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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
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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: • D : True % Reduction in risk of HIV-1 infection • D : Trial estimate of D
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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
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