a mega-mistake…

Posted on Tuesday 24 November 2015

While it may seem that with all the attention being focused on Data Transparency for Clinical Trials and things like the AMA voting to oppose Direct-to-Consumer advertising, we are iterating towards a time when the battle against the corruption of medical practice by commercial interests is making some real progress. But it seems to me like there’s always the rumbling of distant thunder. As physicians, we should be attuned to such early warnings. After all, there’s an important medical principle involved – Preventive Medicine. While talking about such things can begin to sound like early psychosis, the alternatives are too well known to ignore. Particularly dangerous are things that look innocent, maybe even like progressive reform to solve some contemporary problem, but later turn out to have been the proverbial wolf in sheep’s clothing.

In psychiatry, we have a number of examples, but the one that jumps off the page is the Texas Medical Algorithm Project [TMAP]. When the Atypical Antipsychotics were first introduced, we couldn’t have been more primed and ready. They were effective alternatives to our older drugs but with a markely reduced incidence of neurologic side effects. The experts agreed and said so in widely publicized guidelines. Since the majority of antipsychotics are prescribed in public systems, it only made sense to insure that the less fortunate treated in these public systems have access to this medical breakthrough – implemented in Texas through the TMAP Guidelines which prescribed ‘try the Atypical Antipsychotics first.’ It was such a good idea that the Texas Mental Health officials became evangelical, ultimately spreading the gospel to about a third of our states [with a bit of financial help from the manufacturers]. When it was all said and done, the Texas Medicaid program was all but bankrupt; it became clear that the Atypicals were neither more effective nor better tolerated than the older drugs; and they had some toxic side effects all their own.

And now? Well there’s the Trans-Pacific Partnership that many worry will bring many rewards to the pharmaceutical industry including even longer periods of patent exclusivity. I’ll have to admit that my understanding of this trade agreement remains embryonal even after several attempts to understand it. Some of the problem is their secrecy, but I fully admit absolutely no expertise in the area. But there’s another one that, though my understanding of the basics is equally poor, I think the rat I smell is very real.  It’s a bill in Congress called the 21st Century Cures Act that has passed the House already [see The F.D.A.’s Medical Device Problem, 21st Century Cures Act: A huge step backward for FDA standards, and Will the 21st Century Cures Bill Lower Standards for Some Drug Approvals?]. The sheep’s clothing is that getting drugs approved is a long, slow process. And patients, particularly patients with desperate or terminal illnesses understandably don’t want to wait. But the very large wolf is that the proposed solution is "fast-tracking" drugs and devices, without the preapproval Clinical Trials, relying on antedotes and other indirect evidence. That opens Pandora’s Box allowing dangerous drugs on the market, particularly the kind of drugs used to treat dire illnesses.

I fully intend to study that whole bill and parse out the details, but a quick scan is enough. I don’t know if the Representatives drank the PHARMA Koolaid or were bought outright. But whatever happened, this one’s a mega-mistake and could undermine any other reform imaginable.
Mickey @ 4:06 PM


Posted on Monday 23 November 2015

This post is just a remark about history, some of it my own. I wasn’t always a psychiatrist. I started my medical hegira as an Internist, and my first experience practicing was on an overseas Air Force Base seeing active duty soldiers and their dependents [only by referral]. There were a lot of symptoms, and a lot of negative work-ups – people whose psychological difficulties were expressing themselves as physical symptoms and complaints. I got right good at figuring that out, and listening to the stories [many becoming increasingly complex the longer I listened]. "So this is what depression is," I thought naively, and I began my abbreviated career as a jake-leg psychopharmacologist using the Tricyclic Antidepressants of the era [the patients thought that going to a mental health clinic had a negative impact on promotion, so they just wouldn’t go, neither active duty nor their dependents]. At the time, I didn’t know what follows – a couple of key pieces to the story of how the antidepressant drugs came to be:
by Walter A. Brown, M.D. and Maria Rosdolsky, M.D.
American Journal of Psychiatry. 2015 172[5]:426-429.

The major classes of psychotropic drugs were introduced in an extraordinary decade of discovery between the late 1940s and late 1950s. In the present climate of pessimism about the absence of new drug development, it may be instructive to look back at the research methods used during that era. The study that identified the first antidepressant is a case in point. It was conducted by Roland Kuhn, a Swiss psychiatrist working in a remote psychiatric hospital. Kuhn, like the other pioneering researchers of his day, was given access to new drug entities, and the method he used to discover their clinical effects was open-minded, exploratory, comprehensive, clinical observation…

By today’s clinical research standards, Kuhn’s method of unfettered, exploratory, clinical observation was substandard, haphazard, even messy. Yet it produced a major breakthrough—the discovery that a drug can alleviate depression—that has had a lasting impact on the treatment of depression and on the development of antidepressant drugs. Kuhn’s experience might usefully inform our strategies of drug development.
[The graphic is my rendition of Kuhn’s guestimate about response rates]
from Kuhn’s original report:
Über die Behandlung depressiver Zustände mit einem Iminodibenzylderival [G22355]
by Kuhn Roland
Schweiz Med Wochenschr 1957 87:1135–1140.

Symptoms of depressive mood that are obvious when observing the patient’s appearance often improve significantly under treatment with G22355. The facial expression loses rigidity, modulation and expression abilities return. The patients become livelier, the depressive whispering becomes louder, patients become more communicative, and moaning and whining can no longer be heard. If the patient was discontented, querulous or irritated, he changes into a friendly, content and amenable person. Hypochondriac and neurasthenic complaints are no longer dominant or disappear completely. Patients who had great difficulties in getting up in the morning, get out of bed early with their own initiative, at the same time as other patients. They initiate relationships with other people, start conversations, participate in the daily life of the clinic, write letters, and are again interested in their family matters. They start working spontaneously, get their work done, and the slowness in their life is replaced by a normal vitality. With these improvements, the patients become popular in the ward. Their mood and behavior appear to be balanced. Several times, family members were fascinated and told the physician that the patient had not been in such a good condition for a long time.

