka. T.. and B Weisblum (1975). Construction of a Co'.icin El-R Factor Composite Plasmid In Vitro: Means for Amplification of Deoxyribonucleic Acid. ]. Bacteriol. 121. 354-362. 4. Armstrong. K.A.. V. Hershfield. and D.R. Heiinski (1977). Cene Cloning and Containment Properties of Plasmid Co! El and Its Derivatives. Science 196. 172-174. 5. Bolivar. F.. R.L Rodriguez. M.C. Betlach. and H.W. Boyer (1977). Construction end Characterization of Xew Cloning Vehicles : 1. Ampicillin-Resistant Derivative of pMB9. Cene 2. 75-93. 6. Cohen. S.N.. A.C.W. Chang. H. Boyer, and R. Helling (1973). Construction of Biologically Functional Bacterid Plasmids in Vitro. Proc. Nall. Acad. Sci. USA 70. 3240- 3244. 7. Bolivar. F.. R.L. Rodriguez. R.J. Greene, M.C. Butlach. H.L Reyneker. H.W. Boyer. J.H. Cross and S. Falkow (1977). Construction and Characterization of New Cloning Vehicles: II A Multi-Purpose Cloning System. Cene 2. 95-113. 8. Thomas. M.. ).R. Cameron, and R.W. Davis (1974). Viable Molecular Hybrids of Bacteriophage Lambda and Eukaryotic DXA Proc Nat. Acad. Sci. USA 71. 4579-4583. 9. Murray, N.E.. and K. Murray (1974). Manipulation of Restriction Targets in Phage Lambda to Form Receptor Chromosomes for DXA Fragments. Nature 251. 476-481. 10. Ramback. A., and P. Tiollais (1974). Bacteriophage Having EcoR! Endonuclease Sites Only in the Non-Essential Region of tht Genome. Proce. Nat. Acad. Sci.. USA 71. 3927-3930. 11. Blattner. FJL B.C. Williams. A.E. Bleche. K. Denr.is’.on-Thompson. H.E. Faber. LA. Furlong. D J. Gunwald. D.O. Kiefer. D O. Moore. J.W. Shumm. E.L Sheldon, and O. Smithies (1977). Charon Phages: Safer Derivatives of Bacteriophage Lambda for DXA Cloning. Science 196. 163-169. 12. Donoghue. D.J.. ar.d PA. Sharp (1977). An Improved Lambda Vector Construction of Model Recombinants Coding for Konamycin Resistance. Cene 1 . 209-227. _ 13. Leder. P.. D. Tiemeier and L Enquist (1977). EK2 Derivatives of Bacteriophage Lcmbda Useful in the Cloning of DXA from Higher Organisms: The \gt ,VES System. Science 196. 175-177. 14. Skalka. A. (1978). Current Status of Coliphage X EK2 Vectors. Cene 3. 29-35. 15. Szybalski. W . A Skalka. S. Cottcsman. A. Campbell, and D. Botstcin (1978). Standardized Laboratory Tests for EK2 Certification. Cene 3. 36-38. Appendix J — Biotechnology Science Coordinating Committee The following excerpts from its charter (signed October 30. 1985) describe the Biotechnology Science Coordinating Committee: Purpose The Domestic Policy Working Group on Biotechnology has determined that in the area of biotechnology with its rapid growth of scientific discovery, scientific issues of interagency concern will arise frequently and need to be communicated among the various agencies involved with reviews of biotechnology applications. The Federal Coordinating Council for Science. Engineering, and Technology (FCCSET) established by 42 U.S.C. 6651 is an interagency science committee chaired by the Director of the Office of Science - and Technology Policy with the mission of coordinating science activities affecting more than one agency. Committees may be established under FCCSET for addressing particular science issues. Thus, the Biotechnology Science Coordinating Committee (BSCC, is established to provide formally an opportunity for interagency science policy coordination and guidance and for the exchange of information regarding the scientific aspects of biotechnology applications submitted to federal research and regulatory agencies for approval. Functions The BSCC will coordinate interagency review of scientific issues related to the assessments and approval of biotechnology research applications and biotechnology product applications and postmarketing surveillance when they involve the use of recombinant RNA. recombinant DNA. cell fusion or similar techniques. The BSCC will: (a) Serve as a coordinating forum for addresssing scientific problems, sharing information, and developing consensus: (b) Promote consistency in the development of Federal agencies’ review procedures and assessments; (c) Facilitate continuing cooperation among Federal agencies on emerging scientific issues; and (d) Identify gaps in scientific knowledge Authority To accomplish these functions the BSCC is authorized to: (a) Receive documentation from agencies necessary for the performance of its function; (b) Conduct analyses of broad scientific issues that extend beyond those of any one agency; (c) Develop generic scientific recommendations that can be applied to similar, recurring applications; (d) Convene workshops, symposia, and generic research projects related to scientific issues in biotechnology; and (e) Hold periodic public meetings. Members and Chairman The BSCC includes the following initial members: Department of Agriculture Assistant Secretary for Marketing and Inspection Services Assistant Secretary for Science and Education Department of Health and Human Services Commissioner. Food and Drug Administration Director, National Institutes of Health Environmental Protection Agency Assistant Administrator for Pesticides and Toxic Substances Assistant Administrator fer Research and Development National Science Foundation Assistant Director of Biological. Behavorial & Social Sciences The BSCC is chaired by the Assistant Director for Biological, Behavioral and Social Sciences of the National Science Foundation and the Director of the National Institutes of Health on a rotating basis. Administrative Provisions (a) The BSCC will report tc, the FCCSET through the Chair. Recombinant DNA Research, Volume 1 1 [25] 16982 Federal Register / Vol. 51, No. 88 / Wednesday, May 7, 1986 / Notices (b) Meetings of the BSCC shall be held periodically. Some public meetings will 'be held. (c) Confidential business information and proprietary information shall be protected under the confidentiality requirements of each member agency. (d) Subcommittees and working groups, with participation not restricted to BSCC members or full-time Federal employees, may be formed to assist the BSCC in its work. (e) All BSCC members will be full- time Federal employees whose compensation, reimbursement for travel expenses and other costs shall be borne by their respective agencies. (f) Each member of the BSCC shall provide such agency support and resources as may be available and necessary for the operation of the BSCC including undertaking special studies as come within the functions assigned herein. (g) An Office of Science and Technology Policy staff member will serve as BSCC Executive Secretary. Appendix K — Physical Containment for Large-Scale Uses of Organisms Containing Recombinant DNA Molecules This part of the Guidelines specifices physical containment guidelines for large-scale (greater than 10 liters of culture) research or production involving viable organisms containing recombinant DNA molecules. It shall apply to large-scale research or production activities as specified in Section III— B— 5 of the Guidelines. All provisions of the Guidelines shall apply to large-scale research or production activities with the following modifications: • Appendix K shall replace Appendix G when quantities in excess of 10 liters of culture are involved in research or production. • The institutions shall appoint a Biological Safety Officer (BSO) if it engages in large-scale research or production activities involving viable organisms containing recombinant DNA molecules. The duties of the BSO shall include those specified in Section IV-B- 4 of the Guidelines. • The institution shall establish and maintain a health surveillance program for personnel engaged in large-scale research or production activities involving viable organisms containing recombinant DNA molecules which require BL3 containment at the laboratory scale. The program shall include: preassignment and periodic physical and medical examinations; collection, maintenance and analysis of serum specimens for monitoring serologic changes that may result from the employee's work experience; and provisions for the investigation of any serious, unusual or extended illnesses of employees to determine possible occupational origin. Appendix K-l. — Selection of Physical Containment Levels. The selection of the physical containment level required for recombinant DNA research or production involving more than 10 liters of culture is based on the containment guidelines established in Part III of the Guidelines. For purposes of large-scale research or production, three physical containment levels are established. These are referred to as BLl-LS, BL2- LS, and BL3-LS. The BL-LS level of physical containment is required for large-scale research or production of viable organisms containing recombinant DNA molecules which require BLI containment at the laboratory scale. (The BLl-LS level of physical containment is recommended for large-scale research or production of viable organisms for which BLI is recommended at the laboratory scale such as those described in Appendix C.) The BL2-LS level of physical containment is required for large-scale research or production of viable organisms containing recombinant DNA molecules which require BL2 containment at the laboratory scale. The BL3-LS level of physical containment is required for large-scale research or production of viable organisms containing recombinant DNA molecules which require BL3 contaiment at the laboratory scale. No provisions are made for large-scale research or production of viable organisms containing recombinant DNA molecules which require BL4 containment at the laboratory scale. If necessary, these requirements will be established by NEH on an individual basis. Appendix K-II — BLl-LS Level Appendix K-II-A. Cultures of viable organisms containing recombinant DNA molecules shall be handled in a closed system (e.g., closed vessel used for the propagation and growth of cultures) or other primary containment equipment (e.g., biological safety cabinet containing a centrifuge used to process culture fluids) which is designed to reduce the potential for escape of viable organisms. Volumes less than 10 liters may be handled outside of a closed system or other primary containment equipment provided all physical containment requirements specified in Appendix G- II-A of the Guidelines are met. Appendix K-II-B. Culture fluids (except as allowed in Appendix K-II-C) shall not be removed from a closed system or other primary containment equipment unless the viable organisms containing recombinant DNA molecules have been inactivated by a validated inactivation procedure. A validated inactivation procedure is one which has been demonstrated to be effective using the organism that will serve as the host for propagating the recombinant DNA* molecules. Appendix K-II-C. Sample collection from a closed system, the addition of materials to a closed system, and the transfer of culture fluids from one closed system to another shall be done in a manner which minimizes the release of aerosols or contamination of exposed surfaces. Appendix K-II-D. Exhaust gases removed from a closed system or other primary containment equipment shall be treated by filters which have efficiencies equivalent to HEPA filters or by other equivalent procedures (e.g., incineration) to minimize the release of viable organisms containing recombinant DNA molecules to the environment. Appendix K-II-E. A closed system or other primary containment equipment that has contained viable organisms containing recombinant DNA molecules shall not be opened for maintenance or other purposes unless it has been sterilized by a validated sterilization procedure. A validated sterilization procedure is one which has been demonstrated to be effective using the organism that will serve as the host for propagating the recombinant DNA molecules. Appendix K-II-F. Emergency plans required by Section IV-B-3-f shall include methods and procedures for handling large losses of culture on an emergency basis. Appendix K-II I — BL2-LS Level Appendix K-III-A. Cultures of viable organisms containing recombinant DNA molecules shall be handled in a closed system (e.g., closed vessel used for the propagation and growth of cultures) or other primary containment equipment (e.g., Class III biological safety cabinet containing a centrifuge used to process culture fluids) which is designed to prevent the escape of viable organisms. Volumes less than 10 liters may be handled outside of a closed system or other primary containment equipment provided all physical containment requirements specified in Appendix G- II— B of the Guidelines are met. Appendix K-III-B. Culture fluids (except as allowed in Appendix K— III— C) [ 26 ] Recombinant DNA Research, Volume 1 1 Federal Register / Vol. 51. No. 88 / Wednesday, May 7, 1986 / Notices 16983 shall not be removed from a closed system or other primary containment equipment unless the viable organisms containing recombinant DNA molecules have been inactivated by a validated inactivation procedure. A validated inactivation procedure is one which has been demonstrated to be effective using the organism that will serve as the host for propagating the reccmb'nar.t DNA molecules. Appendix K-l/I-C. Sample collection from a closed system, the addition of materials to a closed system, and the transfer of cultures fluids from one closed system to another shall be done in a manner which prevents the release of aerosols or contamination of exposed surfaces. Appendix K-llI-D. Exhaust g3ses removed from a closed system or other primary containment equipment shall be treated by filters which have efficiencies equivalent to HEPA filters or by other equivalent procedures (e g . incineration) to prevent the release of viable organisms containing recombinant DNA molecules to the environment. Appendix K-UI-E. A closed system or other primary containment equipment that has contained viable organisms containing recombinant DNA molecules shall not be opened for maintenance or other purposes unless it has been sterilized by a validated sterilization procedure. A validated sterilization procedure is one which has been demonstrated to be effective using the organisms that will serve as the host for propagating the recombinant DNA molecules. Appendix K-tll-F. Rotating seals and other mechanical devices directly associated with a closed system used for the propagation and growth of viabie organisms containing recombinant DNA molecules shall be designed to prevent leakage or shall be fully enclosed in ventilated housings that are exhausted through filters which have efficiencies equivalent to HEPA filters or through other equivalent treatment devices. Appendix K-11I-C. A closed system used for the propagation and grow th of viable organisms containing recombinant DNA molecules and other primary containment equipment used to contain operations involving viable organisms containing recombinant DNA molecules shall include monitoring or sensing devices that monitor the integrity of containment during operations. Appendix K-II’-H. A closed system used for the propagation and grow th of viable organisms containing the recombinant DNA molecules shall be tested for integrity of the containment features using the organism that will Recombinant DNA Research, serve as the host for propagating recombinant DNA molecules. Testing shall be accomplished prior to the introduction of viable organisms containing recombinant DNA molecules and following modification or replacement of essential containment features. Procedures and methods used in the testing shall be appropriate for the equipment design and for recovery and demonstration of the test organism. Records of tests and results shall be maintained on file. Appendix K-lll-I. A closed system used for the propagation and growth of viable organisms containing recombinant DNA molecules shall be permanently identified. This identification shall be used in all records reflecting testing, operation, and maintenance and in all documentation relating to use of this equipment for research or production activities involving viable organisms containing recombinant DNA molecules. Appendix K-Iil-J. The universal biohazard sign shall be posted on each clcsed system and primary containment equipment when used to contain viable organisms containing recombinant DNA molecules. Appendix K-II1-K. Emergency plans required by Section IV-B~3-f shall include methods and procedures for handling large losses of culture on an emergency basis. Appendix K-IV—BL3-LS Level Appendix K-1V-A. Cultures of viable organisms containing recombinant DNA molecules shall be handled in a closed system (e g., closed vessels used for the propagation and growth of cultures) or other primary containment equipment (e g.. Class III biological safety cabinet containing a centrifuge used to process culture fluids) which is designed to prevent the escape of viable organisms. Volumes less than 10 liters may be handled outside of a closed system provided all physical containment requirements specified in Appendix G- II— C of the Guidelines are met. Appendix K-IV-B. Culture fluids (except as allowed in Appendix K-1V- C) shall not be removed from a closed system or other primary containment equipment unless the viable organisms containing recombinant DNA molecules have been inactivated by a validated inactivation procedure. A validated inactivation procedure is one which has been demonstrated to be effective using the organisms that will serve as the host for propagating the recombinant DNA molecules. Appendix K-IV-C. Sample collection from a closed system, the addition of materials to a dosed system, and the Volume 1 1 transfer of culture fluids from one closed system to another shall be done in a manner which prevents the release of aerosols or contamination of exposed surfaces. Appendix K-IV-D. Exhaust gases removed from a closed system or other primary containment equipment shall be treated by filters which have efficiencies equivalent to HEPA filters or by other equivalent procedures (e.g., incineration) to prevent the release of viable organisms containing recombinant DNA molecules to the environment. Appendix K-IV-E. A closed system or other primary containment equipment that has contained viable organisms containing recombinant DNA molecules shall not be opened for maintenance or other purposes unless it has been sterilized by a validated sterilization procedure. A validated sterilization procedure is one which has been demonstrated to be effective using the organisms that will serve as the host for propagating the recombinant DNA molecules. Appendix K-IV-F. A closed system used for the propagation and growth of viable organisms containing recombinant DNA molecules shall be operated so that the space above the culture level will be maintained at a pressure as low as possible, consistent w ith equipment design, in order to maintain the integrity of containment features. Appendix K-IV-G. Rotating seals and other mechanical devices directly associated with a closed system used to contain viable organisms containing recombinant DNA molecules shall be designed to prevent leakage or shall be fully enclosed in ventilated housings that are exhausted through filters which have efficiencies equivalent to HEPA filters or through other equivalent treatment devices. Appendix K-IV-H. A closed system used for the propagation and growth of viable organisms containing recombinant DNA molecules and other primary containment equipment used to contain operations involving viable organisms containing recombinant DNA molecules shall include monitoring or sensing devices that monitor the integrity of containment during operations. Appendix K-lV-1. A closed system used for the propagation and growth of viable organisms containing recombinant DNA molecules shall be tested for integrity of the containment features using the organisms that will serve as the hest for propagating the recombinant DNA molecules. Testing shall be accomplished prior to the [27] 18984 Federal Register J Vol. 51, No. 88 / Wednesday, May 7, 1986 / Notices introduction of viable organisms containing recombinant DNA molecules and following modification or replacement of essential containment features. Procedures and methods used in the testing shall be appropriate for the equipment design and for recovery and demonstration of the test organism. Records of tests and results shall be maintained on file. Appendix K-IV-J. A closed system used for the propagation and growth of viable organisms containing recombinant DNA molecules shall be permanently identified. This identification shall be used in all records reflecting testing, operation, and maintenance and in all documentation relating to the use of this equipment for research production activities involving viable organisms containing recombinant DNA molecules. Appendix K-IV-K. The universal biohazard sign shall be posted on each closed system and primary containment equipment when used to contain viable organisms containing recombinant DNA molecules. Appendix K-IV-L. Emergency plans required by Section IV-B-3-f shall include methods and procedures for handling large losses of culture on an emergency basis. Appendix K-IV-M. Closed systems and other primary containment equipment used in handling cultures of viable organisms containing recombinant DNA molecules shall be located within a controlled area which meets the following requirments: Appendix K-IV-M-1. The controlled area shall have a separate entry area. The entry area shall be a double-doored space such as an air lock, anteroom, or change room that separates the controlled area from the balance of the facility. Appendix K-F/-M-2. The surfaces of walls, ceilings, and floors in the controlled area shall be such as to permit ready cleaning and decontamination. Appendix K-IV-M-3. Penetrations into the controlled area shall be sealed to permitTiquid or vapor phase space decontamination. Appendix K-IV-M— i. All utilities and service or process piping and wiring entering the controlled area shall be protected against contamination. Appendix K-IV-M-5. Hand-w'ashing facilities equipped with foot, elbow, or automatically operated valves shall be located at each major work area and near each primary exit. Appendix K-IV-M-6. A shower facility shall be provided. This facility shall be located in close proximity to the controlled area. Appendix K-IV-M-7. The controlled area shall be designed to preclude release of culture fluids outside the controlled area in the event of an accidental spill or release from the closed systems or other primary containment equipment. Appendix K-IV-M-8. The controlled area shall have a ventilation system that is capable of controlling air movement. The movement of air shall be from areas of lower contamination potential to area3 of higher contamination potential. If the ventilation system provides positive pressure supply air, the system shall operate in a manner that prevents the reversal of the direction of air movement or shall be equipped with an alarm that would be actuated in the event that reversal in the direction of air movement were to occur. The exhaust air from the controlled area shall not be recirculated to other areas of the facility. The exhaust air from the controlled area may be discharged to the outdoors without filtration or other means for effectively reducing an accidental aerosol burden provided that it can be dispersed clear or occupied buildings and air intakes. Appendix K-IV-N. The following personnel and operational practices shall be required: Appendix K-IV-N-1. Personnel entry into the controlled area shall be through the entry area specifed in Appendix K- IV-M-I. Appendix K-IV-N-2. Persons entering the controlled area shall exchange or cover their personal clothing with work garments such as jumpsuits, laboratory coats, pants and shirts, head cover, and shoes or shoe covers. On exit from the controlled area the work clothing may be stored in a locker separate from that used for personal clothing or discarded for laundering. Clothing shall be decontaminated before laundering. Appendix K-IV-N-3. Entry into the controlled area during periods when work is in progress shall be restricted to those persons required to meet program or support needs. Prior to entry all persons shall be informed of the operating practices, emergency procedures, and the nature of the work conducted. Appendix K-IV-N-4. Persons under 18 years of age shall not be permitted to enter the controlled area. Appendix K-IV-N-5. The universal biohazard sign shall be posted on entry doors to the controlled area and all internal doors when any work involving the organism is in progress. This includes periods when decontamination procedures are in progress. The sign posted on the entry doors to the controlled area shall include a statement of agents in use and personnel authorized to enter the controlled area. Appendix K-IV-N-6. The controlled area shall be kept neat and clean. Appendix K-IV-N-7. Eating, drinking, smoking, and storage of food are prohibited in the controlled area. Appendix K-IV-N-8. Animals and plants shall be excluded from.the controlled area. Appendix K-IV-N-9. An effective insect and rodent control program shall be maintained. Appendix K-IV-N-10. Access doors to the controlled area shall be kept closed, except as necessary for access, while work is in progress. Serve doors leading directly outdoors shall be sealed and locked while work is in progress. Appendix K-IV-N-1 J. Persons shall wash their hands when leaving the controlled area. Appendix K-IV-N-12. Persons working in the controlled area shall be trained in emergency procedures. Appendix K-IV-N-13. Equipment and materials required for the management of accidents involving viable organisms containing recombinant DNA molecules shall be available in the controlled area. Appendix K-IV-N-14. The controlled area shall be decontaminated in accordance with established procedures following spills or other accidental release of viable organisms containing recombinant DNA molecules. Appendix L — Release Into the Environment of Certain Plants Appendix L-I — General Information Appendix L specifies conditions under which certain plants as specified below, may be approved for release into the environment. Experiments in this category cannot be initiated without submission of relevant information on the proposed experiment to NIH, review by the RAC Plant Working Group, and specific approval by NIH. Such experiments also require the approval of the IBC before initiation. Information on specific experiments which have been approved will be available in ORDA and will be listed in Appendix L— III when the Guidelines are republished. Experiments which do not meet the specifications of Appendix L-II fall under Section III-A and require RAC review and NIH and IBC approval before initiation. Appendix L-II — Criteria Allowing Review by the RAC Plant Working Group Without the Requirement for Full RAC Review Approval may be granted by ORDA in consultation with the Plant Working [ 28 ] Recombinant DNA Research, Volume 11 Federal Register / Vol. 51. No. 88 / Wednesday, May 7, 1986 / Notices 16905 Croup without the requirement for full RAC review (1BC review is also necessary) for growing plants containing recombinant DNA in the field under the following conditions: Appendix L-D-A. The plant species is a cultivated crop of a genus that has no ■pedes known to be a noxious weed. Appendix L-Il-B. The introduced DNA consists of well-characterized genes containing no sequences harmful to humans, animals, or plants. Appendix L-D-C The vector consists of DNA (i) From exempt host-vector •ystems (Appendix C): (ii) from plants of the same or closely related species; (iii) from nonpathogenic prokaryotes or nonpathoger.ic lower eukaryotic plants: (iv) from plant pathogens only if sequences resulting in production of disease symptoms have been daleted: or (v) chimeric vectors constructed from sequences defined in (i) to (iv) above. The DNA may be introduced by any suitable method. If sequences resulting in production of disease symptoms arc retained for purposes of introducing the DNA into the plant, greenhouse-grown plants must be shown to be free of such sequences before such plants, derivatives, or seed from them can be used in field tests. Appendix L-II-D. Plants are grown in controlled access fields under specified conditions appropriate for the plant under study and the geographical location. Such conditions should include provisions for using good cultural and pest control practices, for physical isolation from plants of the same species outside of the experimental plot in accordance with pollination characteristics of the species, and for further preventing plants containing recombinant DNA from becoming established in the environment. Review by the IBC should include an appraisal by scientists knowledgeable of the crop, its production practices, and the local geographical conditions. Procedures for assessing alterations in and the spread of Organisms containing recombinant DNA must be developed. The results of the outlined tests must be submitted for review by the ’j}'".. Copies must also be submitted to the Plant Working Croup of the RAC. Appendix L-lll — Specific Approvals As of publication of the revised Guidelines, no specific proposals have been approved. An updated list may be obtained from the Office of Recombinant DNA Activities, National Institutes of Health. Building 31. Room 3B10. Bethesda. Maryland 20G92. lOMB's "Mandatory Information Requirements for Federal Assistance Program Announcements" (45 FR 39592) requires a statement concerning the official government pregrams contained in the Catalog of Federal Domestic Assistance. Normally NIK lists in Its announcements the number and title of affected individual programs for the guidance of the public. Because the guidance in this notice covers not only virtually every NIK program but also essentially every Federal research program In which DNA recombinant molecule techniques could be used, it has been determined to be not cost effective or in the public interest to attempt to list these programs. Such a list would likely require several additional pages. In addition. NIK could not be certain that every federal program would be included as many Federal agencies, as well as private organizations, both national and international, have elected to follow the N'lH Guidelines. In lieu of the individual program listing. NIH invites readers to direct questions to the information address above about whether individual programs listed in the Catalog of Fednrcl Domestic Assistance are affteted.) Dated: April 18. 1986. Tuo.r.as E. Malone, Acting Director. National Institutes of Health. (FR Doc. 86-10120 Filed 5-8-36: 8:45 am] eiUJSO CODE 4U0-01-M Recombinant DNA Research, Volume 1 1 [29] 23150 Federal Register / Vol. 51, No. 122 / Wednesday. June 25, 1988 / Notices Department. Serves as a focal point for interface with the Office of the Assistant Secretary for Planning and Evaluation, other department components, and other Federal agencies on health care financing policy issues and legislative initiatives. Provides technical services and support to the Office of Research and Demonstrations, the Bureau of Eligibility. Reimbursement, and Coverage, other HCFA components, and through ASL to the Congress on the policy implications and technical aspects of new legislative or policy initiatives. B. Division of Legis'otior. ( FBBJ Plans and directs tire legislative planning and development activities of HCFA. Develops and analyzes recommendations concerning legislative proposals for changes to the health care financing programs. Develops long-range legislative plans in substantive areas reiated to the reimbursement, coverage, ar.d eligibility of services under the Medicare and Medicaid programs. Analyzes the impact cf HCFA and congressional legislative proposals affecting HCFA programs and makes recommendations to the Administrator and the Department. Prepares testimony and technical briefing materials fcr congrsssional hearings on HCFA programs and serves as principal advisor to the HCFA sonior staff on congressional legislative initiatives of interest or concern to the Agency. Develops the technical specifications for HCFA legislation. Through the ASL. provides information or. HCFA programs and legislative plans to members of the Congress and the congressional committees as requested. Coordinates legislative activities and prepares for congressional hearings with the Office of the Assistant Secretary for Legislation. C. Division of Legislative Services and Congressional Affairs (FBCJ Provides legislative research and analysis services to HCFA staff, and produces regular and special reports to HCFA. and the Department on legislative issues and activities. Prepares background materials for congressional hearings and briefing sessions and coordinates with HCFA components and A.SL on the preparation of bill reports and biil report clearances. Maintains and services HCFA with a legislative research and reference library'. Responds directly or coordinates responses to written and verbal congressional and legislative requests for information related to HCFA programs. Organizes and prepares materials for briefings of individual Congressmen and their constituents. Monitors the interests or concerns of individual Congressmen and prepares recurring reports on significant congressional contacts. Analyzes alternative responses to congressional issues and makes recommendations to higher officials on specific issues. • Section FP.20.A.5., Office cf Prepaid Operations, is deleted in its entirety along with all subordinate components. This Ofice is being combined with the former Office of Health Maintenance Organizations to form the new Office of Prepaid Health Care found at the new section FC. of this statement. • Section FQ.20.C., Office of Legislation a~d Policy (OLP], is deleted in its entirety along with all subordinate components. This Office is being transferred to report directly to the Office of the Administrator. As stated earlier in this document, OLP is now found at the new section FD. • Section FQ.10. The Office of the Associate Administrator for Policy (FQJ (Organization), is deleted and replaced by the following: Section FQ.10. The Office of the Associate Administrator for Program Development (FQ) Organization) The Office of the Associate Administrator for Program Development (OAAPD), under the direction of the Associate Administrator for Program Development, includes: A. The Bureau of Eligibility, Reimbursement, and Coverage (FQA). B. The Office of Research and Demonstrations (FQE). • Section FQ.20. The Office of the Associate Administrator for Policy (FQ) (Functions), is deleted and replaced by the following: Section FQ.20. The Office cf the Associate Administrator for Program Development (FQ) (Functions) The Associate Administrator for Program Development is responsible for the effective direction and implementation of the development and review of Medicare and Medicaid policies and regulations pertaining to HCFA programs and HCFA's research and demonstrations activities. • Section FQ.20.A., Bureau of Eligibility, Reimbursement, and Coverage, and FQ.20.3., Office of Research and Demonstrations, remain unchanged along with all of their subordinate components. Dated: June 16. 1980. Otis R. Bowen, Secretary. Department of Health and Human Services. (FR Doc. 86-14321 Filed 6-24-86: 8:45 am] BIU.IINC CODE 4120-03-M National Institutes of Health Recombinant DMA Advisory Committee Working Group on Human Gene Therapy; Meeting Pursuant to Pub. L. 92^163, notice is hereby given of a meeting of the Recombinant DNA Advisory Committee Working Group on Human Gene Therapy at the National Institutes of Health. Building 3lC, Conference Room 4, 9000 Rockville Pike, Bethesda, Maryland 20892, on A.ugusl 8, 1986. from approximately 9:00 a.m. to adjournment at approximately 5:00 p.m. to discuss scientific issues ar.d procedures for review of proposals involving human gene therapy. This meeting will be open to the- public. Attendance by the public will be limited to space available. The working Group will also consider a proposal to amend the NIH Guidelines for Research Involving Recombinant DNA Molecules which will subsequently be considered by the Recombinant DMA A.dvisory Committee at its meeting on September 29, 1935. This proposal is published for comment in the accompanying notice of Proposed Action Under Guidelines. Further information may be obtained from Dr. William J. Gartland, Executive Secretary'. Recombinant DNA Advisory Committee Working Group on Human Gene Therapy, National Institutes of Health. Building 31, Room 3B10, Bethesda, Maryland, telephone (301) 4St— 6051. Dated: June 18. 1980. Betty J. Beveridge, Committee Management Officer. NIH. OMB’s “Mandatory Information Requirements for Federal Assistance Program Announcements" (45 PR. 39592) requires a statement concerning the official government programs contained in the Catalog of Federal Domestic Assistance. Normally NIH lists in its announcements the number and title of affected individual programs for the guidance of the public. Because the guidance in this notice covers not only virtually every NTH program but also essentially every federal research program in which DNA recombinant molecule techniques could be used, it has been determined to be not cost effective or in the public interest to attempt to list these proerams. Such a [ 30 ] Recombinant DNA Research, Volume 1 1 Federal Register / Vol. 51. No. 122 / Wednesday, June 25, 1986 / Notices 23153 list would likely require several additional pages. In addition. NIH could not be certain that every federal program would be included as many federal agencies, as well as private organizations, both national and international, have elected to follow the NIH Guidelines. In lieu of the individual program listing, NIH invites to readers to direct questions to the information address above about whether individual programs listed in the Catdog of Federal Domestic Assistance are affected. |FR Doc. 86-14377 Filed 6-24-80. 8:45 am| BILLING COOE 4140-01-M DEPARTMENT OF THE INTERIOR Bureau of Land Management Agency Information Collection Activities Under OM3 Review The proposal for the collection of information listed below has been submitted to the Office of Management and Budget for approval under provisions of the Paperwo-k Reduction Act (41 U.S.C. Chapter 33). Ccpies of the proposed information collectors requirement and rela’ed forms and explanatory material may be obtained by contacting the Bureau of Land Management’s (BLM) clearance officer at the phone number listed below. Comments and suggestions on the requirement should be made directly to the Bureau Clearance Officer and the Office of Management and Budget Reviewing Official at 202-395-7340. Title: Land Use Application and Permit. 43 CFR 2920 Bureau Form Number: 2920-1 Frequency: Once Description of Respondents: Individuals. State and local government entities, and other qualified proponents applying for use of BLM administered land via lease, permit, or easement. Annual Responses: 435 Annual Burden Hours: 3230 Bureau Clearance Officer (alternate): Rebecca Daughtery at 202-653-0853 Guy Bjier. Actirg Ass is ten l Director. Lands and Renewable Resources. May 8. 1986. (FR Doc. 86-14288 Filed 6-24-86: 8:45 am] BILLING COCC O10-B4-M (AA-419521 Alaska Native Claims Selection; Cook Inlet Region, Inc. In accordance with Departmental regulation 43 CFR 2650.7(d). notice is hereby given that a decision to issue conveyance under the provisions of sec. 14(c) of the Abska Native Claims Settlement Act of December 10. 1971 (ANCSA). 43 U.S.C. 1601. 1613(e). and Sec. 12 of the Act of January 2. 1976. Pub L 94-294. 43 U S C. 1611 nt. as amended, and Par. !.C.(2)(a) of the document entitled Terms and Conditions for Land Consolidation and Management : n the Cook Inlet Area, will be issued to Cook Inlet Region. Inc., far approximately 624 acres. The lands involved are within T. 12 N'.. Rs. 5 and 6 W.. and T. 13 N.. R. 5 W.. Seward Meridian. Alaska. A notice of the decision will be published once a week for four (4) consecutive weeks, in the ANCHORAGE TIMES. Copies of the decision may be obtained by contacting the Bureau of Land Management. Alaska State Office. 701 C Street. Box 13. Anchorage. Alaska 99513. ((9C7) 271- 5960) Ary party claiming a property interest which is advemely affected by the decision shall have until July 25. 1308 to file an appeal. However, parties receiving service by certified mail shall have 30 djys from the date of receipt to f.le an appeal. Appeals must be filed in the Bureau of Land Management. Division of Conveyance Management (900). address identified above, where the requirements for filing an appeal can te obtained. Parties who do not file an appeal in accordance with the requirements of 43 CFR Part 4. Subpart E shall be deemed to have waived their rights. Suzanne McWilliams. Acting Section Chief. Branch of A. \'CS A Adjudication. (FR Doc. 86-14294 Filed 6-24-86: 8:45 am) BILLING CODE OlO-JA-U IF-14870-AJ Alaska Native Claims Selection; Kaktovik Inupiat Corp. In accordance with Departmental regulation 43 CFR 2650.7(d), notice is hereby given that a decision to issue conveyance under the provisions of sec. 1431(g)(3) of the Alaska National Interest Lands Conservation Act of December 2, 1980 (ANTLCA), 94 Slat. 2371. 2539. will be issued to Kaktovik Inupiat Corporation for approximately 1,782 acres. The lands involved are in the vicinily of Kaktovik. Alaska. L'miat Meridian, Alaska T. 7 N.. R. 35 E. T 8 N.. R. 36 E. A notice of the decision will be published once a week for four (4) consecutive weeks in the TUNDRA TIMES. Copies of the decision may be obtained by contacting the Bureau of Land Management. Alaska State Office. 701 C Street. Box 13. Anchorage. Alaska 99513. ((907) 271-5960.) Any party claiming a property interest which is adversely affected by the decision shall have until July 25. 1986 to file an appeal. However, parties receiving service by certified mail shall have 30 days from the date of receipt to file an appeal. Appeals must be filed in the Bureau of Land Management. Division of Conveyance Management (660), address identified above, where the requirements for filing an appeal can be obtained. Parties who do not file an appeal in accordance with the reqifrements of 13 CFR Part 4. Suhpart E. shall be deemed to have waived their rights. Helen Gurlcson. Section Chief. Branch ofAUCSA Adjudication. (FR Doc. 86-14296 Filed 6-24-86; 9:45 am] BILLING COOE 4310-JA-44 [E-14879-AI Alaska Native Claims Selection; Kaktovik Inupiat Corp. In accordance with Departmental regulation 43 CFR 2650.7(d), notice is hereby given that a decision to issue conveyance under the provisions of sec. 1431(g)(3) of the Alaska National Interest Lands Conservation Act of December 2, 1980 (ANTLCA), 94 Slat. 2371, 2539. will be issued to Kaktovik Inupiat Corporation for approximately 17,306 acres. The lands involved are in the vicinity of Kaktovik, Alaska. L'miat Meridian. Alaska T. 7 N.. R. 35 E. T. 8 N.. R. 35 E. T. 7 N.. R. 36 E. A notice of the decision will be published once a week for four (4) consecutive weeks in the TUNDRA TIMES. Copies of the decision may be obtained by contacting the Bureau of Land Management, Alaska Slate Office, 701 C Street. Box 13. Anchorage, Alaska Recombinant DNA Research, Volume 1 1 [31] 23210 Federal Register / Vol. 51. No. 122 / Wednesday, June 25, 1936 / Notices DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Recombinant DNA Research; Advisory Committee; Meeting Pursuant io Pub. L. 92^4G3, notice is hereby given of a meeting of the Recombinant DNA Advisory Committee et the National Institutes of Health, Building 31C, Conference Room 6. 9000 Rockville Pike, Bethesda. Maryland 20892. on September 29. 1906, from approximately 9:C0 a.m. to adjournment at approximately 5:00 p.m. This meeting will be open to the public to discuss: Scientific issues in human gene therapy: Amendment of Guidelines: and Other matters to be considered by the Committee Attendance by the public will be limited to space available. Members of the public wishing to speak at the meeting may be given such opportunity at the discretion of the Chair. Dr. William J. Gartland. Executive Secretary, Recombinant DNA Advisory Committee. National Institutes of Health, Building 31, Room 3B10, Esthssda, Maryland 20602, telephone (301) 496-6051. will provide materials to be discussed at the meeting, rosters of committee members, and substantive program information. A summary of the meeting will be available at a later date. Dated: June 18. 1986. Betty J. Beveridge, Committee Mcr.agement Officer. NIH. OMB's “Mandatory Information Requirements for Federal Assistance Program Announcements" (45 FR 39592) requires a statement concerning the official government programs contained in the Cctc.'og of Federal Domestic Assistance. Normally NIH lists in its announcements the number and title of affected individual programs for the guidance of the public. Because the guidance in this notice covers not only virtually every NIH program but also essentially every federal research program in which DNA recombinant molecule techniques could be used, it has baen determined to be not cost effective or in the public interest to attempt to list these programs. Such a list would likely require several additional pages. In addition, NTH could not be certain that every federal program would be included as many federal agencies, as well as private organizations, both national and international, have elected to follow the NIH Guidelines. In lieu of the individual program listing, NIH invites readers to direct Questions to the information address above 3bout whether individual programs listed in the Catalog of Federal Domestic Assistance are affected. [FR Doc. 86-14378 Filed 6-24-86: S:43 am] BILLING CODS 4MO-01-M Recombinant DNA Research: Proposed Action Under Guidelines agency: National Institutes of Health, PHS. DHHS. action: Notice of Proposed Action under NTH Guidelines for Research Involving Recombinant DNA Molecules. summary: This notice sets forth a proposed action to be taker, under the National Institutes of Health (NTH) Guideiir.es for Research Involving Recombinant DNA Molecules. Interested parties are invited !o submit comments concerning th : s proposal. This proposal will be considered by the Recombinant DNA Advisory Committee (RAC) Working Group on Human Gene Therapy ei its meeting cn August 8, 1983. and by the full RAC at its meeting or, September 29. 1936. After consideration of this proposal ard comments by the RAC. the Director of the National Institutes of Health will issue a decision or. this proposal in accord with the Guidelines. DATE: Comments received bv July 31, 1936, will be reproduced and distributed to the Working Group on Human Gene Therapy for consideration at its August 8, 19S6, meeting. Those comments and comments received after July 31, 1986, but prioi to September 19, 1986. will be reproduced and distribuled to the full RAC for consideration at its September 29, 1986, meeting. address: Written comments and recommendations should be submitted to the Director, Office of Recombinant DNA Activities, Building 31, Room 3B10, National Institutes of Health, Bethesda, Maryland 20892. All comments received in timely response to this notice will be considered and will be available for public inspection in the above office on weekdays between the hours of 8:30 a.m. and 5:00 p.m. FCR FURTHER INFORMATION CONTACT: Background documentation and additional information can be obtained from the Office of Recombinant DNA Activities, National Institutes of Health, Bethesda, Maryland 20892, (301) 496- 6051. SUPPLEMENTARY INFORMATION: The National Institutes of Health will consider the following action under the Guidelines for Research Involving Recombinant DNA Molecules. I. Proposal lo Modify Section IIJ-A-4 of the NIH Guidelines The Committee foi Responsible Genetics. Boston. Massachusetts, has submitted the following proposal and ralionule to modify Section HI— A— 4 of the Guidelines: "Proposed Addition to the end of section III-A— 4 of the NIH Guidelines on Redombinant DNA Molecules. "The RAC will net review and the NIH will not approve any human genetic therapy: "1. That is not aimed solely at the relief of a life-thrsalenir.g or severely disabling condition: or “2. That could alter germ line cells. "Furthermore, the RAC will not review and the NIH will not approve any in vitro recombinant DNA experiments that alter human germ lira cells or early human embryos. "Rationale "This addition to the NIK Guidelines is proposed in order to place a clear statement in the public record describing NIH's policy or experiment in human genetic engineering. The published “Points to Consider in the Design and Submission of Human Somatic-Cel! Therapy Protocols" (sic) define a process fc: reviewing protocols but set no limitations and place no boundaries on human gene therapy experiments and on research or. human germ line cells. This proposal is designed to give assurance to the public that, by opening up possibilities of human genetic engineering in areas where there is wide social consensus or. at least, no strong public opposition, the technolog}' will not be applied to other situations where adequate public deba’.t has not taken place. “1. Somatic Cell Therapy for the Treatment of Disease. Medical technologies that have initially been developed with governmental approval for specific purposes are easily adapted to other circumstances without commensurate accountability, once public attention and debate have waned. In our present socioeconomic environment, there are strong professional and business motivations for increasing the application of medical technologies. "Human somatic cell gene therapy (HSCT) is currently being considered for use in life-threatening diseases. An American scientist already has carried out such experiments outside the United States. But the potential range of applications of HSCT is very broad. Genes regulate numerous biochemical processes including the production of [ 32 ] Recombinant DNA Research, Volume 1 1 23211 Federal Register / Vol. 51. No. 122 / Wednesday. June 25. 1986 / Notices ■PWPf TW— I ■— TT- I f ■■■! I — ■ TM ■ ■ — ' ■ 1 — — - 1 — — M — fm ! ■ hormones, enzymes, and antibodies. Once human genetic engineering is established as a clinical treatment for some human disorders it is reasonable to expect, from pest experience, that the research community will seek applications of gene therapy beyond the initial range of cases where some social consensus may have been reached. At the present time, beyond the applications of HSCT to the treatment of life-threatening or severely disabling diseases, r.o justification has been offered for the contention that the potential benefits of such therapy will outweigh the risks to people ar.d serve the general welfare. "Committees like the RAC or Institutional Review Beards serve their social purpc3e after society has reached seme consensus over broad policy issues. The burden of jprocf must be on those who wish to introduce a new technology. Cr.ce bread consensus is reached, the RAC and the IRBs con then implement those policies and. among other things, rendor decisions involving grey areas. To date, the prospect of applying HSCT to cre-d disease has not drawn significant public opposition. Beyond such usc3. we berm to er.tar a range of cortroversiul^pplications about which there has not bean adequate national debate By stipulating the boundaries within which NTH will review HSCT protocols, acknowledgement is given to the limited nature of public discussion ar.d consensus c.n the use cf human genetic •Ogtesering "Arguments advanced tor torbidciing all uses a? HSCT are based on the prediction that once .ve begin to accept cr.y use of this technology, a!! uses aro legitimized. Support for ihi3 thesis is nourished by past failures of our regulatory system to control applications of technology that have been extended beyond their initial public purpose in away that transgress tho boundaries of democratic control. The establishment of restricted zones Of application of HSCT at the cutset will make it possible to support the most urgent and humane applications of HSCT with less fear that such support gives tacit approval to other uses that, propelled by economic and professional pressures, may slip through the review process. "Many technical problems must be overcome if HSCT is to be used in clinical treatment. It is imperative that this therapy net be used on people, even experimentally, until the technical problems of targeting and delivery to specific cells or tissues have been solved. However, the pressure to test gene therapy on human subjects is building rapidly. Some investigators are even willing to forego the usual requirement that human trials await successful animal tests on the grounds that, as a life-saving measure, a patient is entitled to ‘anything available.’ We oppose ‘.his view. Moreover, we do net believe that informed consent by itself is a sufficient standard fer protecting the dignity of individuals with life- threatening or severly disabling illnesses against inappropriate and adventuresome uses cf medical technologies. “2. Enhancement Tharapics. "The application jf HSCT for the alteration of human characteristics such as height or si- n tore raises profound ethical problems. For example, clinically healthy individuals who wish to receive genetic therapy to increase their height because Thortr.ers’ .s devalued in society a.*z seeking a technological solution in response to n 3-cial problem. The concept of an ideal height ideal si. In color. or ideal •ve jr' is a sociel construction. Genetic technologies designed to correct normal variations in human phenotypes '•dp to legitimize on ideology that p'ace? inferior value or. certain ?