without ever talking to the patient…

Posted on Friday 21 October 2016

In bygone days, as a resident and as a director of a busy city/county hospital psychiatric emergency room, I had years of working in collaboration with staff and trainees who were the primary contact person. With many cases, I saw the patient in person only briefly. And as a supervisor, I met with residents who brought the cases they needed help with/ Even now, I wish I had support staff in the clinic where I work but alas, it’s just me. Even with all of that experience "collaborating," I have a visceral negative reaction to what I read about the modern version of collaborative care. So when I ran across this recent APA Report on the model, I decided to spend some time looking it over to see if my reflex reaction could be softened up a bit. It’s 85 pages and is written in a salesmanship style with lots of jargon and slogans. I’ve included the intro below. There’s a case reported scatted throughout the narrative, and I’ve extracted much of it at the end, along with a rough diagram [as accurate as the narrative would allow]:
Spring 2016

There is expert consensus that all effective Collaborative Care Models share four core elements: [1] team-driven, [2] population-focused, [3] measurement-guided, and [4] evidence-based. These four elements, when combined, can allow for a fifth guiding principal to emerge; accountability and quality improvement. Table 1 reviews the core elements of Collaborative Care implementation. Collaborative Care is team-driven, led by a PCP with support from a "care manager" [CM] and consultation from a psychiatrist who provides treatment recommendations for patients who are not achieving clinical goals. Other mental health professionals can contribute well to the Collaborative Care Model. Collaborative Care is population-focused, using a registry to monitor treatment engagement and response to care. Collaborative Care is measurement-guided with a consistent dedication to patient-reported outcomes and utilizes evidence-based approaches to achieve those outcomes. Additionally, Collaborative Care is patient-centered with proactive outreach to engage, activate, promote self-management and treatment adherence, and coordinate services.

Table 1: Essential Elements of Collaborative Care
Team-Driven: A multidisciplinary group of healthcare delivery professionals providing care in a coordinated fashion and empowered to work at the top of their professional training.
Population-Focused: The Collaborative Care team is responsible for the provision of care and health outcomes of a defined population of patients
Measurement-Guided: The team uses systematic, disease-specific, patient-reported outcome measures (e.g., symptom rating scales) to drive dinical decision-making.
Evidence-Based: The team adapts scientifically proven treatments within an individual clinical context to achieve improved health outcomes.

The patient had been seen a year earlier by his PCP [Primary Care Physician] and given Prozac for depression with a "fair" response. This time, he was identified on a medical visit because of his score on a waiting-room PHQ-9. The PCP doubled his Prozac to 40 mg/daily and introduced him to the CM [Care Manager]. She obtained a history of his depressive symptoms and something else:
John has recently moved out of his house, and he and his wife are separating. He is staying with a friend in town…

After a month on the higher dose of Prozac, the patient stops it because of jitters. They’re following him with the PHQ-9 and it goes up. The Psychiatrist suggests changing to Zoloft and has a phone conversation with the PCP about titration [the only direct contact between the Psychiatrist and the PCP recorded]. The patient doesn’t fill the Rx, and a month later, he’s worse. Contacted by the CM, he finally starts the Zoloft and the dose is gradually increased. After several months, the patient is feeling better and he and his wife are "fighting less." 5½ months after the initial contact, he’s back with his wife and feels fine [PHQ-9 is 5]. But two weeks later, he stops the Zoloft, and some of symptoms return and persist, in spite of restarting the Zoloft at a maximum dose. The psychiatrist suggests adding Wellbutrin and later increases the dose. At 9½ months from first contact, he is better and his PHQ is 4.

I think reading it at least helped me clarify my negative reactions:
  • The psychiatrist never saw the patient, and as best I could tell only had one direct contact with the PCP. If the PCP had contact along the way when changing the medications around, it wasn’t apparent. It appears that contact was through the CM [though surely that’s not right with changing drugs and titrating doses?].
  • A PHQ-9 and some comorbidity screening  don’t a diagnosis make [did they actually make a diagnosis?].
  • A PHQ-9 is hardly a precise clinimetric. I’d prefer asking, and I’m pretty sure patients prefer being asked.
  • There are two instances where a high dose SSRI is stopped with no taper. Both suspect for withdrawal [particularly the first] but were interpreted as worsening!
  • What about "John has recently moved out of his house, and he and his wife are separating. He is staying with a friend in town..." Have we just forgotten that a loss like that can cause all of these symptoms? What were the details? Who left who? Is there a clinician in the house?!
  • Given that he got ill when they separated and got better when he moved back in, so I doubt that the Zoloft had much to do with anything [except maybe withdrawal]. It could he that he was just plenty glad to be home…
I realize they can’t put everything in a summary, and I’m Monday Morning Quarterbacking here, but the things I’ve listed are hardly subtle points.

