1. Many Important Issues Covered Current status of ICH E5 and implementation in individual Asian countries Implementation at a regional level (EU) and practical considerations/challenges in multi-country studies Explaining ethnic and other factors by better understanding drug metabolism and action

2. Many Important Issues (cont.) Statistical challenges in analyzing data from several sites (e.g. countries) having possibly differential treatment effects Challenges (scientific, logistical, regulatory) in conducting worldwide clinical trials Genomics: advances in understanding Genomics: use in drug evaluation process Where to go next ??

3. E5 Implementation in Asia Visible progress from last year –E5 is being implemented Different countries (Japan, Singapore, Taiwan, Thailand) have considered how to respond Approaches taken vary considerably: this is to be expected and appropriate –Series of criteria for deciding if a bridging study is needed –Less specificity on exactly what type of study to be done if one is needed –Necessary types of studies judged scientifically through E5 guidelines –Implementation can require greater research support staff and PI responsibility

4. Regional Implementation: EU More extensive history of conducting multinational trials for scientific purposes Development of EU has led to criteria for centralized approval –1 authority, 1 application, 1 assessment, …. –Increased speed in drug approval within all participating countries: patients receive valuable treatments sooner –Greater competitiveness –Electronic data exchange (coming) Outstanding advance !

5. Practical Considerations in Multi-Country Trials These are considerable and must be carefully considered Use of same protocol, evaluation criteria Ensuring uniformly high-quality data Unity in trial management More difficult that a single-country trial, yet if several trials are to be done over a period of years, system can be made efficient Need to take a long-term view of the advantages in proper evaluation of new drugs for the peoples in the region

6. Ethnic (& other) Intrinsic Differences Can partially be explained by pharmacological factors such as differential metabolism rates exhibiting ethnic variation in rapid vs. slow metabolizing enzymes Advantages of such identification –Explanation of differences –Knowledge applicable across several drugs –More informed determination of dosing Still need to consider extrinsic factors, such as supportive care, medical practice, etc.

7. Statistical Methods: accounting for regional differences Assumption that relative efficacy is same at all participating sites in a clinical trial is commonly made in multi-center trials within a region (e.g., in US or in Europe) –Based on experience showing that this usually applies in settings where standards of medical care are similar Assuming no relationship between drug efficacy in different sites means SS in each must be adequate to assess efficacy just in that site (no advantage in multi-center trial)

8. Statistical Methods Several approaches for intermediate situation in which we have some belief of similar drug efficacy but are not yet confident enough to assume this –Ware and Morris, Takeuchi et al, Shih et al. Similarities to random effect methods used in meta-analyis, but applied prospectively Allow the data to determine extent to shrink individual estimates to a common value Over time, experience will be gained in heterogeneity in treatment effects (or lack thereof) and possibly its reasons –Covariate adjustment will increase precision and reduce necessary sample size.

9. Conducting Worldwide and Regional Trials Challenges similar to multi-site trials –Logistical challenges –Management challenges –Data Quality –Interpretation Important to take the long-view –Experience working together improves quality: learn by doing –Resources needed from each participating site (country) are less; potential to greatly accelerate evaluation –More rapid and better understood of the role of a new drug in participating sites (countries)

10. What Next ?? Improved knowledge of drug action, role of genetic factors, and their use in study design and interpretation ； genomics may play a key role here in future, both in bridging and Phase IV studies Development of regional evaluation/ regulatory criteria that will facilitate regional and/or global trials: –EU experience will be helpful yet Asia is beginning with less experience in regional studies; more uncertainty about likely regional variations in treatment effect

11. What’s Next (cont.) –May initially need to have minimal sample size contribution in each country to satisfy that country’s concerns, and to achieve external credibility continued development of statistical methods and simulations can guide these choices –Data management and data flow issues need to be worked out in advance. Pharmaceutical experience in individual countries will be very valuable here; Issues: centralized statistical/DM center based in one of the participating countries?? Part of MOH?? Part of company? Located in academia?? –International Monitoring Committees (DSMBs) GOOD PROGRESS; LOTS TO DO!!!!