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

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

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

Clinical Drug Development Across Regions

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

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

Ethnic Similarities/Differences on drug responses in East-Asia

Differences on PK and Safety: Caucasian vs Japanese

Genetic Similarities among East-Asian Populations

Effects of Green Tea on β-blocker, nadolol responses

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

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

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

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 e-mail, 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

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.

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

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

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