Robert Whitaker, one of psychiatry’s major critics had this to say about where he thought psychiatry might head in the future [see still around…]:

… So I don’t believe it will be possible for psychiatry to change unless it identifies a new function that would be marketable, so to speak. Psychiatry needs to identify a change that would be consistent with its interests as a guild. The one faint possibility I see – and this may seem counterintuitive – is for psychiatry to become the profession that provides a critical view of psychiatric drugs. Family doctors do most of the prescribing of psychiatric drugs today, without any real sense of their risks and benefits, and so psychiatrists could stake out a role as being the experts who know how to use the drugs in a very selective, cautious manner, and the experts who know how to incorporate such drug treatment into a holistic, integrated form of care. If the public sees the drugs as quite problematic, as medications that can serve a purpose – but only if prescribed in a very nuanced way – then it will want to turn to physicians who understand well the problems with the drugs and their limitations. That is what I think must happen for psychiatry to change. Psychiatry must see a financial benefit from a proposed change, one consistent with guild interests.
So even Robert Whitaker sets a higher mark than this APA Collaborative Care piece. I recognize that they’re trying to streamline things, cut costs, etc. But how can one demonstrate any expertise without ever talking to the patient? Who’s going to look for withdrawal, akathisia? Who’s going to say "What’s going with you and your wife?" Who is going to take the history in this system? Make a diagnosis? What is the place of "psycho-social" in any of this? Did we do John J. any favors with our waiting room screening? Well, here’s the essence of the case narrative below. I’d recommend reading this jargon-filled report before signing any contracts [and be sure to renew your malpractice insurance]…

John J.

John J. is a 48-year-old white male visiting his PCP, Dr. Stevens, for a follow-up visit for managing hypertension. During the visit, John’s PHQ-9 score is taken and found to be 16, in the moderate range for major depression. John was treated by Dr. Stevens 12 months ago for depression and remains on fluoxetine 20 mg daily, to which he had a fair initial response. This is John’s first PHQ-9, part of the new Collaborative Care protocol instituted by Dr. Stevens’s clinic.

Dr. Stevens discusses the test results briefly with John during their clinic appointment and introduces him to Ms. Cook, a CM/behavioral health specialist with the clinic’s Collaborative Care team. Ms. Cook is immediately available in the clinic to meet patients coming and going from appointments at the request of the PCP or other clinic staff. John agrees to speak with Ms. Cook after the appointment, and Ms. Cook runs through a few patient screens for behavioral health and substance use conditions that are often comorbid with major depressive disorder. John screens negatively for alcohol use or a history of mania. Ms. Cook discovers that John has recently moved out of his house, and he and his wife are separating. He is staying with a friend in town, and it has been hard for him to make it to work consistently. He often goes to bed late and sleeps in, missing his alarm in the morning, and eventually calls in sick. Ms. Cook shares some of this initial information with Dr. Stevens after their appointment, and Dr. Stevens increases John’s fluoxetine to 40 mg daily. She also engages him in a behavioral activation strategy to improve his mood that includes getting together with his friend Joe over the weekend.

Three days later, Ms. Cook has her weekly meeting with Dr. Brown, the consulting psychiatrist. They discuss John, the new addition to Ms. Cook’s caseload. Dr. Brown acknowledges the PHQ-9 score and the fluoxetine increase and reminds Ms. Cook of additional brief intervention techniques she has reviewed in the past with other patients. Five weeks later, during their caseload review, Dr. Brown notices John’s PHQ-9 score is unchanged. Ms. Cook notes that he stopped taking the fluoxetine the week before because of some ongoing jitteriness. Dr. Brown recommends switching to sertraline instead, and Ms. Cook conveys the recommendation to Dr. Stevens by flagging him in the electronic health record. Dr. Stevens reviews John’s other medications the following day and writes a prescription for sertraline after Ms. Cook has called John to discuss the recommendations of the consulting psychiatrist. John agrees to try the sertraline. Ms. Cook reviews the side effects with John and offers her contact information in addition to Dr. Stevens’s office if he has any problems with the medication. Dr. Stevens phones Dr. Brown and asks about the titration schedule of sertraline and starting dosage to confirm his management is appropriate. They agree to continue with increases in this medication with a target PHQ-9 of less than 5 if possible.

Five weeks after his last appointment, John remains depressed. He did not return Dr. Stevens’s last call regarding some recent lab results, and he no-showed one appointment. During their weekly caseload review, John is eighth on Ms. Cook’s list of 58 patients when sorted by PHQ-9 score severity which leads to a case review. Their registry of patients also has flagged John’s PHQ-9 as overdue and above their target. As she and Dr. Brown are reviewing all the patients, they review John’s score and with the information in the registry are able to quickly recall his latest treatment plan, including the sertraline recommendations. Dr. Stevens did write the prescription, but Ms. Cook is unsure what happened after that. She attempted to call John about 1 week after the sertraline was prescribed and left him a message that wasn’t returned. Ms. Cook and Dr. Brown agree that John needs increased outreach given his recent depression and lack of engagement, and Ms. Cook takes on this task over the next week. They then move on to Sue after spending about 5 minutes discussing John

The following day, Ms. Cook writes a letter from the clinic to John offering assistance and begins to call more frequently. Three days later, John calls back, and he discloses that he never picked up the sertraline and was not sure he was worth the attention of the team. He reports that he didn’t want to feel like a failure again or let anyone down. John’s PHQ-9 score over the phone is 18, and Ms. Cook screens John for suicidal ideation, which is negative. She provides some education around depressive symptoms, the role of the team, and their desire to help him feel better. John agrees to pick up the sertraline from the pharmacy and check-in with Ms. Cook before the weekend to report on how he’s tolerating it.

