Commercial Influence on Psychiatric Drug Studies
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The standard biomedical paradigm for drug treatment of disease follows a straightforward algorithm. A
disease is identified and diagnostic criteria are developed. Promising medications are tested using the
scientific method, especially randomized controlled trials (RCTs), to determine safety and efficacy. The
results of these studies are presented to the scientific community in peerreviewed journals and scientific
debate occurs.
If a drug is approved by the FDA, the results of the trials and the conflicting scientific opinions are
presented to physicians. Practicing psychiatrists must evaluate the results for their own patients and
decide whether the benefits of a medication outweigh its shortcomings.
In this article, we discuss evidence that the pharmaceutical industry influences this paradigm in ways
that encourage sales of their products and that are not always in the best interests of the patient.
Expanding the indications: new diseases
An investigative article in the British Medical Journal by Moynihan and associates1 describes how drug
companies developed an explicit campaign to promote shyness as an important and treatable disorder,
successfully shaping medical and public opinion about social phobia. A senior pharmaceutical industry
executive involved in the promotion of social phobia in Australia acknowledged that marketing efforts
exaggerated the prevalence of disease, and recognized the inherent conflict of interest when a drug
company sponsors publicity about a disease for which it markets a treatment, as his company did with
social phobia.2
An article in the Pharmaceutical Executive (a trade journal) discusses generally the making of a new
disease, and how new markets can be created by defining a new disease (such as the metabolic
syndrome).3 Another way to expand indications for a drug (and thus the market) is to lower the
threshold of normal, rendering more people ill and in need of medication. Some critics think that
pharmaceutical companies have succeeded in medicalizing risk factors or normal experiences, thus
making otherwise healthy people think they need certain drugs.4
Pharmaceutical companies have successfully expanded the FDA approved uses of various selective
serotonin reuptake inhibitors (SSRIs) to include a variety of psychiatric diseases, such as generalized
anxiety disorder, obsessive-compulsive disorder, premenstrual dysphoric disorder, posttraumatic stress
disorder, and bulimia nervosa.5 Trials for many offlabel uses such as premature ejaculation, migraine
headache prophylaxis, and neurocardiogenic syncope are conducted and offlabel uses are often
suggested.6 Drug company efforts to get patients on treatment have been motivated by a variety of
reasons. Although there is no doubt that some patients have benefited from the promotion of treatment
for these syndromes, drug company sales have certainly increased.
[Size=4]In Australia, where direct-toconsumer advertising (DTCA) is not permitted, the value of campaigns
promoting diseases can be clearly seen. At the same time that Mercks hair growth drug finasteride was
approved in Australia, a public relations firm hired by the manufacturer launched a vigorous campaign
about the dangers and tragedy of baldness. Eventually, newspapers published articles about the
emotional trauma associated with hair loss, including expert opinions that losing hair could lead to
emotional problems, harm to mental well-being, and loss of job prospects. These articles did not reveal
that the studies they cited were funded by Merck, and that the experts quoted had been supplied by the
companys public relations firm.[/size]1
Industry funding in the peerreviewed published literature
For many practicing psychiatrists, the results of peer reviewed, published RCTs are an essential element
in making treatment decisions about drug therapy. A systematic review of all clinical trials published in
4 leading, peer reviewed psychiatry journals from 2001 to 2003 found that pharmaceutical sponsorship
was common and was statistically associated with outcomes that favored the sponsor.7 Of the 162 RCTs
published during this time, 70% were funded by pharmaceutical companies and 46% had at least 1
author who had a financial conflict of interest either through employment or by having received direct
financial support from a pharmaceutical company. Studies with at least 1 author with a conflict of
interest were about 5 times more likely to report positive results than were non industry sponsored
studies.7
This article can only point to a strong correlation between industry sponsored studies and the reporting of
positive results but cannot establish causation. A summary of the types of design and reporting
modifications that have been used in industry sponsored psycho pharmacology trials is presented in the
Table.
