Description
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.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
3development program for drug and biological products
Subject of the benefit-risk assessment guidance
drug where there has been no prior determination of safety or effectiveness
Stakeholders
6Entities to discuss drug production using specific cell lines
Bodies responsible for evaluating trial risks and benefits for pregnant participants.; ECs experienced in this population may advise on compensation.
Makes final determination in case of disagreement between pathologists
Body that may propose protocol amendments or maintain trial integrity
Entity responsible for submitting applications under section 524B
Responsible for qualifications, training, and trial conduct; Individual responsible for trial conduct and data governance at a site.; May delegate tasks but retains overall responsibility; Person responsible for the conduct of the clinical trial at a trial site; Responsible for trial conduct and participant safety; Responsible for trial conduct, data integrity, and investigational product management.; Individual responsible for trial conduct at a site and informing the institution.; maintaining
Regulatory Context
Regulatory Activities
6Confirmatory studies intended to provide an adequate basis for approval
Trials conducted in more than one region under a single protocol
Submissions supported by clinical trial data.
Rule does not apply to products marketed under an NDA
making sites available for GCP inspections by regulatory authorities
Sponsors of MRCTs are encouraged to have scientific consultation meetings with relevant regulatory authorities
Document Types
10MRCTs conducted under a single-study protocol
Provided to ensure that the comparator has the same quality in all participating regions.
Inclusion of cybersecurity risks as part of informed consent form; Should include cybersecurity risks for IDE submissions
Document where potential trial adaptations must be pre-specified; Document where the source of external information and prior distribution should be documented.; Should contain core elements and adaptive design rationale.
collect on the case report form (CRF) the Investigator's clinical interpretation
Document for protocol execution; The sponsor should develop a statistical analysis plan that is consistent with the trial protocol; Deviations from this plan must be justified
Document defining the design and conduct of the trial
Defines the standard of veterinary practice and limits for anesthetic regimens
Monitoring plans and other quality checks should be prespecified
Should describe assessment strategies for different doses
Attributes
7Potential impact on efficacy and safety
Biological property that may be altered by manufacturing changes; safety narrative should address bioavailability of the ingredients
Used to justify different dosage forms if differences are negligible.
Reporting enrollment proportions consistent with sex-specific prevalence.
statistically justified calculation required in the plan
genetic differences or different distribution of gene polymorphisms; Factors like genetics affecting drug response; Factors known to affect the treatment response
Diet, environmental factors, cultural or socioeconomic factors; Environmental or cultural factors affecting drug response; Factors known to affect the treatment response
Technical Details
Substances
4vaccine efficacy studies or vaccines specific to local epidemics
Medications permitted or prohibited during the trial.
Should ideally be approved in all participating regions and used from the same source.
Used to increase development efficiency
Testing Methods
9Diagnostic tool for subject selection
Used to evaluate the robustness of overall survival results
Methods using weighted averages of the overall effect estimate and the estimate using data from individual regions.
Analytical approach for evaluation of consistency
Analytical approach to evaluate consistency of treatment effects
Used to provide meaningful descriptive summaries
Used to elucidate precise etiology of genetic disease
Strategy for dose-selection
Model-based approach to identify factors affecting drug response
Processes
5MRCTs are planned under the assumption that the treatment effect applies to the entire target population
May uncover issues requiring modifications to the analysis plan.
Conducted to identify regional differences
Conducted to understand drug response differences
Should cover a broad range of doses
Clinical Concepts
10The choice of which can be adaptively modified based on comparative interim results.; the main outcome measure used to evaluate effectiveness
Increased risk when daily wear lenses are worn overnight
A clinical trial conducted in more than one region under a single protocol.
SAEs collected during interventional clinical trials
Example of disease with similar pathophysiology to psoriatic arthritis
Safety findings including deaths and post-mortem examinations
Harmonization is encouraged to maintain trial quality
Investigation of treatment effects across regions
monitor and mitigate the impact of emerging regional differences in adverse event reporting
description of the treatment effect of interest using natural, non-technical language; The effect being measured and understood through supplementary and sensitivity analyses.
ICH References (10)
General Principles for Planning and Design of Multiregional Clinical Trials
Evaluation of benefit/risk across regions or important subpopulations
Provides definitions for seriousness criteria; ICH E2A recommends blinded therapy should not be reported
Referenced for basic considerations in safety data collection.
Ethnic Factors in the Accessibility of Foreign Clinical Data.
Referenced for safety data collection and adverse event reporting plans.
General Considerations for Clinical Studies
Statistical Principles for Clinical Trials; Discourages deterministic procedures due to high risk of bias; Notes that the use of Bayesian methods in clinical trials may be considered.
Choice of Control Group in Clinical Trials.
Genomic Sampling and Management of Genomic Data
Related MFDS Guidelines
Korean regulatory guidelines covering similar topics
See Also (8)
- E11A Pediatric Extrapolation
- M15 General Principles for Model-Informed Drug Development
- Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product
- Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances
- Rare Diseases: Considerations for the Development of Drugs and Biological Products
- Q3C Impurities: Residual Solvents_2011
- Providing Regulatory Submissions in Electronic Format --Content of the Risk Evaluation and Mitigation Strategies Document Using Structured Product Labeling: Guidance for Industry
- Q4B Annex 5: Disintegration Test General Chapter