June 3, 2003 — A special issue of the British Medical Journal explores the "entangled" relationship between pharmaceutical companies and physicians, reporting that industry-supported trials are biased toward the drugs for which the companies seek marketing approval, saying industry "largesse" is undermining clinical decision-making, and suggesting that doctors share the blame if they don't wean themselves from industry influence.

Systematic reviews in the May 30 issue conclude that there is selective reporting from industry-supported studies used to support new drug applications, and the reviews discuss the effect of industry sponsorship on research outcomes and study balance. A third report ties regular physician contact with drug company representatives to unnecessary prescribing. Finally, two commentaries discuss efforts to promote the "disentanglement" of physicians and industry.

Industry representatives quoted in the BMJ reports and interviewed by Medscape argue that pharmaceutical companies have a valid role to play in educating physicians and point to a year-old, voluntary industry code of conduct that bars many once-common marketing practices. They also argue that government regulators, at least in the U.S., closely watch for evidence of bias in the research underlying the drug approval process.

In the issue's lead editorial, BMJ Editor Richard Smith and Deputy Editor Kamran Abbasi say they're not anti-industry. Virtually all new drugs developed in the past 60 years — "drugs that have transformed medicine" — were developed or made by pharmaceutical firms, they note, and their own employer gets "substantial net income" from the industry. They also agree that "it takes two to entangle.

"Doctors...are perhaps more to blame in coming to depend on drug company largesse," they say. "Doctors and drug companies must work together, but doctors do not need to be banqueted, transported in luxury, put up in the best hotels, and educated by drug companies. The result is bias in the decisions made about patient care."

Nor are medical journals necessarily exempt from industry influence, they argue. "Journals are caught between publishing the most relevant and valid research and being used as vehicles for drug company propaganda," they note.

Because publication of research findings occurs relatively late in the process of study design, execution, data analysis, and interpretation, safeguards against undue corporate influence on trials planning is essential, the editors write. They cite two reviews in the theme issue delineating potential bias in published trials.

One report, a review of 30 studies, based on a MEDLINE search from January 1966 to December 2002 and an EMBASE search from January 1980 to December 2002, found that trials sponsored by a pharmaceutical company were four times more likely to show positive results for that company's drug than were studies funded by other supporters (odds ratio, 4.05; 95% confidence interval, 2.98 - 5.51). The study, by Joel Lexchin, MD, associate professor of health policy and management at York University in Toronto, Ontario, Canada, and colleagues, also found that company-funded research is less likely to be published than research funded by other sources. But none of the 13 studies that analyzed methods found industry-funded studies of poorer quality than others.

"The bias that we see in studies sponsored by pharmaceutical companies is not confined to any single group of drugs or diseases, and it has taken place for over two decades," Dr. Lexchin told Medscape. "From my point of view, these findings are not very surprising, because the drug companies would have many problems if they had negative trials for their products and if these trials were published."

"It's not that the drug companies deliberately deceive, but some decisions they make regarding study design do tend to create bias," Dr. Lexchin says, explaining that one potential source of bias is the choice of comparator, or the comparison for the study drug. "Of course, these potential mechanisms are just my hypothesis — you can't really prove it." Testing the drug against placebo rather than against another active drug enhances the likelihood of getting a positive result, Dr. Lexchin noted. Using too high a dose for the comparison drug could lead to more adverse events while using too low a dose could make the comparator look less effective than the test drug.

Alan Goldhammer, PhD, associate vice president of regulatory affairs for the Pharmaceutical Research and Manufacturers of America (PhRMA), the U.S. industry's Washington, D.C.-based trade group, said in an interview that any arguments about bias, at least from a U.S. perspective, "call into question the role of the FDA [Food and Drug Administration], which is supposed to be an unbiased regulatory agency.

"Regarding the allegation that drug companies choose comparators to be favorable to their product, it's up to the FDA to say that additional or different comparators are needed. So there are many checks and balances here," Dr. Goldhammer said.

However, Dr. Smith points out in a separate article that medical journals and pharmaceutical companies are "uneasy bedfellows," and that as long as journals gain financially from publishing industry-sponsored studies, negative trials are less likely to be published than positive ones. Additionally, he says, "if the sponsors controlled publication and didn't like the results, the papers won't be sent to these journals for publication."

To counteract any potential bias from nonpublication of negative studies, Dr. Lexchin's group proposes a registry of all trials. That way, they say, when authors of reviews look at published reports, they would also know about other, still-unpublished trials.

The author of another review in the theme issue, Hans Melander, PhLic, a senior biostatistician with Sweden's Medical Products Agency, agreed that anyone making a decision about drug treatment should not just rely on published data. Dr. Melander is the lead author of a review of 42 studies submitted to the agency to secure marketing approval for five selective serotonin reuptake inhibitors. Comparing these studies with those actually published between 1983 and 1999, the authors identified three potential sources of bias: duplicate publication, selective publication, and selective reporting.

Examples of duplicate publication included 21 studies reported in at least two publications each, and three studies reported in five publications. Studies showing significant benefits of a drug were published more often than studies with insignificant or unfavorable results, the review found. Many articles ignored the results of intention-to-treat analyses and reported only the more favorable per-protocol analyses, Dr. Melander said. However, he told Medscape, such publication bias is not a problem in drug approval because regulatory agencies have access to all studies and all alternative analyses and also can perform their own analyses.

