# Presentation: 221891

## Some Design Issues in 

**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**

## R

-                             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

## 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**

## R

-                             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

-                             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**

## 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 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**

## 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%

- 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
-                                                        **.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%

- 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

- NCCTG Trial

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

## SURGICAL ADJUVANT THERAPY

- OF COLORECTAL CANCER

- NCCTG Trial

- Cancer Intergroup Trial

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

## SURGICAL ADJUVANT THERAPY

- OF COLORECTAL CANCER

- 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=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

- 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=91
- Levamisole  n=85
- Control        n=86

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

## 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%

- 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

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