DISCUSSION
Instead of lightening the burden of rigorous clinical planning, using
prespecified and planned adaptive designs in the development of
medicinal products under experimental dilemmas is recommended. The
flexibility and other advantages of adaptive designs over traditional
clinical trial designs are being increasingly acknowledged after much
effort was devoted to maintaining the type I error probability. Despite
the warnings about potential biases and possible inflation of type I
error probability, the EMA guidance on adaptive designs acknowledges the
value of adaptive designs to innovate clinical trials in the development
of new drugs and biologics.
After analyzing all available approval documentation, we observed that
adaptive design trials could provide information on clinical efficacy
that impacts regulatory decision-making. Furthermore, we found that
sponsors and regulators increasingly included adaptive design trials in
the approval package. Our study showed that the most popular adaptive
designs were group sequential and seamless designs. Adaptive design can
be pivotal in supporting the development of NASs. However, such trials
face difficulties in supporting accelerated assessment, and AM
requirements must be met.
The less common side effects of medicinal products are often difficult
to identify in the short-term. Therefore, adverse drug reaction (ADR)
reporting is an essential part of the surveillance after the
introduction of new medicines to the market. However, underreporting is
a recognized challenge and is reported to be as high as 94% [11,
12]. To increase ADR reporting, numerous bills were introduced
[13-15]. One of these was AM. The designation of AM is aimed at
encouraging the reporting of spontaneous side effects for new products
for which the safety profile may not be entirely established. The
objective is to collect as much information as possible in order to
interpret the risk profile and inform healthcare professionals and
patients [14, 15]. The concept of AM was introduced by the 2010
pharmacovigilance legislation and became operative in 2012 [16]. The
milestones for adaptive design and the AM list of EMA are presented in
Figure 4.