Oversight and Review of Clinical Gene Transfer Protocols Assessing the Role of the Recombinant DNA Advisory Committee (2014) / Chapter Skim
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3 Oversight of Gene Transfer Research
3 Oversight of Gene Transfer Research
Pages 41-76
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Because clinical gene transfer trials involve both recombinant DNA (rDNA) and human subjects, investigators must submit clinical gene transfer protocols to the Recombinant DNA Advisory Committee (RAC)
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Over time, RAC membership and responsibilities have evolved in response to scientific developments and public concerns. Early Activities of the RAC Early actions by the RAC included defining certain conditions for the awarding of grants for rDNA research pending adoption of more comprehensive guidelines.
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. Changes in the Role of the RAC Initially, the RAC reviewed and approved all gene transfer research protocols included in proposed research at institutions receiving NIH funds for rDNA research, advising the NIH director in issuing official approvals (technically, official approvals came from the director of NIH, based on the RAC's decision (Freidmann, 2001)
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. One response at NIH to the Splicing Life report was the creation in 1984 of what became the Human Gene Therapy Subcommittee (RAC, 1990)
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Among other responses (including attempts to expedite the review process) , NIH and FDA agreed in 1995 that NIH would limit its public reviews to novel protocols, while FDA would assume primary responsibility for reviewing gene therapy protocols (Rainsbury, 2000; Wolf et al., 2009)
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The summary descriptions vary significantly in the extent to which they include specific statements about the likelihood that a reported event can be linked to the gene transfer procedure. In 1995, an ad hoc committee appointed by the director of NIH to advise on the future role of the RAC concluded that gene transfer research was different enough from other research to deserve continued public scrutiny.
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. The current guidelines also specify that research proposals involving the deliberate transfer of recombinant or synthetic nucleic acid molecules, or DNA or RNA derived from such nucleic acid molecules, into human subjects (human gene transfer)
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Human gene transfer trials conducted at or sponsored by institutions receiving NIH funding for rDNA research must be registered with OBA and reviewed by the RAC (NIH, 2013c)
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RAC Review of Individual Clinical Trial Protocols Although the RAC no longer has formal approval authority, all human gene transfer protocols that are directly funded by NIH or conducted at institutions that receive NIH funding for rDNA research must submit responses to Appendix M of the NIH Guidelines for RAC review (see the following section for more information on Appendix M)
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Appendix M of the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules Appendix M of the NIH Guidelines is a "Points to Consider" document that details the process and guidelines for information submission to the RAC for gene transfer protocols and describes the oversight employed by the RAC for clinical trials (NIH, 2013c)
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No More Than 15 Days 8 Weeks Prior to RAC PI Meeting Protocol Initial itial Info Informed Summary/ RAC No Protocol OBA Protocol Member <5 Public Submission review Votes Review ≥5 Votes for Review OBA Full RAC Review at Quarterly Meeting FIGURE 3-1 Summary of the human gene transfer protocol review process. NOTE: PI = principal investigator.
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. Protocols Exempt from RAC Review There are policy exemptions in place for certain types of human gene transfer protocols that are exempt from the RAC review.
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. OTHER ENTITIES WITH REGULATORY OVERSIGHT OF GENE TRANSFER RESEARCH In addition to the RAC oversight, gene transfer research faces several layers of federal and local oversight and regulations, which are required to initiate clinical gene transfer research protocols.
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CBER regulates cellular transfer products, human gene therapy products, and certain devices related to cell and gene transfer. Within CBER, oversight of gene therapy research and products is the responsibility of the OCTGT.
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Unlike NIH's regulations, which require the RAC review for all gene therapy protocols funded by NIH or intended to be carried out at institutions receiving NIH funding for rDNA research, the FDA process applies to all gene therapy research, regardless of source of funding. During FDA's review of INDs and its subsequent review of major steps in the research process (e.g., movement from phase I to phase II studies)
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IND Process As a general rule, when reviewing IND submissions, FDA balances potential benefits and risks to participants of gene therapy clinical trials (Au et al., 2012; Takefman and Bryan, 2012)
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Because vectors and transgenes of gene therapy products may persist for the lifetime of the research subject, FDA has issued guidance for observing subjects for delayed adverse events (FDA, 2006)
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Included in the GeMCRIS summaries is information about the medical conditions under study, institutions where trials are being conducted, investigators carrying out these trials, gene products being used, routes of gene product delivery, and summaries of study protocols. As of summer 2013, GeMCRIS provided information about more than 1,000 human gene transfer protocols, including type of vector and adverse events, and provided abstracts and links to materials from RAC reviews.
