1 Boring Old Man

My first real medical specialty was Rheumatology. I trained at a place that had a strong section, and they spent a lot of time with the trainees – high standards all around. Rheumatology was [and is] an unusual medical specialty. There are more than the usual number of diseases of unknown etiology; fewer cases with classic presentations [a lot of overlap among syndromes]; a lot of mystery about etiology and pathophysiology [mechanisms]; and biological markers with only statistical specificity [not sure things]. I suppose if I’d thought about it, it wouldn’t have been a half-bad prequel to psychiatry, where all of those things are even more true [like I said in the last post, I must be drawn to mystery and ambiguity].

That same fuzziness surrounded treatments. There was almost no disease specificity, some situation where this diagnosis leads to this drug. In a patient with Rheumatoid Arthritis, developing a "hot joint" might be a call for an anti-inflammatory agent, or physical therapy, or even putting on a plaster cast. "It depends…" introduced the answers to most questions in the Rheumatology Clinic. The attendings made up for the lack of precision by being very careful – taking careful histories, doing careful exams, making careful treatment choices – and the best lesson of all, carefully following up their interventions. Every treatment was considered to be a therapeutic trial.

I’ve tried to follow that lead in psychiatry, making every prescription a clinical trial. It was easy in private practice. I saw people for a long time by usual standards, and there weren’t that many who were on medication. I used to joke that I wrote more prescriptions for antihistamines than psychiatric drugs [you’d have to live in Atlanta to understand why]. But in my stint as a volunteer in a charity clinic, I worried that I wouldn’t be able to do that. I was pleasantly surprised to find that it wasn’t true. I work infrequently, so it’s easy to remember patients visit to visit. And I’m surprised how easy it is to develop a therapeutic alliance even in that setting. When I first started, I was horrified at the polypharmacy and drug regimens the patients were on, and wanted to slash and burn. I quickly learned the error of my ways and backed off. These patients lead hard lives, and they become attached to their medications.

What I found was that down the road, it was much easier to get  people off of unnecessary medications once we got to know each other. I’ve been there for six or seven years now, and there’s no-one in the clinic on antipsychotics anymore who doesn’t carry a bonafide psychotic diagnosis.  I’m kind of proud of that. When I started, almost everyone was taking some flavor of Atypical Antipsychotic – sometimes two. But there’s actually something specific that has me on this airy topic.

There are a reasonable number of patients who have a Generalized Anxiety Disorder. In practice, I never saw them. I just wasn’t the person you would refer such patients to. So it was a new experience for me. They’re a very similar lot. They don’t have "fixed" anxiety – meaning anxiety in certain situations or settings. They’re always anxious. You can see it as they walk into the room, trying to not let it show, eyes darting, jumpy. If you’re a me, you start looking for triggers, or conflicts. What you find is nada, just a lifetime of anxiety as far back as they can remember. Often, they say something like "my Mom had it too." There are invariably somatic complaints and fears of imminent catastrophe, with a history of frequent trips to the ER for suspected heart attacks and the like.

I found that if I tried a medication, they rarely took it for much past the first pill. Feeling any medication effect scared them, and they stopped – even with the minor tranquillizers. I read that SSRIs were supposed to help. But one is rarely helped by a medication you won’t take. I began to start them on homeopathic doses, thinking I could sneak my way up after a time of acclimation. So I would start with 5 mg of Citalopam for example. To my surprise, they returned, saying it helped. In cases where I added a Benzo as a prn for anxious situations, the same thing happened. So I prescribed half of an 0.25mg Aprazolam, and heard the same report. 5mg Citalopam? 0.125mg Aprazolam? Who’d have thought? Over the years, I’ve seen enough of these patients, and written enough of these mini-dose prescriptions, to see that as the way to treat such cases straight away. I still do my "therapeutic trial" thing, but in these patients, it always seems to come out the same. I have no clue about the why? of it.

What brought it to mind was seeing a patient in the clinic who I now only see every three months for refills. She was one of the first I tried on these baby doses. She is now working part time and proudly announced that she hadn’t been to the Emergency Room for over a year. Both things are major accomplishments. She was downright effusive about how much better her life is. I rarely have very much good to say about our medications, so I made a mental note to write about it – I guess to prove I’m no therapeutic nihilist.

^{my daughter’s chance meeting on the streets of Boston…}

I’ve always liked a good mystery. Nancy Drew was my favorite book·mobile selection, until I discovered The Complete Sherlock Holmes [my parents finally bought it for me because I would”t return it to the library]. Math problems were like mysteries to me – looking for the hidden answer. Little wonder I was a medical researcher who ended up a psychoanalyst. My own analyst had a field day with all of this – what secrets was I in search of? I learned some interesting things about that, but there was no cure. I still scroll the Netflix roster periodically for some new British Mystery series [before re·watching either the British or Swedish Wallander]. And it’s little wonder I ended up in medical research, then migrated to psychoanalysis.

