Academic·Industrial·Complex II…

Posted on Sunday 19 April 2015

Several years ago, I ran across a business magazine cover with a high level AstraZeneca executive being praised for figuring out how to extend the patent life of their blockbuster Seroquel® by getting Seroquel XR® approved. I could never find it again. I still feel the loss because it proved that Seroquel XR® was just a marketing ploy…

New York Times
APRIL 17, 2015

Last fall, an article in the American Journal of Psychiatry caught the attention of specialists who treat borderline personality disorder, an intractable condition for which no approved drug treatment exists. The article seemed to offer a glimmer of hope: The antipsychotic drug Seroquel XR® reduced some of the disorder’s worst symptoms in a significant number of patients…
I have to interrupt Katie for just a moment. I wrote about that article in July 2014 when it was published on-line. There was no glimmer of hope seen here. I thought it was shameful [see an anachronism…]. Seroquel XR® was just a patent-life extender. Borderline Personality Disorder is a very complex topic and the notion that there will ever be a "right drug" for the condition is about as likely as pigs flying. When I reviewed the article, I located a 2004 Medscape C.M.E. where Dr. Schulz had presented industry-funded studies he’d done with Risperdal®, Zyprexa®, and Seroquel® in patients with Borderline Personality – each one showing some effect; each one written up as if it mattered. I actually saw them as playing the companies off against each other.
In the realm of clinical trials, however, reality is sometimes far messier than the tidy summaries in medical journals. A closer look at the Seroquel XR® study shows just how complicated things can get when a clinical trial involves psychiatric disorders and has its roots in intersecting and sometimes competing interests: a drug company looking to hold onto sales of a best-selling drug, a prominent academic with strong ties to the pharmaceutical industry and a university under fire for failing to protect human study subjects…
This article goes on to mention any number of problems with this study. Dr. Schulz had big  COI problems having been paid over $100K by the sponsor for various things in recent years. 100% of subjects screened were accepted [unheard of, implying that they were taking all comers to boost their sagging enrollment]. But the top story was that two of the subjects turned out to be sex-offenders living at a halfway house who had signed onto the study for the money. And one of them had spiked the breakfast oatmeal at their halfway house with his Seroquel XR®, a stunt that got him sent back to prison.

In Academic·Industrial·Complex I… we read Dr. Schulz’s plan to finance his department by doing «very good clinical trials» and I suggested two criteria for what that might mean 1. trials that were scientifically justified rather that simply commercials [experimercials] and 2. trials that were well executed. Well this whole series of trials on Atypical Antipsychotics generally flunks number 1. and really outdoes itself with Seroquel XR® [after already studying plain old Seroquel®]. And it flunks number 2. in that the execution here is embarrassingly sloppy. This was a Clinical  Trial apparently randomizing all comers, with some outrageous antics along the way, that took five years, cost $700K, involved 100 subjects, and was dolled up and published in the American Journal of Psychiatry as if it said something that mattered. The published results actually made very little sense [see an anachronism…].

Bioethicist Carl Elliot’s main focus is on the conduct of the Clinical Trials in the University of Minnesota’s Department of Psychiatry, and he’s collected an impressive array of examples of dysfunction at multiple levels. The recent investigations by an independent panel appointed by the Association for the Accreditation of Human Research Protection Programs and a report from the Office of the Legislative Auditor not only agreed with Elliot but amplified on his observations. The result was a suspension of all Clinical Trials pending further investigation. Dr. Schulz, Chairman of the Department of Psychiatry stepped down. There is a consensus that the Board of Regents and the University President have little understanding of how to do their jobs. Whistle-blowing nurse Niki Gjere describes an atmosphere of fear, but I was more impressed that everyone from the bottom up seems to be just going through the motions, doing nothing wrong, clueless about the uproar.

While I’m obviously relieved that something is finally going to be done about the situation with the University of Minnesota Clinical Trial program, I don’t think that we’ve yet landed on the most basic ethical dimension of this story. The studies on the table right now are a head to head comparison of three [in-patent at the time] Atypical Antipsychotics in First Episode Schizophrenic cases [CAFE], and a string of Clinical Trials of Atypical Antipsychotics in patients with Borderline Personality Disorder as the drugs arrived on the market. All are studies funded by industry and I believe investigator initiated. I question whether there was any scientific justification for any of these trials at the time they were being conducted. Instead, I would propose that all of them were studies probing for some commercial advantage to the pharmaceutical company paying for the trial, and that a strong motive in proposing these trials in the first place was to finance an Department of Psychiatry.

