Clinical Trial Design—What is the Critical Question for Decision-Making?

Students with statistics or biostatistics majors learned from their classes that by focusing on a single, well-defined question for a given design, the results are more likely to be informative and meaningful. This principle can be studied from many prominent statisticians including RA Fisher and J Neyman. The same principle applies in clinical trial designs. However, when designing clinical trials, statisticians often neglect this principle and make things more complicate than they should be. A poorly designed trial with too many objectives usually cannot answer any question satisfactorily. This manuscript is motivated by the Project Optimus initiative proposed by FDA Oncology Center of Excellence (OCE) 2022. Given the paradigm shift from cytotoxic drugs to target and immunotherapies, the objective is to promote the dose-finding or proof-of-concept design part of the oncology drug development closer to the designs in chronic disease drug development and incorporate patient experience into the safety and tolerability consideration. The design differences exist because of the disease; however, the fundamental principal have been the same and should still be the same. This manuscript attempts to clarify this confusion, with an emphasis on Phase II clinical trials.