If someone were to ask the surviving authors of Study 329 the question: “Knowing what you know now, if you had to do it over, would you agree to participate in that study again?”, many would probably say no. The real title of Study 329 was “Efficacy of Paroxetine in the Treatment of Adolescent Major Depression, A Randomized Controlled Trial”. It was published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) in July, 2001. Although it is probably fairly typical of medical research studies, it has been plagued by more than its share of troubles. Next week, fourteen years and two months after it was published, it is about to take yet another hit, when the Restored version is published.
There were many obstacles to doing the work to write Restoring Study 329: A randomized, controlled trial of the efficacy and harms of paroxetine and imipramine in the treatment of adolescent major depression. The biggest was getting access to the data. It took years to get the data, months to analyze it, and another year to get a version of the restored study that BMJ felt comfortable with. The “Restoration” of Study 329 may not have occurred if Study 329 had been retracted. If JAACAP had heeded the earliest calls for retraction, much of the unfortunate history of Study 329 could have been avoided.
In hindsight, the authors may wish that they had not been so adamant that retraction was unthinkable. Of course, there are probably many flawed studies that remain un-retracted. Many of the pitfalls into which Study 329 fell resulted from bad timing, coincidence, an astute and determined journalist, a Senator who found conflicts of interest in medicine unacceptable, and the unwavering commitment of a small group of medical experts who refused to give up and go away. How could those authors have foreseen?
Study 329’s problems started to surface right after it was published. Several doctors wrote letters to the JAACAP Editor with probing questions, mostly centred on the psychiatric side effects of paroxetine, and the measures used to claim its efficacy in treating adolescents. The authors responded and the questioners did not pursue their concerns further. Except one. Child Psychiatrist Jon Jureidini, M.D. from the University of Adelaide remained convinced that there were serious methodological problems hiding real harms, and he never stopped pushing to expose the truth.
After Study 329 was accepted but before it was published, a Wyoming jury awarded $6.4 million to the relatives of retired oilman Don Schell (Tobin v.SmithKline Beecham). Forty-eight hours after Mr. Schell had been prescribed paroxetine (Paxil), he put bullets through the heads of his wife, Rita, his daughter, Deborah, and his granddaughter, Alyssa. Then he shot and killed himself. The jury decided that Paxil was responsible for the tragedy.
Scottish journalist Shelley Jofre, having learned about the Schell case, did some research on the drug and arranged to do a program on paroxetine, known as Seroxat in the U.K., for BBC’s Panorama. The segment, Secrets of Seroxat, aired in October 2002. It revealed that the drug can cause suicidal and violent thoughts and behaviours, and that many people experience serious withdrawal problems. The show received such a huge public response that a second episode was developed, Emails from the Edge.
Following Secrets of Seroxat, the U.K. public was highly sensitized to the potential problems associated with paroxetine. In December of the year that Emails from the Edge was broadcast, the Medicines and Healthcare Products Regulatory Agency (MHRA) issued an advisory warning to physicians against prescribing SSRI antidepressants, including Seroxat, to people under age 18.
In June of 2004, New York State Attorney General Elliot Spitzer filed a lawsuit accusing British drug giant GlaxoSmithKline PLC of “repeated and persistent fraud” for concealing known problems with efficacy and safety of Paxil (paroxetine) for children and adolescents. Evidence was largely based on documents that had come to light in the Tobin case. The suit was settled for $2.5 million plus a promise by GSK that they would make their drug trial data accessible. Later that year, the FDA required that a “black box” warning label be added for all SSRI antidepressants, including Paxil.
In 2008, US Senator Chuck Grassley investigated serious violations of conflict of interest policies among high-profile academic psychiatrists, including Martin Keller, lead author of Study 329, and three of his coauthors. Senator Grassley’s investigation brought attention to the fact the nominal authors in many research studies are not the real authors. This was the case in Study 329. GSK hired a “ghostwriter”, Sally Laden of STI, to write the study article under GSK direction.
Over the next few years, many lawsuits involving suicidality and violence caused by paroxetine were settled. In addition, Paxil and other SSRI drugs became the target of lawsuits for causing birth defects. The FDA recognized suicidality and violence as side effects of SSRI antidepressants in all age groups and expanded the required “black box” warning.
In 2012, the U.S. Department of Justice brought an action in U.S. District Court to recover damages and civil penalties from GSK under the False Claims Act, and damages and other monetary relief under common law and equity for causing the submission of false or fraudulent claims to federal health care programs. Three drugs were implicated, including Paxil. This action was settled for $3 billion, the largest settlement of its kind.
All in all, the past decade was not an unqualified success for Paxil and its manufacturer. Still, the conclusion of Study 329, that “Paroxetine is generally well tolerated and effective for major depression in adolescents”, has stayed officially intact, since the study was never retracted, and has been widely cited.
In 2013, Peter Doshi and a number of other researchers published a paper in the BMJ entitled “Restoring invisible and abandoned trials: a call for people to publish the findings”. This is part of a larger campaign to make all data from drug trials available for public scrutiny.
