Antidepressants Celexa & Lexapro Ineffective for Childhood Depression

On January 24, 2018, Wisner Baum submitted a 53-page memorandum along with 79 supporting exhibits to the United States Attorney’s Office for the District of Massachusetts detailing how Forest Pharmaceuticals Inc. and Forest Laboratories Inc. (both acquired by Allergan in 2014) deliberately misled the DOJ during its investigation of the drug maker and 2010 settlement of the criminal and civil charges brought against the company.

The government’s investigation of Forest focused on the company’s illegal off-label promotion of a supposedly positive Celexa study (MD-18 or “Wagner study”) and suppression of a negative Celexa study (94404 or the “Lundbeck study,” also known as the “European Study). Documents unearthed during the course of a series of civil lawsuits in Boston have revealed a much deeper deception than the government ever suspected. The government’s case was just the tip of the iceberg.

Read our letter and memo calling on the U.S. Attorney’s Office to investigate and prosecute Forest Labs (now Allergan)

Forest Pled Guilty to Civil and Criminal Charges For Off-Label Promotion of Celexa and Lexapro For Use in Children and Adolescents

In 2010, Forest entered into a series of settlement agreements with the USAO for the District of Massachusetts. As part of the first agreement, Forest pleaded guilty to one count of obstruction and two counts of distributing a misbranded drug under the Food, Drug, and Cosmetic Act. The third count related to Forest’s promotion of Celexa for use in children and adolescents between 1998 and 2002. Forest paid more than $39 million in criminal fines for Celexa’s off-label promotion.

The second agreement resolved various qui tam False Claims Act lawsuits alleging pharmaceutical fraud through off-label promotion for both Celexa and Lexapro for children and adolescents between 1998 and 2005. Forest paid over $149 million to settle the civil claims.

Lastly, Forest entered into a five-year corporate integrity agreement to address its promotional misconduct.

Each agreement was contingent on the others and required complete honesty from Forest. However, according to unsealed Celexa and Lexapro court docs, the scope and extent of Forest’s fraud was not properly disclosed before the 2010 settlement agreements. Per the documents below, Forest misrepresented material facts underlying the USAO’s investigation.

How Did Forest Mislead the FDA and DOJ About Celexa and Lexapro?

First, A Primer on How Clinical Trials to Test the Efficacy of Medications Work

A drug’s efficacy is determined using double-blind randomized controlled trials (“DBRCTs”). A DBRCT involves the systematic comparison of patients taking a drug and patients taking a placebo. Patients enrolled in the clinical trials are randomly assigned into two groups. One group takes the drug and the other takes a placebo. However, neither the investigators nor the patient know which group each patient is in, i.e., they are “double blind.” Once the study is complete, the benefit observed in the two groups is compared, and if the patients taking the drug meaningfully outperform the patients in the placebo group, the clinical trial is considered positive. If the drug does not outperform placebo, it is called negative.

If either the investigator or the patient is unblinded during the clinical trial, it invalidates the data since there is no way to determine whether the effects observed are caused by the drug as opposed to other factors. Blinding is intended to limit the occurrence of conscious and unconscious bias in the conduct and interpretation of a clinical trial. If either the investigator or the patient knows they are receiving the drug, that knowledge will likely influence their assessment. Numerous studies have confirmed this fact. Blinding is a vital factor in medication research.

Forest Regulatory Affairs Manager: ‘Part of My Job is to Create “Masterful” Euphemisms to Protect Medical and Marketing’

A central feature of the government’s prosecution of Forest involved the promotion and dissemination of Forest’s “positive” Celexa Study MD-18 and the suppression of its negative Celexa Study 94404. What the government did not know is that MD-18 only achieved a positive result through the improper inclusion of nine patients in the study for whom “the blind was unmistakenly [sic] violated” or, as Forest’s medical director put it, who were “automatically unblinded” due to a dispensing error.

Upon learning about the dispensing error mishap, Forest informed the FDA that the unblinded patients would appropriately be excluded from the final analysis. But, when Forest realized the unblinded patients would need to be included to produce a positive result (i.e. show that Celexa was better than a placebo or sugar pill), Forest put the unblinded patients back into the MD-18 analysis and falsely told the FDA the patients were not actually unblinded.

In a draft letter to be sent to the FDA regarding the dispensing error, Amy Rubin, a Forest Regulatory Affairs Manager, characterized the error that caused the patients to become unblinded as only having “the potential to cause patient bias.” Dr. Charles Flicker, the Senior Medical Director overseeing MD-18, did not approve of this language:

“Altho ‘potential to cause bias’ is a masterful stroke of euphemism, I would be a little more up front about the fact that the integrity of the blind was unmistakenly [sic] violated.”

Rubin’s response to Dr. Flicker:

“Thanks for the compliement [sic]. Part of my job is to create ‘masterful’ euphemisms to protect Medical and Marketing.”

