E17 General Principles for 
Planning and Design of 
Multiregional Clinical Trials 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
July 2018 
ICH
    
E17 General Principles for 
Planning and Design of 
Multiregional Clinical Trials 
 
Guidance for Industry 
 
 
 
 
 
Additional copies are available from: 
 
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Food and Drug Administration 
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https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm    
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
July 2018 
ICH
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION (1) ....................................................................................................... 1 
A.  Objectives of the Guidance (1.1) ................................................................................................... 1 
B.  Background (1.2) ............................................................................................................................ 2 
C.  Scope of the Guidance (1.3) ........................................................................................................... 2 
D.  Basic Principles (1.4) ...................................................................................................................... 2 
II.  GENERAL RECOMMENDATIONS IN THE PLANNING AND DESIGN OF 
MRCTS (2) ........................................................................................................................ 3 
A.  Strategy-Related Issues (2.1) ......................................................................................................... 3 
1. The Value of MRCTs in Drug Development (2.1.1) ......................................................................... 3 
2. Good Clinical Practice Standards and MRCTs (2.1.2) ................................................................... 5 
3. Scientific Consultation Meetings With Regulatory Authorities (2.1.3) ............................................ 6 
B.  Clinical Trial Design and Protocol-Related Issues (2.2) ............................................................. 6 
1. Preconsideration of Regional Variability and Its Potential Impact on Efficacy and Safety (2.2.1) 6 
2. Subject Selection (2.2.2) .................................................................................................................. 8 
3. Selection of Doses for Use in Confirmatory MRCTs (2.2.3)............................................................ 8 
4. Choice of Endpoints (2.2.4) ............................................................................................................. 9 
5. Sample-Size Planning (2.2.5) ......................................................................................................... 11 
6. Collecting and Handling Efficacy and Safety Information (2.2.6) ................................................ 15 
7. Statistical Analysis Planning (2.2.7) .............................................................................................. 16 
8. Selection of Comparators (2.2.8) ................................................................................................... 18 
9. Handling Concomitant Medications (2.2.9) .................................................................................. 19 
III.  GLOSSARY..................................................................................................................... 21 
  Contains Nonbinding Recommendations 
 
E17 General Principles for Planning and Design of Multiregional 
Clinical Trials 
1
Guidance for Industry  
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION (1)2 
 
A.  Objectives of the Guidance (1.1) 
 
With the increasing globalization of drug development, it has become important that data from 
multiregional clinical trials (MRCTs) can be accepted by regulatory authorities across regions 
and countries as the primary source of evidence to support marketing approval of drugs 
(medicinal products).  The purpose of this guidance is to describe general principles for the 
planning and design of MRCTs with the aim of increasing the acceptability of MRCTs in global 
regulatory submissions.  The guidance addresses strategic program issues and issues that are 
specific to the planning and design of confirmatory MRCTs, and it should be used together with 
other ICH guidances for industry, including E5 Ethnic Factors in the Acceptability of Foreign 
Clinical Data, E6 Good Clinical Practice, E8 General Considerations for Clinical Trials, E9 
Statistical Principles for Clinical Trials, E10 Choice of Control Group and Related Issues in 
Clinical Trials, and E18 Genomic Sampling and Management of Genomic Data.3  
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.  
                                                 
1 This guidance was developed within the Efficacy Implementation Working Group of the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and has been subject to 
consultation by the regulatory parties, in accordance with the ICH process.  This document has been endorsed by the 
ICH Assembly at Step 4 of the ICH process, November 2017.  At Step 4 of the process, the final draft is 
recommended for adoption to the regulatory bodies of the European Union, Japan, and North America. 
2 Arabic numbers reflect the organizational breakdown of the document endorsed by the ICH Assembly at Step 4 of 
the ICH process, November 2017. 
3 We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.   
  1  Contains Nonbinding Recommendations 
 
 
B.  Background (1.2) 
 
In the era of globalization of drug development, it may be challenging to conduct a drug 
development program globally, in part because of distinct and sometimes conflicting 
requirements from regulatory authorities.  At the same time, regulatory authorities face 
increasing challenges in evaluating data from MRCTs for drug approval.  Data from MRCTs are 
often submitted to multiple regulatory authorities without a previously harmonized regulatory 
view on the drug development program.  Currently, no ICH guidances deal specifically with the 
planning and design of MRCTs, although the ICH E5 guidance covers issues relating to the 
bridging of results from one region to another.  
 
MRCTs conducted according to this guidance will allow investigation of treatment effects, 
including safety evaluations in the overall population, as well as investigation of the potential 
impact of intrinsic and extrinsic factors (described as ethnic factors in the ICH E5 guidance) on 
the treatment effect.  MRCTs, which are properly designed and executed according to this 
guidance, may facilitate more efficient drug development and increase the possibility of 
submitting marketing authorization applications to multiple regulatory authorities in different 
regions simultaneously, thus providing earlier access to new drugs worldwide.  In addition, 
MRCTs conducted according to this guidance may enhance scientific knowledge about how 
treatment effects vary across regions and populations under the umbrella of a single-study 
protocol, and how this variation may be explained by intrinsic and extrinsic factors.  
 
C.  Scope of the Guidance (1.3) 
 
In this guidance, MRCT is defined as a clinical trial conducted in more than one region under a 
single protocol.  In this context, a region may refer to a geographical region, country, or 
regulatory region (see section III (3) Glossary).  The primary focus of this guidance is on 
MRCTs designed to provide data that will be submitted to multiple regulatory authorities for 
drug approval (including approval of additional indications, new formulations, and new dosing 
regimens) and for studies conducted to satisfy postmarketing requirements.  Certain aspects of 
this guidance may also be relevant to studies conducted early in clinical development or in later 
phases.  This guidance mainly covers drugs, including biological products, although some 
sections may not be applicable to all drug development programs (e.g., pharmacokinetics not 
used for preventive vaccine dose-finding).  
 
D.  Basic Principles (1.4) 
 
Basic principles for designing MRCTs are described below. Subsequent sections expand on these 
principles in more detail.  
 
1.  Strategic use of MRCTs in drug development programs, properly designed and executed 
according to this guidance, can increase efficiency of drug development.  MRCTs may 
enable simultaneous submission of marketing authorization applications and support 
regulatory decision-making in multiple regions, allowing earlier access to new drugs 
worldwide.  Although MRCTs may generally become the preferred option for 
  2  Contains Nonbinding Recommendations 
 
investigating a new drug for which regulatory submission is planned in multiple regions, 
the potential for regional differences to have an impact on the interpretability of study 
results should be carefully considered.  
 