Most of the time, the patients notice the change, report it, are, of course, very joyous about it and talk about a miraculous cure. The feelings of heaviness, tiredness, weakness, depression, inner tension, rigidity and restlessness subside. The patients feel free again, inhibition of thoughts and activities disappears, thoughts and activities return. A sad, depressed, desperate and fearful mood turns into a neutral unburdened or somewhat cheerful mood with the feeling of healing and increasing strength. Feelings of guilt, delusions of impoverishment or culpability simply disappear or lose their affective importance, move into a distance, and the patient becomes indifferent and unconcerned with respect to these feelings. It happened that a pronounced suicidal intent of a patient suddenly disappeared! If sleep was disturbed by depressive symptoms, it normalizes quickly without sleep-inducing medications, even in cases who did not respond to common hypnotic agents. Nightmares, sometimes occurring in depressive people, with blood, dead bodies, terrible accidents, and gruesome atrocities, frequently accompanied by terrible fear, no longer occur under the treatment. Morning moodiness and other daytime fluctuations of the depressive state are no longer observed. If the patient had no appetite, his appetite returns. Sometimes, constipation due to depression improves.
And here’s the first ever controlled clinical trial of Imipramine:
British Medical Journal. 1959 2:5199:1052-1055.

All the cases included in the trial were out-patients, and anyone showing gross retardation or extreme agitation and those in whom the risk of suicide was considerable were automatically excluded, as they were admitted for in-patient treatment. Nevertheless, a number of the patients included were quite severely depressed…

The results of treatment were assessed as symptom free, greatly improved, somewhat improved, no change, or worse. For the purpose of assessing the value of the drug as a significant therapeutic agent, the first two of these categories have been combined as a good or worth-while result and the other three as a poor result. Patients showing a good result were able to return to their normal activities without undue effort…

Of 55 cases of endogenous depression treated, 27 received imipramine and 28 the placebo. On imipramine 20 responded well, while 7 did badly. On the placebo, 6 did well and 22 badly. This is a highly significant difference, and, with Yates’s correction applied, P<0.01. Of the 42 cases of reactive depression 22 received imipramine and 20 the placebo. Of those given imipramine 13 were improved and 9 were not; while of the 20 controls 4 improved and 16 showed a poor result. This, too, is a significant result [P<0.02]. When improvement occurred it was nearly always evident by the end of the third week,  sometimes as early as the fourth or fifth day. The mean was 9 to 10 days…
Back in those days, I didn’t see anything like Dr. Kuhn’s kind of response to the TCAs – not even close. There were more psychiatrists on our base than internists, busy doing Air Force things. One was a draftee like me and a friend – a very thoughtful guy. I told him about my lackluster experience with the TCAs. He asked me about the cases. After telling him about a number of them, he said he thought I was seeing a lot of people with bad life situations, or neurotic people, or personality disorders, or homesickness, etc. – a lot of unhappiness – but not many people who were clinically depressed. He suggested I do some reading. I took his suggestion [and I’m still at it], but I sort of got his point. I had been using the term depression in an imprecise generic way – expecting a drug to work because of the moniker "antidepressant" without really understanding what either really meant.

Flash forward: A few years later, I was in a psychiatry residency, spending my first year on inpatient units, and I had the second version of my thought, "So this is what depression [really] is." It wasn’t a reported symptom or a way of saying "my life’s a mess". It was something you could see, even feel, as soon as the patient walked into the room. And the distinction made above between Endogenous and Neurotic Depression wasn’t severity – both were severe. I don’t think I had ever seen that kind of palpable depression before my psychiatric residency program except in the occasional patient on Reserpine. But in those days, I understood what my friend had been trying to tell me back on the base a few years earlier.

And in that first year of residency, I did see the kind of dramatic results Kuhn described in this group of patients. I didn’t keep up with the numbers, but the Number Needed to Treat [NNT] of 2 or 3 feels right. I’ve only seen a few in the decades that followed. I just wasn’t in a setting where such patients end up being sent. And when I did see a case, it was only to refer them to someone with in-patient privileges and experience. Whether they were treated in the hospital or not, their treating doctor needed the hospital back-up in case of emergent suicidality. In-so-far as I know, the treatment of these patients has not changed in the forty years since I started in psychiatry. I think that’s remarkable…
Mickey @ 8:28 PM

a recession…

Posted on Sunday 22 November 2015

“We are at an extraordinary moment when the entire scientific foundation for mental health is shifting, with the 20th century discipline of psychiatry becoming the 21st century discipline of clinical neuroscience,” Thomas Insel said before a meeting on the challenges facing mental health research at the Royal Society in London on 31 August… The seismic shift had been driven by what he described as three “revolutionary changes” in thinking, the first of which was that mental illness was increasingly being recognised as a disorder of brain circuitry, rather than as a chemical imbalance, thanks to neuroimaging techniques and the discovery of some key biomarkers.

NIMH Director Tom Insel labeled the time of this speech four years ago as "an extraordinary moment," but I recall it in a different way. The DSM Task Force had just admitted that its push for a neuroscience based DSM-5 was being abandoned [for lack of confirmation]. And it had just become crystal clear that PHARMA was making a massive exodus from CNS R&D [no discoveries, no leads]. The KOL set was at DEFCON 4 and having multiple meetings hoping to get PHARMA to recant. I guess Dr. Insel and I saw it as different kinds of extraordinary moments.