\pr?;sicr.s of human diversity'. Those who would apply genetic therapies to bring an individual closer to a ‘normal range - arz cueght up in an Inherent contradiction. First, the measure af normal range’ changes for each generation and for each culture. Second, the universal application of such dt.! r:ry would artificially alter the normal range without offering any not benefits. Moreover, the mere availability of growth enhancement therapies, for example, crea’es a psychological atmosphere that further enhances the social value of ‘tallness’ ar.d thereby worsens the problem consequently. The potential r via of genetics in erhuncement therapies must be viewed as a social issue that warrants broad public debate. N!H needs to enunciate clear restraints of the use of HSCT for the purpose of enhancement so as to avoid 3 slow and incremental drift toward such applications without adequate social assessment. "3. Genetic Therapy fer the Prevention of Disease. "On the premise that genetic variation may explain differences in the onset of environmentally induced diseases, some companies have initiated genetic screening programs to identify workers who arc supposedly at greater risk from exposure to certain chemicals in the workplace. This shifts the responsibility for reducing occupational disease from management to workers. The availability of gene therapy could put undue pressure on workers, who would have to choose between therapy or loss of jobs. Many people in society strongly oppose the alteration of human genome as a means to protect individuals against unnatural, hostile environments. The moral opprobrium over this use cf HSCT is independent of personal risks. The proposed addition to the guidelines makes explicit the restriction against the use of human subjects for 3ucii purposes. "4. Genetic Manipulation of the Human Germ Line. "Considerable opposition has been expressed from many segments of society against any genetic manipulation of human germ line calls. -Germ line manipulation through genetic additions or deletions in the sperm, egg. or zygote would be tantamount to e p^rimeniaticn cn future generations wit: no possibility or informed consent. It would also set up a direct path to programs of eugenics. Consequently. NTH should state, at ‘he outset, that no germ lire manipulation will be approved." CMD’j "Mandatory Information Requirement for Federal Assi3tar.ee Fragrant Announcements" [43 FP. 30332) requires a statement concerning the official government programs nr. (fined in the Catalog of Federal Corns: is Assistance. Normally NTH lists in its enrouncements tho number and ‘itie of affected individual pregrams fer the guidance of the public. Because the guidance in this notice covers not cniy virtually every' NTH program but also -essentially every' federal research program in which CNA recombinant molecule techniques could be used, it has been determined to be not cost effective or in the public interest to attempt to list these programs. Such a list would likely require several additional pages. In addition. Nil.' could not be certain that every federal pregram would be included as many federal agencies, as well as private organizations, both national and international, have elected to follow the NTH Guidelines. In lieu of the individual program listing. NIH invites readers to d rect questions to the information address above about whether individual programs listed in the Catalog of Federal Domestic Assistance are affected. Dated: June 16, 1986. Bernard Talbot. Acting Director. National Institute of Allergy ar.d Infectious Diseases. [FR Dec. 86-14379 Filed 8-24-86; 8:45 am| BILUNG ccoe 4140-01-11 Recombinant DNA Research, Volume 1 1 [33] 28440 Federal Register / Vol. 51. No. 152 / Thursday. August 7, 1986 / Notices and Miami-Hialeah, FL (Dade. FL). reading as follows: "Merced, CA . . . 1.2134 Merced. CA" C. Page 197-10. In column 1, in Table IIIB titled "Wage Index for Rural Areas", the wage index value for California, "1.1457", is corrected to "1.1385". (Sec. 1102. 1882(v) and 1871 of the Social Security Act (42 U.S.C. 1302, I395.\(v) and 1395hh) (Catalog of Federal Domestic Assistance Program No. 13.773. Medicare-Hospitai Insurance) Dated: July 31. 1986. Hurry A. Hadd. Acting Deputy Assistant Secretary for Management Analysis and Systems. (FR Doc. 86-17810 Filed 8-6-36: 8:43 am) BILLING CCD£ 4120-01-M National Institutes of Health Interagency Committee on Learning Disabilities; Public Hearing Notice is hereby given of a public hearing to be held by the Interagency Committee on Learning Disabilities. The meeting is scheduled for October 15, 1986. in Wilson Hall, Building 1 (Shannon Building) on the NIH Reservation in Bethesda, Maryland, starting at 9:00 a.m. The purpose of the meeting is to gather data and hear the views of individuals and organizations as they relate to the mandate given the Committee by the Congress. The meeting is open to the scientific community and the general public. Members of the Interagency Committee on Learning Disabilities will be in attendance to receive data and to hear and respond to the presentations and recommendations. The Interagency Committee on Learning Disabilities is preparing a report on learning disabilities which will be submitted to the U.S. Congress in May of 1987. As directed by the Congress, the report will include (1) an estimate of the number of persons affected by learning disabilities and the domographic data which describes such persons: (2) a description of the current research findings on the cause, diagnosis, treatment and prevention of learning disabilities; (3) recommendations for legislative and administrative actions to increase the effectiveness of research on learning disabilities and to improve the dissemination of the findings of such research; and respecting specific priorities for research in the cause, diagnosis, treatment, and prevention of learning disabilities. The Committee is holding this public hearing as part of the information gathering activities to prepare its report. Individuals 3nd representatives of organizations wishing to make a presentation at this hearing that is related to the Committee's mandate are requested to obtain further information from and register with the Executive Secretary of the Interagency Committee on Learning Disabilities. Dr. James F. Kavanagh. Associate Director, Center for Research for Mothers and Children. National Institute of Child Health and Human Development, Landovv Building Room 7C03. 9000 Rockville Pike. Bethesda, Maryland 20892. telephone (301) 496-5097. Oral presentations at the public hearing will be limited to 15 minutes: copies of these statements should be submitted in advance to Dr. Kavanagh. Additional written material of any length may be submitted at the time of the hearing for the Committee’s consideration. Dated: July 31, 1936. Thomas E. Malone, Acting Director. Motional Institutes of Hecith. [FR Doc. 86-17733 Filed 8-6-86; 8:45 am] BILLING CODE 4140-01-M National Digestive Diseases Advisory Beard; Meeting Pursuant to Pub. L. 82—163, notice is hereby given of the meeting of the National Digestive Diseases Advisory Board and its subcommittees on September 22, 1986, 8:00 a.m. to adjournment, at the Crystal City Marriott, 1999 Jefferson Davis Highway. Arlington, Virginia 22202. The meeting, which will be open to the public, is being held to discuss the Board’s activities and to continue evaluation of the implementation of the long-range digestive diseases plan. Attendance by the public will be limited to space available. Notice of the meeting room will be posted in the hotel lobby. Mr. Raymond M. Kuehne, Executive Director. National Digestive Diseases Advisory Board. 1801 Rockville Pike, Rockville. Maryland. 20852, (301) 496- 6045. will provide on request an agenda and roster of the members. Summaries of the meeting may also be obtained by contacting his office. Dated: July 31, 1986. Betty J. Beveridge, NIH Committee Management Officer. (FR Doc. 86-17732 Filed 6-6-86; 8:45 am) BILUNG COOE 4140-01-M Naticnal Heart, Lung, and Blood Institute; Arteriosclerosis, Hypertension and Lipid Metalbolism Advisory Committee; Meeting Pursuant to Pub. L. 92-463. notice is hereby given of the meeting of the Arteriosclerosis. Hypertension and Lipid Metabolism Advisory Committee. National Heart. Lung, and Blood Institute. October 2-3, 1986. Building 31, Conference Room 3. C-Wing. National Institutes of Health, Bethesda. Mary land 2C892. The entire meeting will be open to the public from 8:30 a.m. to approximately 5:00 p.m. on Thursday. October 2. and from 3:3C a.m. to adjournment on Friday. October 3. to evaluate program support in Arteriosclerosis. Hypertension and Lipid Metabolism. Attendance by the public will be limited on a space available basis. Ms. Terry Bellicha. Chief, Public Inquiry and Reports Branch, National Heart. Lung, and Blood Institute, Building 31. Room 4A21. National Institutes of Health, Bethesda, Maryland 20892. (301) 496-4236, will provide a summary of the meeting and a roster of the committee members. Dr. G.C. McMillan, Associate Director. Arteriosclerosis, Hypertension and Lipid Metabolism Program, NHLBI. Room 4C12. Federal Building. National Institutes of Health. Bethesda, Maryland 20892. (301) 496-1613, will furnish substantive program information. (Catalog of Federal Domestic Assistance Program No. 13.837, Heart and Vascular Diseases Research, National Institutes of Health) Dated: July 28. 1936. Betty J. Beveridge. NIH Committee Management Officer. (FR Doc. 86-17734 Filed 8-6-86; 8:45 am] BILUNG COCE 4140-01-M Recombinant DNA Advisor/ Committee Working Group on Definitions; Meeting Pursuant to Pub. L. 92—463, notice is hereby given of a meeting of the Recombinant DNA Advisory Committee Working Group on Definitions at the National Institutes of Health, Building 31C, Conference Room 6, 9000 Rockville Pike. Bethesda, Maryland 20892. on September 5, 1986, from approximately 9:00 a.m. to adjournment at approximately 5:00 p.m. to discuss the definitions of "deliberate release" and "recombinant DNA" under the NIH Guidelines for Research Involving Recombinant DNA Molecules. This meeting will be open to the public. [34] Recombinant DNA Research, Volume 11 Federal Register / Vol. 51. No. 152 / Thursday. August 7, I960 / Notices 28441 Attendance by the public will be limited to space available. Further information may be obtained from Dr. William J. Cortland. Executive Secretary. Recombinant UNA Advisory Committee Working Croup on Definitions. National Institutes of Health. Building 31. Room CB'.O. Bethesda. Maryland telephone (301) 436-6051. Dated: |ul> 31. 1986. OMB's "Mandatory Information Requirements for Federal Assistance Prugram Announcements'’ {aj FR 3°3S3] requires a statement concerning "he otTicia! coverrunent programs contained in the Cctclcg of Federcl Domestic Assistance Normally NIK lists in its announcements the number and title of affected individual programs for the outdone? of the public. Because the guidance in (his notice covers not only virtually every MH program but also essentially every federal research program in which ONA recombinant molecule techniques rouid be usi'd. :t has been determined to be not cost effective or in the pubiic interest to attempt to list these programs. Such a list would likely require several additional p.vges. In addition. N1H could not be certain that every federal program would be included as many federal agencies, as well as private organizations, both national and international, have elected to follow the NIH Guidelines. In lieu of (he individual program listing NIH invites readers to direct questions to the information address above about whether individual ptograms listed in the Cctdog of Federal Domestic Assistance are affected. Betty J. Beveridge. Committee Management Officer. NIH. (FR Doc. 86-17735 Filed 8-6-36; 8:45 am| BILL! NO CCOt 1UO-01-M Public Health Service Health Education Assistance Loan Program; ‘‘Maximum Interast Rates for Quarter Ending September 30, 1986 and Rate of Insurance Premium" Section “27 of the Public Heal.h Service Act (42 US C. 294) authorises the Secretary of Health and Human Services to establish a Federal program of student lean insurance for graduate students in health professions schools. A. Section 60.13(a)(4J of the program's implementing regulations (42 CFR Part 60. previously 45 CFR Part 126) provides that the Secretary will announce the interest rate in effect on a quarterly basis. The Secretary announces that for the period ending September 30. 1936. three interest rates are in effect for loans executed through the Health Education Assistance Loan (HEAL) program. 1. For loans made before January 27. 1981. the variable interest rate is 94 percent. Using the regulatory formula (45 CFR 126.13(a) (2) and (3)). in effect prior to January 27. 1981. the Secretary would normally compute the variable rate for this quarter by finding the sum of the fixed annual rate (7 percent) and a variable component calculated by subtracting 3.50 percent from the average bond equivalent rate of 91 -day U.S. Treasury bills for the preceding calendar quarter (6.28 percent), and rounding the result (9.73 percant) upward to the nearest 4 percent (94 percent). Hcwever. the regulatory formula also provides that the annual rate at the variable interest rate for a 3- month period shall be reduced to the highest one-eighth of 1 percent which would result in an average annual rate not in excess of 12 percent for the 12- month period concluded by those 3 months. Because the average rata of the 4 quarters ending September 30. 1S86 is not in excess of 12 percent, there is no necessity for reducing the interest rate. For the previous 3 quarters the variable interest at the annua! rate was as follows: 104 percent fer the quarter ending December 31. 1985; 11 percent for the quarter ending March 31. 1986; and 104 percent for the quarter ending June 30. 1986. 2. For variable rate loans executed during the period af January 27. 1981 through October 21. 1985. the interest rate is 94 percent. Using the regulatory formula (42 CFR 60.13(a)(3)) in effect since January 27. 1981. the Secretary computes the maximum interest rate at the beginning of each calendar quarter by determining the average bond equivalent rate for the 91-day U.S. Treasury bills during the preceding quarter (6.28 percent); adding 3.50 percent (9.78 percent): and rounding that figure to the next higher one-eighth of 1 percent (94 percent). 3. For fixed rate loans executed during the period of July 1. 1988 through September 30. 1986. and for variable rate loans executed on or after October 22. 1985. the interest rate is 94 percent. The Health Professions Training Assistance Act of 1985 (Pub. L. 99-129), enacted October 22. 1985. amended the formula for calculating the interest rate by changing 3.5 percent to 3 percent. Using the regulatory formula (42 CFR 60.13(a) (2) and (3)) and substituting the new statutory change of 3 percent, the Secretary computes the maximum interest rate at the beginning of each calendar quarter by determining the average bond equivalent rate for the 91- day U.S. Treasury bills during the preceding quarter (8.28 percent); adding 3.0 percent (9.28 percent) and rounding that figure to the next higher one-eighth of 1 percent (94 percent). B. Public Law 99-129 also contained modifications to the insurance premium calculation, effective S months after enactment of the statute (July 22. 1986|. Prior to that date, in accordance with § 00.14(b) cf the regulations, the insurance permium continued (o be 2 percent per year of the loan principal for loans executed through the HEAL program. Effective July 22. 1933 in accordance with section 732 of the Act. as amended, the insurance premium is 3 percent of each HEAL loan. A notice announcing this change was published on June 18 (FR 2213SJ. (Catalog of Federal Domestic Assistance No. 13.108. Health Education Assistance Loans). Dated: July 31. 1986. John H. Xeiso. Acting Administrator. (FR Doc. 66-17525 Filed 8-6-86: R:45 ami bilung cooe *teo-is-v DEPARTMENT OF HOUSING AND URBAN DEVELOPMENT (Docket No. N-8S-1622; FR-22$5j Availability of Funding Under the Community Housing Resource Board Program; Competitive Solicitation agency: Office of the Assistant Secretary for Fair Housing and Equal Opportunity. HUD. action: Notice of funds availability. Summary: HUD is soliciting applications from eligible Community Housing Resource Boards (CHRBs) for funding under the CHRB Program. CHRBs must meet certain eligibility criteria in order to qualify for consideration. oate: Applications for funding must be submitted by September 8, 1986. FOR FURTHER INFORMATION CONTACT. Lydia Jackson. Office of Procurement and Contracts. Room 5260. Office of the Assistant Secretary for Administration. Department of Housing ar.c Urban Development. 451 Seventh Street SVV.. Washington, DC 20410. Application kits will be sent only upon written request made after August 7. 1986, to the Office of Procurement and Contracts at the above address. Telephone requests for application kits will not be honored. SUPPLEMENTARY INFORMATION: This Notica of Funds Availability is issued under the regulations for the CHRB Program, published in the Federal Register on March 25. 1982 (47 FR 12926) and codified at 24 CFR Part 120. Interested CHRBs are urged to review these regulations and the factors for award in the application kit to [35] Recombinant DNA Research, Volume 1 1 DEPARTMENT CF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE NATIONAL INSTITUTES CF HEALTH RECOMBINANT DNA ADVISORY COMMITTEE HUMAN GENE THERAPY SUBCOMMITTEE MINUTES OF MEETING 1 AUGUST 8, 1986 The Human Gene Therapy Subcommittee of the Recombinant DNA Advisory Committee was convened at 9:00 a.m. on August 8, 1986, at the National Institutes of Health, Building 31, Conference Room 4, 9000 Rockville Pike, Bethesda, Maryland 20892. Dr. LeRcy Walters was Chair. The following were present for all or part of the meeting: Subcommittee members : Alexander Capron James Childress Susan Gottesr\an Clifford Grobstein William Kelley Maurice Mahoney Amo Motulsky A subcommittee roster is attached (Attachment I). Lias ion representatives : Philip Chao, Food and Drug Administration Charles MacKay, National Institutes of Health Henry Miller, Food and Drug Administration Other National Institutes of Health staff: Robert Murray Robert Rich LeFtoy Walters Anne Witherby William Gartland (Executive Secretary) W. French Anderson, NHLBI Creighton Phelps, NIA Dana Uhger, OD Others : Robert Cook-Deegan, Office of Technology Assessment Barbara Culliton, Science Magazine Valerie Finholm, Hartford Courant Dorothy Jessop, Department of Agriculture Phil Musi, Blue Sheet Stuart Newman, Committee for Responsible Genetics Ann Stevens, Hartford Courant Charles Turbyville, NIH Week Nachama Wilker, Ccmmittee for Responsible Genetics J-The subcommittee is advisory to the RAC, and its recommendations should not be considered as final or accepted. 58/6 [36] Recombinant DNA Research, Volume 1 1 I . OPENING RENARKS Dr. Walters called the meeting to order and said that the subcommittee would be considering a proposal by the Committee for Responsible Genetics to amend the National Institutes of Health (NIH) Guidelines for Research Involving Recombinant DMA Molecules, and would be reviewing the Points to Consider in the Design and Submission of Human Sanat-ic-Cell Gene Therapy Protocols. Cfc-. Walters noted that Cr . W. French Anderson of the NIH has resigned from the siixxmmittee. He welcomed Dr. William Kelley of the Uhiversity of Michigan as a new member of the subcommittee. He also noted that Dc. Elizabeth Milewski has left the NIH. Dr. Walters noted that the Institute of Medicine annual meeting on October 15, 1986, will be devoted to "Human Somatic Cell Gene Therapy: Prospects for Treating Inherited Diseases." II. BIOMEDICAL ETHICS BOARD Dr. Charles MacKay updated the sJd commit tee on the status of the Biomedical Ethics Board and the appointment of a Biomedical Ethics Advisory Committee. III. REVIEW OF POINTS TO CONSIDER The subcommittee considered the September 23, 1985, version of the Points to Consider in the Design and Submission of Human Somatic-Cell Gene Therapy Proto- cols and letters of suggested changes fron Dr. Temin on March 4 and July 22, 1986, and Dr. Kelley on March 3, 1986 (Attachment II), as well as other proposed changes. The subcommittee recommended that the following sentence be added after the first sentence in I-A-2 on page 8: "Wiat objective and/or Quantitative measures of disease activity are available?" The subcommittee recommended that the following new material be added as paragraphs (c) and (d) on page 10: "(c) If co-cultivation of virus-producing cells with target cells is used, how is the absence of contamination by donor cells or by sequen- ces packaqed into infectious particles by the donor (e.g., VL30 sequences) demonstrated? Vhat is the sensitivity of these tests? Vhat cells were used for co>-cultivation? "(d) If methods other than those covered by a-c are used to introduce new genetic information into target cells, how is it demonstrated that the final target cells are free of contamination? Vhat are possible sources of contamination? What is the sensitivity of tests used to monitor contamination?" Recombinant DNA Research, Volume 1 1 [37] The subcommittee recommended that the following sentences be inserted after the first sentence in (d) on page 14: "Are there objective and quantitative measurements to assess the natural history of the disease? Will such measurements be used in following your patients?" The subcommittee recommended that question c. on page 15 be reworded as follows: "c. Vhat precautions will be taken against such spread (e.g., to patients sharing a roam, health-care workers, or family members)?" The proposed revised Points to Consider document, which is to be considered by the full Recombinant DNA Advisory Committee (RAC) on September 29, 1986, appears in Attachment III. PROPOSAL BY COMMITTEE FOR RESPONSIBLE GENETICS The subcommittee considered a proposal by the Committee for Responsible Genetics to amend the NIH Guidelines for Research Involving Recombinant ENA Molecules (Attachment IV). Drs. Capron, Grobstein, and Motulsky began the discussion of this proposal. Dr. Capron addressed the effects of the proposed restrictions and the persuasiveness of the rationale. Dr. Grobstein said that the proposed language was unfortunate in several respects, but that a modified version of the proposal might serve as interim public policy. Er. Motulsky said that it would be unwise to prohibit categorically any DNA manipulation with human germ line cells or early zygotes since such work may lead to scientific insights and/or approaches to prevention or management of birth defects or genetic disease in the future. Many members of the subcommittee shared the view that the proposal is unduly restrictive. After extensive discussion of the issues raised by this proposal, the subcommittee prepared the following statement and recommendation to the RAC: "1. The Committee for Responsible Genetics (CRG) in a letter dated March 26, 1986, has expressed concern about human gene therapy that is not aimed solely at the relief of a life-threatening or severely disabling condition, or that could alter germ line cells. The subcommittee has expressed its concerns about such gene therapy in the introduction to the 'Points to Consider in the Design and Submission of Human Somatic-Cell Gene Therapy Protocols': '(7). ..The RAC and its subcommittee will not at present entertain proposals for germ-line alterations but will consider for approval protocols involving scmatic-cell gene therapy,' and '(11) In recognition of the social concern that surrounds the general discussion of human gene therapy, the subcommittee will continue to consider the possible long-range effects of applying knowledge gained from these and related experiments. Vhile research in molecular bioloav could lead to the development of techniques for gem line [38] Recombinant DNA Research, Volume 1 1 intervention or for the use of genetic means to enhance human capabilities rather than to correct defects in patients, the sub- committee does not believe that these effects will follow immediately or inevitably from experiments with somatic-cell gene therapy. The subcommittee will cooperate with other groups in assessing the possible long-term consequences of somatic-cell gene therapy and related laboratory and animal experiments in order to define appro- priate human applications of this emerging technology.' "2. The CRH has also urged the Recombinant Advisory Caimittee (RAC) and the National Institutes of Health (NIH) not to review or approve any in vitro recombinant DMA experiments that alter human germ line cells or early human anbryos. The subcommittee understands that human germ line cells would be covered by provisions for cells in tissue culture in the NIH Guidelines for Research Involving Recombinant CNA Molecules, and that Federal support for human enbryo research is precluded by statute. fFxecutive Secretary's Note: Subsequent to the meeting the final clause of this point was modified to read as follow^ "that HHS support fot reseach involving human in vitro fertilization is precluded by regulation unless reviewed by an Ethical Advisory Board which must render advice as to the acceptability of the procedure.") "3. The subcommittee shares with the CRG a belief in the need for continued broad, public discussion of these issues, and we believe that the RAC and the subcarmittee provide appropriate forums for such discussion. "4. Because specific proposals for research can provide a helpful impetus for, and illumination of, the discussion of general policy about gene therapy, we believe that the contribution of the RAC and the subcommittee to the public discussion would be detrimentally affected by the prohi- bition suggested by the CRG on the RAC reviewing proposals for certain types of gene therapy. Furthermore, the suggested limitations would diminish the flexibility that is one of the strengths of the RAC's functions of providing advice. "5. With respect to human germ line cells and anbryos, this subcommittee has not specif ically addressed the complex issues involved but expresses its concern that the CRG recommendation would impede research and clinical advance in human reproductive biology. "6. The subcommittee plans to inform the public of its stand on these and other issues. "7. For the above reasons, the subcommittee recommends no change in the NIH Guidelines with regard to the issues raised by the CRG." The subconmittee adopted this statenent and recommendation by a vote of eight in favor, none opposed, and no abstentions. This document is to be considered by the RAC at its meeting on September 29, 1986. Recombinant DNA Research, Volume 1 1 [39] V. LAY SUMMARY OF POINTS TO CONSIDER Ms. Areen, Dr. Mahoney, and Dr. Rich will work with Ms. Withe rby to prepare a "lay summary" for the Points to Consider in the Design and Submission of Human Scmatic-Cell Gene Therapy Protocols. Drs. Gottesman and Miller will serve as consultants to this subgroup. VI. FUTURE MEETINGS The Executive Secretary will schedule future meetings of the si±>ccmmittee when future meeting dates for the RAC have been set. Future meetings will be cancelled if there is little businesss for the subcommittee. VII. ADJOURNMENT The meeting was adjourned at 3:30 p.m. [40] Recombinant DNA Research, Volume 1 1 Respectfully submitted Executive Secretary I hereby certify that, to the best of my knowledge, the foregoing Minutes and Attachments are accurate and complete. tnair Human Gene Therapy Subcommittee Date Recombinant DNA Research, Volume 1 1 [ 41 ] RECCWBINANT DM ADVISORY COMMITTEE HUMAN GENE THERAPY SUBCOMMITTEE CHAIR WALTERS, LeRcy, Fh.D. Center for Bioethics Kennedy Institute of Ethics Georgetown University Washington, D.C. 20057 202 625-2386 AREEN, Judith, J. D. Georgetown University Law Center 600 New Jersey Avenue, N.W. Washington, D.C 20001 202 624-8203 CAPRON, Alexander, LL.B. The Law Center University of Southern California Los Angeles, California 90089-0071 213 743-7734 CHILDRESS, James F., Ph.D. Department of Religious Studies Cocke Hall Charlottesville, Virginia 22903 804 924-3741 GCROVITZ, Samuel, Fh.D. Department of Philosophy University of Maryland 1131 Skinner Hall College Park, Maryland 20742 301 454-2851 GCTTE94AN, Susan K. , Fh.D. Laboratory of Molecular Biology National Cancer Institute, 37/4B09 National Institutes of Health Bethesda, Maryland 20205 301 496-3524 GROBSTEIN , Clifford, Ph.D. Department of Science, Technology, & Public Affairs, Mail Code 0060 University of California, San Diego La Jolla, California 92093 619 452-3352 [42] KELLEY, William N. , M.D. Department of Internal Medicine 310 0A Taubman Center University of Michigan Medical Center Ann Arbor, Michigan 48109-0368 313 936-4340 MAHONEY, Maurice J. , M.D. Department of Human Genetics Yale University 333 Cedar Street, 305 WWW New Haven, Connecticut 06510 203 785-2661 MITCHELL, Robert E. , LL.B. (Ex-officio) Attorney at Law 13915 San Antonio Drive Norwalk, California 90650 213 863-8736 MOTULSKY, Arno G., M.D. Department of Medicine University of Washington Seattle, Washington 98195 206 543-3593 MURRAY, Robert F. , M.D. Division of Medical Genetics Howard University, Box 75 520 W Street, N.W. Washington, D.C. 20059 202 ' 636-6382 RICH, Robert F., Ph.D. Institute of Government Public Affairs University of Illinois 1201 West Nevada Street Urbana, Illinois 61801 217 333-3340 Recombinant DNA Research, Volume 1 1 VARMUS, Harold, Ph.D. Department of Microbiology University of California San Francisco, California 94143 415 476-2824 WITHERBY, Anne R. , B.S. 2 Commonwealth Avenue Boston, Massachusetts 02116 617 247-0123 EXECUTIVE SECRETARY GARTLAND, William J., Jr., Ph.D. Office of Recombinant DNA Activities National Institute of Allergy & Infectious Diseases National Institutes of Health Be the sd a, Maryland 20205 301 496-6051 CONSULTANT TEMIN, Howard M., Ph.D. Department of Oncology McArdle Laboratory for Cancer Research University of Wisconsin Madison, Wisconsin 53706 608 262-1209 LIAISON REPRESENTATIVES McCarthy, Charles, Ph.D. Office of Protection from Research Risks Office of the Director National Institutes of Health, 31/4B09 Be the sd a , Maryland 20205 301 496-7005 MILLER, Henry I., M.D. Office of Biologies Food and Drug Administration, HFN-823 8800 Rockville Pike Bethesda, Maryland 20205 301 443-4864 HARMISON, Lowell, Ph.D. Office of Assistant Secretary for Health, Room 1395 5600 Fishers Lane Rockville, Maryland 20857 301 443-2650 LEE, Bonnie M. Health Assessment Policy Staff Office of Health Affairs Food & Drug Administration, HFY-20 5600 Fishers Lane Rockville, Maryland 20857 301 443-1382 Recombinant DNA Research, Volume 1 1 [43] McARDLE LABORATORY FOR CANCER RESEARCH DEPARTMENT OF ONCOLOGT MEDICAL SCHOOL, UNIVERSITY OF WISCONSIN July 22, 1986 Dr. William J. Gartland, Jr. Recombinant DNA Advisory Committee Building 31, Room 3B10 National Institutes of Health Bethesda, MD 20205 Dear Bill: Thank you for your call. I have two concerns relating to B.l.B. (1) (B) . In this section about the purity of the virus, we should perhaps Indicate explicitly that there Is no contamination of the virus producing cells (as mentioned In my letter of March 4), and that any contaminating materials Include molecules like the rodent VL30 sequences. VL30 sequences are endogenous sequences in rodent cells which produce an RNA that Is very efficiently packaged In retrovirus virions. In fact, Harvey and Kirsten sarcoma viruses are VL30 recombinants. Another problem that might be considered in relation to effect- iveness of the vectors is the requirement of demonstration of good expression In a primate. The recent difficulties in getting expres- sion in animals as opposed to cell culture indicates that there may be difficulty In extrapolating to the human species from other species. I don't think that I shall be able to attend the August 8 meeting. My summer has turned into a time busier than the rest of the year Instead of a let up. With best regards. Sincerely yours. Howard M. Temin [44] Recombinant DNA Research, Volume 11 McARDLE LABORATORY FOR CANCER RESEARCH DEPARTMENT Of ONCOLOGY MEDICAL SCHOOL, UNIVERSITY Of WISCONSIN March 4, 1986 Dr. William J. Cartland, Jr. Recombinant DNA Advisory Committee Building 31, Room 3B10 National Institutes of Health Bethesda , MD 20205 Dear Bill: I am writing with respect to a possible oversight In the Points to Consider for Possible Human Cene Therapy. In recent papers concerned with stem cell Infections of mice, there has been co-cultlvatlon of virus-producing cells with the stem cells followed by subsequent reimplantation of the stem cells Into suitable recipients. When the Points to Consider were being drawn up, it was thought that all Infections would be by cell-free virus stocks. Therefore, there is no explicit question in the Points about the possibility of contamina- tion by the virus-producing cells. This problem may be covered by present questions about contaminating organisms, but might be better explicitly stated. With best regards. Sincerely yours Howard M. Teraln HKT:mjm Recombinant DNA Research. Volume 11 [45] The University of Michigan Medical Center A>m Aihn. Michip* UIOS-OM4 Department of Internal Medicine Offxct of llit Chairman JlOOA Tauhwan Ctnltr (313) 9J6-M0 March 3, 1986 James B. Wyngaarden, M.O. Director, National Institutes of Health Building I, Room 124 9000 Rockville Pike Bethesda, Maryland 20205 Dear Jim: Thank you for your letter of January 2nd in response to my earlier concern with regard to the clinical application of gene transfer technology. Clearly, the working group on human gene therapy represents a distinguished group of individuals covering a broad spectrum of interest. I think the group would be enhanced if one or two individuals were included who had considerable experience with patient related clinical research. I would, of course, be happy to serve but as you know there are many other individuals who would be at least as competent. In general, the guidelines appear highly appropriate. There are several specific suggestions, however, which you may find helpful. 1. With somatic cell gene transfer experiments, there does not appear to be any attempt to demonstrate the absence of contamination of germ cells in the human subjects. There are several reasons to suspect that the use of retroviruses might contaminate germ cells. Obviously, this type of contamination should be excluded with a high degree of certainty. 2. There should be additional emphasis on the utilization of objective measures of disease activity. For example on page 8, I - A - 2, I would add "What objective measures of disease activity are available?" On page 14, I r B- 3 - c, I would add "What objective measures of disease activity are available? Will all be utilized? If not, explain?" I appreciate your attention to this important area of research development. Best regards. Sincerely, William N. Kelley, M.D. John G. Searle Professor and Chairman Recombinant DNA Research, Volume 1 1 [ 46 ] NATIONAL INSTITUTES OP HEALTH POINTS TO CONS I DOR IN THE DESIGN AND SUBMISSION OF HUMAN SOMATIC-CELL GENE THERAPY PROTOCOLS HUMAN GENE THERAPY SUBCOMMITTEE NIH* RECOMBINANT CNA ADVISORY COMMITTEE OUTLINE Applicability Introduction I. Description of Proposal A. Objectives and rationale of the proposed research B. Research design, anticipated risks and benefits 1. Structure and characteristics of the biological system 2. Preclinical studies, including risk assessment studies 3. Clinical procedures, including patient monitoring 4. Public-health considerations 5. Qualifications of investigators, adequacy of laboratory and clinical facilities C. Selection of patients D. Informed consent E. Privacy and confidentiality Recombinant DNA Research, Volume 1 1 [47] 23/3 Subcommittee Draft August 8, 1986 I I . Special Issues A. Provision of accurate information to the public B. Timely communication of research methods and results to investigators and clinicians III. Requested Documentation A. Original protocol B. IRB and IBC minutes and recommendations C. One-page abstract of gene therapy protocol D. One-page description of proposed experiment in non-technical language E. Curricula vitae for professional personnel F. Indication of other federal agencies to which the protocol is being submitted G. Other pertinent material IV. Reporting Requirements [ 48 ] Recombinant DNA Research, Volume 1 1 NATIONAL INSTITUTES OF HEALTH POINTS TO CONSIDER IN THE CESICN AND SUBMISSION OF HUMAN SOMATIC -CELL GENE THERAPY PROTOCOLS Applicability - These "Points to Consider" apply only to research conducted at or sponsored by an institution that receives any support for recombinant DNA research from the National Institutes of Health (NIH). This includes research performed by NIH directly. Introduction (1) Experiments in which recombinant CNA* is introduced into cells of a human subject with the intent of stably modifying the subject's gencme are covered by Section III-A-4 of the NIH Guidelines for Research Involving Reccmbinant CNA Molecules (49 Federal Register 46266). Section III-A-4 requires such experiments to be reviewed by the NIH Recombinant DN\ Advisory Ccmmittee (RAC) and approved by the NIH. RAC consideration of each proposal will be on a case-by-case basis and will follow publication of a precis of the proposal in the Federal Register , an opportunity for public ccmment, and a review of the proposal by the working group of the RAC. RAC reccumendat ions on each proposed will be forwarded to the NIH Director for a decision which will then be published in the Federal Register . In accordance with Section IV-C-l-b of the NIH Guidelines, the NIH Director may approve proposals only if he finds that they present "no significant risk to health or the environment." (2) In general, it is expected that sonatic-cel 1 gene therapy protocols will not present a risk to the environment as the reccmbinant DNA is expected to be confined to the human subject. Nevertheless, Section I-B-4-b of the "Points to Consider" document asks the researchers to address specifically this point. ^Section III-A-4 applies both to reccmbinant DNA as well as to Dt^\ derived from recombinant CNA. Recombinant DNA Research, Volume 1 1 [49] (3) This document is intended to provide guidance in preparing proposals for NIH consideration under Section III-A-4 of the NIH Guidelines for Research Involving Recombinant Dt^ Molecules. Not every point mentioned in the "Points to Consider" document will necessarily require attention in every proposed. The document will be considered for revision as experience in evaluating proposals accumulates ard as new scientific developments occur. This review will be carried out at least annually. (4) A proposal will be considered by the RAC only after the protocol has been approved by the local Institutional Biosafety Camuttee (IBC) ard by the local Institutional Review Board (IRB) in accordance with Department of Health and Human Services (CHHS) Regulations for the Protection of Human Subjects (45 Code of Federal Regulations, Part 46). If a proposal involves children, special attention should be paid to subpart D of these CHHS regulations. The IRB and IBC may, at their discretion, condition their approval on further specific deliberation by the RAC and its working group. Consideration of gene therapy proposals by the RAC may proceed simultaneously with review by any other involved federal agencies^ provided that the RAC is notified of the simultaneous review. Meetings of the camuttee will be open to the public exoept where trade secrets or proprietary information would be disclosed. The camuttee would prefer that the first proposals submitted for RAC review contain no proprietary information or trade secrets, enabling all aspects of the review to be open to the public. The public review of these protocols will serve to inform the ^The Food and Drug Administration (FDA) has jurisdiction ever drug products in- tended for use in clinical triads of human scmatic-cell gene therapy. For general information on FDA's policies ard regulatory requirements, please see the Federal Register , Volume 49, pages 50878-80, 1984. Recombinant DNA Research, Volume 1 1 [ 50 ] fxJalic not only on the technical aspects of the proposals but also on the meaning and significance of the research. (5) The clinical application of recombinant DNA techniques to human gene therapy raises two general kinds of gjestions: (1) the questions usually discussed by IRSs in their review of ary proposed research involving human subjects; and (2) broader social issues. The first type of question is addressed principally in Part I of this document. Several of the broader social Issues surrounding human gene therapy are discussed later in this Introduction and in Part II below. (6) Following the Introduction, this document is divided into four parts. Part I deals with the short-term risks and benefits of the proposed research to the patient 3 and to other people, as well as with issues of fairness in the selection of patients, informed consent, and privacy and confidentiality. In Part II, investigators are requested to address special issues pertaining to the free flow of information about clinical trials of gene therapy. These issues lie outside the usual purview of IRBs and 'led general public concerns about biomedical research. Part III summarizes other requested documentation that will assist the RAC and its working group in their review of gene therapy proposals. Part IV specifies reporting requirements. (7) A distindion should be drawn between making genetic changes in somatic cells and in germ line cells. The purpose of soruatic cell gene therapy is to treat an individual patient, e.g., by inserting a properly fundioning ^The term "patient" and its variants are used in the text as a shorthand designation for ■ patient-sub jed." Recombinant DMA Research. Volume 1 1 [51] gene into a patient's bone marrow cells jm vitro and then reintroducing the cells into the patient's body. In germ line alterations, a specific attempt is made to introduce genetic changes into the germ (reproductive) cells of an individual, with the aim of charging the set of genes passed on to the individual's offspring. The RAC and its working group will not at present entertain proposals for geom line alterations but will consider for approval protocols involving somatic-cell gene therapy. (8) The acceptability of human somatic-cell gene therapy has been addressed in several recent public documents as well as in numerous academic studies. The November 1982 report of the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Splicing Life , resulted from a two-year process of public deliberations and hearings; upon release of that report, a House subcommittee held three days of public hearings with witnesses from a wide range of fields from the biomedical and social sciences to theology, philosophy, and law. In December 1984, the Office of Technology Assessment released a background paper. Human Gene Therapy , which brought these earlier documents up-to-date. As the latter report concluded: "Civic, religious, scientific, and medical groups have all accepted, in principle, the appropriateness of gene therapy of somatic oells in humans for specific genetic diseases. Somatic cell gene therapy is seen as an extension of present methods of therapy that might be preferable to other technologies." [52] Recombinant DNA Research, Volume 1 1 (9) Concurring with this judgment, the RAC and its working group are prepared to consider for approval somatic-cell therapy protocols, pro/ided that the design of such experiments offers adequate assurance that their consequences will not go beyond their purpose , which is the same as the traditional purpose of all clinical investigations, namely, to benefit the health and well-being of the individual being treated v^iile at the same time gathering general - izable knowledge. (10) Two possible undesirable consequences of somatic-cell therapy would be unintentional (1) vertical transmission of genetic changes from an individual to his or her offspring or (2) horizontal transmission of viral infection to other persons with whom the individual cones in contact. Accordingly, this document requests information that will enable the RAC and its working group to assess the likelihood that the proposed somatic-cell gene therapy will inadvertently affect reproductive cells or lead to infection of other people (e.g., treatment personnel or relatives). (11) In recognition of the social concern that surrounds the general discussion of human gene therapy, the working group will continue to consider the possible long-range effects of applying knowledge gained frcm these and related experiments. While research in molecular biology could lead to the development of techniques for geon line intervention or for the use of genetic means to enhance human capabilities rather than to correct defects in patients, the working group does not believe that these effects will follow immediately or inevitably frcm experiments with scrotic-cell gene therapy. The working group will cooperate with other groups in assessing the possible long-term consequences of scma tic-cell gene therapy Recombinant DNA Research, Volume 1 1 [53] and related laboratory and animal experiments in order to define appropriate human applications of this emerging technology. (12) Responses to the questions raised in these "Points to Consider" should be provided in the form of either written answers or references to specific sections of the protocol or its appendices. I. Description of Proposal A. Objectives and rationale of the proposed research State concisely the overall objectives and rationale of the proposed study. Please provide information on the following specific points: 1. Wiy is the disease selected for treatment by means of gene therapy a good candidate for such treatment? 2. Describe the natural history and range of expression of the disease selected for treatment. Wiat objective and/or quantitative measures of disease activity are available? In your view, are the usual effects of the disease predictable enough to allow for meaningful assessment of the results of gene therapy? 3. Is the protocol designed to prevent all manifestations of the disease, to halt the progression of the disease after symptoms have begin to appear, or to reverse manifestations of the disease in seriously ill victims? 4. Vfriat alternative therapies exist? In what groups of patients are these therapies effective? Vhat are their relative advantages and disadvantages as compared with the preposed gene therapy? f541 Recombinant DNA Research, Volume 11 B. Research design, anticipated risks and benefits 1. Structure and characteristics of the biological system Provide a full description of the methods and reagents to be employed for gene delivery and the rationale for their use. The following are specific points to be addressed: a. fcfoat is the structure of the cloned CNA that will be used? (1) Describe the gene (genomic or cDNA) , the bacterial plasnid or phage vector, and the delivery vector (if any). Provide complete nucleotide sequence analysis or a detailed restriction enzyme map of the total construct. (2) Vhat regulatory elements does the construct contain (e.g. , promoters, enhancers, polyadenylation sites, replication origins, etc.)? (3) Describe the steps used to derive the CM\ construct. b. Vhat is the structure of the material that will be administered to the patient? (1) Describe the preparation, structure, and composition of the materials that will be given to the patient or used to treat the patient's cells. (a) If CNA, vhat is the purity (both in terms of being a single DMA species and in terms of other contaminants)? Recombinant DNA Research, Volume 1 1 [55] Vhat tests have been used and vhat is the sensitivity of the tests? (b) -If a virus, how is it prepared from the ENA construct? In vhat cell is the virus grown (any special features)? vhat medium and serum are used? How is the virus purified? What is its structure and purity? Vhat steps are being taken (and assays used with their sensitivity) to detect and eliminate any contaminating materials (nucleic acids, pro- teins, etc.) or contaminating viruses or other organisms in the cells or serum used for preparation of the virus stock? (c) If co-cultivation of virus-producing cells with target cells is used, how is the absence of contamination by donor cells or by sequences packaged into infectious particles by the donor (e.g., VL30 sequences) demonstrated? What is the sensitivity of these tests? What cells were used for co-cultivation? (d) If methods other than those covered by a-c are used to introduce new genetic information into target cells, how is it demonstrated that the final target cells are free of contamination? Vhat are possible sources of contamination? What is the sensitivity of tests used to monitor contamination? [56] Recombinant DNA Research, Volume 1 1 (2) Describe any other material to be used in preparation of the material bo be administered to the patient. For example, if a viral vector is proposed, what is the nature of the helper virus or cell line? If carrier particles are bo be used, what is the nature of these? 2. Preclinical studies, including risk-assessment studies Describe the experimental basis (derived from tests in cultured cells and animals) for claims about the efficacy and safety of the proposed systerri for gene delivery. a. Laboratory studies of the delivery system (1) What cells are the intended recipients of gene therapy? If recipient cells are to be treated _in vitro and returned to the patient, how will the cells be characterized before and after treatment? Vhat is the theoretical and practical basis for assuming that only the treated cells will act as recipients? (2) Is the delivery systen efficient? Vhat percentage of the target cells contain the added DMA? (3) How is the structure of the added ENA sequences monitored and what is the sensitivity of the analysis? Is the added ENA extrachrcmosomal or integrated? Is the added ENA unrearranged? Recombinant DNA Research, Volume 1 1 [57] (4) How many copies are present per cell? How stable is the added DMA both in terns of its continued presence and its structural stability? b. Laboratory studies of gene expression Is the added gene expressed? To what extent is expression only from the desired gene (and not from the surrounding DNA) ? In what percentage of cells does expression from added DN^ occur? Is the product biologically active? Vfriat percentage of normal activity results from the inserted gene? Is the gene expressed in cells other than the target cells? If so, to what extent? c. Laboratory studies pertaining to the safety of the delivery/ expression system (1) If a retroviral system is used: (a) What cell types have been infected with the retroviral vector preparation? Which cells, if any, produce infectious particles? (b) How stable are the retroviral vector and the resulting provirus against loss, rearrangement, recombination, or mutation? What information is available on how much rearrangement or recombination with endogenous or other viral sequences is likely to occur in the patient's cells? Vhat steps have been taken in designing the vector to minimize instability or variation? What (58] Recombinant DNA Research, Volume 1 1 laboratory studies have been performed to check for stability, and what is the sensitivity of the analyses? (c) What' laboratory evidence is available concerning poten- tial harmful effects of the treatment, e.g., development of neoplasia, harmful mutations, regeneration of infectious particles, or immune responses? Vbat steps have been taken in designing the vector to minimize pathogenicity? Miat laboratory studies have been performed to check for pathogenicity, and what is the sensitivity of the analyses? (d) Is there evidence from animal studies that vector CNA has entered untreated cells, particularly germ line cells? V*iat is the sensitivity of the analyses? (e) Has a protocol similar to the one proposed for a clin- ical trial been carried out in non-human primates and/ or other animals? What were the results? Specifically, is there any evidence that the retroviral vector has reconbined with any endogenous or other viral sequences in the animals? (2) If a noo-retrcviral delivery system is used: What animal studies have been done to determine if there are pathological or other undesirable consequences of the protocol (including insertion of DNA into cells other than those treated, particularly germ line cells)? How long have the animals [59] Recombinant DIMA Research, Volume 1 1 been studied after treatment? Miat tests have been used and what is their sensitivity? 3. Clinical procedures , including patient monitoring Describe the treatment that will be administered to patients and the diagnostic methods that will be used to monitor the success or failure of the treatment. If previous clinical studies using similar methods have been performed by yourself or others, indicate their relevance to the proposed study. a. Will cells (e.g., bone marrow cells) be removed frcm patients and treated in vitro in preparation for gene therapy? If so, what kinds of cells will be removed from the patients, how many, how often, and at what intervals? b. Will patients be treated to eliminate or reduce the number of cells containing malfunctioning genes (e.g., through radiation or chemotherapy) prior to gene therapy? c. What treated cells (or vector/DNA combination) will be given to patients in the attempt to administer gene therapy? How will the treated cells be administered? What volume of cells will be used? Will there be single or multiple treatments? If so, over what period of time? d. What are the clinical endpoints of the study? Are there objective and guantitative measurements to assess the natural history of the disease? Will such measurements be used in [ 60 ] Recombinant DNA Research, Volume 1 1 following your patients? How will patients be monitored to assess specific effects of the treatment on the disease? Vfriat is the sensitivity of the analyses? How frequently will follow-up studies be done? How long will patient follow-up continue? e. Wvat are the major potential beneficial and adverse effects of treatment that you anticipate? What measures will be taken in an attempt bo control or reverse these adverse effects if they occur? Can pa re the probability and magnitude of potential adverse effects on patients with the probability and magnitude of deleterious consequences frcm the disease if gene therapy is not performed. f. If a treated patient dies, what special studies will be performed as part of the autopsy? 4 . Public-health considerations Describe any potential benefits and hazards of the proposed therapy to persons other than the patients being treated. Specifically: a. On what basis are potential public health benefits or hazards postulated? b. Is there a significant likelihood that the added ENA will spread from the patient to other persons or to the environment? c. What precautions will be taken against such spread (e.g., to patients sharing a roan, health-care workers, or family members)? Recombinant DNA Research, Volume 1 1 [ 61 ] d. Vhat measures will be undertaken to mitigate the risks, if any, to public health? 5. (Xiallf ications of investigators, adequacy of laboratory and clinical facilities Indicate the relevant training and experience of the personnel who will be involved in the preclinical studies and clinical administra- tion of gene therapy. In addition, please describe the laboratory and clinical facilities where the proposed study will be performed. a. What professional personnel (medical and nonmedical) will be involved in the proposed study? What are their specific quali- fications and experience with respect to the disease to be treated and with respect to the techniques employed in molecular biology? Please provide curricula vitae (see Section III-E) . b. At what hospital or clinic will the treatment be given? Vhich facilities of the hospital or clinic will be especially important for the proposed study? Will patients occupy regular hospital beds or clinical research center beds? Where will patients reside during the follow-up period? C. Selection of patients Estimate the number of patients to be involved in the proposed study of gene therapy. Describe recruitment procedures and patient eligibility requirements, paying particular attention to whether these procedures and requirements are fair and equitable. Recombinant DNA Research, Volume 1 1 [ 62 ] 1. How many patients do you plan to involve in the proposed study? 2. How many eligible patients do you anticipate being able bo identify each year? 3. vhat recruitment procedures do you plan bo use? 4. What selection criteria do you plan to employ? Vhat are the exclusion and inclusion criteria for the study? 