“Not only was the disclosure to the FDA dishonest, according to a Forest Regulatory Affairs manager, it was her job to mislead the FDA and protect medical and marketing,” says Wisner Baumattorney Brent Wisner.

Forest Labs Celexa and Lexapro Court Docs Unsealed

The Exhibits to the January 24, 2018 letter and Memorandum sent by Wisner Baum to the U.S. Attorney’s Office for the District of Massachusetts (which include court documents obtained in discovery and unsealed over Forest’s objection, as well as deposition testimony of Forest employees and former FDA staffers, etc.) are posted below.

Table of Contents

PART I: EXECUTIVE SUMMARY

PART II: CELEXA PEDIATRIC CLINICAL TRIALS

• Celexa Study 94404 Was a Negative Clinical Trial
  Table 1 — Celexa Study 94404 Efficacy Results
• Celexa Study MD-18 Was a Negative Clinical Trial, but Forest Misled the FDA about the Results
  Table 2 – Celexa Study MD-18 Efficacy Results
  • General Overview of MD-18 Study
  • At the Beginning of the Trial, a Packaging Error Caused Nine Patients, and their Investigators, to Become Unblinded
  • Celexa Study Dispensing Diagram
  • Forest Knowingly Misled the FDA about the Nature of the Unblinding by Using, As Forest Regulatory Affairs Manager Put It, “Masterful Euphemisms” to “Protect Medical and Marketing”
  • Despite Misrepresenting the Unblinding to the FDA, Forest Promised to Exclude the Data from the Patients from Its Primary Efficacy Analysis
  • Forest Reneged on its Promise to Exclude the Unblinded Patients from the Primary Efficacy Results and, Again, Misrepresented the Unblinding in MD-18’s Final Study Report
  • The FDA Never Fully Considered the Unblinding Issue and a Reasonable Regulator at the FDA Could Review this New Information and Conclude Study MD-18 Was Negative
  • Forest Also Misled the FDA about the Results of the Secondary Endpoints
    Table 3 — Comparison of MD-18 Study Report & Dr. Heart Medical Review

PART III: FOREST USED FALSE RESULTS FROM MD-18 TO PROMOTE PEDIATRIC USE OF CELEXA AND LEXAPRO

PART IV: THE LEXAPRO PEDIATRIC TRIALS

• Lexapro Study MD-15 Was a Negative Clinical Trial
  Table 4 – Lexapro Study MD-15 Efficacy Results
• Lexapro Study MD-32 Was a “Positive” Clinical Trial for Adolescents, but Did Not Show a Meaningful Difference between Lexapro and Placebo

PART V: FOREST LEVERAGED THE FALSE RESULTS OF MD-18 TO OBTAIN AN ADOLESCENT INDICATION FOR LEXAPRO

PART VI: FOREST USED THE FALSE ASSERTION THAT MD-18 WAS POSITIVE AND THE FDA’s APPROVAL FOR LEXAPRO TO NEGOTIATE REDUCED PENALTIES IN USAO CASE

Exhibits

Exh. 1 Department of Justice Press Release Forest Celexa Lexapro Misled FDA Docs

Exh. 2 Criminal Plea Agreement

Exh. 3 Criminal Information

Exh. 4 Civil Settlement Agreement

Exh. 5 Forest Side Letter Agreement

Exh. 6 Corporate Integrity Agreement

Exh. 7 2016 Deposition Gerard Azzari (redacted)

Exh. 7a Azzari Deposition Excerpts

Exh. 8 2017 Deposition Thomas Laughren

Exh. 8a Laughren Deposition Excerpts

Exh. 9 CIT MD-18 Citalopram Pediatric Depression Study Report Excerpts

Exh. 10 Celexa Product Manager Goetjen Email to Bill Heydorn

Exh. 11 2016 Deposition William Heydorn

Exh. 11a Heydorn Deposition Excerpts

Exh. 12 2016 Deposition Steven Closter (redacted)

Exh. 12a Closter Deposition Excerpts

Exh. 13 Draft of Varner Letter with Flicker Hand Written Comments MDL FORP0168118

Exh. 14 Memo Regarding Deviation Investigation MDL FORP0206957

Exh. 15 Memo Regarding Deviation Report MDL FORP0206959

Exh. 16 Email and Attached Fax Sent to Investigators Regarding Unblinding MDL FORP0168119

Exh. 17 Email Preparing Varner Letter First with Attachment

Exh. 18 Email Preparing Varner Letter

Exh. 19 Varner Letter to Doctor Katz at FDA Regarding Unblinding

Exh. 20 Email Regarding CIT MD-18 Citalopram Pediatric Depression Study

Exh. 21 Email Regarding Notes from Conference October 4

Exh. 22 Doctor Hearst (FDA) Medical Review

Exh. 23 2001 Press Release Regarding Wagner American College Neuropsychopharmacology ACNP Meeting Presentation

