title: Panel forum on multiple comparison procedures: a commentary from a complex trial design and analysis plan.
abstract: Motivated by a complex study design aiming at a definitive evidential setting, a panel forum among academia, industry, and US regulatory statistical scientists was held at the 7th International Conference on Multiple Comparison Procedures (MCP) to comment on the multiplicity problem. It is well accepted that studywise or familywise, type I error rate control is the norm for confirmatory trials. But, it is an uncharted territory regarding the criteria beyond a single confirmatory trial. The case example describes a Phase III program consisting of two placebo-controlled multiregional clinical trials identical in design intended to support registration for treatment of a chronic condition in the lung. The case presents a sophisticated multiplicity problem in several levels: four primary endpoints, two doses, two studies, two regions with different regulatory requirements, one major protocol amendment on the original statistical analysis plan, which the panelists had a chance to study before the forum took place. There were differences in professional perspectives among the panelists laid out by sections. Nonetheless, irrespective of the amendment, it may be arguable whether the two studies are poolable for the analysis of two primary endpoints prespecified. How should the study finding be reported in a scientific journal if one health authority approves while the other does not? It is tempting to address the Phase III program level multiplicity motivated by the increasing complexity of the partial hypotheses framework posed that are across studies. A novel thinking of the MCP procedures beyond individual-study level (studywise or familywise as predefined) and across multiple-study level (experimentwise and sometimes programwise) will become an important research problem expected to face with scientific and regulatory challenges.
authors.affiliation: U.S. Food and Drug Administration, HFD-700, WO 21, MailStop Room 3562, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA. suejane.wang@fda.hhs.gov
authors.forename: Sue-Jane
authors.initials: SJ
authors.lastname: Wang
authors.forename: Frank
authors.initials: F
authors.lastname: Bretz
authors.forename: Alex
authors.initials: A
authors.lastname: Dmitrienko
authors.forename: Jason
authors.initials: J
authors.lastname: Hsu
authors.forename: H M James
authors.initials: HM
authors.lastname: Hung
authors.forename: Mohammad
authors.initials: M
authors.lastname: Huque
authors.forename: Gary
authors.initials: G
authors.lastname: Koch
mesh_terms: D017326:Clinical Trials, Phase III as Topic / Q000379:methods*; D003627:Data Interpretation, Statistical; D006801:Humans; D015337:Multicenter Studies as Topic / Q000379:methods*; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design