Research
and Drugs How Investigators are Influenced
http://mercola.com/2000/may/21/research_and_drugs.htm
Drug companies that pay for
research and clinical tests of new medicines have been
suppressing or manipulating the results. The prestigious,
peer-reviewed Journal also warned the likelihood
that drug test results will be manipulated or suppressed is
even greater when for-profit companies set up specifically to
test drugs conduct the trials.
The findings and the drug
studies, along with a sharply
worded editorial where Dr. Marcia Angell raises the
question "Is Academic Medicine For Sale?" appears
one week after the Journal's
publisher, the Massachusetts Medical Society, announced it
would replace her as editor with a prominent asthma researcher
who has strong ties to the drug industry.
This report comes at a time
when "academic medical centers are no longer the sole
citadels of clinical research and the industry is wielding
more power in conducting large-scale drug tests. Six of the 12
investigators interviewed cited cases of articles whose
publication was stopped or whose content was altered by the
funding company. The companies are not identified.
In one instance, a drug
maker delayed publication of a study's results by requesting
changes to the manuscript to make the product look better.
During the delay, the company secretly wrote a competing
article on the same topic, which was favorable to the
company's viewpoint.
Another investigator found
that a drug he was studying caused adverse reactions. He sent
his manuscript to the sponsoring company for review. The
company vowed never to fund his work again
and published a competing article with scant mention of the
adverse effects.
The New
England Journal of Medicine -- May 18, 2000 -- Vol. 342, No.
20
The following is the full
article that appears in this week's New England Journal:
Uneasy Alliance --
Clinical Investigators and the Pharmaceutical Industry
Thomas Bodenheimer
Clinical practice is
changing rapidly. New cardiovascular drugs, antiinflammatory
drugs, cancer chemotherapy, and other pharmacologic weapons
are being added to physicians' therapeutic armamentarium
virtually daily. Most clinical studies that bring new drugs
from bench to bedside are financed by pharmaceutical
companies. Many of these drug trials are rigorously designed,
employing the skills of outstanding clinical researchers at
leading academic institutions.
But academic medical
centers are no longer the sole citadels of clinical research.
The past 10 years have seen the spectacular growth of a new
research model. Commercially oriented networks of
contract-research organizations (CROs) and site-management
organizations (SMOs) have altered the drug-trial landscape,
forcing academic medical centers to rethink their
participation in industry-funded drug research.
The infusion of industry
dollars into an industry-investigator partnership has clearly
improved clinical practice. Yet the medical literature
contains many articles expressing concern about industrial
funding of clinical research. Stelfox et al. found that
authors whose work supported the safety of calcium-channel
antagonists had a higher frequency of financial relationships
with the drugs' manufacturers than authors whose work did not
support the safety of these medications. (1) Davidson reported
that results favoring a new therapy over a traditional one
were more likely if the study was funded by the new therapy's
manufacturer. (2) Cho and Bero demonstrated that articles from
symposiums sponsored by a single drug company were more likely
than articles without company support to have outcomes
favorable to the sponsor's drugs. (3) Friedberg et al.
reported that 5 percent of industry-sponsored pharmacoeconomic
studies of cancer drugs reached unfavorable conclusions about
the company's products, as compared with 38 percent of studies
with nonprofit funding that reached similar conclusions. (4)
How much influence does
industry have over the work and products of the research
community? Can practicing physicians trust the information
they receive about the medications they are prescribing? Does
the shift from the academic to the commercial research sector
give industry too much control over clinical drug trials?
In this report, I discuss
some of the problems raised by pharmaceutical-industry funding
of drug trials, problems that may deepen as trials are
increasingly conducted by commercial organizations. I
interviewed 39 participants in the process: 6 pharmaceutical
executives, 12 clinical investigators, 9 people from
university research offices, 2 physicians with CROs, 8 people
who have studied the process of clinical drug trials, and 2
professional medical writers. Each interview consisted of
standard questions plus an opportunity for the interviewees to
discuss the industry-investigator relationship in a general
way. Several interviewees preferred not to allow the use of
their names in the article.
The Clinical-Drug-Trial
System
The Food and Drug Administration (FDA) requires manufacturers
to show that their products pass tests of efficacy and safety.
