1 Boring Old Man

Counterpoint from Eric Kaler: U is moving forward on research ethics

And it is, with an action plan on ethics in research that has the potential to be a national model.

Minnesota StarTribune

by Eric W. Kaler

May 30, 2015

Difficult ethical issues are inherent in medical research, especially clinical trials involving human subjects. Research holds the promise of finding lifesaving treatments, but it sometimes depends on the participation of vulnerable patients suffering from serious illnesses. We at the University of Minnesota take seriously our responsibility to patients participating in clinical studies, and our critics are wrong when they assert that we have turned a blind eye to our ethical obligations [“Medical research: Honor code still needs strengthening,” a May 27 commentary by U Prof. Carl Elliott].

Let me be clear about Dan Markingson’s 2004 death by suicide, which is at the center of much of this conversation. The events have been the subject of many proceedings, including two reviews by the U.S. Food and Drug Administration [2005 and 2015], a lawsuit in Hennepin County District Court [2008], complaints to the Minnesota Board of Medical Practice against two doctors [2009 and 2010], and a review by the legislative auditor [2015].

As the legislative auditor concluded, we can never know if Markingson’s tragic death was the result of a clinical study conducted at 26 sites, including the University of Minnesota. However, it is clear we could have done better in our response to the concerns raised about these events. I have apologized to Dan Markingson’s mother, to a legislative committee and at public forums…

To their credit, our university faculty wanted further assurance that our current program was at the highest levels of ethics and science, and in December 2013 the Faculty Senate requested an independent external evaluation of our human subjects protection program…

1. University of Minnesota Faculty Senate to consider probe into research suicide
2. The measure in the U Faculty Senate has passed!
3. "U of M Senate resolves to review human research," from KMSP (Fox 9) Television
4. Kaler on Faculty Senate resolution: "It’s not a review of the Markingson case"
5. Scholars to Kaler: Inquiry must cover the Markingson case and examine whether similar cases exist
6. University of Minnesota bioethics alumni say Kaler should not be allowed to whitewash the Markingson case

Critics are important voices, but there comes a point at which criticism of past actions stops being a catalyst for reform and, instead, becomes a barrier to necessary change in the future. We can’t change the past, but with vigilance, dedication and integrity, we will move forward. I promise all Minnesotans, our faculty and students, and our future patients and their families that the University of Minnesota’s human subjects research program will soon be a model for other universities.

Training for the Future

NIMH: Director’s Blog

by Tom Insel

May 15, 2015

…It’s true that most of the neuroscience and genomics findings are not yet actionable for psychiatry. No one doubts that the brain is the organ of affect and behavior, but no one can point to a biomarker that is essential for clinical practice. In the short-run, we may do much more to bend the curve on suicide mortality by changing public policy [such as through restricting access to means] rather than finding a biomarker for suicidality. But in the long-run, and we need a long-run strategy, policy will hit a wall and we will need better diagnostics and therapeutics. That is where this new initiative can make a difference. The research of 2015 suggests that the clinician of 2025 and certainly the clinician of 2035 will need to know about cortical dynamics, neural networks, and genomic variation. Those entering the field today will need to know how to think about the brain and how to critique brain science. By changing the training of the next generation, we not only prepare for the future, we create it.

Genomic Biomarker for Suicidality Found! Independent Georgia researcher, 1boringoldman, working closely with the CDCwebsite discovers clear evidence of…

As an Internist, I never heard the term "biomarkers" or any of its synonyms. And yet they were part of everyday medical life. They were the tests we ordered to make or confirm diagnoses; the parameters we followed to monitor treatment; and the screening tests we collected to detect risk or early signs of disease. In Psychiatry, there weren’t any. Biomarkers were the thing that we didn’t have. Actually, by the time I showed up, we did have a couple in Melancholic Depression, Dr. Carroll’s Dexamethasone Suppression Test and Dr. Kupfer’s REM Sleep Latency studies. As is often also the case in physical medicine, neither was pathognomonic. But they stacked up well against many of our medical colleagues’ biological tests – particularly in combination. Then, in the most peculiar of moves, we discarded the diagnosis they marked [Melancholic Depression], and that was that for our brief biomarker years [until, of course, my recent breakthrough above!]. So we rely on the more subjective rating scales like the HAM-D or the PANSS.

"To be a true disease, the entity must first, somehow be capable of being approached, measured, or tested in scientific fashion. Second, to be confirmed as a disease, a condition must demonstrate pathology at the cellular or molecular level."

5. There are discrete mental illnesses. They are not myths, and there are many of them.
6. The focus of psychiatric physicians should be on the biological aspects of illness.