In former times, Internists were called Diagnosticians, unraveling those who·dun·it cases that make it to the T.V. shows like House. But by the time I came along, those cases went to specialists, and office practice began to focus on health care management and preventive medicine, sending the mysteries on to the higher ups. And even the specialists see the same mysteries repeatedly. I still spend a week every summer with a group of doctors I worked with as an Internist forty years ago. In an oft-told story, one night, one of the guys [Gastroenterologist] and I were reminiscing, and he said, "You know, nowadays when I see a new case, I know in minutes what they’ve got and what’s going to happen. I still ask all the questions, do all the tests, but I’m rarely wrong." His music was mastery. I said, "I never know for a very long time." My music was mystery.

So there was one part of the evolved role of the General Internist I was assigned to be in a three year tour in the Air Force that I didn’t much like – the focus of health maintenance and preventive medicine. It’s not that I didn’t think it was a good idea for doctors to talk about smoking, obesity, even the perils of being a couch potato. It’s not even that I found it boring, which it was. It was something where I felt like I was treating "proxies" or "surrogates" that I couldn’t really evaluate myself. What I’m talking about are things like how tightly to regulate glucose control in Diabetes; what level of Blood Pressure elevation constituted Hypertension requiring treatment; what was a High Cholesterol level in need of dietary adjustment or medication; when is alcohol consumption something to talk about; and so on and so on. Those may have been mysteries, but I couldn’t solve them. The literature was long on conclusions and short on solid data. A lot of it felt like the opinions of armchair scientists, and didn’t give me much conviction in my dealings with patients – particularly treating hypertension. I just didn’t like treating lab values and physical findings like Blood Pressure. I felt more at home with whole diseases.

Flash forward: In the waning days of my academic career, our new chairman, a disciple of the neoKraepelinian changes in psychiatry, and I had a recurrent discussion. He was a devotee of evidence-based medicine in psychiatry, the beginning search for biomarkers, and the brain science approach that has flowered since those salad days. I claimed that psychiatry was the repository of ambiguity in medicine, each case being its own unique mystery, and things that got "cleared up" would leave psychiatry and become part of general medicine like Syphilis when Penicillin arrived. These were good·hearted discussions, though they became the substrate for my ultimate exodus to the world of practice. And because I had left Internal Medicine, I never made my peace with my questions about treating these surrogates·of·future·health. So some of what goes on in modern medicine brings up those old questions about preventive treatment.

All the enthusiasm about this drug may be premature, and does not appear to be evidence-based.  That clinical research sponsored by organizations that sell health care goods and services may be manipulated to make the sponsors’ products look better than they really are is now an old story.  We have seen multiple instances in which drugs and devices turned out to be less efficacious and/or more dangerous than originally advertised.  Excess enthusiasm about such new innovations may drive up costs, and worse, hurt patients.  Physicians, other health care professionals, and those concerned about health policy ought to be much more skeptical about every new instance of a purportedly wondrous innovation. 

Evidence-based medicine rigorously applied suggests that individual health care and health policy decisions should be driven by the best available evidence, mostly from clinical research, about the benefits and harms of tests, treatments, programs, and so on, in the context of what outcomes matter to patients.  The skepticism EBM should engender could lead to health care that is more about patients and their outcomes, and less about ideology, hype, and hucksterism.

How high must our health care costs go, and how many unproven treatments must eventually be exposed as such before we learn that lesson?

Teenagers, Medication and Suicide

New York Times

by Richard A. Friedman

AUGUST 3, 2015

Is our culture of relentless achievement and success driving our young people to suicide? You would certainly think so, given the prevailing narrative in the media about the recent spate of suicides on college campuses: one high-achieving student after another succumbing to the toxic social pressure for perfection. It’s a plausible but incomplete explanation. No doubt the intense social pressure on young people, especially girls and young women, is daunting, but stress is only part of the story: We should also focus on adolescent mental illness and its treatment.

At least 90 percent of people who commit suicide have a diagnosable and potentially treatable mental illness like depression, or alcohol or other drug abuse problems, often in combination. Suicide is the third leading cause of death among young people and has been rising since 2007. The unidentified killer in this story is untreated psychiatric illness. In 2013, for example, 8.7 percent of people between the ages of 18 and 25 experienced a major depression episode in the previous year, but only half of them received any psychiatric treatment, according to the National Survey on Drug Use and Health. And in 57 percent of these episodes, patients were seen by a general practitioner or family doctor — neither of whom is typically an expert in the treatment of mental illness.

