Yet more on Paxil Study 329, Keller et al

This is from the always excellent CL Psych. As usual I have reproduced the whole of his article – it’s all here and a real eye opener.

If you need to catch up on Study 329, then read this. Otherwise just carry on:

A bombshell has just appeared [April 2008] in the International Journal of Risk & Safety in Medicine. The subject of the paper is Paxil study 329, which examined the effects of the antidepressant paroxetine in adolescents. The study findings were published in the Journal of the American Academy of Child and Adolescent Psychiatry in 2001. These new findings show that I was wrong about Paxil Study 329. You know, the one that I said overstated the efficacy of Paxil and understated its risks. The one that I claimed was ghostwritten. Turns out that due to legal action, several documents were made available that shed more light on the study. The authors (Jureidini, McHenry, and Mansfield) of the new investigation have a few enlightening points. Let’s look at the claims and you can then see how wrong I was, for which I sincerely apologize.

The story is actually worse than I had imagined.

Here’s what I said then:

Article [quote from the study publication]: Paroxetine is generally well-tolerated and effective for major depression in adolescents (p. 762).

Data on effectiveness: On the primary outcome variables (Hamilton Rating Scale for Depression [HAM-D] mean change and HAM-D final score < 8 and/or improved by 50% or more), paroxetine was not statistically superior to placebo. On four of eight measures, paroxetine was superior to placebo. Note, however, that its superiority was always by a small to moderate (at best) margin. On the whole, the most accurate take is that paroxetine was either no better or slightly better than a placebo.

I went on to bemoan how the authors took differences either based on arbitrary cutoff scores or from measures that assessed something other than depression to make illegitimate claims that paroxetine was effective. Based upon newly available data from the study, here’s what happened.

  • The protocol for the study (i.e., the document laying out what was going to happen in the study) called for eight outcome measurements. To quote Jureidini et al: “There was no significant difference between the paroxetine and placebo groups on any of the eight pre-specified outcome measures.” So I was wrong. Paxil was not better on 4 of 8 measures — it was better on ZERO of eight measures. My sincerest apologies.
  • Another quote from Jureidini and friends: “Overall four of the eight negative outcome measures specified in the protocol were replaced with four positive ones, many other negative measures having been tested and rejected along the way.

Let’s break this thing down for a minute. The authors planned to look eight different ways for Paxil to beat placebo. They went zero for eight. So, rather than declaring defeat, the authors then went digging to find some way in which Paxil was better than a placebo. Devising various cutoff scores on various measures on which victory could be declared, as well as examining individual items from various measures rather than entire rating scales, the authors were able to grasp and pull out a couple of small victories. In the published version of the paper, there is no hint that such data dredging occurred. Change the endpoints until you find one that works out, then declare victory.

How About Safety?

I was incensed about the coverage of safety, particularly the magical writing that stated that a placebo can make you suicidal, but Paxil could not. I wrote:

It gets even more bizarre. Remember those 10 people who had serious adverse psychiatric events while taking paroxetine? Well, the researchers concluded that none of the adverse psychiatric events were caused by paroxetine. Interestingly, the one person who became “labile” [i.e., suicidal] on placebo – that event was attributed to placebo. In this magical study, a drug cannot make you suicidal but a placebo can. In a later document, Keller and colleagues said that “acute psychosocial stressors, medication noncompliance, and/or untreated comorbid disorders were judged by the investigators to account for the adverse effects in all 10 patients.” This sounds to me as if the investigators had concluded beforehand that paroxetine is incapable of making participants worse and they just had to drum up some other explanation as to why these serious events were occurring.

Turns out I missed a couple things. Based on looking at an internal document and doing some calculations, Jureidini et al. found that serious adverse events were significantly more likely to occur in patients taking paroxetine (12%) vs. placebo (2%). Likewise, adverse events requiring hospitalization were significantly disadvantageous to paroxetine (6.5% vs. 0%). Severe nervous system side effects — same story (18% vs. 4.6%). The authors of Study 329 did not conduct analyses to see whether the aforementioned side effects occurred more commonly on drug vs. placebo.

