that little thing at the top…

Posted on Monday 8 August 2016

After being stationed together in the UK, five couples have been vacationing together for a week every summer all over North America. We got to be sort of a family back in those days, and that continues, honorary aunts and uncles, nieces and nephews – now over 40 years. Back then we were two internists, a flight surgeon, a primary care guy, and an anesthesiologist. We became a gastroenterologist, psychiatrist, two ophtalmologists, and a hospital administrator. We’ve been to all the weddings and funerals, and our kids travel together too. There are a number of replaced joints and other infirmities, so our activities are more muted. All but one are retired. While we never talk politics or religion, there’s a forty year narrative about medicine and life – which is where I’m headed.

The other internist [gastroenterologist] was the the best clinician I’ve ever known – and the others were top of the line. That’s part of the bond. We learned together and set a good standard for each other back in those post-training days. In the catch-up talk this year, they wanted to know about the Study 329 article I was an author on in the intervening year. It was kind of surprising. They didn’t know about ghostwriting, or guest authoring, or Dollars for Docs, or the Sunshine Act, or the academic-industrial complex, or outcome switching, or all the rest of it. Only the gastroenterologist picked up on what I was talking about. But first, he talked about pharmacology and the changes in his specialty [which he labeled as "miraculous"]. He mentioned antibiotics for ulcer disease [Helicobacter pylori] and the amazing endoscopes they have now. But what he was really talking about were the drugs for turning off stomach acid – H2 blockers and proton-pump inhibitors.

He reminded me of those long nights with GI bleeders in my day, and how, not infrequently, we couldn’t get it stopped and had to call the surgeons. It was a regular on-call event for any internist. "That’s a thing of the past," he said. "With the new drugs, we saw a lot fewer bleeds, and when we did – we could stop them with the scopes." "Chronic ulcer disease? Rare to never." "Surgery required? I can’t recall the last case." Parenthetically, throughout the week, the ophthalmologists talked about the advances over their careers – Lasik, cataract lenses, microscopic surgery, etc. – as did the anesthesiologist – both drugs and equipment. But the gastroenterologist did say, "When the acid switch drugs first came out, they performed as advertised. But later, I thought the newer ones were overblown in the journals. I stopped reading and mostly learned about them at meetings, from colleagues." And then came the punch line. "But you know, you don’t have to read the whole article. You can just read that little thing at the top."

He was referring to the abstract at the beginning of journal articles. I’ve thought about that along the way myself. Back in those days, that’s what I did too – read the abstracts. I got four or five journals a month, reprints left at the office, more in the mail, and I worked 10 hour days. I couldn’t possibly have done more than that. I’d look at the graphs and scan the tables sometimes, but I rarely read the whole articles – certainly not drug studies. To read them like I’ve read them on this blog takes a day or two. Then, I expected the abstract to be just that – an accurate abstract. I might deeply study an article for the odd journal club, but not routinely. I would expect that what I did was the norm, or if anything, I was on the conscientious end of the spectrum.

All I had on last week’s trip was a tablet computer [new and more unfamiliar than I’d planned], but I could get my blog, so I thumbed back through articles I had looked at over the years – just reading the abstracts. Thinking back, in my naiveté, there was a time when I might have even thought that the abstracts were something the journal editorial staff wrote. Whatever I thought, my index of suspicion was woefully low. Nowadays, the abstracts are carefully crafted by ghosts. And looking at them as a group, the abstracts are usually inflated over and above the distortions already in the articles. I concluded that the pharmaceutical marketing departments must know that’s what doctors do, read/scan the abstracts – that little thing at the top.

Recently, Dr. Carroll proposed that the FDA extend its oversight to the published studies [CORRUPTION OF CLINICAL TRIALS REPORTS: A PROPOSAL], which makes perfect sense to me. They are the only ones who have direct access to the Protocol and the the Raw Data from these Clinical Trials needed to insure accuracy. And the FDA is built around statistical and analytic prowess. On one of the list-serves, there was a critique of his proposal, arguing that it was unnecessary because all the information is on the FDA approved package insert for doctors to read [also reprinted in the Physician’s Desk Reference]. The argument was that to do the same thing with journal publications would be redundant. I guess the implication was that doctors are too lazy to read the inserts, aren’t keeping up.

Those inserts are summaries that don’t separate out the individual trials. They are reference materials at best and pretty dense – useful for looking up toxicities but not for much else. The journal articles describe the populations, the metrics, the outcomes, the harms, all in the most easily reviewed format – even if one only reads the abstract. It’s remarkable that the editor’s and peer reviewers don’t have access to the raw data itself. But even more remarkable that they don’t even have the a priori Protocol or the FDA’s analysis. For that matter, neither does the reader. I can think of no reason that the FDA shouldn’t publish their findings and review journal publications that come from Clinical Trials for accuracy, including that little thing at the top – the abstract. They’re the only people that can!
Mickey @ 5:56 PM

a time for change…

Posted on Tuesday 2 August 2016

blog to follow soon

Maria A. Oquendo, M.D.
President, American Psychiatric Association
Columbia University Medical Center
300 West 72nd Street
Suite 1F
New York, NY 10023

RE: CIT-MD-18, Wagner et al., ‘A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents.’ Am J Psych 2004; 161 (6): 1079-1083.