2.  The intrinsic and extrinsic factors important to the drug development program should be 
identified early.  The potential impact of these factors could be examined in the 
exploratory phases before the design of confirmatory MRCTs.  Information about them 
should also be collected during the confirmatory trial for evaluation of their impact on 
treatment effects.  
 
3.  MRCTs are planned under the assumption that the treatment effect applies to the entire 
target population, particularly to the regions included in the trial.  Strategic allocation of 
the sample size to regions allows an evaluation of the extent to which this assumption 
holds.  
 
4.  Prespecified pooling of regions or subpopulations, based on established knowledge about 
similarities, may help provide flexibility in sample-size allocation to regions, facilitate 
the assessment of consistency in treatment effects across regions, and support regulatory 
decision-making. 
  
5.  A single primary analysis approach for hypothesis testing and estimation of the overall 
treatment effect should be planned so that it will be acceptable to all concerned regulatory 
authorities.  A structured exploration to examine the consistency of treatment effects 
across regions and subpopulations should be planned. 
  
6.  In light of diverse regional practices, ensuring high quality of study design and conduct in 
accordance with ICH E6 in all regions is of paramount importance to ensure the study 
results are interpretable.  Careful attention to quality during trial planning, investigator 
training, and trial monitoring will help achieve consistently high trial quality required for 
a successful MRCT.  
 
7.  Efficient communication among sponsors and regulatory authorities is encouraged at the 
planning stage of MRCTs, with the goal of obtaining acceptance of a global approach to 
study design across the different regulatory regions.  
 
 
II.  GENERAL RECOMMENDATIONS IN THE PLANNING AND DESIGN OF 
MRCTs (2) 
 
A.  Strategy-Related Issues (2.1) 
 
1.  The Value of MRCTs in Drug Development (2.1.1) 
 
Historically, drug development focused on regulatory strategies designed for specific regulatory 
regions.  In that context, MRCTs had been recognized as an efficient way to enable recruitment 
of the planned number of trial subjects within a reasonable time frame when the disease and/or 
  3  Contains Nonbinding Recommendations 
 
condition was rare (e.g., an enzyme deficiency disorder), when the disease and/or condition was 
for special (e.g., elderly, pediatric) populations, or when very large numbers of subjects were 
required (e.g., cardiovascular outcome studies, vaccine efficacy studies).  More recently, global 
regulatory strategies are also used to plan and conduct studies more efficiently to facilitate more 
rapid availability of drugs to patients worldwide.  
 
MRCTs allow for an examination of the applicability of a treatment to diverse populations.  The 
intrinsic and/or extrinsic factors that are believed or suspected to have an impact on responses to 
the drug can be further evaluated based on data from various regions using a single protocol.  For 
example, the impact on the treatment effect of genetic differences or different distribution of 
gene polymorphisms in drug metabolizing enzymes or the molecular target of a drug can be 
examined in exploratory and/or confirmatory MRCTs that include subjects with different 
intrinsic factors across regions.  Accumulated knowledge of the impact of intrinsic and extrinsic 
factors and global sharing of experiences in various regions may promote inclusion of additional 
regions in MRCTs.  
 
The primary reason for performing MRCTs is to evaluate the overall treatment effect based on 
data from subjects in all regions.  However, intrinsic and/or extrinsic factors may be expected to 
have an impact on subjects responses to drugs differently across regions and should be 
considered when planning MRCTs.  If major differences in treatment effects are expected, 
available data should be assessed to decide whether it is appropriate and feasible to conduct the 
MRCT.  Even in the case of expected major differences in treatment effects, it may still be 
possible to conduct MRCTs by excluding some regions or a defined subgroup within a region 
after careful consideration.  Additional strategies to study a disease and/or drug in the excluded 
regions should be considered (see ICH E5).  If MRCTs are the source of data in the bridging 
strategy based on the ICH E5 guidance, MRCTs could provide more robust evidence than single 
regional trials for extrapolation of study results.  In some cases, single-region studies may be 
appropriate, such as in the evaluation of drugs to treat or prevent a disease that is prevalent in a 
single region (e.g., anti-malarial drugs, vaccines specific to local epidemics, or antibiotics for 
region-specific strains).  
 
MRCTs can facilitate simultaneous global development of a drug and reduce the number of 
clinical studies conducted separately in each region, thereby minimizing unnecessary duplication 
of studies.  Although MRCTs require more coordination during the planning stage and possibly 
increased start-up time, their use may provide a pathway for earlier access to new drugs 
worldwide by facilitating earlier approval across regions, thereby avoiding significant lag in the 
availability of new drugs in some regions.  
 
As shown in the illustrative examples in Figure 1, the timing of clinical drug development across 
different regions can be synchronized by the use of MRCTs, in comparison to local studies 
conducted independently in each region.  Figure 1 also illustrates the use of MRCTs in the 
overall design of the drug development program, not only in the confirmatory stage but also as 
an option in the exploratory stage, where it is feasible.  Early identification of relevant intrinsic 
and extrinsic factors could set a good foundation for planning confirmatory MRCTs.  
 
  4  Contains Nonbinding Recommendations 
 
Figure 1.  Illustrations of clinical drug development workflow across regions for drug 
submission and regulatory review in independent and global strategies 
 
 
 
*: Marketing Authorization Application/New Drug Application 
 
**: Could be parallel single region trials or MRCTs 
 
 
 
 
It may be plausible and efficient for an MRCT to be the single pivotal trial to support regulatory 
submission, and if this is the case, the MRCT should be designed to provide sufficient and robust 
evidence to support approval.  
 
In summary, strategic use of MRCTs, properly designed and executed according to this 
guidance, can increase efficiency of drug development, allow for exploration of the treatment 
effect to diverse populations, and enable simultaneous submission of marketing authorization 
applications and regulatory decision-making in multiple regions.  Therefore, MRCTs may 
generally become the preferred option for investigating a new drug for which regulatory 
submission is planned in multiple regions.  
 
2.  Good Clinical Practice Standards and MRCTs (2.1.2) 
 
All sites participating in MRCTs should meet applicable quality, ethical, and regulatory 
standards.  Specifically, MRCTs should be conducted in compliance with ICH E6 good clinical 
practice (GCP) standards in all regions and sites, including making sites available for GCP 
inspections by regulatory authorities.  Monitoring plans and other quality checks should be 
prespecified and implemented to address potential risks to subject rights, safety and well-being, 
  5  Contains Nonbinding Recommendations 
 
and the reliability of study results.  Centralized and risk-based monitoring may be particularly 
useful for MRCTs to monitor and mitigate the impact of emerging regional differences in, for 
example, trial subject retention or adverse event reporting (ICH E6).  Timely and accurate flow 
of information should occur between the sponsor, the trial management team, and the 
participating sites.  
 
