part one: the bind…

Posted on Sunday 6 July 2014

by Peter Tyrer, Sally-Ann Cooper, and Angela Hassiotis
British Medical Journal. 2014 348:g4323.

Time to rethink?

Do we still need to be reminded that the drug treatment of people with intellectual disability is often prolonged and not without dangers? We probably do. Drug treatment has been a mainstay for managing a common syndrome subsumed under the label “aggressive challenging behaviour” since chlorpromazine was first introduced for its treatment over 40 years ago… Challenging behaviour is the most common disturbance requiring intervention in intellectual disability services, but it does not have proper diagnostic status in standard psychiatric classifications.

Yet this does not inhibit the wholesale import of adult psychopharmacology into its management. Psychotropic medication in its many forms mainly antipsychotics, sedatives and tranquillisers, antidepressants, and mood stabilisers — has seen extensive off-label prescribing for the past 50 years. Thus, a recent population based cohort study of 1023 adults with intellectual disabilities showed that 49.5% were taking some form of psychotropic drug, with 23.2% taking an antipsychotic despite only 4.4% having a psychotic disorder…

This prescribing would not be a concern if adverse effects were few and easily corrected, but neither of these is true. The high levels of obesity, metabolic syndrome, and diabetes in this population are largely due to these drugs and predispose to premature mortality. National audits such as those carried out by the Prescribing Observatory for Mental Health suggest that more people with intellectual disability are being regularly checked for known and established side effects of antipsychotic medication in secondary care. But there is a lack of primary care data on whether people with intellectual disability prescribed psychotropic drugs receive similar care and are targeted as a higher risk group. Once these drugs are prescribed they far too often become part of long term management, reinforced by the nervousness of care staff with limited knowledge of psychopharmacology and reluctance of practitioners and carers to alter a treatment when it may be wrongly perceived as effective. Attempts to stop these drugs after people have been taking them for many months or years have had only limited success.

What is the evidence for the benefits of these drugs in the treatment of challenging behaviour? Virtually none. Almost all the evidence in favour comes from small trials conducted by drug companies. Yet it would be perverse if doctors continued to prescribe these drugs, knowing about their adverse effects, if they were entirely without efficacy, and many claim that they cannot care adequately for their patients without the option of drug treatment. We therefore need clear indications for drug treatment, as well as to develop a range of more effective psychosocial treatments, for which there is now increasing evidence, but there is still ground to cover. In the interim, a key element is education of prescribers… Good randomised trials, preferably not funded by the drug industry, are needed to show efficacy. At present there are no randomised trials with adequate numbers that can give definitive advice on the value of any drug group in this population..

Drug treatment of challenging behaviour in people with intellectual disability should no longer be on the sidelines of evidence based medicine. If we are going to achieve parity of esteem for people with mental illness, we can no longer tolerate our ignorance on this subject. Quite apart from the deficiencies in evidence allowing dogma and opinion to rule, the cost of prescribing these drugs is enormous. If they truly are unnecessary, clinicians, pharmacists, service managers, and those who fund services for people with intellectual disability need to know, and soon.
The belief that one can control or at least dampen the disruptive [challenging, aggressive, etc] behavior in impaired children with antipsychotics really is in the range of Dogma as this editorial implies. I think I even believe it, though I wish I didn’t. So they’re absolutely correct in saying, "Good randomised trials, preferably not funded by the drug industry, are needed to show efficacy. At present there are no randomised trials with adequate numbers that can give definitive advice on the value of any drug group in this population." Absent that, the belief will persist along with Papal Infallibility and Transubstantiation throughout the ages – Dogma endlessly debated but unresolved. And even if it turns out to be true that these medications are somewhat effective, the problem remains in the form of adverse effects – metabolic syndrome, weight gain [often dramatic], diabetes, neurological symptoms, tardive dyskinesia – because the disruptive [challenging, aggressive, etc] behavior doesn’t just evaporate on its own. It comes with the package and leads to long term use once started, again as this editorial implies.

Which brings me to Hamlet and company, the tragic figures in Shakespeare’s immortal play. Thirty plus years ago, my kid sister [now a retired academic] wrote a paper about that play, Hamlet, "A Man to Double Business Bound", out of her usual genre [Milton]. She analyzed the play using Double Bind theory, and did a mighty fine job of it, if I do say so myself [ignoring my obvious COI]. I knew Double Bind theory, but her paper etched it on my brain, and I thank her for that. It was an invaluable tool in understanding the narratives of the patients I saw over the years, and it was no small factor in working out my own dilemmas – as the life of a physician is filled with Double Binds that never stop coming. A Double Bind, oddly enough, has four commands: Two injunctions that are diametric opposites [thus the synonym - an impossible situation] – one overtly stated and the other usually covert. Then there’s a third injunction – that you have to act, to do something [even though there's nothing right to do]. And the final rule caps the nightmare, you can’t address the obvious impossibility of this complex of commands. All you can think to do is pick one or the other side and surely fail; or give endless soliloquies about a paralysis of mind; or go crazy. Most psychotherapists can think of endless examples in a heartbeat. I sure can [see postscript…].

So you’re a doctor and a parent/caregiver brings a mentally retarded child to see you who is oppositional/challenging/disruptive in the waiting room and in your office. Then you look at the child’s parent/caregiver and you see a person hanging on by a thread, on the edge of tears, spent from dealing with this child. Maybe it’s a Foster Parent, one you already know to be a real trooper, about to give up return the child to DFCS. And you think hope that an antipsychotic might possibly help [or you can't think of anything else to do], knowing full well the long term side effect profile of the drugs. That’s when the prescriptions often get written, even by the most principled doctor in the clinic. If you do nothing, you’ve done nothing, reinforcing the hopelessness the parent/caregiver already feels. If it doesn’t work, you’re in trouble because you’ve implied that medication is the way to go and what’s next? If it does work, you’re committing to a road you might really not want to be on sooner than you think. That’s what a Double Bind feels like – absolutely nothing right to do, and a pressure to act [yesterday].

Tyrer et al have written an excellent editorial. They obviously don’t think these kids should be on antipsychotics or at least not like they are now, but they don’t preach, rant, or moralize like many ["those damn doctors think everybody needs to be on medications!"]. They simply present an all too common clinical problem, one that’s often handled by the gestalt of the moment with no clear evidence-based guidance. And their heading ["Time to rethink?"] is a confrontation of sorts, because they’re implying that this is a topic doctors don’t want to think about [I would add "don't want to think about because it doesn't have any apparent solution"]. And the definition of a confrontation is simple – telling someone something they don’t want to hear.

If you’re not on to my ways, you haven’t figured out that this is the first of several posts [hints: "part one" in the title; this is the last paragraph and I'm not close to an ending]. The take home point for this post is that this is not necessarily a moral problem having to do with the ethical commitment of the doctor. It’s a clinical problem that’s often handled as if it’s acute [as in my scenario], but is actually chronic and needs to be approached as such with the long haul in mind. We obviously need some real data to formulate rational interventions – not quick decisions made in the fog of the moment…
Mickey @ 8:00 PM
Filed under: politics
still watching…

Posted on Sunday 6 July 2014

It has been eight months since this apology was published in JAMA Psychiatry. After over a decade of Dr. Kupfer self-righteously swatting away accusations that his DSM-5 Task Force was riddled with members who had conflicts of interest, he was forced to acknowledge that he had a whopper of a conflict of his own – a company poised to capitalize on his wished-for "dimensional diagnoses" as a screening device:
by Robert D. Gibbons, PhD, David J.Weiss, PhD, Paul A. Pilkonis, PhD, Ellen Frank, PhD, and David J. Kupfer,MD.
JAMA Psychiatry. Published Online: November 20, 2013. doi:10.1001/jamapsychiatry.2013.3888