In August, 2015, BMJ accepted for publication a new analysis of the data from the original Study 329. Restoring Study 329: A randomized, controlled trial of the efficacy and harms of paroxetine and imipramine in the treatment of adolescent major depression will be published online sometime the week of Sept 14, and in the hard copy journal later that week. The new team of authors, including those most active in lobbying for retraction, has taken the same data and reached startlingly different conclusions than the original. Their conclusions should lead us to reassess our assumptions about drug safety regulation.
Stay tuned to this blog as the details continue to unfold. See also 1boringoldman for a thorough ongoing analysis of this remarkable saga…
Today on the Study 329 site we have added a new section under “Background” which provides a summary of the attempts to get the original Study 329 retracted, together with links to the underlying documents.
Terrified, witless, in 2002; was I really all alone with this?
Thirteen years later; this background white noise is music to my ears.
Thank you for providing Background and Timeline and giving us the opportunity to read how it played out.
Thank you, to everyone, who was persistent and didn’t let it go.
The consequences are grave if there is a not a retraction.
http://study329.org/request-to-retract-study-329/
Who knows where all this may be leading?
3.23 minutes with….
http://news.bbc.co.uk/panorama/hi/front_page/newsid_8425000/8425414.stm
If someone were to ask the surviving authors of Study 329 the question: “Knowing what you know now, if you had to do it over, would you agree to participate in that study again?”, many would probably say no.
Do you really think so?
If they were opposed to it then wouldn’t they have made their feelings known by calling for its retraction?
Maybe, they have been ‘warned off’ by GSK not to call for it to be retracted, maybe GSK have told them that any monies paid to them (for adding their names to the study) will be clawed back?
Then again, we know how GSK operate. Maybe they have threatened the authors with some form of character assassination should they call for a retraction?
Keller, it appears, is just about the money, the guy probably has more bling than Ali G.
As for the others, who added their names to the fraudulent study, they have each been commended and, probably, made serious amounts of money on the back of the study (ie; giving lectures over the years)
329 is, in my opinion, worse than the thalidomide debacle. At least then, once it was known, efforts were made to warn the public. It’s taken a bunch of academics to right a wrong, many years of needless prescribing of a drug that was known to cause suicide in kids.
Witty had a golden opportunity to call for its retraction.
In the words of Robert De Niro, Mr Witty, “You had your chance and you blew it.”
A tribute to Shelley Jofre—
the true heroine of this tale of woe…
https://youtu.be/-FIMvSp01C8
My favorite line, which so apply applies to Shelley’s tenacity:
“As a noted scientist, it’s a bit surprising that the girl blinded ME with science.”
Hi ho!
All the news of the restoration of study 329 makes me feel so hopeful that there is going to be a major shift in the attitude towards Pharma. That it won’t just be us from the club who nobody wants to be in led by the few academics and professionals who care about what’s happening. It also makes me feel very emotional thinking about all those people who have died in the long wait for this to happen.
What happened to my son has happened now and can’t be undone. We just have to do the best we can to live with the consequences and he has to live the best life he can with the cards he was dealt. I really hope that a time is coming when others won’t have to.
Seroxat is the mental health thalidomide..
It would be interesting to know how many young people and children were prescribed Seroxat/Paxil/Aropax over the years?..
In 2003, it was reported that “Seroxat …was first licensed in the UK in 1990 for treating depression and last year, 8,000 under-18s were treated with the drug.”
Alasdair breckenridge (MHRA)
Read more: http://www.dailymail.co.uk/health/article-184196/Seroxat-ban-children.html#ixzz3lNntwow8
How many classes of suicidal children were there in that 8000 children in the UK?
If, (according to Alastair Benbow- former GSK representative ) there is a ‘small class size’ of around 1000 children who would get these suicidal effects then were there up to eight class sizes who would have got suicidal reactions? How many of these eight class sizes went on to self harm, attempt suicide, of complete a suicide?
If it was 8,000 a year, how many each year came off it? and how many each year were started on it? Could the figure be higher, per individual factored in?
We can also multiply that figure of ‘small classes of suicidal children’ massively when we take into account the amount of kids who were prescribed it globally over the last 15 years, or more. If it was several thousand in the UK, it was likely tens of thousands, or into hundreds of thousands in North America -Canada and the US (and everywhere else added in- in Europe, Ireland, Australia, New Zealand, and all the other countries which Seroxat/Paroxetine was sold under different brand names etc).
When you add the risk of Alastair Benbow’s ‘small class of suicidal children” up to a global scale, you can see that this small class was really more like dozens of large schools of suicidal children…
And then what of the young adults, and the adults and the older people?
And the miscarriages, birth defects etc?
The scale of human suffering from Seroxat is immeasurable…
https://www.youtube.com/watch?t=39&v=TozBgI5LyGc
“It would be interesting to know how many young people and children were prescribed Seroxat/Paxil/Aropax over the years?..”
This is something that might be powerful alongside the line-up of professionals who participated and benefited from Study 329: a line-up of children who were seriously affected by Seroxat. I haven’t been able to find much right off hand but some of you may already know of a number of these youngest victims and have perhaps already told their stories in other places. Facts and statistics are important yet tend not to have the same emotional impact as a well-chosen photo and/or story of one vulnerable child. (A recent example is the photo of the Syran boy on a Turkish beach).
