Points to Consider for Implementation of the ICH E17 Guideline: Learning from Past Multiregional Clinical Trials in Japan

Abstract

We identified the major points that are described in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guideline but have not been considered in the past multiregional clinical trials (MRCTs) used for drug approval in Japan to elucidate potential challenges in the implementation of the ICH E17 guideline in Japan. Based on the analysis of 167 MRCTs of 130 drugs, several points, such as the same dose setting and consistency between the overall and Japanese populations, in addition to good clinical practice compliance, have been well considered in ≥ 75% of MRCTs. In contrast, the use of relevant guidelines for disease and primary end point definitions, standardization of efficacy/safety information, sample size allocation, as well as training/validation on subject selection and primary end point, have been addressed less adequately and may need to be considered when planning future MRCTs. This study provides useful information for the implementation of the ICH E17 guideline in Japan.

Figure 1

Identification of drugs newly approved in Japan based on data from MRCTs. We collected data of newly approved drugs from the website of the Pharmaceuticals and Medical Devices Agency and identified drugs that were approved between April 2007 and March 2018 based on MRCTs, as the pivotal clinical trial type in Japan. MRCTs, multiregional clinical trials.

Figure 2

Considerations of 18 key principles of the ICH E17 guideline in past MRCTs. GCP, good clinical practice; ICH, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; MRCTs, multiregional clinical trials; PK, pharmacokinetic; PMDA, Pharmaceuticals and Medical Devices Agency.

Figure 3

Considerations of ethnic differences based on PK data between Japanese and non‐Japanese populations. The outer circle shows the ratios of studies that considered ethnic differences based on PK data, and the inner circle shows a detailed breakdown. MRCTs, multiregional clinical trials; PK, pharmacokinetic.

Figure 4

Conducting dose‐response studies for the selection of dose regimens in confirmatory MRCTs. The outer circle shows the ratios of conducting dose‐response studies, and the inner circle shows a detailed breakdown. MRCTs, multiregional clinical trials; PK/PD, pharmacokinetic/pharmacodynamic.

Figure 5

Setting of standardized collection and handling of efficacy and safety information. The outer circle shows the ratios of the setting of standardized collection and handling of efficacy and safety information, and the inner circle shows a detailed breakdown. (a) Setting of standardized collection and handling of efficacy information and (b) setting of standardized collection and handling of safety information.