Around the time of 1998, when GSK were pushing Seroxat for other “disorders” in their bid to steal the crown off Prozac , there was some other interesting stuff going on …
Mostly concerning a pediatric (child ) study , ‘The Infamous Study 329’ ..
Up until 1998 , Seroxat was not licenced for use in children (under 18’s ) , although it was at a doctors discretion and it could be prescribed “off label” to this age group…( and it often was)
But Glaxo desperately wanted to prove that Seroxat worked in this age group (Efficacy) , if they could get a licence to treat childhood disorders with Seroxat , it would increase sales. Their profits were already massive from Seroxat ,( over a billion by 1998 ) but GSK wanted to dominate the market and they stopped at nothing in their pursuit to make Seroxat/Paxil the number one psychotropic drug worldwide.
The only problem was , they were finding it difficult to prove that Seroxat worked for kids, in fact their studies were proving placebos ( sugar pills) to be more effective than Seroxat in under-18’s …
And most disturbing of all, there were indications from Glaxo’s own trials that Seroxat increased the risk of suicide and hostility in Under 18’s, but GSK carried on regardless…
See link :
In the link above, you can access documents relating to study 329 and study 377…
There have been many players in the Seroxat Scam ,One such player was The “Author” of Study 329, an academic psychiatrist called Martin Keller. In the business he is refered to as a “key opinion leader” ..
In other words, his psychiatric and academic voice or opinion is listened to and respected…
But, it seems that Mr Keller didn’t actually write Study 329, he said himself in an interview that he didn’t go through all the raw data… And it seems from interpreting these documents that the study could well have been “ghost written” … So who did Write Study 329? … Was it Glaxo? Was it Glaxo’s marketing team? …
These are excerpts from the Study 329 correspondence ( they were released to the public last year, before that, they were protected under a court order )
RE: PAXll ADOLESCENT DEPRESSION PAPER
I am pleased to enclose a small supply of reprints of the paroxetine-imipramine
adolescent depression paper that was recently pub I ished in Journal of the American
Academy of Child and Adolescent Psychiatry. GSK funded the purchase of the
reprints. A total of 300 went to Marty Keller, who is corresponding author on the
paper, and the balance is being sent to Zach Hawkins for distribution to the
Neuroscience sales force. Samples are also being sent to Rocco and Neil.
The paper looks excellent and demonstrates the commitment of GSK to the field of
psychiatry. Thank you for your support.
Sally K. Laden, MS
Associate Editorial Director
February 6, 2001
Martin B. Keller, MD
Department of Psychiatry and Human Behavior
Brown University School of Medicine
345 Blackstone Blvd
Providence, RI 02906
Dear Dr Keller,
We are pleased to enclose all of the materials you will need to resubmit your manuscript
“Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A
Randomized, Controlled Trial” to the Journal of the American Academy of Child and
Enclosed in this package are the following items:
Two copies of the revised paper with changes highlighted
(submit 1 to the
journal. keep 1 for your files),
• Four copies of the revised paper without the highlighting (submit 3 to the
journal, keep 1 for your files)
On behalf of Sally Laden, it has been a pleasure working with you on this project.
Please keep us apprised of the status of this paper at the journal. Thank you and please
do not hesitate to contact us if you have any questions or need additional assistance.
To: All Sales Representatives Selling Paxil
From : Zachary Hawkins
Paxil Product Management
Significance of article
“Efficacy of Paroxetine in the Treatment of Adolescent Major
Depression: A Randomized, Controlled Trial”
Martin B. Keller, M.D.
J. AM.ACAD. CHILD ADOLESC. PSYCHIATRY2001
2001, July, Vol. 40:7: 762-772
This “cutting-edge,” landmark study is the first to compare
efficacy of an SSRI and a TCA with placebo in the treatmen1 of
major,depression in adolescents. Paxil demonstrates
REMARKABLE Efficacy and Safety in the treatment of
In conclusion, the findings of this study provide evidence of the
efficacy and safety of Paxil in the treatment of adolescent
depression. Here’s another example of GlaxoSmithKline’ s
commitment to Psychiatry by bringing forth “cutting l~dge”
scientific data. Paxil is truly a REMARKABLE product that
continues to demonstrate efftcacy, even in this understudied
GSK finally got what they wanted, an academic interpretation of a clinical trial advocating the use of Seroxat in children…
Only problem was…
Study 329 didn’t actually prove anything …
It was purely GSK marketing gloss…
On the other hand study 377, did prove something…
It proved that Seroxat was no more effective than a sugar pill for the treatment of adolescent/child depression …
Two Studies, Two Results, and a Debate Over a Drug
The two drug trials were known within SmithKline Beecham as Study 329 and Study 377.