We will have an accoount from one such person on RxISK.org next week to coincide with publication – and hope that others will send us in more accounts
D
I think Shelley’s Podcast, where she talks about the Panorama investigations, has been overlooked. It’s equally, if not more, as interesting as the Panorama documentaries.
I grabbed the audio back in 2009
Just press ‘Play’ 🙂
http://fiddaman.blogspot.co.uk/2009/08/podcast-from-shelley-jofre-bbc-panorama.html
Maybe one for the 329 website? I’m sure the Podcast can be downloaded as an mp3 in some form.
Thanks Bob, that is an awesome podcast, with many good details. I think you are right, it would be great on the 329 site. My favourite part is GSK telling Shelley Jofre that David Healy is not to be trusted…
I know Julie.
It’s absurd huh?
There are many great moments in the podcast, it’s a great insight.
GSK telling one person not to trust another really is the pot calling the kettle black.
It’s a defence mechanism when someone telling a lie is caught out. They cannot admit to their lie so they become the victim – it’s akin to your classic bully tactics.
I remember Andrew Witty’s predecessor, JP Garnier upon hearing the news that the British drug regulator wasn’t happy that his company had held back Paxil pediatric data – his response? … “We’ve done nothing wrong.”
Even with overwhelming evidence and convictions by juries, Glaxo still proudly go in front of the press and announce they robustly deny this, that and the other.
When they plead guilty, it then becomes part of an era, “Not on my watch, guv.”
Their lawyers will be all over David’s blog – They would be better off telling their client’s not to put kids in danger any more.
I hope Todd reads this!
Bob.
The “bully” tactics you describe play out the same way in academic clinical settings on the patient care units, where all of the professionals traditionally shared the common goal of providing best care/treatment for patients. That is no longer true.
Inpatient, acute care is where dialogue and debate are expected to happen. This is the frontline for critical assessment of patient treatment safety and treatment efficacy. The patient is right there, verbalizing her response to treatment. All of the care givers can weigh in- parents, nurses, all available for face to face conferencing. This ideal setting to assess and evaluate patient response to treatment and provide critical feedback to the research teams, —-this very important link to maintaining a person centered/ patient centered model of care has been corrupted by *bullies* sending the clear message they will not tolerate dissenting opinions, heretical posturing by any front line clinician(much less a patient or a patient’s loved ones) towards the new, bottom line authority, which so happens to be: The latest clinical trial by prominent academic psychiatrists published in a leading professional journal. Who is the gatekeeper for this bottom line authority ? Academic psychiatrists- who maintained their tenure and managerial positions by NOT challenging the gold standard for developing treatment guidelines. I can only assume—
The suppression of critical thinking and robust debating in academic medicine is a travesty that has yet to be qualified in an official sense , as the preeminent risk to all patients. The bullying, grand standing and subversive, unethical tactics that are topics for investigative journalists are life threatening for the rest of us. No one in mainstream media has brought that message home like Shelley Jofre.
Shelley Jofre uncovered and revealed what can only be called, cold indifference to the suffering of the only real victims of this bullying– children. Cold indifference by every prominent scientist who rubber stamped Paxil Study 329, IS the story. Has Shelley become another victim of this bullying ?
Shelley is every clinician who has gotten close enough to one of these bullies and sincerely asked: “Don’t you care that children are being harmed by this drug?” We all got the same answer, and the same label: “pitiful, contentious fool who does not know how science works”.
If you’re just waiting to see the next Act of this dark tragic play, the response from GSK, prominent KOLs and the medical community at large, to the RIAT report on Paxil Study329, you are missing both the key message of this ground breaking work and all that has made it necessary. Now is the time to put this show on the road, so to speak—. We need to engage the public, make this a political issue and demand protection under the law.
*Note the “Media” section on study329.org There is an inquiry form for media– but how will they know how important their attention to this story is, unless we alert them??
Public outcries for immediate action, occurring in tandem with the tactics we know are in the works from *industry*, will move this issue toward resolution. As the saying goes– “Fool me once, shame on you–” fool me— repeatedly?–
Third category on Background today…The Data
For the harms of treatment…Appendix H….
http://study329.org/the-data/
Thank you, RIAT Team…Up Periscope…
http://www.myabandonware.com/media/screenshots/u/up-periscope-jt/up-periscope_1.gif
I am a pharmacist. My daughter was put on this when she was 14 or 15 to try and help with depression that had been cyclic for years and to try to help prevent migraines. She seemed very much better after taking it for a few weeks. Then she turned into a monster. Very irritable and hostile, even aggressive. Finally, I got her into a counselor who knew right away that the Paxil could be the problem, probably because she had seen other teens with the same results. My daughter insisted on abruptly stopping the drug and became reclusive and I worried about suicide. Fortunately, she is fairly healthy and well adjusted now at 28, but those few months were horrendous. I used to be a lot more trusting of Pharma than I am now. I have become quite cynical and disgusted with this industry.