Proposals to Conduct Randomized Controlled Trials Without Informed Consent: a Narrative Review

Abstract

BACKGROUND: Individual informed consent from all participants is required for most randomized clinical trials (RCTs). However, some exceptions-for example, emergency research-are widely accepted. METHODS: The literature on various approaches to randomization without consent (RWOC) has never been systematically reviewed. Our goal was to provide a survey and narrative synthesis of published proposals for RWOC. We focused on proposals to randomize at least some participants in a study without first obtaining consent to randomization. This definition included studies that omitted informed consent entirely, omitted informed consent for selected patients (e.g., the control group), obtained informed consent to research but not to randomization, or only obtained informed consent to randomization after random assignment had already occurred. It omitted oral and staged consent processes that still obtain consent to randomization from all participants before randomization occurs. RESULTS: We identified ten different proposals for RWOC: two variants of cluster randomization, two variants of the Zelen design, consent to postponed information, two-stage randomized consent, cohort multiple RCT, emergency research, prompted optional randomization trials, and low-risk pragmatic RCTs without consent. CONCLUSION: Of all designs discussed here, only cluster randomized designs and emergency research are routinely used, with the justification that informed consent is infeasible in those settings. Other designs have raised concerns that they do not appropriately respect patient autonomy. Recent proposals have emphasized the importance for RWOC of demonstrating such respect through systematic patient engagement, transparency, and accountability, potentially in the context of learning health care systems. INTRODUCTIONRandomized controlled trials (RCTs) are the gold standard for clinical research. 1 Informed consent, including disclosure of randomization, is an ethical requirement for most RCTs. 2 This principle, intended to protect participants' autonomy and dignity, is firmly embedded in guidelines and regulations. [3][4][5][6] But, critics have argued that modern consent processes often fail to convey information well, can confuse or distress participants, and may even hinder legitimate research endeavors to the point where patients are paradoxically harmed by the lack of research on the safety and effectiveness of commonly used therapies. 7,8 These arguments have led to calls to relax or eliminate informed consent requirements in certain circumstances. An example is the exception for emergency medicine studies in which it is deemed impossible to obtain informed consent and still test an emergent intervention. 9 More broadly, US Federal regulations allow a waiver of informed consent requirements for clinical research given that four requirements are met: (1) Bthe research involves no more than minimal risk to the subjects,^(2) Bthe waiver or alteration will not adversely affect the rights and welfare of the subjects,^(3) Bthe researc...

Informed consent within a learning health system: A scoping review

“…Various studies have shown that at first glance, participants seem to favor an “ask each time” model in research . Those findings are inconsistent with the results of two studies exploring public attitudes toward consent in biobanking, both indicating that a broad one‐time opt‐in is preferred by the public in general .…”

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

“…In the worst scenario, the trial is terminated early 711. We should look for alternatives to the standard written informed consent for low risk pragmatic RCTs 2223…”

How to obtain informed consent for research

“…Based on the fact that patients are assigned to standard care interventions, no informed consent is sought either in low-risk pragmatic RCTs [ 17 ] or in prompted optional randomisation trials [ 18 , 19 ]. However, in a low-risk pragmatic RCT, patients do not have the possibility to choose one of the two standard treatments, whereas in a prompted optional randomisation trial, both the researchers and the enrolled patients can choose one type of treatment over another, despite the randomisation results [ 6 ].…”