Undoubtedly, with time, some of the disorders of unknown etiology will be found to have specific biological etiologies, others to have specific psychological causes, and still others to result mainly from a particular interplay of psychological, social, and biological factors…

Okay. You win. I don’t think my Suicide Biomarker is a breakthrough. And I don’t think Thomas Szasz was a very nice man [he thought a lot of the patients were Malingerers who didn’t want to take responsibility for their lives]. I don’t think Insel is a clinician. And I kind of think the NNCI is forced at best. I watched one of their videos about talking to the patient using neuroscience talk. An obviously competent resident was illustrating talking to a anxious young woman who had a Heroin Relapse when her boyfriend broke up with her. He started with a [downloadable] brain picture and explained about the brain parts involved in "a circuit" [the Ventral Tegmental Area, the Nucleus Accumbens, the Orbital Frontal Cortex, the Prefrontal Cortex, the Amygdala, and the Hippocampus which he referred to as V+N, O, P, A, and H respectively] explaining each one’s part in the relapse and where and how different modalities of treatment worked, making an analogy to a car [the typing part is mine]. She got to take the completed diagram home as a reminder [click image to enlarge].

Today, she presents to your outpatient clinic feeling anxious and demanding that you prescribe alprazolam to her because she has heard that it helps with feeling nervous. A urine drug screen is performed in the clinic and returns positive for heroin. The resident confronts her with the results, and she breaks down crying about how she recently broke up with her boyfriend, happened to drive by her former drug dealer’s home and relapsed. She expresses to the resident how guilty she feels about using again after working so hard to stay clean for 5 years. 

"One thing any addict whose gotten clean knows is that the Heroin solution to pain is seared deep into the brain for all times. It’s like a reflex, whether it has been 5 days or 5 years. The only tools you’ve got in the face of that reflex is what you’ve learned in your mind and what others can do to help you. So when you heard yourself saying that you "happened to drive by [your] former drug dealer’s home," you were already in deep do-do. Did you really believe that? You needed to be driving by your nearest NA meeting, or a Sponsor’s house, or here. Did that occur to you? I have a feeling that with 5 years clean, you know all of that. Here’s what we can do about the relapse, «blah, blah, blah». But maybe right now, the thing we really ought to talk about is the breakup with this boyfriend. You’ve been in a whole lot of hurt, and it obviously threw you for quite a loop. So you just said the hell with it and did something really pretty self-destructive. Tell me about all of that…"

If you don’t know or recall what this is about, I’d suggest reading yellow brick roads… where I first met the NNCI [on Friday the 13th in March of this year] in a JAMA: Psychiatry article [The Future of Psychiatry as Clinical Neuroscience: Why Not Now?], and I’ll pick up where I left off there. In March, I called my post "yellow brick roads" because it reminded me of Dorothy and friends heading off to Oz filled with great hope only to discover that Oz the Magnificent was a huckster. This time, my image was of that poignant scene from Caberet, where the beautiful blonde boy sings "Tomorow Belongs To Me."

2002: Tom Insel is chosen as Directer of the NIMH
2004-2008: DSM-V Symposia – NIMH/APA funded [see DSM-5 retrospective I…]
2005: Insel’s article about Psychiatry becoming Clinical Neuroscience with his own schedule for discovery [Psychiatry as a Clinical Neuroscience Discipline]
2012: The RDoC is launched by the NIMH
2012: Insel’s second article on psychiatry as Clinical Neuroscience [The Future of Psychiatry ( = Clinical Neuroscience)]
2015: The roll out article for the NNCI in JAMA: Psychiatry [The Future of Psychiatry as Clinical Neuroscience: Why Not Now?]

Training for the Future

NIMH: Director’s Blog

by Tom Insel

May 15, 2015

…Until recently these young physician-scientists often discovered that their residency training was completely disconnected from their rigorous scientific background. Psychiatry training comprised required instruction on psychodynamic theory, psychopharmacology, and psychotherapy but little that linked to their interests in brain circuits or brain function. Faculty taught largely what they were taught twenty years ago. There were exceptions—NIMH supports several residency programs to offer research tracks for a few residents to pursue science during their clinical training years—but for most young psychiatrists, training in 2015 is hardly different from training in 1995.

A small band of psychiatrists who are involved in residency training, led by David Ross at Yale, Melissa Arbuckle at Columbia, and Michael Travis at Pittsburgh, set out to change this with the creation of the National Neuroscience Curriculum Initiative [NNCI]. This online set of teaching modules is grounded in principles of adult learning and innovative teaching methods. Take a look at http://www.nncionline.org . You can see the case conferences, experiential learning modules, and a course on neuroscience in the media that the NNCI uses as a toolkit to help residents navigate the new world of brain science.

Why would residents want to know about modern clinical neuroscience? After all, there are very few useful neuroscience-based diagnostic tests or treatments. What Dr. Ross and his colleagues discovered was a hunger for the information from modern brain science. At the annual meeting of residency training directors, the NNCI workshop has been a standing room only event for the past two years. Over 200 individuals from around the country have signed up to be part of the NNCI “learning collaborative,” a group that helps test and develop teaching materials, and more than 25 residency programs have incorporated NNCI material into their training.

