1 Boring Old Man

The American Psychiatric Association Preliminary Scientific Program for the Annual Meeting is on-line, and I was perusing it looking for something specific. I remain awed that the Harvard Master Class Psychopharmacology Course still has veterans from Chuck Grassley’s Senate Investigation [see april fools day – 2016…]. So I was curious to see if they were still prominent on the APA Program as well [that list included Charles Nemeroff, Alan Schatzberg, Joseph Biederman, Timothy Wilens, Thomas Spencer,  Jeffrey Bostic, Martin Keller, John Rush, Karen Dineen Wagner, Melissa Delbello, and Fredrick Goodwin].  At the 2016 APA, Charlie Nemeroff has a session on Personalized Medicine: Depression; Alan Schatzberg has one on the HPA Axis Genetic Variation, Psychosis, and Cognition in Depression and directs the Essential Psychopharmacology Course; and Karen Dineen Wagner leads a session on the Management of Depression in Children and Adolescents. Compared to former years, that’s not much.

But as long as I had the program open and was using find to search the .pdf, I put in some other words. There were two prominent names that were not in the program at all: INSEL and LIEBERMAN. But then I did some how often? word-counting: RDoC 5; DSM-5 13; Borderline 13; Psychodynamic 13; Psychotherapy 14; CBT 21. That’s hardly a scientific study, but it did confirm an impression I had just leafing through the program. At the least, the word psychotherapy appears to be back in the discourse after a prolonged sabbatical. For a very long time, the word psychotherapy primarily appeared in the phrase evidence-based-psychotherapy – which was mostly a synonym for cognitive behavior therapy [CBT] and some of its derivatives – referring to the time-limited, structured psychotherapy originated by Aaron Beck. In the 1970/1980s, there were a number of clinical trials of CBT in depressed patients. The usual design had four groups: placebo, antidepressant, CBT, and CBT+antidepressant. And the usual outcome was that either CBT alone or antidepressant alone beat placebo, but CBT+antidepressant beat all three of the other groups. Psychoanalysis or the the dominant psychiatric psychotherapy of that time, psychodynamic psychotherapy, had no such evidence base and was not considered an evidence-based psychotherapy.

The arrival of the DSM-III in 1980 was not a simple matter. It represented the confluence of more forces than one can even catalog. It solved a lot of problems even as it was compounding others and creating some new ones of its own. That would be expected of something that was such a drastic change, something to work out  in practice by iteration, trial and error, etc. Unfortunately, that’s not what happened, at least not as I saw it then or for that matter, as I see it in retrospect. The affected parties quickly adapted it to their own needs and the landscape underwent rapid fundamental changes. We’re now decades beyond those adaptations, and in another crisis state much like the one that lead to those 1980 changes in the first place. With Dr. Insel, the prophet of Clinical Neuroscience, gone; the failure of the DSM-5 Revision process in bas relief; the slowing of the flow of new drugs from the psychopharmacologic pipeline to a dribble; and the fading prominence of the KOL Psychiatrists; psychiatry appears to be trying to find itself once again – and that process is reflected in the American Psychiatric Association Preliminary Scientific Program – sometimes in extremes. I mentioned the return of psychotherapy, getting psychiatrists back to talking with patients. But to go back to my unscientific-word-counting ways for a minute, Collaborative Care comes in with a word count of 9 – a proposal where psychiatrists don’t even see the patients at all.

from the President

Should Psychotherapy Remain Part of Psychiatry?

PSYCHIATRICNEWS

by Renée Binder,M.D.

January 29, 2016

As we are making huge advances in neuroscience and genomics, the day may come when we can better understand the etiology of mental disorders and devise biologic treatments that target the underlying mechanisms. In one of his blogs, Tom Insel, M.D., immediate past director of the National Institute of Mental Health, wrote about changing the field of psychiatry into the field of clinical neuroscience. I would argue that psychiatrists need to keep the practice of psychotherapy as one of their essential skills, even as the toolbox that psychiatrists use to diagnose and treat our patients will continue to deepen and expand. In the future, as we add modalities for diagnosis and treatment, we also need to improve on existing modalities…

So what is the future of psychotherapy as part of the practice of psychiatry? The 2014 APA resource document titled “Psychotherapy as an Essential Skill of Psychiatrists” states, “Of all mental health practitioners, only psychiatrists are privileged—and able—to provide all therapeutic modalities … and integrated comprehensive treatment.” The position statement on psychotherapy, passed by the Board of Trustees in December 2015, states that APA should advocate for psychiatrists “to be reimbursed by payers in a manner that integrates care and does not provide financial incentives for isolating biological treatments from psychosocial interventions”…

In my opinion, it would be a huge mistake for psychiatrists to give up psychotherapy as one of our essential skills. Other disciplines would gladly provide this treatment instead of us. But we would lose the ability to provide one of our core treatments that are incredibly helpful to our patients. We also would lose the ability to provide one of the most rewarding modalities of psychiatric practice for those of us who chose psychiatry as a specialty because of the ability to develop relationships with patients and understand and treat them as whole human beings. There is a growing but false dichotomy between neuroscientific and psychosocial interventions. We need to advocate for keeping psychotherapy in our toolbox, expanding research on the common elements of psychotherapy, and furthering its use in novel ways in different types of psychiatric conditions.