5. Hew will patients be selected if it is not possible bo include all who desire to participate? D. Informed consent Indicate how patients will be informed about the proposed study and how their consent will be solicited. The consent procedure should adhere to the requirements of CHHS regulations for the protection of human subjects (45 Code of Federal Regulations, Part 46). If the study involves pediatric or mentally handicapped patients, describe procedures for seeking the permission of parents or guardians and, v^iere applicable, the assent of each patient. Areas of special concern highlighted below include potential adverse effects, financial costs, privacy, and long-term follcw-up. 1. How will the major points covered in Sections I -A through I-C of this document be disclosed to potential participants in this study and/or parents or guardians in language that is understandable to them? Recombinant DNA Research, Volume 1 1 [63] 2 . How will the innovative character and the theoretically-passible adverse effects of gene therapy be discussed with patients and/or parents or guardians? Hew will the potential adverse effects be compared with the consequences of the disease? What will be said to convey that seme of these adverse effects, if they occur, could be irreversible? 3. What explanation of the financial costs of gene therapy and any available alternative therapies will be provided to patients anchor parents or guardians? 4. How will patients and/or their parents or guardians be informed that the innovative character of gene therapy may lead to great interest by the media in the research and in treated patients? 5. Hew will patients anchor their parents or guardians be informed: a. That some of the procedures performed in the study may be irreversible? b. That following the performance of such procedures it would not be medically advisable for patients to withdraw from the study? c. That a willingness to cocperate in long-term follcw-up (for at least three to five years) will be a precondition for participation in the study? d. That a willingness to permit an autopsy to be performed in the event of a patient's death following treatment is also a precondition for a patient's participation in the study? [64] Recombinant DNA Research, Volume 1 1 (This stipulation is included because an accurate determination of the precise cause of a patient's death would be of vital importance to all future gene therapy patients.) E. Privacy and confidentiality Indicate what measures will be taken to protect the privacy of gene therapy patients and their families as well as to maintain the confi- dentiality of research data. 1. What provisions will be made to honor the wishes of individual patients (and the parents or guardians of pediatric or mentally handicapped patients) as to whether, when, or how the identity of patients is publicly disclosed? 2. What prevision will be made to maintain the confidentiality of research data, at least in cases where data could be linked to individual patients? Special Issues Although the following issues are beyond the normal purview of local IRBs, the RAC and its working group request that investigators respond to questions A and B below. A. What steps will be taken, consistent with point I-E above, to ensure that accurate information is made available to the public with respect to such public concerns as may arise fron the proposed study? Recombinant DNA Research, Volume 1 1 [65] B. Do you or your funding sources intend to protect under patent or trade secret laws either the products or the procedures developed in the pro- posed study? If so, what steps will be taken to permit as full ccmmuni- cation as possible among investigators and clinicians concerning research methods and results? III. Requested Documentation In addition to responses to the guestions raised in these "Points to Consider," please submit the following materials: A. Your protocol as approved by your local IRB and IBC. The consent form, which must have IRB approval, should be submitted to the NIH only on request. B. Local IRB and IBC minutes and reccmmendations that pertain to your protocol . C. A one-page scientific abstract of the gene therapy protocol. D. A one-page description of the proposed experiment in nontechnical language. E. Curricula vitae for professional personnel. F. An indication of other federal agencies to which the protocol is being submitted for review. G. Any other material which you believe will aid in the review. [ 66 ] Recombinant DNA Research, Volume 1 1 IV. Reporting Requirements A. Serious adverse effects of treatment should be reported immediately to both your local IRB and the NIH Office for Protection fran Research Risks, and a written report should be filed with both groups. A copy of the report should also be forwarded to the NIH Office of Recombinant CNA Activities (ORDA). B. Reports regarding the general progress of patients should be filed at six-month intervals with both your local IRB and OREA. These tw ice-yearly reports should continue for a sufficient period of time to allow observation of all major effects (at least three to five years). In the event of a patient's death, the autopsy report should be submitted to the IRB and OREA. Recombinant DNA Research, Volume 1 1 [ 67 ] 186A South Street Boston, MA 02111 (617) 423-0650 COMMITTEE FOR RESPONSIBLE GENETICS March 26, 1986 Advisory Board Nicholas Ashford. Ph.O. Hull* Balrd-Bimay. M.S. Roy L. Birrwt Jonathan Beckwith. Ph.O. Philip Baraano, J.O.' Eula Bingham. Ph.O. Oavid Brower Llab* Cavaliarl. Ph.O." Jotaph Colllna. Ph.O. Oonald Comb. Ph.O. Barry CommoMr, Ph.O. Molly Coy*. M.D. Osvid Ehranlald. Ph.O.. M.O. Email Englandar. Ph.O. Rich Englar Sam Epstein. Ph.O. Richard Falk. J.O. Rota Faldbarg. Ph.O. Marcut Faldman, Ph.O. Cary Fowlar (.oil Gibbs Tarri Goldberg" Richard Goldstein. Ph.O. Slephan Jay Gould. Ph.O. Colin Gracey* Eric Holtzman. Ph.O. •h Hubbard. Ph.O." ton Jcnsan 4ihan King. Ph.O." Sheldon Krimsky, Ph.O." Mare Lappa. Ph.O." Marvin Lagalor. Ph.O. Bruce Levin. Ph.O. Richard Lavins, Ph.O. Richard Lawonlin. Ph.O. Manning Marable. Ph.O. Anthony Mazzocchi* Evarail Mendelsohn. Ph.O. Albert Mayarhoff, J.O. Clair* Nader. Ph.O." Slush Newman, Ph.O." Oavid Noble. Ph.O. Judy Norsigian Richard Novick, Ph.O. Christina Oliver. M.O. David Ozonofl. M.O. Scon Paradis* Oavid Pimentel. Ph.O. Bernard Rapoport Barbara Rosenberg. Ph.O." Barbara Katz Rothman. Ph.O. Roger Shinn Victor Sldel. M.O. Helen Rodriguez-Trlas. M.O. John Vandermeer, Ph.O. George Wald. Ph.O. Nobel Lauraal* William Winpisinger Slav* Wodka Sidney Wolle. M.O. Susan Wright, Ph.O." "Esecullve Council Nachama L. Wilker Eseculiv* Otfdor William J. Cartland Director, Office of Recombinant DMA Activities Building 31, Room 3B10 National Institutes of Health Bethesda, Maryland 20205 (f) Dear Dr. Cartland: With proposals for human genetic therapy expected to be submitted to the RAC in the near future, the Committee for Responsible Genetics (CRG) believes it is necessary to define now, in advance, the types of gene therapy that will be considered and to rule out, categorically, those that would not be in the public Interest. We therefore propose an amendment to the NIH Guidelines, the wording of which is attached. In support of this amendment we submit the enclosed rationale, and request that it be published in the Federal Register together with the proposed amendment. Although the "Points to Consider" document, prepared by the RAC, states that germ-line therapy proposals will not be entertained by the RAC at present, it also states that the document will be frequently revised. We therefore believe that the restrictive provisions belong in the more permanent parent Guidelines rather than under "Points to Consider." Please let us know when the RAC will take up this proposal. [ 68 ] Recombinant DNA Research, Volume 1 1 J86A South Street Boston. MA 02111 (617) 423-0650 COMMITTEE FOR RESPONSIBLE GENETICS Advisory Board MicTvj*.* AaMowf. pko h«iw e4k« >o»vt(n«n pn o. RtvKb Bataano. J O.' EwM BingNam, PtvO. 0t«4 6<0r. Johnson . Dr. Davis commended Ms. Wilker for what he perceived to be a major shift in position between the original CRG submission and Ms. Wilker's statement before the RAC. Dr. Davis said Ms. Wilker’s use of the term "at this time" is a significant change from the original CRG position which he said he had found to be "ultra-conservative, somewhat resembling perhaps that of the more extreme fundamentalist kinds of religions which are so certain that they're right that there's no room for the kind of democratic process of pragmatic adjustment and shifts from time to time that we're acustomed to in our society." He said the issue now seemed to boil down to whether these issues should be dealt with in the NIH Guidelines or simply as it is at present in the "Points to Consider" document. Dr. Davis stated he agreed with Dr. Newman that it is now possible to instill genes into animal germ cells. However, since a very high percentage of the cells so treated fail and among those that are viable a certain percentage have grave defects introduced in them, no responsible medical researcher would want to undertake such experiments in humans at this time. Ms. Wilker said that CRG has brought the issue up so that public discussion can take place well in advance of the RAC receiving any such proposals, as opposed to discussing the matter while a proposal is on the table. Mr. Mitchell Recombinant DNA Research, Volume 1 1 [ 101 ] said that the Human Gene Therapy Subcommittee meetings are announced well ahead of time and are always open to the public; hopefully CRG members could attend the meetings. Ms. Wilker stated that she appreciates that the process is an open one, but the meetings are still somewhat limited because of their taking place in the Washington, D.C. area; there may be persons who desire to comment who are in other parts of the country. She said, "it's not a comment, necessarily, that the process as it is right now is a problem, but that the process needs to be expanded, and I’m not necessarily putting that in the purview of the RAC itself." Dr. Newman said "Dr. Davis said that the techniques would have to be very much better established in mice before it would be contemplated to do germline genetic engineering on humans, and that seems very much to miss the point that we put forward, which is that no matter how well established in mice these techniques became, to do it on human beings would be to make human beings and the human species as a whole into an experimental system because, of course, we'd have the progeny of genetically engineered individuals and this is precisely what we oppose." Dr. Miller stated that he believed several assertions made by the CRG were ill-chosen or inaccurate. He stated that even if the technology were available to attempt germline gene therapy, that the first attempts would very unlikely be aimed at enhancement or at attempted insertion in dominant genetic diseases, but rather would more likely be an attempt to intervene in recessive genetic diseases where there were two affected parents, homozygous recessives, and where the probability of producing affected off- spring would be 100 percent. Secondly, he believed it disingenuous to suggest there should be widespread consensus before the first human trials of a new technique. He pointed to the first clinical trials of the Jarvik artificial heart and oral contraceptives where the safety and efficacy were really unknown. He said the reason one does clinical trials is that the nuances of these techniques in man are not known, and cannot be known before they are done. This is the reason for stringent regulation by local Institutional Review Boards and central oversight by agencies such as the FDA. Ms. Wilker responded that the reason the CRG is raising these issues at this point in time is that they see the science on the threshhold of new development. They believe it is time for slow progress and for raising questions before moving ahead. She stated that there are certain technologies we use, such as low-dose radiation, in which we are still learning the risks and benefits. We should learn from our experience with these technologies and look closely at emerging technologies. Dr. Korwek stated he was generally opposed to proposals which set out prohibitory language such as, "the RAC will not... and the NIH will not.." If the aim of the CRG is to encourage open discussion, it would be rather better to leave the status quo. Further, he felt ambiguity contained in some of the CRG proposed language further clouds the issues of what is to be prohibited. Therefore, he was opposed to the proposal. Hearing no further comment, Mr. Mitchell called for a vote on the motion to accept the recommendations of the Human Gene Therapy Subcommittee as set forth in tab 1271 and as amended by tab 1278. With a vote of 18 in favor, none opposed, and one abstention, the motion was carried. Mr. Mitchell thanked the members of the CRG and hoped that they will attend future meetings of the Subcommittee on Human Gene Therapy. VH. PROPOSED AMENDED POINTS TO CONSIDER IN THE DESIGN AND SUBMISSION OF HUMAN SOMATIC-CELL GENE THERAPY PROTOCOLS Mr. Mitchell called on Dr. Walters to discuss the proposed amended "Points to Consider in the Design and Submission of Human Somatic-Cell Gene Therapy Protocols" (tabs 1262, 1272, 1273, 1276). Dr. Walters reminded the RAC that there had been a commitment made to review the "Points to Consider" at least annually for possible revision. He stated that tab 1272 specifies four changes which were proposed by the subcommittee at its August 8, 1986, meeting and is followed by a draft of the document incorporating these changes. Dr. Walters went through each of the changes with the RAC. He stated that there had been distributed to the RAC additional technical amendments which are, in part, a response to comments of one of the subcommittee members who could not be at the August 8, 1986, meeting. These amendments are: [ 102 ] Recombinant DNA Research, Volume 1 1 "Page 3, footnote 1: Revise and add to RNA. 'Section III-A-4 applies both to recombinant DNA and to DNA or RNA derived from recombinant DNA.' "Page 4, footnote 2: Update Federal Register reference, ’...please see the Federal Register . Volume 51. p. 23309-23313. 1986.’ "Page 10, part (b): Revise list of contaminating materials, '...eliminate any contaminating materials (for example, VL30 RNA, other nucleic acids, or proteins) or.„' "Page 10, part (c): Revise new point, so that it does not ask investigators to demonstrate the absence of something, '(c) If co-cultivation is employed, what kinds of cells are being used for co-cultivation? What steps are being taken (and assays used with their sensitivity) to detect and eliminate any contaminating materials? Specifically, what tests are being done to assess the material to be returned to the patient for the presence of live or killed donor cells or other non-vector materials (for example, VL30 sequences) originating from those cells?' "Page 10. part (d): Revise new point, so that it does not ask investigators to demonstrate absence, '(d) If methods other than those covered by a-c are used to introduce new genetic information into target cells, what steps are being taken to detect and eliminate any contaminating materials? What are...?* "Page 12, part b, third line: Add a word for clarification. In what percentage of cells does expression from ihs added DNA occur?” Dr. Walters moved that the RAC accept the revised "Points to Consider” at tab 1272 with the further technical amendments just discussed reflecting the recommendations of the Human Gene Therapy Subcommittee and its consultants. Dr. Epstein seconded the motion. Dr. Epstein noted that tab 1276 contains a number of suggestions from Dr. Howard Temin of McArdle Laboratory, University of Wisconsin, most of which were accepted, but one of which (page 6, line 1) was not. Dr. Temin had pointed out that it is possible that cells other than bone marrow cells might be used. Dr. Epstein stated Dr. Temin’s suggestion could be accomplished by eliminating the words "bone marrow" from this sentence which currently reads, "...e.g., by inserting a properly functioning gene into a patient's cells in vitro ..." Dr. Johnson and Dr. Pirone both noted that the language begins with "e.g." and is meant only as an example. Dr. Walters stated that if there were no qualifier on the phrase "into a patient's cells," it could be interpreted that this new gene could go into any cells including possibly germline cells or reproductive cells which is not the intention. Dr. Epstein agreed to drop this issue for now but requested the next time the subcommittee meets they consider changing this sentence to something like, "The purpose of somatic-cell gene therapy is to treat an individual patient's somatic cells," and then add examples if appropriate. Dr. Rapp asked the meaning of the term "contamination" in the new text which had been added as page 10, pan (d); Dr. Epstein replied it presumably meant the same as in pan (b) on the same page which had been previously defined. Dr. Neiman noted that in pan (c) on the same page the clarifying text, "(e.g., VL30 sequences)" appears. The motion was put to a vote by the Chair and was passed unanimously, by a vote of 19 in favor, none opposed, and no abstentions. Mr. Mitchell then called for any other business that any member desired to bring before the committee. Dr. Johnson asked about the committee appointed by the NIH Director to review the Pseudorabies vaccine field test and wondered if the panel had concluded their report. Dr. Talbot replied that the committee had not finished their work but that it was anticipated to be concluded within the next few weeks. Recombinant DNA Research, Volume 1 1 [ 103 ] Vm. FUTURE MEETING PATES Mr. Mitchell directed the committee's attention to tab 1275, a listing of future meeting dates, and reminded the members that the next two meetings of the RAC would take place on February 2, 1987, and June 15, 1987. Mr. Mitchell noted that the Institute of Medicine is planning a symposium on human gene therapy in Washington, D.C., on October 15-16, 1986, and noted Dr. Walters is playing a key role in the program. DC. ADJOURNMENT Mr. Mitchell called for any other announcements or business to come before the committee and hearing none asked for a motion to adjourn. The motion was made by Dr. Davis, seconded by Dr. Cohen, and after duly voting on the motion, Mr. Mitchell declared the meeting adjourned. Date: William J. Gartl^id, Jr., Ph.D. Executive Secretary I hereby certify that, to the best of my knowledge, the foregoing Minutes and Recombinant DNA Advisory Committee [ 104 ] Recombinant DNA Research, Volume 11 RECCMBINANT DNA ADVISORY COMMITTEE CHAIR MITCHELL, Robert E. , LL.B. (87) Attorney at Law 13915 San Antonio Drive Norwalk, California 90650 213 863-8736 BOWMAN, Barbara H. , Ph.D. (87) Professor Departure nt of Anatomy University of Texas San Antonio, Texas 78284 512 691-6441 CLOWES, Roys ton C., Ph.D. (86) Professor Division of Biology University of Texas at Dallas Richardson, Texas 75080 214 690-2501 COHEN, Mitchell L. , M.D. (88) Assistant Director for Medical Science Division of Bacterial Diseases Center for Infectious Diseases Centers for Disease Control Atlanta, Georgia 30333 404 329-3683 DAVIS, Bernard D. , M.D. (88) Di rector Bacterial Physiology Unit Harvard Medical School Boston, Massachusetts 02115 617 732-2022 EPSTEIN, Charles J., M.D. (89) Professor Department of Pediatrics, M-650 University of California San Francisco, California 94143 415 476-2981 Recombinant DNA Research, Volume 1 1 QOTTEEMAN, Susan K., Ph.D. Senior Investigator Laboratory of Molecular Biology National Cancer Institute, 37/4B09 National Institutes of Health Bethesda, Maryland 20892 301 496-3524 JOHNSON, Irving S. , Ph.D. Vice President Eli Lilly and Company Lilly Corporate Center Indianapolis, Indiana 46285 317 261-4391 JOKLIK, Wblfgang K., D.Phil. Professor & Chairman Department of Microbiology & Immunology Duke University Medical Center Durham, North Carolina 27710 919 684-5138 KOFWEK, Edward L. , Ph.D., J.D. Attorney at Law Law Office of Keller and Heckman 1150 17th Street, NW, Suite 1000 Washington, D.C. 20036 202 956-5621 MacNAUCHTON, J. Robert 9605 Weathered Oak Court Bethesda, Maryland 20817 301 469-6670 [105] ( 86 ) ( 88 ) ( 86 ) ( 88 ) (89) SEPTEMBER 1986 McGONIGLE, John F., M.D. (86) Physician 2001 Santa Monica Blvd., Suite 1000 Santa Monica, California 90404 213 829-6771 MILLS, Mark C., M.D. (86) Associate Pathologist Department of Pathology Good Samaritan Hospital Vincennes, Indiana 47591 812 882-5220 MUSGRAVE, Gerald L. , Ph.D. (89) President Economics America, Inc. 543 Church Street Ann Arbor, Michigan 48104 313 995-0865 NEIMAN, Paul E. , M.D. (89) Associate Director for Basic Sciences Fred Hutchinson Cancer Research Center 1124 Columbia Street Seattle, W&shington 98104 206 467-4417 PAGANO, Joseph S. , M.D. (89) Director Cancer Research Center University of North Carolina Chapel Hill, North Carolina 27514 919 966-3036 PIRONE, Thomas P., Ph.D. (87) Professor Department of Plant Pathology University of Kentucky Lexington, Kentucky 40506 606 257-2759 PRAMER, David, Ph.D. (88) Director Waksman Institute of Microbiology P.O. Box 759 Piscataway, New Jersey 08854 201 932-3068 [ 106 ] RAPP, Fred, Ph.D. (87) Professor & Chairman Department of Microbiology Pennsylvania State University Hershey, Pennsylvania 17033 717 534-8253 RCBERTS , Jeffrey W. , Ph.D. (89) Associate Professor Department of Biochemistry, Molecular and Cell Biology Cornell University Ithaca, New York 14853 607 256-2203 SHARPLES, Frances E. , Ph.D. (87) Research Associate Oak Ridge National Laboratory P.O. Box X, FEDC Building Oak Ridge, Tennessee 37831 615 576-0524 VI CAVER, Anne K., Ph.D. (88) Professor Department of Plant Pathology University of Nebraska Lincoln, Nebraska 68583 402 472-2858 WALTERS, LeRoy, Ph.D. (87) Director Center for Bioethics Kennedy Institute Georgetown University Washington, D.C. 20057 202 625-2386 WITHERBY, Anne R. , B.S. (87) 2 Cammonv^alth Avenue Boston, Massachusetts 02116 617 247-0123 EXECUTIVE SECRETARY GARTLAND, William J., Jr., Ph.D. Director Office of Recombinant CNA Activities National Institute of Allergy and Infectious Diseases, 31/3B10 National Institutes of Health Bethesda, Maryland 20892 301 496-6051 Recombinant DNA Research, Volume 1 1 NON-VOTING AGENCY REPRESENTATIVES DEPARTMENT OF AGRICULTURE (USDA) TOLIN, Sue A., Ph.D. Science & Education Administration Cooperative State Research Service Department of Agriculture 213 Justin S. Morrill Building W&shington, D.C. 20250 202 447-5741 SHIBLEY, George P., Ph.D. (ALT) Department of Agriculture Federal Building, Roan 839 6505 Belcrest Road Hyattsville, Maryland 20782 301 436-8674 FULKERSON, John F., Ph.D. (ALT) Science & Education Administration Cooperative State Research Service Department of Agriculture 213 Justin S. Morrill Building Washington, D.C. 20250 202 447-5741 DEPARTMENT OF COMMERCE GREIFER, Bernard, Ph.D. Regulatory & Legislative Analysis Division, Room H-4877 Office of Business Analysis Department of C amerce Washington, D.C. 20230 202 377-3078 SHY KIND, Edwin, Ph.D. (ALT) Trade Development, Room H-4045 International Trade Administration Department of Commerce Washington, D.C. 20230 202 377-4694 DEPARTMENT OF DEFENSE DALRYMPLE, Joel M. , Ph.D. Department of Viral Biology U.S. Army Medical Research Institute of Infectious Diseases Ft. Detrick Frederick, Maryland 21701-5011 301 663-2665 Recombinant DNA Research, Volume 1 1 [ 107 ] DEPARTMENT OF HEALTH AND HUMAN SERVICES (DHHS) DHHS Alcohol , Drug Abuse , and Mental Health Administration GERSHON, Elliot S. , M.D. Clinical Neurogenetics Branch Alcohol, Drug Abuse, and Mental Health Administration 9000 Rockville Pike, 10/3N-218 Bethesda, Maryland 20205 301 496-3665 AUTRY, Joseph H. , III, M.D. (ALT) Division of Extramural Research Prograns Alcohol, Drug Abuse, and Mental Health Administration Parklawn Building, Roan 10-105 Bethesda, Maryland 20857 301 443-3563 DHHS Centers for Disease Control (CPC) NOBLE, Gary R. , M.D. Office of the Director Building 1, Roan 2047 Centers for Disease Control Atlanta, Georgia 30333 404 329-3701 DHHS, CPC, National Institute for Occupational Safety and Health LEMEN, Richard A. National Institute for Occupational Safety & Health 4676 Columbia Parkway Cincinnati, Ohio 45226 513 684-8302 DHHS Food and Drug Administration MILLER, Henry I., M.D. Food and Drug Administration, HF-6 5600 Fishers Lane, Roam 14-90 Rockville, Maryland 20857 301 443-4650 DHHS Health Resources and Services Administration MANLEY, Audrey, M.D. Office of the Administrator Health Resources & Services Administration 5600 Fishers Lane, Roan 14-15 Rockville, MD 20857 301 443-2204 NUTTING, Paul (ALT) Office of Primary Care Studies Health Resources & Services Administration 5600 Fishers Lane, Roan 13-25 Rockville, MD 20857 301 443-6007 [ 108 ] Recombinant DNA Research, Volume 1 1 DEPARTMENT OF ENERGY D(JDA, George, Ph.D. Office of Health & Envir omental Research, EV-33 Department of Energy Washington, D.C. 20545 202 353-3651 EDINGTON, Charles W., Ph.D. (ALT) Office of Health & Environmental Research, ER-70 Department of Energy Washington, D.C. 20250 202 353-3251 DEPARTMENT OF TOE INTERIOR PIMENTEL, Mariano B., M.D. Division of Medical & Health Services, Roan 7045 Department of the Interior 18th & C Street, N.W. Washington, D.C. 20240 202 343-2081 DEPARTMENT OF LABOR YO DAI KEN, Ralph E. Office of Occupational Medicine USDOL/OSHA, Room N-3651 200 Constitution Avenue, N.W. Washington, D.C. 20210 202 523-7047 HAIMES, Stanley C. (ALT) Office of Occupational Medicine USDOL/OSHA, Roan N-3651 200 Constitution Avenue, N.W. Washington, D.C. 20210 202 523-7047 DEPARTMENT OF TRANSPORTATION CUSHIAC, George E. , Ph.D. Research & Special Programs Administration Department of Transportation 400 7th Street, S.W. Washington, D.C. 20590 202 426-2311 ENVIRONMENTAL PROTECTION AGENCY LEVIN, Morris, Ph.D. Office of Research & Development, RD-682 Environmental Protection Agency 401 M Street, S.W. Washington, D.C. 20460 202 382-5967 FCWLE, John R. , III, Ph.D. (ALT) Office of Research & Development, RD-689 Environmental Protection Agency 401 M Street, S.W. Washington, D.C. 20460 202 382-7335 Recombinant DNA Research, Volume 1 1 [ 109 ] MAZZA, Carl, Ph.D. (ALT) Office of Toxic Substances, TS-792 Environmental Protection Agency 401 M Street, S.W. Washington, D.C. 20460 202 382-3381 NATIONAL AERONAUTICS AND SPACE ADMINISTRATION DeVINCENZI, Donald L., Ph.D. Research & Technology Development, Code EBT-3 National Aeronautics & Space Administration Washington, D.C. 20546 202 755-3732 NATIONAL SCIENCE FOUNDATION HARRIMAN, Phillip, Ph.D. Physiology, Cellular, & Molecular Biology, Room 329 National Science Foundation Washington, D.C. 20550 202 357-9687 VETERANS ADMINISTRATION GREEN, Richard J., M.D: Medical Research Service, 151 Veterans Administration (VACO) 810 Vermont Avenue, N.W. Washington, D.C. 20420 202 389-5041 BERMAN, Howard M. (ALT) Medical Research Service, 151D Veterans Administration 810 Vermont Avenue, N.W. Washington, D.C. 20420 202 389-5065 [ 110 ] Recombinant DNA Research, Volume 1 1 LIAISON REPRESENTATIVES IINO, Professor Tetsuo La FONTAINE, Francois Department of Biology Science & Technology Faculty of Science Delegation of the Canmission University of Tokyo of the European Ccmmjnities Hongo, Tokyo 113 2100 M Street, M.W. , Suite 707 Japan Washington, D.C. 20037 JONES, Daniel P., Ph.D. Humanities, Science and Technology Division of Research Prograns National Endowment for the Humanities Washington, D.C. 20506 202 786-0207 202 862-9575 Recombinant DNA Research, Volume 1 1 [ 111 ] AD HOC CONSULTANT McGARRITY, Gerard J. , Ph.D. Department of Microbiology Coriell Institute for Medical Research Camden, New Jersey 08103 609 966-7377 [ 112 ] Recombinant DNA Research, Volume 1 1 SEPTEMBER 1986 STATEMENT OF NACHAMA L. WILKER EXECUTIVE DIRECTOR, COMMITTEE FOR RESPONSIBLE GENETICS BEFORE THE RECOMBINANT DNA ADVISORY COMMITTEE, NATIONAL INSTITUTES OF HEALTH SEPTEMBER 29, 1986 My name is Nachama Wilker, I am the Executive Director of the Committee for Responsible Genetics ( CRG ) . The Committee for Responsible Genetics is a national non-profit organization composed of scientists, public health and public policy professionals, trade unionists, bioethicists and other citizens with a track record of concern for the assessment of societal aspects in biotechnology. The CRG is dedicated to insuring the development of biotechnology that allows for broad public participation. We appreciate the opportunity to appear before you today to share our comments on our proposal to modify section III-A-4 of the NIH guidelines. I would like to address my comments today to three issues that have been raised by the Working Group on Human Gene Therapy in response to our proposal: 1) Why draw the line for genetic engineering of somatic cells at life threatening or severely disabling conditions? 2) Why make a distinction between the Points to Consider document and the more permanent Recombinant DNA Research, Volume 1 1 [113] guidelines? and 3) What role does public discussion play in policy determination? The use of somatic cell therapy, like any other new therapy, has certain unknown and unpredictable risks and benefits associated with its use. We urge a clear statement that, until more is known about the risks involved with the use of somatic cell therapy, human models for risk assessment are developed only for people who have no other options. With this proposal, we are not attempting to distinguish this form of treatment from any other new form of treatment per se, but merely to recognize that we are at the threshold of a new development and should proceed in a manner that is cautious and draws on our past experiences. The "Points to Consider in the Design and Submission of Human Somatic-Cell Gene Therapy Protocols" document addresses many of the difficult ethical and social issues raised by the use of human gene therapy. However, although the document is very specific about not entertaining proposals for germ-line therapy at the present time, it is only a recommendation on how to proceed with a submission of a proposal, and not the articulation of a binding policy. Germ-line manipulation, unlike somatic cell therapy, represents a qualitative leap in the use of genetic [114] Recombinant DNA Research, Volume 1 1 modification of the human species, and moves us into the realm of human experimentation on the newly born or the unborn. Once this realm has been entered, the National Research Act of 1984 requires that informed consent is necessary to carry out these experiments. The notion of informed consent, however, is not a meaningful one for future generations. The proposed additions to the permanent guidelines before you today would be a clear and unambigious policy statement of the RAC's position on germ-line therapy. By limiting an area of research at this time when significant ethical and social questions remain unresolved, the RAC will make a clear statement of public record that human germ-line experiments should not be done at this time. What will RAC do if it receives a proposal for altering human germ line cells? What mechanism will the IRB's or the RAC use to evaluate informed consent for future generations? We argue in favor of an explicit statement in the guidelines that a major review, including public discussion, would be needed before any such proposal would be considered. Although the current review system, based on submission of proposals, may be appropriate for evaluating some forms of somatic cell therapy, it is premature and inadequate to use these same mechanisms for germ- line therapy experiments. Recombinant DNA Research, Volume 1 1 [115] Experiments involving the manipulation of human germ-line cells pose sufficiently important ethical and social questions that they require the kind of discussion necessary to alter a section of the guidelines , not merely a recommendation on how to proceed with a specific proposal. My final point concerns public participation in these decisions. From my experience as the Director of a public interest organization that receives numerous phone calls and letters on this issue from a wide representation of people, my reading of concern of the individuals we are in contact with is that there is: 1) not a significant amount of public opposition to somatic therapy for life threatening or severely disabling conditions, 2) a greater concern for use of somatic therapy for mild disorders and, 3) a feeling of grave apprehension of germ line alterations. The process of review in the United States for these types of experiments is the most open of any industrialized nation, and for that we can be proud. But, we still have not devised a mechanism for concerned citizens to participate in the discussion of germ line therapy, where the greatest moral issues reside. There exists a significant difference between an open process — in this situation one characterized by sparse public attendance of meetings held exclusively in Washington, D.C., and the publication of a proposal in the [ 116 ] Recombinant DNA Research, Volume 1 1 Federal Register — and a fully realized public discourse. A fully realized public discussion, such as now exists for the siting of nuclear power plants and for abortion, requires that people have a better understanding of: 1) what human gene therapy would involve and, 2) how it might affect them in their own lives. Look for a moment at the response of the citizens of Monterey County to a proposed release of a genetically engineered organism into their community. If the local government and community had been previously notified and involved in a discourse or decision about the release, would the same series of events have occurred? Unlike our example in Monterey County, the nuclear debate and the abortion controversy have been characterized by a more democratic process. In the case of human germ-line therapy, this process would involve: 1) more media attention, 2) readable documents that people can understand and talk about — and here we commend the efforts of the Working Group to make a readable guide to the Points to Consider — 3) ways to disseminate the information, and 4) forums in which people are motivated to express their opinion, for example, by writing to their representative in Congress. If a time comes when there is a broad social consensus to use germ line therapy, after a debate such as the one I have Recombinant DNA Research, Volume 1 1 [117] outlined, there is no reason to believe that these guidelines cannot be altered, as the guidelines have been altered numerous times in the past. There have been many instances in which the guidelines prohibited certain classes of experiments until more was known about the risks. The existence of those prohibitions did not restrict policy discussions about these types of experiments, nor did they close off certain areas of inquiry. On behalf of the Committee for Responsible Genetics, I would like to thank you for this opportunity to share our concerns, and to bring this proposal before you today. [ 118 ] Recombinant DNA Research, Volume 1 1 NATIONAL INSTITUTES OF HEALTH POINTS TO CONSIDER IN THE DESIGN AND SUBMISSION OF HUMAN SOMATIC-CELL GENE THERAPY PROTOCOLS HUMAN GENE THERAPY SUBCOMMITTEE NIH RECOMBINANT CNA ADVISORY COMMITTEE OUTLINE Applicability Introduction I. Description of Proposal A. Objectives and rationale of the proposed research B. Research design, anticipated risks and benefits 1. Structure and characteristics of the biological system 2. Preclinical studies, including risk assessment studies 3. Clinical procedures, including patient monitoring 4. Public-health considerations 5. Qualifications of investigators, adequacy of laboratory and clinical facilities C. Selection of patients D. Informed consent E. Privacy and confidentiality 23/3 September 29, Recombinant DNA Research, Volume 1 1 [119] II. Special Issues A. Provision of accurate information to the public B. Timely ccmunication of research methods and results to investigators and clinicians III. Requested Documentation A. Original protocol B. IRB and IBC minutes and recommendations C. One-page abstract of gene therapy protocol D. One-page description of proposed experiment in non-technical language E. Curricula vitae for professional personnel F. Indication of other federal agencies to which the protocol is being submitted G. Other pertinent material IV. Reporting Requirements [ 120 ] Recombinant DNA Research, Volume 1 1 NATIONAL INSTITUTES OF HEALTH POINTS TO CONSIDER IN THE DESIGN AND SUBMISSION OF HUMAN SOMATIC-CELL GENE THERAPY PROTOCOLS Applicability - These "Points to Consider" apply only to research conducted at or sponsored' by an institution that receives any support for recombinant DNA research from the National Institutes of Health (NIH). This includes research performed by NIH directly. Introduction (1) Experiments in which recombinant DNA^- is introduced into oells of a human subject with the intent of stably modifying the subject's genome are covered by Section III-A-4 of the NIH Guidelines for Research Involving Recombinant DNA Molecules (49 Federal Register 46266). Section III-A-4 requires such experiments to be reviewed by the NIH Recombinant DNA Advisory Carmittee (RAC) and approved by the NIH. RAC consideration of each proposal will be on a case-by-case basis and will follow publication of a precis of the proposal in the Federal Register , an opportunity for public oamment, and a review of the proposal by the working group of the RAC. RAC recommendations on each proposal will be forwarded to the NIH Director for a decision which will then be published in the Federal Register . In accordance with Section IV-C-l-b of the NIH Guidelines, the NIH Director may approve proposals only if he finds that they present "no significant risk to health or the environment." (2) In general, it is expected that somatic-cell gene therapy protocols will not present a risk to the environment as the recombinant DNA is expected to be confined to the human subject. Nevertheless, Section I-R-4-b of the "Points to Consider" document asks the researchers to address specif ically this point. 1 Sect ion III-A-4 applies both to recombinant DNA and to Dt& or RLA derived from recombinant DNA. . „ ,_ n/ . September 29, 1986 [ 121 ] Recombinant DNA Research, Volume 1 1 (3) This document is intended to provide guidance in preparing proposals for NIH consideration under Section III-A-4 of the NIH Guidelines for Research Involving Recombinant DN^ Molecules. Not every point mentioned in the "Points to Consider"* document will necessarily require attention in every proposal. The document will be considered for revision as experience in evaluating proposals accumulates and as new scientific developments occur. This review will be carried out at least annually. (4) A proposal will be considered by the RAC only after the protocol has been approved by the local Institutional Biosafety Committee (IBC) and by the local Institutional Review Board (IRB) in accordance with Department of Health and Human Services (DHHS) Regulations for the Protection of Human Subjects (45 Code of Federal Regulations, Part 46). If a proposal involves children, special attention should be paid to subpart D of these DHHS regulations. The IRB and IBC may, at their discretion, condition their approval on further specific deliberation by the RAC and its working group. Consideration of gene therapy proposals by the RAC may proceed simultaneously with review by any other involved federal agencies^ provided that the RAC is notified of the simultaneous review. Meetings of the coamittee will be open to the public except where trade secrets or proprietary information would be disclosed. The committee would prefer that the first proposals submitted for RAC review contain no proprietary information or trade secrets, enabling all aspects of the review to be open to the public. The public review of these protocols will serve to inform the ^The Food and Drug Administration (FDA) has jurisdiction ever drug products in- tended for use in clinical trials of human somatic-cell gene therapy. For general information on FCA's policies and regulatory requirements, please see the Federal Register , Volume 51, pages 23309-23313. 1986. Recombinant DNA Research, Volume 1 1 [ 122 ] public not only on the technical aspects of the proposals but also on the meaning and significance of the research. (5) The clinical application of recombinant DNA techniques to human gene therapy raises two general kinds of questions: (1) the questions usually discussed by IRBs in their review of any proposed research involving human subjects; and (2) broader social issues. The first type of question is addressed principally in Part I of this document. Several of the broader social issues surrounding human gene therapy are discussed later in this Introduction and in Part II below. (6) Following the Introduction, this document is divided into four parts. Part I deals with the short-term risks and benefits of the proposed research to the patient^ and to other people, as well as with issues of fairness in the selection of patients, informed consent, and privacy and confidentiality. In Part II, investigators are requested to address special issues pertaining to the free flow of information about clinical trials of gene therapy. These issues lie outside the usual purview of IRBs and reflect general public concerns about biomedical research. Part III summarizes other requested documentation that will assist the RAC and its working group in their review of gene therapy proposals. Part IV specifies reporting requirements. (7) A distinction should be drawn between making genetic changes in somatic cells and in germ line cells. The purpose of somatic cell gene therapy is to treat an individual patient, e.g., by inserting a properly functioning •^The term "patient" and its variants are used in the text as a shorthand designation for "oatient-subiect ." Recombinant DNA Research, Volume 1 1 [123] gene into a patient's bone marrow cells hi vitro and then reintroducing the cells into the patient's body. In germ line alterations, a specific attempt is made to introduce genetic changes into the germ (reproductive) cells of an individual, with the aim of changing the set of genes passed on to the individual's offspring. The RAC and its working group will not at present entertain proposals for germ line alterations but will consider for approval protocols involving somatic-cell gene therapy. (8) The acceptability of human scmatic-cell gene therapy has been addressed in several recent public documents as well as in numerous academic studies. The November 1982 report of the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Splicing Life , resulted from a two-year process of public deliberations and hearings; upon release of that report, a House subcommittee held three days of public hearings with witnesses from a wide range of fields from the biomedical and social sciences to theology, philosophy, and law. In December 1984, the Office of Technology Assessment released a background paper. Human Gene Therapy , which brought these earlier documents up-to-date. As the latter report concluded: "Civic, religious, scientific, and medical groups have all accepted, in principle, the appropriateness of gene therapy of somatic cells in humans for specific genetic diseases. Somatic cell gene therapy is seen as an extension of present methods of therapy that might be preferable to other technologies." [ 124 ] Recombinant DNA Research, Volume 1 1 (9) Concurring with this judgment, the RAC and its working group are prepared to consider for approval scmatic-cell therapy protocols, provided that the design of such experiments offers adequate assurance that their consequences will not go beyond their purpose , which is the same as the traditional purpose of all clinical investigations, namely, to benefit the health and well-being of the individual being treated while at the same time gathering general- izable knowledge. (10) Two possible undesirable consequences of somatic-cell therapy would be unintentional (1) vertical transmission of genetic changes from an individual to his or her offspring or (2) horizontal transmission of viral infection to other persons with wham the individual cones in contact. Accordingly, this document requests information that will enable the RAC and its working group to assess the likelihood that the proposed scmatic-cell gene therapy will inadvertently affect reproductive cells or lead to infection of other people (e.g., treatment personnel or relatives). (11) In recognition of the social concern that surrounds the general discussion of human gene therapy, the working group will continue to consider the possible long-range effects of applying knowledge gained fran these and related experiments. While research in molecular biology could lead to the development of techniques for germ line intervention or for the use of genetic means to enhance human capabilities rather than to correct defects in patients, the working group does not believe that these effects will follow immediately or inevitably from experiments with somatic-cell gene therapy. The working group will cooperate with other groups in assessing the possible long-term consequences of scmatic-cell gene therapy Recombinant DNA Research, Volume 1 1 [125] and related laboratory and animal experiments in order to define appropriate human applications of this energing technology. (12) Responses to the questions raised in these "Points to Consider" should be provided in the form of either written answers or references to specific sections of the protocol or its appendices. I. Description of Proposal A. Objectives and rationale of the proposed research State concisely the overall objectives and rationale of the proposed study. Please provide information on the following specific points: 1. Vfriy is the disease selected for treatment by means of gene therapy a good candidate for such treatment? 2. Describe the natural history and range of expression of the disease selected for treatment. What objective and/or quantitative measures of disease activity are available? In your view, are the usual effects of the disease predictable enough to allow for meaningful assessment of the results of gene therapy? 3. Is the protocol designed to prevent all nan ifes tat ions of the disease, to halt the progression of the disease after symptcms have begin to appear, or to reverse manifestations of the disease in seriously ill victims? 4. What alternative therapies exist? In what groups of patients are these therapies effective? Wiat are their relative advantages and disadvantages as compared with the proposed gene therapy? [ 126 ] Recombinant DNA Research, Volume 1 1 B. Research design, anticipated risks and benefits 1 . Structure and characteristics of the biological system Provide a full description of the methods and reagents to be employed for gene delivery and the rationale for their use. The following are specific points to be addressed: a. Vhat is the structure of the cloned CNA that will be used? (1) Describe the gene (genanic or cDNA) , the bacterial plasmid or phage vector, and the delivery vector (if any). Prcvide complete nucleotide sequence analysis or a detailed restriction enzyme map of the total construct. (2) Vhat regulatory elements does the construct contain (e.g., promoters, enhancers, polyadenylation sites, replication origins, etc.)? (3) Describe the steps used to derive the CNA construct. b. Vhat is the structure of the material that will be administered to the patient? (1) Describe the preparation, structure, and composition of the materials that will be given to the patient or used to treat the patient's cells. (a) If CNA, what is the purity (both in teams of being a single DNA species and in terns of other contaminants)? Recombinant DNA Research, Volume 1 1 [127] What tests have been used and what is the sensitivity of the tests? (b) If a virus, how is it prepared from the DNA construct? In what cell is the virus grown (any special features)? What medium and serum are used? How is the virus purified? What is its structure and purity? What steps are being taken (and assays used with their sensitivity) to detect and eliminate any contaminating materials (for example, VL30 RNA, other nucleic acids, or proteins) or contaminating viruses or other organisms in the cells or serum used for preparation of the virus stock? (c) If co-cultivation is employed, what kinds of cells are being used for co-cultivation? What steps are being taken (and assays used with their sensitivity) to detect and eliminate any contaminating materials? Specifically, what tests are being done to assess the material to be returned to the patient for the presence of live or killed donor cells or other non-vector materials (for exanple, VL30 sequences) originating from those cells? (d) If methods other than those covered by (a)-(c) are used to introduce new genetic information into target cells, what steps are being taken to detect and eliminate any [128] Recombinant DNA Research, Volume 1 1 contaminating materials? What are possible sources of contamination? What is the sensitivity of tests used to monitor contamination? (2) Describe any other material to be used in preparation of the material to be administered to the patient. For example, if a viral vector is proposed, what is the nature of the helper virus or cell line? If carrier particles are to be used, what is the nature of these? 2. Preclinical studies, including risk-assesgnent studies Describe the experimental basis (derived f ran tests in cultured cells and animals) for claims about the efficacy and safety of the proposed system for gene delivery. a. Laboratory studies of the delivery system (1) What cells are the intended recipients of gene therapy? If recipient cells are to be treated hi vitro and returned to the patient, how will the cells be characterized before and after treatment? What is the theoretical and practical basis for assuminq that only the treated cells will act as recipients? (2) Is the delivery system efficient? What percentage of the target cells oontain the added DNA? (3) How is the structure of the added DNA sequences monitored and what is the sensitivity of the analysis? Is the added Recombinant DNA Research, Volume 1 1 11291 DNA extrachromosomal or integrated? Is the added DNA un rearranged? (4) How many copies are present per oell? How stable is the added Dt& both in terms of its continued presence and its structural stability? b. Laboratory studies of gene expression Is the added gene expressed? To what extent is expression only from the desired gene (and not from the surrounding DNA)? In what percentage of cells does expression from the added DNA occur? Is the product biologically active? What percentage of normal activity results from the inserted gene? Is the gene expressed in cells other than the target cells? If so, to what extent? c. Laboratory studies pertaining to the safety of the delivery/ expression system (1) If a retroviral system is used: (a) Wiat cell types have been infected with the retroviral vector preparation? Which cells, if any, produce infectious particles? (b) How stable are the retroviral vector and the resulting provirus against loss, rearrangement, recombination, or mutation? What information is available on how much rearrangement or recombination with endogenous or other [130] Recombinant DNA Research, Volume 1 1 viral sequences is likely to occur in the patient’s cells? What steps have been taken in designing the vector to minimize instability or variation? What laboratory studies have been performed to check for stability, and what is the sensitivity of the analyses? (c) What laboratory evidence is available concerning poten- tial harmful effects of the treatment, e.g., development of neoplasia, harmful mutations, regeneration of infectious particles, or inmune responses? Vhat steps have been taken in designing the vector to minimize pathogenicity? Vhat laboratory studies have been performed to check for pathogenicity, and what is the sensitivity of the analyses? (d) Is there evidence frcm animal studies that vector CNA has entered untreated cells, particularly germ line cells? What is the sensitivity of the analyses? (e) Has a protocol similar to the one proposed for a clin- ical trial been carried out in non-human primates and/ or other animals? Wi at were the results? Specifically, is there any evidence that the retroviral vector has recombined with any endogenous or other viral sequences in the animals? (2) If a non-retrcviral delivery system is used: Vhat animal studies have been done to determine if there are Datholooical Recombinant DMA Research, Volume 1 1 [131] or other undesirable consequences of the protocol (including insertion of CNA into cells other than those treated, particularly gem line cells)? How long have the animals been studied after treatment? What tests have- been used and what is their sensitivity? 3. Clinical procedures, including patient monitoring Describe the treatment that will be administered to patients and the diagnostic methods that will be used to monitor the success or failure of the treatment. If previous clinical studies using similar methods have been performed by yourself or others, indicate their relevance to the proposed study. a. Will cells (e.g., bone marrow cells) be removed from patients and treated vitro in preparation for gene therapy? If so, what kinds of cells will be removed fran the patients, how many, how often, and at what intervals? b. Will patients be treated to eliminate or reduce the number of cells containing malfunctioning genes (e.g. , through radiation or chemotherapy) prior to gene therapy? c. What treated cells (or vector /Df& combination) will be given to patients in the attempt to administer gene therapy? How will the treated cells be administered? What volume of cells will be used? Will there be single or multiple treatments? If so, over what period of time? [132] Recombinant DNA Research, Volume 1 1 d. What are the clinical endpoints of the study? Are there objective and quantitative measurements to assess the natural history of the disease? Will such measurements be used in following' your patients? How will patients be monitored to assess specific effects of the treatment on the disease? What is the sensitivity of the analyses? How frequently will follow-up studies be done? How long will patient follow-up continue? e. What are the major potential beneficial and adverse effects of treatment that you anticipate? What measures will be taken in an attempt to control or reverse these adverse effects if they occur? Canpare the probability and magnitude of potential adverse effects on patients with the probability and magnitude of deleterious consequences from the disease if gene therapy is not performed. f. If a treated patient dies, vhat special studies will be performed as part of the autopsy? 4. Public-health considerations Describe any potential benefits and hazards of the proposed therapy to persons other than the patients being treated. Specifically: a. On what basis are potential public health benefits or hazards postulated? b. Is there a significant likelihood that the added DNA will spread from the patient to other persons or to the environment? [133] Recombinant DNA Research, Volume 1 1 c. What precautions will be taken against such spread (e.g., to patients sharing a room, health-care workers, or family members)? d. What measures will be undertaken to mitigate the risks, if any, to public health? 