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

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

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!

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

The EWG develops the guideline background background Three ICH meetings: November 2014 in Lisbon June 2015 in Fukuoka December 2015 in Jacksonville step1 sign off in May and step 2 in June 2016 public consultations: 2Q 2016 -1Q 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

background © 2014 DIA, Inc. All rights reserved.

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?

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

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.

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

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.

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

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.

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.

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.

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.

Pooling strategies

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

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

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.

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

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

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

Apr. 2012 Thank you Apr. 2012