The CDC today published prescribing guidelines aimed at opioid painkillers

Pharmalot

by Ed Silverman

March 15, 2016

After months of controversy, the Centers for Disease Control and Prevention today published prescribing guidelines to address the epidemic of deaths and overdoses attributed to opioid painkillers. The guidelines, which focus on chronic pain except for cancer and end-of-life care, arrive amid intensifying concern over the widely prescribed drugs. Every day, more than 40 Americans die from overdoses of opioid painkillers. And each year, 2 million people abuse or misuse the drugs.

Many state lawmakers have responded to the crisis by introducing bills to restrict prescribing. And the Food and Drug Administration is pushing drug makers to develop more tamper-resistant products. But the CDC guidelines, while voluntary, arguably represent the most sweeping effort to address the problem. “We don’t want people getting more opioids than needed,”  said Dr. Debra Houry, the director of the CDC’s National Center for Injury Prevention and Control. “So we hope this will give patients and health care providers help in assessing the risks and benefits.”

The guidelines are targeted at primary care physicians, in particular, since family doctors write the vast majority of prescriptions for painkillers. Notably, the agency recommends doctors prescribe opioids only after other therapies have failed and rely on the lowest possible doses. The CDC also suggests that short-term treatment — typically, just three days, but sometimes seven days — is far more preferable than long-term use. The overriding concern is that patients who take opioids for extended periods are much more likely to become addicted…

The Inadequacy of EBM
Recently, Richardson and Doster suggested the consideration of three dimensions in the process of evidence-based decision:

1. baseline risk of poor outcomes from an index disorder without treatment
2. responsiveness to the treatment option
3. vulnerability to the adverse effects of treatment.

EBM is focused on the potential benefits that therapy may entail as to baseline risk, but it is likely to neglect the other two dimensions. A rational approach to treatment takes into account the balance between potential benefits and adverse effects applied to the individual patient. The achievement of such balance is hindered by the difficult integration of different sources of information. Guidelines tend to place emphasis on systematic reviews and meta-analyses of RCT, which are uniquely geared to highlighting benefits. The clinician needs to have a clear account of the potential benefits of a specific treatment, as well as of the predictors of responsiveness and of the potential adverse events that may be triggered by the therapeutic act. The conceptual model that has generated EBM and guidelines clashes with clinical reality and fosters a dichotomy between medical science and clinical judgment.

The example that immediately came to mind was actually a popular long-running CME Class that I had written about in December 2010 [see cme…]:

It had the reputation of being an upbeat program with a lot of What’s new? and What’s coming down the road? presentations by psychiatry’s front running KOLs. But in December 2010, it struck a discordant note to my ear. By then, the wheels were coming off of KOL Psychiatry. In June of 2008, Senator Grassley and Paul Thacker had exposed widespread unreported PHARMA income and the poster boys were Charlie Nemeroff and Alan Schatzberg [Top Psychiatrist Didn’t Report Drug Makers’ Pay, Grassley Questions Stanford Psychiatrist’s Industry Ties] with both stepping down from their chairs in the aftermath. Then in June of 2009, Allen Frances had joined Robert Spitzer in contesting the directions of the DSM-5 Revision process [A Warning Sign on the Road to DSM-V: Beware of Its Unintended Consequences], and KOL Psychiatry had become COI Psychiatry. To top things off, in November 2010, another shoe had dropped. It seems that a book by Charlie Nemeroff and Alan Schatzberg [Recognition and Treatment of Psychiatric Disorders: A Psychopharmacology Handbook for Primary Care] was ghost-written, paid for by GSK [Drug Maker Hired Writing Company for Doctors’ Book, Documents Say]. So in December 2010 when I read that flyer, I would’ve thought that the Grassley cohort would be discredited. But there they were. I wrote Dr. Salzman a WTF? email and he wrote back assuring me that they were reformed and receiving no PHARMA support [which was hardly my point].

Soon thereafter, I saw two cases in quick succession that taught me an important lesson. I wrote about the first one [evidence-based medicine VI: a case…]. A longtime friend of my daughter’s had come up to see her during a visit. I heard them talking on the porch. she was saying that her Psychiatrist had "finally gotten her meds right" [I think she mumbled the word "Bipolar"]. She said she was on two medications that she named [I cringed]. A couple of months later, my daughter called from North Carolina. She’d gotten a call from her friend [in Atlanta] who was driving around crazed and suicidal. Would I call her? I tried and failed, but found out that she’d driven to a mental hospital and checked herself in. One of those medications was Abilify. She had been gaining a lot of weight so she stopped it. That episode was Abilify Withdrawal that cleared with one pill.  The second case was a Social Worker I worked with. She called me from the side of the road out of town in an agitated state saying she was going crazy. She’d been taking Effexor from her Primary Care Physician for a while. She decided that she didn’t need it anymore and took her last pill the night before. On the phone through her tears she asked, "Could that be it!" She was across the street from a pharmacy, so I called the pharmacist and got her a couple of pills. Not much later, she called back, "That was it!"

