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

On Friday, October 24, the Office for Human Research Protections (OHRP) released a draft guidance document titled “Guidance on Disclosing Reasonably Foreseeable Risks in Research Evaluating Standards of Care.” The draft guidance follows more than a year of deliberation and public consultation prompted by the controversy surrounding the Surfactant, Positive Pressure, and Oxygenation Trial (SUPPORT).

SUPPORT was a multisite randomized trial that took place from 2005 to 2009 and sought to determine, in part, the optimal oxygen saturation for extremely premature infants. Subjects enrolled in the study were randomized to one of two arms: a low oxygen arm, in which the level of oxygen they received was maintained between 85% and 89%, and a high oxygen arm, in which the level of oxygen they received was maintained between 91% and 95%. At the time the study took place, the recognized standard of care was for infants to receive oxygen saturation between 85% and 95%.

In a determination letter dated March 7, 2013, OHRP stated that the informed consent process did not meet the requirements set forth at 45 CFR 46 and that the risks of the research, which measured retinopathy and death as outcomes, were not properly disclosed to the parents of the infants enrolled in the study. As described in previous posts, considerable public debate ensued, and it quickly became apparent that there were real differences in understanding about how the regulations at 45 CFR 46 should apply to research studying interventions that fall within what is referred to as the “standard of care,” including how determinations about which risks are “research risks” should be made, and, accordingly, what risks should be disclosed to potential subjects during the research consent process. With respect to SUPPORT, many argued that since both oxygen values were within the standard of care, the research did not pose any risks beyond those that an individual would encounter in the clinical space.

However, in the October 24 Federal Register notice announcing the draft guidance, OHRP made clear that they did not agree with this assessment. They stated: “…the key issue is that the treatment and possible risks infants were exposed to in the research were different from the treatment and possible risks they would have been exposed to if they had not been in the trial, not that the treatment provided in the trial was within the standard of care.”

This viewpoint is further developed in the draft guidance, which addresses four primary questions:

1. What are “standards of care”?
2. What are “risks of research” in studies evaluating risks associated with standards of care?
3. When is evaluating a risk in a research study considered to be a “purpose” of the research study?
4. Are the risks of research associated with the purposes of studies of standards of care “reasonably foreseeable risks” that must be disclosed to prospective subjects in the informed consent process?

The draft guidance addresses the first question—what are standards of care—by noting the variability of the term “standard of care,” and while the document attempts to elucidate what is meant by the phrase, it offers limited guidance in terms of evaluating whether a protocol has provided sufficient evidence for positing that a procedure, treatment, or practice falls within the standard of care.

In its consideration of the second question, OHRP explains that the “risks of research” are those that emerge when an individual receives treatment that is different from what they would have received were they not enrolled in the study. The guidance states:

OHRP generally considers the risks of a specific standard of care being evaluated to be risks of research if (1) a standard of care that at least some of the individual subjects will be assigned to receive will be different from the standard of care that they would have received if they were not participating in the study, and (2) there might be different risks associated with those standards of care.

Within that framework, if a protocol randomizes subjects between two standards of care, thereby assigning a subject to an intervention that they would not have otherwise received and exposing them to a set of risks they would not otherwise be exposed to, then “the particular risks that the subjects will be exposed to because of being assigned to a special standard of care are risks the subject will be exposed to for the sake of research” (emphasis added). Thus, the subject must be made aware of these risks during the informed consent process.

The US Department of Health and Human Services regulations at 45 CFR 46 state that subjects must be provided a description of any “reasonably foreseeable risks or discomforts” (45 CFR 46.116(a)(2)). How, then, do you determine what is a “reasonably foreseeable risk” of standard of care interventions? OHRP indicates in the guidance that risks connected to the “purpose of the research” should be considered reasonably foreseeable: “If a study is designed to discover the degree to which [a] particular harm will or will not occur, the possibility of that harm occurring is clearly foreseen by those responsible for the design and conduct of the study. The risks should accordingly be disclosed to the people who are being asked to be exposed to that risk as subjects in the study.”

OHRP clarifies, however, that not every outcome measured is a purpose of the study—only the risks “sufficiently important to justify the conduct of the study” should be considered “purposes” of the research. The agency also recognizes that there may be risks that are unknown or unrecognized at the time a study is initiated and indicates that, since evaluating such risks is not to a purpose of the research study, those risks are not reasonably foreseeable, and hence the guidance does not apply. In sum, “OHRP’s general position is that the reasonably foreseeable risks of research include already-identified risks of the standards of care being evaluated as a purpose of the research when the risks being evaluated are different from the risks subjects would be exposed to outside of the study” (emphasis added).

Time and again throughout the draft, OHRP makes clear their intent to limit the scope of the guidance to “research whose purposes include evaluating risks of such standards of care” (emphasis added). Comparative effectiveness research, however, takes on many forms and extends beyond research on comparative risks. Thus, to our mind, the narrow focus raises questions about how broadly applicable the recommendations will be to the wider realm of comparative effectiveness research.

In the coming weeks, PRIM&R’s Public Policy Committee will consider this issue and others as we prepare comments in response to the draft for submission to OHRP. As we begin this process, we encourage and welcome you to share your thoughts on the draft guidance in the comments. We look forward to sharing our comments here once they are finalized.