shrinking…

Posted on Saturday 20 August 2016

by Tara F. Bishop, Joanna K. Seirup, Harold Alan Pincus, andJoseph S. Ros
Health Affairs. 2016 35[7]:1271-1277.

A large proportion of the US population suffers from mental illness. Limited access to psychiatrists may be a contributor to the underuse of mental health services. We studied changes in the supply of psychiatrists from 2003 to 2013, compared to changes in the supply of primary care physicians and neurologists. During this period the number of practicing psychiatrists declined from 37,968 to 37,889, which represented a 10.2 percent reduction in the median number of psychiatrists per 100,000 residents in hospital referral regions. In contrast, the numbers of primary care physicians and neurologists grew during the study period. These findings may help explain why patients report poor access to mental health care. Future research should explore the impact of the declining psychiatrist supply on patients and investigate new models of care that seek to integrate mental health and primary care or use team-based care that combines the services of psychiatrists and nonphysician providers for individuals with severe mental illnesses.
MEDPAGETODAY
by Neel A. Duggal
07·17·2016

The number of practicing psychiatrists in the U.S. has stalled over the last decade, in contrast to an upward trend among many other specialties, researchers found. An analysis of data from the Health Resources and Services Administration [HRSA] revealed a 0.2% decline in the number of psychiatrists in practice, compared with increases for neurologists [35.7%], primary care physicians [9.5%], and all practicing physicians [14.2%], Tara Bishop, MD, MPH, of Weill Cornell Medical College, and colleagues reported in the July issue of Health Affairs.

Co-author Harold Pincus, MD, of Columbia University and New York-Presbyterian Hospital, told MedPage Today that more medical school students were going into psychiatry in the 60s and 70s, but there’s been a "generational shift and this proportion has declined. Thus, psychiatrists are not being replaced at a sufficient rate." He offered two potential reasons for this shift: "First, psychiatrists are one of the lowest compensated specialties," he said. "Secondly, there are a greater number of other professionals providing behavioral health services, such as mid-level providers and counselors"… In addition to the overall totals, they saw a 10.2% decline in the median number of psychiatrists per 100,000 residents in hospital referral regions — compared with a 15.8% per capita increase for neurologists, and stable per capita proportions for primary care doctors and all practicing physicians…

The researchers suggested that the decline in psychiatrists might explain "why people report poor access to mental healthcare and why a large portion of psychiatrists are able to sustain practices without accepting insurance."

Petros Levounis, MD, chair of psychiatry at Rutgers Medical School, who wasn’t involved in the study, noted that there have been policy efforts to increase reimbursement for mental health services, such as the Mental Health and Substance Use Disorder Act of 2008 — but its implementation "has been slow," he said. "Reimbursements are very low," Levounis added. "Thus, many psychiatrists don’t accept insurance, such as those in the greater New York area." From his perspective as a medical school instructor, Levounis said that medical students "are initially interested in mental health and addiction. However, as their education progresses, their interest drops significantly"…

Pincus suggested that giving psychiatrists a supervisory role to guide other behavioral health professionals, while diminishing their own face time with patients, may be the best path to managing population mental health. But Levounis disagrees: he believes such a move will online increase the need for psychiatrists. On the other hand, telemedicine may be able to pick up the slack, although it’s "early to tell the success of their outcomes," Levounis said. The researchers concluded that "policy makers, payers, and the medical community simultaneously must develop strategies to enhance recruitment into psychiatry and rapidly develop and effectively disseminate new care models to use the psychiatric workforce more efficiently in the near term."

Co-authors disclosed financial relationships with Medtronic, Johnson & Johnson, and Blue Cross Blue Shield.
It’s worth reading the brief Wikipedia entry for the Community Mental Health Act of 1963, the last legislation signed by President Kennedy before his assassination – a good idea that never really happened. But as a result, in the days of my Internal Medicine Residency, the government was paying people to go into Psychiatry to deal with the perceived shortage.

psychiatry residency positionsBack then, the need was for physicians [psychiatrists] to staff the mental health centers that were an essential ingredient of the Community Mental Health enterprise. It was actually a good plan in my estimation, though by the time I arrived in the mid·1970s, it was in its waning days – collapsing under the weight of under·funding, under·staffing, and stripped of the necessary hospital backup for stabilization. With the coming of the DSM-III, brain science, and the medicalization of psychiatry, there was the kind of heyday new paradigms often bring. But in general, the relative number of US graduating seniors choosing psychiatry is basically flat compared to other medical specialties.

These authors mention the low pay and competition from other disciplines as explanatory factors. But those things have always been true and are unlikely to explain the more recent state of the specialty. Of course the number of psychiatrists is falling, but the obvious explanations weren’t mentioned here – things like psychiatrists are only covered by insurance to prescribe medications, and heavily criticized for prescribing too much medication; psychiatrists are not covered to talk to patients, and criticized for not talking to their patients; the upper echelons of psychiatry contain a number of tainted key opinion leaders who have gone over to the dark side and allied themselves with the commercial interests of the pharmaceutical industry; and critics see all psychiatrists as members of this tainted group and are globally contemptuous. That’s just for starters. And, oh yeah, I didn’t take insurance because with that came directives about practice that were unacceptable [and in my opinion, wrong]. I preferred to make less money.

And so the authors suggest the solution is for psychiatrists to no longer see patients or to see them even less, but rather direct treatment from afar by working through a Clinical Coordinator AKA Collaborative Care or literally afar through a computer screen AKA Telepsychiatry. Who wants to spend a career doing either? What patient wants to be treated that way? And the authors’ Conflicts of Interest are telling. Their suggestions are exactly what industry wants from psychiatrists [prescribe meds more rationally than the Primary Care docs do, but don’t get involved with talking to or even meeting with the patients because that runs up costs]. So it looks to me as if they’re using the declining number data to justify directing the specialty even further into exactly what Medtronic, Johnson & Johnson, and Blue Cross Blue Shield want it to be.

