The RAC: Double, Double, Toil, and Trouble?
Authors: Hildegund Ertl
Journal: Molecular Therapy (2009)

Many view the Recombinant DNA Advisory Committee (RAC) as a mysterious entity that holds controversial authority over human gene transfer trials and, even worse, creates yet another layer of time-consuming and costly bureaucracy that replicates the efforts of the US Food and Drug Administration (FDA), institutional review boards (IRBs), and institutional biosafety committees (IBCs). As a member of the RAC, I can reassure all that the goal is not to impede clinical research or create redundant paperwork but instead to ensure that recombinant DNA (rDNA) research and clinical gene transfer trials are conducted in a safe and ethical fashion. Through the National Institutes of Health (NIH) Office of Biotechnology Activities (OBA), the RAC issues recommendations to the NIH director on all aspects of research involving human gene transfer. The RAC is by definition a transparent advisory committee without executive power. The quarterly meetings are conducted publicly, broadcast over the Internet, and archived for those unable to attend in person. The RAC comprises up to 21 voting members, who are appointed for at most 4 years by the NIH director. Most members of the RAC are academics with expertise in virology/microbiology, molecular biology, gene therapy, or immunology. Others provide expertise in statistics, public health, or ethics. Ad hoc consultants with additional expertise are solicited when needed. Typically, RAC meetings are attended by nonvoting representatives from public agencies such as the FDA. The RAC has several tasks. It helped develop and continues to be involved in revisions to the NIH Guidelines for Research Involving Recombinant DNA Molecules. Adherence to the guidelines (http://oba.od.nih.gov/rdna/nih_guidelines_oba.html) is mandatory for NIH-funded investigators. rDNA research that poses a potential public threat must be approved by the NIH director following recommendations from the RAC. Specifically, the RAC reviews research that involves the introduction of drug resistance into an infectious agent when human or veterinary medicine or agricultural interests could be impacted. For example, genetic manipulation of a pathogenic bacterium that affects its susceptibility to therapeutically useful antibiotics requires RAC review. The RAC also reviews human gene transfer research conducted at or sponsored by institutions that receive NIH funding for rDNA research. This is our major and most debated task, and it is carried out as follows. Clinical trials that use rDNA are registered with the OBA and then sent to the RAC for review. The RAC receives on average 10–20 protocols per quarter, and each RAC member, unless he or she has a conflict, makes a recommendation on whether a protocol requires in-depth review and public discussion. RAC members, through the OBA, can request additional information on specific points of a protocol before making their recommendation. Protocols are exempted unless at least three RAC members or another federal agency asks for in-depth review or if the NIH director initiates review. When a protocol is exempted from in-depth review, the investigators can proceed and seek IBC approval. Protocols that are selected for review cannot receive IBC approval until the review has been completed. Protocols that use rDNA constructs that have already been shown to be safe in previous clinical trials are generally exempted, unless peculiarities of a specific protocol raise concern. Protocols that use novel constructs or constructs that in previous trials elicited serious or unexplained adverse reactions, protocols that target especially vulnerable populations such as infants, and those that are exceptionally complex are generally selected for review. Once a protocol has been selected for review, the OBA appoints three or four members from the RAC and/or outside experts, if needed. Reviews focus on preclinical, clinical, and ethical considerations. Preclinical data are scrutinized to ensure that the results warrant clinical testing. If preclinical data are incomplete or indicate that the planned intervention is highly unlikely to lead to an effective treatment, the investigators are advised to conduct additional experiments in animals before their clinical trial. As a fictitious and rather extreme example, if one were planning to cure HIV-1 using an adenovirus vector that expresses a silencing RNA for an essential viral gene and the preclinical data in rhesus macaques chronically infected with simian immunodeficiency virus (SIV) showed that the vector transduced only 0.01% of CD4+ cells and effected no reduction in viral load, the RAC would not be persuaded to recommend proceeding with the protocol without additional preclinical studies. RAC reviewers also monitor preclinical data for indications that the planned approach might elicit adverse reactions. Returning to the fictitious example, if one modified the adenovirus gene transfer vehicle so that it achieved high transduction of CD4+ cells, but with this vector two of the SIV-infected monkeys died within days after gene transfer, the RAC would question the safety of the approach and request additional experiments. The RAC might also question the appropriateness of a specific animal model despite stellar preclinical data. For example, the use of an adenovirus vector to demonstrate a cure of hemophilia B in immunodeficient mice with a factor IX (F.IX) knockout mutation could lead the RAC to suggest repetition of the experiments in immunocompetent mice. One may view the request for additional preclinical data as an intrusion, but clinical trials, which always pose a risk to a human volunteer, must be based on sound preclinical data, and if such data are not available, the risk outweighs the potential benefit for human volunteers—and that is not acceptable. Clinical considerations focus on the design of the trial. Are inclusion/exclusion criteria appropriate? Is the dose escalation in a phase I trial suitable for determining maximally tolerated doses without causing undue harm? Is the trial powered to give statistically meaningful results? Are additional screenings required to ensure the safety of a trial? The RAC may recommend a change in dosing or timing of dosing in a phase I trial, or it may suggest additional assays. Recommendations may address further scrutiny for adverse reactions. The