Multi-Regional Studies and Bridging Studies. Simon Day, PhD Johns Hopkins University

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2 Multi-Regional Studies and Bridging Studies Simon Day, PhD Johns Hopkins University

3 Rationale New/different region New age group Changes in vaccine manufacture, storage, etc. Others? 3

4 ICH E5 Adopted 1998 Evaluate the impact of ethnic factors on efficacy and safety Minimize duplication of clinical data Context of extrapolation 4

5 ICH E5 The key terms Bridging Extrapolation Generalization 5

6 ICH E5 Ethnic differences may affect safety, efficacy, dosage, dose regimen Characterize medicines as ethnically sensitive or ethnically insensitive In contrast to intrinsic factors and extrinsic factors 6

7 Ethnic Sensitivity Pharmacokinetics Pharmacodynamics Therapeutic range Metabolism Bioavailability Potential for interactions Genetic polymorphisms Intersubject variability Systemic mode of action Potential for inappropriate use 7

8 Intrinsic and Extrinsic Factors Classification Factor Description Intrinsic Genetic Gender, race Polymorphisms Physiology and pathology Age Liver, kidney, CV Extrinsic Environmental Climate, pollution Cultural Socioeconomic factors Educational status Medical practice Diagnostic and treatment approach 8

9 Bridging Studies To avoid replication of large, expensive trials To avoid replication of whole development programmes To fill in the gaps To show relevance (i.e., link or build a bridge) between completed studies and local (regional) factors 9

10 When Are Bridging Studies Needed?: An Overview Study medication bridging Insensitive to ethnic factors Bridging Sensitive to ethnic factors Region Similar Dissimilar Medical practice Drug class Clinical experience Similar Familiar: need only pharmacodynamics Sufficient Different: need controlled trials Unfamiliar: need controlled trials Insufficient: need controlled trials 10

11 When Do You Need What? Original Clinical Data Package Meets Reg. Requirements Extrapolation Appropriate Further Studies ne Acceptable (New) Package 11

12 Original Clinical Data Package When Do You Need What? Meets Reg. Requirements 12

13 When Do You Need What? Meets Reg. Requirements Extrapolation Appropriate Original Clinical Data Package 13

14 When Do You Need What? Meets Reg. Requirements Extrapolation Appropriate Further Studies ne Bridging Studies Original Clinical Data Package Acceptable (New) Package 14

15 Original Clinical Data Package When Do You Need What? Meets Reg. Requirements 15

16 When Do You Need What? Meets Reg. Requirements Extrapolation Appropriate Original Clinical Data Package 16

17 When Do You Need What? Meets Reg. Requirements Extrapolation Appropriate Further Studies Original Clinical Data Package Clinical Studies Acceptable (New) Package 17

18 When Do You Need What? Meets Reg. Requirements Extrapolation Appropriate Further Studies Original Clinical Data Package Clinical Studies Acceptable (New) Package Bridging Studies 18

19 When Do You Need What? Original Clinical Data Package Meets Reg. Requirements Extrapolation Appropriate Further Studies ne Acceptable (New) Package Bridging Clinical 19

20 International Nature of Endpoints Thresholds for seeking medical attention Thresholds for treating (or not) the disease Varying health care systems Payment Primary/referral 20

21 Cultural Nature of Endpoints Example Have you ever thought about committing suicide? Example Resource utilisation Cost effectiveness studies 21

22 Post-Hoc Arguments: For and Against Justifications are always easy but usually futile We do multi-centre (-country; -region) trials because... It increases recruitment rate It (Informally) gives wider applicability Wider applicability is lost if opportunity is not taken 22

23 What Population (Indication)... to what population will the results apply? Consider before the trial to what population (not sample) you want the results to apply Consider after the trial to what population the results might be expected to apply 23

24 In the Next Lecture We ll Look at... Interim monitoring Some history Data monitoring committees Individual responsibilities Other trial committees 24