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 evaluatorseg., subjective endpoints

- the caregiverseg., hospitalization

- the patient/participanteg., 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 MicrobicidePlacebo ControlUnblinded 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 MicrobicidePlacebo ControlUnblinded 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 MicrobicidePlacebo ControlUnblinded 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 ~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 Guidelinesfor 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

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 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

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

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

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 ~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%

FurtherStudies 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

.025 .0025 .0005

0% 17.5% 21.5% 24% 27% 29.5% 33%

.025 .0025 .0005

Scenario #2: One-sided 0.0025; 405 endpoints

Intermediate Trial Design

Phase 3 Trial Design

-33% 0% 33% 44% 67%

FurtherStudies Positive

-17% 0% 17% 33% 50%Positive

An Illustration of the Useof an Intermediate TrialBefore a Definitive Trial

Surgical Adjuvant Therapyof Colorectal Cancer

5-FU + LevamisoleLevamisoleControl

R

SURGICAL ADJUVANT THERAPYOF COLORECTAL CANCER

Surv

i vin

g, %

0 1 2 3 4 5 6

100 -

80 -

60 -

40 -

20 -

0

Years from randomization

NCCTG Trial

5-FU+LEV n=91Levamisole n=85Control n=86

SURGICAL ADJUVANT THERAPYOF COLORECTAL CANCER

Surv

i vin

g, %

0 1 2 3 4 5 6

100 -

80 -

60 -

40 -

20 -

0

Years from randomization

NCCTG Trial Cancer Intergroup Trial

5-FU+LEV n=91Levamisole n=85Control n=86

SURGICAL ADJUVANT THERAPYOF COLORECTAL CANCER

Surv

i vin

g, %

0 1 2 3 4 5 6

100 -

80 -

60 -

40 -

20 -

0

Years from randomization

NCCTG Trial Cancer 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=91Levamisole n=85Control n=86

5-FU+LEV n=304Levamisole n=310Control 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 THERAPYOF COLORECTAL CANCER

Surv

i vin

g, %

0 1 2 3 4 5 6

100 -

80 -

60 -

40 -

20 -

0

Years from randomization

NCCTG Trial Cancer 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=91Levamisole n=85Control n=86

5-FU+LEV n=304Levamisole n=310Control n=315

RAZT Labor/Delivery/1 wk to I

NVP Single doses to M/I

Illustration of an Intermediate Trial with “Compelling” Results: HIVNET 012

• 8/99 Results Lancet 1999; 354: 795-802

MCT of HIV N 6-8 wks 14-16 wks

AZT 302 59 (21.3%) 65 (25.1%)

NVP 307 35 (11.9%) 37 (13.1%)

1p = 0.0014 1p = 0.0003

Intermediate Trial Design

Phase 3 Trial Design

-33% 0% 33% 44% 67%

FurtherStudies 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