"Landmark Analysis of an Infamous Medical Study Points Out the Challenges of Research Oversight"

[Dolphin]

Landmark Analysis of an Infamous Medical Study Points Out the Challenges of Research Oversight

http://chronicle.com/article/Landmark-Analysis-of-an/233179

This is on the original paper and now re-analysis of a trial of an antidepressant, paroxetine (Paxil, Seroxat, etc.), and why an increase of suicidality wasn't reported.

It touches on a few different issues e.g.
- re-analyses of trial data (still fairly rare)
- the reporting of harms (adverse events)
- retractions (not done in this case)
- what punishments there should be for people who publish flawed papers.

 

[Dolphin]

BMJ editorial on the story:

No correction, no retraction, no apology, no comment: paroxetine trial reanalysis raises questions about institutional responsibility

As a new data analysis adds weight to calls for retraction of a paper on paroxetine in adolescents, Peter Doshi examines the resistance to action of a professional society, its journal, and an Ivy League university

Peter Doshi associate editor, The BMJ
http://www.bmj.com/content/bmj/351/bmj.h4629.full.pdf

 

[Esther12]

Two of the SMC's experts were pretty dismissive of this, but one said a lot of things relevent to PACE:

Dr Sarah Bailey, Senior Lecturer, Department of Pharmacy and Psychopharmacology, University of Bath, said:

“This paper reports a reanalysis of a randomised controlled trial for the use of paroxetine in treating adolescents with depression, originally reported in 2001. This is one of a handful of such papers that have attempted to reanalyse clinical trial data. By going back to the original study protocol, following the methods set down and accessing original trial data, this reanalysis shows that paroxetine is not as effective, and carries a greater risk of adverse effects, than was reported at the time.

“The protocol for a clinical trial is important because it sets out the objectives of a study and your planned analysis before you gather any data so it should be free from any bias. This reanalysis highlights that some of the planned analyses were not carried out at all and some were carried out incorrectly. This paper raises important questions about the conduct of science research: how do we ensure that all clinical trial data is readily accessible for independent analyses? How do we remove misleading publications from the record? This paper demonstrates the importance of access to all of the data gathered for clinical trials and the importance of independent statistical analyses to interrogate data. But there are huge challenges in how we handle “big data” – these large data sets from clinical trials should be made available but doing that is complex – how do you store information, search data, share data and ensure information privacy for medical data. These are challenges faced by all scientists in an era where we are encouraged to make all our data open access.

“In terms of the take home message from this reanalysis that paroxetine is not safe in adolescent depression, this is not a particular advance in knowledge. Shortly after the trial “Study 329” was reported it was recognized as flawed. However, the original publication has never been retracted.

“Since the original publication of Study 329 in 2001 there have been a number of randomised controlled trials looking at the drug treatment and psychological therapies for the treatment of adolescent depression. Indeed, concerns about the safety of paroxetine meant that it was not even tested in some of these trials. Based on these trials (see below for details) and other evidence, the NICE guidance does not recommend the use of paroxetine in adolescent depression.

“The NICE guidance for the treatment of depression in children and young people puts forward a stepped-care model of depression that provides a framework where psychological therapies are introduced and if the depression is diagnosed as moderate or severe then fluoxetine ( a selective serotonin reuptake inhibitor SSRI) is the recommended treatment. All drug treatments carry a risk of side effects – fluoxetine is the only SSRI for which the benefits to the adolescent depressed patient outweigh the risks. What this study does highlight is the lack of effective treatments for adolescent depression and the need for new, better drug treatments.”

Further information from Dr Sarah Bailey:

Treatment of Adolescent Depression Study (TADS)

Silva S, Petrycki S, et al. Treatment for Adolescents with Depression Study (TADS) Team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression. Treatment for Adolescent Depression Study (TADS) randomized controlled trial. J Am Med Assoc. 2004;292:807–820

Adolescent Depression Antidepressant and Psychotherapy Trial (ADAPT)

Goodyer I, Dubicka B, Wilkinson P, et al. Selective serotonin reuptake inhibitors (SSRIs) and routine specialist care with and without cognitive behavior therapy in adolescents with major depression: Randomised controlled trial. Br Med J. 2007;335:106–111.

