1 Boring Old Man

You can’t really erase history, even though we all try. For one thing, it doesn’t go away. It just sits there in the background having an effect even if it has been selectively removed from consciousness. Freud made the analogy of The Mystic Writing Pad [when I was a kid, it was called the Magic Slate]. You wrote on cellophane with a stylus, When you lifted the cellophane, the writing disappeared, but it left traces in the wax below. Freud was using the metaphor to describe memory traces in the Unconscious. It was a good analogy. As a psychotherapist, one learns that it’s not like in the movies – some cave full of repressed memories. But rather, the mind just skips over or goes around unpleasant or traumatic previous experience, almost without noticing. While the gain is comfort, the loss is in not learning the important lessons that experience has to teach – so history repeats. And in eliminating chapters from the story, the book-of-you makes much less sense, because we are our stories, our narrative. What else could we be?

Right now, psychiatry seems to be attempting to erase a piece of its own history – a recent piece at that. We’ve had a couple of decades where many academic psychiatrists have been in an unholy alliance with the pharmaceutical industry, one that allowed industry to control our scientific literature, our continuing medical education, and, indeed, the whole direction of our specialty. The profits from that alliance have become the stuff of Wall Street legend – blockbusters! The ramifications of those years are everywhere around us – in our diagnostic manual, our relationships with patients and other mental health specialties, our place in the third party payment hierarchy, in the eyes of the public. As those years are finally drawing to a close, they seem to be becoming the elephant in the room that nobody’s talking about.

• Example: Right now, the AllTrials campaign is going great guns.  Boehringer Ingelheim, GlaxoSmithKline, Roche, Sanofi, ViiV Healthcare, Pfizer, and now Johnson & Johnson are putting systems in place to allow access to their Clinical Trial data. I’ve been involved with some of the early results of that, and though it’s not a completely easy process, it’s definitely moving in the right direction towards "good enough." But nobody’s saying why they’re doing it. They’re giving us access because they’re good guys. Nobody talks about the stream of ghost written jury-rigged decepticons that flooded our literature for a decade or more, barely disguised drug industry commercials. Nobody talks about the legal settlements that are rapidly escalating to the point where they are going to really start hurting, or the growing clamor for criminal prosecutions. They’re just being generous.
• Example: Right now, Tom Insel is renovating the NIMH. The DSM-anything is out. The RDoC is in, when it gets around to existing. NIMH Clinical Trials have been changed. We’re on a new tack to find new drug targets. The reason the DSM-5 is out? It’s because medications and neuroscience findings don’t map onto the clinical categories. Little is mentioned about the lackey-ing around with drug trials and neuroimaging/genetics/etc. work the NIMH has funded to study and cavort with the industry’s drug output. Nothing is said about the APA/NIMH series of symposia in the lead up to the DSM-5. Not much mentioned that the Research Agenda for the DSM-V essentially laid out the RDoC agenda which came into being as it became apparent that the grand plans for the DSM-5 were going up in smoke. And there’s absolutely no comment about the fact that nothing [not even patients] map well to the DSM because it has been so distorted by outside forces.
• Example: Dr. Lieberman [APA President] and now Dr. Summergrad [APA President Elect] can’t talk enough about something called Collaborative Psychiatry – meaning psychiatrists should work in practices with general physicians. But they don’t mention that psychiatry so bought into the psychiatrists-as-medication-prescribers model and now there are no more new meds to prescribe that they’re trying to find some kind of new identity for psychiatrists to fit into.

We did this already in 1980 – abandoned our history, whether by intent or not. One would’ve thought that the only historical figure that ever mattered was Emil Kraepelin. The psychoanalysts, Adolf Meyers, Harry Stack Sullivan, Karl Jaspers, social psychiatrists, family theorists, psychotherapists [other that CBTers] – the pantheon of psychiatrists who had contributed to our understanding of mental illness were largely forgotten and rarely mentioned in any positive way. And of interest, since the 1980s we haven’t produced any "greats" – only KOLs with a limited shelf-life.

My first encounter with the work of Dr. Robert Gibbons, a statistician and the University of Chicago, was a couple of articles in which he challenged the Black Box warning on antidepressants for adolescents – declaring them both safe and effective. His analysis was based on a private, unavailable dataset. Besides the unavailability of the data to check his work, there was a well planned media roll-out with many interviews accompanying his papers. [an anatomy of a deceit 1…]. Later, I noted a similar low data, high visibility approach to the adverse effects of Chantix and Neurontin – again downplaying adversity and upgrading efficacy [very monotonous…]. And then recently, he published a flurry of articles on a new psychometric  for screening for depression and anxiety – this time forming a company with Dr. David Kupfer to sell this test commercially. The glaring conflict of interest problems have been discussed ad nauseum here [see open letter to the APA…].