To the Editor: We apologize to the editors and readers of JAMA Psychiatry for our failure to fully disclose our financial interests in an article1 that reported a diagnostic tool, the Computerized Adaptive Test for Depression [CAT-DI]. Following acceptance of the paper, we disclosed that “The CAT-DI will ultimately be made available for routine administration, and its development as a commercial product is under consideration.” The company that owns the rights to CAT-DI and several related tests is Psychiatric Assessments, Inc [PAI], which uses the trade name of Adaptive Testing Technologies [ATT] on a website describing these tests. Lead author Robert D. Gibbons, PhD, is the president and founder of PAI,which was incorporated in Delaware in late 2011, then registered to do business in Illinois in January 2012. Dr Gibbons awarded “founder’s shares in PAI” to us, yet all 5 of us failed to report our financial interests in connection with our article and again in a Reply to Letters to the Editor regarding the article. Neither PAI nor ATT has released the CAT-DI test [or any other test] for commercial or professional use, but our ownership interests were relevant to the research article and Reply we submitted and should have been disclosed to the editors. Our submitted disclosure lacked transparency, and we regret our omission.
The APA investigated and said everything was fine. You may or may not have noticed that my letter to the APA and Timeline went unacknowledged [open letter to the APA…]. Since then, we’ve heard little to nothing from Dr. Kupfer, Dr. Gibbons, or their other partners in Adaptive Testing Technologies. This post is just a marker to remind them that we’re still watching…
Mickey @ 8:00 AM
Filed under: politics
no commercial interruptions…

Posted on Saturday 5 July 2014

Why have I reproduced this entire Perspective piece even though it’s available full text on-line? It’s because it’s in the New England Journal of Medicine – that’s why. I want to emphasize its existence in a top flight American Journal. As much as I’ve appreciated all the play Data Transparency has gotten in Europe, it’s time for some official noise like this on this side of the pond. It has been a long time coming. So here it is [with no commercial interruptions]:
by Kevin Outterson, J.D., LL.M.
New England Journal of Medicine. 2014 371:1-3.

This year promises to be an auspicious period for some long-running battles over the dissemination of biomedical research. Some companies seeking more freedom to promote their products have bristled at recent guidance documents from the Food and Drug Administration [FDA] regarding promotion of drugs and devices for off-label uses, claiming that they violate the First Amendment. Simultaneously, industry is divided over calls for increased transparency of clinical trial results. But as the FDA’s regulatory authority is weakened by First Amendment challenges, the need for clinical trial transparency becomes more urgent.

In the recent guidance documents, the FDA recommended that scientific articles used for off-label promotion be scientifically sound, come from peer-reviewed journals, and be distributed in unabridged form with the approved labeling and a comprehensive bibliography. Clinical practice guidelines used for marketing should be based on a systematic review of the evidence and "be developed by a knowledgeable, multidisciplinary panel of experts and representatives from key affected groups." The FDA also recognized the growing importance of social media, describing the situations in which a company is responsible for comments on Facebook and patient advocacy websites focusing on specific diseases and treatments. In early June, the FDA expanded this guidance process to include communications about new risk data for existing drugs. The FDA is concerned that companies might use incomplete new information to weaken the impact of warnings on the approved drug label.

Some companies have complained that these rules overly constrain their marketing practices and impermissibly infringe on commercial speech. These claims find some support in recent cases that have undermined the FDA’s regulatory authority over drug marketing. The First Amendment has emerged as a potent deregulatory weapon for corporations. Governments increasingly face First Amendment challenges to rules related to the marketing of regulated products, not only from the drug industry but also from companies selling tobacco, alcohol, and processed foods. These industries claim that the government violates a core principle of liberty — freedom of speech — by regulating how food, drugs, alcohol, and tobacco are sold. The FDA issued the new guidance documents with these concerns in view.

In recent years, drug companies have paid billions of dollars in fines related to off-label promotion. Whether the First Amendment protects this activity remains an open question. The FDA’s position is nuanced. Under the law, a drug is viewed as "mislabeled" unless "its labeling bears adequate directions for use." The FDA does not require labels to discuss all possible uses, which would be burdensome to the companies, but only those actually intended by the company. One way to prove this intention is to examine company statements about the drug, including promotional activity. Companies can make any truthful and nonmisleading statement about their drugs, but when they choose to speak about any particular use, the label must bear adequate directions for that use. Speech is frequently used to prove elements of other crimes; examples include perjury, premeditated murder, and conspiracy.

Seen in this light, the recent draft guidance documents do not constrain First Amendment values. They provide safe harbors, listing circumstances in which the FDA will not consider actions to be evidence of intent to sell a drug for a particular use. And the guidance is quite lenient: a company can sponsor biomedical research for an off-label use, refuse to submit that research to the FDA for an expanded label, but nevertheless widely distribute reprints of relevant journal articles to physicians and chat about them on Facebook and other social media. The FDA is keeping a respectful distance from the First Amendment, while gentry reinforcing better practices, including peer review and disclosure of conflicts of interest.

If the Supreme Court’s interpretation of the First Amendment continues to constrain FDA influence over the dissemination of research, then even greater importance must be placed on improving research quality and providing the support independent research teams need to reanalyze clinical trial data. Studies have highlighted strategic weaknesses in the research enterprise, including failures in peer review, publication bias, bias introduced by sponsors or investigators, and extensive financial relationships.

Transparency is an important tool for addressing these issues, and many stakeholders are working to improve transparency in biomedical research. The International Committee of Medical Journal Editors has adopted standards to improve the quality of the peer-review process, require registration of clinical trials before patient enrollment, and improve disclosure of conflicts of interest The United States requires advance registration of many clinical trials; since 2007, summary results must also be published. Similar initiatives have been implemented in Europe and beyond, including a global clinical trial registry maintained by the World Health Organization. Advance registration and summary publication are important tools for reducing opportunities for publication bias and making it harder to hide negative studies.

Pressure is now building for two additional data-transparency goals: giving responsible independent researchers access to patient-level data to enable them to replicate studies and perform meta-analyses; and requiring public release of clinical study reports submitted to governments for marketing approval, which have substantial informational value.* Companies have traditionally protected these data as trade secrets,* but maior changes are under way. In the United States, the FDA requested comments in 2013 on a proposal supporting a limited level of transparency for product-masked patient data. Product masking protects the identity of both the drug and the patient, which limits the data’s clinical utility for research. Currently, this effort appears to be on ho!d, awaiting results from a review by the Institute of Medicine. Meanwhile, transparency initiatives by some companies and legislative action in Europe may have reached the tipping point, with momentum growing for transparency that goes well beyond product-masked data.

Limited patient-level data are now being made available to independent researchers. In May 2013, GlaxoSmithKline opened some of its patient-!evel data to responsible researchers, with an independent review pane! acting as the gatekeeper.4 Johnson & Johnson followed suit in January 2014, partnering with a group at Yale. These programs are welcome improvements and should expand across the industry.

I believe that transparency should also extend to the clinical study reports submitted to the FDA and other drug-regulatory authorities. On April 2, 2014, the European Parliament adopted reforms to its rules governing human clinical trials, including a key provision requiring delayed release of clinical study reports submitted to the European Medicines Agency. The next day, AbbVie dropped its lawsuit against the agency, which had sought the release of clinical study reports on two AbbVie drugs. Other litigation remains pending, and the European Union may yet weaken these rules, but these events suggest that disclosure of clinical study reports may soon be the norm in Europe.

In public comments on the European reforms, the drug industry raised objections to the release of clinical study reports. Although companies have no trade-secrecy right to hide safety data on medicines, they make a reasonable point regarding the danger of substantial competitive harm from full transparency. Governments offer non-patent-based incentives for special categories of drugs, such as orphan drugs and biologics. These incentives have frequently rested on data exclusivity, prohibiting other companies from using data for regulatory approval purposes. To the extent that transparency disrupts data-exclusivity incentives and the timing of generic entry, both domestically and internationally, the law will need to be adjusted in order to restore the competitive position of the companies. The alternative is to delay data releases until many years after a drug is approved, but neither the progress of science nor public safety should wait for full transparency. The companies will also retain the full force of patent law to block premature generic entry. If this issue is resolved, the onus will be on the industry to articulate why clinica! study reports should not be immediately released when a drug is approved.