Worse, antidepressants, which can be lifesaving, are probably being underused in young people. Their use fell significantly after the Food and Drug Administration issued its so-called black-box warning in 2004, stating that all antidepressants were associated with a risk of increased suicidal feeling, thinking and behavior in adolescents. That warning was later extended to young adults. One very large study, including 1.1 million adolescents and 1.4 million young adults, examined data for automated health care claims for 2000 to 2010 from 11 health plans in the United States Mental Health Research Network. Disturbingly, the study found that antidepressant use plunged 31 percent among adolescents and 24 percent among young adults within two years after the F.D.A. advisory was issued…

Since there is no evidence that the F.D.A. black-box warning has been helpful, and there is a very reasonable possibility that it has discouraged patients from taking antidepressants and physicians from prescribing these medications, the government should rescind the black-box warning on antidepressants altogether. Parents and teenagers, and their doctors, too, should not be afraid of antidepressants and should know that they can be very helpful. Indeed, with careful use and monitoring, they can be lifesaving. The only thing we should all fear is depression, a natural killer that we can effectively treat.

The unidentified killer in this story is untreated psychiatric illness. In 2013, for example, 8.7 percent of people between the ages of 18 and 25 experienced a major depression episode in the previous year, but only half of them received any psychiatric treatment, according to the National Survey on Drug Use and Health.

Newer generation antidepressants for depressive disorders in children and adolescents

Cochrane Systematic Reviews

by Sarah E Hetrick, Joanne E McKenzie, Georgina R Cox, Magenta B Simmons, and Sally N Merry

14 NOV 2012

… Based on 14 of the trials [2490 participants in total], there was evidence that those treated with an antidepressant had lower depression severity scores than those on placebo, however, the size of this difference was small. Based on 17 trials [3229 participants in total], there was evidence of an increased risk [64%] of suicide-related outcomes for those on antidepressants compared with those given placebo…

Since there is no evidence that the F.D.A. black-box warning has been helpful, and there is a very reasonable possibility that it has discouraged patients from taking antidepressants and physicians from prescribing these medications, the government should rescind the black-box warning on antidepressants altogether.

Clinical Trials for Treatment of Borderline Personality Disorder

by S. Charles Schulz M.D. and Donald W. Black, M.D.

American Journal of Psychiatry. 2015 172[8]:793.

To the Editor: There are currently no standard treatments for borderline personality disorder. Several psychotherapies have been developed, and a few are now considered evidence-based. Medications have also been explored, yet randomized controlled trials are few in number, leading to a lack of consensus regarding the best approach…

To address the potential benefit of quetiapine [approved by the FDA for schizophrenia and bipolar disorder], we conducted a double-blind, placebo-controlled study, which was investigator initiated and sponsored by AstraZeneca. The results showed positive effects of the lower dose tested [150 mg/day], with more than half responding as defined by a 50% decrease in symptom ratings. There were fewer such effects at the higher dose, and there were more side effects and patient attrition. The report was accompanied by an editorial appropriately noting the strengths and limitations of the study, including its 8-week duration for an illness that often lasts many years.

Two subjects initially enrolled at the University of Minnesota site were immediately dropped from the study when their misuse of the study medication was discovered. The University Internal Review Board reviewed what occurred and concluded that we had acted appropriately. Nonetheless, a member of the Ethics Center alleged to the New York Times that the investigators had acted irresponsibly. The newspaper reported this allegation in a recent issue and did not include a statement to the newspaper from the University of Minnesota that no investigator misconduct had occurred.

Many large clinical trials have had issues with behavioral problems and protocol violations by some subjects, and for these reasons all such studies have procedures to dismiss subjects. Such problems are part of both clinical and research care with seriously ill patients. Despite this subject misconduct, the results of the study provide clinicians and patients with new evidence-based guidance on dose, effectiveness, and side effects of quetiapine in borderline personality disorder. The next step is to examine the effect of quetiapine in borderline personality disorder patients in combination with an evidence-based psychotherapy. Our patients deserve no less than the continued investigation of our options for their treatment.

Seroquel in the oatmeal at the sex offender facility: Schulz replies

Fear and Loathing in Bioethics

by Carl Elliot

August 1, 2015

If you recall, in April the Times reported yet another mismanaged clinical trial in the U’s Department of Psychiatry. Two sex offenders were recruited into a clinical trial of Seroquel for Borderline Personality Disorder, despite the fact that they did not actually have the disorder. Then one of them slipped his study medication into the oatmeal at the facility where he was housed. According a report from Alpha House, the sex offender facility:

Some residents noticed pink particles in the oatmeal. After eating breakfast the residents and staff reported feeling sedated and some were "knocked out’ for the remainder of the day. Staff asked X if he had put the study medication into the oatmeal and he denied it. After failing a polygraph test X was re-imprisoned…

Under guidelines governing federally funded clinical trials, the men would have been considered prisoners and their participation given special scrutiny, several outside ethics experts said. Although the trial was not federally funded, many universities follow similar rules for research involving human subjects. [The university asserts the men were not prisoners.]