Study 329 suggested that the company’s popular drug Paxil might help depressed adolescents. Study 377, completed not long afterward, indicated that Paxil provided no more benefit than a sugar pill in treating depressed young people.
But only the favorable study was widely publicized by Paxil’s maker. The company chose not to discuss publicly the trial with negative results, and those findings came to light only when an outside researcher on the study team decided to disclose them at a medical conference.
Federal regulators in this country are now scrambling to reassess the effectiveness and safety of antidepressants like Paxil, after British regulators touched off a controversy last year by asking drug companies for unpublished data from antidepressant trials. That data suggested that several antidepressants, including Paxil, might give rise to suicidal thoughts in some young users – a potential problem not revealed in any published studies.
Yesterday, the New York State attorney general, Eliot Spitzer, entered the fray by taking the unusual step of suing Paxil’s maker, which is now GlaxoSmithKline. Mr. Spitzer’s suit accuses the company of consumer fraud for not disclosing all of its Paxil data.
Officials of GlaxoSmithKline defend their record, saying they provided all the results of their Paxil clinical trials to the Food and Drug Administration, as required by law. But the stories of Study 329 and Study 377 provide a window into a far broader issue – the fact that the results of many human clinical trials of drugs are often never widely publicized and that, in some cases, doctors may never learn that the trials were even conducted.
These days, most drug trials are sponsored by pharmaceutical companies. And for more than a decade, a growing number of medical experts have been urging drug makers to release more trial data and to create uniform means of disclosing results through central registries, so that policy makers and doctors can easily learn the results. Those advocates argue that such central databases are necessary because drug companies, as well as medical journals and researchers, tend to spotlight only trials that show positive results
The fates of Study 329 and Study 377 appear to underscore that point. Both tests were conducted during the mid-1990’s at various hospitals and medical centers – Study 329 at facilities in the United States and Study 377 at test centers outside of this country, including Canada, Mexico, Europe, South Africa and the United Arab Emirates.
Study 329, with its potentially positive findings for Paxil, was completed first. Its results were presented beginning in 1998 at several meetings of medical professionals. Meanwhile, a report of the trial, which was led by Dr. Martin B. Keller, a department chairman at Brown University Medical School, was submitted to a medical journal for publication, a process that subjects a study to peer review by scientists not involved in the trial.
Dr. Keller declined to be interviewed for this article. But Dr. Neil Ryan, a professor at the University of Pittsburgh, who was also involved, said he believed that the study was rejected by some journals before The Journal of the Academy of Child and Adolescent Psychiatry accepted it for publication in 2001.
In the case of Study 377, the one with negative findings, there were no press releases or publications. And without the action of Dr. Milin and a Canadian colleague, Dr. Jovan Simeon, the study’s findings might have been seen only by regulators and a few researchers.
The writer of “clinical psychiatry a closer look” wrote a poignant artice about the the Study 329 shambles… Here are some excerpts …
Tuesday, January 30, 2007
Keller, Bad Science, and Seroxat/Paxil
I will focus on Dr. Martin Keller and some seriously poor science in this post. Panorama did an excellent job of profiling Keller’s role in helping to promote paroxetine (known as Paxil in the USA and Seroxat in the UK). Note this is a lengthy post and that the bold section headings should help you find your way.
Who is Martin Keller? He is chair of psychiatry at Brown University. According to his curriculum vita, he has over 300 scientific publications. People take his opinions seriously. He is what is known as a key opinion leader or thought leader in academia and by the drug industry. What does that mean? Well, on videotape (see the Panorama episode from 1-29-07), Keller said:
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.
Keller and Study 329: GlaxoSmithKline conducted a study, numbered 329, in which it examined the efficacy and safety of paroxetine versus placebo in the treatment of adolescent depression. Keller was the lead author on the article (J American Academy of Child and Adolescent Psychiatry, 2001, 762-772) which appeared regarding the results of this study.
Text of Article vs. the Actual Data: We’re going to now examine what the text of the article said versus what the data from the study said.
Article: 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 What exactly were emotional lability and hostility? To quote James McCafferty, a GSK employee who helped work on Study 329, “the term emotional lability was catch all term for ‘suicidal ideation and gestures’. The hostility term captures behavioral problems, most related to parental and school confrontations.” According to Dr. David Healy, who certainly has much inside knowledge of raw data and company documents (background here), hostility counted for “homicidal acts, homicidal ideation and aggressive events.”
Suicidality is now lability and overt aggression is now hostility. Sounds much nicer that way.
