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.
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 We use examples of published and unpublished AD clinical trials, some successful and some less than successful.
- 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.
In adaptive design trials, the importance of careful design, meticulous planning, and rigorous ethical review cannot be overemphasized.
Thomas Laage, MD, MPH, Director, Product Development Consulting and Regulatory Medical Writing Support, Premier Research
During his tenure at Premier Research, Dr. Laage has assisted with protocol development, clinical study report finalization, business development, regulatory strategy, and medical monitoring in a variety of CNS areas, both adult and pediatric. He is a member of the DIA Adaptive Design Scientific Working Group and has co-authored papers in this area. After residencies and board certification in Internal Medicine and Psychiatry and Neurology, Dr. Laage practiced psychiatry in both in-patient and out-patient settings, holding an appointment as Instructor in Psychiatry at the Harvard Medical School for many years. He completed an MPH in Quantitative Methods at the Harvard School of Public Health in 2011. Prior to joining Premier Research, he worked as an independent contractor for the consulting firm John Lehmann, LLC in medical writing and safety reporting for clinical trials and as an independent medical writer and editor for Edanz Group Ltd in China and Japan, for CE Outcomes LLC in Birmingham, AL, and for the American Physician Institute in Chicago, IL. He is a member of Phi Beta Kappa, Alpha Omega Alpha, the Massachusetts Medical Society, the Regulatory Affairs Professionals Society, and the Drug Information Association.
Jennifer Nezzer, Director of Biostatistics, Premier Research
Jennifer is responsible for the management of biostatistics team members and for providing technical leadership on the biostatistical aspects of numerous development projects in North America and serving as lead statistician on multiple global programs. Prior to her joining Premier 3 years ago, she supported the biostatistical development of numerous global programs at another CRO for more than 5 years.
Jennifer has supervised the statistical aspects of standard Phase I through IV clinical trials from design through analysis including experience in the design and implementation of adaptive trials. Her experience includes a broad range of therapeutic areas including: oncology, endocrine/metabolic, infectious/parasitic diseases, CNS, genitourinary, hematology, diseases of the musculoskeletal system and connective tissue, congenital anomalies and mental disorders.
Jennifer has represented the biostatistics department with interactions with sponsor companies, NDA submissions and represented multiple sponsor in both phone and face to face interactions with regulatory agencies. Prior to her tenure in the Pharmaceutical industry, Jennifer served as a senior biostatistician for Signature Science, LLC for eight years providing statistical support for various quality assurance, field testing and environmental projects. She earned her BA in statistics from Kansas State University, and her MS in statistics from New Mexico State University. She is a member of the American Statistical Association, Phi Beta Kappa and Phi Kappa Phi.
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Premier Research is a leading CRO serving highly innovative biotech, Pharmaceutical and medical device companies. The company has a wealth of experience in rare disease and pediatric research having managed about 100 projects in each area in the last five years alone. Its services include clinical research and regulatory outsourcing in the areas of analgesia; neurology; infectious, cardiovascular, and respiratory disease; dermatology; oncology; and medical devices.
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