Can A Computer Measure Your Mood? [CAT Part 3]

Discover

by Neuroskeptic

March 12, 2014

[full text on-line]

Now, I’m finally going to delve into the statistics to find out: does it really work? The CAT-DI was revealed in a 2012 paper by Robert Gibbons and colleagues in the prestigious Archives of General Psychiatry. In this article (which has been previously criticized), the authors, after introducing the theoretical background of the method, and describing its development, compared the CAT-DI against three widely used, old-fashioned pen-and-paper depression questionnaires, the HAMD, the PHQ9, and CES-D.

Gibbons et al examined the ability of each of these four measures to distinguish between three groups of people: those diagnosed with no depression, with minor depression, or with major depression. An ideal depression scale ought to give, respectively, low, medium and high scores for these three different groups. The importance of this comparison can hardly be overstated. It asks the question: is the CAT-DI any better than what we already have? What, if anything, does the new kid bring to the party? And this is the only head-to-head comparison of the CAT-DI’s performance in the paper…

Overall proportional overlap – which I defined as the total of the two overlaps between the  adjacent bars, divided by the total length of the three bars – was identical to within the margin of error [i.e. 1 pixel] but for what it’s worth, the CES-D was marginally better [with 0.397 ratio vs 0.399]. This is an… unorthodox approach to psychometrics I’ll be the first to admit, but it’s the best that I could do given the [lack of] information provided in the paper, and I feel that it’s more rigorous than just saying ‘in general’.

I’ll have to admit that Dr. Gibbons’ papers are hard for me to evaluate – scientifically and emotionally. I don’t agree with his conclusions before I read his arguments. I don’t think antidepressants are either effective or benign in kids. I’m suspicious that a quickie test like this will end up in the waiting rooms of physicians and result in even more over-medication. I’m put off by the hype, the invariable commercial overtones, and the absence of useful, checkable data in his papers. And, by nature, I prefer gathering subjective data subjectively – by an unhurried interview. I don’t see these things as conflicts of interest, but rather differences of values.

The U of M should thoroughly investigate issues in the Markingson case

MinnPost

By Leigh Turner

03/11/2014

In yet another twist to the University of Minnesota’s longstanding refusal to investigate alleged research misconduct in the Department of Psychiatry, university officials, instead of asking for a credible inquiry, are soliciting “bids” from prospective contractors interested in reviewing “current policies, practices, and oversight of clinical research on human subjects.” This limited review is both absurd and fully consistent with the decade-long refusal by university administrators to promote anything resembling a legitimate inquiry into possible research misconduct involving vulnerable patients with mental illnesses.

The latest episode began in December, when the University of Minnesota Faculty Senate approved a measure titled “Resolution on the matter of the Markingson case.” Dan Markingson was an acutely psychotic young man who was recruited into a psychiatric clinical trial while under a civil commitment order. His psychiatrists kept him in the trial despite the desperate pleas of his mother, Mary Weiss. Markingson stayed in the study until he committed suicide by nearly severing his head with a box-cutter.

In the years since then, many critical questions about the circumstances surrounding his death have remained unanswered or contested: whether Markingson was coerced into the trial, whether he was enrolled without having the capacity to provide informed consent, whether he was given inadequate care by psychiatrists with significant financial conflicts of interest, and whether his privacy rights were violated. Last fall, a group of 181 professors from outside the university wrote to the Faculty Senate, asking it to endorse an investigation of the circumstances surrounding Markingson’s death. The Senate passed a resolution by a vote of 67 to 23; its preamble noted the reputational harm the university has suffered "in consequence of this tragic case and its aftermath," as well as the many unanswered questions raised by Markingson’s death.

Still, university officials continue to dodge a legitimate inquiry. Instead of asking for an investigation by a panel of independent experts in research ethics or a law-enforcement body, university officials have posted a request for proposal [RFP] to the MBid System on the university’s Purchasing Services website. This is the website ordinarily used to solicit bids for services such as furniture reupholstery contracts and laboratory supplies. Unless the Presidential Commission for the Study of Bioethical Issues routinely trolls for contracts on the MBid website, it is unlikely that the kind of organization that registers with MBid is going to have the expertise, credibility, investigative powers, and forensic skills needed to conduct a thorough investigation of possible psychiatric research misconduct. Even if a credible body with relevant expertise receives the contract, it is being given the wrong mandate. According to the RFP:

The intent of this review is to ensure that the University’s processes for clinical research on human subjects meet or surpass the established best practices and norms and to instill confidence among faculty and the public that the University of Minnesota research is beyond reproach. It is to be forward looking, productive, transparent and independent review of current practice by an external expert panel.

