1. ICH E 17: General principles for planning and design of Multi-Regional Clinical Trials
Impact on Global Drug Development Strategy
Regulatory considerations and challenges from a sponsor point of view
Vibeke Bjerregaard, member of ICH EWG, EFPIA topic lead

2. Outline Background for ICH E 17 global vs local
Regulatory considerations
challenges, e.g. endpoints, target groups, controls
collaboration with authorities
Discussion points
sample size allocation, pooled regions, pooled subpopulations, consistency evaluation
Concluding remarks

3. Moving from a regional to a global concept
background
Moving from a regional to a global concept
background
ICH E 17 is about to put trials, conducted in multiple regions, into the centre of a new drug application in all regions
instead of a set of studies in separate regions
and studies in one region to be acknowledged by other regulatory agencies, ICH E 5
Having the need for a regional implementation in mind!

4. The EWG meet F2F and at TCs twice a month
background
The EWG meet F2F and at TCs twice a month
ICH E 17 is now in step 3

5. The EWG develops the guideline
background
background
Three ICH meetings:
November 2014 in Lisbon
June 2015 in Fukuoka
December in Jacksonville
step1 sign off in May and step 2 in June 2016
public consultations: 2Q Q 2017:1018 comments (888 in Nov-16)
two meetings: November 2016 in Osaka, May 2017 in Montreal
step 4 is the aim for the ICH meeting in Geneva, November 2017
Collaboration with other EWG e.g. E6, E9, E11

6. background
© 2014 DIA, Inc. All rights reserved.

7. Early access of global treatments
background
Early access of global treatments
Sponsors aim at
efficient development and marketing
time to first submission of the MAA
time from first submission to last approval
efficient development:
high quality studies
development supporting a product profile
target groups in few trials
effective planning through all phases of development
MRCTs supports efficient development
Compressed, development, efficient i.e. fast, comprehensive and of high quality
All target groups represented in the program
Regulatory convergence towards harmonisation
So no matter where the patients are, they should have access to the medicine.
When further estimating potential ethic differences in treatment effect, the regions to be selected may depends on the expected differences.
Heterogeneity is another term or what we have to consider in MRCTs (vs local studies)
Patients are everywhere, no matter the geographic boarders!
Why is this a timing concern?

8. Exploratory/descriptive
background
Development phases
(as we knew it)
Exploratory/descriptive
Confirmatory
WIT
Dose ranging
Dose response
relationship
Formally compare
new vs. control N C N P
Phase I
Phase II
Phase III
Phase IV
Development programs used to happen phase by phase from I to IV. These days are the phases often overlapping and exploratory studies may run in parallel with confirmatory studies and long term “post authorisation” studies are often initiated as IIIb studies to support a successful marketing authorisation, e.g. conduct of CV outcome studies of long term treatments (antidiabetic drugs, drugs treating lipid disorders and obesity)
WIT=”Whatever It Takes” – commitments to agencies, extension of uses , real word data collection..
Nedjad Losic, Genmab

9. E17 figure 1: From local to global devlopment
background
E17 figure 1: From local to global devlopment
From local to global!
History told us that it used to take several years from patients in the first region have access to new treatments until the last patient have access in the last country. E.g. companies launched products in the US and EU long before these were applied for in Japan (rf. Yoshi).
Early PK and First in man trials are usually conducted in a single region. However it is recommended to consider the global aspects of the development program, planning for MRCTs. E.g. already to get an idea of the sensitivity to the ethic factors of the drug by including Asian and Caucasian subjects in the phase I (second phase of the FIM), dose escalation SS study.

10. Outline Background for E 17 Regulatory considerations
global vs local
Regulatory considerations
challenges, e.g. endpoints, target groups, controls
collaboration with authorities
Discussion points
sample size allocation, pooled regions, pooled subpopulations, consistency evaluation
Concluding remarks

11. Trials must be accepted in each country
regulatory considerations
Trials must be accepted in each country
timing
acceptance by regulatory authorities and ethic committees is needed from each involved region
other bodies may also be involved e.g. authorities for registries, biosamples, ex- and import license
not all countries allow parallel assessments
time from first protocol submission to last approval may be critical
typical European time frames are: 1- 4 months
Regulatory details:
E.g. some Ethic committees do not assess the protocol before the regulators have done an in-depth assessment of the whole application – all IMP documentation, IB, protocol, labels etc., and the other way around, an agency may not allow conduct of a study, if not approved by the relevant ethic committee(s) in the first hand. Biolab assessment is often done after the regulatory approval.
Brazil may take up to 6-9 month
So does India
A timely faction i.e. from 1 submission to last approval of a trial should not extent one year.
Initiation of trials should happen coordinated and when the site is ready, and most sites should be initiated in parallel – so that they can share experiences as the study goes along (centralised monitoring benefits from parallel initiation)
LPLV in each site should also happen in the same timeframe for all sties.

12. Guidelines in US, EU and China for diabetes
regulatory considerations
Guidelines in US, EU and China for diabetes
When developing new treatments for the diabetic conditions, we have several scientific efficacy and safety guidelines describing the requirement from the US and EU regulatory agencies

13. Collaboration with authorities
regulatory considerations
Collaboration with authorities
company strategy:
to consult medical experts
to involve regulators from ICH regions in advises
to involve affiliates and local agencies
agencies with experience in the area e.g. used to assess similar protocols and drugs
agencies in key countries e.g. many sites involved, principal and coordinating investigators
agencies involved with scientific advises
1. Experts from international societies (i.e. diabetes: ADA and EASD, key investigators) and agencies scientific guidelines.
2. Take advices with key agencies e.g. FDA, CHMP, PMDA, Anvisa, Health Canada,…, when the first 3-4 discussions are ready, then proceed in collaboration with affiliates representing the regions to be involved in the MRCT.