Funny how they had time to dredge through every conceivable efficacy outcome but couldn’t see whether the difference in severe adverse events was statistically significant.

One quote from the discussion section of the paper sums it all up:

There was no significant efficacy difference between paroxetine and placebo on the two primary outcomes or six secondary outcomes in the original protocol. At least 19 additional outcomes were tested. Study 329 was positive on 4 of 27 known outcomes (15%). There was a significantly higher rate of SAEs with paroxetine than with placebo. Consequently, study 329 was negative for efficacy and positive forharm.

But the authors concluded infamously that “Paroxetine is generally well-tolerated and effective for major depression in adolescents.”

Enter Ghostwriters. Documentary evidence as shown on indicated that the first draft of the study was ghostwritten. This leaves two roles for the so-called academic authors of this paper:

  • They were willing co-conspirators who committed scientific fraud.
  • They were dupes, who dishonestly represented that they had a major role in the analysis of data and writing of the study, when in fact GSK operatives were working behind the scenes to manufacture these dubious results.

Remember, this study was published in 2001, and there has still been no apology for the fictional portrayal of its results, wherein a drug that was ineffective and unsafe was portrayed as safe and effective. Physicians who saw the authorship line likely thought “Gee, this is a who’s who among academic child psychiatrists — I can trust that they provided some oversight to make sure GSK didn’t twist the results.” But they were wrong.

By the way, Martin Keller, the lead “independent academic” author of this tragedy of a study said, when asked about what it means to be a key opinion leader in psychiatry:

You’re respected for being an honorable person and therefore when you give an opinion about something, people tend to listen and say – These individuals gave their opinions; it’s worth considering.

So is completely misrepresenting the data from a study “honorable”? Is Keller’s opinion “worth considering?” As you know if you’ve read this blog for long, such behavior is, sadly, not a fluke occurrence. Many others who should be providing leadership are leading us on a race to the scientific and ethical bottom. What will Brown University, home of Keller, do? Universities don’t seem to care at all about scientific fraud, provided that the perpetrators of bad science are bringing home the bacon.

Not one of the “key opinion leaders” who signed on as an author to this study has said, “Yep, I screwed up. I didn’t see the data and I was a dupe.” Nobody. Sure, I don’t expect that every author of every publication can vouch for the data with 100% certainty. I understand that. But shouldn’t the lead author be taking some accountability?

This is a Fluke (?) Some may be saying: “But this is just a fluke occurrence.” Is it? I’ve seen much evidence that data are often selectively reported in a manner like this — looks like (sadly) it takes a lawsuit for anyone to get a whiff of the bastardization of $science that passes for research these days. If GSK had not been sued, nobody would have ever known that the published data from Study 329 were negative. A reasonably educated person could see that the writeup of the study was a real pimp job — lots of selling the product based on flimsy evidence, but nobody would have seen the extent of the fraud. Apparently lawyers need to police scientists because scientists are incapable of playing by some very basic rules of science.

See for Yourself. Documents upon which the latest Jureidini et al. paper are based can be found here. Happy digging.

Glaxo refuse to co-operate with the MHRA once again – read the letter

At the end of the recent 4 year long investigation into Glaxo by the MHRA (the probe began after disclosure that Glaxo withheld data from Seroxat clinical trials), Kent Woods (CEO of the UK’s medicines regulator the MHRA) wrote to JP Garnier at GlaxoS mithKline – a small section of the letter read:

“You will be aware that we have reviewed a large quantity of documents from GSK. Legal provisions prevent us from releasing publicly any information gained under our statutory powers in the course of a criminal investigation. However, there has been a significant level of quite legitimate public interest in this case, and I would there like to release that information into the public domain. This of course requires your consent. GSK has regularly asserted that it has nothing to hide in this matter and so I should be grateful if you could confirm in writing your consent to the release.”