John, the patient, calls Ms. Cook, the CM, on Friday and reports that he picked up the sertraline and is taking it without side effects but doesn’t feel much different after 2 days. Ms. Cook reassures John that this is not unusual, and that he needs to stick with the medication for 4-6 weeks at the right dose sometimes before his mood may change. They make a plan to check in once a week. In 4 weeks, John’s PHQ-9 score has gone from an 18 to a 15, and he is tolerating the sertraline without any problems. Dr. Brown, the consulting psychiatrist, recommends they titrate the dose to a higher level and continue to monitor John’s response. Dr. Stevens, the PCP, writes a new prescription for John; Ms. Cook confirms that he picks it up at the pharmacy and takes it; and after another 4 weeks, his PHQ-9 is 13. John reports that he is feeling better and has applied for a new job. He and his wife are fighting less, and they are talking about having him move back in. In spite of these gains, however, Ms. Cook discusses John’s remaining symptoms of prominent guilt and negative self-worth and poor quality sleep, energy, and concentration coupled to overeating—all of which contribute to his current score. They formulate a plan to begin more regular exercise. Because his PHQ-9 is still above 5, Dr. Brown’s advice is to continue to titrate the sertraline to the maximum daily dosage, noting his steady improvements.

Four weeks later, John’s PHQ-9 score is 5. He reports that he feels like his old self again, has moved back in with his wife, is exercising more regularly now, and starting to lose some excess weight. Two months after John achieved early remission from his depression, Ms. Cook calls him for a routine check-in. He notes that he stopped taking the sertraline for a couple of weeks right after their last conversation and had a relapse of some of his symptoms. His PHQ-9 score has jumped from 5 to 13, and John is feeling embarrassed and shameful.

He resumed his sertraline at 200 mg about a month ago but still struggles with energy and has stopped his workout routine. Dr. Brown suggests that they augment the sertraline with bupropion, and Dr. Stevens writes the prescription for John. One month later, John’s PHQ-9 score is 10, and Ms. Cook engages him with Behavioral Activation focused on his exercise regimen again. They discuss the cycle of inaction, guilt, and depression, and John agrees to experiment with a different workout regimen and assess his mood. Dr. Stevens automatically adjusts his bupropion to a higher level since he is tolerating it well, and 1 month later John’s PHQ-9 score is 4.

Mickey @ 4:13 PM

a requiem for a lost tradition…

Posted on Thursday 20 October 2016


Tradition is forgetfulness of origins…
Edmund Husserl
It must be kind of fun to be a philosopher, thinking about the nuts and bolts of something like "Tradition." I’m not constructed for that kind of fun – only an observer from afar. But fortunately for me, there’s always another philosopher that comes along to explain [and argue with] what the last one said – like here:
"For Merleau-Ponty, the fact that geometry propagates itself from generation to generation in an anonymous sense as a set of human operations that began at no particular time in the past and which will be developed further in the present in order to arrive at a more developed science in the future is precisely what tradition is. “Tradition is forgetfulness of origins as empirical origins in order to be an eternal origin”. So tradition, according to Merleau-Ponty, essentially involves forgetfulness of empirical origins with the formation of a sense that can be transmitted over time and involving no conception of an origin...
I got onto this line of thought pondering the notion that "Conflict of Interest is not a problem if it is acknowledged." I can’t imagine thinking that or how it came to be. Last year when New England Journal of Medicine editor Jeffrey Drazen wrote Revisiting the Commercial–Academic Interface, followed by a series suggesting that authors with financial conflicts of interest could write objective expert editorials and reviews, there was a reassuring collective groan heard throughout the land [see a narrative…, not so proud…, the real editors speak out…]. In this case, the origins of the of the NEJM excluding "tainted" authors from editorials and reviews were actually not totally forgotten.  The ban originated with former editor Arnold Relman’s 1980 article, The new medical-industrial complex, and subsequent NEJM policy, but they had come to represent something like a "Tradition", at least in my mind. Our "next" philosopher cleared that point up:
Husserl’s account, as we have laid it out, however does not seem to necessitate such a reading. It is certainly not clear whether Husserl means to say that tradition essentially involves forgetfulness. Husserl does suggest that in order to uncover the structure of traditionality one does not have to concern oneself with empirical facts involving the names of the first geometers and the dates of their achievement. Traditions can develop in the absence of any factual knowledge of the founders of the tradition and the time of its founding. But this certainly does not imply that traditions necessarily require a forgetfulness of the empirical origins of that tradition. Husserls account does not seem to support the stronger claim made by Merleau-Ponty, in this regard…
What about other medical traditions, like primum non nocere ["First, do no harm"]? We identify it as the Hippocratic Oath from the dawn of medical history. But there are a wealth of articles suggesting that’s a post-hoc revision. Many of those articles locate it in its current form to the mid-nineteenth century with varying attributions. That would fit other evidence. It was a period when puerperal fever [the Doctor’s Plague, Childbed Fever] was epidemic [women dying after childbirth or miscarraige].  Ignaz Semmelweis noted that the incidence was remarkably less in women with home deliveries and suspected what was then called contagion, instituting handwashing and other hygienic measures with dramatic results. In spite of his success, the notion that doctors were the cause was rejected by his colleagues and he died in a mental institution [not long before Pasteur’s and Lister’s germ theory of disease exonerated him, and revived Semmelweis’s recommendations]. Around that same time, Oliver Wendell Holmes Sr., a proponent of the emerging germ theory, said:
"If the whole material medica, as now used, could be sunk to the bottom of the sea, it would be all the better for mankind — and all the worse for the fishes."
Highlighting the focus on iatragenic illnesses ["of or relating to illness caused by medical examination or treatment"]. So it would make sense that "First, Do no harm" originated or gained prominence in that era [at least it makes a good story].

