by Ronald Bailey
Ronald Bailey (firstname.lastname@example.org) is the author of
Liberation Biology: The Scientific and Moral Case for
the Biotech Revolution (Prometheus Books). This article
derives in part from research commissioned for a white
paper on scientific conflicts of interest by the
non-profit consumer education consortium the American
Council on Science and Health.
no-strings-attached funding from individuals,
foundations, associations, and corporations. Bailey
would also like to note that he owns various fairly
speculative biomedical stocks that he really hopes will
benefit a lot from industry-academic collaborations. The
number of shares he holds in any one company amounts to
a few hundred at most.
In 2004 GlaxoSmithKline became
the first major drug manufacturer to publicly disclose all the data
from clinical studies of its products, including information that is
usually treated as a trade secret.
It was responding to a lawsuit by
Eliot Spitzer, then New York’s attorney general and now its
governor, who accused Glaxo of hiding data about the safety and
efficacy of one of its drugs. Sure enough, the company had concealed
data indicating its antidepressant Paxil increased the risk of
adolescent suicide. More-recent research suggests that link might
not exist after all, but even if that proves true, it doesn’t excuse
the initial concealment.
A month later, Merck pulled its new pain reliever, Vioxx,
off the market after clinical trial data showed that patients taking
it had a 400 percent greater chance of heart attack than those
taking the comparison drug, naproxen. Merck researchers
implausibly argued that the difference was due not to damage caused
by Vioxx but to the other drug’s cardio-protective
properties. No previous research had found that naproxen
protects the heart.
For critics of the pharmaceutical industry, the Vioxx and
Paxil incidents are evidence that conflicts of interest have
thoroughly corrupted American medical research.
“The Vioxx withdrawal serves as a
reminder of the dangerous potential for conflict of interest
that exists when pharmaceutical and other for-profit businesses
control the dissemination of findings generated by medical
research,” warned a November 2004 editorial in the Dayton
In March 2005, the left-leaning
Center for Science in the Public Interest (CSPI) pointed
out that a Food and Drug Administration (FDA) panel
that reviewed data on the risks posed by COX-2 painkillers
like Vioxx included 10 researchers with financial ties to the
companies that manufactured those drugs. Had the panelists with
conflicts been excluded, a majority of the remaining members would
have voted against approving Vioxx for distribution.
The Paxil incident prompted a June 2004 statement from the
New York Attorney General’s Office warning that,
“the ability of drug companies to
pick and choose the research they provide doctors in support of
their product is an outrageous conflict of interest and puts us
all in harm’s way.”
An August 2005 story about
industry-funded medical research in the San Jose Mercury News
quoted Sheldon Krimsky, a longtime critic of pharmaceutical
companies, who asserted that,
“the entire system of drug testing
is filled with conflicts of interest.”
There’s no question that some companies
have behaved badly in some cases. But are these cases typical or
Activists, politicians, and other critics claim conflicts of
interest are pervasive in pharmaceutical research. Several years ago
CSPI established an Integrity in Science Project to
investigate and publicize the destructive influence of
Not to be outdone, the Union of
Concerned Scientists launched its own Scientific Integrity
“push for reforms that will protect
our health, safety, and environment.”
Politicians are jumping on the
bandwagon, proposing more-stringent regulations of private clinical
Sens. Christopher Dodd (D-Conn.)
and Edward Kennedy (D-Mass.) recently introduced the Fair
Access to Clinical Trials Act, which would require all clinical
trials to be registered in a central government database.
Marcia Angell, a senior lecturer
in social medicine at Harvard University, wants to ban privately
funded clinical trials altogether. Instead, she proposes that drug
companies be forced to pay into a government fund that would finance
a new National Institute of Prescription Drug Trials to
conduct all future clinical testing.
Supporters of such changes argue that conflicts of interest
undermine public trust in and support for scientific research,
endanger research subjects and patients, and boost medical costs by
encouraging physicians and patients to use new treatments that are
no better than cheaper alternatives. Yet public trust in biomedical
research remains high, and that trust seems to be justified.
