1 Boring Old Man

Take for example preregistration. An essential element of any credible clinical trial is a declaration of the outcome variables prior to beginning the study. The elements of the design are Randomization, Double Blinding, Preregistration of Outcomes followed by Replication of positive results with a follow-up study. Here’s a contemporary snapshot of what actually happens:

And looking at the multiple attempts to insist on preregistration, compliance with the rules [some of which are actual laws] mirrors these findings…

clinicaltrials.gov – preregistration/results
rules	Since 2007, the rules have been crystal clear – actual law. Trials are to be registered before they’re begun, and the results published within the first year following completion. There’s no ambiguity in what’s supposed to happen.
reality	If I ever have to justify the name of this blog [1boringoldman], I will probably present a monotonous list of my posts pointing out how the pharmaceutical companies [AND NIMH grant recipients] have been noncompliant with the mandates for timely PRE-registration and later posting results on clinicaltrials.gov. There’s no rational reason for their ignoring this requirement. They already have the data, and the system is simple. They’re given plenty of time. But they’ve just ignored it. This is a partial listing of my posts on this point: transparency!…, studying the studies…, what dreamer?…. non·random missing·ness…, speaking of about time!…, Beware of Shiny Objects!…, back on track…, never been imposed…, a dreamer…, wolf alert! wolf alert!…, etc. And an exempler article [among many] available on-line:. Clinical trial registration, reporting, publication and FDAAA compliance: a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012 by Jennifer E Miller, David Korn, and Joseph S Ross BMJ Open 2015;5:e009758. [full text on-line] Objective: To evaluate clinical trial registration, reporting and publication rates for new drugs by: [1] legal requirements and [2] the ethical standard that all human subjects research should be publicly accessible to contribute to generalisable knowledge. Design: Cross-sectional analysis of all clinical trials submitted to the Food and Drug Administration [FDA] for drugs approved in 2012, sponsored by large biopharmaceutical companies. Data sources: Information from Drugs@FDA, ClinicalTrials.gov, MEDLINE-indexed journals and drug company communications. Main outcome measures: Clinical trial registration and results reporting in ClinicalTrials.gov, publication in the medical literature, and compliance with the 2007 FDA Amendments Acts [FDAAA], analysed on the drug level. Results: The FDA approved 15 drugs sponsored by 10 large companies in 2012. We identified 318 relevant trials involving 99,599 research participants. Per drug, a median of 57% [IQR 32–83%] of trials were registered, 20% [IQR 12–28%] reported results in ClinicalTrials.gov, 56% [IQR 41–83%] were published, and 65% [IQR 41–83%] were either published or reported results. Almost half of all reviewed drugs had at least one undisclosed phase II or III trial. Per drug, a median of 17% [IQR 8–20%] of trials supporting FDA approvals were subject to FDAAA mandated public disclosure; of these, a median of 67% [IQR 0–100%] were FDAAA-compliant. 68% of research participants [67,629 of 99,599] participated in FDAAA-subject trials, with 51% [33,405 of 67,629] enrolled in non-compliant trials. Transparency varied widely among companies. Conclusions: Trial disclosures for new drugs remain below legal and ethics standards, with wide variation in practices among drugs and their sponsors. Best practices are emerging. 2 of our 10 reviewed companies disclosed all trials and complied with legal disclosure requirements for their 2012 approved drugs. Ranking new drugs on transparency criteria may improve compliance with legal [FDAAA] and ethics standards and the quality of medical knowledge. These graphs give an overview – on the left, the number of trials for each drug; – on the right, the percentage of trials for each drug that meet the criteria listed on the abscissa. Like all of this genre of studies, the compliance rates are dismal.

International Committee of Medical Journal Editors
rules	In journal articles are forever…, I mentioned the requirements/recommendations of the International Committee of Medical Journal Editors [using the slash-mark because of their own wording]: "Briefly, the ICMJE requires, and recommends that all medical journal editors require, registration of clinical trials in a public trials registry at or before the time of first patient enrollment as a condition of consideration for publication. Editors requesting inclusion of their journal on the ICMJE website list of publications that follow ICMJE guidance should recognize that the listing implies enforcement by the journal of ICMJE’s trial registration policy." But being listed on the ICMJE database implies that the journal requires preregistration of Clinical Trials [registration before the study begins] as a prerequisite to considering them for publication.
reality	In a recent well-done study from New Zealand [Is Mandatory Prospective Trial Registration Working to Prevent Publication of Unregistered Trials and Selective Outcome Reporting?] surveying articles published since those requirements were finalized, the compliance rate was abysmal [see POM·posity…].

It feels like thinking up new reform strategies is barking up the wrong tree. It would just be an exercise in giving people something else to ignore. We don’t need anything new. What we need is a cop.

1. Manufacture and sale of counterfeit or unapproved drugs
2. Illegal diversion of pharmaceuticals and other regulated products
3. Prescription Drug Marketing Act violations
4. Off-Label promotion of FDA approved drugs and medical devices
5. Health fraud – schemes involving fraudulent treatments/cures/devices
6. New drug application fraud
7. Clinical investigator fraud
8. Product substitution crimes
9. Product tampering
10. Crimes affecting the safety/integrity of the nation’s blood supply
11. Crimes involving the adulteration and/or misbranding of food
12. Internet facilitated criminal violations involving FDA regulated products
13. Illegal importation of FDA regulated products
14. Crimes involving the manufacture, sale or distribution of unapproved FDA regulated products

^{"To protect the public health by ensuring that prescription drug information is truthful, balanced, and accurately communicated.  This is accomplished through a comprehensive surveillance, enforcement, and education program, and by fostering better communication of labeling and promotional information to both healthcare professionals and consumers."}

The FDA oversees one of the most heavily regulated areas in our government. One would’ve thought that, as a physician, I would’ve known a lot about it – but I didn’t. From early on, I always thumbed my way through the Physician’s Desk Reference whenever I ran across a new drug or had any questions about drugs, not really noticing that it is simply a commercial compilation of the FDA approved package inserts from all the approved drugs in our pharmacopeia. I never thought about where it came from [maybe Mount Sinai?]. I didn’t see it as a book to help me know how or when to use drugs, but rather the key reference book to help me be sure I was using medications responsibly – indispensable!

