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Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee (2014)

Chapter: Appendix B: Historical and Policy Timelines for Recombinant DNA Technology

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Suggested Citation:"Appendix B: Historical and Policy Timelines for Recombinant DNA Technology." Institute of Medicine. 2014. Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington, DC: The National Academies Press. doi: 10.17226/18577.
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B

Historical and Policy Timelines for Recombinant DNA Technology

TABLE B-1 Timeline of Key Developments in rDNA Technology During the Late 1960s and Early 1970s


1969–1970 Paul Berg and Peter Lobban independently conceive an approach to create rDNAs in vitro and use them to manipulate genes across species.

1971 Douglas Berg and colleagues isolate the first plasmid bacterial cloning vector, λdvgal 120.

1971 Robert Pollack raises first concerns about potential biohazards of cloning.

1971–1972 David Jackson and colleagues, Peter Lobban, and A. D. Kaiser develop the method for joining DNAs in vitro.

1972 Jackson and colleagues create the first chimeric DNA in vitro.

1972 Janet Mertz and Ronald Davis discover a new approach to create SV40-λdvgal 120 chimeric DNAs in vitro.

1972–1973 Stanley Cohen and colleagues isolate a new cloning vector, pSC101, and create bacterial intra- and interspecies rDNAs.

1973 John Morrow and colleagues clone and propagate ribosomal DNA genes from a eukaryote in E. coli.

Suggested Citation:"Appendix B: Historical and Policy Timelines for Recombinant DNA Technology." Institute of Medicine. 2014. Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington, DC: The National Academies Press. doi: 10.17226/18577.
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TABLE B-2 Timeline of Notable Events in the Oversight of rDNA Research


1972 Scientists publish details of first intentional creation of rDNA molecules (Berg and Mertz, 2010). Some leading researchers delay further investigation pending better understanding of potential biohazards, including cancer-causing potential of laboratory-altered viruses (Swazey et al., 1978).
 
1972–1973 Several conferences feature discussions of rDNA technology and possible safety risks and containment options related to rDNA procedures (Fredrickson, 2001).
 
1973 Participants at the first Asilomar conference consider laboratory safety and containment issues and discuss evidence on the risk of cancer from genetically modified viruses.
 
1973 Concerned researchers draft a letter requesting that the NAS establish a committee to examine the risks and benefits of rDNA research and propose guidelines for such research.
 
1974 July: The chair of the seven-member NAS committee presents the committee’s recommendations, including for the deferral of certain risky types of rDNA research; the establishment by NIH of an advisory committee to assess the risks of the research, develop procedures to limit such risks, and develop guidelines for research; and the convening of a conference to further discuss ways to deal with hazards of rDNA research (Berg et al., 1974).
 
1974 October: The NIH creates the Recombinant DNA Molecule Program Advisory Committee (later called the Recombinant DNA Advisory Committee, or the RAC).
 
1975 Participants at a second Asilomar conference discuss whether research moratorium should continue. The summary statement proposes that research proceed with safeguards tailored to the risks of specific investigations and that education and training in containment methods be developed (Berg et al., 1975).
 
1976 Following a public meeting in February, in June NIH issues guidelines for rDNA research and defines responsibilities of investigators, research institutions, and government (Recombinant DNA research guidelines, 1976).
 
1980 The first gene transfer experiments with humans are conducted by a U.S. investigator in Italy and Israel. The investigator is later censured for misleading regulators and barred from NIH funding (Rainsbury, 2000).
Suggested Citation:"Appendix B: Historical and Policy Timelines for Recombinant DNA Technology." Institute of Medicine. 2014. Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington, DC: The National Academies Press. doi: 10.17226/18577.
×
1982 The President’s Commission for the Study of Ethical Problems in Medicine and Biomedical Research and Behavioral Research releases a report, Splicing Life, which proposed changes in the oversight of rDNA research (President’s Commission, 1982).
 
1984 The RAC establishes a working group on human gene therapy to review and respond to the report of the President’s Commission and establish procedures for reviewing and approving gene transfer research.
 
1984 FDA determines that it will regulate gene therapy products (Rainsbury, 2000).
 
1985 A working group on human gene therapy presents its first version of Points to Consider in its report, “Design and Submission of Human Somatic-Cell Gene Therapy Protocols” (Points to consider, 1985).
 
1988 The RAC approves its first clinical research protocol, one for a gene marker study, amidst controversy over the investigators’ reluctance to provide requested information on safety (Rainsbury, 2000).
 
