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.
Since the RAC’s creation in the early 1970s, its roles and responsibilities have changed from those of a formal regulatory body to an advisory body that functions within a complex regulatory oversight system that includes FDA and oversight bodies at research institutions—IRBs and IBCs. The RAC’s individual protocol review of proposed clinical gene transfer research was instituted at a time when there was a somewhat unique combination of new technology, limited scientific and public understanding, heightened social concern about genetics, and uncertainty regarding the risks to individuals and the environment (Berg, 2004).
The decades since have seen the creation of overlapping and arguably redundant oversight roles for the RAC, FDA, and institutional oversight. With the accumulation of safety data and experience with gene transfer research, its associated risks are becoming better understood, as are the strengths and weaknesses of federal and institutional oversight mechanisms. Hundreds of clinical gene transfer trials—predominantly
phase I trials designed to evaluate safety—have been performed (Ginn et al., 2013). Although public fears and anxieties surrounding gene transfer research have not completely abated, positive public perceptions have also developed, particularly with respect to the promise of more effective treatments or even cures or preventive interventions for devastating and debilitating diseases (see, for example, Seymour and Thrasher ). While all gene transfer protocols must still be submitted to the RAC, over the years, fewer have been selected for additional public review. Indeed, over the past year, the RAC selected only 20 percent of all submitted protocols for additional review (Corrigan-Curay, 2013). Even with the decline over the years in the number of protocols reviewed, however, gene transfer research continues to engage the public imagination. Therefore, it is reasonable to consider whether the concerns articulated in the early days of gene transfer research are still relevant and continue to warrant special oversight today. It is in this context that NIH approached the Institute of Medicine (IOM) for an examination of the role of the RAC. Given the involvement of multiple regulatory and oversight bodies in reviewing and approving gene transfer protocols at the present time, and given arguments that gene transfer is no longer itself so novel, NIH commissioned the IOM to review the current state of the science and regulatory process and to assess whether gene transfer research raises issues of concern that warrant continuing extra oversight, specifically with respect to individual clinical trial protocols by the RAC.
The committee found that many of the main concerns that led to the creation of the RAC have been alleviated. After more than four decades of clinical experience and extensive research efforts, many of the original fears associated with gene transfer, such as the perceived danger of creating transmissible pathogens, causing accidental germ-line modification or contamination, or harming third parties and society at large, have not been borne out. Furthermore, public perception has largely transitioned from negative to positive because of the promise of more effective treatments, cures, or preventive interventions for devastating and debilitating diseases that gene therapy holds today (Yarborough, 2009).
CRITERIA FOR GENE TRANSFER RESEARCH REVIEW
The committee found that although gene transfer research continues to raise important scientific, social, and ethical questions and is constantly evolving, not all of gene transfer research is novel enough or contro-
versial enough to justify all the current forms of additional oversight. Therefore, the committee concluded that individual protocols should not be reviewed by the RAC except in exceptional circumstances, such as when novel gene therapy technologies and treatment strategies move forward into the realm of clinical trials. The committee outlines three criteria that characterize these exceptional circumstances. In-depth public individual protocol review would be warranted only if one or more criteria are satisfied:
|Criterion 1||The protocol uses a new vector, genetic material, or delivery methodology that represents a first-in-human experience, thus presenting an unknown risk.|
|Criterion 2||The protocol relies on preclinical safety data that were obtained using a new preclinical model system of unknown and unconfirmed value.|
|Criterion 3||The proposed vector, gene construct, or method of delivery is associated with possible toxicities that are not widely known and that may render it difficult for local and federal regulatory bodies to evaluate the protocol rigorously.|
When individual gene transfer protocols are reviewed publicly, the purpose will be to advise prospective research participants, the investigator, and NIH’s Office of the Director, as well as to inform the public and other regulatory bodies, such as FDA and IRBs. Emerging technologies in gene transfer science, as presented in new clinical trials protocols (for example, first-in-human trials), may present scientific or ethical concerns that would require additional oversight and represent significant departure from familiar techniques, such that protocol review could not be adequately performed by other regulatory and oversight processes. Furthermore, the committee concluded that in order to minimize the administrative burden of the RAC’s assessment, its protocol review can be accomplished using FDA’s investigational new drug (IND) file, thereby decreasing the administrative burden that investigators shoulder as they deal with the diverse requirements of multiple oversight bodies.
