Methodological Challenges in Biomedical HIV Prevention Trials (2008) / Chapter Skim
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9 Interim Monitoring and Analysis of Results
9 Interim Monitoring and Analysis of Results
Pages 186-203
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From page 186... ...
This chapter explores the challenges entailed in performing interim monitoring and analyzing the results of HIV prevention trials. Ensuring Effective INTERIM MONITORING The evolving interim results of phase 3 and some phase 2 randomized trials are typically monitored by a data monitoring committee (DMC) (also known as a data and safety monitoring board, or a data monitoring board)
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From page 187... ...
This section reviews key aspects of interim monitoring of randomized HIV prevention trials, including the composition of DMCs and the typical format of their meetings, the importance of access to complete information, challenges in monitoring trial assumptions, safety, efficacy, and futility, and the use of information from sources external to the trial. DMC Composition and Meetings The DMC for an HIV prevention trial typically includes statisticians and clinicians and often other scientists such as a virologist or someone with expertise in a key diagnostic test, an ethicist, and a lay participant -- all appointed by the study's investigators or sponsors (Ellenberg et al., 2002; Fleming et al., 2002)
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From page 188... ...
If that is the case, including representatives of local communities on the DMC is critical. For example, in the late-1990s, two mother-to-child HIV prevention trials were undertaken in Thailand, supported by the U.S.
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From page 189... ...
For example, a nonsignificant trend in trial results favoring the control arm could convince the DMC to recommend ending a trial, but a similar trend favoring the experimental arm would typically convince the committee to continue the trial. If the former situation potentially exists, DMC members should unblind themselves, to determine whether the trial should end on the grounds that the experimental arm is not helping subjects as much as the control arm.
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From page 190... ...
Ideally, a charter prepared prior to the start of a trial details the tasks the DMC will perform and the criteria it will use. In HIV prevention trials, these assumptions include the following: • Assumed versus actual rates of subject accrual, and the demographics of enrolled subjects • Assumed versus actual HIV infection rates • Assumed versus actual adherence of subjects to study interventions • Assumed versus actual retention of subjects, including rates of loss to follow-up, and missing data • Assumed versus actual rates of pregnancy and other reasons for discontinuing the product Enough information is usually available during a trial to estimate participant accrual, adherence, behavior, and retention rates precisely.
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From page 191... ...
Such recommendations should be based on specific criteria set forth in the protocol, such as the pooled HIV incidence rate versus the incidence rate in the control group. However, a recommendation to continue accruing subjects because of "interesting trends" in HIV infections across study arms could be problematic, as this will tend to inflate the false positive rate (type I error)
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From page 192... ...
(For an example of early stopping of an HIV treatment trial for efficacy, see Hammer et al., 1997.) In HIV prevention studies, where subjects' adherence and behavior are important determinants of an intervention's effect, investigators must also consider whether the intervention sustains that effect.
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From page 193... ...
. Recommendation 9-4: For effectiveness trials, guidelines for stopping HIV prevention trials based on positive interim results should require evidence of a sustained impact on cumulative HIV incidence.
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From page 194... ...
This underscores the need for a detailed informed-consent process that alerts people to both the risks and benefits of participating in a trial. Rules that encourage investigators to terminate a study based on a low likelihood that the intervention will show adequate efficacy can play an important role in HIV prevention trials.
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From page 195... ...
This is a very different matter from terminating an arm of a trial, or ending a trial altogether, based on external data, as occurred when investigators terminated the African Phambili trial (HVTN 503) of a Merck HIV vaccine based on the findings of the international STEP trial (HVTN 502)
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From page 196... ...
ANALYZING TRIAL RESULTS Analyzing the results of HIV prevention trials is particularly challenging, for several reasons: • HIV infection is a "silent" event -- that is, it is not directly observable -- and the tests used to diagnose infection are imperfect. • When pregnancies occur during a trial, women are often taken off the study product.
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From page 197... ...
Investigators need to take those possibilities into account when analyzing trial results. Excluding Subjects Who Were HIV Infected When Enrolled from Analysis HIV prevention trials have used different approaches in analyzing results from participants who are later suspected of having been HIV infected at the time of enrollment.
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From page 198... ...
Thus, investigators must carefully weigh the potential gains from excluding individuals who may have been infected at enrollment against the possibility that doing so will introduce bias into the comparison of study arms. Even if investigators could theoretically justify the post hoc exclusion of subjects, critics might question the face validity of results from trials that exclude more subjects from the intervention arm than from the control arm.
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From page 199... ...
In that case, similar periodic results would be expected to occur in the study arms under the null hypothesis of no intervention effect. Under these circumstances the following occurs: • Standard Kaplan-Meier estimates of cumulative HIV infection rates are valid at the scheduled visit times.
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From page 200... ...
. Effects of Product Discontinuation and Loss to Follow-Up Participants may stop using an intervention during a trial for several reasons, most commonly adverse treatment effects, an inability to continue the treatment or lack of interest in doing so, or, in some HIV prevention studies, pregnancy.
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From page 201... ...
HIV infection in a pregnant woman is different from that of a nonpregnant women with equal follow-up. Although the evidence for a differential risk of HIV infection during infection is limited and thus somewhat controversial, there have been reports of increased HIV risk in pregnant women (Taha et al., 1998; Gray et al., 2005; Morrison et al., 2007)
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From page 202... ...
2006. Risk compensation: The Achilles heel of innovations in HIV prevention?
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From page 203... ...
1999. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: A randomised controlled trial.
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