Setting aside the suggestion that the primary mandate of the contractor is to engage in a public-relations exercise for the university by “instilling confidence” that research conducted at the University of Minnesota is “beyond reproach,” the emphasis on being “forward looking” while examining only “current” policies, practices, and oversight of clinical research is profoundly disturbing. I believe the purpose of an investigation should not be limited to reviewing current policies, but must also include a careful investigation of past conduct — including alleged misconduct in the Markingson case…

Protocol: "Subjects are free to discontinue their participation in the study at any time, without prejudice to further treatment. Subjects who discontinue from the study should be asked about the reason[s] for their discontinuation and about the presence of any adverse events. If possible, they should be seen and assessed by an investlqator. Adverse events should be followed up and the subject should return all investigational products."

Protocol: "Patients may be withdrawn from the trial for any of the following reasons:
1. Inadequate therapeutic effect [requiring alternative treatment]…
2. Unacceptable side effects
3. Patient decision…
4. Administrative…"

Unlike the usual complaints of over-medication and unnecessary restraint, Markingson was inadequately medicated and placed in an environment that did not offer appropriate restraint. The magnitude of his impairment was neglected in the service of the clinical trial – an unnecessary trial of the expirimercial variety. The absurdity is that until he killed himself, he was on the road to being declared a treatment success since he was still taking the study medicine [albeit anything but voluntarily]. In a more reasonable world, one would expect the Sponsor [AstraZeneca], the Principle Investigator [Jeffrey Lieberman, current APA President], and the organization actually running the trial [Quintiles] to have some interest in knowing what went wrong in their study.

If the story is actually as I have just told it, it is an example of clinical neglect leading to a fatality in the service of performing an unnecessary clinical trial for marketing purposes. At this point, only an outside, unbiased investigation can determine the truth. The Study Coordinator has already been censured by her professional organization for her part in the story, but the University administration has hindered any further general probe. This current tack of limiting the investigation to current conditions, leaving Markingson’s out of the investigation, and putting it out for bidding along with office furniture on a request for proposal site can only be seen as deliberate obstruction of the faculty senate mandate – and a direct insult.

The approach taken in DSM-III is atheoretical with regard to etiology or pathophysiological process except for those disorders for which this is well established and therefore included in the definition of the disorder. Undoubtedly, with time, some of the disorders of unknown etiology will be found to have specific biological etiologies, others to have specific psychological causes, and still others to result mainly from a particular interplay of psychological, social, and biological factors…
Robert Spitzer, in the DSM-III, p 6.

The objections to the clinical diagnostic system were that the psychiatric drugs were not specific for any particular diagnosis. The neuroimaging findings and genetic studies likewise failed to map onto the clinical diagnostic groups. There were no biomarkers of any clinical entity located along the way, nor any biological targets that showed syndrome specificity. We might add that the pharmaceutical industry had run out of clones of the two major classes – SSRIs and Atypical Antipsychotics – and was moving away from CNS drugs after a quarter century feeding frenzy.

NIMH has launched the Research Domain Criteria (RDoC) project to transform diagnosis by incorporating genetics, imaging, cognitive science, and other levels of information to lay the foundation for a new classification system… This approach began with several assumptions:

• A diagnostic approach based on the biology as well as the symptoms must not be constrained by the current DSM categories
• Mental disorders are biological disorders involving brain circuits that implicate specific domains of cognition, emotion, or behavior
• Each level of analysis needs to be understood across a dimension of function
• Mapping the cognitive, circuit, and genetic aspects of mental disorders will yield new and better targets for treatment

It became immediately clear that we cannot design a system based on biomarkers or cognitive performance because we lack the data. In this sense, RDoC is a framework for collecting the data needed for a new nosology. But it is critical to realize that we cannot succeed if we use DSM categories as the “gold standard.” The diagnostic system has to be based on the emerging research data, not on the current symptom-based categories…
Thomas Insel, in Transforming Diagnosis. April 29, 2013

It’s a move supported by the leaders of the DSM-5 task force and other research oriented scientists, for example in this month’s British Journal of Psychiatry:

The Research Domain Criteria: moving the goalposts to change the game

by Joanne L. Doherty and Michael J. Owen

British Journal of Psychiatry. 2014 204:171–173.

