the sequel I…

Posted on Sunday 12 October 2014

The order of things:
  1. the prequel…
  2. unanswered questions…
  3. the sequels
Whether you think the introduction of the DSM-III in 1980 was a necessary specialty-saving intervention, a hostile take-over, a revolution, a bloodless coup d’état, right or wrong, isn’t what this post is about. It’s about the long term ramifications of a professional organization itself orchestrating a major change in the direction of a profession. Here’s what the architect of that change had to say about how that came to be:
    "How could a professional organization engineer a scientific revolution that changed its core? According to conventional wisdom, organizations respond; they do not initiate. By the 1970s psychiatry in the United States had begun to undergo massive changes. The postwar glow had been replaced by the new pressures for accountability on all of medicine. Many leaders in psychiatry deplored the ideological rifts that had divided the field, and they called for a more unified, scientifically based profession. They deplored the "demedicalization" of psychiatry and its severe loss of credibility. I was one of the young leaders who had criticized the ideological divisions within psychiatry and had been searching for ways to improve the scientific status throughout my career. The field’s ideological schisms had weakened us seriously, and psychiatrist’s bitter public disagreements were self-destructive. To cover up these differences or to act solely because of the criticism was not in and of itself sufficient; psychiatry had to adopt a genuine commitment to science rather than to ideology. It needed to change the profession fundamentally if it was to become a respected part of medicine. To accede to the pressure without radical modifications of the field would not have convinced others that the profession had changed. A new strategy was essential! Producing the DSM-III stated emmphatically that psychiatry in America chose an evidence-based practice rather than ideology."
    Dr. Mel Sabshin in Changing American Psychiatry: A Personal Perspective
As one who was much younger in the profession at the time, but not in-the-know, I was oblivious to all of that. So what happened over the next several years was dramatic and unexpected, at least to me [irony I…, irony II…, irony III… ]. Independent of the reasons, the correctness, or the content of what happened in those days, the changes resulted in a consolidation of power within the APA [American Psychiatric Association] that persists to the present – a "top down" power structure as described by Dr. Sabshin.

The turn of the century saw a very different psychiatry from the days that produced the DSM-III. Most practicing psychiatrists were doing medication management using a host of new drugs that had poured from the pharmaceutical industry pipeline. The journals were filled with clinical drug trials and biological research articles. What started in the DSM-III as an open question…
    For most of the DSM-III disorders, however, the etiology is unknown. A variety of theories have been advanced, buttressed by evidence – not always convincing – to explain how these disorders came about. 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.
    DSM-III Introduction – page 7.
… wasn’t so open any more, at least in mainstream psychiatry, and the research thrusts were to solidify the dominant view of biological causality and treatment. An example of the continued centralization of power within the APA was the commissioning of a Task Force at the turn of the century to produce a DSM-5 that was directly keyed to the hypothesized biological substrate of the various disorders.

As mentioned in the prequel…, the 2014 landscape in psychiatry is very different from the year 1980 or even the year 2000. Exposures of scientific and commercial misconduct swept through academic psychiatry and the pharmaceutical industry; the psychopharmacology pipeline ran dry; PHARMA took "a runner" from CNS drug development altogether taking its liberal support of academic institutions and the APA with it; the DSM-5 Revision floundered in something of a public spectacle; and there was a growing backlash against the monocular biomedical directions in psychiatry in general and the efficacy and safety of the widely used medications in specific. Most psychotherapy had been handed off to other disciplines in the 1980s. These days, most medication is being prescribed by Primary Care Physicians. Most Psychiatric hospitals are closed. Many chronically mentally ill patients are in jail, prisons, or shelters. And the ACA [Affordable Care Act] looks to turn the third party system further upside down. After a frantic year or so trying to woo PHARMA back without success, the place and fate of psychiatry are again in question – endangered species? obsolete? severe shortages? train more? train less? train none? are the kind of phrases being thrown around [or hurled].

Most practicing psychiatrists have grown up in the post-1980 era – by which I mean that within the body of the APA, there’s little apparent turmoil or faction. If there’s much of a call for change or reform coming from inside the ranks, I don’t know about it. Incidentally, there are many psychiatrists who are off the grid for a multiplicity of reasons, suggesting that there’s not much room for discord, controversy, or dialog within the APA. And so to the subject: the APA’s continued assumption that it is tasked with defining, rather than representing, the body psychiatric – persistent since the the days of Sabshin and Spitzer.

In unanswered questions…, I was mentioning several articles in the PsyciatricNews where Presidents of the APA are talking about the future of psychiatry being in Integrative Care, Collaborative Care, and Population Health. I added another in which the APA is offering a course on Recovery [with a capital R] meaning Recovery as it is formulated by SAMHSA [Substance Abuse Mental Health Services Agency] or as you might read about it on many websites opposed to the current medication-heavy brief-contact psychiatric practices. That is a huge topic that I’m not going to talk about substantively in this post, not because I don’t have something to say or don’t want to say it, but for the opposite reason. It’s too big for a simple blog post [and there are too many distracting rants along the way]. Right now I want to talk about just one simple thing. There is a growing trend in what’s coming from the upper levels of the APA that the redirection of psychiatry and the redefinition of psychiatrists is what the organization is setting out to do – what it’s supposed to be doing.

That’s a bad habit that needs a great deal of reflection, because that’s what the APA did in 1980 – created a psychiatry that fit the prevailing vision of what physicians should do in the face of Managed Care’s insistence – see sick people, make a diagnosis, give them the treatment for their sickness, then send them on their way. So the APA created a dictionary to catalog those diseases in concrete terms, and industry went about coming up with a compendium of treatments keyed to the catalog. There are some mental diseases that can be classified in that way, and some treatments that can be used in that way. But being the only model in town, it inappropriately generalized to be the model for all comers. Then the medication makers jumped on board, engaged with psychiatry, and made an ill-gained fortune. We now live in a world where the system that the APA actively created, encouraged, and maintained is currently a very big problem – and psychiatrists are villified for going along with it.

Dr. Sabshin’s retrospective above makes it clear he knew that leveraging the DSM-III Revision to change to direction of psychiatric practice was highly unusual…
    "According to conventional wisdom, organizations respond; they do not initiate."
My point is that the resulting consolidation of power persisted to the present along with the role of the APA in a defining psychiatry. And as to the goal of reducing discord …
    "The field’s ideological schisms had weakened us seriously, and psychiatrist’s bitter public disagreements were self-destructive."
… it was achieved in spades. Many psychiatrists converted and others just left – having no place at the table. Third Party payment schedules moved psychiatrists into the medication management slot while psychotherapies and counseling went to panels of other mental health specialties, tightly controlled by Managed Care. There has been little controversy or debate among the membership of the APA since those days. Even in these later years of scandal over conflicts of interest, ghost writing, jury-rigged clinical trial publications, false advertising, speaker’s bureaus, distorted reporting of efficacy and adverse events, etc., the outcry and movements for reform have come from outside the APA, mostly outside psychiatry. And as the chronic mental patients filled up our prisons in the years after de-Institutionalization, the APA has had little to say. We could’ve used a lot more discord along the way.

The APA’s assumption of power may well have been justified in the 1970s, but holding onto it wasn’t. The APA was heavily supported by the Pharmaceutical Industry, and supportive in kind. When the ethical misbehavior, the conflicted commercial connectedness, and the invasions of our literature became crystal clear to the whole world, the APA was silent or defensive. Ironically, the revolution launched with the cry against ideology…
    "Producing the DSM-III stated emphatically that psychiatry in America chose an evidence-based practice rather than ideology."
… has created a professional organization that is a bastion for a particular notion of overall causality and treatment that has all the earmarks of a fixed ideology, and in spite of a massive research effort, an ideology that operates with little in the way of a strong confirming evidence base except in limited areas.

