Researchers Push Ahead with Publication of Results from HIV Study Despite Sponsor's Efforts to Block
In a gutsy move medical ethicists could easily applaud, Stephen Lagakos, chair of the Department of Biostatistics, and a colleague from the University of California, San Francisco (UCSF) have decided to risk legal action rather than tacitly agree to suppress publication of data that indicates an experimental drug did not slow the progression of HIV infection in a recent trial.
Their paper, "An Evaluation of HIV-1 Immunogen, an Immunologic Modifer, Administered to HIV-1-Infected People with 300-549 CD+ T Cells: A Randomized, Controlled Study with Clinical Endpoints" was published in the November 1 issue of the Journal of the American Medical Association (JAMA). The same issue of JAMA includes several other articles on the subject of university and industry relationships, including an editorial by the journal's editor in chief.
In September 1995, Lagakos and James Kahn, associate professor of medicine at San Francisco General Hospital, conducted what is believed to be the largest randomized trial among HIV-1 infected people in the last decade. Lagakos served as the statistician and Kahn as the chair of the study. They led a nationwide team of investigators in evaluating the clinical benefit of the drug Remune, an inactive form of HIV.
The researchers were testing the hypothesis that Remune could boost immune system responses to HIV and thereby stymie the disease. The compound was intended to supplement standard therapies.
The study was sponsored and funded by a pharmaceutical company, which has filed a multimillion-dollar action with the American Arbitration Association against UCSF and Kahn in an unsuccessful attempt to block publication of the results. The University of California has filed a counterclaim, affirming the university's right to publish unfavorable or neutral, industry-sponsored research findings. HSPH and Lagakos have not been named in the action.
For the clinical trial, the researchers enrolled more than 2,500 HIV-infected patients at 77 medical centers in the United States. Most of the patients were receiving anti-retroviral therapies, and none had ever developed the major characteristics associated with HIV's progression to AIDS, including low counts of certain types of T-cells, and potentially lethal opportunistic infections, such as pneumocystis pneumonia.
Half of the patients received the experimental drug, and half received a placebo. Neither the patients, nor their physicians, knew which they received. The primary measure for the drug's efficacy was progression to AIDS or death. The secondary measures were the quantity of the virus in the blood, T-cell counts, and weight.
In May 1999, the study was terminated five months early after an analysis by an independent board showed that the compound had no clinical benefit and that it was unlikely extending the study would show any clinical benefit. Lagakos and Kahn, who were responsible for interpreting the final results, agreed.
The researchers presented the results to the company, which then conducted its own analysis. "They conducted numerous post-hoc analyses until they found something they thought was a sign that the compound was active and then issued what, in my opinion, was a misleading statement about the effectiveness of the drug on viral load," said Lagakos.
Contrary to the provisions of the study protocol and research contract, the company refused to provide the final data unless the researchers agreed to include additional analyses specified by the company. The company also wanted the authority to approve all publications. Lagakos and Kahn believed the terms to be unacceptable and decided to push ahead with publication of a paper based on what they estimated to be 95 percent of the confirmed clinical progressions that would have been available in the final database.
The results of the trial were important not only to the doctors and patients enrolled in the trial but also to the investigators of other trials involving Remune. Lagakos knows of one study recently completed and two others being planned that may be affected by this study's publication. Also, an NIH-funded AIDS clinical trial using Remune was recently stopped after the researchers were made aware of the results of the Kahn-Lagakos study.
Lagakos feels strongly that relationships between private companies and independent groups can be very useful. He describes the situation surrounding the JAMA paper as an aberration and remains firm that he and his colleagues made the right decision to publish.
Joining Lagakos from HSPH in the conduct of the study were Deborah Weng Cherng and Heather Gorski from the Center for Biostatistics in AIDS Research.
For more
information, see press release of October 31, 2000:
UCSF-Harvard Team Publishes Major HIV Therapy Study Over Objections of
Sponsor; Compound Shows No Effect on Slowing Disease Progression
