ZF Clinical Trial Guidelines (EN)

INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED GUIDELINE G ENERAL P RINCIPLES FOR P LANNING AND D ESIGN OF M ULTI -R EGIONAL C LINICAL T RIALS E17 Final version Adopted on 16 November 2017 This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of ICH regions.

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E17 Document History Legal notice: This document is protected by copyright and may, with the exception of the ICH logo, be used, reproduced, incorporated into other works, adapted, modified, translated or dis- tributed under a public license provided that ICH's copyright in the document is acknowledged at all times. In case of any adaption, modification or translation of the document, reasonable steps must be taken to clearly label, demarcate or otherwise identify that changes were made to or based on the original document. Any impression that the adaption, modification or translation of the original document is endorsed or sponsored by the ICH must be avoided.

The document is provided "as is" without warranty of any kind. In no event shall the ICH or the authors of the original document be liable for any claim, damages or other liability arising from the use of the document. The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for reproduction must be obtained from this copyright holder. Code History Date E17 Endorsement by the Members of the ICH Assembly un- der Step 2. 1 June 2016 E17 Adoption by the Regulatory Members of the ICH Assem- bly under Step 4 (document dated 16 November 2017). 16 November 2017

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ICH H ARMONISED G UIDELINE G ENERAL P RINCIPLES FOR P LANNING AND D ESIGN OF M ULTI -R EGIONAL C LINICAL T RIALS E17 ICH Consensus Guideline T ABLE OF C ONTENTS 1. INTRODUCTION ............................................................................................................ 1 1.1. Objectives of the Guideline ................................................................................................ 1 1.2. Background ........................................................................................................................ 1 1.3. Scope of the Guideline ....................................................................................................... 2 1.4.

Basic Principles .................................................................................................................. 2 2. GENERAL RECOMMENDATIONS IN THE PLANNING AND DESIGN OF MRCTS ........................................................................................................................................ 3 2.1 Strategy-related Issues ........................................................................................................ 3 2.1.1 The Value of MRCTs in Drug Development ............................................................ 3 2.1.2 Good Clinical Practice (GCP) Requirements and MRCTs .....................................

6 2.1.3 Scientific Consultation Meetings with Regulatory Authorities ............................... 6 2.2 Clinical Trial Design and Protocol-related Issues .............................................................. 7 2.2.1 Pre-consideration of Regional Variability and its Potential Impact on Efficacy and Safety ................................................................................................................................ 7 2.2.2 Subject Selection ..................................................................................................... 9 2.2.3 Selection of Doses for Use in Confirmatory MRCTs ............................................

10 2.2.4 Choice of Endpoints .............................................................................................. 11 2.2.5 Sample Size Planning ........................................................................................... 13 2.2.6 Collecting and Handling of Efficacy and Safety Information .............................. 18 2.2.7 Statistical Analysis Planning ................................................................................ 20 2.2.8 Selection of Comparators ..................................................................................... 23 2.2.9 Handling Concomitant Medications .....................................................................

25 3. GLOSSARY .................................................................................................................... 26 i

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ICH E17 Guideline 1. INTRODUCTION 1.1. Objectives of the Guideline With the increasing globalisation of drug development, it has become important that data from multi-regional clinical trials (MRCTs) can be accepted by regulatory authorities across regions and countries as the primary source of evidence, to support marketing ap- proval of drugs (medicinal products). The purpose of this guideline is to describe general principles for the planning and design of MRCTs with the aim of increasing the accepta- bility of MRCTs in global regulatory submissions.

The guideline addresses strategic pro- gramme issues as well as issues that are specific to the planning and design of confirma- tory MRCTs, and it should be used together with other ICH guidelines, including E5, E6, E8, E9, E10, and E18. 1.2. Background In the era of globalisation of drug development, it may be challenging to conduct a drug development programme globally, in part due to distinct and sometimes conflicting re- quirements from regulatory authorities. At the same time, regulatory authorities face in- creasing challenges in evaluating data from MRCTs for drug approval.

Data from MRCTs are often submitted to multiple regulatory authorities without a previously har- monised regulatory view on the development programme. There are currently no ICH guidelines that deal specifically with the planning and design of MRCTs, although the ICH E5 guideline covers issues relating to the bridging of results from one region to an- other. MRCTs conducted according to the present guideline will allow investigation of treat- ment effects including safety evaluations in the overall population as well as investiga- tions of the potential impact of intrinsic and extrinsic factors (described as ethnic factors in the ICH E5 guideline) on the treatment effect.

MRCTs, which are properly designed and executed according to this guideline, may facilitate more efficient drug development and increase the possibility of submitting marketing authorisation applications to multiple regulatory authorities in different regions simultaneously, thus providing earlier access to new drugs worldwide. In addition, MRCTs conducted according to the present guideline 1

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