And now the APA is making noises about another major redefinition as we move into the future, and appears to be pitching it to its membership. While there’s much to be said about what’s being pitched [next post], there’s a question that comes before that. Should the APA even be on the pitching mound at this point. The suggested changes aren’t coming from the floor of the membership. They’re not coming from some subgroup of psychiatrists intensely studying a problem, nor a subgroup of practitioners who have long-occupied the suggested roles, nor the halls of physical medicine, nor being introduced as a topic for general debate within psychiatry itself. My premise is obvious, that the centrality of the APA upper echelon in defining psychiatry has been maintained and used to keep psychiatry on a path controlled by industrial and ideological forces – a legacy from Sabshin, Spitzer, and 1980s DSM-III – whether that was their intent or not and it’s being exerted once again.

Now, the APA is pushing a major change in the directions of the profession in the face of the exhaustion of the current paradigm that will have not only an effect on practice and third party reimbursement, it does nothing to deal with the plight of the chronic patients now incarcerated; it does nothing to curb overuse of psychiatric medications particularly by primary care; it moves clinical psychiatry to a non-patient-contact role; it’s based on a theoretical role originating from outside the specialty; and it looks as if it will perpetuate the very things in need of change. These are goals that have been pushed by Managed Care and PHARMA, hardly by psychiatrists or even its opponents – more like retiring the side than reform. And it’s coming from the APA – the only negotiating force in town. Is this to be the legacy from the 1980 revolution? Is the APA representing psychiatry, our patients, or simply itself and some inappropriate assumptions of power and misguided decisions all along the way? Will practicing psychiatrists continue to leave their fate in the hands of an organization that unilaterally lead us down this path?

Undoubtedly, changes need to be made once again. But these changes? as being presented? dictated by the APA? It sounds like the decision of a group that has painted itself into a corner and further abandoned the practice of clinical psychiatry, taking charge at a time it needs to be taking stock, and operating on an anachronistic centralization of power whose utility has long passed…
Mickey @ 9:00 AM
Filed under: OPINION
anything but over…

Posted on Thursday 9 October 2014

Tom Jefferson is a researcher/reviewer with the Cochrane Collaboration. He was involved throughout in the Tamiflu story and the Cochrane meta-analysis of the Tamiflu Trials. He’s as good a resource as we might find for understanding what the EMA’s recent policy decision really says:
British Medical Journal blog
by Tom Jefferson
7 Oct, 14

The European Medicines Agency [EMA] has now released the final version of its policy on the prospective release of clinical reports of trials, which are submitted by sponsors to support marketing authorisation applications [MAAs]. The agency has said that it will—at a future date—determine how to release individual participant data [IPD].

Scope
The policy—to become effective from 1 January 2015—explains what will be released and how. Full clinical study reports will not be released. Rather, selected parts of clinical study reports will be released, including the “core report” [although this is not labelled as such in the text], the statistical analysis plan, protocol and its amendments, and a blank case report form. [To those familiar with clinical study reports, these are sections 1-15, 16.1.1, 16.1.2, and 16.1.9 of the ICH E3 guidelines.] The policy document does not explain why full clinical study reports will not be released.
This «core report» for the CSR [Clinical Study Report] is what I was worried about [beyond the blind…]. And it for sure won’t have the IPD [Individual Participant Data]. Having the «statistical analysis plan, protocol and its amendments» is a good thing. But does it pass the Rolling Stones test?
    You can’t always get what you want
    But if you try sometimes
    Well you just might find
    You get what you need
Ask me in February 2015…
Redactions
The EMA’s policy states: “The Agency respects and will not divulge CCI [commercially confidential information]. In general, however, clinical data cannot be considered CCI.”  That said, commercially confidential information will be redacted, “where disclosure may undermine the legitimate economic interest of the applicant/market authorization holder” and in items that may facilitate identification of trial participants. Sponsors will have primary responsibility for redacting study reports for EMA’s approval prior to their being made accessible under the new policy.
This is the part that got to AllTrials:
    The policy puts primary responsibility for redacting information into the hands of trial sponsors. This means that they get to suggest which information submitted to the EMA should be kept hidden. The EMA has a policy that the information in clinical trial reports should not generally be considered commercially confidential [this is echoed in the EU Clinical Trials Regulation] but it may never become clear which information is being kept hidden.
As it should…

The policy is a landmark, as for the first time it ensures access to clinical study reports of drugs that have obtained a MAA or on which a decision has been made. The EMA may be the first regulator to allow such access and the Nordic Cochrane Centre, the European Ombudsman, and the EMA deserve credit for that.

There’s a lot of good news for researchers in the final version of the policy. Gone is the “Peeping Tom” clause of “viewing only” access to data—described by users of comparable policies as “science through a periscope”—and there is no trace of a threat of legal proceedings for those who produce research that is disagreeable to sponsors.

In a previous post I urged users to adopt Reagan’s maxim of “trust but verify” when reading the EMA’s policies. Ultimately, we will not know how usable and transparent this policy is until it has been in use for some time.
I was prepared to say at this point that Tom’s report adds some disappointments, but that I stick to my guns that it’s a leap forward [beyond the blind…]. But when I went to the AllTrials site to clip their comment, I found this [see also a coup d’état…, the other shoe]:
    Yesterday, the likely European Commissioner for industry who will oversee the regulation of medicines and the EMA said there are risks that need to be balanced with greater clinical trial transparency. MEPs have been questioning the candidates for the new European Commission and, if approved by MEPs, Elzbieta Bienkowska will lead the industry department [DG ENTR].

    The new president of the European Commission, Jean-Claude Juncker, recently moved the responsibility for the regulation of medicines from the health to the industry department. When asked whether this move would allow industry lobbying to affect drug regulations, Ms Bienkowska said, “All my professional experience shows that I am lobbyist-proof. I’m absolutely lobbyist-proof”. Glenis Willmott MEP said, “It is disappointing Ms Bienkowska didn’t answer directly whether or not she thinks pharmaceutical and medical devices should really be in the health commissioner’s portfolio.”

    Ms Willmott also asked Ms Bienkowska if she will ensure the EMA’s commitment to greater clinical transparency will continue. Ms Bienkowska replied that clinical trial transparency is important for Europe; “however, you have to look at the other side and ensure there are adequate levels of safety when it comes to the potential misuse of data.” We’ve heard this claim before and we responded on our “Myths & Objections” page. MEPs will vote to appoint the candidates to the European Commission on 22nd October.

This battle is anything but over.  In the other shoe I ended with a picture of Niccolò di Bernardo dei Machiavelli, the author of The Prince – the Renaissance treatise on how to gain and wield power at any cost. I think of him once again this evening. There is no stopping place for the cause of Data Transparency. PHARMA is always in the background. They have unlimited resources and teams of people being well-paid to spend their days working whatever angles are necessary to win the day and allow PHARMA to hold onto control of the data from clinical trials. It’s not paranoia that leads me to this cynical conclusion, it’s self-evident experience. The only thing to say is that their offering this much consistent resistance says that we’re fighting the right battle. And by the way, endless thanks to MEP Glenis Willmott [see on the right track…]. She’s a true champion for the cause [and it is a cause]…
Mickey @ 12:15 AM
Filed under: OPINION
the prequel…

Posted on Wednesday 8 October 2014

I wrote this before the last post. Even as I wrote it, I knew I was writing it to myself, mainly to get things straight in my own thinking. But I changed my mind about posting it for two reasons. First, many of you aren’t psychiatrists and may not know the chronology so intimately – and I think it might help. History always seems to help me. Second, there’s something I want to say that has to do with George Dawson’s comment to the last post that won’t make sense without this. I apologize for the redundancies, where I lifted phrases to write the last post.