Dear Dr. Oquendo,

We write to you as President of the American Psychiatric Association, and as a staunch supporter of ethics in psychiatry, about our concerns regarding gross misrepresentations made in the above referenced journal article published in the American Journal of Psychiatry in 2004 and reiterated recently in comments that appeared in the American Psychiatric Association’s Psychiatric Newsiv discussing the same clinical trial in 2016.

Specifically, between January 2000 and April 2001 Forest Laboratories, Inc., conducted a multi-site clinical trial of citalopram for depression in children and adolescents, Protocol CIT-MD-I8, IND Number 22,368, with the results published in 2004 by Wagner et al. in the American Journal of Psychiatry.

The article was ghostwritten by agents of the manufacturer and seriously misrepresented both the effectiveness and the safety of citalopram in treating child and adolescent depression.

While substantive problems with CIT-MD-18 and the Wagner et al. article have been exposed in legal actionsi and in the medical literature,ii,iii the article continues to be cited uncritically in the psychiatric literature as evidence of the efficacy of citalopram for treatment of adolescent depressioniv when, in fact, it was no better than placebo.

Our main concern is that children and adolescents are continuing to be harmed because well-intentioned physicians have been misled.

Moreover, the misrepresentation has been compounded by the following issues:
  1. In a letter of May 9, 2016, the Journal’s editor, Dr. Robert Freeman, was asked by three of the undersigned, Drs. Jureidini, Amsterdam and McHenry, to retract the article, but he has curtly refused to do so.
  2. In an email of July 11, 2016, Drs. Jureidini, Amsterdam and McHenry wrote to the former editor of the American Journal of Psychiatry who accepted the Wagner et al manuscript for publication, Dr. Nancy Andreasen, and asked her to support retraction of the article, but she did not respond.
  3. Drs. Jureidini, Amsterdam and McHenry submitted for publication a letter to the editor of the Psychiatric News, Catherine F. Brown, on July 7, 2016 regarding the misrepresentations of Dr. Wagner on CIT-MD-18 and received no response.
The putative research misconduct involved in the CIT-MD-18 study reveals the pervasive influence of Forest’s marketing objectives on the preparation and publication of a ‘scientific’ manuscript written primarily for marketing purposes and only secondarily as a peer-reviewed journal article. Forest’s own internal documents disclosed in litigation show that company staff were aware that there were serious problems with the conduct of this trial but concealed the problems in advancing their commercial objectives. Procedural deviations went unreported (failure to disclose that unblinded patients were included in the final outcome analyses contrary to the study protocol in order to impart statistical significance to a non-significant primary outcome measure). An implausibly large effect size was claimed. Positive post hoc measures were introduced while negative primary and secondary outcomes were not reported. Adverse events were misleadingly analyzed, hiding substantial agitation in the citalopram group. Many of the de-classified Forest documents have now been posted on the Drug Industry Document Archive (DIDA) at the University of California, San Francisco, and many more documents are in the process of being released into the public domain.

We believe that the unretracted Wagner et al. article represents a stain on the high standard of the American Journal of Psychiatry (AJP) and the American Psychiatric Association (APA). Neither the AJP nor the APA can claim to be a leader in scientific research and moral integrity while failing to redress this article that negligently misrepresents scientific findings.

In bringing this matter to your attention, we also ask that you write to the current editor of the American Journal of Psychiatry, Dr. Robert Freedman, supporting our request for retraction of Wagner et al.  journal article.

We are making this letter available to interested parties and for possible posting in the public domain.

Yours sincerely

    Jay D. Amsterdam, MD
    Emeritus Professor of Psychiatry 
    Distinguished Life Fellow of the American Psychiatric Association 
    University of Pennsylvania Perelman School of Medicine
    Philadelphia, Pennsylvania

    Jon N. Jureidini, MB, PhD
    Clinical Professor
    University of Adelaide
    Adelaide, Australia 

    Leemon B. McHenry, PhD
    Lecturer, retired
    Department of Philosophy
    California State University, Northridge
    Northridge, California

    David Healy, MD, FRCPsych
    Professor of Psychiatry
    Department of Psychological Medicine
    Bangor University
    Bangor, Wales, UK
     
    Bernard J. Carroll, MBBS, PhD, FRCPsych
    Emeritus Professor and Chairman 
    Department of Psychiatry and Behavioral Sciences
    Duke University Medical Center
    Durham, North Carolina
     
    John M. Nardo, MD
    Assistant Professor, retired
    Department of Psychiatry
    Emory University
    Atlanta, Georgia

    Thomas A. Ban, MD, FRCP(C) 
    Emeritus Professor of Psychiatry
    Distinguished Life Fellow of the American Psychiatry Association
    Vanderbilt University
    Nashville, Tennessee
     
    Mark Kramer, MD, PhD
    ENEKASUNO, LLC 
    Executive Vice President, C.O.O
    Medical Oncology Research
    Madrid and Barcelona, Spain

    Daniel Carlat, MD
    Associate Clinical Professor of Psychiatry 
    Tufts University School of Medicine
    Boston, Massachusetts
    Publisher and Editor-in-Chief
    The Carlat Psychiatry Report
    daniel.carlat@gmail.com