committee may also aim to enhance the scientific knowledge that can be gained from clinical trials. For example, a phase I trial using an F.IX-expressing adeno-associated virus (AAV) vector for hepatic gene transfer into a hemophilia patient resulted in transient expression of therapeutic levels of F.IX followed by a subclinical transaminitis and loss of transgene expression. Subsequent experiments suggested that CD8+ T cells directed to AAV capsid caused loss of AAV-transduced hepatocytes. The results led some investigators to transiently immunosuppress volunteers who received AAV-mediated gene transfer. The RAC currently recommends that investigators screen for AAV capsid-specific CD8+ T-cell responses before and upon AAV gene transfer to gain further insight into the potential role in causing rejection of AAV-transduced cells. This recommendation has been criticized because the hypothesis remains unproven and may be false. If it is correct, however, it would have critical implications for the design of future AAV gene transfer trials. The requests for additional experiments to shed light on such a scientific question are thus justifiable and in the best interest of the recipients of experimental AAV gene transfer. Ethical considerations address informed consent and potential conflicts of interest. For example, informed-consent forms that use language that cannot be understood by a patient who does not have an advanced degree, that imply therapeutic benefits in a clinical trial, or that fail to state the risks will need to be rephrased. Reviews are submitted to the investigators for a response before the actual RAC meeting. At the RAC meeting, the investigators present their clinical trial design, including pertinent background data. The reviewers subsequently voice their recommendations, and whether and to what degree they have been addressed by the investigators' responses. Other RAC members are then asked to enter the discussion, and at the end, members of the public may verbalize their views. The RAC subsequently formulates a recommendation, which is voted on by the voting members. Before the vote, investigators are permitted to discuss the recommendations. The recommendations are provided in writing within 10 business days to the investigators, the IRB, the IBC, the FDA, and the Office for Human Research Protection. Once the trial enrolls, the investigators are expected to address the recommendations in writing to the OBA. These responses are provided to the RAC for review. IBCs are mandated to take RAC recommendations into consideration in their decision-making process. Once a clinical trial has started, a subcommittee of the RAC monitors reported adverse events. Unexpected or serious adverse events (SAEs) are brought to the attention of the entire committee. In some cases, an ad hoc RAC subcommittee is formed to further discuss a specific SAE. For example, the death of J. Gelsinger following treatment with a replication-defective adenovirus vector expressing ornithine transcarboxylase and that of Jolee Mohr, a rheumatoid arthritis patient who died shortly after receiving an AAV vector expressing a tumor necrosis factor antagonist, were discussed by the RAC. The goal of the RAC in such cases is to determine whether and to what degree the SAE was linked to the gene transfer and whether and how the SAE can be prevented in the future. Deaths of individuals during clinical gene therapy trials such as that of J. Gelsinger are widely discussed by the press, and allegations of unreported deaths, conflicts of interest, and misinformation given to volunteers undermine the public's trust in clinical gene transfer trials. The openness of the RAC process allows for a public discussion of such tragic events, aiming to separate fact from fiction and restore public trust in clinical gene transfer trials. By analyzing and disseminating knowledge gained from such events, the RAC also provides guidance on the design and conduct of subsequent trials. The RAC has functions that complement and in part overlap those of the FDA, IBCs, and IRBs. All four entities review the safety of gene transfer protocols. An IRB, by law, is composed of at least five members. At least one member must be a scientist, at least one member must be a nonscientist, and at least one member must not belong to the institution that initiated the clinical protocol. Investigators and their institutions may have a financial stake in clinical trials, which in turn may taint the public's perception of the IRB's objectivity. An IBC must contain at least five members, of whom at least two must not be affiliated with the institution. In addition, the IBC should have the proper expertise to review human gene transfer research (and ensure that all aspects of Appendix M of the NIH Guidelines have been appropriately addressed). Not only is the RAC larger than most IRBs and IBCs and thus offers a more diverse level of expertise, but it is also governed by even more stringent conflict-of-interest rules. RAC members who are associated with the institutions involved in the clinical trial in any fashion are not permitted to participate in the discussion of the protocol, nor are they allowed to cast a vote. The conflict-of-interest rules are so stringent that, for example, a RAC member who gives a student-invited lecture at an institution is recused for 1 year from reviewing protocols that involve the institution. The RAC, unlike the FDA, scrutinizes not only the safety of a clinical trial but also its scientific value, and this in my mind is one of our most important missions. Human volunteers in clinical trials, although they must be advised not to expect a therapeutic benefit, will nevertheless hope for such a benefit. Even the most carefully worded informed-consent form will be unable to prevent this therapeutic misconception, for such is human nature. Volunteers also expect that their participation will serve science and eventually lead to cures of others with similar afflictions. Clinical trials that are not based on sound preclinical data cannot be justified, because they misuse the volunteers' altruism. The RAC, unlike other review boards, aims to increase the scientific knowledge that can be gained from a clinical trial, because such is in the best interest of the patients as well as society as a whole. This editorial represents the views of the author and not those of any official body, including the RAC.