After decades of criticism about bias in the clinical trial enterprise, new norms are being established that promote transparency. Additional transparency is particularly welcome in the United States, since the Supreme Court has increasingly constrained the FDA’s ability to regulate off-label marketing activities. In the deregulatory environment fostered by First Amendment challenges. clinical trial transparency is perhaps the best remaining option for informing physicians and protecting patients.
One Perspective piece in the New England Journal of Medicine doesn’t mean this issue is resolved, but it’s damn sure better than none…
Mickey @ 10:02 PM
Filed under: OPINION
fine summary…

Posted on Saturday 5 July 2014

Though ChemistryWorld is not one of my usual sites, I give them credit for one fine summary of the current state of the European Medicines Agency Data Transparency story:
by Andy Extance
3 July 2014

Tempers are being tested as the pharmaceutical industry’s journey towards transparency on clinical trial data enters a critical phase. Even as drug companies announce more voluntary access schemes, campaign group AllTrials has accused the European Medical Agency [EMA] of a ‘backroom deal with pharma’ to weaken earlier commitments. The disputes have arisen following EMA consultations over its clinical trial data policy, which it hopes to finalise in mid-July, and bring into force in October. The pioneering plan would be the first of its kind to proactively publish clinical trial reports, giving people access for non-commercial use without needing to request it from companies. After receiving over 1100 comments covering a broad spectrum of opinions, the EMA conducted follow-up meetings in May to discuss the resulting proposals. Following the meetings researchers, AllTrials, and even the EU Ombudsman reacted critically.

The chief concern was a ban on saving, downloading or printing clinical study reports [CSRs], making these huge documents available only on-screen. The Institute for Quality and Efficiency in Health Care [IQWiG], Germany’s national commission for assessing medical procedures, was especially outraged. It took to Twitter with a long series of photos underlining how hard this would make its job. The same groups also warned that the new ‘terms of use’ contract could let trial sponsors sue researchers, creating a legal chill that would deter scrutiny.
I’m particularly glad there was such widespread outrage about their "screen only" proposed interface. Having used such a system for the last months, I was afraid that people wouldn’t realize what a hinderance that really is. Our analogy of going to sea to see the world in a submarine looking through a periscope was no exaggeration.
The EMA’s new redaction policy on what information could be hidden drew fire too. It arose because of comments in the initial consultation that patient privacy, trust in the system, and commercial confidentiality could be put at risk. Richard Bergstrom, director general of the European Federation of Pharmaceutical Industries and Associations [EFPIA], expressed worry over ‘putting transparency – at whatever cost – ahead of public health interests’.

The proposed EMA policy allows drugmakers to propose redactions for text they feel is commercially or otherwise sensitive, although the regulator will retain the final say on what is hidden. Campaigners say this measure and vague policy wording will mean too much is concealed. EMA spokesman Martin Harvey-Allchurch stresses that ‘third parties’ can petition or sue if they think that’s happening, and that the extent of redaction will always be visible.
I hadn’t read that red part elsewhere, but that’s a reasonable request if the process of petitioning is clear. That last part ["the extent of redaction will always be visible"] is reassuring. I’d prefer that there be no redaction clause at all. What business is Commercially Sensitive Information of the European Medical Agency anyway? But one can’t expect to win every battle.
Working too closely?

Yet the new policy still seemed to many a significant departure from the EMA’s previous hard line on data disclosure. Its 2010 ‘access to documents’ policy considers that most CSRs are not commercially confidential information, and promised to disclose CSRs for every drug it had reviewed. The confidentiality point has drawn fire from some drugmakers, with AbbVie and InterMune disputing it in court. But in April, AbbVie dropped its case, the day after the EU passed regulations that will make clinical trial registration and data sharing a legal requirement. Then, at the end of May, InterMune dropped some of its cases against the EMA.

AllTrials subsequently suggested that the price for dropping the cases had been a more industry-favourable transparency policy, something Harvey-Allchurch ‘absolutely refutes’. ‘AbbVie realised that we’re going to stick with our definition of commercial confidentiality – they knew they were not going to win that one,’ he says. ‘They went away, and came back with proposals for what they wanted redacted. In the end, what they proposed was in line with our redaction principles. The main InterMune case is still running.’

Following the pressure over its proposals on 12 June, the EMA’s management board agreed an amended policy. That allows downloading, saving and printing trial data for academic and non-commercial research purposes, although the other controversial areas remain unchanged. Nevertheless Harvey-Allchurch plays down the outcry surrounding the new policy. ‘The whole purpose of these targeted consultation exercises was to listen,’ he says. ‘We heard the feedback, we listened to it, and proposed an alternative to the board.’ But with Harvey-Allchurch underlining that this policy initiative is a bridge to the new EU regulations that will come in some time after May 2016, the final policy wording will be highly significant.
I don’t believe what PHARMA says anymore. That was actually a conscious decision on my part. I made it the day I read GSK’s response in the Chronicle of Higher Education denying an agreement they’d just signed [see the only enduring contract…]. Life has been easier not having to obsess about what to trust. I’d suggest it to all as a general strategy. To stick to my penchant for old sayings: "The best predictor of future behavior is past behavior."
Industry delivers

Meanwhile, pharma companies continue to progress their own schemes to make data available, with Bristol-Myers-Squibb [BMS] becoming the latest to open up its trial results. The Duke Clinical Research Institute at Duke University in Durham, North Carolina will act as the gatekeeper for BMS’ data. It will review study proposals and check final manuscripts ‘for scientific integrity and consistency with the original proposed work’ like Yale is doing for Johnson & Johnson. Boehringer-Ingelheim has also said that it will publish documents for all approved products going back to 1998. That move goes beyond the ‘Principles for responsible clinical trial data sharing’ introduced by the EFPIA and the Pharmaceutical Research and Manufacturers of America [PhRMA] last July.

IQWiG spokesperson Susanne Breuer highlights that a fragmented landscape of company data repositories would be less desirable than the single repository the EMA hosts. ‘The control of data completeness would be much more complicated, and analysing data it would take a lot longer,’ she says. ‘We would appreciate centralised access for scientists.’ Parts of the industry are making progress here, with Eli Lilly and Bayer Healthcare agreeing to make trial data available via They bring the number of companies using the portal, created by GlaxoSmithKline last year, to eight.
I’m on a team looking at the data from a questionable study, and except for the maddening "screen only" interface, I feel comfortable with the access we have to the information we wanted to see. I hasten to add that there was a good deal of negotiating involved in getting it. I think I would be more accepting of these recent examples of industry delivering if they had given in much earlier. I’m suspicious of foxhole conversions and that’s what this is. And there’s really no need for PHARMA to maintain that kind of control. In the end, we really should be privy to everything that goes to the regulatory agencies. That’s also true for all Clinical Trials, but that’s another part of the fight…
Mickey @ 1:38 PM
Filed under: politics
time for a sabbatical…

Posted on Saturday 5 July 2014

Insanity: doing the same thing over and over again and expecting different results.
not Albert Einstein 1
"From Psychiatry to Clinical Neuroscience"
by Mark Moran
June 17, 2014

NIMH Director Thomas Insel, M.D., says that more people are getting more treatment, but outcomes are not getting better, so many of today’s treatments may not be sufficient to “bend the curve.” The field of psychiatry and neuroscience is haunted by four “inconvenient truths” about the diagnosis and treatment of mental illness, said National Institute of Mental Health (NIMH) Director Thomas Insel, M.D., in a lecture titled “From Psychiatry to Clinical Neuroscience” at APA’s 2014 annual meeting in New York in May. These are his four inconvenient truths: the field has failed to “bend the curve” in the prevalence and cost of mental illness; more people are getting more treatment, but outcomes are not getting better; the current knowledge base is insufficient to ensure prevention, recovery, or cure for too many people with serious mental illness; and a transformation of diagnostics and therapeutics is necessary to make significant progress in treating mental illness.