It’s true that most of the neuroscience and genomics findings are not yet actionable for psychiatry. No one doubts that the brain is the organ of affect and behavior, but no one can point to a biomarker that is essential for clinical practice. In the short-run, we may do much more to bend the curve on suicide mortality by changing public policy [such as through restricting access to means] rather than finding a biomarker for suicidality. But in the long-run, and we need a long-run strategy, policy will hit a wall and we will need better diagnostics and therapeutics. That is where this new initiative can make a difference. The research of 2015 suggests that the clinician of 2025 and certainly the clinician of 2035 will need to know about cortical dynamics, neural networks, and genomic variation. Those entering the field today will need to know how to think about the brain and how to critique brain science. By changing the training of the next generation, we not only prepare for the future, we create it.

"INTEGRATING A MODERN NEUROSCIENCE PERSPECTIVE INTO EVERY FACET OF CLINICAL PRACTICE,"

"The overarching goal is that residents will incorporate a modern neuroscience perspective as a core component of every formulation and treatment plan and bring the bench to the bedside."  

"This module is designed to highlight how clinicians can integrate a neuroscience perspective directly into patient care. Each session will begin by reviewing current theories regarding the neurobiological and/or genetic underpinnings of a particular psychiatric disorder. We then use role-play exercises in order to help residents incorporate relevant neuroscience into their own emerging clinical “voice”. In addition, we demonstrate how this knowledge can inform [and in some cases transform] our understanding of patients, their symptoms and potential treatment options.  We also discuss how this approach may be used to potentially strengthen the process of therapeutic communication. "

So my version of this story is very different from his. The way I read it, Dr. Insel who has never practiced psychiatry and has spent his career either in a lab or directing research programs thinks that clinical psychiatry is about dealing with brain disease and has used his position at the NIMH to press that opinion for his thirteen year tenure. He wanted to change psyciatry into a brain-based Clinical Neuroscience from the outset and set out a grandiose scheme about how that might go. He allocated generous funding to the APA’s similar effort with the DSM-V in a series of quickly forgotten symposiums. He’s been extremely controlling in directing funding towards that goal in all of the NIMH dealings. In spite of a lackluster record throughout his reign, he continues to pursue his dream. When the DSM-V flopped, he fled to his as-yet-unknown RDoC program. Now he’s funding and shepherding a program to implement his Clinical Neuroscience in the training of psychiatry residents. Like the DSM-V Task Force, he’s still championing it as if it’s a reality instead of an already tired term for untold millions of research dollars wasted. And now the NIMH has granted the NNCI $150,000 to teach people how to talk the Clinical Neuroscience talk to patients pretending that it’s backed by solid science.

Minnesota Finally Rejects Managed Care

Real Psychiatry

by George Dawson

May 29, 2015

Facing chronic shortages, Minnesota’s mental health system gets a boost

$46 million package will ease shortage of pediatric beds and add preventive services.

Minneapolis Star Tribune

by Chris Serres

May 29, 2015

For years, children who exhibit highly aggressive or violent behavior in Minnesota have been forced to drift from one short-term hospital stay to the next, often returning to their families heavily medicated but with their illness still largely untreated. Most small group homes lack the staff to handle their extreme behaviors, and inpatient psychiatric wards at hospitals are often too crowded to treat them for more than a few days.

This is not surprising to any psychiatrist.  This is the end product of managed care rationing and it occurs whether the patient is a child or an adult.  It happens when businesses and governments collude in providing some bastardized version of psychiatric care.  It happens when psychiatrists in this case are ignored.  When state officials ignore psychiatrists. When psychiatrists who are trained to treat aggressive and violent behaviors are not allowed to do their jobs.  After all, why would anyone with aggressive behavior because of a mental illness be turned away from a psychiatric unit?  Aggressive and suicidal behavior are the main reasons that psychiatrists exist today.  It is what we do.  Let us do our jobs. So far this is one small victory for children’s mental health advocates and my cap is tipped to them.  But to reverse more of the problem we need to acknowledge what it is and it is managed care or more specifically their marketing word for mental illness – behavioral health.

Let’s get rid of it entirely.

The human mind must think with the aid of categories… Once formed, categories are the basis for normal prejudgment. We cannot possibly avoid this process. Orderly living depends upon it. 

Categorical thinking is thinking in general rather than specific terms – putting things into categories rather than seeing the details within them. And one can even think categorically about categorical thinking ["Doctors are locked into disease model thinking, and can’t see the person."]. Then, of course, there’s the almost universal tendency to put the category one belongs to on the top rung of any hierarchy of values.