5. Qualif ications of investigators, adequacy of laboratory and clinical facilities Indicate the relevant training and experience of the personnel who will be involved in the preclinical studies and clinical administra- tion of gene therapy. In addition, please describe the laboratory and clinical facilities where the proposed study will be performed. a. What professional personnel (medical and nonmedical) will be involved in the proposed study? What are their specific quali- fications and experience with respect to the disease to be treated and with respect to the techniques employed in molecular biology? Please provide curricula vitae (see Section III-E). b. At what hospital or clinic will the treatment be given? Which facilities of the hospital or clinic will be especially important for the proposed study? Will patients occupy regular hospital beds or clinical research center beds? Where will patients reside during the follow-up period? Selection of patients Estimate the number of patients to be involved in the proposed study of gene therapy. Describe recruitment procedures and patient eligibility I Recombinant DNA Research, Volume 1 1 requirements, paying particular attention to whether these procedures and requirements are fair and equitable. 1. How many patients do you plan to involve in the proposed study? 2. How marry eligible patients do you anticipate being able to identify each year? 3. What recruitment procedures do you plan to use? 4. fohat selection criteria do you plan to employ? What are the exclusion and inclusion criteria for the study? 5. How will patients be selected if it is not possible to include all who desire to participate? D. Informed consent Indicate how patients will be informed about the proposed study and how their consent will be solicited. The consent procedure should adhere to the requirements of CHHS regulations for the protection of human subjects (45 Code of Federal Regulations, Part 46). If the study involves pediatric or mentally handicapped patients, describe procedures for seeking the permission of parents or guardians and, where applicable, the assent of each patient. Areas of special concern highlighted below include potential adverse effects, financial costs, privacy, and long-term follow-up. 1. How will the major points covered in Sections I-A through I-C of this document be disclosed to potential participants in this study [135] Recombinant DNA Research, Volume 1 1 and/or parents or guardians in language that is understandable to them? 2. How will the innovative character and the theoretically-possible adverse effects of gene therapy be discussed with patients and/or parents or guardians? How will the potential adverse effects be compared with the consequences of the disease? What will be said to convey that some of these adverse effects, if they occur, could be irreversible? 3. What explanation of the financial costs of gene therapy and any available alternative therapies will be provided to patients and/or parents or guardians? 4. How will patients and/or their parents or guardians be informed that the innovative character of gene therapy may lead to great interest by the media in the research and in treated patients? 5. Hew will patients and/or their parents or guardians be informed: a. That some of the procedures performed in the study may be irreversible? b. That following the performance of such procedures it would not be medically advisable for patients to withdraw from the study? c. That a willingness to cooperate in long-term follow-up (for at least three to five years) will be a precondition for participation in the study? [136] Recombinant DNA Research, Volume 1 1 d. That a willingness to permit an autopsy to be performed in the event of a patient's death following treatment is also a precondition for a patient's participation in the study? (This stipulation is included because an accurate determination of the precise cause of a patient's death would be of vital importance to all future gene therapy patients.) E. Privacy and confidentiality Indicate what measures will be taken to protect the privacy of gene therapy patients and their families as well as to maintain the confi- dentiality of research data. 1. What provisions will be made to honor the wishes of individual patients (and the parents or guardians of pediatric or mentally handicapped patients) as to whether, when, or how the identity of patients is publicly disclosed? 2. What provision will be made to maintain the confidentiality of research data, at least in cases where data could be linked to individual patients? Special Issues Although the following issues are beyond the normal purview of local IRBs, the RAC and its working group request that investigators respond to questions A and B below. Recombinant DNA Research, Volume 1 1 [137] A. What steps will be taken, consistent with point I-E above, to ensure that accurate information is made available to the public with respect to Such public concerns as may arise from the proposed study? B. Do you or your funding sources intend to protect under patent or trade secret laws either the products or the procedures developed in the pro- posed study? If so, what steps will be taken to permit as full communi- cation as possible among investigators and clinicians concerning research methods and results? III. Requested Documentation In addition to responses to the questions raised in these "Points to Consider," please submit the following materials: A. Your protocol as approved by your local IRB and IBC. The consent form, which must have IRB approval, should be submitted to the NIH only on request. B. Local IRB and IBC minutes and recommendations that pertain to your protocol. C. A one-page scientific abstract of the gene therapy protocol. D. A one-page description of the proposed experiment in nontechnical language. E. Curricula vitae for professional personnel. F. An indication of other federal agencies to which the protocol is being submitted for review. [ 138 ] Recombinant DIMA Research, Volume 1 1 G. Any other material which you believe will aid in the review. Reporting Requirements A. Serious adverse effects of treatment should be reported immediately to both your local IRB and the NIH Office for Protection from Research Risks, and a written report should be filed with both groups. A copy of the report should also be forwarded to the NIH Office of Recombinant DNA Activities (ORDA). B. Reports regarding the general progress of patients should be filed at six-month intervals with both your local IRB and ORDA. These twice- yearly reports should continue for a sufficient period of time to allow observation of all major effects (at least three to five years). In the event of a patient's death, the autopsy report should be submitted to the IRB and ORDA. Recombinant DNA Research, Volume 1 1 [ 139 ] Federal Register / Vol. 51, No. 209 / Wednesday, October 29, 1986 / Notices 3S5S9 on November 19 from 9:00 a.m. to adjournment. Dated: October 21, 1906. Betty J. Beveridge, Committee Management Officer. N1H. [FR Doc. 86-24381 Filed 10-28-86; 8:45 am] BILUNG CCOE 4140-01-U National Institute of Dental Research; Meeting Eoard of Scientific Counselors Pursuant to Pub. L. 92-463, notice is hereby given of the meeting of the Board of Scientific Counselors, National Institute of Dental Research (NIDR), on December 3-5, 1986, in Conference Room 117, Building 30, National Institutes of Health, Bethesda, Maryland. The meeting will be open to the public from 9:00 a.m. to recess on December 3 and from 9:00 a.m. to 12:00 Noon on December 4, to discuss program policies and issues. Attendance by the public will be limited to space available. In accordance with the provisions set forth in section 552b(c)(6), Title 5, U.S. Code and section 10(d) of Pub. L. 92-483, the meeting will be closed to the public from 1:00 p.m. to recess on December 4 and from 9:00 a.m. to adjournment on December 5 for the review, discussion, and evaluation of individual programs and projects conducted by the NIDR, including consideration of personnel qualifications and performance, and the competence of individual investigators, the disclosure of which would constitute a clearly unwarranted invasion of personal privacy. Dr. Abner Notkins, Director of Intramural Research, NIDR, NIH, Building 30, Room 132, Bethesda, MD 20892 (telephone 301-496-1483) will provide a summary of the meeting, roster of committee members and substantive program information. Dated: Octobe|,2V 1986. Betty J. BeveriiteaL y NIH Committeefyhnagement Officer. [FR Doc. 86-24379 Filed 10-28-S6; 8:45 am] BILLING CODE 4140-C1-M Recombinant DNA Advisory Committee Working Group on Definitions; Meeting Pursuant to Pub. L. 92-463, notice is hereby given of a meeting of a Recombinant DNA Advisory Committee Working Croup on Definitions at the Marriott Hotel, Kenwood Room. 5151 Pooks Hill Road, Bethesda, Maryland 20314, on December 5, 1985, from approximately 9:00 a.m. to adjournment at approximately 5:00 p.m. to discuss the definitions of "deliberate release" and "recombinant DNA" under the NTH Guidelines for Research Involving Recombinant DNA Molecules. This meeting will be open to the public. Attendance by the public will be limited to space available. Further information may be obtained from Dr. William J. Gartland. Exceutive Secretary, Recombinant DNA Advisory Committee Working Group on Definitions, National Institutes of Health, Building 31, Room 3B10, Bethesda, Maryland telephone (301) 496-6051. Dated: October 22. 1938. Betty J. Beveridge, Committee Management Officer, NIH. OMB's "Mandatory Information Requirements for Federal Assistance Program Announcements" (45 FR 39592) requires a statement concerning the official government programs contained in the Catalog of Federal Domestic Assistance. Normally NIH lists in its announcements the number and title of affected individual programs for the guidance of the public. Because the guidance in this notice covers not only virtually every NIH program but also essentially every Federal research program in which DNA recombinant molecule techniques could be used, it has been determined to be not cost effective or in the public interest to attempt to list these programs. Such a list would likely require several additional pages. In addition, NIH could not be certain that every Federal program would be included as many federal agencies, as well as private organizations, both national and international, have elected to follow the NIH Guidelines. In lieu of the individual program listing, NIH invites readers to- direct questions to the information address above about whether individual programs listed in the Catalog of Federal Domestic Assistance are affected. [FR Doc. 86-24330 Filed 10-28-66:8:45 am] BILLING CODE 41O-01-M DEPARTMENT CF THE INTERIOR Bureau of Lanp filanagement [MT-070-07-435 1— iVl ] Off-Read Designations; Montana AGENCY: Bureau of Land Management, Butte District Office, Interior. action: Notice of off-road vehicle designation decision. summary: Decision Notice is hereby given relating to the use of off-road vehicles on public lands in accordance with the authority and requirements of Executive Orders 11644 and 11989, and regulations contained in 43 CFR Part 8340. The following described lands under the administration of the Bureau of Land Management are designated as limited to off-road motorized vehicles use pursuant to the provisions of 43 CFR 8342.1. Affected by the designation are approximately 14,750 acres of public lands in the Garnet Resource Area. The lands are managed under the Garnet Resource Management Plan dated September 1985. They are located in Powell County and are part of the Warm Springs Creek Road Management Area and the Indian Creek/Gallagher Creek- Walk-in Hunting Area. Included are all public lands east of the Brock Creek and Windy Rock roads including public lands in the following sections: Township 11 North, Range 10 West. Sections 14, 24, 26 and 34; Section 15: EVi; Section 22: EVi; Section 28: SVhSEW Township 10 North, Range 10 West, Sections 1, 2, 10, 12 and 24; Section 4: NEVi. Township 11 North, Range 9 West, Sections 18, 20, 28, 30 and 34. Township 10 North, Range 9 West, Sections, 4, 6, 9 and 18. All public lands in the Warm Springs road closure are closed to all motorized vehicles except for authorized administrative uses from April 1 through November 30. All public lands east of the Hoodoo Mountain fire road are closed to all motorized vehicles except for authorized administrative uses from September 1 through November 30. Included are public lands in the following sections: Township 12 North. Range 10 West. Sections 25, 28, 27, 33. 34 and 35. Township 11 North, Range 10 West, Sections 1, 2, 3, 10, 11 and 12. Township 11 North, Range 9 West. Section 8. Detailed maps showing the location of the above-described designations are available from the offices listed below. ADDRESS: for further information about these designations, contact either of the following Bureau of Land Management offices: [140] Recombinant DNA Research, Volume 1 1 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE NATIONAL INSTITUTES OF HEALTH RECOMBINANT DNA ADVISORY COMMITTEE WORKING GROUP ON DEFINITIONS MINUTES OF MEETING 1 DECEMBER 5, 1986 The Wbrkinq Group on Definitions of the Recombinant ENA Advisory Committee was convened at 9:00 a.m. on December 5, 1986, at the Marriott Hotel, Kenwood Roam, 5151 Books Hill Road, Bethesda, Maryland, 20814. Dr. Gerard McGarrity was Chair. The following were present for all or part of the meeting: Working Group members : John Scandal ios Frances Sharpies Anne Vidaver William Gartland (Executive Secretary) A working group roster is attached (Attachment I). Other National Institutes of Health staff: Susan Gottesman Susan Hirano Irving Johnson Edward Korwek Myron Levine Gerard McGarrity Paul Neinan Thcmas Pi rone David Pramer Monica Riley Stanley Bar ban, NIAID Others : M. Brad lev Flynn, Department of Agriculture Charles J. Eby, Monsanto Company Rebecca J. Goldburg, Environmental Defense Fund Alan Goldhanmer , Industrial Biotechnology Association Jaimes Kaper, University of Maryland, Baltimore Elizabeth Milewski, Environmental Protection Agency Henry Miller, Food and Drug Administration David Moore, Association of American Medical Colleges Greg Pearson, Blue Sheet George Shibley, Department of Agriculture Janet Shoemaker, American Society for Microbiology Michael A. Swit, Burditt, Bowles & Radzius, Chartered william Szkryba.lo, Pharmaceutical Marufacturers Association Sue TOlin, Department of Agriculture L. F. Wright, Pfizer, Inc. lThe working group is advisory to the RAC, and its recommendations should not be considered as final or accepted. Recombinant DNA Research, Volume 1 1 [ 141 ] I. Definition of Deliberate Release. Dr. McGarrity called the meeting to order and asked the observers to introduce themselves. He restated the charge to the working group and sunmarized the actions taken at the September 5, 1986, meeting of the working group. He noted that the Recombinant DNA Advisory Committee (RAC) had recommended approval of Dr. Gottesman's proposed amendment of Section III-A-2 of the National Institutes of Health (NIH) Guidelines for Research Involving Recombinant DMA Molecules at its meeting on September 29, 1986. However, the NIH Director has not yet acted on this recommendation. The RAC referred the other recommendations back to the working group for further consideration. Dr. Gartland summarized a meeting on environmental release issues sponsored by the National Research Council at Millwood, VA, on October 27-28, 1986. He also summarized the conclusions and distributed a ccpy of the Report of the Committee to Review Allegations of Violations of the NIH Guidelines for Research Involving Recombinant ENA Molecules in the Conduct of Field Tests of a Pseudorabies Vaccine at Baylor College of Medicine and/or Texas A&M University. In response to a question. Dr. Milewski of the Environmental Protection Agency (EPA) stated that the purpose of the meeting of the EPA Biotechnology Science Advisory Committee subcommittee on environmental release on December 11-12, 1986, is to prepare several options for the definitions of "deliberate release" for use in EPA rulemaking procedures. The working group agreed to focus on matters pertaining to NIH and leave integration of agency decisions to the Biotechnology Science Coordinating Committee. Dr. Vidaver then suggested that a second sentence be added to the definition of "deliberate release" which she had proposed at the September 5, 1986, meeting. The two sentences to be added to Section III-A-2 would read as follows : "The term 'deliberate release' is defined as a planned introduction of recombinant DNA-containing microorganisms, plants, or animals into the environment. This is the experimental use of microorganisms, plants, or animals under conditions considered to be accepted scientific practice." The appendices to be developed would incorporate the accepted practices. Drs. Korwek and Gottesman questioned how unplanned introductions would be treated if this definition is adopted. Drs. McGarrity and Vidaver pointed out that these sentences would be added to Section III-A-2, and the heading of Section III-A, "Experiments That Require RAC Review and NIH and IBC Approval Before Initiation," indicates that Section III-A-2 applies to experimental releases. Dr. McGarrity said that these sentences would presumably be added to the end of Dr. Gottesman's proposed revision of Section III-A-2. Dr. Sharpies then proposed an alternative rewrite of Section III-A-2 as follows: [ 142 ] Recombinant DNA Research, Volume 1 1 "III-A-2. Environmental applications conducted without physical [and biological] containment of any organism containing recombinant ENA, except : "a. Certain plants as described in Appendix L. "b. Deletion derivatives not otherwise covered by these Guidelines. "c. Organisms covered in exemption III-D-2." Dr. Johnson then moved that the two sentences of Dr. Vidaver be added at the end of the proposed further revision of Section III-A-2. After further discussion, Dr. Johnson amended his motion and moved adoption of Dr. Vidaver's first sentence for inclusion in Section III-A-2. The working group accepted the motion by a vote of 11 in favor, none cpoosed , and 1 abstention. Dr. Gottesman then moved that Dr. Vidaver's second sentence be placed under "a" and that Section III-A-2 be revised to read in its entirety as follows: "III-A-2. Deliberate release into the environment of any organism containing recombinant DMA except those listed below. The term 'deli- berate release' is defined as a planned introduction c£ recombinant DNA-containing microorganisms, plants, or animals into the environment. "a. Introductions conducted under conditons considered to be accepted scientific practices in which there is adequate evidence of biological and/or physical control of the recombinant ENA-containing organisms. The nature of such evidence is described in Appendices L, M, N, and 0. "b. Deletion derivatives not otherwise covered by these Guidelines. "c. Organisms covered in exemption III-D-2." Dr. Johnson seconded the motion and the working group passed the motion by a vote of 10 in favor, 1 opposed, and 1 abstention. Dr. Tolin stated that the U.S. Department of Agriculture will be proposing material for inclusion in Appendices L, M, and N. II. Vaccine Development. Dr. Levine presented information to the working group on development of several different varieties of live bacterial vaccines (Attachment II). He said that phase 1 studies of vaccines made by recombinant ENA techniques can be carried out in very closed facilities, but that mechanisms are needed to permit phase 2 and 3 clinical trials which may involve thousands of individuals. He pointed out that non-recanbinant live attenuated vaccines are tested with no special constraints and predicted that superior and more precise vaccines will be made by recombinant DNA techniques. Recombinant DNA Research, Volume 1 1 [143] Dr. Gottesman pointed out that there are already procedures in the NIH Guidelines for approval by other Federal agencies of experiments falling under Section III-A. Presumably these clinical trials would be submitted to the Food and Drug Administration under Investigational New Drug (IND) procedures. Dr. Korwek pointed out that there could be a problem with pre-human testing in animals since an IND is not required at this stage. He said this could be addressed in an appendix to the NIH Guidelines. Dr. Gottesman then moved that: (1) investigators in the field of vaccine development be apprised of the options for exemption from RAC review as specified in paragraph two of Section III-A, and (2) that a working group be organized to develop criteria and procedures for inclusion in an Appendix 0 (Vaccines) of Section III-A-2. The motion passed by a vote of 11 in favor, none opposed, and no abstentions. It was the sense of the working group that Appendix 0 cover vaccines, and that Appendix N ccver microorganisms other than vaccines. III. Definition of Recombinant DNA. In response to a question by Dr. Neiman, Dr. Gartland summarized why the working group had been asked to consider the definition of "recombinant DNA." Dr. Korwek questioned the reasons for reconsidering this definition. Dr. Gottesman said that she is not aware that the definition needs to be changed to take into account any specific experiments. Dr. Korwek said that since Section III-A-2 of the NIH Guidelines will presumably be revised to handle deletion derivatives, he favored not changing the basic definition c£ recombinant DNA. Dr. Riley said she felt it is important to exclude some things from the defintion. She then moved the following amendment of a sentence proposed by Dr. Landy for inclusion in Section I-B at the September 5, 1986, working group meeting: "Genomes which contain only deletions, duplications, transpositions, single-base changes, or rearrangements are not considered to be recombinant ENA irrespective of the method by vhich they were produced. Products of translocations within genomes are considered to be recombinant DNA." Dr. Riley said that this wording would make a distinction between trans- positions and translocations which had not been made earlier. Dr. Korwek questioned why these concerns could not be handled as exemptions. Dr. Gottesman noted that these types of experiments are already exempt in the laboratory. An alternative approach to achieve the same end would be to reword "b" and "c" in a revised Section III-A-2. Dr. Neiman said that these concepts about deletions, etc., pertain particularly to microorganisms, but he did not feel that this revision of the definition would be generally accepted by those in the scientific community vho (teal with more complex organisms with more stable genomes. [ 144 ] Recombinant DNA Research, Volume 1 1 Dr. Gottesman noted that deletions, etc., are already exempt in Section III-D unless they also fall under Section III-A. An alternative approach would be to broaden "b" and "c" in the revised Section III-A-2. Dr. Vidaver suggested that the word "foreign" be added to the current definition in (i) in Section I-B. It was pointed out that- "foreign" would have to be defined in a footnote. Dr. Riley withdrew her motion, and Dr. Gottesman then moved that the following possible changes in the definition of recombinant DNA be presented to the RAC for consideration: 1. The first paragraph of Section I-B would be revised to read as follows (new words in underlined): "In the context of these Guidelines, recombinant ENA molecules are defined as either: (i) molecules which are constructed outside living cells by joining foreign natural or foreign synthetic ENA segments to DNA molecules that can replicate in a living cell, or (ii) ENA molecules that result fran the replication of those described in (i) above. 2. The following new footnote would be added: "Rearrangements involving the introduction of DNA from different organisms or different strains of an organism will be considered recombinant ENA. Deletions, sirgl e-base changes, and rearrangements within a single gencme will not involve the introduction of foreign ENA and therefore would not be considered recombinant DNA." Several members expressed reservations about changing the definition of recanbinant DNA and the rationale for such a fundamental change in the NIH Guidelines. The vote on the motion was 5 in favor, 2 opposed, and 3 abstentions. The working group then voted on the proposal itself, i.e., on the desirability of making these proposed changes in Section I-B and the addition of a footnote. The vote was 2 in favor, 5 opposed, and 3 abstentions. After further discussion, Dr. Gottesman moved the following: "The working group agreed with the concept that certain types of recombinant DNA experiments which do not involve the introduction of foreign ENA need not be subjected to special regulation as 'recombinant DNA.' The vrorking group were split as to whether they preferred dealing with this problem by changing the definition of recombinant ENA or by further modifications of the exemptions (e.g., those in III-A-2). 2 ■^Executive Secretary's Note: The latter part of this sentence was changed by NIH staff to read: "...or by further modifications of other sections of the Guidelines (e.g., those in III-A-2)." in the version published for comment in the Federal Register of December 19, 1986 (51 FR 45650). Recombinant DNA Research, Volume 1 1 [ 145 ] Therefore, the working group presents the following two options for public comment and RAC consideration: "1. Change definition of recanbinant DNA: "The first paragraph of Section I-B would be revised to read as follows (new words underlined): "In the context of these Guidelines, recanbinant ENA molecules are defined as either: (i) molecules which are constructed outside living cells by joining foreign natural or foreign synthetic DNA segments to DNA molecules that can replicate in a living cell, or (ii) DNA molecules that result fran the replication of those described in (i) above. "The following new footnote would be added at the word 'foreign': "Rearrangements involving the introduction of DNA frcm different organisms or different strains of an organism will be considered recombinant DNA. Deletions, single-base changes and rearrangements within a single gencme will not involve the introduction of foreign DNA and therefore would not be considered recanbinant DNA." "2. Modify Section III-A-2 to read as follows: "III-A-2. Deliberate release into the environment of any organisn containing recanbinant ENA except those listed below. The term 'deliberate release' is defined as a planned introduction of recanbinant DNA-containing microorgan ims, plants, or animals into the environment. "a. Introductions conducted under conditions considered to be accepted scientific practices in which there is adequate evidence of biological and/or physical control of the recombinant DNA-containing organisms. The nature of such evidence is described in Appendices L, M, N, and 0. "b. Deletion derivatives and single base changes not otherwise covered by the Guidelines. "c. Rearrangements and amplification within a single gencme. Rearrange- ments involving the introduction of DNA frcm different strains of the same organism would not be covered by this exemption." After voting 9 in favor, 1 opposed, and no absentions on the first sentence of the motion, the working group voted 9 in favor, none opposed, and 1 [146] Recombinant DNA Research, Volume 1 1 abstention that these options be published for comment in the Federal Register and considered by the RAC. The working group members then voted on their preference for Option 1 or 2. The vote for Option 1 , i.e., a change in the definition of recanbinant CNA was 2 in favor, 7 cpposed, and 1 abstention. The vote, for Option 2, i.e., modification of Section III-A-2, was 6 in favor, 2 opposed, and 2 abstentions. Dr. Neiman then moved that the vote taken earlier in the day on what is now Option 1 be superseded by the vote on the proposal to publish for ccmment and present to the RAC both Options 1 and 2. The vote was 9 in favor, none opposed, and one abstention. IV. Adjournment. The meeting of the working group was adjourned at 3:40 p.m. Respectfully submitted, Executive Secretary I hereby certify that, to the best of my knowledge, the foregoing Minutes and Attachments are accurate and /complete. / Date Working Group on Definitions Recombinant DNA Research, Volume 1 1 [ 147 ] RECOMBINANT DNA ADVISORY COMMITTEE WORKING GROUP ON EEFINITIONS CHAIR: MoGARRITY, Gerard J., Ph.D. Department of Microbiology Coriell Institute far Medical Research Camden, New Jersey 08103 609 966-7377 GCOTESMAN, Susan K. , Ph.D. Laboratory of Molecular Biolcgy National Cancer Institute, 37/4B09 National Institutes of Health Bethesda, Maryland 20892 301 496-3524 HIRANO, Susan S. , Ph.D. Department of Plant Pathology University of Wisconsin Madison, Wisconsin 53706 608 262-7236 JOHNSON, Irving S. , Ph.D. Vice President Eli Lilly and Company Lilly Corporate Center Indianapolis, Indiana 46285 317 261-4391 KOFS'JEK, Edward L. , Ph.D., J.D. Attorney at Law Law Office of Keller and Heckman 1150 17th Street, NW, Suite 1000 Washington, D.C. 20036 202 956-5621 LANDY, Arthur, Ph.D. Division of Biology & Medicine Brcwn University Providence, Rhode Island 02912 401 863-2566 [ 148 ] LEVINE, M^ron M., M.D. Center for Vaccine Development Division of Infectious Diseases University of Maryland School cf Medicine Baltimore, MD 21201 301 528-7588 MITCHELL, Robert E. , LL.B. Attorney at Law 13915 San Antonio Drive Norwalk, California 90650 213 863-8736 NEIMAN, Paul E. , M.D. Associate Director for Basic Sciences Fred Hutchinson Cancer Research Center 1124 Columbia Street Seattle, Washington 98104 206 467-4417 PIRDNE, Thomas P. , Ph.D. Department cf Plant Pathology University of Kentucky Lexington, Kentucky 40506 606 257-2759 PRAMER, David, Ph.D. Waksman Institute of Microbiology P.O. Box 759 Piscatavay, New Jersey 08854 201 932-3068 Recombinant DNA Research, Volume 1 1 15/40 EECEMBER 1986 RILEY, Monica, Ph.D. Department of Biochemistry State University of New York Stony Brook, New York 11794 516 246-5047 SCANDALIOS, John G. , Ph.D. Department of Genetics, P.0 Box 7614 North Carolina State University Raleiqh, North Carolina 27695-7614 919 737-7079 SHARPLES, Frances E. , Ph.D. P.O. Box X, FEDC Building Oak Ridge National Laboratory Oak Ridge, Tennessee 37 831 615 576-0524 VI CAVER, Anne K. , Ph.D. Department of Plant Pathology University of Nebraska Lincoln, Nebraska 68583-0722 402 472-2858 EXECUTIVE SECRETARY GARTLAND, William J., Jr., Ph.D. Office of Recombinant ENA Activities National Institute of Allergy and Infectious Diseases, 31/3B10 National Institutes of Health Bethesda, Maryland 20892 301 496-6051 Recombinant DNA Research, Volume 1 1 [149] RAC SUBCOMMITTEE MEETING ON DEFINITIONS Description of Varieties of Live Bacterial Vaccines that Should be Exempt from Guidelines and from Restrictions on "Deliberate Release" The application of modern biotechnology to vaccine devlopment during the past five years has resulted in the appearance of many candidate vaccines. These include improved vaccines against diseases for which immunizing agents already exist as well as new vaccines against diseases which were heretofore without i rnmunopr ophy lactic control measures. Many of the vaccines reaching the point of clinical trials consist of live, attenuated genet i cal 1 y-eng i neer ed bacteria, modified by means of recombinant DNA technology. Certain of the live bacterial vaccines for human and veterinary use that are prepared by recombinant DNA technology should be exempt from the Guidelines and should not require RAC approval or environmental impact statements from federal agencies prior to initiating clinical studies. These varieties of vaccines are reviewed below, along with suggestions for certain characteristics that the strains should possess. 1) "Self-Destructing" Bacterial Vaccines One method of attenuating enteric bacterial pathogens is by means of modifying the production of certain enzymes in the Leloir pathway. As a consequence, grown in the presence of certain substrates, the mutant [ 150 ] Recombinant DNA Research, Volume 1 1 bacteria autolyze as a result of the accumulation of intermediate products of metabolism that cannot be further processed. The best examples of this prototype bacterial vaccine are the attenuated Sal monel 1 a t yph i and Sal monel 1 a t yph i mur i urn gal E mutant strains that have a complete lack of the enzyme UDF'-gal ac t ose-4-ep i rner ase . Ty21a, a gal E mutant of S. t yph i isolated in the early 1970s after chemical mutagenesis, has shown the advantages of this variety of attenuation. Grown in the presence of galactose, which results in the production of smooth 1 i popol ysacchar i de 0 antigen, this vaccine strain is safe, immunogenic and protective but is also rarely recoverable from coprocultures. Large-scale field trials in Egypt and Chile, involving more than 600,000 schoolchildren, have demonstrated the safety and efficacy of the Ty21a live oral typhoid vaccine. Ty21a is presently licensed in many countries of Europe, Latin America, Asia and Africa and is expected to be licensed shortly in the U.S.A. Following ingestion of doses of this live oral vaccine containing circa 1—3 billion viable organisms, the vaccine is not recoverable from copr ocul tur es . This is a consequence of the method of attenuation. Gal E mutants of S. typhi . S. t yph i mur i urn . and Sh i gel 1 a f 1 exner i have been prepared by recombinant DNA techniques, by means of deletions of the gal E gene. These vaccines have distinct potential advantages over chemically mutagenized strains and clinical evaluations of the safety and i mmunogeni c i ty of these vaccine candidates should therefore be expedited. Self-destructing, non-t r ansmi ssi b 1 e vaccine strains of the above variety should be exempt from the guidelines. It should be recommended, however, that vaccine candidates of this variety should contain a marker such as a resistance to Hg++ ions, a stable biochemical marker, or resistance to a clinically irrelevant antibiotic, to allow ready Recombinant DNA Research, Volume 1 1 [151] identification of the vaccine strain and its di f f er ent i at i on from wild type strains. 2) Auxotrophic Strains Another approach by which bacterial pathogens may be suitably attenuated to serve as live vaccine strains is to render them auxotrophic for substrates that are unavailable in the human or animal tissues or body fluids. The best examples of this variety of attenuation are the Aro- derivatives of S. t yph i and S. t yphi mur i urn . These mutants have deletions of the Ar o A gene rendereing them unable to persist in the mammalian body because of the lack of 2,3, dihydroxybenzoate. As a consequence these attenuated mutants cannot proliferate to reach high numbers in the mammmal i an host and cause disease but they persist sufficiently long to stimulate immune responses. Arc- mutants of S. t yph i mur i urn have been shown to be safe and protective vaccines in mice and cattle, while the safety and immunogenic ity of an Arc-, Pur- S. t yphi vaccine strain (541Ty) has recently been demonstrated in Phase 1 clinical studies in man. Auxotrophic mutants can be prepared by recombinant DNA technology, as well as by the classical genetic techniques (using phages to create the deletions) employed to prepare 541Ty. These mutants should possess some stable marker allowing them to be clearly discernable from wild type or gani sms . 3) Proven Attenuated Bacteria Acting as "Carrier" Strains to Express Cloned Genes of other Organisms Attenuated S. typhi strain Ty21a, because of its record of safety and its stimulation of both cel 1 -medi ated as well as humoral immune responses, [ 152 ] Recombinant DNA Research, Volume 1 1 is being used to carry and express cloned genes of critical, putatively protective antigens of other organisms. For example, modified Ty21a expressing the plasmid-encoded 0 antigen of S. sonnei and Ty21a expressing the cloned genes for Vibrio cholerae 01 serotype Inaba have been prepared. Known attenuated strains, such as Ty21a, carrying cloned genes from other organisms should be excluded from the guidelines, as long as the introduced genes do not encode a potent holotoxin. 4) Strains with Deletions of Chromosomal Genes Encoding Critical Virulence Properties For some bacterial pathogens, a chromosomal gene product is an absolute necessity for full expression of pathogenicity. One such example is V. chol er ae 01. The severe diarrheal purging characteristic of cholera gravis is the consequence of the effects of cholera enterotoxin which consists of five B (binding) subunits and one A (biologically active, ADF'-r i bosyl at i ng ) subunit. Ingestion of minute amounts (5 meg) of purified cholera enterotoxin can result in severe purging. Similarly, deletion of the genes encoding the A subunit renders the mutant unable to cause cholera gravis. An example of such a vaccine strain is CVD 103, a genetically-engineered A-B+ mutant of a V. cholerae classical Inaba strain. CVD 103 does not cause severe diarrhea, is highly immunogenic and is highly protective. Live vaccines attenuated by the deletion of critical virulence properties should also be exempt, as long as they have a stable marker to di f f er en t i at e them from wild type strains and particularly if they have a further mutation in the r ec A gene. The latter defect virtually assures that DNA introduced by conjugation will not be incorporated into the Recombinant DNA Research, Volume 1 1 [153] vaccine genome. 5) Vaccine Strains Expressing CRM Toxoids Another approach is to modify the toxin genes of organisms in which toxin is the critical virulence property and where antitoxin is important in protection so that the mutant elaborates a biologically inactive albeit immunogenic toxoid molecule (so-called cross-reacting molecule or CRM). Such mutants should have stable markers and should ideally be rec A minus strains or their equivalent. 6) Bacteria with Plasmids Having Deletions of Critical Virulence Genes For some bacteria the critical virulence genes are plasmid-encoded and often two distinct genes (for example encoding ST and colonization fimbriae) are adjacent. Vaccine strains containing plasmids having deletions of critical virulence genes should also be exempt from the gui del i nes. [154] Recombinant DNA Research, Volume 1 1 45650 Federal Register / Vol. 51. No. 244 / Friday. December 19, 1986 / Notices DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes Of Health Recombinant DNA Advisory Committee; Meeting Pursuant to Pub. L 92—163. notice is hereby given of a meeting of the Recombinant DNA Advisory Committee at the National Institutes of Health. Building 1. Wilson Hall. 9000 Rockville Pike. Bethesda. Maryland 20892. on February 2. 1987, from approximately 9 a.m. to adjournment at approximately 5 p.m. This meeting will be open to the public to discuss: Amendment of Guidelines; and other matters to be considered by the Committee. Attendance by the public will be limited to space available. Members of the public wishing to speak at the meeting may be given such an opportunity at the discretion of the Chair. Dr. William ). Gartland. Executive Secretary. Recombinant DNA Advisory Committee. National Institutes of Health. Building 31. Room 3B10, Bethesda. Maryland, telephone (301) 496-0051, will provide materials to be discussed at the meeting, rosters of committee members, and substantive program informa ton. A summary of the meeting will be available at a later date. OMB's "Mandatory Information Requirements for Federal Assistance Program Announcements" (45 FR 39592) requires a statement concerning the official government programs contained in the Catalog of Federal Domestic Assistance. Normally NIH lists in its announcements the number and title of affected individual programs for the guidance of the public. Because the guidance in this notice covers not only virtually every NIH program but also essenttally every Federal research program in which DNA recombinant molecule techniques could be used, it has been determined to be not cost effective or in the public interest to attempt to list these programs. Such a list would likely require several additional pages. In addition. NIH could not be certain that every Federal program would be included as many federal agencies, as well as private organizations, both national and international, have elected to follow the NIH Guidelines. In lieu of the individual program listing. NIH invites readers to direct questions to the information address above about whether individual programs listed in the Catalog of Federal Domestic Assistance are affected. Dated: December 10. 1986. Betty |. Beveridge. Committee Management Officer. NIH. (FR Doc. 86-26441 Filed 12-8-86: 8:45 ami BtUJNO COO€ 414O-01-M Recombinant DNA Research: Proposed Actions Under Guidelines aqency: National Institutes of Health, PHS. DHHS. action: Notice of proposed actions under NIH guidelines for research involving recombinant DNA molecules. summary: This notice sets forth proposed actions to be taken under the National Institutes of Health (NIH) Guidelines for Research Involving Recombinant DNA Molecules. Interested parties are Invited to submit comments concerning these proposals. These proposals will be considered by the Recombinant DNA Advisory Committee (RAC) at its meeting on February 2. 1987. After consideration of these proposals and comments by the RAC. the Director of the National Institutes of Health will issue decisions on these proposals in accord with the Guidelines. date Comments received by January 22. 1987. will be reproduced and distributed to the RAC for consideration at its February 2. 1987. meeting. aooress: Written comments and recommendations should be submitted to the Director. Office of Recombinant DNA Activities. Building 31. Room 3B10, National Institutes of Health. Bethesda. Maryland 20892. All comments received in timely response to this notice will be considered and will be available for public inspection in the above office on weekdays between the hours of 8:30 • a.m. and 5:00 p.m. FOR FURTHER INFORMATION: Background documentation and additional information can be obtained from the Office of Recombinant DNA Activities. National Institutes of Health. Bethesda. Maryland 20892 (301) 498- eosi. SUPPLEMENTARY INFORMATION: The NIH will consider the following actions under the NIH Guidelines for Research Involving Recombinant DNA Molecules. I. Proposed Amendments of Sections I- A and III— A of the NIH Guidelines Dr. Bernard Talbot. Deputy Director. National Institute of Allergy and Infectious Diseases, has requested that the following proposed amendments of the NIH Guidelines and rationale be published for comment and considered by the RAC: The current NIH Guidelines for Research Involving Recombinant DNA Molecules (Guidelines) contain the following text in section III— A of the Guidelines. If the experiments in this category are submitted for review to another Federal agency, the submitter shall notify ORDA: ORDA may then determine that such review serves the same purpose, and based on that determination, notify the submitter that no RAC review will take place, no NIH approval is necessary, and the experiment may proceed upon approval from the other Federal agency. This text appears in section III— A of the Guidelines and is applicable only to experiments covered by Section UI-A. It requires that: (1) An investigator who has submitted a proposal to another Federal agency notify the NIH Office of Recombinant DNA Activities (ORDA); (2) ORDA determine if the review serves the same purpose (as NIH review); (3) and. if so. ORDA notify the aubmitter that the experiment may proceed upon approval from the other Federal agency. On June 26. 1988. the Office of Science and Technology Policy published in the Federal Register (51 FR 23302) a “Coordinated Framework for Regulation of Biotechnology." it contains a Preamble, followed by Statements of Policy from the Food and Drug Administration. Environmental Protection Agency, U.S. Department of Agriculture. Occupational Safety and Health Administration, and the National Institutes of Health. The Preamble states that. ... for coniained federally funded research for biomedical and agricultural purposes, research approval will be granted by the funding agency. . . . Jurisdiction for release may be under SAE. NSF, APHIS, or EPA. There is no mention in the June 26 Federal Register document of any requirement, once approval for a recombinant DNA experiment is obtained from a Federal agency other than NIH. for communication with the NIH Office of Recombinant DNA Activities. And indeed, I believe that the absence of such a requirement should be the case: not only for experiments covered by Section III— A of the Guidelines, but for all recombinant DNA experiments. Therefore. I propose the following changes in the NIH Guidelines for Research Involving Recombinant DNA Molecules. 1. Delete from section III— A of the Guidelines the following paragraph: If the experiments in this category are submitted for review to another Federal [ 155 ] Recombinant DNA Research, Volume 1 1 Federal Register / Vol. 51, No. 244 / Friday, December 19, 1986 / Notices 45651 agency, the submitter shall notify ORDA; ORDA may then determine that such review serves the same purpose, and based on that determination, notify the submitted that no RAC review will take place, no N1H approval is necessary, and the experiment may proceed upon approval from the other Federal agency. 2. Add at the end of section I-A of the Guidelines the following paragraph: Any recombinant DNA experiment which according to these Guidelines requires approval by the National Institutes of Health (NIH). may be sent by the submitter to the N1H or to another Federal agency that has jurisdiction for review and approval. Once approval for a recombinant DNA experiment has been given by a Federal agency other than the NIH (whether referred to that agency by the NIH. or sent directly there by the submitter), the experiment may proceed without the necessity for NIH review or approval. II. Proposed Revision of Section UI-A-2 of the NIH Guidelines Section III-A-2 of the NIH Guidelines currently reads as follows: III-A-2. Deliberate release into the environment of any organism containing recombinant DNA, except certain plants as described in Appendix L At its meeting on September 29, 1986, the RAC voted to recommend that section III-A-2 be revised to read as follows: III-A-2. Deliberate release into the environment of any organism containing recombinant DNA except: a. Certain plants as described in Appendix L b. Deletion derivatives not otherwise covered by these Guidelines. c. Organisms covered in exemption ui-d-2. This recommendation has not yet been acted upon by the Director, NIH, and therefore has not yet been incorporated into the NIH Guidelines. The RAC Working Group on Definitions met on December 5, 1986, and recommended that section III-A-2 be amended to read as follows: III-A-2. Deliberate release into the environment of any organism containing recombinant DNA except those listed below. The term “deliberate release" is defined as a planned introduction of recombinant DNA-containing microorganisms, plants, or animals into the environment. a. Introductions conducted under conditions considered to be accepted scientific practices in which there is adequate evidence of biological and/or physical control of the recombinant DNA-containing organisms. The nature of such evidence is described in Appendices L. M, N. and O. b. Deletion derivatives not otherwise covered by these Guidelines. c. Organisms covered in exemption III-D-2. It was the intent of the working group that Appendix L would be the current Appendix L dealing with plants with future changes to be recommended by the RAC. Appendices M, N, and O would be parallel sections, to be written, covering respectively animals, microorganisms other than vaccines, and vaccines. The minutes of the December 5, 1986, meeting of the working group will be available prior to the February 2. 1986. RAC meeting. m. Proposed Revision of Section I-B or Section m-A-2 of the NIH Guidelines The RAC Working Group on Definitions at its meeting on December 5, 1986, passed the following motion with regard to the definition of recombinant DNA: The working group agreed with the concept that certain types of recombinant DNA experiments which do not involve the introduction of foreign DNA need not be subjected to special regulation as “recombinant DNA." The working group were split as to whether they preferred dealing with this problem by changing the definition of recombinant DNA or by further modifications of other sections of the Guidelines (e.g- those in IH-A-2). Therefore, the working group presents the following two options for public comment and RAC consideration: 1. Change definition of recombinant DNA: "The first paragraph of section I-B would be revised to read as follows (new words in italics): In the context of these Guidelines, recombinant DNA molecules are defined as either (i) molecules which are constructed outside living cells by joining foreign natural or foreign synthetic DNA segments to DNA molecules that can replicate in a living cell, or (ii) DNA molecules that result from the replication of those described in (i) above. The following new footnote would be added at the word “foreign": Rearrangements involving the introduction of DNA from different organisms or different strains of an organism will be considered recombinant DNA. Deletions, single-base changes and rearrangements within a single genome will not involve the introduction of foreign DNA and therefore would not be considered recombinant DNA. 2. Modify Section III-A-2 to read as follows: III-A-2. Deliberate release into the environment of any organism containing recombinant DNA except those listed below. The term "deliberate release” is defined as a planned introduction of recombinant DNA-containing micro- organisms. plants, or animals into the environment. a. Introductions conducted under conditions considered to be accepted scientific practices in which there is adequate evidence of biological and/or physical control of the recombinant DNA-containing organisms. The nature of such evidence is described in Appendices L, M. N, and O. b. Deletion derivatives and single base changes not otherwise covered by the Guidelines. c. Rearrangements and amplification within a single genome. Rearrangements involving the introduction of DNA from different strains of the same organism would not be covered by this exemption. The minutes of the December 5, 1986, meeting of the Working Group on Definitions will be available prior to the February 2, 1986, RAC meeting. IV. Proposed Revisions of Appendices C-II, C-m, and C-IV Dr. Frank E. Young, Commissioner of Food and Drugs, has submitted the following proposed revisions of Appendices C-H, C-QI, and C-IV, and rationale: On June 26, 1986, a major statement of federal policy, the "Coordinated Framework for Regulation of Biotechnolgy”, was published (51 FR 23301-93). We believe that important clarifications of regulatory policy are to be found there, but that some minor changes in the NIH Guidelines are required for consistency and clarity. As noted on page 23304 of the June 28 document. Appendices C-H. C-M, and C-IV of the NIH Guidelines contain the statement that: For large-scale (LS) fermentation experiments BLl-LS physical containment conditions are recommended. However, following review by the IBC of appropriate data for a particular host-vector system, some latitude in the application of 3L1-LS requirements as outlined in Appendix K-II-A through K-II-F is permitted. The document continues: The appropriate large-scale containment requirements for many low-risk [r]DNA derived industrial microorganisms will be no greater than those appropriate for the unmodified parental organisms. Together, these statements imply that the actions of fBCs should ensure that requirements for physical containment of low-risk microorganisms should be appropriately minimal, i.e., only those that are employed routinely for organisms such as E. coli K-12, B. subtilis, or Saccharomyces cerevisiae. It should be noted that industrial Recombinant DNA Research, Volume 1 1 [ 156 ] 45652 Federal Register / Vol. 51, No. 244 / Friday. December 19. 