In my first 20 years in medicine [1963-1983], I can’t recall any physicians I knew or worked with having a financial relationship with a pharmaceutical company. The first time was a Grand Rounds that was what I would now call an Infomercial – shortly before I left the University [1983-ish]. Checking back in 25 years later, it seems like everyone had multiple such connections. I have no sense of how that happened. It was the same with industry sponsored clinical trials in mainstream academic journals – from never to every. Of course there were doctors who worked for industry, but they weren’t the same ones that populated academic departments. I never recall thinking about it, but I think I assumed it was a "tradition" of medicine. I’ve looked around for some account of how all of that changed, and haven’t found a thing.

Similarly, I’ve tried to find some history of where "Conflict of Interest is not a problem if it is acknowledged" specifically came from. While I agree that if a financial COI is present, acknowledged  is better than secret. But "not a problem"? Not hardly! Whether a guest·author, an employee·author, or a ghost·writer, the problem is the same. None of those categories are synonyms for the meaning of the word "author" that includes "originator" or "creator" – that implies an independent opinion. I might even be willing to go along with "Conflict of Interest is not always a problem if it is acknowledged and there is no money or other direct or indirect benefit involved."

In medical education, one doesn’t start out feeling like you’re a doctor. You’re an outsider looking in. The identity part arrives much later, if it does, indeed, arrive at all. It’s not easy to describe what I mean by that. I know I’m not talking about Evidence-Based Medicine, or the Biological Medical Model of Disease as, for example, the anti-biologists or anti-psychiatrist might explain. It has to do with an ethical tradition that is learned largely through example, by apprenticeship. While it may seem a paradox, the loudest criticisms of physicians come when that ethical tradition is absent – criticisms I find myself agreeing with most of the time. And there is simply no room in that ethical tradition for "Conflict of Interest is not a problem if it is acknowledged" no matter what argument follows.

Rather than further lament the lost idealism of a former time when the integrity of academic physicians could be assumed, where there was an ethical tradition that more or less assured us that our literature could be trusted, it’s time to accept the fact that it has eroded to a point where it’s time to rethink the system. We can no longer look at the name, academic rank, or institutional affiliation of the author of an article [or the publishing journal] and use that as evidence for the opinion it expresses. The obvious solution is a regulatory system that has enough ongoing oversight to insure that it’s not being gamed. We think our Petition fits the bill in the area of industry funded clinical trials [which is why I can’t seem to stop talking about it]. We back up primum non nocere with oversight and laws. Time to put similar teeth into the tradition of academic medical integrity

Note: Listen to Alastair Matheson’s podcast on a very related topic…
Mickey @ 3:33 PM

accountability IV…

Posted on Tuesday 18 October 2016

"He who controls the narrative, controls the debate."

It was after retiring when I first became aware of how unreliable the information I had about the psychiatric medications I was being asked to prescibe as a volunteer physician had become. So I went to the medical resources traditionally available to me. I bought the latest textbooks, read the PDR, began to read review articles and the original articles reporting on the clinical trials of the drugs themselves. I got to know ClinicalTrials.gov and Drugs@FDA. I read the blogs available at that time – furious seasons, soulful sepulcher, carlat, etc. And I read about Conflicts of Interest and learned about Speaker’s Bureaus, Key Opinion Leaders [KOLs], and Senator Grassley’s findings of payola. It was a sadly disillusioning landscape.

That had never happened to me in Medicine. I had the conviction that when I hit a bump in the road I could hit the books and find my way. And this time it didn’t happen. I couldn’t find an anchor, some still point that I could count on. In a forty year medical career, I had counted on the academic literature to be a guide and it just wasn’t there this time. The chairman of the department I was affiliated with was removed from his post for unreported pharmaceutical income. The same was true for the President of the American Psychiatric Association. Such goings on in Medicine were unparalleled in my experience.

Flash forward six or seven years. It’s taken me that long to accept that things just aren’t like they used to be. In the past, I could count on the academic medical literature because of a covenant of integrity that was part of medicine’s academic tradition – embedded in its historic narrative. But there’s something now that really is different, and I credit Alastair Matheson for making it clear, though he did it in slightly different context [see rebranding…]. This is now part of academic medicine’s narrative:

"Conflict of Interest is not a problem if it is acknowledged."

That’s what is different now. And by the way, it’s an absurd declaration. Of course it’s a problem. How could it be otherwise? In the past, that covenant of integrity was the unseen force that allowed me to count on the literature. It’s not there any more, or maybe sleeping very soundly. And the time for lamenting its absence or trying to force it to come back has passed. It’s a time to accept that we’re in a different place now, and have to make adaptations to the world we actually live in. To hold people accountable directly. That false statement is currently controlling the narrative. That’s why we need for the FDA to actively certify, actively offer surveillance, actively intervene. The implicit checks and balances of historic medicine are no longer operating as they have in the past.

It makes me sad too, but it is what it is. Thus, the Petition
Mickey @ 12:50 PM

accountability III…

Posted on Tuesday 18 October 2016

"He who controls the narrative, controls the debate."

