a special pleading

Posted on Tuesday 27 January 2015

In the days when those ancients first disuncovered the rules of logic and logical argument, they must’ve thought they’d found the path to determine absolutes, something like the truth. Alas, it was short-lived, because the senator on the other side of the forum rose and eloquently used those self-same rules of logic and logical argument to reach a diametrically opposite conclusion. And so the march began that lead to laws, the legal profession, courts of law with their judges and juries, our legislatures, etc. – all of those institutions involved in parsing a solution out of human disagreement before warring people end up shooting at each other. And somewhere along this path, there was a new class in the study of logic called logical fallacies – situations where logical arguments are chronically distorted or misused.

I wrote the IOM and sent my blog back on track… in which I was arguing for Data Transparency being retrospective including the legacy trials [older trials]. But the response suggested that they thought I was being critical of their work [the Institute of Medicine]. Actually, I was tickled pink that they weighed in, but my ending comment was, perhaps, accusing:
    So I would encourage Dr. Sim and her colleagues to reconsider playing into this industry manufactured argument and helping medicine get things back on track…
So let me be very public in saying that I was tickled pink that the [IOM] weighed in… and I was further encouraged by this response to another comment:
    1bom: …we can look at the raw data from the original trials. And fortunately, the sleight of hand occurred primarily in the analytic and publication processes that came after the blinds were broken. So those legacy trials are the very ones that need to be reanalyzed and meta-analyzed by independent investigators playing with a full deck. Without an accurate and very public re-appraisal, the problem is going to be perpetuated for decades.
    response: The IOM report fully endorses this type of reasoning for prioritizing the sharing of certain legacy trials. It just wasn’t up to our committee to call out which legacy trials in particular, or to propose a process for prioritization.

But in thinking about all of this, I realized that my argument flies mighty close to one of those logical fallacies I was mentioning – a special pleading. It’s one of those fallacies our poor judges have to listen to day after day. It goes something like this: "I know that the law says «something the law says», but it doesn’t apply to me because «something their lawyer made up to say»." And, if I’m honest, I’m really arguing that although I can see why subject confidentiality might concern the committee in releasing individual patient data, the legacy Clinical Trials in psychiatry are a special case that justifies whatever measures are necessary to protect subject confidentiality and make that data available to independent investigators. I’m arguing that the distortion of scientific data in the psychiatric drug literature was so blatant, so widespread, and so damaging that it needs to be made available to the medical community at large for systematic examination for any number of reasons – at any cost.

The most practical reason is that these medications are in heavy current use throughout medicine and will be for some time to come. Doctors need to know what they’re prescribing and patients need to know what they’re taking. And we don’t. Nobody is going to fork over the money it would take to restudy these drugs, but fortunately, there’s a wealth of raw data from the pre-blind-breaking parts of these legacy studies that would tell us a lot about what we need to know. The second reason is equally important in the long run. While it’s understandable why regulatory agencies landed on Clinical Trials as a way of certifying both efficacy and adverse effects of drugs, it is obviously a special pleading of its own that doesn’t touch the depth of knowledge and information gained from clinical experience – something we need to find a way to take advantage of in a better way than we’re doing now. We need to look long and hard at the whole system to make sure this kind of misuse of science is not driving the practice of medicine. What happened in the realm of psychiatric medicines in the last thirty years more than justifies a special pleading. Here’s what the Nizor Project [a resource for understanding fallacies] says about a special pleading:
    "From a philosophic standpoint, the fallacy of Special Pleading is violating a well accepted principle, namely the Principle of Relevant Difference. According to this principle, two people can be treated differently if and only if there is a relevant difference between them. This principle is a reasonable one. After all, it would not be particularly rational to treat two people differently when there is no relevant difference between them."
The pharmaceutical industry took advantage of the subjective nature of psychiatry and the fact that it was poorly supported, unfortunately engaging many in the profession. The effect on patients, the profession, and the drain on available funding for legitimate research efforts is now very apparent. It has happened elsewhere in medicine, but in sheer magnitude, psychiatry is different. Full Data Transparency goes directly to the heart of the problem. Thus, my special pleading
Mickey @ 7:22 PM
Filed under: OPINION
latter day RCTs – the re in re·search

Posted on Monday 26 January 2015

I sometimes refer to the years since 1980 as the age of antidepressants or the age of psychopharmacology, but I would be closer to the mark if I called it the age of clinical trials. Not only were the pharmaceutical companies turning them out, the NIMH [then under Director Steven Hyman] was regularly funding them. Here are some of the big ones from that time period:

LARGE NIMH CLINICAL TRIALS

STEP-BD Systematic Treatment Enhancement Program – Bipolar Disorder NCT00012558
CATIE Clinical Antipsychotic Trials of Intervention Effectiveness NCT00014001
STAR*D Sequenced Treatment Alternatives to Relieve Depression NCT00021528
TORDIA Treatment of SSRI-Resistant Depression In Adolescents NCT00018902
TADS Treatment for Adolescents with Depression Study NCT00006286

In the last two posts [latter day STAR*D I…, latter day STAR*D II…], I was looking at several independent studies using data from the STAR*D trial to address issues not central to the study itself. I expect that there’s a lot more mileage in that approach, plus, in some cases, a much needed re-analysis of the original research question [see significant III… for an example]. But the number of NIMH sponsored trials pales in the face of the industry run and funded clinical trials – and the same points apply in terms of both re-purposing and re-analyzing that data.

In back on track… I was arguing that it’s the legacy RCTs that actually need to be included in the Data Transparency programs because the out-of-patent drugs are going to be in use for a very long time, and much of what we think we know about them is suspect. The argument about Commercially Confidential Information obviously falls by the wayside with out-of-patent drugs. And the more I think about it, so does the argument about patient confidentiality for reasons I’ve already mentioned. I would suggest that the Institute of Medicine, the NIH, the EMA, the FDA, etc. begin to have committees and meetings looking into how to effectively anonymize the data rather than succumbing to the industry’s co-opting medical confidentiality as an excuse for continued secrecy. There’s a wealth of important medical information locked away in file drawers that needs inspecting, harvesting.

I don’t think we [psychiatrists] knew a lot about RCTs in those medicalizing days. I sure didn’t. And by the 1990s, our journals were filled with RCTs. It seems in retrospect that they quickly became the currency of the land, fitting right in with the emphasis on biomedical treatment and psychiatry’s new preoccupation with evidence-based medicine. I doubt that it ever occurred to me or many of us that they were financed by PHARMA, conducted by contract Clinical Research Organizations, or that the authors on the byline didn’t do the study, the analyses, even the writing. I only thought about those things a decade or more after the fact. I expect most of us looked at the graphs of rating scale scores like they were precise chemical measurements rather than results from subjective questionnaires or raters opinions. We looked at p rather than NNT or Effect Sizes. In the process of medicalizing, we took on the trappings of medical science too quickly without getting in up to our elbows and evaluating the instruments that were directing us. My point is that we were naive, gullible, ill-prepared to critically review what we were reading – and it showed in our performance.

