1. Quintiles East Asia Ltd Singapore
Evolution of MRCTs:
What to expect in Asia?
Meenakshi Rao Ph.D, RAC
American
Quintiles East Asia Ltd Singapore

2. Multi-Regional Clinical Trials
Simultaneous conduct of a clinical trial in multiple geographical regions. 
Major role in providing patients with access to innovative new medicines.
Unmet medical needs & faster access to medicines
Limited patient pools in individual countries
Large patient pool required (e.g. CV outcomes studies)
Facilitate drug development by reducing number of trials conducted separately in each region
Avoid ethical issues of unnecessary duplication studies
Sharing of experience and knowledge
Need for
MRCTs

3. Asia Pacific Economic Co-operation (APEC)
An increasingly important destination
Drug development and testing are globalized
21-member countries
Emerging market
Emerging patient base in RCTs
Country-specific bridging requirements
often of inadequate sizes to draw valid region-specific conclusions

4. Clinical Drug Development Across Regions

5. Roadmap to Promote MRCTs
To attract investment of these clinical trials
Medical product regulatory procedures
Regulatory science human resource capacity
Regulatory Convergence
Critical for APEC region to achieve regulatory convergence

6. Roadmap to Promote MRCTs
APEC LSIF Regulatory Harmonization Steering Committee (RHSC) –
tasked to achieve regional convergence on regulatory approval procedures for medical products by 2020.
The Duke-NUS Centre of Regulatory Excellence (CoRE) was designated as an APEC Center of Excellence (CoE) for conducting regulatory training in Multi-Regional Clinical Trials (MRCTs).
Roadmap to promote Multi-Regional Clinical Trials (MRCT) led by Japan is highly advanced and has entered implementation phase.
Goal is to facilitate MRCT and acceptance of these trial results for review by regulatory authorities.
The LSIF Regulatory Harmonization Steering Committee (MRCT) met in Jakarta in February 2013 and agreed to pilot an APEC MRCT Regulatory Science Center of Excellence.
APEC MRCT CoE Pilot co-sponsored by National University of Singapore (NUS), HSA and Duke University was held 1-4th March 2016.
Faculty= Industry + Academia + Regulators
Three-day hands-on sessions: each participant mentored by a faculty in a multi-country team

7. Ethnic Similarities/Differences on drug responses in East-Asia

8. Differences on PK and Safety: Caucasian vs Japanese

9. Genetic Similarities among East-Asian Populations

10. Effects of Green Tea on β-blocker, nadolol responses

11. Should be based on knowledge of the disease, the mechanism of action of the drug, on a priority knowledge about ethnic factors and their potential impact on drug response in each region, as well as any data available from early exploratory trials with the new drug
The study is intended to describe and evaluate this treatment effect, acknowledging that some sensitivity of the drug with respect to intrinsic and/or extrinsic factors may be expected in different regions and this should not preclude consideration of MRCTs.
Ethnic factors are a major point of consideration. They should be identified during the planning stage, and information about them collected and evaluated when conducting MRCTs.
Based on the understanding of accumulated knowledge about these intrinsic and extrinsic factors, MRCTs should be designed to provide information to support an evaluation of whether the overall treatment effect applies to subjects from participating regions
Goal of
MRCTs
To ensure treatment effect is clinically meaningful and relevant to all regions being studied

12. Issues and Challenges with MRCTs
Regional Variability
intrinsic factors race, genetic polymorphism, drug metabolism, receptor sensitivity which can impact PK/PD and efficacy and safety of the drug
extrinsic factors background treatment, social factors, health care system, medical practices, standard of care, concomitant medications
Subject selection should be carefully considered ( I/E criteria) to reduce variability
Selection of Doses for use in Confirmatory MRCTs
PK/PD data form different population/region should be obtained and considered
Choice of end-points
Different regulatory endpoints for different region can be challenging
Clinical
Predefining the region
Methods for sub ground analysis; statistical significance versus clinical trend analysis when evaluating clinical efficacy in sub-populations
Power and estimation of sample size (the margin should be pre-specified) for the region
Statistical

13. Issues and Challenges with MRCTs
Adherence to Protocols
Record Keeping
Proper follow-up for drop-outs, reasons for discontinuation
Challenges when transitioning from phase II to phase II to post marketing (SOP, clinical SOP’s, data handling SOP’s drug supply, IVRS, randomization, data management, quality etc.
Operational
Adequate protection of subjects
Informed consent
Integrity, transparency
Data collection privacy
Ethical
Regulatory
Differing regulatory requirements
Divergence in requirements for the control arm
The active comparators must be approved in all participating regions

14. Towards Regulatory Harmonization: ICH E17
General Principles on Planning/Designing MRCTs
Timing
Approval of Concept Paper by Steering Committee
June 2014
Establishment of EWG
2Q 2014
First face-to-face EWG Meeting
4Q 2014
Discussion by , web-based conference or teleconference
4Q 2014 – 3Q 2015
Second face-to-face EWG Meeting for adaption of Step 2 document
4Q 2015
Public consultation
4Q 2015 – 2Q 2016
Revision of guideline based on comments received
2Q 2016 – 3Q 2016
Third face-to-face EWG Meeting for adaption of Step 4 document
4Q 2016 – 1Q 2017
Provide common points to consider in planning/designing MRCTs and minimize conflicting opinions from regulatory bodies
Increase acceptability of MRCTs in global submission
Submission to multiple regulatory Agencies simultaneously for approval

15. Introduce a new use of “pooled population” to help regulatory decision making
Some regions may be pooled at the design stage, if subjects in those regions are thought to be similar enough with respect to intrinsic and/or extrinsic factors relevant to the disease area and/or drug under study.
Consideration could also be given to pooling a subset of the subjects from a particular region with similarly defined subsets from other regions to form a pooled subpopulation whose members share one or more intrinsic or extrinsic factors important for the drug development program.
Both pooled subpopulations and pooled regions should be specified at the study planning stage and be described in the study protocol.
The guiding principle for determining the overall sample size in MRCTs is that the test of the primary hypothesis can be assessed, based on combining data from all regions in the trial.
The sample size allocation to regions or pooled regions should be determined such that clinically meaningful differences in treatment effects among regions can be described without substantially increasing the sample size requirements based on the primary hypothesis.

16. Impact of ICH E17 on Drug Development
Provide better evidences for drug approval in each region
Encourage better planning and design of MRCTs based on the latest scientific knowledge and experiences
e.g.; By implementing new use of “pooled population”
Promote international harmonization
A globally harmonized approach to drug development should be considered first.
ICH E17
Avoid duplication
Reduce the need to conduct standalone regional or national studies including bridging studies.
Reduce drug lag timelines
Impact of ICH E17 on Drug Development

17. MRCTs MRCTs in Asia are here to stay.
MRCTs currently carried out to meet local regulatory requirements are likely replaced by larger a more harmonized approach for trials that will be accepted by multiple regulatory bodies.
Encourage to conduct MRCTs in an exploratory stage as well as a confirmatory stage
MRCTs can play an important role in drug development programs beyond their contribution at the confirmatory stage for instance in post approval settings
For example, exploratory MRCTs can gather scientific data regarding the impact of extrinsic and intrinsic factors on pharmacokinetics and/ or pharmacodynamics (PK/PD) and other drug properties, facilitating the planning of confirmatory MRCTs.
MRCTs may also serve as the basis for approval in regions not studied at the confirmatory stage through the extrapolation of study results

18. Thank you