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Innovation in Drug Development: Adaptive

Designs for Clinical Trials

Definitions, Classification, Regulatory Responses, Operational

Considerations and Recommendations: Version 2.0

Anastassios D. Retzios, Ph.D.

Abstract

In the last decade there has been an increased interest in adaptive designs for clinical trials. These designs allow the modification of several provisions of the clinical study protocol following an interim analysis while preserving the validity and integrity of the study. The elements that can be modified include the sample size of the study, the type of patient enrolled, the randomization algorithm, the primary endpoint and others. These designs promise a reduction of the attrition rate in new medical entities in development and reductions in time and money required to develop new agents. The experience so far is limited and such claims remain to be verified. A number of industry groups have attempted to define and promote the use of these designs. The Pharmaceutical Research and Manufacturers of America (PhRMA) defined adaptive designs a “study designs that uses accumulated data to modify elements of the study without undermining the validity and integrity of the study”, a definition that has met with wide acceptance although recently the FDA introduced a new definition that more closely matches regulatory views of these designs. There are various classifications of these designs. The one introduced in this paper is essentially operational and it is based on the degree of design heterogeneity introduced in parts of the study after the interim analysis(es). Thus, we discern four main groups: model- dependent/continuous assessment method; group sequential/sample size re-estimation; group sequential/response adaptive and adaptive randomization designs. The regulatory response to these designs has been surprisingly uniform in the US and Europe. The FDA and the EMA noted the promise of these designs but also sounded a note of caution regarding several practices. Neither of these agencies has produced a full official guidance at this stage. Members of the FDA and the EMA have published papers in industry journals examining aspects of these designs. The FDA has released a draft guidance for comments and the EMA has produced a reflection paper on adaptive designs used in confirmatory clinical trials. This report examines these publications and summarizes the current regulatory approach to these designs. It is expected that the regulatory position would evolve with the increased utilization of these designs. There are a number of operational considerations in the application of these designs. The potential beneficial effect of adaptations depends highly on the information derived by data collected from each patient treated in the study (in continual assessment method designs) or at the interim analysis (for group sequential designs). Thus, it is imperative that the study management makes certain that compliance to the study is strictly enforced and that data are collected in a timely and accurate fashion. A high number of deviations or many missing data will undermine the validity of the analysis and the quality of the decision from the small set of data at the interim. In addition, when unblinding is required for the interim analysis, the appropriate firewalls should be in place and should be copiously documented. It is imperative that no bias is introduced by either the sponsor or independent committees that render decisions on various study adaptations. This paper provides an analysis of regulatory concerns and guidelines as expressed by major agencies and certain recommendations for meeting the operational demands of these studies.

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