UCSF-Harvard team publishes major HIV therapy study over objections of sponsor; compound shows no effect on slowing disease progression

October 31, 2000

Researchers led by University of California, San Francisco and Harvard School of Public Health are reporting the largest randomized trial among HIV-1 infected persons conducted during the 1990s. The compound tested in the trial, intended to boost the immune response of HIV patients, had no effect on slowing disease progression, the research team reports.

The researchers and their colleagues submitted their paper to JAMA, where it is published in the November 1 issue, despite the attempt by the company sponsoring the trial to block publication.

The company has filed an action with the American Arbitration Association against the University of California and lead author James O. Kahn, MD, UCSF associate professor of medicine in the Positive Health Program at San Francisco General Hospital Medical Center, to block publication. The study, established in 1995, was led by Kahn and senior author Stephen W. Lagakos, PhD, Professor of Biostatistics at the Harvard School of Public Health.

The company's action against the University of California and Kahn continues, and includes a demand for $7 million to $10 million from Kahn and the University, which the company contends would be the financial damage to the company from publication of the findings.

The University of California has filed a counterclaim, arguing that the agreements between the company and the University give the University the right to publish the data, and that the company has wrongfully withheld the final data from Kahn.

The decision to publish the study results affirms the University of California's right to publish unfavorable or neutral, industry-sponsored research findings.

The trial was sponsored and funded by a private pharmaceutical company which entered into agreements with UCSF (Kahn) and Harvard (Lagakos) in September 1995 to allow Kahn to act as the study chair and Lagakos to act as statistician for a nationwide team of investigators in evaluating the clinical benefit of the drug.

The drug investigated, HIV-1 Immunogen (known as Remune), is a disabled, inactivated form of HIV. It was administered in small doses to patients with the hope that it would act as an immune stimulator, prompting the immune system to ramp up its response against HIV proteins, and thus reduce the rate of disease progression.

The intention was for the compound to supplement standard anti-retroviral therapies. These approved medications, including classes such as reverse transcriptase inhibitors and protease inhibitors, lead to a decrease in HIV in the blood and to an increase in the numbers of CD4+ T cells - white blood cells that fight infection - and thus contribute to longer patient survival. However, despite the enormous improvements these therapies have provided, the risk for eventual HIV disease progression remains high.

Mild viral immunizations, with products such as the compound studied in this trial, have been considered a low cost, well tolerated, potentially good solution for augmenting anti-retroviral therapies, but their efficacy has remained unclear. (Efforts to develop a vaccination that would wipe out or prevent HIV infection altogether are also underway at many institutions, including UCSF and Harvard). The current trial was intended to clarify the efficacy of a specific compound developed from a disabled, inactivated form of HIV. The trial involved 2,527 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 CD4+ 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, making this a so-called randomized, double-blind study. The primary measure for the drug's efficacy was HIV clinical progression or death. The secondary measures were the quantity of the virus in the blood, CD4+ T-cell counts, and body weight.

The trial, begun in 1996, was intended to continue until all patients had been followed for two and a half years. However, the study was terminated five months early, in May 1999, after the second of three scheduled interim analyses of the data by an independent Data Safety and Monitoring Board (DSMB) showed that the compound had no clinical benefit and that it was unlikely any clinical benefit would be shown by extending the study. The study leadership, which held the responsibility for making the final interpretation of the results, agreed with the DSMB recommendation, and the trial was stopped.

"Not only was there no indication of improvement, but the patients receiving the drug and those receiving the placebo were so evenly balanced that there was very little chance that continuing the study would yield a significant difference between the two groups," says Kahn.

Lagakos concurs. "It was clear the drug had failed to improve the conditions of patients and that it was highly unlikely that any benefit would appear in the final months of the trial."

Following the termination of the trial, participating patients were seen for their final scheduled clinical visits. The team did not receive data from these final visits, but the researchers estimate that they did have 95 percent of the confirmed clinical progressions that would have been available in the final database. Still, in order to prepare a paper on their research findings, the researchers sought the final data from the company that manufactures the drug and which funded the study. However, the company refused to provide the final data unless the researchers agreed to the inclusion of additional analyses specified by the company. In addition, the company demanded the authority to approve all publications. Because these conditions were unacceptable to the team, Kahn and his co-authors prepared a paper based on the interim data analysis used by the DSMB.

"Full disclosure and academic freedom is a nonnegotiable item with us." says Zach Hall, PhD, UCSF vice chancellor of research affairs. "That's what we stand for. It's one of our core values. The University must vigorously defend the right of its faculty to publish their results."

"This is not just for issues of academic rights. We are doing this on behalf of the more than 2,500 patients and our colleagues at the 77 sites. This is part of our public service and responsibility to fully and fairly report on our findings," says Kahn.

In addition to maintaining University of California's right to publish the data, the University is also seeking an order that the data be turned over to the study team.

"The final set of data would include information about how patients responded to the drug and how patients developed responses while receiving different anti-retroviral therapies, and different doses. Therefore, the full data set could provide important information about the effectiveness of other HIV treatments and could be very valuable as we plan other studies," says Kahn.

The data also could have provided more information on any adverse reactions to the drug, as assessed through the final patient visit and laboratory evaluation, he says.

Moreover, notes Lagakos, the researchers were unable to obtain from the company the addresses of the site co-investigators who participated in the trial, so the manuscript and data could not be shared with them. "We are publishing this data on behalf of the more than 2,500 patients and the researchers at the 77 sites participating in this study, who were not allowed to see the data as analyzed by the study team," says Kahn. "Some of those patients would have benefited from knowing that the drug failed - they could have moved into other experimental drug trials."

"This was a study that showed a product did not work," he says. "It's often difficult to get studies of ineffective experimental drugs published in a high profile journal. The fact that we believed in the importance to publish this study is an indication that we are

informing other individuals who may need these results in order to make an informed choice whether to participate in other clinical studies involving this product."
The study co-chairs were Dr. Kenneth Mayer, MD, a professor of medicine at Memorial Hospital of Rhode Island and Brown University, and Dr. Henry Murray, MD, a professor of medicine at Henry Weil Medical College of Cornell University. The other co-author of the study was Deborah Weng Cherng, MS, a biostatistician at the Harvard School of Public Health.

University of California - San Francisco

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