Comment

It is a great pleasure to have this opportunity to comment on the excellent review by Pritchett and colleagues. Sample size reestimation (SSR) is an increasingly popular design feature in clinical trials, but no consensus has yet emerged on best practices and a variety of statistically and operationally sub-optimal approaches are used even in pivotal trials. The authors have made what I am sure will prove to be valuable contributions to practitioners by surveying SSR methodologies and, especially, by discussing practical considerations for choosing or not choosing SSR designs in a product development program. The 2010 FDA draft Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics (U.S. Food & Drug Administration 2010) discusses both blinded and unblinded SSR designs (bSSR and ubSSR, respectively, in Pritchett’s notation). bSSR designs are described as “generally well-understood,” meaning that they are wellestablished and require no statistical correction to account for Type I error inflation. ubSSR designs, by contrast, are described in the draft Guidance as “less well-understood,” meaning that they raise concerns involving control of the study-wide Type I error rate, bias in treatment effect estimates, or the interpretability of trial results. Although I would not presume to judge who understands what nor how well (personally, I find at least some ubSSR designs quite straightforward and at least some bSSR designs less so), the draft Guidance properly raises cautions on the use of ubSSR designs and describes issues that need to be addressed before implementing a less well-understood design, including demonstration of Type I error control. However, adaptive design is a fast-developing field, and the intent of describing ubSSR designs as “less wellunderstood” was not to put them completely and forever off the table for confirmatory trials, but rather to indicate that more experience was required before one could expect the kind of routine application associated with more familiar approaches such as group sequential designs (GSDs). After all (as has been politely pointed out to me several dozen times by concerned industry practitioners at conferences and workshops), GSDs, like ubSSR designs, use unblinded estimates of treatment effect and raise potential Type I error inflation issues, yet are described as generally well-understood in the draft Guidance. Pritchett et al.’s (2011) review summarizes some of that necessary accumulating experience, and adds to it. Our recent experience at the FDA’s Center for Biologics Evaluation and Research (CBER) supports the conclusion that SSR designs, both b and ub, are of ongoing interest in confirmatory trials. Lin et al. (in press) recently described a survey of CBER’s review experiences with adaptive design Investigational New Drug (IND) and Investigational Device Exemption (IDE) submissions from 2008 to 2013. After GSD, SSR designs (including SSR designs with additional adaptive features) were by far the most common type of adaptive design proposal seen in confirmatory studies, accounting for roughly 40% of proposals. This included both blinded and unblinded SSR (as well as, unfortunately, some proposals too vague to classify), but ubSSR was more common. The CBER survey also showed the same upward trend in adaptive design submissions from 2008 to 2011 reported in the DIA Adaptive Design Scientific Working Group survey (and