Seroxat Link 4 : Seroxat Holocaust : The First Wave : 1991

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
granted.

Dr Healy also indicates their was manipulation of the original Seroxat Trial data before licencing in a letter to the MHRA in 2004…

Regulatory Complicity

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.

Seroxat Link 3 : The Yugoslavia Trials : GSK & Paroxetine

Ok, so we know that Seroxat (chemical : paroxetine ) first emerged from the labs at Ferossan , and we know that B.I. (boehringer-ingelheim) originally filed paroxetine in the class of “hypnotics”..

So how did GSK get it passed by the drug Regulators as an anti-depressant?…

This is how…. (for the full transcript of Breggins Article , click on the text )

From 1980-1991, approximately 5000 patients were tested on Paxil during SKB’s clinical trials.Eighty-three (83) different Paxil trials were conducted.Various time periods were involved in the individual trials.Many patients were tested for only a month or 6 weeks.Some were tested longer, including approximately 400 who were in trials longer than a year.SKB pulled out all the stops to ensure the trials were successful.Only two (2) positive trials are required for FDA market approval.By any reasonable person’s perspective, Paxil’s track record in the clinical trials was poor.After a decade of juggling data in the 83 different trials, SKB was finally able to cite four (4) “positive” trials and three (3) “supportive” trials to justify Paxil’s approval.Dropouts in most trials were rampant.Most of the dropouts occurred because Paxil caused adverse experiences, and the victims wanted nothing more to do with the drug.

Paxil’s clinical trials were a statistical sham.Rather than deal with real numbers, SKB created a fraudulent measuring standard called “patient years” (or “patient exposure years”).The need for “patient years” became obvious in the 1980′s.It was obvious in the late 1980′s and into the 1990′s that Paxil clinical patients were attempting suicide and suffering “adverse experiences” at an alarmingly high rate.Moreover, as indicated above, hundreds of Paxil volunteers dropped out because they could not tolerate the drug.The dropout rate was 20%.Fifty-eight (58) patients alone attempted suicide after they were given Paxil.Hundreds of additional Paxil patients suffered adverse experiences caused by the drug.In 1991, SKB “ran the numbers” and discovered the absolutely horrible Paxil record.The 58 attempted suicides out of the patient base constituted a suicide rate of 0.77% in real numbers.Under clinical standards, a rate of 1% is considered a “frequent” occurrence.On those numbers, Paxil patients approached a “frequent” suicide rate.This was a far greater suicide rate than “placebo” or the other active drug being tested on the patient population.To avoid a company disaster on the Paxil project, SKB had to change the rules, and shift to the “patient years” sham.

22.The “patient years” standard is a sham by anyone’s common sense.It works like this.Assume 366 patients are selected at random to test Paxil.Three hundred and sixty five (365) patients take Paxil and suffer horribly the first day–immediately quitting the test.These patients are called, not surprisingly, “losers.”The 366th patient, however, tolerates Paxil quite well, and even improves on the drug, staying in one or more trials for a full year.This patient is a “winner” by SKB standards.Like a champion race horse, this “winner” is entered in all the sweepstake trials for Paxil–and these trials are intentionally programmed to be long.Knowing they have a champion race horse, SKB racks up “points.”By anyone’s common sense standards, 365 failures out of 366 attempts would render the drug a dismal failure.But not so under “patient years.”Under patient years, the one Paxil patient who tolerated the drug for one year counts the same as the 365 patients who couldn’t tolerate the drug and dropped out the first day.The “score” in this example is “one patient year” for each side.Not surprisingly, the mathematicians who go along with this voodoo math are subordinate to the physicians and clinicians in the corporate chain of command, and the physicians at the top of the FDA chain of command.

