Kaitlin Montagano, PharmD

September 6, 2018

General Principles for Planning and Design of Multiregional Clinical Trials: A Guidance for Industry

Objective of Guidance: to facilitate the acceptability of data from multiregional clinical trials for drug
approvals by regulatory authorities in multiple regions and/or countries

Multiregional Clinical Trial (MRCT): a clinical trial conducted in more than one region (i.e., geographical
region, country, or regulatory region) under a single protocol to evaluate an overall treatment effect
based on data from all subjects in all regions

Challenges:
• Data from MRCTs that are not properly designed and executed are often submitted to multiple
regulatory authorities with differing (and sometimes conflicting) requirements for drug
development and approval
• MRCTs require more planning and coordination up-front, which may delay the start of new trials

Benefits
• Properly conducted MRCTs could increase efficiency in drug development and worldwide
availability of new drugs
o Facilitating the submission of acceptable data to regulatory agencies across regions
o Enroll a sufficient sample size more quickly
• Observe variations in drug efficacy and safety across a range of populations under a single study
protocol
• Minimizes duplication of clinical trials by reducing the number of separate clinical trials
examining the same treatments and outcomes

Good Clinical Practice Standards (GCPS)

• All sites must comply with GCPS & make sites available for inspection by regulatory authorities
• Monitoring plans should be prespecified and address potential risks to subjects
Kaitlin Montagano, PharmD
September 6, 2018

Regulatory Authorities: meetings between regulatory agencies and study sponsors should occur
regularly, especially during the development of study protocols to facilitate acceptability of MRCT data
by various agencies

Regional Variability: must be considered during the planning stage to determine its potential impact on
study results
• Early trials and/or previous experiences with the drug class can help inform potential regional
variability
• Intrinsic and extrinsic factors
o Identify and evaluate their influence on the treatment effects
o Variability due to these factors can often be mitigated by study design and execution in
affected regions
▪ Balance mitigation of variability with generalizability of results
o MRCTs often stratified by regions to further account for regional variability
Varying Factors across Regions Mitigation
Disease definition, diagnosis, and Precisely define inclusion & exclusion
endpoints criteria and study procedures
Medical practice and treatment Standardized protocol and training for
differences → impact results and their investigators and study personnel in each
interpretation region
Diet, environmental, cultural, Use specific factors to inform mitigation
socioeconomic factors, and access to strategy
healthcare → impact results, recruitment,
compliance, and retention
Individual subjects’ responses to different Consider during planning of MRCT
drugs may have varying sensitivities to
intrinsic factors, leading to regional
variability (e.g., differences in genes, body
weight, and age)

Subject Selection
• Appropriate subject selection helps mitigate potential regional variability
• Specific and uniform criteria for disease diagnosis are necessary

Dose Selection for Confirmatory Trials

• Early trials should be conducted to evaluate PK/PD parameters that might vary across regions
and affect dosing
• Dose-response studies should include a broad range of doses and should be conducted in the
populations expected to be enrolled in the confirmatory MRCT
Kaitlin Montagano, PharmD
September 6, 2018

• Dose-selection strategies should be discussed with regulatory agencies in advance to ensure

their acceptability
• Dose regimens should be the same in all participating regions
o Unless, earlier trials showed a clear difference in dose-response for a given population

Endpoint Selection
• Primary Endpoint
o Relevant to the target population in all regions in terms of the drug, disease, and
population characteristics of those regions
o Clinically relevant, accepted in medical practice, and sufficiently sensitive and specific to
detect the anticipated treatment effect
o Must be precisely and uniformly defined
o Acceptable to all regulatory agencies to ensure consistent interpretation of results
• Secondary Endpoints
o Consistency of secondary endpoints across regions is desirable
o Some regulatory agencies may include secondary endpoints they deem relevant for
their area
o All secondary endpoints (even region-specific) must be described in the study protocol

Sample Size
• Sample size must be large enough to evaluate overall treatment effect across all subjects and
regions included in the MRCT
• MRCTs allow for the evaluation of whether a treatment effect will apply to an entire target
population (i.e., within all included regions)
o Stratified by region for randomization and analysis
o Inconsistencies in treatment effect should be explored for potential attribution to
intrinsic or extrinsic factors
• Considerations especially important for MRCTs → may require larger sample sizes than
individual trials
o Size of the treatment effect that is considered clinically relevant to all regions in the trial
o Expected variability of the primary outcome variables based on combining data across
regions
• Sample size allocation across regions: consider disease prevalence, size and expected
enrolment of each region, and intrinsic and extrinsic factors affecting treatment effects.
Allocation approaches include:
o Proportional allocation: allocation of subjects is proportional to the size of the region
and disease prevalence
o Equal allocation: allocation of equal numbers of subjects to each region
o Preservation of effect: allocation of subjects to one or more regions based on
preserving some specified proportion of the overall treatment effect
Kaitlin Montagano, PharmD
September 6, 2018

o Local significance: allocation of a sufficient number of subjects to be able to achieve

significant results within each region
o Fixed minimum number: allocation of a fixed minimum number of subjects to a region
• Pooled subpopulation: 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
o May help facilitate sample size allocation to regions, consistency in treatment effects
across regions, and regulatory decision-making

Data Collection and Handling

• Data collection and management methods should be standardized across regions. The sponsor
should utilize a system to manage design, conduct, oversight, recording, evaluation, reporting,
and archiving MRCTs.
• Consistency of documents in different languages should be ensured by reverse-translation
• Some MRCTs (i.e., long duration, with special concerns identified, large operational regions)
benefit from centralized independent data monitoring to maintain trial integrity
• A centralized laboratory should be used (or sufficient cross-validation between multiple
laboratories) for endpoints requiring laboratory or imaging assessments

Statistical Analysis
• Should enable the qualitative and/or quantitative evaluation of benefit/risk across regions or
important subpopulations in the MRCT
• Relevant regulatory agencies should approve of a single primary data analysis strategy prior to
the start of the trial
• Consistency of treatment effects in different regions/subpopulations should be evaluated in the
data analysis process
o Descriptive summaries o Test of treatment-by-region
o Graphical displays interaction
o Model-based estimation (e.g.,
covariate-adjusted analysis)
• Estimation of regional treatment effects should be incorporated into data analysis based on an
understanding of the effects of regional intrinsic/extrinsic factors and appropriate statistical
methods
• Factors that may impact trial quality (e.g., subject follow-up and retention) should be
consistently managed across regions

Comparator Selection
• Comparators should be based on available standard therapies, international treatment
guidelines, and ethical considerations
• Comparator selection should involve and be agreed upon by relevant regulatory authorities
• Active controls should be dosed and administered in the same manner in all regions
Kaitlin Montagano, PharmD
September 6, 2018

• The same source should be used to supply the comparator to all regions

Concomitant Medications
• Ideally, concomitant medications would be the same across regions
• Differences in concomitant drugs/dosages may be acceptable as long as they are not expected
to significantly alter trial results. Allowable concomitant drugs and dosages should be defined in
the trial protocol.

Reference:

US Food and Drug Administration. E17 General Principles for Planning and Design of Multiregional
Clinical Trials: Guidance for Industry. Available at:
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
Published July 2018. Accessed August 30, 2018.