by Elisa A. Hurley, PhD, Executive Director, and Avery Avrakotos, Education and Policy Manager

Research on the comparative effectiveness of commonly used interventions is becoming increasingly common as clinicians, researchers, and healthcare funders seek to improve the efficiency and effectiveness of health care by developing a strong evidence base about medical interventions. With the growth of such efforts, questions have emerged about how oversight rules and mechanisms for the protection of human subjects should apply to such endeavors. In October, following more than a year of deliberation and public consultation, the Office for Human Research Protections (OHRP) released draft guidance regarding how the federal regulations for the protection of human subjects apply to research evaluating alternative interventions that all meet the standard of care for preventing, diagnosing, or treating a particular condition. In an earlier post, we provided an overview of the draft guidance, titled “Guidance on Disclosing Reasonably Foreseeable Risks in Research Evaluating Standards of Care,” and today, we are pleased to make available PRIM&R’s response to the draft. PRIM&R appreciates the OHRP’s efforts to foster public discussion and provide the research community with guidance on how to ensure adequate protections for human subjects in research evaluating one or more interventions that are within the standard of care. PRIM&R believes, however, that the current document does not provide the comprehensive assistance needed by investigators and IRBs, and, in our comments, urges the OHRP to rewrite the document to provide clearer guidance. Concerns Regarding the Current Draft Guidance In our response, PRIM&R expresses concern that the draft guidance appears to be limited to research whose purpose is to evaluate the risks of two or more “standard of care” interventions. PRIM&R does not believe such an approach provides the comprehensive guidance on comparative effectiveness research (CER) that is needed, given, for instance, the fact that studies of marketed drugs are typically designed to compare efficacy/effectiveness or benefits, as opposed to differences in risks. While PRIM&R agrees with the draft guidance that any significant differences in the “foreseeable risks” of research must be disclosed, we also suggest that a shift in emphasis would better achieve the OHRP’s main goal, namely, “that the distinction between receiving clinical care and participating in research must be made clear to subjects.” Thus PRIM&R encourages the OHRP to place less emphasis on risks and focus instead on the need for investigators to make clear to potential subjects that they have a choice of whether to receive one of the interventions in a clinical context, or to assist investigators in learning more about comparative benefits, risks, costs, and so forth by receiving one or another of the interventions on a randomized basis in a trial. Furthermore, we suggest that, when there are significant differences in the potential harms of the interventions being compared, those differences likely affect potential subjects’ decisions of whether or not to participate in the trial. But that there should be no implication that when differences in potential harms are much smaller, or even nonexistent, there is thus nothing left for subjects to decide. Indeed, it is PRIM&R’s view that the central concern in research evaluating one or more accepted interventions should be ensuring that potential subjects understand (a) that they are being asked to participate in research, (b) the nature of the research question being investigated, and (c) how their care as research subjects may differ from care they would receive in the clinical context. Given the importance of providing guidance in this area, we strongly urge the OHRP to use this opportunity to reformulate the draft guidance to better address that concern. Recommendations for Future Guidance To assist the OHRP with the process of rethinking and reformulating its guidance in this area, PRIM&R puts forward three recommendations:

1. Investigators, sponsors, and IRBs should ensure that protocols involving the comparison of two or more interventions that meet the relevant standard of care make clear what question(s) are being studied and the importance of the question(s) under study. IRBs should also ensure that the study, as designed, can provide answers to those questions.
2. IRBs, investigators, and sponsors should make certain that the information provided to potential subjects during recruitment or consent for research evaluating one or more standard-of-care interventions adequately conveys, in an understandable fashion, what is being studied, the importance of the question under study, and how a potential subject’s care may differ in the clinical research context, as opposed to the clinical context alone. Potential subjects should also be made aware how interventions will be assigned (e.g., randomly) and that, when so specified by the protocol, neither they nor their health care practitioner will select the intervention they receive.
3. Explanations provided to potential subjects should reflect the magnitude of the potential risks and benefits associated with the interventions under study, while ensuring that potential subjects are provided with all of the information necessary to make an informed decision.

We encourage you to read PRIM&R’s complete response to OHRP, and to share your thoughts about PRIM&R’s comments or the OHRP’s draft guidance below.