Whether paroxetine, a selective serotonin reuptake inhibitor made by GlaxoSmithKline, should be prescribed to depressed children and adolescents has been the subject of recent clinical controversy (see Lancet 2004; 363: 1335). Debate over the drug's efficacy and safety has been mostly confined to the academic medical and drug-regulatory communities. But last week the issue was catapulted into a much wider arena, with the filing of a lawsuit against GSK in New York by that state's Attorney General, Eliot Spitzer. The state accuses the company of fraud, by depriving consumers of the information they and their doctors need to make informed decisions about treatment, and seeks the return of all profits obtained through fraudulent means.
The stakes are high, for all concerned. GSK's net income in 2002 was more than US$6.9 billion, and in the first quarter of 2004, sales of paroxetine were $533 million. 2.1 million paroxetine prescriptions for children were written in the USA in 2002.
The story of this drug has been full of twists and turns, approvals and warnings. Paroxetine is approved for the treatment of various psychiatric disorders in adults but is not approved, either in Europe or North America, for use in patients younger than 18. But not uncommonly, doctors can prescribe drugs for unapproved indications, if they believe this is in the best interest of the patient. “Off-label” prescribing in the USA is governed not by the Food and Drug Administration (FDA) but by individual states, which regulate the practice of medicine. So the state of New York can claim a fiduciary duty to protect patients.
Paroxetine's safety and efficacy in children have been tested in at least five studies sponsored by GSK, only one of which has been published. Although that trial's results were mixed, they were heralded in a memorandum entitled “Paxil demonstrates REMARKABLE Efficacy and Safety in the treatment of adolescent depression”. The other studies showed either mixed or negative results: paroxetine was no better than placebo at treating depression in children, and was associated with a possibly increased risk of suicidal thinking and acts. What constituted suicidal behaviour was eventually coded as “emotional lability”. Doctors were able to obtain some, though not all, of this information, only by specific request.
An internal memorandum issued at GSK in 1998, now disavowed, was aimed at managing “the dissemination of these data in order to minimize any potential negative commercial impact”.
The lawsuit alleges that GSK suppressed the results of these studies, failing to make them available to doctors, in a demonstration of “repeated and persistent fraud”. By providing only partial information about safety and efficacy, GSK caused doctors to have a biased and misleading picture of the drug. Doctors were thus unable to assess the balance of its risks and benefits and could not discharge their professional duties to their patients.
GSK maintains that it has “acted responsibly” in undertaking studies and in disseminating their results. Disclosure of the results, however, by GSK's own admission, has been limited to the FDA and other regulatory agencies. The company claims to “have publicly communicated data from all pediatric studies”, apparently in abstract form at conferences attended almost exclusively by specialists.
GSK appears to be floundering in the semantic depths. While it has been earnestly parsing the meaning of “suicidal thinking and acts” and “publicly”, it appears to have forgotten what lies behind those words—people. People enrolled in GSK's studies; people bought the drug; people gave consent to participate in trials, presumably believing the results would be made public. Many researchers and journals have argued strongly that all clinical trials should be registered and all their results published. But as the lawsuit pointedly demonstrates, the time has come for these matters to be revealed in a bright and public light. By moving the issue into the public sphere, the pharmaceutical industry may be forced to acknowledge that all its results, whether positive or negative, are obtained only by virtue of the voluntary cooperation of the public.
This contest ought to follow the example set by recent tobacco-company litigation. GSK must create a public archive of all documents relating to paroxetine in under-18s. If GSK has nothing to hide, as it claims, it should open its files before being ordered to do so by a court—and do so right now.
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