When Corporations Pay for Research

When a data safety monitoring board found the AIDS drug Remune provided little benefit to patients involved in clinical trials, the principal investigator, James O. Kahn, put an end to the project. But when he and his colleagues at the University of California, San Francisco and Harvard University decided to publish the results, they ran into an obstacle: their project's corporate sponsor. Immune Response Corp. (IRC), the drug's manufacturer, filed legal documents alleging that the UCSF team had violated its contract for financial support by publishing confidential proprietary material without the company's consent. Three months before the report was scheduled to appear in the Journal of the American Medical Association, IRC, which was paying 35 percent of Kahn's salary to UCSF, demanded that the principal investigator and the university pay $7 million in damages. Kahn published anyway,1 bringing to light an ethical problem that researchers often end up stewing over in solitude. When corporations pay the bill for research, they may demand control over the final product, and that forces investigators to make the difficult choice between alienating a financial backer and muzzling--or worse, massaging--their results. "What we need to ask is: If industry is a coequal partner with government, should we give up the illusion that the academic research side is pure and admit that it is going to be part of the market?" queries Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania. "Do we believe or not believe that close connections with industry, while costly, still bring us more drugs and better products?" Changing Times The goal of creating better pharmaceuticals often sends investigators who seek stable funding sources to places that are outside academia. But increasingly, according to ethicists, that pursuit leads the researchers out of the comfortable territory of pure science and into commerce. "I've been involved in conflict-of-interest issues for the last 10 years, and up until about the last year or so, this was all a pretty quiet topic," notes Margaret Dale, associate dean for faculty affairs at Harvard Medical School. "All of a sudden, I think in large part because of what happened in Pennsylvania, this seems to have leaped to the forefront." Dale refers to the death of University of Pennsylvania gene-therapy patient Jesse Gelsinger in September 1999, and the subsequent review of conflict-of-interest issues related to Penn's Institute of Human Gene Therapy's ties to industry.2 Many observers track the mounting attention to the ethics of industry-supported research to the Bayh-Dole Act of 1980, which gave educational institutions ownership of inventions developed with federal dollars and created the impetus to pursue ties with commercial interests. Wendy Baldwin, deputy director for extramural research at the National Institutes of Health, wants scientists to understand that modern science has, almost by its nature, the potential for financial conflicts of interest. "After Bayh-Dole, the incentives were there so that your institution is expected to patent and license [scientific discoveries]." Conflict often occurs, notes Dale, when researchers are far along in their discussions with a company and then find out there are potential roadblocks. Dale and others advise scientists to enlist the help of knowledgeable people on their own campuses to identify these obstacles before they happen. These experts can be found in the offices of grants administration and technology transfer. From his own experience, Kahn advises scientists to make sure their contracts allow the investigators to publish data. He adds: "Do not be intimidated by sponsors and make sure that your institution will support your position." The Data Divide When Kahn and his team launched their evaluation of HIV-1 Immunogen, which IRC produces under the name Remune, in March 1996, they held a contract defining--in somewhat ambiguous words--publication terms. The agreement stated that IRC could withdraw proprietary information from any data released, but that "approval by the sponsor otherwise is not required prior to publication." IRC appointed an independent data safety monitoring board to track the research. In May 1999, the data safety monitoring board determined that Remune essentially provided no benefit to the patients, and recommended the trials be terminated, according to Kahn's report. Laura Hansen, a spokesperson for IRC from Susan E. Atkins & Associates in San Diego, said the company sought arbitration to create a complete and detailed representation of all of the data from the clinical trials that other clinical investigators and the company believed were important for publication. The company did not express disagreement about the significant findings, according to Kahn. All agreed that Remune provided no clinical benefit, with only a modest CD4 immune cell increase and with no viral load changes. The disagreement centers on the inclusion of data that Kahn contends was not included in the approved trial protocol. "We balked at that," he says. "That's really data dredging." According to Hansen, IRC wanted to include the debated patient results expressly because they were part of the design protocol. "Both the company and other clinical investigators thought that the inclusion of those data in detail was very important for the publication," she says. "When Dr. Kahn and other authors on the paper couldn't come to an agreement in the publication of those data with the company, that's when they entered into arbitration to let a third party decide." When Kahn elected to publish despite the arbitration, the IRC withheld the complete data set. The researchers ended up publishing their JAMA paper with what they surmise was only 95 percent of the clinical data, 80 percent of the viral load and CD4 results, and about 70 percent of the safety data. This subset was also similar to the one used by the independent reviewers in deciding to end the study, he says. An analysis of the disputed data now appears in the April issue of HIV Medicine.3 This paper's authors conclude that Remune had a beneficial effect on a predefined, random set of subjects. In fact, Remune is being tested in a Phase III trial with Aguron Pharmaceuticals of La Jolla, Calif., to test its effects (in combination with HAART [Highly Active Anti-Retroviral Therapy]) on viral loads. But Kahn hasn't changed his view about the research. "We were trying to do what was right for the patient and right for the science; in our view this product was no different from the placebo in affecting death, infecting symptoms," he says. Doing the Right Thing Kahn credits the UCSF administration, in part, for his ability to take a strong position in the dispute without jeopardizing his job. But not every researcher can look for such protection. And scientists should be hesitant to tie their academic credentials to any commercial venture, says Ronald Collins, director of the Integrity in Science Project for the Center for Science in the Public Interest in Washington, D.C. If scientists do elect to pursue private market financing, Collins recommends they follow a few steps to avoid conflicts: Maintain independence in the design of any studies or clinical trials; Maintain independence as to publishing the results of their findings; Take care to scrutinize all proposed contractual arrangements; Avoid equity interests in any company for which they do research; Make sure there are adequate and meaningful safeguards for those involved in the clinical trials; and Adhere to a strict policy of regular full disclosure. Collins views Kahn as a role model for other researchers caught in potential conflicts of interest involving their corporate sponsors: "Insofar as science is subverted, it is necessary to have subversive scientists to counter that. I think the whole future of science depends on those quote 'modern day subversives' like Kahn." Karen Young Kreeger (kykreeger@aol.com) is a contributing editor for The Scientist. Paula Park can be contacted at ppark@the-scientist.com. References 1. J.O. Kahn et al., "Evaluation of HIV-1 Immunogen, an immunologic modifier, administered to patients infected with HIV having 300 to 549 x 10(6)/L CD4 cell counts: A randomized controlled trial," Journal of the American Medical Association, 284:2193-202, Nov. 1, 2000. 2. E. Russo, "Penn restructures gene therapy institute," The Scientist, 14[12]:12 June 12, 2000. 3. J. Turner et al., "The effects of an HIV-1 Immunogen (Remune) on viral load, CD4 cell counts and HIV-specific immunity in a double-blind, randomized, adjuvant-controlled subset study in HIV infected subjects regardless of concomitant antiviral drugs," HIV Medicine, 2[2]:68-77, 2001. Tips to Avoid Conflict To help scientists develop familiarity with conflict-of-interest issues, Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania, recommends investigators review academic, corporate, and legal guidelines on conflicts of interest: Find out what guidelines departments, divisions, and individual faculty members must follow. Familiarize yourself with the patenting and licensing requirements for inventions at your institution, and find out who advocates for faculty, and especially for junior faculty, in these matters. Learn who got promoted recently and why. Did they get promoted because of their publication record? Were they promoted in part because of their patents and the commercial potential of their research? Find out if your department plays a role in ensuring investigators get trained in research ethics. Check how many young investigators serve on the institution's review board. Find out how well whistleblowers are backed up by the university. --Karen Young Kreeger

When Corporations Pay for Research

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