3.  Scientific Consultation Meetings With Regulatory Authorities (2.1.3) 
 
Sponsors of MRCTs are encouraged to have scientific consultation meetings with relevant 
regulatory authorities.  These interactions should take place during the planning stage of MRCTs 
to discuss the regulatory requirements for the overall development plan and the acceptability of 
MRCT data to support marketing authorization.  Conducting such consultation meetings early in 
the planning stage of MRCTs will enable the comments received from regulatory authorities to 
be taken into consideration.  The sponsor should prepare the protocol and other relevant 
documents, and it may be beneficial to include information about which authorities are providing 
regulatory advice, and how that advice is being taken into consideration.  Consultation with 
authorities may happen at various stages, affecting different aspects of protocol development.  
Inter-authority scientific discussions are encouraged to allow for harmonization of study 
requirements.  
 
B.  Clinical Trial Design and Protocol-Related Issues (2.2) 
 
1.  Preconsideration of Regional Variability and Its Potential Impact on Efficacy and 
Safety (2.2.1) 
 
At the planning stage, regional variability, the extent to which it can be explained by intrinsic 
and extrinsic factors, and its potential to influence the study results should be carefully 
considered in determining the role MRCTs can play in the drug development strategy.  To 
facilitate taking into consideration differences among regions in intrinsic and extrinsic factors, 
we recommend that investigators and experts representing participating regions be consulted in 
the planning and design of MRCTs.  
 
The most current and relevant data should be used to understand the potential sources of regional 
variability (e.g., early trials, previous experience of the drug class).  If historical data are used, 
the sponsor should consider whether these data are still relevant in terms of scientific and 
methodological validity and in the current treatment context.  The magnitude of such variability 
could be examined in exploratory studies before the planning and design of confirmatory 
MRCTs.  
 
The intrinsic and extrinsic factors important to the drug development program should be 
identified during the planning stage of an MRCT, and information about these factors should be 
collected during the confirmatory trial for later evaluation of their impact on treatment effects.  
The ICH E5 guidance describes intrinsic and extrinsic factors that may affect the treatment 
effect.  In the MRCT setting, the following factors are particularly important and should be 
considered to identify regions that are suspected to show differences in treatment effects 
compared to the overall trial results.  
  6  Contains Nonbinding Recommendations 
 
 
1.  Disease definitions, methods of diagnosis, and the understanding of certain endpoints 
may vary between regions.  These differences could be mitigated by precisely defining 
inclusion and exclusion criteria as well as study procedures. 
  
2.  There may be differences in medical practices and treatments across regions.  Such 
differences may have an impact on the trial results and/or their interpretation.  
Standardized protocol and training for investigators and study personnel in each region 
before initiating the trial in that region may reduce some of the impact of this variability. 
  
3.  Diet, environmental factors, cultural or socioeconomic factors (e.g., contraceptive use, 
preferences for a particular route of administration), and access to health care may have 
an impact on trial results.  They may also have an impact on recruitment, compliance, and 
study subject retention, and may inform relevant mitigation strategies.  
 
4.  Subjects responses to different drugs may be more or less sensitive to intrinsic factors, 
leading to regional variability.  For example, genetic polymorphisms in drug metabolism 
or receptor sensitivity (described in ICH E5, Appendix D) or body weight and age may 
have an impact on pharmacokinetics-pharmacodynamics, as well as efficacy and safety of 
the drug.  This impact applies not only to the investigational drug but also to comparators 
and concomitant medications and should be taken into account during planning of 
MRCTs.  
 
Some sensitivity of the treatment effect to intrinsic and/or extrinsic factors may be expected in 
different regions, but should not preclude consideration of MRCTs.  Often, the degree of 
variability based on the factors mentioned above can be mitigated by proper design and 
execution of MRCTs.  Providing additional support as needed (e.g., logistical, infrastructure, 
laboratory) for specific regions or other mitigation strategies should be considered and 
implemented to reduce variability.  However, it is important to consider whether the degree of 
mitigation may have an impact on the generalizability of the study results.  
 
Even with the mitigation strategies described above, regional differences may still exist, and 
these differences are usually because of underlying intrinsic and extrinsic factors.  In this sense, 
region is an indicator for other, often unknown (or unanticipated) factors causing regional 
differences in treatment effects.  For this reason, MRCTs are usually stratified by region (see 
section II.B.5 (2.2.5)).  Figure 2 illustrates the way in which intrinsic and/or extrinsic factors 
such as disease severity (Figure 2a) or ethnicity (Figure 2b) may manifest as regional differences 
in treatment response.  However, these factors may explain such apparent differences across 
regions.  In Figure 2a, response to treatment increases with disease severity, and disease severity 
differs by region.  This scenario is manifested by observed regional differences in response to 
treatment that are explained by differences in the distribution of the underlying factor (disease 
severity) among regions.  The same phenomenon is illustrated in Figure 2b, where regional 
differences in response to treatment can be explained by differences in the ethnic distribution of 
the regions.  This type of investigation is dependent on appropriate stratification and sample size 
allocation to regions (see section II.B.5 (2.2.5)).  
 
  7  Contains Nonbinding Recommendations 
 
Figure 2.  Illustration:  primary  endpoint modulated by intrinsic and extrinsic factors across 
regions; (2a) by severity of disease, (2b) by ethnic group.  
 
 
 
2.  Subject Selection (2.2.2) 
 
In MRCTs, subject selection should be carefully considered to better understand and possibly 
mitigate potential sources of regional variability and their impact on trial results.  Clear and 
specific inclusion and exclusion criteria that are acceptable and can be applied across regions 
should be included in the protocol.  
 
To harmonize subject selection, uniform classification and criteria for diagnosis of the disease or 
definition of the at-risk population should be implemented, such as the use of relevant guidelines 
for disease definitions.  When diagnostic tools (e.g., biochemical testing, genetic testing) are 
needed for the selection of subjects, these tools should be clearly specified including the degree 
to which local validated tools and qualified laboratories may be used.  In particular, when subject 
selection is based on subjective criteria (e.g., use of symptom scales in rheumatoid arthritis), the 
same methods (e.g., validated symptom scales and/or scores in the appropriate language) should 
be used uniformly across regions.  Even so, reporting of symptoms may vary by region and may 
lead to differences in the types of subjects included in the studies.  This aspect should be 
considered in the planning stage to implement training requirements and other strategies for 
potential mitigation of the impact.  
 