But my real reason for writing this is to point out that the policy wonks neither mention the widespread corruption of the academic·pharmaceutical complex nor the ubiquitous inaccurate information about our drugs. That absence in this discussion is particularly striking…
Mickey @ 10:32 AM

the best predictor…

Posted on Thursday 18 August 2016

I don’t know anything about Ketamine except what I read. It is an FDA Approved off-patent anesthetic by day, and a club drug by night [Special K]. We began to hear about it as an antidepressant around the time that it became apparent that PHARMA was abandoning CNS drug development in 2012. It’s given iv and is a lightweight hallucinogen. The excitement was that the antidepressant effects seemed to persist for a variable period of time [days] after the druggie effects wore off [hours]. And in a modern world, there was another problem – it’s generic – ergo no blockbuster potential in sight [or so I thought]. But then the cynical part of my mind got engaged when I saw commentaries by major KOLs  suggesting caution[???] [full text on-line]:
These are not the kind of people who suggest caution[???] about drugs, and I freely admit that I was immediately suspicious that they were holding out for something PHARMA could market and downplaying Ketamine itself [call me paranoid? or call me wise?]. That last Nemeroff paper was a review article and I wrote about it in a touch of paralysis…. I did think they were talking up Rapastinel, a patented Ketamine analog and that the evidence base for that drug was beyond shaky [see infomercials… and shame on us]. Then shortly after the Nemeroff article was published, another contender came on the scene from Johnson and JohnsonEsketamine. Esketamine and Ketamine are enantiomers – moleculers that have the same chemical formula but are mirror images that can’t be superimposed on each other. There is some evidence that their properties as drugs differ, summarized here. In November 2015, Johnson and Johnson received a Breakthrough Therapy Designation for  treatment resistant depression based on this report of a phase 2 clinical trial:
by Jaskaran B. Singh , Maggie Fedgchin, Ella Daly, Liwen Xi, Caroline Melman, Geert De Bruecker, Andre Tadic, Pascal Sienaert, Frank Wiegand, Husseini Manji, Wayne C. Drevets, and Luc Van Nueten
Biological Psychiatry. November 3, 2015. EPub ahead of print.

BACKGROUND: The purpose of this study was to assess the efficacy and safety and to explore the dose response of esketamine intravenous [IV] infusion in patients with treatment-resistant depression [TRD].
METHODS: This multicenter, randomized, placebo-controlled trial was conducted in 30 patients with TRD. Patients were randomly assigned 1:1:1 to receive an IV infusion of .20 mg/kg or .40 mg/kg esketamine or placebo over 40 minutes on day 1. The primary end point was change in Montgomery-Åsberg Depression Rating Scale total score from day 1 [baseline] to day 2. Nonresponders who received placebo on day 1 were randomly assigned again 1:1 to IV esketamine .20 mg/kg or .40 mg/kg on day 4. Secondary efficacy and safety measures were also evaluated.
RESULTS: Of the enrolled patients, 97% [29 of 30] completed the study. The least squares mean changes [SE] from baseline to day 2 in Montgomery-Åsberg Depression Rating Scale total score for the esketamine .20 mg/kg and .40 mg/kg dose groups were -16.8 [3.00] and -16.9 [2.61], respectively, and showed significant improvement [one-sided p = .001 for both groups] compared with placebo [-3.8 [2.97]]. Esketamine showed a rapid [within 2 hours] and robust antidepressant effect. Treatment-emergent adverse events were dose dependent. The most common treatment-emergent adverse events were headache, nausea, and dissociation; the last-mentioned was transient and did not persist beyond 4 hours from the start of the esketamine infusion.
CONCLUSIONS: A rapid onset of robust antidepressant effects was observed in patients with TRD after a 40-min IV infusion of either .20 mg/kg or .40 mg/kg of esketamine. The lower dose may allow for better tolerability while maintaining efficacy
But that was just for starters. They’ve been working on an intranasal delivery version for seven years, recently presented [reference: Canuso C, et al. "Esketamine for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Subjects Assessed to be at Imminent Risk for Suicide." Society of Biological Psychiatry 71st Annual Scientific Meeting. May 12-14, 2016.]. Now Johnson and Johnson has just been granted Breakthrough Therapy Designation for the intranasal version for both treatment resistant depression and major depressive disorder with imminent risk for suicide [Breakthrough Therapy Designation is essentially a fast-track FDA Approval process for promising and much-needed drugs].
Johnson and Johnson: Press Release
August 16, 2016

Janssen Research & Development, LLC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, announced today that the U.S. Food and Drug Administration [FDA] has granted a Breakthrough Therapy Designation for  esketamine, an investigational antidepressant medication, for the indication of major depressive disorder with imminent risk for suicide. If approved by the FDA, esketamine would be one of the first new approaches to treat major depressive disorder available to patients in the last 50 years.

This also marks the second time esketamine has received a Breakthrough Therapy Designation from the U.S. regulatory authority. Esketamine was first granted this designation for treatment-resistant depression in November 2013. Breakthrough Therapy Designation is intended to expedite development and review timelines when preliminary clinical evidence indicates the drug may demonstrate substantial improvement on one or more clinically significant endpoints over available therapies for serious or life-threatening conditions.

The esketamine Phase 2 clinical trial data presented by Janssen in May 2016 at the Society of Biological Psychiatry 71st Annual Scientific Meeting in Atlanta, Georgia, provided preliminary clinical evidence to support the Breakthrough Therapy Designation for major depressive disorder with imminent risk for suicide.

