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

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

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

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

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

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

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

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

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

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

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  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 

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

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

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

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  for both comparisons and –one-sided p  for ≥ 1 comparison

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

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

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

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

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

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  ^

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

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

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

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

SURGICAL ADJUVANT THERAPY OF COLORECTAL CANCER Surviving, % Years from randomization NCCTG Trial 5-FU+LEV n=91 Levamisole n=85 Control n=86

SURGICAL ADJUVANT THERAPY OF COLORECTAL CANCER Surviving, % Years from randomization NCCTG TrialCancer Intergroup Trial 5-FU+LEV n=91 Levamisole n=85 Control n=86

SURGICAL ADJUVANT THERAPY OF COLORECTAL CANCER Surviving, % Years from randomization NCCTG TrialCancer Intergroup Trial 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

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)

SURGICAL ADJUVANT THERAPY OF COLORECTAL CANCER Surviving, % Years from randomization NCCTG TrialCancer Intergroup Trial 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

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: MCT of HIV N 6-8 wks wks AZT (21.3%) 65 (25.1%) NVP (11.9%) 37 (13.1%) 1p = p =

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

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