There is increasing concern that a reliance on the descriptive, syndrome-based diagnostic criteria of ICD and DSM is impeding progress in research. The USA’s major funder of psychiatric research, the National Institute of Mental Health (NIMH), have stated their intention to encourage more research across diagnostic categories using a novel framework based on findings in neuroscience…

• There’s something wrong with the diagnostic system in the first place. We know that’s true with the most common diagnosis of them all – Major Depressive Disorder [MDD]. In the 1970s, there was something of a growing consensus that Melancholic Depression and the Depressions associated with Manic Depressive Illness were prime candidates for biological research. The genetics were right. The clinical syndrome was unique. There were promising biomarkers [DST, REM Latency]. But with the DSM-III, all clinically significant depressions were lumped together and remain so to this day. So maybe the heterogeneity of the patients in that group dilutes out any possibility of pursuing a biological cause. There are other examples but that one is in the center ring.
• Maybe our medications are symptomatic medications, not "diaease-specific" at all. This is the concept proposed eloquently by Joanna Moncrieff. The analogy might be digitalis for heart disease. It helps with most kinds of heart failure, but no heart disease specificity is conjured up to explain its effectiveness.
• And where is the evidence that the majority of patients seen by psychiatrists have something wrong with their brains? When I see patients in the clinic tomorrow, I’m not likely thinking that many of them have brain diseases. The colossal failure of the research enterprise to find anything may be that there’s not anything to find. I don’t believe there’s nothing to find myself, but I think it’s way less than indicated by Insel’s ["Mental disorders are biological disorders involving brain circuits that implicate specific domains of cognition, emotion, or behavior"]. The only possible way to even hypothesize such a thing would be to severely restrict what he defines as "Mental disorders."

In Charlie Brown’s version of Occam’s razor…

1. the unforgotten unremembered… [01/06/2014]
2. the twilight zone… [01/09/2014]
3. learning from mistakes… [01/28/2014]
4. perhaps bigger… [02/17/2014]

So now, twenty years later, Richard wrote an article about it, noting that we have all forgotten that it even happened, and suggested that since 20 years have passed, maybe we could take a look at back then. He submitted it to Psychiatric Times, and they eagerly accepted it. It was published on-line on December 6, 2014, but a week later, it disappeared. When Richard inquired why, it seemed that one of the psychiatrists had objected and apparently threatened litigation. After that, Psychiatric Times was going to publish it, then they weren’t, then they were, now it’s in maybe·limbo. I’ve lost track of how many times they’ve waffled back and forth.

The Recurrence of an Illusion:
The Concept of “Evil” in Forensic Psychiatry

by James L. Knoll, IV, MD

The Journal of the American Academy of Psychiatry and the Law. 2008 36:105–16.

[full text on-line]

The author notes an increased interest in the concept of “evil” in the fields of psychiatry and psychology. In particular, there is some interest in defining and testifying about evil. It is argued that evil can never be scientifically defined because it is an illusory moral concept, it does not exist in nature, and its origins and connotations are inextricably linked to religion and mythology. Any attempt to study violent or deviant behavior under the rubric of this term will be fraught with bias and moralistic judgments. Embracing the term “evil” into the lexicon and practice of psychiatry will contribute to the stigmatization of mental illness, diminish the credibility of forensic psychiatry, and corrupt forensic treatment efforts.

An ancient reaction to fear, distress, and calamity has been to rely on religion. “When cause and cure are unknown, magic and religion supply welcome hope”. In biblical times, mental illness was seen as the opposite of what was “good.” During the Middle Ages, most progress in medical science was severely squelched. The Christian church, consumed with superstition and demonic possession, rode herd on the diagnosis and treatment of mental illness. During the Renaissance, an obsession with evil in the form of witches became prominent. The official practice guidelines on detecting witches, the Malleus Maleficarum [1486], assisted inquisitors in finding evil lurking amid women, the socially disenfranchised, and the mentally ill.

The witch-hunting of the 15th and 16th centuries serves as a fascinating and sobering example of an official recognition of a hitherto unknown form of deviance.14 Once the crime of witchcraft was officially recognized, serious problems developed in providing “proof ” and legal restraints to the hysteria. The powerful legal and religious emphasis on the reality of witchcraft helped to reinforce the legitimacy of the trials, in addition to the public’s belief that there was evil afoot. It has been theorized that the English government’s systematic efforts for dealing with witchcraft served as a form of repressive deviance management. In addition, one of the benefits to church and state of the witch-hunting hysteria was that it effectively shifted public attention away from growing demands for more equitable redistribution of wealth.

