Cory E. Goldstein

Do doctors have a duty to take part in pragmatic randomised trials

For society to benefit from new clinical knowledge the expectation should be to participate in research, writes Marion K Campbell; Charles Weijer and colleagues agree but argue that the fundamental need for consent makes this an imperfect duty

When and how should we cluster and cross over: methodological and ethical issues

Spence et al. describe the need for more randomized controlled trials to provide rigorous evidence of the realworld effectiveness of treatments and treatment strategies in anesthesia practice. This call is supported by evidence citing a large degree of individual practice variability among cardiac anesthesiologists regarding benzodiazepine use within the standard of care. They describe the cluster randomized crossover design as ideal for this purpose. In the proposed approach, they ‘‘seek to evaluate the impact of two different approaches to cardiac anesthesia, one where nearly all patients receive intraoperative benzodiazepines unless there are contraindications (routine benzodiazepine arm), and the other where nearly all patients receive no intraoperative benzodiazepines unless there are contraindications (benzodiazepine restricted arm)...during 12, four-week crossover periods’’. The interventions are implemented as policies such that all eligible patients in the hospital during each period receive the allocated interventions by default without any patient recruitment or consent. While we do not dispute the need for rigorous evidence to inform policy and practice, we have concerns regarding the methodological and ethical issues raised in trials such as the B-Free trial.

TwiC or treat? Are trials within cohorts ethically defensible?:

Pragmatic randomized controlled trials (RCTs) seek to evaluate interventions in real-world conditions and, thereby, directly inform decisions made by patients, health providers and health system managers. The recent rise in novel methods to push trials toward being more pragmatic raises several complex issues. Two articles in this issue of Clinical Trials explore the ethical issues raised by one new design, called trials within cohorts (TwiCs). In this commentary, we critically evaluate the TwiC design, with an emphasis on informed consent. Relton et al. first proposed the TwiC design to ‘‘recruit a greater quantity and more representative sample of patients.’’ The basic idea of TwiCs is to create a longitudinal cohort of patients to serve as a platform for the conduct of multiple RCTs. First, patients with a condition of interest are enrolled in a large longitudinal cohort in which their health data are collected from the electronic health record. Second, for each RCT, all eligible patients within the cohort are identified and a subset is randomly selected to be offered the study intervention. The outcomes of patients selected for the intervention group are compared to those of all remaining eligible patients in the cohort who receive usual care as determined by their physician. It is important to note that in the TwiC design the experimental intervention cannot be one that is routinely available to all members of the cohort. Furthermore, the control group cannot receive a protocolized intervention, even a drug that is routinely prescribed in practice. Finally, the outcomes of interest must be routinely collected outside the trial. The article by Kim et al. offers a thoughtful analysis of the ethical issues raised by the TwiC design. The approach to consent originally used in the TwiC design involves no pre-randomization discussion of future RCTs. At the time of enrollment into the longitudinal cohort, patients are informed of data collection procedures but are not informed of ‘‘the possibility of future randomization and future contact for intervention studies.’’ Patients who are randomly selected for the intervention group in a subsequent RCT provide informed consent for that intervention; those in the control group provide no further informed consent, as they have already consented to the use of their data and usual medical care. Kim et al. argue that this approach may be ethical in some cases and maintain that ‘‘those not selected [for the intervention group] do not need to give consent for that random selection any more than individuals who are not selected in a random-digit-dial telephone survey need to give prior consent for randomization.’’ Informed consent is only required when ‘‘randomization leads to any potential alterations in the way subjects are treated.’’ Notwithstanding this argument, they admit that this approach is unlikely to fulfill regulatory requirements. Given these ‘‘regulatory obstacles,’’ Kim et al. proffer a new approach involving pre-randomization broad consent. At the time of recruitment into the cohort, patients provide ‘‘specific consent for the cohort study and also broad consent.’’ Broad consent involves consent to participation in future RCTs, including ‘‘information about randomizations for future [RCTs], for future contact if randomized to the intervention arm ... of [an RCT], and for use of their data in future [RCTs] if randomized to the control arm.’’ As noted above, only patients randomly selected for the intervention group provide consent for the study intervention. Thus, the authors assert, all participants will ‘‘have given informed consent to every aspect of their research participation in the TwiC’’ and no waiver of consent is required. In a second paper, Vickers et al. provide a detailed defense of this approach, which they call ‘‘just-in-time consent.’’ They point out that the usual informed consent process may ‘‘cause significant and persistent

Ethical issues in pragmatic randomized controlled trials: a review of the recent literature identifies gaps in ethical argumentation