This was the MHRA beating its breast in a very public manner.

Unfortunately it seems that Glaxo’s reply has not been treated in the same way. The MHRA actually had a reply dated 18 March and a pdf file is hidden away on the MHRA website. Perhaps the MHRA’s embarrassed silence over Glaxo’s reply can be explained by the very final paragraph of the two page letter:

“Finally, it is our strong wish to be as transparent as possible in disclosing information around this investigation. However, from GSK’s standpoint there are legitimate concerns which would need to be addressed prior to any disclosure. These include, for example, the identification of individual employees, independent clinicians and patients, as well as the need to preserve commercial confidentiality of certain information. On this basis, we would be happy to consider requests for information, under the Freedom of Information Act, on a case by case basis in relation to specific documents or categories of documents.”

There you have it. GSK will consider FOI requests (which will have to sent to the MHRA as the FOI Act does not cover GSK) to release “specific documents or categories of documents”.

The only problem is that I can’t ask for“specific documents or categories of documents” as the MHRA can’t release any information into the public domain without GSK’s consent. Oh and another thing – approximately 1,000,000 pages of documentation were reviewed by the MHRA in its investigation.

So – I’m looking for a needle in a haystack, but I’m not allowed to know which haystack it’s in or even if it’s in a haystack – or even if it’s a needle I’m looking for.

GSK is in no way being “as transparent as possible” in this matter – their reply to the MHRA is a de facto refusal to release any of the information the MHRA has reviewed.

For more on this subject please look here and here.

To read the full MHRA report on the investigation read here.

Seroxat withdrawal warnings ignored by Glaxo…

…and do you know the worst thing about this… the clinical trial talked about here is from the end of the 1980s

This exchange is from Taken on Trust – a Panorama programme from 2004 (thanks to Truthman30).

JOFRE: One psychiatrist above all others has insured that we’ve heard information about Seroxat that its
manufacturer would rather we hadn’t. On Panorama’s previous programme Doctor David Healy explained
what he’d found in the secret archives of GlaxoSmithKline during an American legal action, evidence he
says proves the company has known all along that Seroxat can make all age groups suicidal.
In your view does Seroxat make some adults self harm and become suicidal?

Prof PETER TYRER
Head of Psychological Medicine
Imperial College
Yes, I’ve had a patient that I treated myself who found this effect. He found it only on a certain dose and
when the dose was changed it disappeared, but the fact is, it was clearly related and she actually
experimented with the dosage and found that she could almost predict the suicidal effects.

Prof PETER TYRER
Head of Psychological Medicine
Imperial College
For a time, even only in a matter of a few years, almost critical scepticism, the objectivity were suspended
in favour of the all out rush to develop these new drugs and develop new markets.

JOFRE: Because there was such an excitement created about them.

TYRER: Yes, as the head of GlaxoSmithKline once said: “There’s a lot of runway space out there for
Seroxat you know, let’s get the planes down.”

JOFRE: Getting the planes down, would the company hoped, lead to their second billion. It applied to
extend Seroxat’s licence for the treatment of five more illnesses, some familiar like obsessive compulsive
disorder, some not so familiar like social phobia. Each of Glaxo’s planes landed safely with the regulator’s
full approval. As more and more people are being prescribed Seroxat for a bewildering array of illnesses,
another massive problem has emerged, a problem not as devastating as suicide, but one that affects a much
larger number of patients, many people on the drug say they’ve become hooked. Again, the regulator has
failed to issue proper warnings, even though the evidence has been staring them in the face for years. When
Seroxat was first licensed it was marketed with the regulator’s approval as a safe non addictive drug, back
then even Dr Healy believed the hype.