(5,6) For such drugs as antibiotics for acute infections,
large populations and long time lines are seldom needed to
establish efficacy and safety. With the new emphasis on
prevention and treatment of chronic diseases, however,
clinical drug research has changed. Many people must take
antihypertensive drugs and lipid-lowering drugs for many years
in order to prevent relatively few undesired clinical end
points. (7) To establish the efficacy and safety of preventive
products and products designed to treat chronic disease,
clinical trials must be large, lengthy, and conducted at
multiple centers, because a single site cannot recruit enough
patients to ensure statistical validity.
The average cost of
developing one new drug is estimated to be $300 million to
$600 million. (8) Of the $6 billion in industry-generated
money for clinical trials worldwide yearly, about $3.3 billion
goes to investigators in the United States. (9) Seventy
percent of the money for clinical drug trials in the United
States comes from industry rather than from the National
Institutes of Health (NIH).
The Shift to Commercial
Drug Networks
Until recently, the pharmaceutical industry needed academic
physicians to perform drug trials for three reasons: companies
did not have the in-house expertise to design trials
themselves, academic medical centers provided patients as
subjects for trials, and companies needed the prestige of
academic publications to market their products. Lately,
industry's dependence on academia has weakened: industry
employs top-level research physicians to design and interpret
drug trials, and community physicians have become a reliable
source of patients.
Moreover, pharmaceutical
firms are frustrated with academic medical centers. Most
medical schools and teaching hospitals require that
industry-investigator agreements be approved by an office of
sponsored research. Slow review of industry proposals by
academic research offices and institutional review boards
(which must review all trials to protect patients' safety
(10)) delays the starting dates of trials. Since academic
physicians have multiple responsibilities in teaching,
research, and patient care, trials may proceed more slowly
than the pharmaceutical firms desire. For each day's delay in
gaining FDA approval of a drug, the manufacturer loses, on
average, $1.3 million. Speed is paramount for pharmaceutical
firms.
To expedite trials,
industry is turning from academic medical centers to a growing
for-profit marketplace whose key players are CROs and SMOs.
(11,12,13) In 1991, 80 percent of industry money for clinical
trials went to academic medical centers; by 1998, the figure
had dropped precipitously to 40 percent. (14) Evidence
suggests that the commercial sector completes trials more
rapidly and more cheaply than academic medical centers. (11)
Because multicenter trials
may involve hundreds of sites and investigators, few
pharmaceutical manufacturers choose to manage the trials
themselves. CROs, which employ physician-scientists,
pharmacists, biostatisticians, and managers, offer
manufacturers a menu of services. Large drug companies often
create their own study designs and contract with CROs to
develop a network of sites, implement the trial protocol at
those sites, and send report forms to the sponsoring company,
which performs the data analysis. Smaller pharmaceutical firms
may hire a CRO to manage the entire trial, including study
design, data analysis, and preparation of FDA applications and
journal articles. Several hundred CROs compete for the
drug-trial business; the largest are Quintiles Transnational
and Covance.
CROs may use both academic
medical centers and community physicians to recruit patients
for a trial. In the community arm of drug trials, yet another
intermediary has entered the picture, the SMO. CROs may
subcontract with for-profit SMOs to organize networks of
community physicians, ensure rapid enrollment of patients, and
deliver case-report forms to the CRO. Some trials have four
layers (manufacturer, CRO, SMO, and physician-investigator), a
situation reminiscent of the multitiered managed-care model
(employer, health maintenance organization, independent
practice association, and physician). Three of the largest
SMOs are Clinical Studies Limited, Hill Top Research, and
Affiliated Research Centers. SMOs provide community-physician
investigators with administrative support and help market
investigators' services to pharmaceutical companies. (15) They
have been criticized for producing data of poor quality,
inadequately training investigators, and costing more than a
system of independent sites unassociated with an SMO. (13,15)
Competition for drug-trial
money has stiffened as hundreds of CROs, SMOs, academic
medical centers, and independent nonacademic sites scramble
for a larger piece of the pie. According to Gregg Fromell of
Covance, a leading CRO, "academic medical centers have a
bad reputation in the industry because many overpromise and
underdeliver." In contrast, critics, including Dr. Sidney
Wolfe of Public Citizen, view CROs and the commercial
drug-trial network as handmaidens of pharmaceutical companies,
concerned with the approval and marketing of drugs rather than
with true science. Whereas the academic and commercial
drug-trial sectors can be seen as distinct networks with
conflicting cultures, they also interlock, since CROs often
act as intermediaries between drug companies and academic
investigators.