Other concerns about the study were raised even before the oatmeal drugging. The study’s safety officer, Dr. Scott Crow, noted in a memo that not a single patient had failed the screening process for enrollment in the study, even though outside experts said it was unlikely that everyone who applied would meet the criteria. Dr. Schulz said the failures were not recorded because the patients were formally screened only after undergoing initial telephone interviews that eliminated unlikely candidates.

“What a sloppy trial,” said Nancy Dubler, a bioethicist who served for years on the Institutional Review Board, or I.R.B., at Montefiore Medical Center in the Bronx. She is an expert on the inclusion of prisoners in clinical trials and said closer attention should have been paid to the events at Alpha…

Borderline patients come in many sizes and shapes. They are united as a group by certain shared phenomena with varying intensity. They are intolerant of being alone. They tend to simplify other people [good/bad] and any given person can jump from one to the other designation in a heartbeat. They are needy, but confused about what they need, so they end up coercing others into doing things that are ultimately to their own detriment. Rather than having periodic life crises, they often live crisis lives in a pattern where the solution to the last problem/crisis sets the stage for the next problem/crisis. The term "borderline" stuck because they confound every treatment. The basic difficulty is an infantile need for attachment combined with an equally infantile inability to maintain a consistent view of another. As I said in an anachronism… and Academic·Industrial·Complex II…, the notion that any drug will have a lasting benefit is unlikely. They go through drugs just as they go through people [and therapists]. So the clinical trials are more for the sponsors than the afflicted. They are treatable with modified therapies – psychodynamic or behavioral [dialectic behavior therapy] – but in either case, it is "heroic" psychotherapy and success is hardly guaranteed. Antics like the ones reported here [the Seroquel in the oatmeal] or sexual acting out [polymorphous sexual perversion] are not uncommon. While I’ve focused here on the difficulty these patients pose for others, they live difficult and painful lives and successful treatment is well worth the effort if it can be mustered.

So back to my response of sadness to the letter. I don’t get the sense that Dr. Schulz really understands the Borderline patients and where they hurt. He sure didn’t understand Katie Thomas’ article in the NYT [A Drug Trial’s Frayed Promise], what Carl Elliot was getting at, and why some statement from UMn was immaterial. I had the same feeling when I read that oral history interview [Interview with S. Charles Schulz, M.D.]. He was troubled by Carl Elliot’s campaign about Dan Markingson, but seemed clueless about why Carl was so upset and persistent. The place where I felt it most strongly was in his response to a letter from Mary Weiss back in the day, worrying about her son – Dan Markingson’s psychotic state. Instead of going to see Dan to see what she was talking about, he conclaved with co-investigator Dr. Stephen Olson to frame a response letter saying that they were doing nothing wrong.

Patients with First Episode Schizophrenia or Borderline Personality Disorder are in intense emotional tangles. They aren’t orderly. They don’t fit into routines. They’re too busy inside their minds and need a lot of attending to. Even the "sex offender" who flavored the oatmeal with his Seroquel was probably actually "Borderline" and needed to be seen rather than just removed for bad subject behavior. Dan Markingson was definitely in need of being seen at the time his mother wrote her frantic plea, not dealt with by a falsely reassuring letter. Carl Elliot and Leigh Turner of the University’s Bioethics Department deserved to be seen and engaged rather than discounted from afar – treated as nuisances. Reading of Dr. Schulz’s plans to make the UMn a Research Center for Psychiatry when he came to Minnesota and his pride in building his program in the Interview with S. Charles Schulz, M.D. added to the sad feeling, because he didn’t seem to grasp that his remoteness, lack of active engagement, and defensiveness was much of the reason things finally went so badly for him, for Dan, for his program.

Well, I didn’t plan it, but this post actually turns out to be a sequel [maybe prequel] to another post from two weeks ago [probably approximates zero…]. There, I was reporting on an analysis that showed that the major use of antipsychotics in children is not to treat psychosis, but rather to control disruptive impulsiveness in developmentally challenged children – aka behavior control. Remember that the first Atypical Antipsychotic, Risperdal®, came out of the gate looking for an FDA Approval for that very indication with a study by Janssen’s Risperidone Disruptive Behavior Study Group [Double-Blind, Placebo-Controlled Study of Risperidone for the Treatment of Disruptive Behaviors in Children With Subaverage Intelligence 2002] and were turned down. That study was later repurposed, ghost written, and republished under Dr. Joseph Biederman’s name to support a claim of efficacy in his proposed Bipolar Child diagnosis [Risperidone for the treatment of affective symptoms in children with disruptive behavior disorder: a post hoc analysis of data from a 6-week, multicenter, randomized, double-blind, parallel-arm study 2006]. Many of us believe that the Bipolar Child designation was more a rationalization to use Antipsychotics in children for behavior control than a valid psychiatric condition.