Subjects in clinical trials hardly ever
suffer serious harm, and instances in which dangerous side effects
turn up after drugs are approved are relatively rare. Rather than
making medicine unnecessarily expensive, pharmaceutical innovation
ultimately reduces health care costs, because new drugs usually have
advantages that pay off in lower medical bills.
The critics’ concerns are not entirely groundless. Driven by
self-interest, drug companies and researchers do occasionally hide
data or run drug trials that produce data of scant clinical value.
But private initiatives by medical
journals, universities, and companies are already addressing these
challenges, making government action unnecessary.
In 2005 The Journal of the American Medical Association
reported that 5.6 percent of health spending in the U.S. goes to
biomedical research, more than in any other country. In nominal
dollars, funding for biomedical research in this country rose from
$37 billion in 1994 to $94 billion in 2003. Even adjusted for
inflation, that’s an increase of almost 100 percent.
The National Institutes of Health
provided 28 percent of that funding; industry gave 57 percent;
state, local, foundation, and other federal agencies accounted for
This cooperation between academia and industry has been essential to
speeding new treatments from lab bench to hospital bedside.
“By any measure, the interactions
between academic research and industrial research and
development, as epitomized by biotechnology, have been
overwhelmingly positive,” wrote Thomas Stossel, a
professor of medicine at Harvard and a co-director of the
Hematology Division at Boston’s Brigham and Women’s Hospital,
in a 2005 New England Journal of Medicine article.
“We should celebrate their
achievements and protect the process that led to them.”
But one man’s beneficial cooperation is
another’s conflict of interest, a phrase that has acquired an
inappropriately sinister connotation.
As defined by the former Harvard
epidemiologist Kenneth Rothman in a widely cited 1993 New
England Journal of Medicine article, a conflict of interest is,
“any situation in which an
individual with responsibility to others (which includes
professional responsibilities) might be influenced, consciously
or unconsciously, by financial and personal factors that involve
Such conflicts are not at all unusual.
David Korn, senior vice president
for biomedical and health sciences research at the Association of
American Medical Colleges, noted in 2000 that,
“conflicts of interest and
commitment are ubiquitous in academic life (and indeed, in all
professional life), and conflicting pressures inherent in the
academic milieu, e.g., for faculty advancement, obtaining
sponsored research funding, winning the acclaim of one’s
professional peers, competing for prestigious research prizes,
and yes, desiring to alleviate human pain and suffering, all may
be more powerful in influencing faculty behavior than the
prospect of material enrichment.”
Such conflicts do not in themselves
imply wrongdoing, Korn stressed:
“Since these conflicts can never be
eradicated from professional life, their existence must be
accepted and not equated with professional misconduct.”
To illustrate the dangers allegedly posed by conflicts of interest,
industry critics repeatedly point to a handful of atypical cases
featuring erroneous results, suppressed data, or harmful side
effects. (See “Ties
That Blind,” page 38.)
In addition to such anecdotal evidence,
they cite studies that show a correlation between industry funding
and results that are favorable to the sponsors. As the researchers
themselves acknowledge, however, there are benign explanations for
In 1998 The New England Journal of Medicine published an
article that claimed to show how commercial interests influenced the
scientific evaluation of data on the relative safety and
effectiveness of calcium-channel blockers, a class of drugs used to
control high blood pressure.
The study found that,
“authors who supported the use of
calcium-channel antagonists were significantly more likely
than neutral or critical authors to have financial relationships
with manufacturers of calcium-channel antagonists (96
percent vs. 60 percent and 37 percent, respectively).”
The authors concluded that this,
“strong association” meant the
“medical profession needs to develop a more effective policy on
conflict of interest.”
But the study did not actually
demonstrate that researchers had been inappropriately influenced by
their ties to industry.
The authors acknowledged as much,
“We believe that the authors we
surveyed expressed their own opinions and were not influenced by
financial relationships with pharmaceutical manufacturers.”
If financial relationships had no
clearly discernible influence on the clinicians, what were the
study’s authors concerned about? Appearances.