Recommended tools, such as validated imaging instruments and measurements of biomarkers, 
should be available or made available in all regions when these tools are used for subject 
selection.  Imaging methods, as well as methods for specimen collection, handling, and storage, 
should be clearly defined and standardized across regions to the degree required.  
 
3.  Selection of Doses for Use in Confirmatory MRCTs (2.2.3) 
 
It is important to execute well-planned early development programs that include 
pharmacokinetic (PK) and/or pharmacokinetic-pharmacodynamic (PK-PD) studies of applicable 
parameters to identify regional differences that may have an impact on dose selection.  To 
understand the impact of ethnicity on pharmacokinetics and/or pharmacokinetics-
  8  Contains Nonbinding Recommendations 
 
pharmacodynamics, data may be obtained from single-region trials in multiple regions or from a 
trial with multiple ethnicities conducted in one region.  Alternatively, early phase MRCTs may 
be considered if they aid in efficiently gathering such data and improve the understanding of 
regional differences in pharmacokinetics-pharmacodynamics.  
 
PK studies should be conducted in the major ethnic groups most relevant to the regions to be 
included in MRCTs, if differences are expected that are not yet adequately understood (see ICH 
E5).  Adequate PK comparisons between subpopulations known to be associated with 
differences in pharmacokinetics will allow for decisions with respect to the need for 
pharmacodynamic studies and dose-response studies in different regions and/or subpopulations.  
 
We encourage sponsors to collect genetic data (e.g., genotypes of drug metabolizing enzymes) 
from subjects enrolled in the early studies to examine the effects of genetic factors on 
pharmacokinetics and pharmacodynamics.  Such early data may provide useful information 
when determining dosing regimen or regimens for future studies in which subjects with specific 
genotypes may be considered a subpopulation.  
 
A strategy for dose-selection involving population PK approaches and/or model-based 
approaches (e.g., exposure-response models) may be useful to identify important factors 
affecting drug responses in different populations, and to set an appropriate dose range for further 
dose-response studies.  Dose-response studies should cover a broad range of doses and generally 
include the populations to be enrolled in confirmatory MRCTs.  However, it may not be 
necessary to obtain PK-PD or dose-response data from subjects in all regions planned to be 
included in confirmatory MRCTs, if important regional differences in pharmacokinetics and/or 
pharmacodynamics and dose-response are not anticipated (e.g., response to the drug is unlikely 
to be sensitive to intrinsic and extrinsic factors) (see ICH E5, Appendix D).  
 
The acceptability of dose-selection strategies should be discussed with the relevant regulatory 
authorities in advance.  If substantial differences are anticipated (e.g., the drug response is 
sensitive to intrinsic and/or extrinsic factors), further investigations may be needed.  These could 
include a PK-PD or dose-response study conducted in a particular ethnic population or studies 
conducted for a broader population that would allow further evaluation of the impact of intrinsic 
and extrinsic factors on dose-response.  
 
The dose regimens in confirmatory MRCTs (based on data from studies mentioned above) 
should, in principle, be the same in all participating ethnic populations.  However, if earlier trial 
data show a clear difference in dose-response and/or exposure-response relationships for an 
ethnic population, it may be appropriate to use a different dosing regimen, provided that the 
regimen is expected to produce similar therapeutic effects with an acceptable safety margin, and 
provided it is scientifically justified in the study protocol.  Prospective careful planning of 
assessment strategies for which different doses are used should be tailored to each case and 
described in the analysis plans.  
 
4.  Choice of Endpoints (2.2.4) 
 
The general principles for endpoint selection and definitions that are provided in ICH E9 apply.  
  9  Contains Nonbinding Recommendations 
 
The aspects of particular importance to MRCTs are described in the following subsections.  
 
Primary Endpoint  
 
The primary endpoint should be relevant to the target population.  In MRCTs, this relevance 
should be considered for all regions in the trial and with respect to the various drug, disease, and 
population characteristics represented in those regions (see section II.B.1 (2.2.1)).  An ideal 
clinical trial endpoint is one that is clinically relevant, accepted in medical practice (e.g., by 
regulatory guidance or professional society guidelines), and sufficiently sensitive and specific to 
detect the anticipated effect of the treatment.  For MRCTs, the primary endpoint, whether 
efficacy or safety, should satisfy these criteria, as well as be acceptable to all concerned 
regulatory authorities, to ensure that interpretation of the success or failure of the MRCT is 
consistent across regions and among regulatory authorities.  Agreement on the primary endpoint 
ensures that the overall sample size and power can be determined for a single (primary) endpoint 
based on the overall population and also agreed upon by the regulatory authorities.  If agreement 
cannot be reached because of well-justified scientific or regulatory reasons, a single protocol 
should be developed with endpoint-related subsections tailored to meet the respective 
requirements of the regulatory authorities.  In this case, because regulatory approvals are based 
on different primary endpoints by different authorities, no multiplicity adjustment is needed for 
regulatory decision-making.  
 
Using MRCTs may introduce the need for further consideration regarding the definition of the 
primary endpoint.  Although endpoints like mortality or other directly measurable outcomes are 
self-explanatory, other endpoints may require precise and uniform definitions (e.g., progression-
free survival).  Of specific concern in MRCTs are those endpoints that could be understood 
and/or measured differently across regions.  Examples are hospitalization, psychometric scales, 
assessment of quality of life, and pain scales.  To guarantee that such scales can be properly 
interpreted, the scales should be validated and their applicability to all relevant regions justified 
before starting the MRCT.  
 
The primary endpoint of MRCTs should be one for which experience is already available in the 
participating regions.  In cases where prior experience with an endpoint only exists in one or a 
subset of regions involved in the MRCT, its adoption as primary endpoint will require discussion 
and agreement with regulatory authorities regarding the basis for the evidence, keeping in mind 
that the forthcoming trial can add information about clinical relevance of the agreed-upon 
endpoint.  
 
In addition to endpoint selection and definition, regulatory agreement should also be obtained on 
the timing and methods of the primary endpoint assessment.  
 
Secondary Endpoints  
 
When possible, harmonization of secondary endpoints is encouraged to maintain the feasibility 
and improve the quality of trial conduct.  However, in some cases, individual regulatory 
authorities may propose different secondary endpoints relevant to their interests and experience.  
Even in such cases, all secondary endpoints, including those selected only for a particular local 
stakeholder (e.g., regulatory authority), should be described in the protocol.  It is in the interest 
  10  Contains Nonbinding Recommendations 
 
of the sponsor to describe the specific advantages of the investigational drug, in terms of 
secondary endpoints, as precisely as possible during the planning stage of MRCTs to reduce the 
need for (and impact of) multiplicity adjustments for multiple endpoints, thereby improving the 
chance for successfully demonstrating the intended effect.  
 