Recommendation 4-1: Restrict individual gene transfer protocol reviews to exceptional cases that meet specified criteria.
The National Institutes of Health’s (NIH’s) Office of the Director should continue to register all gene transfer protocols and, in consultation with appropriate regulatory and/or oversight authorities, should identify protocols for additional public review only if both items 1 and 2 below are satisfied
- Protocol review could not be adequately performed by other regulatory and oversight processes (for example, institutional review boards, institutional biosafety committees, the U.S. Food and Drug Administration);
- One or more of the criteria below are satisfied:
• The protocol uses a new vector, genetic material, or delivery methodology that represents a first-in-human experience, thus presenting an unknown risk.
• The protocol relies on preclinical safety data that were obtained using a new preclinical model system of unknown and unconfirmed value.
• The proposed vector, gene construct, or method of delivery is associated with possible toxicities that are not widely known and that may render it difficult for local and federal regulatory bodies to evaluate the protocol rigorously.
Even if the protocol does not meet the foregoing criteria listed in items 1 and 2, the NIH director in consultation with appropriate regulatory and/or oversight authorities should have the flexibility to select protocols for review that may present significant societal or ethical concerns.
EVOLUTION OF OVERSIGHT OF EMERGING CLINICAL RESEARCH
The RAC was designed to respond to the human applications of an emerging area of science: recombinant DNA technology. The area was of great public interest, with risks and benefits only barely understood. The RAC has successfully provided oversight over a complex technolo-
gy for nearly 40 years, providing a valuable service to NIH, the scientific community, and to the public. Its value has been demonstrated by its help in assembling experts from diverse fields with the shared goal of ensuring safe clinical protocols. By engaging the public in a focused discussion on the technology and its potential societal impacts, the RAC engendered trust and credibility. Gene transfer research, although still not entirely without areas of uncertainty or public concern, is now better understood, and many of its risks have been minimized. Therefore, the committee recommends that the RAC’s review of gene transfer oversight be narrowed to those areas still in need of special review or expertise.
The committee also notes that the experience with gene transfer research may offer valuable lessons for how to proceed with human trials of other medical advances that depend on emerging technologies. For this reason, it recommends that NIH assess whether other areas of clinical research might benefit from a venue for targeted, transparent oversight beyond that provided by existing regulatory mechanisms. If so, then consideration of an appropriate mechanism would be in order.
The RAC’s origins lie in a particular confluence of events. Gene transfer research used a disruptive technology, one that dramatically altered human capacity to alter the natural environment, including humans themselves. This not only meant that its risks and benefits would be particularly difficult to predict, but also that it pushed on the edges of what some thought should be the limits of human control (Berg, 2004). The most recent example of another disruptive technology has been nuclear fission, which brought both electrical power and the atomic bomb. Recombinant DNA technology and its power to create new properties in old organisms came into public consciousness at the same time that public appreciation for the fragility of the ecosystem was rising, as evidenced by the spate of federal initiatives to protect land, water, and air.1 It also arrived hard on the heels of a world war that, among its many horrors, had demonstrated the evils of eugenics, a field linked to (though obviously distinct from) genetics, gene transfer, and gene therapy.
Today, various areas of laboratory and clinical research share some of these characteristics. Nanotechnology presents basic science questions about the chemical, optical, and other properties of familiar materials in unfamiliar sizes. In the context of human applications, these questions
1See, for example, Marine Protection, Research and Sanctuaries Act. 1972. Public Law 92-532. October 23; Safe Drinking Water Act. 1974. Public Law 93-523. December 16; Surface Mining Control and Reclamation Act. 1977. Public Law 95-87. August 3.
may affect how well we are able to assess risks to subjects, as well as risks to the manufacturing workforce that handles the materials and to the environment as the materials are excreted. Synthetic biology has the potential to raise public concerns once again about the appropriate scope of human endeavors to shape the natural world. Neurobiology may blur the line between what is commonly thought of today as body and soul. Gene transfer research no longer stands alone as the only human application of an emerging technology that might benefit from additional avenues of oversight. Nor is it even necessarily the one most deserving of such attention. This is why the committee recommends that NIH explore whether a need exists for additional or different oversight for other clinical applications of emerging technologies, and if so, whether some of the procedures used by the RAC to provide both expertise and a venue for public deliberation might serve as a good model. Taking these questions seriously is a logical next step and constitutes a commitment to forward thinking.