Aristotle’s first shot at rules of logic was designed to insure that we didn’t make categorical errors – called Categorical Syllogisms. You might recall them as the "some" or "all" logic:

^{Major premise: All humans are mortal.
Minor premise: All Greeks are humans.
Conclusion: All Greeks are mortal.}

^{Major premise: All rabbits have fur.
Minor premise: Some pets are rabbits.
Conclusion: Some pets have fur.}

Young physicians often offend patients by ‘talking to the disease‘ rather than the specific person – assuming the textbook version rather than some unique variant within the many possible presentation of any affliction [the "classic heart attack" that really is "indigestion," and the more ominous reverse]. Another common error is using using disease or category names as personal nouns – "a Schizophrenic", "a Cirrhotic", "a Chronic Lunger", "a Borderline".

"Why would the American Psychiatric Association elect Lieberman president in 2012? Because psychiatry sees nothing wrong with these psychotic symptom exacerbation and provocation experiments."

The Nuremberg Code of research ethics, established after the horrific human experiments by doctors in Nazi Germany, states that medical experiments on human subjects “should be so conducted as to avoid all unnecessary physical and mental suffering and injury.” This is obvious ethics, as one would hope that only Nazi doctors would see nothing wrong with using human subjects to test whether hypothesized harmful agents are in fact harmful.

Systematic Review and Meta-Analysis: Early Treatment Responses of Selective Serotonin Reuptake Inhibitors in Pediatric Major Depressive Disorder

by Varigonda AL, Jakubovski E, Taylor MJ, Freemantle N, Coughlin C, Bloch MH

Journal of the American Academy of Child & Adolescent Psychiatry 2015, Published on-line in advance.

Objective: Selective serotonin reuptake inhibitors [SSRIs] are the first-line pharmacological treatment for pediatric major depressive disorder [MDD]. We conducted a meta-analysis to examine [1] the time-course of response to SSRIs in pediatric depression, [2] whether higher doses of SSRIs are associated with an improved response in pediatric depression, [3] differences in efficacy between SSRI agents; and [4] whether the time-course and magnitude of response to SSRIs is different in pediatric and adult patients with MDD.

Method: We searched PubMed and CENTRAL for randomized controlled trials comparing SSRIs to placebo for the treatment of pediatric MDD. We extracted weekly symptom data from trials in order to characterize the trajectory of pharmacological response to SSRIs. Pooled estimates of treatment effect were calculated based on standardized mean differences between treatment and placebo group.

Results: Meta-analysis included 13 pediatric MDD trials with a total of 3,004 patients. A logarithmic model indicating the greatest benefits of SSRIs occurred early in treatment best fit the longitudinal data {log [week] =0.10 [95% CI, 0.06 to 0.15, p<0.0001]}. There were no significant differences based on maximum SSRI dose or between particular SSRI agents. SSRIs were demonstrated to have a smaller benefit in pediatric compared to adult MDD.

Conclusion: Treatment gains in pediatric MDD are greatest early in treatment and are on average minimal after 4 weeks of SSRI pharmacotherapy in pediatric MDD. Further research is needed using individual patient data to examine the power of early SSRI response [e.g. 2-4 weeks] to predict outcome in short-term pharmacological trials.

^{[reformatted to fit]}

"The larger the effect size, the greater the difference between treatment groups in the outcome measure. There are no universally accepted standards for describing values of d. However, it has been suggested that an effect size of 0.8 (8/10ths of a standard deviation) is “large,” a value of 0.5 (half a standard deviation) is “medium,” and a value of 0.2 (one fifth of a standard deviation) is small."

from the BMJ Endgames by Philip Sedgwick

^{[recolored and reformatted to fit]}

There are interesting findings scattered throughout this meta-analysis. The choice of drug or dose didn’t seem to matter [think about all the time clinicians expended listening to the comparative hype from the pharmaceutical reps and KOLs spread under our noses].

"Systematic reviews and meta-analyses regarding SSRI pharmacotherapy in pediatric depression have been common. These meta-analyses have demonstrated that SSRI pharmacotherapy is effective for pediatric depression. SSRIs as a class provide around a 25% greater chance of responding over the short-term when compared to placebo and have a number needed to treat [NNT]=10. Meta-analysis of response rates in pediatric antidepressant trials are high [61%], but so is the response rate to placebo [50%]. Systematic reviews have demonstrated that treatment estimates of SSRI efficacy were previously exaggerated by publication bias and time-lag bias in the distribution of negative trial results."

"Regarding the use of SSRIs in pediatric depression, the American Academy of Child and Adolescent Psychiatry [AACAP] Practice Parameter recommends that “patients should be treated with adequate and tolerable doses for at least 4 weeks. Clinical response should be assessed at 4-week intervals, and if the child has tolerated the antidepressant, the dose may be increased if a complete response has not been obtained. At each step, adequate time should be allowed for clinical response, and frequent, early dose adjustments should be avoided. However, patients who are showing minimal or no response after 8 weeks of treatment are likely to need alternative treatments. Furthermore, by about 12 weeks of treatment, the goal should be remission of symptoms, and in youths who are not remitted by that time, alternative treatment options may be warranted.” These AACAP recommendations mimic American Psychiatric Association [APA] Practice Guidelines in adults with MDD."