So, at least in psychiatry, there’s more at stake than just the individual RTCs from the last thirty years. We need to re·search these studies to learn how to critically evaluate their content and find their place in making good clinical decisions. In my mind, that’s another strong reason we need for Data Transparency to include access to the raw data from those studies we’ve been reading about in our journals all these years. At least in our specialty, having independent teams re-evaluating that information is an important piece of our path to learning what we needed to know in the first place about the ins and outs of medical science [but didn’t]. We drank the Kool-Ade…
Mickey @ 8:30 PM
Filed under: OPINION
latter day STAR*D II…

Posted on Monday 26 January 2015

Scales like the HAM-D, BDI, MADRS, CDRS, IDS, QIDS, etc are designed to quantify the gamut of depressive symptoms. They’re either administered by a trained rater or self-administered. And they’re used both to certify diagnosis and to follow the progress of treatment in Clinical Trials of MDD [Major Depressive Disorder]. The Q-LES-Q was developed for the second function – following treatment – to measure the subjective experience [Quality of Life] rather than changes in the more objective depressive symptoms. It was collected periodically in the STAR*D Trial:
by IsHak WW, Mirocha J, James D, Tobia G, Vilhauer J, Fakhry H, Pi S, Hanson E, Nashawati R, Peselow ED, Cohen RM.
Acta Psychiatrica Scandanavia. 2015 131[1]:51-60.

OBJECTIVE: This study examines the impact of major depressive disorder [MDD] and its treatment on quality of life [QOL].
METHOD: From the Sequenced Treatment Alternatives to Relieve Depression [STAR*D] trial, we analyzed complete data of 2280 adult MDD out-patients at entry/exit of each level of antidepressant treatments and after 12 months of entry to follow-up. QOL was measured using the QOL Enjoyment and Satisfaction Questionnaire [Q-LES-Q]. The proportions of patients scoring ‘within-normal’ QOL [within 10% of Q-LES-Q community norms] and those with ‘severely impaired’ QOL [>2 SD below Q-LES-Q community norms] were analyzed.
RESULTS: Before treatment, no more than 3% of MDD patients experienced ‘within-normal’ QOL. Following treatment, statistically significant improvements were detected; however, the proportion of patients achieving ‘within-normal’ QOL did not exceed 30%, with >50% of patients experiencing ‘severely impaired’ QOL. Although remitted patients had greater improvements compared with non-remitters, 32-60% continued to experience reduced QOL. 12-month follow-up data revealed that the proportion of patients experiencing ‘within-normal’ QOL show a statistically significant decrease in non-remitters.
CONCLUSION: Symptom-focused treatments of MDD may leave a misleading impression that patients have recovered when, in fact, they may be experiencing ongoing QOL deficits. These findings point to the need for investigating specific interventions to ameliorate QOL in MDD.
I wasn’t familiar with the Q-LES-Q. It’s a pretty simple questionnaire, reproduced here FYI:

[click image for full screen version]
As the article is short and available on-line, I just clipped out a representative piece illustrating their point that the symptom reduction measured by the QIDS doesn’t directly correlate with an improvement in the Quality of Life. The QOL improvement is much less impressive – consistent with our clinical experience which doesn’t match the often glowing reports in the literature:
Their punchline:
To conclude, the present analysis highlights the major pitfalls associated with MDD treatments that are purely symptom-focused. Such treatments can give the misleading impression that a patient has recovered, when in fact the patient continues to experience ongoing deficits in QOL. QOL did not improve further after the acute treatment phase even in remitters, and non-remitters showed a statistically significant decline at follow-up after one year. Consequently, clinicians and researchers need to move beyond the mere assessment of symptoms when treating and/or researching MDD, by incorporating QOL measurement, and by investigating specific and personalized interventions to ameliorate QOL.
Like the study in the last post [Depression is not a consistent syndrome…, latter day STAR*D I…], these investigators were able to use the STAR*D dataset available from the NIMH to address a straight-forward question without getting tangled in the problems of the STAR*D study itself. And like in the previous post, one wonders Why didn’t someone do this earlier? It makes intuitive sense that the objective criteria used to define a condition wouldn’t necessarily be the best choice of parameters to follow when assessing subjective improvement. Putting aside for the moment the question of whether Major Depressive Disorder is even a valid diagnostic entity, the antidepressants are, in my mind, symptomatic medications. In the office, at least my office, I don’t go down some checklist of criteria on a follow-up visit after prescribing medication. I let the patient tell me what they think - is it helping or not?
Mickey @ 12:38 PM
Filed under: OPINION
latter day STAR*D I…

Posted on Monday 26 January 2015

The initial fanfare with the SSRIs introducing the Antidepressant Age [Prozac 1988] was followed by a period of disillusionment as the lower than hoped [hyped] response rates became apparent. While the logic behind what came next isn’t totally clear to me, the non-responding patients were seen as having Treatment Resistant Depression, as if this were some variant of Major Depressive Disorder, and the concept developed that the efficacy of the SSRIs could be enhanced by sequencing, combining, or augmenting the therapeutic power of these drugs using some algorithm or treatment guideline. I don’t know how this idea came into being, but I know where. It was in Texas at UT Southwestern, and was implemented as TMAP [the Texas Medication Algorithm Project], followed by a series of NIMH funded Clinical Trials [and others], looking for ways to improve the efficacy of these drugs:
These studies cost the NIMH well over $50 M, produced hundred of articles, are mentioned in 125 posts on this blog, and came to naught. Here’s the conclusion to my last post on STAR*D [retire the side…]:
    These attempts to turn clinical psychiatry into algorithms for medications driven by symptoms, often gathered by questionnaires, have yielded nothing. Worse, they trivialize both the human experience of patients and the practitioners’ efforts to help them. Let’s hope that the chart up there has finally run out of iterations and we can retire the side…
The STAR*D dataset is available for other uses from the NIMH, and recently several independent investigations have appeared that make interesting use of the data from this large cohort:
by Eiko I. Fried and Randolph M. Nesse
Journal of Affective Disorders. 2014 172C:96-102.

