November 7, 2014
Adaptive designs allow planned modifications based on data accumulating within a study. The promise of greater flexibility and efficiency stimulates increasing interest in adaptive designs from clinical, academic, and regulatory parties. When adaptive designs are used properly, efficiencies can include a smaller sample size, a more efficient treatment development process, and an increased chance of correctly answering the clinical question of interest. Both the European Medicines Agency (EMA) as well as the Food and Drug Administration (FDA) have published guidance documents addressing the potentials and limitations of adaptive designs in the regulatory context. In addition, the EMA also offers a key service of scientific advice and protocol assistance, which sponsors of medicines, can avail early in the marketing authorization process.
Whether this service proves to be vital for sponsors is discussed in an article publishes in Trials where Elsäßer et al. analyzed 59 scientific advices that address adaptive study designs in Phase II and III clinical trials and discussed 3 case studies submitted to the EMA and analyzed by the CHMP/SAWP. The authors found that “most frequently proposed adaptation was sample size reassessment, followed by dropping of treatment arms and population enrichment”. The authors report an increase in submissions in 2011 and while many of the trials were on a rare disease, not all of them had an orphan designation. Promisingly, the authors found that a majority of proposals were accepted “as is” or with conditions attached, however they also reported that Type I error were more frequent than expected. The case studies presented in this paper illustrated how advice on sample size reassessment, interim dose selection and post-hoc adaptations were handled by the CHMP. Although the authors discussed the case studies and the numbers in a fair amount of detail, it is difficult to draw conclusions on marketing authorization based on them, as the CHMP views applications as a whole. However, the article gives a flavour of how the CHMP tackles issues relating to adaptive clinical trial and what questions the sponsors could ask while planning such a trial.