1 Boring Old Man

Johnson & Johnson, Risperdal And A Lack Of Clinical Trial Disclosure

Pharmalot

by Ed Silverman

11/05/2013

In the wake of the $2.2 billion settlement that Johnson & Johnson will pay to resolve both criminal and civil charges leveled by US authorities has focused attention on off-label marketing practices and kickbacks paid to physicians and a nursing home pharmacy [back story with links]. But court documents reveal another troubling issue – withholding clinical trial data. The disclosure comes amid a heated debate over the extent to which drugmakers are willing to disclose trial data. The pharmaceutical industry is, by and large, fighting a proposal by the European Medicines Agency [read here and here] as well as a separate online campaign to provide patient-level data, claiming such a move would compromise trade secrets [look here and here].

The episode involving J&J’s Janssen unit occurred a decade ago, but serves to underscore the cries for transparency. In this instance, there were safety signals found in the trial, which tested the Risperdal antipsychotic for treating psychosis in Alzheimer’s patients. At the same time, though, the healthcare giant was allegedly marketing the drug for unapproved uses to the elderly, placing them at risk. In an August 2003 memo, a J&J consultant who worked on the design and protocol for a trial called RIS-232, wrote that there were problems with subject enrollment – a “substantial number” should have not been enrolled. As a result, the study failed. The consultant, whose name was redacted along with the name of the recipient, also warned that cherry picking subjects would not yield the desired indication.

There was more: J&J “has been sitting on the trial results for a long time. Yet it has a moral and ethical responsibility to publish results quickly and in a way that can be understood and makes clinical sense. It has an obligation not just to publish the clinical efficacy data, which could very well be informative and supportive of the use of risperidone if considered properly, but also the safety data, including event that have been labeled in the past as ‘cerebrovascular adverse events’ and deaths" [here is the memo]. Another document, which is an e-mail written in March 2004 by a trial investigator whose name was similarly redacted, indicates there was apparently concern about whether to include results from RIS-232 in a pooled analysis of three other studies. And this correspondence also raises the issue that J&J was reluctant to release the trial data. “At this point, we must be concerned that this gives the strong appearance that Janssen [the J&J unit] is purposely withholding the findings from RIS-232,” the investigator writes. The name of the recipient is also redacted. “…As an investigator who is loyal to this program, I really do have to speak out and urge that Janssen avoids embarrassment and accusations about suppressing information that is relevant to providers and consumers" [here is the e-mail]…

At the time, J&J’s Janssen unit had already established a strategy that emphasized establishing Risperdal as a market leader in treating the geriatric population and expand its reach by treating elderly patients who had psychotic symptoms of Alzheimer’s, according to a 2001 business plan. This plan, by the way, noted that study RIS-232 had to maintain its timelines [look here]. The healthcare giant was locked in competitive battle for the growing antipsychotic market. At the time, the business plan noted that AstraZeneca, which markets Seroquel, and Eli Lilly, which markets Zyprexa, had a “strong presence” at medical meetings and were increasing promotional activity that yielded market share gains. Moreover, Pfizer was set to introduce its own pill.

The study was eventually published in 2006 in The American Journal of Geriatric Psychiatry, according to Howard Feldman of the University of British Columbia, who chaired the Data Safety Monitoring Board [see this and this]. The study noted that earlier findings were not confirmed. As the agreement with the US Department of Justice noted, the Janssen unit pleaded guilty to misbranding by promoting the drug to treat psychotic symptoms and associated behaviors that were displayed by elderly patients. While these patients suffered from dementia, they were not schizophrenic, even though the drug was approved by the FDA only to treat schizophrenia.

As part of the deal, J&J signed a Corporate Integrity Agreement, which requires the healthcare giant to establish various compliance systems and procedures to ensure bad behavior does not get repeated. These include registering studies on ClinicalTrials.gov and publication of trial results in peer-reviewed journals within “applicable timeframes” [see the appendices]. Whether this mandate is sufficient to prevent a repeat is uncertain. In the interim, the J&J executive team may want to reiterate their commitment to the famed company credo that places their first responsibility to the people who use their products by recognizing the benefits of disclosing clinical trial data.

While there were psychiatrists in high places who went along with these schemes, most of the rest of us were passively complicit. We’d grown up with the neuroleptics, the first generation of antipsychotics that had a dictionary full of side effects, some of which were tragic, including Tardive Dyskinesia. And we’d lived in a world where the option for hospitalization for psychosis had evaporated. The allure of an effective antipsychotic that was soft on side effects was appealing. So when Risperidal®, the first usable Atypical Antipsychotic came along, it filled a niche that was ready and waiting.

Randomized Clinical Trials address two major areas: Efficacy and Adverse Effects. With the antidepressants, the "depression market" was assured, so the hanky-panky was mostly Efficacy inflation with clinical trials and some Adverse Event manipulation on the side. When the Atypicals came along, the suppression of Adverse Events moved to the fore. All three of the big guys [J&J, AstraZeneca, and Lilly] were in a war, suppressing their own Adverse Events and attacking those of their opponents. But there was more. The psychosis market wasn’t big enough, so they worked on expanding it. J&J lead the way going after "non-help-seeking" populations: difficult kids brought by parents and particularly foster-parents; people in public systems like prisons and mental health centers; and the aged in long termed care facilities. While Risperidal® was advertised as an antipsychotic, it was detailed as an anti-agitation drug. Their job was to prove it was safe in these settings, to use its newness to get around the known dangers of the old neuroleptics. And J&J did that by flooding the literature with experimercials, withholding data that was contradictory to this new safety meme, and invading systems like State Mental Health [TMAP], hospital corporations [Omnicare], and buying child people like Dr. Biederman at MGH and many others. The  clinical trial literature was harvested for export and managed like picking only the good apples off the tree.