Drug company accused of altering study by top SickKids pediatrician

Toronto Star

By David Bruser and Jesse McLean

July 31, 2015

A medical journal article co-authored by SickKids hospital’s top pediatrician was manipulated by a drug company and understated the risks of a powerful antipsychotic used to treat kids with behavioural problems, the former head of the U.S. drug regulator alleges. The 2003 article concluded there was no correlation between long-term use of Risperdal and an increased risk of certain side-effects, including the growth of breasts in boys. The listed authors included respected experts in the pediatric field — Toronto’s Dr. Denis Daneman and two U.S. doctors — and three employees from Janssen, which makes Risperdal.

The medical article was singled out in recent U.S. lawsuits against Janssen as an alleged example of drug company influence on doctors and published research. A court exhibit shows a draft of the study describing an association with certain side-effects — a finding that a Janssen employee internally flagged as “significant.” This information is not in the published version of the article.

“My name is on an article in which there is some data that has been left out. That, to me, crosses a line,” Daneman, pediatrician-in-chief at the Hospital for Sick Children, told the Star…

This is a story about the role of a drug company in the production of a scientific journal article. The alleged manipulation of the medical article is outlined in a report by expert witness Dr. David Kessler, former head of the U.S. Food and Drug Administration and a pediatrician by training. The report, filed in U.S. court, said Janssen “controlled and influenced” more than 40 manuscripts, including the one co-authored by Daneman. Kessler called the company’s alleged promotion of the drug for unapproved use in vulnerable children “deeply troubling”…

An independent biostatistician is now reanalyzing the 2003 study’s data to determine whether the original results stand or if they need to be corrected on the public record, Daneman said. “If, indeed, these allegations are true, then I would feel used,” he said, adding that his contributions to the paper “were made in good faith and based on the assumption that my colleagues and I had access to all the relevant data.” He said he was not included in internal Janssen discussions about certain revisions to the article. “There is this deception there that is intolerable,” he said…

In a 2012 deposition where he was questioned by a U.S. plaintiff’s lawyer, Daneman, a pediatric endocrinologist, agreed the study he participated in had data calculation errors that had the effect of understating the frequency of side-effects. In an interview with the Star, Daneman said there was no intent on his part to exclude significant results…

The 2003 study analyzed results from five Janssen clinical trials to investigate prolactin levels in children and teens taking Risperdal, and “explore any relationship with side-effects hypothetically attributable to prolactin.” Daneman said his role in the study was commenting on parts of the article and suggesting changes and that somebody else wrote it. He told the Star he was paid about $1,000 by Janssen for his participation. “I gave the money to charity because of the concerns that had been raised about potential conflicts of interest,” he said…

Prolactin levels during long-term risperidone treatment in children and adolescents.

by Findling, Kusumakar, Daneman, Moshang, De Smedt, and Binder.

Journal of Clinical Psychiatry. 2003 64[11]:1362-1369.

BACKGROUND: This analysis was designed to investigate prolactin levels in children and adolescents on long-term risperidone treatment and explore any relationship with side effects hypothetically attributable to prolactin [SHAP].

METHOD: Data from 5 clinical trials [total N = 700] were pooled for this post hoc analysis. Children and adolescents aged 5 to 15 years with subaverage intelligence quotients and conduct or other disruptive behavior disorders received risperidone treatment [0.02-0.06 mg/kg/day] for up to 55 weeks. Outcome measures analyzed included serum prolactin levels, reported adverse events, and the conduct problem subscore of the Nisonger Child Behavior Rating Form.

RESULTS: Mean prolactin levels rose from 7.8 ng/mL at baseline to a peak of 29.4 ng/mL at weeks 4 to 7 of active treatment, then progressively decreased to 16.1 ng/mL at weeks 40 to 48 [N = 358] and 13.0 ng/mL at weeks 52 to 55 [N = 42]. There was no relationship between pro-lactin levels and age. Females returned to a mean value within the normal range [</= 30 ng/mL] by weeks 8 to 12, and males were close to normal values [</= 18 ng/mL] by weeks 16 to 24. At least 1 SHAP was reported by 13 [2.2%] of 592 children. There was no direct correlation between prolactin elevation and SHAP.

CONCLUSION: With long-term risperidone treatment in children and adolescents, serum prolactin levels tended to rise and peak within the first 1 to 2 months and then steadily decline to values within or very close to the normal range by 3 to 5 months.