.
In Paxil’s clinical trials, SKB ultimately achieved positive results–as it were–because of emphasis on “subjective” testing data.Objective data is very scientific.Subjective data is less scientific.The latter requires more stringent controls to be applied scientifically.Subjective data is subject to the biases, opinions, and prejudices of the person(s) collecting the data.SKB’s subjective data to justify Paxil’s approval was obtained both from physicians, principal investigators (“PI”) (most of whom were physicians) and from patients.The physicians and PI’s were compensated handsomely by SKB for their participation in the trials.On information and belief, plaintiffs allege these individuals were hired only after appropriate screening to ensure they were friendly to the drug industry and SKB.

.It was in mid 1992 that Dr. Laughren was directed by the FDA to be the staff point person for the October 5, 1992 Paxil committee hearing.Dr. Laughren had earlier concluded he would recommend Paxil’s approval.Dr. Laughren was also getting promoted and had only recently assumed the higher position.He was being assigned to take over the position occupied by the FDA official who had telephoned SKB on the PR nature of the Prozac problem.Dr. Laughren was taking over the higher position very late in the game insofar as Paxil’s application was concerned.The earlier incumbent–as described–had already taken a position favoring Paxil’s approval, and was not modest in voicing full support for SSRI’s.It would have been highly unusual for the FDA to place in that position an individual who would upset the apple cart and refute what his/her predecessor had committed to on the Paxil decision–and of course that didn’t happen.Dr. Laughren fell in line with his predecessor and validated all of his predecessor’s findings.In preparation for the upcoming October 5, 1992 committee proceedings, Dr. Laughren wished to be “hands on” before committee members.His wished to make it appear that the FDA staff was totally in command of their domain.Here, however, is where the FDA regulatory system breaks down–and was broken in this instance.It is where, essentially, the government bureaucrat depended on the “regulated” in order to look good in the job and get through a particular project–and that’s what happened here.Both players–FDA staff and SKB–recognized they were dependent on each other to look good before the committee.Like the telephone tipoff on the suicide issue, this was a poor environment for checks and balances, or fostering effective FDA regulation on behalf of public safety.For several weeks leading up to October 5, 1992, Dr. Laughren depended on SKB to get up to speed for his expected presentation before the committee.This was notwithstanding that FDA had been provided all of Paxil’s trial documentation as the clinical trials had progressed throughout the previous decade.As Dr. Laughren was preparing for the committee hearing, he made several urgent fax appeals to SKB headquarters to help him prepare his presentation.He was not modest.He asked numerous questions.He asked for numerous, individualized research scenarios.Some were provided immediately from SKB’s computer.Others had to be specially gathered by SKB and forwarded later.To facilitate Dr. Laughren’s support for their product, SKB promptly and fully complied with all of his requests.These SKB and FDA principals operated on a “first name” basis in their fax exchanges.SKB officials were so friendly with Dr. Laughren, they addressed him as “Tom” in front of the committee podium.

When the FDA committee convened in Rockville, Maryland, on October 5, 1992, the FDA staff made their presentation first.SKB’s presentation followed.Dr. Laughren’s presentation was lengthy, and essentially constituted the FDA staff’s position on Paxil.In his overview to the committee, Dr. Laughren addressed many Paxil issues.Knowing the six (6) voting members would be interested in the “withdrawal” issue, Dr. Laughren felt obligated to explain to the committee FDA’s understanding on the Yugoslavia trial.That was that the Paxil withdrawal issue was not formally studied during the tests.Laughren told the committee in regard to the Yugoslavia trial:”There was no systematic effort really to look at the withdrawal syndrome, but in looking at the patients coming off of…(Paxil)…in the clinical trials, there was no strong suggestion of a withdrawal syndrome.”That was strange language coming from a top FDA official commenting on clinical trials.Proper science and clinical analysis do not permit a “strong suggestion” of anything without scientifically imposed controls to justify such a conclusion.

