1. Use of Foreign Data for Approval Ann Farrell, MD Division of Oncology Drug Products Center for Drug Evaluation and Research Food and Drug Administration

2. Disclaimer The views expressed are the result of independent work and do not necessarily represent the views or findings of the United States (US) Food and Drug Administration (FDA) or the United States.

3. FDA Acceptance of Foreign Data Guidance for Industry- Acceptance of Foreign Clinical Studies –if performed under an IND - 21 Code of Federal Regulations (CFR) 312 –if not performed under an IND- 21 CFR 312.120 (c)(4)

4. FDA Acceptance as the sole basis for marketing approval 21 CFR 314.106 –applicable to the US population and US medical practice –studies performed by competent clinical investigators –valid data

5. ICH - E5 Drug development package must satisfy the regulatory requirements of the new region. Drug development package must allow extrapolation to the new region.

6. ICH E-5 Definitions Extrinsic Ethnic Factors--Factors associated with environment and culture in which a person resides. These factors tend to be less genetically, more culturally and behaviorally determined. Intrinsic Ethnic Factors--Factors that help to define and identify a subpopulation and may influence the ability to extrapolate clinical data between regions.

7. ICH E-5 Intrinsic and Extrinsic Factors Intrinsic –Genetic (polymorphisms, gender, race) –Physiologic/Pathologic (age, liver impairment, renal impairment, cardiac disease) –height/weight Extrinsic –Environmental (cultural, socioeconomic, medical practice, regulation, clinical trial design /conduct /endpoints) –Habits (smoking, alcohol)

8. ICH E5-No Bridging Studies Necessary if the drug is ethnically insensitive and extrinsic factors are similar if drug is ethnically sensitive, but the two regions are ethnically similar and there is sufficient clinical experience with pharmacologically related compounds

9. ICH E-5 Pharmacologic Bridging Studies if the region are ethnically dissimilar and the drug is ethnically sensitive, but extrinsic factors are generally similar and the drug class is familiar in the new region, a controlled PD study reflecting relevant drug activity may suffice Simultaneous PK encouraged

10. ICH E-5 Controlled Clinical Bridging Trial Required Doubts about the choice of dose Little experience with acceptance of controlled clinical trials carried out in foreign region Medical practice is different--concomitant meds, conduct of clinical trials Drug class is not familiar to new region

11. ICH E5- Bridging Studies for Safety A study to assess efficacy, such as a dose- response study, could be powered to address rates of common adverse events A separate safety study could be required –Concerns about reporting differences –Index case of serious adverse event in foreign clinical data package

12. Bridging Studies The request for a bridging study using either pharmacologic endpoints or controlled clinical trials does not infer that foreign clinical data is of poor quality.

13. New Molecular Entities 1997- present 28 New Drug Applications (NDAs) submitted and granted approval 4 NDAs had pivotal trials which were conducted exclusively in the United States 20 NDAs had pivotal trials which were conducted in the United States and other regions

14. NMEs 1997 to present (continued) Other regions were other North American countries, Western and Eastern Europe (Slovakia, Russia), Middle East (Israel, Lebanon, Egypt), Africa (Republic of South Africa, Tunisia), South America, Asia (Taiwan, Japan, India, China), Australia, New Zealand

15. NMEs 1997 to present (continued) 4 NMEs did not have pivotal trials which enrolled United States patients Indications - advanced stage breast cancer and lung cancer 2 NMEs had supporting or pharmacokinetic/pharmacodynamic studies which included United States patients 2 NMEs did not

16. Foreign data acceptable for NMEs 1997 to present because met the FDA regulatory requirement for adequate and well- controlled trials etiology, natural history, pathology, prognosis and treatment of the disease - similar in both regions ethnically similar

17. Foreign data acceptable for NMEs 1997 to present (continued) control group used was widely accepted as the standard of therapy in the US pivotal trials usually conducted under the auspices of cooperative groups such as EORTC, NCIC endpoints acceptable based on stage of disease trials were replicated

18. Recent Unsuccessful NDA Submissions with Foreign data natural history, etiology, staging and prognosis differ medical practice differs endpoints not acceptable no replication of results

19. FDA CDER Oncology division Although differences in intrinsic ethnic factors may exist between the two regions, currently differences in extrinsic ethnic factors are playing a more important role in designing types of bridging study requirements in oncology.

20. Intrinsic Ethnic Factors –Patient Size, Lean Body Mass--may be corrected by use of body surface area dosing –Use of maximum tolerated doses (unique to oncology) could theoretically unmask genetic polymorphic differences –For intrinsic ethnic factors, oncology drugs may not pose any unique situations than other drugs

21. Extrinsic Differences in Oncology Oncology medical practices differ Patient and societal view on cancer Different cancer epidemiology Clinical trial design and execution Endpoints used for approval

22. Medical Practice Differences Who administers cancer care? –US and Western Europe- Medical Oncology as a academic discipline, conducting trials, primary care for cancer patients –Multidisciplinary care emphasis coordinating efforts of medical, radiation, surgical oncologists and oncology nursing –Other regions may have other providers as primary care for cancer patient

23. Medical Practice Differences Outpatient vs inpatient administration-- reflects schedules of agents Different chemotherapy doses--acceptance of toxicity by patients and physicians, differences in supportive care Different drugs and therapy duration --oral agents, prolonged adjuvant therapy

24. Patient Factors, Epidemiology regional differences in what information a patient has and patient’s participation in care patients not being told diagnosis regional differences in prevalence and etiology for various cancers

25. Clinical Trial Infrastructure Who conducts oncology drug trials in US? –Role of Medical Oncologist –Role of site data manager, research nurse –Continuing education, special protocol meetings

26. Clinical Trial Infrastructure Who conducts oncology trials in US? –National Cancer Institute –Cooperative Groups (SWOG, ECOG), established 30-40 years ago with significant expertise in trial design and execution –Industry trials--physicians employed on industry to design, execute, interpret trials

27. Need for controlled bridging clinical trials doubts about dose and schedule little or no experience with acceptance of controlled clinical trials carried out in foreign region Medical practice (e.g. use of concomitant medications and design and/ or conduct of clinical trials are different) drug class is not familiar one in the new region

28. Recent recommendations for Pre- IND and IND meetings Sponsor wished to do entire clinical development plan in different region –FDA - recommended that one trial could be conducted in foreign region and another trial be conducted in the US lack of familiarity with clinical trials in that region less well developed cancer treatment infrastructure etiology of that particular cancer differs in the region compared with the US

29. Recent Recommendations from Pre-IND and IND meetings Sponsor wanted to use all foreign clinical data especially PK data –FDA considered that (1) the ethnicity of the patients who participated in the PK study constituted a small percentage of the ethnicity of the US population (2) potentially some genetic differences in metabolism exist that a US PK study would be helpful and that the results of both studies would be in the label

30. Keys to a Successful Submission Plan ahead and schedule a pre-IND meeting with the FDA Discuss development strategy –planned regional development –consider potential intrinsic and extrinsic ethnic factors (especially clinical trial design, endpoints, and trial execution)