Comparative effectiveness research (CER) aims to provide high-quality evidence to help patients and clinicians make informed clinical decisions and to assist health systems in improving the quality and cost-effectiveness of clinical care.1 Recently, the Department of Health and Human Services indicated that the regulatory framework for protecting human subjects is inadequate to evaluate the multifaceted risks of CER randomized, controlled trials (RCTs).2 As the federal Common Rule states, risks to subjects must be “reasonable in relation to anticipated benefit.” Institutional review boards (IRBs) are directed to “consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research).” Furthermore, unless the requirement for informed consent is waived by the IRB, subjects must be informed of “any reasonably foreseeable risks or discomforts” associated with participation. The enmeshment of research and standard clinical care makes evaluation of the risks posed by a CER RCT complex. In order to provide ethically appropriate oversight and informed consent, investigators should consider, manage, and communicate with potential participants about at least nine different types of potential risk — some unique to CER RCTs, some common to all RCTs.

1. Risks associated with the standard of care. All patients, when receiving the standard of care, are at risk for both the ills of the underlying disease processes and iatrogenic harm. Patients should be informed about undesired events or outcomes that are likely to occur with some frequency or that would be severe. Patients who are not participating in research studies may not be as thoroughly informed about the absolute risks associated with the proposed treatment or the relative risks of alternative treatments. A collateral benefit of trial participation is access to better information.

2. Risks (and benefits) of intervention A as compared with intervention B. CER studies are warranted when, within the range of the standard of care, more than one intervention is in common use for the same diagnostic, therapeutic, or other core clinical purpose, when there is debate among clinicians about which intervention is superior, and when evidence from a clinical trial could resolve the dispute and improve outcomes. In such situations, the relative risks associated with interventions A and B may be unknown, or one intervention may be known to be more risky or more costly but may have the potential to offer compensatory benefits. CER measures the difference in the marginal risks and benefits of A and B relative to each other.

3. Risks due to randomization. In CER RCTs, randomization dictates which intervention a participant will receive — nothing more, nothing less. If common treatments A and B were identical, the risk difference would be zero. In RCTs of two different interventions, when the differential risks of A as compared with B are unknown — hovering in a state of so-called clinical equipoise — the risks posed by assigning patients to one of the two interventions either by randomization or by uncertain clinician preference are not marginally different.

4. Risks due to experimental assignment versus practice variation. Patients receive care at particular sites, where the staff often prefers and offers one treatment over another. Thus, from the patient’s perspective, trial enrollment entails a describable alteration in the likelihood of receiving intervention A or B. If the patient is at a site that has mostly used intervention A, then entering the study entails an increased likelihood of exposure to B, and vice versa. Participants at a specific site should be given this site-specific information so they can evaluate the ways in which their treatment in the study might differ from what they would have received outside the study.

5. Risks due to masking of “standard” interventions. Keeping participants and investigators blind to treatment assignment can reduce outcome-measurement bias but can also introduce risk. In attempting to mask standard interventions, researchers must consider how blinding may affect the overall care of the participant as a patient. Research participants and health care professionals must be made fully aware that they will not be allowed to either choose or know the treatment assignment.

6. Risks due to protocol fidelity. In standard clinical care, disease- or condition-specific pathways or protocols are often suspended or altered when a patient is not doing well. Deviations from routinized care may or may not benefit the patient but are common practice. CER RCTs need to identify those junctures at which a particular intervention should be altered or stopped according to standard-of-care practices and to evaluate and minimize the risk associated with delays in such alterations of standard medical care. Prospective participants need to understand the investigator’s obligation to ensure fidelity to the protocol, the protocol-specified limits to that obligation, and their own right to withdraw from the study.

7. Risks of being assigned to the study group that receives less benefit. In CER RCTs, neither treatment option is universally accepted as the default or control. This symmetry has implications for informing participants about both risks and benefits. Since each intervention is simultaneously presumed to be effective (albeit to a different yet unknown degree), participants may perceive the risks as low. In the end, however, one treatment may yield greater benefit. The participants assigned to the other group may perceive their lower benefit as an actual harm. Potential participants should be informed of this possibility and should understand that the relative difference between the treatments is not currently known.

8. Risks due to acknowledgment of uncertainty. When providing potential participants with information during the consent process, investigators must clarify the existing uncertainty regarding the interventions. This clarification may cause psychological discomfort in patients who find uncertainty disconcerting. Although concealing uncertainty may avert this discomfort, concealment would constitute a failure to respect the patient. Patients need facts in order to make informed decisions. These psychological risks are therefore unavoidable in the ethical conduct of randomized trials. But it is important to recognize that these risks also exist for patients receiving the standard-of-care interventions if they receive appropriately complete information about treatment alternatives.3

9. Risks associated with being in the trial as compared with not being in it. Overall, if participation in clinical trials posed risks to participants, then participants in clinical trials would be observed to experience more harm or poorer outcomes than those receiving care outside clinical trials. There is no evidence that they do. Instead, participants in clinical trials usually have outcomes equivalent to those among similar patients not enrolled in studies who receive the same treatments.4 Unless specific reasons dictate otherwise, participants in CER RCTs should be informed that their outcomes will most likely be the same, but could be better or worse, if they do not participate.

In sum, CER RCTs carry multiple risks and benefits. Analysis of the overall risks and benefits of such studies — by IRBs or federal oversight committees — must take into account each of these domains separately and then integrate them into an assessment of the risks and benefits of the study as a whole. This approach often requires analysts to make judgments when comparing one sort of risk to another. The communication of information on these various forms of risks and benefits to potential study participants requires a balancing act. Detailed explanation of each separate risk may be overwhelming and confusing. Summaries of the risks may oversimplify or underemphasize particular risks.5 Evaluation of the acceptability of studies and of the adequacy of consent forms must reflect consideration and communication about these potential risks and benefits both separately and as a whole.

Source: NEJM