So why insist that the FDA certify the a priori declarations and analysis plan entered into ClinicalTrials.gov prior to beginning the study?
    That one is easy. The FDA is the only agency that can. Usually, the a priori Protocol and Statistical Analysis Plan have been filed with the FDA Registration and the IRB report, so the certification os no hardship. But why insist? Far and away, the commonest bit of deceit in these reports is "outcome switching" – selecting an outcome after the fact that gives the statistical results that are most favorable to the drug. The only way to prevent that kind of sleight of hand is to have a bona fide certified listing from before the study begins. Only the FDA has the power to get that.

So why insist that the FDA certify the entries into the ClinicalTrials.gov RESULTS database at the time of submission to the FDA?
    First, the FDA is the only agency that has direct access to that information. At the time of submission, the Sponsor has those RESULTS and can easily put them into the ClinicalTrials.gov RESULTS database to be checked during the FDA Approval process. If they’re not right, the FDA can insist that they be made right before proceeding. Again, this is a necessary check to prevent the ubiquitous "outcome switching." 

Any other reason to insert the FDA into this process?
    Absolutely! The FDA is a governmental agency tasked specifically to insure that our pharmacopoeia is safe and populated with drugs displaying at least some degree of efficacy. There is beyond ample evidence that the current version of that process hasn’t worked. The FDA has done a fairly decent job of approval/disapproval, but has turned a blind eye to the gross distortion of many trial results in journal publications – distortions that they alone have the data and power to correct. Is that part of their charge? Absolutely! It’s false advertising in plain sight. They’re not charged with riding herd on what journals publish, but they are definitely tasked with surveillance for false advertisement, and academic journal articles have become a [if not the] major vehicle for pharmaceutical advertisement.

Why petition Congress?
    The suggested change would make fundamental changes in the system. ClinicalTrials.gov would become the official interface betweem the FDA and the public rather than something that is either optional or treated as optional. The FDA would become accountable for both the timing and content of the information available to the public about our pharmaceuticals. Such a change would mean that the FDA would itself need oversight and authority. In our system, such things come from Congress, not the Agencies themselves. Likewise, it would make willful ignoring the mandate to comply a potentially criminal offense.

Currently, the FDA is an unwitting part of the problem. Maybe they have to keep the actual data from clinical trials private as things stand now. But currently, they are keeping the results private as well, and that’s unacceptable. It has had disastrous consequences well known by all. If the FDA is to be the eyes and ears for the public and the medical profession, they need to tell us what they see and hear – need to be accountable for what they tell us. If they find that Paxil® Study 329 is a failed study [which they did] and it is published as positive by treating non-protocol variables as if they are Primary Outcome Variables [which it was], we shouldn’t have to wait fourteen years for confirmation [which we did]. We need to know that shortly after they know it – by law – rather than allowing the pharmaceutical industry to "control that narrative"…
Mickey @ 10:27 AM

accountability II…

Posted on Monday 17 October 2016

"He who controls the narrative, controls the debate."

I’ve always had something of a love affair with the medical literature. I think I was awed that so many physicians contributed, and felt proud to be in a profession where there was such a rich community dialog among us. And for whatever reason, I was drawn to case reports rather than disease reports. I read the latter, and the review articles, but it usually started with a case and ended there too. And I’m sure that my wandering from internal medicine to psychiatry/psychoanalysis had something to do with the case by case focus in the mental health world. That’s still true for me today, 50+ years later. I don’t do it here because of confidentiality, but I often have to actively stop myself. When I left [or was extruded from] my full time academic position, I continued to teach a lot, but my reading seemed to change. It became more focused on the areas I taught and patients I treated, whereas before I read most everything that came in front of me. I realized later that the literature had changed on me. Case reports essentially disappeared, and I let my subscriptions run out. Everything seemed like speculations about future things and was frankly boring, too unpopulated for the likes of me. So I don’t know when the drug trial articles appeared. I think I must’ve been long gone by then.

I think if I had read our Petition [that one I keep talking about] even two years ago, I wouldn’t have understood it, even though by then I had filled this blog with complaints about the distortions in clinical trial reporting and matters ClinicalTrials.gov to overflowing. What wouldn’t I have understood? First, why the insistance on declaring the primary and secondary outcome variables and analytic methods in ClinicalTrials.gov before starting the study? And for that matter, why insist that the FDA review and certify those entries? Similarly, why insist on filling out the ClinicalTrials.gov RESULTS database before any FDA submission? And why demand that the FDA check it for concordance with the FDA information [and certify that concordance]? For further, why ask Congress to make these things part of the Law of the Land rather than ask for just a change in FDA/NIH procedures? That comes across as pretty controlling.Looking  Is it really necessary?

Looking back over this era, the majority of the FDA Approvals seem Legit to me. Efficacy standards are low, two statistically significant trials. The promary charge of the FDA is safety. Efficacy and usage is for the medical profession to work out. But there’s a huge loophole in the system in that the same trials that make it through the FDA as "weak sisters" look like "liquid gold" in the academic Journals that publish the self-same trials. And this discordance is never addressed, actually it’s often undetectable or at least undetected.  That’s what those two ostriches in the graphic are not seeing. How can the same data reach such divergent conclusions? Often, the answer is simple – what Ben Goldacre calls "outcome switching."