BackgroundPragmatic randomized controlled trials (RCTs) are designed to evaluate the effectiveness of interventions in real-world clinical conditions. However, these studies raise ethical issues for researchers and regulators. Our objective is to identify a list of key ethical issues in pragmatic RCTs and highlight gaps in the ethics literature.MethodsWe conducted a scoping review of articles addressing ethical aspects of pragmatic RCTs. After applying the search strategy and eligibility criteria, 36 articles were included and reviewed using content analysis.ResultsOur review identified four major themes: 1) the research-practice distinction; 2) the need for consent; 3) elements that must be disclosed in the consent process; and 4) appropriate oversight by research ethics committees. 1) Most authors reject the need for a research-practice distinction in pragmatic RCTs. They argue that the distinction rests on the presumptions that research participation offers patients less benefit and greater risk than clinical practice, but neither is true in the case of pragmatic RCTs. 2) Most authors further conclude that pragmatic RCTs may proceed without informed consent or with simplified consent procedures when risks are low and consent is infeasible. 3) Authors who endorse the need for consent assert that information need only be disclosed when research participation poses incremental risks compared to clinical practice. Authors disagree as to whether randomization must be disclosed. 4) Finally, all authors view regulatory oversight as burdensome and a practical impediment to the conduct of pragmatic RCTs, and argue that oversight procedures ought to be streamlined when risks to participants are low.ConclusionThe current ethical discussion is framed by the assumption that the function of research oversight is to protect participants from risk. As pragmatic RCTs commonly involve usual care interventions, the risks may be minimal. This leads many to reject the research-practice distinction and question the need for informed consent. But the function of oversight should be understood broadly as protecting the liberty and welfare interest of participants and promoting public trust in research. This understanding, we suggest, will focus discussion on questions about appropriate ethical review for pragmatic RCTs.

Developing a framework for the ethical design and conduct of pragmatic trials in healthcare: a mixed methods research protocol

BackgroundThere is a widely recognized need for more pragmatic trials that evaluate interventions in real-world settings to inform decision-making by patients, providers, and health system leaders. Increasing availability of electronic health records, centralized research ethics review, and novel trial designs, combined with support and resources from governments worldwide for patient-centered research, have created an unprecedented opportunity to advance the conduct of pragmatic trials, which can ultimately improve patient health and health system outcomes. Such trials raise ethical issues that have not yet been fully addressed, with existing literature concentrating on regulations in specific jurisdictions rather than arguments grounded in ethical principles. Proposed solutions (e.g. using different regulations in “learning healthcare systems”) are speculative with no guarantee of improvement over existing oversight procedures. Most importantly, the literature does not reflect a broad vision of protecting the core liberty and welfare interests of research participants. Novel ethical guidance is required. We have assembled a team of ethicists, trialists, methodologists, social scientists, knowledge users, and community members with the goal of developing guidance for the ethical design and conduct of pragmatic trials.MethodsOur project will combine empirical and conceptual work and a consensus development process. Empirical work will: (1) identify a comprehensive list of ethical issues through interviews with a small group of key informants (e.g. trialists, ethicists, chairs of research ethics committees); (2) document current practices by reviewing a random sample of pragmatic trials and surveying authors; (3) elicit views of chairs of research ethics committees through surveys in Canada, UK, USA, France, and Australia; and (4) elicit views and experiences of community members and health system leaders through focus groups and surveys. Conceptual work will consist of an ethical analysis of identified issues and the development of new ethical solutions, outlining principles, policy options, and rationales. The consensus development process will involve an independent expert panel to develop a final guidance document.DiscussionPlanned output includes manuscripts, educational materials, and tailored guidance documents to inform and support researchers, research ethics committees, journal editors, regulators, and funders in the ethical design and conduct of pragmatic trials.

Accommodating quality and service improvement research within existing ethical principles

BackgroundQuality and service improvement (QSI) research employs a broad range of methods to enhance the efficiency of healthcare delivery. QSI research differs from traditional healthcare research and poses unique ethical questions. Since QSI research aims to generate knowledge to enhance quality improvement efforts, should it be considered research for regulatory purposes? Is review by a research ethics committee required? Should healthcare providers be considered research participants? If participation in QSI research entails no more than minimal risk, is consent required? The lack of consensus on answers to these questions highlights the need for ethical guidance.Main bodyThree distinct approaches to classifying QSI research in accordance with existing ethical principles and regulations can be found in the literature. In the first approach, QSI research is viewed as distinct from other types of healthcare research and does not require regulation. In the second approach, QSI research falls within regulatory guidelines but is exempt from research ethics committee review. In the third approach, QSI research is deemed to be part of the learning healthcare system and, as such, is subject to a different set of ethical principles entirely. In this paper, we critically assess each of these views.ConclusionWhile none of these approaches is entirely satisfactory, we argue that use of the ethical principles governing research provides the best means of addressing the numerous questions posed by QSI research.

