GlaxoSmithKline, Paxil and selective serotonin reuptake inhibitors (SSRIs). It was the story that foreshadowed and strikingly paralleled the controversy surrounding Merck, Vioxx and Cox-2 inhibitors.
Longstanding evidence of harm from a heavily advertised, blockbuster medicine. Company and regulatory refusal to consider disturbing evidence of dangerous side effects. Suppression of Food and Drug Administration (FDA) regulators willing to look coldly at the evidence. And an eventual, but too long delayed breakthrough in appropriate health messages to the public.
With the antidepressant Paxil (generic name: paroxetine), the story was driven primarily from the United Kingdom, by the BBC Program “Panorama,” and a public interest group called Social Audit. They called attention to the severe side effects from the drugs — notably that they are addictive and lead to increased suicidality in youth.
In 2003, the evidence of dangerous side effects had piled too high for British regulators to continue to ignore it. In June, the UK health experts advised that children should not be prescribed Paxil.
In February 2004, Panorama reported on internal documents from GlaxoSmithKline (GSK) showing the company knew that Paxil could not be proved to work in children.
In March 2004, days after the Medicines and Healthcare Products Regulatory Agency — the UK's drug regulatory agency — advised that Paxil dosages should be kept to low levels, an expert participating in the Paxil review resigned, claiming the agency had possessed evidence for more than a decade suggesting that Paxil dosages should be kept low, but failed to act on it.
By this time, the story had started to heat up in the United States. Dr. Andrew Mosholder, of the FDA Office of Drug Safety, had conducted an analysis of clinical trials related to antidepressant use in children, and found a heightened risk of suicide. But his superiors refused to let him present his findings to an advisory panel convened to look at the issue in the wake of the British action.
According to an investigation by Senator Charles Grassley, R-Iowa, the FDA actually tried to get Mosholder to present data that deceptively underrepresented the risk of suicide.
Although Paxil is not approved by the FDA for prescription to children, doctors routinely write “off-label” prescriptions for the product for children, a practice permitted under FDA rules. More than two million prescriptions for Paxil were written for children and adolescents in the United States in 2002. Nearly 900,000 of these prescriptions were for youngsters whose primary diagnosis was a mood disorder, the most common of which is depression.
In April 2004, the Lancet, the prestigious British medical journal, published a paper showing that clinical test data did show problems with prescribing Paxil and other SSRIs to children. The Lancet would later name this article the scientific paper of the year.
In June, New York State Attorney General Eliot Spitzer filed suit against Glaxo, charging the giant drug maker with suppressing evidence of Paxil's harm to children, and misleading physicians.
“By concealing critically important scientific studies on Paxil, GSK impaired doctors' ability to make the appropriate prescribing decision for their patients and may have jeopardized their health and safety,” said Spitzer in announcing the suit.
GSK responded in a statement that it “has acted responsibly in conducting clinical studies in pediatric patients and disseminating data from those studies. All pediatric studies have been made available to the FDA and regulatory agencies worldwide. We have publicly communicated data from all pediatric studies.”
Spitzer's complaint cited a 1998 GSK memo which states that the company must “manage the dissemination of these data in order to minimi[z]e any potential negative commercial impact.”
Responding to Spitzer's suit, GSK claimed that, “As for the 1998 memo, it is inconsistent with the facts and does not reflect the company position.”
The New York complaint asserted as well that “GSK has repeatedly misrepresented the safety and efficacy outcomes from its studies of paroxetine as a treatment for MDD [Major Depressive Disorder] in a pediatric population to its employees who promote paroxetine to physicians.”
Later in June, GSK announced a new policy, whereby it would post on the Internet summaries of the results of clinical trials it conducts. In August, the company settled with Spitzer for $2.5 million, plus a commitment to maintain the policy of posting clinical trial results, for all drugs marketed by the company.
The next month, the Star-Ledger of New Jersey reported on a Glaxo memo from the year before, instructing the company's sales force not to talk to doctors about company data showing dangers from prescribing Paxil to kids. Glaxo says sales people do not discuss off-label uses with doctors.
In October, the FDA ordered Glaxo and other SSRI makers to include a “black box” warning — the agency's strongest warning — with their pills. The warning says SSRIs double the risk of suicide in children, though some medical researchers say the number should be higher. At least one GSK clinical trial showed 7.5 percent of youth taking Paxil suffering from suicidality (versus zero percent among those taking a placebo).
Glaxo continues to insist that it disclosed information to appropriate authorities as soon as it discerned important results from its clinical studies.
Thanks largely to Glaxo and other drug companies' bombardment of the airwaves with ads touting the wonders of drug treatments for all kinds of emotional disorders, childhood use of antidepressants and other pills is skyrocketing — even for drugs that haven't been shown to help kids. No one should understate the sometime difficulties of adolescence and the trauma that many youth must deal with. But overdosing kids is no answer — and pushing ineffective drugs that spike their risk of suicidality is deplorable.
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