About Esketamine
Esketamine for intranasal administration is an investigational compound being studied by Janssen as part of a global development program. Esketamine is a non-competitive and subtype non-selective activity-dependent N-methyl-D-aspartate [NMDA] receptor antagonist, which has a novel mechanism of action, meaning it works differently than currently available therapies for depression. The program in treatment-resistant depression is currently in Phase 3, with six ongoing clinical trials…
Alex GorskyI’ll have to admit that the notion of seeing a suicidal patient and offering them a sniff of some version of Special K as a treatment strikes me as borderline ludicrous, hard for me to say with a straight face – but stranger things have happened. That’s not why I’m writing about it. Remember, this is Johnson and Johnson, the people who gave us TMAP and all of the Risperidal® sheenanigans. The CEO is still Alex Gorsky – West Point graduate and lifelong Boy Scout, who brought in Billions with all kinds of hanky-panky, flooding the literature with articles churned out by Excerpta Medica. Johnson and Johnson gladly paid the cost-of-doing-business fines of around $2.2 B – trivial in the face of their ill-gotten gains.  And with Risperidal®, they were also first-on-the-market:

Here’s a roster of their Esketamine clinical trials from clinicaltrials.gov. As you can see, they’re going long on Esketamine. It’s a hungry market and they’re going after it. And then there’s that old saying, "The best predictor of future behavior is past behavior."

NCT #
 
  Title   Status Phase Start
NCT01394757 Network Dysfunction, Schizophrenia and Pharmacological Magnetic Resonance Imaging [phMRI] Completed 08/2011
NCT00847418 Pharmacokinetics and Pharmacodynamics of Nasally Applied Esketamine Completed 1 02/2009
NCT01780259 A Study to Assess the Pharmacokinetics, Safety, and Tolerability of Intranasally Administered Esketamine in Healthy Participants Completed 1 12/2012
NCT02060929 A Study to Evaluate the Pharmacokinetics of Intranasal Esketamine Administered With and Without a Nasal Guide on the Intranasal Device Completed 1 10/2013
NCT01980303 A Study to Assess the Pharmacokinetics of Intranasally Administered Esketamine in Healthy Japanese and Caucasian Volunteers Completed 1 11/2013
NCT02129088 A Pharmacokinetic, Safety and Tolerability Study of Esketamine in Healthy Elderly and Adult Participants Completed 1 03/2014
NCT02094378 A Study to Evaluate the Effect of Intranasal Esketamine on Cognitive Functioning in Healthy Subjects Completed 1 06/2014
NCT02154334 Study to Assess the Effects of Allergic Rhinitis and Co-administration of Mometasone or Oxymetazoline on the Pharmacokinetics, Safety, and Tolerability of Intranasal Esketamine Completed 1 06/2014
NCT02228239 Study to Assess the Effects of Esketamine on Safety of On-road Driving in Healthy Participants Completed 1 09/2014
NCT02345148 Pharmacokinetic, Safety, and Tolerability Study of Intranasally Administered Esketamine in Elderly and and Healthy Younger Adult Participants Completed 1 12/2014
NCT02343289 A Study to Evaluate the Absolute Bioavailability of Intranasal and Oral Esketamine and the Effects of Clarithromycin on the Pharmacokinetics of Intranasal Esketamine in Healthy Participants Completed 1 01/2015
NCT02568176 Pharmacokinetic Study of Intranasal Esketamine and Its Effects on the Pharmacokinetics of Orally-Administered Midazolam and Bupropion in Healthy Participants Completed 1 10/2015
NCT02611505 A Study to Assess the Effects of Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Intranasally Administered Esketamine Recruiting 1 11/2015
NCT02606084 A Study to Assess the Effects of Renal Impairment on the Pharmacokinetics, Safety, and Tolerability of Intranasally Administered Esketamine Recruiting 1 12/2015
NCT02846519 Pharmacokinetic, Safety, and Tolerability Study of Intranasally Administered Esketamine in Healthy Han Chinese, Korean, Japanese, and Caucasian Participants and the Effects of Rifampin on the Pharmacokinetics of Intranasally Administered Esketamine Completed 1 02/2016
NCT02682225 Crossover Study to Evaluate the Abuse Potential of Intranasal Esketamine Compared to Racemic Intravenous Ketamine in Nondependent, Recreational Drug Users Recruiting 1 03/2016
NCT02674295 A Mass Balance Study With a Microtracer Dose of 14C-esketamine in Healthy Male Participants Recruiting 1 03/2016
NCT02737605 A Study to Evaluate the Effects of Esketamine on Cardiac Repolarization in Healthy Participants Not yet recruiting 1 07/2016
NCT02857777 Pharmacokinetic, Safety, and Tolerability Study of Intranasally Administered Esketamine in Elderly Japanese, and Healthy Younger Adult Japanese Subjects Not yet recruiting 1 08/2016
NCT01640080 A Study of the Efficacy of Intravenous Esketamine in Adult Patients With Treatment-Resistant Depression Completed 2 06/2012
NCT01998958 A Study to Evaluate the Safety and Efficacy of Intranasal Esketamine in Treatment-resistant Depression Completed 2 01/2014
NCT02133001 A Double-blind Study to Assess the Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Participants Who Are Assessed to be at Imminent Risk for Suicide Completed 2 05/2014
NCT02417064 A Study to Evaluate the Efficacy, Safety, and Tolerability of Fixed Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression Recruiting 3 08/2015
NCT02418585 A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression Recruiting 3 08/2015
NCT02422186 A Study to Evaluate the Efficacy, Safety, and Tolerability of Intranasal Esketamine Plus an Oral Antidepressant in Elderly Participants With Treatment-resistant Depression Recruiting 3 08/2015
NCT02497287 A Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression Recruiting 3 09/2015
NCT02493868 A Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Adult Participants With Treatment-resistant Depression Recruiting 3 10/2015
NCT02782104 A Long-term Safety Study of Intranasal Esketamine in Treatment-resistant Depression Recruiting 3 06/2016
Mickey @ 6:25 PM

