Introduction
The cost of drug development has risen dramatically in recent decades. Even so, the rising costs of clinical trials have not contributed to a higher success rate in approval. For instance, as recorded by BioMedTracker, for 4275 clinical trials that released their results from 2003 to 2010, the overall success rate for final approval of the trial drug or intervention was only 9% [1]. Some factors that may be contributing to the low success rate include the enactment of more regulations and laws concerning medicines. Factors such as the complexity of the health insurance system and the limit to using original biological technology in trials often add to the costs of trials. In traditional clinical trials, a long time is needed to recruit and follow up with patients during the development of medicines. Conventionally, the duration of phase II is more than 18 months, while phase III lasts for another 2 years after that [2]. To address this problem, much thought has been given to ways to reduce the cost of drug development and increase the efficiency of study designs without compromising the integrity and validity of the development.
In 1989, Bauer [3] initially proposed an confirmatory methodology in “Multistage testing with adaptive designs”, which allowed multistage design modifications in ongoing trials without compromising on the type I error rate. In contrast to traditional clinical trials, studies planned with adaptive design allow for prospectively design modifications on one or more aspects of the design—such as sample size, randomization ratio, number of treatment arms—on the basis of accumulating data from patients in the trial at an interim analysis with full control of the type I error.
Originally, the most popular adaptive design was sample size re-estimation. The release of regulatory guidance documents in Europe [4] and the United States [5] further expedited the development of adaptive designs. According to a survey of scientific advice letters from the European Medicines Agency (EMA), Elsäßer et al. concluded an overall positive opinion for the majority of proposed adaptive clinical trials [6]. However, according to the EMA guidance, the adoption of adaptive designs should be undertaken with caution. The most frequent concerns raised by the Committee for Human Medicinal Products (CHMP)/Scientific Advice Working Party (SAMP) were insufficient justifications for the adaptation strategy, type I error rate control, and bias [6].
Considering the increasing interest in adaptive design, the question arises as to whether the challenges of maintaining the integrity of the adaptive design trial and the safety concerns can impact regulatory decision-making. It is not the intention of this study to discuss specific clinical scheduling issues associated with adaptive design trials but rather to systematically evaluate the role of adaptive design in the regulatory approval process of the EMA by comparing and characterizing all approvals that use adaptive design.