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(Drug information on 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 Whittington and associates17 reviewed published data on SSRIs in children and adolescents and compared them with unpublished data obtained by the UK’s Committee on Safety of Medicines (CSM). The CSM obtained the unpublished data during an investigation of SSRI safety in children.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of the published data suggests that SSRIs have a favorable risk-benefit ratio; however, the addition of the unpublished data would suggest an unfavorable riskbenefit profile.17 A review of the unpublished data led Britain’s Medicine and Healthcare Regulatory Authority to ban the pediatric use of all SSRIs other than fluoxetine(Drug information on 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(Drug information on 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 highimpact 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 peerreviewed papers often differs from the conclusions of independent authors. An industry-supported paper on donepezil(Drug information 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, nonindustry-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(Drug information on 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(Drug information on 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 physician’s 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.