Dr. Goldhammer said he didn't see how Dr. Melander's analysis applied in the U.S., "where all clinical trials are reviewed by the FDA.

"Drug companies can promote their products based only on what the FDA allows on the drug label," he added. "If there is a claim of superiority to another drug, that data has to be generated and submitted to the FDA for review."

But while regulators may look at all data, physicians may rely on what's published. Acknowledging that his study may not necessarily be generalizable to all drugs, Dr. Melander urges physicians to seek out independent sources of drug information, such as that available on the FDA Web site (Summary Basis of Approval) and the European Agency for the Evaluation of Medicinal Products (EMEA) Web site (European Public Assessment Report), as well as on the Web sites of some national European agencies.

Dr. Lexchin points out that journal editors also have a responsibility to ensure that study funding and potential conflicts of interest — from any source — are declared. "Government-funded studies may have biases too; for example, their bias might be to show that the least expensive drug for a given indication is as good as the most expensive," he says. "If an article doesn't state the source of funding, it should be regarded more skeptically than those that do report it."

One information source not likely to be unbiased, however, is the industry representative, found a systematic review by Christopher Watkins, MB, BS, PhD, FRCGP, a general practitioner with the Backwell and Nailsea Medical Group in Bristol, U.K.

"[Among] British general practitioners, high levels of contact with drug industry representatives are associated with factors that indicate professional isolation, a lack of involvement with training future general practitioners, and a preference for educational support provided by the drug industry," Dr. Watkins told Medscape. "These characteristics provide a major challenge to those who wish to develop acceptable educational interventions."

In his study of more than 1,000 general practitioners randomly selected from 200 practices in England, Dr. Watkins found that those "detailed" by drug industry representatives at least once weekly were more likely to express views leading to unnecessary prescribing, as indicated by a set of component characteristics outlined in the study. These included greater willingness to prescribe new drugs, acquiescence to patients' requests to prescribe drugs not clinically indicated, dissatisfaction with consultations ending in advice only, and "receptiveness to drug company advertisements and promotional literature."

"High levels of contact with drug industry representatives is also associated with general practitioner attitudes and behaviors that discourage critical attitudes towards prescribing practice, encourage unrealistic healthcare-seeking behavior in patients and thus increase the workload of [clinicians]," Dr. Watkins said.

He encourages physicians to be aware of these influences and to examine them critically to facilitate cost-effective prescribing. Future research, he argued, should focus on alternative, more appropriate educational interventions for those clinicians who now rely heavily on drug industry representatives.

Ray Moynihan, a journalist in Washington, D.C., and a guest editor for the BMJ special issue, agreed, telling Medscape that "the challenge facing physicians is how to get quality, unbiased information about drugs quickly." Company representatives are not that source, he argued. A better approach, he said, might be to have "academic detailers" sponsored by public funding who essentially do what industry representatives do, without any financial incentive to promote a particular product. The U.K. has Pharmacy Advisors to fulfill this function, and Australia has the National Prescribing Service. In the U.S., Mr. Moynihan acknowledges, such programs "are in their infancy."

He also argues that pharmaceutical companies' efforts to influence physicians include supporting hundreds of thousands of continuing medical education (CME) conferences and other events annually. Some associations and academic centers are now declining or considering saying no to such support, as well as contemplating closing the door to pharmaceutical representatives out of concern about efforts to inappropriately influence physicians or students.

PhRMA representatives noted that the industry, concerned about some of the same issues, implemented a voluntary, self-regulatory code last year that explicitly outlined the proper — and improper — ways industry representatives could interact with physicians. The PhRMA code, one of a number of new or proposed regulatory initiatives aimed at the industry, rejects as improper several once-common perks — including travel and entertainment — that had more to do with marketing than education or scientific discussion.

John Kelly, MD, PhRMA's senior vice president for scientific and regulatory affairs, was quoted in one of the BMJ articles as saying that the new code benefits patients. He also told the BMJ that numerous organizations representing practicing physicians continue to acknowledge the important role industry plays in underwriting educational activities for physicians. Supported CME also benefits patients, Dr. Kelly told the BMJ, because it facilitates physicians' access to the "best available information."

However, several of the BMJ articles express concern that patients' interests may actually be compromised by industry involvement. Drs. Abbasi and Smith note that drug companies often fund patient organizations and public relations companies but that the extent of that support is not always disclosed.

None of the reviews or studies in the BMJ theme issue was supported by industry or other interest groups. Drs. Lexchin, Melander, and Watkins reported no pertinent financial conflicts of interest. Mr. Moynihan is an independent journalist.

BMJ. 2003;326:1167-1170, 1171-1173, 1178-1179, 1189-1196, 1208-1210

Reviewed by Gary Vogin, MD

Medscape Executive Editor Bill Silberg edited and helped to write this story.

Laurie Barclay, MD Writer for Medscape Medical News Medscape Medical News is edited by Deborah Flapan, a news coordinator at Medscape. Send press releases and comments to news@webmd.net. Medscape Medical News 2003. © 2003 Medscape