-Caveat Lector-
http://www.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.
References on his website.
--
To: Blockbuster Video - This petition is meant to show Blockbuster Video that the DVD
community does want rent and/or purchase widescreen DVDs. The film studios actually
listen to Blockbuster, and if they see that Blockbuster is only stocking Full Frame
DVDs, it could ruin the entire DVD format for those who enjoy true film.
http://www.petitiononline.com/widedvd/petition.html
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