    Samuel Gershon, MD, FRCP
    Emeritus Professor of Psychiatry
    University of Pittsburgh 
    Pittsburgh, Pennsylvania

    Robert T. Rubin, MD, PhD
    Distinguished Professor Emeritus
    Distinguished Life Fellow of the American Psychiatric Association
    Department of Psychiatry and Biobehavioral Sciences
    David Geffen School of Medicine 
    UCLA
    Los Angeles, California

    James G. Williams, PhD
    Emeritus Professor of Religion
    Syracuse University
    Syracuse, New York

    Barry Blackwell, MD
    Emeritus Professor and Chairman
    Department of Psychiatry
    Milwaukee Clinical Campus
    University of Wisconsin School of Medicine
    Milwaukee, Wisconsin

    Edmund C. Levin, MD
    Distinguished Life Fellow and Diplomate of the American Psychiatric Association Senior Life Fellow and Diplomate of the American Academy of Child and Adolescent Psychiatry
    Department of Psychiatry
    Alta Bates Medical Center
    Berkeley, California

    Steven A. Ager, MD, MS, DLFAPA, FCPP
    Adjunct Clinical Associate Professor of Psychiatry
    School of Medicine
    Temple University 
    Philadelphia, Pennsylvania

    Julie M. Zito, PhD
    Professor of Pharmacy and Psychiatry
    University of Maryland, Baltimore
    Baltimore, Maryland
i United States v. Forest Pharmaceuticals, Inc., Cr. No. 10-10294-NG (D. Mass.); Celexa and Lexapro Marketing and Sales Practices Litigation: Master Docket 09-MD-2067-(NMG)
ii Martin A, Gilliam WS, Bostic JQ, Rey JM. Letter to the editor. Child psychopharmacology, effect sizes, and the big bang. Am J Psych 2005; 162 (4): 817;
iii Jureidini J, Amsterdam J, McHenry L. The citalopram CIT-MD-18 pediatric depression trial: A deconstruction of medical ghostwriting, data manipulation and academic malfeasance,” International Journal of Risk & Safety in Medicine, 28, 2016: 33-43
iv Levin, A. Child psychiatrists look at specialty from both macro, micro perspectives. Psychiatric News, 51/12, June 17, 2016: 23.
Mickey @ 11:28 PM

see you next week…

Posted on Sunday 31 July 2016

Mickey @ 4:00 PM

pdufa?…

Posted on Sunday 31 July 2016

Here are a few versions describing the Prescription Drug User Fee Act [PDUFA] [1] Wikipedia [2] FDA [3] PhRMA. Essentially it’s a deal between PhRMA and the FDA. The drug manufacturers pay when they register an NDA [New Drug Application], and in return, the FDA uses the money to speed up the evaluation process. It accounts for a large chunk of the FDA budget.

PharmaGuy is one [of many] who question the whole idea of PDUFA. Fearing that the FDA is rushing drugs through and in the process approving dangerous drugs. Last year, in a blog Do PDUFA Fees Encourage Approval of Dangerous Drugs and/or Undermine FDA’s Regulatory Oversight of Approved Drugs? he cited a Public Citizen Report that showed that "drugs released after the 1992 enactment of the Prescription Drug User Fee Act (PDUFA) … were more likely to be withdrawn or have a black box warning" [Safety Concerns About New Drugs Revealed]. He also reported that with PDUFA, the FDA is issuing fewer warning letters:

Now PharmaGuy‘s back with some other indirect evidence:
Pharma Marketing Blog
by PharmaGuy
July 25, 2016

An estimated 128,000 hospitalized patients die each year from Adverse Drug Reactions [ADRs. aka Adverse Events, AEs], which matches stroke as the 4th leading cause of hospital deaths [see here]. Deaths and serious reactions outside of hospitals would signicantly increase the totals. This does not include deaths and hospitalizations from over-dosing, errors, or recreational drug use. We know this because of  hundreds of thousands of drug "Adverse Event Reports" [AERs] received by the FDA every year directly from healthcare professionals [HCPs such as physicians, pharmacists, nurses and others], consumers [such as patients, family members, lawyers and others], and drug companies, which are normally required to send AERs it receives from HCPs to the FDA. The following chart shows the trend in AERs received by the FDA from 2004 through 2015:

I have analyzed data from 2003 through 2014 to look at the number of AERs submitted by HCPs versus consumers, the number of serious adverse events versus the number of adverse events involving death, and the correlation between serious AEs and user fees paid to the FDA by drug companies. I see some interesting trends in the data.

In 2014 – for the first time – more AERs were submitted by consumers than by HCPs as shown in the following two chart.

Not only is the FDA receiving more AERs every year, the number of serious AEs and AEs involving death are also increasing rather dramatically as shown in the following chart.

Click on image for an enlarged view.

