Simultaneous Global New Drug Development

Multi-Regional Clinical Trials after ICH E17

Gang Li, Bruce Binkowitz, William Wang, Hui Quan, Josh Chen, Gang Li, Bruce Binkowitz, William Wang, Hui Quan, Josh Chen

• Publisher: Chapman and Hall/CRC
• Year: 2021
• eBook ISBN: 9781000485066
• Edition: 1
• Topic: Mathematics
• Subtopic: Biostatistics
• Index: Mathematics

Global simultaneous development is becoming more necessary as the cost of developing medical products continues to grow. The strategy of using multiregional clinical trials (MRCTs) has become the preferred method for developing new medicines. Implementing the same protocol to include subjects from many geographical regions around the world, MRCTs can speed up the patient enrolment, thus resulting in quicker drug development and obtaining faster approval of the drug globally.

After the publication of the editors' first volume on this topic, there have been new developments on MRCTs. The International Council for Harmonisation (ICH) issued ICH E17, a guideline document on MRCTs, in November 2017, laying out principles on MRCTs. Beyond E17, new methodologies have been developed as well.

Simultaneous Global New Drug Development: Multi-Regional Clinical Trials after ICH E17 collects chapters providing interpretations of principles in ICH E17 and new ideas of implementing MRCTs. Authors are from different regions, and from academia and industry. In addition, in contrast to the first book, new perspectives are brought to MRCT from regulatory agencies.

This book will be of particular interest to biostatisticians working in late stage clinical development of medical products. It will also be especially helpful for statisticians in regulatory agencies, and medical research institutes.

This book is comprehensive across the MRCT topic spectrum, including

• Issues regarding ICH E17 Implementation
• MRCT Design and Analysis Methodologies
• Perspectives from authorities in regulatory agencies, as well as statisticians practicing in the medical product industry
• Many examples of real-life applications based on actual MRCTs

1 General Introduction of E17

Yoshiaki Uyama, Yasuto Otsubo, Shuji Kamada, and Yoko Aoi

DOI: 10.1201/9781003109785-1

1.1 Paradigm Shift of the Drug Development Strategy

In the past, clinical trials for the purpose of regulatory approval of a drug in Japan were conducted independently from those in the United States (US) or European Union (EU) because of concerns that ethnic differences between the Japanese and the Western populations might affect drug responses (efficacy and safety). This strategy made it possible to obtain clinical trial data specifically for the Japanese population. However, in general, the strategy initiating development in one region following up with similar studies in subsequent regions would result in duplication of studies and delayed development with late market access in the subsequent regions. This situation was actually seen in Japan before 2010 known as the drug lag (a situation in which a drug is not available in Japan for several years even after its first launch in the Western countries) (Uyama et al. 2005; Hirai et al. 2010). To increase the efficiency of drug development and to minimize the duplication of clinical trials, the E5 guideline entitled “Ethnic factors in the acceptability of foreign clinical data” was established in February 1998 by the International Conference on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), followed by regulatory implementation in March 1998 in the EU, June 1998 in the US, and August 1998 in Japan (see Chapter 7).

Since 1998 several drugs have been approved in Japan based on the ICH E5 guideline (Uyama et al. 2005). In such approvals, a bridging study, which is typically designed as a pharmacokinetic study and comparative dose-response study, is usually included in the clinical data package for regulatory submission to allow both an examination of the impact of ethnic factors on drug responses and extrapolation of foreign clinical data to the Japanese population (Uyama et al. 2005). Drug development via a bridging study is helpful to shorten the duration of clinical development in Japan by minimizing the clinical trials that have to be conducted in the country (e.g., phase III trials could be skipped), but it does not completely resolve the drug lag caused by the delayed initiation of drug development in Japan (Figure 1.1) (Uyama et al. 2005; Hirai et al. 2010).

Figure 1.1 Limited impact of the bridging strategy based on the ICH E5 guideline on the drug lag.

The drug lag still exists because the initiation of drug development in Japan is usually started only after phase II data have been obtained in the US or the EU.

In 2007, a new guideline entitled “Basic principles on global clinical trials” was published in Japan to promote simultaneous drug development and resolve the drug lag, followed by two related guidelines published in 2012 (“Basic Principles On Global Clinical Trials (Reference Cases) (PFSB/ELD Administrative Notice)” 2012) and 2014 (“Basic Principles for Conducting Phase I Trials in the Japanese Population Prior to Global Clinical Trials (PFSB/ELD Administrative Notice)” 2014). Through these efforts, the number of multi-regional clinical trials (MRCTs) conducted in Japan has increased markedly (Asano, Uyama and Tohkin 2018). In fact, the percentage of drug approval for which an MRCT provided pivotal clinical data for regulatory review increased from approximately 1% in 2007 to approximately 48% in 2019 (Figure 1.2). Relative to local drug development, the drug lag has also been significantly shortened in the case of global drug development using MRCTs (Ueno et al. 2014).

Figure 1.2 Trends in MRCT-based approved drugs in Japan.

