Regulatory Perspectives on Multiplicity in Adaptive Design Clinical Trials throughout a Drug Development Program

Abstract

A clinical research program for drug development often consists of a sequence of clinical trials that may begin with uncontrolled and nonrandomized trials, followed by randomized trials or randomized controlled trials. Adaptive designs are not infrequently proposed for use. In the regulatory setting, the success of a drug development program can be defined to be that the experimental treatment at a specific dose level including regimen and frequency is approved based on replicated evidence from at least two confirmatory trials. In the early stage of clinical research, multiplicity issues are very broad. What is the maximum tolerable dose in an adaptive dose escalation trial? What should the dose range be to consider in an adaptive dose-ranging trial? What is the minimum effective dose in an adaptive dose-response study given the tolerability and the toxicity observable in short term or premarketing trials? Is establishing the dose-response relationship important or the ability to select a superior treatment with high probability more important? In the later stage of clinical research, multiplicity problems can be formulated with better focus, depending on whether the study is for exploration to estimate or select design elements or for labeling consideration. What is the study objective for an early-phase versus a later phase adaptive clinical trial? How many doses are to be studied in the early exploratory adaptive trial versus in the confirmatory adaptive trial? Is the intended patient population well defined or is the applicable patient population yet to be adaptively selected in the trial due to the potential patient and/or disease heterogeneity? Is the primary efficacy endpoint well defined or still under discussion providing room for adaptation? What are the potential treatment indications that may adaptively lead to an intended-to-treat patient population and the primary efficacy endpoint? In this work we stipulate the multiplicity issues with adaptive designs encountered in regulatory applications. For confirmatory adaptive design clinical trials, controlling studywise type I error and type II error is of paramount importance. For exploratory adaptive trials, we define the probability of correct selection of design features, e.g., dose, effect size, and the probability of correct decision for drug development. We assert that maximizing these probabilities would be critical to determine whether the drug development program continues or how to plan the confirmatory trials if the development continues.