Several academic medical
centers are fighting to regain lost market share, transforming
themselves into research networks to compete with the
commercial drug-trial sector. (14,16) Columbia University,
Cornell University, and New York Presbyterian Hospital have
created a Clinical Trials Network as a joint venture. With
funding from both industry and NIH sources, the network brings
together academic researchers and community-based physicians
in cardiology, hepatology, neurology, and oncology. The
network has instituted required training for all participants
and has centralized contracting, budgeting, and reimbursement
systems. The network plans to be financially self-sufficient
in a few years. Director Michael Leahey says, "Our goal
is to take clinical research back from for-profit companies
and place it where it rightfully belongs -- in networks that
are partnerships between academic medicine and community
practice. We are trying to formulate a real alternative to the
for-profit drug-trial entrepreneurs."
In 1997 the University of
Pittsburgh Medical Center Health System chartered the
Pittsburgh Clinical Research Network (PCRN), a single point of
contact between industry and clinical researchers in academic
and community sites. PCRN provides the administrative
procedures associated with clinical trials in such areas as
contracting, institutional-review-board approval, and project
management. Academic research expertise and a large hospital
and community-practice network give PCRN resources unavailable
to most commercial SMOs. PCRN's medical director, David
Watkins, feels that "academic medical centers are
sleeping giants that are beginning to awaken and respond to
industry's needs."
Duke University and the
University of Rochester are also leaders in developing
academic clinical-research networks. Some academic medical
centers will probably succeed in revamping their drug-trial
business; others will fail.
Industry-Investigator
Relationships Trial
Design
A company seeking FDA
approval for a product often designs a clinical trial in its
research division and circulates the proposed design to
recognized investigators in that field. If the company has no
in-house expertise, outside investigators are asked to design
the trial. In some cases, company and academic investigators
form a steering committee to discuss a trial protocol. In an
interview, Dr. Thierry LeJemtel, of the Albert Einstein
College of Medicine Division of Cardiology, said that 20 years
ago outside investigators designed the studies, but that now
companies write the protocols and bring in outside
investigators pro forma, with little intention of changing the
study design. In-house control is more likely in the
commercial sector than in the academic sector, because of the
limited expertise of many community-physician investigators.
Sometimes an investigator
will propose a drug trial to the drug's manufacturer. Two
investigators interviewed, including Steven Cummings,
professor of medicine and epidemiology at the University of
California at San Francisco, found that companies' marketing
departments, which often rule on studies to be conducted after
a drug has received FDA approval, declined to fund clinically
important studies at least partly because the results might
reduce sales of the drug.
Companies may design
studies likely to favor their products. Bero and Rennie, in an
article worth study by all physicians, catalogue the methods
companies can use to produce desired results. (17)
If a drug is tested in a
healthier population (younger, with fewer coexisting
conditions and with milder disease) than the population that
will actually receive the drug, a trial may find that the drug
relieves symptoms and creates fewer adverse effects than will
actually be the case. (17) Rochon et al. found that only 2.1
percent of subjects in trials of nonsteroidal antiinflammatory
drugs were 65 years of age or older, even though these drugs
are more commonly used and have a higher incidence of side
effects in the elderly. (18)
If a new drug is compared
with an insufficient dose of a competing product, the new drug
will appear more efficacious. (17) Rochon et al. concluded
that trials of nonsteroidal antiinflammatory drugs always
found the sponsoring company's product superior or equal to
the comparison product; in 48 percent of the trials, the dose
of the sponsoring company's drug was higher than that of the
comparison drug. (19) According to Johansen and Gotzsche, most
trials comparing fluconazole with amphotericin B used oral,
not intravenous, amphotericin B, thereby favoring fluconazole,
because oral amphotericin B is poorly absorbed. (20)
Clinical trials often use
surrogate end points that may not correlate with more
important clinical end points. Companies may study many
surrogate end points and publish results only for those that
favor their product. (7,17,21)
Data Analysis
A study's raw data are
generally stored centrally at the company or CRO.