^{Patients with SHAP were classified according to 2 sets of criteria, SHAP[A] and SHAP[B]. The criteria used to define the SHAP[A] population were breast enlargement [gynecomastia], amenorrhea, menorrhagia, lactation nonpuerperal, menstrual disorder, and vaginal hemorrhage. An alternate definition of SHAP was used for the SHAP[B] population. SHAP[B] excluded males 10 years or older with gynecomastia, females with less than 31 days of breast enlargement [gynecomastia], and females with amenorrhea < 1 week. It is considered normal for males to have gynecomastia at some point in the evolution of puberty, with the frequency estimated as high as 50%. Adolescent gynecomastia may be unilateral or bilateral, occurs most frequently during stages 3 and 4 of puberty, and lasts a few months to 2 years [in one series, 27% of cases lasted 1 year and 7% lasted 2 years]. Females during puberty tend to experience breast enlargement and irregular menstrual cycles, and therefore these symptoms were not classified as SHAP.}

There are no data in children as to the degree of prolactin elevation that warrants concern in relationship to potential inhibition of growth or sexual development or potential side effects, such as gynecomastia or galactorrhea. It is the experience of the authors [pediatric endocrinologists T.M. and D.D.] that prolactin levels above 18 ng/mL but below 30 ng/mL are rarely, if ever, associated with clinical manifestation or alterations of the hypothalamic-pituitary-gonadal axis. Prolonged elevations of prolactin approaching serum concentrations of 100 ng/mL warrant careful clinical investigation.
…and…
The first analysis, SHAP[A], used a more inclusive definition of SHAP, and the second analysis, SHAP[B], excluded additional symptoms that the pediatric endocrinologist authors [T.M. and D.D.] attributed to puberty. SHAP[A] included gynecomastia irrespective of age, amenorrhea, menorrhagia, breast enlargement, lactation nonpuerperal, menstrual disorder, and vaginal hemorrhage. Dysmenorrhea during puberty was excluded.

My point in this post isn’t just about Dr. Daneman’s culpability in this obviously wrongly interpreted study twelve years ago. He was a key link in Janssen’s campaign to maximize its Risperdal® profits by developing an off-label pediatric market. I admit that this is a particular sticking point for me. I sat through the TMAP trial in 2012 and listened to drug reps and marketing managers describe campaigns targeting child psychiatrists and pediatricians to use Risperdal® off label – campaigns based on outright lies [see on every call…]. But my main point is Dr. Daneman’s argument that Janssen with-held evidence from him. It wasn’t his fault, he didn’t write that paper. He just commented on it. He even gave away the money he received.

Daneman said his role in the study was commenting on parts of the article and suggesting changes and that somebody else wrote it.

au·thor []

    noun

      One that creates, founds, or originates:

• placebo controlled: The subjects on the drug and the controls get identical pills…
• randomized: subjects are assigned to groups by a random number generator…
• double blind: Neither the subjects nor staff know who’s on what until it’s over…
• protocol: Analytic methods and outcome parameters are defined before the trial begins…

And so to, "there’s something backwards about Randomized Clinical Trials"

This was a low standard. Approval was never intended to tell doctors what to do with the drugs. The RTCs required for approval weren’t the end of anything. They were only a rough beginning – where things started. It was assumed that Medicine itself would take over after approval and figure out how to use the drugs in practice through its collective clinical experience. That’s why my introduction to the last post [the why of it…] was so awkward. I didn’t know how to say where I learn about new drugs, because it is from everywhere – bedside, clinic, colleagues, mentors, conferences, case reports, reps, the PDR, meetings, textbooks, journals, CME, my patients, your patients, even RCTs, etc., and it never really stops. It’s just part of the ongoing stuff of doctoring.

But then along came Evidence Based Medicine [wince]. At first glance, that term ought to be sacrosanct. Who wants a doctor who shoots from the hip? makes wild guesses? Of course, a doctor should base decisions on evidence. But that’s not what Evidence Based Medicine has come to mean. It now seems to mean «backed up by a positive clinical trial». And that’s what I mean by "there’s something backwards about Randomized Clinical Trials." The weakest link, the one most vulnerable to manipulation and distortion, has been elevated to the position of being the gold standard. How that happened is a long story that I don’t know as well as I’d like. But the why and the consequences are painfully obvious.

Since the pharmaceutical and device industries pay for and essentially write-up the RCTs, it gives them an enormous control over what physicians do. Their jury-rigged articles are further distorted in the direct-to-consumer and other advertisements. And even a trial that is honestly analyzed and published is only a crude approximation of the clinical reality of widespread usage. This kind of Evidence Based Medicine based on RCTs gives Managed Care a tool to deny medications or other treatments [and lots of other things]. It reduces the needs of an individual patient to membership of a proxy grouping. It implies a precision and generalizability to medical science never realized [or realizable]. It trivializes and marginalizes the other very important resources that we physicians traditionally use to learn about and prescribe drugs ourselves. And it takes the responsibility away from a doctor to assess in an ongoing and diligent process all the evidence in his/her clinical decision making.

