1. ICH E17 General Principles for Planning and Design of MRCTs
I chun Lai MD, MS
Team Leader/Medical Reviewer
Division of New Drugs

2. DISCLAIMER
This presentation was not officially cleared, and the views offered here do not necessarily represent the official positions at MOHW, including TFDA.

3. Outline Background & Current Status Key Considerations Conclusion

4. Background & current status

5. ICH Organization http://www.ich.org/about/organisation-of-ich.html

6. ICH Guideline Process Step 1: Building scientific consensus
EWG
Step 1: Building scientific consensus
Step 2: SC Agrees on draft text
Step 3: Open for public consultation
Step 4: Adopting harmonized guidelines
Step 5: Implementing guidelines in ICH regions
SC: Steering Committee (changed to General Assembly)
EWG: expert working group
IWG: implementation working group
IWG

7. ICH E17 Process Topic endorsed by steering committee in June 2014 EWG
Lisbon Portugal, Nov 2014
Fukuoka Japan, June 2015
Jacksonville USA, Dec 2015
E17 Step 2 version, May 2016
Osaka Japan, Nov 2016

9. Key considerations

10. Table of Contents
1.Introduction Objectives/ Background Scope/ Basic Principles 2.General Recommendations 2.1 Strategy-related Issues to Clinical Trial Design & Protocol- related Issues to 2.2.9

11. E17 Objective
Increasing the acceptability of MRCTs in global regulatory submissions
What is a MRCT?
A clinical trial conducted in more than one region under a single protocol

12. What is a “Region”? Region Regulatory region
Geographic region, country, or regulatory region
Regulatory region
A region for which a common set of regulatory requirements applies for drug approval (e.g., European Union, Japan).

13. MRCT? A clinical trial conducted in
Northern Taiwan + Southern Taiwan ?
Japan + Taiwan + China + Korea ?
E17 objective: increasing the acceptability of MRCTs in global regulatory submissions

14. Old vs New Drug Development Strategy
Independent strategy
ICH E5: bridging approach
New: E17 MRCT

15. E17跟E5有什麼不同? E5 Ethnic factors E17 MRCT
直接在planning stage就納入所有應考慮的regions
直接進行MRCT
以MRCT的結果進行查驗登記
已經完成的
試驗結果
是否可以外推至
另一個region

16. E17 Simultaneous Confirming Parallel
Bridging
Sequential
E17 Simultaneous Confirming Parallel

17. Independent vs Global strategy歐洲
各自為政
Phase I
Phase II
Phase III
Phase I
Phase II
Phase III 亞洲
Phase I
Phase II
Phase III
團結力量大
歐亞美洲

19. MRCTs in Overall Development Program
MRCTs can play an important role in drug development programmes beyond their contribution at the confirmatory stage.
For example, exploratory MRCTs can gather scientific data regarding the impact of extrinsic and intrinsic factors on (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

20. Basic Principles: Promote MRCT
MRCTs are generally the preferred option for investigating a new drug for which regulatory submission is planned in multiple regions
The underlying assumption of the conduct of MRCTs is that
the treatment effect is clinically meaningful and relevant to all regions being studied
while also acknowledging that some regional variation is expected

21. Severe disease with better response
因疾病嚴重度不同:Region I的response< Region II
Overall treatment effect applies to all regions
some regional variation is expected

22. Consideration of Ethnic Factors (1)
As in ICH E5, ethnic factors are defined as
Intrinsic factors (eg. genetic, physiological)
Extrinsic factors (eg. medical practice)
Should be identified during the planning stage, information about them should be collected and evaluated when conducting MRCTs
MRCTs should be designed to provide information to support an evaluation of whether the overall treatment effect applies to subjects from participating regions

23. Consideration of Ethnic Factors (2)
Evaluation of subgroups defined by intrinsic and extrinsic factors
Pre-specified in the protocol & SAP
Plausibly predictive of differential response to treatment
examples of subgroups
Disease stage (mild/mod/severe)
Race and/or ethnicity (Asian, Black, Caucasians)
Genetic factors (polymorphisms of drug metabolizing enzymes)