In retrospect, evil (in the form of witches) was nothing more than what the English legal system claimed that it was. Those who were found to be witches were often ill equipped and powerless to fend off this creative label of deviance. Once the definition of witchcraft was officially accepted, very little could be done to prevent or limit the system’s abuse of the term. As a result, large populations of “deviant” witches were discovered, particularly among vulnerable lower-class groups, which, in turn, fostered the growth of an “industry” revolving around the detection, prosecution, and punishment of witches. The industry included the proliferation of “rackets,” and entrepreneurs seeking to profit from its operation…

The Justice and Therapeutic Promise of Science-Based Research on Criminal Evil

by Michael Welner, MD

The Journal of the American Academy of Psychiatry and the Law. 2009 37:442–9.

[full text on-line]

Forensic science research intended to standardize the distinction of the worst criminal behavior, specifically the Depravity Scale, has been the topic of academic and public discussion in the Journal and elsewhere. Some early impressions have been published without substantive attention to the goals of this research and the application of the results. In a recent article in the Journal, for example, James Knoll argued, “Evil can never be scientifically defined because it is an illusory moral concept,” adding, “it does not exist in nature”.

It is my contention that evil does exist in nature. In fact, evil exists in the very law with which advanced societies judge the actions of man. In the United States, different state and federal sentencing guidelines distinguish among heinous, atrocious, cruel, vile, horribly inhuman, and, yes, evil criminal behavior. Such designations elevate culpability in a variety of offenses, ranging from murder to burglary,  and affect parole eligibility in states as diverse as California and Louisiana…

To be clear, I am not here condemning philosophical investigation into the problem of evil. Rather, it is the search for it through a scientific lens that I caution against. As regards the philosophical route for studying evil, we might keep in mind that “the honest course is always to begin at home”. Surely, this is the more difficult, yet profitable course. Tracking down the roots of evil is a process that requires delving inward in an attempt to discern what we don’t know about ourselves, yet do to the other. In closing with this point, perhaps it is fitting to quote a piece of poetry popular in our age:

I shouted out,
“Who killed the Kennedy’s?”
When after all,
It was you and me.

NIMH to Implement New Strategy for Evaluating Psychiatric Research Proposals

PsychiatricNews Alert

March 5, 2014

Changing NIMH Clinical Trials:
Efficiency, Transparency, and Reporting

National Institute of Mental Health

by Nitin Gogtay, M.D., and Tom Insel, M.D.

February 27, 2014

A New Approach to Clinical Trials

Director’s Blog: NIMH

by Tom Insel M.D.

February 27, 2014

NIMH has been in the spotlight lately for proposing the Research Domain Criteria or RDoC, a new framework for classifying mental disorders. One of the aims of RDoC is to help refocus clinical research, aligning it with what we are learning from biological, cognitive, and social science. This week, we are taking the first step in an initiative that, like RDoC, aims to realign research—but this time, the target is treatment development, an area in which progress has been frustratingly slow. In a series of funding announcements released this week, NIMH is making three important changes to how we will fund clinical trials.

First, future trials will follow an experimental medicine approach in which interventions serve not only as potential treatments, but as probes to generate information about the mechanisms underlying a disorder. Trial proposals will need to identify a target or mediator; a positive result will require not only that an intervention ameliorated a symptom, but that it had a demonstrable effect on a target, such as a neural pathway implicated in the disorder or a key cognitive operation. While experimental medicine has become an accepted approach for drug development, we believe it is equally important for the development of psychosocial treatments. It offers us a way to understand the mechanisms by which these treatments are leading to clinical change. Moreover, a subset of the funding announcements will support clinical trials that evaluate the effectiveness or increase the clinical impact of pharmacological, somatic, psychosocial, rehabilitative, and combination interventions.

Second, future trials will need to meet new standards for efficiency, transparency, and reporting. In an accompanying article, Changing NIMH Clinical Trials: Efficiency, Transparency, and Reporting, Nitin Gogtay, NIMH Associate Director for Clinical Research, and I review the clinical trials portfolio at NIMH for each of these measures. Recent performance in our clinical trials program is not acceptable: recruitment is too slow, registration in public databases is not consistent, and reporting takes too long to meet the needs of the public for better treatments. To respond to the public concern that “time matters,” we will be establishing new requirements for timelines, trial registration, publication, and data sharing.

