Feb. 23, 2018 – Los Angeles, California – A group of researchers sent a letter this week to Dr. Robert Freedman, Editor of the American Journal of Psychiatry, calling for the retraction of a Celexa study the researchers claim is rife with “serious misrepresentations.” The study, known as the MD-18 ‘Wagner’ study, was published in the June 2004 issue of the American Journal of Psychiatry.
Citing unsealed court documents from Celexa litigation in Massachusetts, the researchers assert that MD-18 should be retracted because the study represents “a serious stain on the reputation of the American Journal of Psychiatry, the American Psychiatric Association, and the profession of academic and clinical psychiatry at large.” The researchers argue the drug manufacturer’s improper conduct with respect to MD-18 speaks to a larger issue of “industry manipulation of clinical trial data.”
This is not the first time the researchers have asked for a retraction of MD-18. In 2016, they wrote to Dr. Freedman after completing a research paper dissecting some of the issues with MD-18 that were uncovered during discovery in the Celexa litigation. The previous effort at retraction went unanswered.
Issues with the MD-18 ‘Wagner’ Study
In order to obtain approval from the Food and Drug Administration (FDA) for pediatric use of Celexa, Forest had to demonstrate the drug could outperform a placebo. The MD-18 study was vital to the FDA’s evaluation of Celexa for pediatric use.
According to the court documents, drug maker Forest Laboratories (now Allergan) deliberately obscured key data that showed Celexa (citalopram) was not effective in children. If Forest accurately disclosed the negative outcome of MD-18, the FDA almost certainly would not have approved the drug for pediatric use. Aware of this possible outcome, Forest misrepresented the data as positive in its submission to regulators in the hopes of securing approval for pediatric use of Celexa.
During the study, several patients were inadvertently given pink Celexa pills instead of white placebo pills due to a packaging error. Two of the study’s investigators who reported the packaging error to Forest became unblinded, as they knew which patients were receiving Celexa and which were receiving a placebo.
The MD-18 study protocol specifically stated:
“Any patient for whom the blind has been broken will immediately be discontinued from the study and no further efficacy evaluations will be performed”
Forest initially excluded these patients in its outcome calculation, which resulted in a negative primary efficacy outcome (i.e. Celexa did not outperform the placebo). However, those patients were ultimately thrown back into the final analysis, which turned the (marginally) statistically insignificant outcome into a statistically significant outcome (i.e. Celexa outperformed the placebo). Forest was only able to achieve the result the company wanted by adding in the unblinded patients back into the equation.
‘Implausible’ That Lead Author of MD-18 Was Unaware of Unblinding
In their letter to Dr. Freedman, the researchers noted that four of the unblinded patients in the MD-18 study were from MD-18 lead author Dr. Karen Wagner’s investigative site, where she was the lead investigator. According to the letter, “it is implausible that she was unaware of the unblinding problem during the CIT MD 18 study; yet Dr. Wagner completely failed to report this information in the published article in the American Journal of Psychiatry.”
When Forest settled a lengthy government investigation into off-label promotion of Celexa and Lexapro for pediatric use in 2010, the Justice Department and the U.S. Attorney’s Office did not have the full story on the MD-18 study. As such, attorneys representing plaintiffs in the Celexa litigation have asked federal officials to reopen an investigation into Forest’s alleged fraud.
In a letter and memo to the U.S. Attorney’s Office, the law firm of Baum Hedlund Aristei & Goldman alleges that Forest’s decision to promote the false results of MD-18 was deliberate. The letter cites a de-designated internal Forest email obtained in the Celexa litigation wherein Amy Rubin, a Forest Regulatory Affairs Manager, characterized the MD-18 dispensing error that caused patients to become unblinded as having “the potential to cause patient bias.”
In a response email, 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 upfront about the fact that the integrity of the blind was unmistakenly [sic] violated.”
Rubin’s response:
“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, but it was also her job to mislead the FDA and protect medical and marketing,” said R. Brent Wisner, attorney at Baum Hedlund Aristei & Goldman.
Retraction of MD-18 Celexa Study and Allegations of Ghostwriting
According to the letter to Dr. Freedman, it appears that Dr. Wagner was aware that the MD-18 manuscript was ghostwritten by Weber Shandwick and Prescott Medical Communications on behalf of Forest Laboratories. Declassified internal emails and court testimony from Dr. William Heydorn (Forest co-author on the Wagner study) clearly show that Dr. Wagner personally interacted with the manuscript ghostwriters, Natasha Mitchner and Mary Prescott, and knew the manuscript produced in her name was, in fact, ghostwritten on Forest’s behalf (see Dr. William Heydorn deposition page 314-315).
Per the letter:
“We would also bring to your attention that, in the Editor’s Note published in the American Journal of Psychiatry 166:8, August 2009, pp. 942-43, you specifically requested that Drs. Wagner, Robb, and Findling provide information on their contribution to the drafting of the original CIT-MD-18 manuscript, and you were informed that the alleged authors had contributed to the manuscript production and had no knowledge that Dr. Heydorn of Forest Laboratories had outsourced the writing of the Wagner et al. manuscript to a medical ghostwriting outfit. Dr. Heydorn testified that what was reported to you was not a true statement…”