.At that juncture, SKB’s plan for the committee was proceeding smoothly.The FDA was in their corner, and the FDA staff had told the committee exactly what SKB had hoped they would.Then in the afternoon it was SKB’s turn to address the committee.SKB was not content to rest on Dr. Laughren’s commentary regarding the Yugoslavia study.SKB boldly went to the next level.SKB asserted to the committee that SKB had studied “whether or not there is a discontinuation syndrome in patients who are abruptly discontinued from Paxil.”The SKB representative continued:”To end with a brief discussion of whether or not there is a clear withdrawal syndrome, we have pulled upon the …(Yugoslavia trial)…”Then, SKB made an outrageous and categorical falsehood.The SKB representative told the committee SKB in the Yugoslavia trial attempted to “systematically assess a discontinuation syndrome.”This statement was in direct contradiction of Dr. Laughren’s earlier statement in the day that “There was no systematic effort really to look at the withdrawal syndrome.”Having refuted the FDA representation that there were no “systematic” tests on Paxil withdrawal, SKB then further claimed the tests were successful in that regard.The SKB representative told the committee they examined the data on the Phase II placebo group and that “few numbers of patients experienced any adverse event after being randomized off…(Paxil)…into the placebo group and the percentages are certainly very small.”What SKB failed to add was that no “adverse events” were reported on the placebo group because the eighteen (18) placebo victims’ symptoms were reported by SKB to have been “relapse” symptoms.Given the high bar established by SKB for relapse, the 18 placebo victims constituted a staggeringly high 45% of the placebo group.Had a reasonable clinical standard for “relapse” been set, it is quite possible 75% or 90% an or even higher casualty rate would have been recorded.

.Then a most startling and telling exchange occurred before the committee.The SKB proclamation that “systematic” withdrawal testing had been accomplished in the Yugoslavia trial caught the FDA staff representative, Dr. Laughren, completely off guard.Hearing the SKB representative directly contradict him on “systematic” withdrawal testing, and further hearing that placebo patients suffered no adverse effects after being taken off Paxil, Dr. Laughren interrupted the SKB speaker.From his perspective sitting in the audience, Dr. Laughren understood there were “crossed signals” before the committee between the FDA staff and SKB, and that the discrepancy required immediate correction.Dr. Laughren additionally understood there was now a gap in the testimony.Dr. Laughren understood the placebo group’s statistics meant nothing without comparison to the Paxil group.He then yelled up to the podium to the SKB representative, and the following exchange occurred:
Laughren:”Unfortunately you did not contrast…(the placebo group)…with the rates…(of adverse experiences)…in the patients who continued on…(Paxil)…”
SKB:”Right.I know the point you are going to raise, that it really does not look that different…”
Laughren:”That was my impression.”
SKB:”…from what you saw in the…(Paxil)…group, and that is a well founded point.So we very much agree with your earlier conclusion that there is no clear withdrawal syndrome but this was our attempt to try and investigate it in somewhat of a controlled fashion.”
In effect, SKB had just pulled off a coup.SKB had successfully and deceitfully maneuvered Dr. Laughren into making the case before the committee that withdrawal tests were conducted, and they proved Paxil “clean” on the withdrawal issue.SKB got Dr. Laughren to do their heavy lifting before the committee on a subject the FDA official had no personal knowledge of.SKB simply stepped aside and put icing on the cake with a polite “we very much agree with…(Dr. Laughren’s)…earlier conclusion that there is no clear…(Paxil)…withdrawal syndrome.”

.SKB’s tactic to skirt the withdrawal issue at the committee hearing was thus successful.After representation to them that Paxil had been systematically tested for withdrawal and that the tests were successful, the committee voted to approve Paxil.

Seroxat link 2 : NeuroSearch/Buus Lassen : The Birth Of Seroxat

 

Where did Seroxat Come from ?..
Who created it?..
What can we learn from its origins?…

In the middle of the 70s, reports of a new breed of antidepressant began emerging from small laboratories in Scandinavia. It was found that certain drugs like reserpine, a popular tranquillizer and anti-hypertensive treatment that depleted serotonin levels had an interesting side effect: it produced depression-like symptoms.

