1 Boring Old Man

I decided that trying to summarize Why is the Diagnostic and Statistical Manual of Mental Disorders so hard to revise? Path-dependence and "lock-in" in classification in the last post [a curious inertia…] was too much, but rereading it this morning, I changed my mind. Independent from how the DSMs came into being, this article has something to say about any future attempts to change it no matter what changes are proposed [and changing it yesterday would be absolutely okay with me]. As Allen Frances tweeted about this article, "DSM is so hard to change not because it’s right –  it’s that every change has harmful unintended consequence."

Actually path-dependence and lock-in  aren’t two separate things, but two parts of the same process. The article brings up an interesting example – the QWERTY keyboard…

I’m a self-taught typist with a spastic technique. I actually look at the keyboard, so I never knew why the keyboard is laid out so oddly. But in the day, fast typists could jam up pretty easily if the keybar from the last letter isn’t out of the way of the next. So the keyboard layout is designed to put keys that frequently follow each other in words far apart. Very clever! Now, that doesn’t matter with the computer keyboards, but because all jillion of you real typists out there would rise up in arms if it got changed to the Dvorak layout, it stays the same – QWERTY. And if there were a major revision of the DSM, the administrative and actuarial changes would fall into the "Y2K" range. If I may be allowed an editorial comment, the third party carriers don’t trust us to make reasonable treatment recommendations. Instead they force us to squeeze patients into these often ill-fitting categories with somewhat fixed coverage. The profoundly depressed Melancholic and the situationally depressed may have the same coverage – a silly use of a Dx category…

Why is the Diagnostic and Statistical Manual of Mental Disorders so hard to revise? Path-dependence and "lock-in" in classification.

by Cooper R

Studies in History and Philosophy of Biological and Biomedical Sciences. 2015 51:1-10.

The latest edition of the Diagnostic and Statistical Manual of Mental Disorders, the DSM-5, was published in May 2013. In the lead up to publication, radical changes to the classification were anticipated; there was widespread dissatisfaction with the previous edition and it was accepted that a "paradigm shift" might be required. In the end, however, and despite huge efforts at revision, the published DSM-5 differs far less than originally envisaged from its predecessor. This paper considers why it is that revising the DSM has become so difficult. The DSM is such an important classification that this question is worth asking in its own right. The case of the DSM can also serve as a study for considering stasis in classification more broadly; why and how can classifications become resistant to change? I suggest that classifications like the DSM can be thought of as forming part of the infrastructure of science, and have much in common with material infrastructure. In particular, as with material technologies, it is possible for "path dependent" development to cause a sub-optimal classification to become "locked in" and hard to replace.

"The DSM provides a common language for mental health research, policy and care. Almost all papers published in psychiatric journals refer to the DSM; the use of DSM categories to select subject populations for study is near universal. Worldwide, textbooks for mental health professionals, and treatment guidelines, tend to be structured around DSM categories. In the US, the DSM also plays an important bureaucratic and economic role; in particular, the DSM contains the codes that insurers commonly require before paying for mental health treatment."

It is unlikely that many of us have subscriptions to Studies in History and Philosophy of Biological and Biomedical Sciences, or will run across it in a waiting room somewhere, but I think it adds a perspective to the endless deliberations about the DSMs that would be helpful to anyone interested in the topic. I hope that it will find its way to the Internet in full at some point. It’s one of the few things I’ve run across that actually made me feel some sympathy for the dilemmas faced by the Task Force that was asked to revise it. No, I haven’t gone over to the dark side. It didn’t make me feel that sympathetic. But it did help me at least understand how the DSM has developed such a curious inertia, keeping it from iterating into something more useful…

Offline: The BMJ vs NEJM—lessons for us all

by Richard Horton

Lancet. 2015 385:2238.

It’s hard to recall now, but there was a time in medicine’s recent past when interactions between physicians and the pharmaceutical industry were seen as positively virtuous. During medical school [a long time ago, 1980–86, at the University of Birmingham], most of our general medicine teaching was organised by the Department of Pharmacology and Therapeutics, led by the inspirational Martin Kendall. In weekly “roadshows”, 180 students would discuss clinical scenarios from a pharmacological perspective. Martin Kendall would lead the class through vignettes of patient management. He would do so by testing the students on stage, a ritual we all endured and enjoyed in equal part. An appreciation of, and respect for, the contribution of the pharmaceutical industry to clinical medicine was embedded in our training, and I think most of us felt better prepared for the practical aspects of subsequent ward work as a result. This mutuality extended to research. In 1985, I spent 3 months working at the Astra Laboratories in Mölndal, near Gothenburg, Sweden. At that time, the great Swedish cardiovascular physiologist, Björn Folkow, was at the University of Gothenburg. It was accepted [and encouraged] that senior faculty in Folkow’s department, together with post-docs and PhD students, would move seamlessly between university and industry. This symbiosis is hard to comprehend today. The conflict between those who see industry as an enemy to the values of medicine and those who see great possibilities from collaboration is exemplified by the recent argument between two great general medical journals, The New England Journal of Medicine and The BMJ.

