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.