Multicentre trials: a US regulatory perspective

Abstract

Multicentre trials are very common in the field of drug development. In recent years, multicentre trials have taken on a multinational and multiregional aspect. We provide a conceptual framework for the use of multicentre trials in the context of drug development, from the perspective of drug regulation in the United States. In this paper, we review some regulatory history, milestones and standards as they relate to multicentre trials. Special attention is given to the similarities and differences in the approaches to multicentre trials in the following documents; Guideline for the Format and Content of the Clinical and Statistical Sections of New Drug Applications, International Conference on Harmonization, Draft Guideline on Statistical Principles for clinical trials and the Guidance for Industry Providing Clinical Evidence of Effectiveness for Human Drug and Biologic Products. The paper includes a consideration of some of the issues in the analysis of data from multicentre trials.

Does patient volume affect clinical outcomes in adult intensive care units?

“…Senn [42] described this phenomenon in the context of randomized trials very effectively. The greater the number of participating centres, the better the external validation of the study will be [43]. The extent to which these results can be generalised is therefore debatable.…”

Reply to Hurley

“…From a statistical perspective, an IPD meta-analysis is equivalent to the analysis required for a multi-centre study, where the increased number of patients and centres increases both the power of the study and the generalisability of the findings [1,2]. In accordance with the appropriate analysis techniques for multicentre studies [3], we agree with Hurley that it is imperative for any meta-analysis to examine heterogeneity between studies.…”

Blinded sample size recalculation in multicentre trials with normally distributed outcome

“…In consequence of this endorsement, the cited FDA Guideline appears to be viewed as no longer relevant in the regulatory context. This is reflected by the statements made by Anello, O'Neill and Dubey (2005), who are FDA employees and write that "With regard to the alleged controversy between US and European colleagues when dealing with interaction in the model and the choice between type II and type III sums of squares when analysis of variance is indicated, we think that the differences are not real. We believe weighting by clinical size does make good sense."…”