Thinking clearly about the FIRST trial: addressing ethical challenges in cluster randomised trials of policy interventions involving health providers

The ethics of the Flexibility In duty hour Requirements for Surgical Trainees (FIRST) trial have been vehemently debated. Views on the ethics of the FIRST trial range from it being completely unethical to wholly unproblematic. The FIRST trial illustrates the complex ethical challenges posed by cluster randomised trials (CRTs) of policy interventions involving healthcare professionals. In what follows, we have three objectives. First, we critically review the FIRST trial controversy, finding that commentators have failed to sufficiently identify and address many of the relevant ethical issues. The 2012 Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials provides researchers and research ethics committees with specific guidance for the ethical design and conduct of CRTs. Second, we aim to demonstrate how the Ottawa Statement provides much-needed clarity to the ethical issues in the FIRST trial, including: research participant identification; consent requirements; gatekeeper roles; benefit-harm analysis and identification of vulnerable participants. We nonetheless also find that the FIRST trial raises ethical issues not adequately addressed by the Ottawa Statement. Hence, third and finally, we raise important questions requiring further ethical analysis and guidance, including: Does clinical equipoise apply to policy interventions with little or no evidence-base? Do healthcare providers have an obligation to participate in research? Does the power-differential in certain healthcare settings render healthcare providers vulnerable to duress and coercion to participant in research? If so, what safeguards might be implemented to protect providers, while allowing important research to proceed?

In reply: When and how should we cluster and cross over: methodological and ethical issues (letters 1 and 2)

To the Editor, In their article, Spence et al. argue that cluster randomized crossover trials are ‘‘the preferred method to evaluate questions of effectiveness’’ in anesthesia, and that ‘‘individual RCTs are not the preferred design.’’ To illustrate the utility of this design, the authors discuss the B-Free pilot trial and ‘‘expect to begin the [full-scale] trial in the summer of 2018.’’ In our commentary, we argue, ‘‘individual (not cluster) randomization is the gold standard study design to evaluate questions of both efficacy and effectiveness.’’ Our arguments are not specific to the B-Free trial since, to date, no protocol has been published. Our conclusion is general: ‘‘the cluster crossover design... raises methodological and ethical concerns that must be carefully addressed.’’ Lee et al. agree that we make ‘‘correct statements about methodological concerns for cluster crossover trials in general.’’ They agree that these include increased risks of bias, limited external validity, imbalances in baseline characteristics, and carry-over and period effects, and they explain how each will be addressed in the full-scale B-Free trial. We note that Lee et al. make no effort to defend the original thesis that cluster crossover trials are generally the preferred design to evaluate questions of effectiveness. We disagree with several points made by Spence et al. First, they conflate units of randomization and intervention. A cluster level intervention, such as community public health messages, is indivisible at the individual level. But the institutional policy of benzodiazepine administration is an individual-level intervention, as it is divisible individually. Patients in the intervention arm will receive benzodiazepines ‘‘unless there are contraindications’’— and refusal to consent should be a contraindication. Second, they assert that we take the ‘‘extreme position that informed consent is always required for individuallevel interventions.’’ This is false. Our position is that ‘‘[g]enerally . . . [for] individual-level interventions, informed consent is required.’’ The qualifier ‘‘generally’’ implies that exceptions may be justifiable. The presumption of consent is shared by other ethical analyses and guidelines specific to cluster randomized trials. Third, they claim that ‘‘established requirements to justify a waiver’’ and the existence of ‘‘many completed and ongoing cluster trials... where a waiver has been accepted’’ show the permissibility of conducting the BFree trial without consent. Yet this ignores the novelty of the cluster crossover design. Canadian and U.S. guidelines were not written with cluster trials in mind. As a result, local research ethics committees that review cluster randomized trials may be unfamiliar with the specific guidelines of this unique design. Finally, with respect to the flu vaccine trial, contributor roles are outlined in the trial publication: the trial was in progress when Dr. Taljaard joined as an independent collaborator to supervise the statistical analysis.

Does Consent Form Follow Function

are in evidence. For the first time, developments in molecular biology render the idea of direct human germline alteration tangible. While there is still too much uncertainty about the safety of these technologies to allow clinical trials, it is likely that future progress will bring germline editing into the clinic (Evitt et al. 2015). Even though direct approval for such research cannot be obtained from future children, consent is far from meaningless here. As the approach by Dickert and colleagues suggests, there are additional functions of consent beyond respect for individual autonomy that have a role to play in this endeavor. When Louise Brown was born 40 years ago, it is said that her parents did not know that she was the first child conceived by in vitro fertilization. Developments in genetics and human reproductive technologies are too sensitive to let history repeat itself. When the first genetically modified child is born, it is imperative that the highest standards of research ethics were applied. Informed consent remains foremost among the central principles. &