1.2 Backstory of the ICH E17 Expert Working Group

1.2.1 Why Were the ICH E17 Guidelines Established?

In recent years, global development, including MRCTs, has been widely happening in populations from different parts of the world (Japan, the US, the EU as well as other regions and countries) (Thiers, Sinskey and Berndt 2008; Asano, Uyama and Tohkin 2018). Regulatory authorities have faced challenges in evaluating data from MRCTs for drug approval (Ichimaru, Toyoshima and Uyama 2010; Asano et al. 2013). In the later 2000s, guidelines and other related documents relating to MRCTs were published in Japan and the EU (“Basic Principles On Global Clinical Trials (PFSB/ELD Notification No. 0928010)” 2007 “Basic Principles on Global Clinical Trials (PFSB/ELD Notification No. 0928010)” 2007; “Reflection Paper On The Extrapolation Of Results From Clinical Studies Conducted Outside The EU To The EU-Population” 2009 “Reflection Paper on the Extrapolation of Results From Clinical Studies Conducted Outside The EU To The EU-Population” 2009). The US Food and Drug Administration (FDA) also published a perspective regarding regulatory and scientific issues on the use of foreign data in support of new drug applications (Khin et al. 2013). At that time, however, there were no internationally harmonized guidelines on MRCTs, especially one focusing on scientific issues in the planning and/or design of MRCTs. Although the Q&A section of the ICH E5 guideline partly covers issue relating to MRCTs, more specific guidelines on MRCTs was expected to further promote the conduct of MRCTs in a harmonized way and to increase the efficiency of drug development, thereby avoiding duplicative works in drug development and enabling better regulatory decisions.

1.2.2 The History of the ICH E17 Guideline

In 2014, the Pharmaceuticals and Medical Devices Agency (PMDA) submitted to the ICH a concept paper proposing new harmonized guidelines on general principles for planning and design of MRCTs (“Final Concept Paper E17: General Principle On Planning/Designing Multi-Regional Clinical Trials” 2014). In June 2014, an ICH-steering committee endorsed the concept paper and decided to establish a new expert working group (EWG), known as “E17 EWG”, for creating the new internationally harmonized guideline entitled “General Principles for Planning and Design of Multi-Regional Clinical Trials.” As shown in Figure 1.3, after the establishment of E17 EWG, the members actively discussed the proposed guidelines through face-to-face meetings, regular web conferences, and e-mails. Consensus on the draft ICH E17 guideline was reached within the E17 EWG in June 2016, and the guideline was then published in each region for comments. More than 1000 comments were received from many regions during the public consultation period. The E17 EWG carefully reviewed all comments and discussed the best solutions to reflect the points raised in the comments. Active and constructive discussions were again made through face-to-face meetings, as well as regular web conferences and e-mails. Ultimately, consensus on the final ICH E17 guideline was reached at a meeting in Geneva in November 2017 (“ICH E17 Guideline” 2017). Each regulatory authority subsequently worked to implement the ICH E17 guideline under local legislation. Importantly, the ICH E17 guideline was officially implemented in many regions including the EU and Japan in June 2018, followed by the US in July 2018, the Republic of Korea in October 2018, Canada in April 2019, Brazil in May 2019, and China in November 2019.

Figure 1.3 A history of the ICH E17 guideline.

After the establishment of the ICH E17 guideline, ICH continued to work to provide training materials aiming for proper implementation of the ICH E17 guideline on the correct understanding of the E17 principles. Standardized training materials aid the implementation of the ICH E17 guideline consistently across regions. The final training materials were published in August 2019 and are available on the ICH website (https://www.ich.org/page/efficacy-guidelines). They describe more practical details about the key principles of the ICH E17 guideline, such as pre-consideration of regional variability, selection of doses, sample size allocation, pooling strategies, evaluation of consistency, and selection of comparators (see Chapters 3, 4, 5, and 6 for more details).

1.3 Key Principles of the ICH E17 Guideline

The ICH E17 guideline describes practical issues relating to MRCTs, such as common points to consider in their planning and design and how to minimize conflicting opinions from regulatory authorities. This guideline should be used toge...

Table of contents

• Cover
• Half Title
• Series Page
• Title Page
• Copyright
• Contents
• Preface
• Editor Biographies
• List of Contributors
• 1 General Introduction of E17
• 2 New Principles in Global Development Using ICH E 17 Guideline
• 3 Consideration of “Ethnic Factors” in Design and Conduct of Multiregional Clinical Trials (MRCT)
• 4 Pooling Strategies
• 5 Overall Sample Size and Allocation to Regions
• 6 Consistency Evaluation in MRCTs
• 7 Implementation of the ICH E17 Guideline in Japan
• 8 ICH E17 and MRCT: Implementation and Regulatory Perspective in China
• 9 Lessons Learned from Actual Multi-Regional Clinical Trials with Signals of Treatment Effect Heterogeneity
• 10 Leveraging Foreign Clinical Data Extrapolation to Accelerate Global Drug Development: A Case Study in Hematological Oncology
• 11 Analysis Models for Multi-regional Clinical Trials
• 12 Utilization of Robust Estimates of Treatment Effects via Semiparametric Models in MRCT
• 13 Hierarchical Linear Models for Multi-Regional Clinical Trials
• 14 Local Treatment Effect Estimation by Borrowing Information from Similar Regions in Multi-Regional Clinical Trials
• 15 Global Drug Development: Multi-Regional Clinical Trials (MRCTs) – China's Pursuit
• 16 Statistical Considerations in Design, Execution, and Analysis of Multiregional Clinical Trials: Consistency Evaluation and Adaptive Trials
• 17 Multiple Endpoints in Multiregional Clinical Trials
• 18 Multi-regional Clinical Trials with Heterogeneous Regional Treatment Effects
• 19 Regional Sample Size Calculation in Multi-regional Equivalence and Non-inferiority Trials
• Index