Introduction
In clinical development, adequate and well-controlled randomised clinical trials are often conducted for evaluation of the safety and efficacy of a test treatment under study. The purpose is to provide substantial evidence in support of regulatory submission for demonstration of the safety and efficacy of the test treatment under investigation. To provide an accurate and reliable assessment of the test treatment under investigation, adequate and well-controlled randomised clinical trials should follow good clinical practice (GCP) at different phases (ie, phases 1 to 3) of clinical development. In practice, some controversial statistical issues inevitably occur regardless of the compliance of GCP. Controversial issues, referred to as debatable issues, are commonly encountered during the conduct of clinical trials. These debatable issues could be raised from (1) compromises between theoretical and real-world practices, (2) miscommunication, misunderstanding and/or misinterpretation in medical and/or statistical perception among regulatory agencies, clinical scientists and biostatisticians and (3) disagreement, inconsistency, miscommunication/misunderstanding and errors in clinical practice.
Basically, these controversial issues present conceptually different perspectives from clinicians (investigators/sponsors), biostatisticians and regulatory reviewers for evaluation of the test treatment under investigation. The major concern from the clinicians is whether the observed difference is of clinical meaning; whereas, the biostatisticians are interested in determining whether the observed difference is of any statistical meaning (ie, whether the observed difference is by chance alone). On the contrary, the reviewers from regulatory agencies, such as the United States Food and Drug Administration (FDA), would like to make sure if the observed clinically meaningful difference (clinical benefits) has reached statistical significance before they can approve the test treatment under investigation. Most regulatory reviewers consider these debatable issues as review issues (in the sense that only regulatory reviewers can make the final judgement). Thus, a clinical trial is considered successful in clinical development when it meets the expectations of clinicians, biostatisticians and regulatory reviewers.
In the subsequent sections, background and relevant information regarding these controversial issues and their potential impacts on clinical development are briefly described. Whenever possible, resolutions for each controversial issue are provided. A final concluding remark is given in the last section.