1986 / Notices fermentation has a long and distinguished history and currently accounts for products valued at more than $2 billion annually (attachment Tables 1-7). All but a minuscule proportion of this production employs non-pathogenic organisms and is carried out safely under conditions significantly less restrictive than the N1H Guidelines' BLl-LS, which requires that recombinant organisms be handled in a closed system, that culture fluids containing viable organisms not be removed from a closed system, that exhaust gases removed from a closed system be treated by Alters equivalent to HEPA Alters, etc. To ensure compliance with the NIH Guidelines, the £. coJi and Saccharomyces cerevisiae production organisms used to manufacture the Ave DNA-derived pharmaceuticals approved by FDA (human insulin, human growth hormone, two alpha-interferons, and hepatitis B vaccine), are indeed grown under containment conditions at least BLl-LS. This degree of containment is expensive, unwieldy and unnecessary. Despite the interpretation discussed above of the language in the )une 28 document. FDA has received numerous inquiries and requests from academics, industrial representatives, and others who have found the language in the June 28 document and the NIH Guidelines not explicit enough for purposes of strategic planning. Therefore, we propose the following amendment to the NIH Guidelines: In Appendices C-Il. C-IU. and C-IV, delete the followinng language: For these exempt laboratory experiments. BLl physical containment conditions are recommended. For large-scale (LS) fermentation experiments BLl-LS physical containment conditions are recommended. However, following review by the 1BC of appropriate data for a particular host-vector system, some latitude in the application of BLl-LS requirements as outlined in Appendix K-D-A through K-tl-F is permitted. And substitute: For these exempt laboratory experiments, the appropriate physical containment conditions need be no greater than those for the host organism unmodified by recombinant DNA techniques. For large-scale (LS) fermentation experiments, the appropriate physical containment conditions need be no greater than those for the host organism unmodified by recombinant DNA techniques. Thank you. We hope that this proposal will receive consideration by the RAC at the earliest opportunity. OMB's "Mandatory Information Requirements for Federal Assistance Program Announcements” (45 FR 39592) requires a statement concerning the official government programs contained in the Catalog of Federal Domestic Assistance. Normally NIH lists in its announcements the number and title of affected individual programs for the guidance of the public. Because the guidance in this notice covers not only virtually every NIH program but also essentially every Federal research program in which DNA recombinant molecule techniques could be used, it has been determined to be not cost effective or in the public interest to attempt to list these programs. Such a list would likely require several additional pages. In addition, NIH could not be certain that every Federal program would be included as many Federal agencies, as well as private organizations, both national and international, have elected to follow the NIH Guidelines. In lieu of the individual program listing, NIH invites readers to direct questions to the information address above about whether individual Programs listed in the Catalog of Federal Domestic Assistance are affected. Dated: December 11, 1988. Bernard Talbot, Acting Director. National Institute of Allergy and Infectious Diseases. (FR Doc. 88-28442 Field 12-18-88; 8:45 am] SI LUNG CODE 4140-01-41 Recombinant DNA Research. Volume 1 1 ( 157 ] DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE NATIONAL INSTITUTES OF HEALTH RECOMBINANT DNA ADVISORY COMMITTEE HUMAN GENE THERAPY SUBCOMMITTEE LAY SUMMARY WORKING GROUP Minutes of Meeting! January 9, 1987 The Lay Summary Wbrkinq Group of the Human Gene Therapy Subcommittee, Recanbinant DNA Advisory Carmittee, was convened at 10:00 a.m. on January 9, 1987, at the National Institutes of Health, Building 31 A, Room 10A34, 9000 Rockville Pike, Bethesda, Maryland 20892. Ms. Anne Witherby was Chair. The following were present for all or part of the meeting: Wbrkinq Group members: Judith Areen Maurice Mahoney Robert Rich LePoy Wla Iters The working group roster i Anne Witherby William Gartland (Executive Secretary) attached (Attachment I). Other National Institutes of Health staff: Robert Wieder, NHLBI Others: Henry Miller, Food and Drug Administration Meeting Summary: A summary of the meeting prepared by Ms. Anne Witherby is attached (Attachment II). •*-The working group is advisory to the subcommittee and the RAC, and its recommendations should not be considered as final or accepted. [158] Recombinant DNA Research, Volume 11 Respectfully submitted Date William J. Galjtland, Executive Secretary I hereby certify that, to the best of my knowledge, the foregoing Minutes and Attachments are accurate and complete. Aruvfc- fyKU^Ffs, blf Anne R. Witherby, B.S. Chair Human Gene Therapy Subcommittee Lay Summary working Group f Recombinant DNA Research, Volume 1 1 [ 159 ] RECOMBINANT DNA ADVISORY COMMITTEE HUMAN GENE THERAPY SUBCOMMITTEE LAY SUMMARY WORKING GROUP CHAIR WITHERBY, Anne R. , B.S. 2 Commonwealth Avenue Boston, Massachusetts 02116 617 247-0123 AREEN, Judith, J.D. Georgetown University Law Center 600 New Jersey Avenue, N.W. Washington, D.C. 20001 202 662-9048 MAHONEY, Maurice J., M.D. Department of Human Genetics Yale University 333 Cedar Street, 305 W7W New Haven, Connecticut 06510 203 785-2661 RICH, Robert F. , Ph.D. Institute of Goverrment Public Affairs University of Illinois 1201 West Nevada Street Urbana, Illinois 61801 217 333-3340 WALTERS, LeRoy, Ph.D. Center for Bioethics Kennedy Institute of Ethics Georgetown University Washington, D.C. 20057 20 2 62 5-2386 EXECUTIVE SECRETARY GARTLAND, William J. , Jr., Ph.D. Office of Recanbinant ENA Activities National Institute of Allergy & Infectious Diseases National Institutes of Health Bethesda, Maryland 20892 301 496-6051 [ 160 ] Recombinant DNA Research, Volume 1 1 JANUARY 1987 58/32 report of the working group of the human gene therapy SUBCOMMITTEE ON A GENERAL INFORMATION DOCUMENT RAC Meeting February 2, 1987 The Working Group of the Human Gene Therapy Subcommittee has taken on the job of putting together a brief explanatory document for the benefit of the general public. The purpose of the document is to afford the non-scient i f ic public an understanding of Human Gene Therapy. The document is largely based on "Points to Consider in the Design and Submission of Human Somatic-cell Gene Therapy Protocols". On January 9th. the following people met at the HIH: Dr. LeRoy Walters-- of the Center for Bioethics, Georgetown University, and Chairman of the Human Gene Therapy Subcommittee . Dr. Maurice Mahoney -- of the Department of Genetics at Yale University. Dr. Robert Rich -- of the Institute of Government Public Affairs at the University of Illinois. Attorney Judith Areen -- of the Georgetown University Law Center. Dr. William Gartland -- Executive Secretary of RAC. Dr. Henry Miller -- of the Food and Drug Administration. Dr. Robert Wieder -- of the Heart, Lung and Blood Institute, and I, Anne Witherby -- public representative. We discussed the scope of the project which was to write what was originally referred to as a "Lay Summary" of the "Points to Consider". The following are a few of our conclusions: We will make an effort to limit the document to two or three pages which could be attached to the "Points to Consider". We think the two or three sheets document could also be mailed separately and that it might, at some future time, be enlarged and elaborated into material for a broad variety of educa- tional purposes. > We suggest the title of; OVERSIGHT OF RESEARCH INVOLVING GENE THERAPY FOR HUMAN PATIENTS - GENERAL INFORMATION, We plan to divide the paper into four sections. The first, an Introduction , will include an explanation of Human Gene Therapy using non-hereditary cells. This section will also describe the purpose of the therapy, why it is different from other medical treatment and make the distiction between somatic- cell and germ-line gene therapy. Drs. Mahoney and Wieder have taken on this section of the GENERAL INFORMATION document. The second section of the document will refer more specifi- cally to the "Points to Consider" and is subtitled Governmental and Public Oversight . Attorney Judith Areen and I are working on this section. Recombinant DNA Research, Volume 1 1 [ 161 ] The third section is being put together by Drs. Walters and Rich and will include possible anticipated concerns and adverse effects on the one hand, and on the other, some examples of the acceptability of human somatic-cell gene therapy. A final section will list some references, a few articles and books for those who wish to study the subject further. This section will include an offer to send some NIH materials such as copies of the "Points to Consider", the Guidelines and the OPRR pamphlet, upon request. Our working to the Human Gene April 24th. When will v presented to be Chairman, Working group plans to present a draft of the document Therapy Subcommittee when it meets next on the Subcommittee has finalized the document, i the RAC for approval. Anne R. Witherby Public Representative and Group on a General Information Document. Additions, February 11, 1987 1 ♦ The third section will include two parts: (1) the above, as stated, which refers to a portion of the Introduction in the "Points to Consider" [ page 6 (8) and page 7 (9) , ( 10) ] . (2) a basic summary of numbers I through IV in the "Points to Consider". 2 . Please include Dr. Susan K. Gottesman as a consultant to the Working Group on a General Information Document. SrtvJ [ 162 ] Recombinant DNA Research, Volume 1 1 DEPARTMENT OF HEALTH AND HUMAN SERVICES PURLIC HEALTH SERVICE NATIONAL INSTITUTES OF HEALTH RECOMBINANT DNA ADVISORY COMMITTEE MINUTES OF MEETING FEBRUARY 2, 1987 Recombinant DNA Research, Volume 1 1 [163] TABLE OF CONTENTS Part Page I. Call to Order and Introductory Remarks 4 II. Minutes of the Meeting of September 29, 1986 5 III. Report on the Working Group on Definitions and Proposed Revision of Section III-A-2 of the NIH Guidelines 5 IV. Proposed Revision of Section I-R or Section III-A-2 of the NIH Guidelines 10 V. Proposed Amendment of Sections I-A and III-A of the NIH Guidelines 16 VI. Proposed Revisions of Appendices C-II, C-III, and C-IV to the NIH Guidelines 19 VII. Report from the Human Gene Therapy Subcommittee 23 VIII. Future Meeting Dates 23 IX. Adjournment 23 [ 164 ] Recombinant DNA Research, Volume 1 1 DEPARTMENT OF HEALTH AND HUMAN SERVICES FUBLIC HEALTH SERVICE NATIONAL INSTITUTES OF HEALTH RECOMBINANT DNA ADVISORY COMMITTEE MINUTES OF MEETING 1 FEBRUARY 2, 1987 The Recombinant DNA Advisory Canmittee (RAC) was convened for its thirty-sixth meeting at 9:00 a.m. on February 2, 1987, in Building 1, Wilson Hall, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892. Mr. Robert Mitchell (Chair) , Attorney at Law in California, presided. In accordance with Public Law 92-463, the meeting was open to the public. The following were present for all or part of the meeting: Committee members: Barbara H. Bcwman Donald C. earner Don Bert Clewell Mitchell L. Cohen Bernard D. Davis Charles J. Ostein Robert P. Erickson Susan K. Gottesman Irving S. Johnson Edward L. Korwek Robert E. Mitchell Gerald L. Musgrave Paul E. Neiman Joseph S. Pagano Jeffrey W. Roberts Frances E. Sharpies Anne K. Vidaver LeRoy Walters William J. Gartland, Jr. (Executive Secretary) A canmittee roster is attached (Attachment) . Ad hoc consultants : Royston C. Clowes, University of Texas Gerard J. McGarrity, Coriell Institute for Medical Research Robert W. McKinney, National Institutes of Health L iaison representative : Daniel P. Jones, National Endowment for the Humanities 1-The RAC is advisory to the National Institutes of Health (NIH) , and its recommendations should not be considered as final or accepted. The Office of Recombinant DNA Activities should be consulted for NIH policy on specific issues. Recombinant DNA Research, Volume 1 1 [ 165 ] Non-voting agency representatives : Howard M. Berman, Veterans Administration Joel M. Dalrymple, U.S. Army Medical Research Institute of Infectious Diseases George Duda, Department of Energy Bernard Greifer, Department of Ccmmerce Phillip Harriman, National Science Foundation Elizabeth Milewski, Environmental Protection Agency Henry I. Miller, Food and Drug Administration Sue A. Tolin, Department of Agriculture William J. Walsh, Department of State National Institutes of Health staff : terianne £bbs, NI AID W. French Anderson, NI AID Stanley Barban, MAID Becky Lawson, NI AID Rachel Levinson, OD Lynn Ann Lewis, NI AID Barbara Harrison, OD Bernard Talbot, NIAID Others : Carter Blakey, Federation of American Societies for Experimental Biology Irene Brandt, Eli Lilly and Company Dennis Carroll, General Accounting Office Chia Ting Chen, Department of Labor Mark Cranford, Science Isabelle R. Davidson, Pfizer, Inc. Charles J. Eby, Mansanto Company Diane Edwards, Science News Joseph R. Fordham, Novo Laboratories, Inc. Jeffrey L. Fox Mary Gant, Office of Science and Technology Policy, Executive Office of the President Irene Glowinski, U.S. Congressional Staff Rebecca J. Goldburg, Environmental Defense Fund Alan R. Goldhammer, Industrial Biotechnology Association George H. Irwin, MDnsanto Agricultural Company Dorothy Jessup, Department of Agriculture Peter L. Joseph, Department of Agriculture Attila T. Kadar, Food and Drug Administration John H. Keene, Abbott Laboratories Patricia W. Kener, Monsanto Company Lori Lamore, Ccmmerce Clearing House Alvin G. Lazen, National Academy of Sciences David F. Long, Veterinary Biologies Consultant A. S. Lubiniecki, Genentech, Inc. [ 166 ] Recombinant DNA Research, Volume 1 1 Jack J. Manis, Upjohn Company James H. Maryanski, Food and Drug Administration Margaret Mellon, Environmental Law Institute David Moore, Association of American Medical Colleges Phil Musi, Blue Sheet Robert B. Nicholas, Blum, Nash, and Railsback Michelle Owings, Burditt, Bc*/les, Radzius Harvey S. Price Jeremy Rifkin, Foundation on Economic Trends Edward Lee Rogers, Attorney, Washington, D.C. Alex Samofal, Department of Agriculture Mark Segal, Environmental Protection Agency Valerie P. Setlow, Office of the Assistant Secretary for Health Janet Shoemaker, American Society for Microbiology David E. Smolin, American Cyanamid Company Cynthia L. Spencer, Cooper Laboratories, Inc. Clarence E. Styron, Monsanto Company William Szkrybalo, Pharmaceutical Manufacturers Assoda tion Charles Turbyville, NIH Week Joseph Van Houten, Schering-Plough Corporation Winona Wagner, E. I. Du pont De Nemours & Company John Whalen, National Institute of Occupational Safety and Health David Wheeler, Chronicle of Higher Education Doug Yarrow, British Bnbassy Stephanie Zobrist, Embassy of Switzerland Recombinant DNA Research, Volume 1 1 [ 167 ] I. CALL TO ORDER AND INTRODUCTORY REMARKS Mr. Mitchell, Chair, called the meeting of the Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health (NIH) to order at 9:00 a.m. , February 2, 19 87 . He said the meeting was called pursuant to Federal Register notice of December 19, 1986, which being 30 or more days prior to today's date met the NIH Guidelines for Research Involving Recombinant DNA Molecules requirements. He stated that the meeting would remain open to the public for its entirety, and that he expected the meeting to adjourn at approximately 4:00 p.m. Mr. Mitchell noted that with new appointments the RAC now was at full membership with 25 members and requested Dr. Gartland to ascertain whether a quorum was present. Dr. Gartland stated that a quorum was present, and Mr. Mitchell declared that the committee could proceed with business. Mr. Mitchell noted that he intended to make every effort to abide by the distributed agenda with respect to time estimates for each item of business and added there were four items on the agenda which, having been duly published in the Federal Register 30 or more days prior to the meeting date, the RAC could take official action on at this meeting. He then reminded the committee that in recognizing persons for canments he would use the follo/ing order: primary and secondary reviewers on each item as set forth in the agenda; other members of RAC; ad hoc consultants to the RAC; NIH staff members; members of the public who had submitted written documents; and finally, other members of the public. He underlined that RAC was advisory to the Director of NIH and that in light of this persons with minority opinions should voice then so as to provide Dr. Wyngaarden with the entire spectrum of RAC 'opinions on a given topic. Mr. Mitchell then told the committee that in all voting he would call first for the affirmative, then for the negative, and finally for abstentions, and underlined that if any voting member felt compelled to abstain due to conflict of interest that such member should notify the Chair so that the record could duly reflect such. Mr. Mitchell then made note of Mailings I and II which were sent to members prior to the meeting. He also noted that materials that had been recently received were supplied at the table for each member. Mr. Mitchell then introduced three new members of RAC who were present at the meeting: Mr. Donald C. earner. Dr. Don Bert Clewell, and Dr. Robert P. Erickson. He briefly outlined each new member's background and affiliations and stated that he and other members of the committee welcomed them and looked forward to their contributions on the committee. [ 168 ] Recombinant DNA Research, Volume 1 1 Mr. Mitchell then announced that three ad hoc members were in attendance at the meeting: Dr. Royston Clowes of the University of Texas, Dr. Robert McKinney of the NIH, and Dr. Gerard McGarrity of the Coriell Institute for Medical Research. He briefly touched on their professional expertise and welcomed their participation. II. MINUTES OF THE MEETING OF SEPTEMBER 29, 1986 Mr. Mitchell then called upon Dr. LeRoy Walters to review the minutes of the September 29, 1986, meeting of the RAC (tab 1288). Dr. Walters said he had read the minutes and found them clear and complete; however, he felt some minor grammatical corrections should be made, not affecting the substance of the minutes, and he offered to take these up later with the Office of Recombinant DNA Activities (ORDA) staff. Dr. Bowman stated she had reviewed the minutes and moved that they be accepted. Dr. Davis asked whether such motion would allow for the grammatical corrections which Dr. Walters would recanmend, and Mr. Mitchell said snail stylistic changes not affecting the substance would be allowable under the current motion . Mr. Mitchell then put the motion to a vote. The motion passed unanimously with two members abstaining. Mr. Mitchell then stated that in light of the number of pertinent ccmments received after Mailings I and II had gone out, that it be appropriate for the RAC to take a short recess to allow members time to review fully these comments. Mr. Mitchell then recessed the committee for a half hour prior to discussion of the next agenda item. III. REPORT OF THE WORKING GROUP ON DEFINITIONS AND PROPOSED REVISION OF SECTION III-A-2 OF THE NIH GUIDELINES Mr. Mitchell reconvened the meeting at 9:45 a.m. and stated that this agenda item would include a discussion of materials contained in tabs 1285, 1286, 1288, and 1289. He further stated that an additional comment had just been handed to members which was received f ran the American Society for Microbiology. He said that in light of the Federal Register notice being published 30 or more days prior to this meeting, that the RAC could take final action on this agenda item today and that discussion would be broken into two parts with Dr. McGarrity leading off the discussion. Dr. McGarrity stated that ORDA had asked the RAC Working Group on Definitions to examine the two terms “recombinant DNA" and "deliberate release" into the environment. The working group met Recombinant DNA Research, Volume 1 1 [ 169 ] on September 5, 1986, and a report of that meeting was made to the RAC at the September 29 , 19 86 , meeting. At that time, the RAC had voted to refer the matter back to the working group for further discussion. He noted that the RAC, during the same meeting, had approved a motion to modify Section III-A-2 dealing with environmental release. Dr. McGarrity stated that the working group had met on December 5, 1986, and the minutes of that meeting were contained at tab 1285. He reported the first proposal to the RAC from the working group (endorsed by a vote of 10 in favor, 1 opposed, and 1 abstention) was to revise Section III-A-2 of the NIH Guidelines to read in its entirety as follows (tab 1286/11): "Deliberate release into the environment of any organism containing recombinant DNA, except those listed below. The term 'deliberate release' is defined as a planned introduction of recombinant DNA-containing microorganisms, plants, or animals into the environment. “a. Introductions conducted under conditions considered to be accepted scientific practices in which there is adequate evidence of biological and/or physical control of the recombinant DNA-containing organism. The nature of such evidence is described in Appendices L, M, N, and 0. "b. Deletion derivatives not otherwise covered by these Guidelines. "c. Organisms covered in exemption III-D-2." Dr. McGarrity then stated the intent of the working group was that Appendix L, referred to in the proposed wording, would be the current Appendix L dealing with plants, with future changes to be recommended by RAC. Appendices M, N, and 0 would be parallel sections, yet to be written, covering respectively animals, microorganisms other than those used in vaccines, and vaccines . Dr. McGarrity reported that the working group unanimously approved a motion that: "Investigators in the field of vaccine development be apprised of the options for exemption from RAC review as specified in paragraph two of Section III-A, and that a working group be organized to develop criteria and procedures for inclusion in an Appendix O (Vaccines) of Section III-A-2." [170] Recombinant DNA Research, Volume 1 1 Dr. McGarrity said a revised Section III-A-2 had been recommended by the RAC at its September 29, 1986, meeting although it still had not been acted upon by Dr. Wyngaarden. He noted differences between the wording recommended at the September 1986 meeting and the proposed language above. He said a multidisciplinary effort will be needed to develop Appendices M, N, and 0. Dr. McGarrity said in closing that regardless of RAC's action on this proposal that he strongly urged “that an immediate effort be made to develop standards for the environmental issues surrounding vaccines developed by recombinant techniques. - Dr. Gottesman said she felt the proposal included changes which were significant in setting up a structure for including Appendices M, N, and 0. However, even if the proposed changes were to be made part of the NIH Guidelines, nothing would change in the review of specific applications until the actual text of Appendices M, N, and 0 was written. A RAC working group would formulate Appendices M, N, and 0, and then put these out for public comment. Before becoming part of the NIH Guidelines, the RAC would review the proposed text of the appendices. She stated that a vote in support of the new proposed Section III-A-2 is thus basically a vote in support of a concept with a chance to subsequently review the actual text of the appendices. The second sentence of the proposed Section III-A-2 is an attempt to get more substance into the term "deliberate release" and to indicate that it should not have a pejorative connotation. Sections b. and c. of the proposed Section III-A-2 are identical to recommendations voted on by RAC at the previous meeting and under consideration by Dr. Wyngaarden. She said she favored the revision of Section III-A-2 of the NIH Guidelines proposed by the working group. Dr. Korwek asked how this proposed change in Section III-A-2 found at tab 12 86/11 related to a further change in Section III- A-2 found at tab 1286/III. Drs. Gottesman and Talbot pointed out that the RAC proposed certain changes in Section III-A-2 at the previous RAC meeting. Tab 1286/11 proposes certain additional changes, and RAC should consider this first. Tab 1286/III proposes further changes, and this will subsequently be con sider ed . Dr. Sharpies reminded the RAC she had voiced considerable objection to the changes in Section III-A-2 recommended by the RAC at its September 29, 1986, meeting and clarified that her ranarks today were not to be taken as referring to those changes; she had not changed her mind regarding her obj ections to those changes. In regard to the further changes proposed in tab 1286/11, she stated she had no objection to the incorporation of the term "planned introduction" to describe or amplify what constitutes a "deliberate release." However she said that she Recombinant DNA Research, Volume 1 1 [171] personally did not think this wording does much to improve or clarify concepts. She said there were two conceptual points with regard to deliberate release that needed to be spelled out: (1) that deliberate release is of concern if other organisms will be exposed to the organism being released and that this exposure might be harmful; and, (2) that deliberate release is of concern if the organism that is being released will have the opportunity to exchange genetic information with other organisms that are in the environment. She said that adding the words about "planned introduction" did nothing to clarify these concepts. This wording "is not a definition? it is just a description." Dr. Sharpies said that with Appendices M, N, and 0 not yet being in existence the referencing of such appendices in the NIH Guidelines was unacceptable. She had no objection to an effort being made to create these appendices and felt their construction would represent real progress in the area. However, she felt it would take some time to accomplish this. In regard to Dr. McGarrity's statement that a multidisciplinary effort would be needed to complete these appendices. Dr. Sharpies agreed and said she hoped all relevant scientific disciplines would be represented in the working groups convened to work on the appendices. Further, as a member of the Public Affairs Canmittee of the Ecological Society of America, she said she was certain the society would be willing to assist NIH and the RAC working groups by providing expertise available from within its membership. Dr. Sharpies then called attention to the existing Appendix L which states that: “Appendix L specifies conditions under which certain plants, as specified below, may be approved for release into the environment. Experiments in this category cannot be initiated without submission of relevant information on the proposed experiment to NIH, review by the Plant Working Group and specific approval by NIH. " Dr. Sharpies said that for experiments meeting the Appendix L criteria, it is not that these experiments will not be reviewed, but that the Plant Working Group instead of the full RAC would re/iew them. For Appendices M, N, and 0, she urged use of the same concept of working group approval in lieu of full RAC appr oval . Dr. Vidaver indicated she supported the working group's proposal, and that many of Dr. Sharpies' concerns could be covered in the appendices. She said Appendix L was already in place, and the USDA is considering Appendices M and N. Dr. Clowes said he fully supported the working group's proposal. [172] Recombinant DNA Research, Volume 1 1 He would like to see it extended even further. Rather than s pecif ical ly citing only exemption III-D-2, he would like all organisms which are already exempt from the NIH Guidelines for laboratory work to also be exempt for deliberate release to the environment. This would then include all recombinations made between organisms that freely exchange genetic material in nature and thus where nothing new is likely to arise from the recombinant DNA technique. Dr. Gottesman said that Dr. Sharpies had pointed out that Appendix L currently provides for review by the RAC Plant Working Group in lieu of the full RAC. She said that in writing the new Appendices M, N, and 0, “you could imagine putting into those appendices some mechanisms whereby a proposed experiment would revert to the laboratory experimentation level, seme that would require working group review and some that would continue to come before the entire RAC." She felt that an important part of constructing the new appendices would be to decide what the appropriate mechanism should be for dealing with any particular class of "deliberate release" experiment. Dr. Gottesnan then moved that the RAC accept the proposed revision of the NIH Guidelines as contained in tab 1286/11. Dr. lpstein seconded the motion. Dr. Korwek noted Dr. Sharpies' objections to the revision were on the basis that Appendices M, N, and 0 were not in place. However, he replied that the status quo was not being changed in that even were the proposed reference to these appendices added to the NIH Guidelines, the approval process for any deliberate release experiment would not change until the actual text of the appendices was incorporated into the NIH Guidelines. Dr. Davis then made a motion to remove from tab 1286/11 the following sentence: "The term 'deliberate release' is defined as a planned introduction of recombinant DNA-containing micro- organisms, plants or animals into the environment. - He said this sentence did not add anything to the understanding of what is meant by "deliberate release." Dr. Walters seconded the motion so that discussion of this motion could take place. Dr. Johnson said he felt the wording should be looked at in an historical context in that at the last meeting the RAC asked the Working Group on Definitions to look again at this wording. The working group had come to agreement that the RAC is concerned with planned experiments. Therefore, the words “planned introduction" were appropriate. Further, he added that the votes in the working group on this issue were virtually unanimous resulting in this wording being a consensus of the working group. Mr. Mitchell then put Dr. Davis' motion to a vote. The motion Recombinant DNA Research, Volume 1 1 [173] was rej ected by a vote of 2 in favor, 11 opposed, and 4 absten tion s . Mr. Mitchell then called for further discussion on Dr. Gottesman's original main motion. Mr. Lee Rogers, attorney for the Foundation on Economic Trends and Jeremy Rifkin, said the status quo was not being maintained. He saw this as allowing a change in the NIH Guidelines to go forward anticipating the development of satisfactory appendices. In the absence of the appendices, the amended language was "not workable because of the lack of flesh on the body." Dr. McGarrity replied that this was a setting up of a superstructure of hew environmental releases would be judged in the future. From a practical standpoint it would be better to have the superstructure and mechanisms approved now. He noted that the revision of Section III-A-2 which had been recommended at the September 29, 1986, RAC meeting had still not been finally approved by Dr. Wyngaarden. Therefore, if this revision today were to be recommended, it would undoubtedly be a matter of several months before the NIH Director would act on it, thereby allowing time for development of Appendices M, N, and 0. Dr. Sharpies asked about the status of the revision recommended at the previous RAC meeting. Dr. Talbot stated that NIH staff had prepared an environmental assessment (EA) at Dr. Wyngaarden' s request. However, the Director was not fully satisfied with that EA and had requested that further information be put in the EA. The revised EA should be resubmitted to the Director soon. Subequent to Dr. Wyngaarden' s approval of the EA, a Federal Register notice promulgating the change in the NIH Guidelines would be prepared for his review and approval. At this point, there being no further discussion on the motion, the motion to recommend the NIH Guidelines changes at tab 1286/11 was put to a vote. The results of the voting were 16 in favor of the motion, none opposed, and one abstention. Mr. Mitchell thanked Dr. McGarrity and the members of the Working Group on Definitions for their fine work on this proposal. IV. PROPOSED REVISION OF SECTION I-B OR SECTION III-A-2 OF THE NIH GUIDELINES Mr. Mitchell called on Dr. McGarrity to explain the proposal (tab 12 86/III). Dr. McGarrity said the Working Group on Definitions considered the term "recombinant DNA. " The working group agreed with the concept that certain types of recombinant DNA experiments which do not involve the introduction of foreign DNA need not be subjected to special regulation as “recombinant DNA." The working group was split as to whether it preferred dealing with this problem by changing the definition of recombinant DNA or by further modifications of other sections of the NIH [ 174 ] Recombinant DNA Research, Volume 1 1 Guidelines (e.g., those in Section III-A-2) . Therefore, the working group presented two options for public ccrunent and RAC consideration. Dr. McGarrity said the working group had overwhelmingly favored Option 2 as published in the Federal Register as the preferred choice by a vote of 9 in favor, 1 opposed, and no abstentions. Dr. McGarrity added that he felt perhaps the working group's choice had been swayed by an opinion offered by a lawyer on the working group that to change the definition was more radical than changing other portions of the NIH Guidelines. Dr. McGarrity reviewed the major changes proposed in the two options. Dr. Gotteanan reviewed sane of the public canments received on the two options. She pointed out that option one would eliminate from RAC review certain hunan gene therapy experiments but that option two would leave review of such experiments within the purview of RAC. Drs. Korwek, Sharpies, Clowes, and Cohen all said they preferred Option 2 to Option 1. Dr. Neiman said that at the previous RAC meeting he had stated that rearrangements, deletions, and amplifications within higher organisms that do not rapidly change their genomes are not necessarily as innocent as those that occur in microorganisms. Therefore, he felt that modification of Section III-A-2 of the NIH Guidelines would be a more favorable approach than a change in the definition of "recombinant DNA. “ Dr. Korwek moved that further consideration of Option 1 be rejected, and Dr. Epstein seconded the motion. Mr. Mitchell called for discussion on the motion and called on Dr. Henry Miller from FDA. Dr. Miller said FDA's view was that the purpose of the NIH Guidelines was to circumscribe a unique or special set of experiments and organisms that required some special attention, not necessarily due to risk involved, but due instead to the use of recombinant DNA in cases which did not occur naturally or were special in seme other way. Because of this. Option 1 is preferred. Option 1 would say that it isn't simply cutting and ligating that defines recombinant DNA in a meaningful way; rather it is the joining of heterologous DNAs . He said that changing the definition of "recombinant DNA" right up front was clearer than altering it by changing exemptions. Dr. Davis agreed with Dr. Miller. He felt it would better guide the courts in making it clear that even if recombinant DNA technology was used, that in our judgnent no recombinant DNA existed unless heterologous segments were introduced into the gencme. This would appropriately shift emphasis from the procedure to the product. The basic issue is whether the product contains foreign DNA. He said he could not vote for Option 1 as written because the use of the word "organism" in the proposed Recombinant DNA Research, Volume 1 1 [175] footnote was ambiguous and should be replaced by the word "genome. “ Dr. Cohen said that the prime concern had always been whether you had the potential to create something unique. One method is to create unique things by mixing genomes, but another is to accelerate the rate of evolution many thousand-fold. Dr. Clowes said he would rather leave the definition vague and then exempt certain classes rather than trying to build everything into the definition. Dr. Johnson said he had somewhat the same problems with the Option 1 footnote as Dr. Davis in the use of the words "organism" and "strain"; he said it was unclear whether “organism" and "strain" refers to organisms at the genus or species level. There being no further discussion on the motion to reject Option 1, Mr. Mitchell called for a vote. The motion carried by a vote of 11 in favor, 6 opposed, and no abstentions. After a brief summary of the specific changes in language encompassed in Option 2, Dr. Walters moved that Option 2 be adopted. Dr. Neiman seconded the motion. Mr. Mitchell asked for discussion on the motion. Mr. Rogers referred to comments by the Ecological Society of America which had concern that intergeneric manipulations could pose serious ecological threats. He asked for further discussion on this issue. Dr. Gottesman said this had been discussed at the previous meeting and was so noted in the minutes. No one had said that all deletions and rearrangements were innocuous. She saw the RAC's mandate as concentrating on unique recombinant DNA constructs. It is not clear that deletions, rearrangements, amplifications, and single base changes should fall under this man da te. Dr. Epstein asked whether these now to be excluded releases would be reviewed by any agency other than NIH. Mr. Rogers said that was also his concern, i.e., that intergeneric transfers would not be re/iewed by anyone and further that the NIH had the most experience in this type of review. Dr. Sharpies explained to Mr. Rogers that intergeneric transfer was not the issue in this proposal, but rather that self -cloning mechanisms, such as deletions and rearranganents within the same organism, were the basic issue. Further, Dr. Sharpies said that she believed Dr. Gotteanan's view of the RAC's mandate was incorrect; RAC has a duty to make certain that experimental research using recombinant DNA technology is carried out in such [176] Recombinant DNA Research, Volume 1 1 a way as to protect the public and the environment from harm whether or not "foreign" DNA is involved. Dr. Margaret Mellon from the Environmental Law Institute asked for clarification of the relationship of the NIH Guidelines to the evolving role of the US DA. Dr. Talbot responded by saying that the USDA had been using the NIH Guidelines. In the June 26, 19 86, ".Coordinated Framework," they had published their own guidelines for public comment which were modelled after the NIH Guidelines. A subsequent Federal Register notice said that in lieu of separate USDA Guidelines, USDA would propose new provisions relating to agricultural research for inclusion in the NIH Guidelines. Dr. Sue Tolin said that the USDA indeed had relied on the NIH Guidelines but "we see the need to get sane additional things into it. The approaches that are being discussed in terms of developing Appendices L, M, N, and 0 will certainly go a long way towards those and we plan to be working very closely with NIH on those areas." She also added that not only does USDA sponsor research, but they also have statutory regulatory authority. Dr. Gottesman said that scientists involved in genetic research other them recombinant DNA technology would be selecting strains with deletions or rearrangements which they may wish to introduce into the environment. If they wish to introduce such strains into the environment this would have to be dealt with by regulatory agencies. An organism engineered by recombinant DNA technology to produce these same deletions and rearrangements should require no more and no less regulation merely because of the process used to arrive at the same end product. Removing the extra layer of RAC and NIH review still leaves the standard re/iew by the regulatory agencies. Dr. Cohen agreed that there was no need for RAC or NIH review of rearrangements or deletions in microorganisms, but said with higher organisms you are dealing with something different. Dr. Davis said it was a case of probabilities. He felt the probability of making a bacterium more dangerous by deletion or rearrangement was exceedingly low. He felt this was not necessarily the case with viruses, although there were other mechanisms to ensure safety of virus vaccines. He said that unnecessary review of safe experiments could be very expensive and time-consuming. Dr. Walters said that he seemed to be hearing two separate concerns, one concern for eukaryotes and one concern for microorganisms. He asked what the risks were with higher organisms that were not adequately covered by some other mechanism. If there are no major concerns about higher organisms, then the only thing left to debate is environmental Recombinant DNA Research, Volume 1 1 [177] release of microorganisms containing deletions and rearrangements . Dr. Gottesman summarized the major changes in tab 1286/III/Option 2, as compared to what had pre/iously been recommended by RAC as: extension to include "single base changes" in part b; and extension to include chromosomal as well as extr achr omos anal rearrangements in part c. Dr. Johnson said he was still concerned with the use of the word “organism" as to whether it referred to genus or species. He proposed an amendment to the wording of Section III-A-2-c, to substitute the word "species" for “strains." Mr. Mitchell asked for a second on the motion. There being no second for the motion the motion died. Dr. Davis said he had obj ection to the word "organism" in the same section, and he would move to have it replaced with the word "species." Dr. Gottesman seconded the motion. Dr. Grief er from the Department of Commerce said that in his opinion changing the language at this point would be denying public canment on it. Dr. Talbot said that in the past the NIH Director had accepted changes suggested at RAC meetings, sometimes based on public comment, but that major broadening at this stage would not be acceptable without a new opportunity for public canment. He said that the change being contemplated, namely substituting the word "species" for "organism,", was in his view a minor clarification and should not have to be resubmitted for public comment. Mr. Mitchell then called for a vote on amending the language in Section III-A-2-c to read: "Rearrangements and amplifications within a single genome. Rearrangements involving the introduction of DNA from different strains of the same species would not be covered by this exemption. " The motion to amend passed by a vote of 16 in favor, none opposed, and 1 abstention. Mr. Mitchell asked for further discussion on the motion as amended. Dr. Neiman requested amplification on Dr. Gottesman' s point as to whether if an experiment could be performed utilizing standard genetic techniques, this should be viewed differently when performed utilizing recombinant DNA technology. A lengthy discussion took place during which it was argued that there was no difference. Depending on the possible hazard to the [ 178 ] Recombinant DNA Research, Volume 1 1 environment and to humans, there may be cause to not allow environment al release of such an organism. This evolved into a debate as to whether plants, bacteria, viruses, or animals should be treated differently in this regard with many opinions being expressed. Finally, Mr. Mitchell asked that over the luncheon recess Dr. Qastein meet with other members of the RAC to formulate an amendment which could be considered by the committee after the lundieon recess. Whereupon, Mr. Mitchell recessed the committee for lunch, to reconvene at 1:30 p.m. Mr. Mitchell reconvened the committee at 1:30 p.m. Mr. Rogers said that other agencies do not have complete jurisdiction, so there will not be complete coverage without NIH retaining jurisdiction. He suggested instead of NIH "abrogating its responsibility" that "lesser levels of review" be put into place for those types of experiments that in RAC's opinion do not warrant full committee review. Dr. Rebecca Goldburg of the Environmental Defense Fund also said the question of risk should be evaluated whether the organism in question existed in nature or not. She supported Mr. Rogers' proposal of same level of review for all releases. Dr. Clowes said that RAC was created to oversee experiments done with recombinant DNA which could create novel genotypes and not to deal with organisms extant in nature. Dr. Q^stein proposed amended wording for the first sentence of the proposed Section III-A-2-c to read: “For extr achramos amal elements and microorgani sms (including viruses), rearrangements and amplifications within a single genome." The rest of this paragraph would remain unchanged from the version at tab 1 2 86/III/Option 2, with the exception of the substitution of the word "species" for "organism" which had already been voted upon and amended. Dr. Sharpies asked whether this change was substantive enough to force resubmission to the Federal Register for public comment. Dr. Talbot said he did not believe so, since this was constricting the exemptions not broadening them. In the past, the NIH Director had accepted those kinds of restrictive changes made by the RAC. Dr. Tolin asked why plants and animals were being restricted since she felt there was a larger body of kncwledge concerning genetically altered plants and animals than altered microorganisms. Dr. Miller agreed. Recombinant DNA Research, Volume 1 1 [179] Dr. Walters reminded the committee that what was being considered only was referring to a small class of deliberate release experiments. Mr. Rogers again brought up the issue of public comment on this proposed change. Dr. Talbot explained that what was being contemplated by Dr. Epstein's proposed change was a constriction of exemptions, a tightening of the NIH Guidelines, as compared to what was published in the Federal Register at tab 1286/III/Option 2/part c. This would result in fewer exemptions f rcm RAC oversight. In the past, the NIH Director has accepted such RAC changes without additional public comment. There being no further discussion. Dr. Epstein's amendment for modification of Section III-A-2-c was put to a vote by Mr. Mitchell. The motion was passed by a vote of 11 in favor, 4 opposed, and 1 abstention. At this point, Mr. Mitchell called for a vote on the main motion, i.e. , to recanmend modification of Section III-A-2 of the NIH Guidelines as it appeared in the F ederal Register at tab 12 86/III/Option 2 with Dr. Epstein's amendment of Section III-A- 2-c. The motion passed with a vote of 15 in favor, one opposed, and no abstentions. V. PROPOSED AMENDMENT OF SECTIONS I- A AND III -A OF THE NIH GUIDELINES Dr. Johnson said he favored this proposal (tabs 1283, 1286/1) which would eliminate the requirement for concurrence by the NIH Office of Recombinant DNA Activities for approval of an experiment approved by another Federal agency. He said it is consistent with the new Federal coordination effort. He stated he believed there may be exclusions over which' the RAC may want to continue to maintain jurisdiction such as the human gene therapy. Dr. Korwek said he supported the proposal. However, he felt there was a problem in the wording of the proposal which deals with "approval' 4 by other agencies in that seme agencies do not approve certain requests but merely do not object to them. He cited Investigational New Drug (IND) applications which the FDA does not approve but which become effective for lack of FDA objection. He added the EPA does much the same in their PMN process where after 90 days with no agency objection the manufacturer may proceed. Dr. Davis said he supported the proposal since he was eager not to see bureaucratic restrictions proliferate and not to have multiple levels of review. In regard to Dr. Korwek‘,s problon with the word "approval". Dr. Davis offered the suggestion that perhaps "clearance" would be a better word. Dr. Korwek said that [ 180 ] Recombinant DNA Research, Volume 1 1 he had alternative language which he would propose after further discussion of the proposal. Dr. Sharpies said that the NIH up to this point has been collecting information on a wide variety of things and at this point is a repository of information regarding recombinant DNA technology. She asked if this change in submittal policy might nob cause the NIH in future years to have to reconstruct a system to collect the information which it may not possess if this proposal is put in place and the NIH is bypassed. Dr. Talbot said that today many applications from industry are going directly to EPA or FDA without NIH having any information concerning them. Individuals desiring information can go directly to each of the relevant agencies and ask what they have approved. Dr. Walters said he agreed with the thrust of the proposal as he believed it of value to eliminate duplication in coordination among Federal agencies. However, the proposal should be modified to retain RAC oversight of human gene therapy. Therefore, he proposed the following additional language be added at the end of the proposed text: “However, any experiment that involves the adninis tra tion of gene therapy to human subj ects (see Section III-A-4 of the NIH Guidelines) may not proceed without prior review by the NIH Recombinant DNA Advisory Committee and NIH approval." He said that since the RAC and the NIH have made such a strong commitment to public review for NIH funded human gene therapy experiments that it would be unwise to withdraw that commitment at this point. Dr. Epstein seconded the motion. Dr. Miller stated that the FDA strongly supported the proposal but would object to Dr. Walters' amendment in that, "...especially in human gene therapy there is an even greater acute need to avoid reduplication of reviews and delays than in other areas...." He said human gene therapy proposals will be reviewed by the local Institutional Review Boards (IRBs) and by the FDA and that going through the Human Gene Therapy Working Group and and the full RAC would be an extra layer of bureaucracy. He said that when a need for rapid approval has been necessary, such as in anti-AIDS therapeutics, the FDA has managed to react and approve these very quickly, some within a week of submission. Dr. Walters pointed out that over the last 2 1/2 years the RAC has consistently made the judgnent that there are important reasons to bring human gene therapy proposals before the RAC for Recombinant DNA Research, Volume 1 1 [ 181 ] public discussion and review; FDA consideration of these proposals will not be public. Mr. Mitchell asked Dr. Talbot if an investigator proposing to do hunan gene therapy would have his choice under the proposal to submit the experiment for approval to NIH or to the FDA. Dr. Talbot replied that under the proposal, as published in the Federal Register at tab 1286/1, an investigator submitting such a proposal to FDA would not have to submit it to NIH. However, Dr. Talbot said that he supported Dr. Walters' proposed amendment to require RAC review and NIH approval. Dr. Korwek commented that there was no question that such a proposed experiment would have to be brought to FDA but that the issue was whether it should be brought before the RAC. Mr. Mitchell re-read Dr. Walters', amendment before putting it to a vote. Ihe motion passed by a vote of 12 in favor, one opposed, and 3 abstentions. Mr. Mitchell then called for further discussion on the main proposal. Dr. Korwek proposed an amendment to reword the second sentence of the proposal to read: "Once approval, or other applicable clearances, have been obtained from a Federal agency other than the NIH (whether the experiment is referred to that agency by the NIH, or sent there directly by the submitter), the experiment may proceed without the necessity for NIH review or approval . “ He explained the purpose of this would be to take into account the situation in which an agency does not “approve" an application but merely does not oppose it as in the IND situation that was discussed earlier. Dr. Davis seconded the motion. Dr. Margaret Mellon asked about cases which are within NIH's jurisdiction, and where USDA judges them to be outside of its jurisdiction. Dr. Talbot stated that in such a case the USDA would not give approval if they said it was out of its jurisdiction and this proposed paragraph in the NIH Guidelines would not be applicable since there would be no approval or clearance from USDA. Mr. Mitchell then called for a vote on the proposal as amended. The amended proposal is to delete a paragraph from Section III-A of the NIH Guidelines and add at the end of Section I-A of the NIH Guidelines the following: "Any recombinant DNA experiment which according to these guidelines requires [ 182 ] Recombinant DNA Research, Volume 1 1 approval by the National Institutes of Health (NIH) , may be sent by the sutmitter to the NIH or to another Federal agency that has jurisdiction for review and approval. Cnee approval, or other applicable clearances, have been obtained from a Federal agency other than the NIH (whether the experiment is referred to that agency by the NIH or sent directly there by the submitter), the experiment may proceed without the necessity for NIH review or approval. However, any experiment that involves the administration of gene therapy to human subjects, (see Section III-A-4 of the Guidelines) will not proceed without prior review by the NIH Recombinant DNA Advisory Canmittee and NIH approval . " The proposal was put to a vote and the result of the voting was 17 in favor, none opposed, and no abstentions. VI_. PROPOSED REVISIONS OF APPENDICES C-II, C-III, AND C-IV TO THE NIH GUIDELINES Mr. Mitchell then asked Dr. McKinney to discuss the proposal (tabs 1284, 1286/IV) made by Dr. Frank Young, Commissioner of FDA, to revise Appendices C-II, C-III, and C-IV of the NIH Guidel ines . The proposal is to delete the following language from these ^?pen dices : "For these exempt laboratory experiments, BL1 physical containment conditions are recommended. "For large-scale (LS) fermentation experiments BL1-LS physical containment conditions are recommended. However, following review by the IBC of appropriate data for a particular host-vector system, some latitude in the application of BL1-LS requirements as outlined in Appendix K-II-A through K-II-F is permitted." And substitute: "For these exempt laboratory experiments, the appropriate physical containment conditions need be no greater than those for the host organism unmodified by recombinant DNA techniques. Recombinant DNA Research, Volume 1 1 [183] “For large scale (LS) fermentation experiments, the appropriate physical containment conditions need be no greater than those for the host organism unmodified by recombinant DNA techniques." Dr. McKinney reviewed sane of the written comments that had been received on this proposal and noted that some contained alternative language to the proposal. Dr. McKinney asked to be placed on record as opposing the adoption of the portion of the proposed language which refers to laboratory level experiments in that BL1 requirements represent nothing more than good laboratory practices and are not restrictive. As far as the application of BL1-LS in large-scale production of exempt organisms. Dr. Young had referred in his letter to manufacturers who utilized conditions of at least BL1-LS "to ensure compliance with the NIH Guidelines." Dr. McKinney noted that these manufacturers were not obligated to comply with the NIH Guidelines and that even in complying with the NIH Guidelines the recommendation to use BL1-LS is just that, a recommendation. In closing. Dr. McKinney stated he felt the proposed amendment by Dr. Young dealing with large-scale fermentation did not offer any advantage over present language and suggested the RAC reject the proposal . Dr. McGarrity said he had come to a different conclusion than Dr. McKinney. He stated the word ".latitude" could be interpreted many different ways. IBCs may interpret it differently, and Dr. Young's proposal clarifies this in a more objective manner. Further, he felt the fact that this proposal came from the Commissioner of FDA does carry some weight in that he is the chief regulator in this whole area. Dr. Cohen suggested the proposal be split in two. For the first part dealing with laboratory experiments, no change, in his view, was necessary since BL1 conditions are simply good laboratory practice. However, with respect to large-scale, he agreed that the wording "sane latitude" is not really helpful to the IBCs. He said he would like to see the terminology reworded for large- scale production to encourage modifications appropriate to the degree of safety required. Dr. Gottesman said she agreed on not changing the sentence dealing with laboratory experiments. For large-scale experiments, she felt it important to maintain IBC oversight on a case-by-case basis. But she agreed that to strengthen this concept of latitude there should be a rewording of that statement and she suggested a statement such as: [ 184 ] Recombinant DNA Research, Volume 1 1 “For large-scale (LS) f ermentation experiments, the IBC shall review physical containment conditions. Generally conditions need be no greater than those for the host organism unmodified by recombinant DNA techniques. IBC review should include consideration of the description of BL1-LS in Appendix K-II." Dr. Johnson stated that since Dr. Young was a previous member of the RAC and is knowledgeable in the molecular biology of B. subtil is , that the RAC should take his suggestions seriously. He then stated he took issue with Dr. McKinney's statement that there was no requirement for manufacturers to obey the NIH Guidelines in light of the fact that industry has indicated it will obey the NIH Guidelines voluntarily and that regulatory agencies insist upon it. Dr. Johnson said that in the vast experience with E. coli , B. subtil is , and S_. cerevisiae there have been no health associated risks involving large-scale production with these organisms except for occasional hypersensitivity to secondary metabolites in the fermentation process. Dr. Johnson said that while he generally supported the thrust of the proposal, since the proposal came from an agency which regulates the company which anploys him, he felt there could be an apparent conflict of interest and that he would like the public record to show that he would be abstaining from any vote on the proposal. Dr. Sharpies asked if the wording proposed by Dr. Young applied only to S^. cerevisiae , B. subtil is , and E. coli , to which Dr. Talbot replied that that was the case. Dr. William Szkrybalo of the Pharmaceutical Manufacturers Association stated that his organization