Considerations in the evaluation and determination of minimal risk in pragmatic clinical trials

Abstract

The classification system for categorizing the riskiness of a clinical trial is largely defined by the body of federal regulations known as the Common Rule (45 CFR 46, Subpart A) and by regulations governing the US Food and Drug Administration (FDA) codified in 21 CFR 50. This rule is applied according to the interpretation of institutional review boards (IRBs) charged with overseeing the research. If a clinical trial is determined by an IRB to constitute “minimal risk,” there are important practical implications: the IRB may allow waiver or alteration of the informed consent process; the study may be carried out in certain vulnerable populations; or the study may be reviewed by IRBs using an expedited process. However, it is unclear how the risk levels of pragmatic clinical trials (PCTs) should be assessed. Such trials typically compare existing, widely used medical therapies or interventions in the setting of routine clinical practice. Some of the therapies may be considered risky of themselves but the study comparing them may or may not add to that pre-existing level of risk. In this paper, we examine current research regulations and common interpretations of those regulations and suggest that current interpretation and application of regulations governing minimal-risk classification are marked by a high degree of variability and confusion, which in turn may ultimately harm patients by delaying or hindering potentially beneficial research. We advocate for a clear differentiation between the risks associated with a given therapy and the incremental risk incurred during research evaluating those therapies as a basic principle for evaluating the risk of a clinical study. We then examine two studies that incorporate aspects of PCTs and consider how various factors including patient perspectives, clinical equipoise, practice variation, and research methods such as cluster randomization contribute to current and evolving concepts of minimal risk, and how this understanding in turn affects the design and conduct of PCTs.

A framework for analysis of research risks and benefits to participants in standard of care pragmatic clinical trials

“…The Equal Estimated Welfare condition may be what some have in mind when they describe SCPCTs in which “[t]here are a number of such products …with substantial differences in price but without substantial differences in efficacy or side effects” 6 and “equally well-supported treatment option that falls within the standard range of care.” 9 Similarly, the Equal Probability of Allocation condition is what some commentators mentioned above may have in mind when they state: “to the extent that there is widespread practice variation, the resulting allocation of treatments will look very much like the allocation that will result from randomization.” 2, 7 …”

“…[45CFR46.111(2)] Second, research risks must be identified to meet the requirements for informed consent, both for assessing whether it could be a candidate for a waiver or alteration [45 CFR 46.116c] but also for assessing what research risks should be included among the “reasonably foreseeable” risks that must be disclosed. [45 CFR 46.116a(2)] 2, 28, 29 According to the regulations, research risks (and benefits) are “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).”[45 CFR 46.111(2)] The interpretive task, therefore, is to understand the phrase “therapies subjects would receive even if not participating in research” both in determining that a SCPCT has reasonable risks and in identifying reasonably foreseeable risks relevant to informed consent (and waiver or alteration) requirements. Should it be a random patient perspective or a specific patient perspective?…”

“…Since minimal risk studies are candidates for less restrictive rules, such as a waiver or alteration of informed consent, there is great interest in examining SCPCTs’ risk status. 2 …”

Low risk pragmatic trials do not always require participants’ informed consent

“…Low risk pragmatic RCTs pose no or minimal incremental risk compared with usual clinical care5 and are typically head to head comparisons of medicines that are routinely prescribed according to their marketing authorisations. There are several approaches to conducting low risk pragmatic RCTs of medicines.…”

Targeted Consent for Research on Standard of Care Interventions in the Emergency Setting

“…Yet, there is considerable debate over whether standard-of-care research can be categorized as minimal risk (4). Even more controversial is the possibility of categorizing standard-of-care research in the emergency setting as minimal risk.…”