Clinical trials research on atypical or secon dgeneration antipsychotics (SGAs) provides an example of
this association between a trials sponsorship and its outcome.9 Of 59 RCTs studying SGAs, those
sponsored by the vendors of SGAs were significantly more likely to find them superior to first generation
anti psychotics than were non industry-funded RCTs (P = .02). Furthermore, studies with first authors
employed by the industry showed a strong trend (P = .05) toward favoring SGAs over conventional
antipsychotics, compared with articles whose first authors were independent of industry.
Could the industry-sponsored trials simply have been bigger, better, and more able to identify a true
superiority of the sponsored drug? Two lines of evidence argue against this possibility. First, the
researchers who reported this difference in outcome found a trend (P = .07) toward higher overall RCT
quality score in the studies that were not industry funded. The second line of evidence is indirect. A
review by Hogan and associates10 of studies comparing one cholinesterase inhibitor with another for
Alzheimer disease (AD) concluded that, All studies were funded by pharmaceutical companies,
coauthored by their employees, and reported results that favoured the sponsors product. Similarly,
industry-funded studies that compared 2 long-acting inhaled corticosteroids and found a difference
between them, found evidence in favor of the sponsors product in 37 of 38 of the peer-reviewed
published RCTs.
Negative trials that disappear: SSRIs
Pharmaceutical sponsorship is widespread in the SSRI research literature; 96% of comparative trials
involving SSRIs published from 1980 to early 2005 received some form of industry support.12 In 2003,
Melander and associates13 found that when data submitted to the Swedish drug regulatory authority
were compared with the published literature on SSRIs, several negative industry-sponsored trials were
identified that had never been published or had appeared only within publications reporting pooled data.
In contrast, positive data were often published more than once, both as standalone publications and in
publications that pooled data. Of the 42 studies submitted to the agency, only half showed the SSRI to
be better than placebo and 19 of these 21 were published in 22 standalone publications. Of the 21 studies
that showed nonsignificant differences, only 6 were published in stand-alone publications. The
International Committee of Medical Journal Editors now requires registration of all clinical trials, which
will make it more difficult to conceal negative data.14
In at least 1 context, the suppression of negative studies on SSRIs has proved to be deliberate and
explicit. An internal document released by Glaxo- SmithKline written in 1998 discussed how to manage
the results of 2 negative clinical trials of paroxetine in the pediatric population. The document stated that
the clinical trials results were insufficiently robust to support an application for a regulatory approval for
use in pediatric depression and recommended that the company effectively manage the dissemination of
these data in order to minimize any potential negative commercial impact. It went on to state, It would
be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this
would undermine the profile of paroxetine.15 Only 1 of 3 studies of paroxetine in children was
eventually published.16
Selective publication may affect clinicians impressions of safety as well as efficacy. Whittington and
associates17 reviewed published data on SSRIs in children and adolescents and compared them with
unpublished data obtained by the UKs Committee on Safety of Medicines (CSM). The CSM obtained
the unpublished data during an investigation of SSRI safety in children. The meta-analysis of the
published data suggests that SSRIs have a favorable risk-benefit ratio; however, the addition of the
unpublished data would suggest an unfavorable risk benefit profile.17 A review of the unpublished data
led Britains Medicine and Healthcare Regulatory Authority to ban the pediatric use of all SSRIs other
than fluoxetine. In contrast, the research rhetoric of the sponsored trials tends to spin the meaning of the
findings in published, positive studies.14 One published trial, for example, concluded that paroxetine is
generally well tolerated and effective for major depression in adolescents.18
The rhetoric and discourse of science
The use of ghostwriting and public relations/marketing firms has become commonplace. During the
course of a lawsuit, it was disclosed that 85 internal documents about sertraline were coordinated or
prepared for Pfizer by a medical information company. Article drafts had been prepared, then awaited an
author with good academic credentials, often to be determined, to be added before submission to a
high impact journal. Articles coordinated by the medical information company were published in bigger
name journals (with higher impact factors) and were likely to be cited more often than articles not
prepared by the company.19
Internal memos outline how SmithKline Beecham used a public relations firm to ghostwrite letters to the
editor to counterattack claims by a rival drug maker about discontinuing paroxetine because of side
effects.20 The willingness of academics to participate in this strategy is a sad chapter indeed in the
history of science.
