Validity and Interpretation of Meta-Analyses and One Pivotal Study
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0092-8615/2001 Copyright 0 2001 Drug Information Association Inc.
VALIDITY AND INTERPRETATION OF META-ANALYSES AND ONE PIVOTAL STUDY JURGEN
KUBLER,PHD
Director, PH-PD Integrated Analyses, Bayer AG, Pharmaceutical Research Center, Wuppertal, Germany
The International Conference on Harmonization E9 guideline indicates that meta-analyses can be used not only for summarizing safety and efficacy in an application but also for providing pivotal evidence of efficacy. Furthermore, this guideline states that “in some circumstances” a single confirmatory trial may be sufficient to provide pivotal evidence of the eficacy of drug. Howeve6 little guidance is given as to how these circumstances are defined. In this papec we will focus on the role of meta-analysis and one pivotal trial in clinical drug development to provide pivotal evidence of effectiveness of a drug. Key Words: Integrated summaries; Meta-analyses; One pivotal study; Pivotal evidence
INTRODUCTION THE INTERNATIONAL CONFERENCE on Harmonization (ICH) E9 guideline (1) indicates that meta-analyses can be used not only for summarizing safety and efficacy in an application but also for providing pivotal evidence of efficacy. Furthermore, this guideline states that “in some circumstances” a single confirmatory study may be sufficient to provide pivotal evidence of the efficacy of a drug. However, little guidance is given as to how these circumstances are defined. In order to overcome this problem the Food and Drug Administration (FDA) issued a guidance for industry (2) that addresses the question of how to provide clinical evidence of effectiveness, including an in-depth discussion of the reliance on one pivotal study.
Presented at the DIA Workshop “Statistical Methodology in Clinical R&D,” April 2-4, 2001. Vienna, Austria. Reprint address: JUrgen KUbler, PhD, Director, PHPD Integrated Analyses, Bayer AG, 42096 Wuppertal, Germany.
Recently, the Committee for Proprietary Medicinal Products (CPMP) published a draft points to consider document (3) on validity and interpretation of meta-analyses and one pivotal study, which motivated this paper. In this paper, we will focus on the role of meta-analysis and one pivotal study in clinical drug development to provide pivotal evidence of the efficacy of a drug. Their role should be derived from the amount of information needed to provide adequate information for the approval of a drug for a specific indication. Meta-analytic techniques are widely accepted for summarizing results from a series of studies as, for instance, described in the ICH M4 guideline (4) The application of meta-analytic techniques in integrated summaries will, therefore, also be briefly explored. The paper is organized as followed: We first explore the scientific background for current standards in clinical drug development. After having explained the information needs which must be fulfilled for approval of a new drug, we discuss how these requirements can be met with only one pivotal study
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