1. Global Drug Development To Bridge or Not to Bridge

2. Points to Consider in Bridging Specific Country Requirements What is the Societal value of the product? What are the cultural differences that may influence the acceptance of bridging? It is possible?

3. Points to Consider in Drug Development

4. Bridging is Now Old ICH E5 reached Step 4 on February 5, 1998 –More than 8 years ago! What was it really? –A excellence guide to drug development irrespective of ethnicity What is really next?

5. Global Development of Medications for Type 2 Diabetes Type 2 Diabetes as a global disease The ethnicity of type 2 diabetes –Controversy -cell dysfunction Insulin resistance BMI confusion Bridging & Global development Ethnicity and the concerns of Regulatory Authorities

6. Type 2 diabetes as a global disease

8. T2DM - Heterogeneous Disease The concept of heterogeneity –Has a long history Phenomenological (Empiric) –Type 1 (Juvenile diabetes, IDDM, etc.) »Generally autoimmune –Type 2 (Adult diabetes mellitus, NIDDM, etc.) » -cell dysfunction »insulin-resistance) –MODY

9. T2DM - Heterogeneous Disease The concept of heterogeneity (Type 2) –MODY as a model Glucokinase HNFs Other... –Differences in body size. High BMI versus Lower BMI Impaired -cell (little pancreas) versus Insulin resistance (big pancreas) –Observed differences in insulin secretion

10. T2DM - Ethnically Heterogeneous Disease

14. Popular view of diabetes in Asia Popular view of diabetes in the West Need for Special Asian studies Western studies not relevant to Asia

15. Consequences of Difference Full (extensive) development in each Region –Pathogenic differences –Different cultures Foods Medical Practice –Different perceptions of risk & benefit Looks different, therefore, risk assessment is different

16. Foundation of Type 2 Diabetes Undoubtedly with genetic roots –> 90% of monozygotic twins are concordant – 38% of siblings are concordant Known genetic polymorphisms - MODY –Found in all ethnic groups (Caucasian, Japanese, Chinese, etc…) –Account for a small percentage of diabetes None of the candidate genes explain a significant percentage of cases The geneticists nightmare

17. Foundation of Type 2 Diabetes Undoubtedly with genetic roots –Biomarkers must exist –Comparisons among populations (and individuals) are justified Comparisons are, however, confounded –Multiple sources of bias Sampling differences –Differences in duration of disease –Differences in awareness of disease –Differences in medical practice Differences of assay methods Temporal differences (varying degrees of affluence) –Differences of interpretation of results

18. Foundation of Type 2 Diabetes Common themes and controversies – -cell dysfunction –Insulin resistance +++ -cell + Insulin resistance + -cell +++ Insulin resistance

19. Foundation of Type 2 Diabetes Controversial but basic agreement –Combination of -cell dysfunction Insulin resistance

20. Foundation of Type 2 Diabetes Evidence for similarities among ethnic groups Impairment in insulin secretion is observed in many ethnic groups. –Japanese –Caucasians –Mexican Americans –African Americans

21. Foundation of Type 2 Diabetes Evidence for similarities among ethnic groups Evidence of insulin resistance –Japanese –Caucasians –Mexican Americans –African Americans

22. Foundation of Type 2 Diabetes Evidence for similarities among ethnic groups Similar behavior of associated biomarkers –Reduced adiponectin associated with T2DM »Japanese »Caucasians »Chinese »African Americans

23. Foundation of Type 2 Diabetes Evidence for similarities among ethnic groups Similar behavior of associated biomarkers –Increased C-reactive protein associated with T2DM »Japanese »Caucasians »Chinese »African Americans »Mexican Americans

24. Foundation of Type 2 Diabetes Actual situation of T2DM in Asia Actual situation of T2DM in the West

25. Points to Consider in Drug Development Bridging or global drug development –ICH E5 guideline (considerations for development in different ethnic groups FDA has issued guideline for development in various ethnic groups

26. Points to Consider in Drug Development Bridging has been applied primarily to the registration of various medications in the Japan and some other Asian markets. By and large it has been successful

27. Points to Consider in Drug Development Thus far only one development for T2DM has been bridged –NovoRapid However, it should not be concluded: –Bridging is not possible –Japan and other Asian nations cannot contribute to global drug development

28. Points to Consider in Drug Development ICH GCP has been adopted –US –EU (Western & Central Europe) –Japan –Many Asian nations (Korea, Taiwan, etc.) Infrastructure improving –Asia –Central Europe

29. Points to Consider in Drug Development Logistics of a Global Development –A global development program Protocols Endpoints Assays Analytical methods

30. Points to Consider in Drug Development Logistics of a Global Development –Endpoints ( Good news) HbA1c widely accepted –HbA1c is standardized for the measurement of stable HbA1c Not so good news –Slight differences persist between Regions

31. Points to Consider in Drug Development Logistics of a Global Development –Endpoints (Area of potential controversy) Insulin assays are NOT standardized C-reactive protein assays are NOT standardized Adiponectin assays are NOT standardized

32. Points to Consider in Drug Development Logistics of a Global Development –Insulin Assay (example) Same population –US –Demographics (Age, Sex distribution, BMI) Very different baseline IRI

33. Points to Consider in Drug Development Logistics of a Global Development –Insulin Assay (Consequences) Interpretation of HOMA-IR –(F-IRI ( U/mL) X FPG (mmol/L))/22.5

34. Recommendations to Consider in Drug Development Global KOL panel (US, EU & Asia) Many prominent Japanese & Korean KOLs have trained extensively in US or Europe Global Protocol –Primary Endpoint Identical across regions Global Core Laboratory –HbA1c, Insulin, other biomarkers

35. Recommendations to Consider in Drug Development Global approach to Regulatory Authorities –US –EU –Japan –Asia Pacific (China, Taiwan, Korea)

36. Recommendations to Consider in Drug Development Requires engagement with Investigators from different regions Requires modifications within the R&D organization