Insel contrasted the remarkable progress of the last several decades in reducing morbidity and mortality associated with major medical conditions such as stroke, heart disease, pediatric cancers, and AIDS with the stubbornly high rates for mental illness. He noted, as an example, that the suicide rate in the United States is as high as it has ever been. “I can’t tell you a success story as I can for pediatric cancer or AIDS when we talk about suicide,” he said. “It’s rather remarkable that over the last two decades the suicide rate hasn’t budged at all. With about 38,000 suicides a year, we are as high in absolute numbers as we have ever been.”

Knowledge of the brain, despite enormous advances in recent years, is still in its infancy, Insel pointed out. “The brain is a world consisting of a number of unexplored continents and great stretches of unknown territory,” he said.But he also described a promising future in which mental illness is reenvisioned as a disorder of brain circuitry that will be greatly advanced by President Obama’s BRAIN Initiative, announced in April 2013. Research is revealing how chemical imbalances can lead to circuit dysfunction, and in turn to behavioral symptoms, and Insel said the connections that are emerging can be used in the development of diagnostic tests for brain disorders that are today diagnosed late through observation of symptoms. “We can now study the mind with the tools of neuroscience,” he said. For instance, he presented evidence that is revealing attention-deficit/hyperactivity disorder to be a disorder of delayed cortical maturation. He also presented evidence of schizophrenia as a neurodevelopmental disorder with distinct risk and prodromal stages that allow for early intervention.

Finally, he described the NIMH Research Domain Criteria (RDoC) project, which he said will work in tandem with DSM. “DSM/ICD will continue to be the basis of clinical care,” he said. “RDoC is a framework for research in which NIMH will support researchers to deconstruct current diagnostic categories or identify dimensions that extend across categories. RDoC will develop through an information commons that integrates data from many sources, transforming the way we diagnose mental disorders in the future.”
New Opportunities, New Expectations
by Thomas R. Insel,MD and Nitin Gogtay,MD
JAMA Psychiatry. 2014 71[7]:745-746.

There can be little question that we need better treatments for mental disorders. The recent Global Burden of Disease Study demonstrates how neuropsychiatric disorders are a leading source of medical disability in the United States, increasing since 1990 despite a concomitant increase in pharmacologic treatments. Although there have been many commercially successful medications for anxiety, depression, and psychosis, few compounds have shown truly new mechanisms of action, and even fewer represent true breakthroughs in efficacy. For many of our most serious clinical challenges, such as anorexia nervosa, posttraumatic stress disorder, the core symptoms of autism, and the cognitive deficits of schizophrenia, to name a few, we lack effective medications altogether.

With this background, in 2010, the NIMH asked its advisory council for guidance on the best way to address the urgent need for new treatments. The National Advisory Mental Health Council’s report, “From Discovery to Cure,” recommended several changes to the NIMH clinical trials portfolio. Among those recommendations was a call to accelerate the development process, moving quickly into humans for proof-of-concept studies, and a request for trials that identify and validate new targets. From these recommendations, the NIMH has developed a focus on experimental therapeutics, in which interventions are used as probes of disease mechanisms, as well as tests of efficacy.

In February of this year, the NIMH released 4 new funding announcements to transform its investments in clinical trials. These new announcements can be summarized as calling for changes in “what” and “how” trials are conducted. What are we looking for in these new announcements? Each of the 4 covers a different phase or area of clinical investigation, but they all share a focus on learning more about the disorders, as well as the mechanisms of intervention. Each requires a demonstration of target engagement, in addition to assessing changes in symptoms. And each seeks to identify a critical dose and duration of intervention that would engage or modulate the target in addition to assessing symptom change, with a goal of informing further research or treatment strategies.

These changes are the result of the changing ecosystem of treatment development, the advent of new tools to look at mechanisms of change, and the advice of experts both within and outside of our field. They are also a response to many patient advocates who remind us that “time matters.” The current timetable for a clinical trial, which spans nearly a decade from proposal to publication, is not acceptable to families with a child with autism or an adolescent with psychosis. However, in addition to fixing the delay, these families need to know that we are doing everything possible to deliver treatments that are better than what is available today. New treatments will require a deeper understanding of the disorders and a new approach based on experimental therapeutics for pharmacological, psychosocial, and neuromodulatory interventions.
I first became aware that PHARMA was giving up on CNS drug development three years ago when Dr. Stahl let loose with a rant of cosmic proportions [myopia – uncorrected…]. Within a month, the DSM-5 Task Force admitted their planned "biological" DSM-5 wasn’t going to fly, the RDoC from the NIMH was brought to the fore, and Dr. Insel began to talk about brain wiring [class action in the air…] initiating any number of schemes to jump·start CNS drug discovery – all the while whining endlessly about the inadequacy of our current drugs. The timetable for his Clinical Neuroscience seems to have been abandoned around then, though the term is never far from his lips.

I’m so regularly moved to criticize everything he writes that I’m even tired of readng myself. So I thought that, for a change, I would take a moment and consider why I’m so negative whenever I read something from him. The first thing that was immediately apparent – he doesn’t stop and think himself. He doesn’t sit under a tree and consider the fact that the NIMH has been in a constant state of flux, mostly at his beckoning, and has essentially gone nowhere for years [his years]. He’s always coming up with new plans, programs, initiatives and they just flow from one to the other with little to show for the effort. My overused heroic graphic is borrowed from an old Russian Red Army poster, but when I first made it, I was looking for something else I couldn’t find – a picture I remember of Jeb Stuart from our Civil War. At least in popular lore, Stuart and his Cavalry were out racing pell-mell through the country-side with adrenaline flowing and the wind blowing in their hair, forgetting their assigned mission [intelligence], contributing to Lee’s loss at Gettysburg. That’s how I see Dr. Insel – bouncing from experimental medicine to translational science to personalized medicine to connectomes  to whatever-the-RDoC-is to experimental therapeutics without taking a long enough breath to take stock of the state of play.

I suppose another thing is that he seems to think he knows where we’re going and is frustrated that he can’t make us get there with his incentives [like in this JAMA Psychiatry opinion piece]. It’s easy to say all kinds of negative things about the pharmaceutical companies and their disreputable marketing ways, but they also happen to represent a massive, well financed, scientific consortium. They haven’t been able to find what they [and Dr. Insel] are looking for in decades – and they were looking plenty hard. CNS-anythings were selling like hot-cakes and they would have been as pleased as punch to find new targets and new animal models instead of watching those tired rodents floating in beakers eking out me-too antidepressants. PHARMA gave it their all and came up mostly empty handed. What makes Tom Insel think that he can beat their record by taking over their failed quest with his pea-shooter budget?

Were Dr. Insel able to transcend his fixation on Clinical Neuroscience and the as-yet-unfound-novel-breakthroughs-around-the-corner he’s chasing, and could sit quietly under the Bodhi tree beside the river, what faint music might he hear building in the stillness as he mused on his koans? "Why are the people who so embraced the DSM-III so turned off by its current incarnation? or his RDoC proxy?" "Why is there so much negativity about the drugs that were cheered as they flowed from the pipeline not so very long ago?" "Why have so many gurus of the past faded into obscurity, or retirement [or exile in Miami]?"

That music might just say to him that these are the signs and symptoms of Thomas Kuhn’s phase of paradigm exhaustion, a time when something once new and filled with such hope and explanatory power has all its warts showing in bas relief, a time when it’s hard to even recall the former glitter or even that there was such a golden time. All that shows are the exceptions and failings of the now tired paradigm. And the aging former messiahs seem like old men clinging to a dream past its time. What’s supposed to happen is that the passing era gets reconstructed through a more realistic set of lens than the the rose colored glasses that came with the passion of new discovery. But what’s supposed to happen rarely does happen. The proponents try to keep the dream alive, and in the process add a dark patina that increases and prolongs the depth of the period of disillusionment.

