Forest Under Fire

Allegations of suppressed research, promotion of drugs for unapproved uses, payment of kickbacks to physicians, and ghostwriting of a major journal article surfaced recently when the Department of Justice unsealed a civil complaint against Forest Laboratories and Forest Pharmaceuticals, Inc.

Filed in the District Court in Massachusetts, the 34-page complaint charged that for more than half a decade, Forest illegally marketed Celexa (citalopram) and Lexapro (escitalopram) for off-label use in pediatric patients when both medications had been approved only for adult use. (The 2 drugs were licensed to Forest by H. Lundbeck A/S, a Danish company.)

The complaint also accused Forest of deceiving physicians by promoting the results of a positive study on pediatric use of citalopram,¹ while failing to disclose the results of a contemporaneous negative study conducted in Europe for the same pediatric use (the Lundbeck study). Forest was also accused of using “illegal” inducements to physicians to get them to prescribe citalopram and escitalopram.

“By knowingly and actively promoting these antidepressants for off-label pediatric use without disclosing the results of the negative pediatric study and by paying kickbacks, Forest caused false claims to be submitted to federal health care programs [Medicaid, TRICARE/CHAMPUS] in violation of the False Claims Act [FCA],” the complaint said.

Before filing its complaint, the government had intervened in 2 separate whistleblower actions against Forest brought by Christopher Gobble, a former Forest employee, and Joseph Piacentile, MD.

Forest’s response
While the complaint has been unsealed, and Forest is aware of it, Frank Murdolo, Forest Laboratories’ vice president of investor relations, told Psychiatric Times that as of March 6, the company had not been served with the complaint.

In a statement posted on Forest Laboratories’ Web site-http://www. frx.com/news/PressRelease.aspx? ID=1260234-the company said it is “currently reviewing the complaint, [and] will respond to this action at the appropriate time” and that it understands 11 states along with the District of Columbia intend to intervene as plaintiffs in the action.

Murdolo added that as disclosed in its filings with the Securities and Exchange Commission (SEC), Forest “has been cooperating with the government investigation since 2004.”

Forest’s 10-Q filed November 10, 2008, noted that the US Attorney’s Office (USAO) had subpoenaed the company and requested documents from 1997 to the present related to the marketing and promotion of Celexa and Lexapro as well as Namenda (memantine) and Combunox (oxycodone and ibuprofen).

In its statement, Forest added that the company is “committed to adhering to the highest ethical and legal standards, and off-label promotion and improper payments to medical providers have consistently been against Forest policy.”

Studies controversy
Part of the controversy over the 2 citalopram studies emanates from governmental efforts to encourage drug manufacturers to conduct pediatric studies of drugs used in adults by offering an additional 6 months of patent exclusivity for previously approved, on-label drugs.

In 1999, according to the complaint, the FDA asked Forest to conduct 2 independent, well-controlled clinical trials in pediatric depression. Later that year, Forest submitted FDA protocol for 2 pediatric studies: a double-blind, placebo-controlled pediatric study being conducted in Europe by Lundbeck (the Lundbeck study) and a double-blind, placebo-controlled pediatric study to be conducted in this country. The principal investigator for the American study was Karen Dineen Wagner, MD, PhD, now Marie B. Gale Centennial Professor and vice chair of the department of psychiatry and behavioral sciences at the University of Texas Medical Branch (UTMB) at Galveston. Wag­ner serves on Psychiatric Times’ editorial board and writes columns on child and adolescent psychiatry.

The 8-week trial, conducted at 21 US centers, involved 174 outpatients (aged 7 to 17 years) who met DSM-IV criteria for major depressive disorder (MDD) and were randomized, 89 to citalopram and 85 to placebo. It showed that citalopram “produces a statistically and clinically significant reduction in depressive symptoms in children and adolescents” on the Children’s Depression Rating Scale–Revised (CDRS-R) and that “there were no serious adverse events observed in the citalopram group.”

The Lundbeck study, according to the complaint, was negative in that it did not show citalopram to be any more effective than placebo in treating pediatric depression. “Furthermore, 14 patients taking citalopram attempted suicide or reported suicidal ideation compared with 5 patients taking placebo,” the complaint said.

The European trial conducted by H. Lundbeck A/S, “a double-blind study comparing citalopram tablets” (Lu 10-171, 10 to 40 mg/g) and “placebo in the treatment of major depression in adolescents,” identified as Study 94404, is summarized on Forest’s Clinical Trial Registry-www.forestclinicaltrials.com/CTR/CTRController/CTRHome. That 12-week study conducted at 31 sites in 7 countries involved 244 hospitalized patients and outpatients aged 13 to 18 years. The response over time based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present episode version (Kiddie-SADS-P) was similar (P = .968) for both citalopram and placebo, the researchers concluded.