1990 Researchers undertake the first approved gene transfer study on a child with SCID disorder (Coutts, 2011).
 
1991 FDA issues a guidance document, Points to Consider in Human Somatic Cell Therapy and Gene Therapy, updated again in 1998 (FDA, 1991, 1998).
 
1992 NIH director approves a “compassionate use” exemption to allow gene transfer procedures to be used in individual patients without regular protocol review.
 
1993 Responding to industry concerns and questions, FDA publishes a description of its regulatory authority and approach to regulating gene therapy products.
 
1995 NIH and FDA outline an agreement for FDA to assume review of gene therapy research protocols, with the RAC and FDA jointly determining which protocols warrant public review by the RAC (Advisory Committee to the Director, 2000).
 
1996 NIH Director proposes ending the RAC (Notice of intent, 1996).
Suggested Citation:"Appendix B: Historical and Policy Timelines for Recombinant DNA Technology." Institute of Medicine. 2014. Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington, DC: The National Academies Press. doi: 10.17226/18577.
×
1997 NIH guidelines confirm the shift of the RAC to an advisory role; FDA assumes sole authority to approve gene transfer protocols as well as gene therapy products (Advisory Committee to the Director, 2000; U.S. Congress, 2000).
 
1997 The RAC minutes start to include summary tables of adverse event reports received.
 
1999 Jesse Gelsinger dies while participating in a gene transfer trial; subsequent investigations identify several shortcomings in research oversight.
 
2000 FDA announces a new gene therapy clinical trials monitoring plan to strengthen protections for trial participants.
 
2000 NIH amends guidelines to place the RAC advisory review of protocols before IBC and IRB review (Recombinant DNA research: Action under the guidelines, 2000).
 
2002 FDA elevates the administrative unit that evaluates cellular, tissue, and gene therapy products from division to office.
 
2003 FDA imposes a temporary moratorium on gene transfer trials using retroviral vectors in blood stem cells, and eases the restrictions later the same year.
 
2004 NIH launches GeMCRIS, an interactive Web-based database allowing public access to information about gene transfer trials (NIH, 2004).
 
2013 NIH proposes to revise the rDNA guidelines to remove the requirement for IBC review of certain low-risk gene transfer clinical trials that follow a dose safety trial previously approved by an IBC (Recombinant DNA research: Proposed actions under the NIH Guidelines for research involving recombinant or synthetic nucleic acid [NIH Guidelines], 2013).

SOURCE: Adapted from Berg and Mertz, 2010.

REFERENCES

Advisory Committee to the Director. 2000. Enhancing the protection of human subjects in gene transfer research at the National Institutes of Health. July 12. http://oba.od.nih.gov/oba/rac/acd_report_2000_07_12.pdf (accessed November 1, 2013).

Berg, P., and J. E. Mertz. 2010. Personal reflections on the origins and emergence of recombinant DNA technology. Genetics 184(1):9–17.

Suggested Citation:"Appendix B: Historical and Policy Timelines for Recombinant DNA Technology." Institute of Medicine. 2014. Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington, DC: The National Academies Press. doi: 10.17226/18577.
×

Berg, P., D. Baltimore, H. W. Boyer, S. N. Cohen, R. W. Davis, D. S. Hogness, D. Nathans, R. Roblin, J. D. Watson, and S. Weissman. 1974. Potential biohazards of recombinant DNA mlecules. Science 185(4148):303.

Berg, P., D. Baltimore, S. Brenner, R. O. Roblin, and M. F. Singer. 1975. Summary statement of the Asilomar conference on recombinant DNA molecules. Proceedings of the National Academy of Sciences of the United States of America 72(6):1981.

Coutts, M. C. 2011. Human gene transfer research, scope note 24. Bioethics Research Library: Georgetown University.

FDA (U.S. Food and Drug Administration). 1991. Points to consider in human somatic cell therapy and gene therapy. Human Gene Therapy 2(3):251–256.

———. 1998. Guidance for human somatic cell therapy and gene therapy. Rockville, MD: FDA. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/ucm081670.pdf (accessed September 1, 2013).

Fredrickson, D. S. 2001. The recombinant DNA controversy: A memoir: Science, politics, and the public interest 19741981. Washington, DC: ASM Press.