Background: The DSM-5 encompasses a wide range of symptoms for Major Depressive Disorder [MDD]. Symptoms are commonly added up to sum-scores, and thresholds differentiate between healthy and depressed individuals. The underlying assumption is that all patients diagnosed with MDD have a similar condition, and that sum-scores accurately reflect the severity of this condition. To test this assumption, we examined the number of DSM-5 depression symptom patterns in the “Sequenced Treatment Alternatives to Relieve Depression” [STAR*D] study.
Methods: We investigated the number of unique symptom profiles reported by 3703 depressed outpatients at the beginning of the first treatment stage of STAR*D.
Results: Overall, we identified 1030 unique symptom profiles. Of these profiles, 864 profiles [83.9%] were endorsed by five or fewer subjects, and 501 profiles [48.6%] were endorsed by only one individual. The most common symptom profile exhibited a frequency of only 1.8%. Controlling for overall depression severity did not reduce the amount of observed heterogeneity.
Limitations: Symptoms were dichotomized to construct symptom profiles. Many subjects enrolled in STAR*D reported medical conditions for which prescribed medications may have affected symptom presentation.
Conclusions: The substantial symptom variation among individuals who all qualify for one diagnosis calls into question the status of MDD as a specific consistent syndrome and offers a potential explanation for the difficulty in documenting treatment efficacy. We suggest that the analysis of individual symptoms, their patterns, and their causal associations will provide insights that could not be discovered in studies relying on only sum-scores.
It’s not easy to see what they did from the abstract and the full paper isn’t on-line, but here’s the gist of it. They looked at the intake QID-16 screening metric [Quick Inventory of Depressive Symptoms] and fractionated it into 12 Symptoms that correlated with the DSM-IV Major Depressive Disorder criteria:
Each item on the QID-16 is scored 0 to 4. They coded each symptom as absent [score 0 or1] or present [score 2 or 3]. That gave them a way to reclassify the 3703 subjects by twelve symptom profile. Here’s the punchline:
There was a striking heterogeneity of symptom profiles among this large cohort of patients diagnosed as having the DSM-IV Major Depressive Disorder. Striking! To my way of thinking, this simple study is totally brilliant. My only question about this paper is Why hasn’t someone done this before? They only used the intake QID-16, so they avoided the mess STAR*D became as it progressed and they started bouncing from metric to metric. And it showed something that many of us think already in a simple yet convincing way: Major Depressive Disorder is not a unitary diagnostic entity – far from it.
 
I would have probably reached a slightly different conclusion – one best articulated by historian Dr. Edward Shorter in his book, Before Prozac:

    "Bottom Line: Major Depression doesn’t exist in Nature. A political process in psychiatry created it…"
Mickey @ 8:00 AM
Filed under: OPINION
a categorical difference? a speculation…

Posted on Sunday 25 January 2015

Neuroskeptic‘s blog on Discover is one my favorites. His current post is about Diederik Stapel, the Dutch Social Psychologist, now famous as an admitted fraud who fabricated a lot of data. Diedrik actually became a regular on another favorite blog, Ivan Oranski’s Retraction Watch [Diederik has 54 Retractions to date]. If you don’t know the story, here are some links [in the New York Times, Neuroskeptic’s post, and on Retraction Watch]. Stapel also wrote a book:
"Two years ago, Dutch science fraudster Diederik Stapel published a book, Ontsporing [“Derailment”], describing how he became one of the world’s leading social psychologists, before falling from grace when it emerged that he’d fabricated the data in dozens of papers. Stapel wrote Ontsporing in Dutch, but now his story has been translated into English, under the title of Faking Science – thanks to the efforts of Nick Brown."
The link to Faking Science is a free download of Brown’s translated book [224 pages]. This story about Diederik Stapel comes shortly after a report on how another frequent flyer on Retraction Watch, Anil Potti, the Duke Cancer Researcher, was exposed [see Duke Officials Silenced Med Student Who Reported Trouble in Anil Potti’s Lab]. In the case of Potti, his work was being questioned by other researchers in the field, but it was a Med Student in his lab that blew the whistle [one that wasn’t listened to by the higher ups for a long time]. In Stapel’s case, a group of graduate students blew the whistle that was apparently heard definitively the first time around.

Who among us doesn’t have personal memories of early experimentation with embellishments or outright lies? or dealt with the experimentation of our children? or recall disillusioning encounters with friends or colleagues once exposed? And it’s the unusual case of someone in psychotherapy who doesn’t get around to shamefully confessed secrets of such things. Here are Stapel’s comments on his step over the line, quoted by Neuroskeptic [QRP: The study he references is available online, a survey of "Questionable Research Practices" among psychologists that reports a surprisingly high prevalence]:
After years of balancing on the outer limits [of scientific integrity], the grey became darker and darker until it was black, and I fell off the edge into the abyss. I’d been having trouble with my experiments for some time. Even with my various “grey” methods for “improving” the data [i.e. ‘QRPs‘], I wasn’t able to get the results the way I wanted them. I couldn’t resist the temptation to go a step further. I wanted it so badly. I wanted to belong, to be part of the action, to score.

I really, really wanted to be really, really good. I wanted to be published in the best journals and speak in the largest room at conferences. I wanted people to hang on my every word as I headed for coffee or lunch after delivering a lecture.

I felt very alone. I was alone in my tastefully furnished office at the University of Groningen. I’d taken extra care when closing the door, and made my desk extra tidy. Everything had to be neat and orderly. No mess.

I opened the file with the data that I had entered and changed an unexpected 2 into a 4; then, a little further along, I changed a 3 into a 5. It didn’t feel right. I looked around me nervously. The data danced in front of my eyes. When the results are just not quite what you’d so badly hoped for; when you know that that hope is based on a thorough analysis of the literature; when this is your third experiment on this subject and the first two worked great; when you know that there are other people doing similar research elsewhere who are getting good results; then, surely, you’re entitled to adjust the results just a little?…
I suppose that we would say he was already "over the line" ["the grey became darker and darker"] before this moment:
No. I clicked on “Undo Typing.” And again. I felt very alone. I didn’t want this. I’d worked so hard. I’d done everything I could and it just hadn’t quite worked out the way I’d expected. It just wasn’t quite how everyone could see that it logically had to be. I looked at the door of my office. It was still closed. I looked out the window. It was dark outside. “Redo Typing.” And again. For a moment I had the feeling that someone was standing behind me. I turned round slowly, fearfully. There was nobody there. I looked at the array of data and made a few mouse clicks to tell the computer to run the statistical analyses. When I saw the results, the world had become logical again. I saw what I’d imagined. I felt relieved, but my heart was heavy. This was great, but at the same time it was very wrong.
Any modern discussion of Moral Development usually has that word development in it, because morality is not something that just comes with the package. We acquire it along the way. And the terms used to describe it [Superego, Conscience, Moral Compass, Jiminy Cricket] imply it’s an attachment, rather than an integral component. Stapel‘s description of someone standing behind me, is pretty common. Many describe this moral agency as the personified part of the mind [as we acquire it from other people and it’s experienced as a presence]. My point is that we all know people whose morality depends on whether someone is looking or not – it hasn’t become an internalized part of the mind, but remains dependent on an outside monitor like it is in parts of childhood. In a later vignette, also quoted by Neuroskeptic, after Diederik Stapel has been confronted, he’s still thinking he can continue to fool the outside agent, and is fabricating new, more elaborate stories.