“We wonder how the public would
interpret the debate over calcium-channel antagonists,”
the authors mused, “if it knew that most of the authors
participating in the debate had undisclosed financial ties with
Reviewing the data from that study,
Thomas Stossel, the Harvard hematologist, noted that consultants
working for companies that were not producing calcium-channel
blockers were as likely to favor the drugs as those that consulted
for companies that did produce them. Do scientists who do consulting
work for one company have an interest in promoting its competitors’
Stossel suggests a more logical
explanation is that the researchers who consult with drug companies
are better informed.
That argument seems credible, especially since, according to a 2002
meta-analysis of blood pressure treatments in the Journal of the
American College of Cardiology, calcium-channel blockers have
turned out to be at least as safe and effective as alternative
drugs. Calcium-channel blockers are still widely used to control
A 2005 study published in The Lancet
found that a combination of calcium-channel blockers and
angiotensin-converting enzyme (ACE) inhibitors was safer
than a more conventional treatment combining diuretics with beta
blockers. People with high blood pressure who take
calcium-channel blockers are significantly less likely to
develop diabetes than those treated with cheaper diuretics.
At the time of the 1998 New England Journal of Medicine
article, activists claimed drug companies were duping physicians and
patients into using more expensive treatments that were no more
effective than earlier, cheaper medicines. Nine years later, further
research shows the situation is more complicated: There is no
one-size-fits-all treatment for hypertension.
Based on what we know now, the more
benign interpretation - that companies consulted with the most
knowledgeable experts rather than that researchers favored companies
that paid them - is more plausible.
A number of other studies have concluded that research results are
biased by industry funding. Thirty-seven of those investigations
were summed up in a review article by three Yale Medical School
researchers that was published in The Journal of the American
Medical Association (JAMA) in 2003.
This meta-analysis found that,
“industry-sponsored studies were
significantly more likely to reach conclusions that were
favorable to the sponsor than were non-industry studies.”
But it also noted that “there are several possible reasons for
this finding. It is possible that, given limited resources,
industry only funds potentially winning therapies.”
That explanation was bolstered by a 2006
study, also published in JAMA, that analyzed the outcomes of 202
randomized trials evaluating cardiovascular drugs reported between
2000 and 2005.
Forty percent of the randomized drug
trials funded by nonprofit organizations favored newer agents,
compared to 54 percent of the jointly sponsored trials and 65
percent of the industry-funded trials.
The authors of the analysis suggested an explanation for these
“When the first trial report of a
truly novel therapy is null or negative, it becomes less likely
that any funding source will support subsequent studies. On the
other hand, when the first trial of a truly novel therapy is
positive, the likelihood of further trials is increased. These
subsequent trials understandably and perhaps appropriately are
more likely to be funded by for-profit organizations.”
In other words, government and
foundations are more likely to fund earlier stages of drug
development, where the risk of failure is higher.
Companies jump in to sponsor drug
research at later stages of development, when success is more
likely. Thus it is not surprising that industry-funded research is
more likely to reach positive conclusions. If a drug company’s
trials regularly turned up negative findings, that would signal
serious flaws in its drug discovery process.
Another concern related to conflicts of interest is that publication
bias dangerously skews the medical literature by favoring studies
that reflect well on new therapies.
“Studies with positive findings are
more likely to be published than studies with negative or null
results,” said American Medical Association trustee
Joseph M. Heyman at the organization’s 2004 meeting.
“We are concerned that this pattern
of publication distorts the medical literature, affecting the
validity and findings of systematic reviews, the decisions of
funding agencies, and, ultimately, the best practice of
Any tendency to put negative results
into a file drawer and forget them can bias reviews of treatments
reported in the medical literature, making them look more effective
than they really are.
Because of the fear that industry funding and commercial motives
skew research results, most prominent life science journals now
require financial disclosures from researchers whose work they
JAMA’s disclosure policy is one of the
more demanding, requiring authors to,
“provide detailed information about
all relevant financial interests and relationships or financial
conflicts within the past 5 years and for the foreseeable future
(e.g., employment/affiliation, grants or funding, consultancies,
honoraria, stock ownership or options, expert testimony,
royalties, or patents filed, received, or pending), particularly
those present at the time the research was conducted and through
publication, as well as other financial interests (such as
patent applications in preparation) that represent potential
future financial gain.”