The Wagner and Lundbeck studies were unblinded in mid-2001, and their results were disseminated to senior Forest executives, according to the complaint.

In April 2002, Forest submitted the results of both the Lundbeck and Wagner studies to the FDA to support its request for a patent exclusivity extension and a pediatric indication for Celexa, but the submission was not made public. The FDA granted the 6-month extension but denied Forest’s request for a pediatric indication.

Although the senior executives learned about the negative Lundbeck results in mid-2001, Forest, according to the complaint, failed for the next 3 years to disclose the negative data to, among others, company sales representatives; pediatric specialists hired to give promotional speeches on Celexa and Lexapro; its executive advisory board of leading psychiatrists; and “even its own pediatric researchers, such as Dr Wagner.”

At the same time, Forest aggressively promoted the Wagner study, thereby conveying the false impression that the only available pediatric data on Celexa were positive, the complaint said. For instance, a poster of the study was presented at the American Psychiatric Association, the American College of Neuropsychopharmacology, and the Collegium Internationale Neuro-Psychopharmalogicum.

“Over the course of 2002, Forest and CME, Inc. [a division of UBM, parent company of CMPMedica, which owns Psychiatric Times] arranged for Dr Wagner to give promotional presentations on the pediatric use of Celexa and to serve as the chair of a 7-city Continuing Medical Education (CME) program on treat-ing pediatric depression,” the complaint said. “Forest also sponsored 20 CME teleconferences that addressed the Wagner study results.”

Because not even Wagner was aware of the negative Lundbeck data, the complaint said, she never discussed those data in her many Forest-sponsored talks addressing the pediatric use of the drugs. Wagner declined to be interviewed, but Raul Reyes, speaking on behalf of Wagner and UTMB, told Psychiatric Times, “It is inappropriate to comment on an ongoing legal matter.”

In another section, the complaint charges “Forest paid a medical writing firm to ghostwrite an academic article on the Wagner study, and Forest arranged to have the article published in the June 2004 issue of the American Journal of Psychiatry, with Wagner listed as the lead author.” Among the 5 coauthors listed, at least 2 were Forest employees at the time-Marcelo Gutierrez, PhD, in the department of pharmacokinetics, and William Heydorn, PhD, director of scientific communications.

On June 21, 2004, according to the complaint, the New York Times published an article by Barry Meier that discussed the Wagner study and revealed the negative results of the Lundbeck study.

On June 24, 2004, Forest issued a press release (www.frx.com/news/ PressRelease.aspx?ID=585078) that addressed questions raised in the New York Times article. Forest pointed out that efficacy and safety analyses of both the US and European citalopram pediatric depression trials were disclosed at the 2003 annual meeting of the American Academy of Child and Adolescent Psychiatry, in a Danish textbook, and in submissions to US and United Kingdom regulatory authorities, among other venues.

Alleging kickbacks
The complaint also alleges that Forest engaged in a “widespread campaign to promote the drugs for pediatric use by paying pediatric specialists to give promotional speeches to other physicians on pediatric use and by selectively distributing publications on pediatric uses, among other strategies. The complaint mentioned Jeffrey Bostic, MD, assistant clinical professor of psychiatry at Harvard Medical School and director of school psychiatry at Massachusetts General Hospital (MGH): “From 1999 through 2006, one pediatric specialist, Dr Jeffrey Bostic . . . gave more than 350 Forest-sponsored talks and presentations, many of which addressed pediatric use of Celexa and Lexapro.”

In response, MGH issued a statement emphasizing that the complaint was brought against Forest Laboratories, not Bostic. It described Bostic as a “highly regarded practitioner and educator in the field of psychiatry.”

“The complaint consists of characterizations and allegations by the United States, not established facts. During the government’s investigation, Dr Bostic provided the government with information about the speaking engagements for which he was paid by Forest. In those speaking engagements, Dr Bostic talked to fellow physicians about the treatment of patients with various mental health conditions,” the statement said.

With regard to inducements to encourage physicians to prescribe the drugs for children and adolescents, the complaint described how Forest hosted more than 900 local or regional “advisory boards” on the 2 drugs between 2000 and 2005. More than 19,000 advisory board attendees whom Forest called “consultants” received honoraria of $500 each.

In 2004, citalopram and escitalopram, along with other antidepressants, began to carry prominent black box warnings noting that antidepressants increased the risk compared with placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in shortterm studies of MDD and other psychiatric disorders.

References:

1.Wagner KD, Robb AS, Findling RL, et al. A randomized,placebo-controlled trial of citalopram for thetreatment of major depression in children and adolescents.Am J Psychiatry. 2004;161:1079-1083.