Transcript S6-4_Meenakshi Rao_Evolution of MRCT`s What to Expect in Asia

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
Need for
MRCTs
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
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
Regulatory
product
science human
Regulatory
regulatory
resource
Convergence
procedures
capacity
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.
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.
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).
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 EastAsia
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
Goal of
MRCTs
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.
To ensure treatment
effect is clinically
meaningful and
relevant to all regions
being studied
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
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
Clinical
• 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
Predefining the region
Statistical
Methods for sub ground analysis; statistical significance versus
clinical trend analysis when evaluating clinical efficacy in subpopulations
Power and estimation of sample size (the margin should be prespecified) for the region
Issues and Challenges with MRCTs
Adherence to Protocols
Record Keeping
Operational
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.
Adequate protection of subjects
Ethical
Informed consent
Integrity, transparency
Data collection privacy
Differing regulatory requirements
Regulatory
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 confer
ence or teleconference
4Q 2014 – 3Q 2015
Second face-to-face EWG Meeting for a
daption of Step 2 document
4Q 2015
Public consultation
4Q 2015 – 2Q 2016
Revision of guideline based on commen
ts received
2Q 2016 – 3Q 2016
Third face-to-face EWG Meeting for ada
ption of Step 4 document
4Q 2016 – 1Q 2017
Provide common points to c
onsider in planning/designin
g MRCTs and minimize confli
cting opinions from regulato
ry bodies
Increase acceptability of MR
CTs in global submission
Submission to multiple regul
atory Agencies simultaneous
ly 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.
Provide better evidences for
drug approval in each region
Promote international
harmonization
• Encourage better planning and
design of MRCTs based on the latest
scientific knowledge and experiences
• e.g.; By implementing new use of
“pooled population”
A globally harmonized approach
to drug development should be
considered first.
Avoid duplication
Reduce the need to conduct
standalone regional or
national studies including
bridging studies.
ICH E17
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
Thank you