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| Farber | HIVNET 012, according to its original 1997 protocol, was intended to be a four-arm, Phase III, randomized, placebo-controlled trial.6 Its sole sponsor was listed as the National Institute of Allergy and Infectious Diseases (NIAID), though one of the investigators was a Boehringer employee. The “sample size” was to be 1,500 HIV-1 infected Ugandan women more than thirty-two weeks pregnant. The four arms they would be divided into were 1) A single dose of 200mg nevirapine at onset of labor and a single 2mg dose to the infant forty-eight to seventy-two hours post-delivery, and 2) a corresponding placebo group; 3) 600mg of AZT at onset of labor and 300mg until delivery, with a 4mg AZT dose for the infant lasting seven days after birth, and 4) a corresponding placebo group. There were to he 500 women in each “active agent” arm and 250 in each placebo arm. The study was to last eighteen months, and its “primary endpoints” were to see how these two regimens would affect rates of HIV transmission from mother to child, and to examine the “proportion of infants who are alive and free of HIV at 18 months of age.” Another primary objective was to test the “safety/tolerance” of nevirapine and AZT. HIVNET's architects estimated that more than 4,200 HIV-positive pregnant women would deliver at Mulago hospital each year, allowing them to enroll eighty to eighty-five women per month. Consent forms were to be signed by either the mother or a guardian, by signature or “mark.” One of the exclusion criteria was “participation during current pregnancy in any other therapeutic or vaccine perinatal trial.” |
| Gallo | Farber describes how the HIVNET 012 protocol was changed implying this rendered its quality sub-optimal. There is nothing unusual or inappropriate about changing a study protocol if logistics or new scientific developments require it. If the study protocol became unacceptable, it would be rejected for publication. The results of HIVNET 012 were published in The Lancet, a leading medical journal. 41 |
| RA | According to Fundamentals of Clinical Trials [1], written by three experts in clinical trials, including one division director at the National Institutes of Health, “A clinical trial must contain a control group against which the intervention group is compared.” By eliminating the placebo control group, the trial lost its power to identify the safety and effectiveness of nevirapine except by comparison with AZT, which is a drug with high toxicity and limited effectiveness. At this point this research no longer qualified as a clinical trial to answer the question “Is Nevirapine safe and effective”, but could only answer the question “Is Nevirapine as safe (or “no more toxic”) and as effective (or “no more ineffective”) than AZT?”. Without an appropriate control group researchers relied on their instincts to classify virtually all adverse effects as not caused by the study drug, resulting in the absolute conclusion that the drug is safe and effective when, in fact, only a relative claim could be made. If the serious loss of records identified by the Farber article, including many records of adverse events, is also considered, the validity of the research shrinks even further. Claiming that publication would be assured if the study was invalid flies in the face of evidence that even long-term outright fraud does not prevent publication in major medical journals. The July 30, 2005 issues of both the Lancet and the British Medical Journal contained several articles describing their “Expression of Concern” that the work of Ram B. Singh and his “Indo-Mediterranean Diet Heart Study” were, in the words of statisticians hired by BMJ, “the data from the diet trial were either fabricated or falsified”. [2] They were examining a study published in BMJ in 1992 about which, the editors wrote, “doubts about the validity of the data…arose soon after we had published it”. [3] Yet, almost 10 years later, the Lancet accepted a follow-on study by the same prolific author. And it was not carelessness on their part: “Peer review was completed by three subject experts, together with a statistician. In detailed appraisals, our advisers commented that this trial was ‘excellent work’ which ‘builds upon the author’s previous research’.” [4] The inability of journals to deal with severe problems like this indicates that poor quality (or worse) data can attain publication without great difficulty. Publication in a “leading medical journal” such as Lancet is no guarantee of the quality of the data. |
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