1. Some Design Issues in Microbicide Trials August 20, 2003 Thomas R. Fleming, Ph.D. Professor and Chair of Biostatistics University of Washington FDA Antiviral Drugs Advisory Committee

2. Selected Design Issues Blinding & the Choice of Controls Required Strength of Evidence Phase 2 vs Phase 2B vs Phase 3

3. Selected Design Issues Blinding & the Choice of Controls Required Strength of Evidence Phase 2 vs Phase 2B vs Phase 3

4. Blinding ~ Bias can occur in certain trials if the treatment the patient is receiving is known to: - the evaluators eg., subjective endpoints - the caregivers eg., hospitalization - the patient/participant eg., pain, efficacy vs effectiveness

5. Potential Mechanisms of Action of a Microbicide Intervention ~ Antimicrobial effects ~ Physical Barrier effects ~ Effects on ~ Lubrication effects Risk Behavior ~ Other effects Design to Address Multiple Mechanisms Active Microbicide Placebo Control Unblinded Control R

6. Should one blind? Some factors to consider(Pocock) Practicality Treatments need to be of a similar nature cannot induce obvious side effects Ethics Blinding should not result in harm/risk Avoidance of Bias Is the placebo truly inert? How serious is the risk of bias without blinding? … subjective vs objective endpoints Importance of understanding Efficacy vs. Effectiveness

7. Potential Mechanisms of Action of a Microbicide Intervention ~ Antimicrobial effects ~ Physical Barrier effects ~ Effects on ~ Lubrication effects Risk Behavior ~ Other effects Design to Address Multiple Mechanisms Active Microbicide Placebo Control Unblinded Control R

8. Potential Mechanisms of Action of a Microbicide Intervention ~ Antimicrobial effects ~ Physical Barrier effects ~ Effects on ~ Lubrication effects Risk Behavior ~ Other effects Design to Address Multiple Mechanisms Active Microbicide Placebo Control Unblinded Control R

9. Antimicrobial effects vs. Physical Barrier, Lubrication, & Other effects Annual Risk in: Active / Placebo / Unbl Control 2% / 2% / 3% 3% / 4.5% / 3% PLA carries full effect Effectiveness << Efficacy ~ Use PLA in clinical practice ~ Avoidable by advocacy for adherence to condoms 2% / 2.5% / 3% 2.4% / 3.6% / 3% PLA carries some effect MIC very effective ~ Use MIC in clinical practice (yet Effectiveness < Efficacy) 3% / 3% / 3% 2% / 3% / 3% No effect MIC very effective

10. Selected Design Issues Blinding & the Choice of Controls Required Strength of Evidence Phase 2 vs Phase 2B vs Phase 3

11. Strength of Evidence Guidelines for Regulatory Approval Two Adequate and Well Controlled Trials Statistical significance (for each trial) based on strength of evidence corresponding to a one-sided p  0.025 A Single Pivotal Trial (Resource intensive trials, with major clinical endpoints) Strength of evidence (SOE) that would be “robust and compelling” Proposed Guideline: SOE corresponding to a one- sided p  0.0025-0.005

12. Illustration: HPTN 035 Design Four arms: –BufferGel –PRO 2000/5 Gel (P) –Placebo control –Unblinded (condom only) control 33% effectiveness 24 months follow-up

13. Sample Size (for pairwise comparisons) Scenario #1: Statistical significance based on strength of evidence corresponding to a one-sided p  0.025 256 endpoints (4025 participants) required for 90% power to detect 33% effectiveness Scenario #2: Statistical significance based on strength of evidence corresponding to a one-sided p  0.0025 405 endpoints (6125 participants) required for 90% power to detect 33% effectiveness

14. Illustration: HPTN 035 Trial Illustration: Percent Reduction in HIV Risk Scenario #1: One-sided 0.025; 256 endpoints.025.0025.0005 0% 17.5% 21.5% 24% 27% 29.5% 33%.025.0025.0005 Scenario #2: One-sided 0.0025; 405 endpoints

15. Illustration: Targeted Strength of Evidence Setting: Dual Control Arms –Microbicide Regimen –Placebo control –Unblinded (condom only) control Illustration of Target Strength of Evidence –one-sided p  0.025 for both comparisons and –one-sided p  0.0025 for ≥ 1 comparison

16. Antimicrobial effects vs. Physical Barrier, Lubrication, & Other effects Annual Risk in: Active / Placebo / Unbl Control 2% / 2% / 3% ( Neg ) 3% / 4.5% / 3% ( Neg ) PLA carries full effect Effectiveness << Efficacy ~ Use PLA in clinical practice ~ Avoidable by advocacy for adherence to condoms 2% / 2.5% / 3% ( Pos ) 2.4% / 3.6% / 3% ( Pos ) PLA carries some effect MIC very effective ~ Use MIC in clinical practice (yet Effectiveness < Efficacy) 3% / 3% / 3% ( Neg ) 2% / 3% / 3% ( Pos ) No effect MIC very effective

