Posted on October 16, 2018 at 5:31 PM
by Jeffrey P. Kahn, Ph.D., M.P.H. and Anna C. Mastroianni, J.D., M.P.H.
National Institutes of Health Director (NIH) Francis S. Collins and Food and Drug Administration Commissioner Scott Gottlieb recently co-authoreda New England Journal of Medicinecommentary suggesting that special oversight of gene transfer research in humans was no longer necessary. Their views followed on the 2014 recommendations of an Institute of Medicine (IOM) consensus committee, and are reflected in proposed policy changes recently made available for public comment. If implemented, those changes would mark a significant departure from the over 40 years of special national safety and ethics oversight of so-called gene therapy research through the Recombinant DNA Advisory Committee (RAC).
Perhaps not surprisingly, some commentators have reacted with concern to the proposed changes in the RAC’s role, mostly suggesting that such changes would remove longstanding and effective oversight for risky and uncertain research that continues to raise societal issues. At first blush, risky and uncertain research seems like exactly the category of research deserving enhanced protections for research subjects through dedicated review and oversight as could be provided by bodies like the RAC. But much research on humans is risky and it is always uncertain (which is why it is categorized as research rather than already approved as therapy), and further is often subject to peer review as well as institutional oversight through institutional review boards (IRBs). And gene transfer research is subject to additional, local institutional review by institutional biosafety committees (IBCs). So what made gene transfer research special and deserving of additional oversight?
The answer at the time of the creation of the RAC was that gene transfer involved attempts to introduce somatic-cell genetic modification in individuals with serious diseases through techniques that were novel and carried high risk and uncertain consequences for not only the patient-subject but for those around them due to the viral vectors employed. Clinical trials subject to RAC review often represented first uses in humans and almost always involved patients with serious life-threatening diseases for which existing treatments were unavailable or had failed. RAC oversight was thus introduced in response to a constellation of safety, ethics and social issues: societal concerns, novelty, high degree of uncertainty, significant risks to patient-subjects, their partners, and others, and challenging consent contexts due to the critical illnesses faced by the subjects. Gene transfer research was high stakes publicly-funded research subject to high levels of scientific and public interest and scrutiny. There is no question that the novel technology with the potential for downstream benefits for critically ill patients merited cautious oversight beyond that required for any clinical research.
Ultimately, RAC oversight has managed and paced the development of a tremendously complex and emerging area of science with attentiveness to nuances that might escape traditional forms of oversight. A national level of oversight implicitly acknowledged the limited number of experts at the time who could competently discuss and review proposed highly technical interventions in humans. Further, an important aspect of the RAC’s work has been the public nature of its review and discussion, not only of clinical research issues but of societal concerns as well. RAC oversight, housed at NIH, supplemented FDA registration and review, creating a parallel (and some have argued overlapping) review process, with the RAC carrying out its review separate from but informed by the FDA review, and separate from and sometimes informed by, and other times informing IRB review. Notably FDA review was and is not subject to public scrutiny due to the proprietary nature of the information supplied by investigators and sponsors. Without public support and awareness, failures—inevitable in any novel research—could have created political pressure to end the research entirely, ultimately stymieing the eventual successes such as recent FDA approval of three gene therapy products treating vision loss and certain cancers.
What should happen when the features of research that initially justified the additional review provided by the RAC are no longer part of the research being reviewed? Do all the features that marked the early years of gene transfer research—novelty, societal concerns, high degree of uncertainty, significant risks to patient-subjects and/or others, challenging consent contexts, small numbers of qualified experts—need to be present to warrant such additional oversight, and what should be the process for deciding that what was once novel and uncertain should now be considered regularized and predictable?
For us, the current proposal raises two foundational questions about special oversight of emerging biotechnologies—when should it be undertaken, and just as important when should it be ended? Just what features of a new, emerging, or advancing biotechnology that raises societal concerns should trigger aspects of oversight that are additional to the oversight and protections otherwise applied to research? The RAC and gene transfer provide one example, but we need to describe and anticipate the general characteristics of research that require such oversight going forward. Our oversight system has even less experience with the second question: what features can demonstrate that a biotechnology has sufficiently emerged and that societal concerns it prompts have been sufficiently managed to no longer require additional oversight and protections beyond that already provided by the systems in place?
The IOM (2014) report on Assessing the Role of the RAC attempted to answer this question, and found that while gene transfer had been a novel research modality for many years, that as of the early 2010s that was no longer the case—the approaches used had become well-studied, appropriate dosing quite well-understood, and side-effects predictable and manageable. Those sound like the characteristics of much clinical research rather than of an area deserving special and heightened scrutiny. And while a forum for discussion of societal issues related to gene transfer may be warranted, is a process of public oversight of individual protocols the best, most efficient, cost-effective, or otherwise appropriate means to achieve that goal? If the foregoing observations are accurate, then it may be time to declare the victory of a process that shepherded a new area of biomedical research over 40 years, from novel and uncertain to an approach with predictable and manageable outcomes (if limited successes). That seems to be exactly how additional oversight should work. What’s missing are the principles and a mechanism to decide that it is no longer necessary. More is at stake than an oversight process becoming less relevant and less effective over time. Without clear criteria for when special review has fulfilled its goals, there will be far greater reticence to undertake oversight of new technologies in the future. So as the sun sets on the RAC and the work of its members over four plus decades, let’s focus not only on why and how it came to be but on why, when, and how its work should end. Ironically, focusing on the end of oversight in one area of research may be the most helpful path to the birth of the next.
Disclosure and Notes
JPK and ACM served as members of the NIH RAC in the early 2000s. JPK also served as a member of the referenced 2014 IOM committee.
1As of this writing, the public comment period was scheduled to close on October 16, 2018 (DHHS, 2018)