How does that get to the Harvard CME Course? I hadn’t really seen withdrawal symptoms from psychiatric meds – only heard about them. I didn’t/don’t prescribe antipsychotics to non-psychotic people. I didn’t/don’t prescribe the short-acting antidepressants like Effexor and Paxil. And I’ve always tapered all psych meds routinely. So I had no feel for the syndrome. After those cases, I started reading about withdrawal. Most of what I found was from patient reports, and from Alto’s SurvivingADs site. So I got in touch with an old friend who was serving as president of our State Association at the time to suggest a program at one of the meetings on the withdrawal syndromes. He was nice but told me that they didn’t have that kind of program. "That’s for CME," he said. He then told me that he got his yearly CME by going to the Harvard Master Class. I asked if they taught about withdrawal, and he said "no." When I got off the phone, I realized that he really didn’t know what I was talking about – about the withdrawal syndromes. And why was that interchange five years ago on my mind when I read Dr. Fava’s editorial? That one’s easy. The flyer for this year’s Harvard Master Class was already  open on my computer’s desk-top for a future post:

^{[click image for the full sized original]}

It’s five years later, and the same people are still at it! still talking about the same topics! still upbeat, still populated with the alumni from Senator Grassley’s Senate investigation – Alan Schatzberg, Charlie Nemeroff. Old standby’s Jeffrey Lieberman and Stephen Stahl are still in the house. I have no transcript, but I can guarantee that this group of speakers will do exactly what Dr. Fava was talking about – accentuate the positive, eliminate the negative, and latch on to the affirmative, but don’t mess with mister in-between. They always have.

I belatedly became aware of the magnitude of the Conflict of Interest [COI] problems in our literature in 2008 with the revelations of Senator Chuck Grassley and his investigator Paul Thacker. But in the years since, I’ve realized that by then what was once unthinkable had already verged on routine, particularly in the industry-sponsored clinical drug trials, particularly in psychiatry. Recently, we’ve seen several articles advocating an even further laxing of COI standards. In this editorial, Dr. Fava goes beyond just decrying the COI problem – he lays out how it came into being and the forces that sustain it. Then he talks about what we can do about the problem…

The Hidden Costs of Financial Conflicts of Interest in Medicine

by Giovanni Fava

Psychotherapy and Psychosomatics. 2016 85:65-70.

[full text on-line]

A series of three articles by Lisa Rosenbaum in the New England Journal of Medicine called for a reexamination of the views and regulations of financial conflicts of interest in medicine. Her conclusions appeared to be clear: ‘The bad behavior of the few has facilitated impugning of the many.’ The effects of this behavior were amplified by journalists who fed a vicious cycle in which each story generates more distrust in the public. Dr. Rosenbaum suggested that current restrictive rules may ‘undermine potentially productive research collaborations, dissemination of expertise, and public trust.’ She acknowledged that studies by pharmaceutical companies are more likely to have outcomes favorable to the sponsor and that physicians who attend events funded by pharmaceutical companies tend to prescribe the featured drugs. However, she claimed that these interactions might actually be beneficial to the patient and that much of the harm was ‘invented’. Dr. Rosenbaum’s views were in sharp contrast with the history of the journal where they were published. The New England Journal of Medicine pioneered the need of disclosure of financial conflicts of interests and the importance of having authors of editorials and review articles free from commercial ties, yet time seems to be ripe for getting rid of these worries and to return to business as usual.

A recent viewpoint published in the JAMA moves toward this direction. Also, these authors complain of the policies on conflicts of interest that were developed in reaction to a limited number of investigators but, once introduced, applied to all. They suggested substituting the pejorative term of ‘conflict of interest’ with ‘confluence of interest’. A name change can be important. When withdrawal reactions started being described following the discontinuation of second-generation antidepressant drugs [selective serotonin reuptake inhibitors, SSRI] they were promptly labeled as ‘discontinuation syndromes.’ The name successfully conferred a harmless nature, which was in sharp contrast with the withdrawal reactions that occurred with other drugs like benzodiazepines. SSRI thus replaced benzodiazepines in the treatment of anxiety disorders, even though discontinuation syndromes of SSRI are actually withdrawal reactions, and the clinical evidence was pointing to just the opposite [benzodiazepines are more effective, with fewer side effects]. The shift from benzodiazepines to SSRI has probably been the most successful achievement of pharmaceutical propaganda in psychiatry, with full endorsement of guidelines and professional societies. Will the term ‘confluence of interest’ achieve the same success? Let us examine the development of the problem, its implications and what can be done about it…

[1] Definition of Financial Conflict of Interest

"Researchers with substantial conflicts of interest are not suitable for writing and participating in reviews, editorials, meta-analyses and guidelines …"

"… the industry may interact with academic investigators through consulting agreements that benefit the university but not the investigator, eliminating any source of direct financial benefit for the individual from the company."