felt the proposed revisions were highly important clarifications of the NIH Guidelines. They will provide “appropriate consistency of policy and practice throughout the research process." He said that at present IBCs are reluctant to use the "seme latitude" provision. He cited the industry's long and distinguished record in fermentation techniques. His organization supports Dr. Young's proposal and believes it will enhance the strategic planning process at member companies and the competitive position of U.S. biotechnology and pharmaceutical industries. Dr. Miller said he would not have a strong obj ection to maintaining the original language where it describes containment at laboratory-scale, but that the important change is for large- scale and the proposed change for laboratory-scale was added for consis tency . Recombinant DNA Research, Volume 1 1 [185] Dr. McKinney noted that Section III-B-5 of the NIH Guidelines inposes upon the IBCs the obligation to establish the containment level for large-scale experiments. Dr. Gottesman underlined the fact that the proposal would not change the requirement for IBC review. She suggested not accepting the first sentence of Dr. Young's proposal, i.e. , keeping the text as is for laboratory- scale experiments. For the large-scale experiments, she suggested accepting Dr. Young's proposal, but with the addition of the word "generally", i.e., "....conditions generally need be no greater..." She said the word "generally" would involve overall advice to the IBCs, but they could raise containment in specific cases if they believed it was indicated. Mr. Mitchell asked Dr. Gottesman if she meant this wording to apply to all three sections being discussed. She replied that she did. Dr. Gottesman then moved that the RAC not accept the first sentence proposed by Dr. Young but accept the second sentence, modified to read: "For large-scale (LS) fermentation experiments, the appropriate physical containment conditions generally need be no greater than those for the host organism unmodified by recombinant DNA techniques." Dr. Qpstein seconded the motion, and Drs. Walters and McKinney said they supported it. Dr. Vidaver suggested that the clause "provided that the new product is neither toxic nor allergenic to humans, " might be added to the end of the sentence. Dr. Gottesman stated that if such cloning produced molecules which were highly toxic for vertebrates they would be covered under Section III-A-1 of the NIH Guidelines. Dr. Cohen said that perhaps one could say: "Ihe appropriate physical conditions are those consistent with good manufacturing processes as used for the host organism without recombinant DNA. " Dr. John Keene f ran Abbott Laboratories said that the RAC should be dealing with the safety associated with recombinant DNA, not the product. In industry, one looks at the safety of personnel and protecting them from any untoward effects regardless of the use of recombinant organisms. Mr. Mitchell then asked Dr. Gottesman to state the current motion as amended for purpose of a vote. She stated the proposal is to change that paragraph in Appendices C-II, C-III, and C-IV which currently begins, "For large-scale..." to now read: [186] Recombinant DNA Research, Volume 1 1 “For large-scale (LS) fermentation experiments, the appropriate physical containment conditions generally need be no greater than those for the host organism unmodified by recombinant DNA techniques." The motion, being duly made and seconded, was approved by a vote of 13 in favor, none opposed, and 2 abstentions. It was noted that Dr. Johnson abstained from voting for reasons of potential conflict of interest. VII. REPORT FROM THE HUMAN G PI E THERAPY SUBCOMMITTEE Mr. Mitchell then called on Dr. Walters to present the report from the Human Gene Therapy Subcommittee. Dr. Walters reported that the Lay Language Working Group had met in January and developed a plan of action for producing a document entitled. Oversight of Research Involving Human Gene Therapy for Human Patients: General Information . He noted that Ms. Ann Witherby, who could not attend today's meeting because of illness in her family, had provided a copy of the working group report which had been distributed to all RAC members. The document to be produced will probably have four parts including: a brief explanation of how gene therapy will work; discussion of the general oversight framework of the Federal Government; a lay language summary of the Points to Consider in the Design and Submission of Human Scmatic-Cell Gene Therapy Protocols; and information about other publications and films available to the public for further information. Dr. Walters said the Human Gene Therapy Subcommittee would review this document at its April 24, 1987, meeting and that it was anticipated to be brought before the full RAC for review at the next RAC meeting. VIII. FUTURE MEETING DATES Dr. Gartland noted the only future meeting date currently scheduled was for June 15 , 19 87 . IX. ADJOURNMENT Having concluded the agenda and there being no further business to be discussed, Mr. Mitchell adjourned the canmittee at 3:25 p.m. , on February 2, 1987. William J. Cortland, Jr. , Ph Executive Secretary Recombinant DNA Research, Volume 1 1 [187] I hereby acknowledge that, to the best of my knowledge, the foregoing Minutes and Attachments are accurate and complet .man Recombinant DNA Advisory Committee National Institutes of Health Recombinant DNA Research, Volume 1 1 [ 188 ] RECCMBINANT Dt^ ADVISORY COMMITTEE CHAIR MITCHELL, Robert E. , LL.B. (87) Attorney at Law 13915 San Antonio Drive Norwalk, California 90650 213 863-8736 BOWMAN, Barbara H. , Ph.D. (87) Professor Department of Anatomy University of Texas San Antonio, Texas 78284 512 567-3800 CARNER, Donald C. (90) President Camer, Ltd. 98 Main Street, Suite 216 Tiburon, California 94920 415 435-1123 CLEWELL, Don Bert, Ph.D. (90) Professor Molecular Microbiology Uhit - D.R.I. University of Michigan 300 N. Ingalls Building, 1198 S.E. Ann Arbor, Michigan 48109-2007 313 763-0117 COHEM, Mitchell L. , M.D. (88) Assistant Director for Medical Science Division of Bacterial Diseases Center for Infectious Diseases Centers for Disease Control Atlanta, Georgia 30333 404 329-3683 DAVIS, Bernard D. , M.D. (88) Director Bacterial Physiology Uhit Harvard Medical School Boston, Massachusetts 02115 617 732-2022 Recombinant DNA Research, Volume 1 1 EPSTEIN, Charles J., M.D. (89) Professor Department of Ftediatrics, M-650 University of California San Francisco, California 94143 415 476-2981 ERICKSON, Robert P. , Ph.D. (90) Director Division of Fediatric Genetics, Box 0178 D1225 Medical Professional Building University of Michigan School of Medicine Ann Arbor, Michigan 48109-0718 313 764-2430 GOTTESMAN , Susan K., Ph.D. (86) Senior Investigator Laboratory of Molecular Biology National Cancer Institute, 37/4B09 National Institutes of Health Bethesda, Maryland 20892 301 496-3524 JOHNSON, Irving S. , Ph.D. (88) Vice President Eli Lilly and Company Lilly Corporate Center Indianapolis, Indiana 46285 317 261-4391 JOKLIK, Wolfgang K., D.Phil. (86) Professor & Chairman Department of Microbiology & Immunology IXike University Medical Center Durham, North Carolina 27710 919 684-5138 [ 189 ] FEBRUARY 1987 ( 87 ) KORWEK , Edward L. , Ph.D. , J.D. (88) Attorney at Law Law Office of Keller and Heckman 1150 17th Street, N.W. , Suite 1000 Washington, D.C. 20036 202 956-5621 MacNAUGHTON, J. Robert (89) 9605 Weathered Oak Court Rethesda , Maryland 20817 301 469-6670 MILLS, Mark C., M.n. (86) Associate Pathologist Department of Pathology Good Samaritan Hospital Vincennes, Indiana 47591 812 882-5220 MUSGRAVE, Gerald L. , Ph.D. (89) President Economics America, Inc. 543 Church Street Ann Arbor, Michigan 48104 313 995-0865 NEIMAN, Paul E. , M.D. (89) Associate Director for Basic Sciences Fred Hutchinson Cancer Research Center 1124 Columbia Street Seattle, Washington 98104 206 467-4417 PAGANO, Joseph S., M.D. (89) Director Cancer Research Center University of North Carolina Chaoel Hill, North Carolina 27514 919 966-3036 [ 190 ] PIRONE, Thomas P. , Ph.D. Professor Department of Plant Pathology University of Kentucky Lexington, Kentucky 40506 606 257-2759 PRAMER, David, Ph.D. (88) Director Waksman Institute of Microbiology P.O. Box 759 Piscataway, New Jersey 08854 201 932-3068 RAPP, Fred, Ph.D. (87) Professor & Chairman Department of Microbiology Pennsylvania State University Hershey, Pennsylvania 17033 717 534-8253 ROBERTS, Jeffrey W. , Ph.D. (89) Associate Professor Department of Biochemistry, Molecular and Cell Biology Cornell University Ithaca, New York 14853 607 255-2430 SHARPLES, Frances E. , Ph.D. (87) Research Associate Oak Ridge National Laboratory P.O. Box X, FEDC Building Oak Ridge, Tennessee 37831 615 576-0524 VIDAVER, Anne K., Ph.D. (88) Professor Department of Plant Pathology University of Nebraska Lincoln, Nebraska 68583 402 472-2858 Recombinant DNA Research, Volume 1 1 WALTERS, LeRoy, Ph.D. Di rector Center for Bioethics Kennedy Institute Geo roe town University Washington, D.C. 20057 (87) WITHERBY, Anne R. , B.S. 2 Cannonwealth Avenue Boston, Massachusetts 02116 617 247-0123 (87) 202 625-2386 EXECUTIVE SECRETARY GARTLAND, William J., Jr., Ph.D. Director Office of Recombinant CNA Activities National Institute of Allergy and Infectious Diseases, 31/3B10 National Institutes of Health Bethesda, Maryland 20892 301 496-6051 Recombinant DMA Research, Volume 1 1 [ 191 ] NON-VOTING AGENCY REPRESENTATIVES DEPARTMENT OF AGRICULTURE (USDA) TOLIN, Sue A., Ph.D. Science & Education Administration Cooperative State Research Service Department of Agriculture 213 Justin S. Morrill Building Washington, D.C. 20250 202 447-5741 SHIBLEY, George P., Ph.D. (ALT) Department of Agriculture Federal Building, Room 839 6505 Belcrest Road Hyattsville, Maryland 20782 301 436-8674 FULKERSON, John F. , Ph.D. (ALT) Science & Education Administration Cooperative State Research Service Department of Agriculture 213 Justin S. Morrill Building Washington, D.C. 20250 202 447-5741 DEPARTMENT OF COMMERCE CJ*EIFER, Bernard, Ph.D. Regulatory & Legislative Analysis Division, Room U-4877 Office of Business Analysis Department of Commerce Washington, D.C. 20230 202 377-3078 SHYKIND, Edwin, Ph.D. (ALT) Trade Development, Roam H-4045 International Trade Administration Department of Commerce Washington, D.C. 20230 202 377-4694 DEPARTMENT OF DEFENSE DALRYMPLE, Joel M., Ph.D. Department of Viral Biology U.S. Army Medical Research Institute of Infectious Diseases Ft. Detrick Frederick, Maryland 21701-5011 301 663-2665 Recombinant DNA Research, Volume 1 1 DEPARTMENT OF HEALTH AND HUNAN SERVICES (DHHS) DHHS Alcohol, Drug Abuse, and Mental Health Adninistration SKIRROLL, Lana, Ph.D. Office of Science, Roan 13-103 5600 Fishers Lane Rockville, Maryland 20857 301 443-4336 AUTRY, Joseph H. , III, M.D. (ALT) Office of Policy Coordination Alcohol, Drug Abuse, and Mental Health Administration Parklawn Building, Room 12C-06 Rockville, Maryland 20857 301 443-4111 DHHS Centers for Disease Control (CPC) NOBLE, Gary R. , M.D. Office of the Director Buildinq 1, Roan 2047 Centers for Disease Control Atlanta, Georgia 30333 404 329-3701 DHHS, CPC, National Institute for Occupational Safety and Health LEMFN, Richard A. National Institute for Occupational Safety & Health 4676 Columbia Parkway Cincinnati, Ohio 45226 513 684-8302 DHHS Food and Drug Administration MILLER, Henry I., M.D. Food and Drug Administration, HF-6 5600 Fishers Lane, Roan 14-90 Rockville, Maryland 20857 301 443-4650 DHHS Health Resources and Services Administration MANLEY, Audrey, M.D. Office of the Administrator Health Resources & Services Administration 5600 Fishers Lane, Roan 14-15 Rockville, MD 20857 301 443-2204 NUTTING, Paul (ALT) Office of Primary Care Studies Health Resources & Services Administration 5600 Fishers Lane, Roan 13-25 Rockville, P1D 20857 301 443-6007 Recombinant DNA Research, Volume 1 1 [1 93] DEPARTMENT OF ENERGY DURA, George, Ph.D. Office of Health & Environmental Research, EV-33 Department of Energy Washington, D.C. 20545 202 353-3651 DEPARTMENT OF THE INTERIOR PIMENTEL, Mariano B., M.D. Division of Medical & Health Services, Room 7045 Department of the Interior 18th & C Street, N.W. Washington, D.C. 20240 202 '343-2081 DEPARTMENT OF LABOR YODAIKEN, Ralph E. Office of Occupational Medicine USDOL/OSHA, Roan N-3651 200 Constitution Avenue, N.W. Washington, D.C. 20210 202 523-7047 HAIMES, Stanley C. (ALT) Office of Occupational Medicine USDOL/OSHA, Roan N-3651 200 Constitution Avenue, N.W. Washington, D.C. 20210 202 523-7047 DEPARTMENT OF TRANSPORTATION CUSHMAC, George E. , Ph.D. Research & Special Programs Administration Department of Transportation 400 7th Street, S.W. Washington, D.C. 20590 202 426-2311 ENVIRONMENTAL PROTECTION AGENCY LEVIN, Morris, Ph.D. Office of Research & Development, RD-682 Environmental Protection Agency 401 M Street, S.W. Washington, D.C. 20460 202 382-5967 KUTZ, Frederick W. , Ph.D. (ALT) Pesticides, Toxic, & Air, RD-682 Environmental Protection Agency 401 M Street, S.W. Washington, D.C. 20460 202 382-5967 1194 ] Recombinant DNA Research, Volume 11 MILEW3KI, Elizabeth, Ph.D. (ALT) Office of Pesticides & Toxic Substances, TS-788 Environmental Protection Agency 401 m Street, S.W. Washington, D.C. 20460 202 382-2914 NATIONAL AERONAUTICS AND SPACE ADMINISTRATION DeVINCENZI, Donald L. , Ph.D. Research & Technology Development, Code ERT-3 National Aeronautics & Space Administration Washington, D.C. 20546 202 755-3732 HARRIMAN, Phillip, Ph.D. Physiology, Cellular, f, Molecular Biology, Poem 329 National Science Foundation Washington, D.C. 20550 202 357-9687 WALSH, William J. , III Coordinator for Biomedical Research & Health Affairs, Room 4325 State Department 22 & C Streets, N.W. Washington, D.C. 20520 202 647-8772 NATIONAL SCIENCE FOUNDATION STATE DEPARTMENT VETERANS ADMINISTRATION GREEN, Richard J., M.D. Medical Research Service, 151 Veterans Administration (VACO) 810 Vermont Avenue, N.W. Vfashington, D.C. 20420 BERMAN, Howard M. (ALT) Veterans Administration 810 Vermont Avenue, N.W. Washington, D.C. 20420 Medical Research Service, 151D 202 389-5041 202 389-5065 Recombinant DNA Research, Volume 1 1 (195] LIAISON REPRESENTATIVES La FONTAINE, F'rancois Science & Technology Delegation of the Commission of the European Communities 2100 M Street, N.W. , Suite 707 Washington, D.C. 20037 202 862-9575 JONES, Daniel P., Ph.D. Humanities, Science and Technology Division of Research Programs National Endowment for the Humanities Washington, D.C. 20506 202 786-0207 UNO, Professor Tetsuo Department of Biology Faculty of Science University of Tokyo Hongo, Tokyo 113 Japan fc [ 196 ] Recombinant DNA Research, Volume 1 1 AD HOC CONSULTANTS MCKINNEY, Robert, Ph.D. Safety Operations Branch Occupational Safety & Health Branch National Institutes of Health, 13/3KD4 Be the sd a , Maryland 20892 301 496-2960 McOARRITY, Gerard J., Ph.D. Department of Microbiology Coriel 1 Institute for Medical Research Camden, New Jersey 08103 609 966-7377 CLOWES, Roys ton C. , Ph.D. Division of Biology University of Texas at Dallas Richardson, Texas 75080 214 690-2501 Recombinant DMA Research, Volume 1 1 [ 197 ] FEBFUARY 1987 Federal Register / Vol. 52. No. 47 / Wednesday, March 11. 1987 / Notices 7525 DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Recombinant DNA Research: Proposed Action Under Guidelines agency: National Institutes of Health. PHS, DHHS. ACTION: Notice of proposed action under NIH guidelines for research involving recombinant DNA molecules. SUMMARY: This notice sets forth a proposed action to be taken under the National Institutes of Health (NIH) Guidelines for Research Involving Recombinant DNA Molecules. Interested parties are invited to submit comments concerning this proposal. This proposal will be considered by the Recombinant DNA Advisory Committee (RAC) at its meeting on June 15, 1987. After consideration of this proposal and comments by the RAC, the Director of the National Institutes of Health will issue a decision on this proposal in accord with the NIH Guidelines. DATES: Comments received by May 29, 1987, will be reproduced and distributed to the RAC for consideration at its June 15, 1987, meeting. ADDRESS: Written comments and recommendations should be submitted to the Director, Office of Recombinant DNA Activities, 12441 Parklawn Drive, Room 58, Rockville, MD 20852. All comments received in timely response to this notice will be considered and will be available for public inspection in the above office on weekdays between the hours of 8:30 a.m. and 5:00 p.m. FOR FURTHER INFORMATION: Background documentation and additional information can be obtained from the Office of Recombinant DNA Activities, 12441 Parklawn Drive, Room 58, Rockville. Maryland 20852, (301) 770- 0131. SUPPLEMENTARY INFORMATION: The NIH will consider the following action under the NIH Guidelines for Research Involving Recombinant DNA Molecules: Proposed Amendment of Section I-C Section I-C of the NIH Guidelines currently reads as follows: I-C General Applicability The Guidelines are applicable to all recombinant DNA research within the United States or its territories which is conducted at or sponsored by an institution that receives any support for recombinant DNA research from the National Institutes of Health (NIH). This includes research performed by the NIH directly. An individual receiving support for research involving recombinant DNA must be associated with or sponsored by an institution that can and does assume the responsibilities assigned in these Guidelines. The Guidelines are also applicable to projects done abroad if they are supported by NIH funds. If the host country, however, has established rules for the conduct of recombinant DNA projects, then a certificate of compliance with those rules may be submitted to NIH in lieu of compliance with the NIH Guidelines. The NIH reserves the right to withhold funding if the safety practices to be employed abroad are not reasonably consistent with the NIH Guidelines. In a letter dated January 9, 1987, Mr. Edward Lee Rogers of Washington, DC, Counsel for the Foundation on Economic Trends and Jeremy Rifkin, has proposed that the following text be inserted after the first sentence of the third paragraph of Section I-C: For the purposes of the preceding sentence, the term 'project' includes any research or development of the recombinant organism or other product or process in question. Including all such work that is reasonably foreseeable when the NIH support is received. NIH support includes both money grants and any type of in-kind support, including research conducted directly by NIH. supplies, equipment the use of facilities, and biological research materials. NIH support has been given where the source of funds or in-kind support is, directly or Indirectly, the NIH. OMB'8 "Mandatory Information Requirements for Federal Assistance Program Announcements" (45 FR 39592) requires a statement concerning the official government programs contained in the Catalog of Federal Domestic Assistance. Normally NIH lists in its announcements the number and title of affected individual programs for the guidance of the public. Because the guidance in this notice covers not only virtually every NIH program but also essentially every Federal research program in which DNA recombinant molecule techniques could be used, it has been determined to be not cost effective or in the public interest to attempt to list these programs. Such a list would likely require several additional pages. In addition, NIH could not be certain that every Federal program would be included as many Federal agencies, as well as private organizations, both national and international, have elected to follow the NIH Guidelines. In lieu of the individual program listing, NIH invites readers to direct questions to the information address above about whether individual Programs listed in the Catalog of Federal Domestic Assistance are affected. Dated: March 3, 1987. Bernard Talbot, Acting Director. National Institute of Allergy and Infectious Diseases. [FR Doc. 87-4904 Filed 3-10-87; 8:45 am] BIL1JNQ CODE 4140-01-M [198] Recombinant DNA Research, Volume 1 1 Federal Register / Vol. 52. No. 60 / Monday. March 30, 1987 / Notices 10169 Dated: March 18. 1887. Betty J. Beveridge. Committee Management Officer. NIH. [FR Doc. 87-8870 Filed 3-27-87: 8:45 am] BUXOM COOt 4140-01-44 National Institute of Neurological and Communicative Disorders and Stroke; Meetings Pursuant to Pub. L 92-463, notice is hereby given of the meetings of the committees of the National Institute of Neurological and Communicative Disorders and Stroke. These meetings will be open to the public to discuss administrative details or other issues relating to committee business as Indicated in the notice. Attendance by the public will be limited to space available. These meetings will be closed to the public as indicated below in accordance with the provisions set forth in sections 552b(c)(4) and 552b(c)(6). Title 5. U.S.C. and section 10(d) of Pub. L 62-463, for the review, discussion and evaluation of individual grant applications. These applications and the discussions could reveal confidential trade secrets or commercial property such as patentable material, and personal information concerning individuals associated with the applications, the disclosure of which would constitute a clearly unwarranted invasion of personal privncy. Summaries of meetings, rosters of committee members, and other information pertaining to the meetings can be obtained from the Executive Secretary indicated. Name of Committee: National Advisory Neurological and Communicative Disorders and Stroke Council and Ita Planning Subcommittee. Date: May 13. 1887 (Planning Subcommittee). Place: National Institutes of Health. Building 31. Conference Room 8A49. 9000 RockviUe Pike. Bethesda. Maryland 20892. Open: 1 p.m.-3 p.m. Agenda: To discuss program planning, program accomplishments and special reports. Closed: 3 p.m. -5 p.m. Closure Reason: For review of grant applications. Dates: May 14-15. 1987 (Council). Place: National Institutes of Health. Building 31 C. Conference Room 8. 9000 Rockville Pike. Bethesda. Maryland 20892. Open: May 14. 8 a.m.-l p.m. Agenda: To discuss program planning, program accomplishments and special reports. Closed: Moy 14. 1 p.m. — recess: May 15. 8:30 a.m. — adjournment. Closure Reason: For review of grant applications. Executive Secretary: John C Dalton. Ph.D.. Director. NINCDS-EAP. National Institutes of Health. Bethesda. Maryland 20892. Telephone: 301/496-9248. Name of Committee: Neurological Disorders Program Project Review B Committee. Dates: June 8-10. 1987. Place: Capitol Holiday Inn. The Federal Center Plaza. Washington. DC 20024. Open: June 8. 8 p.m.-8:r0 p.m. Agenda: To discuss program planning, program accomplishments and special reports. Closed: June 8. 8:30 p.m. — recess: ]une 9. 8 a.m. — recess; June 10. 8 ajn. — adjournment. Closure Reason: To review grant applications. Executive Secretary: Dr. A. Beau White. Federal Building, 'loom 9C-14. National Institutes of Health. Bethesda. Maryland 20892. Telephone: 301/408-9223. Name of Committee: Communicative Disorders Review Committee. Dates: June 11-12. 1987. Place: Hyatt Rsgency-Bethesda. One Bethesda Metro Canter. Bethesda. Maryland 20814. Open: June 11. 8:30 a.m.-9 a.m. Agenda: To discuss program planning, program accomplishments and special reports. Closed: ]une 11. 9 a.m. — recess: June 12. 8 a.m. — adjournment. Closure Reason: To review grant applications. Executive Secretary: Dr. Marilyn Semmee, Federal Building. Room 90-14. National Institutes of Health. Bethesda. Maryland 20892. Telephone: 301/496-9223. Name of Committee: Neurological Disorders Program Project Review A Committee. Dates: June 18-20. 1987. Place: Cues! Quarters. 7335 Wisconsin Avenue. Bethesda. Maryland 20814. Open: June 18. 8 p.m.-8:30 p.m. Agenda: To diecuss program planning, program accomplishments and special reports. Closed: June 18. 8:30 p.m.— recess; June 19, 8:30 a.m. — recess: June 20. 8 a.m. — adjournment Closure Reason: To review grant applications. Executive Secretary: Dr. Herbert Yellln. Federal Building. Room 9C-14. National Institutes of Health. Bethesda. Maryland 20892. Telephone: 301/498-9223. (Catalog of Federal Domestic Assistance Program No. 13.853. Clinical Basis Research: No. 13.854. Biological Basis Research) Dated: March 18. 1987. Batty J. Beveridge, Committee Management Officer. NIH. [FR Doc. 87-6889 Filed 3-27-87: 8:45 am) BIIXJNO coot 4140-01-44 Recombinant DNA Advisory Committee Working Group on Human Gone Therapy; Meeting Pursuant to Pub. L 92-463, notice Is hereby given of a meeting of the Recombinant DNA Advisory Committee S -094999 0044<02X27-MAR-I7- 15:5046) Human Gene Therapy Subcommittee at the National Institutes of Health. Building 3lC. Conference Room 9, 9000 Rockville Pike. Bethesda. Maryland 20892. on April 24. 1937, from approximately 9:00 a.m. to adjournment at approximately 5:00 p.m. to discuss scientific issues and review submission of preclinical data for information purposes. This meeting will be open to the public. Attendance by the public will be limited to space available. Further information may be obtained from Dr. William J. Gartland. Executive Secretary. Recombinant DNA Advisory Committee Human Gene Therapy Subcommittee. Office of Recombinant DNA Activities. 12441 Parklawn Drive. Suite 58. Rockville. Maryland 20852. telephone (301) 770-0131. OMB'a "Mandatory Information Requirement* for Federal Assistance Program Announcements" (45 FR 39592) requires a statement concerning the official government programs contained in the Catalog of Federal Domestic Assistance. Normally NlH lists in Its announcements the number and title of affected individual programs for the guidance of the public. Because the guidance in this notice cover* not only virtually every NIH program but also essentially every Federal research program In which DNA recombinant molecule techniques could be used, it has been determined to be not cost effective or in the public interest to attempt to list these programs. Such a list would likely require several additional pages. In addition. NIH could not be certain that every Federal program would be Included as many Federal agencies, as well as private organizations, both national and International, have elected to follow the NIH Guidelines. In lieu of the individual program listing. NIH invites readers to direct questions to the information address above about whether individual Programs listed in the Catalog of Federal Domestic Assistance are affected. Dated: March 20. 1987. Betty J. Beveridge. Committee Management Officer. NIH. (FR Doc. 87-8887 Filed 3-27-87: 8:45 am| •11X1)40 CODE 4140-01-44 DEPARTMENT OF HOUSING AND URBAN DEVELOPMENT Office of Administration (Docket No. N -87-1687) Submission of Proposed Information Collections to OMB aoency: Office of Administration. HUD. action: Notices. SUMMARY: The proposed information collection requirement described below hove been submitted to the Office of Management and Budget (OMB) for Recombinant DNA Research, Volume 1 1 [199] DEPARTMENT CF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE NATKML INSTITUTES CF HEALTH RECCMBINANT DNA ADVISORY CCMMITTEE HUMAN GENE THERAPY SUBCOMMITTEE Minutes of Meeting * April 24, 1987 The Human Gene Therapy Subcommittee, Recombinant ENA Advisory Committee, was convened at 9:00 a.m. on April 24, 1987, at the National Institutes of Health, Building 31C, Conference Room 9, 9000 Rockville Pike, Bethesda , Maryland 20892. Er. LeRoy Walters was Chair. The following were present for all or part of the meeting . Subconrnittee mem bers: Judith Areen James Childress Susan Gottesnan Samuel Gorovitz William Kelley Arno Motulsky The subcommittee roster is attached. Robert Murray LeRoy Walters Anne Witherby William Gartland (Executive Secretary) Liaison representatives: Robert Cook-Deegan, Office of Technology Assessment Bonnie Lee, Food and Drug Administration Charles McCarthy, National Institutes of Health Henry Miller, Food and Drug Administration Other National Institutes of Health staff: W. French Anderson, NHLBI Stanley Barban, NLAID Michael Gottesman, NCI Charles MacKay, OD Cecilia Mulrennan, OD Robert Wieder, NHLBI -*-The subcommittee is advisory to the Recombinant ENA Advisory Committee and its recommendations should not be considered as final or accepted. 59/19 [ 200 ] Recombinant DNA Research, Volume 1 1 Others: Martin Buechi, Swiss Bnbassy Keith Haglund, Medical Tribune Philip E. Musi, The Blue Sheet Harold M. Schmeck, Jr., New York Times Lisa White, F-D-C Reports, Inc. Recombinant DMA Research, Volume 1 1 I. Call to Order and Opening Remarks Dr. Walters called the meeting to order and noted that a system for rotation of the membership of the subccmmittee had been established. He said that the members whose terms would be completed in June 1987, Drs. Gorovitz, Grobstein, Motulsky, and Rich, would be invited to assist the subccmmittee as ad hoc consultants. II. Submission of Preclinical Data Drs. Anderson, Blaese, Nienhuis of the National Institutes of Health (NIH), and Dr. O'Reilly of Memorial Sloan Kettering Cancer Center, submitted a document entitled "Human Gene Therapy Preclinical Data Document" to the subccmmittee. [This document is not attached to these minutes because of its length but is available from the Office of Recanbinant CNA Activities.] Dr. Anderson stated that the document was submitted in response to an invitation that investigators supply preclinical data for information purposes as part of an education process for the subcommittee and submitters. It is not being submitted for formal review and approval at this time. He said he felt that many of the issues are not controversial, but several issues have no absolute answers. He said that each of the questions raised in the "Points to Consider in the Design and Submission of Human Saratic-Cell Gene Therapy Protocols" document had been addressed in a general way. He said that three critical questions, with no absolute answers, haw emerged: 1. Will the postulated in vivo growth advantage of adenc6ine deaminase (ADA) plus cells in ADA-def icient patients be sufficient for clinical improvement? 2. Will the vector-delivered ADA gene be expressed at a sufficiently high level in stem cells and their progeny so that the postulated _in vivo growth advantage will be maintained throughout the life cycle of the T-cell? 3. Must the retroviral vector particle preparation be totally free of helper virus in order to make the risk/benefit ratio satisfactory? With regard to the last question, Dr. Anderson said that a totally helper- virus-free system is not currently available and may not be possible. In general, Dr. Anderson said that the submission had been prepared to provide data to the subccmmittee and the public, to clarify the issues, and to determine what additional information the subcommittee wants. Dr. Miller said that the document appears to be in a form acceptable to the Food and Drug Adminstration (FDA); he said new Investigational New Drug regulations placed more enphasis on safety than on efficacy in early clinical trials. [ 202 ] Recombinant DNA Research, Volume 1 1 Dr. Anderson then sumnarized the contents of the following sections of the document : I. Description of Proposal A. Objectives and rationale of the proposed research B. Research design 1. Structure and characteristics of the biological systan a. Structure of the cloned DNA b. Structure of the material that will be administered (1) Viral particle preparation (2) Producer cells 2. Preclinical studies a. Delivery system b. Expression c. Safety 3. Clinical procedures 4. Public health considerations 5. Qualifications of investigators C. Selection of patients D. Informed consent E. Privacy and confidentiality II. Special Issues III. Requested Documentation Appendix Contents References Dr. Anderson surmarized a monkey safety protocol in Appendix A in which a large quantity of a replication defective amphotrcpic vector will be injected intravenously into a primate. A high dose of wild-type amphotrcpic helper [203] Recombinant DNA Research, Volume 1 1 virus will be injected into another primate. The primates will nonitored for adverse effects. Dr. Murray asked if submitters should be required to do experiments in addition to those that would be required by the FDA. Dr. Motulsky said he thought that Dr. Anderson was paying an exceptional anount of attention to hypothetical hazards. Dr. Anderson noted that pages 62-69 of the document are written as a clinical protocol although it is not being submitted formally as a protocol. In response to a question frcm Dr. Gorcvitz regarding an alternative approach to enzyme replacement for ADA deficiency cited on page 13 of the submission. Dr. Anderson said that it is too early to knew how effective this approach might be. This approach involves injection of bovine ADA conjugated to polyethylene-glycol. Dr. Kelley noted this treatment would be analogous to administering insulin to a diabetic; it would need to be repeated at regular intervals for each patient. After hearing Dr. Anderson's summary, the subcommittee agreed that the document should be considered a preliminary draft of a proposal and submitted for review by outside consultants who will be asked to submit written comments that will become part of the public record of review. Names of potential consultants were suggested to the executive secretary. III. General Information Document Ms. Witherby suimarized the latest draft of a general information document on gene therapy which had been prepared on April 23, 1987. Dr. Mac Kay of the NIH suggested that the document needs additional infor- mation about gene therapy itself. Several other changes were suggested by members of the subcommittee and liaison representatives. Dr. Walters said that he would take the comments into consideration and prepare a revised draft of the document. IV. Adjournment The meeting was adjourned at 2:30 p.m. [ 204 ] Recombinant DNA Research, Volume 1 1 Respectfully submitted, U J. -i. jLl t\land, Jr., Ph.D. eL Willian J. Gar Executive Sec re :ary I hereby certify that, to the best of my knowledge, the foregoing Minutes and Attachments are accurate and complete. 1 f 7 LeRoy Wal,ters, Ph.D. Chair Human Gene Therapy Subcommittee Recombinant DNA Research, Volume 1 1 [ 205 ] RECOMBINANT DNA ADVISORY COMMITTEE HUMAN GENE THERAPY SUBCOMMITTEE CHAIR WALTERS, LeRoy, Ph.D. (89) Center for Bioethics Kennedy Institute of Ethics Georgetown University Washington, D.C. 20057 202 625-2386 AREEN, Judith, J.D. (90) Georgetown University Law Center 600 New Jersey Avenue, N.W. Washington, D.C 20001 202 662-9048 CAPPOM, Alexander, LL.B. (89) The Law Center University of Southern California Los Angeles, California 90089-0071 213 743-7734 CHILDRESS, James F., Ph.D. (90) Department of Religious Studies Cocke Hall Charlottesville, Virginia 22903 804 924-3741 GOPOVITZ , Samuel, Ph.D. (87) Dean of Arts and Humanities Syracuse University Syracuse, NY 13210 315 423-2201 GOTTESMAN, Susan K. , Ph.D. (89) Laboratory of Molecular Biology National Cancer Institute, 37/4B09 National Institutes of Health Bethesda, Maryland 20205 301 496-3524 GROBSTEIN, Clifford, Ph.D. (87) Department of Science, Technology, & Public Affairs, Mail Code 0060 University of California, San Diego La Jolla, California 92093 619 534-3189 [ 206 ] KELLEY, William N. , M.D. (89) Department of Internal Medicine 3100A Taubman Center University of Michigan Medical Center Ann Arbor, Michigan 48109-0368 313 936-4340 MAHONEY, Maurice J., M.D. (90) Department of Human Genetics Yale University 333 Cedar Street, 305 WWW New Haven, Connecticut 06510 203 785-2661 MITCHELL, Robert E. , LL.B. (88) Attorney at Law 13915 San Antonio Drive Norwalk, California 90650 213 863-8736 MDTULSKY, Arno G., M.D. (87) Department of Medicine University of Washington Seattle, Washington 98195 206 543-3593 MURRAY, Robert F., M.D. (88) Division of Medical Genetics Howard University, Box 75 520 W Street, N.W. Washington, D.C. 20059 202 636-6382 RICH, Robert F., Ph.D. (87) Institute of Government Public Affairs University of Illinois 1201 West Nevada Street Urbana, Illinois 61801 217 333-3340 Recombinant DNA Research, Volume 11 VAFWUS, Harold, Ph.D. (88) Department of Microbiology University of California San Francisco, California 94143 415 476-2824 WITHERBY, Anne R., B.S. (88) 2 Commonweal th Avenue Boston, Massachusetts 02116 617 247-0123 EXECUTIVE SECRETARY GARTLAND, William J. , Jr., Ph.D. Office of Recombinant DIA Activities National Institutes of Health 12441 Parklavn Qrive, Suite 58 Rockville, Maryland 20852 301 770-0131 CONSULTANT TEMIN, Howard M., Ph.D. Department of Oncology McArdle Laboratory for Cancer Research University of Wisconsin Madison, Wisconsin 53706 608 262-1209 LIAISON REERESENTATIVES COCK -EE EGAN, Robert, M.D. Office of Technology Assessment U.S. Congress Washington, D.C. 20510 202 226-2034 LEE, Bonnie M. Health Assessment Eblicy Staff Office of Health Affairs Food S. Drug Administration, HFY-20 5600 Fishers Lane Rockville, Maryland 20857 301 443-1382 Recombinant DNA Research, Volume 1 1 McCarthy, Charles, Ph.D. Office of Ftotection frcm Research Risks Office of the Director National Institutes of Health, 31/4B09 Bethesda, Maryland 20205 301 496-7005 MILLER, Henry I., M.D. Food and Drug Administration, HF-6 5600 Fishers Lane, Roan 14-90 Rockville, Maryland 20857 301 443-4650 [207] I [ 208 ] Recombi, Recombinant DNA Research, Volume 11 Selected Letters and Documents January 1 986 through April 1 987 Recombinant DNA Research, Volume 1 1 ( 209 ] 0 1 HIAlty DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service National Institutes of Health Bethesda, Maryland 20892 Building : 31 Room : 3B10 (301) 496- 6051 February 25, 1986 MEMORANDUM To: Interested Parties Fran: Executive Secretary Working Group on Hurra n Gene Therapy Recorihinant DNA Mvisory Committee Subject: Review of Preclinical Data The Working Group on Hunan Gene Therapy of the Recorihinant DNA Advisory Committee, at its meeting on December 16, 1985, indicated that it is willing to accept preclinical cbta on construction and packaging of vectors, studies in tissue culture and intact aniirals, etc. leading towards development of techniques for human scmatic-cell gene therapy. The working group errphasized that submission of such preclinical data will not be part of the formal review and approval process stipulated by Section I II -A— 4 of the NTH Guidelines for Research Involving Recombinant ENA Molecules, but rather will be for information purposes and part of an education process for the working group ard submitters . I am attaching a copy of the Points to Consider In the Design and Submission of Human Scmatic-Cell Gene Therapy Protocols . Please feel free to contact me at (301) 496-6051 for additional information. I I William J. Gartland, Jr., Fh.D. Attachment [ 210 ] Recombinant DNA Research, Volume 11 DEPARTMENTOF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Rockville MD 20857 JUL 2 5 1985 Dr. W.J. Gartland, Jr. ORDA Building 31, Room 3B-10 NIH Bethesda, Maryland 20205 Dear Bill, I wish to convey briefly FDA’s views on the revision of the NIH Guidelines proposed by the Committee for Responsible Genetics in their communication dated March 26, 1986. In summary, we believe that while the proposals raise some important generic medical-ethical Issues, the proposals are unnecessary. Current regulations and guidelines are adequate to address the kinds of situations apparently of concern to the Committee for Responsible Genetics, and at the same time provide the flexibility that is necessary for regulating clinical Investigations, especially in areas of evolving medical technologies. Moreover, the rather rigid proposals, if adopted, would diminish the flexibility that is one of the strengths of the RAC's function of advice and consent. We urge their rejection by the Working Group. I look forward to the meeting of the Working Group on August 8. Sincerely, Henry I. Miller, M.D. Office of the Commissioner Recombinant DNA Research, Volume 1 1 [ 211 ] San Francisco State University 1600 HOLLOWAY AVENUE • SAN FRANCISCO, CALIFORNIA 94132, (415) 469-1548 DEPARTMENT OF BIOLOGY August 25, 1986 Director Office of Recombinant DNA Activities Building 31, Room 3-B-10 National Institutes of Health Bethesda, Maryland 20892 Dear Sir/Madam: I want to comment on the proposal to modify Section III-A-4 of the NIH Guidelines made by the Committee for Responsible Genetics, Boston, Massachusetts, which would ensure that germ line gene therapy proposals in humans would not be reviewed by RAC or approved by NIH. I am strongly in favor of the proposed alterations in the guidelines and I am in agreement with the rationale presented in the Federal Register (Vol. 51, No. 122, June 25, 1986, p. 23210-23211) by the Boston Committee. It is particularly appropriate as the committee noted^ that such therapy not be undertaken prior to full and open discussion of the issues by the public. Ri nrprel u lrnnrc Professor of Biology RGD : wt [ 212 ] Recombinant DNA Research, Volume 1 1 BOSTON WOMEN'S HEALTH BOOK COLLECTIVE 15 Sept 1986 rffcScJritxtaixKKit. 47 Nichols A Watertown, MA 02172 USA 617-924-0271 Dr. William Gartland Director, Office of Recombinant DNA Activities Building 31, Rm 3B10 NIH Bethesda, MD 20892 Dear Dr. Gartland: We are writing to express our support for the Committee for Responsible Genetics proposal now before the Recombinant DNA Advisory Committee to modify section III-A-4 of the NIH guidelines. We'd like to emphasize the following re. human gene therapy: - It needs to be stated as a matter of public record that the RAC will not fund human germ line therapy experiments at this time. A statement to this effect in the "Points to Consider" section is not binding and therefore not adequate. - It is crucial to have a public education campaign that outlines in clear language the positions and procedures of the RAC and its working committees. It is also important to organize public forums on the ethical and social questions surrounding the use of human gene therapy. - There need to be more opportunities to discuss general policies about human gene therapy. What avenues are available at this time? Sincerely, Judy Norsigian Co-director Recombinant DNA Research, Volume 1 1 [ 213 ] CURRENT PROJECTS Boston Women's Health Book Collective Co-authors of THE NEW OUR BODIES, OURSELVES 97 Nichols Ave Watertown, MA 0E17E 617-9E9-0271 Spring y2ffieDlS_t!eilt!l_lDformatioD_QBDtti:- Our center probably the most extensive collection of women’s health information in the country, much o.f which is available from no other single source. In addition to established journals, books and other reference materials, the works of women’s health centers, social scientists, grassroots groups, lawyers, students and legislators give our collection its expansive scope and unique perspective. Each year hundreds write to us for information or come in person to do research and consult with our staff; use of the Center has increased 300 per cent since 198S. The Women’s Health Information Center is also the base for our speakers bureau and other activities: d*=di.a Outreach. Our office receives at least twenty calls a week from the media. Complex health issues affecting women need not only a clear and accurate description, but also the feminist analysis we bring. Because media attention, to health issues has increased so much, our top priority for the next year is to establish a regular information service to 200 selected media representatives interested in women’s health. Nuestros Cuerpos t Nuestras Vidas ^ Responding to a lack of women’s health information in Spanish, the Collective since 1977 has published and distributed C^yesiLcs Cyerpos , Nue§tra§ Vidas , the U.S. Spanish-1 anguage edition of Qur Bodies, Qur.gel.yes. Almost 50,000 copies are now in circulation, many of them provided at no cost to family planning and community clinics, farmworker organiza- tons, and individuals with limited income. Over two thousand copies have been sent to a dozen countries in Latin America. Currently, we are working with several women’s groups in Latin America eager to undertake their own region- al editions in Spanish and Portuguese. A«igas_Latinas_En_Acgion_Prg_§alud .. Otherwise known as ALAS, this is a group of Latina women who conduct bi- lingual discussion groups and workshops on women’s health. Most recently they offered a program to women in prison and will be producing innovative bilingual women’s health lit- erature like their upcoming working paper on sexuality. Recombinant DNA Research, Volume 1 1 1986 has [ 214 ] guRRENI PRQJECIS I§3!B2D_PC2 Jg£l • Toxic shock syndrome (TSS) is still kill- ing women and uniform labeling is crucial for reducing the number of cases. The Collective's mailing alerts and pub- lic statements calling for uniform absorbency labeling have generated hundreds of letters to the Food and Drug Administration (FDA). We are the major group in the country initiating consumer pressure on the FDA and have assisted over a dozen reporters with special articles on tampons and TSS. Recently* the leading tampon manufacturer agreed to introduce absorbency labeling following the recommendation of several consumer groups like ours. lo£.£CQ 3 t i 2 D£l_Qutrg££h • Hundreds of women write* call and visit the Collective from countries all over the world. We have worked with women's groups in a dozen countries on the tr ans 1 at i on/adap tat i on of Qyr Bcdi.es> QuCSelvgs and Our- S2lvg§ find QuC CDildLeD* distributed materials free of charge to women in developing countries, and participated in international meetings in Europe, New Zealand* Latin Amer- ica and elsewhere. We wrote and published, in collabora- tion with ISIS (Women’s Information and Communication Ser- vice, then based in Rome and Geneva) the first loitCDitign- al Wgmgn grid Hga^th Rgsoyrce Quid? • In 1985 one of us attended the UN’s NGO Women’s Conference in Nairobi, Kenya, where she led several work- shops on women and health. As a result of discussions at that time, we are collaborating with even more women’s health activists from all parts of the world. Da5£a2bu&£l£s-£2LLS&li2Qal-lD5liluli2Q_y2a)£nls-bsallti gDd_LE3CDiD9_CeDieC • This ground-breaking project, con- tracted through the Hass. Department of Public Health, has already served over 1,000 women in prison faced with problems of violence, substance abuse, poor health and parenting. Now Learning Center staff are advocating for alternatives to imprisonment for pregnant women (over ^0 pregnant women are committed to MCI Framingham annually). Soon the Learning Center will function independently of the Collective as part of the newly-formed Social Justice for Women. We will continue to participate and provide support as needed. •The Collective puts 100 percent of our book royalties into projects for women, but we continually need additional funding. If you would like to contribute to the support of these projects, please know your donation is tax— deduct- ible . Recombinant DNA Research, Volume 1 1 [215] TUFTS UNIVERSITY Department of Urban and Environmental Policy September 15, 1986 Dr. William Gartland Director, Office of Recombinant DNA Activities Bind! ing 31, Rm. 3B10 National Institutes of Health Bethesda, MD 20892 Dear Dr. Gartland: I am writing to register my support for the proposal submitted to the RAC by the Committee for Responsible Genetics (Fed. Reg. 51(122), June 25, 1986). It seems to me that the two areas cited by the CRG, namely, somatic cell human gene therapy for other than life-threatening or severely disabling conditions and manipulation of human germ line cells represent applications of genetic engineering for which there is still considerable public unease. I recognize that the RAC does not at present entertain proposals for germ-line alterations. Why then shouldn't this be stated in the guidelines? There have been many instances in which the guidelines prohibited certain classes of experiments until more was known about the risks. These prohibitions were removed subsequently. However, the existence of those prohibitions dtd not restrict policy discussions about these types of experiments nor did they close off certain areas of inquiry. The CRG proposal follows the tradition of the earlier guidelines: when entering an area of research with unknown risks whether related to ethics or biohazards, it is reasonable to set clear boundaries, at least initially, until one can be confident of a substantial consensus. I find the recommendations of the RAC Working Group on Human Gene Therapy in response to the CRG proposal rather curious (August 8, 1986 memo). The Working Group states that an explicit prohibition of certain forms of human gene therapy in the guidelines would impede public discussion of the general policy issues. Precisely the opposite took place when certain classes of experiments were prohibited. When the boundaries are made explicit, public discussion is enhanced, for there is at least a principle to which one can address. idelines have been used as a standard by many nations of the world, reasc/n then to make what is explicit and implicit in the "Points to a part of the guidelines since it will continue to serve this useful ona/i/ function. fours, iMvifp Krjmsky,/ Ph.D. Irofes'sor Jmsetts 02155 6p 628-5000, extension 3394 [ 216 ] Recombinant DNA Research, Volume 1 1 P.O. Box 232 Kerr vi lie, Texas 78029 August 4, 1986 Director, Office of Recombinant DNA Activities Building 31, Room 3B10 National Institutes o-f Health Bethesda, Maryland 20892 Dear sir: I am writing in response to the proposal to ammend section III-A-4 [Federal Register, Vol 51 ( 122) : 23210-2321 1 , June 25, 19861 o-f the NIH Guidelines on Recombinant DNA Molecules. Although I do not doubt the good intentions o-f this ammendment, the specific wording does present some potentially serious problems that should be considered prior to acceptance of the ammendment, since in practice, the "Guidelines" essentially set precedence and have the force of law. III-A-4. "The RAC will not review and the NIH will not approve any human genetic therapy:..." This statement allows no discretion by the RAC on review of proposed research if it falls under either of the categories listed below, even if such research may prove to be greatly beneficial to the public welfare. Since development of research technology involving DNA manipulation as well as advances in knowledge regarding DNA structure and function are rapidly progressing, it is not possible to predict the safety nor benefit of future research proposals. This aspect becomes very important if you consider the intent of certain individuals or groups to impede such research without regard to potential benefit, and that these individuals or groups could cite the specific wording of the guidelines (if ammended) and use judicial intervention to prevent consi der ati on of such proposals, even if circumstances have substantially changed the percieved ethical or biological risks involved. I strongly urge alteration of the wording of the proposed ammendment to preserve d i scr et i onar y authority of the RAC to review any recombinant DNA research proposals or topics that the committee believes to be wi thing reasonable bounds of its di screti onsry authority to regulate or to provide a public forum. III-A-4. "... 1. That is not aimed sol el v at the relief of a life-threatening or severely disabling condition; or 2. That could alter germ line cells. Furthermore, the RAC wll not review and the NIH will not approve any in vitro recombinant DNA experiments that alter human germ line cells or early human embryos." Secondly, the words " sol el v " and "or" under condition 1 of the proposed ammendment are unreasonably restrictive of the discretion of the committee in that: (a) a proposed therapy could not be considered even for relief of 1 l f e-threateni ng conditions if the therapy could conceivably alter germ line cells (even in non-r eproduct i vel y active or sterilised individuals) due to the word "or" in condition 1 of the proposed ammendment. Recombinant DNA Research, Volume 1 1 [ 217 ] (b) relief of a life-threatening or severely disabling condition would not be permitted if germ line alteration as a result of therapy would be investigated, since the latter would be a reasonable aim of gene therapy research which is not permissible because of the word " solely ". Thus, even non-reproduct i ve individuals would be denied potentially life-saving therapy if follow-up research into germ line effects resulting from therapy is anticipated. It is not difficult to envision scenarios in which recombinant DMA technology could provide the potential for therapeutic use in human medicine. In addition to severe disorders arising from genetic conditions such as lay Sach’s syndrome and "inborn errors of metabolism", potential therapeutic use for treatment of infectious conditions (such as retroviral infection including AIDS-related conditions, some cancers, and other disease states), or onset of disfunction with genetic cause or treatment (diabetes) can easily be anticipated. It seems clear from the text of the announcement in the Federal Register that it is not the intent of the ammendment to categorically prohibit review and approval of proposals which may strongly serve the public interest through development of recombinant DMA therapies for life-threatening conditions. However, the warding of the ammendment as written may, in fact, have the effect of such prohibition if interpreted literally. Therefore, I suggest that the committee consider alteration of the ammendment to reads "The RAC reserves the authority to refuse to review any proposed human genetic therapy: 1. the principle aim of which is other than the relief of a life-threatening or severely disabling condition; or 2. that could reasonably be expected to affect future generations through alteration of human germ line cells. The NIH will not approve any human genetic therapy without the review and approval of the RAC. Furthermore, the RAC wl 1 not review and the NIH will not approve any in vitro recombinant DNA experiments that alter human germ line cells or early human embryos. " I believe that this wording would preserve the di scret i onary authority of the RAC to consider research topics which are appropriate for the time, with minimal legal interference. It is my firm conviction that timely consideration of such topics is in the public interest, and preserves the e t h i c a .1 a u t h o r i t y a n d r e s p o n s i b i 1 i t y w h i c h has be e n v e s t e d i n t h e committee. Failure to preserve the ethical responsibility and authority of the the RAC to consider research topics in a timely fashion would violate the public trust. T h a n k you f a r y o u r c o n s i d e r a t i o n o f t h i s m a 1 1 e r . Si ncerel y , * Mi crob i ol agist [ 218 ] Recombinant DNA Research, Volume 1 1 DEPARTMENT OF CELLULAR AND DEVELOPMENTAL BIOLOGY HARVARD UNIVERSITY The Biological Laboratories 16 Divinity Avenue Cambridge. Massachusetts 02138 September 12, 1986 Dr. William Gartland Director, Office of Recombinant DNA activities Building 31, Room 3B10 National Institutes of Health Bethesda, MD 20892 Dear Dr. Gartland: I am writing to express my support for the proposal submitted by the Committee for Responsible Genetics (CRG) to modify section III-A-4 of the N.I.H. guidelines. I have read the criticisms of that proposal raised by the working group on human gene therapy, but disagree with some of them. I strongly believe that it is important for the RAC to state clearly and as a matter of public record that the N.I.H. will not fund any human germ line therapy experiments at this time. Further I believe that there needs to be a public education campaign that describes in clear language the positions and procedures of the RAC and its working committees. This educational effort needs to include public forums on the ethical and social questions raised by the possible uses of human gene therapy — germ line and somatic. For example, at present it is not widely known that federal support for human embryo research is precluded by statute. Therefore this should be stated explicitly in the RAC guidelines. People are aware that the RAC guidelines are revised as circumstances change. Human germ line experiments constitute a sufficient departure from past scientific procedures as to warrant a discussion and exposition of the types of issues that might legitimate changes and the types of procedures that would be required to change the guidelines to permit such experiments to go forward. The working group argues that restrictions on work in tissue culture cover experiments on human germ line cells, but I wonder whether these provisions in fact are sufficient given the special status of germ line cells. I also disagree with point 4 of the working group's recommendations. These issues need to get a public airing long before they reach the stage of a proposal to the RAC. When it comes to human gene therapy, we are talking about issues of broad public interest and significance. They must therefore be discussed in forums to which the public has readier access than it has to RAC meetings or the deliberations of institutional review boards . If we scientists want to increase public understanding of our work and public confidence in its social character, we must open the deliberations Recombinant DNA Research, Volume 1 1 [219] of issues that have major social significance to public input and scrutiny. I believe that the CRG’s proposal in no way weakens the guidelines, but instead strengthens them by stating clearly what limits at present exist, and are envisioned, for gene therapy. ^ Sincerely yours, » Ruth Hubbard Professor of Biology [ 220 ] Recombinant DNA Research, Volume 11 DEPARTMENT OF MICROBIOLOGY AND MOLECULAR GENETICS HARVARD MEDICAL SCHOOL 2S SMATTUCK STHtCT BOSTON. MASSACHUSETTS 02113 617-732- TX-. Willi'a*-* Direct 6 va. "TLtA^t|H^ SxIo^Wol "t© “tta. RArC Co *»a*aa'HxjC f-'y l^i.y|>(rv~v>\o U. . "TU<. yoti |XJVa 4 V*^A- lx jys. ^/jp^ * (OCA^_^if I U/iA DAiA jc^ls^UvU. &/s OU^ i^OAvC^A£ } lAJa^p4M5*4,tx V WW«^XtA(rw ^ D ^ fit itaoUca^o cJlo ^ V) ITWIAa^V^aAvA^^ “t* 'VWaa. A-(Aa«Na. p-vrtc/i Ae-^Vwj 'HwviUk^' "to Iaaav^-AJ«aaA t— A Wv ^KcA L+4 \u+y\ UAotL^yA^fxX U~ U/v^j (Vs^L oiu^'t.Vwi ^ tcr+L a-a . M~c^ U\-LA \ c^.vv^ 0 cajoJL ( jX- “t>< aAxi LAa (T-a ^ -^W. Ut«X r-l -\ / W^ 5 . K^rv^ftvc^ \ < prs^U-k. Mji^a CA&ir^o K(5m UHv u^cH\a.mlK <3^-A cLi^c,€a^vv^. 