Richard Lehman’s journal review

[NEJM 21 May 2015 Vol 372]

British Medical Journal

26 May, 15

The NEJM has the highest reputation of any medical journal, so it’s impossible not to feel dismay when it lets its standards slip towards the near-nonsensical. When the first part of Lisa Rosenbaum’s three-part series on conflicts of interest appeared, I wondered if it might be some kind of elaborate joke: but sadly it seems not. I hate to see it when a clearly talented young writer is encouraged to write below standard, and at great length for no obvious reason. This final article, “Beyond Moral Outrage,” is an attempt to describe people who worry about conflicts of interest as beyond rationality. In a typical section she writes: “As Haidt concludes, moral reasoning is not ‘reasoning in search of truth,’ but rather ‘reasoning in support of our emotional reactions.’” Interesting that Haidt was actually citing an example not of moral reasoning but of emotional reasoning from the start [unless you count putting the American flag down the toilet as a moral issue], and in which no-one was harmed. Is Lisa actually suggesting that the pharmaceutical industry just flushes away used American flags and has never harmed anyone or concealed harm? But there I go — I am responding to wholly unserious arguments seriously, which I suppose must be the purpose of this exercise. I think the NEJM has shot itself in the foot. And also exposed some awful editorial decisions. Please, if you are going to publish someone attempting to persuade us against bias, don’t let through a sentence like “Being a pharmascold conferred the do-gooder sheen many of us coveted.” The only unbiased words in it are “being,” “a,” “the,” and “of”…

"Dr. Marcia Angell succeeded Dr. Kassirer as editor in chief pending a search committee’s choice of a new editor. Dr. Angell, who was a finalist, withdrew recently as a candidate and said she was retiring to write a book on alternative medicine."

"It is no secret that the other Journal editors and I were dismayed by the society’s decision to let Kassirer go, and that we shared many of his concerns about the use of the Journal’ s name to promote other products. The society’s action precipitated a crisis unique in the Journal’s 187-year history. There was even talk of a mass resignation by the editors, an event from which the Journal might never have recovered. Faced with the possibility of irretrievably damaging the Journal, both the society and the editors drew back from the brink. After intense discussions between the society’s leadership and the editors, Evjy and I issued a joint statement on August 4…"

If you follow these things, you’ve already read this NYT Op-Ed. But I’m still going to post it in toto as a testimony to people like Carl [and Mike and Mary and Leigh] who will persevere against any kind of gradient they meet until the job gets done. They intuitively knew that what happened to Dan Markingson was a lot more than just another tragic casualty of someone with Schizophrenia [as if that’s not bad enough]. They saw that it was a was a pointer to a whole system that was corrupted in a very specific way, and they were absolutely correct. Here, Carl focuses in on the piece of the system charged with ferreting out such things and protecting research subjects from things like this happening – the Institutional Review Boards. That was certainly not the only problem at the University of Minnesota, to be sure. But it’s the designated "cop" in the system, and it just didn’t function, not just with Dan’s case, but in general. It’s supposed to be an anchor, but at the "U", it was just another weak link in an altogether weak chain.

The University of Minnesota’s Medical Research Mess

New York Times

By CARL ELLIOTT

MAY 26, 2015

IF you want to see just how long an academic institution can tolerate a string of slow, festering research scandals, let me invite you to the University of Minnesota, where I teach medical ethics.

Over the past 25 years, our department of psychiatry has been party to the following disgraces: a felony conviction and a Food and Drug Administration research disqualification for a psychiatrist guilty of fraud in a drug study; the F.D.A. disqualification of another psychiatrist, for enrolling illiterate Hmong refugees in a drug study without their consent; the suspended license of yet another psychiatrist, who was charged with “reckless, if not willful, disregard” for dozens of patients; and, in 2004, the discovery, in a halfway house bathroom, of the near-decapitated corpse of Dan Markingson, a seriously mentally ill young man under an involuntary commitment order who committed suicide after enrolling, over the objections of his mother, in an industry-funded antipsychotic study run by members of the department.

And those, unfortunately, are just the highlights. The problem extends well beyond the department of psychiatry and into the university administration. Rather than dealing forthrightly with these ethical breaches, university officials have seemed more interested in covering up wrongdoing with a variety of underhanded tactics. Reporting in The Star Tribune discovered, for example, that in the felony case, university officials hid an internal investigation of the fraud from federal investigators for nearly four years.

