BMJ: Pharmaceutical Industry-Physician
"Entanglement" Affects Research, Care
Laurie Barclay, MD
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
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
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
"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
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
"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
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
"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
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
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
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,
Reviewed by Gary Vogin, MD
Medscape Executive Editor Bill Silberg edited and helped to write
Barclay, MD Writer for Medscape Medical News
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