Therefore, the committee makes the following recommendation.
Recommendation 4-2: Consider integrating oversight for gene transfer and other applications of emerging technologies.
The National Institutes of Health (NIH) director should convene an ad hoc working group that will be responsible for considering whether additional oversight and a venue for public deliberation are indicated for other applications of emerging technologies, and if so, to explore procedural options, including the possibility of an integrated oversight body. In this task, the focus should be on those human clinical applications that may be of particular interest to the public, or that feature uncertain risk, may pose harms to individuals or to the public’s health, and which could not otherwise be adequately assessed by existing regulatory and oversight processes. If additional oversight is deemed appropriate, the Recombinant DNA Advisory Committee (RAC) should be used as one possible model, particularly with regard to these functions:
• Provide a public forum for the review and discussion of emerging areas of science.
Include the capacity for a partnership to consult, inform, and educate institutional review boards (IRBs) and institutional biosafety committees (IBCs).
• Provide a venue to foster scientific and public awareness regarding emerging science in order to address concerns about clinical investigation and future societal implications.
• Integrate the capacity to surveil, aggregate, and analyze adverse events across related trials of emerging technologies.
• Perform an additional level of review of individual protocols that are identified by the NIH director, in consultation with one or more IRBs and IBCs, on the basis of exceptional issues raised as articulated in the committee’s gene-transfer protocol criteria.
For the present, however, the RAC should continue to review individual gene transfer protocols but use the criteria set forth in Recommendation 4-1 to help limit review and focus resources on exceptional cases.
The committee recommends that any expanded process established to evaluate and advise on new technologies be focused on those that are anticipated to be part of clinical research interventions and that pose uncertain risk and consequences to individual and/or public health. To be clear, the criteria presented in Recommendation 4-1 are meant to be used to select gene transfer protocols that require an exceptional level of review and are not meant to apply in whole or in part to other technologies. Similar concepts may be considered, however, if in the future there is a need to select protocols for review in other areas of emerging science.
The committee’s recommendations reflects its view that the RAC has been an example of a valuable forum in which members of the research community can discuss and disseminate new information and share best practices, and where members of the public can express and discuss their concerns. Equally important, whatever processes are used, they should complement the efforts of existing regulatory bodies, not hamper or duplicate them. Thus, oversight and review should focus only on the cases where the existing regulatory structure lacks that capacity to do so or when there is significant expression of public concern. To the extent that the new forums can provide guidance generally and increase institutional capacity and expertise, the need for review of selected individual protocol should be a relatively uncommon occurrence.
Berg, P. 2004. Asilomar and recombinant DNA. http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1980/berg-article.html (accessed October 25, 2013).
Corrigan-Curay, J. 2013. NIH Recombinant DNA Advisory Committee (RAC) and gene transfer research. Independent review and assessment of the activities of the NIH Recombinant DNA Advisory Committee—Meeting one. June 4. Washington, DC. http://www.iom.edu/~/media/Files/Activity%20Files/Research/ReviewNIHRAC/Presentations%20Meeting%201/Corrigan-Curay_RAC%20Presentation.ppt (accessed July 1, 2013).
Ginn, S. L., I. E. Alexander, M. L. Edelstein, M. R. Abedi, and J. Wixon. 2013. Gene therapy clinical trials worldwide to 2012—an update. Journal of Gene Medicine 15(2):65–77.
Seymour, L. W., and A. J. Thrasher. 2012. Gene therapy matures in the clinic. Nature Biotechnology 30(7):588–593.
Yarborough, M., and R. R. Sharp. 2009. Public trust and research a decade later: What have we learned since Jesse Gelsinger’s death? Molecular Genetics and Metabolism 97(1):4–5.