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.