1. The ICH E5 Guidance: An Update on Experiences with its Implementation The ICH E5 Guidance: An Update on Experiences with its Implementation Robert T. O’Neill, Ph.D. Director, Office of Biostatistics CDER, FDA To be presented at the 3rd Kitasato University - Harvard School of Public Health Symposium, October 2-3, 2002

2. Outline of talk u Recent ICH meetings and their purpose u Summary of FDA report on experiences u Some draft Question and Answers to clarify E5 u Plans for E5 as a result of Washington meeting u Some thoughts on bridging and prospective planning

3. Why ? u Four years of experiences u Agreement that some clarification is needed u The need for more data - how much

4. Bridging Studies u When u Why u What type E5 is purposely vague on how to do this or what their design should be

5. The Spirit and Intent of E5 u Not intended to request bridging studies every time u Intended to permit the requesting of one ‘confirmatory’ phase 3 clinical trial (bridge study) in the region (not specifically defined, nor meant as ‘country’) if needed or necessary to extrapolate. u Recognized that there would be a period of time where experience with foreign clinical studies would be accumulated and evaluated - not to be confused with always asking for a new confirmatory trial in local region.

6. ICH meetings on E5 Implementation u Brussels: February 6-7, 2002 u Washington, D.C: September 10-11, 2002

7. E5 Informal Discussion Group

8. Brussels discussions u Acknowledgement that E5 has made a major contribution towards acceptance of foreign data. u Each of 6 parties summarized experience u MHLW has most experience of regulatory authorities to date with E5 implementation, described their experience u Determine strategies for clarification of E5 in view of experiences

9. FDA’s experiences based upon: u An informal survey of medical review divisions regarding their experiences in asking for bridging studies and relying on foreign clinical trial data for regulatory decisions. u A review of approved applications in calendar year 2001 with respect to number of clinical trials all of whose data was foreign, and/or multi-national in nature u A summary of the number of domestic and foreign clinical trials documented in 18 of 30 New Molecular entities approved in 1998

10. Summary of FDA experience u Majority of NDA’s contain foreign clinical trial data, often used as primary evidence of efficacy and safety - rarely, does the entire data base on efficacy consist of foreign clinical data u Until recently, discussion have rarely been held with sponsors during IND/NDA development stages that specifically consider bridging strategies when relying on foreign clinical data

11. Summary of FDA experience u Some, but not all review divisions, during the process of evaluation of the clinical efficacy data examine regional differences in efficacy and safety. Part of the reason for this is that sponsors have not, a priori, designed the clinical trials with this objective in mind -this may be chaning u Most multi-national trials have included patients from Western Europe, U.S., Canada, New Zealand and Australia. Minimal but increasing experience with Latin America Eastern Europe.

12. Summary of FDA experience u Few examples of formal bridging studies done in the U.S. that were performed subsequent to development of a complete clinical data package, and that were carried out in response to an FDA request u Generally, when FDA asks for more data/studies, it is because the clinical trial evidence in the NDA is not convincing and other formal phase 3 studies conducted in the U.S. are needed. u Despite the inclusion of foreign clinical data in an NDA, sponsors have anticipated an FDA request by carrying out U.S. trials without being asked. Sometime these trials are ongoing at the time of NDA submission

13. Summary of FDA experience u As trials come from new regions, it may become critical to agree in advance on the sources of data u There has not often been a prospective evaluation during the IND of differential pk, pd or clinical endpoints to treatment response u About 7 examples illustrating the types of issues faced.

14. Plans from the Brussels meeting u MHLW to provide more detailed and comprehensive description of its experience with E5 implementation, since MHLW has most experience with bridging strategies u Industry to provide more specifics about case studies u All six parties to specify questions for consideration for possible Q & A doc.

