no judgement at nuremberg…

Posted on Saturday 9 November 2013


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]…
It looks like I’m going to be reposting this whole piece by Ed. It’s too good not to and so rich with the references needed to understand this settlement. So here’s the rest…
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.
What’s not in Ed’s post is that this kind of exploitation wasn’t just limited to the elderly, it was J&J’s Modus Operandi throughout their patent life with Risperidal®. They weren’t satisfied with simply promoting off label uses of Risperidal®, they found ways to influence whole systems to promote the use of their drug. They funded the creation of guidelines by a consortium of academic centers [1999…], then passed those guidelines to the Texas Medical Algorithm Project which they also funded [detestable…] and had the whole Texas public medical system using their medication [over equivalent generics] in one of the largest health care systems in the world. They then funded the Texas officials traveling from place to place pushing the TMAP system and pulled off the same scam in seventeen other states [it even went to Washington with George Bush as Teen Screen]. They bought Joseph Biederman’s signature on an exhumed article recommending Risperidal® to treat the mythic Bipolar Child by funding his Center at MGH [trial 93: a bad penny…, trial 93: a very bad penny…, trial 93: a very very bad penny…]. They had an army of ghostwriters at Excerpta Medica [“designated author “…, gpp?…] around the corner from their corporate headquarters turning out ghost-written journal articles faster than they could recruit academic authors to sign on. And their sales reps were trained to actively lie about side effects "on every call" [on every call…]. The Risperidal® enterprise was suffused with what I would call criminal intent.

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.

So Ed is absolutely right to bring up the current Data Transparency movement in the context of this settlement [and others]. The general opposition of industry to Data Transparency hides behind "subject confidentiality," but is defended by arguments that have phrases like "trade secrets" and "competative edge" embedded within – the things that make the J&J story so tawdry. The Data Transparency advocacy in the current war is fracturing somewhat over the solution. Some are willing to settle for a compromise that accepts parts of the pharmaceutical industry’s ownership of data. Others point to behavior like in this suit and are in a scorched earth posture. It feels a bit like kids feel when their parents are fighting, creating an uncomfortable polarization. I think about that fault line building in the Data Transparency movement a lot, and I’m currently trying to formulate my thinking for the next post where I want to weigh in. Coming soon. But as for this J&J settlement, they got off too light and there were no jail sentences, no Judgement at Nuremberg. We could use such a trial with no settlement options to expose this in the public domain…
  1.  
    Bernard Carroll
    November 9, 2013 | 1:19 PM
     

    Let’s not forget also that JNJ went after the depression market with Risperdal. The usual suspect KOLs leading this effort were Charles Nemeroff and his successor at Emory, Mark Rapaport, not forgetting Martin Keller at Brown, too. They published a trial report in the journal Nemeroff edited. It was so bad that I called for it to be retracted: http://www.ncbi.nlm.nih.gov/pubmed/18033236 [free full text]. In the end, they fessed up that their positively slanted report was indeed a negative study.

    The enabling of corporate malfeasance by highly visible KOLs is another dark chapter in this story. Where are the professional and academic societies when we need them to speak publicly about this stain?

  2.  
    wiley
    November 9, 2013 | 3:33 PM
     

    Alzheimer’s has been a very popular disease. In the eighties there was wall to wall coverage of it on all the news channels (marketing vnrs). Not too long after the craze started I read an article that said a lot of people who were being diagnosed with Alzheimer’s were really in the late stages of alcoholism. Dementia is a symptom of hepatic encephalopathy which can be discovered with lab work and feeling the liver.

    Alzheimer’s only proves itself in autopsy, which makes it significantly different from psychosis. It seems to me that using an anti-psychotic for dementia should have been questioned from the start. That antipsychotics were being used to make the elderly easier to handle should have been evident. That antipsychotics cause problems with gait and make falling much more likely should have been a concern for clinicians from the beginning.

    That our society doesn’t want to spend more money to allow our elderly disabled to be properly cared for, does not reflect well on us. Frail people with dementia are difficult to handle, especially since the nursing homes are understaffed and are in it for profit.

    In the end, if we want to do what can be done to make the lives of the elderly and children, and the mental distressed better, we’re going to have to spend the money. Two point two billion is a start, but it’s not enough.

  3.  
    Bernard Carroll
    November 9, 2013 | 5:15 PM
     

    Wiley, allow me to help out a little here regarding Alzheimer’s disease. The article you read back in the 1980s doesn’t seem reliable.

