The First Circuit Court of Appeals has reversed a district court’s dismissal of lawsuits filed by a mother and a trade union health care fund who alleged Forest Laboratories, Inc. (now part of Allergan) fraudulently induced them to buy Celexa and Lexapro for use in children and adolescents despite evidence the drugs were not effective in this population.
Renee Ramirez and Painters and Allied Trades District Council 82 Health Care Fund, whose lawsuits were joined in multidistrict litigation in Massachusetts in 2009, may now continue their actions against Forest. The three-judge panel reversed the lower court’s dismissal of the cases, sending the cases back to the district court and allowing the cases to move forward to trial.
In January 2018, the district court judge overseeing the cases granted Forest’s motion for summary judgment (dismissing the cases in their entirety) stating that Ramirez and Painters had not offered competent proof that Celexa and Lexapro were ineffective.
The appeals court disagreed.
The First Circuit stated in its ruling:
“The record in this case strongly suggests that Forest engaged in a comprehensive off-label marketing scheme from 1998 through 2009 aimed at fraudulently inducing doctors to write pediatric prescriptions of Celexa and Lexapro when Forest had insufficient reason to think that these drugs were effective for the treatment of depression in children and adolescents. Plaintiffs have pointed to substantial evidence that Forest sought to achieve this illicit aim by: (1) promoting Celexa’s efficacy for the treatment of pediatric depression at medical conferences, at continuing-medical-education programs, and in press releases; (2) concealing negative clinical studies concerning Celexa’s efficacy and safety; and (3) directly encouraging physicians to prescribe Celexa and Lexapro for the treatment of pediatric depression.”
Forest Guilty of Illegally Promoting Drugs
In 2010, Forest pled guilty to off-label promotion of Celexa between 1998 and 2002 and paid a $39 million fine. Forest paid more than $313 million to settle criminal and civil claims related to its alleged illegal activities.
Clinical Trials Fail to Prove Celexa or Lexapro Are Better than a Sugar Pill
The appeal court’s finding was crystal clear:
[P]laintiffs have provided competent and sufficient evidence — through DBRCTs [double-blind, random controlled trials], expert-testimony, and peer-reviewed literature — to raise a genuine issue of material fact as to the efficacy of these drugs for pediatric use.
The appeals judges noted that Forest conducted four clinical trials while trying to win FDA approval for its drugs. Two of the trials, one Celexa trial (study 94404) and one Lexapro trial (MD-15), were negative – showing the drugs were not effective in reducing depression symptoms. A second Celexa trial, MD-18, achieved statistically positive results, but only by including data from several subjects who were “unblinded.”
What Does it Mean to Have a Blind Drug Study?
In clinical trials, pills containing active medication and those with no medication, the placebos or sugar pills, are supposed to be indistinguishable. Neither the investigators nor the patients should be able to tell if a pill contains medication or not. Both should be “blind” to the content of the pills. Patients who know they are receiving active drug treatment have cause to believe they will get better, and that belief alone can cause powerful positive effects, particularly on depression.
Knowing that a patient is receiving active medication could also unfairly influence the viewpoint of an investigator.
In MD-18, nine patients, over a four-week period, were given pink, oval-shaped, Forest-branded, and dose stamped commercial Celexa tablets – pills that did not look anything like the pills being given most patients.
The First Circuit noted that “[t]he efficacy results of MD-18 are difficult to assess because Forest bungled the study: Some participants randomized into the active treatment group were dispensed non-generic, pink tablets in one portion of the trial, potentially unblinding both the individuals who received these pills and the researchers conducting the study. The MD-18 study only demonstrated statistically significant positive results when these potentially unblinded participants were included.”
Investigators in the MD-18 trial were also unblinded. By the rules of the study investigation (the study “protocol”), rules established by the investigators themselves, those patients should never have been included in the statistical analysis of study outcomes. But Forest did include them. Without including those subjects, MD-18 was – and remains – a negative study. The details of Forest’s MD-18 trial strongly suggest that the company intentionally deceived the FDA. As the First Circuit panel pointed out, “Study MD-18 was corrupted and showed no beneficial effect in children and adolescents unless the potentially unblinded participants are included in the results.”
That makes three negative studies. A fourth study, MD-32, achieved statistically significant positive results for Lexapro, but plaintiffs’ experts offered testimony that the results of the study were not clinically significant. In other words, many patients taking the drug, and the clinicians treating them, would not have noticed a significant decline in depression.
Internal Forest documents, FDA documents, and the testimony of the FDA official who approved Lexapro for adolescents in 2009, demonstrate that Forest successfully misled the agency regarding multiple negative outcomes of MD-18. The evidence strongly suggests that, had the agency been given the full truth about the trial, it would have concluded MD-18 was a negative study and Lexapro would never have been approved for adolescents.
This fact is critical. The FDA generally requires drug makers to submit two positive clinical trials before it will approve a drug for marketing. Even though MD-18 was a Celexa trial, the FDA agreed to count it, along with the MD-32 trial, towards the approval of Lexapro, due to the close similarity of the two drugs.
Without the fraudulent MD-18 Celexa study, Forest would not have been able to present the FDA with two positive studies and Lexapro would never have been approved for the treatment of adolescent depression.
The appeals court also concluded, contrary to Forest’s argument, that, just because the FDA approved Lexapro for adolescents in 2009, does not mean plaintiffs are foreclosed from arguing the drug is ineffective. The First Circuit decidedly ruled that “the FDA’s approval of Lexapro does not preclude proving that pre-approval uses of these drugs were ineffective.”