15. Washington, D.C September 10-11, 2002 ICH Meeting

16. Summary of Discussions at the Washington meeting u Evaluation of all written Q and A from 6 parties u Evaluation of the case studies from MHLW and EFPIA which illustrate bridging issues and examples u Categorization of Q and A in selected topic areas to reduce redundancy and build consensus u Discussions on selected Q and A that all parties agreed to be important

17. Examples of the type of Q and A’s that will be developed

18. Questions and Answers (Q&A’s) to clarify intent of E5 Q1. I am planning to develop my new drug globally. Does E5 provide guidance for this approach? Q2. I have developed my drug in one region, addressing safety, efficacy, dosing, etc., as well as use in special populations such as patients with renal/hepatic impairment, the elderly, children, and pregnant and lactating women. If I can successfully demonstrate (e.g., through a bridging study), that my safety, efficacy, and dosing information in the general population are relevant to the new region, will I also need to further address the extrapolatability of the special populations data?

19. Questions and Answers (Q&A’s) to clarify intent of E5 Q3. My drug is sensitive to ethnic factors and the medical settings in which it is used may vary between regions. Does that mean that my efficacy study in one region is of no value in support of my application in another? Q4. My drug is insensitive to ethnic factors and there are no significant, relevant differences in extrinsic factors, including the practice of medicine, among the regions. The pharmacokinetics of the drug are insensitive to intrinsic and extrinsic factors. The diagnosis and therapy of the condition in the indication do not significantly vary among regions. Nonetheless, the regulatory authority of the new region is requiring an additional study of safety and efficacy for bridging. Is that requirement inconsistent with E5?

20. Questions and Answers (Q&A’s) to clarify intent of E5 Q5. My drug has been approved in 2 ICH regions and I am about to meet with regulatory authorities in the third region to discuss an application for marketing. I believe that the present data should be accepted by the new regulatory authority and that little or no additional data should be required by that regulatory authority. What information should I submit to support my case that additional data are not needed? Q6. My drug is insensitive to ethnic factors and drugs in its class have similar activity in all regions. However, the endpoints I studied (or control group I used) were acceptable to regions in which the studies were conducted but not to the new region. Does E5 indicate that the new region should accept those data as evidence of efficacy?

21. Q and A Summary Topics u Need for Safety Data u Considerations on Special Populations u Multiple Indications u Global Development Strategy/Global Study (Study Design Issues) u Medical Practice u Requesting One More Study u Responsibility to Justify Bridging

22. Plans for the next year u An Implementation Working Group will be constituted under ICH auspices to complete the Q and A’s and to collect new issues as experience accrues u Final Q and A’s need to be consistent with intent of E5 and with regulatory policy in each region u Timeframe: Feb 2003, Tokyo or July 2003, Brussels

23. Some thoughts on bridging studies and strategies u Many different bridging strategies, depending upon data, disease and individual circumstances of studies u There are clinical study design issues which need to be addressed at the planning stage to facilitate extrapolation and interpretability for both u Multi-regional studies u Simultaneous global drug development u Similar designed studies in two different regions (1 year vs. 2 year endpoints)

24. Issues to consider at the planning stage u Definition and diagnoses of disease and patient u Variation in frequency or rarity of clinical endpoint -impacts benefit risk evaluation (Number needed to treat) u Medical practice, concomitant medications u Prospectively, planning to examine a regional subgroup in a manner that may be different than overall treatment effect [e.g. more emphasis on one of the endpoints, certain entrance criteria]

25. Issues to consider u Same or different endpoints in each region u Same or different comparator treatments in different regions u Difficult issue; implications for interpretation in superiority and non-inferiority trials u Size of regional component of multi-regional study to evaluate similarity of response u Dose response u Benefit/risk (efficacy and safety data)

26. Concluding Remarks u The intent of the updated Q and A’s is to clarify some areas of perceived misunderstanding u More dialogue with regulators on study design strategies will continue and experiences with completed studies and bridging approaches shared u My talk is primarily intended to be an update on the informal working group ICH meetings u