1+ u 4 ^X 0 "fc vaa(a^c/L “tAjk C'R S’ b JX«tjvj>hJ^ CnJui. aX^Voco i'K-C^J. /Mcvt- , 'tW C& 6* ^ /v~»^o-s«X c*-££o J^r*- ^^A^cAXtrvv s — vAa £A»£^ fl"fXA^tO “"Wa*. 4xAAtCJp “tU. t->'fc o^. i^uchov^ Li» cA-MTw^'VBVA^Jt. 0/v/A. 1U p Iaa^Vl-^J. pvT^t-vvj^ ifw C^sAa*w (twjto ^ #.4 A»~J ky i i *^g_ to "t Owoiw. 'VVv«l4' OjLcc^ wjtA^C ^-tXotftAx \Aa.LA- O.CCflVwy> iC«A-^j' *^rs. t-W^ltvystM cCAaJ (Tw. iA - COaa* C-uvcA^.'ts.'cfv^o >a«M(_joUuu. l li - U3 CA^OCA-V^ AX^-jvtTv^4^1a^Urt^ "fcU< ^.AC 0'H>a^ va^wCv-c^ CaX 6 C vwfV p- — t->Cvc /u^y^o . \ vw /Wa* 'VWcC^ u|du. woCX OvJ^xax "ttv> VA^'owva ItA^Xo CfvNtx^p oaJL \a,^^k^Sj\vv^aX^i^ vM^-/acAj^'tai's CoVvC4vv\-^w^ "t^*- |W>Vpv^lvivc l/» U-C*J£a^ HtUvaa^ /VU^a.’c* 4 «$ clv«MCA»CN January 15, 1987 The Director Office of Recombinant DNA Activities Building 31, Room 3B10 National Institutes of Health Bethseda, MO 20892 Oear Sir: I am writing to comment on the Notice ‘Recombinant DNA Research: Proposal Actions Under Guidelines* published In the Federal Register on December 19, 1986 (51 FR 45650-45652). I heartily support all of the proposals listed In this Notice, but I particularly want to support the changes In the "NIH Guidelines for Work with Recombinant ONA Organisms* that are proposed by Dr. Frank E. Young, Commissioner of Food and Drugs (51 FR 45651, Column 3, to 51 FR 45652, Column 2). Dr. Young's comments state the Justification, and the need, for relaxing the NIH Guidelines to allow safe recombinant organisms to be cultured In the same way that one cultures organisms of the same type that are genetically unmodified by recombinant DNA techniques. Dr. Young's comments are concise and they are accurate; and they deserve to be supported. My company (Universal Foods Corporation) Is one of the world's largest manufacturers of baker's yeast ( Saccharomyces cerevl slae ) and other yeast products. Our brand name for yeast products Is *Red Star™,* and we manufacture and market these products In nine countries around the world In addition to the United States. This product has been consumed as a food, and as a constituent of food products, by people the world over for centuries. Without exception, baker's yeast In all of Its forms Is recognized as a wholesome food material that Imparts aesthetically pleasing qualities to many food products (especially flavor and leavening to bakery products). And, various forms of the yeast Saccharomyces cerevlslae (such as baker's yeast and brewer's yeast) are also recognized to be Important sources of vitamins and minerals, and they are consumed for these beneficial constituents by many people. There Is certainly unanimous agreement that the yeast Saccharomyces cerevlclae Is a safe organism. And the Insertion of genetic material for safe proteins, and for enzymes that promote Innocuous reactions, Into the yeast Saccharomyces cerevlslae does not change the safe nature of the original organism. For Instance, In our laboratory, we have Inserted genes for ■lactose permease* and for *beta-galactos1dase" from the yeast K1 yveromyces lactls Into a baker's yeast strain of Saccharomyces cerevlslae in order to TECHNICAL CENTER € ' A 3 NORTH 6 0 STREET MILWAUKEE. WISCONSIN 52216 4 141 27I-67S5 Recombinant DNA Research, Volume 1 1 [239] Office of Recombinant DNA Activities January 15, 1987 prepare a baker's yeast that can be grown on lactose which Is available In cheese whey, a byproduct of cheese manufacturing. There Is nothing unsafe about either yeast strain Involved In this product of recombinant DNA work, and the new properties of the recombinant DNA baker's yeast strain are entirely Innocous. There Is no conceivable reason why this new, genetically engineered baker's yeast should not be considered to be as safe as any baker's yeast that Is unmodified by recombinant DNA techniques. We are also working with a strain of the yeast Saccharomyces cerevi siae that has been modified by recombinant DNA techniques to produce the human protein "alpha-l-antltrypsln. " In this case. It Is Inconceivable that a health hazard exists from contact with this yeast, and It Is virtually Impossible for this yeast to compete In open environments because of the useless metabolic load Imposed by the "alpha-l-antltrypsln" gene. Again, there Is no reason not to handle this recombinant yeast strain In the same way that one handles strains of the yeast Saccharomyces cerevi siae that are not modified by recombinant DNA techniques. Above are two examples of the yeast Saccharomyces cerevi siae modified by recombinant DNA techniques that are certainly as safe as strains of the yeast Saccharomyces cerevi siae that are not modified by recombinant DNA techniques. It should certainly be concluded that these new genetically engineered strains of yeast should be allowed to be handled by the same methods used for strains of Saccharomyces cerevisiae that are not genetically modified by recombinant DNA techniques. And this conclusion should be generalized as Dr. Frank E. Young, Commissioner of Food and Drugs, has recommended. In conclusion, I would like to point out that there has not been even one unpredicted product of genetic modification of organisms by recombinant DNA techniques In the entire world. This record stands even after more than a decade of thousands of experiments In hundreds of laboratories around the world. Certainly, thousands of people have been exposed to such genetically modified organisms for hundreds of hours as a result of all this work, and surprising adverse results have never been recorded. It is time to acknowledge that modification of organisms by recombinant DNA techniques produces organisms that are no more dangerous, nor more safe, than the organisms from which the genetically modified organism was derived. And this fact should be reflected in the Guidelines, and the Regulations, that pertain to any aspect of recombinant DNA work with organisms . I do hope that the recommendations proposed in the referenced Notice are accepted and that the NIH Recombinant Advisory Committee Guidelines are amended accordingly. Vice President, Research GWS/slb [240] Recombinant DNA Research, Volume 1 1 The Public Health Research Institute of the City of New York. Inc. 4SS First Avenue, new York. N. Y. lOOie Til. (212) 578 0600 Office of the Director January 16. 1987 Dr. William S. Gartland Office of Recombinant DNA Activities Building 31, Room 3310 National Institutes of Health Be the sda , MD. 20892 Dear Bill, I am writing to support Option 1 of the proposal to amend the Guidelines as stated in FR 51, p. 45651, December 19, 1986. I have previously submitted materials in support of this concept and I enclose herewith two documents. First is a proposal to amend the guidelines essentially as in Option 1, that I prepared last year to be submitted on behalf of the five members of the original "Plasmid forking Group" (PVG) who drafted the document that became the actual basis of the guidelines. This proposal was approved by all except Stan Cohen who had some reservations that were never addressed; consequently, the proposal was never submitted. The second document is the text of a piece I had written at the time in hope of publication in the New Tork Times. It never got published but I submit it herewith as a more elaborate statement of the same position. It contains diagrams which may be informative to the lay members of RAC. I believe these documents state fairly clearly my support for Option 1. I know Jon Ring and Liebe Cavalieri have argued that deletions constructed in vitro by splicing techniques are not equivalent to natural deletion. This argument is not supportable on genetic grounds — the relevant property of a deletion is that it does not revert; while it is true that the precise endpoints of an in vitro deletion are unlikely to be the same as any natural deletion, I do not see how this fact could have any possible biological consequences per se . or could possibly impact on the biohazard question, or could possibly be used to defend the position that in vitro deletions are in principle different from in vivo ones — after all, it is only unlikely, not impossible that the two could be identical. Sincerely yours. enc. RN/de Recombinant DNA Research, Volume 1 1 ( 241 ] The Public Health Research Institute of the City of New York. Inc. 455 First Avenue. New York. N. Y. 10015 TEL. (212) 578 0000 May 6, 1986 MEMORANDUM TO: Recombinant ENA Committee FROM: R. Novick R. Clowes S. Cohen R. Curtiss III S. Falkow RE: Amendment to Guidelines In view of the recent success enjoyed by Jeremy Rifkin and the Foundation on Economic Trends in blocking the release of ice-crystal mutants of Pseudomonas and the testing of a pseudo rabies vaccine, we should like to propose a re-affirimation of the basic philosophy of the Guidelines in the form of an amendment. When preparing our draft proposal for Asilomar we considered organisms containing material from two or more species as novel and therefore conceivably hazardous. The entire proposal and, we believe, the guidelines themselves, were based entirely upon this concept. Subsequent scientific progress has resulted in the ability to eliminate any specific gene in a microorganism by cloning, in vitro deletion, and subsequent recombinational replacement. Ihis results in a local deletion and the organism is not in any sense recombinant; indeed, this technology is merely a more sophisticated, more precise, and infinitely more reliable means of accomplishing what plant and animal breeders have been doing for several millenia and what geneticists have been doing for the better jpart of a century. [242] Recombinant DNA Research, Volume 1 1 Sane how, the critical distinction between this method of mutation induction and the creation of truly novel recombinant organisms by gene splicing has never been made and therefore the regulatory superstructure that has grcwn up around recombinant DNA has automatically included both. It is this scientifically invalid and retrogressive situation that has spawned the opportunistic litigation of Rifkin et al and it needs to be corrected on legal as well as on philosophical grounds. It is proposed that paragraph I-B of the guidelines be amended to read: " (i) molecules which are constructed outside living cells by joining synthetic DNA segments or DNA segments from one or more -foreixm species to DNA molecules that can replicate " The new language is underlined and, as you will perceive, it totally excludes all self-cloning from the Guidelines. While this exclusion is broader than that of just deletions, we feel that it represents an absolutely logical division, based on the above argument; although the objection will be raised that it excludes such experiments as cloning a toxin gene on a high copy plasnid, etc., we would argue (a) that one can easily generate hyper-producing strains without gene splicing and (b) since many toxin genes are transposable, their attachment to a high copy plasmid, specifically, could also occur by natural means. Recombinant DNA Research, Volume 1 1 [ 243 ] When is 3 . spliced gene not spliced? In recent months, Jeremy Rifkin and the Foundation on Economic Trends have scandalized the scientific carnnunity and the fledgling biotechnology industry by obtaining legal injunctions against the continued testing and projected use of two nutait microorganisms developed with the aid of gene splicing. The two engineered microorganisms are a strain of Pseudomonas bacteria that can no longer produce a substance around which plant-damaging ice crystals form and an avirulent derivative of pseudorabies virus for use as a vaccine. These two strains have potentially major economic benefits, promising to alleviate frost damage to certain crop plants and to control pseudorabies, a very serious disease of swine. They are thus among the exciting first fruits of modem biotechnology. Although neither of the new strains contains foreign DNA or any spliced gene, the mutant organisms are technically covered by the NIH Guidelines for Recombinant Dt^V Research, merely because gene splicing techniques were utilized in their development. Consequently, because the laboratories developing and testing the new strains may not have adhered precisely to the extant regulations, based on the Guidelines, that govern the release of gene- spliced organisms into the environment, they left themselves vulnerable to litigation. Admittedly, the legal decisions in both cases were technically correct; but the true basis of this unfortunate sequence of events is a scientifically invalid provision of the Guidelines that has carried over into legally binding regulations. As chairman of the group of five scientists who prepared a document that served as the first draft of the guidelines in 1974, I can state with some assurance that our purpose was to ensure that novel hybrid organisms produced by the splicing in the test tube of genes from two or more progenitor species would [ 244 ] Recombinant DNA Research, Volume 1 1 be handled with care because of the possibility that they might have unpredictable, harmful biological properties. A potentially hazardous experiment that was commonly cited as an exanple at the time is the construction of hybrid £. coli bacteria able to produce diphtheria toxin. Appropriately, biological studies of diphtheria toxin cloned in E. coli are performed at the highest available level of containment to avoid any possibility of accidental release; safety precautions are also appropriate during testing of recently developed hybrid vaccinia viruses potentially useful as vaccines against AIDS, herpes, etc., to ensure that these virues are not inadvertently released before their safety has been adequately assessed. The Pseudomonas and pseudorabies strains, however, do not pose the same safety issue precisely because they were not produced by joining genes from two or more species; instead, they represent an entirely different application of gene splicing, namely a precise, accurate, and virtually fail-safe method of eliminating a single specific gene from any microorganism. In this method, the unwanted gene is first cloned into a laboratory strain of E. coli . where it can be conveniently manipulated. An essential segment of the gene is then snipped out (deleted) and the now inactive gene is returned to its parent organism where a natural recombination process inserts the defective gene in place of the native, active one. The net effect is the precise removal of an essential part of the unwanted gene; no foreign genetic material is involved. The power of gene splicing technology in this case is that it permits the isolation, anplification and manipulation of the gene in the test tube. All of the test tube steps are, of course, performed in accordance with the Guidelines, since these do involve gene splicing. This type of genetic manipulation is, basically, nothing but a more sophisticated method of accomplishing what plant Recombinant DNA Research, Volume 1 1 ( 245 ] and animal breeders have been doing for several millenia and what geneticists have been doing for over a century, namely selecting or creating nutations that alter a specific genetic trait, either for practical or for experimental purposes. There has not been, nor should there be, any type of regulation of these older types of experiments since they involve siirply the utilization of entirely natural processes. The use of gene-splicing methods tor permanently and precisely inactivating specific genes was sinply not foreseen in the early 70's when the Guidelines were written; indeed, the critical distinction between this type of gene splicing and that involving the creation of hybrid organisms containing genetic material from two or more different species has never been made. Had specific gene inactivation been foreseen, I am certain it would have been expressly excluded from the Guidelines because altered organisms of this type pose no environmental hazard different in principle from that posed by any ordinary new strain of plant, animal, or microorganism derived through the occurrence of conventional mutations; in fact, the modem variety are much safer because the genetic change is permanent and irreversible, in contrast to classical mutations vrtiich can often revert to the wild-type state; indeed, there are cases in vtfrich conventional vaccine strains of viruses have reverted to virulence with fatal consequences. This unfortunate possibility is precluded by the modem method of gene inactivation. Jeremy Rifkin and the Foundation on Economic Trends appear to act on the basis of a general mistrust of the gene splicing technology and its applications to enforce the letter of the law in a scientifically misinformed manner. The result is inhibition of an entirely non-hazardcus and exemplary application of modem biotechnology to real and tractable problems. This type of legalistic [ 246 ] Recombinant DNA Research, Volume 1 1 opportunism can be prevented only by rationalizing the regulatory system that has permitted it. The Recombinant DtPk guidelines thus require amendment to exclude experiments in which no foreign genetic material is added to an organism's genetic complement; ideally, such an amendment should precede and then be reflected in any legislative initiatives such as current efforts by Congressman Fuqua and Senator Gore to create a national committee to oversee recombinant DNA policy. Recognizing the genetic distinction between the addition of foreign genes and the removal of native ones would focus on substantive questions of biology rather than on technical details and would unfetter the ingenuity that the new technology allows; hopefully attention could then be directed toward issues of real concern such as the use of gene splicing for biological warfare. Recombinant DNA Research, Volume 1 1 [ 247 ] Construction of Specific Gene Deletion Chromosomal of original organism \j xl yjJ a** i-t-J / -<=Z===Z=ZJ ~~ r . - V 5 \ Excised segment, prepared by treating with a restrictive enzyme which raxes cuts at specific locations.' ^ - X) The excised gene with sane extra DiA at each end is then ligated to DNA of a vector plasnid that has been treated with the same restriction enzyme. The hybrid vector plasmid is transferred to E. coli bacteria to allow multiplication of cloned gene. [248] Recombinant DNA Research, Volume 11 Hybrid plaanid DN\ purified, treated with a second restriction enzyme that acts at two sites (Y) within the unwanted gene. Ligation then ties together the two new ends leaving out the unwanted segment. This reconstructed hybrid plasmid is then re-transferred to E. coli for anplif i cation, then re-introduced into parent organism, in vbich it cannot nultiply on its own. Recombinant DNA Research, Volume 1 1 [ 249 ] Homologous DNA regions line up; recombination between plasmid and chromosome occurs at x's replacing intact gene with deletion-containing derivative; plasmid, which new contains intact gene again, cannot survive in this organism and is lost. Net effect is the precise removal of a segment of the native gene, leaving behind no foreign DNA and resulting in no other change in the organism's genetic material. Note that the biology and biochemistry is such that each step in the outline has a very low probability of occurrence. Splicing technology is totally dependent on the pewer of microbial genetics, which enables one to select for these rare events. [ 250 ] Recombinant DNA Research, Volume 1 1 1900 Oak Terrace Lane/Thousand Oaks, California 91 320/Telephone 80 5 499-5725 ITT Telex # 4994440 Telecopier 805 499-9315 Ralph Smalling Regulatory Attairs Specialist January 19, 1987 Director, Office of Recombinant DNA Activities Building 31, Room 3810 National Institutes of Health Bethesda, MO 20892 Ladies/Gentlemen, Amgen, a California-based biotechnology company, wishes to comment on the proposals to be considered by the Recombinant DNA Advisory Committee (RAC), as outlined in The Federal Reqister, Vol. 51, No. 244, dated Friday, December 19, 1986. We believe these proposals are progressive steps in the rational oversight of experiments using recombinant DNA technology. The proposals seem to us to reflect the scientific data which has been, and continues to be, gathered in this field. Amgen agrees with the concept that experiments involving dele- tions, single-base changes and rearrangements within a single genome (work in which no foreign DNA is inserted) need not be subjected to special regulation as recombinant DNA experiments. In addition, initiation of experiments in- volving r-DNA technology following approval by the federal agency with appro- priate jurisdiction, without the need for NIH approval, should eliminate unnecessary delay and duplication of effort. It is hoped that the new BSCC framework will insure a consistent approach to such agency reviews. Amgen agrees that the requirement for BL1-LS containment for the production of r-DNA derived products from low-risk microorganisms is expensive, unwieldy, and unnecessary. We support the proposal that large-scale (LS) fermentation physical containment conditions need be no greater than those for the host organism unmodified by r-DNA techniques. We hope the NIH viewpoint concerning BL1-LS conditions will be extended to other governmental agencies with author- ity for reviewing manufacturing applications. Such a position is consistent with the long and distinguished history of U.S. industrial fermentation, and the recognition that BL1-LS conditions are unnecessary for the manufacture of the five DNA-derived pharmaceuticals currently approved by FDA. Recombinant DNA Research, Volume 1 1 [251] Director, Office of Recombinant DNA Activities January 19, 1987 Please include this letter as a part of the written comments and recommend- ations to FR Docket 86-28442. Thank you. Sincerely, Ralph Smalling RJS/jdh 0004-0187A [252] Recombinant DNA Research, Volume 1 1 GENEI\ COR ire. ' 'w * Lii iv S.H,!h 3-jn Frarc sco CA 3-1C3G 'e.ei.'nor's Ai •j-533 - jA,’5 January 19, 1987 Dr. William J. Gartland, Jr. Office of Recombinant DNA Activities National Institutes of Health Bethesda , MD 20892 RE: Proposed Actions Under Guidelines (51 FR 45650) Dear Dr. Gartland: Genencor, Inc., an enzyme manufacturing company which utilizes rDNA technology and voluntarily complies with the NIH Guidelines for Research Involving Recombinant DNA Molecules, is writting in support of all four proposed revisions to the Guidelines as described in the Federal Register of December 19, 1986 (51 FR 45650). I. Proposed Amendments of Sections I-A and III-A of the NIH Guidelines The revisions proposed in this section acknowledge that various regulatory agencies have specific statutory authority to review products created through recombinant DNA technology and can review experiments which might otherwise be reviewed by NIH. Implementation of this change will eliminate the potential of dual review by NIH and the responsible regulatory agency and will implement the statement in the Preamble of the "Coordinated Framework for Regulation of Biotechnology" regarding research approvals. Incorporating the proposed change into the Guidelines will remove any questions concerning review authority. II. Proposed Revisions of Section III-A-2 of the NIH Guidelines Genencor supports the proposed revisions to Section III-A-2 and the development of the associated appendices M, N, and 0. The proposed definition, when implemented, will provide needed clarity for the definition and exclude certain organisms when used under adequate, defined biogical and/or physical controls. This will eliminate unnecessary oversight for organisms meeting the criteria outlined in Appendices L, M, N and 0. We urge the NIH-RAC to approve this proposed revision and to form working groups with the appropriate scientific expertise to develop appendices M, N and 0 so that the proposals can be implemented. III. Proposed Revisions of Section I-B or Section III-A-2 of the NIH Guidelines While Genencor supports the intent of the proposed changes set forth in options 1. and 2., we encourage the NIH-RAC to adopt option 1. Recombinant DNA Research, Volume 1 1 [253] GENE1VCOR Dr. William J. Gartland, Jr. January 19, 1987 Option 1 would define recombinant DNA at the beginning of the Guidelines and ensure that there is no ambiguity as to when an organism is defined as recombinant. Option 2, on the other hand, may lead to ambiguity as it endeavors to incorporate the definition of rDNA with the definition of deliberate release. The exemption of organisms created through single base changes, deletions, and rearrangements within a single genome is based on sound scientific principles and will lead to consistent treatment of such organisms created through rDNA technology and naturally occurring organisms or those derived through traditional genetic manipulations such as mutation and selection. IV. Proposed Revisions of Appendices C-II, C-III, and C-IV Genencor supports the changes proposed under this section. As Dr. Young stated, the host organisms in these three Appendices, E. coli K-12, B. subtilis and Saccharaomvces cerevisiae . have been used safely at both the laboratory and production scale for many years. Their exemption from the Guidelines as host-vector systems is further acknowledgment that they are considered safe for recombinant DNA work as well. The "Coordinated Framework for Regulation of Biotechnology" stated that "The appropriate large-scale containment requirements for many low-risk [ r ] DNA derived industrial microorganisms will be no greater than those appropriate for the unmodified parental organisms." Dr. Young's proposal incorporates the long history of safe use of these organisms as well as the statement in the Coordinated Framework. Incorporation of the changes proposed by Dr. Young will eliminate any prior ambiguity in the Guidelines and make it clear to IBC's that it is accepted practice to handle these organisms at less than BL1-LS containment. As Dr. Young indicated, without this clarity, IBC's have been reluctant to reduce containment requirements, resulting in levels of containment that are needlessly expensive, unwieldy and unnecessary. Genencor wishes to thank the NIH-RAC for the opportunity to comment on these proposals and hopes that our comments are useful to you in the decision making process. Sincerely, QjLcJL J/ f Alice J. Caddow Director of Regulatory and Environmental Affairs [254] Recombinant DNA Research, Volume 1 1 THE UPJOHN COMPANY Theodore Cooper, ivi L) , r'n.L) Kalamazoo Michigan 4900' USA Vice Chairman TELEPHONE ( 616 ) 323-4000 (616) 323-709 5 January 19, 1986 Director Office of Recombinant DNA Activities Building 31, Room 3B10 National Institutes of Health Bethesda MD 20892 Dear Sir: The Upjohn Company strongly supports the proposed revisions in Appendices CC-II, C-lll and C-IV of the National Institutes of Health Guidelines for Research Involving Recombinant DNA Molecules ( Federal Register, Vol. 51, No 24, December 19, 1986, pp 45650-45652). The revisions proposed by the Commissioner of the Food and Drug Administration are progressive and significantly clarify the appropriate containment for large-scale recombinant fermentation experiments. These revisions will make it easier for industry to engage in strategic planning. They also bring into focus the safe history of the fermentation industry and the generally innocuous natures of microorganisms used to produce antibiotics, proteins, amino acids and vitamins. All evidence accumulated to date on Escherichia coli K-12, Bacillus subtilis and Saccharamyces cerevisiae support their inclusion in the classification of non-pathogenic and innocuous microgranisms The introduction of foreign genetic information into such organisms does not change their natures unless the foreign DNA encodes for biosynthesis of toxic molecules or antibiotic resistance, as described in Sections lll-A-1 and lll-A-3 of the Guidelines Finally, the Commissioner addresses the important economic aspects of developing and applying recombinant DNA technology. If the United States is to achieve significant commercialization of this technology, the capital costs of large-scale recombinant processes must be competitive with both foreign-based recombinant process and conventional domestic ones. The proposed changes will help in this regard, and they will allow the United States to retain its role as the world's leader in biotechnology. The proposed changes in Appendices C-ll, C-lll and C-IV are progressive in both a scientific and an economic sense, and they will not put the public at any greater risk. We recommend their adoption. Sincerely, / < Theodore Cooper, M. D , Ph D. Vice Chairman of Board of Directors Recombinant DNA Research, Volume 1 1 [255] GRADE Vincent F. Simmon, Vice President Research Division W.R. Grace & Co. 7379 Route 32 Columbia. Maryland 21044 (301) 531-4417 January 19, 1987 Dr. Bernard Talbot Deputy Director National Institute of Health 9000 Rockville Pike Bethesda, MD 20892 Dear Dr. Talbot: We are in favor of the clarification language proposed as an amendment to the NIH Guidelines in Appendices C-II, C-III, and C-IV. Respectfully yours Vincent F. Simmon, Ph.D Vice President VFS : esc [256] Recombinant DNA Research, Volume 1 1 uwbc University of Wisconsin Biotechnology Center Dr. Richard R. Burgess Director, UWBC 1710 University Avenue Hadi son, WI 53705 January 19, 1987 Di rector Office of Recombinant DNA Activities Building 31, Room 3B10 National Institute of Health Bethesda, HD 20892 Dear Sir, I am writing in support of the Proposed Amendments of NIH Guidelines (51 FR 45650-45652). RAC has, in my opinion, served the citizens, scientists and businessmen of this country well by taking a cautious position with regard to the safety of recombinant DNA research and then relaxing the guidelines when experience shows that to be warranted. The proposed amendments, especially III and IV, are in that tradition. Amendment IV will have a tremendous positive effect on research and development at the University of Wisconsin, especially on projects associated with the Biotechnology Center. In addition, the biotechnology industry will be able to manufacture recombinant DNA derived protein products more efficiently and cheaply. I hope this evaluation and review by RAC will continue and that other regulatory agencies will also be cautious but reasonable. Sincerely yours. Richard R. Burgess RRB : jas Recombinant DNA Research, Volume 1 1 [257] HOFFMANN-LA ROCHE INC. NUTL NEW JERSEY ! 0 Drug Regulatory Affairs (201)235-5000 January 20, 1987 Director, Office of Recombinant DNA Activities National Institutes of Health Building 31, Room 3B10 8800 Rockville Pike Bethesda, Maryland 20892 Gentlemen : Hoffmann-La Roche Inc. would like to provide the following comments and recommendations to the notice published in the Federal Register. Vol . 51 , No. 244, Friday, December 19, 1986. Proposed Revisions of Appendices C-II, C- III, and C-IV We propose the following rewording of the two paragraphs on page 45652 of the Federal Register notice; the new paragraph should read: "The appropriate physical containment conditions need be no greater than those of the host organism unmodified by recombinant DNA techniques for fermentation and the subsequent processing of fermentation broths and cell pastes at laboratory or production scale for host vector systems that are exempt from these Guidelines." The above modifications further clarify the word "experiments" and allow the processing of live cells in an uncontained mode. It is especially important to include research experiments and production activities, since other sections of the NIH Guidelines and amendments to the Guidelines reference "manufacture" of DNA-derived pharma- ceuticals approved by the Food and Drug Administration. Sincerely HOFFMANN-LA ROCHE INC. Linda S. Dujack, Ph.D. Associate Director Drug Regulatory Affairs (201) 235-2983 LSD:gm HLR No. 87053 Copy to: Dr. William Szkrybalo (PMA) [ 258 ] Recombinant DNA Research, Volume 1 1 Lilly Research Laboratories A Division of Eli Lilly and Company Lilly Corpofaie Center Indianapolis. Indiana 46285 Irving S Johnson. Ph 0 Vice Presdem (317) 276-4391 January 20, 1987 Dr. William J. Gartland, Jr. Director, Office of Recombinant DNA Activities National Institute of Allergy and Infectious Diseases, 31/3B10 National Institutes of Health Bethesda, Maryland 20205 Dear Dr. Gartland: Eli Lilly and Company is a research-based corporation that develops, manufactures, and markets human medicines, medical instrument systems, diagnostic products, agricultural products, and cosmetics. We are actively involved in recombinant DNA research in several areas of life sciences. Therefore, we would like to make the following comments on the proposed actions published in the December 19, 1986, Federal Register , 5 1 , No. 244. I. Dr. Talbott proposes amendments to Sections I-A and III-A of the NIH Guidelines to relieve the need for the NIH Recombinant Advisory Committee (RAC) to review experiments submitted to other federal agencies with notification of ORDA of the action taken. We support adoption of the proposed revisions. II. The Working Group on Definitions of the RAC proposes definitions of deliberate release by revisions of Section III-A-2 of the NIH Guidelines. We support adoption of the proposed revision of this section which adds clarity to the Guidelines and properly addresses the issue of deliberate release. III. The Working Group on Definitions of the RAC proposes two alternatives for the definition of recombinant DNA by revision of Section I-B or Section III-A-2 of the NIH Guidelines . Recombinant DNA Research, Volume 1 1 [259] Dr. William J. Gartland, Jr. January 20, 1987 We support adoption of the proposal to clearly redefine recombinant DNA by revision of Section I-B. The concept that certain types of recombinant DNA experiments which do not involve the introduction of foreign DNA need not be subject to special regulation is an extremely important concept. Modification of the definition in Section I-B to define this concept insures that exemptions from special rDNA regulations will be applied throughout the research process and not only in the deliberate release phase. However, we would propose changes in the wording of the footnote to clarify what we perceive as ambiguities caused by the use of the words "organism" and "strain." It is unclear whether "organism" as presented in this context refers to organism at the genus or species level. The use of the word "strain" in this section is more restricting than current guidelines and creates confusion as it relates to Section III-D (Experiments which are exempt from Guide- lines) of the Guidelines. In an attempt to clarify these ambiguities we would propose the following wording for the footnote : Rearrangements involving the introduction of DNA from different species of an organism will be considered recombinant DNA, deletions, single-base changes and rearrangements within a single genome will not involve the intro- duction of foreign DNA and therefore would not be considered recombinant DNA. In the event that the RAC would choose to redefine recombinant DNA by revision of Section III-A-2 of the Guidelines, we would offer the same justification for changing the wording of the proposal (Section III-A-2-C) from "different strains of the same organism" to "different species of the same organism." IV. Dr. Frank Young proposes revisions of Appendices C-II, C-III, and C-IV which would permit the large-scale fermen- tation of E. coli K-12, B. subtilis , or S. cerevisiae if modified by recombinant DNA techniques under the same levels of physical containment as the unmodified organism. We support the proposed revisions which are significant changes that provide appropriate consistency throughout the [ 260 ] Recombinant DNA Research, Volume 1 1 Dr. William J. Gartland, Jr. January 20, 1987 research process. Specific comments regarding the proposed changes are: A. Industrial experience from decades (E. coli and B. subtilis ) to hundreds of years (S. cerevisiae ) supports the contention that fermentations using nonrecombinant strains of E. coli , B. subtilis and S. cerevisiae are essentially benign. L-asparaginase , produced by Eli Lilly and Company in the early 1970s, was among the first examples of a commercially available E. coli fermentation product to be used clinically. (Grinnan, E. L. , L-Asparaginase : A Case Study of an E. coli Fermentation Product, In: Insulins, Growth Hormone, and Recombinant DNA Technology , John L. Gueriguian, ed.. Raven Press, New York, 1981). L-asparaginase was produced in conventional fermenters at the 40,000L scale with no untoward safety problems either to workers or to the environment. Furthermore, we have a long and distinguished record in fermentation techniques which utilize large-scale production of a wide range of organisms, most notably Streptomyces , Actinomyces , Penicillium , and Cephalosporium . Over the last forty years, with the exception of isolated cases of hyper- sensitivity reactions, we have experienced no health associated risks involving large-scale production processes with these organisms. These reactions when they occurred were always associated with the product from the fermentations rather than any inherent problem associated with the organism itself. If this proposed revision is approved by the NIH Recombinant Advisory Committee and accepted by the Director, NIAID, it would be the policy of this company to immediately report any novel and unexpected health or environmental problem which could be a result of this proposed revision, to the NIAID and the local IBC, as well as the steps taken to address the problem. B. Risk assessment studies have consistently failed to show any significant risk associated with any of the above- mentioned hosts carrying plasmids coding for peptides of animal or human origin. C. As was made clear at the Asilomar Conference, the 10L volume limit stipulated in the laboratory Guidelines was one merely of convenience and was not intended to imply that large volumes are significantly more hazardous than Recombinant DNA Research, Volume 1 1 [261] Dr. William J. Gartland, Jr. January 20, 1987 small volumes (most participants used or had access to standard 10L laboratory fermenters). D. As expressed in the current Guidelines, the IBC has the responsibility for setting containment requirements for large-scale fermentations using exempt microorganisms. Most IBCs , including ours, look to the Guidelines for guidance on these issues. The explicit proposed wording is most helpful in providing that guidance. We appreciate the opportunity to comment on these proposed changes to the Guidelines. Experience has indicated that as more scientific information accumulates and more experience is gained, such modifications in the Guidelines are appropriate. Sincerely yours, ISJ/rl [ 262 ] Recombinant DNA Research, Volume 1 1 UNIVERSITY OF WASHINGTON SEATTLE, WASHINGTON 98195 20 January 1987 Recombinant DNA Advisory Committee ORDA NIAID National Institutes of Health Bldg. 31, Room 3B-10 Bethesda, MD 20205 Dear RAC Members: I wish to comment on several aspects of the proposals In the Federal Register for December 19, 1986 which you will be discussing at your February 2, 1987 meeting. As a threshold issue, let me express concern that your Committee and its subgroups appear to be getting a very skewed range of input on their proposals and work. The procedures of the Federal bureaucracy are such that the Register reaches most people only a few days before comments are due, a process which largely precludes reflective commentary. Only if one is on an "inside track" will it be generally possible to provide effective input, and that requires a presence in D.C. and/or lobbyists or paid staffers to monitor meetings, etc. In other words, your current procedures do not facilitate the receipt of a balanced range of views, and instead favor the over-amplification of the positions of private interests with means and of the bureaucracy itself. For example, none of the non-member attendees at the December 5 meeting of the Working Group on Definitions represented public interest groups. Do you honestly believe that no environmental organizations, to give but one example, have any interest in deliberate release? I urge you to promptly devote some attention to improving your outreach activities and assuring that interested persons have, in fact, enough time to respond to your proposals so that publication in the Federal Register is not just a sham legal formality. I was mailed the minutes of the December 5th meeting in response to a phone call several weeks ago to obtain information for constructing meaningful comments. These arrived on January 13th with a cover note from an ORDA staffer requiring comments to be received in Bethesda on January 14 if they were to be available for "prior review" by RAC! Recombinant DNA Research, Volume 1 1 [263] For persons who do not share your level of intimate knowledge of the Guidelines, the Federal Register notice regarding deliberate release is sene what incomplete . Although the current language of II1-A-2 is quoted on page 45651, the context within which it exists is not given, and neither grammatically nor logically can it stand alone. Is it an exception to a general rule? Is it a definition? etc. In other words, do the changes proposed (topics II and III of the notice) expand or contract the possibilities or ease of environmental release? While the naterial can certainly presuae that readers have a secondary education, providing context is at least courteous and, indeed, nay be essential for co-rprehers ibility . Substantively, I wish to address the guidelines relevant to gene deletions. I oppose relaxing the Guidelines on this point, as would occur under the definitions of "deliberate release" and or "reconbinant DMA" in topics II and III of the Register notice. My reasons are several: o Mo experimental evidence is cited in support of the proposal and even if the deletion of a gene in one species has only benign consequences this certainly is not scientific proof that the deletion of any other gene in that species, or any gene in any other species, would also be benign. o The proposal seers to be bottomed on logic instead of enpiricisn, and such logic could well be risleading and faulty although apparently straightfeward and simple (see ry article "Institutional Biosafety (remittees and the Inadequacies cf Risk Regulation," Science, Technology and Hunan Values , Vol. 9, Issue No. -9, Fall I9S-, pp. 16-34.) Sinplistic syllogisrs, such as are behind this deletion proposal, are not always valid. The reasoning seers to be A is harmless or of known harm 3 constituent is harmless Therefore, A- 5 is no rore harmful. Yet if A is a moderate solution of lye (sodium hydroxide' and 3 is water, then the conclusion is false. If the syllogism need not held for inanimate substances, how can we rely on it for living material with all its additional vagaries and possibilities cf interaction. o The deletion of a gene would appear likely to result in the elimination of the production of any proteins that gene codes for, but dc we know it will have no effect on the coding sequences of other, perhaps adjacent, genes? I do not believe enough is known about intracellular interactions to reach a conclusion with certainty. o The deletion of a gene, and any proteins it helps to produce or regulate, could have substantial ecological effects by altering the organism's pool of available protein substances and thus. [ 264 ] Recornfcanant DNA Research. Volume 1 1 perhaps, Its ability to compete for ecological niches; the organism might be afforded an advantage (It extends Its realm) or a disadvantage (Its range contracts) and this alteration of the environmental balance of organisms could have deleterious effects for human beings (e.g. reducing the occurrence of an economically Important species) or for ecological well-being Itself . Therefore, I urge you not to relax the Guidelines regarding gene deletions. The proponents of such a change do not seem to have satisfied a reasonable burden of proof to Justify It. Philip L. fcereano Associate Professor -ftccr-ce-arr sea wwrcr i'jxj-e. ' * 186 A South Street Boston, MA 02111 (617) 423-0650 / January 20. J 9K 7 COMMITTEE FOR RESPONSIBLE GENETICS 91 Advisory Board Nicholas Ashford. Ph.D. Heather Baird-Barney. M.S. Roy L. Barnes Jonathan Beckwith, Ph.D. Philip Bereano. J.D.' Eula Bingham, Ph.D. David Brower Liebe Cavalieri, Ph.D.' Joseph Collins. Ph.D. Donald Comb. Ph.D Barry Commoner. Ph.O. Molly Coye. M.D. David Ehrenfeld. Ph.D., M.D. Ernest Englander, Ph.D. Rich Engler Sam Epstein. Ph.D. Richard Falk, J.D. Ross Feldberg. Ph D. Marcus Feldman, Ph.D Cary Fowler Lois Gibbs Terri Goldberg' Richard Gdldstein. Ph.D. Stephen Jay Gould. Ph D. Colin Gracey' Eric Holtzman, Ph.D. Ruth Hubbard. Ph D.' Vernon Jensen Jonathan King, Ph.D.' Sheldon Krimsky, Ph D." Marc Lappe, Ph.D.' Marvin Legator, Ph.D. Bruce Levin, Ph.D. Richard Levins. Ph.D. Richard Lewontin, Ph.D Manning Marable. Ph.D. Anthony Mazzocchi' Everett Mendelsohn, Ph.D. Albert Meyerhoff, J.D. Claire Nader. Ph.D.' Stuart Newman, Ph D.' David Noble, Ph.D. Judy Norsigian Richard Novick, Ph.D. Christine Oliver. M.D. David Ozonoff, M.D. Scott Paradise David Pimentel. Ph.D. Bernard Rapoport Barbara Rosenberg, Ph.D.' Barbara Katz Rothman, Ph.D. Roger Shinn Victor Sidel, M.D. Helen Rodriguez -Trias, M.D. John Vandermeer, Ph.D George Wald. Ph.D. Nobei Laureate William Winpisinger Steve Wodka Sidney Wolfe, M.D. Susan Wright, Ph.D.' 'Executive Council Nachama L. Wilker Executive Director Willliam A. Gar Hand Recombinant DNA Advisory Committee Building 31, Room 3B10 National Institutes of Health Bethesda. Maryland 20892 Dear Dr. Gartland: On behalf of the Committee for Responsible Genetics (CRG), 1 would like to submit the following comments to the Federal Register notice of December 19. We will focus our comments primarily on items II and III, the proposed revision of Section III-A-2 of the NIH Guidelines and item IV. the proposed revisions of Appendices of C-II, C-III. and C-IV. 1 ) The CRG supports leaving unchanged the definition of recombinant DNA and recommends citing each exemption to the definition within the guidelines. We do not see sufficient empirical justification within the scientific disciplines of the intrinsic safety of deletion mutants of microorganisms to warrant broad exemptions of these products of recombinant DNA from review by RAC. As an example of this, we refer the RAC to the comments of Robert Colwell et al. concerning the Coordinated Framework for Regulation of Biotechnology submitted to the Office of Science and Technology 1 Policy concerning the Federal Register notice of June 26, 1986 for a concise review of many of the questions raised within the scientific community. Dr. Colwell and his colleagues point out that: ... Because regulatory regions in the genome serve to control the level of production of gene products, in some cases turning production on or off entirely, ecologically important aspects of phenotype, such as substrate utilization, can certainly be altered by changes in regulatory sequence In the same vein, deletion of regulatory sequences (e g the removal of a repressor, or of a promoter) clearly can also control gene expression : the deletion of an entire gene certainly does However "precisely constructed" an organism may be genetically, its ecological phenotype is not so easily predicted, and is nonetheless a matter for discovery and testing by careful experiments. 2 1 Referring to proposed changes on section III-A-2 c of the guidelines, the CRG objects to the use of the criterion for exemption of laboratory [ 266 ] Recombinant DNA Research, Volume 1 1 experiments as sufficient reasoning to exempt those same organisms for deliberate release. The scale and concentration of organisms involved in an environmental release, in conjunction with the complexity of ecological systems, makes the situations of laboratory and of landscape distinctive One obvious difference is competition. In a laboratory setting one is not necessarily concerned about competition in the ecosystem, such as the displacement of INA* with INA' We therefore oppose the proposed change that would exempt organisms from RAC review based solely on this criterion. 3 1 In reference to the proposed revisions of Appendices C-II. C-III and C-IV. the CRG stronglv opposes lessening the BL1 -LS physical containment conditions in the NIH guidelines for large-scale fermentation experiments. This action represents a fundamental change in the NIH guidelines and would be a major action for the RAC. The rationale for this position suggests that BL1-LS containment presents an obstacle to commercial development. The CRG does not accept this reasoning as the basis for changing a major policy. The proposal also neglects to take into account the implications for worker, as well as community, health and safety and what the basis for this exemption should be. At the very minimum the CRG recommends, 1 ) that this proposal be reviewed by NIOSH and OSHA before implementation and 2) that conclusive evidence be presented for public comment that the removal of the requirement for closed system large scale manufacturing using recombinant organisms will not have a negative impact on the health and safety of the workers in the plant, or on the communities surrounding these plants. Thank you for considering these comments. ^inrprplv Nachama L. Wilker Executive Director Recombinant DNA Research, Volume 1 1 [ 267 ] Corporate Quality Assurance Abbott Laboratories Abbott Park North Chicago, Illinois 60064, U.S.A. January 21 , 1987 Director, Office of Recombinant DNA Activities Building 31 , Room 3B10 National Institutes of Health 9000 Rockville Pike Bethesda, MD 20892 Dear Sirs: We wish to comment upon proposals III and IV, No. 244, p. 45651, as proposed actions under the NIH Guidelines for research Involving recombinant DNA molecules . III. Proposed Revision of Section I-B or Section III-A-2 of the NIH Guidelines We strongly support the proposal to modify the NIH Guidelines to exempt DNA experiments which do not Involve the Introduction of foreign DNA. Option 1 is preferable In that It will clarify the concept of exempting experiments not Involving foreign DNA, by stating a definition of what constitutes recombinant DNA, and will refocus the NIH Guidelines to those areas of research which may, by their nature, require oversight of the Institutional Biosafety Committee and the RAC of the NIH. IV. Proposed Revisions of Appendices C-II, C- I II, and C-IV As a major member of the fermentation Industry, we applaud the proposed action to treat the large-scale fermentation containment under appendices C-II, III and IV the same as the fermentation containment for the host organism. This Is appropriate given the experience of the fermentation Industry and the experience gained working with these recombinant organisms. We appreciate the opportunity to comment upon these proposals and urge the RAC to act positively upon them. Sincerely, RDNA Biosafety Committee [ 268 ] Secretary and Biological Safety Officer RDNA Biosafety Committee Recombinant DNA Research, Volume 1 1 ANIMAL HEALTH INSTITUTE January 21 , 1987 Director, Office of Recombinant DMA Activities National Institutes of Health Building 31, Room 3B10 9000 Rockville Pike Bethesda , HD 20892 RE: Notice of proposed actions under NIH guidelines for research involving recombinant DNA molecules, 51 Fed. Reg. 45650 (December 19, 1986) Dear Director: The Animal Health Institute is composed of the major U.S. manufacturers of animal health products. We are pleased to have the opportunity to comment on the changes proposed in the NIH Guidelines, which will have direct or indirect effects on our members engaged in research and development involving recombinant DNA molecules. We are in full agreement with the changes proposed in Section I, ■Proposed Amendments of Sections I-A and III -A of the NIH Guidelines," and Section IV," Proposed Revisions of Appendices C-II, C-III, and C-IV." The changes are justified for the reasons stated in the notice, and we recommend their prompt adoption. Section II, "Proposed Revision of Section III-A-2 of the NIH Guidelines," offers us a choice. We recommend adoption of the approach of the RAC Working Group on Definitions. We particularly support this approach because of the planned development of Appendix 0, which would apparently provide more specific guidance on "deliberate release" of recombinant DNA-containing organisms in connection with use of a vaccine. With regard to Section III of the notice, "Proposed Revision of Section I-B or Section III-A-2 of the NIH Guidelines," we have no preference between the options, bearing in mind our recommendation regarding vaccines described above. We thank you for the opportunity to provide these comments, and we congratulate you on the good effort. FHH:dbk Office Address: 119 Oronoco Street • Alexandria, Virginia 22314 • Telephone: 703/684-0011 Mailing Address: PO. Box I4I7-D50 • Alexandria. Virginia 22313 • Telecopier: 703/684-0125 Si ncerel y yours , Fred H. Holt President Recombinant DNA Research, Volume 1 1 [269] ENVIRONMENTAL DEFENSE FUND 257 Park Avenue South New York, NY 10010 (212)505-2100 January 21, 1987 1616 P Street. NW Washington. DC 20036 (202) 387-3500 1405 Arapahoe Avenue Boulder. CO 80302 (303)440-4901 2606 Dwight Way Berkeley, CA 94704 (415)548-8906 1 108 East Main Street Richmond. VA 23219 (804)780-1297 Director Office of Recombinant DNA Activities Building 31, Room 3B10 National Institutes of Health Bethesda, MD 20892 Dear Members of the RAC: Please consider the following comments concerning the proposed changes to the NIH Guidelines for Research Involving Recombinant DNA Molecules (Federal Register 51:45650-3). As section I is a reasonable procedural change, and section II is difficult to assess before Appendices M, N, and 0 are written, these comments focus on sections III and IV of the proposed revisions. SECTION III : Working Group Proposition The Working Group on Definitions presents a proposition- -recombinant DNA experiments that do not involve the introduction of foreign DNA should not continue to be subject to regulation as "recombinant DNA"- -and two options for implementing it. However, RAC should consider the merits of this proposition before considering its implementation. The rationale for this proposition is based on laboratory observations of the labile nature of prokaryote genomes. Because DNA deletions and rearrangements are common in laboratory populations , it is assumed that such changes regularly occur in all species in nature. Therefore, the argument goes, releases of comparably altered organisms should not be subject to special scrutiny. It is necessary to ask, however, whether these laboratory observations accurately portray the genetics of natural populations of prokaryotes. Although laboratory observations led to the notion a few years ago that there might be complete gene exchange among many types of bacteria (see discussion in Selar.der, 1985) , recent studies of the population genetics of bacteria reveal that many populations have high levels of linkage disequilibrium; these populations are collections of independent clones (e.g. Caugent et al . , [ 270 ] Recombinant DNA Research, Volume 1 1 1986; Musser et al., 1985; Selander, et al . 