Following on from Part I.
In summary, In 1988 GSK, then SmithKline Beecham (SKB) sponsored clinical trials in Yugoslavia. The purpose of the trials was to show how Paxil (known as Seroxat in the UK) could, when stopped, cause a relapse in depression. SKB never took into account that those relapsing (after stopping Paxil) could have been suffering withdrawal symptoms.
With the results they wanted, SKB then provided the FDA with apparent evidence that showed patients staying on Paxil continued to enjoy a normal, "depression free" life, but that those abandoning the drug would suffer relapse back into a depressive state.
One thing that was irksome to SKB was that they had to convince the FDA that the relapses shown in the study were not simply patients suffering withdrawal.
Enter Dr. Thomas Laughren of the FDA.
This from the legal brief.
SKB decided to massage the problem through back channel communications with Thomas Laughren, MD, a high official in the FDA.SKB felt if they could convince Dr. Laughren of the good "relapse" statistics in the Yugoslavia trial, they could avert the hard questioning of the FDA committee members on the withdrawal issue.Having "FDA" on your side before the FDA committee, it was felt, was good politics and a way to subtly shift responsibility for the issue away from SKB. To implement their tactic, SKB emphasized to Dr. Laughren that the Yugoslavia trial protocol was designed to detect relapse.At the same time, SKB told Laughren, they would do their best to detect and report on Paxil's withdrawal issues during Phase II. Given that "withdrawal" at that moment was not a front burner issue, that explanation satisfied the FDA official.
On October 5, 1992, the FDA's Psychopharmacologic Drugs Advisory Committee voted unanimously that Paxil be recommended for approval for the treatment of depression.
FDA Neuropharmacological Drug Products Division Director Paul Leber, MD, opened the meeting by stating: "The division's clinical review team and its statistical consultants have concluded that the evidence submitted in SmithKline Beecham's NDA for paroxetine convincingly documents that paroxetine...is both a safe and effective antidepressant."
SKB had shown that the 172-patient, 52-week Yugoslavian study of paroxetine for prevention of depression relapse showed "a highly significant difference" between drug and placebo, they showed that in that trial, 15% of Paxil-treated patients relapsed in a year, with an average time to relapse of 30 months, while 39% of placebo patients relapsed in an average of 17 weeks after the study began.
SKB had finally got their foot on the bottom rung of the antidepressant ladder, it had taken longer than usual because around the time another antidepressant, Prozac, was making news.
Here's the legal brief again...
There had been press reports that Prozac, originally appearing on the market in 1988, had caused many suicides.FDA was thus compelled to review Prozac and--obviously--considered it in their own interest to tread softly before approving additional SSRI's for the market.Condemning Prozac and acknowledging the suicide issue, however, would suggest in many quarters that FDA was to blame for allowing a dangerous drug on the market in the first place. Few bureaucracies admit they are wrong, and all have a tendency to herald the status quo.Thus while assuring Congress and the media that they would thoroughly investigate the recent Prozac allegations, the FDA was actually in cahoots with the SSRI manufacturers on the suicide issue. On October 3, 1990, an FDA official, the Director of Neuropharmacological Drug Products, telephoned SKB headquarters. He asked to speak to SKB's Regulatory Affairs director, a Ph.D. The call was made at a location that could not be traced back to the FDA official's office. This person making the call was the senior FDA official responsible for Paxil's application. The official made clear to SKB his purpose. It was not to "lay down the law" and ensure SSRI testing was refined. It was to tell SKB how to get around the suicide problem for Paxil's upcoming application--and further not to worry.
By the way, the "legal brief" I am referring to is the entire formal complaint brought against SmithKline Beecham that was filed in California on August 19, 2000. (Nguyen & Farber, plaintiffs vs. SmithKline Beecham Corporation) - The full brief is publicly available and makes very interesting reading. You can download it here.
When the FDA committee convened on October 5, 1992 there were 6 panel judges who would decide whether or not Paxil would be 'good to go'.
Dr. Laughren told the panel, "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."
Do you, like me, find this statement utterly bizarre?
If there was no efforts made to look at withdrawal then how did he, or SKB for that matter, arrive at, "...there was no strong suggestion of a withdrawal syndrome?"
When SKB addressed the panel they pulled out all the stops.
Here's the legal brief...
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.Dr. Laughren, on hearing SKB contradict his earlier statement,
The legal brief...
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.
2015 UK Seroxat litigation.
Almost 9 years ago a group action was filed against GlaxoSmithKline by UK patients who alleged pretty much the same as the 3,000 or so in the Nguyen & Farber, plaintiffs vs. SmithKline Beecham Corporation case.
No effort has been made by GlaxoSmithKline to resolve the UK litigation. At the time of filing a GSK spokesperson said, "We believe there is no merit in this litigation. Seroxat has benefited millions of people worldwide who have suffered from depression.''
Meantime, the UK group action continues in its fight to seek damages for those British patients who, just like American patients, suffered severe withdrawal at the hands of Seroxat.
If the difference between judicial law in America and the UK show one thing in this case, it's timescales. Nguyen & Farber, plaintiffs vs. SmithKline Beecham Corporation was filed in 2000 and resolved in 2002. The UK litigation was filed in 2008 and GlaxoSmithKline, it appears, remain unconvinced that they have a case to answer.
More on the UK Seroxat litigation at a later date.