Investigators may receive only portions of the data. Some
principal investigators have the capacity to analyze all the
data from a large trial, but companies prefer to retain
control over this process.
A physician-executive at
one company explained, "We are reluctant to provide the
data tape because some investigators want to take the data
beyond where the data should go." Several investigators,
including Dr. LeJemtel, countered that industry control over
data allows companies to "provide the spin on the data
that favors them." In the commercial sector, where most
investigators are more concerned with reimbursement than with
authorship, industry can easily control clinical-trial data.
Publishing the Results
For academic investigators,
publication in peer-reviewed journals is the coin of the
realm. For pharmaceutical firms, in contrast, the essential
product is the new-drug application to the FDA. In the absence
of FDA approval, no journal article is worth a cent to a drug
company. Yet publication in prestigious journals is important,
to persuade physicians to prescribe the company's products.
Some multicenter trials
have publication committees, which may be dominated by
in-house or outside investigators, that write up the results
for publication. In other cases, the company or CRO writes the
reports for publication, circulating draft manuscripts to the
investigators who will be listed as authors. Authorship may be
determined by such criteria as who participated in designing
the study, who enrolled the most patients, and who has a
prominent name in the field.
Control over Publication
Many academic medical
centers review contracts between industry and investigators,
insisting on the investigator's right to publish the trial's
results and allowing the company prepublication review, with a
time limit of 60 to 90 days. Nikki Zapol, head of the
sponsored-research office of Massachusetts General Hospital,
estimates that 30 to 50 percent of contracts submitted by
companies have unacceptable publication clauses that must be
renegotiated.
In a survey of life-science
faculty members, 27 percent of those with industry funding
experienced delays of more than six months in the publication
of their study results. (22) Chalmers argues that the results
of substantial numbers of clinical trials are never published
at all. (23)
In 1996, Canadian
investigator Nancy Olivieri and colleagues found that
deferiprone, used to treat thalassemia major, could worsen
hepatic fibrosis. Apotex, the sponsoring company, threatened
legal action if Olivieri published the findings. The contract
between Apotex and Olivieri forbade disclosure of results for
three years after the study without the company's consent. An
article was eventually published. (24,25)
In 1987, the manufacturer
of Synthroid (levothyroxine) contracted with University of
California researcher Betty Dong to study whether Synthroid
was more effective than competing thyroid preparations. In
1990, Dong found Synthroid to be no more effective than other
preparations, including generic preparations. The sponsoring
company refused to allow the findings to be published; the
contract with Dong stipulated that no information could be
released without the consent of the manufacturer. An article
was finally published in 1997. (26)
Six investigators
interviewed for this report cited cases of articles whose
publication was stopped or whose content was altered by the
funding company. In one case, according to Dr. Cummings, the
company held up the prepublication review process for over
half a year, then requested pages of detailed revisions that
would have made the manuscript more favorable to the company's
official marketing position. During the delay, the company
secretly wrote a competing article on the same topic, which
was favorable to the company's viewpoint.
In another case, the drug
being investigated did not work. The investigator argued that
scientific integrity required publishing the findings. The
company never refused to publish, but it stalled until the
investigator lost interest.
Another investigator, most
of whose relations with industry have been without problems,
related the case of two trials of the same drug, one more
favorable to the company. Despite a protest from the
investigator, the results of the less favorable trial were
never published.
A fourth investigator found
that a drug he was studying caused adverse reactions. He sent
his manuscript to the sponsoring company for review. The
company vowed never to fund his work again and published a
competing article with scant mention of the adverse effects.
Dr. Curt Furberg, professor
of public health sciences at Wake Forest University School of
Medicine and principal investigator in a study whose results
were unfavorable to the sponsoring company, refused to place
his name on the published results of the study, because the
sponsor was "attempting to wield undue influence on the
nature of the final paper. This effort was so oppressive that
we felt it inhibited academic freedom." (27)
A sixth investigator
recounted two examples of suppressed manuscripts regarding
negative studies whose results were sufficiently important to
publish.
In scenarios such as these,
the frequency of which is unknown, companies repeatedly delay
publication, eventually exhausting investigators who are busy
with other projects. One industry executive explained that
such cases result from priority setting within the company;
with limited personnel to produce publications, certain trials
take precedence over others. However, as one investigator
described it, "when results favor the company, everything
is great. But when results are disappointing, there is
commonly an effort to spin, downplay, or change
findings." A CRO executive added that "industry
obstruction to publishing is a big problem. They are nervous
if bad data comes out and gets into the mass media."
