Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov

Abstract

ObjectivesThis review investigates characteristics of implemented adaptive design clinical trials and provides examples of regulatory experience with such trials.DesignReview 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.Results142 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.ConclusionsWider 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 in Surveys and Clinical Trials: Similarities, Differences and Opportunities for Cross-fertilization

“…The review of adaptive designs by Bothwell et al . () had similar results to those in Hatfield et al . (), except that biomarker adaptive designs (where design modifications are based on treatment effect estimates in groups defined by biomarkers such as baseline disease severity or a genetic marker) were added to the list of most common adaptations.…”

“…Mistry et al (2017), who reviewed the use of adaptive designs in oncology trials, found that group sequential designs were the most common type of adaptation. The review of adaptive designs by Bothwell et al (2018) had similar results to those in Hatfield et al (2016), except that biomarker adaptive designs (where design modifications are based on treatment effect estimates in groups defined by biomarkers such as baseline disease severity or a genetic marker) were added to the list of most common adaptations. These reviews are consistent with the earlier review by Morgan et al (2014).…”

“…A walled-off statistical centre periodically prepares reports and presents them to the DMC, with a subsequent report given to the Principal Investigator and other study leaders with recommendations for continuing, modifying or stopping the study. There is on-going discussion on how best to structure DMCs for adaptive designs since they are responsible not only for patients' safety but also for implementing the adaptations according to the study protocol (Chow et al, 2012;Bothwell et al, 2018).…”

Alter-Standardizing Clinical Trials: The Gold Standard in the Crossfire

“…This shift is driven by the promise of adaptive trial techniques 'to fix experiments before they fail' and to evaluate the clinical potential of candidate treatments faster, which is seen as an opportunity to save costs, time and to recruit fewer patients (Montgomery, 2017, p. 248). For these reasons, the pharmaceutical industry has increasingly adopted adaptive trials (Bothwell et al, 2018). The US Food and Drug Administration (FDA) and the European Medicine Agency (EMA) have recently released guidance documents on adaptive trial designs (FDA, 2016(FDA, , 2018a(FDA, , 2018bEMA, 2017).…”

“…The US Food and Drug Administration (FDA) and the European Medicine Agency (EMA) have recently released guidance documents on adaptive trial designs (FDA, 2016(FDA, , 2018a(FDA, , 2018bEMA, 2017). These documents have enabled drug application sponsors to use adaptive trials for licensing procedures (Bothwell et al, 2018).…”