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.