I hope that the situation at the University of Minnesota is exceptional. But I know that at least one underlying cause of our problems is not limited to us: namely, the antiquated bureaucratic apparatus of institutional review boards, or I.R.B.s, which are supposed to protect subjects of medical experimentation. Indeed, whether other institutions have seen the kinds of abuses that have emerged at the University of Minnesota is difficult to know, precisely because the current research oversight system is inadequate to detect them. The current I.R.B. system of research protection arose in the 1970s. At the time, many reformers believed the main threat to research subjects came from overambitious government and university researchers who might be tempted to overlook the welfare of research subjects. As a result, the scheme put in place for protecting subjects was not a formal regulatory system but essentially an honor code. Under the I.R.B. system, medical research studies are evaluated — on paper — by a panel of academic volunteers. I.R.B.s do not usually monitor research as it is taking place. They rarely see a research subject or even a researcher face to face. Instead, they simply trust researchers to tell the truth, report mishaps honestly and conduct their studies in the way that they claim to be conducting them

These days, of course, medical research is not just a scholarly affair. It is also a global, multibillion-dollar business enterprise, powered by the pharmaceutical and medical-device industries. The ethical problem today is not merely that these corporations have plenty of money to grease the wheels of university research. It’s also that researchers themselves are often given powerful financial incentives to do unethical things: pressure vulnerable subjects to enroll in studies, fudge diagnoses to recruit otherwise ineligible subjects and keep subjects in studies even when they are doing poorly. In what other potentially dangerous industry do we rely on an honor code to keep people safe? Imagine if inspectors never actually set foot in meatpacking plants or coal mines, but gave approvals based entirely on paperwork filled out by the owners.

With so much money at stake in drug research, research subjects need a full-blown regulatory system. I.R.B.s should be replaced with oversight bodies that are fully independent — both financially and institutionally — of the research they are overseeing. These bodies must have the staffing and the authority to monitor research on the ground. And they must have the power to punish researchers who break the rules and institutions that cover up wrongdoing. Here at the University of Minnesota, we have reached a critical point. Two months ago, after two blistering external investigations, university officials finally agreed to suspend recruitment for psychiatric drug studies. Yet they still refuse to admit any serious wrongdoing. An honor code is a fragile thing. All the parts have to be in place: pride in the integrity of an institution, vigilant self-policing, a collective sense of shame when the code is violated and a willingness to punish those who break it. At the University of Minnesota, we have very few of those things. And so without sustained, relentless pressure from the outside, I am afraid we are doomed to more of the same.

The Journal and Its Owner — Resolving the Crisis

by Marcia Angell

The New England Journal of Medicine. 1999 341:752.

This week I succeed Jerome P. Kassirer as editor-in-chief of the Journal. Kassirer’s highly successful tenure was cut short after eight years when the Massachusetts Medical Society, which owns and publishes the Journal, decided not to renew his contract. Most observers were baffled by the decision, since the Journal was obviously flourishing under Kassirer’s superb leadership. In a joint announcement on July 25, Kassirer and Jack T. Evjy, president of the society, referred only to “honest differences of opinion between Dr. Kassirer and the Medical Society over administrative and publishing issues.”

Behind this oblique explanation lay a long-standing struggle between Kassirer and the society’s leadership over the latter’s ambitious plans to expand its role as a medical publisher, both in print and on line, by launching and acquiring new publications, repackaging the Journal’ s content for consumers, and entering into joint arrangements [“cobranding”] with various information-based commercial enterprises. Kassirer privately questioned the wisdom of many of these ventures, but what he strongly opposed in his capacity as editor-in-chief was the use of the Journal’s name to promote products for which he and his staff had no responsibility. To him, these activities threatened the Journal’ s credibility. To the society’s leadership and publishing staff, such leveraging not only was good business practice, but also furthered the society’s educational mission.

There were other, related disputes between Kassirer and the Journal’ s owner. The society for some time had talked of moving the Journal’ s editorial offices from the present location in Boston to the society’s headquarters in suburban Waltham. Kassirer resisted such a move, primarily because he felt it would lead to the incorporation of the Journal’ s staff into the larger organization and thereby threaten the Journal’ s quality and independence. There was also some concern that editorial autonomy might be eroded.

It is no secret that the other Journal editors and I were dismayed by the society’s decision to let Kassirer go, and that we shared many of his concerns about the use of the Journal’ s name to promote other products. The society’s action precipitated a crisis unique in the Journal’s 187-year history. There was even talk of a mass resignation by the editors, an event from which the Journal might never have recovered. Faced with the possibility of irretrievably damaging the Journal, both the society and the editors drew back from the brink. After intense discussions between the society’s leadership and the editors, Evjy and I issued a joint statement on August 4, which read, in part, as follows:

The Massachusetts Medical Society and Dr. Marcia Angell, Executive Editor of the New England Journal of Medicine, are negotiating the terms of an agreement by which she will become interim Editor-in-Chief. We are committed to ensuring that the NEJM maintains its special position as the world’s pre-eminent medical journal. To that end, we have agreed on the following three principles:
1. The Editor-in-Chief and her staff will continue to enjoy complete editorial independence and be fully responsible for content and editorial policy. The Editor-in-Chief will continue to confer on important editorial matters with the Society’s Committee on Publications and keep it informed, but neither that committee nor any other agent of the Society will have authority over content or editorial policy.
2. The Editor-in-Chief will have authority over the use of the name, logo, and content of the New England Journal of Medicine, in print or any other form. Consumer versions of the content will also be subject to her approval or that of her staff. There will be no use of the name, “The New England Journal of …” for other products, as, for example, “The New England Journal of Cardiology.” Neither the logo nor the name of the NEJM will be used on other products or in marketing them, without the approval of the Editor-in-Chief, although such products may be identified as coming “from the publishers of the New England Journal of Medicine.”
3. The Society recognizes the unique status of the NEJM within its publishing division and understands the concerns about moving the editorial offices to Waltham. No decision about moving has yet been made and none will be made without the full and active involvement of the Editor-in-Chief and her staff. In any event, no move will occur until the arrival of a permanent Editor-in-Chief.
In view of our mutual commitment to these principles, we hope to reach rapid agreement on a detailed contract. [This has now been done.] In that case, Dr. Angell will serve as Editor-in-Chief until a permanent Editor-in-Chief assumes the post. Her present intention is to retire at that time. A blue-ribbon Search Committee, with representation from the professional editorial staff and the wider academic medical community, will be appointed as soon as possible.

The above principles provide a clear framework for a better relationship between the Journal and its owner, one that will permit the Journal to continue to thrive as the unique and independent institution it is. In agreeing to these principles, the leadership of the society recognized that the Journal, while legally its property, has a much broader “ownership.” For many in the academic research community, it is an invaluable and integral part of their professional lives; furthermore, much of the research published in the Journal is publicly funded, and its peer reviewers are all volunteers. The Massachusetts Medical Society bought the Journal for a dollar in 1921. Since then, it has for the most part exercised its stewardship with wise restraint and an awareness of the Journal’s larger constituency. I am optimistic that in the wake of the summer’s crisis, there will be a recommitment to this kind of stewardship. The society should take pride in such a resolution.

MARCIA ANGELL , M.D.

The new medical-industrial complex.

by Relman A. S.

New England Journal of Medicine. 1980  303[17]:963-970.

[partial text here]

In wtf? for real…, I was lamenting current Editor Jeffrey Drazen advocating an easing up on this restriction on editorialists and review authors. I cited Relman’s 1980 editorial and a later one by his wife, Marcia Angell, in 2000 when she was editor for a time [Is Academic Medicine for Sale?] as the strong ethical stands I preferred. But, as Sandra Steingard pointed out in a comment, I had left out Jerome Kassirer who was also an advocate against commercial influences in the journal’s articles and the businification of medicine in general. In his editorial in 1996 written with Marcia Angell, then his Assistant Editor, they directly addressed this issue of editorialists and review article authors.

EDITORIALS AND CONFLICTS OF INTEREST

by MARCIA ANGELL , M.D. and JEROME P. KASSIRER , M.D.

New England Journal of Medicine. 1996 335[14]:1055-1056.

…Since 1990 the Journal has had a policy that prohibits editorialists and authors of review articles from having any financial connection with a company that benefits from a drug or device discussed in the editorial or review article. This policy was an extension of our earlier policy, announced in 1984, that required authors merely to disclose their financial connections with industry. In the case of scientific reports, disclosure seemed adequate. Scientific reports are self-contained. They present original data, and readers can judge for themselves whether the authors’ interpretations are supported by the data. Editorials and review articles are different. They are not self-contained, and there are no primary data. Instead, editorialists and authors of review articles evaluate an issue on the basis of what they select from the literature as relevant. In the case of editorialists, their task is to use the study they have been asked to editorialize about as a springboard for an open-ended consideration of an important issue. It is expected that they will provide an unbiased and authoritative opinion about the matter. That is why we insist that editorialists have no financial ties to products that figure prominently in their work…

After the Journal instituted its 1984 policy requiring disclosure of conflicts of interest, other major medical journals adopted similar policies, but so far we stand alone in our contention that disclosure is not enough in the case of editorials and review articles. In our view, the increasing involvement of researchers in commercial activities makes this policy all the more important. Readers must be able to rely on editorialists to be disinterested. We hope that we will soon be joined in our policy by our sister journals.

Editor Forced to Resign in Dispute Over Marketing of Medical Journal’s Name

New York Times

By LAWRENCE K. ALTMAN

July 27, 1999

The top editor of The New England Journal of Medicine is resigning under pressure in a dispute with its owners, the Massachusetts Medical Society, over the marketing of the journal’s prestigious name as part of an expanding publishing empire. Dr. Jerome P. Kassirer, 66, will step down as editor on Sept. 1 and then begin a seven-month sabbatical until his contract expires on March 31, he and Dr. Jack T. Evjy, the society’s president, said in interviews yesterday. Dr. Kassirer and Dr. Evjy declined to provide specifics of the dispute beyond saying it involved sharp differences in "administrative and publishing issues."