We don’t need a new program. We need a new programmer…
Mickey @ 12:08 AM
Filed under: politics
have a good 4th…

Posted on Friday 4 July 2014

Mickey @ 7:00 AM
Filed under: politics
all databases are not created equal…

Posted on Thursday 3 July 2014

The Black Box Warning added to antidepressant labeling in 2004 by the FDA created something of a cottage industry attempting to either discredit it or  reverse it. Those efforts are well documented throughout this and many other blogs. And there have been multiple attempts to say that the net effect has been an increase in suicidality resulting from the fall in prescribing attributed to untreated depression in children and adolescents. This claim has been based on data from large databases from several sources.

This most recent article in the British Medical Journal [Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study] relies primarily on the Mental Health Research Network [3], data from multiple large health plans [not for profit HMOs]. But there are other datasets involved in the analysis: PHARMetrics Patient Centric Database [1], BC Ministry of Health, and the Nationwide Inpatient Sample [2] – the latter two chosen because they include complete ICD-9 E-Codes [codes for external injury]. PHARMetrics is a commercial enterprise used for marketing intelligence [I've extracted the descriptions of these datasets from the referenced papers at the end of this post with links to their abstracts and full texts when available. I also added some charts from the reported ages.].

While I’m still grumbling about the Lu et al papers [3], my main agenda in this post is something else – the use of these large databases in research papers. The story begins with a problem – the commercial databases don’t have usable E-Codes, the ICD-9CM codes that directly address suicide attempts. In their Letter to the Editor [3], Lu et al prove that the database they are using doesn’t have these E-Codes with any consistency across sites. So they bring up Patrick et al [2] who did a study trying to deal with the missing E-Codes by locating other parameters that could be used as a proxy for suicide attempts. They tried a number of combinations and came up with an algorithm involving psychiatric diagnosis and injury to the lower arm or asphyxiation or overdose with psychotropic medications using two government databases that had required E-Codes as their gold standard.

In their Letter to the Editor [3], they essentially rewrite Patrick et al’s paper by saying:
"Patrick et al. developed and tested algorithms for identifying hospitalizations for deliberate self-harm in a population aged 10 years and over. This study used the US National Inpatient Sample data and data from British Columbia; both data sources had E-code completeness rates above 85 %. The gold standard for deliberate self-harm was defined as hospitalizations with a diagnosis of E950-958. Patrick et al. found that an algorithm combining diagnoses for psychiatric disorders [including depression] and injury/poisoning can produce a positive predictive value as high as 87.8% for identifying hospitalizations for deliberate self-harm [with specificity of 99.4% and sensitivity of 57.3%]. In the context of our longitudinal study on the impact of Food and Drug Administration warnings on antidepressant use and subsequent suicidality in youth, using Patrick’s algorithm may introduce ascertainment bias because rates of depression diagnosis declined subsequent substantially after the warnings."
Speaking of bias, the references in that last sentence point to yet another set of studies [1], industry funded, from articles clearly attempting to discredit the Black Box Warning using a marketing research database. They said it again in their BMJ paper [3]:
Because previous studies showed that rates of depression diagnosis changed after the warnings and that outpatient claims are often incomplete for mental health conditions such as depression, to avoid introducing selection bias, we did not limit our cohorts to those with a coded diagnosis of depression.
And used Patrick et al’s validation numbers for the truncated algorithm as if they applied to their own data:
Non-fatal poisoning by psychotropic drugs [predominantly tranquilizers] has a positive predictive value of 79.7% for suicide attempts [sensitivity was 38.3% and specificity was 99.3%], outperforming other types of injuries or poisonings.
So Lu et al take the algorithm suggested as a suicide attempt proxy from two government datasets [2], modify it based on two other articles using data from a marketing research database [1], and then apply the modified algorithm to yet another dataset collected from an HMO consortium [3]. Further, while they validate that the E-Codes are unusable in their database, but don’t test their own database to confirm that there have been changes in the diagnosis of depression or other psychiatric conditions. Further do they didn’t check their own database to see if the the patients they identified with their jury-rigged algorithm were on antidepressants at the time they were identified. Nor did they show us the results of using Patrick et al’s full algorithm on their own data.

Even though the intervals vary, just looking at the age ranges [at the end of this post], it’s apparent that these are different datasets. Further, they were created for different reasons, from different sources, and their ontogeny can’t be vetted, at least by me. All those things heighten the need to reproduce the findings of others in their own database, something not very hard to do [and obvious]. I would suggest that this study is uninterpretable, and shouldn’t have been published in a mainstream journal as is, but rather sent back suggesting resubmission when they’d done their necessary homework. My broader point is that population studies are hard enough to interpret when done thoroughly. Making the assumption that the results from any given dataset can be applied to any other dataset freely is untenable [also obvious]. A simple rule for such studies:

all databases are not created equal…


Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs.
by Libby AM, Brent DA, Morrato EH, Orton HD, Allen R, Valuck RJ.
American Journal of Psychiatry. 2007 164[6]:884-891.
[full text online]
Persisting decline in depression treatment after FDA warnings.
Libby AM, Orton HD, Valuck RJ.
Archives of General Psychiatry. 2009 66[6]:633-639.
[full text online]
Data for this study come from the PHARMetrics Patient Centric Database, the largest national database of longitudinal integrated health care claims data commercially available from PHARMetrics, a Unit of IMS, Inc [llagerstown, Maryland], under unrestricted license. Data came from integrated medical, specialty, facility, and pharmacy-paid claims from more than 95 managed care plans nationally, representing more than 53 million covered patienls from January 1999 to December 2007. Patients were unidentified and anonymous; therefore, an ex- pedited review was obtained from the Colorado Multiple In- stitutional Review Board..
Identifying a cohort of new episodes of depression was the first step in building the analytic file. The definition of a new episode of depression was based on specifications of the National Committee for Quality Assurance Health plan and Hm- ployer Data and Information Set.’617 The resulting time hori- zon that accounted for episode creation, follow-up, and seasonality spanned from July 1999 to June 2007- The total cohort of 643 313 individual patients was separated into 3 depression cohorts comprising 792 807 episodes of diagnosis and possible treatment There were 91748 pediatric cases [aged 5-18 years at time of diagnosis], 70 311 young adult cases [aged 19-24 years at diagnosis], and 630 748 adult cases [aged 25-89 years at diagnosis]. Average ages for each cohort were 15 years for pediatric, 21 years for young adults, and 44 years for adults. Female patients accounted for roughly 60% of pediatric cases and 70% of adult cases; 4% of cases were receiving managed Medicaid benefits at the start of the episode.


Identification of hospitalizations for intentional self-harm when E-codes are incompletely recorded
by Amanda R. Patrick, Matthew Miller, Catherine W. Barber, Philip S. Wang, Claire F. Canning and Sebastian Schneeweiss
Pharmacoepidemiology and Drug Safety. 2010 19:1263–1275.
Data were derived from two large population-based hospital discharge abstract databases. We chose to use two different databases in the interest of gaining some insight regarding the generalizability of our findings. These data were drawn from two countries with different suicide rates, different practice patterns, and different hospital payment schemes, which may translate into differences in coding practice. In addition, there is variation in the number of diagnosis and procedure codes recorded and the availability of patient-level linkable data on prior inpatient hospitalizations, physician visits, and prescription drug use.
Data from British Columbia [BC], Canada, were obtained from the BC Ministry of Health. The database includes records of hospitalizations for all patients in BC’s publicly funded healthcare system. Data elements include patient age and sex, up to 25 diagnosis codes including E-codes, up to five procedure codes, length of stay, and discharge disposition. An evaluation of this database found good specificity and completeness of diagnosis codes. We used data from 1999 through 2001, a period immediately prior to the transition from ICD-9-CM to ICD-10-CA diagnosis codes in BC.
Data from the United States came from the Nationwide Inpatient Sample [NIS], a publicly available dataset designed to approximate a 20% representative sample of all non-federal hospitals in the United States. The NIS is produced by the Agency for Healthcare Research and Quality [AHRQ] from hospital inpatient discharge records submitted by state health data organizations. The 2003 NIS included data from 37 states. Data elements include hospital location [state], patient age, sex, and race, up to 15 diagnosis codes, up to 15 procedure codes, up to 4 E-codes, length of stay, primary payer, and discharge disposition.