So that’s what’s backwards about Randomized Clinical Trials"

^{For as much time as I’ve spent thinking about Randomized Clinical Trials in my retirement years, I never gave them a moment’s thought in two different medical careers. I didn’t really have much of an idea how drugs became approved, or how drug patents worked. As odd as that may sound, I expect that was true for the overwhelming majority of my contemporaries. In Internal Medicine, I learned about medications from textbooks rather than journal articles. In psychiatry, a person like me practicing psychotherapy doesn’t write many prescriptions, and I still relied on textbooks or review articles rather than looking at Randomized Clinical Trials. With rare exceptions, I rode on the "trailing edge" of medications, waiting until drugs were in widespread use before learning about them or prescribing them. The concept of a "pipeline" delivering a stream of new medications wasn’t even in my consciousness. I guess I thought that new medications came along when and if they were discovered. Writing this makes me feel incredibly naive – but I think that’s just the way it was. The only class of drugs I can recall actively keeping up with were the antibiotics – and that was because of those microbes’ incredible ability to become resistant.}

Top Psychiatrist Didn’t Report Drug Makers’ Pay

New York Times

By GARDINER HARRIS

October 3, 2008

One of the nation’s most influential psychiatrists earned more than $2.8 million in consulting arrangements with drug makers from 2000 to 2007, failed to report at least $1.2 million of that income to his university and violated federal research rules, according to documents provided to Congressional investigators. The psychiatrist, Dr. Charles B. Nemeroff of Emory University, is the most prominent figure to date in a series of disclosures that is shaking the world of academic medicine and seems likely to force broad changes in the relationships between doctors and drug makers…

Flash forward to the present. Over the intervening seven years, I’ve learned a lot about RCTs. About halfway back, I realized that the pharmaceutical companies being able to keep the raw data secret, or being able to simply not publish results they didn’t like, were an essential ingredients in the problem and I’ve spent a lot of my time involved in the fight for Data Transparency. There’s a lot more wrong – things like the alliance between academic medicine and industry, guest authors and ghost authors, the intrusions of third party carriers into medical care, etc. But frankly, I’ve spent so much time learning the ropes [with the help of some really good teachers], that it has been hard to get far enough away from the details to have an overall perspective on the big picture.

When I first read David Healy’s book, Pharmageddon [2012], I was still learning about Randomized Clinical Trials [RCTs], and I had looked at a number of them in as much depth as I could given the inaccessibility of the actual trial data. I could see how much subtle distortion there had been in the analyses and presentations in journal articles. The book added the history of RCTs and gave me a valuable perspective on how this tangled system had come into being  over the years. But there was one point that I didn’t intuitively grasp at the time. He seemed to be saying that there was a basic flaw in the RCT system over and above the distortions. At the time, It seemed to me that if the RCTs were properly conducted, properly analyzed, and properly reported that everything would be fine. I could tell he thought otherwise, but I just didn’t get the why of it on first reading. 

• Restoring Health: The Crusoe Report 1
• What’s Poisoning Health: The Crusoe Report 2

Pharmalot… PharmaWhat?… Until We Meet Again…

Pharmalot

By Ed Silverman

June 30, 2015

Once again, another working week will soon draw to a close and – along with it – the latest iteration of Pharmalot. Yes, you got that right. After a brief, but rewarding stay here at The Wall Street Journal, we are taking our act to a different theater. As our bubbe used to say – the only constant is change.

Before discussing our destination, we would like to thank the many long-standing Pharmalot readers and, of course, the more recent arrivals, who make Pharmalot an exceptionally interesting and pleasurable experience. Without your feedback – whether posted online or sent privately – this gig would not be nearly as fulfilling. You know who you are.

Over the years, in fact, we have come to regard the Pharmalot community as something of a virtual garden party, where news emerges, views are swapped and insights are gained. And we are better off having absorbed the suggestions, criticisms and, of course, the juicy tips. We would be remiss, however, if we did not thank Dennis Berman and Stefanie Ilgenfritz for their helpful stewardship during our tenure here.

As for our next step, we are shifting our Pharmalot endeavors to Stat, a forthcoming website that will devote itself to tracking the fascinating ins and outs of life sciences. For those who are unaware, Stat will emerge out from under the umbrella of The Boston Globe. Further details will become available shortly. Meanwhile, you can reach us at pharmalot@gmail.com and follow the usual @pharmalot Twitter handle.

And now, the time has come to daydream about weekend plans. Have a wonderful summer and see you online soon.

Pharmalot blogger Silverman joining Boston Globe

Talking Biz News

by Chris Roush

July 30, 2015

Ed Silverman, the Wall Street Journal reporter who runs the Pharmalot blog that covers the drug industry, is joining the Boston Globe. With the Globe, Silverman will be joining the Globe’s new health care news called Stat that debuts in the fall. He’ll be taking Pharmalot with him and writing a weekly column, too.

Silverman had been laid off from the Journal last month…

Boston Globe’s life sciences initiative finally has a name – ‘Stat’

Poynter.org

by Gurman Bhatia

July 17, 2015

The Boston Globe’s life sciences initiative led by former Politico executive editor Rick Berke now finally has a name. They want you to read the news urgently, hence – Stat. The name, which evokes urgency, is a reference to the medical term stat. Stat is derived from a Latin word that means “immediately.” The company acquired the domain www.statnews.com on Thursday. Berke later made it official with an announcement in a staff meeting Friday. “We take you inside science labs and hospital wards, biotech boardrooms and political backrooms,” Stat’s mission statement reads. “Stat will examine controversies, introduce power brokers and puncture hype.”