I was only casually aware of matters psychiatric during the 1960s. For me, it was the era of medical school, Internal Medicine training, and bench research. But from what I recall, the psychiatric residents got a generous government bonus for choosing the specialty. There was a shortage, it seems. In retrospect, that was because of de·Institionalization, and psychiatrists were needed to staff the Mental Health Centers that were to take their places as patients were moved from the hospitals into the community. By the latter half of the 1970s when I was in psychiatric training and early on the faculty, public mental health services were in crisis as the community services and hospital resources disappeared, even as the patient load from de·Institionalization grew [it was before they started filling up the jails and prisons]. Within psychiatry, there was a backlash against the prominence of psychoanalysts. Outside of psychiatry, the criticisms of psychiatry had a broad base: the heavy use of medications in treating psychosis; both the psychoanalytic and medical models; charging third party payers for psychotherapies; the question of whether mental illness was disease; the power of psychiatrists in involuntary commitment and medication. It was a tumultuous time. In the background, the revision of the diagnostic manual was marching towards release in 1980, a force that would make massive changes in the specialty and its practice. One part of that oft-told story is that those changes in psychiatry were orchestrated by the American Psychiatric Association [APA] under the guidance of its Board of Trustees, its Medical Director Dr. Melvin Sabshin, the chair of the DSM-III Task Force, Dr. Robert Spitzer, and the strong influence of the neoKraepelinians centered at Washington University in Saint Louis. Dr. Sabshin further consolidated the power of the APA by founding the American Psychiatric Publishing, Inc. [APPI].

The course of psychiatry in the US has been steered by the American Psychiatric Association since those 1980 changes. I don’t know if that central control was present before then, but it has certainly been true during my time. Many of us have withdrawn our membership for a variety of reasons in that time period. The medical·ization and medicine·ization of the specialty built through the ensuing quarter century, an era when much of academic and organized psychiatry was actively engaged with the pharmaceutical industry and the neuroscientific focus of the NIMH. It was a period of dramatic change with third party payers paying psychiatrists for outpatient medication management, and contracting with other specialties for psychosocial treatments. Another change – our prisons filled with chronic mental patients creeping toward the numbers of the confined prior to de·Institionalization.

The first decade of the new century began at the apogee of the now aging new psychiatry. The APA embarked on a DSM Revision that would realize a dream of connecting clinical diagnosis with measurable biology. Dr. Tom Insel of the NIMH advocated reframing psychiatry as Clinical Neuroscience. And the pharmaceutical industry was maintaining a steady pipeline of new medications coming onto the market [along with a publishing arm of its own]. But by the end of the decade, things were once again changing dramatically, as we all know. The involvement of academic psychiatrists with industry came to public attention with the revelations of Senator Grassley about unreported income, but the focus soon generalized to the whole issue of a corrupted alliances between a prominent sector of psychiatry and drug manufacturers – and we began to learn about ghost writing, and guest authorship, and industry financing out-front and in the background. Suits against pharmaceutical companies flourished exposing false advertising, exaggerated efficacy, minimizing of adverse reactions, and the involvement of the "KOLs" with industrial interests which became a source of public shame for us all. Meanwhile, the enthusiasm for a "biologic" DSM-5 choked in a desert of non-confirmation. Then the pipeline dried up, and PHARMA began to exit CNS drug development en masse. Quite an impressive decade of changes in fortune.

Here at the near midpoint of the second decade of the century, it would be hard to summarize the current state of play. We’ve seen several years of intense efforts to reform the clinical trials of drugs through Data Transparency, though at least in psychiatry, at present there’s not a lot of actual action in that arena with a dry pipeline – so, the "closing the stable door after the horse has bolted" adage seems to apply. The DSM-5 effort mercifully limped to its lackluster conclusion, but not before being abandoned by the NIMH, now creating a diagnostic system of its own – the Research Domain Criteria project [RDoC]. If anything, the DSM-5 Task Force process exposed the APA to further scorn – particularly with it’s chairman being exposed as involved in an entrepreneurial enterprise. And to complexify matters further, there’s another huge general issue on the table at the moment, the changing landscape of practice, finance, and health policy coming with the Affordable Care Act [ACA] among other things.

Where is the American Psychiatric Association in all of this? The DSM-5 is certainly not the catalyst for a paradigm shift like its predecessor, the DSM-III. It’s a code book at best, one still haunted by the process of its creation. While there’s continued wide usage of the medications from the earlier decade, the accompanying enthusiasm for psychopharmacology has undergone considerable dampening in recent years. The mainstay triad of promising future biological discovery [proteinomics, neuroimaging, and genomics] has lost some of its star-power. Likewise, the publicity around the ubiquitous conflict of interest issues have taken a heavy toll on the reputation of psychiatry in general, as they should. As I mentioned above, the APA has been the prime driving force for the direction of American psychiatry since at least 1980. While still in the leadership position, the APA is now operating in a dramatically different environment with the only clarity being that change is inevitable, though the shape and direction of that change is unclear…
Mickey @ 4:35 PM
Filed under: OPINION
unanswered questions…

Posted on Wednesday 8 October 2014

In my home town, there was a 19th century bridge across the Tennessee River. It was designed with bolts that were intended to be tightened and loosened with the seasons, but that never happened. Over a 90 year period, the subtle stresses and strains of seasonal expansion and contraction rendered it unsafe for auto traffic – unfixable. It’s now a tourist attraction as a pedestrian bridge.

The APA’s DSM-III revision in 1980 ultimately lead mainstream psychiatry to an exclusively biological focus and a deep entanglement with the pharmaceutical industry. My primary "dog in this hunt" has been the resulting corruption of the industry sponsored clinical drug trials in our peer reviewed psychiatric literature, and the collusion of the academic KOLs who signed on as authors. But the ‘subtle stresses and strains‘ from the ensuing three plus decades of inattention to the traditional domains of psychiatry have taken their toll in many arenas, and left the specialty ill prepared for the challenge of a dramatic change in the healthcare landscape and a growing disillusionment with the medication-heavy approach to matters mental.

Beginning in 2007 when Senator Grassley exposed a number of academic psychiatrists who were failing to report personal drug-company income, there followed a steady stream of revelations of scientific misbehavior and corrupt practices eroding confidence in psychiatry in general. Then, the exit of PHARMA from CNS drug development three years ago took things from bad to worse. The DSM-5 Revision had begun life a decade earlier dreaming of a triumphant transition to a biologically based diagnostic system, but floundered in a desert of non-confirmation – limping to its release barely even revised. Periods of paradigm exhaustion in science are rarely smooth, but this one has been abetted by disillusioning revelations and a reactionary and paralyzed establishment unwilling to deal directly with much of anything.

Comes now Paul Summergrad as an APA President and Saul Levin as Medical Director. I know very little about either one of them. Unlike Jeffrey Leiberman, the immediate past president, Dr. Summergrad isn’t part of the identified KOL establishment that has been such a problem and he doesn’t seem to be writing things like Leiberman’s «Time to Re-Engage With Pharma?» or «DSM-5: Caught between Mental Illness Stigma and Anti-Psychiatry Prejudice». Looking over the From the President blogs for the last several presidents, they seem to see the future of psychiatry in something called Integrative Care or Collaborative Care. Just looking at today’s PsychiatricNews, there are new things these days: a course for psychiatrists on Recovery Oriented Care [as in the Recovery Movement - see the other guy…]…
PsychiatricNews
by Vabren Watts
September 15, 2014
an innovative and heavily jargoned piece on Population Health…
PsychiatricNews
by Mark Moran
September 23, 2014
And a big president’s blog on Integrative/Collaborative Care highlighting the APA’s 2014 Institute on Psychiatric Services at the end of the month entitled, Integrating Science and Care in a New Era of Population Health.
PsychiatricNews
From the President
by Hunter McQuistion and Paul Summergrad
September 26, 2014
and it was there last year…
PsychiatricNews
From the President
by Jurgen Unützer and Jeffrey Lieberman
November 12, 2013
At least they’ve stopped talking exclusively about medications, the coming magical advances around the corner, and using that tiredest of lines about the global burden of depression.

All healthcare specialties are currently trying to figure out how to fit into the new world of the Affordable Care Act – adapting their traditional identities to a new set of rules and a new theater of operations. Psychiatry doesn’t have that luxury – more starting from scratch, trying to create a new brand – a consultative identity that is as yet amorphous and very different from medication manager of recent years or the general psychiatrist of the past. It’s hard to see through the upbeat rhetoric what they envision psychiatrists actually spending their time doing, or if the primary care physicians they plan for psychiatrists to collaborate with are interested, or if psychiatrists are interested in filling that particular role. And it’s unknown how [or if] they intend to address the widespread misadventures of their predecessors – those longstanding ignored stresses and strains.