Letter to the Editor
How complete are E-codes in commercial plan claims databases?
by Christine Y. Lu, Christine Stewart, Ameena T. Ahmed, Brian K. Ahmedani, Karen Coleman, Laurel A. Copeland. Enid M. Hunkeler, Matthew D. Lakoma, Jeanne M. Madden, Robert B. Penfold, Donna Rusinak, Fang Zhang, and Stephen B. Soumerai
[full text in a madness to our method – a new introduction… ]
Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study
by Christine Y Lu, Fang Zhang , Matthew D Lakoma analyst, Jeanne M Madden, Donna Rusinak, Robert B Penfold, Gregory Simon, Brian K Ahmedani, Gregory Clarke, Enid M Hunkeler, Beth Waitzfelder, Ashli Owen-Smith, Marsha A Raebel, Rebecca Rossom, Karen J Coleman, Laurel A Copeland, Stephen B Soumerai
British Medical Journal. 2014 348:g3596.
[full text online]
This study included 11 geographically distributed US healthcare organizations that provide care to a diverse population of 10 million people in 12 states. All organizations are members of the Mental Health Research Network. a division of the larger HMO Research Network, an established consortium of 19 research centers affiliated with large not for profit integrated healthcare systems. Members are enrolled through employer sponsored insurance, individual insurance plans, and capitated Medicare and Medicaid programs. Members served by these systems are generally representative of each system’s geographic service area [see supplementary table A]…
To examine changes in suicide attempts after the warnings, we used the same denominator population as defined previously. While encounters for suicide attempts can be identified in administrative databases using external cause of injury codes [E-codes]], they are known to be incompletely captured in commercial plan databases. Our preliminary analysis found that E-code completeness varied across study sites, treatment settings, and years. Therefore, instead of deliberate self harm E-codes, we used poisoning by psychotropic agents [international classification of diseases, ninth revision, clinical modification 969], a more reliable proxy for population level suicide attempts. Poisoning by drugs or toxic substances is the most common method of suicide attempt leading to hospital admission and emergency room treatments. Non-fatal poisoning by psychotropic drugs [predominantly tranquilizers] has a positive predictive value of 79.7% for suicide attempts [sensitivity was 38.3% and specificity was 99.3%], outperforming other types of injuries or poisonings.

Mickey @ 1:52 PM
Filed under: politics
you can’t put a company in jail…

Posted on Thursday 3 July 2014

by Jack Friday
July 2, 2014

South China Morning Post’s Toh Han Shih reports that British/Chinese-American corporate investigator couple Peter Humphrey and Yu Yingzheng, who were arrested last summer during a bribery investigation into their clients GlaxoSmithKlinewill stand trial in Shanghai on July 29th.
    Chinese prosecutors originally wanted to charge Humphrey and Yu with several offences, including some relating to illegal business operations. But they decided to drop all of them except for one of illegally buying information, a source close to the family said. Although each faced only one charge, they risked being jailed if found guilty, the source added. Prosecutors had made Humphrey and Yu’s lawyers sign a non-disclosure agreement preventing them from revealing certain information to the couple, the source said. [Source]
News of the trial follows reports about a covert sex tape of GSK’s top China executive, which the pair had been hired to investigate. From Laurie Burkitt at The Wall Street Journal:
    The British drug maker regarded the video — apparently shot without the executive’s knowledge — as a breach of security, the person said. The executive in the video, Mark Reilly, directed the company to hire a Shanghai-based private investigation firm run by a British national and his Chinese-born wife to investigate the breach, the person said. …Until this weekend’s disclosure about the video, it wasn’t clear whether ChinaWhys had been working for Glaxo when its owners were seized by authorities. The details of the video were reported by Britain’s Sunday Times newspaper. …Chinese law enforcement in May accused Mr. Reilly of ordering subordinates to commit bribery that generated billions of yuan in revenue for Glaxo’s China operations. Authorities alleged that Mr. Reilly, a Briton, ordered his sales team and other employees to bribe hospital doctors, health-care organizations and other parties on “a large scale” to boost drug sales in China. [Source]
Chasing links, I ran across this one that had lots of info:
Digital China Times
by Josh Rudolph
May 14, 2014

    After ten months of investigation, police found that William Mark Reilly, a British national and executive of GSK China, had ordered his subordinates to commit bribery, said the police of Changsha, capital of central China’s Hunan Province, in a statement. Reilly allegedly pressed his sales teams to bribe hospitals, doctors and health institutions through various means and gained an illegal revenue worth of billions. He and two other executives, Zhang Guowei and Zhao Hongyan, were also suspected of bribing officials with the industry and commerce departments of Beijing and Shanghai. [Source]
GSK has not yet been charged, but is carrying out internal investigations for corruption allegations in other countries, including Iraq, Jordan and Lebanon. In 2012, GSK plead guilty to criminal charges in the U.S. and paid a $3 billion fraud settlement.

    The Ministry of Public Security alleged that Reilly, GSK vice-president Zhang Guowei and GSK legal affairs supervisor Zhao Hongyan formed an emergency group in 2012 to bribe law enforcement and other officials in Beijing, Shanghai and elsewhere to block a government investigation of GSK. “Reilly and other senior GSK executives proactively covered up the bribery activities and strongly maintained the financing channels through which the bribes were funnelled,” the ministry alleged. Since 2010, GSK’s Chinese subsidiary GlaxoSmithKline (China) Investment (GSKCI) had spent tens of millions of yuan bribing hospitals to use GSK’s liver drugs instead of Chinese-produced drugs, the Ministry of Public Security claimed. GSKCI spent 13 million yuan buying gifts like cars, television sets and video cameras, which were given as bribes to clients in health-care organisations, it said. [...] The prosecution of foreign nationals by the Chinese authorities is likely to prompt or accelerate similar investigations by the regulators of other countries, said Keith Williamson, head of forensic and dispute services for Asia at Alvarez & Marsal, an international professional services firm. [Source]
This becomes the highest-profile corruption scandal involving a foreign company in China since 2009, when four executives of British-Australian mining company Rio Tinto were arrested for bribery and espionage. The four—one of whom was an Australian citizen—were sentenced to between 7 and 14 years in prison. Under China’s Criminal Law, “serious” cases of bribery can carry a maximum sentence of life imprisonment, and a minimum 5-year prison sentence. Coverage from Reuters notes surprise at the bribery charge among the foreign business community, and GSK’s place in China’s lucrative and rapidly growing pharmaceutical market:
    Kenneth Jarrett, president of the American Chamber of Commerce Shanghai, said he was surprised at the “strong response” from the police. “I would agree that it’s not what I would have expected because it seemed like GSK were cooperating very closely with the authorities,” he told Reuters. [...] China is a key growth market for large drugmakers, which are counting on its swelling middle class to offset declining sales in Western countries. China is set to be the second-biggest pharmaceuticals market behind the United States within three years, according to consultants IMS Health. [...] “Later they could bring an action against the company and seek penalties against the company and I wouldn’t be surprised if they did that actually, because the claim is so egregious that the company could be charged and fined,” said Steven Dickinson, Qingdao-based partner with law firm Harris Moure. “But the thing is you can’t put a company in jail and they want someone in jail. They want Mr. Reilly in jail for about 10 years. That’s what they’re looking to do,” he added. [Source]
As the initial probe was spreading to the wider pharmaceutical industry last year, commentators noted that foreign firms operating in China are sometimes compelled towards questionable business practice to keep up in an industry overrun by corruption.
If you’ve done much wandering in the world, you learn that bribing officials and such is standard operating procedure in a number of places, but also that "when in Rome, do as the Romans do" isn’t very good advice. They know their own lines not to cross, and we usually don’t. Sounds like Mr. Reilly stepped way over any number of lines, and the comment at the end of the article has the feel of an informed prediction. “Later they could bring an action against the company and seek penalties against the company and I wouldn’t be surprised if they did that actually, because the claim is so egregious that the company could be charged and fined. But the thing is you can’t put a company in jail and they want someone in jail. They want Mr. Reilly in jail for about 10 years. That’s what they’re looking to do.