These disclosures, which must be
included with each manuscript before it’s submitted to peer
reviewers, are typically published on the last page of the article.
Advocates of such precautions argue that they will help restore
public trust in biomedical research. But public trust is already at
a very high level. A 2006 Harris poll found that physicians and
scientists are among the professional groups most trusted by
Americans. Indeed, medicine is the single most trusted profession,
with 85 percent of Americans saying doctors can be trusted to be
Trust in scientists is only slightly
lower, at 77 percent.
More tellingly, a 2006 survey of cancer patients participating in
five research trials found that the vast majority (more than 90
percent) were unconcerned about any financial ties their doctors
might have with drug companies. According to the poll results,
published in The New England Journal of Medicine last
November, large majorities of the patients said they would have
enrolled in the trial even if the drug company had paid the
researcher for speaking or consulting, if the researcher had
received royalty payments, or if he owned stock in the drug company.
More than 80 percent of the patients
believed it was ethical for researchers to receive speaking or
consulting fees from the company. Most patients said they opposed
bans on relationships between researchers and drug companies, and
some said they would be more likely to participate in a trial if a
drug company were involved.
Even among the respondents with at least
some post-graduate training, less than a third said they wanted to
know about potential financial conflicts.
That trust appears to be justified. It’s hard to get firm numbers,
but the Boston-based medical information and publishing firm
CenterWatch, which tracks
clinical trials, estimates that more than 40,000 are in progress,
involving more than 20 million subjects. There are very few
documented examples in which research subjects were seriously
Looking at studies that led to the
approval of one-third of all new drugs between 1987 and 2001,
CenterWatch found that one in 30 subjects experienced a serious
The 2001 report also noted that,
“each year, an average of 3.6 deaths
attributed to study drug effects are reported to the FDA for
The FDA does not collect systematic data
for injuries and deaths in studies of drugs that don’t get approved.
“unlike industry-sponsored clinical
trials that are regulated by the FDA,” CenterWatch noted,
“government-funded studies conducted by individual investigators
at academic medical centers frequently have risks that go
unreported” to the federal Office for Human Research
CenterWatch President Ken Getz
summed up the evidence in a 2002 interview with the San Francisco
“It is not a patient-beware
situation. The vast, vast majority of clinical trial
participants have very positive experiences.”
What about the patients who use drugs
after they’re approved?
“Between 1997 and 2004,” the
pharmaceutical industry critic Sheldon Krimsky noted in a
2005 op-ed piece in the Newark Star-Ledger, “12 major
prescription drugs, with a market value of billions of dollars,
were recalled by the FDA.”
Krimsky claims such dangerous drugs have
been allowed to reach the market because,
“conflicts of interest have become
endemic in the system of drug evaluation,” a trend that “has
been exacerbated by the rise of for-profit clinical trials,
fast-tracking drug approvals, government-industry partnerships,
direct consumer advertising and industry-funded salaries for FDA
regulators” since the mid-1990s.
There’s little evidence that the FDA is
more likely to approve harmful drugs than it was in the past.
A 2005 report by the Tufts University
Center for the Study of Drug Development found that faster
approval times do not correlate with more frequent drug withdrawals.
The share of drugs withdrawn for safety reasons was 3.2 percent in
the 1980s, 3.5 percent in the ’90s, and 1.6 percent from 2000 to
2004. The approval times for drugs that are withdrawn are not
appreciably shorter than the average approval time for all drugs.
the FDA removes dangerous drugs
from the market much sooner than it used to. The average time
between FDA approval and subsequent safety withdrawal dropped from
3.7 years in the 1980s to 1.4 years in the ’90s and is now
seven-tenths of a year.
The bad news is that an overcautious
FDA can kill people too.
A 2005 study by economists at the
University of Chicago calculated that the speed-up in FDA drug
approvals that occurred after 1992 may have been responsible for
saving the equivalent of 180,000 to 310,000 life-years (the sum of
the years of life that would have been lost had the new drugs not
been available). Over the same period, about 56,000 life-years at
worst were lost to drugs that were eventually withdrawn for safety
Unfortunately, it’s much easier to identify people who are harmed by
drugs than those who are saved by drugs.
