Research Article: Sample size determination for a specific region in multiregional clinical trials with multiple co-primary endpoints

Date Published: June 30, 2017

Publisher: Public Library of Science

Author(s): Wong-Shian Huang, Hui-Nien Hung, Toshimitsu Hamasaki, Chin-Fu Hsiao, Tim Friede.

http://doi.org/10.1371/journal.pone.0180405

Abstract

Recently, multi-regional clinical trials (MRCTs), which incorporate subjects from many countries/regions around the world under the same protocol, have been widely conducted by many global pharmaceutical companies. The objective of such trials is to accelerate the development process for a drug and shorten the drug’s approval time in key markets. Several statistical methods have been purposed for the design and evaluation of MRCTs, as well as for assessing the consistency of treatment effects across all regions with one primary endpoint. However, in some therapeutic areas (e.g., Alzheimer’s disease), the clinical efficacy of a new treatment may be characterized by a set of possibly correlated endpoints, known as multiple co-primary endpoints. In this paper, we focus on a specific region and establish three statistical criteria for evaluating consistency between the specific region and overall results in MRCTs with multiple co-primary endpoints. More specifically, two of those criteria are used to assess whether the treatment effect in the region of interest is as large as that of the other regions or of the regions overall, while the other criterion is used to assess the consistency of the treatment effect of the specific region achieving a pre-specified threshold. The sample size required for the region of interest can also be evaluated based on these three criteria.

Partial Text

Recently, global drug development has attracted much attention from pharmaceutical companies. Unlike traditional clinical trials, the design of MRCT recruiting subjects from many countries around the world under the same protocol has led to a new strategy for drug development. This kind of design has been widely adopted by global pharmaceutical companies, which seek simultaneous drug development, submission, and regulatory approval throughout key world markets to hasten the market availability of the drug, as well as improved patient access to new and innovative treatments. However, a key issue for conducting MRCTs is how to demonstrate the efficacy of a drug in all participating regions while also evaluating the possibility of applying the overall trial results to each region. To address the difficulties related to global drug development, in 1998 the International Conference on Harmonization (ICH) published “Ethnic Factors in the Acceptability of Foreign Clinical Data”, known as the E5 guideline. The idea of an MRCT was first raised in the 11th Q& A of E5 [1]. In recent years, the trend for simultaneous clinical development in the world has been rapidly rising. To establish a framework for how to demonstrate the efficacy of a drug in all participating regions while also evaluating the possibility of applying the overall trial results to each region by conducting an MRCT, the ICH released the draft E17 guideline “General principle on planning/designing Multi-Regional Clinical Trials” [2] in 2016 to describe general principles for the planning and the design of MRCTs; another aim of the work was to increase the acceptability of MRCTs in global regulatory submissions.

The aim of an MRCT is to show the efficacy of a drug in various global regions, and simultaneously to evaluate the possibility of applying the overall trial results to each region. However, in MRCTs sponsors are challenged by how to demonstrate consistency between a specific region and the overall results. In this paper, three criteria have been established to assess the similarity between a specific region and the overall regions in an MRCT with multiple co-primary endpoints. Regulators and sponsors can easily adopt these criteria to conduct statistical assessments of the consistency of treatment effects between the specific region and the entire trial, and consequently to help registration of the new drug in the specific region.

 

Source:

http://doi.org/10.1371/journal.pone.0180405

 

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