Conveniently defining depression: On page 770 of the study report, the authors opined that “…our study demonstrates that treatment with paroxetine results in clinically relevant improvement in depression scores.” The only measures that showed an advantage for paroxetine were either based on some arbitrary cutoff (and the researchers could of course opt for whatever cutoff yielded the results they wanted) or were not actually valid measures of depression. The only measures that were significant were either a global measure of improvement, which paints an optimistic view of treatment outcome, or were cherry-picked single items from longer questionnaires.
Also, think about the following for a moment. A single question on any questionnaire or interview is obviously not going to broadly cover symptoms of depression. A single question cannot cover the many facets of depression. Implying that a single question on an interview which shows an advantage for paroxetine shows that paroxetine is superior in treating depression is utterly invalid. Such logic is akin to finding that a patient with the flu reports coughing less often on a medication compared to placebo, so the medication is then declared superior to placebo for managing flu despite the medication not working better on any of the many other symptoms that comprise influenza.
Whitewashing safety data: 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” 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. David Healy has also discussed this fallacious assumption that drugs cannot cause harm.
Did Keller Know the Study Data? I’ll paraphrase briefly from Panorama, which had a video of Keller discussing the study and his role in examining and analyzing its data. He said he had reviewed data analytic tables, but then he mentioned soon after that on some printouts there were “item numbers and variable numbers and they don’t even have words on them – I tend not to look at those. I do better with words than symbols. [emphasis mine].”
Ghosted: According to Panorama (and documents I’ve obtained), the paper was written by a ghostwriter. Keller’s response to the ghostwriter after he saw the paper? “You did a superb job with this. Thank you very much. It is excellent. Enclosed are some rather minor changes from me, Neal, and Mike. [emphasis mine].” And let’s remember that Keller apparently did not wish to bother with looking at numbers. It would also appear that he did not want to bother much with the words based upon those numbers.
Third Party Technique: This is a tried and true trick – get several leading academics to stamp their names on a study manuscript and suddenly it appears like the study was closely supervised in every aspect, from data collection to data analysis, to study writeup, by independent academics. Thus, it is not GlaxoSmithKline telling you that their product is great, it is “independent researchers” from such bastions of academia as Brown University, the University of Pittsburgh, and University of Texas Southwester Medical Center and the University of Texas Medical Branch at Galveston which are stamping approval of the product. More on this in future posts.
Keller’s Background… It is relatively well-known that Keller makes much money from his consulting and research arrangements with drug companies. In fact, several years ago, it was documented that Keller pulled in over $500,000 in a single year through these lucrative deals. When looking at how he stuck his name on a study he did not write, endorsing conclusions that were clearly far from the actual study data, can one seriously believe that Keller operated as an independent researcher? Can you believe that this is an isolated incident?
See, for example, Keller’s involvement in a study examining the effects of Risperdal (risperidone) for the treatment of depression. This study was presented a number of times, and he never appeared as an author of any of the presentations. Yet when the study was published, his name appeared as an author. The real kicker was that he allegedly helped to design the study, according to the published article. If he had played a major role in the study, he would have been acknowledged earlier (via being listed as a presentation author), so he apparently helped design the study after it was completed, which is obviously a major feat! The whole story is here. Why put his name on the paper? So that readers would believe more strongly in the study due to his big name status.
In addition, Keller wrote about how Effexor reduces episodes of depression in the long-term though he clearly misinterpreted the study’s findings. To be fair, many other researchers have made the same mistake in believing that SSRI’s reduce depression. To quote an earlier post:
In other words, because SSRIs and similar drugs (e.g., Effexor) have withdrawal symptoms that sometimes lead to depression, it looks like they are effective in preventing depression because people often get worse shortly after stopping their medication. The drug companies (Wyeth, in the case of Effexor) would like you to believe that this means antidepressants protect you from re-experiencing depression once you get better, that they are a good long-term treatment. A more accurate statement is that antidepressants protect you from their own substantial withdrawal symptoms until you stop taking them.
Again, Keller is way off from the study data.
Keller on Camera: Keller’s response to being asked about the increased suicidality among participants taking paroxetine in Study 329 was interesting:
None of these attempts led to suicide and very few of them led to hospitalization.
Well then I suppose a huge increase in suicidal thoughts and gestures is okay, then? This is the commentary of an “opinion leader” – if statements such as the above shape opinions among practicing psychiatrists, then we really are in trouble.
Next: Well, consider this post just the start regarding Paxil/Seroxat. The way the data were pimped by GSK merits more discussion as does more discussion of allegedly detached academics and their role in this debacle.