In the face of this information
asymmetry, regulators tend to focus on reducing lives lost to unsafe
drugs rather than preventing deaths by speeding effective new
therapies to patients.
by Spending More
What about the charge that biased reporting of scientific results
boosts overall medical costs by encouraging physicians and patients
to select new, expensive treatments that are no better than older,
“The cost of pharmaceutical drugs -
and health care in general - in America continues to skyrocket,”
Jennifer Washburn of the New America Foundation wrote in
the June 2005 In These Times.
“Expensive new drugs are
aggressively marketed on TV and in doctors’ offices the moment
they hit the market. Yet physicians warn that many of these
hyped prescriptions are simply ‘me-too drugs’ that vary only
slightly from medications already on the market, despite being
far more expensive.”
Health care as a share of U.S. gross
domestic product has tripled from 5 percent in 1960 to 16 percent
today. Some analyses project the number will reach 25 percent by
But this inflation is not due to
spending on drugs. In a 2002 study for the National Bureau of
Economic Research, the Columbia University economist Frank
Lichtenberg estimated that, on average,
“reducing the mean age of drugs used
to treat a condition from 15 years to 5.5 years… increases
prescription drug spending by $18 [averaged over the total
population] but reduces other medical spending by $129, yielding
a $111 net reduction in total health spending. Most of the
savings are due to reductions in hospital expenditure ($80) and
in physician office-visit expenditures ($24).”
In other words, using newer drugs
reduces other medical expenditures by more than seven times the
extra amount spent on drugs.
30 percent of the $2.2 trillion
Americans spend on health care each year goes to hospitals
physicians get 20 percent
10 percent pays for dental and
other professional services
All of these are labor-intensive
By comparison, prescription drugs
account for about 10 percent of health care spending.
“Within a generation or two,”
Peter Huber of the Manhattan Institute noted in the
July 2006 Commentary, “they will undoubtedly account for most of
it - which will be another good thing. Pharma’s biochemical
cures always end up far cheaper than the people-centered
services they replace.”
Marcia Angell rails against the
pharmaceutical industry’s “obscene profits.”
But Princeton health economist Uwe
Reinhardt told USA Today in October 2006 that he had,
“once calculated that if you rebated
all the drug company profits to patients, health spending would
only go down by 1.2%.”
Seizing drug company profits would do
nothing to address the current health care spending “crisis,” but it
would shut off the flow of funds to many biomedical researchers and
drastically slow the discovery and development of new and more
effective drugs. As for “me-too” drugs, the implication is that
companies are trying to take market share from each other without
providing any “real” benefits to patients.
Of course, “trying to take market share
away” is better known as “competition,” which ultimately results in
Although critics of the drug industry exaggerate the problems
created by conflicts of interest, in rare instances drug companies
have withheld or misreported data, and some researchers have put
their financial gain above the safety of their patients. It
therefore makes sense to keep an eye on potential conflicts.
One safeguard - disclosure in journals - is here to stay.
Even Stossel, a strong proponent
of industry-financed research, favors disclosure.
“To be sure,” he wrote in a February
2005 Forbes column, “it is reasonable to require disclosure of
corporate sponsorship by investigators and institutional
monitoring of collaborations. But academic administrators and
government officials respond to rare incidents of misconduct and
to the barrage of criticism that follows by rushing to pile on
Peer review has been the traditional
means of assuring a study’s validity.
By requiring disclosure, journal editors
are in effect admitting peer review’s failure. Since their reviewers
are not competent to evaluate findings based solely on the data,
warning labels need to be slapped onto industry-funded studies.
And peer review overlooks honest errors
as well as deliberate fraud.
“Peer review doesn’t necessarily say
that a paper is right,” said Martin Blume,
editor-in-chief of the American Physical Society's nine
journals, in a January 2006 interview with Science.
“It says it’s worth publishing.”
Fortunately, a new age of more-robust
peer review is dawning.