Every Clinical Trial is human experimentation. We’ve decided that human experimentation is allowed if there have been careful limited trials to assess safety and that the potential outcome of the trial will be of wide benefit to others. There is no reasonable argument that suggests a time release version of Seroquel® will be more effective than the already tested regular Seroquel® in any situation. For that matter, there’s nothing that I know about the Borderline Personality Disorder that suggest any medication will be of lasting benefit. Here’s Dr. Schulz’s slide of the drugs that have already been tried:

And as to CAFE – is it reasonable to recruit patients with a First Episode of Psychosis [likely the biggest event in their lives] into a study that commits them to a year of medication [blinded] in order to use the outcome in some future commercial or sales pitch? I think not.

And so to the heart of the Academic·Industrial·Complex and the ethical dilemma that it contains. The academic part of the pairing agrees to test the drugs [or at least sign off as a tester], to serve as a ticket into the peer reviewed academic journals, and often to promote the drug as a speaker or in a CME presentation, in return for the funds desperately needed to finance Medical Education. The payoff for industry is obvious. And human experimentation in the form of Clinical Trials sits at the interface between the academy and industry. Is the Borderline or First Episode Psychotic patient told that the study is being done for its commercial value? Is some of the lackluster and torpid performance of the Clinical Trial staff because they know either directly or intuitively that a given study is not really for the advancement of science? but rather for sales and marketing like in the email mentioned earlier in Academic·Industrial·Complex I…
… R&D is no longer responsible for Seroquel® research – it is now the responsibility of Sales and Marketing. So preclinical research studies aimed at mode of action, although very interesting to both of us, do not translate to marketable messages that will impact sales [at least this is what my commercial colleagues say]. On the other hand, clinical studies that extend the indications for Seroquel® can directly impact sales. With limited budgets, funding of clinical studies will therefore come first.
    Bernard Carroll
    April 20, 2015 | 12:08 AM

    It is also worth recalling the Escher staircase phenomenon made famous by a report in 2006. The authors surveyed recent comparative studies of atypical antipsychotic drugs, and they called attention to the recursive nature of the results thusly: “Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine…”

    Such experimercials confirm the drift of many clinical trials programs from patient-centered efforts with a scientific subtext to commercially driven exercises. When they meet themselves coming up the down staircase, any material importance of the results dissipates. They weren’t designed to be important beyond a corporate narrative. But they do get in the way of serious clinical science. As has been said, “… the danger is that innovation is paradoxically retarded because both partners commit to flawed paradigms out of misguided self-interest and perverse incentives.” And in the process, patients are viewed as commodities rather than as our altruistic partners in clinical science.

    Mike Howard
    April 20, 2015 | 4:40 PM

    I have a very lay persons question to ask, something that has bothered me for years and I have never quite gotten an answer. AstraZeneca sponsored the CAFE’ study and their drug Seroquel at the time was recommended to be taken twice or even three times a day, mainly I’m guessing because of the short half-life of the drug in the system. Zyprexa and Risperdal were recommended to be taken just once a day. So what happened is they split the doses of both Zyprexa and Risperdal to keep the blinding in place so those two drugs were at only half of their normal potency each time and all the drugs were then taken twice a day in the study. Did that alone cause a favorable advantage for Seroquel? and by that I mean would have affected the efficacy of the other two drugs? Any help would be greatly appreciated…or simply tell me I’m out in left field somewhere…..

    Bernard Carroll
    April 20, 2015 | 5:44 PM

    Mike, this could have introduced a minor bias, but I don’t think it would be a major issue. Anyway, Seroquel didn’t outperform on any measure. Discontinuation rates were almost identical for all 3 drugs. At 12 weeks the reductions of PANSS positive symptom scores were greatest for Zyprexa and Risperdal. At week 52, Zyprexa had the largest effect on PANSS positive symptom scores. And Mr. Markingson was taking Seroquel, not one of the other two drugs.

    Mike Howard
    April 20, 2015 | 7:25 PM

    Dr. Carroll, thank you, I really appreciate your response.