In 1980, the American Psychiatric Association was able to effect a dramatic, specialty wide change in practice aided by the pharmaceutical industry and the third party payers who, for different reasons, supported the change. Can the APA bring it off again? …going it alone? Will practitioners follow their lead? Should they follow this lead? All unanswered questions with no guarantees…
Mickey @ 8:00 AM
Filed under: OPINION
two weeks!…

Posted on Sunday 5 October 2014

    A response to:

by
  1. Javier Arnedo, M.S.
  2. Dragan M. Svrakic, M.D., Ph.D.
  3. Coral del Val, Ph.D.
  4. Rocío Romero-Zaliz, Ph.D.
  5. Helena Hernández-Cuervo, M.D.
  6. Molecular Genetics of Schizophrenia Consortium
  7. Ayman H. Fanous, M.D.
  8. Michele T. Pato, M.D.
  9. Carlos N. Pato, M.D., Ph.D.
  10. Gabriel A. de Erausquin, M.D., Ph.D.
  11. C. Robert Cloninger, M.D., Ph.D.
  12. Igor Zwir, Ph.D.
American Journal of Psychiatry. Published in advance on September 15, 2014.
  1. Gerome Breen, PhD [Institute of Psychiatry, King’s College London, London, UK]
  2. Brendan Bulik-Sullivan [Broad Institute, Cambridge, MA, USA]
  3. Mark Daly, PhD [Broad Institute, Cambridge, MA, USA]
  4. Sarah Medland, PhD [QIMR Berghofer, Brisbane, Australia]
  5. Benjamin Neale, PhD [Broad Institute, Cambridge, MA, USA]
  6. Michael O’Donovan, MD PhD [Cardiff University, Cardiff, UK]
  7. Stephan Ripke, PhD [Broad Institute, Cambridge, MA, USA]
  8. Patrick Sullivan, MD [Karolinska Institutet, Stockholm, Sweden]
  9. Peter Visscher, PhD [University of Queensland, Brisbane, Australia]
  10. Naomi Wray, PhD [University of Queensland, Brisbane, Australia]

In this study published on September 15, Arnedo et al. asserted that schizophrenia is a heterogeneous group of disorders underpinned by different genetic networks mapping to differing sets of clinical symptoms. As a result of their analyses, Arnedo et al. have made remarkable and perhaps unprecedented claims regarding their capacity to subtype schizophrenia. This paper has received considerable media attention. One claim features in many media reports, that schizophrenia can be delineated into “8 types”. If these claims are replicable and consistent, then the work reported in this paper would constitute an important advance into our knowledge of the etiology of schizophrenia.

Unfortunately, these extraordinary claims are not justified by the data and analyses presented. Their claims are based upon complex [and we believe flawed] analyses that are said to reveal links between clusters of clinical data points and patterns of data generated by looking at millions of genetic data points. Instead of the complexities favored by Arnedo et al., there are far simpler alternative explanations for the patterns they observed. We believe that the authors have not excluded important alternative explanations – if we are correct, then the major conclusions of this paper are invalidated.

Analyses such as these rely on independence in many ways: among variables used in prediction, absence of artifactual relationships between genotypes and clinical variables, and between the methods of assessing significance and replication. Below we identify five specific areas of concern that are not adequately addressed in the manuscript, each of which calls into question the conclusions of this study.
    A. Ancestry/population stratification…
    B. X chromosome [chrX]…
    C. Linkage disequilibrium [LD]…
    D. SNP selection…
    E. Replication…
Conclusions: Given the remarkable claims made by Arnedo et al., it is essential that alternative explanations be excluded. Unfortunately, the authors do not provide the necessary evidence. As presented, their methodology is opaque [even to experts], meaning that their results cannot be independently validated. Arnedo et al. do not consider alternative explanations for the phenomena that they observe, such as confounding from ancestry and LD, even though these are well-known issues for the statistical methods that they employ and have been studied extensively in the statistical and population genetics literature. In addition, their multistep analysis approach is subject to multiple issues as noted above. We believe that it is highly likely that the results of Arnedo et al. are not relevant for schizophrenia. We urge great caution in the interpretation of the results of study.
Well, that didn’t last very long – just two week. We mortals aren’t really capable of vetting these genetic studies on such large populations, working with so many genes and complicating factors. We’re just spectators in a Colosseum watching a Battle of the Titans. At least that’s where I am when it comes to this kind of research. The criticisms in A-F above that I left out of my summary are far reaching – untested confounding factors like ancestry and gender, faulty analytic and statistical methodology, replication errors. And their conclusion…
    We believe that it is highly likely that the results of Arnedo et al. are not relevant for schizophrenia.
… is almost as definite as that in the original paper, in the opposite direction:
    Schizophrenia is a group of heritable disorders caused by a moderate number of separate genotypic networks associated with several distinct clinical syndromes.
I’m not reporting this with an opinion about who is right here, or if either is right. I just wanted to make a couple of observations. First, this is how the moving edge of science feels – back and forth, confusing, various investigators and groups working on something we don’t know, almost in a competition for who is going to get there first, or if there is even a "there" to get to. In the case of these genetic studies, it’s more like an athletic contest with teams than between individuals – football as opposed to wrestling. The thing that’s a bit different here is that they are so definite. This is not a tentative hypothesis versus a light critique. It’s dogma [a truth] versus dogmatic skepticism [it isn't true]. When I wrote about the original paper [short-list?…], I was tempted to say that the authors would either end up on a podium in Stockholm [Nobel Prize] or in the annals of Retraction Watch [but decided that was a too-tacky comment]. It did seem like an attempt to knock the ball out of the park instead of simply to get a base hit. The modern "Translational Science" motif pushes for that kind of speed to discovery [as if it's possible to push a rope].

But the main thing I wanted to write about was PubMed Commonssomething whose power I hadn’t quite realized Heretofore, once an article was posted in PubMed, it may have had a few things appended over time. Retracted articles were usually annotated. If there were published letters, they might be referenced with links. But it required journal access to see the letters and they were slow in coming. So a questionable article often languished for many months before any sign of the dissent showed up, if it showed up at all. Many of the disreputable industry funded clinical trials have nothing in PubMed to let a reader know of the problems. In the case above, an international consortium was on the case within two weeks. Take a look. Then look at the infamous Paxil Study 329 with the old links above, and the new below, a comment added when PubMed Commons went live a year ago. Here’s Dr. Karen Dineen Wagner’s write-up about an equally questionable pair of Zoloft trials with many links, but no comment [just waiting for the comments it deserves]. Any author indexed in PubMed can open a Commons Account and leave a comment. Among the major contributors to the problem with clinical trials of the psychiatric drugs, first was that no one much was looking, but even if they were, there was no easy public way to post comments to flag the literature.

It’s easy to get discouraged when reforms that seem so obviously right move so slowly or come in only an incomplete form [beyond the blind…, what we claim to be…], but probably the most important thing isn’t necessarily the enduring safeguards, but rather the ongoing awareness and the mechanisms to alert people to instances that need attention. Right now, there’s a heightened awareness of the problems in our literature. But what matters is that the vigilance lasts beyond the news cycle and we don’t have to look at empty spaces like this anymore:

Mickey @ 9:00 PM
Filed under: OPINION
stands on its own…

Posted on Saturday 4 October 2014

by Pat Bracken
World Psychiatry. 2014 13[3]:241-243.

TOWARDS HERMENEUTICS
I contend that good psychiatry involves a primary focus on meanings, values and relationships, both in terms of how we help patients as well as identifying from whence their problems arise. This is not to deny that psychiatry should be a branch of medicine, or that other doctors sometimes deal with problems of meaning. However, interpretation and "making sense" of the personal struggles of our patients are to psychiatry what operating skills and techniques are to the surgeon. This is what makes psychiatry different from neurology. When we put the word "mental" in front of the word "illness", we arc demarcating a territory of human suffering that has issues of meaning at its core. This simply demands an interpretive response from us. 1 think that many psychiatrists would recoil from the idea that they should train themselves to be uninterested in the problems of their patients, as the New York Times interviewee described.