With the advent of online journals like
those published by the Public Library of Science (PLoS),
peer review is changing from a one-time appraisal of a
self-contained research article to a continuous online process.
Since 2003 PLoS has launched eight open-access, peer-reviewed
biomedical journals. In 2006 it started a new comprehensive online
journal, PLoS One, which will feature reports of primary research
from all disciplines in the biological and physical sciences.
The editorial board will make prompt
decisions on whether papers merit publication and may refer them to
With PLoS, unlike print journals, publication is not the end of the
peer review process. Once an article has been published in PLoS One,
community-based post-publication peer review begins, in full view of
anyone who visits the site. Post-publication reviewers can post
corrections, additions, or links to other relevant articles. They
can engage in online debates concerning the content, conclusions,
and consequences of a specific paper.
Users can assign ratings to papers.
(Anonymous annotations are not allowed.)
According to the PLoS good practice guidelines, post-publication
reviewers should confine their criticisms to the content of papers
and avoid speculation about the motivations or prejudices of
authors. That may be considered good practice now, but in the future
post-publication reviewers may begin to note any associations they
believe relevant to the findings reported in the paper.
In other words, if a researcher doesn’t
disclose potential conflicts, someone will do it for him.
All the Data
That Are Fit to Post
Private initiatives are also achieving the goal that Sens. Dodd and
Kennedy want to legislate: registration of all clinical trials. In
2004 the International Committee of Medical Journal Editors (ICMJE)
adopted a policy that requires, as a condition of consideration for
publication in their journals, registration of clinical trials in a
Trials beginning after July 1, 2005,
must be registered at or before the onset of patient enrollment. The
ICMJE established criteria that each trial must meet to insure
transparency and required that the registry be accessible to the
public free of charge. At the time, the only website that qualified
ClinicalTrials.gov, run by the
United States National Library of Medicine.
The ICMJE policy has had an effect. After the policy was announced,
the number of clinical trial registrations increased by 73 percent -
from 13,153 to 22,714. As of April 2007, the registry contained over
40,000 trials, with more than 200 new trial registrations occurring
weekly. Now four other clinical trials registries meet the ICMJE
criteria, and many more journals have adopted the ICMJE clinical
trials registration policy.
Also in 2004, the Pharmaceutical Research and Manufacturers
Association announced that it was launching an online registry
of clinical trial results. The association’s members, which include
the world’s leading drug companies, will provide the results of all
clinical trials completed after October 1, 2002, at
And since May 2006, researchers no longer can complain that journal
editors will not publish negative or inconclusive results. PLoS’s
journal PLoS Clinical Trials explicitly addresses the problem
of publication bias: It will publish the results of randomized
trials from all medical and public health disciplines.
Publication does not depend on the
trial’s outcome, size, or implied importance. Even negative results
provide useful information about the effectiveness of treatments,
alerting other researchers not to waste their time and resources on
therapeutic dead ends.
Indeed, researchers arguably have a
moral obligation to publish their results, whether positive or
negative, since subjects undertake risks to generate the data.
Collaboration between academia and industry should be
encouraged, not attacked. In most areas of research, including
computer science, geology, and chemistry, such ties are correctly
seen as a source of innovation that has dramatically improved the
quality of our lives during the last half-century.
Given the potential life-or-death consequences for patients,
collaboration between the pharmaceutical industry and medical
researchers needs to be monitored, and adjustments should be made
whenever abuses come to light.
But through such private efforts as
financial disclosure requirements, registration of clinical trials,
and peer-reviewed publication of all clinical trial results, the
scientific research enterprise has shown itself capable of
protecting the validity of research results without new government
“In a transparent atmosphere,
misconduct can be detected, challenged, and if necessary, purged
and punished,” Stossel noted in his 2005 New England Journal of
“The intense energy currently
dedicated to demonizing academic-industrial research
relationships should be redirected toward developing better ways
to identify and facilitate the type of partnerships that have
brought more good, by far, than harm.”
“The public wants trustworthy
science, and it can get that without new ethical rules. Even
more it wants results - real lives saved - and it can’t get
those if commercial sponsorship of research is made difficult,