some design issues in microbicide trials august 20, 2003 thomas r. fleming, ph.d. professor and...

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

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

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

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


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

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


.025 .0025 .0005

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

.025 .0025 .0005




-33% 0% 33% 44% 67%


-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


Surv

i vin

g, %

0 1 2 3 4 5 6

100 -

80 -

60 -

40 -

20 -

0


NCCTG Trial Cancer Intergroup Trial



Surv

i vin

g, %

0 1 2 3 4 5 6

100 -

80 -

60 -

40 -

20 -

0



0 1 2 3 4 5 6 7 8 9

100 -

80 -

60 -

40 -

20 -

0




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)


Surv

i vin

g, %

0 1 2 3 4 5 6

100 -

80 -

60 -

40 -

20 -

0



0 1 2 3 4 5 6 7 8 9

100 -

80 -

60 -

40 -

20 -

0




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



-33% 0% 33% 44% 67%


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

Conclusions: Selected Design Issues




some design issues in microbicide trials august 20, 2003 thomas r. fleming, ph.d. professor and...

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antimicrobial effects

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