Writing in The BMJ this week, two former Editors-in-Chief of the NEJM, Jerry Kassirer and Marcia Angell, call three recent NEJM articles [by the journal’s national correspondent, Lisa Rosenbaum] and an editorial [by the journal’s current Editor-in-Chief, Jeff Drazen], “A seriously flawed and inflammatory attack” on financial, largely pharmaceutical and device manufacturer, conflicts of interest. “We find it sad”, they write, “that the medical journal that first called attention to the problem of financial conflicts of interest among physicians would now backtrack so dramatically, and indulge in ad hominem attacks on those who disagree”. They accuse the NEJM of downplaying the importance of conflicts of interest in medicine. They allege the journal has “little understanding of the meaning of the term”. They call Lisa Rosenbaum’s three essays “rambling”, “fanciful”, and “data-free”. They also attack Drazen, their successor, for weakening the NEJM‘s conflict of interest policy. In an accompanying editorial, the BMJ‘s Editor-in-Chief, Fiona Godlee, together with the journal’s heads of research and education, notes that they are “deeply troubled” by Drazen’s “possible retreat from policies that prevent experts with relevant commercial ties from authoring commentary or review articles”. “We don’t find much to agree with in NEJM‘s anecdotal analysis…It is a mistake by NEJM to suggest that rigorous standards should be revisited.” There have been few such sharp rebukes by one journal editor against another. What led to this surprising assault?

Lisa Rosenbaum posed a series of questions that have upset those who believe in the inimical influence of industry in medicine. For example, Rosenbaum asked whether it was reasonable to conclude that a physician with industry ties is motivated by a desire for financial gain? To what extent are reactions to industry influenced by reason or emotion? Why do we not take non-financial conflicts as seriously as financial entanglements? What unanticipated negative consequences might accrue from a hunt for wrongdoing? Why are the benefits of industry–academic collaborations persistently ignored? It would seem within the spirit of scientific inquiry to pose questions that challenge received orthodoxies. Rosenbaum accepts that gifts to doctors can have unacceptable influence. She agrees that past wrongdoings should not be excused. She believes that oversight of industry should not be eliminated. And she discusses evidence that industry-sponsored studies are more likely to be positive. Therefore, I don’t agree with the NEJM‘s critics that the Rosenbaum papers represent a reversal of policy by the NEJM. But while I don’t agree with these critics, I do think that the BMJ‘s analysis should be welcomed. A clear division of opinion in this argument helpfully clarifies both positions. The truth is likely to lie somewhere between these extremes. It’s time we found it.

By the beginning of 2011, I was finally catching on to the extent of the the problem with the Psychopharmacology literature. I had written a sarcastic post about inventing a computer to generate Clinical Trials mixing every drug with every condition [NIMH·receptalator…] and I got a comment from someone in Texas pointing out that such a computer program was already proposed. It was a paper by Madhukar Trivedi at UT Southwestern. He had written a computer program to implement an algorithm driven treatment of Major Depressive Disorder on an NIMH grant. The paper was talking about his attempted Clinical Trial [IMPACT] to test the algorithm. He’d had to abandon the Trial, because the clinic doctors wouldn’t use the computer unless Dr. Trivedi was there looking at them. In the paper, he was speculating about why they wouldn’t use it [strange bit of psychologizing for a biological psychiatrist, I thought]. Then I looked at his COI declaration [see evidence-based medicine I…]  and my jaw fell to the floor. That’s when I started blogging consistently about the pharmaceutical invasion of psychiatry. I’d never seen anything like that before.

I had found that five year grant for IMPACT [MH064062] which had been paid out at a total of $3.3 M [which seemed like a lot for a study that never happened]. Working backwards got me to STAR*D. While it had >100 articles, they never published the results of the Primary Outcome Variables – just some secondary rating scales [see a thirty-five million dollar misunderstanding…]. Yes, it cost $35 M in all and essentially told us very little about treatment. Moving further back in time, I ended up at TMAP, with Trividi in c harge of nthe Mood Disorder Algorithms. And that opened up learning about the biggest industry/psychiatry scam of them all, TMAP – getting in-patent drugs into the State formularies was a gold rush for PHARMA. Somewhere back around 2008, John Rush left UT for the Duke Program in Singapore. At that time, Trivedi inherited all the NIMH Projects at UT. He finished up CO-MED, a negative study involving combining antidepressants. Then he got a NIMH Grant for a project of his own [EMBARC] to look for biomarkers that discriminated between Zoloft or Wellbutrin responders – a personalized medicine quest of dubious value at best. The NIMH has paid out $9+ M so far, the grant cycle has elapsed, and yet it’s currently listed as still recruiting on ClinicalTrials.gov. Altogether, I’d say the four NIMH studies [STAR*D, IMPACT, CO-MED, and EMBARC] came to well over $50 M total.