I have no idea what he was referring to with "mental illness was increasingly being recognised as a disorder of brain circuitry, rather than as a chemical imbalance, thanks to neuroimaging techniques and the discovery of some key biomarkers." I still don’t know. I assumed at the time that he was rallying the disheartened troops with hope for the future. I specifically recall the quote because it was the first time I heard the term "chemical imbalance" from a psychiatrist, and it was absolutely the first time I ever heard "a disorder of brain circuitry" from anyone – ever.

I now see that summer of 2011 as marking a change in Dr. Insel. Before that he seemed to be an inspired neuroscience cheerleader filled with a boyish exuberance.  Since that summer, he’s talked a lot about how inadequate the current drugs are; lamented the intransigence of the mental illness statistics; come up with scheme after scheme to jump-start drug development; broken away from the APA’s DSM diagnoses; declared his nebulous RDoC to be a prerequisite for NIMH Grant money. It seems like he began to talk as if we know nothing, like we’re starting over from scratch.

What brought all of this to mind was reading some of the recent war of words between Psychiatrist Ronald Pies and antipsychiatrist Philip Hickey, centering on who said what when about "chemical imbalances" [My Response To Dr. Pies]. Reading it, I remembered Insel’s quote above, and in the process of looking it, I ran across this article from Insel’s presentation at the 2014 APA meeting – From Psychiatry to Clinical Neuroscience:
PsychiatricNews Update
by Tom Insel
May 3, 2014

The diagnosis and treatment of mental illness is haunted by four “inconvenient truths.” That’s what NIMH Director Thomas Insel, M.D., told APA members today in his annual meeting lecture “From Psychiatry to Clinical Neuroscience.” Those inconvenient truths are these:
  1. We have failed to “bend the curve” in the prevalence and the cost of mental illness
  2. More people are getting more treatment, but outcomes are not getting better. So, more of today’s treatments may not be sufficient to bend the curve.
  3. We don’t know enough to ensure prevention, recovery, or cure for too many people with serious mental illness.
  4. We need to transform diagnostics and therapeutics if we are going to make significant progress.
Insel outlined some of the problems that have hindered efforts to bend the curve. These include the fact that diagnosis is limited to observable symptoms, and detection is almost invariably late; etiology of most mental illness is unknown; and prevention is not well developed for most disorders. Treatment is trial and error, and there are no cures and no vaccines.

Moreover, what is known as the mental health “system” is a poorly integrated maze of nonspecific pathways of care, with some people entering through the emergency department, criminal justice system, the primary care system, or nonprofessional services. Diagnosis and treatment vary from provider to provider and from patient to patient.
Again, that’s another indictment from someone who has been in a position of power, someone who might have had an impact on these things. But then he goes back to his usual cheerleading mode – outdoing earlier versions with the part in red [though again I’m not sure what research he’s referring to]:
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 Insel also described a promising future in which mental illness is re-envisioned as a disorder of brain circuitry that will be greatly advanced by the 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 ADHD to be a disorder of delayed cortical maturation. He also presented evidence of schizophrenia as 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.”
And now, a year and a half later, he’s abruptly moving on to Google, and his parting remarks  though spoken softly, also sound like an indictment – in the range of bitter:
Silicon Valley offers a fresh way to tackle conditions such as schizophrenia says US mental-health expert Thomas Insel
The New Scientist
By Sally Adee
Nov 4, 2015

… after giving heart and soul to mental-health problems over the last 13 years working in government, I have not seen any improvement for either morbidity or mortality for serious mental illness – so I’m ready to try a different approach. If it means using the tools available in the private sector, let’s go for it.

… but I don’t think complicated problems like early detection of psychosis or finding ways to get more people with depression into optimal care are ever going to be solved solely by government or the private sector, or through philanthropy. Five years ago, the NIMH launched a big project to transform diagnosis. But did we have the analytical firepower to do that? No. If anybody has it, companies like IBM, Apple or Google do – those kinds of high-powered tech engines…
For as much as I’ve criticized Dr. Insel over the years, I have to say that I have sympathy for some of his bitterness. He came to the job at the pinnacle of what I call "the KOL Age" in my mind. The drug pipeline was still flowing, nobody much had caught on to the guest-author/ghost-author/PHARMA racket. TMAP was spreading from state to state, and the APA was sure that a biological DSM was around the corner. Dr. Nemeroff, Insel’s most recent chief, was still the "boss of bosses." Senator Grassley and Paul Thacker were years in the future. Articles like Paxil Study 329 were the rule and there was no sobering Black Box Warning yet in place. Dr. Insel’s dreams of neuro-biological research and of psychiatry becoming Clinical Neuroscience made a lot more sense to a lot more people then than they do now. After all, the genome had just been cracked. There were new neurotechnologies all over the place. With all that, breakthroughs were surely just around the corner.

Were I to speculate about what went wrong, I’d list a number of things. Everything about his NIMH’s effort was based in technology and ideology rather than precise clinical medicine and high standards in scientific reporting. Insel was right when he figured out that the DSM was a big problem – no basis for research. But the problem wasn’t clinical diagnosis, it was that system itself. Instead of limiting the domain by careful case selection, almost every study went for a home run. He would’ve done well to go back to basics. He was too controlling about what the applicants did instead of setting high standards for how they did it and how it was reported. Instead of locating and developing solid scientists, he supported the usual suspects. There is likely a segment of mental illness where his Clinical Neuroscience is an appropriate model, but he drank the koolade and  saw it as everything. So instead of home runs, he ended up giving us a fist full of rain checks. But my Monday morning quarterbacking isn’t the point. The point is that Tom Insel wanted to officiate a paradigm shift, and he seems bitter and somewhat blaming about the results. That’s just not what was in his cards. Instead, he was around for a recession.

