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

Abstract

Background/Aims Standard of care pragmatic clinical trials (SCPCTs) that compare treatments already in use could improve care and reduce cost but there is considerable debate about the research risks of SCPCTs and how to apply informed consent regulations to such trials. We sought to develop a framework integrating the insights from opposing sides of the debate. Methods We developed a formal risk-benefit analysis framework for SCPCTs and then applied it to key provisions of the U.S. federal regulations. Results Our formal framework for SCPCT risk-benefit analysis takes into account three key considerations: the ex ante estimates of risks and benefits of the treatments to be compared in a SCPCT, the allocation ratios of treatments inside and outside a SCPCT, and the significance of some participants receiving a different treatment inside a SCPCT than outside the trial. The framework provides practical guidance on how the research ethics regulations on informed consent should be applied to SCPCTs. Conclusions Our proposed formal model makes explicit the relationship between the concepts used by opposing sides of the debate about the research risks of SCPCTs and can be used to clarify the implications for informed consent.

Ethical issues in pragmatic trials of “standard‐of‐care” interventions in learning health care systems

“…To waive or alter informed consent, the research procedures must meet the following criteria listed in Table . These criteria are more thoroughly discussed elsewhere . For the present purpose, I simply present the type of issues that need to be addressed in applying the criteria.…”

“…But this will depend on a few issues. It can be shown formally that if one or both of the following conditions are met, then the average incremental risk attributable to research participation will be minimal: (1) if the ex ante risk estimate of the 2 standard‐of‐care interventions is similar; (2) if the allocation ratio of the 2 interventions is similar inside and outside the RCT …”

“…A full explication of the above 2 conditions can be found elsewhere but for present purposes, we note that not all standard‐of‐care RCTs have 2 interventions with similar ex ante risk and benefit profiles. It may be that there have been a series of small RCTs favoring one intervention over another, but the data are not definitive enough . For instance, the United Kingdom Dermatology Clinical Trials Network compared the effectiveness of antibiotic prophylaxis (vs no prophylaxis) for recurrent cellulitis .…”

“…These criteria are more thoroughly discussed elsewhere. [20][21][22][23] For the present purpose, I simply present the type of issues that need to be addressed in applying the criteria. The fourth criterion of debriefing is not discussed here as it is an after the fact issue, and the focus here is on prospective deviations from usual practice of informed consent.…”

“…It may be that there have been a series of small RCTs favoring one intervention over another, but the data are not definitive enough. 21,27 For instance, the United Kingdom Dermatology Clinical Trials Network compared the effectiveness of antibiotic prophylaxis (vs no prophylaxis) for recurrent cellulitis. 28 Prior to the trial, 4 randomized controlled trials had suggested possible benefits of antibiotic prophylaxis, although none of the studies were seen to provide definitive results, either because the sample size was small (2 studies) or because the benefits observed were statistically marginal (2 studies).…”