Evaluation System of Bridging Study in Taiwan

1. Evaluation System of Bridging Study in Taiwan Chien-Hua Wu Statistical Reviewer at CDE Oct. 2, 2002 The views expressed in this presentation are not necessary those of Center for Drug Evaluation in Taiwan

2. 77 Announcement • On July 7th 1993, 40 evaluable patients was required for registration in Taiwan • Receive the marketing exclusivity for 5 years

3. 1212 Announcement • Due to world trade barrier for 77 Announcement • Bridging study was proposed on Dec. 12th, 2000 • Transitional period from 2000 to 2003, sponsor have choice to conduct either 40-evalauble patients or bridging study • Bridging study will be completely required after Jan. 1, 2004 • But no marketing exclusivity for bridging study

4. BPA Sponsor CDE • Bridging data package • Summary of self-evaluation Checking list acceptance Internal review meeting Consultants Supplemental documents sponsor meeting Bridging Study notrequired Drug review committee Bridging Study required Evaluation Process

5. Does the drug meet DOH announcements for waiving a bridging study and the requirements of submitting ethnic insensitivity data? Yes No Submit relevant documents according to DOH announcements and request for waivingbridging studies Does the submitted preclinical and clinical data package meet the regulatory requirements? Yes No Does the package include clinical data of Asian populations*? Submit additional relevant information Accessing the Requirement of a Bridging Study

6. Does the package include clinical data of Asian populations*? Yes No Is the medicine sensitive to both intrinsic and extrinsic factors? Are the clinical differences in efficacy and safety significant? Have any early phase orglobal clinical trials that meet the DOH requirements of bridging studies been conducted in Taiwan? Yes No Yes Bridging study required No bridging study required Is the resultacceptableas a bridging study? Yes No No Is it reasonable to extrapolate from foreign clinical data that the medicine is insensitive to both intrinsic and extrinsic factors in Asians and that its clinical differences in efficacy and safety are acceptable? (See ICH E5 guidelines) No bridging study required**

7. Is it reasonable to extrapolate from foreign clinical data that the medicine is insensitive to both intrinsic and extrinsic factors in Asians and that its clinical differences in efficacy and safety are acceptable? Yes No No bridging study required Is it reasonable to extrapolate from foreign clinical data that the concentration (dose)-response relationship is similar between foreign and Asian populations ? No Yes No bridging study required Are PK and/or PD data of Asian populations available for dosage adjustment or efficacy/safety predication? Yes No Available data will be used directly to estimatethe proper dosage for Chinese populations. Bridging studyrequired

8. CDE Bridging Study Evaluation Items (1) • Linearity PK profile • Steep PD profile • Narrow therapeutic dose range • Highly metabolized through a single pathway, potential drug-drug interaction • Genetic polymorphism (e.g. CYP2D6, CYP2C19, etc.) • Administration as a prodrug. • High inter-subject variation in biovailability

9. CDE Bridging Study Evaluation Items (2) 8. Low bioavailability, susceptible dietary absorption effect 9. High likelihood of use in a setting of multiple co-medications 10. High likelihood for inappropriate use 11. Different indications and/or epidemiology 12. Other important factors of ethnic sensitivity (e.g. medical practice)

10. I 18(69%) • BS waived (29)(73%) 11(79%) II Results of BS Evaluation from Jan. 1, 2001 to July 31, 2002 I 26 • Case evaluated (40) 14 II I: With Asian data; II: Without Asian data

12. Statistical Approaches of Bridging Study Chien-Hua Wu Assistant Professor National Taipei University Oct. 2, 2002

13. Outline • Weakness of Evaluation System in CDE • Strategy for Bridging Study • Statistical Approaches to Detect the Ethnic Sensitivity • Dose Adjustment • Sample Size Reduction

14. Bridging Study Evaluation in Taiwan (1) • “Assessment of the extrapolation of foreign clinical data for registration purposes” published by Lin et. al. in Drug Information Journal (2002)

15. Bridging Study Evaluation in Taiwan (2)

16. Bridging Study Evaluation in Taiwan (3) • 7 of 20 cases considered ethnic difference between original country and Taiwan in 2001 • 5 of 7 cases were related to safety issues • 2 cases due to lack of sufficient data to support efficacy in original country • Conclusion: it seems like using PK/PD profile may not be able to tell the ethnic sensitivity in some circumstance

17. CDE Bridging Study Evaluation Items (1) • Linearity PK profile • Steep PD profile • Narrow therapeutic dose range • Highly metabolized through a single pathway, potential drug-drug interaction • High inter-subject variation in biovailability

18. CDE Bridging Study Evaluation Items (2) 8. Low bioavailability, susceptible dietary absorption effect 9. High likelihood of use in a setting of multiple co-medications 10. High likelihood for inappropriate use 11. Different indications and/or epidemiology 12. Other important factors of ethnic sensitivity (e.g. medical practice)

19. Weakness of Evaluation System in CDE • If 1st item fails but not for the rest of it, can we conclude that there is an ethnic difference??? • PK/PD profile may not be able to judge the ethnic difference if few evaluated items do not fit well • According ICH E5, the acceptability of foreign data should be evaluated based on similarity of dose response, efficacy and safety between foreign and new region

20. Strategy for Bridging Study Step 1: Detect ethnic sensitivity by looking at the PK/PD evaluation items and using statistical approaches Step 2: No need to conduct a bridging trial if there is no sufficient evidence to tell the ethnic difference between original region and local region Step 3: Adjust dose if ethnic difference does exist Step 4: Conduct a bridging trial to show efficacy in the local region using new dose