Exh. 25 Email Regarding American College Neuropsychopharmacology ACNP Meeting Pediatrics Abstract

Exh. 26 Emails Regarding Wagner American Academy of Child and Adolescent Psychiatry ACCAP Meeting

Exh. 27 Email Regarding Manuscript for American Academy of Child and Adolescent Psychiatry ACCAP Meeting

Exh. 28 Selection of Off Label Call Notes

Exh. 29 Lexapro Tactical Presentation (2002)

Exh. 30 FDA Guidance for Industry E10 Choice of Control Group and Related Issues in Clinical Trials

Exh. 31 FDA Guidance for Industry E9 Statistical Principles for Clinical Trials

Exh. 32 Ghooi Assessment and Classification Protocol Deviations 2016

Exh. 33 George Data Fraud in Clinical Trials

Exh. 34 FDA Guidance for Industry Multiple Endpoints in Clinical Trials

Exh. 35 94404 Integrated Clinical Study Report Citalopram Adolescent Depression Excerpts

Exh. 36 Initial Disclosure of 94404 Integrated Clinical Study Report Citalopram Adolescent Depression Results

Exh. 37 Email Regarding 94404 Integrated Clinical Study Report Citalopram Adolescent Depression Headline Results

Exh. 38 Excerpts of 2007 Deposition William Heydorn

Exh. 39 Email Regarding Publications for Pediatric Manuscript

Exh. 40 New York Times Medicines Data Gap

Exh. 41 Press Release Forest Discusses Disclosure of Citalopram Clinical Trial

Exh. 42 94404 Integrated Clinical Study Report Citalopram Adolescent Depression Publication

Exh. 43 CIT MD-18 Citalopram Pediatric Depression Study Protocol

Exh. 44 Emails Regarding Urgent CIT MD-18 Citalopram Pediatric Depression Study

Exh. 45 2016 Deposition Charles Flicker

Exh. 45a Flicker Deposition Excerpts

Exh. 46 Jureidini Expert Report

Exh. 47 Glenmullen Expert Report

Exh. 48 Email Regarding CIT MD-18 Citalopram Pediatric Depression Study Drug

Exh. 49 Lexapro Approvable Letter for Adolescent Indication

Exh. 50 Draft with Flicker Hand Written Comments to CIT MD-18 Citalopram Pediatric Depression Study

Exh. 51 FDA Letter Denying Supplimental New Drug Application for Pediatric Major Depressive Disorder

Exh. 52 Thomas Laughren (FDA) Memo Regarding Recommendation for Non-Approval

Exh. 53 Excerpt of 2013 Deposition of Thomas Laughren

Exh. 54 Email Regarding Pediatric Targets

Exh. 55 Email Regarding American College of Physicians American Society of Internal Medicine ACP ASIM

Exh. 56 Email Regarding Wagner Hot Topics Slides

Exh. 57 Excerpts of 2015 Deposition of Natasha Mitchner

Exh. 58 Wager Continuing Medical Education CME Slides

Exh. 59 Emails Regarding Second Draft of Pediatric Manuscript

Exh. 60 Emails Regarding Citalopram

Exh. 61 Email Regarding American College Neuropsychopharmacology ACNP Pediatrics Abstract

Exh. 62 Emails Regarding Update on American College Neuropsychopharmacology ACNP Press Releases

Exh. 63 Wagner Citalopram for Major Depression in Children and Adolescents (Celexa)

Exh. 64 Editors Note Regarding Wagner Publication

Exh. 65 Transcript of Arraignment

Exh. 66 2016 Azzari Deposition Excerpts

Exh. 66a 2016 Deposition of Gerard Azzari

Exh. 67 Excerpts of MD-15 Study Report Efficacy in Pediatric Depression

Exh. 68 Letter from FDA Regarding Questions by Forest

Exh. 69 Excerpts of MD-32 Study Report Escitalopram Pediatric Major Depressive Disorder

Exh. 70 Defining a Clinically Meaningful Effect

Exh. 71 Emslie Escitalopram in the Treatment of Adolescent Depression (Lexapro)

Exh. 72 Email Regarding BLANK (with attachment)

Exh. 73 Email Regarding DRAFT Lexapro Road Map

Exh. 74 Medical Review by Roberta Glass FDA

Exh. 75 Team Leader Review Lexapro for Adolescents FDA

Exh. 76 Statistical Review and Evaluation Lexapro for Adolescents FDA

Exh. 77 Laughren Memo Regarding Approval for Lexapro

Exh. 78 Linkedin Profile for Doctor Thomas Laughren

Exh. 79 Psychatric News June 17, 2016

Letter and Memo to United States Attorney’s Office Massachusetts