Many Important Issues Covered

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!!!!