JOFRE: In the late 1980s, before Seroxat was licensed, GlaxoSmithKline funded a clinical trial into the
drugs affects on depressed patients. The man they asked to conduct it was Professor Peter Tyrer a world
expert on drug dependence. He came across a problem that would go on to affect millions of patients
around the world. After six weeks on Seroxat some of his patients were feeling better, but some of them
were also hooked.

Prof PETER TYRER
Head of Psychological Medicine
Imperial College
After the trial ended they said: “Can we continue on these tablets because we feel we’ve got to have them
because they seem to be so effective”, but more concerning.. was more concerning to us was the fact that
they were saying: “I cannot tolerate the symptoms when I stop it”.

JOFRE: As far as you were concerned then were these people dependant on Seroxat?

TYRER: They were showing yes signs of dependence…

JOFRE: And this was after..

TYRER: ..after only six weeks.

JOFRE: …just six weeks on the drug.

TYRER: Yes.

JOFRE: Some of the withdrawal effects were very disturbing.

TYRER: They also felt more anxious, they felt this feeling of dysphoria, the feeling of being depressed and
in some cases entertaining suicidal thoughts.

JOFRE: That sounds pretty serious then if people were thinking of suicide when they stopped.

TYRER: Yes it is serious and in particular we were led to believe that these drugs were particularly
effective against suicidal thoughts and therefore, having them at any stage during the course of treatment..
and on withdrawal was a matter of great concern.

JOFRE: Professor Tyrer didn’t investigate these problems any further at the time, but he did tell
GlaxoSmithKline what he found, he says they weren’t very interested.

TYRER: It was very important to concentrate on the positive, so we didn’t expect that they would rush in
and investigate this problem as a matter of priority.

JOFRE: And as far as you’re aware they didn’t investigate the problem.

TYRER: No.

JOFRE: We asked GlaxoSmithKline if further studies were commissioned as a result of Professor Tyrer’s
findings on withdrawal. They didn’t say. What they did tell us was ‘The company reviewed reports of such
symptoms in all its clinical trials as a matter of course’. If the drug company didn’t investigate it, what
about the regulator? Since the early 90s its Yellow Card scheme has been throwing out signals that many
patients are hooked on Seroxat, the drug has attracted more Yellow Card complaints about withdrawal
problems than any other prescription medicine. The MHRA says: “Patients should have been well aware of
the risks before they started taking it.”
JOFRE: Really, up until last year the patient leaflet said that withdrawal symptoms were “not common”
and “you cannot become addicted to Seroxat”. The leaflets wording was approved by the regulator.

So was it helpful to tell patients that they couldn’t become addicted to Seroxat?

TYRER: No it wasn’t.

JOFRE: What do you think patients would have understood by that?

TYRER: Well they would have understood that it wasn’t habit forming and that really when the time came
for them to stop their drugs they would have no problem in stopping them, and clearly, the evidence didn’t
support that.

JOFRE: Do you think the regulator should have insisted on something clearer in the patient information
leaflet?

TYRER: Yes.

Steptoe & Johnson – Seroxat FOI request to the MHRA

It seems that you can’t keep away from Bob Fiddman’s blog Seroxat sufferers for too long, otherwise you’ll miss something.

Following on from my last post it seems a law firm made an interesting Freedom of information request to the MHRA about Seroxat:

From: [redacted]
Sent: 15 December 2005
14:59
To: Pharmacovigilance, [MHRA]
Cc: Subject: Request for Information

Dear Sirs
Attention: Pharmacovigilance Team

I wish to make a request for information pursuant to the Freedom of Information Act 2000 for the following information:

1. please identify the statute(s) and regulations which obligate the pharmaceutical industry to report suspected serious adverse drug reactions to the MHRA, and which include a definition of “serious” adverse drug reactions; and

2. a Drug Analysis Print for paroxetine [Seroxat/Paxil]which lists all of the adverse drug reactions which have been reported to the MHRA (and the former MCA) by all sources (including those reported by the marketing application holder) up to 1 May 2001.

