Understanding the FDA guidance on adaptive designs: historical, legal, and statistical perspectives.

The recent Food and Drug Administration (FDA) guidance for industry on adaptive designs is perhaps one of the important undertakings by CDER/CBER Office of Biostatistics. Undoubtedly, adaptive designs may affect almost all phases of clinical development and impact nearly all aspects of clinical trial planning, execution and statistical inference. Thus, it is a significant accomplishment for the Office of Biostatistics to develop this well-thought-out and all-encompassing guidance document. In this paper, we discuss some critical topical issues of adaptive designs with supporting methodological work from either existing literature, additional technical notes, or accompanying papers. In particular, we provide numerous sources of design, conduct, analysis, and interpretation bias that arise from statistical procedures. We illustrate, as a result, and caution that substantial research is necessary for many adaptive designs to meet required scientific standards prior to their applications in clinical trials.