But for me, it was always the journals that I paid attention to – in medicine, in psychiatry, in psychoanalysis. Sometimes in the library, I’d even pick up a journal from a distant specialty and get engrossed in some article or another. There weren’t many abstracts in my journals that I didn’t read. So when the major psychiatry journals changed so dramatically in the 1980s, it was real loss for me. But that’s another story. Sticking to the thread of therapeutics, in that period there came several sort of newish kinds of articles – industry-funded clinical trial reports, reviews of what drugs might be coming in the future [the pipeline], and speculative articles about the neurobiology of something-or-another. Case reports used to be common, but they essentially disappeared.

In-so-far as I knew, journals were an academic enterprise with none of the kind of oversight described above.  Articles were accepted by the editorial staff, aided by the voluntary work of peer reviewers. I don’t recall ever thinking about the fact that with the Clinical Trial reports, all the editors and reviewers had to go on was the submitted paper itself – with no access to the study’s actual Raw Data. And it also never crossed my mind that the data analysis was done by the sponsors’ statisticians, or that the papers were now usually written by professional writers contracted by the sponsors, or that the listed academic authors were authors-in-name-only [with financial-conflicts-of-interest with the funding sponsors].

In the last decade, there have been gradual but important changes. Articles now declare funding sources, the trial registry codes [now usually registered on-time], the authors-in-name-only’s financial-conflicts-of-interest, the presence of  ghost authors, and now there’s a widening understanding of how Clinical Trials have been misreported and jury-rigged. But enduring reform will obviously require more than simply cosmetics. The definitive fix is full Data Transparency – giving the reader and independent researchers access to the actual Raw Data from these Clinical Trials. So long as the Data stays hidden, it will be dolled-up and misrepresented. The stakes are just too high to expect anything else. It was true in antiquity with the necromancers’ potions; then came the patent medicines; and now  the emerging drug industry’s modern pharmaceuticals. It’s Medicine’s stated purpose to oppose those outside forces: primum non nocere, "first, do no harm". And in this case, the voice of Medicine comes from our literature – in the specific, our medical journals.

It’s medical journal articles that are on trial at the moment. While we might fault the FDA for colluding in keeping Raw Data secret, or perhaps being too quiet, or succumbing to pressure from all sides to approve more drugs – faster, Medicine‘s collective voice actually speaks through our medical journals. And in spite of all the complex regulations imposed on the process of medicinal development through the FDA, the journals operate virtually regulation-free. Medicine has always been self regulating, which I support, but it has its vulnerabilities. The captivity of the voice of the journals by commercial interests abetted by a subset of academic physicians is a complex topic – too big for me to fathom understanding in full. But the task at hand is simple. It needs to be stopped. We can probably sympathize with whatever forces made the journal editors susceptible [almost all money matters]. But at the end of the day, the journals themselves have to return to and remain the champion of Medicine’s scientific and ethical voice, not the medium of its corruption.

ICMJE Clinical Trial Registration Policy
• "Briefly, the ICMJE requires, and recommends that all medical journal editors require, registration of clinical trials in a public trials registry at or before the time of first patient enrollment as a condition of consideration for publication. Editors requesting inclusion of their journal on the ICMJE website list of publications that follow ICMJE guidance should recognize that the listing implies enforcement by the journal of ICMJE’s trial registration policy. "
• "The ICMJE defines a clinical trial as any research project that prospectively assigns people or a group of people to an intervention, with or without concurrent comparison or control groups, to study the cause-and-effect relationship between a health-related intervention and a health outcome."
• "An acceptable registry must include the minimum 20-item trial registration dataset [here or here] at the time of registration and before enrollment of the first participant."
• "The ICMJE encourages posting of clinical trial results in clinical trial registries but does not require it."

The registry minimum 20-item dataset is shown in this table [this WHO version is mirrored by clinicaltrials.gov]:

Agreement to comply with these recommendations has grown. I listed the status of some of the psychiatry journals in this table. Most of the majors are on-board:

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.

blog to follow soon

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:

FDA’s Dependence on User Fees & "Institutional Corruption" Blamed for Dramatic Increase in Drug Adverse Events and Deaths

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.

What Happens When Underperforming Big Ideas in Research Become Entrenched?

by Michael J. Joyner, Nigel Paneth, and John P. A. Ioannidis

JAMA. published online 07/28/2016.

[full text on-line]

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.

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:

^{"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…"}

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.”

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.

NIH names Dr. Joshua Gordon director of the National Institute of Mental Health

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…

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.

…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…

A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents.

by Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, Heydorn WE.

American Journal of Psychiatry. 2004 161[6]:1079-1083.

[full text on-line]

RE: Am J Psychiatry 2004; 161:1079–1083 We are not retracting this article. Robert Freedman MD

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…].

The citalopram CIT-MD-18 pediatric depression trial: Deconstruction of medical ghostwriting, data mischaracterisation and academic malfeasance

by Jureidini, Jon N., Amsterdam, Jay, D, and McHenry, Leemon B.

International Journal of Risk & Safety in Medicine, 2016 28[1]:33-43.

[full text on-line]

[background notes]

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.