“If we don’t [fund it], who will?” said Syngenta spokesperson Sherry Ford in an April 12 U.S. News and World Report article that delves into the complex and often tense relationship between science and industry. “It” refers to “cutting-edge research,” the government support for which “has fallen from a high of 73 percent in 1965 to below 60 percent,” wrote the article’s author, Ulrich Boser.
Boser traced the boom in industry-supported research to the 1980 Bayh-Dole Act, which allowed schools to profit from federally funded discoveries, and reported that 62 percent of all biomedical research is being supported by industry today compared with 32 percent in 1980. Along with increased corporate funding, the article referenced a 1980-2002 literature review published last year in the Journal of the American Medical Association in which Justin Bekelman and colleagues reported a 3.6 to 1 likelihood that research supported by a company will favor that company.
In the current era of uneasy interdependence, science and industry, perhaps differing only in primary motivation, strive to advance medical science and benefit patients. But the process is akin to a game of tug-of-war in which individual players switch sides at any time, and the boundary continually moves. As differing priorities create conflict which simmers and occasionally boils over into the public arena, the media documents progress and pitfalls toward ethical and productive relationships.
August Report Documents Uneasy Alliance
The amount of influence a funder may have on the line of inquiry researchers undertake is among the questions addressed in Michigan State University’s external review, released Aug. 1, of the intensely scrutinized agreement between biotechnology company Novartis, now Syngenta, and the University of California, Berkeley. The amount of industry money-$25 million over 5 years-and the fact that nearly an entire department was funded made the 1998 agreement unusual. After a two-year inquiry, external reviewers in general found the deal to be “consistent with the behavior of universities adjusting to the emerging norms of university-based economic development,” although they also characterized the deal as an “icon for larger issues.”
Principal investigator Lawrence Busch, a sociologist at Michigan State University, suggested in an Aug. 9 National Public Radio interview that subtle influences of industry funding are difficult to determine when dealing with the broad applications of basic science that were funded by the Novartis-Berkeley agreement. “Another company might have decided they wanted things that were much closer to product development and in that instance might have put a great deal of pressure on faculty members to pursue certain kinds of research projects that would lead to products rather quickly and to avoid others,” he said.
While direct impact on the university was found to be minimal, the report’s nine recommendations included a provision for greater transparency of such collaborations and culminated with a call to examine the role of a public university today.
Toward Greater Transparency
Greater transparency also is the motivation behind a recent call for a clinical studies comprehensive registry as well as reaffirmation of major medical journals’ publication rules.
Clinical Trials Registry At its annual meeting in June, the American Medical Association endorsed a policy calling for the Department of Health and Human Services to establish “a comprehensive registry for all clinical trials conducted in the United States” that would “ensure that trials with negative as well as positive results are publicly available, by providing every clinical trial with a unique identification and ensuring publication or placement on an electronic database of all results from registered trials.”
Earlier the same month, on June 2, the state of New York filed suit against GlaxoSmithKline, manufacturer of the antidepressant Paxil, charging that the company committed consumer fraud by withholding information on the effectiveness and harmful side effects of the drug when prescribed “off label” to children and adolescents.
“The general public and the medical community should not have to fear that clinical findings of significance regarding a medication may be suppressed and remain unavailable to their physicians because the findings may be deemed unfavorable to the financial interests of the manufacturer,” said Barry B. Perlman, MD, president of the New York State Psychiatric Association, in a statement that took no position on the merits of the litigation.
The complaint said that the company’s literature focused on one study of the drug’s effect on adolescents and failed to disclose four studies that showed no effect or increased risk of suicidal thoughts and behavior, the Washington Post reported.
The favorable study was published in the Journal of the Academy of Child and Adolescent Psychiatry in 2001. None of the unfavorable studies was published. Psychiatrist Robert Milin of the Royal Ottawa Hospital in Canada, reported the results of one of the unfavorable studies at a 1999 conference, according to The New York Times, which quoted Dr. Milin’s view that “If they had got a positive outcome I would suspect that they would have pushed to get it published.”
New Editorial Rules An additional impetus for the registry dates to September 2000, when JAMA published research suggesting that the deleterious effects of arthritis drug Celebrex were less severe than those of similar medications, without the editors’ knowledge that six months of data were withheld from the paper. The discrepancy came to light the following year when complete data were published on the U.S. Food and Drug Administration’s Web site as part of the FDA’s review process, and some FDA advisory committee members realized the discrepancy and expressed their concern.
In August 2001 the Washington Post reported the story and quoted Thomas Wolfe, the gastroenterologist who had written an editorial accompanying the JAMA article, as saying he was “flabbergasted” and “furious” that the data hadn’t been made available. The Post also quoted Catherine D. DeAngelis, MD, JAMA’s editor, saying, “I am disheartened to hear that they had those data at the time that they submitted [the manuscript] to us…We are functioning on a level of trust that was, perhaps, broken.”
In September 2001, 12 major medical journals-among them JAMA, The Lancet, and Annals of Internal Medicine-published “Sponsorship, Authorship, and Accountability.” The editorial announced a new policy designed to ensure researchers’ independence from sponsors. Journal editors had agreed to the new rules, which among other things require authors to sign statements fully disclosing their role and that of any sponsors, earlier that year at the annual meeting of the International Committee of Medical Journal Editors.
