1. Dejun Tang, Novartis Pharma, China PSI Webinar July 16, 2015 Challenges and Opportunities on Multi-regional Clinical Trials Including Asian Countries

2. Outline  Introduction  Regulatory requirements  Opportunities and challenges Regulatory Trial design Sample size Statistical analysis Operational  Summary and discussion | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities2

3. Introduction  Multiregional trials are widely conducted | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities3

4. Introduction  Multiregional trials are widely conducted  Increasing number of global trials including Asia | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities4

5. Introduction  Multiregional trials are widely conducted  Increasing number of global trials including Asia | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities5

6. Introduction  Multiregional trials are widely conducted  Increasing number of global trials including Asia  However, there are many challenges on trial design and execution for such trials | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities6

7. Relevant Guidance in ICH E5 Q & A  The multiregional trial would have to satisfy requirements of the region where the application is to be filed  A multiregional study should be designed with sufficient number of subjects so that there is adequate power to have a reasonable likelihood of showing an effect in each region of interest  It is critical to provide efficacy and safety results by region  Although Japan is the only ICH member in Asia, it is a good practice to follow ICH-GCP when conducting clinical trials including Asian countries | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities7

8. Proposed ICH E17  This topic was endorsed by ICH in June 2014 It is proposed to provide guidance on general principles of planning/designing Multi-Regional Clinical Trial (MRCT)  Statement: Regulatory agencies are currently facing some challenges in evaluating data from MRCTs for drug approval and it was deemed necessary to developed a harmonized international Guideline to promote conducting MRCT appropriately, especially focusing on scientific issues in planning/designing MRCTs. This new Guideline will complement the guidance on MRCTs provided in ICH E5(R1) Guideline and facilitate MRCT data acceptance by multiple regulatory agencies.  Expected timeline: 2017 | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities8

9. CFDA IMCT Guidance  CFDA Guidance on International Multi-center Clinical Trials (IMCT) Published on January 30, 2015 Tentative implemented on March 1, 2015  In general, most of its items are in-line with ICH and scientifically sound  Some items are controversial Sample size requirements Trend analysis for -Asian vs non-Asian -Chinese vs non-Chinese (actually China vs non-China) | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities9

10. Challenge – Different Regulatory Focuses  Requirements are different from EU and US | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities10 Sample size, Mainland China population Safety, dose, data quality Standalone report

11. Challenge – Region or Country | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities11 Taiwan Hong Kong

12. Challenge – Region or Country | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities12 Taiwan Hong Kong What is a region?

13. Other Regulatory Challenges | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities13 Lack of detailed guidance documents

14. | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities14 Lack of detailed guidance documents No formal health authority consultation in many countries Other Regulatory Challenges

15. | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities15 Lack of detailed guidance documents No formal health authority consultation in many countries Inconsistency among reviewers and countries Other Regulatory Challenges

16. | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities16 Lack of detailed guidance documents No formal health authority consultation in many countries Inconsistency among reviewers and countries Competency of independent external consultants Other Regulatory Challenges

17. Study Design Challenges Background Inclusion / exclusion criteria (TW) Sensitivity to diseases (symptoms, reactions) Epidemiology 17 | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities

18. Background Inclusion / exclusion criteria (TW) Sensitivity to diseases (symptoms, reactions) Epidemiology Enrollment Sample size determination (will present more details later) 18 | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities Study Design Challenges

19. Background Inclusion / exclusion criteria (TW) Sensitivity to diseases (symptoms, reactions) Epidemiology Enrollment Sample size determination (will present more details later) Data CRF design Systems for data collection Data standards 19 | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities Study Design Challenges

20. Sample Size Consideration  For MRCTs, how to allocate the sample size for each region/country should be carefully considered  Currently there is no agreed rules on sample size allocation for regions/countries  Here we present the sample size requirements from China and its possible impacts  PMDA in Japan has some recommendations on sample size based on efficacy and we won’t discuss here | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities20

21. Sample Size Requirements in China Provisions for Drug Registration (SFDA order NO. 28), Chapter IV Application and Approval of New Drugs, Article 26: | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities21 The number of cases in the clinical study of a drug should be decided in accordance with the objective of the clinical trials and shall meet both the statistical requirements and the minimal cases required by this Regulation for a clinical study.