Retraction Watch is an interesting study of the fragility of human morality – high functioning people who step into the "grey," and then it gets "darker and darker." And it’s almost always "loners" doing the fabrication – I presume looking over their shoulders. This story attracted my attention at a time when I’ve been thinking about the issue of Data Transparency in Clinical Trials and all the distorted Clinical Trial reports strewn about in our medical literature. In Ben Goldacre’s now famous 2012 TED Talk, he mentioned that industry-funded Clinical Trials are better conducted than many independent trials. That was anti-intuitive to me when I first heard it, but I have to admit that now, having looked a a lot of trials, I reluctantly agree. There are a number of trials where the design is biased [wrong dosing of comparators, for example], but I haven’t run across fabrication of data – the kind of thing that’s common in the examples on Retraction Watch. The trouble comes after the blind gets broken. Negative studies go unpublished. And often, small [and trivial] effects are amplified with a whole host of "grey" techniques [that carefully stay out of the "black"].

What I’m implying [because I apparently don’t know how to say it clearly] is that the widespread embellishment and deceit seen in the Clinical Trial publications is categorically different from the cases we see in the people who show up on Retraction Watch. Each instance in a Clinical Trial includes the involvement of multiple people: guest authors, statisticians, scientists, medical writers, marketeers, legal consultants, CEOs, etc. And there’s an intentionality in staying "in the grey rather than the black." It is a widespread practice, a culture, with similar methods showing up from seemingly independent groups who are otherwise in competition. And throughout this struggle over Data Transparency, the individual companies and their collective [PhRMA] are fighting to hold onto as much control of data access as they can muster. The only reason I can think of for their dogged persistence is to maintain the latitude for embellishment and deceit in the future – as if it is potentially an essential element.

Maybe I can say it clearly after all. The fraudsters are, indeed, betraying their own morality. Diederik Stapel even describes being haunted by it’s presence in an empty room in the vignette above, and is now engaged in a reparative campaign eg a confessional book and a TEDx Brain Train talk. In that talk Stapel discusses how he lost his connections with others in the process. Whereas, those involved in the distortions of the Clinical Trials aren’t betraying a morality, they’re living up to a different, corporate moral standard. They don’t lose connections – their shared morality connects them and appears to be mutually reinforcing. It is, in fact, the rare whistle-blower who betrays this ethic [as in ethos, culture] and is ostracized. That moral difference should have implications for how we approach dealing with the seemingly similar problems the fraudsters and the trialists create…
Mickey @ 7:25 AM
Filed under: OPINION
back on track…

Posted on Friday 23 January 2015

With the Institute of Medicine [Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk] and the National Institute of Health [Honoring Our Promise: Clinical Trial Data Sharing] joining the call for Data Transparency, we’re beginning to approach the details, wherein dwells the devil – what data? which trials? The whole notion of proprietary ownership of the raw dat from Clinical Trials never made any real scientific sense in the first place [see except where necessary to protect the public…, a crushing setback…, the end game… ] being justified by trade agreements. The main two arguments in this last year against Data Transparency have been protecting Commercially Confidential Information and Patient Confidentiality. But first, yet another review of the landscape:

what data?

In the discussion that follows, Summary Data refers to the CSR [Clinical Study Report] which does not necessarily or usually contain the raw data. It’s got means, standard deviations, summary tables, etc. But it doesn’t have the individual test scores or the actual clinical observations of adverse events. The IPD [Individual Participant Data] does have the raw numbers from the individual participants, but the clinical observations are in tabular form – transcribed from the CRFs [Case Report Forms] which is as close as one can get to being there. And one mustn’t forget the a priori Protocol – the plan for the study before it commenced.

which Trials?

There seems to be a consensus developing that, going forward, the more comprehensive data [IPDs and CRFs] should be available for independent review to qualified reviewers. It levels the playing field between the sponsors/investigators and the independents. But what about Clinical Trials from the past [called below legacy trials]? Here, Ed Silverman interviews one of the members of the IOM panel on that very point:

Pharmalot: WSJ
By Ed Silverman
January 20, 2015

Last week, the Institute of Medicine issued an eagerly awaited report about sharing clinical trial data that recommends government agencies and companies provide access from research studies that they fund. The agency suggested timetables for such things as summary results and complete data packages. The move comes after heightened controversy over sharing data, how much data and the best way to do so. Among the issues that remain unsettled is the extent to which data from older trials will be shared. We spoke with Ida Sim, a professor of medicine at the University of California, San Francisco and a member of the IOM committee that prepared the report, about reaching back to past studies. This is an excerpt.

Pharmalot: To what extent did the committee look at sharing data from older trials?
Sim: It is addressed. We did think about it. But there are special considerations for sharing data from legacy trials… The first distinction to be made is between summary level data and individual patient level data. The average result of the trial, which is the summary, is a sort of bottom line – that’s an average result. Advocacy groups like Alltrials are asking for the release of summary level data. But the report focused on some sense of the value of individual patient-level data, and sharing the specific numbers that go into the average is much more complicated, especially for legacy trials.

Pharmalot: How so?
Sim: The primary challenge is the issue of informed consent. Patients who participated in trials in the past were most likely in trials that did not include [a provision for] sharing data publicly. So if we want to now share data, ethically, investigators should go back to get informed consent from the participants. There’s another complication. Very often investigators and the staff associated with a trial have scattered. So it can be expensive and challenging to pursue a team of people, maybe years later, to have them pursue this.

Pharmalot: Should that preclude all older trials?
Sim: Well, that said, for major significant trials that do influence decisions for clinical care, we recommend that, on a case-by-case basis, legacy studies should be prioritized for data sharing. But we have to be pragmatic and realistic. These are issues that have been going on for a long time. I think the committee has been building on prior work [of others] and recognizing there were instances of cherry picking of results, which started the whole movement of registration disclosure [registering trials with ClinicalTrials.gov]. Now, we’re pushing for the next level. But it’s incremental.

Pharmalot: Do you worry that companies may be let off the hook?
Sim: They have been really. The real question is what to extent can we go back and put them on the hook. It’s a question of balance. There are studies from academic investigators, who also have not been upfront [about disclosure]. There are problems of transparency across the whole clinical trial enterprise and the concerns apply to all clinical trials. The ones from the pharmaceutical industry are just more apparent to the public…
Personally, I’m not conflicted about this issue. I don’t think Clinical Trial participants fall under the same confidentiality umbrella as patients. Their data has already been shared as part a published article. The IPDs, even the CRFs, can be easily anonymized, and reveal only their scores on standardized rating scales and comments on Adverse Events. It’s not exactly like those documents contain any deep dark secrets. And the participants know that their results are part of a research effort from the start. Plus, what does an independent reviewer care about personal details outside the focus of the study? So I see the patient confidentiality issue in Clinical Trials as something more like a mechanism used by sponsors to keep data secret rather than any real concern. And certainly, the Commercially Confidential Information in legacy trials is a non-issue as the commercial period is long-passed [and the subjects are a good deal older].