Third, to ensure that these new requirements become the norm and not the exception, we will not support new clinical trials under past funding announcements. We will complete the current clinical trials in our portfolio, but new trials will be reviewed according to these new criteria, which include target engagement and new performance metrics…

Why these changes to our clinical trials enterprise? Treatment development has stalled. The pharmaceutical industry pipeline for medications is depleted, after several decades of “me too” drugs. For anxiety, mood disorders, and psychosis, there are few viable new targets because of an inadequate understanding of the biology of the disorders. For autism, anorexia nervosa, post-traumatic stress disorder, and the cognitive deficits of schizophrenia, we lack effective medications. Psychosocial interventions have seen more innovation in the past decade with successful new treatments for anorexia nervosa and borderline personality disorder, as well as broader application of cognitive behavior therapy. But these treatments may not be disseminated or reimbursed in the new healthcare environment without evidence for the required dose and duration of treatment, necessary information for developing measures of fidelity to a validated treatment model. Neuromodulatory treatments, such as brain stimulation, have seen the most innovation but will need considerably more rigor in terms of establishing mechanisms of action and required dose.

In the past, NIMH has supported early phase treatment development, with industry mounting the large-scale trials required for FDA approval. This approach was successful for generating new compounds but not for developing more effective treatments. Over the past decade, NIMH has supported large-scale, expensive effectiveness trials, such as CATIE and STAR*D. These trials were useful for identifying the limits of current treatments, but not helpful for improving outcomes. In the current climate, with funding tight and clinical needs urgent, we will be shifting to trials that focus on targets as a way of defining the next generation of treatments. The goal is better outcomes, measured as improved real-world functioning as well as reduced symptoms.We believe that better outcomes will require a deeper understanding of the disorders. These new clinical trials are designed to provide that…

Tom Insel stepped from his training into the intramural program at the NIMH where he spent a decade and a half doing research on SSRIs and the effect of hormones on behavior. In the early 90s, he moved to direct the Yerkes Primate lab and later a Translational Research program, both in the Department chaired by Dr. Charlie Nemeroff. It was the decade of the brain, and Emory/Atlanta was an epicenter for matters brain and drug. That orientation followed him to the NIMH where his directive style and bent towards Clinical Neuroscience has created a cohort of NIMH Grantees that have dutifully followed his direction.

Now, Tom Insel and former NIMH director, Steven Hyman, seem to be looking to lead us out of this current crisis [one that they each had some part in shaping]. Hyman still hopes to lure PHARMA back into the game [hope and hype…]. Insel at least appears to have a dawning awareness that we might need to change something about our directions. But I’m not sure that either understands the state of play well enough to be doing any leading at this point, because they both see the problem as a function of the Exodus of PHARMA.

We often use cracks as a metaphor: unwanted things [like weeds] shooting up through the cracks or things disappearing by falling through the cracks. The last post [kudus to AL·AK·AR·ID·IN·NC·OK·RI·UT·WI…], is an industry attempt to insure a crack in the new Sunshine Law – drug reps handing out reprints from peer reviewed journals to doctors without declaring industry’s part in the process. This is a huge crack that has allowed them to give out selected reprints [often from industry-sponsored clinical trials] as a way of advertising their wares in the guise of legitimate science. It has been a very effective marketing tool, and they’re afraid that making it public will make it less effective [let’s hope].

But cracks go both ways, letting things in and out. And one thing about things falling through the cracks, you don’t necessarily see it happen. You don’t know that something was there and then disappeared, it’s an empty space that doesn’t show. With snowfall on a deck, you can see the absences – the cracks. With pharmaceutical clinical trials, unless you know how to look, unpublished trials aren’t apparent.

SmithKlineBeecham/GlaxoSmithKline gave us a classical example with the infamous Paxil® Study 329. They actually did three Clinical Trials [701, 377, 329] on Paxil® in adolesence, all completed before study 329 was published in 2001. That was the reprint handed out by the reps, promoting "off-label" use. The other two studies [701 & 377] were published after Paxil went off-patent 5 years later [as a CYA move]. Those studies were so negative that no amount of jury-rigging could save them. So, through the cracks they tumbled.

Clinical studies still not being published

Pharmafile

04/03/14

Half of all trials registered on a US clinical study database are not being published in public journals.