    The big three causes of dementia are AD, vascular disease, and alcoholism. These can also coexist to varying degrees, and each can make the primary condition worse. However, when an alcoholic becomes demented it’s not the direct result of hepatic encephalopathy but of actual brain atrophy. Hepatic encephalopathy results in delirium. Dementia is the residual state that follows episodes of delirium and B vitamin deficiency with brain atrophy. The pattern of brain atrophy on MRI scans can help to differentiate AD from alcohol related dementia and vascular dementia. And it is now possible with amyloid imaging studies to make a reasonably definite diagnosis of AD in vivo.

    As for giving antipsychotic drugs to patients with dementia and behavioral disturbances, there certainly are times when that is necessary and helpful to the patient. I say that from a background of directing a 100-bed psychogeriatric service for 7 years. We had excellent nursing and ancillary staff but still there were times we needed to use those drugs. The issue in the JNJ case was not judicious off-label use of the drug but rather the blitzing of nursing homes with drug reps and misleading information designed to promote unnecessary use.

  4.  
    TinCanRobot
    November 9, 2013 | 9:33 PM
     

    Bernard Carroll,

    Are you sure “amyloid imaging” has been demonstrated to reliably work? I read there were false positives somewhere, medscape had an article on it.
    http://www.medscape.com/viewarticle/808149

    It wouldn’t be the first time a likely fraudulent AD test was brought to use. I’m almost sure the ‘amyloid imaging’ thing is the same deal.
    http://www.ahrp.org/cms/content/view/848/70/

    I wish there was money for pure research on AD..

    I just read this on the news the other day,
    “Rules to Require Equal Coverage for Mental Ills”
    One more way J&J got away…
    http://www.nytimes.com/2013/11/08/us/politics/rules-to-require-equal-coverage-for-mental-ills.html?hp&_r=1&

    The Director the NIMH found another way to stall for time to keep attracting tax payer investment in the NIMH. Now the failure to find Genes for mental illness is because the brain has it’s own genes.. I doubt anyone will consent to brain biopsy’s but.. yikes.
    http://www.nimh.nih.gov/about/director/2013/one-person-many-genomes.shtml

  5.  
    Bernard Carroll
    November 9, 2013 | 11:21 PM
     

    TinCan: there is a shakeout period in progress right now with amyloid imaging. Folks are getting a handle on appropriate use criteria and on differential diagnosis in a range of non-AD pathology. Not for the first time, clinicians need to be educated on how best to use the new test in context with clinical data. There will always be false positives, even with very good tests. That is why we say to use them as confirmatory tests and to refrain from using them as screening tests. To quote myself quoting R.D. Gillespie from a few days ago, no one sign will serve as a touchstone for diagnosis.

    I would caution against a too quick assumption of fraud in matters like this. It’s the expected situation of new ideas being proposed, appropriately challenged by skeptics, maybe modified, and eventually finding their right applications. As for your second example of “likely fraudulent” research, I would think the lawsuit is likely frivolous. I have known the Principal Investigator, Marilyn Albert, for many years and I have always been impressed by her integrity. As the case seems not yet to have been decided, your prejudgment comes across as unfortunate.

    While we are on the topic of physicians, the FDA, and off-label use of medications, it might be helpful to revisit the statutory relationship between the FDA and physicians. Put simply, the FDA has no mandate to regulate the practice of medicine. That is the province of State medical licensing boards. Congress chartered the FDA to regulate the claims and behavior of manufacturers and distributors, not to regulate the discretionary medical practice of individual physicians. Even physicians lose sight of this firm separation at times.

  6.  
    TinCanRobot
    November 9, 2013 | 11:53 PM
     

    Carroll,
    Thanks for the reply,

    Perhaps I shouldn’t jump the gun, Innocent until proven guilty.

    I worry off-label prescriptions create a situation where abuses (like illegal marketing campaigns) can’t be addressed.

  7.  
    November 10, 2013 | 1:33 PM
     

    Dr. Mickey, love the map.

  8.  
    November 10, 2013 | 1:51 PM
     

    http://www.cbsnews.com/8301-18563_162-57610994/leading-generic-drug-maker-faked-test-results-for-fda-approval/

    November 5, 2013
    Leading generic drug maker faked test results for FDA approval

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