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Wednesday, September 16, 2015

Reanalysis of Glaxo's 329 Study Goes Public







It's been a long time coming, 14 years give or take.

Today sees the publication of a damning reanalysis of GlaxoSmithKline's infamous Study 329, a study, or a review of which, that was first published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) in 2001.


BACKGROUND

The study made claims that paroxetine (Paxil, Seroxat, Aropax) was a safe and effective medication for treating major depression in adolescents and has, for the past 14 years, been widely cited in the medical literature, providing physicians with assurances about the usefulness, and safety, of paroxetine in this patient population.

Despite many calls for its retraction it remains unretracted and still provides false and misleading information to physicians and, in many cases, parents, who read it.

Let's take a look at the findings of the original study...

"Paroxetine is generally well tolerated and effective for major depression in adolescents."

Initially, the study looked plausible, after all, it had the backing of high ranking child psychiatrists who had, so we were led to believe, trawled through the data and supported the claim that paroxetine was safe and effective for children and adolescents.**

The new groundbreaking study published today shows how the claims and subsequent support of the claims were misleading and, in actual fact, false.

The reanalysis, Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence - Joanna Le Noury (Lead author), John M Nardo, David Healy, Jon Jureidini, Melissa Raven, Catalin Tufanaru, Elia Abi-Jaoude, concludes that...

"Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs."


More on this new study and commentary from me, further down this post of mine.


With an initial study that made claims of safety and efficacy doctors and patients were led to believe that there would be no problems ingesting paroxetine and that it would make a lot of troubled children and teenagers well. Behind the scenes the pediatric Paxil machine was turning its wheels. GlaxoSmithKline, the company that sponsored the original study and manufactured the pill, had learned, some three years previous to the original publication, that the study did not show efficacy in this patient population but they had spent a lot of time and money trying to gain a licence in children and unfavourable results would mean losing out to a lucrative market.  Internal company memos, sent to senior management set the stall. It showed how they, with silence and denial could convince doctors and journals to play along with the claim that Paxil was safe and effective.

One has to ask why they would do this. One can only arrive at the answer that Glaxo did it for the profit, nothing more, nothing less. In fact, it's a good question to ask Glaxo officials - Why did they claim a study drug was safe and effective when they knew that it wasn't?

How do we know this?

Well, a company email surfaced via litigation in the US. It was dated Oct 14, 1998 and told senior management that...

“As you will know, the results of the studies were disappointing in that we did not reach statistical significance on the primary end points and thus the data do not support a label claim for the treatment of Adolescent Depression.”
So, how did we get from this to this?

 “This ‘cutting edge,’ landmark study is the first to compare efficacy of an SSRI and a TCA with placebo in the treatment of major depression in adolescents. Paxil demonstrates REMARKABLE Efficacy and Safety in the treatment of adolescent depression.”
Well, it has to do with not being fruitful with the truth. The study results were sent to a PR firm who, after reading through them came to the conclusion that paroxetine was indeed safe and effective. Here's the rub though, Glaxo only provided the PR firm with a summary of the study, roughly 200 pages. The actual study results (raw data) was over 77,000 pages long. Neither the PR firm or the authors who added their names to the study actually saw the raw data, more importantly, nae bizarrely, neither the PR firm or the original study authors asked to see the raw data. One has to ask why?

Glaxo didn't want the negative results leaking out to doctors, the public or their sales staff so they, once again internally, sent out the following to senior management..

“TARGET
To effectively manage the dissemination of these data in order to minimize any potential negative commercial impact…. It would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine.”

It worked as, one year after the JAACAP article went public, some two million American children and adolescents were prescribed Paxil. That figure is America only - add to it the number of children and adolescents elsewhere in the world that have been prescribed it and you will see why this was a lucrative market for GlaxoSmithKline.

The subsequent marketing of Paxil by its sales representatives to physicians is discussed on pages 11-12. United States of America Vs GlaxoSmithKline.



RESTORING STUDY 329

In as much as proving that the original 329 study was deeply flawed and misleading, the restoration (reanalysis) shows severe problems with the way studies are accepted by medical journals and also highlights how study authors merely put their names to ghostwritten reviews, in this case Glaxo hired a PR firm (1 & 2) to draft the misleading evidence that Paroxetine was generally well tolerated and effective for major depression in adolescents, despite evidence to the contrary, evidence that, allegedly, the PR firm did not see.