Other Considerations  
 
Although endpoints may not require formal validation, some endpoints may be subject to subtle 
differences in understanding when used in different cultural settings.  For example, certain types 
of adverse events may be more sensitively reported (e.g., more or less frequently) in some 
regions than others, resulting in differences in reporting patterns because of cultural variation 
rather than true differences in incidence.  Use of these variables as endpoints in MRCTs will 
require careful planning.  Approaches to minimize the impact of this variation in data collection 
and interpretation of the trial results should be described and justified in the study protocol.  
 
Endpoints that are only of interest to one or a few regions could be considered for a regional 
subtrial of the MRCT.  However, sponsors should take care to ensure that ascertainment of 
regional subtrial endpoints do not hamper the conduct of the main trial.  In particular, they 
should consider the impact of additional burden to study subjects and study personnel, and the 
potential to induce reporting bias with respect to other endpoints, in determining whether 
regional subtrials can be conducted or whether a separate trial is needed.  
 
5.  Sample-Size Planning (2.2.5) 
 
General Considerations 
 
The key consideration for sample-size planning is ensuring sufficient sample size to be able to 
evaluate the overall treatment effect, assuming that the treatment effect applies to the entire 
target population, particularly to the regions included in the trial.  MRCTs offer a unique 
opportunity to evaluate the extent to which this assumption holds true.  MRCTs are usually 
stratified by region for both randomization and analysis.  Consistency of treatment effects across 
regions is evaluated, and if clinically relevant differences are observed, there should be further 
exploration to determine whether these differences can be attributed to differences in intrinsic or 
extrinsic factors (see section II.B.7 (2.2.7)).  These considerations should be reflected in the 
overall design of the MRCT and will influence the sample-size planning and allocation to 
regions. 
  
Overall Sample Size 
  
The primary objective of an MRCT generally corresponds to an evaluation (estimation and 
testing) of the treatment effect averaged across all subjects in all regions of the MRCT.  The 
overall sample size is determined to ensure that this objective can be met.  Examples of 
commonly defined treatment effects also used in MRCTs are hazard ratios for morbidity or 
mortality, differences between treatment groups in average blood pressure levels (adjusted for 
baseline), and relative risks of either favorable or adverse events.  
 
The same general principles provided in ICH E9 for determining sample sizes of clinical trials 
  11  Contains Nonbinding Recommendations 
 
apply to MRCTs.  Two additional factors are particularly important in the MRCT setting:  (1) the 
size of the treatment effect that is considered clinically relevant to all regions in the trial, and (2) 
the expected variability of the primary outcome variables based on combining data across 
regions.  These factors may result in a sample-size increase for an MRCT compared to a single 
trial in one region.  The extent of this increase will depend on the specific disease and the 
mechanism of action of the drug, as well as the intrinsic and extrinsic factors and their potential 
impact on drug response in each region.  Data from early exploratory trials with the 
investigational drug in relevant populations may inform sample-size determination. 
  
Sample-Size Allocation to Regions  
 
The MRCT should be planned to include an evaluation of the consistency of treatment effects 
among regions, when consistency is defined as a lack of clinically relevant differences.  If 
clinically relevant differences among regions are observed, then the MRCT provides a unique 
opportunity for additional learning about the factors that may explain these differences.  
Regional allocation should have a scientific basis (rather than arbitrary targets), support the 
evaluation of consistency, and provide the information needed to support regulatory decisions.  
 
Sample-size allocation to regions should consider patterns of disease prevalence across regions, 
the size and expected accrual rate of each region, the intrinsic and extrinsic factors understood 
(or hypothesized) to influence treatment effects, the prevalence of those factors in each region, 
and other logistical considerations thought to have an impact on accrual.  A regional allocation 
strategy that balances these considerations will help to ensure that enrollment can be completed 
in a timely fashion and that the MRCT objectives are met.  
 
There is no uniformly acceptable or optimal approach to sample-size allocation in an MRCT.  
Some approaches currently in use include:  
 
1.  Proportional Allocation: Allocation of subjects to regions in proportion to size of region 
and disease prevalence. 
  
2.  Equal Allocation: Allocation of equal numbers of subjects to each region.  
 
3.  Preservation of Effect: Allocation of subjects to one or more regions based on preserving 
some specified proportion of the overall treatment effect.  
 
4.  Local Significance: Allocation of a sufficient number of subjects to be able to achieve 
significant results within each region.  
 
5.  Fixed Minimum Number: Allocation of a fixed minimum number of subjects to a region.  
 
Proportional allocation facilitates recruitment by allocating subjects to the regions with the 
greatest disease burden and, absent other impediments, will generally minimize the time needed 
to complete enrollment.  The disadvantage is that some regions may end up with too few or no 
subjects, while other regions may dominate the outcome of the trial.  Equal allocation has the 
advantage of optimizing the power available to detect differences in treatment effects between 
  12  Contains Nonbinding Recommendations 
 
regions for a given overall sample-size target.  The disadvantage is that recruitment may be 
slowed to a possibly unacceptable level, particularly if disease prevalence or ease of recruitment 
varies substantially among the regions in the MRCT.  A balance between proportional and equal 
allocation is recommended to ensure that recruitment is feasible and able to be completed in a 
timely fashion, but also to provide sufficient information to evaluate the drug in its regional 
context.  
 
Allocation to preserve a proportion of the overall effect is not practical if many regions in the 
trial have this requirement.  Allocation based on achieving local significance of regional 
treatment effects is also not practical, because this strategy may inflate the sample size beyond 
feasibility and brings into question the concept of conducting an MRCT.  Allocating a fixed-
minimum sample size for regions is not recommended, if there is no scientific justification for 
selecting the minimum.  
 
In practice, sample-size allocation deliberations will reflect both scientific and logistical 
considerations.  For example, an initial allocation may be determined that targets the population 
affected by the disease, taking disease prevalence and regional size into account.  This initial 
allocation should ensure that the overall sample size can be achieved.  The allocation would then 
be modified to reduce any large imbalances in regional sample sizes and to support an evaluation 
of consistency of treatment effects across regions.  This modification could entail pooling some 
regions (as described below) to provide flexibility in sample-size allocation.  Minimum regional 
sample-size targets that are scientifically justified could also be considered at this step.  One 
example would be to specify a minimum sample size to provide meaningful descriptive 
summaries (e.g., forest plots) with sufficient accuracy and precision.  
 
