# Presentation: 710238

## Design of Phase III Microbicide Trials: Choice of Control GroupAugust 20, 2003

- Rosalie Dominik, DrPH
- Director of Biostatistics
- Institute for Family Health
- Family Health International

## n-9 HIV/STI Research in Cameroon

- Observational study of n-9 suppositories
- Zekeng et. al., *AIDS 1993*; 7(5): 725-731.
- Blinded randomized controlled trial (RCT) of n-9 film versus placebo film control
- Roddy et al., *N Engl J Med 1998*; 339:504-510.
- Unblinded RCT of n-9 gel versus condom-only control
- Roddy et al., *JAMA 2002*; 287:1117-1122.

## Potential Labeling?

**Use of *****MICROBICIDE***** *****Gel *****reduces a woman’s risk of HIV infection during vaginal intercourse.**
- To **best** protect against the risk of HIV infection during vaginal intercourse, **use a condom during every act of intercourse.**
- Use of ***MICROBICIDE***** *****Gel ***provides additional or back-up protection against HIV infection.

## Primary Question of Interest

- Does use of the microbicide formulation reduce the risk of HIV acquisition compared to non-use, _holding all other risk factors constant_
- Gold standard : Blinded RCT of microbicide gel versus a truly inactive placebo
- Use ‘best available’ placebo

## Microbicide vs Condom-Only 

- Those assigned to condom-only know they don’t have the potential protection that the microbicide might provide
- Motivation to use condoms or to avoid risky acts would not be the same in the two groups
- Choices to be made differ, and so behaviors will likely differ.

_**Condom-Only Arm:**_
-  Condoms (As counseled)
-  Nothing

_**Microbicide Arm:**_
-  Gel + Condoms (As counseled)
-  Gel Alone
-  Condoms Alone
-  Nothing

## Example 1: Increased Chance of Missing a Protective Effect 

- Assume condoms reduce risk by 95% when used
- Assume that microbicide _reduces HIV risk by 50%_compared to true placebo but that a condom-only control arm will be included
- Design study to have **~90%**  power to detect a 50% reduction (alpha=.05, 2-sided)
- If condom use is truly 65% in microbicide arm and 75% in the condom-only arm, study will have **~50%** power  to conclude microbicide provides protection

## Example 1 (continued)

- Assume that _microbicide reduces HIV risk by 50%_ compared to true placebo but that a condom-only control arm will be included
- If condom use is truly 80% in microbicide arm and 90% in condom-only arm, study will have **~15%**** ****power** to find protective effect
- and, **~** **20%** chance of seeing more HIV infections in the microbicide arm than in the condom only arm!

## Example 1: Conclusion 

- _Concern_: Requiring a study that shows significantly fewer infections in a microbicide arm vs condom-only arm could lead to failure to promptly identify a product that protects against HIV.

## Example 2: Increased Chance of False Positive Finding

- Now assume that microbicide _truly has no effect_ on HIV risk compared to a true placebo but that a condom-only control arm will be included
- If condom use is truly 90% in microbicide arm and 80% in condom-only arm,  **~65%** chance of falsely concluding that the microbicide provides a protective effect (as compared to the 2.5% chance of a type I error in this direction when behaviors are balanced)

## Placebo vs Condom Only 

- May provide evidence that ‘placebo’ actually protects against HIV
- If we assume that condom only arm will use condoms at least as much as the placebo arm
**and** we see significantly fewer HIV infections in the placebo arm.

## Conclusion

- What we most want to know is ‘*does use of the microbicide reduce the risk of HIV acquisition?*’.
- A blinded two-arm trial of a microbicide versus the best available placebo can provide sufficient evidence to support a claim that use of a new microbicide can reduce the risk of HIV acquisition.