Mickey @ 8:00 AM
Filed under: politics
wisdom here…

Posted on Wednesday 2 July 2014

Before now, J&J et al’s TMAP scheme to sell Atypical Antipsychotics to our government programs held the lead in pharmaceutical greed. But they only replaced a "just as good" generic with expensive in patent drugs. Roche jumped way out front with Tamiflu®, a drug essentially inert as a life-saver sold to governments by the barge load to save us from a flu epidemic. The story of the Cochrane quest to bring this drug’s worth to light is one of the century’s better scientific achievements [as well as a passable good sleuthing story]. So Roche’s rapid response to the BMJ is more than just a day late and a dollar short:
Pharmalot WSJ
By Ed Silverman
July 1, 2014

Three months after a study concluded the widely used Tamiflu® treatment was not proven to reduce the spread of the flu or its complications, Roche has struck back by calling the analysis “seriously flawed” and warns the conclusions could lead to public health risks by confusing patients and physicians. In a letter to the British Medical Journal, which published the study, the drug maker claims the authors made “basic errors” in assessing effectiveness data, “over-interpreted” the “limited” safety data that was evaluated and “wholly ignored” other types of data in reaching their conclusion.

The study authors “have drawn many conclusions that would not be supported by a methodologically robust and comprehensive analysis of all relevant [Tamiflu®] data,” Roche scientists wrote. “Equally important, they have not exhibited the diligence necessary when working with large clinical trial datasets and extensive regulatory documents.”

The missive was made in response to a study by the Cochrane Collaboration, a non-profit, global network of health care academics. They concluded that Tamiflu® was no more effective than aspirin, and one of its authors said governments that stockpiled the drug had thrown money “down the drain.” The study, however, did not question the ability of Tamiflu® to treat flu symptoms.

One of the Cochrane researchers wrote us that the authors stand by their conclusions. “Their response was disappointing window dressing designed for those who do not know the story,” Tom Jefferson, a study co-author, wrote us. He adds that a complete rebuttal will soon be provided in BMJ.

Tamiflu® was approved by the FDA in 1999 and became a big seller several years ago as governments moved to stockpile the treatment in the wake of the H1N1 swine flu pandemic. This prompted the Cochrane researchers to assess the effectiveness. They analyzed results from 46 of 107 trials pertaining to both Tamiflu® and Relenza®, a less widely used flu drug sold by GlaxoSmithKline.

But their study was released only after they battled, sometimes publicly, with Roche over access to Tamiflu data, because most of the trial information was unpublished. The episode, which played out in the pages of BMJ as the researchers often chronicled their efforts to convince Roche to release data, became a linchpin in the wider debate over access to clinical trial data harbored by drug makers.

As a result, the European Parliament recently passed a law requiring drug makers to publish all clinical trials related to a drug, but only those approved since January 2014. Both Roche and Glaxo now say they are committed to publishing all clinical study reports on all their drugs, although some Cochrane researchers have also squabbled with Glaxo about data for its Paxil antidepressant.
If you don’t know the whole story, here are a couple of catch-me-ups…
…and a reference to the actual data [if you've got an extra decade with nothing to do]:
BMJ: Rapid Response
by Carl Heneghan, Tom Jefferson, and Peter Doshi
6 April 2014

With the publication of our systematic reviews on oseltamivir and zanamivir for influenza in adults and children, we are making all 107 full clinical study reports publicly available. Despite the worldwide stockpiling of antivirals, these reports have never been reviewed by the World Health Organization, the US Centers for Disease Control and Prevention [CDC] and its European counterpart, the ECDC.

It took us four years to obtain the full set of reports. The story relating to the acquisition has been documented at the BMJ’s open data campaign []. If you disagree with our findings, or if you want to carry out your own analysis or just want to see what around 150,000 pages of data look like, they are one click away [].
This story has already become a legend in the saga of our pharmaceutical industry’s race to profit with new medications. To connect this story to my more usual topics on this blog, there’s little doubt in my mind that the SSRI drugs have demonstrable antidepressant properties, or at least some effect on brain function that shows up in our subjective measures of depression. At issue is the clinical relevance of those effects when measured against adverse effects from the medications. And that’s true of most medications - desirable effect, strength of effect, adverse effect, consequences of adverse effect, all dancing around in many of the treatment decisions a sick person makes. I have little doubt that Tamiflu® [Oseltamivir] has a viracidal effect on the influenza virus at some early point in the virus’ cycle. But the nature of viral illness is such that for the respiratory viruses, the damage is done very quickly. Many of the symptoms of the common cold, for example, are from the body’s response to the viral assault after the fact, when the virus is long gone. There are a couple of important comments in the BMJ Rapid Response from Public Health physicians that put the medical side of this story into better perspective:
Peter M English
Public Health Physician

The comments colleagues and I made previously still stand:

Early in the "containment phase" of the pandemic the health secretary promised that everybody with flu-like symptoms would be given antivirals. The effect of this was that we were obliged to honour this promise. There were not the resources to do this in a timely fashion: most people, while I was involved, were delivered the antivirals a week after the onset of symptoms. We were unable to prioritise high-risk patients.

The government has claimed that the "containment phase" was effective; that the reduction in viral shedding that may plausibly have been a consequence of antiviral treatment slowed the spread of the pandemic. There is no reason to believe that antivirals given more than 48 hours after the onset of symptoms had any other benefit; although respiratory physicians tell me they believe it may have had some benefit in the most seriously ill patients.
Patrick J Saunders
Professor of Public Health
John Middleton
University of Staffordshire

… We remain concerned however, that the insights of service providers on the ground during the pandemic have not been given the same level of public consideration. It is well documented that even drugs which may be effective in clinical trials can be inefficient, or fail to deliver the patient benefit predicted by trial results, when subject to limitations of general service use. The lessons from service insights in the pandemic are: the wanton abandonment of first principles such as isolation, basic control of infection measures and clinical assessment in favour of the stubborn insistence on managing ‘England as a single epidemiological unit’; and the irrational maintenance of the ‘containment’ phase which led directly to perverse and damaging interventions and over-reliance on antivirals in mass prophylaxis exercises particularly in schools. Anti-viral collection centres became loci for the spread of infection as thousands of symptomatic and sub-clinical cases [there is good evidence that flu can be spread by asymptomatic patients] and unaffected contacts convened for a wonder drug with serious potential side effects, and which would now appear to be no more effective in pandemic management than paracetamol [US name: acetaminophen or Tylenol].