There are a couple of commentaries about him and his tenure worth looking at [Thomas Insel Leaves NIMH for Google – What can it mean?, Blazing Trails in Brain Science]. I expect there will be others. I hope down the road, he can give us a more introspective and helpful review than his comments so far…
Mickey @ 3:24 PM

never been imposed…

Posted on Friday 20 November 2015

We live in a time of meta-analyses [studies of studies]. This one selected the 15 new drugs approved during 2012 from large pharmaceutical companies [from among 48 new drugs approved that year]. They looked at all trials [from all phases] to see if they were registered, reported, published, or reported-or-published [public]. They also partitioned them in various ways [for ethical versus legal compliance], then created transparency criteria to rank the studies. Be warned – the text is dense. One reason it’s here is that it explains when public disclosure is required and quantifies the compliance rates:
by Jennifer E Miller, David Korn, and Joseph S Ross
BMJ Open 2015;5:e009758.

Objective: To evaluate clinical trial registration, reporting and publication rates for new drugs by: [1] legal requirements and [2] the ethical standard that all human subjects research should be publicly accessible to contribute to generalisable knowledge.
Design: Cross-sectional analysis of all clinical trials submitted to the Food and Drug Administration [FDA] for drugs approved in 2012, sponsored by large biopharmaceutical companies.
Data sources: Information from Drugs@FDA, ClinicalTrials.gov, MEDLINE-indexed journals and drug company communications.
Main outcome measures: Clinical trial registration and results reporting in ClinicalTrials.gov, publication in the medical literature, and compliance with the 2007 FDA Amendments Acts [FDAAA], analysed on the drug level.
Results: The FDA approved 15 drugs sponsored by 10 large companies in 2012. We identified 318 relevant trials involving 99,599 research participants. Per drug, a median of 57% [IQR 32–83%] of trials were registered, 20% [IQR 12–28%] reported results in ClinicalTrials.gov, 56% [IQR 41–83%] were published, and 65% [IQR 41–83%] were either published or reported results. Almost half of all reviewed drugs had at least one undisclosed phase II or III trial. Per drug, a median of 17% [IQR 8–20%] of trials supporting FDA approvals were subject to FDAAA mandated public disclosure; of these, a median of 67% [IQR 0–100%] were FDAAA-compliant. 68% of research participants [67,629 of 99,599] participated in FDAAA-subject trials, with 51% [33,405 of 67,629] enrolled in non-compliant trials. Transparency varied widely among companies.
Conclusions: Trial disclosures for new drugs remain below legal and ethics standards, with wide variation in practices among drugs and their sponsors. Best practices are emerging. 2 of our 10 reviewed companies disclosed all trials and complied with legal disclosure requirements for their 2012 approved drugs. Ranking new drugs on transparency criteria may improve compliance with legal [FDAAA] and ethics standards and the quality of medical knowledge.
These graphs give an overview – on the left, the number of trials for each drug; – on the right, the percentage of trials for each drug that meet the criteria listed on the abscissa. Like all of this genre of studies, the compliance rates are dismal. For example 20% of these approved drugs had no accessible Phase III trial information [neither reported on clinicaltrials.gov nor published in a journal]. But I’ll leave further exploration of that gloom in your hands, and get to my point. The last two sentences of the following section are the main reasons I posted this article:
Transparency by legal standards

There are at least three reasons why compliance with current disclosure laws might be suboptimal. First, legal requirements are perceived to be unclear or ambiguous, as a spectrum of interpretations of FDAAA has emerged…

Second, mergers, acquisitions, collaborations and licensing agreements may complicate compliance. Two companies in our sample acquired or licensed drugs initially developed by smaller companies, and another used a partner company for some trials, raising questions about whose responsibility it was to ensure trials complied with FDAAA.

Finally, compliance may be affected by a perceived lack of enforcement. FDAAA empowers the FDA to impose a $10,000 a day penalty for non-compliance. To date, this penalty has never been imposed.
Let me repeat those lines for emphasis: "FDAAA empowers the FDA to impose a $10,000 a day penalty for non-compliance. To date, this penalty has never been imposed." And while I’m at it, let me nominate suboptimal compliance and perceived lack of enforcement for understatements of the year. Like almost everything we’ve learned about these industry funded clinical trials, it’s an elaborate system that creates massive amounts of data, but it just doesn’t work. Since its inception in 1962, there have been many reforms – new procedures, new rules for reporting, etc. But they seem to only add more layers of bureaucracy and make little impact because there’s no real oversight or enforcement.  This group envisions repeating their analyses in an ongoing yearly surveillance effort and apparently has the funding support to do it:
Motivating transparency

Given the wide variation in compliance with both legal and ethical standards across drugs and companies, we propose continuing our clinical trials transparency monitoring, evaluations and scoring of new drugs approved by the FDA, along with their sponsors. These ongoing rankings— developed initially with support from Harvard University, Duke University, Susan G. Komen Foundation and the Raskob Foundation [for a full list of sponsors, see the Acknowledgements section] — will be conducted annually under the auspicious of Bioethics International, with grant support from the Laura and John Arnold Foundation.