As you can see, it’s become something of a hobby of mine, following Dr. Trivedi’s projects since that first one in 2011. He’s very adroit at getting NIMH funding, though he’s less adept at finishing the projects. He actually completed CO-MED as advertised. Other than that, STAR*D, IMPACT, and EMBARC never got published as the completed research they were funded to be, though there were plenty enough papers generated by STAR*D for a small library. And TMAP just quietly faded away after almost bankrupting the Texas Mental Health budget [bailed out by Governor George Bush prior to leaving for Washington]. In Dr. Trivedi’s defense, the gross corruption and PHARMA collusion exposed had to do with the Atypical Antipsychotics rather than with Dr. Trivedi’s Antidepressant algorithms, though I don’t know that the Antidepressant part of TMAP received a thorough vetting.

Psychiatrist Dr. Madhukar Trivedi receives American Psychiatric Association’s top research award

UTSouthwestern Medical Center: Newsroom

May 18, 2015

DALLAS – Dr. Madhukar Trivedi, Director of the Center for Depression Research and Clinical Care at UT Southwestern Medical Center and an internationally recognized expert in depression and mood disorders, is receiving the 2015 American Psychiatric Association Award for Research, the Association’s most significant award for research. First awarded in 1949 as The Hofheimer Prize, the award is given in recognition of a single distinguished contribution, body of work, or lifetime contribution that has had a major impact on the field and/or altered the practice of psychiatry, according to the American Psychiatric Foundation, which identifies the awardees. Dr. Trivedi, Professor of Psychiatry and Chief of the Division of Mood Disorders at UT Southwestern, will present an honorary lecture May 18 at the APA Annual Meeting in Toronto…

^{click on the graphic for the meeting guide
see page 105}

Dr. Trivedi previously served as one of the Principal Investigators of the Sequenced Treatment Alternatives to Relieve Depression [STAR*D] study, which at the time was the largest and longest study on the treatment of major depressive disorder and is considered a benchmark in the field of depression research. Dr. Trivedi also helped author innovative treatment guidelines called the Texas Medication Algorithm Project [TMAP], a set of comprehensive management tools for doctors treating severely mentally ill patients within Texas’ publicly funded mental health care system.

He also served as Principal Investigator for NIMH grants examining treatment for chronic depression, identifying specific signaling proteins found in blood cells that may predict whether a depressive person will respond better to workouts or medications, a computerized decision support system for depression, and one using specific antidepressant combinations to increase remission rates by treating a broader spectrum of depressed patients and by capitalizing on additive pharmacological effects…

Competing interests

---

Madhukar H. Trivedi, M.D. has been a consultant for Abbott Laboratories, Inc.; Akzo (Organon Pharmaceuticals Inc.); AstraZeneca; Bayer; Bristol-Myers Squibb Company; Cephalon, Inc.; Cyberonics, Inc.; Eli Lilly & Company; Fabre-Kramer Pharmaceuticals, Inc. Forest Pharmaceuticals; GlaxoSmithKline; Janssen Pharmaceutica Products, LP; Johnson & Johnson PRD; Eli Lilly & Company; Meade Johnson; Neuronetics; Parke-Davis Pharmaceuticals, Inc.; Pfizer, Inc.; Pharmacia &; Upjohn; Sepracor; Solvay Pharmaceuticals, Inc.; VantagePoint; and Wyeth-Ayerst Laboratories.

He has served on speakers bureaus for Abdi Brahim; Akzo (Organon Pharmaceuticals Inc.); Bristol-Myers Squibb Company; Cephalon, Inc.; Cyberonics, Inc.; Forest Pharmaceuticals; GlaxoSmithKline; Janssen Pharmaceutica Products, LP; Eli Lilly & Company; Pharmacia &; Upjohn; Solvay Pharmaceuticals, Inc.; and Wyeth-Ayerst Laboratories.

He has also received grant support from Bristol-Myers Squibb Company; Cephalon, Inc.; Corcept Therapeutics, Inc.; Cyberonics, Inc.; Eli Lilly & Company; Forest Pharmaceuticals; GlaxoSmithKline; Janssen Pharmaceutica; Merck; National Institute of Mental Health; National Alliance for Research in Schizophrenia and Depression; Novartis; Pfizer Inc.; Pharmacia &; Upjohn; Predix Pharmaceuticals; Solvay Pharmaceuticals, Inc.; and Wyeth-Ayerst Laboratories.

The study chart above is all government funded research aiming to making direct recommendations to clinicians about how they should treat patients using Guidelines and Algorithms. It is not possible for someone with that level of Conflict of Interest to make unbiased recommendations. In my estimation, no-one with those competing interests should have ever received NIMH grant support in the first place.