It would be irresponsible for these lessons not to underpin current planning for pandemics and any subsequent responses. We believe there is no place for antiviral distribution in a pandemic based on the current evidence of the effectiveness of the drugs, their ineffectiveness for mass prophylaxis and the likely spread of infection brought about by bringing people to a centre for the drugs.
Great wisdom here. Even if Tamiflu® works, there’s a small window and it’s likely passed by the time the drug comes along. So what about it stopping the spread [shedding]? Same problem – that window may have already passed. And what about having people all heading to some distribution center to get their Tamiflu®? a place teeming with flu to waiting to be caught? Better to stay home, lock your door, and cross your fingers…
Mickey @ 8:30 PM
Filed under: politics
an anachronism…

Posted on Wednesday 2 July 2014

I thought we might be getting beyond these industry funded Clinical Trials of psychiatric medications being published in our peer reviewed journals, but they’re still there [though much less frequently]. This one is in the AJP published online last week ahead of print. It tests the effects of Seroquel XR® on patients with Borderline Personality Disorder using as the primary outcome measure the Zanarini scale [funded by AstraZeneca of course]. AstraZeneca pulled off some sleight of hand getting Seroquel XR® approved as Seroquel’s patent was running out. There’s nothing I know of that would suggest that Seroquel XR® would be any different from regular Seroquel®, but AstraZeneca continues with the Clinical Trials as if Seroquel XR® is something special:
by Donald W. Black, M.D. Mary C. Zanarini, Ed.D. Ann Romine, R.N. Martha Shaw, B.A. Jeff Allen, Ph.D. S. and Charles Schulz, M.D.
American Journal of Psychiatry. 2014 Jun 27. [Epub ahead of print]

Objective: The authors compared the efficacy and tolerability of low and moderate dosages of extended-release quetiapine in adults with borderline personality disorder.
Method: Ninety-five participants with DSM-IV borderline personality disorder were randomly assigned to receive 150 mg/day of quetiapine [the low-dosage group; N=33], 300mg/day of quetiapine [the moderate-dosage group; N=33], or placebo [N=29]. Total score over time on the clinician-rated Zanarini Rating Scale for Borderline Personality Disorder [“Zanarini scale”] was analyzed in a mixed-effects model accounting for informative dropout.
Results: Participants in the low-dosage quetiapine group had significant improvement on the Zanarini scale compared with those in the placebo group. Time to response [defined as a reduction of 50% or more on the Zanarini scale total score] was significantly shorter for both the low-dosage quetiapine group [hazard ratio=2.54, p=0.007] and the moderate-dosage quetiapine group [hazard ratio=2.37, p=0.011] than for the placebo group. Among participants who completed the study, 82% in the low- dosage quetiapine group were rated as “responders,” compared with 74% in the moderate-dosage group and 48% in the placebo group. Treatment-emergent ad-verse events included sedation, change in appetite, and dry mouth. The overall completion rate for the 8-week double-blind treatment phase was 67% [67% for the low-dosage quetiapine group, 58% for the moderate-dosage quetiapine group, and 79% for the placebo group]. Participants who experienced sedation were more likely to drop out.
Conclusions: Participants treated with 150 mg/day of quetiapine had a significant reduction in the severity of borderline personality disorder symptoms compared with those who received placebo. Adverse events were more likely in participants taking 300 mg/day of quetiapine.
In a number of ways, this Clinical Trial embodies the story of the last thirty years. If there’s any solid evidence that there’s a biological antecedent to this disorder, I don’t know about it. Certainly nothing that would suggest that an atypical antipsychotic would be treatment other than as a "calmer downer" in an agitated crisis state. But Dr. Schulz has been trying various medications in this condition for a very long time. In an industry funded Medscape CME, he shows a slide of the drugs that have been tried:
The most recent Cochrane review [2010] says:
by Stoffers J, Völlm BA, Rücker G, Timmer A, Huband N, and Lieb K.
Cochrane Database Systematic Review 2010 Jun 16;[6]:CD005653.
AUTHORS’ CONCLUSIONS: The available evidence indicates some beneficial effects with second-generation antipsychotics, mood stabilisers, and dietary supplementation by omega-3 fatty acids. However, these are mostly based on single study effect estimates. Antidepressants are not widely supported for BPD treatment, but may be helpful in the presence of comorbid conditions. Total BPD severity was not significantly influenced by any drug. No promising results are available for the core BPD symptoms of chronic feelings of emptiness, identity disturbance and abandonment. Conclusions have to be drawn carefully in the light of several limitations of the RCT evidence that constrain applicability to everyday clinical settings [among others, patients' characteristics and duration of interventions and observation periods].
And the Seroquel XR® study is no different, having no significant effect on core symptoms [speaking of significance, the higher dose Seroquel XR® was not statistically significant]. This study is a classic "experimercial" aiming towards fostering the off-label use of Seroquel XR® in this condition. This whole enterprise of doing Clinical Trials in Borderline Personality Disorder is not science based, more a shotgun approach to see what sticks. Here’s another one from four years ago, funded by Eli Lilly aiming to study Zyprexa in this group of patients, also by Dr. Schulz. Similar results:
by Mary C. Zanarini, EdD; S. Charles Schulz, MD; Holland C. Detke, PhD; Yoko Tanaka, PhD; Fangyi Zhao, PhD; Daniel Lin, PhD; Walter Deberdt, MD; Ludmila Kryzhanovskaya, MD; and Sara Corya, MD
Journal of Clinical Psychiatry. 2011 72[10]:1353–1362.

Objective: To examine the efficacy and safety of olanzapine at low and moderate doses for the treatment of borderline personality disorder.
Method: In this 12-week randomized double-blind placebo-controlled trial, 451 outpatients aged 18–65 years with DSM-IV borderline personality disorder received olanzapine 2.5 mg/d [n = 150], olanzapine 5–10 mg/d [n = 148], or placebo [n = 153]. The trial was conducted from February 2004 through January 2006 at 59 community-based and academic study centers in 9 countries [United States, Italy, Poland, Romania, Turkey, Chile, Peru, Argentina, and Venezuela]. The primary efficacy measure was mean change from baseline to last-observation-carried-forward endpoint on the Zanarini Rating Scale for Borderline Personality Disorder [ZAN-BPD] total score. Secondary measures included the Montgomery-Asberg Depression Rating Scale, the Modified Overt Aggression Scale, the Global Assessment of Functioning, the Symptom Checklist-90-Revised, and the Sheehan Disability Scale.
Results: An overall mean baseline ZAN-BPD total score of 17.2 [SD = 4.9] indicated moderate symptom severity. Only treatment with olanzapine 5–10 mg/d was associated with significantly greater mean change from baseline to endpoint in ZAN-BPD total score relative to placebo [−8.5 vs −6.8, respectively; P = .010; effect size = 0.29; 95% CI, 0.06–0.52]. Response rates [response indicated by ≥ 50% decrease from baseline in ZAN-BPD total score] were significantly higher for olanzapine 5–10 mg/d [73.6%] versus olanzapine 2.5 mg/d [60.1%; P = .018] and versus placebo [57.8%; P = .006]. Time to response was also significantly shorter for patients taking olanzapine 5–10 mg/d than for placebo-treated patients [P = .028]. Treatment-emergent adverse events reported significantly more frequently among olanzapine-treated patients included somnolence, fatigue, increased appetite, and weight increase [all P values < .05]. Mean weight change from baseline to endpoint was significantly greater for olanzapine-treated than for placebo-treated patients [olanzapine 2.5 mg/d: 2.09 kg; olanzapine 5–10 mg/d: 3.17 kg; placebo: 0.02 kg; P < .001]. The overall completion rate for the 12-week double-blind treatment period was 65.2% [ie, 64.7% for olanzapine 2.5 mg/d, 69.6% for olanzapine 5–10 mg/d, and 61.4% for placebo].
Conclusions: Olanzapine 5–10 mg/d showed a clinically modest advantage over placebo in the treatment of overall borderline psychopathology. This advantage in effectiveness should be weighed against the risk of adverse events [particularly weight gain], which were consistent with the known safety profile of olanzapine.
    a·nach·ro·nism  [-nkr-nzm]
       a thing or person that belongs to another, especially an earlier, time.
It’s time for our journals to realize that they’re not roadside billboards and put an end to publishing articles whose primary purpose is advertising expensive drugs, off-label, particularly the major journals like the American Journal of Psychiatry. That’s just not what they’re for. That’s never been what they are for…
Mickey @ 12:47 AM
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