At the Danish firm of Ferrosan, the head of research was a man called Jørgen Buus Lassen, who supported the theory that the specific enhancement of serotonin might lift a depressive mood. He tested about 100 compounds before deciding on one that became known as paroxetine. ‘We did all the clinical trials,’ he says today from his office in Glostrup, near Copenhagen, ‘and what created most excitement among our scientists was that in some trials we saw that some patients who had been totally hopeless on the existing drugs and not at all responsive to treatment, were gradually becoming better and better. Some who had been unable to work for several years and had been in and out of psychiatric hospitals gradually came into normal life again.’

Dr Jorgen Buus Lassen wrote the first scientific paper on paroxetine in 1975, in the paper he was frank about the drugs limitations.’It didn’t work with all patients,’ he remembers. ‘In most studies we could just show that we had about the same efficacy as the older tricyclic antidepressants. We didn’t see a better effect, but we saw fewer side effects [mainly nausea].’

 

Dr. Jørgen Buus Lassen (Danish) received his DVM from the Royal School of Veterinary and Agriculture Science in Copenhagen. Dr. Lassen is co-founder of NeuroSearch A/S and has been the President and CEO of NeuroSearch since May 1989. He has more than 25 years’ experience within neuropharmacology and has authored or co-authored more than 30 publications, including the first paper published with respect to Paroxetin (Paxil, Seroxat), an antidepressant. From 1980 to 1988, Dr. Lassen served as Managing Director of Ferrosan A/S` research and development division, where Dr. Lassen was responsible for the expansion of all pre-clinical and clinical activities. He is chairman of the boards of NsGene A/S and Gudme Raaschou Healthcare Invest A/S and member of the boards of Bavarian Nordic A/S, Neurosearch A/S and NicOx S.A. Board member of Pharmexa since 1997. Reference is made to Pharmexa’s address.

Dr Jorgen Buus Lassen is also connected with NeuroSearch, he is the President and CEO of Neurosearch

 

http://www.neurosearch.com/

Which is affiliated with GSK…

NeuroSearch and GlaxoSmithKline form strategic RD alliance

19 December 2003 – Announcement

PDF version

NeuroSearch and GlaxoSmithKline (GSK) today announced a five-year research and development alliance. The alliance comprises a number of research programmes within ion channels and the treatment of diseases of the central nervous system (CNS) including depression, anxiety, and schizophrenia. The new alliance combines NeuroSearch’s innovative research and development, and strong technology platform with GSK’s research, development, and commercial strength.

The option agreement gives GSK access to new drug candidates from NeuroSearch’s research and development within the defined area. This includes the Phase II triple monoamine re-uptake inhibitor NS2359, the Endovion programme and several other research programmes. The existing collaboration with GSK in depression disorders is integrated in the new agreement.

President CEO Jørgen Buus Lassen of NeuroSearch says, I am pleased that we were able to conclude this important strategic alliance with GSK as our two companies have had a well-functioning and trustful partnership within depression research for three years. I have a strong expectation that this extended partnership will be a major success for both companies.

http://findarticles.com/p/articles/mi_hb033/is_200301/ai_hibm1G197351003

GlaxoSmithKline (www.gsk.com) and the Danish company NeuroSearch (www.neurosearch.com) will collaborate to discover and develop “triple-action” monoamine reuptake inhibitors to treat depression and other mood disorders. (Development Updates).(depression and other mood disorders)(Brief Article)

For more info on Ferossan , Buus Lassen and the Origins of Paroxetine and how it came to be unleashed on an unsuspecting public see link on Seroxat link 1 (hypnotic narcotic) .. A very informative post by Rob Robinson on Paxil Progress…

www.paxilprogress.org/forums/showthread.php?t=11984&highlight=paroxetine+hypnotic