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

ABSTRACT: Institutional review boards, which are charged with overseeing research, must classify the riskiness of proposed research according to a federal regulation known as the Common Rule (45 CFR 46, Subpart A) and by regulations governing the US Food and Drug Administration codified in 21 CFR 50. If an institutional review board determines that a clinical trial constitutes "minimal risk," there are important practical implications: the institutional review board may then allow a 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 institutional review boards using an expedited process. However, it is unclear how institutional review boards should assess the risk levels of pragmatic clinical trials. 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 article, we examine the common interpretations of research regulations regarding minimal-risk classifications and suggest that they 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 pragmatic clinical trial. We then examine two pragmatic clinical trials and consider how various factors including clinical equipoise, practice variation, research methods such as cluster randomization, and patients' perspectives may contribute to current and evolving concepts of minimal-risk determinations, and how this understanding in turn affects the design and conduct of pragmatic clinical trials.

SUBMITTER: Lantos JD

PROVIDER: S-EPMC4703320 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Lantos John D JD Wendler David D Septimus Edward E Wahba Sarita S Madigan Rosemary R Bliss Geraldine G

Clinical trials (London, England) 20150915 5

Institutional review boards, which are charged with overseeing research, must classify the riskiness of proposed research according to a federal regulation known as the Common Rule (45 CFR 46, Subpart A) and by regulations governing the US Food and Drug Administration codified in 21 CFR 50. If an institutional review board determines that a clinical trial constitutes "minimal risk," there are important practical implications: the institutional review board may then allow a waiver or alteration o ...[more]

PMID: 26374686

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Project description:PurposeGeneral notification offers a possible alternative to written informed consent for pragmatic randomized controlled trials (pRCTs). It involves patients being informed through brochures, posters, and letters that research is being conducted simultaneously to providing clinical care and that patients will be enrolled in pRCTs without study-specific consent. A previous survey found that a substantial minority of respondents endorsed general notification. We aimed to know who is willing to enroll in this type of trials using general notification rather than written consent.MethodsThe previous study was a cross-sectional, probability-based survey, with a 2 × 2 factorial design. Two scenarios were assessed: two low-risk pRCTs in hypertension, one comparing two drugs with similar benefit/risk ratio and the other taking the same drug in the morning or at night. Each scenario had two routes: written consent vs verbal consent and written consent vs general notification. In this study, we were interested in the latter route in both scenarios. Respondents' preferences were measured based on their recommendation to the research ethics committee and the respondent's personal preference. We aimed to investigate the characteristics of those supporting general notification in either outcome or the variables explaining consistency and inconsistency between their personal preference and their recommendation. Based on the results of the original survey, we aimed to have at least 200 inconsistent respondents; to this end, the sample size was increased accordingly in a second wave of the survey.ResultsOne thousand six hundre and ten respondents were included; 1003 from the original survey and 607 new ones belonging to the second wave. Thirty-nine percent of respondents chose general notification as personal preference and/or recommendation. Respondents with lower education levels were more prone to accept general notification than those holding a university degree [OR (95% CI)], primary school [2.959 (2.069-4.232)], secondary school [2.899 (2.09-4.021)], or high school [1.620 (1.184-2.217)]. Also unemployed [1.372 (1.064-1.770)] and retired [1.445 (1.049-1.990)], but not students, showed preference for general notification in comparison with those employed. Individuals more than 24 years old and having received high school or university (or postgraduate) education were statistically significantly more consistent in their decisions.ConclusionsThirty-nine percent of respondents is open to not to be asked for their informed consent in low-risk pRCTs; of these, those being less educated and not having current job or being retired are significantly more open to general notification. The use of this alternative method to written consent for simultaneous conduct of pRCTs and care should be considered and educational programs settled up to, in the case of public acceptance, ensure its ethical appropriateness.

Project description:AimsPragmatic randomized clinical trials (pRCTs) collect data that have the potential to improve medical care significantly. However, these trials may be undermined by the requirement to obtain written informed consent, which can decrease accrual and increase selection bias. Recent data suggest that the majority of the US public endorses written consent for low-risk pRCTs. The present study was designed to assess whether this view is specific to the US.MethodsThe study took the form of a cross-sectional, probability-based survey, with a 2 × 2 factorial design, assessing support for written informed consent vs. verbal consent or general notification for two low-risk pRCTs in hypertension, one comparing two drugs with similar risk/benefit profiles and the other comparing the same drug being taken in the morning or at night. The primary outcome measures were respondents' personal preference and hypothetical recommendation to a research ethics committee regarding the use of written informed consent vs. the alternatives.ResultsA total of 2008 adults sampled from a probability-based online panel responded to the web-based survey conducted in May 2016 (response rate: 61%). Overall, 77% of respondents endorsed written consent. In both scenarios, the alternative of general notification received significantly more support (28.7-37.1%) than the alternative of verbal consent (12.7-14.0%) (P = 0.001). Forty per cent of respondents preferred and/or recommended general notification rather than written consent.ConclusionsThe results suggested that, rather than attempting to waive written consent, current pRCTs should focus on developing ways to implement written consent that provide sufficient information without undermining recruitment or increasing selection bias. The finding that around 40% of respondents endorsed general notification over written consent raises the possibility that, with educational efforts, the majority of Spaniards might accept general notification for low-risk pRCTs.

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

Publications

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

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