The Harvard Edmond J. Safra Center for Ethics reports that a forthcoming article in the Journal of Law, Medicine and Ethics ["Institutional Corruption of Pharmaceuticals and the Myth of Safe and Effective Drugs"] will present "systematic, quantitative evidence that since the industry started making large contributions to the FDA for reviewing its drugs, as it makes large contributions to Congressmen who have promoted this substitution for publicly funded regulation, the FDA has sped up the review process with the result that drugs approved are significantly more likely to cause serious harm, hospitalizations, and deaths. New FDA policies are likely to increase the epidemic of harms" [read "Risky Drugs: Why The FDA Cannot Be Trusted"].

The authors of the JLME paper contend that "in return for paying user fees, companies required the FDA to guarantee that it would review priority applications within six months and standard applications within 12 months of submission. Shortened review times led to substantial increases in serious harms." I thought this was an interesting because I have been following the negative correlation between the rise in user fees and the decrease in FDA warning letters, which may encourage approval of dangerous drugs by the FDA [see the data charted in this post: "Do PDUFA Fees Encourage Approval of Dangerous Drugs and/or Undermine FDA’s Regulatory Oversight of Approved Drugs?"].

So, I decided to plot the number of AERs involving serious side effects along with the rise in user fees collected by the FDA from pharma companies and came up with the following chart.

Of course, this does not prove a correlation between PDUFA fees and serious AERs, but it does lend support to the "institutional corruption" argument posit in the above article.

PDUFA is approved every 5 years, and comes up for renewal when it expires in September 2017. The current proposal aims to lower the rate of fee escalation for the next cycle [FDA PDUFA VI “goals” expected to slow rate of user fee increases]. I’ll have to admit total ignorance about PDUFA, though it does seem a very odd compromise to have reached – the FDA earning it’s funding from PHARMA by fast tracking approval? Since the fees are ultimately paid by sick people buying the drugs, it appears to me that they’re being taxed [without representation] to pay for something that may well be to their detriment. I can see why PharmaGuy questions PDUFA and its impact.

Note to Self: When you get back from vacation, look into the Prescription Drug User Fee Act
Mickey @ 12:00 PM

a simple truth…

Posted on Saturday 30 July 2016

by Michael J. Joyner, Nigel Paneth, and John P. A. Ioannidis
JAMA. published online 07/28/2016.

For several decades now the biomedical research community has pursued a narrative positing that a combination of ever-deeper knowledge of subcellular biology, especially genetics, coupled with information technology will lead to transformative improvements in health care and human health. In this Viewpoint,we provide evidence for the extraordinary dominance of this narrative in biomedical funding and journal publications; discuss several prominent themes embedded in the narrative to show that this approach has largely failed; and propose a wholesale reevaluation of the way forward in biomedical research…

Exploring Some Key Examples
In 1999, Collins envisioned a genetic revolution in medicine facilitated by the Human Genome Project and described 6 major themes:
  • common diseases will be explained largely by a few DNA variants with strong associations to disease,
  • this knowledge will lead to improved diagnosis;
  • such knowledge will also drive preventive medicine;
  • pharmacogenomics will improve therapeutic decision making;
  • gene therapy will treat multiple diseases; and
  • a substantial increase in novel targets for drug development and therapy will ensue.
These 6 ideas have more recently been branded as personalized or precision medicine. Similarly, there is the increasing interest in and expectation that:
  • stem cell therapy—a seventh theme—can treat common diseases.
To avoid the misconception that big ideas are all related to biological sciences, an eighth theme is:
  • the emphasis in the narrative on the clinical and research value of converting medical records to electronic formats.
As of April 2016, the Centers for Medicare & Medicaid Services had paid $34 billion in financial incentives to service providers for implementing electronic health record [EHR] systems. EHRs are an important aspect of this narrative because they are thought to provide the structural underpinnings of precision medicine. It has been suggested by some that some combination of these 8 big ideas will yield substantial cost savings for health care…

What they go on to say is that these big ideas haven’t panned out, have consumed research funds well beyond any usefulness, have become inappropriately self perpetuating, and that it’s time to put them on the shelf and move on to other pastures.

IF JOHN IOANNIDIS NEVER WRITES ANOTHER WORD FOR THE REMAINDER OF HIS DAYS, HE STILL DESERVES A SPECIAL SEAT IN HEAVEN FOR THIS ARTICLE.

In the early 80s when our new biologically oriented chairman was trying to convert me from my misbegotten ways as a psychotherapist, he suggested that since I was an Immunologist and also a psychiatrist, I should look into psychoimmunology. I had never heard those two words combined before. He went on to explain that the future was in brain scans, genetics, and biomarkers. In 2005, I read Dr. Insel’s Psychiatry as a  Clinical Neuroscience Discipline with its timetable, it said the same thing.

And looking back at Kupfer et al’s 2002 A Research Agenda for the DSM-V, that’s what it said too – speaking of entrenched ideas [2016 – 1980 = 36 years][and billions].

I’m sad to report that Electronic Medical Records [EMR] have come to my mountain clinic. It’s a remarkably obtuse system that I can’t figure out, so I put medications in with the notes and move on. I can’t imagine that it’s a good idea to look at a computer while seeing a patient, and entering stuff takes longer than seeing the patient [they’re thinking about getting me a scribe]. Last week while I was working, the CMS site visitors were in town. I overheard a little piece of the "feedback session" and they were talking about the importance of the EMR. I snuck out of a side door and hightailed it for home. Even if the software were usable, it would be an interference. I once asked "who reads what’s entered?" The answer: Inspectors.