Hermeneutics is based on the idea that the meaning of any particular experience can only be grasped through an understanding of the context [including the temporal context] in which a person lives and through which that particular experience has significance. It is a dialectical process whereby we move towards an understanding of the whole picture by understanding the parts. However, we cannot fully understand the parts without understanding the whole. The German philosopher H.-G. Gadamer suggested that the idea of hermeneutics is particularly relevant to the work of the psychiatrist.

By adopting a hermeneutic approach to epistemology, we can attempt to understand the struggles of our patients in much the same way as we attempt to understand great works of art. To grasp the meaning of Picasso’s Guernica, for example, we need to understand what is happening on the canvas, how the artist manages to create a sense of tension and horror through the way he uses line, colour and form. We also need to understand where this painting fits in relation to Picasso’s artistic career, how his work relates to the history of Western art and the political realities of his day that he was responding to in the painting. The meaning of the work emerges in the dialectical interplay of all these levels and also in the response of the viewer. The actual physical painting is a necessary, but not a sufficient, factor in generating a meaningful work of art. A reductionist approach to art appreciation would involve the unlikely idea that we could reach the meaning of a painting through a chemical analysis of the various pigments involved.

CONCLUSION
I do not believe that we will ever be able to explain the meaningful world of human thought, emotion and behaviour reductively, using the "tools of clinical neuroscience". This world is simply not located inside the brain. Neuroscience offers us powerful insights, but it will never be able to ground a psychiatry that is focused on interpretation and meaning. Indeed, it is clear that there is a major hermeneutic dimension to neuroscience itself. A mature psychiatry will embrace neuroscience but it will also accept that "the neurobiological protect in psychiatry finds its limit in the simple and often repeated fact: mental disorders are problems of persons, not of brains. Mental disorders are not problems of brains in labs, but of human beings in time, space, culture, and history."
hat tip to Mad in America… 
I’m always pleased when I run across something by Dr. Pat Bracken. The last time [a long and lonely wait…], I had this to say:
    So when I read this commentary that mirrors the beginnings of a career that I actually feel like I got to have, I feel a sadness in the place of the sense of joy and hope I would like to feel reading it. Some of the sad is altruistic, thinking about damage done and opportunities lost. But I think a lot of it is personal – about having finally found an identity that fit but then no longer having a place at the table. If you read this blog, you know that my attachment to the ways and means of hard science are clearly still living and well [I never met a graph I didn't like]. And I completely agree that the pre-1980 psychiatry had to change, but if this hasn’t been an example of "throwing the baby out with the bathwater," they ought to retire the saying. I wish this group the best in their attempts "to develop a different sensibility towards mental illness itself and a different under-standing of our role as doctors." If they see that as a new discovery, so be it. But it has been a long and lonely wait for it to come back around…
Pat Bracken is a favorite. I envy his ability to say simply and clearly what I have always thought, but couldn’t come close to saying so eloquently. While I’m about to lodge a minor complaint, or maybe just flag a difference, it doesn’t detract from the wisdom of his words. And as I said in my past commentary, for me it’s not a change in paradigm, rather a welcom reminder of something abandoned by too many along the way.

For most of my career, I was comfortable with the term «mind·brain dichotomy». Actually, it wasn’t anything I gave much thought. It was just a descriptor – a way of separating two areas that I knew something about. I didn’t pay attention to the «mind·brain dichotomy» part, as in mutual exclusivity or contrast. My primary interests were in the «mind·brain dichotomy» part, but that didn’t mean I didn’t care about the «mind·brain dichotomy» part. I was certainly aware that in the halls and meetings of psychiatry and psychology, this was a true «mind·brain dichotomy» and the controversy was endless. Mainstream psychiatrists like APA presidents and NIMH Directors were careful to always say brain diseases or even clinical neuroscience, and critics raled against the bio·bio·bio medical model. I frankly thought it was all a bunch of turf fighting with the many psychiatrists asserting their "medical·ness" and way overdoing the whole neoKraepelinian thing, perpetuating their war with the psychoanalysts, and the critics were on the same tack as Dr. Szasz and the 1970s behaviorists. The battling feels anachronistic, like straw man arguments, to me, and I try to avoid it whenever possible in line with my life rule, "never accept an invitation to go crazy."

But as an older retired psychiatrist, I have had other thoughts. I now think that explicitly or implicitly dichotomizing  brain disease or human psychological processes is only destructive, and that it is a «false dichotomy» in the end. I personally think that the psychotic mental illnesses are likely biologically determined, or at least have prominent biological determinants. I don’t know that like I do about Systemic Lupus Erythematosis [SLE], but it’s what I think. I would be likely to use medications in cases of psychotic illness, but not because I think I’m treating the underlying cause. I would be using them because psychosis can be disruptive to the person’s life and sometimes fatal, and the medicine can help with that. I’m way on the side of using medications only when there’s a reason and not as a maintenance. The drugs are too toxic for maintenance and there’s increasing evidence that less is better in the long term [I think of Lithium as an exception to that statement]. I think the same thing about Lupus. Steroids or immunosuppressives don’t treat whatever Lupus is [like Vitamin C treats Scurvy]. They treat the damage to the body by suppressing the pathological immunological mechanisms. Antipsychotics can suppress psychotic damage, also a mechanism of disease. The analogy goes further in that. Both steroids and antipsychotics are toxic, dangerous, and not for casual or prolonged use. But that has nothing to do with the minds of these patients. I happen to think many patients with the schizophrenic illnesses are candidates for a kind of psychotherapy adapted to their specific mentation – and that it involves their learning to live with the difficulties in abstraction, emotional experience, and their propensity to psychotic reactions in the face of life’s confusions. Those patients have minds too and often need [and want] help with some aspect of their mental life, on meds or not [by the way, adaptive counseling often helps Lupus patients live with their illness as well\.

So as much as I like Dr. Bracken and as much as I agree with "I do not believe that we will ever be able to explain the meaningful world of human thought, emotion and behaviour reductively, using the "tools of clinical neuroscience", and even though I say things like that sometimes, I'm trying to get over doing it. And as much as I am infuriated when Dr. Nemeroff flashes slides that say things like this implying that he knows something the rest of us don't:

 

I say let him think what he thinks. I doubt that many are listening much anymore.

I realize that in this piece, Dr. Bracken is reacting to people like Dr. Nemeroff, Dr. Insel, and many of the mainstream psychiatrists who have dehumanized psychiatry and tried to make an unleapable leap. He's part of a group that call themselves the Critical Psychiatry Network for that very reason. But I think they make a mistake to even engage with those people on the other side, as destructive as they can sometimes be. There are destructive forces on both sides [and will be so long as the notion of "sides" persists]. Dr. Bracken and others in this group have so much to teach us, to restore a rational balance, but not by arguing with the caricatured enemy. The biologists and neuroscientists have much to teach us too, at least some of them do, and I look forward to learning about it when they get it straight.

The early neoKraepelinians caricatured and destructively wrote off the whole «mind» side of the «mind·brain» equation, and it was neither good for psychiatry nor our patients [nor correct]. The temptation is strong right now to do the same thing in reverse and attack the «brain» side [when they're down on their luck]. I frankly think all of that has more to do with the influence of industry and finance that with the mentally ill – and I’d hate to see us go through another round of straw men and caricatures making yet another version of simplifications analogous to Dr. Nemeroff’s silly slide. A Hermeneutic Shift isn’t the swinging of a pendulum to me, or a dichotomy, it’s the reclaiming and elaboration of a somewhat lost tradition and line of productive thinking that needs no straw man for support. It’s part of the basic science of psychiatry, and it stands on its own. For that matter, it’s a basic science of medicine as Dr. Bracken says in his opening…
Mickey @ 12:00 PM
Filed under: OPINION
what we claim to be…

Posted on Friday 3 October 2014

anime eyes

I was kind of surprised how much letting the EMA decisions sit for a day softened my reaction, because my first take was to catalog what was missing from my wish list and privately groan [worry…, beyond the blind…]. I’m hungry too. And so there was more reflection to be done, and what I came up with may well be idiosyncratic – but that’s not for me to decide. So I’ll just say what I think.