Stat’s leadership ranks include Gideon Gil, managing editor of enterprise and partnerships and Jeff DelViscio, who is senior editor of multimedia and creative. Gil was the former health and science editor of The Globe and DelViscio was a Web producer on the science and environment desk of The New York Times. While Stat is still hush-hush about who it has hired, Berke said the reporters’ names will be recognizable once they’re disclosed.

The company is also looking to hire for at least six senior positions for the Stat multimedia team. DelViscio’s ambition is to incorporate video, photo and interactive content within Stat’s storytelling stream. These jobs include a video editor, an interactives editor and a social media editor. DelViscio aims at integrating a full-stack multimedia team in the newsroom, drawing on its expertise from the very beginning of the storytelling process. “It is also a question of what constitutes a multimedia element,” DelViscio said. “Often something as simple as a GIF can have a little impact on the story, in sort of a teaching mentality. There is a visual quality to the life sciences that is often not utilized.”

The initiative can be expected to feature both short and longform video, be it shareable short clips focused towards social media, or mini-documentary style footage. With the interactives editor, the aim is to explore data visualization and the potential on that side right from the start. “At its core, Stat is supposed to be a watchdog,” DelViscio said. “There is so much money in the system and no people are looking at it consistently. That is the huge part of our mission. Although we are at a nascent stage right now, the possibilities also include searchable databases for public health information that aren’t otherwise readily accessible, something places like ProPublica and Center for Public Integrity do so well.”

Although the website doesn’t have a launch date yet, the team would start publishing Stat-branded content on The Boston Globe in late summer. Staffers would work towards building a national audience with that and promotion on social media. According to Berke, Stat has recruited people in Boston, New York, Washington, D.C. and the West Coast. “This will eventually be of national scope,” he said. What used to be a formal-looking publisher suite on the third floor of the Boston Globe building is now being revamped for Stat. The launch date is still several months away, but as the team works on creating an office space and reporters come in, Berke says it already has the feel of an excellent newsroom.

Exclusive: GSK faces new corruption allegations, this time in Romania

Reuters

By Ben Hirschler

Jul 29, 2015

Drugmaker GlaxoSmithKline, which was fined a record 3 billion yuan ($483 million) for corruption in China last year and is examining possible staff misconduct elsewhere, faces new allegations of bribery in Romania.

GSK confirmed it was looking into the latest claims of improper payments set out in a whistleblower’s email sent to its top management on Monday. A copy of the email was seen by Reuters.

The company is already probing alleged bribery in Poland, the United Arab Emirates, Lebanon, Jordan, Syria and Iraq…

UK May Require Doctors to Report Their Financial Ties to Drug Makers

Pharmalot: WSJ

By Ed Silverman

Jul 27, 2015

U.K. doctors and public health officials may be required to report any financial ties to drug makers under plans that are being considered by U.K. government officials, The Telegraph reports. The move comes after the paper ran an undercover investigation showing how National Health Service staffers were allegedly paid by drug makers that lobby health care providers to use specific medicines.

Some staff, who say they worked as industry consultants, charged more than $23,000 to organize so-called ‘advisory board’ meetings for drug makers and many of the meetings took place in five-star hotels in other countries, according to the paper. Some attendees told the Telegraph they were taken to “flashy” restaurants and paid large sums while considering whether to “switch” drugs.

NHS staffers who participated in the advisory boards argue their involvement helps them make “best use” of government money by analyzing drugs and providing expert advice, the paper wrote. Meanwhile, a dozen NHS staffers who attended one meeting in Germany told the paper they reported the trip and payments from a drug maker to their employers, and were not involved in subsequent decisions to adopt the drugs that were discussed. Each was paid nearly $800 a day.

An NHS England spokesman tells the paper “these are extremely serious allegations so we have immediately directed NHS Protect [an investigative agency] to launch a full investigation of each and every case identified by this press report.” He adds the U.K. may want to pass a law requiring “full disclosure of any payments” made by companies to health professionals or NHS employees…

NHS staffers who participated in the advisory boards argue their involvement helps them make “best use” of government money by analyzing drugs and providing expert advice…

Last night MPs on the Commons health select committee called on the NHS to investigate whether the practice was “widespread”. NHS England and Mr Hunt are looking at the merits of introducing a so-called Sunshine Act, akin to US legislation introduced in 2010 to shed light on financial relationships between pharmaceutical companies and health professionals.

An NHS England spokesman said: “These are extremely serious allegations so we have immediately directed NHS Protect to launch a full investigation of each and every case identified by this press report. “These allegations also raise the question of whether this country should now legislate for a so-called Sunshine Act, requiring full disclosure of any payments made by a pharmaceutical or device company to a health professional or NHS employee”…