Did I mention that:

IF JOHN IOANNIDIS NEVER WRITES ANOTHER WORD FOR THE REMAINDER OF HIS DAYS, HE STILL DESERVES A SPECIAL SEAT IN HEAVEN FOR THIS ARTICLE.
Mickey @ 9:00 PM

carpet-baggers…

Posted on Saturday 30 July 2016

"During this growing time of behavioral healthcare, the State of Recovery Conference will bring together treatment providers from the substance abuse, mental health and eating disorder community nationwide and provide a focus on the business side of the behavioral healthcare including treatment center startup, revenue growth and total treatment program efficency…"

"The substance abuse treatment and behavioral health fields have grown and expanded at unprecedented rates in the past 5-8 years. Much of this is due to federal legislation including the Parity Act and the Affordable Care Act. Also impacting the field are the significantly increased rates of heroin and opiate use and concomitant overdose deaths associated with their use. All have led to an increase in interest in the substance abuse treatment field both by those in this field and notably, by those previously outside of our field. This, in turn, has led to a swell of new business partners and business practices. Our field now has the attention of investors, marketers, media experts, advertisers, diagnostic laboratories, pharmacogenomics experts, design groups, billing and patient management companies as well as therapists, counselors, nurses and physicians…"

Keynote panel Discussion: The Business of Behavioral Health: Establish – Grow – Merge or Sell
"Successful organizations are not only finding ways to ensure robust finances along with strong marketing strategies and productive revenue cycle management solutions, they’re also attracting the interest of investors looking to help them grow their operations. A panel of experts will discuss relevant business issues facing providers of all stripes on mental health, substance use, and eating disorder treatment organizations…"

How did I end up on the website of last week’s State of Recovery Conference? It was a Google flag on "Nemeroff" – fabled chairman of psychiatry at Miami and his comments in an article about Mariel Hemingway’s talk at this conference:
Dr. Charles B. Nemeroff, chairman of the psychiatry department at UHealth — University of Miami Health System, agrees with Hemingway’s assessment on the pervasive stigma against depression-related issues. “It’s robust in many ways,” he says. “We have this fabulous cancer center at UM. It’s so successful in raising money for research. But compare the amount Sylvester can raise compared to what we can raise in psychiatry — it’s a mere fraction. Strokes and Parkinson’s are brain diseases. So is depression. What’s different? They’re both above-the-neck diseases. We still fight this tremendous stigma.

According to the Centers for Disease Control and Prevention, suicide is the 10th-leading cause of death for Americans — “the only cause of death in the top 10 that’s increasing, not decreasing,” Nemeroff says. A member of the board of directors of the American Foundation for Suicide Prevention, he attributes misconceptions about depression and suicide to a variety of factors, including poor insurance reimbursements for mental health care and an ongoing lack of funding and research. Raising awareness, he says, is key, which is why any celebrity to speak out about the subject is helpful.

“Patty Duke was one of the first. Carrie Fisher has done it. Jane Pauley. There’s a local actor here in Miami, Gabrielle Anwar [of “Burn Notice”] who has followed in Mariel’s footsteps and was able to speak about her own issues with depression,” Nemeroff says. “They say you can’t solve a problem by throwing money at it. But yes, you can. Look at AIDS.
carpet·baggers...I get a Nemeroff alert every month or so. They’re usually like this – something that gives him a chance to say depression is brain disease, and something about money. I usually just let them pass, but this one caught my eye because of the State of Recovery Conference. What was that about? The quotes above make it crystal clear. It’s a gathering of business entrepreneurs looking to capitalize on the funds now available from the Affordable Care Act and the Parity Act by getting into the behavioral health business [if there’s any discussion of quality of care in there, I missed it]. It’s all about business opportunities [written in dense business-ese].

In my mind, I call such people carpet·baggers, borrowing the name for the entrepreneurs that flooded the South after the Civil War. At least in the Southern mythology, they were exploiters who were motivated more by greed than anything like Reconstruction. And that is certainly how I saw this State of Recovery Conference reading their web site. We already have something like that in the area where I live – public mental health services delivered by a private contractor. They are constantly changing their program to fit the guidelines from the State [depending on what they will pay for]. So I often see their patients in waves when there has been a policy change that extruded some group of them. They use a telepsychiatrist [or telepsychiatrists – a different one every visit], responsible for some of the egregious examples of overmedication I’ve mentioned in these pages. Sometimes they do the right things, but it’s hit or miss.

I already use that term [carpet·baggers] in my mind when I think about the group of highly placed psychiatrists we call KOLs. Academic Medical Departments have always been largely self supporting. About the same time that traditional sources of funding [public psychiatry, private hospitals, state and federal government training grants, etc] dried up, the neoKraepelinian movement in psychiatry took hold as a reform movement. Came then a new breed who were willing to sign on with the pharmaceutical industry, and natural selection did what it always does. In this case, the surviving fittest were the ones who could [and would] negotiate Institutional Grants, land Pharma’s Clinical Trials, and author their publications. It was something of a perfect storm – the basis for what we now call the Academic·Pharmaceutical Complex, home to the KOLs.

