Abstract
In recent years, the use of adaptive design methods in clinical research and development based on accrued data has become very popular due to its flexibility and efficiency. Based on adaptations applied, adaptive designs can be classified into three categories: prospective, concurrent (ad hoc), and retrospective adaptive designs. An adaptive design allows modifications made to trial and/or statistical procedures of ongoing clinical trials. However, it is a concern that the actual patient population after the adaptations could deviate from the originally target patient population and consequently the overall type I error (to erroneously claim efficacy for an infective drug) rate may not be controlled. In addition, major adaptations of trial and/or statistical procedures of on-going trials may result in a totally different trial that is unable to address the scientific/medical questions the trial intends to answer. In this article, several commonly considered adaptive designs in clinical trials are reviewed. Impacts of ad hoc adaptations (protocol amendments), challenges in by design (prospective) adaptations, and obstacles of retrospective adaptations are described. Strategies for the use of adaptive design in clinical development of rare diseases are discussed. Some examples concerning the development of Velcade intended for multiple myeloma and non-Hodgkin's lymphoma are given. Practical issues that are commonly encountered when implementing adaptive design methods in clinical trials are also discussed.
Highlights
In the past several decades, it is recognized that increasing spending of biomedical research does not reflect an increase of the success rate of pharmaceutical development
The Critical Path Opportunities List interprets it as the encouragement for the use of innovative adaptive design methods in clinical trials and the potential use of Bayesian approach in clinical research and development
The use of adaptive design methods in clinical trials is motivated by its flexibility and efficiency, there are still some challenge in implementation
Summary
In the past several decades, it is recognized that increasing spending of biomedical research does not reflect an increase of the success rate of pharmaceutical (clinical) development. It is to outline challenges in prospective adaptations, impact on concurrent adaptations, and obstacles of retrospective adaptations being made of on-going trials, and to discuss issues that are commonly encountered when implementing adaptive design methods in clinical trials. It is to discuss strategies for clinical development of rare diseases using adaptive design methods.
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