[2] The Pursuit of Critical Thinking in Clinical Practice and Research

"Preserving intellectual freedom in the setting of proliferating connections between pharmaceutical and biotechnology industries and the physicians is a major ethical challenge of medicine today. Loosening rules that were developed over an incredible sequence of scandals and jeopardized the credibility of medicine would not offer a suitable solution…"

"As Wilkes commented on the consequences of inappropriate industry-physician interactions: ‘When trust goes, so does the healing power of physicians.’ Similarly, medical journals do not lose their function to the extent that they foster critical thinking as to clinical matters and do not lose their credibility. Such critical thinking may also be increased by the opportunity at scientific meetings for in-depth discussions among clinical scientists with no substantial conflicts of interest – a pause from information overload."

[3] The Inadequacy of EBM

"Recently, Richardson and Doster suggested the consideration of three dimensions in the process of evidence-based decision: baseline risk of poor outcomes from an index disorder without treatment, responsiveness to the treatment option, and vulnerability to the adverse effects of treatment. EBM is focused on the potential benefits that therapy may entail as to baseline risk, but it is likely to neglect the other two dimensions. A rational approach to treatment takes into account the balance between potential benefits and adverse effects applied to the individual patient."

"EBM certainly made an important contribution to questioning unsubstantiated therapeutic claims. Time has come, however, to become more aware of its considerable limitations, including overall reductionism, disregard of patient-physician relationships and patient preferences, and insufficient consideration of problems related to financial conflicts of interest."

[4] Support of Researchers Free from Substantial Conflict of Interest

At the same time, researchers without substantial conflicts of interest need support. Otherwise, the scientific community would soon drain itself of a reservoir of truly independent experts who can be called upon to advise policy makers on the safety and efficacy of treatments, the hazards of chemicals and the safety of technology. Lines of support for independent researchers, including priority for obtaining grants from public agencies supported by taxpayers’ money and for editorship positions in medical journals, have been outlined [38].

[5] Boycotting Commercial Medical Education and Professional Societies

"The process of regaining intellectual independence does not only involve researchers but also each clinician and society member. Fugh-Berman and Hogenmiller suggested that, in many cases, CME stands for Commercial Medical Education and argued that avoidance of industry-sponsored CME is associated with more rational prescribing. The misleading indications of Commercial Medical Education are more dangerous when sponsoring is subtle and not clearly disclosed. Similar considerations may apply to certain professional societies that are inadequate in handling issues related to conflicts of interest and produce guidelines that are biased. Boycotting such initiatives and societies may yield important effects. Such stands have personal costs but are in line with the expression of intellectual freedom."

I’ve shamelessly and unapologetically co-opted Dr. Fava’s editorial by turning his suggestions into rules. Frankly, I think we’ve come to that at this point. But I reiterate that his editorial isn’t written that way. Over the years of writing this blog, I’ve been awed at how frequently and effectively efforts that began as reforms [or at least looked that way] have been perverted into tools for the opposite purpose. Continuing Medical Education was introduced to force doctors to stay current – a perfectly reasonable goal. But it became corrupted to the point where I almost think we’d be better off without it. We’ve seen that Professional Organizations and Medical Societies can be as destructive as constructive – and in the case of psychiatry, the former has unfortunately been all too common in our recent past. Clinical Trials became required as a way of insuring that inert compounds were kept off the market, but have become a way of allowing statistical efficacy to substitute for clinical efficacy. Guidelines have been a particularly easy mark to introduce programs that lead to overmedication. In psychiatry, even our diagnostic system, introduced as an attempt at reform, has been used to advance any number of inappropriate agendas.

Editorial

US Preventive Services Task Force Recommendation Statement on Screening for Depression in Adults Not Good Enough

by Charles F. Reynolds III, MD and Ellen Frank, PhD

JAMA Psychiatry. 2016 73[3]:189-190.

The US Preventive Services Task Force [USPSTF] has recommended screening for depression in the general adult population, including pregnant and postpartum women, with the use of brief, self-report instruments like the Patient Health Questionnaire 9 that typically take less than 5 minutes to complete. It further underscores the need for screening to be linked with adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up. The recommendation is silent, however, with respect to the ideal screening interval and the settings with highest potential yield. These are major shortcomings in our opinion.

In our view, this recommendation, while more limited in scope than is warranted by the available data, is nonetheless of first-rank importance, given the immense public health burden of depression across the life cycle and its downstream sequelae. The latter include recurrence of major depressive episodes and chronic illness course, emergence of treatment resistance, poor adherence to treatment for coexisting medical disorders, amplification of disability and of family caregiver burden, and increased risk for dementia, suicide, and early mortality from co-occurring medical disorders.

A central feature of the USPSTF recommendation, which we endorse whole-heartedly, is the need to integrate behavioral health services and primary care medicine. Most patients with major depression receive treatment in the general medical, not specialty mental health, sector. This state of affairs reflects patient preferences, issues of stigma that pose a barrier to help seeking [especially among racial and ethnic minorities], lack of an adequate mental health workforce, difficulties navigating the mental health care “system” and accessing expertise, and financial barriers to receiving mental health services…

Our view is that the risk architecture inherent in major depression should inform recommendations for screening intervals, especially in patients who have experienced episodes of major depression. In our opinion, annual screening for depression and its recurrence would be medically appropriate, given the liability of patients with previous episodes for recurrence and chronicity. There is now a strong evidence base for the efficacy of maintenance pharmacotherapy and psychotherapy to reduce the risks for recurrence and chronicity…

