| ||||||
 |  |
|  | | | |
| Farber | The 1986 Phase II trial that preceded the FDA’s unprecedented rapid approval of AZT was presented as a double-blind, placebo-controlled study, though it was anything but that. As became clear afterward through the efforts of a few journalists, as well as the testimony of participants, the trial was “unblinded” almost immediately because of the severe toxicity of the drug. Members of the control group began to acquire AZT independently or from other study participants, and eventually the study was aborted and everyone was put on the drug. As in the case of HIVNET, documents obtained by journalist John Lauritsen under the Freedom of Information Act subsequently suggested that data-tampering was widespread. Documents were altered, causes of death were unverified, and the researchers tended to assume what they wished to prove, i.e., that placebo group diseases were AIDS-related but that those in the AZT group were not. So serious were the deviations from experimental protocol at one Boston hospital that an FDA inspector attempted to exclude data from that center. In the end, however, all the data were included in the results, and the FDA approved the drug in 1987. |
| Gallo | Farber describes the AZT study that resulted in FDA approval as a phase II study but that was actually presented as a double-blind, placebo controlled study. The AZT study referred to was a double-blind placebo controlled phase III study, known as BW 002. 54 Incidentally, it was for the treatment of HIV, not for the prevention of MTCT. Farber does not make this clear. Other studies demonstrated AZT's efficacy at reducing MTCT transmission. |
| RA | A 1987 New England Journal of Medicine paper reported on BW 002, advertised as a double-blind, randomized, placebo-controlled study led by Margaret Fischl of the University of Miami in which 19 participants on placebo died but only one on AZT. Opportunistic infections (blamed on immune suppression caused by HIV) occurred in about twice as many on placebo as on AZT. In addition, the number of CD4 immune cells rose quickly in those taking AZT. [1] Based on interim results of this trial, AZT was approved a few months later by the US Food and Drug Administration (FDA) as the first AIDS drug. Most doctors quickly accepted it as a proven lifetime treatment, even though the trial was terminated when fewer than two-thirds of the participants had been taking AZT or placebo for more than 16 weeks, and only about 10% (27 people) for the full length of the trial (24 weeks/6 months). By doing this, the FDA over-ruled the recommendations of Harvey Chernov, its analyst who analyzed AZT toxicology data and noted its carcinogenic potential. The impact of this published success has been that few placebo-controlled trials of AIDS drugs have been conducted since. Most compare an older drug (often AZT) or combination of older drugs alone or used with a newer drug. Consequently, it is very important that the results of this first AZT trial are valid. The trial has been seriously criticized by some, including John Lauritsen in his book AZT: Poison by Prescription [2], Dr. Peter Duesberg in Inventing the AIDS Virus [3] and Lynn Gannett whose eyewitness account of the trial is posted at http://www.virusmyth.net/aids/data/lgazt.htm [4]. These authors claim that the trial was fraudulent and consequently the results are meaningless. John Lauritsen obtained papers on the trial under the Freedom of Information Act. Even though many parts were blacked out, he found evidence of tampering with documents reporting adverse effects and evidence that sicker patients were purposely put in the placebo arm. The trial may have been quickly unblinded by the toxicity of AZT, which was admitted even by its proponents. [1] AZT also causes some blood cells to grow larger, making the use of the drug obvious to medical staff. Some participants pooled their pills because of the widespread belief that this was a miracle drug, to try to ensure that everyone benefited. Others had their pills tested. Patients with severe toxicity would be taken off the drug, effectively putting them on placebo, but their results would be included in the AZT arm of the trial. [2] Lauritsen’s charges are supported by papers retained by Gannett who was data manager for the Syracuse, New York trial center. When she reported the incredible array of protocol violations in the trial to the NIH in 1990 she was brushed off. [4] The FDA was aware of some of the problems with the trial, and considered eliminating the information from some data centers, such as Boston. However, this might have eliminated the statistical significance of the results, so they agreed to allow all information to be included, despite its flaws. If there were any benefits to AZT, they may have been due to the blood transfusions that were necessary to keep people taking AZT alive. 21% of people taking AZT but only 4% of those taking placebo (some of whom may have been taking AZT secretly) were given multiple red blood cell transfusions. A deficiency of neutrophils (a kind of white blood cell) occurred in 16% of AZT recipients, but only 2% of placebo recipients. [5] A longer follow up report on the original AZT trial tried hard to put a positive spin on the results, but had to admit that its benefits quickly vanished. [6]. If the extraordinary benefits of the ‘blinded’ portion of the trial are omitted, 60% of people randomized to AZT who survived to 6 months survived another 15 months to the end of the monitoring period, but 66% of people randomized to placebo survived 15 months on ‘open label’ AZT. The rate of opportunistic infections that had been significantly higher in the placebo arm until 24 weeks (including the randomized portion of the study) suddenly flipped and became significantly lower at most time points in the group originally given placebo and, over the entire period of observation, the rate of opportunistic infections was lower in this group compared to the group originally randomized to AZT. It is very difficult to draw strong conclusions from this study because authors admitted that at any time, only about half of the people in the study were actually taking AZT, significantly blurring the results. But the adverse effects of AZT were still quite clear, even to the researchers, 10% of all subjects receiving AZT required more than 10 blood transfusions during the study. Other serious adverse affects that were associated with AZT by the researchers were muscle wasting and liver damage. |
| Refs |
|