18 Deaths Linked to drug – Serzone Removed from European market, not US

18 Deaths Linked to drug – Serzone Removed from European market, not US

Fri, 17 Jan 2003

Bloomberg News reported that the antidepressant, Serzone had been linked to 25 cases of liver damage and 18 deaths. On Jan 8, 2003 European authorities removed the drug from the European market. On Jan. 9, 2003, the FDA required a black box warning to be added to the Serzone label but left it on the American market.

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Bloomberg News
January 9, 2003, Thursday

BUSINESS/FINANCIAL DESK

COMPANY NEWS; BRISTOL-MYERS TO PULL DRUG IN EUROPE BUT NOT IN U.S.

The Bristol-Myers Squibb Company will pull the antidepressant Dutonin from the European market after 18 patients who took it died. Twenty-five cases of liver failure, including the 18 deaths, were linked to the drug worldwide, a Bristol-Myers spokesman, Bob Laverty, said. European sales make up less than 10 percent of the drug’s $409 million in revenue, analysts said. The company will keep selling the drug in the United States as Serzone.

The label carries the Food and Drug Administration’s highest alert, which notes that liver failure has been reported. Susan Cruzan, an F.D.A. spokeswoman, said, “The F.D.A. continues to monitor it and take everything into consideration.” Bristol-Myers has been sued by former users of Serzone.

Published New York Times: 01-09-2003, Late Edition- Final, Section C, Column 1 , Page 3

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Why do FDA officials think Americans deserve less protection from unsafe drugs than do Europeans?

Drug analysts who have examined the clinical trial data submitted to the FDA prior to gaining approval, have found that the much-touted antidepressant drugs known as selective serotonin reuptake inhibitors (SSRI) show little, if any, greater positive effect on depression than placebo. [See, for example, [JAMA Vol. 287 No. 14,April 10, 2002 http://jama.ama-assn.org/issues/v287n14/rfull/joc11936.html;

But, unlike placebo, these drugs come with severe adverse reactions, including dependence and withdrawal symptoms. [See: David Healy, MD, Dependence on Antidepressants at: http://www.seroxatusergroup.co.uk/WITHDRAWAL2.pdf

Serzone failed six out of eight clinical trials during pre-marketing testing. The “positive” findings of two trials were found to have been manipulated to exclude unfavorable results from the “findings.”

In 1997 Thomas J. Moore (author of Prescription for Disaster) wrote an insightful (highly readable) analysis of the FDA Serzone trial data and of the drug’s approval process. [Thomas J. Moore, “Hard to Swallow” published in The Washingtonian at:
http://www.washingtonian.com/health/hardtoswallow.html]

Moore noted that “Serzone failed to show a clear benefit in six of the eight clinical trials. Three more clinical trials were discontinued before results were available.” “Serzone was tested further at a higher dose. One of these high-dose trials failed by everyone’s evaluation, and two more were borderline. However, two other trials were declared a success.”

“If six Serzone trials failed or were inconclusive, what results did the two claimed successes achieve? In one ‘successful’ trial the placebo patients showed a dramatic improvement. Their depression scores dropped 17 points in six weeks. Serzone patients didn’t do as well, with average scores improving 14 points.”

Among the adverse effects suffered by patients in clinical trials: confusion, impaired memory, abnormal dreams, decreased concentration, lack of coordination, psychomotor retardation, and tremors. Some experienced seizures, episodes of mania, addiction, and heart problems, and some committed suicide.

FDA data reveal that suicide was disturbingly frequent in clinical trials testing SSRIs. Moore reported the suicide results for patients given Serzone compared to Placebo in 6-week trials:

Serzone treated patients: 3,496
Placebo group: 875
Suicides by Serzone patients: 9
Suicides in placebo group: 0
Suicide attempts by Serzone patients: 12
Suicide attempts in placebo group: 1
Attempted suicide rate in patients prescribed Serzone: 1 in 166
Suicide rate in patients taking placebo: 1 in 875

Clearly, the evidence reveals that suicides and suicide attempts occurred among those taking Serzone, not those given a placebo.

“On this data, a rational patient would choose to take the placebo rather than the drug.”

But FDA officials and an FDA advisory panel whose members had financial ties to drug companies ensured that the drug was approved despite the negative findings. Moore reports how these “experts” diverted the focus from the drug’s poor showing and high suicide rate for patients taking Serzone. They allowed negative results to be excluded from consideration, pointing instead to minor details which they declared “an interesting fact” to justify FDA approval of Serzone.

But, Moore, points out, “excluding results unfavorable to Serzone after the fact was like conducting a jury trial and, if no guilty verdict resulted, allowing the prosecution to remove the jurors with doubts. But even when the most unfavorable results were excluded, Serzone patients’ depression scores improved by 13 points, the placebo patients’ by 12.”

Moore describes how the statistical analysis was tainted by selective inclusion exclusion of data. The high drop out rate during trials was not calculated, “it was permissible to pretend that those who dropped out had continued to the end of the trial. The final results included all the scores, even for those who had quit after one week.”

“Suppose, for example, that a Serzone patient had improved dramatically at the third-week examination but was hospitalized the next week for severe adverse effects. The three-week score showing a great benefit still would be included–and there would be no penalty for the participant’s not continuing to the end.”

“This is using statistical adjustments to try to prove an effect that was not detected by direct scientific observation. What’s more, it makes the test an unrealistic estimate of what will be achieved in actual use. Antidepressants are prescribed for months and sometimes years.”

By disregarding the negative results–which will have an adverse impact on millions of future patients–FDA’s advisory panel recommended approval of Serzone in 1993. The panel was headed by Dr. Carol Tamminga, whose research ethics were severely criticized in 1998 in (among others) The New York Times and The Boston Globe: http://www.ahrp.org/AHRPinNews/NYTimes051998.php http://www.boston.com/globe/nation/packages/doing_harm/day1.htm

[Complete article by Moore at:
http://www.washingtonian.com/health/hardtoswallow.html]

For adverse drug reports, see:
http://www.fda.gov/medwatch/SAFETY/2002/safety02.htm#serzon

FDA Patient Information:
http://www.fda.gov/medwatch/SAFETY/2002/serzone_PPI.pdf

Bristol Myers Dear Doctor:
http://www.fda.gov/medwatch/SAFETY/2002/serzone_deardoc.PDF

Complete package insert:
http://www.fda.gov/medwatch/SAFETY/2002/serzone_label.pdf