Ethical Considerations in Adaptive Design Clinical Trials

Speakers: Thomas Laage, MD, MPH, Senior Project Director, Product Development Consulting and Regulatory Medical Writing Support, Premier Research and Jennifer Nezzer, Director of Biostatistics, Premier Research

Background
Adaptive design is generally accepted as an advance in clinical trial methodology, but trials planned and executed with AD present special challenges for observing the Belmont Report’s ethical principles in research involving human subjects.

Methods
We review the features of particular design adaptations and discuss the ethical obstacles they present, and potentially resolve. We use examples of published and unpublished AD clinical trials, some successful and some less than successful.
Results

• Confirmatory trials for treatments widely accepted on the basis of uncontrolled case series or open-label trials can raise issues about clinical equipoise and “justice” in the sense of who, in the Belmont Report’s words, will “receive the benefits of research and bear its burdens.” (Infantile hemangioma and propranolol)

• Analysis of interim results by unblinded data and safety monitoring committees, designed to protect the scientific basis of a trial, can withhold from patients information necessary to make informed judgments. (BIG 1-98 trial)

• Adaptations can include sample-size reassessment and dose adjustment via dropping or adding treatment arms. This allows fewer subjects to produce a statistically significant result, exposes fewer subjects to ineffective or toxic doses, and gives more subjects doses showing tolerance and treatment activity. (ECMO and Neuromyelitis Optica trials)

• The increased complexity of adaptive design trials can enhance the challenges of therapeutic misconception. Adaptive randomization can produce inferential problems that must be balanced against any ethical benefit. (Trastuzumab versus taxane in advanced gastric cancer and the ADVENT trials)

• Successful use of AD can lead to more efficient allocation of societal resources for research, both in the public and commercial realms. (Sunesis VALOR trial)

• Regulatory acceptance of novel ADs can be uncertain. (Indicaterol trial)

• New forms of AD, including platform, umbrella, and basket trials, can offer additional efficiencies. (I-SPY II, BATTLE, Lung-MAP, EPOC, and PREPARE trials)

• Regulatory agencies have adapted to the realities of highly selective and targeted therapies, providing fast-track and breakthrough designations and allowing priority reviews for these treatments.

Conclusions
In adaptive design trials, the importance of careful design, meticulous planning, and rigorous ethical review cannot be overemphasized.