Comment.

We congratulate the authors on their comments on innovative approaches to drug development that fall out of the traditional mold and may result in more quickly bringing safe and effective treatments to patients. Changes in the overall clinical develop approach are most relevant to "breakthrough" therapies, which have generally yielded exceptional efficacy data in early clinical studies, motivating exploration of accelerated development and regulatory approaches, as well as a potential ethical need for crossover upon progression in randomized controlled studies (Horning et al., 2015). As is clear from the manuscript, it will be important to develop an understanding of what works well and where the pitfalls in new approaches are. We comment briefly on the four topics mentioned by the authors, combining comments on items 2 and 3: 1) non-proportional hazards, 2) interpretability of extended Phase I trials, 3) single-arm trials as a basis for approval, and 4) recent innovations in trial design.