    April 20, 2015 | 8:30 PM

    Let us also note these studies get thrown into the hopper for Cochrane reviews, recirculating the lies into yet more faux-authoritative studies.

    April 20, 2015 | 9:02 PM


    Nope. They don’t buy it either…

    Pharmacological interventions for borderline personality disorder

    Jutta Stoffers2, Birgit A Völlm3, Gerta Rücker4, Antje Timmer5, Nick Huband3, Klaus Lieb1,*

    Editorial Group: Cochrane Developmental, Psychosocial and Learning Problems Group

    Published Online: 16 JUN 2010
    Drug treatment for borderline personality disorder

    Many people with borderline personality disorder (BPD) receive medical treatment. However, there are no drugs available for BPD treatment specifically. A certain drug is most often chosen because of its known properties in the treatment of associated disorders, or BPD symptoms that are also known to be present in other conditions, such as depressive, psychotic, or anxious disorders. BPD itself is characterised by a pervasive pattern of instability in affect regulation (with symptoms such as inappropriate anger, chronic feelings of emptiness, and affective instability), impulse control (symptoms: self-mutilating or suicidal behaviour, ideation, or suicidal threats to others), interpersonal problems (symptoms: frantic efforts to avoid abandonment, patterns of unstable relationships with idealization and depreciation of others), and cognitive-perceptual problems (symptoms: identity disturbance in terms of self perception, transient paranoid thoughts or feelings of dissociation in stressful situations). This review aimed to summarise the current evidence of drug treatment effects in BPD from high-quality randomised trials.

    Available studies tested the effects of antipsychotic, antidepressant and mood stabiliser treatment in BPD. In addition, the dietary supplement omega-3 fatty acid (commonly derived from fish) which is supposed to have mood stabilising effects was tested. Twenty-eight studies covering 1742 study participants were included.

    The findings tended to suggest a benefit from using second-generation antipsychotics, mood stabilisers, and omega-3 fatty acids, but most effect estimates were based on single study effects so repeat studies would be useful. Moreover, the long-term use of these drugs has not been assessed. The small amount of available information for individual comparisons indicated marginal effects for first-generation antipsychotics and antidepressants.

    The data also indicated that there may be an increase in self-harming behaviour in patients treated with olanzapine. In general, attention must be paid to adverse effects. Most trials did not provide detailed data of adverse effects and thus could not be considered within this review. We assumed their effects were similar to those experienced by patients with other conditions. Available data of the studies included here suggested adverse effects included weight gain, sedation and change of haemogram parameters with olanzapine treatment, and weight loss with topiramate. Very few beneficial effects were identified for first-generation antipsychotics and antidepressants. However, they may be helpful in the presence of comorbid problems that are not part of BPD core pathology, but can often be found in BPD patients.

    There are only few study results per drug comparison, with small numbers of included participants. Thus, current findings of trials and this review are not robust and can easily be changed by future research endeavours. In addition, the studies may not adequately reflect several characteristics of clinical settings (among others, patients’ characteristics and duration of interventions and observation periods).

    April 21, 2015 | 6:28 AM

    Mike Howard,
    I would also add that it is not clear to what extent dosing frequency has an impact on any of the antipsychotic drugs. Risperidone was initially marketed with a recommendation for twice daily dosing but that quickly faded away. It does not seem that having a steady blood level is critical as it more likely is with anti-seizure drugs or antibiotics. Some of these drugs (ziprasidone) have much better absorption when taken with food and that is very hard to monitor. That would be a drug at a distinct disadvantage in drug trials. Many people now give the original form of quetiapine (Seroquel) in single daily dosing (at night since it is so sedating). In fact an efficacy study of the XR form and the IR form in single daily dosing would actually have been informative but I do not think that was done. It would have been against the commercial interests of the company to do that. I found this study but it gave the IR form in divided doses (and notice the dosing which appears to be an attempt to try to favor the XR form).
    But in doing a Pub Med trial one can easily see the experimercial push for the XR drug.
    This has inspired me to pull together the data on antipsychotic drugs that appear to offer an advantage with dosing.The big push right now in the schizophrenia advertising world is on the long acting injectables (they remain on patent). But the data to support them is not nearly as strong as one might expect.

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