But, as Dr. Sim says, those legacy trials are going to contain a lot of jury-rigged science. And as a scientist/physician, I feel betrayed, and I want it exposed in all its gory detail. I, and the rest of medicine, have been actively misinformed – on purpose. Our patients have been actively misinformed – on purpose. And I personally believe that the companies and their medical allies will just do it again if there’s not a truth and reconciliation period to mark what happened in stone.  But that’s my opinion, my bias that surely affects my logic supporting full Data Transparency for legacy trials. From my vantage, the operative saying here is, "Don’t do the crime, if you can’t do the time."

But there’s another good very reason for full Data Transparency for legacy trials, particularly in psychiatry. The drugs in question are now off-patent – widely available in generic form, inexpensive, and still in heavy use. Managed Care reviewers still hawk them as cost-cutters. And they’re not going to be replaced any time soon. Nor is it likely that Bill Gates, PHARMA, or the NIMH will finance any new trials to restudy them properly. But we can look at the raw data from the original trials. And fortunately, the sleight of hand occurred primarily in the analytic and publication processes that came after the blinds were broken. So those legacy trials are the very ones that need to be reanalyzed and meta-analyzed by independent investigators playing with a full deck. Without an accurate and very public re-appraisal, the problem is going to be perpetuated for decades.

So I would encourage Dr. Sim and her colleagues to reconsider playing into this industry manufactured argument and helping medicine get things back on track…
Mickey @ 3:35 PM
Filed under: OPINION
two chances to be a blip

Posted on Wednesday 21 January 2015

It looks as if the idea of Data Transparency has finally become mainstream. Pharmalot is reporting on the report from the Institute of Medicine [Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk]. Johnson & Johnson has signed on to the Yoda Project at Yale [Johnson & Johnson Will Make Clinical Data Available to Outside Researchers]. Add in the NIH commitment to require the use of ClinicalTrials.gov as it was intended [Honoring Our Promise: Clinical Trial Data Sharing], the EMA’s new policies [EMA opts for trial data transparency], and that makes for an encouraging start for the coming year. But in every one of these moves towards Data Transparency, there’s a question of what can and will be withheld. What is Summary Data? What is Commercially Confidential Information? Who can look at the data? At this point, we can caution and question until we’re blue in the face, but we won’t really know until we actually see what’s released and to whom. So in as much as the idea of Data Transparency is beginning to bloom, the proof that we will actually be able to thoroughly vet and count on any given Randomized Clinical Trial lies in the future as these advertised modes of access become realities.

two chances…

So below, we’re offered two chances to comment on the coming changes in Data Transparency policy – with the Europeans Medicines Agency and the NIH. The last time the EMA asked, many of us responded and they actually changed what they were doing. And I got a note from the main poopah. And this time, I got a personal request to comment [well sort of personal as in "Dear all"]. But my point holds. If there were ever a right time to respond, this is our moment. Same with the NIH. We‘re on their radar now and it’s time to start being a blip. Please click the red underlined links…

Dear all,

Please be aware that we have today launched a public consultation on how the transparency rules of the European Clinical Trial Regulation will be applied in the new clinical trial database.  More information on the consultation is available in our press release and full details and how to submit comments is available on our website, here. Given your expertise and interest in the area of clinical trials and transparency, we would highly value your input into this public consultation.  The deadline for comments is 18 February 2015.

For a brief background:
The European Clinical Trial Regulation aims to create an environment that is favourable to conducting clinical trials in the European Union, with the highest standards of safety for participants. The Regulation transforms the level of information publicly available for each clinical trial carried out in the European Union by requiring transparency on the authorisation, conduct, and results of the trial.  The Regulation will apply to clinical trials that are registered once the Regulation is in operation [not before 28 May 2016]. The key instrument to deal with clinical trials in a transparent way is the new clinical trial portal and database. It will be used for submission and maintenance of clinical trial applications and authorisations within the EU. It will serve as the source of public information on the clinical trial applications assessed, and all clinical trials conducted in the EU. According to the European Regulation, the European Medicines Agency [EMA] is responsible for the development and maintenance of the portal and database, while the authorisation and oversight of clinical trials will remain with the EU Member States.

The document under consultation sets out proposals for the application of the transparency rules of the European Clinical Trial Regulation in the new clinical trial database for stakeholders to review and comment on.  The proposals aim to balance the right of patients and the public to access extensive and timely information on clinical trials, and developers’  and researchers’ need to benefit from investments. This will support the EU as a suitable location for innovative, cutting-edge research and development of medicines. Please note that this public consultation refers only to the practical application of transparency rules for the clinical trial portal and database that is established within the European Clinical Trial Regulation. The European Clinical Trial Regulation is distinct from EMA’s policy on the publication of clinical data, which has already come into force (January 2015). We look forward to receiving your feedback [here].

Many thanks and kind regards,


Commenting on the NPRM and proposed NIH Policy
The public may comment on any aspect of the NPRM or proposed NIH Policy. Written comments on the NPRM should be submitted to docket number NIH-2011-0003. Commenters are asked to indicate the specific section of the NPRM to which each comment refers. Alternatively, written comments on the proposed NIH Policy should be submitted electronically to the Office of Clinical Research and Bioethics Policy, Office of Science Policy, NIH, via email at:
mail: at 6705 Rockledge Drive, Suite 750, Bethesda, MD 20892, or by fax: at 301-496-9839. The agency will consider all comments in preparing the final rule and final NIH Policy.

Mickey @ 9:00 PM
Filed under: OPINION
currently unsolved problem…

Posted on Wednesday 21 January 2015

PsychiatricNews
Paul Summergrad, M.D.
January 2015

It was APA, along with NIMH and academic psychiatry leadership in the latter part of the last century, that helped the field to develop to its current prominence. It is incumbent upon us to focus our attention on these issues so that our academic departments remain strong enough to allow care, new treatments, and education to move forward effectively at a time when our services have never been more essential or the potential for fundamental breakthroughs greater.
It is actually unfair of me to snip out this last paragraph from Dr. Summergrad’s most recent commentary. He’s the first thoughtful President of the APA in memorable history, and this piece appropriately focuses on a real problem. He lays out the forces involved reasonably well – until his last paragraphs where, from my vantage, he could’ve appropriately written…
    It was APA, along with NIMH and academic psychiatry leadership in the latter part of the last century that lead the field to its current dilemma.
… and been more accurate. Certainly, the problems psychiatry faced fifty years ago were daunting and needed to be addressed. The Community Mental Health Movement collided with changes in the collective American attitude towards government involvement in social issues, and it began to wane before it really got started. The psychoanalytic and other psychotherapeutic paradigms had reached a point of exhaustion, yet remained over-represented in the hierarchy of psychiatry. Long psychotherapies were being billed to medical insurance, a practice that had to change. And there were competitive wars with other mental health specialties. All were problems in need of urgent attention. While there was nothing so wrong with the manifest solution [the APA’s DSM-III], the method of change [post without an end…], the over-representation of the neoKraepelinian point of view in the background, and the major unmentioned forces [PHARMA and Managed Care] were  specters that would haunt psychiatry’s rise "to its current prominence" throughout.