22. Simplified Version of Requirements in China Sample size for Phase III trials  Chemical products New drug – 300 Marketed drug – 100 pairs  Biological products 300 treated  Both have to meet statistical requirements as well  Our interpretations Statistical requirements likely for efficacy evaluations Minimum number requirements likely from safety considerations | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities22

23. Discussions on Sample Size in China For global trials including China as a country  It could lead to a huge overall sample size to keep comparable same sizes cross the regions  Or it may have very unbalanced sample sizes for different regions due to predominate Chinese patients  It could make this type of trials less attractive, or even not feasible to conduct  Shall we take intrinsic and extrinsic ethnic factors into the consideration (or at least in Asia)? | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities23

24. Newly Issued IMCT Guidance from CFDA  Does it mean that the things are getting changed for MRCTs in China? | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities24 Sample size should be reasonably distributed among different countries/centers. In addition to satisfying the statistics requirements of the trial, sample size is also required to satisfy the needs for subgroup evaluation with fully consideration of the epidemiological characteristics of disease, the representativeness of the sample selected and other relevant factors for appropriate patients numbers distribution among different countries and regions.

25. Challenges for Statistical Analysis | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities25 Subgroup analysis (small center / region) Heterogeneity Innovative methods Multi-dimensional safety assessments Meta-analysis

26. Trend Analysis in CFDA’s IMCT Guidance | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities26 Statistical method to evaluate if there is a trend consistency between a subgroup result and the overall results should be established in advance. The difference between subgroups should be compared for primary and key second endpoints.

27. Trend Analysis in CFDA’s IMCT Guidance | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities27 Statistical method to evaluate if there is a trend consistency between a subgroup result and the overall results should be established in advance. The difference between subgroups should be compared for primary and key second endpoints. For safety signals in the overall population, consistency tests among subgroups (country/center) should be done. The reason, severity and acceptability should be analyzed for any differences found.

28. Trend Analysis in CFDA’s IMCT Guidance | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities28 Statistical method to evaluate if there is a trend consistency between a subgroup result and the overall results should be established in advance. The difference between subgroups should be compared for primary and key second endpoints. For safety signals in the overall population, consistency tests among subgroups (country/center) should be done. The reason, severity and acceptability should be analyzed for any differences found. Comparison between Chinese vs non-Chinese and Asian vs non-Asian should be done if using data for China registration application.

29. Other Operational Challenges  Long time for CTA approval in China  Languages and translations of documents  Qualification of clinical sites  Data integrity Different understanding for data quality  Quality control and compliance  DMC / Interim analysis | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities29

30.  Long time for CTA approval in China  Languages and translations of documents  Qualification of clinical sites  Data integrity Different understanding for data quality  Quality control and compliance  DMC / Interim analysis | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities30 Other Operational Challenges

31.  Long time for CTA approval in China  Languages and translations of documents  Qualification of clinical sites  Data integrity Different understanding for data quality  Quality control and compliance  DMC / Interim analysis | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities31 Other Operational Challenges

32.  Long time for CTA approval in China  Languages and translations of documents  Qualification of clinical sites  Data integrity Different understanding for data quality  Quality control and compliance  DMC / Interim analysis | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities32 Other Operational Challenges

33.  Long time for CTA approval in China  Languages and translations of documents  Qualification of clinical sites  Data integrity Different understanding for data quality  Quality control and compliance  DMC / Interim analysis | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities33 Other Operational Challenges

34.  Long time for CTA approval in China  Languages and translations of documents  Qualification of clinical sites  Data integrity Different understanding for data quality  Quality control and compliance  DMC / Interim analysis | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities34 Other Operational Challenges

35. Opportunities  Health authority collaborations  Scientific-based sample size determination  Enhanced drug development environment Government / Academia / Industry  Maximizing the use of advanced technology Drug research, IT, Statistics  Knowledge and experience sharing  “Big data” implication | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities35

36. Summary and Discussion  Many challenges to conduct clinical trials including Asian countries  Careful consideration and planning is essential  Sample size for each region/country is one of the most controversial issues  Many questions have been addressed, but a lot more are still remaining  More collaborations among all parties involved would make progress faster! | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities36

37. | PSI Webinar | Dejun Tang | July 16, 2015 | Challenges and Opportunities37