and then there was one…

Posted on Wednesday 17 August 2016

I’ve gotten email along the way asking me [or chiding me] about my being preoccupied with clinical trials that are more than a decade old, I guess implying that it’s even too boring for the likes of me. I’d like to respond, because I think there’s something very important in the answer. These trials are designed to detect short term efficacy and log adverse effects to determine regulatory approval. They were never intended to direct clinical use of the drugs in practice. And yet they’ve frequently been treated as if they’re the final word, the gold standard in clinical psychiatry. And further, in the published reports, the subjects’ self-rating scales are often insignificant, if they’re even reported, even though the thing that really matters with many of the conditions is the patient’s subjective experience of symptom relief. Then after a drug is approved, further testing is directed towards greener pastures, lucrative approvals for other diagnoses. And as to the continued relevance of these ancient trials, Karen Wagner’s update at the 2016 APA meeting relied on her same old studies [see Child Psychiatrists Look at Specialty From Both Macro, Micro Perspectives]:
Notice my formatting. I think that the 2001 Paxil Study 329 and the 2004 CIT-MD-18 papers have been convincingly debunked by the recent exhaustive second looks: Restoring Study 329… and The citalopram CIT-MD-18 pediatric depression trial…. And as long as we’re in the neighborhood, what about Wagner’s 2003 Pfizer-funded Sertraline trial?
by Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D; and the Sertraline Pediatric Depression Study Group
Journal of the American Medical Association. 2003, 290[8]:1033-41.

CONTEXT: The efficacy, safety, and tolerability of selective serotonin reuptake inhibitors [SSRIs] in the treatment of adults with major depressive disorder [MDD] are well established. Comparatively few data are available on the effects of SSRIs in depressed children and adolescents.
OBJECTIVE: To evaluate the efficacy and safety of sertraline compared with placebo in treatment of pediatric patients with MDD.
DESIGN AND SETTING: Two multicenter randomized, double-blind, placebo-controlled trials were conducted at 53 hospital, general practice, and academic centers in the United States, India, Canada, Costa Rica, and Mexico between December 1999 and May 2001 and were pooled a priori.
PARTICIPANTS: Three hundred seventy-six children and adolescents aged 6 to 17 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined MDD of at least moderate severity.
INTERVENTION: Patients were randomly assigned to receive a flexible dosage [50-200 mg/d] of sertraline [n = 189] or matching placebo tablets [n = 187] for 10 weeks.
MAIN OUTCOME MEASURES: Change from baseline in the Children’s Depression Rating Scale-Revised [CDRS-R] Best Description of Child total score and reported adverse events.
RESULTS: Sertraline-treated patients experienced statistically significantly greater improvement than placebo patients on the CDRS-R total score [mean change at week 10, -30.24 vs -25.83, respectively; P=.001; overall mean change, -22.84 vs -20.19, respectively; P=.007]. Based on a 40% decrease in the adjusted CDRS-R total score at study end point, 69% of sertraline-treated patients compared with 59% of placebo patients were considered responders [P=.05]. Sertraline treatment was generally well tolerated. Seventeen sertraline-treated patients [9%] and 5 placebo patients [3%] prematurely discontinued the study because of adverse events. Adverse events that occurred in at least 5% of sertraline-treated patients and with an incidence of at least twice that in placebo patients included diarrhea, vomiting, anorexia, and agitation.
CONCLUSION: The results of this pooled analysis demonstrate that sertraline is an effective and well-tolerated short-term treatment for children and adolescents with MDD.
Figure 2. Weekly and Overall Adjusted Mean CDRS-R Scores
CDRS-R indicates Children’s Depression Rating Scale—Revised Best Description of Child total score. Data are least square means at each visit week, with mean scores averaged to give the overall mean, from a repeated-measures mixed-model analysis with age category, site, treatment, week, and week-by-treatment interaction used as fixed effects, subject as a random effect, and baseline effect as a covariate. Error bars indicate SE of the adjusted means, derived from the repeated-measures mixed-model procedure. P values are as follows: week 1. P=.09; week 2, P=.08; week 3, P =.01; week 4, P=.008; week 6, P=.37; week 8, P=.18; week 10, P=.001; and mean response, P=.007.

Right out of the gate, we have good reason to question these conclusions just by looking at the primary outcome variable graph which only achieved significance at 3, 4, and 10 weeks. But there’s a lot more to give us pause. In all of the depositions, Wagner makes it clear that she neither saw all the data nor checked the analysis in this study either, and that it was written at Pfizer with her coming in as the drafts were revised. Pfizer has gotten off light in the critiques of these clinical trials in that they had a writing firm, Current Medical Directions, that ghost wrote their Zoloft articles faster than they could find KOLs to sign up as guest authors [see zoloft: beyond the approval I… for this part of the story].

But there’s something else that has always bothered me about this paper, and it’s right there in the title – … two randomized controlled trials. What’s that about? Everywhere this trial is reported, they say some version of, "Data from both studies were pooled in a prospectively defined combined analysis." So we are to believe that they had two identical studies that they planned to pool together for analysis, and the obvious question is what makes them two studies? Sounds like one big study to me [and plenty of others reading this paper]. If you were planning two identical studies, it would be likely that you were trying the speed things up to get the two studies needed for FDA Approval. And then we read this from one of the study group investigators in the study:

To the Editor: Dr Wagner and colleagues reported that sertraline was more effective than placebo for treating children with major depressive disorder and that it had few adverse effects. As one of the study group investigators in this trial, I am concerned about the way the authors pooled the data from 2 trials, a concern that was raised by previous letters critiquing this study. The pooled data from these 2 trials found a statistically marginal effect of medication that seems unlikely to be clinically meaningful in terms of risk and benefit balance.