Reading Dr. Summergrad’s summary of the problems faced by academic psychiatry today is a déjà vu for me – the quicksand I experienced during the late 1970’s directing an academic psychiatric training program. Put simply, there was no fiscal support in sight. Like the Kalahari Desert on a Discovery Channel special, the verdant plains of a forgotten rainy season had given way to a barren desert with no future promise on the horizon. Whether PHARMA or Managed Care was involved in bringing about psychiatry’s radical changes is immaterial now. But in retrospect, their involvement was an integral part of the story going forward. For PHARMA, it portended a large potential psychopharmacology market that was realized beyond its value. And for Managed Care, that dovetailed into a cost cutting windfall. For practicing psychiatrists, it ultimately became a reimbursable commodity – as medication managers. And there was a lucrative source of grant funds flowing from PHARMA ‘s good fortune into the embattled academic departments. Research in neuro-anything flourished, and the Clinical Research Industry grew like a weed with academic guest-authorship. The other mental health professions prospered – providing psychotherapy services with negotiated medical payment.

But now it’s the dry season again. PHARMA finally exited the picture three years ago, and the impact of its absence on the economy of academic psychiatry is obviously widely felt. The APA’s recent failed DSM-5 enterprise also did little for the current state of the specialty. There has been more than a quarter-century-long alliance among academic psychiatry departments, the APA, the NIMH, and the pharmaceutical industry. The practice of psychiatry has come to be centered on outpatient medication management, and many patients have been "left behind." Add in countless examples of scientific misbehavior and misrepresented authorship in the Clinical Trial literature, particularly with these psychoactive drugs. So while the controversies and some of the players may be similar, this is not the same psychiatry that faced that dry season in the 1970s.

It’s the comments in the penultimate paragraph of this essay that actually caught my attention…
Also, many in the pharmaceutical and biotechnology industries have shifted from clinical neuroscience research to lower-risk areas with more well-developed genetic targets such as oncology. The net result is that clinical research in departments of psychiatry is systemically challenged. The greatest impact of this change in industry funding is, of course, on patients and families. We are deeply in need of new pharmacotherapies and neurotherapeutics based on specific genetic and neuroscience processes. Highly specific treatments, as the physician and noted author Lewis Thomas reminded us, are not only more effective but generally less toxic. These changes in industry funding, when paired with reductions in the true dollar amount of NIH funding, impact the success and potentially the longer-term viability of academic psychiatry departments. All of this is challenging for the field at what should be a time of enormous promise…
  1. "We are deeply in need of new pharmacotherapies and neurotherapeutics based on specific genetic and neuroscience processes".
    It’s in the area of Major Depressive Disorders that the notion of "pharmacotherapies and neurotherapeutics based on specific genetic and neuroscience processes" have been most vigorously pursued. Yet:
    • There is no compelling or replicated evidence that what has been called "Major Depressive Disorders" since the DSM-III Revision is a discrete biological or even clinical condition, much less a disorder with either unitary genetic or neuroscientific roots.
    • There is no compelling or replicated evidence that the current psychoactive drugs are disease or disorder specific.
    • For these reasons, the NIMH has abandoned the DSM-system altogether and is now chasing other rainbows [the RDoC].
    • Studies claiming treatment specificity based on biological markers remain in the range of speculation in spite of intense and expensive efforts otherwise.
    This is the almost ubiquitous future-think – always looking for something just around the corner or down the pike, things that never seem to arrive.
  2. "These changes in industry funding, when paired with reductions in the true dollar amount of NIH funding, impact the success and potentially the longer-term viability of academic psychiatry departments."
    While the extent of the industry support of academic psychiatry departments has been widely known about for some time, here, Dr. Summergrad implies that their very "longer-termed viability" has depended on that industry support. He’s not talking about gravy, or even dessert, he’s talking about meat and potatoes here – basic sustenance. Thinking back, there was no way that the academic department I was a member of in the late 1970s could’ve survived long term once the government and private hospital support began to dry up. There is essentially no university institutional support or service derived income for post-graduate psychiatric education like there is in other medical specialties.
There are certainly lots of things that suggest that there’s more than a spiritual tie to PHARMA among academic psychiatry departments and the APA. It’s been more like Superglue, or maybe a Joint Account.
  • The APA bet their whole ship on the DSM-5 making a definitive transition to a biological paradigm with no solid evidence to back up such a shift in tow. Why? It was as bad a bet in 2002 [A Research Agenda for DSM-V] when they announced their plan as it was in 2011 when they had to call it off [Neuroscience, Clinical Evidence, and the Future of Psychiatric Classification in DSM-5].
  • When the scientific and financial misbehavior of ranking members of the APA or academic psychiatry have been exposed, we haven’t heard a peep out of the APA or, for that matter, the NIMH. Why not?
  • The NIMH under Stephen Hyman and Tom Insel have preferentially funded and supported innumerable large scale psychopharmacology trials.Why?
  • When it became apparent that PHARMA was abandoning CNS drug development, there was a collective wail heard from every rafter, followed by an all out [and ongoing] campaign to woo them back. Why so loud? so passionate?
  • The number of highly placed academics who have been willing to sign on to shaky industry funded clinical trials or industry speaker bureaus is  shocking  surprising. Why so many?
I think that I’ve been naive all along, quantitatively blind. We all know that PHARMA has been throwing money at academic psychiatrists and their departments since early on in this age of psychopharmacology, but I think I saw it as something like supplemental income, Before I read the phrase, "the longer-term viability of academic psychiatry departments," it hadn’t really occurred to me that the PHARMA money was the vital artery supporting the body of psychiatric education. The conflict of interest implications of an academic psychiatry that is dependent on industry funding for survival are obvious to anyone that looks – mind boggling.

I don’t mean to malign Dr. Summergrad in discussing his comments. I appreciate his candor and his commitment to education. He is both a Department Chairman [Tufts] and the President of the American Psychiatric Association, and he’s speaking from experience about a problem that is fundamental and has to be addressed – financing the academic psychiatry programs that teach medical students and residents in psychiatry. It was a front-burner problem in the 1970s when I was a part of it and experienced it first hand. And it’s apparently a big problem now. In the interim, it appears that the income from industry flowing in by various routes has kept the wolf away from the door. Unlike the way things work in most academic settings, in the clinical part of medical education, almost no one gets paid just to teach – no ivory tower. Except for a few administrators, the full-time faculty have clinical jobs [and also teach]. There are also huge volunteer physician faculties who teach for no pay except an academic credential [clinical faculty], a parking sticker, a library card, and maybe free access to the school gym. But there are still plenty of expenses, and the residents have to be paid. Grants may fund research but they don’t fund the necessary infrastructure.