Industry-sponsored rhetoric in peer reviewed papers often differs from the conclusions of independent
authors. An industry-supported paper on donepezil states that use of the drug is associated with delayed
nursing home placement in patients with AD and concludes with the statement: . . . doctors and
caregivers need to be educated that, in the same way as the actual benefits of treating hypertension or
hyperlipidemia are seen only after years of treatment, treatment of AD with donepezil needs to be
maintained to see important long-term benefits.21 In comparison, an independent, systematic,
non industry-sponsored review concludes: Because of flawed methods and small clinical benefits, the
scientific basis for recommendations of cholinesterase inhibitors for the treatment of AD is questionable.
22
Translating the research findings into practice
How the findings of clinical trials are translated into clinical practice is a key feature in the evolution of
medical care. The pharmaceutical industry is heavily involved in this aspect of drug use. An analysis of
the exhibition hall at the 2002 American Psychiatric Association (APA) Annual Meeting showed that
54% of all companies with booths were in violation of APA or FDA rules about marketing to
physicians.23 One drug company brought in more than 30 psychiatrists from Mexico to the APA
meeting in 2002, all expenses paid, a practice that is against the PhRMA Code of Interactions with
Health Care Professionals24 and the AMA Code of Ethics.25
The character and extent of promotional activities can be extravagant. In 2004, the vendors of
gabapentin agreed to plead guilty and pay more than $430 million to resolve criminal charges and civil
liabilities in connection with their illegal and fraudulent promotion of the drug.26
DTCA is an acknowledged marketing technique. Advertisements for paroxetine, marketed for social
anxiety disorder, and atomoxetine, marketed for adult attention deficit disorder, take common symptoms
experienced at least occasionally by many healthy people (eg, fear of public speaking, being distracted
and disorganized) and suggest that these may be symptoms of a treatable disease, which should be
discussed with physicians.26
The effectiveness of DTCA, from an industry point of view, is suggested by a comparative study of
patients in the United States with those in Canada (where DTCA of prescription drugs is illegal). More
of the US patients requested drugs that were advertised on television, and US patients were more likely
to leave the physicians office with a new prescription. About half the time, however, the prescribing
physicians felt that these new prescriptions were unlikely or only possible choices for patients with those
complaints.28
Conclusion
Industry influence in clinical trials is here to stay. The pharmaceutical industry funds the majority of
clinical trials, spending about $12 billion in 2002.29 This spending has led to advances in science and
the discovery of new drugs that have benefited patients enormously. The industry also spends large
sums to promote their products, many of which provide little actual benefit at great expense to patients.
By itself, industry sponsorship does not mean that a clinical trial is flawed; however, the corporations
fiduciary duty to make profits for their stockholders virtually ensures that promotional considerations
will affect the way diseases are identified, drugs are studied, studies are written, decisions are made
about publication, and information from the sponsored trials is disseminated.
The increased transparency that will come from the registration of clinical trials13 and the more stringent
rules concerning disclosure of conflict of interest are important steps in trying to limit promotional
influences on putatively scientific activities. Nonetheless, the psychiatric literature will likely continue
to be contaminated by rhetoric that promotes the use of drugs or touts the superiority of one drug over
another on the basis of questionable data. The challenge for physicians is obvious.
Dr Shah is a clinician-educator fellow in geriatrics at the Johns Hopkins School of Medicine in
Baltimore. He is board-certified in internal medicine. Dr Finucane is professor of medicine, chair of the
ethics committee, and a clinician at the Johns Hopkins Bayview Medical Center in Baltimore. The
authors report no conflicts of interest concerning the subject matter of this article.
liabilities in connection with their illegal and fraudulent promotion of the drug.26
Commercial Influence on Psychiatric Drug Studies.pdf (26.9 KB)
