In this article (the AHRP & The New York Times) – we discover just how bad Dr Thomas Laughren’s memory must be… it seems he can’t recall important events and he even suppressed release of troubling (for drug makers) data.
I have to ask once again why it is that the FDA in America and the MHRA in the UK seem to be run for the benefit and profit of the pharmaceutical industry rather than for the safety and protection of patients?
Now read on:
“At last, the FDA in America is going to ask drug makers to include questions about suicidality in clinical trials of some new drugs.
In the new spirit of transparency, FDA officials would not say which drugs or how many drugs would be examined.
The FDA claims new interest in suicidality was sparked by the results of Columbia University’s analysis a few years ago showing increased risk of suicidality in pediatric patients using antidepressants. Dr. Thomas Laughren, director of the FDA Division of Psychiatric Products, confesses: “Clearly we were somewhat surprised when this signal emerged in the pediatric antidepressant data.”
Surprised? Really?
We remind Dr. Laughren that back in 1991, a team from Yale University published a paper entitled “Emergence of Self-Destructive Phenomena in Children and Adolescents during Fluoxetine Treatment” [King et al, Journal of the American Academy of Child and Adolescent Psychiatry 1991;30(2):179-86].
That same year, Dr. Laughren attended the FDA advisory committee meeting at which the safety of fluoxetine (Prozac) was discussed and his boss, Dr. Paul Leber, proclaimed: “nobody in the agency dismisses the possibility that antidepressants may have the capacity to cause untoward injurious behaviors, acts and/or intensify them.”
In 1991, Drs. Laughren and Leber listened as the chairman of the advisory committee, after seeing the data presented, concluded: “yes there is a signal there.” However, FDA officials maneuvered to steer the divided vote against changing the label to warn physicians and patients about the potential risk. Dr. Martin Teicher, who first raised concern about the suicide link to Prozac [Teicher MH, Glod C, Cole JO: Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry 1990; 147(2):207-10] predicted prophetically: “what is going to happen, people are going to say it is free of all risk.”
Dr. Leber sought to reassure the committee with promises that their concerns would be addressed: “The likelihood is that we will probably write a talk paper at some point on behalf of the agency which will probably say what is obvious from the votes that people reasonably remain concerned about the possibility that there are areas of information that we need that we do not have and we will pursue things as we ordinarily do.”
For public consumption, the FDA announced that the agency had found “no credible evidence” that antidepressant drugs cause suicidal behavior. [The Lancet 1991;338:875-6] No talk paper expressing concern about the potential risk that Dr. Leber acknowledged at the advisory committee meeting was ever released.
More than a decade later, an FDA reviewer in the Office of Drug Safety division looking at antidepressants in the pediatric population took it upon himself to combine clinical trials for different antidepressants (a meta-analysis) and found that suicidal behavior among the kids who received antidepressants was nearly twice the rate among kids who received a placebo. Dr. Andrew Mosholder raised his concern with Dr. Laughren who had issued the approval for these antidepressants.
Dr. Laughren, being the cautious type–where industry interests are concerned–calmed the reviewer and suppressed release of the troubling results.
Instead [Link] the FDA decided give the data to Columbia University to re-classify the cases so that FDA’s Office of New Drugs could re-analyze the data, then wait some more until the results could be presented to another advisory committee.
However, the Alliance for Human Research Protection obtained and posted Dr. Mosholder’s suppressed report: [Link]
In September, 2004, a Congressional hearing was held at which it was learned that Laughren’s presentation of the data analysis to the FDA advisory committee–failed to include both Dr. Mosholder’s conclusion about the suicide risk, but Dr. Laughren’s presentation failed to include the data that substantiated that conclusion. [Link]
Finally in September 13-14, 2004 we saw the numbers: the results from the Columbia reclassification of cases showed that the relative risk of serious suicidal events for antidepressants was 1.81 times greater than the risk for placebo. The original analysis conducted on the data submitted by the drug companies and analyzed by the FDA Office of Drug Safety (now the Office of Safety Evaluation) had produced a relative risk of 1.86.
One of the things we can learn from this exercise is that the re-classification of cases by Columbia University showed the same increased risk with antidepressants as was obtained using the original data submitted by the drug companies and gathering dust in the FDA files all these years. In other words, the Columbia case definition and suicidality scale were completely unnecessary. The answer was right there in the data submitted routinely by drug companies to the FDA.
Like Dorothy and her ruby slippers, the FDA all along had the ability to see that antidepressants increase the risk suicidal behavior . All they had to do was look. The problem was not the lack of a suicidality questionnaire, or the drug companies’ inability to recognize and report suicidal behavior. The problem is that suicidal behavior, like most serious adverse events, occurs too rarely to be associated with drugs reliably in individual clinical trials of the size required by FDA for approval.
The solution to this problem is-wait for it-yes, get more data. Did you hear the drug companies gasp? Larger studies take longer to complete and time, as we all know, is profit.
But there are all sorts of ways to get the necessary data, even without lengthening the approval process. For instance, the FDA could issue a conditional approval (during which time all advertising would be prohibited) pending timely completion of large safety studies.
Even simpler, the FDA could as a matter of routine conduct meta-analyses in which individual trials (even including different drugs within the same class with similar effects) are analyzed together. A meta-analysis, such as the one eventually conducted by the Office of Drug Safety would have shown years earlier that antidepressants cause rather than prevent suicidal behavior.
The underlying problem, however, is that the FDA still does not take safety seriously.
In 1990, Dr. Teicher identified a suicide risk in patients prescribed Prozac–surely a serious adverse side effect. In 1991, Dr. King independently identified the same risk in children. Both reported the suicidal behavior link to Prozac in leading psychiatric journals. When separate re-challenge case reports were also positive in increasing suicidality, the event was linked by physicians to antidepressants.
The Chairman of the FDA advisory committee concluded that a signal is present. Yet, FDA officials told us there was “no credible evidence.”
The FDA judged the data to be insufficient, but for more than a decade they did nothing to address the alleged shortcomings of the data. Perhaps they prayed at night that in the morning new data would somehow manifest itself.
Today, the FDA still has not implemented the structural changes recommended by the Institutes of Medicine, but some drugs will now use the Columbia suicide questionnaire that had been contracted by the FDA.
However, reclassification of terminology will not change the culture at the FDA that trivializes safety issues.”