21. Statistical Approaches to Detect Ethnic Sensitivity • Check treatment by region interaction • Reproducibility and generalizability probability (Shao and Chow (2002)) • Conduct a non-inferiority or equivalent trial • Conduct a local trial for 40 evaluable patients (Baysian approach) • Conduct a multinational trial

22. 1st Statistical Approach: Treatment by Region Interaction • H0: No Interaction • Fail to reject the interaction does not mean there are no differences between two regions. • HA: Treatment effect is different between two regions • Magnitude of difference is of any clinical relevance? Sufficient sample size? • See Comments from ICSA (2002)

23. 2nd Statistical Approach: Reproducibility Probability • “Reproducibility probability in clinical trials” by Shao J. and Chow S.C. (2002)

24. Reproducibility Probability • H0: 1-2=0 • Power of test statistic: function of =(1-2)/(1/n1+1/n2)(1/2) • Replace parameter  by its estimate T(x) • Reproducibility probability: estimated power

25. Evaluation Process for Bridging Study Step 1: If the reproducibility probability fails to meet regulatory requirement of reproducibility, say >80%, then bridging study is not needed. Step 2: Measure the signal-to-noise for population difference Step 3: Compute the generalizability probability

26. Generalizability Probability • When the study drug product is applied to a similar but different patient population in the new region, it is expected that the mean and variance of response will be different. • Population mean difference change to 1- 2+ • Population variance change to C2 2 • Measure of change in signal-to-noise for population difference: ={1+/(1- 2)}/C • Generalizability probability: replace  in power by T(x)

27. Recommendation Based on Generalizability Probability

28. Example • A schizophrenia study • 104 patients: 56 patients using new treatment and 48 patients for standard therapy • T=-2.88 and p-value=0.004 • Reproducibility probability=0.814 > 80%, thus a bridging trial is required • =0.9 and desired power=80%, then n=118

29. Generalizability Probability and Sample Size Requirement

30. Comments on Reproducibility and Generalizability Probability • Regulatory requirement of reproducibility and generalizability probability are subjective. • Need to know the population mean and variance for new region • Sample size of the bridging trial is larger than that of original trial if <1 • Fail to address the similarity between the new and original regions required by ICH E5 (Liu, et. at. 2002)

31. 3rd Statistical Approach: Non-inferiority or Equivalent Trial (1) • “Sample size requirement for evaluation of bridging evidence” by Liu, et. al. (2002)

32. Non-inferiority or Equivalent Trial (2) • Definition of Similarity: no substantial difference (equivalence) • Purpose: issue on sample size in planning bridging study and evaluation of similarity • Hierarchical model: trials have been conducted for the approval of the drug product in original region and a bridging trial is being conducted in a new region for registration after the approval in the original region

33. Example

34. Non-inferiority or Equivalent Trial (4) • What is the definition of similarity stated in ICH E5? • How to choose the margin? • Comments in ICSA (2002) • Controversial selection of equivalence limit (Temple and Ellenberg (2000), Ellenber and Temple (2000), Fisher et al. (2001), Hung (2001), Snappin (2001), Tsong, et. al. (2001), Wittes (2001)

35. 4th Statistical Approach: Baysian Approach (1) • Proposed by Shih in 2001 in Controlled Clinical Trials

36. Baysian Approach (2) • k study centers • wi stands for test statistic i=1,…,k • wi approximately follows N(μ,1) for large sample size • Predictive probability density function can be obtained with vague prior for μ • New trial is consistent with reference studies if p(v|w)>min{p(wi|W), i=1,…,k}

37. Comments on Baysian Approach (3) • Correction is needed for small sample in a particular center • More reference studies, greater chance to be consistent

38. 5th Statistical Approach: Multinational Trial (1) Spilker in 1991 outlined the motivations of conducting a multinational trial • Gaining more rapid patient enrollment • Expediting the development of a new medicine • Conducting a trial that otherwise might be impossible • Gaining experience and being able to compare patients of different nationalities Takeuchi (2002) also raise the issues of the importance in global drug development

39. Multinational Trial (2) • H0: 1-2=0 • Ti represents for the test statistic where i=1,…,r • Tl represents for the test statistic for local region • Goal: check Tl to see if it is an outlier (not similar). • If it exists, then the ethnic difference is appeared.

41. If Ethnic Difference Exists • A clinical trial is essentially required to prove the effectiveness of study drug in the local region (adjust the dose if needed) • ICH E5: avoid unnecessary repetition of costly and time-consuming clinical trials (sample size reduction)

42. Asian Caucasian AUC or Cmax Dose Dose Adjustment

43. Sample Size Reduction • “Sample Size Reduction in Bridging Study Using Regression Estimator” by Wu et. al. (2001)

44. Sample Size Reduction (2)

45. Sample Size Reduction (3)

46. Sample Size Reduction (4) • Means, S.D. and slope need to know from previous study in order to calculate the sample size • Interim analysis may be needed to re-estimate means, S.D. and slope

47. Example • Acute Asthma study • Primary endpoint: FEV1 • Compare study drug and placebo • Mean difference: 0.10 L • S.D.=0.31

49. Conclusions • Under process to develop the statistical approaches in CDE to detect the ethnic sensitivity other than assessing PK/PD profile • Dose adjustment may be needed if ethnic difference does exist • Reducing sample size is considered if a bridging trial is needed