24. New Concept: Pooled Regions
For sample size planning & evaluating consistency across regions
如果有相似的intrinsic/extrinsic factors
Some regions may be pooled at the design stage
例如把歐洲視為一個pooled region
Or 把台、日、韓、陸視為一個pooled region (East Asia)

25. New Concept: Subpopulation
Overall population
Overall study population included in MRCT
Subpopulation
Defined by one or more intrinsic/extrinsic factors
May span across multiple regions
Pooled subpopulation

26. Response可能依ethnicity之不同而有variation
Group B in Region I is a subpopulation
Group B in Region II is a subpopulation
把Region I & II的Group B加在一起=pooled subpopulation
Ex: Hispanics in North & South America, Caucasians in Europe & North America
Group B that can largely be enrolled from Region I could alternatively be enrolled globally (eg. Region II)

27. Pooled regions/pooled subpopulations
Belongs to subgroup analysis
In order to evaluate treatment effect consistency
May provide a basis for regulatory decision making

28. Achieve statistical significant results within one or more regions
Evaluate treatment consistency

29. Sample size MRCT的sample size取決於test of primary hypothesis
based on combing data from all regions in the trial
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

30. Allocation to Regions (1)
1st: show similar trends
allocate equal number to each region
may not be feasible or efficient
2nd: proportion of preservation
would be difficult if all regions have this requirement
3rd: proportion to regional size
may result in very small sample size within some regions
insufficient to support any evaluation of treatment consistency

31. Allocation to Regions (2)
4th: achieve stat significance within one or more regions
then why conduct MRCT?
5th: fixed min number per region
any local safety requirement for min number of subjects is a programme level consideration
should not be a key determinant of the regional sample size

32. Allocation to Regions (3)
A balanced approach is needed to ensure that the trial is feasible but also provides sufficient information to evaluate the drug in its regional context.
Therefore, sample size allocation should take into consideration
region size,
the commonality of enrolled subjects across regions based on intrinsic and extrinsic factors and
patterns of disease prevalence,
as well as other logistical considerations to ensure enrolment is able to be completed in a timely fashion

33. Basic Requirements Unified hypothesis with common comparators
Clear & specific I/E criteria
Primary endpoint should be clinically meaningful in all regions
If agreement can’t be reached
A single protocol should be developed with endpoint-related sub-sections
In this case, since regulatory approvals are based on different primary endpoints by different authorities, no multiplicity adjustment is needed for regulatory decision-making

34. Dose Selection (1) In order to select the dose for confirmatory MRCTs,
it is necessary to execute well-planned development programmes during phase I – II
that include PK and/or PK/PD studies of applicable parameters,
in order to be able to identify important regional differences which may impact dose selection.
When applicable, PK investigations should be undertaken in subjects from major subpopulations that are intended to be included in MRCTs (eg, Asian, Black, Caucasians)

35. Dose Selection (2)
Dose regimens in confirmatory MRCTs should in principle be the same in all participating regions
If early trial data show a clearly defined dose/exposure/response relationship that differs for a region,
it may be appropriate to use a different dosing regimen in that region,
provided that the regimen is expected to produce similar therapeutic effects with an acceptable safety margin

36. Consultation with Regulatory Agencies
Encourage discussion with regulatory agencies in the planning stage
Understand different regulatory requirements
Obtain their agreement with the proposed analysis strategy
How the analyses of pooled regions and/or pooled subpopulations may provide a basis for the regulatory decision-making for relevant regulatory authorities

37. Ensuring Trial Quality
Ensuring trial quality is of paramount importance
Ensure scientific validity of results
Follow ICH E6 GCP
Centralized & risk-based monitor
Build up trial infrastructure & capability
Efficient global drug development

38. conclusion

39. E17: Think Globally Promote MRCTs Harmonized approach
Provide earlier access to new drugs worldwide

40. Thank you for your attention
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