To paraphrase a colleague, there was a time when chairmen and academicians were great teachers, researchers, ethical role models, AND able administrators [including fund raising]. When the pharmaceutical money began to flow, the fund raising skill predominated and here we sit. The academic journals have suffered the same fate. As funding [subscriptions] disappeared, advertising and sales of reprints became a new revenue stream. So, like with the carpet·baggers among the service providers [eg State of Recovery Conference], the Academic·Pharmaceutical Complex is proving to be very resilient because there is yet no solid untainted alternative funding source for academic programs or journals.

Mickey @ 8:47 AM

a new kid on the block…

Posted on Thursday 28 July 2016

National Institute of Health
July 28, 2016

National Institutes of Health Director Francis S. Collins, M.D., Ph.D., announced today the selection of Joshua A. Gordon, M.D., Ph.D., as director of the National Institute of Mental Health [NIMH]. Dr. Gordon is expected to join NIH in September. ”Josh is a visionary psychiatrist and neuroscientist with deep experience in mental health research and practice.  He is exceptionally well qualified to lead the NIMH research agenda to improve mental health and treatments for mental illnesses,” said Dr. Collins. “We’re thrilled to have him join the NIH leadership team”…

Dr. Gordon will join NIH from New York City, where he serves as associate professor of Psychiatry at Columbia University Medical Center and research psychiatrist at the New York State Psychiatric Institute. In addition to his research, Dr. Gordon is an associate director of the Columbia University/New York State Psychiatric Institute Adult Psychiatry Residency Program, where he directs the neuroscience curriculum and administers the research programs for residents.

Joining the Columbia faculty in 2004, Dr. Gordon’s research has focused on the analysis of neural activity in mice carrying mutations of relevance to psychiatric disease. The lab studies genetic models of these diseases from an integrative neuroscience perspective and across multiple levels of analysis, focused on understanding how a given disease mutation leads to a particular behavior. To this end, the lab employs a range of neuroscience techniques including neurophysiology, which is the study of activity patterns in the brain, and optogenetics, which is the use of light to control neural activity. His work has direct relevance to schizophrenia, anxiety disorders and depression, and has been funded by grants from NIMH and other research organizations.  Dr. Gordon maintains a general psychiatric practice, caring for patients who suffer from the illnesses he studies in his lab.

Dr. Gordon pursued a combined M.D./Ph.D. degree at the University of California, San Francisco. Medical school coursework in psychiatry and neuroscience convinced him that the greatest need, and greatest promise, for biomedical science was in these areas. During his Ph.D. thesis, Dr. Gordon pioneered the methods necessary to study brain plasticity in the mouse visual system. Upon completion of the dual degree program at UCSF, Dr. Gordon went to Columbia University for his psychiatry residency and research fellowship…
I’m about to leave for a vacation, so this week has been filled with that getting-things-done activity that I’d rather have than catching-up-on-things when I come back. Part of that was working extra in the clinic to maintain some continuity of care. Tuesday, I saw a young man [20 y/o] that I’ve seen a few times. He is on first meeting a classic case of what has been called Asperger’s – the upper end of the Autism Spectrum. Tuesday, his mother was with him, and though she didn’t say much, there was a pleading look in her eyes. We have no services for him where I live in the mountains, and I had written the Autism Center at Emory in Atlanta in hopes that I could refer him. I  had gotten a very helpful response with offers of a variety of just-what-he-needed services – a medication clinic, socialization training, vocational rehabilitation, etc. Everything I had hoped for. On a hunch, instead of talking to the two of them, I scheduled a further meeting with his mother today. She obviously wasn’t saying what she needed to say when he was in the room.

It was a pretty good hunch. This young man had been well cared for by his family who had been devoted to him. He was teased in school, and quit in the ninth grade. He lives at home, and has been unable to find any place where he fits in. They’ve taken him to therapists and doctors throughout his life, but had never been given a diagnosis – in spite of his having been hospitalized after an angry outburst at a kid that was tormenting him. He had been started on courses of most psychiatric drugs along the way but none ever helped. So I spent about an hour today explaining the diagnosis  and the possibilities up ahead to his mother. Her relief was palpable. It was as if twenty years of her tension began to melt. She had harbored the fear that he had "schizophrenia" [a  condition she had a very distorted understanding of]. She left with a page of phone numbers to call for appointments, and I predict good things.

Driving home, I was thinking about Dr. Insel who was involved with that same Autism Center when he was at Emory before going to the NIMH. And I was thinking about why I have been such his critic. In person, I had liked him, personable, committed, obviously bright. He was not, nor had he ever been, a clinician. I don’t remember what he said at the reception at that Autism Center so long ago where I met him that made me think it, but I left thinking that his zeal for scientific discovery wasn’t tempered by a focus on clinical reality. I remembered that encounter some years later when I felt the same thing as I developed an interest in his NIMH activities – something I called his future-think – an almost desperate race to hit a home run instead of aiming to get on base.