By the time a drug is in the NDA [New Drug Approval] Phase III trials, it has already shown that there’s a signal that it has the desired medicinal effect and that it’s probably safe [from Phase I and Phase II trials] approved as such by an Institutional Review Board. So the likelyhood that it’ll have some kind of significant result on some metric is high [if you look at enough metrics!]. But that’s not how statistical analysis works, poring over the data in search of something that suits [p-hacking]. You have to select your parameters in advance, 1° and 2°].  So that’s one reason for both insisting that the outcome parameters are set in stone before you start anything. To guarantee that you haven’t gone over and over the data to make something fit [which has happened over and over], but it can’t be proved because it all happens in secret. What if the Sponsor picked wromg? Do another study with the new choice. This loophole has been exploited quite enough, thank you!

And why so rigid about the RESULTS database? For one thing, there’s no reason for a lag. If you have done the analysis for the submission, you have the RESULTS. But beyond that, Journal Editors, Peers reviewers, Doctors, Patients – all need to see those RESULTS to evaluate the submissions, articles, and advertisement that we are being bombarded with. The journal can’t deny responsibility for what they publish if they have the FDA certified ClinicalTrials.gov data filled out in front of them. Without it, the editors, peer reviewers, clinicians, and patients only have the submitted article to go on – and we all know that has not been a reliable source. In my specialty, I’m having troub;e with coming up with any major articles that didn’t have some evidence of some of this kind of fudging along the way, in spite of the ouvert support for data integrity coming from industry [the narrative under control].

But there’s more. To be continued…
Mickey @ 8:22 PM

accountability I…

Posted on Monday 17 October 2016

"He who controls the narrative, controls the debate."

In this particular American political season, one would have to be close to stage four Coma to doubt the veracity of those words. But we have plenty of examples in American medicine that make the same statement. One version that still amazes me is the notion that the raw data from a clinical trial of medication is treated as proprietary, intellectual property. The rationale is that releasing it might breach patient confidentiality, or expose commercially confidential information. They’re not "patients," they are "subjects" who volunteered for one thing. And what’s commercially confidential about their response to an intervention? Yet, in spite of the uproar, industry has held onto that right, making access to data still a rare exception, and very difficult at that. Our re-write of Study 329 was an enormous undertaking, primarily because of the restrictive window we were given to access the data. The sensible program adopted by the European Medicines Agency to release data has likewise been essentially undermined. Data Transparency is on the lips of everyone, including industry – only it just hasn’t happened in real life. The intellectual property meme continues to control the narrative.

Alastair Matheson has recently clarified another example – ghost writing. Most industry-funded clinical trials are conducted by commercial Contract Research Organizations [Clinical Research Organizations][CROs]. The resultant data is analyzed by company statisticians working with the companies; marketing departments, and a summary of the results are forwarded to a professional medical writers who create a first draft. At that point, the recruited COI-ladened KOL authors enter the review process along with the industry-doctors also on the author by-line. In the past, the medical writers were either unmentioned or mentioned as editorial support. When challenged as ghost-writers – the medical writers/pharma denied it. But then came the new narrative pointed out by Matheson. They claimed that if they’re mentioned in the Acknowledgements by name, they’re no longer ghosts. As absurd as that is, they’ve stuck to the explanation like super-glue.

While I believe that someday the battle for Data Transparency will finally be won, I expect it’s a long way off. The enemy has very deep pockets. But industry can’t possible claim that the RESULTS are proprietary. They publish them themselves. However, with a little help from the regulatory agencies, industry has essentially created a situation where the RESULTS are similarly under their control, just like the data access:
  • By ignoring the requirement to declare outcomes a priori in the ClinicalTrials.gov database, they’ve undermined having a certified statement as an anchor that couldn’t be changed.
  • Even more damning, they’ve ignored even posting the RESULTS until relatively recently.
We all likely know those few studies where we can prove that they’ve changed outcomes [Paxil Study 329, CIT-MD-18, Paxil Study 352, etc]. Many of them are in the past [because it took so long to get hold of the information!]. But few people seem to realize that "outcome switching" is an everyday occurrence in the present, in articles published recently.One way we know that is through the efforts of Ben Goldacre [physician, psychiatrist, epidemiologist, researcher, journalist, author, activist, bundle-of-energy, etc]. In his COMPare study, he and his colleagues took a look: 
Between October 2015 and January 2016, the COMPare team systematically checked every trial published in the top five medical journals, to see if they misreported their findings.

And what they found:

67 9 354 357

And when they wrote the Journals:

58 18 8 32

I encourage you to look at their website, particularly the Blog and the different reactions among the journals. It’s straightforward. Each study looked at is well documented. See also Goldacre’s academic colleague, , and his review of the FDA Requirements. These results couldn’t be clearer.

But you probably  didn’t know that changing outcomes was still that common, well in the majority. You and I have been reading the narrative being handed to us with industry falling all over itself to aver their commitment to the cause of  Data Transparency and ClincalTrials.gov compliance, stroking the largely fictitious narrative. And if you’re a denizen of that web-site like some of us, you’ve noticed how recently the RESULTS database has been filled out on-time [for a change]. Maybe not on point, but at least on-time.