This is according to a new report from Thomson Reuters Cortellis Clinical Trials, which found that of 600 studies chosen randomly from Clinicaltrials.gov – only 50% had their results published in a journal. ClinicalTrials.gov is the main registry and results database of publicly and privately supported clinical studies of human drug trials conducted around the world.  The report called ‘Developments in Clinical Trials’, notes that lack or ambiguity in reporting clinical outcome achievement “could potentially be detrimental to clinical healthcare improvements”. It also found that some of the trials taking place today not only go unpublished, but also unregistered. “This might reduce a patient’s potential to find a suitable treatment, as well as lower the capability of the trial to include an appropriate and representative patient cohort,” the authors say.

This comes at a difficult time for the industry as in Europe new rules by both the European Medicines Agency and the European Parliament are set to be debated over the coming weeks. In fact on 3 April the Parliament is set to approve a new directive that will require anyone running a clinical trial to register it and publish a summary of results in a publicly accessible EU database. Currently these types of data are stored on a database that can only be accessed by the EMA. On top of this, full clinical study reports [CSRs] are also expected to be published following marketing authorisation of the product, or if the marketing authorisation is withdrawn.

This will be enforced by fines for any company or group that doesn’t adhere to the new transparency rules. But the industry has been fighting hard against this, arguing that it can self-regulate when it comes to releasing data. The UK pharma lobby group the ABPI said recently that new analysis – which it commissioned – found that more than three-quarters [76%] of all industry-sponsored clinical trials for new medicines recently approved by the Agency EMA had ‘some results disclosed’ within a year of completion or of regulatory approval. It also found that rates of disclosure have ‘continued to rise’ and almost nine out of 10 [89%] of these trials had disclosed results by 31 January 2013. But these data have been criticised by the UK transparency campaign group AllTrials, which says that independent analysis shows the rates of disclosure remain low.

The AllTrials initiative has also maintains that only half of all research studies are published, with those that have positive results appearing twice as frequently as those with negative results. These latest data from Thomson Reuters Cortellis will only serve to corroborate the stance taken by AllTrials, and fuel greater discussion over this divisive issue ahead of the European debate on the topic next month.

hat tip to pharmagossip… 

To my way of thinking, cracks in regulations have been of major import to the whole history of deceptive marketing practices of the pharmaceutical industry. David Healy’s under-read Pharmageddon catalogs the story of how regulations that were designed to be reform measures have actually been turned into marketing tools by finding the cracks and exploiting them. And who would’ve thought that a company would go to all the trouble and great expense to just put it in a file drawer and let it collect dust. The FDA regulations have a crack big enough to drive a truck through. To prove efficacy and get approved, you have to have two well-conducted positive studies – a generous concession to industry. But what happened was that if the drug had any effect at all, no matter how weak, it could be turned into approval by doing a bevy of clinical trials and submitting two positive ones and not publishing [or mentioning] all of the failures. It looks like Roche was able to exploit that crack with the blockbuster Tamiflu® to the tune of billions.

In the case of Paxil® in adolescent depression, besides the not-publishing crack, they found some other cracks by messing with the protocol and omitting some essential analyses – turning Paxil® Study 329 into something they thought they could get away with calling a positive outing. It wasn’t really close. Here are the endpoints of the Primary Efficacy Variables in all three studies:

Are these practices of slipping in and out of the cracks just something they’ve happened onto? I don’t think so. For example, in kudus to AL·AK·AR·ID·IN·NC·OK·RI·UT·WI…, it looks to me like they’re trying to actively maintain a crack in the system of the new Sunshine Act. And from where I sit, it looks to me like industry is doing everything in its power to put cracks in the inevitable Data Transparency in the future – cracks that can be exploited at some later date. For example, AbbVie’s lawyer Neal Parker was dancing as fast as he could to put some cracks in the EMA’s resolve to release trial data [a deal-breaker?…]. Industry and their organizations fought Data Transparency tooth and toenail, and when it became inevitable, they have continued to try to leave openings. The current compromise they’re offering is to allow access to Clinical Trial data via "independent" boards deciding about access based on the merit of the request.

I’m suspicious. Where’s the crack? or the potential crack? While their argument that they don’t want competitors seeing their stuff makes some sense, I don’t trust them and am suspicious of their "independent" boards. The best predictor of future behavior is past behavior, and their past behavior is pretty rotten. I got myself in trouble questioning J&J’s turning that function over to Yale. While I’m sorry I offended Dr. Krumholtz [a placemarker…, reassure us…, a patch of blue…], I still think this is no time to let down any guards. I don’t think all the cracks that Pharma has turned to their advantage are simply good fortune, I think they’ve created opportunities for marketing tricks even as reforms have been being put in place. And I’m still suspicious of what these "independent" boards will become somewhere down the road.