I think what happened with PHARMA and Medicine was at least as much our own fault as PHARMA’s, and I’m including myself in the indictment. I’m not talking about the KOLs or in the case of psychiatry, the ones who jumped into the quick visit/psychopharmacology-for-symptoms mode because it was lucrative or because "it just was what happened." They deserve whatever blame comes their way. I’m talking about all of us who passed responsibility to others to maintain a standard of scientific integrity and medical ethics. We just didn’t pay attention.

When the great reform of requiring clinical trials came along in 1962, it was seen as a plan that would keep PHARMA honest. It worked for a while and we stopped looking. In psychiatry, when the DSM-III came along, it made an equal place for the biological side of the equation, but opened the door to making that the only side. It was obvious the day it was published, but we didn’t keep on top of it. When the CROs and PHARMA took control of Clinical Trials, we just didn’t pay attention. Many of us didn’t even notice. When the reform of ClinicalTrials.gov was added, PHARMA basically ignored many parts of it, mostly the reporting requirements, and that continued even when they were strengthened. We acted like reforms solved the problem, and ignored the fact that such things need constant monitoring – because the response to reforms from the other side is to evolve creative solutions that undermine their essence. And like what happened to the great reform of state mental hospitals, things festered when they were out of sight and out of mind.

At least in medicine, there have been some watchdogs along the way: David Healy, Bernard Carroll, Bob Rubin, Danny Carlat come quickly to mind in psychiatry, but they are exceptions in a sea of sheep who didn’t pay enough attention to the wolves in drag wandering among the flock. So in my view, we can’t expect the EMA, or NICE, or the FDA to maintain the scientific and ethical standards of medicine or psychiatry. The forces of Hospital Corporations, Managed Care, Governmental Agencies, and the Pharmaceutical and Device Industries are powerful, but they all feed off of medicine. Only medicine can provide the required ongoing oversight, and we just haven’t done it. The "good guys" have been so quiet that many have forgotten that there are still any left.

So the real solution to these problems is the development of a "watchdog class" inside of medicine.  We   Medicine itself dropped the ball, and it has been a disaster. Data Transparency is worth nothing without a lot of eyes looking at the data. To force an analogy from close to home [the South], we had the bloodiest war imaginable over human rights, but it didn’t solve the problem and segregation replaced slavery pretty quickly. The second time around a century later, we’d learned that we needed an ongoing "watchdog class" to keep things on track. I think it’s a fair analogy. The government can only do so much. And that’s true of the regulatory agencies. We have to make it part of medicine’s own task. So I’m more ready to settle than many, because this ball is really in our court. If we have the same information as the regulatory agencies promptly, we should be able to spot what we need to raise issues with. We can no more delegate medical ethics to the EMA than to PHARMA. If we don’t wake up and focus a lot of our own eyes on the integrity of our formulary in an ongoing way, we just aren’t what we claim to be – and that would be a sad state of affairs indeed…
Mickey @ 8:00 PM
Filed under: OPINION
beyond the blind…

Posted on Friday 3 October 2014

In the course of life, I had a hand in the later raising of an orphan, and I knew nothing of an orphan mentality. She hadn’t been abused, but she had been chronically deprived for much of her life. To my surprise, she was never satisfied. She had no concept of "enough" – so she always felt disappointed and was only comfortable in a somewhat deprived state. I had to learn that my natural inclination to be on the indulgent side [making up for the past] only made her sick, and that the right course of action was to provide only the "right amount" and accept her chronic state of disappointment as her necessary comfort zone. "Too much" was just as disastrous as "not enough." I’m pleased to report that it worked out in the end, but the path was slow and had more than its share of bumps. While it’s a trivial adage, "don’t go to the grocery store hungry" seems to apply.  Substitute the word "starved," and you’re close to understanding the orphan dilemma.
EMA adopts landmark policy to take effect on 1 January 2015
Press release
October 2, 2014

The European Medicines Agency [EMA] has decided to publish the clinical reports that underpin the decision-making on medicines. Following extensive consultations held by the Agency with patients, healthcare professionals, academia, industry and other European entities over the past 18 months, the EMA Management Board unanimously adopted the new policy at its meeting on 2 October 2014. The policy will enter into force on 1 January 2015. It will apply to clinical reports contained in all applications for centralised marketing authorisations submitted after that date. The reports will be released as soon as a decision on the application has been taken.

“The adoption of this policy sets a new standard for transparency in public health and pharmaceutical research and development,” said Guido Rasi, EMA Executive Director. “This unprecedented level of access to clinical reports will benefit patients, healthcare professionals, academia and industry.”

The new EMA policy will serve as a useful complementary tool ahead of the implementation of the new EU Clinical Trials Regulation that will come into force not before May 2016. EMA expects the new policy to increase trust in its regulatory work as it will allow the general public to better understand the Agency’s decision-making. In addition, academics and researchers will be able to re-assess data sets. The publication of clinical reports will also help to avoid duplication of clinical trials, foster innovation and encourage development of new medicines.

According to the policy’s terms of use, the public can either browse or search the data on screen, or download, print and save the information. The reports cannot be used for commercial purposes. In general, the clinical reports do not contain commercially confidential information. Information that, in limited instances, may be considered commercially confidential will be redacted. The redaction will be made in accordance with principles outlined in the policy’s annexes. The decision on such redactions lies with the Agency.

The policy will be implemented in phases. The first phase starts on 1 January 2015. Once a medicine has received a marketing authorisation, EMA will publish the clinical reports supporting applications for authorisation of medicines submitted after the policy’s entry into force. For line extensions and extensions of indications of already approved medicines, the Agency will give access to clinical reports for applications submitted as of 1 July 2015 after a decision has been taken.

In future, EMA plans to also make available individual patient data. To address the various legal and technical issues linked with the access to patient data, the Agency will first consult patients, healthcare professionals, academia and industry. It is critically important for EMA that the privacy of patients is adequately protected before their data are released.

The policy does not replace the existing EMA policy on access to documents. It will be reviewed in June 2016 at the latest.
The decision of the EMA has been long awaited and is still incomplete. When it showed up yesterday, I scanned it and some of the reactions – then let it sit for a while. I realized that in this case, I’m in the orphan class ["been down so long it looks like up to me"]. And reading worry…, it’s easy to see that I’m primed to be disappointed. It’s not hard to see paranoia in others, but not nearly so simple in the mirror. Inserting some time is a good antidote. So if I can be allowed to revive my monotonous graphics:

There are four documents generated from a Clinical Trial: a Protocol, the CRFs [Case Report Forms], the IPD [Individual Participant Data], the CSR [Clinical Study Report]. Oh yeah, I guess we could add the published [or maybe unpublished] journal article, bringing the total to five documents [see it matters…]. In the absence of outright fraud, three of them come from "behind the blind," in other words, they are what the investigators [and sponsors] see when the "blind is broken." If you have those three things, the playing field is level. Someone evaluating the study from afar is in the same boat as those who did it. We’re talking about a gajillion pages [every piece of paper from every visit by every subject, the CRFs, AND the tables compiled into the IPD of everything that can be objectified and tabulated]. It’s an overwhelming stack of stuff.

