Ethical Considerations in Adaptive Design Clinical Trials

While adaptive design is associated with many potential benefits, it may also present challenges to observing the basic ethical principles of research in human subjects. In this white paper, we review the features of particular clinical trial design adaptations and discuss the ethical obstacles they can present and those they can potentially resolve.

The value of adaptive design

In today’s drug development and regulatory environment, lengthy research and development programs, high clinical trial attrition rates, and increasing costs all demand a smarter, more efficient approach to drug development. Adaptive designs are clinical trial methodologies that incorporate pre-specified changes in design or analyses guided by examination of the accumulated data at an interim point in the trial. As part of their Critical Path Initiative for driving innovation in the way regulated products are developed, evaluated, and manufactured, the U.S. Food and Drug Administration (FDA) has identified adaptive design as one way to improve clinical trial efficiency at all phases of development. Compared to conventional study designs, adaptive design approaches can lead to studies that:

  • More efficiently provide the same information
  • Increase the likelihood of achieving the study objective
  • Yield improved understanding of the investigational product’s effect

Adaptive design may help to address the issue of how to best utilize limited funding to advance knowledge and patient care and how to minimize economic waste in the conduct of clinical trials. In the exploratory phases of drug development, adaptive design can improve resource allocation or result in the combining of development phases, thus saving time. In confirmatory trials, adaptive design may enable:

  • Early trial termination for either efficacy or futility
  • Change in the treatment arms included or the treatment group allocation ratios to allocate more subjects to effective treatments and minimize the number of subjects exposed to either ineffective or toxic doses (i.e., a “drop- the-losers” design)
  • Reassessment and adjustment of the sample size (i.e., sample size re-estimation) to minimize the likelihood of a trial failing due to lack of statistical power

Challenges of adaptive trial designs

While adaptive design is generally accepted as an advance in clinical trial methodology, it can present both opportunities and challenges from an ethical perspective. The Belmont Report issued by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1978 summarizes ethical principles and guidelines for research involving human subjects. The report identifies three core principles:

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