Celexa and Lexapro RICO Claims
The Racketeer Influenced and Corrupt Organizations Act (RICO) is a United States federal law that provides a civil cause of action for acts performed as part of an ongoing criminal organization. The RICO Act focuses specifically on racketeering and allows the leaders of a syndicate to be tried for the crimes they ordered others to do or assisted them in doing, closing a perceived loophole that allowed a person who instructed someone else to commit a crime to be exempt from the trial because they did not actually commit the crime personally.
Racketeers offer a deceitful service to fix a problem that otherwise wouldn’t exist. The term derives from the word racket, a criminal activity that cheats individuals out of their money.
Concerning the Plaintiffs’ RICO claims, the appeals court considered the question of whether physicians would have prescribed Celexa and Lexapro based simply on their own medical judgment (which they are allowed to do) even if Forest had not illegally promoted the drugs? Or would that prescribing not have taken place except for the fact that Forest engaged in an organized criminal act: pushing ineffective drugs.
Again, the First Circuit Court sided with the plaintiffs. There is “ample evidence,” it wrote, that Forest induced doctors to prescribe its drugs to pediatric patients and sufficient evidence to bring before a jury the question of whether Forest’s off-label marketing caused people to pay for prescriptions they would not otherwise have purchased.
The First Circuit stated, “There is ample evidence that Forest spent money inducing doctors to prescribe its drugs to pediatric patients and that it would not have done so had the effort not been worth the money.”
The Pharmaceutical Industry is Rife with Corruption
On January 15, 2009, about two months before the FDA approved Lexapro for adolescent depression, The New York Review of Books published an article by former New England Journal of Medicine editor, Dr. Marcia Angell, entitled “Drug Companies & Doctors: A Story of Corruption.” In that article, Dr. Angell wrote, “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines.”
Dr. Angell’s piece echoed the views of the editors of two other leading medical journals. In March 2004, Richard Horton, editor of the Lancet, wrote, “Journals have devolved into information laundering operations for the pharmaceutical industry.” A year or so later, Richard Smith, who edited the British Medical Journal for 25 years, expressed the view that journals had become “an extension of the marketing arm of pharmaceutical companies in publishing trials that favour their products.”
The corruption demonstrated by Forest’s actions – and even pled guilty to – is not unique to Forest. Indeed, it is rampant in the pharmaceutical industry, particularly among manufacturers of psychiatric drugs.
Ghostwriting – Putting Sales Before Science
Pharmaceutical companies frequently hire companies to write studies so they can control the content of studies published in medical journals. After the paper is written, the drugmaker adds the names of prominent academics or physicians to the study as the alleged “authors.” Pfizer and GlaxoSmithKline made extensive use of ghostwriting to promote their antidepressants (Zoloft and Paxil, respectively).
When the Celexa MD-18 study was published in the American Journal of Psychiatry (AJP) in 2004, it appeared that the lead author was prominent psychiatrist Karen Dineen Wagner. This was a ruse. The AJP study was ghostwritten by a commercial medical writer under the direction of Forest’s marketing department.
Publishing Bias and Media Spin
Only in recent years has it been discovered that antidepressants as a class of drugs are not as effective as previously claimed, even in adults. This has been proven time and again in scientific research. Harvard’s Irving Kirsch found that antidepressants are statistically only slightly better than placebo at reducing symptoms and that small difference is not clinically significant.
But drug makers can make the drugs appear to be effective by publishing only positive studies, keeping the public in the dark about negative outcomes, as Forest did, and spinning the results of trials in the media.
Through publishing bias, makers of antidepressants have created the impression that 94% of clinical trials were positive. In fact, only half (51%) were positive. In the other half, there was no significant difference between those taking the drug and those taking a placebo.
The results of the STAR-D antidepressant trials, which were sponsored by the National Institute of Mental Health, were broadly trumpeted in the media. 70% of patients became symptom-free according to an NIMH press release. However, a re-analysis of the results found that only 108 patients (3%) out of the initial group of 3,671 who entered the trial, got well, and stayed that way during a year-long follow-up.
The Failure of Government Regulation
Government regulation has so far failed to put a halt to rampant corruption and criminality in an industry that has demonstrated time and again that it requires strict control. Settlements totaling millions or billions of dollars have little effect when a drug company can earn tens of billions by ignoring the law.
The appeals court had it exactly right. Why should we “reward unlawful conduct aimed at getting children to consume unapproved drugs?” But it is being rewarded, and so it continues. What should be done?
Penalties that might get the attention of drug company executives would include:
- Prison time for company executives engaged in fraudulent conduct.
- Much stiffer financial consequences, including paying back revenue earned from a drug while the company engaged in the marketing of ineffective drugs, as well as a percentage of all revenues generated by the drug in the future.
- A moratorium on new drug applications. Place restrictions on the ability of a company to bring new drugs to market if the company has a record of failing to bring drugs to market via the proper legal channels or has engaged in scientific or marketing misconduct.
- Reducing or eliminating the exclusivity period for the drug that was fraudulently promoted.
It can take years of litigation to uncover the lies and deception a drug maker has used to sell its products. With properly enforced regulations, pharmaceutical fraud – and the extraordinary effort it takes to reveal it – could be significantly reduced, if not eliminated.
The MDL is In Re: Celexa and Lexapro Marketing and Sales Practices Litigation, case numbers 18-1146 and 18-1147, in the U.S. Court of Appeals for the First Circuit. Ramirez and Painters are represented by R. Brent Wisner, Bijan Esfandiari, and Michael L. Baum of Baum Hedlund Aristei & Goldman PC and Christopher L. Coffin of Pendley Baudin & Coffin LLP.