November 3, 2000
On November 1, 2000 The New York Times reported that the Immune Response Corporation "tried to block the publication of a scientific paper that showed its HIV vaccine was not effective, and it has asked for damages of more than $7 million from the universities and researchers who published the findings."(1) The disputed paper was published in the same day's issue of JAMA (Journal of the American Medical Association,(2) along with several articles and editorials on relationships with industry and conflict of interest in medical research.(3,4,5,6)The New York Times story was picked up or rewritten by many news outlets. Also see Los Angeles Times, November 1, 2000.
Because we learned about this dispute shortly before press time, we have not had time for our own investigation. But in this case we see credible people on both sides -- and beyond the obvious issues, some difficult ones which did not come out in the headlines. Of course it is wrong when companies take legal action to pressure researchers and universities to spin scientific results their way -- that is a no-brainer, and the community must support researchers' right to report, especially when persons have volunteered for participation medical research studies. This is part of an enormous problem ["when an investigator has a financial interest in or funding by a company with activities related to his or her research, the research is lower in quality (2 references), more likely to favor the sponsor's product (5 references), less likely to be published (2 references), and more likely to have delayed publication (1 reference)"(6)], and to that extent, the public was well served by the press coverage.
But tougher questions about how best to serve the public interest arise from the fact that today immune-based therapy is an enormously important research area, and yet there is no satisfactory way to test such treatments for clinical efficacy in patients (see "FDA Meeting on Approving Immune Therapies: Background and Comment," AIDS Treatment News #353, October 20, 2000). Immune Response Corporation did what it had to do and ran a huge trial originally designed to look for differences in survival between those who did or did not receive Remune, the HIV immunogen developed by the late Dr. Jonas Salk; both the treatment and placebo arms had more than a thousand patients each, who were allowed to use any antiretroviral therapy they chose (including experimental treatments, or including no antiretroviral therapy at all), in addition to the immunogen or placebo, which was administered every three months. But after the trial was designed, the introduction of protease inhibitors reduced overall AIDS deaths enough that the trial could not have detected that the treatment improved survival even if it did -- so the trial was quickly changed to include AIDS-related illnesses as well as deaths as end points.
The treatment certainly did increase HIV-specific immunity as shown by lymphocyte proliferation assay (p<.001),(2) but this measure is not currently accepted as a surrogate marker of drug efficacy, because there is no proof at this time that increasing this response is clinically beneficial to patients.
The company has long had a reputation of looking for creative ways to interpret its data, which angers some researchers and activists. A serious communication problem with unconventional ways to look at data is that even if they are valid, outside analysts have a hard time verifying that -- because they must ask, "If we were given unlimited access to the raw data, and months to play with it (months which we don't have), might we have found equally convincing ways to come to very different conclusions?" Yet when facing a serious situation where conventional ways of analyzing studies of immune-based treatments do not work, it might or might not serve the public interest to insist on strict adherence to established data-interpretation rules. Sometimes it is necessary to push ahead on faith in what one is doing, break some rules and take some risks, or nothing will happen.
The controversy over the publication of this study re-emphasizes the importance of developing workable, well-accepted standards for the relationship between researchers and industry. But here again there are complications. For example, telling sponsors to keep hands off of the scientific publication clearly seems like a good idea. But in this case the press, investors, and the public ended up with a bottom line which is at least questionable, if not wrong -- that the "HIV vaccine was not effective" in general and not just in this trial. Certainly this study did not find a clinical benefit -- but if no such finding were possible because of unrelated improvements in HIV treatment, the study did not find that the treatment was not effective, either; rather, the result was inconclusive. Can standards decree that a sponsor has no legitimate interest in preventing such misunderstandings?
In this trial the treatment consisted of killed HIV plus an adjuvant -- a substance which makes vaccines work better. The placebo consisted of the adjuvant alone. Has it been ruled out that the adjuvant itself might have been beneficial, without the killed virus -- since the volunteers already had their own HIV, including dead virus, on board? This seems unlikely, given the lack of HIV-specific lymphocyte proliferation in the "placebo" arm -- but much is still unknown, and if the adjuvant itself were effective, the study result could have been negative even if the product being tested were beneficial.
The paper included other information which should not be overlooked because of the distraction due to the controversy.
"This study provided the first information regarding disease progression among a large group of well-treated patients with CD4 cell counts between 300 and 549 x 106/L that was collected in the controlled setting of a randomized trial. The progression rate of 1.8 per 100 person-years of observation was one third of what had been reported in the literature prior to the widespread introduction of protease inhibitors. This provides additional evidence of the long-term benefits of highly active antiretroviral therapies. . . ."
The study also found a surprisingly high incidence of lymphoma, "the second most common clinical progression event" (the most common was oral candidiasis).
ISSN # 1052-4207
Copyright 2000 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.
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