Adaptive Design: A Review of the Technical, Statistical, and Regulatory Aspects of Implementation in a Clinical Trial

Abstract

In an adaptive trial, the researcher may have the option of responding to interim safety and efficacy data in a number of ways, including narrowing the study focus or increasing the number of subjects, balancing treatment allocation or different forms of randomization based on responses of subjects prior to treatment. This research aims at compiling the technical, statistical, and regulatory implications of the employment of adaptive design in a clinical trial. Review of adaptive design clinical trials in Medline, PubMed, EU Clinical Trials Register, and ClinicalTrials.gov . Phase I and seamless phase I/II trials were excluded. We selected variables extracted from trials that included basic study characteristics, adaptive design features, size and use of independent data-monitoring committees (DMCs), and blinded interim analysis. The research retrieved 336 results, from which 78 were selected for analysis. Sixty-seven were published articles, and 11 were guidelines, papers, and regulatory bills. The most prevalent type of adaptation was the seamless phase II/III design 23.1%, followed by adaptive dose progression 19.2%, pick the winner / drop the loser 16.7%, sample size re-estimation 10.3%, change in the study objective 9.0%, adaptive sequential design 9.0%, adaptive randomization 6.4%, biomarker adaptive design 3.8%, and endpoint adaptation 2.6%. It is possible to infer that the use of Adaptive Design is an ethical and scientific advantage when properly planned and applied, since it increases the flexibility of the trial, shortens the overall clinical investigation time of a drug, and reduces the risk of patient exposure to adverse effects related to the experimental drug. Its greater methodologic and analytic complexity requires an adequate statistical methodology. The application of "adaptive clinical designs" for phase II/III studies appear to have been limited to trials with a small number of study centers, with smaller extensions of time and to experimental drugs with more immediate clinical effects that are amenable to risk/benefit decisions based on interim analyses. According to the reviewed studies, simple adaptive trial designs-such as early study terminations due to futility and sample size re-estimation-are becoming widely adopted throughout the pharmaceutical industry, especially in phase II and III studies. The pharmaceutical industry and contract research organizations (CROs) are implementing simple adaptations more frequently and the more complex adaptations-biomarker adaptive design, endpoint adaptation-are more sporadic.