October 26

FDA Forced Wyeth to REMOVE Suicide Warning from Effexor Label

FDA Forced Wyeth to REMOVE Suicide Warning from Effexor Label

Wed, 8 Sep 2004

The Wall Street Journal reports that FDA officials forced Wyeth to remove the label warning stating: “In pediatric clinical trials, there were increased reports of hostility and, especially in Major Depressive Disorder, suicide-related adverse events such as suicidal ideation and self-harm.”

In August 2003, Wyeth issued a warning to doctors about clinical trial evidence linking its antidepressant Effexor to suicidal thoughts in young patients, and the company added that warning in the drug’s label. See Wyeth Aug 22, 2003 letter: https://ahrp.org/risks/effexorLtr082203.php

The FDA forced Wyeth to replace this explicit warning with the watered down, equivocating version that the FDA-approved for all SSRI and SNRI antidepressants.

This provides the American public with clear evidence that the FDA is the major problem regarding drug safety issues. Senior FDA officials have been aiding and abetting drug manufacturers in the concealment of evidence, because to disclose the real evidence may harm manufacturers’ profit margins.

Responsibility for the current crisis rests mainly with the senior officials at the very agency whose mandate it is to protect the public from undisclosed drug hazards.

The FDA has been hijacked by a drug cartel that is causing far more harm than any illicit drug traffickers ever did.

Of note, Effexor is closest in mode of action to Eli Lilly’s newly approved drug Straterra, which is being promoted for use in children. Yet, Straterra trials have not undergone FDA’s recent review for suicidal risk by FDA’s medical officers–as was Effexor, Paxil, Zoloft, Prozac and the others. Why?

Contact: Vera Hassner Sharav
Tel: 212-595-8974

Congress Will Discuss Drug-Trial Issues
September 8, 2004; Page B1

In August 2003, pharmaceutical giant Wyeth warned doctors that its antidepressant Effexor might be linked to suicidal thoughts in young patients, based on findings from clinical trials.

But months after the company added the precaution to the medicine’s label, it ran into an objection from an unexpected source: the Food and Drug Administration.

The FDA asked Wyeth to remove the caution and replace it with a more general warning urging doctors to monitor patients of all ages taking antidepressants — matching the same warning it was requesting on all major antidepressants.

Now a new FDA analysis of antidepressant clinical trials appears to back up Wyeth’s original conclusion. Among six antidepressants that were compared directly in the analysis, Effexor showed the strongest evidence of a possible link to suicidal thoughts and behavior in young people. Indeed, the potential risk appeared to be sharply higher than that of the other drugs.

In a statement, a spokeswoman for the FDA said the agency had asked Wyeth to change the label because it felt there was a “discrepancy” between the company’s original precaution and the warning the FDA recommended to makers of all major antidepressants this past March. That warning noted that no causal tie had been confirmed between the drugs and suicidal tendencies. FDA officials decided that “as an interim measure … it would be best to remove” the Wyeth sentence while the agency re-examined the data on the antidepressants, the FDA statement said.

The back-and-forth over Effexor’s labeling is the latest incident to underscore the complex issues involved in disclosing potential risks posed by drugs. The FDA tries to strike a balance between alerting the public to possible dangers while avoiding raising unnecessary alarms — a delicate task that has drawn the attention of Congress. Tomorrow, a House Energy and Commerce subcommittee will hold a hearing focusing on antidepressants and disclosure issues.

Much of the controversy involving the FDA has centered on the agency’s decision not to allow a staffer, Andrew Mosholder, to publicly discuss his conclusion that there was evidence of a possible link between antidepressants and suicidal tendencies in young people. At a February FDA advisory committee meeting, the agency revealed the data Mr. Mosholder’s examined, but not his conclusion. Officials have said they considered the finding premature and planned a new analysis.

Questions about the safety of antidepressant use among young people had emerged long before. By the summer of 2003, British and U.S. regulators were examining clinical trials to try to determine if there was a problem.