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, which was issued by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in response to a mandate from Congress "to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research."11 The nationwide infrastructure for local review of research involving human subjects focuses on the protection of human participants in research and the consideration of ethical issues involved in such research. In recent years, the number of IRBs has dramatically increased, from 491 in 1995 to about 4,000 in 2008 (Catania et al., 2008)
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Additional safeguards have been included in the study to protect the rights and welfare of vulnerable subjects, such as children, prisoners, pregnant women, and handicapped or disabled persons. 12 Institutional Review Boards.
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as among those research risks that fall within the purview of its responsibility."13 A centralized IRB is one that conducts reviews on behalf of all study sites that agree to participate in a centralized review process. For sites at institutions that have an IRB that would ordinarily review research conducted there, the central IRB should reach agreement with the institutions and their IRBs about how to apportion the review responsibilities 13 Public Welfare: Protection of Human Subjects.
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These shortcomings included investigator conflicts of interest, unapproved changes in the trial protocol, omissions in informed-consent documents and procedures, insufficient resources for the IRB, problems in trial record keeping and monitoring by the investigators, and deficient reporting of adverse events. Among subsequent regulatory responses to reporting deficiencies were a strengthening of requirements for prompt reporting of adverse events, review of reports by independent analysts, sharing with NIH of FDA adverse event data from gene transfer trials, creation of an improved reporting system for adverse events in gene transfer trials, and 14 Institutional Review Boards.
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, Nancy King noted a need for increased education for investigators and local oversight bodies. King points out that "IRBs that review a lot of gene transfer research have a relatively limited experience of gene transfer review in comparison with other fields, simply because the overall volume is small.
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At each research institution covered by the NIH Guidelines, an IBC is charged with assessing risks to the environment of rDNA research and ensuring that the research is conducted safely and in compliance with the NIH Guidelines. The specific roles and responsibilities of the IBC are to provide independent assessment of containment levels required by the NIH Guidelines; provide assessment of facilities, procedures, practices, and the training and expertise of personnel involved in the research; ensure that all aspects of Appendix M of the NIH Guidelines have been addressed by the principal investigator; ensure that no research subject is enrolled in a human gene trans fer experiment until the RAC review process has been completed and IBC approval has been obtained; for human gene transfer protocols selected for public RAC re view and discussion, consider the issues raised and recommenda tions made as a result of review and consider the principal investigator's response to the RAC recommendations; and implement contingency plans for handling accidental spills and personnel contamination.
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. Since FDA was given jurisdiction over human gene therapy products in 1986, however, there has been increasing interaction through dual agency review of human gene therapy trials.
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. In contrast, the RAC reviews address broader scientific, social, and ethical issues raised by gene transfer research, and the RAC is permitted to address these broader questions in its review of individual protocols as well (NIH Guidelines, see Section IV-C-2-e)
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. To guide local IRBs, NIH issued additional guidance on informed consent in gene transfer trials specifically intended to help investigators, IRBs, and others understand and follow the NIH Guidelines and regulations on rDNA research (NIH, 2002)
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Internationally, the regulation of gene transfer research is based on national policies, most of which apply to clinical research more generally. Many countries have voluntarily adopted international guidelines for the conduct of clinical research, and some have adopted special policies for the review of gene transfer trials.
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. One analysis of the RAC review examined 53 full public reviews of gene transfer clinical trial protocols performed by the RAC between December 2000 and June 2004 to determine what trial design concerns or suggestions the RAC members raised during written review or public discussion or in a formal letter to investigators post-review (Scharschmidt and Lo, 2006)
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At the outset, the RAC review of individual protocols and the opportunity for public discussion were deemed necessary to shepherd in the new medical intervention in a responsible manner. Furthermore, at the time of the formation of the RAC, other regulatory entities were not yet in place to properly oversee the safety and ethical consideration of gene transfer research.
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and gene transfer research. Independent review and assessment of the activities of the NIH Recombinant DNA Advisory Committee -- Meeting one.
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2006. Guidance for industry: Gene therapy clinical trials -- observing subjects for delayed adverse events.
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2004. NIH and FDA launch new human gene transfer research data system.
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2012. NIH oversight of human gene transfer research involving retroviral, lentiviral, and adeno associated virus vectors and the role of the NIH Recombinant DNA Advisory Committee.
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Siegel, Director of the Office of Therapeutics Research and Review, CBER, FDA, concerning gene therapy.
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