New information about these trials has since become available. The recent review of pediatric antidepressant trials by a British regulatory agency includes the separate analysis of these 2 trials. This analysis found that the 2 individual trials, each of a good size [almost 190 patients], did not demonstrate the effectiveness of sertraline in treating major depressive disorder in children and adolescents.
    E. Jane Garland, MD, FRCPC
    Department of Psychiatry
    University of British Columbia
    Vancouver
Committee on Safety of Medicines. Medicines and Health Care Products Regulatory Agency. Selective Serotonin Reuptake Inhibitors [SSRIs] — overview of regulatory status and CSM advice relating to major depressive disorder [MDD] in children and adolescents: summary of clinical trials. Available at: http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/ssrioverviewclintnaldata_101203.htm. Accessibility verified March 12, 2004.
Well, if that’s not enough of a nail in this coffin, there’s even more in Wagner’s response to Dr. Garland’s letter:
Reply: In response to Dr Garland, our combined analysis was defined a priori, well before the last participant was entered into the study and before the study was unblinded. The decision to present the combined analysis as a primary analysis and study report was made based on …
I won’t even finish her explanation because it doesn’t matter, since a priori means before the study starts, not "well before the last participant was entered into the study and before the study was unblinded" [this ploy of redefining the meaning of a priori is familiar to us from a similar bit of sleight of hand in Paxil Study 329]. So looked at from any angle, this is yet another negative clinical trial reported as positive after much jury-rigging – just as worthy of retraction as the other two.
Wagner is scheduled for her usual presentation [Treatment of Depressive Disorders in Children and Adolescents] at the October American Academy of Child and Adolescent Psychiatry annual meeting. I wonder what she’ll find to talk about this year?
Mickey @ 11:30 PM

ignor·ance…

Posted on Tuesday 16 August 2016

Ignorance is a state of being uninformed [lack of knowledge]. The word ignorant is an adjective describing a person in the state of being unaware and is often used to describe individuals who deliberately ignore or disregard important information or facts.
    ig·nore (ïg-nôr′)
    verb
          To refuse to pay attention to; disregard.

It’s telling that the words ignorance and ignorant come from the verb ignore, implying a chosen version of not knowing. It certainly comes up a lot in matters surrounding clinical trials. For example, the rules for  preregistration or resuls posting on clinicaltrials.gov or preregistration of outcomes as a prerequisite to being considered for publication have been regularly ignored [see the wrong tree…]. Long before we conceived of our RIAT reanalysis of Paxil Study 329, I made a formal request to the Ethics Coimmittee of the American Academy of Child and Adolescent Psychiatry. The committee [and the president-elect] responded, investigated, and told me that the question would be discussed at their yearly meeting. Nothing happened and it was not discussed. I later learned that the editor, Andres Martin, found out and insisted they have no more contact with me [ignored, disregarded] and that was the end of that.

In general, the major organizations [AACAP, APA] have ignored distortion of clinical trial reports in medical journals, including their own official journals when it has been pointed out. In spite of our reanalysis, that paper’s notoriety, and the $3 B settlement, the  Study 329 article still sits in our literature – unretracted. And now, there’s another obvious candidate – the Citalopram trial in children and adolescents called CIT-MD-18. The recent article about that paper reveals how it was actively distorted by the sponsor – Forest Laboratories [see this tawdry era…]:
by Jureidini, Jon N., Amsterdam, Jay, D, and McHenry, Leemon B.
International Journal of Risk & Safety in Medicine, 2016 28[1]:33-43.

OBJECTIVE: Deconstruction of a ghostwritten report of a randomized, double-blind, placebo-controlled efficacy and safety trial of citalopram in depressed children and adolescents conducted in the United States.
METHODS: Approximately 750 documents from the Celexa and Lexapro Marketing and Sales Practices Litigation: Master Docket 09-MD-2067-[NMG] were deconstructed.
RESULTS: The published article contained efficacy and safety data inconsistent with the protocol criteria. Procedural deviations went unreported imparting statistical significance to the primary outcome, and an implausible effect size was claimed; positive post hoc measures were introduced and negative secondary outcomes were not reported; and adverse events were misleadingly analysed. Manuscript drafts were prepared by company employees and outside ghostwriters with academic researchers solicited as ‘authors’.
CONCLUSION: Deconstruction of court documents revealed that protocol-specified outcome measures showed no statistically significant difference between citalopram and placebo. However, the published article concluded that citalopram was safe and significantly more efficacious than placebo for children and adolescents, with possible adverse effects on patient safety.
The authors wrote the American Journal of Psychiatry where the original article is published requesting a retraction of Wagner et al’s A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents. That letter is in the Background Notes, and it received only this terse, belated reply:
RE: Am J Psychiatry 2004; 161:1079–1083 We are not retracting this article. Robert Freedman MD
In a rational world, one might think that an editor might be embarrassed a bit, but generally be glad to hear about an article that’s as far in left field as this one and look into it – particularly an article he himself had censured in the past for undeclared ghost-writing and omitting a negative european study [see collusion with fiction…]. By the way, throw in its centrality in a pricey legal suit [Drug Maker Forest Pleads Guilty: Will Pay More Than $313 Million to Resolve Criminal Charges and False Claims Act Allegations]. But Freedman’s disregarding imperative [We are not retracting this article] is anything but that kind of response – more in the range of a scowl in text.

