The previous link was in regard to the FDA approval of Seroxat … (Paxil in the US) in 1993
But… It was actually first Licensed in the UK in 1991 (which undoubtedly swayed and influenced the FDA’s decision to grant it a licence too)…(Seroxat was then re-licensed by the MHRA in 1998.. )
Seroxat was licensed in the UK on 11th December 1990 for the treatment of mild to moderate depression. By 1993, 78 Yellow Card notification reports of adverse withdrawal effects had been received by the Committee for the Safety of Medicines (CSM) and Medicines Control Agency (MCA)2. This exceeded the total number of adverse reaction reports received for all of the benzodiazepines combined even though the SSRI’s were represented as safer drugs. The CSM/MCA responded issuing a single paragraph statement in a newsletter to GPs reminding doctors of the need for gradual withdrawal. They failed to mention that often withdrawal symptoms were being mistaken for depression relapses, for which GPs were prescribing even higher doses of the drug.
Charles Medawar and others claim that the practice of describing suicidal thoughts and acts in vague nomenclature is one method that has been used to disguise adverse effects. For example, ‘suicide’ repeatedly being described as ‘emotional lability’ in published reports, has been passed unchallenged by the MHRA.
Panorama revealed that Prof. David Healey, a psychiatrist and researcher in Bangor University, had for many years been concerned that the so called ‘depressive relapses’ experienced by Seroxat users were in fact withdrawal symptoms. On perusing the data comprising the Seroxat healthy control studies Healey discovered that these participants, who had never suffered from depression or suicidal thoughts or acts, started to experience suicidal thoughts on taking the drug, along with a cluster of distinctive withdrawal symptoms including the now well known symptom of ‘electric zap’ sensations in the brain. Moreover, Prof. Healey reported his concern that results had not been published of a controlled experiment undertaken by GSK in which 85% of healthy volunteers suffered adverse effects and one committed suicide. Prof. Heay claimed that GSK knew that approx. 1 in 60 adults on Seroxat made a suicide attempt while the figure for placebo was 1 in 550. It would therefore appear that GSK were aware of the risks Seroxat posed prior to their licence application. The question remains ‘how could Seroxat have ever received the endorsement of the licensing authorities – the MCA (now MHRA) in the UK and the FDA’?
For more on the Seroxat UK licencing debacle .. ( see link )
All new patients or volunteers on SSRIs regardless of their mental condition, child or adult,
face a finite risk of drug induced suicide in excess of any risk of suicide that they had
before medication. GSK presented randomised clinical trial (RCT) results to the MCA for
Seroxat in 1990 in their UK licence application. This showed that Seroxat was 8 times more
likely to cause suicide or suicide attempts than placebo giving a rate of 236 suicides per
100K patients, zero for placebo. After some debate the application was withdrawn.
GSK then manipulated the results of the same trial, shifting suicides from Seroxat onto
placebo, and re-applied in 1991. The adjusted figures showed that placebo was now twice
as dangerous as Seroxat, giving a rate for Seroxat of 168 suicides/100K patients and an
incredible 361/100K for placebo. This affront to medical ethics, logic and common sense
did not dismay the MCA and on the basis of this data the MCA granted the lifetime UK
licence for Seroxat, which was never to be scientifically and critically reviewed
subsequently. This dangerous, inexplicable and incompetent approval in the UK
undoubtedly influenced the FDA to follow suit 2 years later when the Paxil licence was
Dr Healy also indicates their was manipulation of the original Seroxat Trial data before licencing in a letter to the MHRA in 2004…
In February 1990. the Teicher article raised concerns that the recently licensed fluoxetine might trigger suicidality in depressed patients. In fact, as the meta-analysis of the clinical trial literature on SSRIs mentioned above (appendix 1) and submitted to you indicates, as of 1988, there was a demonstrable doubling of the relative risk of a suicidal act on an SSRI in these trials compared to placebo, even though the data on zimelidine had not been reported in the published papers.
By October of 1990, FDA had decided the issue of suicide on antidepressants was as Martin Brecher of FDA put it: “not .. a real issue, but rather as a public relations problem” (Brecher 1990)(appendix 7). My question is whether CSM/MCA had made a similar decision.
This determination that the issue of suicide induction was a public relations rather than a substantive issue was made without holding a scientific advisory meeting. When FDA held an advisory meeting on the issue of antidepressants and suicide in September 1991, evidence on two other SSRIs, sertraline and paroxetine, already with FDA for close to two years, was withheld from the meeting. The suicide and suicidal act data on SSRIs or other antidepressants has never been shown to an FDA advisory panel and has not until this year been reviewed thoroughly by MHRA. Viewing the issue as a public relations matter has been a crucial misstep that I would argue has led both regulatory agencies down a path of twisting the science to fit their position.
Although data submitted to FDA and CSM/MCA showed that there was an increased rate of suicides on antidepressants compared with placebo, this simple but crucial finding was obscured and continues to be obscured by two sleights of hand. First the results were biased by the inclusion in the placebo group of “washout” or “run-in” suicidal acts that had occurred before patients were randomised, as outlined above for the sertraline data. This spuriously increased the placebo rate. A further biased elevation of the placebo rate occurred by including post-continuation suicidal acts under the heading of placebo. These were acts that occurred either after patients had completed the randomised phase of the trial, and were potentially in withdrawal, or were taken from selected trials that were not part of the original clinical regulatory trial portfolio. The effect of these manipulations is laid out schematically in figures 1 & 2.