At the  Mayflower Conference, on Personalized Medicine in October 2009, Dr Trivedi said: “… clinicians have to decide on treatments and therefore the best goal, interim goal at least, we may want to understand the pathophysiology better and I’m not against that, but I think we have to help clinicians decide on one versus the other treatment." I disagree. The body of that work aims to tell clinicians what choices to make rather that give them the accurate efficacy, safety, and pathophysiologic information to make these decisions in concert with their patients. After reading that first article, I made this sketch:

^{"Bubonic plague and warfare reduced population numbers throughout Europe during this period. France lost half its population during the Hundred Years’ War. Normandy lost three-quarters of its population, and Paris two-thirds. The population of England was reduced by 20 to 33 percent due to plague in the same period."   Wikipedia}

Anybody recall what it was about? I remembered the Black Death, Joan of Arc, the introduction of the longbow in the Battle of Agincourt. As for what it was about? England v France, Kings and things – that’s about all I could remember. One thing I never knew, the distinct cultural identities of France and England, including languages, were formed and consolidated during that conflict. Apparently a good war is a powerful organizer of national unity and cultural identity.

One of my memories from early childhood was of standing in our front yard when everyone had gone crazy. People were beating on pans and shooting guns, laughing and hugging each other – my parents included. My mother noticed I was frightened, crying I think. She said something like, "Don’t worry. We’re happy. The War is over! [WWII]. But that made things worse, because I didn’t know that "War" was something that was ever "over". Where would it go? I thought war was just a part of life [actually, I think I might have been right about that at age 4]. Oh, by the way, the War of Roses started a few years after the end of the Hundred Years War.

The thing that got me on this topic [conflicts that don’t seem to end] was thinking about all the discord lately around the questions of using maintenance antipsychotic medication in Schizophrenia and the long term use of psychiatric medications in general. I remembered similar debates from forty years ago. And I thought about how much professional identity had [and has] to do with where people stand on this issue. all of which relates to the recent Maudsley Debate… «Does long term use of psychiatric drugs cause more harm than good?» [speaking of British Wars].

The Maudsley Debate didn’t do a much for me. The Yes camp had Sami Timimi, a British child psychiatrist with the Critical Psychiatric Network and Peter Gøtzsche of the Nordic Cochrane Group and author of Deadly Medicines and Organised Crime: How Big Pharma has Corrupted Healthcare. On the No side, we had Allan Young, Mood Disorders researcher at Kings College, London with heavy industry ties and John Crace, who writes for The Guardian and spoke as a patient. The audience was on the Yes side both before, [during,] and after the debate. The moderator did her best trying to hold the speakers and questioners to the topic [but her best wasn’t enough with such a polarized issue].

I knew what each of them was going to say [as will you]. And I didn’t like the question. My mind kept saying things like "For whom?" "Which Patient?" "Which drug? in Which Patient? For What?" I expect that in a world of indiscriminate or rampant overprescribing, I might go for a Yes. But I don’t do indiscriminate or rampant overprescribing, so I’d be a No. But the audience at this debate might think otherwise and lump me in one or the other bad guy camp. etc. etc. I don’t like the question. But I think I might spend some time thinking about why, and blogging about that [at a later time] rather than responding to the question on the table [at a later time].

^{The Maudsley}

The Maudsley Debates occur three times a year. The debate last month was on the topic «Does long term use of psychiatric drugs cause more harm than good?». Since it’s mentioned in the recent commentary so frequently, I thought I’d post the video and some of the comments from the BMJ for those who haven’t followed it. Locating the pieces can get tedious. My comments will come later:

• May 12, 2015
  Does long term use of psychiatric drugs cause more harm than good?
  by Peter C Gøtzsche, Allan H Young, and John Crace
• May 13, 2015
  Does long term use of psychiatric drugs cause more harm than good?
  by David I Tovey, Rachel Churchil, Clive E. Adams, and Geraldine Macdonald
• June 2, 2015
  Author’s reply to Tovey and colleagues
  by Peter C Gøtzsche
• June 2, 2015
  Corruption impairs discussion on long term use of psychiatric drugs
  by Robert Whitaker and Lisa Cosgrove

In deeply troubling…, I started in 2001 with the publication of the Paxil Study 329 paper looking at Karen Dineen Wagner’s history, but perhaps I should’ve started a couple of years earlier with the now infamous TMAP project. And then there was an appearance at a SmithKline Beechum Neuroscience Division meeting that bears mentioning…

TMAP/TCMAP

In 1997-98, TMAP, with pharmaceutical industry funding, began working on the Texas  Children’s Medication Algorithm Project [TCMAP]. An "Expert Consensus" panel was assembled to determine which drugs would be best for the treatment of mental and emotional problems in children and adolescents. The panel consisted almost exclusively of persons already involved in TMAP or associated with TMAP officials. A survey was not necessary. These persons simply met and decided that the identical drugs being used on adults should also be used on children. There were no studies or clinical trial results whatsoever to support this consensus…

One of the members of the children’s "expert consensus panel" was Graham J. Emslie,M.D., Professor and Chair, Division of Child and Adolescent Psychiatry. University of Texas Southwestern Medical Center, [a TMAP site] and Director. Bob Smith Center for Research in Pediatric Psychiatry, Dallas, TX…

The panel also included Dr. Karen Dineen Wagner…

In 1998, without any published trial data and based on the "consensus opinion" of Emslie, Wagner and others, TCMAP began widespread usage of these SSRIs and other drugs on children within the Texas state Juvenile Justice system and state Foster Care System…