On Aug. 22, 2003, Wyeth sent its letter to doctors, saying it planned to add to the “precautions” section of Effexor’s label the following sentence: “In pediatric clinical trials, there were increased reports of hostility and, especially in Major Depressive Disorder, suicide-related adverse events such as suicidal ideation and self-harm.” The company also sent notice to the FDA that it planned the change.

“We felt there was a growing body of evidence that practitioners should know about,” says Bruce Burlington, Wyeth’s executive vice president for quality, regulatory, safety and audit, and a former FDA official. The company knew that at least a small portion of antidepressant prescriptions to children and adolescents were for Effexor, although the drug wasn’t approved for such use.

Last September, British regulators warned that Effexor shouldn’t be used for depressed children and teens because clinical trials showed “an increase in the rate of harmful outcomes including hostility, suicidal ideation and self-harm” in the young people taking the drug, compared to those who got placebo pills.

This March, the FDA unveiled a proposed label change for all major antidepressants, including Effexor. The agency wanted drug makers to warn that health-care providers should carefully monitor all patients — adult and pediatric — taking antidepressants for signs of worsening depression or suicidal tendencies, especially as they started on the drugs. In its advisory, the FDA also noted that it had “not concluded that these drugs cause worsening depression or suicidality.”

At the same time, the FDA quietly asked Wyeth to remove the sentence about risks to young people that it had added to the Effexor label’s “precautions” section the previous fall. “Clearly they wanted us to conform with the class labeling,” says Dr. Burlington. “When the regulators say do it, you do it.”

In a letter to doctors dated June 3, Wyeth announced its new label language. It noted that “patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications …” It cautioned that a “causal role for antidepressants” in worsening depression and increasing suicidal tendencies “has not been established,” but urged that patients “should be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose changes …”

The FDA statement said that the agency believed the original Wyeth sentence “might be interpreted as suggesting causality,” contradicting the agency’s stance last March that there wasn’t a proven link. At the time, the FDA was working on its new analysis to try to determine whether there was a causal relationship. In the meantime, it thought it would be best for Wyeth “to remove the vague Pediatric Use language and add the prominent Warning” language that had been requested for all the major antidepressants. The new warning also “encouraged observation for emergence of both suicidality and hostility,” the statement said.

Another, more subtle issue also may have come into play. Drug labels are supposed to represent the judgment of FDA scientists, as well as the companies, so the agency can be reluctant to allow safety cautions on labels if it believes they are unproven. Sometimes, such cautions are cited by companies as a defense in lawsuits brought by patients’ attorneys.

On Aug. 20, almost exactly a year after Wyeth’s original warning to doctors, the FDA posted on its Web site its latest analysis of the possible risks of antidepressants to young people. The analysis, by an FDA medical officer, relied on clinical trial data that had been examined and classified by outside researchers led by professors at Columbia University.

The analysis showed varying results depending on the drug, but Effexor stood out sharply. When the results of three of Wyeth’s clinical trials were combined, the data showed that young people who took Effexor were nearly five times as likely to have suicidal thoughts or behavior as those who took a placebo. When only data from the two Effexor trials involving depression were used, the suicidal tendencies were 8.8 times as likely in the young people who took the drug. The absolute risk was very low — no young person in any of the trials committed suicide.

The next-highest ratio was for GlaxoSmithKline PLC’s Paxil — 2.65, for a combination of all of the trials. That result didn’t have statistical significance.

Unlike several of the drugs it competes against, Effexor affects two brain chemicals that are thought to play a role in mood, serotonin and norepinephrine, though it’s not clear that this is connected to the results of the pediatric trials.

The FDA has said that it intends to translate the results of its new analysis into changes to antidepressant labels — which might end up adding more specific concerns about suicidal tendencies in pediatric patients to Effexor and other drugs. It plans to bring up the matter in an advisory committee meeting next week.

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