Ethical Considerations in Adaptive Design Clinical Trials

Abstract

Adaptive design clinical trial methodologies offer both opportunities and challenges for observing basic ethical principles in human subject research. Using both published and unpublished adaptive design clinical trials, we have selected and reviewed examples of clinical trials with different design adaptations to discuss the ethical obstacles presented and often successfully resolved by these approaches, including (1) confirmatory trials for treatments widely accepted on the basis of uncontrolled case series or open-label trials (clinical equipoise and "justice" in the sense of which trial groups will "receive the benefits of research and bear its burdens") (infantile hemangioma/propranolol); (2) interim results analysis by unblinded data monitoring committees ("withholding information necessary to make a considered judgment" ["respect for persons"] versus compromising the trial's scientific basis) (BIG 1-98); (3) adaptations involving sample size reassessment or dose adjustment via dropping or adding treatment arms, allowing fewer subjects to produce statistically significant results, fewer subjects treated with ineffective/toxic doses, and more subjects given doses showing tolerance and treatment activity ("beneficence" or "protecting from harm and making efforts to secure wellbeing") (ECMO, Neuromyelitis Optica); (4) adaptive randomization inferential problems balanced against ethical benefits (trastuzumab vs taxane in advanced gastric cancer; ADVENT); (5) more efficient allocation of societal resources for research, in both public and commercial realms, versus uncertain regulatory acceptance (indicaterol; VALOR); and (6) platform, umbrella, and basket trials offering additional efficiencies (I-SPY II, BATTLE, Lung-MAP). The importance of careful design, meticulous planning, and rigorous ethical review of adaptive design trials on a case-by-case basis cannot be overemphasized.

The Evolution of Master Protocol Clinical Trial Designs: A Systematic Literature Review

“…Thus, the infrastructure in the master protocol needs to have the flexibility introduced from the beginning so that it is clear to health authorities, institutional review boards, and ethics committees what has changed by the adding of a new substudy. Operational obstacles of platform trials have been discussed by Schiavone et al 283 Further challenges from investigator, sponsor, and regulatory views are discussed by Cecchini et al 284 Laage et al 285 reviewed ethical considerations of adaptive design elements potentially used in trials with master protocols, and Strzebonska and Waligora 286 highlight ethical challenges in umbrella and basket trials. Klauschen et al 287 investigated the combinatorial complexity introduced by cancer precision medicine approaches and proposed a novel clinical trial design that combines elements of basket and umbrella trials to overcome this problem.…”

Modernizing Clinical Trial Eligibility Criteria: Recommendations of the ASCO–Friends of Cancer Research Prior Therapies Work Group

“…By deconstructing the decision-making process into its basic elements of safety and efficacy, the working group was able to develop recommendations within the context of patient-centeredness, keeping with the ethical principles of distributive justice and beneficence. (18,19) These considerations guided the thought process behind the ClinicalTrials.gov exercise and the recommendations proposed by this working group.…”

The Real‐World Ethics of Adaptive‐Design Clinical Trials

“…For example, concerns have been raised that adaptive trials can be less efficient than standard designs due to the added trial complexities, more complicated planning, lengthened regulatory review of adaptive designs, or some adaptations that reduce efficiency through sample‐size enlargement in the pursuit of finding treatment effects . In addition, prespecified decision rules for trial adaptations can be based on miscalculations of the appropriate threshold for making adaptations, and this can undermine trial integrity and reduce efficiency in the research process . If adaptive trials are less efficient than conventional trials without providing offsetting benefits, burdening the research development process with the adaptive trial methods is ethically problematic.…”