Alternatively, an equal allocation to regions could be planned as the first step, with modification 
to better reflect regional sample sizes, disease prevalence, and trial logistics at the second step.  
With either strategy, care should be taken to ensure that no single region or regions dominate 
enrollment, thereby dominating the trial outcome.  
 
The five approaches discussed above are not exhaustive.  New approaches for sample-size 
allocation in MRCTs may be developed in the future, and innovation in this area is encouraged. 
  
Pooled Regions and Pooled Subpopulations 
  
Prespecified pooling of regions or subpopulations may help provide flexibility in sample size 
allocation to regions, facilitate the assessment of consistency in treatment effects across regions, 
and support regulatory decision-making.  For definitions of pooled regions and pooled 
subpopulations, see 3. Glossary.  The pooling strategy should be justified based on the 
distribution of the intrinsic and extrinsic factors known to affect the treatment response, and the 
disease under investigation and similarity of those factors across regions.  For example, pooling 
Canada and the United States into a North American region is often justified because of similar 
medical practices and similar use of concomitant medications.  Pooling strategies should be 
specified in the study protocol and statistical analysis plan, if applicable.  
 
As discussed earlier, region is often a surrogate for the underlying intrinsic and extrinsic factors 
  13  Contains Nonbinding Recommendations 
 
that tend to differentiate regions or populations from each other.  If there is sufficient knowledge 
about these factors at the trial design stage, it may be possible to define subpopulations based on 
those factors, and then incorporate these newly defined subpopulations in the stratification and 
analysis, in addition to region.  Formally, the term pooled subpopulation refers to pooling of a 
subset of the subjects from one region with similarly defined subsets from other regions whose 
members share one or more intrinsic or extrinsic factors important for the drug development 
program.  
 
Ethnicity usually crosses regional boundaries and can be an important risk factor for the disease 
or related to treatment response (as the example in Section 2.2.1. Figure 2b illustrates).  Pooling 
ethnic subpopulations across regions in an MRCT provides an opportunity to evaluate the impact 
of ethnicity on treatment effects.  Examples include Hispanics living in North and South 
America, or Caucasians living in Europe and North America.  Pooling across regional 
boundaries by other intrinsic or extrinsic factors may also be considered (e.g., by genotype).  
 
The sample size allocation should consider the planned analysis of variability of treatment effect 
among pooled subpopulations, and the principles described above for allocation to regions may 
also apply to pooled subpopulations.  Note that information about the extrinsic and intrinsic 
factors used to define pooling strategies should be collected for subjects enrolled in the trial to be 
able to monitor the recruitment strategy and ensure adequate regional and subpopulation 
representation.  
 
Other Sample Size Considerations  
 
The factors that influence sample size and sample size allocation should be agreed upon in 
advance with the different regulatory agencies governing the regions represented in the trial.  For 
non-inferiority or equivalence trials, regulatory agreement is also needed on the relevant margin.  
If, after extensive attempts to reach consensus among regulatory authorities, it is the case that 
different regulatory requirements remain due to well-described scientific arguments, the most 
stringent margin should be considered for sample size calculation.  
 
There are some situations that do not fit into the framework for sample size allocation described 
above and where more flexibility will be required.  In studies of rare diseases or an infectious 
disease outbreak, for example, disease prevalence may differ substantially between regions, and 
it may be necessary to allow one or more regions to dominate the trial for recruitment to be 
feasible.  The recruitment strategy should be discussed with the regulatory authorities during 
planning.  
 
In summary, comparing with sample size requirements in regional or local studies, the potential 
increase of the overall sample size in MRCTs should be due primarily to the increased variability 
anticipated for a multiregional population and not due to overly stringent or arbitrary regional 
sample size requirements.  The use of a well-justified and prespecified strategy for pooling 
regions and/or subpopulations in conjunction with a carefully thought out sample allocation plan 
can facilitate meeting the objectives of the MRCT.  
 
  14  Contains Nonbinding Recommendations 
 
6.  Collecting and Handling Efficacy and Safety Information (2.2.6) 
 
Adherence to GCP, as described in ICH E6, is critical for any clinical trial to meet its stated 
objectives and is particularly important in an MRCT, because of the coordination required to 
conduct a trial in diverse geographic regions.  Methods of collecting and handling efficacy and 
safety information should be standardized across participating regions.  It is also important to 
provide standardized training for investigators and study personnel in each region before 
initiating the trial in that region to ensure that the trial objectives are met through standardized 
implementation of the study protocol.  
 
Safety reporting should be conducted in accordance with ICH E2.  When local regulations 
specify different requirements, such as timelines and criteria for expedited reporting, these 
regulations should also be adhered to locally.  The specific time frame for safety reporting should 
be described in the protocol, and the investigators should receive sufficient training in 
accordance with ICH E6 and other relevant guidelines.  In the case of MRCTs, important safety 
information should be handled with adherence to any local regulations and adherence to ICH 
E2A.  Important safety information should always be provided to the relevant stakeholders (e.g., 
investigators, ethics committees) in a timely manner.  
 
In MRCTs of long duration, when special concerns (e.g., serious adverse events) have been 
identified and/or when operational regions are quite large (usually phase 3 confirmatory studies), 
the use of a central independent data monitoring committee (with representation from 
participating regions to adequately assess the context of the trial) should be considered to 
monitor the accumulating efficacy and/or safety information from the MRCT while maintaining 
integrity of the ongoing trial.  If adjudication of endpoints and/or events is planned, a centralized 
assessment by a single adjudication committee should be considered.  
 
For endpoints based on laboratory or imaging assessments, it is generally recommended that a 
centralized laboratory or centralized adjudication of imaging be used.  If multiple laboratories are 
used, appropriate cross-validation of methods between laboratories should be conducted before 
testing clinical samples.  
 