“It’s an utterly serious matter when any part of the healthcare system withholds information that could be helpful to patients and doctors in deciding what to do,” Annals of Internal Medicine Editor Harold Sox, MD, in a September 2001 American Medical News article explaining the reasons for the new editorial policy.
The AMA reaffirmed its support for the editorial policy this summer at its annual meeting.
Ethical Guidelines Define Boundaries
Industry likewise has struggled with the shifting parameters of its role. As Jeff Trewhitt of the Pharmaceutical Research and Manufacturers Association pointed out in the same American Medical News story, “A company cannot afford to have its reputation damaged with doctors, patients and the Food and Drug Administration.”
PhRMA Codes On June 20, 2002, PhRMA adopted a voluntary set of principles that delineate the responsibilities of its member companies when involved in clinical research.
“These principles reaffirm our members’ strong commitment to the safety of research participants to ensure the integrity of research and the timely communication of research results,” said PhRMA President Alan F. Holmer in a statement announcing the guidelines.
Effective for trials begun after Oct. 1, 2002, PhRMA’s Principles for Conduct of Clinical Trials and Communication of Clinical Trial Results originally was published in July 2002 and was just updated in June 2004. While originally published information remains intact through page 28, the balance of the 53-page document offers additional guidance for 17 new questions. In addition, a new document, Clinical Trials Questions and Answers, acts as a companion for the principles.
In July 2002, PhRMA additionally published voluntary guidelines governing its member companies’ relationships with medical professionals. The PhRMA Code on Interactions With Healthcare Professionals was adopted on April 18, 2002, and became effective the following July. In general, the code says that permitted interactions are those that support scientific information and education and that have a benefit to patients. As summarized in a New York Times article discussing the code, “Anatomical models for examination rooms are OK; World Series tickets for a doctor’s family are not.”
The AMA in 1992 issued its own guidance for physicians when offered gifts from industry. This summer the AMA rejected a proposal to modify those guidelines, siding with doctors who said they feel pressure from drug companies seeking to influence them, Modern Physician reported.
OIG Compliance Program The federal government, which through the Office of the Inspector General has stepped up efforts in recent years to combat fraud and abuse, also has addressed matters of appropriate conduct. Published in the Federal Register on May 5, 2003, the OIG Compliance Program Guidance for Pharmaceutical Manufacturers recommended that “pharmaceutical manufacturers at a minimum comply with the standards set by the PhRMA code” and further warned that “arrangements that fail to meet the minimum standards set out in the PhRMA code are likely to receive increased scrutiny from government authorities.”
AdvaMed Code Most recently, the technology industry has weighed in on the matter of ethical conduct. In September 2003 the Advanced Medical Technology Association, representing more than 1,100 medical technology companies, adopted its Code of Ethics on Interactions With Health Care Professionals, which became effective Jan. 1 of this year. The guidelines, updated from AdvaMed’s 1993 Code of Ethics, mirror many provisions of the PhRMA code and, like the PhRMA guidelines, compliance is voluntary.
In a letter to healthcare professionals announcing the new code, AdvaMed President Pamela G. Bailey said it was adopted “in response to…scrutiny and to the rapidly changing healthcare fraud enforcement environment” a situation which “presents risks to the industry itself, and to physicians and other healthcare industry professionals who are so critical to the delivery of life-saving and life-enhancing therapies.”
Over the Line/But the Line Moved
As all players acclimate to evolving rules governing science-industry relationships, some are struggling with the changes. On June 27 The New York Times reported a federal investigation into drug marketing practices. Under investigation are accusations that Schering-Plough paid doctors either directly-up to six figures to prescribe a drug for hepatitis C-or indirectly by sponsoring “pseudo-trials” of the drug. The article said Schering-Plough indicated that it has instituted new marketing practices since 2003, and that the investigation is targeting prior practices.
Peter Barton Hutt, identified as a former FDA general counsel who now advises drug companies, summarized the issue this way: “The industry has…had to reshape entirely what they are doing, but it was too late to redo what they’d been doing for years.”
The article also contained a warning: “Once the new Medicare drug benefit takes full effect in 2006, the government will pay for almost half of all medicines sold in the nation. So the marketing programs will cost the government even more money and, if they are uncovered and determined to be illegal, will probably result in even larger fines.”
Manda J. Seaver is staff editor of the Bulletin.
For Further Information
Advanced Medical Technology Association, www.advamed.org
American Medical Association, www.ama-assn.org
American Medical News, www.ama-assn.org/amednews
Federal Register, www.gpoaccess.gov/fr
Journal of the American Medical Association, https://jama.ama-assn.org
Modern Physician, www.modernphysician.com
National Public Radio (“Morning Edition”), www.npr.org/programs/morning
The New York Times, www.nytimes.com
Novartis-Berkeley External Review, www.berkeley.edu/news/media/releases/2004/07/external_novartis_review.pdf
Pharmaceutical Research and Manufacturers Association, www.phrma.org
U.S. News and World Report, www.usnews.com
Washington Post, www.washingtonpost.com