So it was ironic to walk in and read an email that his replacement had been named. I know nothing of Dr. Gordon. I’m encouraged that he has a practice and works with residents. I hope he’s a clinician who can bring some needed balance to the NIMH. In my view, Medicine is a clinical science that has no intrinsic meaning outside of its focus on the patients we see. In my book, the kinds of services I hope my patient can get at the Autism Center are on a par with the lab guys who are looking to find out how neural networks might have something to do with the Autism he and his family struggle with. We need both and that’s not what we have had at the NIMH for a very long time.

I hope Dr. Gordon brings a new vision to the NIMH. And I hope that his first act in September is to disentangle the grant award process from all of the pet projects so important to his predecessor [things like Translational this-and-that; the RDoC; etc.] and give our scientists the latitude to compete for funding based on their own creative ideas rather than fitting into boxes preferred by the Director.
Mickey @ 8:06 PM

what’s it going to take?…

Posted on Sunday 24 July 2016

At this summer’s American Psychiatric Association meeting, Karen Dineen Wagner, president elect of the American Academy of Child and Adolescent Psychiatry discussed the treatment of depressed children and adolescents, saying:
…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…
She’s referring to a 2004 Citalopram study [in which she was the Principle Investigator and first author]:
by Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, Heydorn WE.
American Journal of Psychiatry. 2004 161[6]:1079-1083.
Meanwhile, based on their recent deconstruction of that same study, Jon Jureidini, Jay Armstrong, and Leemon McHenry were waiting for word from the American Journal of Psychiatry [AJP] editor Robert Freedman about their request that this same article be retracted. Dr. Freedman has now responded by email:
RE: Am J Psychiatry 2004; 161:1079–1083 We are not retracting this article. Robert Freedman MD


Had I read this story in college while I was thinking about what comes next, I wonder if I might have been so disillusioned that I would’ve made other choices? Or later when I was thinking about switching my career direction from Internal Medicine to Psychiatry, would I have made the change? It involves the president of the main organization for child and adolescent psychiatry and the editor of the official journal of the professional organization for all of psychiatry. What if I knew then that this is not just an isolated incident, but rather something more like business as usual? I can’t answer those questions, but I know for sure it would’ve mattered, just like it matters now…

The truth about this article has emerged more slowly than for its cousin Paxil Study 329. Shortly after it was published, people noticed that it had a big error in reporting an effect size [see more Wagner et al]. But in 2009 [shortly after this study was an essential ingredient in FDA Approval for use in adolescents], in a suit alleging off-label marketing, discovery documents revealed it was ghost written, that the listed authors weren’t chosen until the study was over and the article was already drafted. Also, it failed to mention another completed study that was negative [see collusion with fiction…]. That suit was settled for $149M. While the AJP published a stern note, they did not retract the article [see the jewel in the crown…].

Now, in the wake of litigation for yet another legal suit, more internal documents make it abundantly clear that  just about everything about the study was jury-rigged – including the outcome switching mentioned in wonky science…. It’s all detailed in this recent publication by Jureidini et al:
by Jureidini, Jon N., Amsterdam, Jay, D, and McHenry, Leemon B.
International Journal of Risk & Safety in Medicine, 2016 28[1]:33-43.

OBJECTIVE: Deconstruction of a ghostwritten report of a randomized, double-blind, placebo-controlled efficacy and safety trial of citalopram in depressed children and adolescents conducted in the United States.
METHODS: Approximately 750 documents from the Celexa and Lexapro Marketing and Sales Practices Litigation: Master Docket 09-MD-2067-[NMG] were deconstructed.
RESULTS: The published article contained efficacy and safety data inconsistent with the protocol criteria. Procedural deviations went unreported imparting statistical significance to the primary outcome, and an implausible effect size was claimed; positive post hoc measures were introduced and negative secondary outcomes were not reported; and adverse events were misleadingly analysed. Manuscript drafts were prepared by company employees and outside ghostwriters with academic researchers solicited as ‘authors’.
CONCLUSION: Deconstruction of court documents revealed that protocol-specified outcome measures showed no statistically significant difference between citalopram and placebo. However, the published article concluded that citalopram was safe and significantly more efficacious than placebo for children and adolescents, with possible adverse effects on patient safety.

Their difficulties getting this paper published are discussed in the background notes. And in addition to the internal emails, Dr. Wagner’s deposition in the case makes it clear that she never even personally reviewed the data or the statistical analyses that were published under her name [see author·ity…]. So this article is just an advertisement, deceptively written by a drug company [Forest Laboratories], not a science-based report for physicians and their patients.

Why would Dr. Freedman, editor of the AJP, send this hostile email with only six words ["We are not retracting this article"] instead of taking the mountain of information about this article seriously? Why does Dr. Wagner continue to quote this article as clinically meaningful [even promoting off-label use in children] in the face of it being so thoroughly discredited? What’s it going to take to put an end to this kind of irresponsible, deceitful behavior at the upper levels of psychiatry? Whatever it is, it’s way past due…
Mickey @ 7:34 PM

Posted on Saturday 23 July 2016

Note: I am pleased to announce that Google has moved me from This site may have been hacked to This site is not mobile friendly status. I see this as a real step up in the world and will look into the mobile friendly issue the next time I’ve got nothing else to do. I do appreciate that Google is now monitoring such things. It’s going to mean a safer more useful Internet – a good thing…


Figure A1. A continuum of experimental exploration and the corresponding continuum of statistical wonkiness. On the far left of the continuum, researchers find their hypothesis in the data by post hoc theorizing, and the corresponding statistics are “wonky”, dramatically overestimating the evidence for the hypothesis. On the far right of the continuum, researchers preregister their studies such that data collection and data analyses leave no room whatsoever for exploration; the corresponding statistics are “sound” in the sense that they are used for their intended purpose. Much empirical research operates somewhere in between these two extremes, although for any specific study the exact location may be impossible to determine. In the grey area of exploration, data are tortured to some extent, and the corresponding statistics are somewhat wonky.