Between 1998 and 2003, state doctors following the TCMAP guidelines routinely and regularly prescribed these antidepressant drugs to children in accordance with the TCMAP algorithm requirements…

The Texas Children’s Medication Algorithm Project: Report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Major Depressive Disorder

by CARROLL W. HUGHES, GRAHAM J. EMSLIE, M. LYNN CRISMON, KAREN DINEEN WAGNER, BORIS BIRMAHER, BARBARA GELLER, STEVEN R. PLISZKA, NEAL D. RYAN, MICHAEL STROBER, MADHUKAR H. TRIVED, MARCIA G. TOPRAC, ANDREW SEDILLO, MARIA E. LLANA, MOLLY LOPEZ, A. JOHN RUSH, AND THE TEXAS CONSENSUS CONFERENCE PANEL ON MEDICATION TREATMENT OF CHILDHOOD MAJOR DEPRESSIVE DISORDER

Journal of the American Academy of Child and Adolescent Psychiatry, 1999 38[11]:1442-1454.

The consensus panel agreed on categorizing 3 levels of "data" hierarchically in formulating stages and differential branching of the treatment algorithm. Level A data consist of both child and adult randomized controlled clinical trials, level B data consist of open trials and retrospective analyses, and level C data are based on case reports and panel consensus as to recommended current clinical practices. Level A takes precedence over level B, and B over C…

The recommended monotherapy antidepressant for stage 1 are SSRIs [fluoxetine, paroxetine, or sertraline]. [Fluvoxamine and citalopram may be added to the list at a future date with additional research and experience]…

SSRIs are deemed first-line treatments because of supporting efficacy data for fluoxetine in children and adolescents and paroxetine in adolescents [level A], open trials of sertraline [level B], and clinical experience [level C]. Information extrapolated from adults further supports the initial use of SSRIs given the minimal need for dosage titration [level A in adults and level C in children/adolescents] and favorable side effect profiles [levels A and C]…

With the coming of Jones’ whistle blower suit and the mounting awareness of adverse effects that lead to the Black Box Warning, TCMAP just disappeared. TCMAP was never adjudicated, and the only specific TMAP suit I know of was the settlement in Allen Jones and the State of Texas v. J&J.

Paxil in Pediatric Depression and «The Launch»

We all know about the famous Paxil Study 329, published in July 2001 in the JAACAP with 24 authors [Karen Dineen Wagner among them]. The Acute phase of Study 329 ran from 04/1994 until 03/1997 [blind broken]. In October 1998, this internal memo went out:

The draft of the paper came from ghost writer Sally Laden to First Author Martin Keller in February 1999, and by August 1999, he had submitted the paper to the JAMA. It was turned down there in November 1999. In December 1999 and again April 2000, there were emails saying that they were rethinking it, planning to go for the AJP. But in June 2000  [?], it was at the JAACAP where it was accepted in January 2001 and published in their July 2001 issue.

"As many of you know, SB is preparing an indication for adolescent depression for Paxil next year! SB’s clinical study demonstrating the success of Paxil in treating depression among adolescents will be published in a peer reviewed journal during first quarter 2000…"

"Dr. Wagner said the window of opportunity is before SB. Several other competing SSRls and other compounds have studies ongoing. But Paxil and Prozac are the only two SSRIs that have any published data to date and many physicians have already found success in treating adolescent patients with Paxil…"

"The paroxetine study measured treatment of adolescent depression. It is the largest study to date, involving 275 adolescents at 12 sites for eight weeks. In the study, one of three treatments was possible: imipramine, paroxetine, or placebo. Results:

• 66% of paroxetine group improved
• 52% imipramine improved
• 48% of placebo improved."

"As a result of this large study," Dr. Wagner said, "We can say that paroxetine has both efficacy and safety data for treating depression in adolescents."

At the time she gave this presentation, that first paragraph  simply wasn’t true. SB had long before decided not to go for an indication for Paxil in adolescents. The paper had just been rejected by the JAMA – with no publication in sight. The JAMA reviewers pointed to the low HAM-D cut-off, the effect of supportive care, the high Placebo response, the small or absent differences in rating scales, the significant incidence of Serious Side Effects with Paroxetine, and the inappropriate dosing of Imipramine. For that matter. I have no clue where those results came from, not from the paper or the CSR.

A look at the work of one medical school researcher, Dr. Karen Dineen Wagner, shows the challenges and possible pitfalls such research can entail. For example, from 1998 to 2001, university records show, Dr. Wagner was one of several academic researchers participating in more than a dozen industry-financed pediatric trials of antidepressants and other types of drugs. While some of the results were published, many were not. 

I ran across this 2004 article from the New York Times by Barry Meier [Contracts Keep Drug Research Out of Reach]. An excellent article, it prominently mentions Dr. Wagner and reminds us that this was the heyday of industry-funded Clinical Trials and that Dr. Wagner was one of a handful of Academic Child Psychiatrists who were involved with almost every study published – people who were and who remain prominent figures in the American Academy of Child and Adolescent Psychiatry, the organization Dr. Wagner was just elected to lead.