I frankly doubt that even the people at the FDA, the NIH, or ClinicalTrials.gov actually realize how common this practice of changing outcomes really is or why it’s such a game changer. And it’s likewise probable that few know why prompt a priori Registration and RESULTS posting on that site matters so much. The recent reforms by the NIH and ClinicalTrials.gov focus on the importance of using that web site, filling it out, but don’t provide for checks on its content [see what to do? the final rule?…] and allow for unnecessary delays in populating both the outcome parameters at registration and the RESULTS. Both of those things are mission critical

to be continued…
Mickey @ 4:49 PM

bru  bach  beck, 1956…

Posted on Sunday 16 October 2016

Mickey @ 8:00 AM

starting the ball…

Posted on Saturday 15 October 2016

New York Times
OCT. 14, 2016

The United States government recently announced its new director of the National Institute of Mental Health, Dr. Joshua Gordon. If you think that’s just bureaucracy as usual, think again. Mental health research, under the leadership of the previous director, Dr. Thomas Insel, underwent a quiet crisis, one with worrisome implications for the treatment of mental health. I hope Dr. Gordon will resolve it. For decades, the National Institute of Mental Health provided crucial funding for American clinical research to determine how well psychotherapies worked as treatments [on their own as well as when combined with medications]. This research produced empirical evidence supporting the effectiveness of cognitive behavioral therapy, interpersonal psychotherapy and other talking treatments.

But over the past 13 years, Dr. Insel increasingly shifted the institute’s focus to neuroscience, strangling its clinical research budget. Dr. Insel wasn’t wrong to be enthusiastic about the possibilities of neuroscientific research. Compared with the psychiatric diagnoses listed in the Diagnostic and Statistical Manual of Mental Disorders [D.S.M.], which can be vague and flawed, brain-based research holds out the promise of a precise and truly scientific understanding of mental illness…

In 2010, the institute introduced a system of brain diagnostics known as “research domain criteria.” These criteria discard diagnoses like post-traumatic stress disorder, examining instead phenomena such as “response to an acute threat” [i.e., fear] at various scientific levels: genes, the molecules they produce, cells, brain circuits, physiology and behavior. Establishing links up and down this ladder — linking a gene to a neurohormonal molecule, and ultimately to a behavior — produces what is called “translational” research…

Nonetheless, translational research has become virtually required for funding. Although the “neurosignature” targets of the research domain criteria are not demonstrably any more useful than D.S.M. diagnoses, and though they are far more distant from clinical symptoms and treatments, the institute favors them. As a result, clinical research has slowed to a trickle, now accounting for only 10 percent of the institute’s budget. Many clinical researchers like myself worry that this kind of research will disappear. We have too often been reluctant to voice our protest, for fear of incurring the institute’s displeasure [and losing whatever opportunities we still have for funding]…

We need both neuroscience and clinical research. I hope the institute will re-establish that balance.
The Research Domain Criteria [RDoC] have been vague at best. The idea rests on the notion that mental illnesses are biologically determined – that if we collect a large enough cohort and a database full of their biological parameters and responses, "big data" techniques will identify the elusive groupings. I assume it has been a bust, and that’s why he left. That’s based on a comment he made in a New Scientist interview as he was exiting:
Question: Are you saying Google is a better place to do mental-health research than the NIMH?
Answer: I wouldn’t quite put it that way, 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.
Much of what he said on leaving was like that, vaguely bitter, like the NIMH had let him down, disappointed him. Not long after arriving as Director, he announced that Psychiatry was to become Clinical Neuroscience and gradually colonized the NIMH in the manner Markowitz describes in his op-ed. It’s not an overstatement to suggest it gradually became the National Institute of whatever Tom Insel was thinking about. An even bigger problem was that when he jumped from one fad to the next, the older projects kept on – so by last year, when he left, there wasn’t much space for anyone to think in.

I think he really believes that mental illnesses are all brain disorders, a belief it would be hard for any practitioner to sustain. But then he wasn’t "any practitioner" – having never seen a patient after finishing his Residency. I always thought his notion of Psychiatry as a Clinical Neuroscience was strange since he was never in the Clinic himself. In my view, he was paradoxically a detriment to Biological Research. Rather than allow researchers to follow their own Muses, he had them boxed in following his – and his blew about in the wind from shiny object to shiny object.

The taint of Insel’s NIMH will linger long. Good on Dr. Markowitz for starting the ball rolling…
Mickey @ 12:41 PM

congressional action time, redux…

Posted on Friday 14 October 2016

… at the time of Registration [before the study started], the ClinicalTrials.gov database defined the a priori Primary and Secondary Outcome Parameters and the methods by which they were to be analyzed.
… at the end of rhe study [after the blind was broken], the ClinicalTrials.gov results database were populated with the results as defined at the time of registration [Primary and Secondary Outcome Parameters].
… by simply looking at the ClinicalTrials.gov site, one could decide for yourself quickly if it were a positive or negative study.
… you knew how to do a few simple calculations, you could generate the Effect Sizes [NNT, OR, Cohen’s d, etc] to estimate the robustness of the drug’s effect.
… at the end of rhe study [after the blind was broken], the ClinicalTrials.gov results database were populated with tabulations of adverse effects and severe adverse effects, you could reach something of a conclusion about the drug’s short-term safety profile.