Another strong rationale for shorter screening intervals, on the order of 6 to 12 months, is the high prevalence of subsyndromal depression in primary care patients, especially in persons living with psychosocial and medical risk factors. Such patients can benefit from what has been termed by the Institute of Medicine indicated prevention of depression (and other associated common mental disorders) in order to prevent transitions to episodes of frank clinical (major) depression or to prevent chronicity of subthreshold symptoms and their disabling effects…

WAIT JUST ONE MINUTE! You started with an editorial by a Geriatric Psychiatrist from Pittsburgh and his psychologist colleague saying that the recent recommendation for screening for depression by the US Preventive Services Task Force wasn’t strong enough. Why in the hell are you talking about a Statistician in Chicago and the DSM-5 Task Force? Have you got your comments hooked up with the wrong article?…

WAIT JUST ONE MINUTE! What are you getting at? Just because they are colleagues doesn’t mean these things are related – depression screening, this editorial, the company you mentioned. Have you been at this too long? Seeing conspiracies and secretive COI deals behind every bush?…

"Dr Frank receives royalties from the American Psychological Association and Guilford Press; she and her spouse serve on an advisory board to Servier International; she and her spouse have equity in HealthRhythms and Psychiatric Assessments, Inc. No other disclosures were reported."

11/20/2013 Failure to Report Financial Disclosure Information
by Gibbons, Weiss, Pilkonis, Frank, and Kupfer.
JAMA Psychiatry. 2013 71[1]:95.
"To the Editor We apologize to the editors and readers of JAMA Psychiatry for our failure to fully disclose our financial interests in an article that reported a diagnostic tool, the Computerized Adaptive Test for Depression [CAT-DI]… 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… Our submitted disclosure lacked transparency, and we regret our omission."

ADDENDUM: And if that’s not enough Screening/Measurement Conflict of Interest for you, check out HEALTHRHYTHMS…

• a touch of paralysis… 
• infomercials…
• maybe nowhere… 

Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent.

by Preskorn S, Macaluso M, Mehra DO, Zammit G, Moskal JR, Burch RM, and the GLYX-13 Clinical Study Group

Journal of Psychiatric Practice. 2015 21[2]:140-149.

NCT01234558

BACKGROUND: Approximately 45% of patients with major depressive disorder [MDD] do not remit when treated with biogenic amine antidepressants. Consequently, there is a significant need for antidepressant agents with different mechanisms of action. Early proof of concept [POC] studies with such novel agents play a significant role in helping drug developers identify agents and mechanisms of action that merit more intensive research. Studies have demonstrated that high affinity N-methyl-Daspartate [NMDA] receptor blockers [eg, ketamine] can produce rapid antidepressant effects in patients who have not responded to currently available agents, but treatment with these agents is accompanied by psychotomimetic effects that make their use problematic. This column describes a POC study involving GLYX-13, an N-methyl-D-aspartate receptor glycine site functional partial agonist.

METHOD: In this double-blind, randomized, placebo-controlled study, a single intravenous [IV] dose of GLYX-13 [1, 5, 10, or 30 mg/kg] or placebo was administered to 116 subjects with MDD who had not benefitted from a trial of at least one biogenic amine antidepressant during the current episode. The primary outcome measure was score on the Hamilton Depression Rating Scale-17 [Ham-D17], which was used to rate overall depressive symptoms at baseline and at 24 hours and days 3, 7, 14, and, in some arms, days 21 and 28 after administration.

RESULTS: GLYX-13, 5 or 10 mg/kg IV, reduced depressive symptoms as assessed by the Ham-D17 at days 1 through 7. Onset of action as assessed using the Bech-6 occurred within 2 hours. GLYX-13 did not elicit psychomimetic or other significant side effects.

CONCLUSION: In this early POC study, GLYX-13 reduced depressive symptoms within 2 hours and this effect was maintained for 7 days on average in subjects with MDD who had not responded to another antidepressant agent during the current depressive episode. The findings of this study support the hypothesis that modulation of the NMDA receptor is a valid target for the development of antidepressant drugs and the need for additional studies to further evaluate the effects of GLYX-13. POC studies such as the one described here play a pivotal role in allowing drug researchers to decide whether to move forward with larger and more expensive studies, and they enable them to focus available resources on those molecules that appear to have the most therapeutic promise. Based on the POC study described here, a multiple dose study has been completed which showed sustained therapeutic benefit with repeated dosing of GLYX-13 for more than 6 weeks. Phase 3 studies are now being planned.

 

Allergan’s Rapastinel Receives FDA Breakthrough Therapy Designation for Adjunctive Treatment of Major Depressive Disorder [MDD]

DUBLIN, Jan. 29, 2016 /PRNewswire/ — Allergan plc. [NYSE: AGN], a leading global pharmaceutical company today announced that its Phase III ready investigational medication rapastinel [GLYX-13] received Breakthrough Therapy designation from the U.S. Food and Drug Administration [FDA] for adjunctive treatment of Major Depressive Disorder [MDD]. This follows the Fast Track Designation for rapastinel granted by the FDA in 2014.