This is hard for me to personally understand. Dr. Wagner has essentially made her career advocating the use of psychophatmacologic agents in the treatment of children – having covered the gamut of conditions, drugs, and worked with many of the front-running drug companies who make and profit from these drugs. Surely the broad membership of the AACAP knows that, and knows about the dark side of her work – ghost-writing, financial COI, withheld negative studies, TMAP, training sessions for PHARMA. At a time when such things are moving closer and closer to the front burner, why would the AACAP membership choose her as President? Are her colleagues unaware of her history? Is that possible? Is this a sign that her position represents the consensus of the members? For that matter, why would she even run for that office instead of lowering her profile? It’s similar to the questions asked when people like Drs. Alan Schatzberg or Jeffrey Lieberman have been elected to the APA Presidency.

Justifying conflicts of interest in medical journals: a very bad idea

by Robert Steinbrook, Jerome P Kassirer, and Marcia Angell

British Medical Journal. 2015 350:h2942

[full text online]

A series of articles in the New England Journal of Medicine has questioned whether the conflict of interest movement has gone too far in its campaign to stop the drug industry influencing the medical profession. Here, three former senior NEJM editors respond with dismay

A seriously flawed and inflammatory attack on conflict of interest policies and regulations appeared recently in a most unexpected location: the venerable and trusted New England Journal of Medicine [NEJM]. In a series of rambling articles, one of the journal’s national correspondents, Lisa Rosenbaum, supported by the editor in chief, Jeffrey Drazen, tried to rationalise financial conflicts of interest in the medical profession. As former senior editors of the NEJM, we find it sad that the medical journal that first called attention to the problem of financial conflicts of interest among physicians would now backtrack so dramatically and indulge in personal attacks on those who disagree.

Physicians and the public rely on journals as unbiased and independent sources of information and to provide leadership to improve trust in medicine and the medical literature. Yet financial conflicts of interest have repeatedly eroded the credibility of both the medical profession and journals. As the Institute of Medicine explained in its 2009 report, a conflict of interest is “a set of circumstances that creates a risk that professional judgment or actions regarding a primary interest will be unduly influenced by a secondary interest.” The key issue is that “a conflict of interest exists whether or not a particular individual or institution is actually influenced by the secondary interest.” The report drew heavily on a 1993 NEJM article by Dennis Thompson, not cited by Rosenbaum, which made clear that the rules “do not assume that most physicians or researchers let financial gain influence their judgment. They assume only that it is often difficult if not impossible to distinguish cases in which financial gain does have improper influence from those in which it does not.”

The NEJM has now sought to reinterpret and downplay the importance of conflicts of interest in medicine by publishing articles that show little understanding of the meaning of the term. The concern is not whether physicians and researchers who receive industry money have been bought by the drug companies, as Drazen writes, or whether members of guideline panels or advisory committees to the US Food and Drug Administration with ties to industry make recommendations that are motivated by a desire for financial gain, as Rosenbaum writes. The essential issue is that it is impossible for editors and readers to know one way or the other.

Judges are expected to recuse themselves from hearing a case in which there are concerns that they could benefit financially from the outcome. Journalists are expected not to write stories on topics in which they have a financial conflict of interest. The problem, obviously, is that their objectivity might be compromised, either consciously or unconsciously, and there would be no easy way to know whether it had been. Yet Rosenbaum and Drazen seem to think it is insulting to physicians and medical researchers to suggest that their judgment can be affected in the same way. Doctors might wish it were otherwise, but none of us is immune to human nature.

Straw men
Rosenbaum’s language is colorful, but her arguments for the purported harms of conflict of interest policies and regulations are fanciful and data-free. No one is proposing that “we prevent the dissemination of expertise, thwart productive collaborations, or dissuade patients from taking effective drugs,” or allow “true experts to be replaced?on advisory panels, as authors of reviews and commentaries, in other capacities of authority by people whose key asset is being conflict-free.” Where is the evidence of “a loud chorus of shaming,” or “a stifling of honest discourse,” or that “the license to trample the credibility of physicians with industry ties has silenced debate?” Silliness and fear mongering about straw men are masquerading as scholarly analysis.

In 2014, under the Open Payments program [the Physician Payment Sunshine Act which is part of the Affordable Care Act], the Centers for Medicare and Medicaid Services in the United States published 4.45 million financial transactions from healthcare industries to physicians and teaching hospitals over just the last five months of 2013; the total value was nearly $3.7bn [£2.4bn; €3.4bn]. When full data for 2014 are reported later in 2015, the amounts may well exceed $9bn. Drug and device companies are investor owned businesses that are required to maximize profits by any legal means. These companies are not charities, so they expect to get something in return for all the largesse; the evidence is that they do, and it is naive to explain the situation otherwise.