The "authors" of the original review, unlike the authors of  'Restoring Study 329' didn't actually get to see the raw data and signed off the review (passed it off as their own clinical findings) - it's akin to structural engineer inspectors taking it as gospel that a building is safe because the builders told them so.

Restoring Study 329 also showed significant increases in the paroxetine and imipramine arms, including serious, severe, and suicide related adverse events, all of which became apparent when the data were made available for reanalysis.

One has to ask some serious questions here about the original 329 authors, all of whom have, over the past 14 years, refused to retract their names from the study.

In an accompanying feature in the British Medical Journal (BMJ) Peter Doshi associate editor, The BMJ, writes...

"The first draft of the manuscript ultimately published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) was not written by any of the 22 named authors but by an outside medical writer hired by GSK. And the paper’s lead author, Brown University’s chief of psychiatry, Martin Keller, had been the focus of a front page investigation in the Boston Globe in 1999 that documented his under-reporting of financial ties to drug companies.
"But for those who have been calling for a retraction of the Keller paper for many years, the system has failed. None of the paper’s 22 mostly academic university authors, nor the journal’s editors, nor the academic and professional institutions they belong to, have intervened to correct the record. The paper remains without so much as an erratum, and none of its authors, many of whom are educators and prominent members of their respective professional societies, have been disciplined."


Doshi also picks up on Karen Wagner who was one of the original 329 study authors. He writes...

Karen Wagner, is a coauthor of the JAACAP paper. Wagner, a psychiatrist at the University of Texas, is also named eight times in the 2011 US Department of Justice complaint against GSK. According to the complaint, Wagner promoted paroxetine at a 1999 GSK sales force event. A GSK newsletter cited in the complaint quotes Wagner as telling the sales force that major depression was “a lethal disorder and it requires treatment.” Based on the results of Study 329, which were at the time still unpublished, “Dr Wagner said: ‘We can say that paroxetine has both efficacy and safety data for treating depression in adolescents.’”

At a telephone press conference (BMJ kindly invited me to participate) on Monday (14th Sept) Doshi spoke about the two studies. "What we have here is one paper published in 2001 saying that paroxetine is safe and effective and a new analysis that says that the drug is unsafe and ineffective, different conclusions and I think the RIAT authors have it right." (RIAT is the name given to the restoration authors - restoring invisible and abandoned trials)

On answering if criminal charges may be brought against any of those connected with the original study, Fiona Godlee, editor in chief of the BMJ, said, "I think there are movements, and this debate is ongoing, about the extent to which research and misconduct, which I think we can all agree, seems to have happened here and certainly many other instances could be the subject of criminal proceedings."

GlaxoSmithKline have had a copy of the RIAT findings since March. I asked one of the co-authors, David Healy, who was also part of the teleconference, if Glaxo had responded to it. He told me, "Not to us, that we're aware of."

RIAT author, Jon Jureidini, a child psychiatrist, also spoke of the study. "You will see from our paper that the harms associated with this drug in this trial were quite striking - twice the severe adverse events, four times the psychiatric events and high levels of suicide (events) and self harm, all of which were unclear in the previous publication." The high levels of suicide that Jureidini spoke of are  shocking. There were 11 suicidal patients in the paroxetine group compared to just one in the placebo group.


In an accompanying video (link at foot of this post) Jureidini shows how the RIAT team found more adverse events than the FDA and how Martin Keller, the lead author in the original study, under reported events, even though they had been identified by GlaxoSmithKline.

Speaking of videos, in 2003, some five years after GSK sent internal emails to senior management stating efficacy had not been proven with paroxetine, Alistair Benbow, then GSK's Head of Psychiatry, was asked on national televison if he thought paroxetine could be safe in children. He answered, "Absolutely, it could be... the evidence, however, is clear, these medicines are not linked with suicide, these medicines are not linked with an increased  rate of self-harm."

24 secs.






COMMENTARY


It's 'take a bow' time for the restoration study authors, Joanna Le Noury, John M Nardo, David Healy, Jon Jureidini, Melissa Raven, Catalin Tufanaru, and Elia Abi-Jaoude.

This is a significant piece of history and the British Medical Journal should be applauded too for finally showing some common sense and for not bowing down to pressure from British pharmaceutical giant, GlaxoSmithKline.