So the authors appealed to a higher power, Maria A. Oquendo, M.D., President of the American Psychiatric Association. Dr. Oquendo appears to be one of the good guys, able to have a distinguished and successful academic career without the taint of KOL-dom like her predecessor as Chairman at Penn, Dwight Evans [on Senator Grassley’s list of COI violators among other things]. That letter is posted here on this blog [a time for change…], and cosigned by a number of impressive people [and others]. It has been two weeks since it was sent, and there’s been no response yet.

Juriedini et al’s Deconstruction of CIT-MD-18 is substantively different from our Restoring Study 329 article, even though they’re in the same genre. Ours was a reanalysis, and while we were able to access the Raw Data and definitively show it was a negative study, the RIAT format didn’t allow for the subpoenaed emails that expose internal goings on. The CIT-MD-18 Deconstruction brings the corrupt processes out into the light of day as well as showing that this trial was also negative. This paper is important for two reasons: this study was part of the FDA Approved indication in adolescents AND it doesn’t have the negative notoriety of Paxil Study 329. In fact, first author Karen Dineen Wagner used it in her presentation of antidepressant use in kids at the May 2016 APA meeting. So its findings are still very much in use [see what’s it going to take?…].


It’s time for the upper levels of academic psychiatry and journal editors to stop ignoring these corrupt clinical trial reports that literally haunt our literature, moving forward as if none of what happened ever really did happen. They have tainted the reputation of the specialty and the profession in general. These papers sit in the literature like rotten fruit in a barrel and they’re not going to go away. This particular study is unusually influential and must be dealt with. As for the authors, "don’t do the crime if you can’t do the time." I suspect that many of them had no idea what they were signing on to, but that’s no excuse. In the case of Dr. Wagner, the first author [and principal investigator], by her own testimony she neither looked at the whole data set nor checked the statistical analysis [see author·ity…].

So the task before Dr. Oquendo is a big one. Is she going to stick her head in the sand? ignore the obvious? or step up to the plate?…
Mickey @ 10:46 PM

it didn’t work…

Posted on Monday 15 August 2016

Well, I couldn’t do it. I thought I could just log the last post and keep my mouth shut, but it didn’t work. I made the mistake of reading this article again. So with apologies, I have some more things to say:
New England Journal of Medicine. 2016; 375:405-407.

… A key motivation for investigators to conduct RCTs is the ability to publish not only the primary trial report, but also major secondary articles based on the trial data. The original investigators almost always intend to undertake additional analyses of the data and explore new hypotheses. Moreover, large, multicenter trials with large numbers of investigators often require several articles to fully describe the results. These investigators are partly motivated by opportunities to lead these secondary publications. We believe 6 months is insufficient for performing the extensive analyses needed to adequately comprehend the data and publish even a few articles. Once the investigators who have conducted the trial no longer have exclusive access to the data, they will effectively be competing with people who have not contributed to the substantial efforts and often years of work required to conduct the trial.

… In summary, we recommend that the ICMJE come together with trialists and other stakeholders to discuss the potential benefits, risks, burdens, and opportunity costs of its proposal and explore alternatives that will achieve the same goals efficiently. Moreover, we recommend modifying the proposal as follows. First, the timeline for providing deidentified individual patient data should allow a minimum of 2 years after the first publication of the results and an additional 6 months for every year required to complete the study, up to a maximum of 5 years. Second, to enhance readers’ confidence in published data, an independent statistician should have the opportunity to conduct confirmatory analyses before publication of an article, thereby advancing the ICMJE’s stated goal of increasing “confidence and trust in the conclusions drawn from clinical trials.” Finally, persons who were not involved in an investigator-initiated trial but want access to the data should financially compensate the original investigators for their efforts and investments in the trial and the costs of making the data available.
I ran across a blog post that mirrored some of my reactions and brought up a few interesting points that hadn’t occurred to me:
techdirt
by Glyn Moody
August 8, 2016
This NEJM article sounds like Nero playing his violin while Rome burns to me. I can think of nothing in Medicine that comes even close the level of corruption achieved in the distortion of Clinical Trial results in the fifty years since the Kefauver-Harris Amendment made trials a pre-requisite for drug approval – something that was intended to be a reform, a check on the often inert patent medicines of the day. There’s nothing wrong with that piece of legislation itself. It’s what people did with these clinical trials that has wreaked so much ongoing havoc.

While the standard for approval is low, FDA approval isn’t intended to direct clinicians. It simply means that the drug has demonstrated medicinal properties and is deemed safe for human use. The malignant problem has arisen from the version of those trials that has made it into the medical literature, regularly inflating efficacy, downplaying toxicity, and laying a base for advertising campaigns that opportunize on our patien’ts desire for symptom relief and/or wellness. The aura of FDA approval and publication in the scientific literature has been parlayed into billions of dollars in ill-gotten profits. Worse, it has catapulted medication induced mortality and morbidity into the majors.

Clinical Trials are referred to as "research" and the people in charge of these studies call themselves "researchers." Research is exploration in search of new findings. These clinical Trials aren’t research, they’re product testing – governed by strict rules to be validating. And so many of the published results make a mockery of these basic rules: Randomization, Double Blinding, Preregistration of Outcomes followed by Replication of positive results. The NEJM article describes a mythical process bearing little resemblance to what actually happens in these largely commercially conducted trials. The analysis could, and perhaps should, be done the day the trial ends and the blind is broken. If they want to play around with the data for some kind of exploratory research, they could simply hold on to the original protocol directed analysis until their other data play is finished. Truth-be-told, this plea for time to play around with the data is an admission of guilt – Hypotheses After Results Known!