Put simply, financial conflicts of interest in medicine are not beneficial, despite strained attempts to justify them and to make a virtue of self interest. Unmistakably, collaborations between academia and industry can speed medical progress and benefit patients. Such partnerships, however, can flourish with far less money in aggregate flowing from drug and device manufacturers to physicians and their institutions, and without the web of other lucrative ties between industry and physicians that lack a clear scientific or medical purpose. There are few reasons for physicians and other investigators to have financial associations with industry other than research support and bona fide consulting related to specific research programs and projects. Physicians who develop products and hold patents or receive royalties should not evaluate the product. Other types of payments, such as speakers’ and other personal fees, payments to be ghost authors of review articles, and ill defined consulting arrangements, distort physicians’ work and undermine our independence, as has been repeatedly documented. And there are no excuses for outright gifts, such as meals, travel, lodging expenses, and entertainment.

Editorial responsibility
In 1984, the late Arnold S Relman, then the NEJM’s editor in chief, instituted the first conflict of interest policy at any major medical journal.10 The policy required authors of research papers to disclose all financial ties they had to health industries, and if the ties were deemed significant they were published. In 1990, Relman extended the policy to prohibit authors of editorials and review articles from having any financial interest in a company [or its competitor] that was discussed in the article, since these types of manuscripts do not contain primary data but rely exclusively on the authors’ judgment in citing and interpreting the literature.11 As Relman’s successors, two of us [JPK and MA] continued these policies. We found that it was sometimes difficult, but nearly always possible, to find outstanding authors with the needed expertise and without a conflict of interest to write editorials and review articles. In 2002, however, after Drazen succeeded Angell, the policy was weakened, so that it only applied to authors with “any significant financial interest in a company [or its competitor] that makes a product discussed in the article.” To its credit, The BMJ has taken the opposite approach and implemented a zero tolerance policy on educational articles by authors with industry ties.

The privilege to serve as an editor of a major medical journal is accompanied by the responsibility to provide leadership on the critical issues that define the profession. How medicine responds to conflicts of interest and earns the trust of the larger society in which we exist is one such issue. In 1990, it was a bad idea for authors of editorials, review articles, and other opinion articles in medical journals to have financial conflicts of interest. A quarter of a century later, it is a very bad idea. The articles by Rosenbaum and the supportive editorial by Drazen could presage a further weakening of the conflict of interest policy at the NEJM, or they could serve as a wake-up call for all medical journals and the profession. It is time to move forward, not backward.

Revisiting the commercial-academic interface in medical journals

by Elizabeth Loder, Catherine Brizzell, and Fiona Godlee

British Medical Journal. 2015 350:h2957

[full text online]

The New England Journal of Medicine goes on an ill advised journey
Public trust in the pharmaceutical and biotechnology industry is low. Many practising physicians share that mistrust and are inclined to discount the results of otherwise sound studies that are industry funded. There are good historical reasons to be sceptical. But has suspicion degenerated, as some have charged, into “mindless demonisation?” The New England Journal of Medicine [NEJM] seems to think so. It has published a series of commentaries and an editorial suggesting there have been serious negative consequences of strict, “oversimplified” conflict of interest and disclosure policies, including the development of a “hostile climate” and “loss of trust.” Editor in chief, Jeffrey Drazen, says the “divide” between academic researchers and industry is not in the best interests of the public because “true improvement can come only through collaboration.”

A close reading of Drazen’s editorial suggests he is having second thoughts about policies put in place by many journals—including The BMJ—that make it “harder and harder for people who have received industry payments or items of financial value to write editorials or review articles … Having received industry money, the argument goes, even an acknowledged world expert can no longer provide untainted advice.” These policies, he says, came about “largely because of a few widely publicized episodes of unacceptable behavior.” He urges revisiting of the reasons that “medical journal editors remain concerned about authors with pharma and biotech associations.”

We are deeply troubled by a possible retreat from policies that prevent experts with relevant commercial ties from authoring commentary or review articles. The pharmaceutical and biotechnology industries may well be our medical saviours, but that is not a good reason to return to past practices. Such policies were not motivated solely by a few events, as Drazen asserts, but by recognition of extensive, systemic problems. These problems are far from solved, including internationally, as shown by recent events in India and China.

Checks and balances remain important
We agree that people with industry affiliations may be capable of expressing impartial views about matters affecting the commercial interests with which they are associated. Journal readers and editors, however, have no reliable way of identifying which industry affiliated views are disinterested and which are inappropriately influenced by commercial considerations, particularly in subtle ways. Bias is not always overt or easily detected. Authors with industry ties may be likely to approach a topic from a perspective shaped by their associations, so that their views will reflect industry assumptions, priorities, and preferences. The existence of academic and non-financial conflicts of interest does not reduce the need to be wary about conflicts that arise out of the powerful economic incentives associated with industry connections.

In our view, no one has such superior knowledge that he or she is the only one qualified to write an article on a subject. Checks and balances are important in any system. In the case of medical evidence, they should be based on the assumption that it is a mistake to combine evidence production and appraisal functions in a single person or group. Some academics must work closely with industry to develop and commercialise new medical treatments, but they should not also author editorials, reviews, or guidelines that appraise them. These are different professional responsibilities, and they clash.