I don't expect for one minute that we will get any form of apology from either GlaxoSmithKline, the original study authors or, indeed, the Journal of the American Academy of Child and Adolescent Psychiatry. They have had nigh on 14 years to make retractions to the fraudulent study and they have each, individually declined. Today's publication of the reanalysis should, however, shake the boots of the authors. What they have done here is become part of Glaxo's murky history and hopefully every single one of the authors (22 in all) will, at some point in the future, come under scrutiny from law enforcers. Fraud is fraud, whatever way you slice it and each of the 22 have, knowingly or unknowingly, been part of that fraud, a fraud that put children and adolescents at risk, a fraud that has for 14 years been part of the reason why Paxil, this non-efficacious and unsafe antidepressant with side-effects such as suicidal thinking, has found its way into the mouths of children and adolescents.

For their part in this lack of care and duty to children they will have to face tough questions from family, friends and the media. Pleading ignorance just won't cut the mustard anymore.

The universities who have stood behind these authors also need to feel shame today, they have also been part of the reason why so many kids have been put at great risk and, arguably, many kids who have gone on to complete suicide induced by Paxil.

The original study, given the thumbs up by the original 329 review authors, was also taken as gospel by doctors who referred to it when checking to see if it was safe to prescribe kids Paxil off-label. Had Glaxo had been truthful then kids such as Sara Carlin, Sharise Gatchell and Adrian Keegan, to name but a few, would probably still be alive today. The same can be said for the authors, had they had asked to see the raw data then they would have drawn the same conclusion as the restoration authors, had they had called for the study to be retracted then kids who are now in the ground would, more than likely, be above the ground and enjoying their young lives. The JAACAP also needs to hold up its hand here as do the Universities who have, it appears, backed the authors associated with them.

There are different degrees of murder and manslaughter, someone, if not all, should be held accountable here. No better place to start than the current CEO of GlaxoSmithKline, Andrew Witty. Failing a murder or manslaughter charge then why not bring those responsible to trial under The Federal Child Abuse Prevention and Treatment Act, child neglect under this law states, "An act or failure to act which presents an imminent risk of serious harm.". I think the risks have been clearly proven, don't you?  Am I wrong to suggest that those responsible should face criminal charges? Ironically, in England, the National Society for the Prevention of Cruelty to Children (NSPCC) use the tagline, "Every Childhood Is Worth Fighting For," yet I cannot find one single piece of legislation that protects children from unsafe prescription drugs, or those that market and promote these drugs. This needs to change!


GSK BOXING CLEVER

On April 26, 2013, RIAT team member, Jon Jureidini, sent Andrew Witty a letter calling for the retraction of the JAACAP 329 article (fig 1). In a cleverly drafted response (fig 2) from GSK's Head of Governance, John E. Kraus, GSK told Jureidini that they did not agree that the journal article was false and misleading, they added that the article, "accurately reflects the honestly held views of the clinical investigator authors." In essence, GSK are correct, and it is yet another example of GSK's spin.

What GSK are saying here is that the article (not the actual study) stands up to scrutiny. Of course it does! The JACCAP article was based on a summary of the actual study and the findings of the PR firm hired to write the findings of that summary. Remember, GSK omitted negative findings in the summary sent to the PR firm and ghostwriter, Sally K. Laden. (Letters obtained from http://study329.org/)



FIG 1




FIG 2


I really can't find words to describe GlaxoSmithKline's attitude. I am, for the first time since the conception of this blog, utterly dumbfounded by GlaxoSmithKline's 'shrug of the shoulders' and lack of respect for those harmed by their product approach. Glaxo will argue until they are blue in the face that it has never been proven that Sara Carlin, Sharise Gatchell, Adrian Keegan and many more killed themselves because of paroxetine induced suicide. They can say this with confidence because no subject in the original trial, as far as we know, went on to complete suicide. The truth of the matter is, since its launch, paroxetine has been implicated in many suicides. In Britain alone there have been 65 reported suicides associated with paroxetine, these are just reports sent in to the British drug regulator when family members or doctors suspect that paroxetine may have been attributed to the individual suicides. Many more are not sent in - and herein lies the problem of the original study. If a patient kills themselves whilst on paroxetine the treating physician may once again refer to the original 329 review, and what will they see?

"Paroxetine is generally well tolerated and effective for major depression in adolescents."

No mention of a suicide threat, so any of the subsequent articles about Paxil related suicides and black box warnings will be largely ignored because, at the end of the day, a doctor is going to believe the word of 22 academics rather than a tabloid newspaper or documentary.

