Methodological Challenges in Biomedical HIV Prevention Trials (2008) / Chapter Skim
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2 Basic Design Features: Size, Duration, and Type of Trials, and Choice of Control Group
2 Basic Design Features: Size, Duration, and Type of Trials, and Choice of Control Group
Pages 69-87
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From page 69... ...
A number of factors influence these choices, including the anticipated HIV incidence rate for the control group(s) , the rates of product nonadherence and discontinuation owing to pregnancy and other reasons, and the rates of loss to follow-up, as well as the uncertainty surrounding these assumed rates and the resulting effect on the power of the trial.
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From page 70... ...
Table 2-1 illustrates six designs with different combinations of periods for accruing participants and trial durations that will give the desired power. Phase 3 effectiveness trials typically last for 2 to 4 years. The table assumes that time until infection follows an exponential distribution, that an equal number of participants are randomized to each group, that all participants are followed for the duration of the trial, and that there are no dropouts.
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From page 71... ...
The above designs suggest that subjects would be enrolled and develop HIV infection at given rates, and therefore that the trials would be completed in the indicated durations of time. However, actual enrollment rates and HIV incidence rates may vary from these assumptions.
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From page 72... ...
1 0.9 0.8 0.7 0.6 Power 0.5 0.4 0.3 0.2 0.1 0.4 0.45 0.5 0.55 0.6 0.65 0.7 0.75 0.8 Relative Risk Figure 2-1 Power of design 5 as a function of actual product efficacy, as measured by the RR between intervention and control groups. 2-1 N OTE: The table assumes a control group incidence rate of 3 percent and a type I error of 5 percent.
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From page 73... ...
If investigators overestimate incidence rates when designing a trial, the power to detect an intervention effect could be low. Table 2-2 shows how the power of a study changes as a function of the HIV incidence rate in the control group, assuming a 50 percent reduction in risk in the intervention arm.
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From page 74... ...
needed to complete a trial with satisfactory power may not be feasible, or the results might be less relevant because of advances in the field. Thus, investigators need to monitor results during a trial to assess whether actual HIV incidence rates are close enough to the assumed rates that the trial remains feasible.
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From page 75... ...
Although an events-driven approach can compensate for inaccurate assumptions about participant accrual or HIV incidence rates, investigators and sponsors must consider the cost of such a trial, the sponsor's willingness to provide longer-term support, and the relevance of the trial result if the time to completion is substantially longer than originally anticipated.
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From page 76... ...
Efficacy trials usually overestimate the real-world effectiveness of an intervention for the outcome in question, and are often undertaken as a "proof of concept" to determine if the intervention, if taken as designed, can lower the risk of becoming infected from an exposure to HIV. Thus, since efficacy does not necessarily imply effectiveness in a real-world setting, a successful efficacy trial would commonly be followed by an effectiveness trial (see, for example, Fleming and Richardson, 2004)
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From page 77... ...
Because no one has yet identified a biological or clinical marker that can reliably serve as a surrogate endpoint for HIV infection in efficacy trials of biomedical interventions, they must rely on HIV infection as the outcome just as effectiveness trials do. This means that efficacy and effectiveness trials will have the same basic design, differing only in the type of study population, duration, and sample size, and perhaps in the steps study staff take to promote product adherence and counsel participants to avoid risky behavior.
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From page 78... ...
Investigators would therefore normally expect the RR of a particular intervention to be as strong or stronger in an efficacy trial than in an effectiveness trial. However, it is not clear which design would have a larger HIV incidence rate in the control group.
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From page 79... ...
Moreover, setting up and initiating a trial entails considerable costs and work, and large efficacy trials with short follow-up may cost more than smaller effectiveness trials with a longer follow-up, assuming an equal number of person-years of observation. Thus the value of short-term efficacy trials in the case of HIV prevention is sometimes unclear, given the substantial resource commitment their large sample size would require, and the ethical concerns about undertaking a placebo-controlled effectiveness trial if an intervention turns out to be promising in an efficacy trial.
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From page 80... ...
In considering the implementation of such a design, cost and practicality issues would need to be considered. • Phase 3 trial with stopping rules for futility: Similarly, a longerterm effectiveness trial can include an interim analysis that compares the intervention and control groups with respect to cumulative HIV incidence at some early time point, such as 6 months.
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From page 81... ...
for assessing the efficacy of biomedical HIV prevention products is a challenging, yet critical scientific goal that requires further research. At present, using an HIV infection endpoint, efficacy and effectiveness trials differ primarily in duration, anticipated HIV incidence rates in the control group, and the relative risks of intervention versus control.
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From page 82... ...
Although this also would apply to many HIV prevention trials of biomedical interventions, there are circumstances where the use of a blinded control group can be disadvantageous in shedding light on the effectiveness of the intervention if used in the community. The limitations arise from the possibility that people's risk-taking behavior will depend on their knowledge of the intervention they are (or are not)
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From page 83... ...
on the completeness of study visits and retention and comparable counseling. However, numerous unblinded HIV prevention trials have produced excellent and nondifferential retention rates (Guay et al., 1999; Thior et al., 2006)
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From page 84... ...
However, another view is that the trial results reflect what might happen if the diaphragm were introduced into the community: a possible protective effect per sexual act might not translate into a reduced overall risk of HIV infection because of lower condom use. The next section considers the potential advantages and limitations of three design strategies in the case of a microbicide gel trial.
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From page 85... ...
If the P and C groups had similar HIV incidence rates and behaviors during follow-up, future studies in the same population may not require both control groups. A comparison of the relative risks of M:P and M:C would potentially reflect the efficacy versus effectiveness of the intervention.
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From page 86... ...
2006. Risk compensa tion: The Achilles' heel of innovations in HIV prevention?
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From page 87... ...
1998. The role of needle exchange programs in HIV prevention.
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