Elsevier

Contraception

Volume 72, Issue 6, December 2005, Pages 408-413
Contraception

Original research article
Will microbicide trials yield unbiased estimates of microbicide efficacy?

https://doi.org/10.1016/j.contraception.2005.06.063Get rights and content

Abstract

Objective

To evaluate the effect of adherence and condom use on apparent efficacy of microbicides.

Design

Hypothetical trial designs and scenarios.

Methods

Mathematical calculations of effectiveness.

Results

In a randomized trial of a candidate microbicide and a placebo, nonuse of the microbicide will result in underestimation of microbicide efficacy, with the magnitude of this difference between effectiveness and efficacy increasing directly with the level of microbicide nonuse. Adding condoms to the trial will not change this expected result as long as use of condoms and microbicide is independent, and microbicide use is the same in the trials with and without condoms. However, if microbicide use is lower in the trial with condoms, then effectiveness will be lower than in the trial without condoms, with the magnitude of the difference between effectiveness and efficacy being even greater. Moreover, condom and microbicide use may not be independent. If participants tend to use condoms rather than nothing, the trial result will more closely approximate microbicide efficacy. If, however, participants substitute condom use for microbicide use, then the expected estimate of effectiveness will less closely approximate microbicide efficacy and could be closer to or further away from the expected estimate of effectiveness than in the trial without condoms. In another trial design, where there is either simultaneous use of microbicide and condoms or no use of either (guaranteed when condoms are packaged with either a microbicidal or a placebo gel), expected effectiveness will fall short of microbicide efficacy. If nonuse is the same in a trial without condoms and a trial with microbicidally lubricated condoms, then the trial with condoms will produce an estimate of effectiveness that less closely approximates microbicide efficacy than would the trial without condoms. If there is less nonuse in the trial with condoms, then the expected estimate of effectiveness will more closely approximate microbicide efficacy and could be closer to or further away from the expected estimate of effectiveness than in the trial without condoms.

Conclusions

Nonuse of a microbicide and use of condoms may seriously impair our ability to identify an effective microbicide.

Introduction

The clearest scientific design for assessing the efficacy of a candidate microbicide in reducing acquisition of sexually transmitted infections — that is, how well it works under ideal conditions when used correctly at every coital act — would be random assignment to the microbicide or a placebo. Trial participants would use the assigned product at every act of intercourse for the intended duration of their participation in the trial, and access to other means of preventing infections, such as condoms, would be denied. If there were equal numbers of participants in each group and no early discontinuations from the trial, the relative risk (RR) would be estimated as the number of infections in the microbicide group divided by the number of infections in the placebo group. Efficacy would be estimated as 1−RR, the proportionate reduction in the risk of infection. For example, if 60 infections occurred in the microbicide group and 100 in the placebo group, then RR=0.60, and the estimated proportionate reduction in the risk of infection through the end of the follow-up period is 40%.

In reality, of course, such a trial cannot be implemented. Since all participants in a microbicide trial are likely to be at risk for sexually transmitted infections, withholding condoms, which are now the only proven method for preventing these infections, would be unethical; in fact, current standards require that condom use be strongly encouraged in both study arms. Moreover, we cannot force trial participants to follow instructions exactly; intercourse without the assigned microbicide or placebo will inevitably occur. Thus, in a typical trial [1], participants are randomly assigned to a microbicide-plus-condom arm or to a placebo-plus-condom arm, and some nonadherence with these assignments is expected.

In this paper, we explore the potential impact of nonadherence to microbicide use and different patterns of condom use on the interpretation of the results of such a study.

Section snippets

Effect of nonadherence

First, consider the effect of nonadherence in a situation in which condoms (and other preventive measures) are prohibited or simply not used. Let:

    N

    the number of participants in each arm (assumed to be equal in the microbicide and placebo groups)

    R

    infection rate in the absence of microbicide (or placebo) use

    em

    microbicide efficacy (the reduction in infection risk caused by the microbicide)

    ep

    placebo efficacy (the reduction in infection risk caused by the placebo)

    γ

    proportion of those who use

Effect of addition of condoms

We consider next the trial design in which participants in both the microbicide and the placebo arms are counseled to use condoms. Let:

    N

    the number of participants in each arm

    R

    infection rate in the absence of microbicide (or placebo) or condom use

    ec

    condom efficacy (regardless of whether microbicides are also used)

    em

    microbicide efficacy (regardless of whether condoms are also used)

    α

    proportion of those who use condoms in the placebo arm

    β

    proportion of those who use condoms in the microbicide arm

    γ

Conclusions

We have shown that both microbicide nonadherence and some patterns of condom use may seriously impair our ability to identify an effective microbicide. Under many plausible assumptions, effectiveness results of typical trials will substantially underestimate the efficacy of the candidate microbicide product being studied. Therefore, we could have a microbicide that is highly efficacious but not be able to tell that from our trials. The underestimation of effectiveness cannot be resolved merely

Acknowledgment

We are grateful to Elizabeth Raymond for helpful comments on a draft of this paper.

References (3)

There are more references available in the full text version of this article.

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