After the blind is broken and the data is at hand, it is collated, analyzed, and turned into the CSR – a manageable report for regulators that will later be simplified further to become a journal article [or not]. While there are plenty of computers whirring at this point in the process, there are real live people with real live motives also in the mix, and this is where the problems have come from – beyond the blind:

What the orphan in me wants is all of it. I want the Protocol, the CRFs, and the IPD. I want to to be level with the investigators/sponsors. I’m understandably "starved." The CSR will contain the Protocol and in some cases, the IPD as Appendices, but that last part isn’t guaranteed, and I doubt it will continue under this policy. The raw CRFs won’t be in the CSR. So where does that leave us? The downside is that the CSR is prepared by those pesky, motivated humans. So the possibility of sleight of hand is there as it is with the messy journal articles we’ve lived with for too long. And, they get to pick what’s in them. On the other hand, it puts us on the same level as the regulators who have the ultimate power – saying "No" to approving the drug. And that first paragraph up there has a key sentence, "The reports will be released as soon as a decision on the application has been taken." And this promise sounds pretty good too, "In future, EMA plans to also make available individual patient data." Not guaranteed, but at least an acknowledgement of the need. The piece that’s missing is the CRFs, necessary for a thorough vetting of the Adverse Events.So does it pass the Rolling Stones test:
    You can’t always get what you want
    You can’t always get what you want
    You can’t always get what you want
    But if you try sometimes
    Well you just might find
    You get what you need
Some may see this as a Neville Chamberlain conclusion, but on reflection, it seems to me that the European Medicines Agency is giving us the same thing they get for themselves, and we can’t ask for much more than that. The one thing missing is a retrospectoscope. There are lots of previously approved drugs we need to know about, because, as Ben Goldacre says, they’re still in use. That’s an area where we need to challenge the EMA. But the other part, the IPDs and the CRFs which are needed to vet questionable studies is probably a fight that needs to be taken directly to the drug manuacturers through the data portals they are creating. It seems naive to ask the EMA to take on the responsibility of getting us something they don’t even have themselves. I give them a B+ [but reserve the right to change my mind]…

UPDATE: This from Ben Goldacre:
    “Firstly, the EMA records are woefully incomplete for informed decision making: EMA only holds CSRs for a small proportion of all the trials done on all the medicines we use today. We need a radical overhaul giving retrospective transparency on all CSRs from industry, and clear transparency on methods and results for all trials done by academics. Secondly, this policy does nothing to move forward on the safe sharing of individual patient data – whilst respecting patient privacy – which was promised by EMA in 2012. Lastly, there are serious concerns around the redactions process. For this, we can only go on recent performance, which is not encouraging. EMA reached an agreement this year with AbbVie to censor information on protocol changes from the public release of a CSR. Protocol changes in a trial are precisely the kind of information that researchers need, to make an informed decision about whether that trial was a “fair test” of the treatment. It is hard to see how it is justifiable to hide protocol changes, in a trial from eight years ago, on over-riding grounds of commercial confidentiality.”
UPDATE: And the big picture reaction from Ed Silverman at Pharmalot [EMA Remains Under Fire for its Policy on Disclosing Clinical Trial Data]. People are understandably pretty hungry…
Mickey @ 7:35 AM
Filed under: OPINION
gibbons everlasting…

Posted on Thursday 2 October 2014

… it keeps turning up like a bad penny
    The Internet tells me that this phrase comes from 18th century England [when a penny was serious money]. Pennies were frequently counterfeited in those times. So if if one turned up in one’s purse, it was spent quickly. There were so many in circulation that you were likely to get another one soon. Thus, "turns up like a bad penny" – something unwanted of dubious value that keeps showing up.
Dr. Robert Gibbons, a statistician at the University of Chicago, seems to have a fixation on Black Box Warnings in general [Neurontin®, Chantix®, SSRIs], but specifically on the warning of suicidality in adolescents on SSRIs. That warning was added to the product labels in 2004, and since then, he can’t seem to stop trying to find some way to convince us to ignore it:
  1. Gibbons RD, Hur K, Bhaumik DK, Mann JJ.
    Arch Gen Psychiatry. 2005 Feb;62(2):165-72.
  2. Gibbons RD, Hur K, Bhaumik DK, Mann JJ.
    Am J Psychiatry. 2006 Nov;163(11):1898-904.
  3. Nakagawa A, Grunebaum MF, Ellis SP, Oquendo MA, Kashima H, Gibbons RD, Mann JJ.
    J Clin Psychiatry. 2007 Jun;68(6):908-16.
  4. Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Mann JJ.
    Am J Psychiatry. 2007 Jul;164(7):1044-9.
  5. Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Erkens JA, Herings RM, Mann JJ.
    Am J Psychiatry. 2007 Sep;164(9):1356-63.
  6. Brown CH, Wyman PA, Brinales JM, Gibbons RD.
    Int Rev Psychiatry. 2007 Dec;19(6):617-31.
  7. Gibbons RD, Segawa E, Karabatsos G, Amatya AK, Bhaumik DK, Brown CH, Kapur K, Marcus SM, Hur K, Mann JJ.
    Stat Med. 2008 May 20;27(11):1814-33.
  8. Gibbons RD, Mann JJ.
    Drug Saf. 2011 May 1;34(5):375-95.
  9. Reanalysis of the Randomized Placebo-Controlled Studies of Fluoxetine and Venlafaxine
    Robert D. Gibbons, C. Hendricks Brown, Kwan Hur, John M. Davis, and J. John Mann
    Archives of General Psychiatry. Online February 6, 2012. [full text on-line]
  10. Synthesis of 6-Week Patient-Level Outcomes From Double-blind Placebo-Controlled Randomized Trials of Fluoxetine and Venlafaxine
    Robert D. Gibbons, Kwan Hur, C. Hendricks Brown, John M. Davis, and J. John Mann
    Archives of General Psychiatry. Online March 5, 2012.
  11. Gibbons RD, Coca Perraillon M, Hur K, Conti RM, Valuck RJ, and Brent DA
    Pharmacoepidemiologic Drug Safety. 2014 Sep 29. doi: 10.1002/pds.3713. [Epub ahead of print]
This last outing came out this week:
by Gibbons RD, Coca Perraillon M, Hur K, Conti RM, Valuck RJ, and Brent DA
Pharmacoepidemiologic Drug Safety. 2014 Sep 29. doi: 10.1002/pds.3713. [Epub ahead of print]

PURPOSE: In the 2004, FDA placed a black box warning on antidepressants for risk of suicidal thoughts and behavior in children and adolescents. The purpose of this paper is to examine the risk of suicide attempt and self-inflicted injury in depressed children ages 5-17 treated with antidepressants in two large observational datasets taking account time-varying confounding.
METHODS: We analyzed two large US medical claims databases (MarketScan and LifeLink) containing 221,028 youth (ages 5-17) with new episodes of depression, with and without antidepressant treatment during the period of 2004-2009. Subjects were followed for up to 180 days. Marginal structural models were used to adjust for time-dependent confounding.
RESULTS: For both datasets, significantly increased risk of suicide attempts and self-inflicted injury were seen during antidepressant treatment episodes in the unadjusted and simple covariate adjusted analyses. Marginal structural models revealed that the majority of the association is produced by dynamic confounding in the treatment selection process; estimated odds ratios were close to 1.0 consistent with the unadjusted and simple covariate adjusted association being a product of chance alone.
CONCLUSIONS: Our analysis suggests antidepressant treatment selection is a product of both static and dynamic patient characteristics. Lack of adjustment for treatment selection based on dynamic patient characteristics can lead to the appearance of an association between antidepressant treatment and suicide attempts and self-inflicted injury among youths in unadjusted and simple covariate adjusted analyses. Marginal structural models can be used to adjust for static and dynamic treatment selection processes such as that likely encountered in observational studies of associations between antidepressant treatment selection, suicide and related behaviors in youth.
While he’s not a clinician, he often speaks or makes recommendations as if he is. The other thing that characterizes his writing is that he uses statistical techniques most of us are unfamiliar with and don’t understand, yet his papers are descriptions of the various mathematics he’s basing things on without enough data to attempt to reproduce or even follow his various calculations – as in:
The statistical analysis was comprised of two stages. In the first stage, a logistic regression model was used to predict antidepressant usage on each of the 6months conditional on fixed covariates (demographics and prior suicide attempt and self-inflicted injury) and time-varying covariates (comorbid conditions, concomitant medications (listed above), psychiatric hospitalizations and psychotherapy above). The predicted probability of treatment at time point t was computed as the continued product of probabilities from baseline to time point t . The inverses of these estimated probabilities were then used as weights W(t) in the second stage analysis that related actual treatment (dynamcally determined on a month by month basis) to suicide attempt and self-inflicted injury using a discrete time survival model. In practice, W(t) is highly variable and fails to be normally distributed. To overcome this problem, Robins suggested use of the stabilized weight:
where L is the set of all baseline and time-varying covariates, V is a subset of L consisting of only the baseline covariates (i.e. time invariant effects), A(k) is the actual treatment assignment at time k , and à (k) is the treatment history…