I wish I could say something positive to industry for their generous support of medical education. Unfortunately, such lofty motives don’t come close to describing how all of this went down. It would be more accurate to say that PHARMA bought themselves a tract of academic psychiatry real estate, and parlayed it into an extremely profitable investment by hook or crook. Rather than lament PHARMA moving on, we would do better to celebrate the exodus and lock the door behind them – even though it leaves organized and academic psychiatry with a huge, currently unsolved problem. Perhaps we can find a less destructive solution this time around…
Mickey @ 8:00 AM
Filed under: OPINION
the fiction – and another thing…

Posted on Saturday 17 January 2015

Special Reports, Psychopharmacology, Suicide
Psychiatric Times
By Robert D. Gibbons, PhD and J. John Mann, MD
December 31, 2014
[full text on-line with free registration]

There has been much debate about whether certain classes of medications [eg, antidepressants] increase the risk of suicidal behavior and whether that risk is greater in children, adolescents, and young adults. In 2004, the FDA placed a black box warning on all antidepressants because of concerns that the medications increase risk of suicidal thoughts and behavior in youths; in 2006, the warning was extended to include young adults [up to age 26]. The FDA based its black box warning on results of its meta-analyses of randomized controlled trials [RCTs] conducted in pediatric and adult psychiatric and nonpsychiatric populations.

Questions regarding a possible relationship between antidepressants and suicide were first raised in 1990 with the publication of a series of case reports in which the then newly introduced SSRIs were associated with the apparent emergence of suicidal thoughts and behavior. This led to FDA hearings in 1991, but no evidence of an increased risk of suicidal acts associated with antidepressants was found. In October 2004, concerns raised over paroxetine use in children and adolescents eventually led the FDA to issue a black box warning regarding antidepressants and suicide for children younger than 18 years…

This next report is from the testimony at the first FDA Hearing about suicidality with Prozac® held in 1991:
… My husband was given Prozac on January 24 of 1990. On the evening of February 8, 1990, he killed himself. I am told his death was instantaneous, but I believe his cleat actually began the moment he took his first dose of Prozac. Before Prozac, my husband was very involved with people, our family, and his work. He was very much in charge of his business. But within days after he started taking Prozac I noticed a personality change in him. He showed sign of restlessness, akathisia, agitation, pacing, and his appearance was very drawn. He developed severe insomnia, extreme fatigue, chills, racing heart, dry mouth, and upset stomach. His hands would shake uncontrollably at times. This really alarmed him. I would ask him what was wrong and his only reply was, "I don’t know, I don’t know."
In the article by Gibbons and Mann above, they talk about "suicidality" as if it’s an isolated phenomenon and address the question of whether it occurs with an increased incidence in depressed people on antidepressants. That’s common in articles that address this issue, but it doesn’t fit with my understanding of the question on the table, either clinically or with the Black Box Warning. What I think this is all about are cases like this one – a patient that develops what this man’s wife is describing [which I know by the term – Akathisia]. It’s another example of a confusion of tongues – people talking at each other without clarifying shared meanings.

My own experience as a low prescriber was that when Prozac® first came out, I had a couple of patients who took it for a day or two, then stopped saying, "That stuff made me crazy" and "I was coming out of my skin." I was told by colleagues that it was activating, but I stopped prescribing it anyway. Over the years, I had occasional new patients who described the same agita talking about being given an SSRI by someone else before I saw them. The Black Box Warning came after I retired, and I was oblivious. Not long after I started volunteering, I gave Celexa® to an adolescent, who had an extreme Akathesia reaction with suicidal thoughts. That’s how I learned about it. Since then, I’ve seen two suicides in other peoples’ cases that I’m sure were SSRI induced, and multiple others with the Akathisia syndrome who immediately stopped the medication and it cleared quickly [I warn all patients]. In both suicide cases, the people around them mentioned personality change as part of the picture.

Here are a couple of concise descriptive references to the SSRI · Akathisia · Suicidality connection:
When I read something like this Gibbons/Mann piece, my first thought is that they must not see many patients. They talk about suicidality with SSRIs like the question is, "Does the medication ‘turn up’ the usual suicidal thoughts of depression?" Maybe that’s a question some people think about, but I’m not one of them. What I’m talking about is a distinct syndrome with inner restlessness, agitation, aggressive thoughts and actions, disinhibition, and sometimes lethal violence. It’s distinct from the depressive syndromes being treated – something else. Far and away, the commonest outcome is for the medication to be discontinued abruptly by the patient and it clears quickly. My guess is that these are some of the early drop-outs in clinical trials [see Healy above]. And I doubt they make it into population studies often, if at all.

I don’t like being this blunt, but when I read these Gibbons/Mann papers, I don’t think they know what they’re talking about [literally]. In my mind, the Black Box Warning is about an infrequent, idiosyncratic syndrome that can be associated with aggression, suicidality, suicide itself, and even homicide; one that likely has a physiologic basis affecting the extrapyramidal nervous system. I can find no mention of the syndrome in any of their papers [cataloged in the fiction…]. It’s certainly not something you would go lookiing for in some health plan database…
Mickey @ 10:45 AM
Filed under: OPINION
the fiction…

Posted on Friday 16 January 2015

University of Chicago Statistician Robert Gibbons was a voting consultant on the 2004 FDA Pediatric Advisory Committee that elected to add the Black Box Warning to the labeling of the Antidepressants:
    Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children and adolescents in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Prozac or any other antidepressant in a child or adolescent must balance this risk with the clinical need…
Since that time, he and Dr. John Mann, a Professor of Psychiatry at Columbia, have challenged that Warning with a steady stream of articles occasionally joined by other groups. Here’s the summary from their most recent offering:
Special Reports, Psychopharmacology, Suicide
Psychiatric Times
By Robert D. Gibbons, PhD and J. John Mann, MD
December 31, 2014
[full text on-line with free registration]

Summary
The data show that in adults, antidepressants appear to protect against suicidal events. SSRIs are associated with lower overall suicide rates compared with other classes of antidepressants [eg, TCAs]. Antidepressants are effective in reducing symptoms, which, in turn, mediates suicidal events in adults and the elderly. This does not appear to be the case for youths, for whom antidepressant medications can reduce the severity of depression but appear to have no effect one way or the other on suicidal thoughts and behavior. Conversely to what is seen in adults, it may be that aggressive-impulsive traits play a more important role in youth suicide than does depressed mood. The impact of antidepressants on these traits remains unclear. Youth suicide may also be potentially related to illicit drug use and social factors, such as bullying, that are not directly affected by antidepressants.

The black box warning and the earlier public health advisory have shown that discouraging the medication treatment of depression in children is not an effective solution in preventing suicidal behavior. Careful monitoring and treatment of depression and monitoring suicide risk in children is clearly essential. Overall, the clinical evidence is that the majority of patients, young and old, benefit from antidepressants, without increased risk of suicide.

Ten years after the introduction of the black box warning, it is time that the FDA reevaluates this decision and that the results be made public. Moreover, the labeling language should be rewritten to clearly delineate the risks of treatment compared with the risks of no treatment.

