In recognition that the evidence base is too thin for much of the medical care delivered in the United States, the Affordable Care Act (ACA) included a big boost in funding—an additional $1.1 billion —to support comparative effectiveness research. Comparative effectiveness research enables comparisons of treatments and prevention strategies to determine which work best for which populations and under what circumstances. It is frequently governed by federal regulations issued by the Department of Health and Human Services (HHS) Office of Human Research Protections (OHRP), found at 45 C.F.R. Part 46 (otherwise known as the Common Rule).

The Common Rule governs human subjects research that is conducted or funded by HHS or takes place in entities that have agreed to be bound by these rules for all human subjects research, regardless of funding source. Human subjects research includes research utilizing a patient’s identifiable health information.

The Challenge of Assessing Research Risk

OHRP recently released draft guidance for research evaluating “standards of care.” Standard of care research evaluates treatments or procedures that are already recognized and used in practice, but where there is insufficient evidence regarding which work better for a given condition and/or a specific population. (Click to read the guidance.)

The Common Rule generally requires a review by an Institutional Review Board (IRB) for human subjects research. The IRB evaluation must consider the risks and benefits that would result from the research, as distinct from the risks and benefits patients would experience if they were not participating in the study. When the patient’s consent is required, that consent must be informed. The information the patient receives must include a description of any “reasonably foreseeable risks.”

When there is more than one standard of care for treating the patient—and a lack of evidence about which treatment offers the greatest effectiveness or lowest risk—it is often difficult for researchers and IRBs to compare the risks associated with studying those treatments versus the ordinary risks a patient seeking treatment would face. Without clear evidence on comparative efficacy and risk, patients often receive the treatment that their particular provider is accustomed to delivering or that may be covered by their health benefit plan. Under what circumstances does studying the competing standards of care create greater risks than a patient would face in an ordinary treatment circumstance?

How the OHRP Draft Guidance Addresses Risk in Standard of Care Studies

The draft guidance attempts to provide more information about how OHRP believes IRBs and researchers should assess research risk in standard of care studies. It focuses on studies involving randomization —i.e., research in which patients are randomly assigned to receive one treatment or the other. The guidance states that:

“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.” (Emphasis added.)

The guidance goes on to state:

“When a research study assigns the specific version of the accepted standards of care to be used, it is almost certain that at least some of the subjects will receive a different standard of care than they would have received if not participating in the research.”

The guidance seems to presume that randomization itself (at least at the individual patient level) always introduces risk, even in circumstances where there is no evidence that one standard of care is better, or less risky, than another. The guidance further states that “[i]t is equally important to recognize that the risks of the research do not include the risks that are created by the medical condition for which the person is being treated, or the risks associated with any available standard of care treatment that they would receive for that condition outside of the research.” Consequently, studies that compare outcomes for individuals where the patients were not assigned to a particular treatment (for example, analysis of outcomes data or observational research) do not introduce additional research risks.

Of note, the guidance does not specifically mention “cluster” randomization, where instead of the randomization occurring at the individual patient level, an entire setting (e.g., hospital or physician practice) is randomized to a particular treatment or prevention approach.

The guidance also offers assistance on determining which risks of research are “reasonably foreseeable” and therefore need to be disclosed to patients as part of the informed consent process. If evaluating a particular risk is a purpose of the research, that risk is “reasonably foreseeable” and needs to be disclosed.

HHS is seeking comments on the draft guidance, which must be submitted in writing by December 23, 2014. Click to read the HHS notice. For additional commentary on the regulations governing comparative effectiveness research, click to read a summary of “Ethics, Regulation and Comparative Effectiveness Research” recently published in The Journal of the American Medical Association.