Coordinated site initiation is particularly important in MRCTs to ensure proper conduct, 
completion, and reporting of results without any delays among regions.  To comply with the 
quality management described in ICH E6, the sponsor should implement a system to manage 
quality in design, conduct, oversight, recording, evaluation, reporting, and archiving of MRCTs.  
In this aspect, centralized and risk-based monitoring may be particularly useful for MRCTs to 
identify variability across regions and sites in protocol compliance (e.g., differences in follow-
up, compliance with study medications, adverse event reporting and/or extent of missing data).  
Mitigation approaches should take regional variations into consideration.  Using electronic data 
capturing and reporting could also be considered to gather information and data (including 
relevant intrinsic and extrinsic factors) from all regions in a standardized way without delays.  If 
trial-related documents (e.g., a case report form) are translated to local languages, consistency of 
documents between languages should be ensured (e.g., by reverse translation).  As described 
above, careful attention to quality during trial planning, investigator training, and trial 
monitoring will help achieve the consistently high trial quality required for a successful MRCT.  
  15  Contains Nonbinding Recommendations 
 
 
7.  Statistical Analysis Planning (2.2.7) 
 
ICH E9 provides general statistical principles for planning and conducting statistical analyses of 
randomized clinical trials.  Aspects of analysis planning that are particularly important for 
MRCTs are described below.  The analysis strategy should be planned to enable the qualitative 
and/or quantitative evaluation of benefit/risk (ICH M4E) across regions or important 
subpopulations represented in the MRCT.  
 
Obtaining Regulatory Input on Analysis Strategy 
  
It is recommended that the sponsor have early discussions with the regulatory authorities 
involved in the MRCT, and that the sponsor obtain the authorities agreement on the proposed 
analysis strategy.  The standard is to specify a single primary analysis approach in the statistical 
section of the study protocol to be agreed upon with the authorities in advance of initiating the 
trial.  If in an MRCT, regulatory requirements for the primary analysis strategy differ because of 
well-justified scientific or regulatory reasons, the analysis strategies planned to satisfy the 
different requirements should be described in the study protocol.  If, in addition, a statistical 
analysis plan is required as a separate document by more than one regulatory authority, a single 
analysis plan integrating the different regulatory requirements should be developed.  The 
analysis strategy for an MRCT should be finalized before unblinding of treatment assignments, if 
applicable, to ensure trial integrity.  
 
Primary Analysis  
 
In planning an MRCT, the primary analysis strategy should carefully consider: (1) the target 
population, (2) the endpoints/variables of primary interest, (3) the relevant intrinsic and extrinsic 
factors in the multiregional, multi-subpopulation context, and (4) the population-level summary 
of data required to describe the treatment effect.  For most MRCTs, the primary analysis will 
correspond to a test of the hypothesis about the treatment effect and the estimation of that effect, 
considering data from all regions and subpopulations included in the trial.  
 
If randomization is stratified by region, the primary analysis should adjust for regions using 
appropriate statistical methods.  If some regions were pooled based on intrinsic and/or extrinsic 
factors, or if pooled subpopulations were defined for stratification purposes during trial planning, 
then this pooling should be reflected in the analysis. 
  
Examination of Consistency Across Regions and Subpopulations 
  
The statistical analysis strategy should include the evaluation of the consistency of treatment 
effects across regions and subpopulations.  For this purpose, consistency in treatment effects is 
defined as a lack of clinically relevant differences between treatment effects in different regions 
or subpopulations.  Various analytical approaches to this evaluation (possibly used in 
combination) include, but are not limited to: (1) descriptive summaries; (2) graphical displays 
(e.g., forest plots); (3) model-based estimation, including covariate-adjusted analysis; and (4) test 
of treatment-by-region interaction.  There are strengths and limitations to any method (e.g., 
interaction tests often have very low power), and these strengths and limitations should be 
  16  Contains Nonbinding Recommendations 
 
carefully considered during analysis planning. 
  
If clinically relevant differences in treatment effects among regions are observed, a structured 
exploration of these differences should be planned.  The exploration could proceed in the 
following steps:  
 
1.  Factors known a priori to vary among regions and hypothesized to be prognostic or 
predictive should be planned for and evaluated in the analysis model.  Examples of 
intrinsic and extrinsic factors likely to be prognostic include disease severity, race, other 
subject characteristics (e.g., smoking status, body mass index), medical 
practice/therapeutic approach (e.g., different doses of concomitant medications used in 
clinical practice), or genetic factors (e.g., polymorphisms in drug metabolising enzymes) 
that are well-established for the disease or therapy and suggested from early stages of 
investigation.  
 
2.  Even with careful planning, unexpected regional differences may be observed, and post-
hoc analyses should be used for further investigation.  Factors known to be prognostic for 
the disease would be examined first, because they are often found to be predictive of 
differential treatment effects as well.  If the distribution of a prognostic factor is found to 
differ between regions, then apparent regional differences in treatment effects may be 
explained by differences in the prognostic factors.  
 
3.  Regional differences not explained by examination of known factors may require further 
post-hoc investigation to either identify plausible reasons for the differences or to better 
understand the observed heterogeneity.  In some cases, additional data, including data 
from other clinical trials, or supportive evidence from other sources, may be needed to 
understand the regional differences observed.  
 
These eventualities should be carefully considered at the planning stage.  
 
Planned Subgroup Analyses  
 
In addition to analyses intended to investigate any regional or pooled subpopulation differences 
in treatment effects that may be observed in an MRCT, other subgroup analyses will usually also 
be of interest, just as they are for any clinical trial (e.g., analyses to investigate differential 
treatment effects by sex and age) and should be planned.  If subgroup differences in overall 
treatment effects are observed, then exploring whether the subgroup differences are consistent 
across regions or pooled regions may be informative.  
 
In summary, the assessment of consistency of treatment effects should be done with diligence to 
inform regulatory decision-making.  The credibility of regional, pooled subpopulation, or 
subgroup findings should consider biological plausibility, internal consistency (e.g., similar 
patterns of regional variability observed for other secondary endpoints) and/or external 
consistency (e.g., similar patterns observed in another clinical trial of the same drug), the 
strength of evidence, the clinical relevance, and the statistical uncertainty.  The more the 
aforementioned considerations support a potential finding, the greater the likelihood the finding 
  17  Contains Nonbinding Recommendations 
 
is not false.  The evaluation of consistency will benefit from joint clinical and statistical 
perspectives. 
  
Estimation of Regional Treatment Effects  
 
The statistical analysis section of the protocol should describe appropriate statistical methods for 
estimating and reporting treatment effects and measures of their uncertainty for individual 
regions.  This plan should include a determination of the adequacy of sample sizes to support 
robust estimation within each region or pooled region for which reporting of treatment effect is 
of interest.  If the sample size in a region is so small that the estimates of effect will likely be 
unreliable, the use of other methods should be considered, including the search for options for 
additional pooling of regions based on commonalities, or borrowing information from other 
regions or pooled regions using an appropriate statistical model.  Covariate adjusted models may 
be especially important in this setting as a way to account for intrinsic and extrinsic factors.  
Methods using weighted averages of the overall effect estimate and the estimate using data from 
individual regions (shrinkage estimates) may be considered, particularly when regional sample 
sizes are small and outlying values may be overly influential.  The choice of model should reflect 
an understanding of how intrinsic/extrinsic factors affect the regional estimates and should be 
based on appropriate statistical methods.  Sensitivity analyses should be planned that vary the 
assumptions required for the model. 
  