"Rapastinel is the first Allergan medicine to be granted Breakthrough Therapy designation by the FDA, underscoring our commitment to innovative research and development that addresses significant unmet medical needs. Breakthrough Therapy designation will allow us to work more closely with the FDA to bring this important therapy to patients as rapidly as possible," said David Nicholson, Executive Vice President and President of Global R&D brands at Allergan. "There remains an unmet medical need for agents in depression that demonstrate a rapid onset of action. We believe that rapastinel has great potential to fulfill that unmet medical need in major depressive disorder."…

The Breakthrough Therapy designation was based on preclinical and preliminary clinical evidence for rapastinel, which supports a rapid [within 1 day] and sustained antidepressant effect over the course of the Phase II studies. Rapastinel has been found to be well tolerated in studies to date, with no psychotomimetic or hallucinogenic side effects observed…

Enacted as part of the 2012 FDA Safety and Innovation Act [FDASIA], Breakthrough Therapy designation is intended to expedite the development and review of a potential new medicine if it is intended to treat a serious or life-threatening disease and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies. The Breakthrough Therapy designation is distinct from FDA’s other mechanisms to expedite drug development and review…

• a narrative…
• not so proud…

Jerome P Kassirer: A Canadian purge

BMJ Blogs

4 March 2016

Earlier this week the Canadian Medical Association [CMA] fired the editor in chief of the Canadian Medical Association Journal [CMAJ], citing slipping journal revenue and declining reputation as a cause. The journal’s oversight committee [JOC] — set up in 2006 to safeguard the journal’s editorial independence against political and economic transgressions — negotiated with both the CMA and the CEO of the corporation that runs the journal, hoping that a compromise could be reached.

But now the JOC exists no more. Simultaneous with the firing of the CMAJ editor, members of the JOC were invited to attend a conference call where they, too, were dismissed. This act was a shocking breach of faith, in direct contravention of the processes that the CMA had put in place and repeatedly reaffirmed over the years. In an Orwellian form of logic, the CMA, having dismissed both the editor and the committee, asserted that it was strengthening and reaffirming editorial independence. Given that a new editor will report to the CMA Board or some other entity appointed by the board, it is difficult to imagine how a new editor’s independence could be preserved.

Journal oversight committees are no panacea, and there are circumstances that justify dismissing a journal editor, but the expertise of the JOC volunteers cannot be assailed. By design, it included a tenured professor of journalism with decades of experience as a professional journalist, a generalist physician who has spent 30 years in rural practice and founded a rural medicine journal, an academic clinical investigator with publishing experience for a national organization, a former dean of a medical school who had also been editor in chief of a cardiology journal and had served on the Pound Committee, and one American [myself].

Medical journals are no longer as profitable as they were when I was an editor of a major journal. Many young physicians no longer subscribe and they get their medical information online. Smartphones are rapidly overtaking many other information sources. Advertising revenues, which made up most of the profits in the past, have declined and online revenues have not kept up. If the CMAJ is not considered sufficiently profitable, CMA members have a choice, namely to support the journal from membership dues or not. But to expect the journal to publish high quality work, improve its web presence, and continue to comment on the critical issues facing Canadian medicine on a bare bones, depression-scale budget was never a realistic option.

Medical journals, like the scholarly exchanges of academia, are a public good. Whether journals are owned or operated by industry or medical societies, they share a tight bond with academia. Their editors are recruited from academia, their content is derived from the research and opinions of academic physicians, and academic institutions evaluate their faculty based on where their papers are published. Given these attributes, journal owners are expected to abide by some basic precepts: fairness, openness, and dedication to editorial independence. CMA members should question their allegiance to an organization that fires its journal editor when expedient, treats its professional advisors with disdain, and bends so readily to corporate and financial influences.

• Heparin – a naturally occurring compound found in certain cells. As a drug, it has to be given by injection, acts immediately, is short acting [hours], and blocks the action of any number of clotting factors. It can be reversed [with Protamine Sulfate].
• Warfarin [Coumadin] – Originally introduced as a Rat Poison, Warfarin interferes with the the metabolism [re-use] of Vitamin K which is necessary for the creation and action of a number of those factors [in red], specifically their binding of Calcium. It takes several days to work [produce a Vitamin K deficient state], is sensitive to dietary factors and many drugs, and has to be monitored with frequent [monthly] blood tests. It can be fairly quickly reversed with Vitamin K injections.

A few years back, I ran across something new. A friend [with limited means] developed Atrial Fibrillation and was prescribed a drug I’d never heard of before. He was fretting over the cost, and I looked into it. It was one of the new ones,  Pradaxa®, and it would’ve been a big out-of-pocket expense for a retired "man of the cloth." He was told that there weren’t the restrictions and you didn’t have to get all of those blood tests. It was "better." So I hit the Internet and learned about Xarelto® and Pradaxa®. The restrictions, the hassle of the blood tests, the dosage adjustments weren’t necessary sure enough, but underscore avoid having a big car wreck! two or three times, because at the time I was looking, there was no easy antidote except time. In the figure, their action is more specific, way down at the bottom of the cascade – and there was no off switch then

We had endlessly teased my friend and his wife, calling them Gypsies, because they were always on the road visiting many friends. But his doctor got him a discount somehow, so he opted for the new drug and had no problems, later dying from something unrelated. But in my searching around, I decided that these were "drugs of convenience" rather than "better." I have to admit that my negativity probably has to do with having spent some long nights when I was younger with several wreck victims on Coumadin who I doubt would’ve survived without that off switch.