This system will help identify best practices, incent better behaviours and standardise the industry’s practices and thereby contribute importantly to an enrichment of medical knowledge. Moreover, the scorecard and rankings have the potential to benefit consumers of clinical trial information by helping to assure them of the integrity and completeness of their data. Not least, full transparency of clinical trials would also strengthen the protection of human research participants by avoiding their unknowing recruitment into already failed experiments.
We’re about to have a new head of the FDA [likely Dr. Robert Califf]. While there’s an growing cadre of people focusing on Data Transparency, particularly with the industry funded trials, without the FDA’s full cooperation, it might be a hopeless endeavor. One would think that it’s the FDA Director’s job make this system function as intended, and we need to hold him to the task. The liberal imposition of some of these already approved fines would be a really great place to start…

Mickey @ 7:21 PM

doctor power…

Posted on Thursday 19 November 2015

I have rarely been so surprised as I was last night when I read the AMA Press Release about Direct-To-Consumer [DTC] advertisements on television [reprinted here in pinch me!…]. I remember when they started back in the late 1990s. One day, a patient said, "Do you think I-forget-which-drug is right for me?" And I remember thinking it was an odd thing to say. A couple of nights later, I saw my first DTC television ad, and on the spot developed a very annoying habit – talking to the television set. I’m sure my family members begin to cringe when one of those ads came on, because I apparently am constitutionally unable not to talk back to the voice-over, particularly when the ad is about a psychiatric medication, but also in general. I do things like accuse the pretty ophthalmologist in the Restasis® ads of wearing tinted contact lenses, indict the lady in the blue slip in the Cialis® ads of being a porn star, and add my two cents to the mumbled side effects towards the end of the ads. In the rest of my life, I don’t talk to media and am generally an uncritical and accepting person.

I won’t list all the reasons that these ads make me so angry, but I do want to mention one that has been added since I moved to a rural area. I’ve always been someone who prescribes generic drugs if possible – not just because of cost, but because they’ve been around long enough to pass the test of time. There’s nothing in medicine that says newer is better. But working in the charity clinic, the patients see those ads and think that the generics we provide are "less than." In truth, in those instances where a new drug is genuinely better, we go out of our way to procure it through scholarships or our general medical fund. They’ve never not gotten such a drug when I’ve asked for it. But that’s not the point.

But my surprise was that the AMA voted to oppose these ads. That says something positive about our medical community that was unexpected. Who knows? Maybe next on the agenda will be a move to stop ordering un-necessary scans and lab tests? to actively oppose the gajillion fee-churning maneuvers that happen in our emergency rooms and hospitals [including inappropriate screening]. And how about those faux-televisions in the waiting rooms with their infinitely looping infomercials for diabetic supplies and vitamins? Doctor-Power. I like it!
Mickey @ 1:55 PM


Posted on Thursday 19 November 2015

The author of the blog Psych Practice and I are psychoanalysts who have lived through the massive changes in psychiatry [and psychoanalysis] in the span of our times. By any measure, Psych Practice is a good blog to follow, but I found this post particularly well framed – Lieberman Speaks. It’s about a panel held at the William Alanson White Institute about the book, Shrinks: The Untold Story of Psychiatry, with author Jeffrey Lieberman on the panel. Psych Practice has had several other posts about the book – Analytic Evidence, "Shrinks" Review-Introduction, Shrinks: The Untold Story of Jeffrey Lieberman’s Oedipal Victory Over Papa Freud – and adds this earlier quote to this post:
Lieberman, [or maybe it’s Ogas] writes with particular vehemence about the period when most psychiatrists did analytic training. It made me wonder if he was rejected from a training program at one point, or if he was in an analysis that he quit because he found it intolerable. I have absolutely no basis for these thoughts- they’re just conjecture.
I can’t imagine that there’s a psychoanalyst alive who hasn’t had a similar thought. For that matter, I expect many non-psychoanalysts had some version of that thought too. It’s hard to even skim through this book and take it at face value without wondering what’s behind its writing, even if you agree with Lieberman’s version of history.

Speculating about the self-serving motives of others isn’t all that hard. We almost all do it – particularly when we disagree with what the other person is saying. In the process, we are discounting what’s being said, sometimes for valid reasons, sometimes colored by self-serving motives of our own. Speculating with therapeutic intent is a different enterprise. The speculation itself is only of value if it’s confirmed by some positive change in attitude, understanding, or behavior. Many psychoanalysts of yore died on the vine by treating their speculations as having an intrinsic value outside of that context.

And since I’m absolutely sure I have no therapeutic intent when it comes to Jeffrey Lieberman, I’ll skip to the end of Psych Practice’s report – the question and answer period:
… Then it was my turn, and I was the last questioner, which suited me fine because the room had cleared out a lot by then. I’m a pretty comfortable public speaker, so I was surprised to note how much my voice was shaking, until I realized it was rage, not stage-fright.

I told him I had read his book, that there’s a lot more evidence for PSA than he’s allowing for, and I paraphrased the passage where he states that if Willem Reich’s patient were alive today, she would be diagnosed with an anxiety disorder and treated with an SRI and CBT, which made it sound easy. I pointed out that he was concerned about gaining credibility by fessing up to psychiatry’s history, but the fessing up was selective, and that nowhere does he mention the difficulties with treatment, including things like metabolic effects of antipsychotics, or Paxil Study 329, and how does he mean to engender trust in the public by omitting those kinds of facts?