17. Selected Design Issues Blinding & the Choice of Controls Required Strength of Evidence Phase 2 vs Phase 2B vs Phase 3

18. Development Strategies After Phase 1: What should be the next step? ~ Phase 2 ~ Phase 2B (Intermediate Trial) ~ Phase 3

19. Why Conduct a Phase 2 Trial? Obtain improved insights: Safety and biological activity Refinements in dose/schedule Improving adherence to interventions Improving quality of trial conduct - Timely accrual - High quality study implementation - High quality data, including retention

20. Development Strategies After Phase 1: What should be the next step? ~ Phase 2 ~ Phase 2B (Intermediate Trial) ~ Phase 3

21. The Randomized Phase 2B “Intermediate Trial” Illustration: HPTN 035 Intermediate Trial Primary endpoint: HIV-1 Infection Rate 100 endpoints (per pairwise comparison) Notation:  : True % Reduction in risk of HIV-1 infection  : Trial estimate of  ^

22. Intermediate Trial Design Phase 3 Trial Design -33% 0% 33% 44% 67% Further Studies Positive -17% 0% 17% 33% 50% Positive  ^  ^

23. Illustration: HPTN 035 Trial Illustration: Percent Reduction in HIV Risk Scenario #1: One-sided 0.025; 256 endpoints.025.0025.0005 0% 17.5% 21.5% 24% 27% 29.5% 33%.025.0025.0005 Scenario #2: One-sided 0.0025; 405 endpoints

24. Intermediate Trial Design Phase 3 Trial Design -33% 0% 33% 44% 67% Further Studies Positive -17% 0% 17% 33% 50% Positive  ^  ^

25. An Illustration of the Use of an Intermediate Trial Before a Definitive Trial Surgical Adjuvant Therapy of Colorectal Cancer 5-FU + Levamisole Levamisole Control R

26. SURGICAL ADJUVANT THERAPY OF COLORECTAL CANCER Surviving, % 0 1 2 3 4 5 6 100 - 80 - 60 - 40 - 20 - 0 Years from randomization NCCTG Trial 5-FU+LEV n=91 Levamisole n=85 Control n=86

27. SURGICAL ADJUVANT THERAPY OF COLORECTAL CANCER Surviving, % 0 1 2 3 4 5 6 100 - 80 - 60 - 40 - 20 - 0 Years from randomization NCCTG TrialCancer Intergroup Trial 5-FU+LEV n=91 Levamisole n=85 Control n=86

28. SURGICAL ADJUVANT THERAPY OF COLORECTAL CANCER Surviving, % 0 1 2 3 4 5 6 100 - 80 - 60 - 40 - 20 - 0 Years from randomization NCCTG TrialCancer Intergroup Trial 0 1 2 3 4 5 6 7 8 9 100 - 80 - 60 - 40 - 20 - 0 Years from randomization 5-FU+LEV n=91 Levamisole n=85 Control n=86 5-FU+LEV n=304 Levamisole n=310 Control n=315

29. Important Observations Confirmatory trials of promising results from Intermediate Trials can be performed successfully Confirmatory trials - can reveal true positives (eg, 5-FU+Lev) - can reveal true negatives (eg, Levamisole)

30. SURGICAL ADJUVANT THERAPY OF COLORECTAL CANCER Surviving, % 0 1 2 3 4 5 6 100 - 80 - 60 - 40 - 20 - 0 Years from randomization NCCTG TrialCancer Intergroup Trial 0 1 2 3 4 5 6 7 8 9 100 - 80 - 60 - 40 - 20 - 0 Years from randomization 5-FU+LEV n=91 Levamisole n=85 Control n=86 5-FU+LEV n=304 Levamisole n=310 Control n=315

31. R AZTLabor/Delivery/1 wk to I NVPSingle doses to M/I Illustration of an Intermediate Trial with “Compelling” Results: HIVNET 012 8/99 ResultsLancet 1999; 354: 795-802 MCT of HIV N 6-8 wks 14-16 wks AZT 30259 (21.3%) 65 (25.1%) NVP 30735 (11.9%) 37 (13.1%) 1p = 0.0014 1p = 0.0003

32. Intermediate Trial Design Phase 3 Trial Design -33% 0% 33% 44% 67% Further Studies Positive -17% 0% 17% 33% 50% Positive  ^  ^

33. Conclusions: Selected Design Issues Blinding & the Choice of Controls Required Strength of Evidence Phase 2 vs Phase 2B vs Phase 3