Investigators in the commercial sector may be less concerned
than those in academia with contract clauses guaranteeing
their right to publish, thereby giving industry greater
control over publications.
Authorship
In the past, publications
were written by a study's principal investigator. More
recently, a practice that one might call the nonwriting
author-nonauthor writer syndrome has developed. Many
interviews conducted for this report confirmed the wide
prevalence of this syndrome in publications of drug-trial
reports, editorials, and review articles. The syndrome has two
features: a professional medical writer
("ghostwriter") employed by a drug company, CRO, or
medical communications company, who is paid to write an
article but is not named as an author; and a clinical
investigator ("guest author"), who appears as an
author but does not analyze the data or write the manuscript.
(28,29,30) Ghostwriters typically receive a packet of
materials from which they write the article; they may be
instructed to insert a key paragraph favorable to the
company's product.
The nonwriting author, who
may be uninvolved in the research and have been requested to
author the article to enhance its prestige, has final control
over the manuscript. But many of these authors are busy and
may not perform a thorough review. This guest-ghost syndrome
(31,32) is a growing phenomenon, particularly in the
commercial sector, where community-physician investigators
have little interest in authorship.
In one study, 19 percent of
the articles surveyed had named authors who did not contribute
sufficiently to the articles to meet the criteria for
authorship of the International Committee of Medical Journal
Editors. Eleven percent had ghostwriters who contributed to
the work but were not named as authors. (33,34) In justifying
the nonwriting author-nonauthor writer syndrome, one industry
executive explained that professional medical (ghost) writers
are well trained, that investigators may be too busy to write,
and that "nonwriting authors" are at fault if they
do not carefully review ghostwritten manuscripts. An
alternative view, articulated by Eric Campbell, of the
Institute for Health Policy at Massachusetts General Hospital
and Harvard Medical School, holds that "a manuscript
represents the accumulation of the intellectual and physical
processes conducted under the aegis of a study and should be
produced by the people who have actually been involved in the
design, conduct, and supervision of the research." Tim
Franson, Vice President for Clinical Research and Regulatory
Affairs at Eli Lilly, believes that "any parties, be they
industry staff, investigators, or others who contribute to the
content of articles should have their names listed on the
article."
Conclusions
Without industry funding, important advances in disease
prevention and treatment would not have occurred. In the words
of Lee Goldman, chairman of the Department of Medicine,
University of California at San Francisco, "companies
translate biologic advances into useable products for
patients. They do it for a profit motive, but they do it, and
it needs to be done." Investigators interviewed for this
report confirmed that many collaborations with pharmaceutical
companies were conducted on a high professional level.
But when results are
disappointing for a company, conflicts may develop. Dr.
Furberg, with years of experience in industry-funded drug
trials, stated: "Companies can play hardball, and many
investigators can't play hardball back. You send the paper to
the company for comments, and that's the danger. Can you
handle the changes the company wants? Will you give in a
little, a little more, then capitulate? It's tricky for those
who need money for more studies."
Although academic-industry
drug trials have been tainted by the profit incentive, they do
contain the potential for balance between the commercial
interests of industry and the scientific goals of
investigators. In contrast, trials conducted in the commercial
sector are heavily tipped toward industry interests, since
for-profit CROs and SMOs, contracting with industry in a
competitive market, will fail if they offend their funding
sources. The pharmaceutical industry must appreciate the risks
inherent in its partnership with the commercial drug-trial
sector: potential public and physician skepticism about the
results of clinical drug trials and a devaluation of the
insights provided through close relationships with academic
scientists.
A number of authors have
recommended changes to resolve the problems of clinical drug
trials. (11,35,36,37) An essential ingredient of any solution
is increasing the independence of investigators to conduct and
publish their research. Some investigators interviewed for
this article felt that drug trials should be funded by
industry but that design, implementation, data analysis, and
publication should be controlled entirely by academic medical
centers and investigators. The rise of the commercial sector
-- which reduces rather than enhances the independence of
investigators -- appears to be moving drug trials in the
opposite direction.
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