I know I was far less eloquent in my phrasing, and what I just wrote is not so great to begin with. I think he cut me off towards the end, because I never said anything about the severe limits of what we actually know about mental illness. He rolled his eyes and said, "Medications have side effects. Am I supposed to list every side effect in the book?" I have the impression he was still yelling something, but I could be wrong…
This panel was in part a failed attempt to inform Dr. Lieberman of what psychoanalysis has become in his absence – a vibrant enterprise separated from psychiatry now primarily teaching psychodynamic psychotherapy to an eager audience [from all academic disciplines including psychiatry]. It is becoming what it should’ve been well before 1980, where many of us tried to move it even back then. But that’s another history for another time and perhaps another author.

The book Shrinks is billed on Amazon.com as "The fascinating story of psychiatry’s origins, demise, and redemption, by the former President of the American Psychiatric Association." The story-line of psychoanalysis capturing psychiatry, and its liberation with the coming of the DSM-III, medicalization, the newer psychotropic drugs, and the advances in neuro-matters has been with us for three plus decades, delivered by Dr. Lieberman with an unusually heavy dose of contempt. But it’s his response, or perhaps his non-response, to the question at the end of Psych Practice’s comment that deserves attention: "… and that nowhere does he mention the difficulties with treatment, including things like metabolic effects of antipsychotics, or Paxil Study 329, and how does he mean to engender trust in the public by omitting those kinds of facts?"

It’s the redemption part of Dr. Lieberman’s playbill that doesn’t pass muster. And his eye-rolling sarcastic "Medications have side effects. Am I supposed to list every side effect in the book?" doesn’t address the question asked. What about the academic·pharmaceutical complex with its guest authors, ghost authors, conflicts of interest, speaker’s bureaus, commercially oriented CME, and its jury-rigged or invisible clinical trials? How about the minimized adverse effects of the drugs – the metabolic syndrome, akathisia with violence, the withdrawal symptoms, tardive dyskinesia, addiction, etc? And then there’s the part of the question Psych Practice didn’t get to ask, "…he cut me off towards the end, because I never said anything about the severe limits of what we actually know about mental illness." Dr. Lieberman’s and his colleagues’ over-simplification of the complex human experiences we call mental illness imply an unsupportable level of mastery. So this is hardly a period of redemption – by any stretch.

In science, paradigm shifts occur when a dominant paradigm become more known by its exceptions than its explanatory powers. When some new conceptual model comes along, the former paradigm doesn’t disappear but rather endures by becoming refined and more limited – "right-sized." Meanwhile, the new model begins its expandsive, then contracting journey on the same predictable arc. Dr. Lieberman’s Shrinks is written more on the template of Sodom and Gomorrah followed by the New Jerusalem, or perhaps Armageddon leading to the Rapture. His inability [or unwillingness?] to address the dark side and limitations of his particular brand of psychiatry jumps from the pages of his writings and presentations in spite of his attempts to shout it down.
Mickey @ 10:59 AM

pinch me!…

Posted on Wednesday 18 November 2015

Nov. 17, 2015
For immediate release:

ATLANTA –Responding to the billions of advertising dollars being spent to promote prescription products, physicians at the Interim Meeting of the American Medical Association (AMA) today adopted new policy aimed at driving solutions to make prescription drugs more affordable.

Physicians cited concerns that a growing proliferation of ads is driving demand for expensive treatments despite the clinical effectiveness of less costly alternatives.

“Today’s vote in support of an advertising ban reflects concerns among physicians about the negative impact of commercially-driven promotions, and the role that marketing costs play in fueling escalating drug prices,” said AMA Board Chair-elect Patrice A. Harris, M.D., M.A. “Direct-to-consumer advertising also inflates demand for new and more expensive drugs, even when these drugs may not be appropriate.”

The United States and New Zealand are the only two countries in the world that allow direct-to-consumer advertising of prescription drugs. Advertising dollars spent by drug makers have increased by 30 percent in the last two years to $4.5 billion, according to the market research firm Kantar Media.

New AMA policy also calls for convening a physician task force and launching an advocacy campaign to promote prescription drug affordability by demanding choice and competition in the pharmaceutical industry, and greater transparency in prescription drug prices and costs.

“Physicians strive to provide the best possible care to their patients, but increases in drug prices can impact the ability of physicians to offer their patients the best drug treatments,” said Dr.  Harris. “Patient care can be compromised and delayed when prescription drugs are unaffordable and subject to coverage limitations by the patient’s health plan. In a worst-case scenario, patients forego necessary treatments when drugs are too expensive.”

New AMA policy responds to deepened concerns that anticompetitive behavior in a consolidated pharmaceutical marketplace has the potential to increase drug prices. The AMA will encourage actions by federal regulators to limit anticompetitive behavior by pharmaceutical companies attempting to reduce competition from generic manufacturers through manipulation of patent protections and abuse of regulatory exclusivity incentives.

The AMA will also monitor pharmaceutical company mergers and acquisitions, as well as the impact of such actions on drug prices. Patent reform is a key area for encouraging greater market-based competition and new AMA policy will support an appropriate balance between incentives for innovation on the one hand and efforts to reduce regulatory and statutory barriers to competition as part of the patent system.

Last month, the Kaiser Family Foundation released a reportExternal Link saying that a high cost of prescription drugs remains the public’s top health care priority. In the past few years, prices on generic and brand-name prescription drugs have steadily risen and experienced a 4.7 percent spike in 2015, according to the Altarum Institute Center for Sustainable Health Spending.

