The undoing of Pharma’s promotion of antidepressants as safe and effective for young people

The treasure trove: Annotated links to some relevant materials.

treasure troveMy recent post at Mind the Brain, Study protocol violations, outcomes switching, adverse events misreporting: A peek under the hood  concerns a must-read IJRSM article:

Jureidini, JN, Amsterdam, JD, McHenry, LB. The citalopram CIT-MD-18 pediatric depression trial: Deconstruction of medical ghostwriting, data mischaracterisation and academic malfeasance. International Journal of Risk & Safety in Medicine, vol. 28, no. 1, pp. 33-43, 2016

Which offers a detailed critique and re-analysis of:

Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, Heydorn WE. A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. American Journal of Psychiatry. 2004 Jun 1;161(6):1079-83.

Letters to the Editor concerning the AJP article

 Shortly after the original article appeared in AJP, there was a series of letters to the editor commenting on the article and the authors responded:

RÉMY P. BARBE, M.D.,  Child Psychopharmacology, Effect Sizes, and the Big Bang

ANDRÉS MARTIN, M.D., M.P.H., WALTER S. GILLIAM, Ph.D., New Haven, Conn., JEFFREY Q. BOSTIC, M.D., Ed.D., Boston, Mass., and JOSEPH M. REY, M.D., Sydney, Australia. Child Psychopharmacology, Effect Sizes, and the Big Bang

MAJU MATHEWS, M.D., M.R.C.Psych., BABATUNDE ADETUNJI, M.D., F.A.S.A.M., JOANNE MATHEWS, M.D., BIJU BASIL, M.D., VINU GEORGE, M.D., MANU MATHEWS, M.D., KUMAR BUDUR, M.D., and SHINY ABRAHAM, M.D., Kottayam, Child Psychopharmacology, Effect Sizes, and the Big Bang

KAREN DINEEN WAGNER, M.D., Ph.D., ADELAIDE S. ROBB, M.D., ROBERT L. FINDLING, M.D., and JIANQING JIN, Ph.D., Dr. Wagner and Colleagues Reply

Additional Background Notes for the IJRSM article posted by JM Nardo

Here are links to more rich material, including documents that were received from Forest Laboratories and a history of attempts to get this article published. For these and other materials, I am grateful to John M Nardo, MD. I’ve included some other links to his relevant blog post as well

In addition to detailing the history of the IJ RSM article, Dr. Nardo provides:

Other relevant blog posts from JM Nardo

In this series of blog posts, Nardo comments on both the deconstruction of citalopram CIT-MD-18, but also a reanalysis in which he was involved that was published in The BMJ, Restoring Study 329.  Links to that important paper and relevant materials will be presented in the section below this one on his blog posts.

the jewel in the crown… Posted on Thursday 5 May 20

Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence
In our paper, we were able to obtain the raw data as the result of over a decade of work coming from multiple foci. Analyzing the data using the manufacturer’s own a priori protocol we found that the reported efficacy of the drug disappeared and that the safety of the drug had been exaggerated.

Having been intimately involved in one of these articles and knowing the authors of the other, I can attest to the herculean effort required to produce them. Both are the result of unfunded research. There were no Conflicts of Interest and they were largely done by senior people with no need for further credentialing. Unfortunately, the primary articles they analyzed are not exceptions. And at least in the domain of industry funded RCTs of CNS drugs, they’re the rule. Even worse, both studies involved medications for vulnerable youth. The mandate for change is clear as a bell…

the obvious irony… Posted on Thursday 12 May 2016

Having been intimately involved in one of these articles and knowing the authors of the other, I can attest to the herculean effort required to produce them. Both are the result of unfunded research. There were no Conflicts of Interest and they were largely done by senior people with no need for further credentialing. Unfortunately, the primary articles they analyzed are not exceptions. And at least in the domain of industry funded RCTs of CNS drugs, they’re the rule. Even worse, both studies involved medications for vulnerable youth. The mandate for change is clear as a bell…

this tawdry era… Posted on Saturday 14 May 2016

While this is only one example of many similarly misreported Clinical Trials, the access to the internal industry documents allowed these authors to leave nothing to our imagination. They prove that it’s ghost written; that it was framed by the industry executives for commercial gain before any academic author got near the data; that it was deceitfully written to hide its failings, on purpose; and that it was a negative Clinical Trial presented as positive and subsequently used to gain FDA Approval. Those points and more are abundantly clear in this easy-reading article…

I think it’s now our job to insure that all this dedicated work is rewarded with a wide readership, one that helps us move closer to putting this tawdry era behind us…

Dr. Nardo’s article in The BMJ:

Le Noury J, Nardo JM, Healy D, Jureidini J, Raven M, Tufanaru C, Abi-Jaoude E. Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. BMJ 2015; 351: h4320

 

The article from which data were re-analyzed:

Keller MB, Ryan ND, Strober M, Klein RG, Kutcher SP, Birmaher B, Hagino OR, Koplewicz H, Carlson GA, Clarke GN, Emslie GJ. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. Journal of the American Academy of Child & Adolescent Psychiatry. 2001 Jul 31;40(7):762-72.

30 Rapid responses to the BMJ article

The BMJ article by Le Noury, Nardo and colleagues has so far received 30 Rapid Responses Including a 18 January 2016  response from Martin Keller and the authors of the original Study 329, as well as the 03 February 2016 reply from Jon N Jureidini and the authors. Click here for the links.

Guilty pleas from Forest Laboratories and GlaxoSmithKline

The two pharmaceutical companies that produced ghost authored papers were subject to criminal and civil proceedings. They both pleaded guilty. Some excerpts from these proceedings are summarized in another blog post, When the US government cracked down on drug companies promoting antidepressants for children and teens. Other links to the proceedings are below:

Justice Department Files Suit Against Forest Laboratories for Illegally Marketing Celexa, Lexapro for Children

The actual filing

Drug Maker Forest Pleads Guilty; To Pay More Than $313 Million to Resolve Criminal Charges and False Claims Act Allegations

Complaint: United States ex rel. Greg Thorpe et at [Consolidated] Plaintiffs vs GlaxoSmithKline PLC, and GlaxoSmithKline LLC Defendents

GlaxoSmithKline to Plead Guilty and Pay $3 Billion to Resolve Fraud Allegations and Failure to Report Safety Data: Largest Health Care Fraud Settlement in U.S. History