A medical reviewer at the Food and Drug Administration recommended earlier this year that the agency adopt a tough “risk management strategy” urging doctors to stop prescribing most antidepressants to children, but the FDA rejected his advice and instead asked drug companies only to warn patients and doctors about possible risks to young patients, The Chronicle has learned.
Dr. Andrew Mosholder, an epidemiologist in the FDA’s Office of Drug Safety, analyzed 22 clinical trials of nine antidepressants and concluded that the drugs appeared to double the risk of suicidal behavior among children. A copy of his report, obtained by The Chronicle, shows that Mosholder recommended that the FDA adopt a “risk management strategy directed at discouraging off-label pediatric use of antidepressants” other than Prozac in the treatment of children with depression.
As reported by The Chronicle at the time, Mosholder’s presentation to an FDA advisory committee in February was removed from the agenda by his superiors at the agency.
The FDA opted not to issue a recommendation to doctors that they stop prescribing the drugs to children, as British regulators did last year and as Mosholder had urged. Instead, the agency took a much milder step last month and called on drug companies to include warnings in the prescribing information provided to doctors about the risks of negative side effects among patients who start taking a drug or increase its dosage.
The agency also contracted with a group of doctors at Columbia University to reanalyze the clinical trial data provided by drug companies, the same data Mosholder reviewed, to see whether suicidal events were correctly classified. Agency officials have argued that the data from those trials are sometimes vague and that some behaviors such as a child slapping herself in the head may have been labeled wrongly as suicidal events by researchers conducting the drug company-funded studies.
Committees in both the House and Senate have opened investigations into the withholding of Mosholder’s report and into efforts by the FDA’s Office of Internal Affairs to identify the staff members who leaked information to The Chronicle.
One congressional source predicted that the investigation was likely to trigger congressional hearings. “I think eventually there will be some hearings,” the source said. “There’s no way to put a good face on this decision not to allow Dr. Mosholder to present his conclusions to the advisory committee.”
Despite repeated requests, senior FDA officials declined to comment for this story.
However, in a letter sent Wednesday to House Energy and Commerce Committee Chairman Joe Barton, R-Texas, an agency representative defended the agency’s decision to keep Mosholder from presenting his report. Agency officials “decided that having Dr. Mosholder present his conclusion to the Advisory Committee, with the appearance that it was an agency determination, would be potentially harmful to public health as it might lead patients who were actually benefiting from the use of these drugs to inappropriately discontinue therapy,” wrote Amit Sachdev, acting associate commissioner for legislation.
Critics of the FDA’s handling of the antidepressant ruling reacted to details of the Mosholder report with outrage. “It’s astounding that FDA officials actively blocked vital, possibly life-saving information about the suicide risks to children” of these drugs, said Vera Sharav, president of the Alliance for Human Research Protection, an advocacy group. “Every day that doctors and parents are not informed about the risks, children are at risk of dying.”
In arguing that the agency should take strong action rather than wait for the reanalysis by the Columbia University group, Mosholder made much the same point in his report.
“Given the strength of the association shown by the present data, the clinical importance of the apparent effect, and the fact that the additional analyses are likely to take several more months to complete while considerable numbers of pediatric patients are being exposed to these drugs, I favor an interim risk management plan,” he wrote.
Mosholder’s report found that 74 children out of 2,298 who took antidepressants engaged in a “suicide-related event,” compared to 34 of the 1, 952 patients who took placebos, or fake pills. The drugs presenting the highest risk were Effexor and Paxil, which nearly tripled the risk of a suicidal event, and Zoloft, which more than doubled the risk, his research showed.
Prozac, which is now available in generic form, had the lowest risk among the major drugs, and is the only new-generation antidepressant specifically approved by the FDA for treating depressed children. For that reason, Mosholder recommended that Prozac alone continue to be prescribed to children.
But since drugs that have been cleared by the FDA for treatment of adults can be prescribed “off label” to children, other drugs including Paxil, Zoloft, Effexor, Luvox, Remeron, Celexa, Serzone and Wellbutrin are widely prescribed for children and teenagers. The FDA estimates that nearly 11 million antidepressant prescriptions were written for children in 2002, 2.7 million of them for children under 12.
Joseph Glenmullen, a clinical instructor in psychiatry at Harvard University, said the agency’s withholding of the Mosholder report and its failure to take stronger action was an example of the FDA’s failure to protect the public from the dangerous side effects of antidepressants.
“They have mishandled this issue for 15 years,” he said. “They have not adequately protected American children.”