Posted on Monday 22 August 2016
Population Of US Practicing Psychiatrists Declined, 2003–13, Which May Help Explain Poor Access To Mental Health Careby Tara F. Bishop, Joanna K. Seirup, Harold Alan Pincus, andJoseph S. RosHealth Affairs. 2016 35:1271-1277.
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.
MEDPAGETODAYby Neel A. Duggal07·17·2016
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.
Back 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.
Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Studyby 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 NuetenBiological 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
Esketamine Receives Breakthrough Therapy Designation from U.S. Food and Drug Administration for Major Depressive Disorder with Imminent Risk for SuicideJohnson and Johnson: Press ReleaseAugust 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…[see also Party drug ketamine closer to approval for depression – CNN]
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."
|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|
Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trialsby Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D; and the Sertraline Pediatric Depression Study GroupJournal of the American Medical Association. 2003, 290:1033-41.
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.
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].
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
VancouverCommittee 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.
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 …
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.
The citalopram CIT-MD-18 pediatric depression trial: Deconstruction of medical ghostwriting, data mischaracterisation and academic malfeasanceby Jureidini, Jon N., Amsterdam, Jay, D, and McHenry, Leemon B.International Journal of Risk & Safety in Medicine, 2016 28:33-43.
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.
RE: Am J Psychiatry 2004; 161:1079–1083 We are not retracting this article. Robert Freedman MD
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…].
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.
Medical Researchers Want Up To Five Years Exclusivity For Clinical Trial Data Derived From Volunteerstechdirtby Glyn MoodyAugust 8, 2016
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!
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].|
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]:
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|
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.
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:  legal requirements and  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|
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.
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 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.
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
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|
J. of the American Academy of Child and Adolescent Psychiatry
British Medical Journal
American Journal of Psychiatry
Journal of Clinical Psychiatry
New England Journal of Medicine
British Journal of Psychiatry
Journal of Psychiatric Research