I would prefer to receive the information electronically via email, but you may otherwise post the requested information to my attention at: Steptoe & Johnson, Clements House, 14-18 Gresham Street, London EC2V 7JE.

So who does Steptoe & Johnson work for I wonder…

Read the whole story here

MHRA staff co-operate with Glaxo to monitor critical comment on the internet..

My last post bemoaned the fact after during the recent 4 year long investigation into Glaxo by the MHRA (the probe began after disclosure that Glaxo withheld data from Seroxat clinical trials), it was announced by the MHRA that Glaxo and individual Glaxo employees declined “invitations to attend interviews…”

Glaxo employees simply decided not to co-operate with the criminal investigation into their actions and said they would not answer questions.

However, in an ironic twist we now have evidence that Glaxo, the MHRA and Glaxo’s lawyers, are happy to work together to monitor the internet, in particular Bob Fiddaman, who has noticed some interesting recent visitors to his blog (Seroxat Sufferers).

Now, I’ve always said the MHRA and Glaxo were too close by half, but it seems that some MHRA employees are even closer than I thought..

Makes you think, doesn’t it?

Glaxo staff decide not to co-operate with the MHRA’s criminal investigation

A very interesting answer to a Freedom of information request from Bob Fiddaman.

In the recent 4 year long investigation into Glaxo by the MHRA (the probe began after disclosure that Glaxo withheld data from Seroxat clinical trials), it was announced by the MHRA that Glaxo and individual Glaxo employees declined “invitations to attend interviews… but did provide three written witness statements – two on behalf of the drugmaker and one on behalf of an unnamed employee.

One of the questions Bob asked was this:

“Why were MHRA enforcement investigators unable to question GSK staff?”

The MHRA replied to him:

Under UK criminal law suspects in criminal investigations can not be compelled to answer questions, they have a right to remain silent. Lengthy negotiations were conducted with solicitors acting for individual members of GSK staff and for GSK itself with a view to persuading them to attend interviews under caution. The conclusion of the correspondence was that all the potential interviewees indicated that they would not attend an interview under caution.

The individual suspects (as opposed to the corporate entity GSK) could have been arrested and required to attend an interview under caution. However they could still not be compelled to answer questions and, given that their solicitors had clearly indicated that they would not answer questions, the investigation team concluded that there was nothing to gain by carrying out arrests.

So there you have it, in black and white. Glaxo employees simply decided not to co-operate with a criminal investigation into their actions and said they would not answer questions.

Good to know that Glaxo employees are serious about the safety profile of their drugs and are seen to be acting in best interests of us patients at all times.

I wonder why they decided not to co-operate?

I wonder who they are?

Glaxo hides yet more trial data

I wonder, can you see a pattern forming here?

This time it’s not Seroxat but Avandia – read on from the Chicago Tribune:

GlaxoSmithKline PLC, Europe’s largest drugmaker, failed to properly disclose studies of Avandia, the diabetes pill linked to potentially deadly side effects, U.S. regulators said.

The violations “are serious and may be symptomatic of underlying post-marketing safety reporting failures,” the Food and Drug Administration said in a letter posted on its Web site. The agency said it was never told about nine studies, and an additional 11 weren’t included in required annual reports from 2001 to 2007.

Avandia sales plunged last year after a May 21 report in the New England Journal of Medicine linked the drug to a 43 percent increased risk of heart attacks, prompting U.S. and European regulators to strengthen warnings on its prescribing information. The FDA found unreported research while inspecting paperwork at London-based Glaxo’s offices in Research Triangle Park, N.C., from August to November, according to the letter.

Meanwhile, Glaxo said 247 lawsuits have been filed in the U.S. over Avandia.

And just one other thing – I thought’d read somewhere that Glaxo proudly boasts it places all clinical trial data on the internet… well, almost all it seems.

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