14. Outline Background for E 17 global vs local Regulatory considerations
challenges, e.g. endpoints, target groups, controls
Acceptance of ONE protocol
collaboration with authorities
Discussion points re. E 17
sample size allocation, pooled regions, pooled subpopulations, consistency evaluation
Concluding remarks
© 2014 DIA, Inc. All rights reserved.

15. Some definitions
region : a geographical region, country or regulatory region for which a common set of regulatory requirements applies pooled regions: some geographical regions or countries or regulatory regions may be pooled, if subjects in those regions are thought to be similar enough with respect to intrinsic and/or extrinsic factors relevant to the disease and/or drug under study. pooled subpopulations: pooling a subset of the subjects from a particular region with similarly defined subsets from other regions, whose members share one or more intrinsic or extrinsic factors important for the drug development programme.
© 2014 DIA, Inc. All rights reserved.

16. Samplesize: some special considerations relevant to MRCTs
the size of the treatment effect that is considered clinically meaningful and relevant to all regions in the trial
the expected variability of the primary outcome variables based on combining data across regions
Consideration of both 1. and 2. is informed by a) knowledge of the disease, b) the mechanism of action of the drug , c) a priori knowledge about intrinsic and extrinsic factors and their potential impact on drug response in each region, and d) data available from early exploratory studies with the investigational drug.  
ICH E 9 (R1) – revision – estimand and definition of the treatment effect
© 2014 DIA, Inc. All rights reserved.

17. Pooling strategies

18. Pooling regions and subpopulations
discussion points
Pooling regions and subpopulations
overall sample size calculated to achieve the primary objective
pooled-regions or pooled subpopulations
pooling strategies to be justified based on the distribution of the intrinsic and extrinsic factors known to affect the treatment response and the disease under investigation and similarity of those factors across regions.
e.g.,
pooled region: North American Region (US and Canada)
pooled subpopulation: Hispanics living in North and South America, or Caucasians living in Europe and North America.
consistency evaluation
to be based on a descriptive or qualitative framework

19. overall sample size to achieve primary objective
Sample size allocation; “balanced” approach
discussion points
large imbalance among regions may make assessment of regional differences difficult
regions described
in the protocol
subpopulation P
subpopulation Q
subpopulation R
total
region A
region B
region C
region D
[ideally]
equally
allocated
for the purpose
of comparison among regions
overall sample size to achieve primary objective
pooled subpopulation
Hi Vibeke
To be clear, we did not randomise separately to the different regions, but we did define these up front as subgroups of interest. As such, it was pre-specified to look at the primary endpoint (time to first MACE) separately for each region, although this was exploratory as of course the trial was not adequately powered for such subgroup comparisons.
Anyway, the AdCom slide with demographic breakdown is attached. We only presented percentages, numbers of patients by region on a world map are also attached. We have not compiled any slides of the various requests that have come in to date – still too busy actually fulfilling the requests J. But it is safe to say that most Health Authorities like to see results within their country, and we provide these when there are sufficient numbers (i.e., in US). When there are not, then we try to agree on the most homogeneous population possible, as in the examples from W. Europe and Asia excluding India.
BR Bryan
Komiyama Osamu, Pfizer

20. Outline Background for E 17 global vs local Regulatory considerations
challenges, e.g. endpoints, target groups, controls
Acceptance of ONE protocol
collaboration with authorities
Discussion points
sample size allocation, pooled regions, pooled subpopulations, consistency evaluation
Concluding remarks
© 2014 DIA, Inc. All rights reserved.

21. MRCTs supports know how building about new treatments
concluding remarks
MRCTs supports know how building about new treatments
inclusions of variable ethic groups of patients will allow
efficacy and safety data collected in parallel across different ethics groups
better understanding of efficacy and safety of the treatments across regions,
total exposure is not expected to be increased
more subjects may be needed in some MRCTs due a high variability among subjects
skipping local studies and/or duplication of studies

22. MRCTs support early access of new treatments
concluding remarks
MRCTs support early access of new treatments
including global target populations in MRCTs allows for simultaneous submissions of marketing applications in multiple regions
parallel assessments of MRCTs will promote global collaboration among authorities
simultaneous submissions will allow early marketing authorisations
MRCTs supports early access of new treatments to patients

23. Regulatory challenges
concluding remarks
Regulatory challenges
variable regional cultures and traditions
harmonised approach is needed
variable availability of medicines in regions
need for same comparator(s) across regions
different regional scientific guidelines
a common approach to different requirements are needed
a harmonised approach to content and assessment of trial applications among authorities
a harmonised approach to trial applications is needed
support regional assessment of the global development
communication with health authorities is important
Variable cultures and traditions, will call for a harmonised approach!
Can we have a eCTD format for clinical trial applications (CTAs)?
How can we discussion global assessment of CTAs
It is happeing: NN has

24. Apr. 2012
Thank you
Apr. 2012