The study published today highlights the suicide threats in the original study, the subjects who, remember were just children and adolescents, who felt suicidal whilst in the trial. Many more were self harming, a precursor to suicidal thinking - GlaxoSmithKline did not label these subjects as suicidal, instead they opted for the term "emotional lability." A code they used, one can only assume, to prevent questions being asked - to me, a layperson, the term "emotional labilty" just means the subject was unstable. In fact, the medical dictionary defines it as "a condition of excessive emotional reactions and frequent mood changes." Glaxo will, once again, argue that suicidal thinking could fall into this definition but to actually label an adverse reaction as a suicidal thought would have probably meant that the original study would not have been published and hailed as a landmark study in the treatment of depression in children and adolescents.

I guess the results of the restoration study will show the world just how abhorrent this British company are when it comes to the welfare of children and adolescents. It's not the intention of the study to show that, it's just my view. It will also show how the whole process of clinical trials are deeply flawed and one sided and how paying highly respected child psychiatrists to endorse a drug takes precedence over actually allowing those same highly respected child psychiatrists to see the actual raw data.

Two studies, two opposite outcomes...and a whole bunch of internal company memos that show how this one company knowingly managed the dissemination of the negative study results so perfectly, making a huge profit as a result and, at the same time, putting children and adolescents at risk.

Clinical trials should be about science and about rigorously checking raw data. Restoring 329 is, I believe, the very first study that has used these models.

I anticipate that  Le Noury, Nardo, Healy, Jureidini, Raven, Tufanaru, Abi-Jaoude and the BMJ will now fall under the radar of GSK and the mud-slinging will begin. That's how Glaxo operate. They do it with reps who bring it to the attention of senior management that illegal activities are occurring within the company, they do it with expert witnesses who offer evidence against their products in court rooms, an example of this can be seen here, they do it with anyone who basically questions their ethics.

The RIAT team need to be applauded, it's not been easy to wade through 77,000 pages of raw data, a task made even harder by GlaxoSmithKline when the study authors learned that they could not simply save information off Glaxo's database, they had to painstakingly do it the old-fashioned way, by using a pen and paper.

Many others need to be applauded for their efforts over the years too. Leemon McHenry and Shelley Jofre spring to mind, as do investigative journalists Evelyn Pringle and Alison Bass. The LA based law firm, Baum Hedlund have also been instrumental in getting the information out as have the infinite amount of bloggers, not forgetting, of course, the Healthy Skepticism team and the Citizen's Commission on Human Rights.

It will be interesting to see, over the coming weeks and months if any of the original authors reject the findings of the restoration study - chances are they will, likelihood is that they won't be able to tell you why they reject these new findings. Science, particularly where raw data is used, cannot be argued.

For the record, the 22 authors of the original study are:

Martin B. Keller (lead author), Neal D. Ryan, Michael Strobber, Rachel G. Klein, Stan P. Kutcher, Boris Birmaher, Owen R. Hagino, Harold Koplewicz, Gabrielle A. Carlson, Gregory N. Clarke, Graham J. Emslie, David Feinberg, Barbara Geller, Vivek Kusumakar, George Papatheodorou, William H. Sack, Michael Sweeney, Karen Dineen Wagner, Elizabeth B. Weller, Nancy C. Winters, Rosemary Oakes, and James P. McCafferty.

As for GlaxoSmithKline, they will do everything to minimize the fallout of this study, after all they have shareholders whom they wish to continue buying their shares. If those same shareholders had any morals they would disassociate themselves with a company who knowingly put profit before the safety of children and adolescents - then again, money blinds people - the original 329 study is crystal clear evidence of that.


Make a habit of two things: to help; or at least to do no harm. - Hippocrates




Bob Fiddaman.





** I use the term 'children and adolescents' because, to me at least, there is no definitive cross-over when a child becomes an adolescent.


Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence (BMJ 2015)  -  Joanna Le Noury, John M Nardo, David Healy, Jon Jureidini, Melissa Raven, Catalin Tufanaru, Elia Abi-Jaoude

No correction, no retraction, no apology, no comment: paroxetine trial reanalysis raises questions about institutional responsibility (BMJ 2015) - Peter Doshi associate editor, The BMJ

Restoring Study 329 Website

Link to author video



Related news: Glaxo go to trial in the UK within the next 12 months where they will defend allegations that Paxil (known as Seroxat in the UK) caused severe withdrawal issues and dependency in a number of people who were prescribed it.


FOR SARA