Sometimes, a good cartoon can say things better than volumes of written word. This one comes from the exaplanatory text accompanying a republication and translation of Adrian de Groot‘s classic paper on randomized trials explaining why they must be preregistered [see The Meaning of “Significance” for Different Types of Research, the hope diamond…, Why we need pre-registration, For Preregistration in Fundamental Research]. It’s the central point in the proposal suggested by Dr. Bernard Carroll’s Healthcare Renewal blog [CORRUPTION OF CLINICAL TRIALS REPORTS: A PROPOSAL].

Our journals are filled with articles where the data has been tortured [center above] or had the outcome moved to fit the data [left above]. But RCTs [Randomized Clinical Trials] are intended to test an already defined hypothesis, not make one up. They’re like Galileo’s famous experiment [right above]. Define the conditions in advance, then do the experiment to see if those conditions are met. And the only way to insure that the trial follows and is analyzed by those preregistered conditions is to publicly declare them before the experiment is done and afterwards publicly post the analyses done by the preregistered methods. Anything else ends up in wonky·land. Comes now this…
The COMPare Trials Project.
Ben Goldacre, Henry Drysdale, Anna Powell-Smith, Aaron Dale, Ioan Milosevic, Eirion Slade, Philip Hartley, Cicely Marston, Kamal Mahtani, Carl Heneghan.
We know Ben Goldacre from his books, his TED talk, and his AllTrials campaign, but I think his finest achievement is his current enterprise – The COMPare Project. The idea is simple. Compare the a priori Protocol defined outcome variables with those in a published journal article. I personally discovered the  importance of that working on our Paxil Study 329 article, and ever since have gone looking for protocols on the Clinical Trials that have come along. Sometimes they’re listed on clinicaltrials.gov [and sometimes not]. But even if they’re there, there’s rarely enough to do the proper protocol defined analysis. I’ve never found a full a priori portocol except in cases where it has been subpoenaed in litigation. So I wondered how Goldacre’s group was getting them. Here’s what he says:
"Our gold standard for finding pre-specified outcomes is a trial protocol that pre-dates trial commencement, as this is where CONSORT states outcomes should be pre-specified. However this is often not available, in which case, as a second best, we get the pre-specified outcomes from the trial registry entry that pre-dates the trial commencement. Where the registry entry has been modified since the trial began, we access the archived versions, and take the pre-specified outcomes from the last registry entry before the trial began." He explains this further in the FAQ on their website…

He has some hard working medical students and volunteer faculty working on his team and they checked all the trials in five top journals over a four month period last winter, comparing protocol defined outcomes against published outcomes. Here’s what they found:

TRIALS
CHECKED
TRIALS WERE
PERFECT
OUTCOMES NOT
REPORTED
NEW OUTCOMES
SILENTLY ADDED
67 9 354 357

And when they wrote the editors about the discrepancies, only 30% were published. And when authors do respond, they are sometimes combative or defensive [sometimes the COMPare guys get it wrong and apologize, but that’s not often]. I won’t go on and on. The web site is simple and has all the info clearly presented. Epidemic Outcome Switching! Check and Mate!

They haven’t published yet, but we look forward to what’s coming. I personally think the COMPare Project has landed on the center of the problem. We’ve complained about not being able to see the data itself, but to have this much distortion of the specified outcome variables is even more basic. There is no justification for this level of scientific misconduct…
Mickey @ 12:36 AM

modern times…

Posted on Thursday 21 July 2016

So Charlie Chaplin tried to warn us about technology in his 1936 classic, Modern Times. The french philosophers Jean-Paul Sartre, Simone de Beauvoir and Maurice Merlau-Ponty even named their journal, Les Temps modernes, after the film. But neither Chaplin nor the Existentialists warned us about this…

While the site was operating normally, this message appeared on a Google search of 1boringoldman.com. I contacted my hosting service as soon as I was informed. They ran a scan and found malware so they shut the site down on discovery. A quickscan of my computer came up clean, but a full scan found this:

which I removed:

For a fee, my hoster professionally scrubbed my site on the server and it’s back on-line now. The four posts marked as suspicious have been deleted [all ancient history], and my most recent post. Apparently, the hacker attacked my site through an unused website [8 years obsolete!] that had an old version of WordPress. All WordPress versions are now updated and the unused sites deleted.  I’m currently involved in getting Google to recrawl the site [which ain’t easy]. Insofar as I know, I’m squeaky clean, but I’m not going to post anything until Google’s crawler wanders through and the This site may be hacked message disappears.

I would suggest a full scan of your computer. I am profoundly sorry if this bit of modern times affected you too…
Mickey @ 2:40 PM