The paper is based on the analysis of two large longitudinal claims databases from which they extracted a number of covariates. He describes, but does not show, his analyses which I couldn’t exactly follow, but he could disappear the correlation between SSRIs and suicidality by his factor analysis. And like many of his papers, there’s nothing to say [because there's nothing to see]. And like so much of his work, in spite of all the jargon, the only way there is to accept his conclusions is to take them on faith. I’m not willing to do that based on vetting his previous work [cataloged above]. As Neuroskeptic tweeted:

the thing is, I might be willing to buy Gibbons et al’s argument about confounding, *but* I just can’t trust…
…him to present an unbiased analysis of the data, judging by what I’ve seen of the "CAT"….
  [see Can A Computer Measure Your Mood? (CAT Part 3)]

Well I certainly agree, but my skepticism goes further – beyond his CAT work, and the conduct of many of the studies on the list. Besides his practiced opaqueness and monotonous conclusions, I doubt that any population study of the problem of Akathisia and suicidality will ever shed any meaningful light on this question based on clinical experience. I’ve seen cases of agitation, and suicidality, and know of several related completed suicides. The most common version is a patient who gets put on an SSRI and becomes agitated, aggressive and they stop taking it either themselves or at the request of their parents – and they never go back to see the person that prescribed it. So they wouldn’t show up at all in a longitudinal population database. If you’re a clinician and you’ve seen these cases, even though they’re infrequent, you have no questions about the syndrome. It’s not subtle. These population studies use suicidality and completed suicides as an end-point rather that the full range of the presentations of Akathisia.

What I really think is that these articles tell the story of someone whose research starts with a conclusion, and he just plugs away at trying to find a way to reach it. My only question is why it keeps getting funded:
ACKNOWLEDGEMENTS This work was supported by NIMH grant MH8012201 (RDG) and AHRQ grants 7U19HS021093-03 (RDG) and T32HS000084 (MCP)… Dr. Gibbons has been an expert witness in suicide cases for the US Department of Justice, Wyeth and Pfizer.
Mickey @ 2:22 PM
Filed under: OPINION
worry…

Posted on Wednesday 1 October 2014

This is a commentary by a British law firm about tomorrow’s announcement of their data transparency policy:
The European Medicines Agency (EMA) is set to finalise its new policy on access to clinical trial data this week
Out-Law.com
30 Sep 2014

Guido Rasi confirmed to the European Parliament that the EMA’s management board will approve the new policy on Thursday, according to a report by EU news website euractiv.com. A spokesperson for the EMA confirmed to Out-Law.com that the body will release details of the new policy after the management board’s meeting either on Thursday afternoon or Friday. "Our new policy will spell out clearly what will be the principles to gain access," Rasi said, according to the euractiv.com report. "The decisions, however, will always be taken by the EMA. Next Thursday, our management board will approve this new version of the policy. That should give us, from the start of 2015, the possibility to start to actively make data available. By 2016, we should have the first clinical trials data available."

Paul Ranson, a specialist in the regulation of clinical trials at Pinsent Masons, the law firm behind Out-Law.com, said that the EMA is expected to announce that it will, as a first step, make Clinical Study Reports (CSRs) available after product assessment subject to the redaction of identified commercially confidential information. CSRs are documents that contain all the details of a clinical trial that are submitted to regulators by a company seeking authorisation to market a new product.

The EMA previously announced that its new policy would not address issues concerning the disclosure of individual patient data (IPD) generated from clinical trials. Ranson said that the EMA is still engaged with stakeholders in discussing what conditions to impose on access to IPD. However, he said many companies have already adopted their own policies and allow restricted access to IPD using a gatekeeper model, which is where a trusted third party control access to the data and impose privacy safeguards. Some, like GSK, have created their own ‘safe havens’ where certain data can be viewed but not extracted, whilst others, such as Bristol Myers Squibb, are making the data available through a collaborative safe haven, Ranson said. "An important consideration for companies is what is said about data reuse and data sharing in the consent form signed by participants," Ranson said. "This is likely to be more of an issue for past trials as data sharing and reuse can be addressed in the consent forms for new trials."

Earlier this year the European Ombudsman Emma O’Reilly criticised EMA draft plans which she said would, if introduced, allow clinical trials data only to be accessible on screen using an interface provided by the EMA. O’Reilly claimed further "wide restrictions" would apply to how the data could be used, something which the EMA denied at the time. It said it intended to make clinical trial data publicly accessible online and that restrictions it was considering were designed to prevent those who access the information using it for commercial gain.

Competing interests surround the issue of whether and to what extent clinical trial data should be made publically available. Many stakeholders believe that medical research would be enhanced if there was full transparency from the results of clinical trials. However, others believe that at least an element of confidentiality is required to protect the significant investments drug companies make in carrying out clinical trials and developing new drugs. They believe rival companies should not be able to piggy-back on their investment and launch new products onto market at their expense.

Expert in life sciences Helen Cline of Pinsent Masons said: "There is a whole spectrum of benefits that could arise from making the clinical trial process and clinical trial data more transparent from improving the efficiency of drug discovery to the public health benefits.”  Earlier this year, the Council of Ministers and the European Parliament voted in favour of a new Clinical Trials Regulation which will require pharmaceutical companies and other medical researchers to post results of all their European clinical trials on a publicly-accessible database.
I hope to eat these words tomorrow, but I don’t much like what I’ve been reading about the goings on with the EMA recently. There are too many phrases like "subject to the redaction of identified commercially confidential information", "new policy would not address issues concerning the disclosure of individual patient data", "many companies have already adopted their own policies and allow restricted access to IPD using a gatekeeper model", "important consideration for companies is what is said about data reuse and data sharing in the consent form signed by participants". The changes are more in the feel of the communications. Originally, the net vector was to release the data. Recently, what we hear about is restrictions, safeguards, permissions, and now about the company’s portals rather than the EMA’s portals. In feels like the EFPIA/PhRMA campaign to maintain control have wotked and their language is cropping up in the policy. I hope I’m wrong about that. I guess we’ll find out tomorrow.

Having just spent the year poring over the information from a real clinical trial, I have a better sense of what’s needed to thoroughly vet such a study. None of it is commercially sensitive in the way I understand the terms. The only way it would be commercially sensitive would be if the truth meant the drug couldn’t be as profitable as the maker might like because it wasn’t very effective or had prohibitive side effects – which are the reasons to do a trial in the first place. How effective is it? What are the harms? So I’m not sure what they mean by Commercially Confidential Information.

For an Efficacy evaluation, one needs the a priori protocol which spells out how the study is to be conducted; the outcome variables and what parameters will be collected; and finally  how the data will be analyzed. There’s nothing about commerce in all of that. The Adverse Event analysis requires the rawest form available of the adverse events for each subject – before being transcribed and coded. Again, nothing about commerce in any of that – just the clinical facts.

The CSR [Clinical Study Report [CSR] is a "write up" of the study. If it contains the original protocol and the tables of the raw results for the outcome variables for each subject, it’s fine for the efficacy evaluation. But if it’s simply a summary and only contains the processed or analyzed information, it’s of no use. You can jury rig a CSR just as easily as a paper for publication. So when they throw around the term, CSR, we need to know specifically what’s in it. What’s needed is the protocol and the IPD [individualized participant data]. If they aren’t both there, it’s not data transparency. It’s something else [see it matters…]. So when I read, "new policy would not address issues concerning the disclosure of individual patient data" – I worry. For an evaluation of Adverse Events, one needs the CRF’s [Clinical Report Forms]. We need to know what the evaluator saw and what the subject said – not some compilation or already coded list. I don’t read about that here and so I worry some more.

The whole point isn’t finding out trade secrets or interfering with anyone’s privacy. I don’t think we’re asking for that. We just want to see the information that was available the day the blind was broken to check the analysis described in the protocol. What I read up there doesn’t comfort me that the EMA is going to deliver on the promise to give us that. So I worry… that the industry forces have gotten to the EMA.
Mickey @ 11:30 PM
Filed under: OPINION