Treatment of SSRI-Resistant Depression in Adolescents study (TORDIA)

Brent DA, Emslie GJ, Clarke GN, et al. Switching to venlafaxine or another SSRI with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. J Am Med Assoc. 2008;299:901–913.

Sequenced Treatment Alternatives to Relieve Depression study (STAR*D) March J,

Rush AJ, Warden D, Wisniewski SR, et al. STAR*D: revising conventional wisdom. CNS Drugs.2009;23:627–647

http://www.sciencemediacentre.org/e...oxetine-in-adolescents-with-major-depression/

 

[Simon]

Interesting stuff

Landmark Analysis of an Infamous Medical Study Points Out the Challenges of Research Oversight

In the years since then, Paxil — made by GlaxoSmithKline and generically known as paroxetine — has generated many billions of dollars in sales, and become a poster child for claims of poor medical ethics. The Keller study has provoked repeated calls for retraction by the journal that published it. Demands for universities to punish those involved. Protests that one of its authors was just chosen to head the leading association of adolescent psychiatrists. And, a few years ago, a key role in the nation’s largest-ever health-care-fraud settlement.

Key to building that framework, they said, would be the routine disclosure of patient-level data from clinical trials on the scale that Glaxo was forced to make because of legal action brought by patients.

"For us, this is the main point behind the article," said one of Mr. Jureidini’s co-authors, David Healy, a professor of psychiatry at Bangor University, in Wales. "This is why we need access to the data. It is only with collaborative efforts based on full access to the data that we can manage to get to a best possible interpretation."

another BMJ editorial on the subject: Liberating the data from clinical trials | The BMJ

1. David Henry, professor1,
2. Tiffany Fitzpatrick, meta-data specialist2

Liberated trial data have enduring potential to benefit patients, prevent harm, and correct misleading research

The original blog closes with a caveat:

The type of analysis published in The BMJ is highly valuable, said John P.A. Ioannidis, a professor of health research and policy at Stanford University. And for now, Dr. Ioannidis said, that kind of work will rely on volunteers such as Mr. Jureidini. "This may also entail a risk of recruiting reanalyst volunteers who even have a bias to show that the original results are wrong," he said.

.."We can’t protect ourselves completely from our own biases," Mr. Jureidini said.

Finally, the BMJ paper Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence

Results The efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome.

 

[Dolphin]

Here is the basic info about suicidality or self-harming which I didn't notice, or else can't remember, from the two articles I posted:

In their re-analysis of the trial, published in the British Medical Journal, they say the beneficial effects of paroxetine on young people were far less and the harmful effects far greater than the study suggested.

Out of 275 children and adolescents in the trial, 11 taking the drug and one in the group given a placebo developed suicidal or self-harming behaviour. The original publication of the study reported five on the drug and one on placebo. There were no reports of suicidality on a second drug, imipramine, which was also tested in study 329.

David Healy, professor of psychiatry at Bangor University in Wales, said it was hard to see how so many suicidal children could have been overlooked. “We think if you were to go in and look at this data, anyone without training will find there are at least of the order of 12 children becoming suicidal on this drug out of about 93 [who were given it],” he said.

“This is a very high rate of kids going on to become suicidal. It doesn’t take expertise to find this. It takes extraordinary expertise to avoid finding it.”

From Guardian article: http://www.theguardian.com/science/2015/sep/16/seroxat-study-harmful-effects-young-people

 

[Sean]

No correction, no retraction, no apology, no comment: paroxetine trial reanalysis raises questions about institutional responsibility

As a new data analysis adds weight to calls for retraction of a paper on paroxetine in adolescents, Peter Doshi examines the resistance to action of a professional society, its journal, and an Ivy League university

Peter Doshi associate editor, The BMJ
http://www.bmj.com/content/bmj/351/bmj.h4629.full.pdf

Elephant. Room. Mote in one's own eye. Look into this mirror. Etc.

 

[Dolphin]

This trial was discussed in Ben Goldacre's "Bad Pharma" book. All (or most? of this has now been posted online at:
http://1boringoldman.com/index.php/2012/12/21/hide-and-go-seek/#comment-233379

The initial blog post is also on the trial. The blogger is frustrated the trial hasn't been retracted:
http://1boringoldman.com/index.php/2012/12/21/hide-and-go-seek/