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Restoring invisible and abandoned trials: a call for people to publish the findings

BMJ 2013; 346 doi: (Published 13 June 2013) Cite this as: BMJ 2013;346:f2865

Re: Restoring invisible and abandoned trials: a call for people to publish the findings

Call to action: RIAT reanalysis of Forest Laboratories CIT-MD-18: A Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Citalopram in Children and Adolescents with Depression

I write to issue a call to action to restore the reporting of CIT-MD-18: A Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Citalopram in Children and Adolescents with Depression

CIT-MD-18, IND Number 22,368, was one of two RCTs used in the 2009 FDA approval of escitalopram in the treatment of adolescent depression, however, citalopram failed to outperform placebo on the protocol-specified primary and secondary outcomes measures. The study was conducted between 1999 and 2002 and was designated as a 9-week, 20-site, randomized, double-blind comparison of the safety and efficacy of citalopram verses placebo in children age 7-11 and adolescents age 12-17 with major depressive disorder. It was designated a Phase III registration trial supporting an FDA indication for depression in pediatric patients. 174 patients were enrolled in the study, 89 in the citalopram group and 85 in the placebo group. The study protocol specified that the primary efficacy measure was the change from baseline to week 8 on the Children’s Depression Rating Scale-Revised (CDRS-R) total score. Protocol-specified secondary efficacy measures included the Clinical Global Impression Severity and Improvement Subscales, Kiddie Schedule for Affective Disorders and Schizophrenia―Depression Module, and Children’s Global Assessment Scale.

The report of CIT-MD-18 was published in 2004. [1] Jureidini, Amsterdam and McHenry have argued elsewhere that study CIT-MD-18 has been misreported. [2] Other researchers before us have also found serious problems with the published article. [3] CIT-MD-18 is still cited as a positive RCT in some prescribing guidelines for citalopram use in pediatric depression.[4] As a result, I am submitting the rapid response as a call to action to restore the record.

Forest’s CIT-MD-18 is easily compared to GlaxoSmithKline’s study 329 for pharmaceutical industry manipulation facilitated by ghostwriting. [5] Study 329 was one of the first RCTs subjected to RIAT reanalysis. [6]

The status of the data de-classified from litigation: 42 pages of study protocol, 15 pages of CSR, Internal Forest Email correspondence.

Forest Laboratories was acquired by Allergan which is now in the process of being acquired by Activas.

Research questions include:

*To what extent was safety data accurately reported?

*To what extent were secondary outcome measures misreported prior to week 8?

*What was the correct effect size?

*Which sites were affected by the dispensing error?

*Which site investigators were unblinded by the dispensing error?

*How did the unblinding affect the calculation of the primary outcome analysis?

*What were the original sample size estimates performed for the determination of statistical significance for drug versus placebo?

*What power estimates were used to obtain the protocol-designated sample size?

* What subject samples were used to make the drug versus placebo estimates (e.g. drug versus placebo for the entire sample of children plus adolescents, or drug versus placebo for individual sub-groups, i.e., children or adolescents)?

*Assuming the sample size needed to show statistically significant superiority of drug over placebo was based upon a total sample comprising both children plus adolescents, how did Forest handle the ‘interaction’ effect in their protocol-specified ANCOVA analysis which showed no statistically significant benefit of drug over placebo in the children subgroup?

*If the ANCOVA interaction effect did demonstrate the null for children (versus adolescents), was this based upon a power (i.e., sample size) comprising both subject sub-groups, in which case neither subgroup may have demonstrated true drug versus placebo superiority?

Leemon McHenry

[1] 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. Am J Psych 2004, 161: 1079-1083.

[2] Jureidini J, Amsterdam J, McHenry L. The citalopram CIT-MD-18 pediatric depression trial: A deconstruction of medical ghostwriting, data manipulation and academic malfeasance. Int J Risk Saf Med 2016, 28: 33-43.

[3] Martin A, Gilliam WS, Bostic JQ, Rey JM. Letter to the editor. Child psychopharmacology, effect sizes, and the big bang. Am J Psych 2005; 162 (4): 817.

[4] Sussex Partnerships NHS, Guidance on the use of antidepressants in children and adolescents, Version 2, January 2014.

[5] Amsterdam J, McHenry L, Jureidini J. Industry-corrupted psychiatric trials. Psychiatr Pol 2017, 51: 993-1008.

[6] 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, Sep 16;351:h4320.

Competing interests: Research consultant to the law firm of Baum, Hedlund, Aristei & Goldman, Los Angeles, California, USA

13 June 2018
Leemon B. McHenry
Lecturer and Research Consultant
California State University, Northridge
Department of Philosophy, 18111 Nordhoff Street, Northridge, California 91330