NIH (National Institutes of Health). 2004. NIH and FDA launch new human gene transfer research data system. Bethesda, MD: NIH. http://www.nih.gov/news/pr/mar2004/od-26.htm (accessed October 1, 2013).

Notice of intent to propose amendments to the NIH Guidelines for research involving recombinant DNA molecules (Notice of intent). 1996. Federal Register 61(131):35774–35777.

Points to consider (Points to consider in the design and submission of human somatic-cell gene therapy protocols). 1985. Federal Register 50(160): 33463-33464.

President’s Commission for the Study of Ethical Problems in Medicine and Biomedical Research and Behavioral Research (President’s Commission). 1982. Splicing life: A report on the social and ethical issues of genetic engineering with human beings. Washington, DC: U.S. Government Printing Office.

Rainsbury, J. 2000. Biotechnology on the RAC-FDA/NIH regulation of human gene therapy. Food and Drug Law Journal 55:575–600.

Recombinant DNA research: Action under the guidelines. 2000. Federal Register 65(196):60328–60332.

Recombinant DNA research: Proposed actions under the NIH Guidelines for research involving recombinant or synthetic nucleic acid (NIH Guidelines). 2013. Federal Register 78(92):27977–27980.

Recombinant DNA research guidelines. 1976. Federal Register 41(131):27902–27943.

Swazey, J. P., J. R. Sorenson, C. B. Wong. 1978. Risks and benefits, rights and responsibilities: A history of the recombinant DNA research controversy. Southern California Law Review 51(6):1019–1078.

Suggested Citation:"Appendix B: Historical and Policy Timelines for Recombinant DNA Technology." Institute of Medicine. 2014. Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington, DC: The National Academies Press. doi: 10.17226/18577.
×

U.S. Congress, Senate, Subcommittee on Public Health and Senate Committee on Health, Education, Labor, and Pensions. 2000. Statement of Amy Patterson, Director of the Office of Biotechnology Activities, NIH. 106th Cong., 1st Sess. February 2.

Suggested Citation:"Appendix B: Historical and Policy Timelines for Recombinant DNA Technology." Institute of Medicine. 2014. Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington, DC: The National Academies Press. doi: 10.17226/18577.
×
Page 103
Suggested Citation:"Appendix B: Historical and Policy Timelines for Recombinant DNA Technology." Institute of Medicine. 2014. Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington, DC: The National Academies Press. doi: 10.17226/18577.
×
Page 104
Suggested Citation:"Appendix B: Historical and Policy Timelines for Recombinant DNA Technology." Institute of Medicine. 2014. Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington, DC: The National Academies Press. doi: 10.17226/18577.
×
Page 105
Suggested Citation:"Appendix B: Historical and Policy Timelines for Recombinant DNA Technology." Institute of Medicine. 2014. Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington, DC: The National Academies Press. doi: 10.17226/18577.
×
Page 106
Suggested Citation:"Appendix B: Historical and Policy Timelines for Recombinant DNA Technology." Institute of Medicine. 2014. Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington, DC: The National Academies Press. doi: 10.17226/18577.
×
Page 107
Suggested Citation:"Appendix B: Historical and Policy Timelines for Recombinant DNA Technology." Institute of Medicine. 2014. Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington, DC: The National Academies Press. doi: 10.17226/18577.
×
Page 108
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Gene transfer research is a rapidly advancing field that involves the introduction of a genetic sequence into a human subject for research or diagnostic purposes. Clinical gene transfer trials are subject to regulation by the U.S. Food and Drug Administration (FDA) at the federal level and to oversight by institutional review boards (IRBs) and institutional biosafety committees (IBCs) at the local level before human subjects can be enrolled. In addition, at present all researchers and institutions funded by the National Institutes of Health (NIH) are required by NIH guidelines to submit human gene transfer protocols for advisory review by the NIH Recombinant DNA Advisory Committee (RAC). Some protocols are then selected for individual review and public discussion.

Oversight and Review of Clinical Gene Transfer Protocols provides an assessment of the state of existing gene transfer science and the current regulatory and policy context under which research is investigated. This report assesses whether the current oversight of individual gene transfer protocols by the RAC continues to be necessary and offers recommendations concerning the criteria the NIH should employ to determine whether individual protocols should receive public review. The focus of this report is on the standards the RAC and NIH should use in exercising its oversight function. Oversight and Review of Clinical Gene Transfer Protocols will assist not only the RAC, but also research institutions and the general public with respect to utilizing and improving existing oversight processes.

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