The stakes are high. Editorials, reviews, and guidelines legitimise medical knowledge and shape clinical practice. Society needs a group of people who can evaluate medical evidence completely free of the appearance of commercial taint. One goal of The BMJ’s zero tolerance policy on education pieces by authors with industry ties was to offer unconflicted authors “prominence and visibility.” The success or failure of this policy can be evaluated only after the distinction between these different responsibilities—developing treatments or evaluating their place in practice—has been established long enough to influence the career choices of young doctors.

Disclosure does not solve the problem of bias and might make it worse. Advisers who disclose conflicts may subsequently feel more comfortable giving biased advice, a phenomenon called moral licence. Those who receive advice from a biased adviser often do not discount it sufficiently. Finally, “requiring disclosure is much easier than changing the status quo … I’d rather tell you I’m on the gravy train than get off it.”

We don’t find much to agree with in NEJM’s anecdotal analysis, but we do agree that criticism of the pharmaceutical and biotechnology industry is often reflexive and unfair. In fact, industry leads academia in complying with trial registration and reporting requirements. Many companies have embraced the open data movement. These are good things, but improvements in obvious problems should not be a pretext for regressive change. Instead, we should encourage all medical journals to separate the functions of evidence generation from those of appraisal. Policies that prevent experts with commercial ties from participating in evidence evaluation institutionalise this protection instead of making it optional. They are an important safeguard against bias and a defence against the perception of a “trial-journal pipeline” in which “companies treat trials and journals as marketing vehicles.” We agree with Steinbrook and colleagues that journal editors have a responsibility to lead on this issue and that “financial conflicts of interest in medicine are not beneficial.” It is a mistake by NEJM to suggest that rigorous standards should be revisited. To do so would undermine the trustworthiness of medical journals and be a disservice to clinical practice and patient safety.

• NEJM reignites conflict-of-interest debate with reader poll
• Former NEJM editors slam “backtrack” on conflict of interest

• 2001: Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial. "Paroxetine is generally well tolerated and effective for major depression in adolescents."
  by Keller MB, Ryan ND, Strober M, Klein RG, Kutcher SP, Birmaher B, Hagino OR, Koplewicz H, Carlson GA, Clarke GN, Emslie GJ, Feinberg D, Geller B, Kusumakar V, Papatheodorou G, Sack WH, Sweeney M, Wagner KD, Weller EB, Winters NC, Oakes R, and McCafferty JP
  Journal of the American Academy of Child and Adolescent Psychiatry, 2001, 40(7):762–772.
  ghost-written by Sally Laden of STI.
• 2002: Fluoxetine for Acute Treatment of Depression in Children and Adolescents: A Placebo-Controlled, Randomized Clinical Trial. "Fluoxetine was superior to placebo in the acute phase treatment of major depressive disorder in child and adolescent outpatients with severe, persistent depression."
  by Emslie GJ, Heiligenstein JH, Wagner KD, Hoog SL, Ernest DE, Brown E, Nilsson M, and Jacobson JG
  Journal of the American Academy of Child and Adolescent Psychiatry, 2002, 41(10):1205–1215.
• 2003: Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. "…sertraline is an effective and well-tolerated short-term treatment for children and adolescents with MDD."
  by Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D; and the Sertraline Pediatric Depression Study Group
  Journal of the American Medical Association. 2003, 290(8):1033-41.
  ghost-written [see A Cure Worse Than the Disease TRIAL reference 21.].
• 2004: A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. "…treatment with citalopram reduced depressive symptoms to a significantly greater extent than placebo treatment and was well tolerated."
  by Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, and Heydorn WE
  The American Journal of Psychiatry. 2004, 161:1079-1083.
  ghost-written Note: This article received a special public rebuke from the AJP editor when they discovered it was ghost-written [see collusion with fiction…].

• 2006: ACNP Task Force Report on SSRIs and Suicidal Behavior in Youth.
  by Mann JJ, Emslie G, Baldessarini RJ, Beardslee W, Fawcett JA, Goodwin FK, Leon AC, Meltzer HY, Ryan ND, Shaffer D, and Wagner KD
  Neuropsychopharmacology. 2006  31:473–492.

• 2008: Statement of Senator Charles E. Grassley Before the United States Senate, Payments to Physicians, September 9, 2008.

• 2006-2015: Articles promoting antidepressants in MDD, stimulants in ADHD, antipsychotics in childhood Bipolar Disorder, and opposing the FDA Black Box Warning. List of the 27 articles.

I just closed the comments on the talk that matters… because a tit-for-tat was about to break out. I removed both comments, because that seemed fair. I’ve decided that that’s the only way to deal with such things. It keeps others from commenting for me to close things, but looking back over what happens when one of those things get going, the discussion invariably stops anyway and people join in the conflict. That’s not to say I’m going to censor negative opinion, or negative comments directed towards me [unless they get monotonous]. I can even live with conflict among commenters. But the first hint of contemptuous, sarcastic, uncivil banter and I’m afraid that this is going to be my response. I’ve tried everything else I know. If my belief that that kind of thing shouldn’t be here is idiosyncratic to me – as Popeye says, "I am what I am."