The AMA’s new policy recognizes that the promotion of transparency in prescription drug pricing and costs will help patients, physicians and other stakeholders understand how drug manufacturers set prices. If there is greater understanding of the factors that contribute to prescription drug pricing, including the research, development, manufacturing, marketing and advertising costs borne by pharmaceutical companies, then the marketplace can react appropriately.
Mickey @ 10:34 PM

will the office make the man?…

Posted on Tuesday 17 November 2015

By Ed Silverman
November 16, 2015

As a US Senate committee meets on Tuesday to consider Dr. Robert Califf for the top job at the Food and Drug Administration, an open question remains whether he is biased toward industry. Califf is held in high regard by drug makers and academics alike. A cardiologist by training, he spent years as a professor at the Duke University School of Medicine and is one of the most influential biomedical authors in the world. He’s also run numerous clinical trials and served on various FDA advisory committees. But ever since Califf was named a deputy commissioner at the FDA in January and then nominated to be chief regulator in September, his long-standing working relationship with the pharmaceutical industry has prompted debate. Among those opposing his nomination are Democratic presidential aspirant Bernie Sanders and Public Citizen, a consumer advocacy group.

Califf was the founding director of the Duke Clinical Research Institute, which conducts studies for companies. Last year, six drug makers — including Merck and Novartis — partly supported his salary, and several others paid him for consulting work. He has also authored numerous papers with industry researchers. No other commissioner in the recent past has held such close ties to pharmaceutical manufacturers. [The last commissioner, Margaret Hamburg, for example, was a career public health administrator.] All this has led some to challenge whether Califf can be an honest broker. “I do think hard questions should be asked,” said Daniel Carpenter, a Harvard University political scientist, who has studied the FDA but has not taken a position on Califf. “He will have a fair amount of power to push for change”
Ed continues with a good summary of Dr. Califf’s assets and debits if you’re not already familiar with them. See also:
Boston Globe
By Sheila Kaplan
November 17, 2015
Unfortunately, this kind of information only raises questions, but doesn’t answer them. And that’s likely to be true of the hearings. Of course he will answer the congressional queries and say the right things. And he’s obviously accomplished as a scientist and as an administrator, so I would be very surprised if he’s not confirmed. I just searched this blog for Califf looking to review what I said earlier, and it popped up an unexpected link from two years ago – before my more recent comments [at least it’s movement…]. Dr. Califf was the senior author on a non-inferiority study between the new anticoagulant [blood-thinner], Xarelto®, and the old stand-by, Warfarin. I was writing about it for other reasons. But on a lark, I looked at the acknowledgements in the paper:
Supported  by  Johnson  &  Johnson  Pharmaceutical  Research and Development and Bayer HealthCare…

Dr. Califf, receiving consulting fees from Kowa, Nile, Orexigen, Sanofi Aventis, Novartis, and Xoma and grant support from Novartis, Merck, and Amilyn/Lilly and having an equity interest in Nitrox…
No kickback from Johnson & Johnson or Bayer? Well that’s kind of encouraging, though every other author was tainted by a Johnson & Johnson or Bayer connection, some being employees. But it got me thinking about some things. Xarelto® isn’t better than Warfarin, it’s just more convenient [by the way, Xarelto® costs a mint]. You don’t have to get frequent blood tests [a nuisance]. But if you’re in a car wreck and bleeding to death, Vitamin K will reverse the effect of Warfarin. There’s no antidote for Xarelto®. So predictably, the suits are beginning to appear about deaths from fatal bleeding in car crashes with Xarelto®. Looking at that paper, a 2+ year comparison of bleeding events in a large cohort, Xarelto® actually came out a little better than Warfarin. And there were fatal bleeding events with both. So Dr. Califf was a participant in an industry-funded Clinical Trial obviously aimed at selling a profitable new drug. As best I could tell, the trial was properly conducted with straightforward conclusions. I believed the study.

I would prefer that Dr. Califf were as clean as a whistle and had no financial connections with any pharmaceutical company. And I would be much happier if he didn’t bother messing with drugs of convenience. Even reading his paper, I wouldn’t take or recommend Xarelto®. My focus would be on being either being the patient or the doctor in the situation when there was a bad car wreck, and I’d say to hell with convenience if I could save a life with a Vitamin shot instead of watching someone bleed to death, I don’t mind insisting on the countless routine blood tests it took to keep that possibility open. But that’s my clinical decision, that would be made in concert with my patient when we’re both playing with a fully informed deck of cards – including this study. I said that to my friend [which was the whole point of my even looking at the paper], and he chose Xarelto® anyway. That’s what his doctor recommended, and that’s what he did [by getting a needed scholarship from J&J]. Their choice. But my friend was fully informed, so I did my job. And in so far as I could tell, so did Dr. Califf [I hope. See this article by the POGO Editor in Chief: Drug Problems: Nominee to Head FDA Led Clinical Trial FDA Faulted].

Looking at other things I’ve written about Dr. Califf, the one real negative was guilt by association [predictable repetitions]. It was an editorial in the New England Journal of Medicine, Revisiting the Commercial–Academic Interface, by Dr. Jeffrey Drazen supporting Dr. Califf for FDA head  [see also a contrarian frame of mind…, wtf?…, wtf? for real…, a narrative…, not so proud…]. In the first place, since when is the editorship of the NEJM a position from which to weigh in on such matters? And Dr. Drazen’s recent showing with his editorial and series on industry-tainted authors writing review articles was an outrageous rationalization, worthy of considering a change in his employment. He’s the paradigm of an industry-friendly guy who assured us fifteen years ago that his PHARMA-connections were behind him and it was… well, it just wasn’t true [sleeper cell comes to mind]. I have no idea how he and Dr. Califf are connected, but I don’t have a bit of question about Dr. Drazen’s Conflicts of Interest. So I see that endorsement from Dr. Drazen as a major black-mark on Dr. Califf’s resume.

