The University of California, San Francisco and UCSF AIDS researcher James O. Kahn, MD, strongly rejected claims made in a press statement issued Tuesday (October 31) by a company that attempted to block publication of an important AIDS research study.
Kahn cited numerous inaccuracies in the company statement. The dispute stems from the attempt by the company to block Kahn and his colleagues at Harvard School of Public Health, Brown University and Cornell University Medical Center from submitting for publication the results of a large, multi-institutional trial of a drug, HIV-1 Immunogen, which it was hoped would boost the immune system of patients with HIV-1.
The study, established in 1996, was led by Kahn, UCSF associate professor of medicine in the Positive Health Program at San Francisco General Hospital Medical Center, and senior author Stephen W. Lagakos, PhD, Professor of Biostatistics at the Harvard School of Public Health. 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 showed no evidence of clinical benefit. The Data Safety and Monitory Board was established by the company and the study team to monitor the data being gathered in the clinical trial.
However, in January 2000, the company informed the university researchers that it would not provide them with the final data set from the study, but would instead have the data analyzed by a consultant hired by the company. This move was contrary to the provisions of the study protocol, which provided that the study team would perform the analysis. When the study team challenged this unauthorized protocol change, the company said it would provide the final data set only if the study team agreed to give it veto power over any publications.
Because these conditions were unacceptable to the study team, the researchers decided to publish the data it had available from the DSMB analysis. (The research team decided to proceed with publication because they estimated they had 95 percent of the confirmed clinical progressions that would have been recorded in the final database. However, they still seek the full data set because it could provide important information about how patients responded to the drug and what responses patients developed while receiving different anti-retroviral therapies, which most received while taking Immunogen.) When Kahn, director of the study, provided the company in July 2000 with a copy of the manuscript that the researchers had prepared, the company filed an arbitration demand in September 2000 seeking to block publication.
The researchers submitted the manuscript to the Journal of the American Medical Association, where it is published in the November 1 issue.
The primary measure for the drug's effectiveness was HIV progression or death. Secondary measures were the quantity of the virus in the blood, CD4+ T-cell counts, and body weight.
Kahn and the University offered the following responses to specific claims and suggestions made by the company:
The company press release issued on October 31, 2000, suggests that the research team failed to include in their paper a critical data sub-set measuring the product's effect on levels of HIV in the bloodstream. This is false. The results from the sub-set were included in the final manuscript and can be found on page 2,199, column 3 in the text of the article. The method by which the sub-set data was analyzed is the one called for in the original study protocol.
The study team did not include the company's analysis of the sub-set data because the company used an inappropriate method of analysis that was not pre-specified, Kahn said.
"This approach was not specified in the study protocol and gives erroneous results," Kahn said. "It is a fundamental tenet of the clinical trial process that a research team agree beforehand how it is going to analyze the data, rather than try, posthoc, to see which method of analysis provides the most favorable results," says Zach Hall, PhD, UCSF vice chancellor of research. "This approach is critical to preserving the integrity of the clinical trial process."
"For UCSF, as an academic health care institution, there are two core values at stake here: the first is our ability to freely communicate research results; the second is our special obligation in human subject research, both to those who participate in trials and to the larger patient community, to publish the results of studies fully, accurately and objectively. What is at risk is the trust of the public in the clinical trial process. Any attempt to selectively choose the data taints the process and jeopardizes this trust," Hall said.
In the sub-set of 250 patients who had their blood drawn more frequently than other participants, the researchers found no statistically significant difference in the patients' viral load when measured using the analysis method specified in advance in the protocol. The 250 patients had specialized HIV immunogenicity studies performed and it was clear the drug was active and that it elicited an immune response, but the patients in this group showed no statistically significant difference in viral load, CD4 counts or body weight. This data is included in the manuscript.
The company, however, wanted the researchers to include the company's analysis that patients in the sub-set who received the drug had a steeper drop in viral load than those receiving the placebo. This was not an accurate interpretation of the data, according to the study team. Rather than following the viral load in the blood over time, the company focused posthoc on selected time points that had not been agreed upon in advance.
"One might see a small difference doing this type of analysis, but it's not appropriate," Kahn said. "There are no differences at certain interim time points and there are differences at others. One cannot pick and choose data points to suit one's needs."
The company statement falsely contended that Kahn excluded clinical investigators and sponsor comments in the publication of the data. The researchers included some suggestions by the company in their analysis, and they included all available data from the study in their paper.
The trial began in 1996 and was intended to continue until all patients had been followed for two and a half years. However, the study was terminated after the analysis by the independent 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.
The study team attempted to share their findings with, and get comments on the draft manuscript from, the investigators at the 77 sites participating in the study. However, despite repeated requests to the company to receive the list of investigators and their addresses, the company refused to provide them. "We asked many times for the list of investigators to circulate the manuscript and to solicit their opinions," says Kahn. "As the national principal investigator, I had a responsibility to all sites, and if I were to short circuit the process by sending our analysis only to colleagues we knew, we'd be doing a disservice to all of the sites.
"By refusing to give addresses, the company was thwarting academic freedom," says Kahn. "We took the higher road by saying we must send the information to all sites, and the only way to effectively distribute was through a scientific publication like JAMA."
The researchers submitted a manuscript based on the data available to the DSMB. On July 4, the study team provided the company with a copy of the manuscript, and the company replied with comments on August 8. On August 23, the study team returned a revised manuscript incorporating some of the company's comments. On September 1, the company initiated the arbitration proceedings to block publication.
According to the company's October 31 press release, "the public was informed" about the study results in May 1999.
"The public was not informed," says Kahn. "They received the company's press release. It did not reflect the analysis of the study team. The analysis presented by the company did not reflect the data drawn from the entire study population, nor the three virologic analyses put out by the study team -- which is why it is so important to publish the results."
"The company's press release in May 1999 stated that there was an anti-viral effect, which our analyses demonstrated was insignificant," Kahn said. "The pre-specified analysis of all patients participating in the study, as well as a pre-specified analysis of the sub-set, were not statistically significant."
Journal
JAMA