But the regularity of corruption in Clinical Trial reporting in the medical journals trumps any argument they might muster, any violin they might play. This is likely the biggest scandal in the history of Medicine. Rome really is on fire…
Mickey @ 11:36 PM

no neutrality…

Posted on Monday 15 August 2016

In 1980, Arnold Relman, then editor of the New England Journal of Medicine, gave us a dire warning. He saw what was coming and laid it out for all to see:
While he underestimated the involvement of the pharmaceutical industry, he was still dead on in general – that industry was poised to invade Medicine with a ferocity the rest of us couldn’t yet imagine. And this very problem played out in the editorial offices of his journal itself not very many years later resulting in the firing of Relman’s successor, Jerome Kassirer [see a narrative… and not so proud…]. For the last year, Relman‘s point has been the subject of a debate, largely in the pages of the New England Journal of Medicine. But this time, the  editor, Jeffrey Drazen, has been on the other side. Here are the relevant articles, arranged by date, all available full-text on-line:
I listed the primary sources for you to read for yourself because I have no neutrality in this matter. From my point of view, Jeffrey Drazen, presumably backed by the current powers that be at the New England Journal of Medicine, has shamed his journal and our profession. He’s used the time-honored medical journal of record to push his own corporate-friendly agenda. Let’s hope he and his like-minded associates find a way to move on quickly…
Mickey @ 11:33 AM

the wrong tree…

Posted on Saturday 13 August 2016

On my trip, I was thinking about the years of the abuse of the clinical trial system – wondering what could be done to put a stop to it? What creative reform would finally save the day? There have been so many attempts, and yet it goes on and on, at least with the psychiatric drugs I’m familiar with. And it dawned on me that I might be asking the wrong question. There’s nothing wrong with the reforms that have already been instituted, nothing except for one not-so-minor detail – they’ve been largely ignored.

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

outcome switching – The COMPare Project

rules It is imperative that a trial sponsor declare the outcome variables before the trial begins [see The Meaning of “Significance” for Different Types of Research, the hope diamond…, Why we need pre-registration, For Preregistration in Fundamental Research].

reality

Ben Goldacre has been a tireless campaigner against the secrecy afforded the pharmaceutical industry with their clinical trial data. His AllTrials campaign has alerted us all to the problem, but it has been stymied and undermined by industry every step of the way. It’s still viable, but disappointing in that we still don’t have the data access we need. But he’s got another trick up his sleeve that seems to be moving right along in his campaign. He’s looking at how closely recent Clinical Trials adhere to preregistration, something he calls Outcome Switching:

The COMPare Trials Project.
by Ben Goldacre, Henry Drysdale, Anna Powell-Smith, Aaron Dale, Ioan Milosevic, Eirion Slade, Philip Hartley, Cicely Marston, Kamal Mahtani, Carl Heneghan.

Here again, the rule is to report on the a priori declared outcome variables. This is what Goldacre’s group reports finding on recently reported trials [major journals]:

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

After the data is in hand, one can do all kinds of statistical tests on the results, thumbing through all the possible outcome variables until you find something that gives you the p-value you want. This is probably the most abused rule of them all in the jury-rigging of clinical trial results.

9 ÷ 67 = 13%. That’s pitiful…

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

clinicaltrials.gov – preregistration/results

rules
Since 2007, the rules have been crystal clear – actual law. Trials are to be registered before they’re begun, and the results published within the first year following completion. There’s no ambiguity in what’s supposed to happen.

reality
If I ever have to justify the name of this blog [1boringoldman], I will probably present a monotonous list of my posts pointing out how the pharmaceutical companies [AND NIMH grant recipients] have been noncompliant with the mandates for timely PRE-registration and later posting results on clinicaltrials.gov. There’s no rational reason for their ignoring this requirement. They already have the data, and the system is simple. They’re given plenty of time. But they’ve just ignored it. This is a partial listing of my posts on this point: transparency!…, studying the studies…, what dreamer?…. non·random missing·ness…, speaking of about time!…, Beware of Shiny Objects!…, back on track…, never been imposed…, a dreamer…, wolf alert! wolf alert!…, etc. And an exempler article [among many] available on-line:.
    by Jennifer E Miller, David Korn, and Joseph S Ross
    BMJ Open 2015;5:e009758.

    Objective: To evaluate clinical trial registration, reporting and publication rates for new drugs by: [1] legal requirements and [2] the ethical standard that all human subjects research should be publicly accessible to contribute to generalisable knowledge.
    Design: Cross-sectional analysis of all clinical trials submitted to the Food and Drug Administration [FDA] for drugs approved in 2012, sponsored by large biopharmaceutical companies.
    Data sources: Information from Drugs@FDA, ClinicalTrials.gov, MEDLINE-indexed journals and drug company communications.
    Main outcome measures: Clinical trial registration and results reporting in ClinicalTrials.gov, publication in the medical literature, and compliance with the 2007 FDA Amendments Acts [FDAAA], analysed on the drug level.
    Results: The FDA approved 15 drugs sponsored by 10 large companies in 2012. We identified 318 relevant trials involving 99,599 research participants. Per drug, a median of 57% [IQR 32–83%] of trials were registered, 20% [IQR 12–28%] reported results in ClinicalTrials.gov, 56% [IQR 41–83%] were published, and 65% [IQR 41–83%] were either published or reported results. Almost half of all reviewed drugs had at least one undisclosed phase II or III trial. Per drug, a median of 17% [IQR 8–20%] of trials supporting FDA approvals were subject to FDAAA mandated public disclosure; of these, a median of 67% [IQR 0–100%] were FDAAA-compliant. 68% of research participants [67,629 of 99,599] participated in FDAAA-subject trials, with 51% [33,405 of 67,629] enrolled in non-compliant trials. Transparency varied widely among companies.
    Conclusions: Trial disclosures for new drugs remain below legal and ethics standards, with wide variation in practices among drugs and their sponsors. Best practices are emerging. 2 of our 10 reviewed companies disclosed all trials and complied with legal disclosure requirements for their 2012 approved drugs. Ranking new drugs on transparency criteria may improve compliance with legal [FDAAA] and ethics standards and the quality of medical knowledge.