But other editors said the dispute reflects tensions generated as the society, like other traditional nonprofit medical organizations, seeks to generate more revenues to expand its influence in an increasingly competitive and political world of health care. Founded in 1812, the journal, based in Boston, has a circulation of 240,000 and is widely regarded as one of the world’s most rigorously edited scientific publications. In recent years, though, the Massachusetts Medical Society has added other publications for doctors and health newsletters intended for the general public. The society also recently built a plush headquarters in suburban Waltham and hired more staff members to deal with health and political issues.

Dr. Kassirer resisted this trend. "Does the society want to become a business?" he asked in his annual report last year. The report described ”a perceptible change in the nature of internal discussions about the Journal” and criticized what it called proposals for the society to ”brand” the journal by using its logo and name in creating new publications.

Dr. Kassirer has earned praise for his stewardship as the journal’s editor-in-chief since 1991. He was credited with appointing larger numbers of foreign scientists to the journal’s editorial board and attracting larger numbers of papers from foreign scientists. He also expanded the number of reviews and other features to lessen the journal’s esoteric nature and broaden its appeal to practicing doctors. Dr. Kassirer said he ”expected to stay a longer time, but it is not in the cards.” His resignation had nothing to do with the content of journal and he never felt constrained in expressing his opinion, he said, and "the medical society never tried to interfere"…

One of the journal’s main competitors, the Journal of the American Medical Association, is also searching for a new top editor. In January, Dr. George Lundberg was dismissed as editor for timing publication of a survey on attitudes toward sex during the impeachment hearings of President Clinton.

Goodbye, for Now

by Jerome P. Kassirer, M.D.

New England Journal of Medicine. 1999 341:686-687.

Because the officers of the Massachusetts Medical Society and I could not resolve our differences over administrative and publishing issues, they decided to seek a new editor-in-chief, and I leave the post in a few days…

I have been privileged to use the Journal’s bully pulpit. In my 70 editorials I have criticized for-profit medicine’s shortcomings, managed care’s flaws, the federal government’s misguided actions, and organizations that tried to undermine science for political motives. I have called attention to the progressive fragmentation of the health care system and the increasing number of uninsured persons. I have been critical of the American Medical Association and the National Rifle Association (several times each), the American Association of Health Plans, and the Health Care Financing Administration. I have been an advocate of high ethical standards and professionalism and have repeatedly called attention to financial incentives that might erode the integrity of physicians and threaten patient care. Very recently I offered a definition of editorial

Is Academic Medicine for Sale?

by MARCIA ANGELL, MD

New England Journal of Medicine. 2000 342[20]:1516-1518.

[full text on-line]

New England Journal of Medicine Names Third Editor in a Year

New York Times

By LAWRENCE K. ALTMAN

May 12, 2000

Dr. Jeffrey M. Drazen, a leading asthma researcher at Harvard with strong ties to the drug industry, was named the editor of The New England Journal of Medicine here today. But the journal’s tough conflict-of-interest rules will prevent Dr. Drazen from writing certain articles and editorials for at least two years. Pledging to protect the integrity of The Journal’s information, Dr. Drazen, a professor of medicine at Harvard, said he would recuse himself from the editorial process for any papers submitted that relate to asthma or to nine major companies from which he has received research grants or consultation fees.

Dr. Drazen, 53, helped pioneer asthma drugs now taken by four million asthmatics worldwide. In today’s news conference, he strongly defended the need for doctors to work closely and carefully with the drug industry. He called the industry a powerful force without which basic research findings made through taxpayer grants from the National Institutes of Health could not be converted into new therapies to improve patient care and public health.

Last February, after an internal investigation prompted by articles in The Los Angeles Times, The Journal found that it had violated its own rules in publishing 19 articles by Dr. Drazen and other authors with industry ties. The Journal said the articles should have been written by scientists without such connections, but its editors blamed themselves and said Dr. Drazen had disclosed his industry support.

Asked today at the news conference about that episode, Dr. Drazen said that as The Journal’s new editor in chief he would hand over all manuscripts dealing with his specialty or products made by the nine companies to deputies "and make sure that they are on the agenda at a time when I do not come to the editorial meeting." In such cases, Dr. Drazen said he wanted "The Journal to be able to judge the science that comes in, if it is good or bad, without me having anything to do with it."

"I do not want to influence things in either a positive or a negative way,” he said. ”We want the good science and good information to get out there” in The Journal, which is one of the most influential in the world. Dr. Drazen, who will leave his Harvard post, will be the Journal’s third editor in chief in less than a year. His selection follows several years of turmoil between the editors of The Journal and its owner, the Massachusetts Medical Society, concerning the society’s increasing business ventures. Dr. Jerome P. Kassirer was fired as the top editor last summer because of conflicts with society officials over proposals to promote Web sites and create new specialty journals using The New England Journal of Medicine logo. In recent years, The Journal has become a huge source of revenue for the medical society, largely through increased drug company advertising. And the society has become heavily dependent on the Journal’s profits to maintain its new $50 million headquarters here…