Impact of Trial Quality on Analysis  
 
Differences in trial conduct across regions can negatively have an impact on the power to detect 
an overall treatment effect, as well as the ability to examine consistency of treatment effects at 
the analysis stage.  Important factors having an impact on the quality of the trial, such as follow-
up of study subjects, should be managed consistently across regions, and issues identified during 
the trial should be corrected as early as possible.  
 
During the conduct of an MRCT, trial monitoring and blinded data review may uncover various 
issues that require modifications be made to the analysis plan for the trial.  For example, for 
better assessment, it might be necessary in an MRCT to modify pooling strategies for regions or 
subpopulations, which were carefully defined during trial planning, after sufficient data have 
been accumulated on the baseline characteristics (e.g., intrinsic and extrinsic factors) of the 
multiregional population.  However, such changes should be justified, discussed with the 
relevant regulatory authorities, and carried out in a way that preserves trial integrity.  
 
8.  Selection of Comparators (2.2.8) 
 
The choice of control groups should be considered in the context of the available standard 
therapies, the adequacy of the evidence to support the chosen design, and ethical considerations.  
The selection of comparators should be discussed and agreed upon with the relevant regulatory 
authorities.  Comparators in MRCTs should, in principle, be the same in all participating regions.  
Because of the complexity in setting up MRCTs, some key points are addressed in the following 
paragraphs, focusing on practical and ethical issues associated with the use of comparators: 
  
  18  Contains Nonbinding Recommendations 
 
  The choice of comparators should be justified in the study protocol based on scientific 
and other relevant information, including international treatment guidelines. 
  
  Active controls should, in principle, be dosed and administered in the same way in all 
regions.  If the approved dosing regimen of active comparators are different among 
regions, the proposed study dosing regimen should be justified by available data, and the 
justification should be included in the study protocol.  Additionally, the impact of such a 
dosage difference on analysis and evaluation of MRCT data should be considered in the 
planning stage. 
  
  The same dosage form (e.g., liquid drugs versus tablets) for active comparators should 
generally be used among regions participating in MRCTs to ensure consistency of 
treatment effects and data interpretability.  Different dosage forms could be used if the 
dissolution profiles and bioavailability are well characterized, and differences are 
negligible.  
 
  To ensure the consistent quality of the active comparators, it is recommended that the 
same source be used in all participating regions.  When active comparators from different 
sources are used in MRCTs, justification should be provided (e.g., in form of 
Certification of Analysis or report from the manufacturer on equivalence or dissolution 
studies) to ensure that the comparator has the same quality in all participating regions. 
  
  It is recommended that the most comprehensive product information in a region be used 
consistently in all participating regions.  If the product information differs from local 
product information (e.g., differences in the warnings, adverse reactions), this difference 
should be explained in the local informed consent form. 
  
  If different drugs in the same or similar drug class are proposed to be used as active 
comparators, justification should be provided in the protocol based on available scientific 
evidence. 
  
The above considerations may also be applicable in cases where comparators are selected based 
on investigators choice of local standard care.   
 
Active comparators in MRCTs should ideally be approved in all participating regions.  However, 
there could be situations where active comparators used in MRCTs are not approved or not 
available in specific regions, but have been approved and available in some ICH regions.  The 
justification (including safety considerations) for the use of an unapproved drug should therefore 
be described in the protocol based on scientific information, treatment guidelines, and other 
relevant documents.  Development status (e.g., no plan for development, under development, 
under regulatory review) of the unapproved drug in the region should also be described in the 
protocol.  Plans for post-study treatment, including continued access to unapproved comparator, 
should be considered and provided to the patient in the informed consent.  
 
9.  Handling Concomitant Medications (2.2.9) 
 
  19  Contains Nonbinding Recommendations 
 
In general, drugs used concomitantly with the investigational drug should be the same 
throughout the regions to the extent possible, but there may be some differences in the drugs 
and/or doses actually used because of variations in medical practices.  This difference could be 
acceptable if not expected to substantially have an impact on trial results.  The clinical trial 
protocol should specify allowable and not allowable concomitant medications and doses.  
 
Concomitant medications may be required in the protocol as an important part of the treatment.  
In circumstances where approved drugs are combined with an investigational drug (e.g., a 
combination regimen of anticancer drugs), the same dosage regimen in all regions should 
generally be applied.  If required by protocol, concomitant medications that are not approved in a 
region should have their use justified based on scientific information, treatment guidelines, and 
other relevant documents.  This justification could include documentation that the concomitant 
medication is approved in at least one of the ICH regions.  It should generally be allowed to use 
an unapproved concomitant medication; however, the impact of using the unapproved 
concomitant medication in the relevant regions should be discussed with regulatory authorities 
and described in the protocol.  The medication will need to be supplied in regions in which it is 
otherwise not available or only available in a different strength and/or dosage form, or in regions 
that cannot secure continuous supply during the course of the trial.  
 
Regional differences in the use and dosing of concomitant medications that may have an impact 
on drug responses should be considered in advance, and these medications, including changes in 
doses, should be documented during the trial.  The previous considerations may also be 
applicable to concomitant therapy other than medications (e.g., compression stockings in the 
post-operative setting, medical devices).  
 
  20  Contains Nonbinding Recommendations 
 
III.  GLOSSARY 
 
Consistency of treatment effect:  A lack of clinically relevant differences between treatment 
effects in different regions or subpopulations of an MRCT. 
 
Multiregional Clinical Trial, MRCT:  A clinical trial conducted in more than one region under 
a single protocol. 
  
Region:  A geographical region, country, or regulatory region.  
 
Regulatory Region:  A region comprised of countries for which a common set of regulatory 
requirements applies for drug approval (e.g., European Union). 
 
Pooled regions:  Pooling some geographical regions, countries, or regulatory regions at the 
planning stage, if subjects in those regions are thought to be similar enough with respect to 
intrinsic and/or extrinsic factors relevant to the disease and/or drug under study. 
 
Pooled subpopulations:  Pooling a subset of the subjects from a particular region with similarly 
defined subsets from other regions whose members share one or more intrinsic or extrinsic 
factors important for the drug development program at the planning stage.  Pooled 
subpopulations are assumed to be ethnicity-related subgroups and are particularly important in 
the MRCT setting.  
  21