1986; Selander, 1985). Thus the assertion that genetic changes that occur in the laboratory are necessarily commonplace in nature does not hold (Stotzky and Babich, 1984). We do not know rates of genetic flux- -especially genetic rearrangements --in nature (let alone how natural selection operates on these changes). Of course, even if we do not know rates of change, there is no doubt that changes within genomes occur in nature. But, accepting the notion that such genomic changes regularly occur and using this idea to justify releases of engineered organisms are not the same. Two such justifications are standard. The first is the assertion that all prospective genetically engineered organisms exempted by the Working Group's proposition have already occurred, and therefore been "tested," in nature. This cannot be true. For example, it has been estimated that there are 10 atoms in the universe (Ayala and Valentine, 1979). Y^t, one organism, heterozygous at only 232 structural gene loci, can produce 10 kinds of gametes. Furthermore, the genotype of a released engineered organism does not fully predict the role the organism will play in the environment it is released into. As experience with introduced species attests, whether or not an organism is historically novel, it can produce novel consequences in a novel environment. Can we believe that any engineered organism covered by this proposition will already have been "tested" in all environments into which it might be released? One might then ask why new evolutionary adaptations ever occur! In addition, natural genetic changes occur in isolated individuals, but releases of engineered organisms will typically involve tremendous numbers of individuals. The ecological effects and viability of such large numbers of individuals may be entirely different than that of an isolated individual. Afterall, epidemiologists know that the spread of microbes depends on the size of source-pools, ecologists understand that many organisms are colonial because of the advantages of living in groups, and evolutionary biologists have established the existance of frequency dependent selection. The second justification for releases is to assert that since changes within a genome occur naturally, and extensive problems have not resulted from classical breeding programs (although there have been some (Colwell et al . , 1985), the releases covered by the Working Group's proposition need no special scrutiny. However, just because an event can potentially occur in nature, does not mean that it should be freely promoted by humans; "natural" is not a justification just as "artificial" should not be a condemnation. For example, invasions of species into novel environments regularly occur in nature; otherwise volcanic islands would not have native faunas and floras, organisms would not currently be recolonizing Mount St. Helens, and much of the Northern hemisphere would not have been recolonized after the last glacial maximum. Yet, USDA wisely does not allow free introduction of organisms into this country. There is, however, some merit to the above assertion; one can use recombinant DNA techniques to accomplish more precisely genetic changes that could be made through classical techniques. And, on average . the risks of releasing organisms covered by this proposition are likely to be lower than the risks of releasing organisms altered with "foreign" DNA. Nevertheless, it Recombinant DNA Research, Volume 1 1 [271] is premature to exempt all releases involving all classes of genetic change within virtually any genome from all review. (In particular, this exemption includes eukaryotic genomes even though the rationale for it is largely based on prokaryotes.) A low level of review, similar to that outlined in Appendix L, coupled with more specific exemptions that can emerge from experience with, rather than conjecture about, releases is far more appropriate for the organisms covered by the Working Group's proposition. An additional benefit of low level review is that releases would be registered and thus a safety record would develop. Definition of Recombinant DNA The definition of recombinant DNA should not be revised so that it includes only organisms altered with "foreign" DNA. The rationale presented at the Working Group meeting, for implementing that group's proposition as a change in definition instead of an exemption, is that recombinant DNA created with "foreign" DNA is different from recombinant DNA created from material within a genome. But of course DNA does not differ among species or strains, and, although exchange within genomes is undoubtedly more common than exchange between genomes in nature, exchange between genomes does occur. Thus the difference between recombinant DNA created with "foreign" and "non- foreign" DNA is quantitative rather than qualitative. Such a change in definition will have far-reaching and probably unintended effects. Will parts of the Guidelines no longer function as intended? For example, will recombinant pathogens containing no "foreign" DNA be exempt from review? Can any organism with altered genes for toxins or drug resistance be released? (If not, does this mean that the definition of recombinant DNA depends on what organism is genetically altered?) How many rearrangements, amplifications, deletions, and single-base changes can be made and the "same" genome maintained? This last question may seem silly, given the atmosphere of good faith in which RAC operates. But, in order to maintain consistency under the Coordinated Framework for Biotechnology this revised definition would probably also be used for regulatory purposes, in which good faith cannot always be assumed. In closing, I wish to note that the Federal Register note concerning the Working Group's sentiments about changing the definition of recombinant DNA was misleading. Calling the Working Group "split" as to whether they wished to change the definition of recombinant DNA does not adequately portray the fact that the group voted against changing the definition, 2-7-1. SECTION IV Consideration of Section IV raises two questions. First, why should BL1 containment be relaxed for laboratory experiments covered by Appendices C-II, C-III, and C-IV? The BL1 containment guidelines are hardly unreasonable; beyond standard microbiological practices essentially all they stipulate is that laboratories be designed for ready cleaning, pest control be practiced, and any uncontaminated wastes be transported from laboratories in closed containers. Second, why not simply revise these appendices so that unwieldy, [ 272 ] Recombinant DNA Research, Volume 1 1 expensive, and unnecessary requirements for large-scale containment are specifically replaced by less stringent requirements, instead of exempting organisms covered by Appendices C-II, C-III, and C-IV from all containment guidelines? Because these questions are not addressed, the changes proposed in Section IV appear intended to incorporate into the NIH Guidelines the passage from the Coordinated Framework for Biotechnology that states that, "...large-scale containment of many low risk DNA derived industrial microorganisms need be no greater than those appropriate for the unmodified parent organisms," as much as to relieve the fermentation industry of containment responsibilities. A subsequent passage from the same page of the Coordinated Framework (Federal Register 51:23304) notes that, "By the time a genetically engineered product is ready for commercialization, it will have undergone substantial review and testing during the research phase, and thus, information regarding its safety should be available." Given this point, it seems more appropriate to specify relaxed BL1-LS containment on a case-by-case basis than to completely exempt all organisms covered by Appendices C-II, C-III, and C- IV- - including untested organisms in the research phase- -from the NIH Guidelines. A list of engineered organisms currently employed by the fermentation industry to which relaxed containment guidelines apply could be added to Appendix C. Thank you for your attention. Yours truly, Rebecca J. Goldburg, Bh.D. Staff Scientist Recombinant DNA Research, Volume 1 1 [273] References Ayala F.J. and J.W. Valentine. 1979. Evolving : the Theory and Process of Organic Evolution . Benjamin Cummings, Menlo Park, CA. Cited in Regal, P.J. 1986. Models of genetically engineered organisms. In: H.A. Mooney and J.A. Drake (eds.) Ecology of Biological Invasions of North America and Hawaii . Springer-Verlaug , New York. Caugent, D.A., L.O. Froholm, K. Bovre, E. Holten, C.E. Frasch, L.F. Mocca, W.D. Zollinger, and R.K. Selander. 1986. Intercontinental Spread of a genetically distinctive complex of Neisseria meningitidis causing epidemic disease. P.N.A.S. 83:4927-4931. Colwell, R.K. , E.A. Norse, D. Pimentel, F.E. Sharpies, and D. Simberloff. 1985. Genetic engineering in agriculture. Science 229:111-112. Musser, J.M., D,M. Granoff, P.E. Pattison, and R.K. Selander. 1985. A population genetic framework for the study of invasive diseases caused by serotype b strains of Haemophilus influenzae . P.N.A.S. 82:5078-5082. Selander, R.K. 1985. Protein polymorphism and the genetic structure of natural populations of bacteria. In: T. Ohta and K. Aoki (eds.) Population Genetics and Molecular Evolution . Japan Sci. Soc. Press, Tokyo, and Springer-Verlag, Berlin. Selander, R.K. , T.K. Korhonen, V. Vaisanen-Rhen, P.H. Williams, P.E. Pattison, and D.A. Caugent. 1986. Genetic relationships and clonal structure of strains of Escherichia coli causing neonatal septicemia and meningitis. Infection and Immunity 52:213-222. Stotzky, G. and H. Babich. 1984. Fate of genetically- engineered microbes in natural environments. Recomb. DNA Tech. Bull. 7:163-186. [ 274 ] Recombinant DNA Research, Volume 1 1 Genentechjnc Swl" -6^ =, ?rj:d. C ; . ' Z C3 " d 5 ■n * v January 21, 1987 Dr. William Gartland, Jr. Executive Secretary Recombinant DNA Advisory Committee National Institutes of Allergy and Infectious Diseases Building 31 , Room 3B10 National Institutes of Health Bethesda, Maryland 20892 Re: Notice of Proposed Actions under NIH Guidelines for Research Involving Recombinant DNA Molecules Dear Dr. Gartland: Genentech, Inc. is involved in the research, development and manufacture of human pharmaceuticals produced via recombinant DNA technology. As such, we are interested in how commercial rDNA technology is affected by NIH policy and practices; and welcome this opportunity to comment on the proposed changes to the guidelines set forth in the Federal Register, 19 December 1986. We endorse the four proposed revisions contained in Sections I, II, III and IV. The refined definitions and clarifications will offer Institutional Biosafety Committees clearer guidance in determining appropriate complaince. They will also aid the commercial sector utilizing rDNA techniques in development and manufacture of new products, by establishing appropriate large-scale containment practices based on the knowledge gained through the use of industrial microbes. Comments on specific proposed actions follow. Recombinant DNA Research, Volume 1 1 [275] SECTION I The revisions proposed in this section are appropriately consistant with the regulatory process presented in the published "Coordinated Framework for Regulation of Biotechnology". The proposal makes it clear that duplicative review by Federal agencies is unnecessary. SECTION II The proposed revisions provide a useful clarification of what constitutes deliberate release into the environment. However, it is crucial that Appendices M, N and 0 be prepared by those with appropriate scientific expertise, published for comment, and incorporated into the guidelines in a timely manner. SECTION III We agree with the conclusions of the RAC working group that certain types of experiments in which no foreign DNA is introduced into an organism are appropriately not subject to special regulation as "recombinant DNA". Option 1, to revise the definition of recombinant DNA molecules in Section I-B, is preferred; however, to be consistent with section III-D-3, the phrase "or different strains of an organism" should be deleted . SECTION IV Commissioner Young of FDA has proposed changes to the guidelines which we agree are consistent with production-scale practices utilizing safe microorganisms in the pharmaceutical industry. We have experience utilizing recombinant B. subtilis , S. cerevisiae and E. coli host-vector systems which are exempt from the guidelines for small-scale laboratory uses. Once safety has been determined for the inserted sequences, the appropriate containment at any scale should be based on the biology of the host organism. In our experience at production scale (e.g. utilizing the recombinant E. coli strain used to produce Protropin), safety characteristics of the host-vector system such as infectivity or pathogenicity have not been changed in the transition from laboratory to manufacturing. We have established a safe record of proceeding from small to large-scale production with a variety of microbial host-vector systems and believe that the proposed change to the guideline reflects this safety-in-use experience . [276] Recombinant DNA Research, Volume 1 1 Physical containment facilities will continue to be designed and operated based on the biological containment features of the production organism. In addition, containment practices and other environmental and occupational health issues relevant to pharmaceutical manufacturing are thoroughly assessed by FDA as part of their regulatory responsibility. We hope these comments are helpful as NIH-RAC considers the proposed changes, and we are pleased to see the continuing review of the guidelines based on the growing experience with recombinant DNA technology. Sincerely , CAROL LAX HOERNER, Ph.D. Manager, Environmental Health Biosafety Officer CLH : smd 4/48 Recombinant DNA Research, Volume 1 1 l 277 l CENTRAL RESEARCH PFIZER INC.. EASTERN POINT ROAD. GROTON.CONNECTICUT 06340 203-441-4541 RICHARD L. HINMAN, Ph D. Senior Vice President Chemical Products Research and Development January 21, 1987 The Di rector Office of Recombinant DNA Activities Building 31, Room 3B10 National Institutes of Health Bethesda , MD 20892 Dear Sir: Re : 51 FR 45650-52. Notice of Proposed Actions under NIH Guidelines for Research Involving Recombinant DNA Molecules - Amendments to Sections I-A, III -A , III-A-2, and Appendices C-II, C-III and C-IV We welcome the opportunity to comment on the above FR proposal and would like to go on record in support of the amendments to Sections I-A, III-A, III-A-2, and Appendices C-II, C-III and C-IV. Furthermore, we would like to offer additional comments in support of the proposal of the Commissioner of Food and Drugs (Dr. Frank R. Young) to amend the subject appendices to the NIH Guidelines. The NIH Guidelines of June 26, 1986, point out that large-scale containment requirements for many low-risk R.DNA derived industrial microorganisms will be no greater than those for the parent organisms. Dr. Young's proposed revision would explicitly state this principle in the Guidelines. In view of the indus- try's exemplary safety record in handling the parent organisms, we endorse the Commissioner's proposal. The fermentation industry has a long and distinguished history of safe opera- tion of processes involving Baci 1 1 us subtil is , Escherichia col i K-12 and Saccharomyces cerevisiae at manufacturing scale. Pf i zer ' s incident-free experience with Baci 1 1 us subti 1 i s used in the production of detergent enzymes on a worldwide basis for many years is a part of this history of safe commer- cial operation. We believe that the industry in general and Pfizer Inc. in particular has demonstrated an exemplary record of safety in handling these organisms through methods which are soundly based on good engineering principles of design and practice. We believe that the requirement of containment of the exempted organisms identified above at the BL1-LS level during large-scale cultivation is unwarranted based on the industry's extensive experience and health and safe . ecord. [ 278 ] Recombinant DNA Research, Volume 1 1 We agree that amendment of the language of the NIH Guideline Appendices as pro- posed by the Commissioner would serve to ameliorate the cost of implementing unwieldy and unnecessary containment measures by industry. Such action would not, in our opinion, lead to decreased safety margins for employees of corpora- tions engaged in fermentation production of recombinant molecules or lead to increased risk to public health and welfare. Moreover, relief from unnecessary costs of meeting BL1-LS compliance at large scale could help to increase the industry's international competitiveness in the rapidly-advancing area of recombinant DNA production technology. Accordingly, we support the proposed substitution of the language recited in 51 FR 45652 for Sections I-A, 1 1 1 -A , III-A-2, and Appendices C- II, C-III and C-IV of the NIH Guidelines for Research Involving Recombinant DNA Molecules. Si ncerely Richard L. Hinman Recombinant DNA Research, Volume 1 1 [279] John Jennings. MD. V)CE PRESIDENT sc;enc= and Technology Pharmaceutical ]VIanufacturers Association January 21, 1987 Dr. William T. Gartland Director, Office of Recombinant DNA Activities Building 31, Room 3B10 National Institutes of Health Bethesda, Maryland 20892 Dear Dr. Gartland: Re: Recombinant DNA Research: Proposed Actions under Guidelines . Federal Register Notice (Vol. 51, pp. 45650-45652, Doc. 66-28442, December 19, 1986) The Pharmaceutical Manufacturers Association ( PMA) is a voluntary non-profit trade association representing over 100 companies engaged in research on, and the development, manufacturing and marketing of, prescription and ethically promoted drugs, biologicals and in vivo diagnostic products. Increasingly, these therapeutic and diagnostic products are created through biotechnological processes. We are, therefore, vitally interested in how biotechnology is addressed under national science policy and in regulatory decisions that affect research and development of biotechnology-derived products. Accordingly, we welcome this opportunity to comment on proposed changes in NIH recombinant DNA ( rDNA ) research guidelines. Overall, the PMA recommends adoption of each of the amendments proposed in Sections I, II, III and IV of the Federal Register notice. Detailed comments concerning individual sections are given below. Section I The modifications suggested in this section are appropriate and important clarifications of the regulatory processes for review of proposed experiments and reduce the possibility of unnecessary, duplicative review and/or notification. Section II The proposed changes, while relatively minor, are important steps toward defining "deliberate release" and allow exemptions for cases where experience provides adequate evidence of biological and/or physical control of the rDNA containing [280] 1100 Fifteenth Street NW. Washinorton. DC 20005 • Tel: 202-835-3540 • TWX: 7108229494-PMAWSH Recombinant DNA Research, Volume 1 1 organisms. It is important that preparation and publication for comment of Appendices M, N and 0, respectively, be completed quickly . Section III Of the two options that are presented. Option 1 is preferred because modification of the definition of rDNA assures that exemption from special rDNA regulation will be applicable throughout the research process and not only in the "deliberate release" portion of the research. Within Option 1, insertion of the word "foreign" in the first paragraph of Section 1-B of the guidelines is appropriate, as proposed. In the proposed footnote, the phrase "or different strains of an organism" should be deleted in order to avoid confusion with Section III-D of the guidelines. The remainder of the proposed footnote is appropriate as written. Section IV The proposed revisions described in this section are highly important clarifications of the guidelines for rDNA research and will provide appropriate consistency of policy and practice throughout the research process. Furthermore, the proposed revisions represent the consensus of both the primary pharmaceutical regulatory agency and the industries that are representative of pharmaceutical research using these techniques. Specific comments relevant to the proposed changes in Section IV are: 1. Prior to proceeding to large-scale studies, an evaluation will already have been completed wherein the particular host-vector and vector-construct system has been demonstrated to present no significant safety issues and is deemed exempt at small scale. Once the safety has been determined for the inserted sequences the appropriate containment at any scale is based on the biology of the host organism. 2. While existing guidelines indicate that "some latitude" in the application of BL1-LS requirement is permitted, of the five pharmaceutical products already on the market, none of the products’ sponsors utilized the "some latitude" provision, but used BL1-LS containment in large-scale experiments. This suggests that in actual practice local IBCs are reluctant to take the lead in using the "some latitude" provision. Hence, these IBCs require more specific guidance from the NIH RAC. 3. The pharmaceutical industry has a long and distinguished record in fermentation techniques, and member companies will be submitting documentation of their individual histories in this field. The industrys' experience with E. Coli , B. subtilis and Saccharomyces cerevisiae is not as extensive as it is with some other host organisms, but in the time the Recombinant DNA Research, Volume 1 1 [ 281 ] industry has been using these organisms, no untoward safety problems have arisen or been suggested in either small and large scale applications. More specifically, many decades of experience in the brewing industry with Saccharomyces cerevisiae indicate the safety of it as a host. Similar experience, using B. subtilis as a host in the detergent industry, exists. E. Coli K-12 has been used safely in medical research for 60 years and as a recombinant host in small and large-scale pharmaceutical applications for 10 years . 4. We support Dr. Young's proposed revisions in the guidelines and believe that they will enhance the competitive position of the U.S. biotechnology and pharmaceutical industries. We also believe that more explicit guidelines will enhance the strategic planning process at member companies and thus help them compete in the world's market place. 5. As a means to further clarify the language in Appendices C-II, C-III, and C-IV to be consistent with Dr. Young's proposed revisions, we recommend that the following phrase be inserted into the existing second paragraph found on page 45652 uner the paragraph beginning with: And Substitute : For large-scale [LS] fermentation experiments, and, [insert] where applicable subsequent manufacturing processes, [end insert] the appropriate physical containment conditions need be no greater than those for the host organism unmodified by recombinant DNA techniques . Lastly, the PMA appreciates the continuing review of the NIH guidelines. Experience has indicated that modifications of the guidelines are appropriate, not only as we gain more experience in the laboratory, but also as we gain more experience at the scale-up stage. PMA member firms are committed to continued voluntary compliance with reasonable guidelines for rDNA research and development. [ 282 ] Recombinant DNA Research, Volume 1 1 January 22, 1987 IBA Industrial Biotechnology Association 1625 K Street. N W Suite 1100 Washington, D C. 20006 (202) 857 0244 FAX (202)857 0237 Dr. William J. Gartland, Jr. Executive Secretary Recombinant DNA Advisory Committee National Institutes of Health Building 31, Room 3B10 Bethesda, MD 20892 Alan R. Goldhammer. Ph D. Director o( Technical Allans Re: Proposed Revisions of NIH Guidelines Dear Dr. Gartland: Dirvctora Off* c*r» CtW irman G torgr B Rjihrrunn A/ngrn Vic* Chairman Hug* A. O'Ardradr Sctwrmq Plough Corp Srcr.forv John R Norefl PhJIipy Petroleum Co T reawrn Jerry O Caulder Mytoqen Corporation Ronald E Cape C«us Corporation Will 0 Carpenter Monsanto Company Ralph E Chnstolfenen The Uprohn Company Nicholas M Frey Pioneer H Bred International. Inc L Patrick Gaqe Hotfmann La Roche. Inc Ralph W F Hardy BnTechraca International. Inc David A Jackson E I du Pom de Nemours & Co Gabnrl Schmergel CenetKS Institute. Inc Hubert J P Schoemaker Centocor Robert A Swanson Genentech. Inc These comments on the proposed revisions of the NIH Guidelines for Recombinant DNA Research to be discussed at the February 2 NIH Recombinant DNA Advisory Committee (NIH-RAC) meeting are submitted on behalf of the Industrial Biotechnology Association (IBA). IBA is a trade association of 56 member companies engaged in biotechnology ventures. A current membership roster is attached to this letter. IBA supports all four of the revisions as set forth in the Federal Register of December 19 (51 FR 45650). These revisions will provide needed clarification in several areas. The new definitions will make the Guidelines less ambiguous in regards to the types of genetically altered organisms that will fall under its purview. Additionally, the role of the various federal regulatory agencies will be explicitly recognized under the changes proposed. Specific comments to the proposed revisions are given below. SECTION I The changes outlined in this section, proposed by Dr. Bernard Talbot, recognize that various federal regulatory agencies have specific statutory authority to review products created through recombinant DNA technology. Implementation of this change will eliminate the requirement for possible dual reviews when that product is reviewed by the appropriate regulatory agency. IBA believes that the authority of the various regulatory agencies and NIH was set out in the Coordinated Framework for Regulation of Biotechnology (51 FR 23302). This new wording brings the Guidelines into accord with that framework. Recombinant DNA Research, Volume 1 1 [283] Dr. William J. Gartland, Jr. January 22, 1987 Section II IBA supports the proposed revision to Section III-A-2 and the development of the associated appendices M,N, and 0. This would refine the definition of deliberate release that was acted upon at the NIH-RAC meeting of September 29, 1986. In addition, it goes a step further in establishing criteria for appropriate environmental releases of recombinant organisms. Having established guidelines will ultimately expedite experiments with those recombinant organisms where adequate physical and/or biological control can be demonstrated. It important in the implementation of this proposal to convene groups with the appropriate scientific expertise to develop appendices M, N, and 0. Section III IBA supports the full intent of the proposal set forth section and we suggest that NIH-RAC select Option 1. It is important to note that there is no difference between those microorganisms created through recombinant DNA technology that are phenotypical ly the same as might arise naturally or through traditional genetic manipulations such as mutation and selection. Hence, the exemption from the Guidelines of those organisms composed of single base changes, deletions, and rearrangements within a single genome are based on sound scientific principals; their naturally occurring counterparts have caused little concern in the past. Because Option 1 changes the definition of recombinant DNA at the outset of the Guidelines, IBA believes that this will add more clarity. It will insure that there is no ambiguity as to when an organism is defined as recombinant, regardless whether research on this organism is conducted in a contained or field environment. Option 2 may confuse some individuals because it will be located in a later section that is meant to define "deliberate release". Section IV IBA supports the proposed changes in this section that are offered by FDA Commissioner Frank Young. The increasing commercial applications of biotechnology in health care and other fields have necessitated the large scale production of recombinant microorganisms. Virtually all of the research and development work as well as production has involved microbial host-vector constructs that are exempt from the laboratory research guidelines. field is working in this [ 284 ] Recombinant DNA Research, Volume 11 Dr. William J. Gartland, Jr. January 22, 1987 The host microorganisms, E^_ col i K-12, Bacillus subtilis and Saccharomyces cerves iae have been safely used at both laboratory and production-scale levels for many years. Recombinant derivatives of these organisms have been demonstrated to be safe, resulting in the exemption from the Guidelines for certain laboratory uses. The safety consideration of recombinant microorganisms are the same regardless of whether they are being used under laboratory conditions or for the large-scale production of cloned gene products. Biological containment is already inherent in these host-vector constructs. Under the provisions of Appendices C-II, C-11I, and C-IV; IBC's are required to set containment conditions when culture volumes greater then 10 liters are being employed. The NIH Guidelines suggest that where appropriate conditions outlined in Appendix K should be followed. However, a certain flexibility is given to the 1BC in the three Appendices under consideration in this proposal. Unfortunately, the present wording is ambiguous and IBC's have been reluctant to interpret the term "some latitude" in a meaningful way. This has complicated strategic planning at those companies where facilities to scale-up production are being designed. As a result, all of the pharmaceuticals approved by FDA are produced at BLl-LS, the most restrictive containment option for the two organisms used as hosts. Dr. Young's proposal would establish criteria for facility design which IBA believes is entirely appropriate. This would give to the IBC's a continuum of containment options to consider. It is important to remember that those products that are produced by the commercial sector are all regulated by an appropriate federal agency such as EPA or FDA. The product review requires a thorough assessment of the manufacturing process and the regulatory agency must be satisfied that the containment conditions for production are safe and environmentally sound. Historically, these regulatory agencies have looked to the NIH-RAC to provide expert advice on scientific questions about recombinant DNA research. IBA believes that NIH-RAC approval of this specific proposal would be in keeping with that advisorial role. IBA hopes that these comments are useful to NIH-RAC as they deliberate on these issues. Sincerely , Recombinant DNA Research, Volume 1 1 [285] OF CO. NSC. e -*v ,'c\ 5.'\\ £ .C. \S3.5' 1 « „ VOS *N.' V* V£ OlVO LAW OFFICES EDWARD LEE ROGERS SUITE T -200 17 IS P STREET, N. WC W ASHKNGTON, E>- C. 20036 ®02) 3S~-I600 January 28, 1987 Director Office of Recombinant DNA Activities Euildina 31, Room. 3E10 National Institutes of Health Betfcesda, Maryland 2C892 Re: Comments on proposed Revisions tc Guidelines, 51 Fee. Rec . 4565C (December 19, 1960^ These comments are submitted on behalf of the Foundation on Economic Trends and Jeremy Rifkin. Paragraph numbers herein coincide vith those of the Notice. I. The difficulty vith the proposed change is that, vhile it is intended to cover the situation where both NIE and another agency have jurisdiction to review the experiment, it fails tc suggest any mechanism for resolving the overlap in a prudential, ciscret icnary manner. Instead, the proposal simply calls for NIE to abdicate its role, regardless of whether NIE is satisfied that the review by the ether agency "serves the same purpose" as that which would be conducted by the RAC and NIE, is cf comparable quality, or that the other agency, rather than NIE, has the most appropriate expertise tc bring to bear or. the particular questions raised by the experiment. Instead cf the withdrawal of NIE review-decision authority as proposed, we suggest that after preliminary review by CRDA anc by the ether agency ^ or agencies) of the nature cf the proposed experiment, that they confer and decide — on the basis cf appropriate criteria such as expertise and capability — which agency is to conduct the review. It may be that through a memorandum cf agreement with other agencies, those cecisicns can be made in advance for certain categories cf experiments. It most instances, even those where the other agency must issue a permit, license, or approval, it will r.everthless be desirable that the RAC- NIE review— approval process be implemented, and that the other agency have the benefit of that review and decision. A vivid example cf the reed for NIE review and oversight is the situation involving the conduct of field tests for a P»1 = ecc»~cirant I N.- =essartr. » our-e * * pseudorabies vaccine at Baylor College of Medicine and/or Texas A & M University (tests conducted by Dr. Saul Kitt and Novagene, Inc., with participation by USDA) in violation of the NIH Guidelines. See Memorandum dated October 9, 1986, from Director, NIGMS, to Director, NIH. It is certainly preferable to have the RAC-NIH review conducted before, rather than after, licensing, approval, and marketing of a product by another agency, as occurred in that instance. While it would be desirable that other federal agencies have the experience and expertise that NIH has in reviewing recombinant experiments, the fact is that many of them do not. Yet at this time, there is a growing need for such expertise. The proposal in question, then, is counter-productive at this time, for assuring adequate and timely review of proposed experiments. Nothing should be done at this time to encourage researchers to bypass the IBCs or RAC where they may well prove to be the most appropriate reviewing institutions. II. Because of the overlapping nature of the proposals in part II and III of the Notice, certain of the comments herein also refer to segments of part III. As a preliminary matter, each of the proposed revisions to Section III-A-2 of the Guidelines attempt to define "deliberate release" as "a planned introduction . . . into the environment." The difficult questions — alluded to, but not resolved in the publication entitled "Coordinated Framework for Regulation of Biotechnology," 51 Fed. Reg. 23302 (June 26, 1986) — as to when and under what circumstances an organism (however defined) may be deemed to have been introduced "into the environment" are not addressed in the Notice in question. The several federal agencies dealing with this issue may well have differing views as to its resolution. For example, EPA's definition of deliberate release for purposes of the superfund law (CERCLA) may be different from that deemed appropriate by NIH or USDA. The definition of "deliberate release" as determined by the meaning of the phrase "into the environment" will be of great significance in many instances in determining whether a deliberate release is involved. Inasmuch as NIH is attempting to coordinate its review/decision efforts with those of other agencies (as is reflected, for example, in proposal I in the Notice discussed above), and that both NIH and applicants need guidance as to the applicability of Section III-A-2, that definition is of practical importance. We therefore suggest that NIH address that question as part of its proposed amendments by developing, at this time, general Recombinant DNA Research, Volume 1 1 [287] criteria as to the meaning of "into the environment" in coordination with other federal agencies. While, as is true of many regulatory situations, that criteria may have to be modified as experience dictates, it can be made sufficiently flexible to include all experiments that must be reviewed and, at the same time, provide much needed guidance. Turning to the RAC Working Group recommendation developed on December 5, 1986, a fundamental problem with proposed Section III-A-2 and subsection a thereof (in both parts II and III of the Notice) is that the essence of the change from the current III-A-2 is the expansion of the exemptions as will be established by the evidence to be described in Appendices L, M, N and 0. With the exception of existing Appendix L for certain plants, the other appendices are not yet developed. Therefore, at this time, there is no basis whatsoever for approving their creation or for making the other proposed changes in III-A-2 and developing subsection a to accomodate them. In short, the proposal is premature. We request that if and when it is decided to develop the appendices, there be full and adequate represention of the wide variety of disciplines relevant to that undertaking among the voting members of the working group or committee assigned that responsibility, including micro-ecologists and other ecologists. Our other comments relating to part II are discussed below. III. We oppose both options submitted by the Working Group. While the Notice states that "[t]he working group were split as to whether they preferred dealing with this problem by changing the definition of recombinant DNA or by further modification of other sections of the Guidelines," the overwhelming majority voted against changing the definition (Option 1) by 7 to 2 with 1 abstention . One obvious problem with Option 1 is that it would mean no NIH review of deletions and rearrangements within the human genome. A problem with both options (and with proposed Section III-A-2 and subsections a and b under II), is that the mutations included within subsections b and c can present serious risks of adverse ecological and health effects. Some of these problems were described by Dr. Frances Sharpies, a member of the Working Group, at the most recent meeting of the RAC. The significant and continuing controversy over these (and similar) proposed taxonomic definitions as a basis for [288] Recombinant DNA Research, Volume 1 1 determining the extent and nature of regulatory review is well documented, both within the federal agencies and by the comments and concerns of outside experts. See, e.g, "Summary: EPA Biotechnology Workgroup Retreat," July 31, 1985, pp. 2-3; "Briefing Materials" for "Briefing for Jack Moore OTS Biotechnology Issues," August 5, 1985 (section dealing with "Issue: What Commerical Products Should We Review, i.e.. What is 'New' Under TSCA"); "OPTS Biotechnology Issues for Assistant Administrator Resolution," July 1985 (Draft, July 24, 1985) (EPA), pp. 7-9; "Review of Draft Federal Register Notice on Biotechnology" (Work Assignment No.: L-86-10/28-09 ) Work Assignment Title: Expert Review of Biotechnology Proposal, Work Assignment Reports (Dec. 6, 1985) (EPA) — Work Assignment Report by Dr. Dorothy Jones ("It is not true that genera are stable. . . If the terms intra- and inter-generic, which occur throughout the policy statement, are removed (and in my opinion that should be) one is left with the repetition of the rather clumsy 'similar' and 'dissimilar' organisms, but to my mind this is a better solution. It would be quite wrong to include in the document a statement which is just not true." (Pp. 2-3; see also pp. 4-8)); Work Assignment Report by Dr. Bruce R. Levin ("I believe that the inter- ' genus ' criteria for regulated genetic manipulation is, in the cases of microbes, somewhat arbitrary. . . . I also believe that there are problems with the pathogen, non-pathogen criteria for regulation" (p. 3) (and see his more expansive comments on the same points at pp. 5-7); Work Assignment Report by Dr. Daniel Simberloff ("It is odd to view deletion products as not having new combinations of genetic material. . . . [A] deletion could quite readily combine traits that are not normally found together." (p. 3) (and see his comments about the "degree of circularity in this [inter-intra-generic] distinction, which is the linchpin of the entire proposal" and that "the way around this is to emphasize phenotypes more." (p. 4)); Work Assignment Report of Dr. Max Summers (". . . it is difficult to predict how sound EPA's proposed policy concerning the relative hazards of inter-or intragenic combinations are since there is very limited experimental data availabe to assess this judgement in an environmental context. ... I think there will be many exceptions to the rule." (p. 1); "I would be reluctant to advise on the validity of EPA's proposed policy. It makes more sense to base the evaluation upon the nature of the gene/function/trait which is of question." (p. 2)); Memorandum (EPA) dated March 26, 1985, "Subject: Comments on BSCC Definition of 'Inter-Generic Microorganism,' 'Pathogen' and 'Environmental Release'" from Don Clay, Director, Office of Toxic Substances to John A. Moore, Assistant Administrator for Pesticides and Toxic Substances; [Prepared] Testimony of Elliott A. Norse, Ph.D., Director, Public Affairs Office, The Ecological Society of America on The Recombinant DNA Research, Volume 1 1 [289] Coordinated Framework for the Regulation of Biotechnology before the U.S. House of Representatives Committee on Science and Technology Subcommittees on Investigation and Oversight, Natural Resources, Agriculture Research and Environment and Science, Research and Technology (July 23, 1986). Because of the concerns expressed by these and other persons highly knowledgable in the field that the exemptions proposed in the Notice are not scientifically well founded, and may lead to the inadvertent failure to review and regulate experiments with serious risks, we request that those exemptions not be adopted. Sincerely yours Counsel for Foundation on Economic Trends and Jeremy Rifkin [290] Recombinant DNA Research, Volume 1 1 PUBLIC AND SCIENTIFIC AFFAIRS BOARD 1913 I Street, N.W. AMERICAN SOCIETY FOR MICROBIOLOGY Washington, D.C. 20006 Telephone: (202 ) 822-9229 January 29, 1987 Dr. William Gartland Director, Office of Recombinant DNA Activities Bldg. 31, Roan 3 BIO National Institutes of Health Bethesda, MD 20892 Dear Dr. Gartland: On behalf of the American Society for Microbiology (ASM), we are submitting the following comments in response to the proposed actions involving the National Institutes of Health (NIH) Guidelines for Recombinant DtA Research, published in the Federal Register of December 19, 1986 (51:244). Hie A£J1 is the largest single biological life science organization in the world with an active membership of over 34,000. Hie ASM membership includes scientists fran the government, academe and industry, who are experienced in molecular biology and genetics, environmental microbiology, microbial physiology, agricultural and industrial microbiology. I. Hie ASM supports adoption of the revisions proposed by Dr. Bernard Talbot to amend Sections I-A and 1 1 1- A of the NIH Guidelines. Hi is proposed revision is consistent with the policies established by the June 26, 1986 "Coordinated Framework for Regulation of Biotechnology," and will clarify for submitters that recombinant DNA experiments requiring approval under the NIH Guidelines need not be reviewed by the NIH Recombinant Advisory Committee (RAC) once review and approval has been given by another agency with the appropriate jurisdiction. II. Hie ASM supports adoption of the revisions, proposed by the RAC Working Group on Definitions to Section III-A-2 of the NIH Guidelines , which define deliberate release and clarify conditions under which a deliberate release experiment would be exempt from review by RAC. We believe these revisions represent the proper approach to dealing with the issue of deliberate release and will assure proper planning and participation by scientists in the decision-making process. III. Hie ASM agrees with the motion passed by the RAC Working Group on Definitions "that certain types of recombinant DNA experiments which do not involve the introduction of foreign DNA need not be subjected to special regulation as ' recombinant DNA. ' " We endorse the second option for dealing with this problem by further modifying Section III-A-2 of the NIH Guidelines. Under this option, deliberate release experiments involving genetically engineered organisms created by deletions, single base changes, rearrangements and amplification within a single genome would be exempt from RAC review. We believe the current definition of recombinant DNA should remain unchanged and the RAC should continue its past practice of recommending exemptions. Recombinant DNA Research, Volume 1 1 [ 291 ] IV. Die ASM concurs with the proposed revisions of Appendices C-II, C-III and C-IV. We believe that containment for low-risk microorganisms should be minimal and endorse the proposed change with the understanding that it does not include organisms otherwise covered under the guidelines and that the experiments performed will be consistent with good laboratory or manufacturing practice. We appreciate the opportunity to comment on these proposed actions under the Guidelines for Recombinant DNA Research. Sincerely, /^t IsfL&btuA — £). (On. S. ■ * Jean E. Brenchley, Ph.D. U President, American Society for Microbiology fetASOO Kenneth I. Be ms, M.D. , Ph.D. Chairman, Committee on Medical Microbiology and Immunology Harlyn Halvorson, Ph.D. Chairman, Public and Scientific Affairs Board Rudy J.ywodzinski, Ph.D. Chairman, Committee on Agricultural, Food and Industrial Microbiology [2S2] Recombinant DNA Research, Volume 1 1 •Jn:ied States Opartment of Agriculture Animal and Plant Health Inspection Service Washington, D C. 20250 January 29, 1987 Dr. William Gartland, Director Office of Recombinant DNA Activities Building 31, Room 3B10 National Institutes of Health Bethesda, Maryland 20892 Dear Dr. Gartland: We wish to take this opportunity to respond to "Recombinant DNA Research: Proposed Actions Under NIH Guidelines" which appeared in the Federal Register on December 19, 1986, (51 FR 45650-52). We support the proposed deletion of the current language in Section III-A and favor the proposed addition of the described paragraph at the end of Section I-A of the Guidelines. While the proposed change would continue the National Institutes of Health (NIH) review requirement for experiments covered by Section III-A of the Guidelines, it would eliminate NIH review for all other DNA experiments because the review would be conducted by another Federal agency. Such a change would be consistent with the development of regulatory authority in Federal agencies in response to the expanding commercialization of products derived from biotechnological procedures. This proposed change would also help eliminate possible confusion about the agency to which an experiment should be submitted for review and approval. In Section III-A of the current Guidelines, experiments which require specific NIH-Recombinant DNA Advisory Committee (NIH-RAC) review and approval by both NIH and the Institutional Biosafety Committee (IBC) may be submitted to another Federal agency. If the NIH Office of Recombinant DNA Activities (ORDA) determines that such reviews serve the same purpose, NIH approval is unnecessary and the proposed experiment may be Initiated with approval from the other Federal agency. At the present time, there are no provisions or requirements for the transfer of such information between the NIH and another Federal regulatory agency. Because the review by another Federal agency serves the same purpose as that currently conducted by NIH, it would be redundant to require overlapping reviews. Each regulatory Federal agency may also require unique criteria not normally required by NIH. Currently, the NIH Guidelines provide the conditions under which only plants containing recombinant DNA molecules may be released in the environment. The RAC Working Group on Definitions, at their meeting on December 5, 1986, recommended the establishment of new appendices, similar to Appendix L "Release Into the Environment of Certain Plants" which would be written to include conditions of release for animals, microorganisms other than vaccines Recombinant DNA Research, Volume 1 1 ( 293 ] APHIS • Protecting American Agriculture Dr. William Gartland and vaccines. We favor the proposal by the RAC's Working Group on Definitions to amend Section III-A-2 by adding parallel sections to be written as Appendices M, N. and 0 covering respectively animals, microorganisms, other than vaccines, and vaccines. We also urge appropriate Federal, private, and public involvement in the preparation of the criteria for these new Appendices . During the December meeting, the RAC Working Group on Definitions passed a motion concerning changing the definition of recombinant DNA. It was felt that certain types of such experiments which do not include the introduction of foreign DNA need not be subjected to these Guidelines. Of the two options presented, we favor option 2 for the following reasons. The proposed modification of Section III-A-2 provides clear, concise and much needed clarification of the concept that deliberate release is essentially a dangerous event. The proposed use of describing such releases as "planned introductions" under accepted scientific practices in which there is adequate evidence of biological and/or physical control of the recombinant organisms is consistent with Departmental, environmental, and safety concerns. Although the proposed changes would exempt experiments involving deletion derivatives, single base changes, rearrangements and amplifications within a single genome, these same types of experiments would still require other Federal agency review and approval before release from containment. The final proposal in this notice deals with reducing the physical containment requirements for low risk microorganisms used in industrial fermentations. We support Dr. Frank Young's proposal to reduce unnecessary containment procedures currently described in BLl-LS for such large scale fermentations. We feel that the containment conditions need to be no greater than those employed for unmodified host organism experiments. Sincerely Administrator [294] Recombinant DNA Research, Volume 1 1 AUTHOR INDEX OF LETTERS AND DOCUMENTS Bereano, P.L 263 Keene. J.H ... 268 Berns, K.I 291 Kelly, W.N 46 Brenchley, J.E 291 Krimsky, S ... 216 Burgess, R.R 257 Mellon, M.G ... 223 Caddow, A.J 253 Miller. H.l ... 211 Cavalieri, LF 230 Moore, J.A ... 224 Cooper, T 255 Norsigian, J ... 213 Doell, R.G 212 Novick, R ... 241 Dujack, LS 258 Flifkin, J ... 230 Gartland, W.J 210 Rogers, E.L . 226, 228, 235, 286 Goldburg, R.J 270 Goldhammer, A.R. . . . 283 Sanderson, G.W ... 239 Simmon, V.F ... 256 Hah/orson, H.O 291 Smalling, R ... 251 Hawkins, B.W 293 Heilman, A 234 Temeyer, K.B ... 217 Hinman, R.L 278 Temin, H.M . 44, 45 Hoerner, C.L 275 Holt, F.H 269 Wadley, C.S ... 268 Hubbard, R 219 Wilker, N.L 68, 113, 266 Wodzinski, R.J ... 291 Jennings, J 280 Johnson, I.S 259 Recombinant DNA Research, Volume 1 1 [295] [ 296 ] Recombinant DNA Research, Volume 1 1 INSTITUTION INDEX OF LETTERS AND DOCUMENTS Abbott Laboratories 268 Hoffmann-La Roche, Inc. . . 258 American Society for Microbiology 291 IBA . . 283 Amgen 251 Animal Health Institute .... 269 Lilly and Co . . 259 Boston Women’s Health McArdle Laboratory . . . . 44, 45 Book Collective 213 Public Health Research Institute of Department of New York City . . 241 Commerce 234 NIH, ORDA . . 210 Committee for Responsible Genetics 68, 113, 266 Pfizer, Inc . . 278 PMA . . 280 Enviornmental Law Institute 223 San Francisco Environmental Defense State University . . 212 Fund 270 EPA 224 Tufts University . . 216 FDA 211 Universal Foods . . 239 Foundation on Economic University of Michigan Trends 226, 228, 230, 235 Medical Center . . . 46 University of Washington . . 263 Genencor 253 University of Wisconsin Genentech, Inc 275 Biotechnology Center . . . . . 257 Grace, W.R. & Co 256 Upjohn Company . . 255 USDA, APHIS . . 293 Harvard Medical School . . . 221 Harvard University Biological Laboratories .... 219 Recombinant DNA Research, Volume 1 1 [297] Recombinant DNA Research, Volume 1 1 RECOMBINANT DNA RESEARCH PUBLICATION HISTORY Volume Period Publication Date 1 February 1975 - June 1976 August 1976 2 June 1 976 - November 1 977 March 1978 3 November 1977 - September 1978 September 1978 3A November 1 977 - September 1 978 September 1978 4 August 1978 - December 1978 December 1978 4A August 1978 - December 1978 December 1978 5 January 1979 * January 1980 March 1980 6 January 1 980 - December 1 980 April 1981 7 November 1 980 - August 1 982 December 1982 8 September 1 982 - September 1 984 May 1986 9 September 1 984 - March 1 985 May 1986 10 March 1 985 - December 1 985 May 1986 11 January 1 986 - April 1 987 December 1990 NIH Environmental Impact Statement on NIH Guidelines October 1977 for Research Involving Recombinant DNA Molecules Recombinant DNA Research, Volume 1 1 [ 299 ] to US.GOVEFNMENT PHNTNG OFFICE:! 901 -292/582 am kiin o « Esih LIBRARY http , ; //n\h»brary.n»h.gov !0 Center Drive . mo 20892-H 50 Publication No. 91-3203 December 1990