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Abstract
Objectives This review investigates characteristics of implemented adaptive design clinical trials and provides examples of regulatory experience with such trials.
Design Review of adaptive design clinical trials in EMBASE, PubMed, Cochrane Registry of Controlled Clinical Trials, Web of Science and ClinicalTrials.gov. Phase I and seamless Phase I/II trials were excluded. Variables extracted from trials included basic study characteristics, adaptive design features, size and use of independent data monitoring committees (DMCs) and blinded interim analyses. We also examined use of the adaptive trials in new drug submissions to the Food and Drug Administration (FDA) and European Medicines Agency (EMA) and recorded regulators’ experiences with adaptive designs.
Results 142 studies met inclusion criteria. There has been a recent growth in publicly reported use of adaptive designs among researchers around the world. The most frequently appearing types of adaptations were seamless Phase II/III (57%), group sequential (21%), biomarker adaptive (20%), and adaptive dose-finding designs (16%). About one-third (32%) of trials reported an independent DMC, while 6% reported blinded interim analysis. We found that 9% of adaptive trials were used for FDA product approval consideration, and 12% were used for EMA product approval consideration. International regulators had mixed experiences with adaptive trials. Many product applications with adaptive trials had extensive correspondence between drug sponsors and regulators regarding the adaptive designs, in some cases with regulators requiring revisions or alterations to research designs.
Conclusions Wider use of adaptive designs will necessitate new drug application sponsors to engage with regulatory scientists during planning and conduct of the trials. Investigators need to more consistently report protections intended to preserve confidentiality and minimise potential operational bias during interim analysis.
- adaptive design
- flexible design
- clinical trial
- review
- history
- regulation
- policy
- FDA
- EMA
- data monitoring committee
- interim analysis
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Footnotes
Contributors LEB, ASK: wrote/revised manuscript. LEB, ASK, JA: designed research. LEB, NFK: performed research and analysed data.
Funding This work was supported by the Harvard Program in Therapeutic Science and a Brigham and Women’s Hospital Innovation Hub grant (no grant numbers). Dr Kesselheim’s work is also supported by a grant from the Laura and John Arnold Foundation with additional support from the Engelberg Foundation.
Competing interests All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: ASK had financial support from the Laura and John Arnold Foundation and Harvard Program in Therapeutic Science and LEB had support from Brigham and Women’s Hospital Innovation Hub for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement This review draws on publicly available trials and regulatory review documents only. No new data were generated in undertaking this study.