Isn’t that an overly simplistic view? What are you trying to do, put the journals out of business? Of course it’s simplistic. But RCTs are themselves simplistic. They’re not intended to be the standard for clinical medicine. They’re only designed to say something about the short-term safety of a drug and it’s medicinal properties. The actual worth of the drug as a therapeutic agent is to be determined in clinical use – not the heavily structured environments of a multicentered RTC.

But of course there’s a lot a journal can tell us. It can show us the longitudinal response – over time. It can display the self-rated scales from the subjects themselves.  But RCTs themselves are not the gold standard for anything. They’re the getting started standard for regulators. And even at that, the gold standard for these getting started RCTs is replication, not a single or even a collage of studies. As an aside, we have something of a quirk in our approval process in that we base our approval on two positive studies rather than the replication of a positive study [those aren’t the same thing]. And the over-valuing of single RCTs is pretty ubiquitous. A recent example:

by Aaron Levin
June 16, 2016

In the clinic, managing mental illness in young people requires subtle but significant shifts in thinking, said Karen Dineen Wagner, M.D., Ph.D., a professor and chair of psychiatry and behavioral sciences at the University of Texas Medical Branch, Galveston…

As for treatment, only two drugs are approved for use in youth by the Food and Drug Administration [FDA]: fluoxetine for ages 8 to 17 and escitalopram for ages 12 to 17, said Wagner. “The youngest age in the clinical trials determines the lower end of the approved age range. So what do you do if an 11-year-old doesn’t respond to fluoxetine?”

One looks at other trials, she said, even if the FDA has not approved the drugs for pediatric use. For instance, one clinical trial found positive results for citalopram in ages 7 to 17, while two pooled trials of sertraline did so for ages 6 to 17. Another issue with pediatric clinical trials is that 61 percent of youth respond to the drugs, but 50 percent respond to placebo, compared with 30 percent among adults, making it hard to separate effects.

When parents express anxiety about using SSRIs and ask for psychotherapy, Wagner explains that cognitive-behavioral therapy [CBT] takes time to work and that a faster response can be obtained by combining an antidepressant with CBT. CBT can teach social skills and problem-solving techniques as well. Wagner counsels patience once an SSRI is prescribed…
Note: This is the 7th time I’ve quoted this particular blurb from PSYCHIATRICNEWS [1, 2, 3, 4, 5, 6]. I guess I see it as a paradigm of sorts – a paradigm for something very, very wrong. Each time, I want to insert "Take a history!" after the second paragraph – or even better, "Refer the kid to someone who knows something about children besides how to write prescriptions!" <expletive deleted>

It’s the concreteness of Dr. Wagner’s remarks that I want to call attention to. Prozac® was approved for children and teens early in the game, based on a couple of studies [see tuning the quartet… and eyes wide shut open III…]. While it’s data has never been independently confirmed, the studies are accepted as showing a significant signal though some of us would question that. A recent meta-analysis lists it as the only such drug though doesn’t recommend using it [see antidepressants in kids? a new meta-analysis…]. So Doctor Wagner poses the example of an 11 year old who doesn’t respond to Prozac®. She suggests going off-label and mentions two clinical trials [she was an author on both]! The first, Celexa®, is a trial finally taken down definitively on any number of grounds, including outcome switching [see the jewel in the crown…]:
by Jon Jureidini, Jay Amsterdam, and Leemon McHenry
International Journal of Risk & Safety in Medicine. 2016 28[1]:33-43.
is an analysis of…
by Karen Dineen Wagner, Adelaide S. Robb, Robert L. Findling, Jianqing Jin, Marcelo M. Gutierrez, and William E. Heydorn
American Journal of Psychiatry. 2004 161:1079-1083.
The second suggestion, Zoloft®, also comes from one of her papers:
by Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D; and the Sertraline Pediatric Depression Study Group
Journal of the American Medical Association. 2003, 290[8]:1033-41.
… which I consider one of the worst of the worst. They glued two negative trials together somewhere in mid-study[s] and declared the combo positive [?!?], and there was more [see and then there was one…]. At least this time around, she left out Paxil® Study 329 [also one of hers]. So we’re making progress.

There’s so much wrong here it’s hard for me to stay on point. Dr. Wagner takes the pronouncement of over a decade before based on a couple of RCTs about Prozac® as if it is gospel. And brings up two thoroughly debunked trials from twelve and thirteen years ago as off-label alternatives – without mentioning that other similar studies were negative or that the ones she mentions are destined to the hall of the infamous. But beyond all of that, have we learned nothing more in the last decade plus? Once a clinical trial is published, does it enter some realm of infallability in perpetuity?

back to the future:

At last I make it back to my point! While I don’t know about the two papers used for the initial approval of Prozac® because the information just isn’t available, I do know that none of the papers mentioned in this post [Celexa®, Zoloft®, Paxil®] would make it through the simple scheme proposed at the beginning. Every one of them is a gross example of switching the outcome parameters during the study, probably from peeking through the blinds or thereafter. We can never prove that, but there’s really little doubt in the mind of anyone who has looked closely. Dr. Wagner is an author on all of them except the first Prozac® study, so you’d surmise she should’ve known that.

By the way, that scheme suggested above is the essence of our proposal in The Petition [in case you’ve neglected signing it yet]…
Mickey @ 5:28 PM

richard twardzic 1954…

Posted on Friday 14 October 2016

a crutch for the crab

Mickey @ 10:00 AM