From the letter in the last post…

The tragedy of this letter is in who signed it:

The Sunshine Law requires acknowledging that industry is handing out articles they’ve selected that push their products and they don’t want to have to report what they are doing. Selective sunshine. So they get all of these medical societies to sign on to this letter. Why did they sign on? Why indeed!

Growth in health spending has slowed markedly in almost all OECD countries since 2008. After years of continuous growth of over 4% per annum, average health spending across the OECD grew at only 0.2% between 2009 and 2011. Total health spending fell in 11 out of the 34 OECD countries between 2009 and 2011, compared to pre-crisis levels. Not surprisingly, the countries hit hardest by the economic crisis have witnessed the biggest cuts in health expenditure growth. For example, Greece and Ireland experienced the sharpest declines, with per capita health care spending falling by 11.1% and 6.6%, respectively, between 2009 and 2011. Health spending growth also slowed significantly in Canada and the United States. Only in Israel and Japan has health spending growth accelerated since 2009…

 

As Full Disclosure Nears, Doctors’ Pay for Drug Talks Plummets

As transparency increases and blockbuster drugs lose patent protection, drug companies have dramatically scaled back payments to doctors for promotional talks. This fall, all drug and medical device companies will be required to report payments to doctors.

ProPublica

by Charles Ornstein, Eric Sagara, and Ryann Grochowski Jones

March 3, 2014

Some of the nation’s largest pharmaceutical companies have slashed payments to health professionals for promotional speeches amid heightened public scrutiny of such spending, a new ProPublica analysis shows. Eli Lilly and Co.’s payments to speakers dropped by 55 percent, from $47.9 million in 2011 to $21.6 million in 2012. Pfizer’s speaking payments fell 62 percent over the same period, from nearly $22 million to $8.3 million. And Novartis, the largest U.S. drug maker as measured by 2012 sales, spent 40 percent less on speakers that year than it did between October 2010 and September 2011, reducing payments from $24.8 million to $14.8 million.

The sharp declines coincide with increased attention from regulators, academic institutions and the public to pharmaceutical company marketing practices. A number of companies have settled federal whistleblower lawsuits in recent years that accused them of improperly marketing their drugs. In addition, the Physician Payment Sunshine Act, a part of the 2010 health reform law, will soon require all pharmaceutical and medical device companies to publicly report payments to physicians. The first disclosures required under the act are expected in September and will cover the period of August to December 2013.

Within the industry, some companies are reevaluating the role of physician speakers in their marketing repertoire. GlaxoSmithKline announced in December that it would stop paying doctors to speak on behalf of its drugs. Its speaking tab plummeted from $24 million in 2011 to $9.3 million in 2012. Not all companies have cut speaker payments: Johnson and Johnson increased such spending by 17 percent from 2011 to 2012; AstraZeneca’s payments stayed about flat in 2012 after a steep decline the previous year…

I have a bit of a hobby over the last several years. When the APA Annual Meeting program comes out, I scan it for names from the old guard – people on Senator Grassley’s unreported income list, various other KOLs, etc. Some are still there. Alan Schatzberg is reporting on iSPOT and doing a Recent Advances in Antidepressants gig. Biederman’s got something about Bipolar Children and ADHD. Nemeroff, Keller, Rush, Wagner, DeBello, are not there so far. But then I scanned for Dr. Kupfer, a new addition to my watch list. No, he’s not talking about the DSM-5, but look what is on the roster in the preliminary program:

• Development of a computerized adaptive test for depression
  by Gibbons, Weiss, Pilkonis, Frank, Moore, Kim, and Kupfer.
  Archives of General Psychiatry. 2012 69[11]:1104-12.
• The Computerized Adaptive Diagnostic Test for Major Depressive Disorder [CAD-MDD]: A Screening Tool for Depression
  by Gibbons, Hooker, Finkelman, Weiss, Pilkonis, Frank, Moore, and Kupfer.
  Journal of Clinical Psychiatry. 2013 74[7]:669–674.
• Development of the CAT-ANX: A Computerized Adaptive Test for Anxiety
  by Gibbons, Weiss, Pilkonis, Frank, Moore, Kim, and Kupfer.
  American Journal of Psychiatry. published on-line Aug 9, 2013

• Failure to Report Financial Disclosure Information

  by Gibbons, Weiss, Pilkonis, Frank, and Kupfer.

  JAMA Psychiatry. 2013 71[1]:95.