These graphs give an overview – on the left, the number of trials for each drug; – on the right, the percentage of trials for each drug that meet the criteria listed on the abscissa. Like all of this genre of studies, the compliance rates are dismal.


International Committee of Medical Journal Editors

rules
In journal articles are forever…, I mentioned the requirements/recommendations of the International Committee of Medical Journal Editors [using the slash-mark because of their own wording]:
    "Briefly, the ICMJE requires, and recommends that all medical journal editors require, registration of clinical trials in a public trials registry at or before the time of first patient enrollment as a condition of consideration for publication. Editors requesting inclusion of their journal on the ICMJE website list of publications that follow ICMJE guidance should recognize that the listing implies enforcement by the journal of ICMJE’s trial registration policy."
But being listed on the ICMJE database implies that the journal requires preregistration of Clinical Trials [registration before the study begins] as a prerequisite to considering them for publication.

reality

In a recent well-done study from New Zealand [Is Mandatory Prospective Trial Registration Working to Prevent Publication of Unregistered Trials and Selective Outcome Reporting?] surveying articles published since those requirements were finalized, the compliance rate was abysmal [see POM·posity…].

 

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

The elements of the design are Randomization, Double Blinding, Preregistration of Outcomes followed by Replication of positive results in a follow-up study.
Mickey @ 7:00 AM

journal articles are forever…

Posted on Wednesday 10 August 2016

In spite of the way drug company advertisements are often written, FDA Approval is not meant to be a medical recommendation. It simply means that a compound is safe for human use and that it has statistically significant medicinal properties demonstrated in two well conducted Clinical Trials. The FDA certified document [package insert] included with each medication has information on dosage, drug interactions, adverse events, indications, and warnings where appropriate. The process for approval and release are heavily regulated by the FDA, which also has the power to recall a medication from use in the case of adverse events that come to light with general usage. The FDA has its own Office of Criminal Investigations [OCI] to investigate infractions:
  1. Manufacture and sale of counterfeit or unapproved drugs
  2. Illegal diversion of pharmaceuticals and other regulated products
  3. Prescription Drug Marketing Act violations
  4. Off-Label promotion of FDA approved drugs and medical devices
  5. Health fraud – schemes involving fraudulent treatments/cures/devices
  6. New drug application fraud
  7. Clinical investigator fraud
  8. Product substitution crimes
  9. Product tampering
  10. Crimes affecting the safety/integrity of the nation’s blood supply
  11. Crimes involving the adulteration and/or misbranding of food
  12. Internet facilitated criminal violations involving FDA regulated products
  13. Illegal importation of FDA regulated products
  14. Crimes involving the manufacture, sale or distribution of unapproved FDA regulated products
In addition, among the  labyrinth of sections in the FDA, there’s the The Office of Prescription Drug Promotion [OPDP]:
    "To protect the public health by ensuring that prescription drug information is truthful, balanced, and accurately communicated.  This is accomplished through a comprehensive surveillance, enforcement, and education program, and by fostering better communication of labeling and promotional information to both healthcare professionals and consumers."

my first PDR - 1963The FDA oversees one of the most heavily regulated areas in our government. One would’ve thought that, as a physician, I would’ve known a lot about it – but I didn’t. From early on, I always thumbed my way through the Physician’s Desk Reference whenever I ran across a new drug or had any questions about drugs, not really noticing that it is simply a commercial compilation of the FDA approved package inserts from all the approved drugs in our pharmacopeia. I never thought about where it came from [maybe Mount Sinai?]. I didn’t see it as a book to help me know how or when to use drugs, but rather the key reference book to help me be sure I was using medications responsibly – indispensable!


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

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

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

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

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

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

WHO Trial Registration Data Set [v 1.2.1]
1. Primary Registry and Trial Identifying Number     
2. Date of Registration in Primary Registry
3. Secondary Identifying Numbers
4. Source[s] of Monetary or Material Support
5. Primary Sponsor
6. Secondary Sponsor[s]
7. Contact for Public Queries
8. Contact for Scientific Queries
9. Public Title
10. Scientific Title
11. Countries of Recruitment
12. Health Condition[s] or Problem[s] Studied
13. Intervention[s]
14. Key Inclusion and Exclusion Criteria
15. Study Type
16. Date of First Enrollment
17. Target Sample Size
18. Recruitment Status
19. Primary Outcome[s]
20. Key Secondary Outcomes

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

Journals Following the ICMJE Recommendations
LISTED
JAMA Psychiatry
J. of the American Academy of Child and Adolescent Psychiatry  
British Medical Journal
Biological Psychiatry
American Journal of Psychiatry
Journal of Clinical Psychiatry
New England Journal of Medicine
Lancet
NOT LISTED
Schizophrenia Bulletin
British Journal of Psychiatry
Psychological Medicine
Journal of Psychiatric Research
Addiction
Neuropsychopharmacology



This post began as an introduction to the articles on Data Sharing in the New England Journal of Medicine this last week, but I found myself chasing down a lot of unfamiliar details and information, so it took on a life of it’s own. I reckon those articles can wait. After all, journal articles are forever…
Mickey @ 9:04 PM

that little thing at the top…

Posted on Monday 8 August 2016

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

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

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

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

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

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

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

a time for change…

Posted on Tuesday 2 August 2016

blog to follow soon

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

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

Dear Dr. Oquendo,

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

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

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

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

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

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

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

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

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

Yours sincerely

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

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

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

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

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

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

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

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

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

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

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

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

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