Figure 4. Milestones for adaptive design and additional monitoring list of EMA
In addition to the issue that adaptive designs might expand type I errors, there are other concerns, such as blinding and operational bias, interim analyses bias, and so on. We found that 90% of the approvals with adaptive designs in the past 5 years were required to undertake AM, which reflected the cautious attitude of the regulator even though AM was originally for ADR purposes. However, in 2017, the EMA conducted a public survey to assess the awareness of reporting ADRs, including for medicines under AM. This survey showed that the perceived level of AM varied in different groups. Among all respondents, fewer than half displayed a preferable understanding of the concept. In other words, fewer than half of respondents were aware of reporting ADR spontaneously. AM status played an indecisive role in the reporting of ADR. Therefore, it is easy to wonder how well AM protects against the risks from adaptive designs.
In general, cancer patients do not have time to wait for the results of randomized clinical trials, so they need access to drugs that demonstrate safety profiles in phase I/II studies [17]. Based on these justifications, antitumor drugs may be more likely to be granted marketing authorization before the completion of the whole clinical trial once the efficacy and safety profile have fulfilled the requirements of regulatory authorities. Therefore, group sequential design might be considered a preliminary approach in the long-term development of antitumor medicines, especially for rare diseases or public health emergencies. However, after examining 17 group sequential designs, our results showed that only 4 of them complied with rules for stopping early based on interim efficacy results. This suggests that the success rate for the other 13 drugs was not increased even though their trials used adaptive designs. Furthermore, as well as being stopped for efficacy, group sequential designs can also be halted based on futility to reduce the high cost of drug development. In our study, 41.46% of clinical studies containing adaptive designs continued after the drug was approved. Although study progression might not have an influence on the decision of granting marketing authorization to products, this result revealed the pervasiveness and power of these studies to build up an eligible efficacy and safety profile. Our review of the regulatory measures of EMA showed that products granted marketing authorization with ongoing trials were more likely to be required to submit safety or efficacy studies in postauthorization or to be granted CMAs, which are valid for 1 year and can be renewed annually.