• Document Claims Drug Makers Deceived a Top Medical Journal
  New York Times
  by Katie Thomas
  March 1, 2016

Antidote for Factor Xa Anticoagulants
Jean M. Connors, M.D.
New England Journal of Medicine. 2015 373:2471-2472

• Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation
  by Manesh R. Patel, Kenneth W. Mahaffey, Jyotsna Garg, Guohua Pan, Daniel E. Singer, Werner Hacke, Günter Breithardt, Jonathan L. Halperin, Graeme J. Hankey, Jonathan P. Piccini, Richard C. Becker, Christopher C. Nessel, John F. Paolini, Scott D. Berkowitz Keith A.A. Fox, Robert M. Califf, M.D., and the ROCKET AF Steering Committee, for the ROCKET AF Investigators
  New England Journal of Medicine 2011 365:883-891.
• FDA Draft Briefing Document for the Cardiovascular and Renal Drugs Advisory Committee (CRDAC)
• FDA Drug Approval Package on Drugs@FDA.gov

• Alere INRatio2 PT/INR Professional Test Strips: recall — higher INR when performed by central laboratory Food and Drug Administration. December 5, 2014

• Data on trial of anticoagulant is to be reanalyzed after discovery that investigators used faulty device
  BMJ 2015 351:h6431
• Point-of-Care Warfarin Monitoring in the ROCKET AF Trial
  by Manesh R. Patel, Anne S. Hellkamp, Keith A. A. Fox, for the ROCKET AF Executive Committee and Investigators
  New England Journal of Medicine. 2016 374:785-788.
• F.D.A. Asks If Faulty Blood Monitor Tainted Xarelto Approval

  New York Times

  by Katie Thomas

  February 22, 2016

Document Claims Drug Makers Deceived a Top Medical Journal

New York Times

By KATIE THOMAS

MARCH 1, 2016

It is a startling accusation, buried in a footnote in a legal briefing filed recently in federal court: Did two major pharmaceutical companies, in an effort to protect their blockbuster drug, mislead editors at one of the world’s most prestigious medical journals? Lawyers for patients suing Johnson & Johnson and Bayer over the safety of the anticlotting drug Xarelto say the answer is yes, claiming that a letter published in The New England Journal of Medicine and written primarily by researchers at Duke University left out critical laboratory data. They claim the companies were complicit by staying silent, helping deceive the editors while the companies were in the midst of providing the very same data to regulators in the United States and Europe…

Duke and Johnson & Johnson contend that they worked independently of each other. Bayer declined to comment. And top editors at The New England Journal of Medicine said they did not know that separate laboratory data existed until a reporter contacted them last week, but they dismissed its relevance and said they stood by the article’s analysis. But the claim — that industry influence led to the concealing of data — carries echoes, some experts said, of an earlier era of drug marketing, when crucial clinical data went missing from journal articles, leading to high-profile corrections and a wave of ethics policies to limit the influence of drug companies on medical literature…

Last month the Duke researchers published an analysis in The New England Journal of Medicine and concluded that the problems with the device did not change the trial’s results. But some in the medical community questioned their findings because their method required them to essentially guess which groups of patients were more likely to be affected by the malfunctioning device. A better way to evaluate the device, other researchers said, would be to compare the device readings with test results that were done at a central laboratory. Investigators did that at two points in the trial, drawing blood from more than 5,000 of the patients who took warfarin and sending the samples for testing. The blood was taken 12 and 24 weeks after patients enrolled in the trial. But the Duke researchers made no mention of the lab data in their letter. In an interview, journal editors said they did not know about the lab data until last Tuesday, when a reporter for The New York Times asked them about it. “At the time we published the letter, we didn’t know that it existed,” said Dr. Jeffrey M. Drazen, editor in chief of The New England Journal of Medicine…

In a footnote, the lawyers said that during the process of vetting the Duke researchers’ letter, a peer reviewer asked about the existence of lab data that would allow a comparison with the device’s readings. “Despite being provided this opportunity to respond to the peer reviewers,” the lawyers said, the “defendants remained silent on this point, thereby misleading the NEJM.” Dr. Drazen confirmed that a peer reviewer, whose identities are kept confidential, had asked about such data, but said the editors had rephrased the question to ask whether such data was available throughout the course of the trial. Duke then answered no, he said. The letter’s three authors, two from Duke and one affiliated with the University of Edinburgh in Scotland, declined to comment, as did a spokesman for Duke…

Dr. Steven Nissen, a cardiologist at the Cleveland Clinic, served on the Food and Drug Administration advisory panel that voted to approve Xarelto in 2011. He was one of two members who voted against the drug. He expressed doubt that any after-the-fact analysis would give doctors and patients answers. “Given the fact that the device was inaccurate, there is no way anybody can tell you what would have happened in the trial,” he said.

