Review of the HIVNET 012 Perinatal HIV Prevention Study (2005) / Chapter Skim
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Executive Summary
Executive Summary
Pages 1-10
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labeling change for the drug using HIVNET 012 as a registrational trial for its application in the United States. The decision to use the HIVNET 012 study as support for the labeling change made the trial subject to reviews that were conducted in a manner that was far more in-depth than would ordinarily occur for a clinical trial that, like HIVNET 012, was not originally intended to generate data to support a submission to FDA for approval of a new drug or new indication for an old drug.
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, and staff of the HIVNET statistical center (SCHARP) responded to the Westat Site Visit Report, providing additional information that explained or resolved some negative audit findings (FHI, 2002; HIVNET 012 Investigators, 2002; SCHARP, 2002)
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In addition, the committee obtained copies of a subset of primary source documents from Uganda, as well as information from the study database maintained for HIVNET 012 by the Statistical Center for HIV/AIDS Research and Prevention (SCHARP)
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The committee finds that the HIVNET 012 investigators used appro priate practices for packaging and distributing study drugs, so that the assigned drug was consistently provided to the appropriate mothers and their infants. Evidence from cord blood specimens indicates that 1The trial was continued as a two-arm trial comparing NVP to ZDV and designed to select NVP as the preferred regimen if the difference in rates of mother-to-child transmission of HIV between the NVP and ZDV arms was 3% or less.
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Using these data, the committee conducted its own evaluation of the accuracy, completeness, and timeliness in reporting of adverse events and serious adverse events, survival status, and HIV infection status of infants in the sample. Based on its detailed examination of study data, the committee found no evidence of misrepresentation of the study results.
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information in the source documents used to assess HIV-1 infection status was accurately transferred to the SCHARP database, and done so in a timely manner so that all results available at the time of the data freeze for study publications were included in the analyses. The committee finds that infant deaths, hospitalizations and visits where an infant experienced an SAE were accurately reported to the SCHARP database, although, in some instances, not all concomitant SAEs were reported.
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Safety Report, was not an appropriate upper limit of normal value for bilirubin in newborns, whose bilirubin levels change rapidly over the first few days after birth and are normally substantially higher than those in adults. The committee also concurs with DAIDS' decision to withdraw its initial IND safety report finding of excess hyperbilirubinemia because it was derived from the applica tion of an incorrect criterion to study data.
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The validity of the study's findings is sustained by the fact that the trial was conducted in accordance with FDA requirements and met international standards for the ethical management of clinical trials. The committee finds no evidence that the definitions used for adverse events and serious adverse events in HIVNET 012 placed human sub jects at increased risk.
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The committee finds that the failure to obtain such additional paternal consent was based on the practical unavailability of the fathers and the ethical constraints that prevented the research staff from contacting fathers in the absence of the mother's support and consent. The committee finds that while auditors reported procedural lapses by the Ugandan IRB, there was evidence of rapid and appropriate re sponse by the IRB in approving modification of the design of HIVNET 012 and discontinuation of placebo arms.
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2002. Response to Westat Site Visit Report.
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