But when it’s all said and done, I don’t really think that the FDA is a major problem except in two areas. I don’t like the fact that the boss over-rode the opinion of the evaluator on drugs like Zoloft or Latuda, but those aren’t my main beefs. They are that the FDA continues to honor industry’s claim that Clinical Trial data and the submitted Clinical Study Reports or Individualized Participant Data are proprietary – keeping secrets for industry – and have made none of the moves towards data transparency like those occurring in the European Medicines Agency. My second complaint is that the trials known as Phase IV [post-marketing] Trials which should be rigorous and ongoing are essentially worthless. They’re done by PHARMA, and rarely mentioned. In reading about a drug, even late in its patent-life, we still mostly hear about those PHASE III Clinical Trials done to get the various approvals. We need to know how the drugs perform [or don’t perform] once they’re out there, and we don’t know – at least in any formal way. The whole Contract Research Organization industry was built to get drugs approved. Once approved, they’re in the hands of the marketeers and then later the Civil and Federal Courts. The latter may be getting better at punishment, but that’s hardly the point.

What matters is what happens once the drug is in general use. I can "vet" products I order on-line from Amazon.com not long after they appear [Amazon.com is the major store for those of us who line in the woods], but even as a doctor, I can’t do that with drugs until they’re almost out of patent except by word of mouth or trial and error. Dr. Healy’s giving it a really serious try with RxISK, but he’s going to need a lot of help. The FDA has a reporting system but it’s woefully lackluster.

The FDA isn’t mandated to do anything but certify safety and minimal efficacy. The agency has no control over drug pricing, and really isn’t set up to survey advertising in a comprehensive way.  It just picks up on big lies, not spin. So the questions that matter in today’s hearings are about Data Transparency and post-marketing Trials. I doubt they’ll be asked, but I sure hope they are. And when it comes down to it, the real question is whether Dr. Califf is a person of integrity who will make the right hard decisions when the issues that really matter come across his desk [two of my favorite unlikely heros, James Comey and Earl Warren, come to mind]? Or will he follow Dr. Drazen’s sleeper cell mentality? Will the Office make the man? I don’t know how one knows something like that in advance…

post-hearing update:
Boston Globe
Sheila Kaplan
November 17, 2015
Regulatory Affairs
By Zachary Brennan
17 November 2015
Washington Post
By Brady Dennis
November 17, 2015
Mickey @ 12:32 PM


Posted on Sunday 15 November 2015

hat tip to the universe…        
Mickey @ 6:48 PM

ombudsman envy…

Posted on Sunday 15 November 2015

When it’s all said and done, I’m not impressed that our kvetching about the state of affairs with clinical trials, regulatory approval, pharmaceutical marketing, and the corruption and glitches along these processes will be particularly effective in the long run. We now know the problems, and we know they are sustained by a powerful set of forces. Furthermore, we know the solution [or at least an important part of the solution] – Data Transparency – and for that, we need structural reform. If the trial data is available, we can bypass all the spin and sin and see for ourselves [of course that depends on some "we" who is willing to do the surveillance and re-analysis]. So for a number of reasons, that has focused my attention on the goings-on in the European Union:
  • The European Medicines Agency [EMA] has embraced the concept of Data Transparency [a no-brainer] and is working out its policy.
  • The EMA is centralized, seems more transparent, more distant from the "powerful set of forces" and is more accessible than our FDA.
  • The same drugs are independently evaluated by the EMA and FDA, so transparency in one becomes transparency for both.
  • And then, there’s the European Ombudsman.
British Medical Journal
by Tom Jefferson
13 Nov, 2015

The institution of the European Ombudsman celebrated its first 20 years of activity with a party for staff and all those who have and still are contributing to its work. The shindig was held in the European Parliament. In the words of the current Ombudsman, Emily O’Reilly, the Ombudsman’s function “was born out of the debate on the emerging European citizenship in the early 1990s, and its purpose precisely is to enable those European citizens to hold the ever more powerful EU institutions to account, as the direct effect of what they do impacts more and more on the daily lives of the people. It acts in a complementary way to the courts and to the parliament, as a check on EU institutional power.

In the current climate, O’Reilly’s words may seem like a wish rather than reality. Except that the office’s record in the matter of access to secret clinical data is exemplary. It is to the Ombudsman that the Nordic Cochrane Centre referred in its attempt to access clinical study reports from the European Regulator, the European Medicines Agency [EMA], and it was the Ombudsman who sided with Peter Gotzche and colleagues. This led to the recognition that data relating to clinical trials cannot be considered confidential, as it is a public good.

I have chronicled the evolution of the EMA’s policy and its forthcoming release of large quantities of reports. Reports have also been released since the Ombudsman’s ruling in 2010. The visibility of such documents has finally lead to the realisation that clinical trials published in journals may not be trusted because they do not provide sufficient information and detail to understand the strengths and weaknesses of a trial…
If you’ve tried to deal with the FDA or the ORI or our other agencies, I hope you have better luck than I have. Responses are sluggish and rarely lead one anywhere. On the other hand, the European Ombudsman’s office responds quickly and is quite a contrast to the tired bureaucracy of our equivalent agencies [give me a young government every time]. And as the links above document, they’re on a roll with Data Transparency. Here‘s my crude timeline. In my humble opinion, if we are to get somewhere with Data Transparency, it will be coming from the EMA. Hopefully, they’ll pull us along. Nothing but Kudus for the European Ombudsman! [and her supporters] from the 1boringoldman campus]…
Mickey @ 12:57 PM