Standardized Evaluation of Mental Health Treatment on the Way

Medscape Medical News: Psychiatry

by Alicia Ault

February 25, 2016

Starting in 2017, the Joint Commission will require the 2300 behavioral healthcare organizations it accredits to initiate standardized measurement of interventions designed to improve patients’ mental health outcomes. "We’re going to put in place a measurement-based care requirement," said Margaret VanAmringe, the Joint Commission’s executive vice president for public policy and government relations, at a meeting sponsored by the Kennedy Forum and the Satcher Health Leadership Institute’s Kennedy Center for Mental Health Policy and Research.

Attendees from government agencies, patient and mental health advocacy groups, philanthropic organizations, and academic institutions applauded the announcement. Systematically tracking and reporting outcomes could help build an evidence base of best interventions and practices. In turn, the data could be used to reduce coverage exclusions, which are still common despite laws that require benefit parity for medical and mental health services, such as the Mental Health Parity and Addiction Equity Act of 2008.

According to the State of Parity report released at the February 26 meeting by the Kennedy Forum, founded by former congressman Patrick Kennedy in 2013 and the Scattergood Foundation, "insurers still circumvent the [Parity] law’s requirements." Samuel Nussbaum, MD, executive vice president and chief medical officer for Anthem, Inc, said that insurers are often stymied when trying to apply both the letter and the spirit of parity, in part because of a lack of evidence. "How do we determine what works?" Dr Nussbaum asked.

The Joint Commission hopes to help answer that question with its new requirement, VanAmringe told Medscape Medical News. The current standard for the 2300 behavioral healthcare organizations it accredits requires outcomes assessments, but there is no requirement to use standardized measurement tools or to aggregate patient data, she added. The new policy will require a standardized method of measurement that is sensitive enough to show that an intervention improved a patient’s outcome. Organizations will also be required to assess outcomes on a population-wide basis and to use the information for continuous quality improvement, VanAmringe said.

That kind of data collection can "make your organization more valuable" to insurers, she said, "because you show that you are improving outcomes." The data can also be used to show that mental health care services work, she said. "Too often, people don’t think that they are that effective," said VanAmringe. A Joint Commission committee will review the proposed requirement in March. The requirement will then be made available for comment by accredited organizations, and it will be reviewed by the Joint Commission’s board. It is hoped that the new standard will be announced in July, VanAmringe told Medscape Medical News.

Use of the new standard would not be required until January 2017 — about the time that the Centers for Medicare and Medicaid Services will start payment for its collaborative care model, which was made final in the 2016 Medicare fee schedule rule. The model, developed at the University of Washington, creates a team involving a primary care physician, a care manager, and a psychiatric consultant. It is still not clear what that model will look like or how physicians will be reimbursed. The CMS will "propose the details of that methodology" this year, said Patrick Conway, MD, the agency’s acting principal deputy administrator, at the meeting.

It’s 1980 again, or maybe still – the same rhetoric. The only place that this really fit was in the medical modeling of certain physical diseases, so that’s the direction things took. Known diseases, diagnosed with clear criteria, treatable with defined treatments [time limited] – something like psychic pneumonia. We built a diagnostic system based on that model [and even messed up the places where it fit eg depression], and set out to prove drug efficacy based on clinical trials of treatments aiming towards creating guidelines that could then be generalized to those diagnostic groupings. Medications were approved based on the specific diagnoses. Since we had no markers or lab tests, the clinical scales or their derivatives from the clinical trials became the proxies. So the whole system became modeled on the Randomized Controlled Trial [RCT]. Now, the whole system will actually become a Randomized Controlled Trial [RCT] with outcome variables.

• There’s no provision for the actual mental illnesses that come closest to fitting their model – Schizophrenia, Manic Depressive Illness, Melancholia [or whatever you choose to call them]. Are the PCP’s to treat them too?
• Practically speaking, the only available treatment to recommend will be medications, or some different medication, and right now we’re at the end of that road rather than the beginning like we were in 1980. This system is based on the fantasy that a psychiatrist can help a primary care physician use medications better, yet we are in a time when the limitations of symptomatic medication alone are staring us in the face. How will this make anything better?.
• Candidly, this is backwards, "Samuel Nussbaum, MD, executive vice president and chief medical officer for Anthem, Inc, said that insurers are often stymied when trying to apply both the letter and the spirit of parity, in part because of a lack of evidence. ‘How do we determine what works?’ Dr Nussbaum asked." A better version might be, "How are we to determine that insurers are actually interested in the treatment of their client’s mental illnesses [speaking of a lack of evidence]?"

Guidance for the publication of clinical data

Requirements for industry now available on submission of clinical data for publication

03/03/2016

The European Medicines Agency [EMA] has published detailed guidance for pharmaceutical companies on the requirements to comply with its policy on the publication of clinical data.

EMA’s pioneering policy entered into force on 1 January 2015 and applies to clinical reports contained in all marketing-authorisation applications submitted on or after this date. The first reports are currently foreseen to be publicly available in September 2016.

"With this guidance, the Agency is moving towards the operational implementation of its proactive publication policy, which launched a new era of transparency," says Noël Wathion, EMA’s Deputy Executive Director. "The guidance will ensure that companies are aware of what is expected of them and are ready for the publication of these critical data"…