Dr Gibbons is Professor of Biostatistics in the departments of medicine, public health sciences, and psychiatry, and Director of the Center for Health Statistics at the University of Chicago. Dr Mann is the Paul Janssen Professor of Translational Neuroscience in the department of psychiatry at Columbia University, and Director, Molecular Imaging and Neuropathology Division, the New York State Psychiatric Institute, New York. The authors report no conflicts of interest concerning the subject matter of this article.
You would think that as much time as they’ve spent on this quest, they’d at least understand the domain of the FDA’s power. After approval of a new drug based on proof of efficacy and safety, the FDA is charged with monitoring safety ongoing, even pulling drugs from the market that prove to be toxic. The obvious reason is to alert physicians to the risks using the drugs as new information becomes available. Drugs are only approved for specific conditions, and manufacturers are constrained from advertising for anything except the FDA approved uses. On the other hand, the FDA has absolutely no authority over how physicians actually prescribe the drugs. So first, there’s the simple matter of what Drs. Gibbons and Mann are asking the FDA to do, "the labeling language should be rewritten to clearly delineate the risks of treatment compared with the risks of no treatment." That’s not remotely an authority the FDA has or should ever have. The FDA doesn’t give opinions about risk/benefit ratios or treatment. That’s for the medical profession to determine with clinical use. The FDA simply certifies minimal efficacy based on a few short term clinical trials, and reports on the adverse events from the trials and later spontaneous reports. It’s actually an absurd request, well outside either the charge or expertise of the FDA. Surely the authors know that. So one has to wonder why they would even propose such a thing?

Then there’s a fundamental misunderstanding of the practice of medicine that runs throughout their ten year thread of challenges. The information about clinical decisions comes from many places: the doctor’s own experience, the experiences of others over time, clinical trials and other studies, the wisdom of the ages, the specifics of the patient being treated, etc. But at the end of the decision making process, it’s only the patient in front of the doctor that’s being treated – not some nameless group defined simply by age and diagnosis. Just that one patient. Gibbons et al argue that because antidepressant prescription rates fell [or didn’t continue to climb] with the Black Box Warning, kids are being deprived of necessary treatment. And they even propose motives. First, that "discouraging the medication treatment of depression in children is not an effective solution in preventing suicidal behavior" as if that’s what the FDA did or was tasked to do. Again, the FDA warned that these drugs can, at times, be associated with suicidality – as a drug effect! That’s their job – drug effects. What doctors do with the information isn’t the FDA’s business [or Dr. Gibbons’]. The FDA is supposed to help us by telling us what bad things can happen – and that’s what they did. And further, these authors propose to know the psychology and motives of doctors, that we were afraid to prescribe these drugs for inappropriate reasons [like getting sued] because of all the publicity about the warning – so we are withholding treatment. They ignore the much more obvious explanation that knowing of the danger, we became appropriately more cautious ["Anyone considering the use of Prozac or any other antidepressant in a child or adolescent must balance this risk with the clinical need…"]. And they imply an efficacy for antidepressants in teens that’s mythologic. Only two of the antidepressants were approved for teens, and they had anything but a robust effect. They apparently think that population statistics should determine the treatment of any given patient. If that’s the case, we don’t need doctors, we only need computers and statisticians.

And then there’s this decade-long cascade of papers with arguments that keep changing as they attempt to prove their point using population statistics on large databases or a meta-analysis of other people’s studies [with no public access to the data]. There are at least fifty other posts on this blog looking at the details in these papers [just put "gibbons black box" into the search box below]. In particular, see persistence…. It’s about number 11. below, which has my letter [unpublished] and letters from two others that were ultimately published in the journal.
  1. Gibbons RD, Hur K, Bhaumik DK, Mann JJ.
  2. Gibbons RD, Hur K, Bhaumik DK, Mann JJ.
  3. Charles B. Nemeroff, Amir Kalali, Martin B. Keller, Dennis S. Charney, Susan E. Lenderts, Elisa F. Cascade, Hugo Stephenson, and Alan F. Schatzberg
  4. Nakagawa A, Grunebaum MF, Ellis SP, Oquendo MA, Kashima H, Gibbons RD, Mann JJ.
  5. Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Mann JJ.
  6. Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Erkens JA, Herings RM, Mann JJ.
  7. Brown CH, Wyman PA, Brinales JM, Gibbons RD.
  8. Gibbons RD, Segawa E, Karabatsos G, Amatya AK, Bhaumik DK, Brown CH, Kapur K, Marcus SM, Hur K, Mann JJ.
  9. Barry CL and Busch SH.
  10. Gibbons RD, Mann JJ.
  11. Robert D. Gibbons, Hendricks Brown, Kwan Hur, John M. Davis, and J. John Mann
  12. Christine Y Lu, Fang Zhang , Matthew D Lakoma analyst, Jeanne M Madden, Donna Rusinak, Robert B Penfold, Gregory Simon, Brian K Ahmedani, Gregory Clarke, Enid M Hunkeler, Beth Waitzfelder, Ashli Owen-Smith, Marsha A Raebel, Rebecca Rossom, Karen J Coleman, Laurel A Copeland, Stephen B Soumerai
  13. by Gibbons RD, Coca Perraillon M, Hur K, Conti RM, Valuck RJ, and Brent DA
  14. by Robert Gibbons and J. John Mann
  15. by Mark Moran
  16. by Richard A. Friedman, M.D.
  17. Robert D. Gibbons, PhD and J. John Mann, MD
As I said last week:
    I’m obviously not writing about this because I’m conflicted about the Black Box Warning. I’ve seen enough adolescent patients with the Akathisia syndrome from SSRIs to know it’s a real thing. And I know of completed suicides that I am sure were SSRI induced.
I’m suspicious that the six articles in 2014 [12.-17.] are harbingers of an effort to get the FDA to convene yet another hearing to revoke the Black Box Warning, now ten years after its adoption, based on the monotonous arguments in the articles listed here. Again from last week:
    They are proposing that warning the clinicians of a potential problem has lead to what they think is an error, so we shouldn’t warn the clinicians?? however rare?? They speculate that operating without being warned, they may ultimately help more people in their ignorance [or silence]?? And perhaps we shouldn’t warn our patients either, so they’ll follow our [proxied] advice?? There’s nothing I know about Medicine that supports that confusion of tongues. These highly placed doctors are not thinking like clinicians, and their group-think has no place in the hierarchy of Medicine as I know it. They’re not speaking the right language… Individual physicians have to construct an individualized risk/benefit estimate on every shared decision from a baby aspirin a day to dangerous and life threatening chemotherapy using known poisons. You can’t do that living in the dark about risk…
The majority of this four page Psychiatric Times piece is designed to bolster the fiction that the Black Box Warning was motivated to affect suicide rates rather than what it says: to warn doctors of Akathisia and suicidality – an idiosyncratic drug effect that afflicts some child and adolescent patients.
Mickey @ 8:00 PM
Filed under: OPINION