Reconsidering ‘minimal risk’ to expand the repertoire of trials with waiver of informed consent for research

Abstract

BackgroundProgress in therapeutic research is slowed by the regulatory burden of clinical trials, which provide the best evidence for guiding treatment. There is a long delay from evidence generation to adoption, highlighting the need for designs that link evidence generation to implementation.ObjectiveTo identify clinical trial designs that confer minimal risk above that inherent in clinical care, to obviate the need for cumbersome consenting processes to enrol patients in prospective clinical research studies. These designs extend the scope of the Learning Healthcare System, a framework for leveraging retrospective ‘big data’ to advance clinical research, to include data collected from prospective controlled trials.SummaryPragmatic trials may use simplified eligibility criteria, unblinded interventions and objective outcome measures that can all be monitored through the electronic health records (EHR), to reduce costs and speed study conduct. Most pragmatic trials continue to suffer from substantial regulatory burden. Written consent to participate in research can be waived only if the research produces minimal risk above what is encountered in everyday life. However, the ‘consent’ processes for prescribing Federal Drug Administration-approved medications in clinical medicine are informal, even when they involve decisions of uncertain benefit and higher levels of risk. We propose that trial designs that mimic clinical decision-making in areas of uncertainty (clinical equipoise) and in which no data are generated outside of usual care (ideally by EHR embedding) confer minimal additional risk. Trial designs meeting this standard could, therefore, be conducted with minimal documentation of consent, even when interventions contain different risks. To align with risk encountered in clinical practice, allocation to treatment arms should change (adaptive randomisation) as data are collected and analysed. Embedding of informatics tools into the EHR has the additional benefit that, as adaptive randomisation progresses, evidence-generation transitions into implementation via decision-support tools—the ultimate realisation of the Learning Healthcare System.

A rapid review of community engagement and informed consent processes for adaptive platform trials and alternative design trials for public health emergencies

“…Fostering culturally sensitive consent processes and an understanding of trial procedures through consultation with the community was recommended 59 . Lengthy information sheets and informed consent forms may also present a barrier to full understanding of trial processes and to trial enrolment 3 , 5 , 60 , 61 , 69 – 71 . The context of public health emergencies, where disruption, fear and confusion are common, was also described as presenting challenges for informed consent 41 , 45 , 51 and potential for therapeutic misconceptions 45 , 51 .…”

“…A key issue for informed consent to APTs relates to the information that is provided regarding trial-specific adaptations and the optimal level of detail about trial design. In a PHE, streamlined consent processes and simplified consent forms are important for rapid enrolment 70 , 71 , 74 , 75 . Potential challenges to simplified informed consent processes are unfamiliarity of research stakeholders with APTs 62 and the possibility of therapeutic misconceptions, argued to be heightened in PHE contexts 3 , 60 , 61 , 76 .…”

“…Optimising recruitment and informed consent processes to enable rapid recruitment is a common theme to discussion articles on COVID-19 and on GHEs in general particularly for low risk studies involving repurposed drugs with good safety profiles 60 , 61 , 70 , 71 , 78 . For incapacitated patients, deferred consent, or consent by proxy by family members or legal representatives has been recommended and approved by ethics committees, with a further recommendation that patients can later be consented during therapeutic windows 5 , 75 .…”

“…For incapacitated patients, deferred consent, or consent by proxy by family members or legal representatives has been recommended and approved by ethics committees, with a further recommendation that patients can later be consented during therapeutic windows 5 , 75 . Monach et al ., describing the range in trial candidates, from RCTs exploring different doses of drugs with known safety profiles and off-label drugs with a well-described safety profile, to investigational drugs with unknown safety profiles, recommends a nuanced approach to consent 71 . For low risk trial candidates, waivers (opt-out) they argue, can be considered, whilst opt-in oral and written consent is more appropriate for higher risk trial candidates with unknown safety profiles.…”

“…Casey and colleagues argue that tight regulation would have prevented the implementation of RECOVERY in the USA, but that the protocolisation of research integrated into care in the UK minimised the wide clinical use of unproven therapies like hydroxychloroquine 20 . On one hand, over-complicated information materials, consent forms and processes can impede research 60 , 61 , 70 , 71 , while therapeutic misconception, on the other, can lead to long-term mistrust in research 61 .…”