1 Boring Old Man

Speaking as a Physician

PsychiatricNews

by Paul Summergrad, M.D.

June 27, 2014

I recently covered on our inpatient psychiatry service at Tufts Medical Center. It is always valuable to see patients at the bedside and to spend time with wonderful psychiatric residents. As usual, the level of both medical psychiatric comorbidity and clinical complexity was challenging, as were the efforts to find the right clinical care and navigate a mental health system that is often fragmented and difficult at best. It was nevertheless greatly rewarding to see patients, to learn something about their life stories, and try to select care that was based on the best available science, and, when none was available, upon clinical experience and judgment…

By this I meant that we must always remember, first and foremost, that we are physicians. It is thus incumbent upon us to be aware of the best scientific evidence available when we make clinical decisions, doing so in the context of the total needs — medical and otherwise — of our patients. It means to speak on their behalf even when it may bring us into conflict with others whose primary focus may be financial, legal, or ideological. It requires us to be deeply knowledgeable not only about the scientific literature and best practices, but also to have more than a passing familiarity with the limitations of that literature and to be prepared to speak when we must despite those limitations. And to do so on our patients’ behalf, not our own…

Even more importantly, we must always be mindful that as physicians we have a special responsibility to speak from our rich clinical experience, and most importantly, from the best science available, wherever that may take us and regardless of opposition. These values and clinical and scientific expertise must be the primary touchstones of our policies and public statements about psychiatry. People may not always like what we have to say, and they may often disagree with it. But if we speak as physicians from our best understanding of what the science of our field is, and our honest view of the best interests of our patients, then they do listen. Ultimately, they will often trust, respect, and rely on our opinion…

1. a madness to our method…
2. are you listening?…
3. another campaign?…
4. read me him…
5. a madness to our method – a new introduction…

Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study

by Christine Y Lu, Fang Zhang , Matthew D Lakoma analyst, Jeanne M Madden, Donna Rusinak, Robert B Penfold, Gregory Simon, Brian K Ahmedani, Gregory Clarke, Enid M Hunkeler, Beth Waitzfelder, Ashli Owen-Smith, Marsha A Raebel, Rebecca Rossom, Karen J Coleman, Laurel A Copeland, Stephen B Soumerai

British Medical Journal. 2014 348:g3596.

[full text online]

[extra material]

Objective To investigate if the widely publicized warnings in 2003 from the US Food and Drug Administration about a possible increased risk of suicidality with antidepressant use in young people were associated with changes in antidepressant use, suicide attempts, and completed suicides among young people.

Design Quasi-experimental study assessing changes in outcomes after the warnings, controlling for pre-existing trends.

Setting Automated healthcare claims data [2000-2010] derived from the virtual data warehouse of 11 health plans in the US Mental Health Research Network.

Participants Study cohorts included adolescents [around 1.1 million], young adults [around 1.4 million], and adults [around 5 million].

Main outcome measures Rates of antidepressant dispensings, psychotropic drug poisonings [a validated proxy for suicide attempts], and completed suicides.

Results Trends in antidepressant use and poisonings changed abruptly after the warnings. In the second year after the warnings, relative changes in antidepressant use were −31.0% [95% confidence interval −33.0% to −29.0%] among adolescents, −24.3% [−25.4% to −23.2%] among young adults, and −14.5% [−16.0% to −12.9%] among adults. These reflected absolute reductions of 696, 1216, and 1621 dispensings per 100 000 people among adolescents, young adults, and adults, respectively. Simultaneously, there were significant, relative increases in psychotropic drug poisonings in adolescents [21.7%, 95% confidence interval 4.9% to 38.5%] and young adults [33.7%, 26.9% to 40.4%] but not among adults [5.2%, −6.5% to 16.9%]. These reflected absolute increases of 2 and 4 poisonings per 100 000 people among adolescents and young adults, respectively [approximately 77 additional poisonings in our cohort of 2.5 million young people]. Completed suicides did not change for any age group.

Conclusions Safety warnings about antidepressants and widespread media coverage decreased antidepressant use, and there were simultaneous increases in suicide attempts among young people. It is essential to monitor and reduce possible unintended consequences of FDA warnings and media reporting.

Study cohorts and outcome measures

…Because previous studies showed that rates of depression diagnosis changed after the warnings and that outpatient claims are often incomplete for mental health conditions such as depression, to avoid introducing selection bias, we did not limit our cohorts to those with a coded diagnosis of depression.

…To examine changes in suicide attempts after the warnings, we used the same denominator population as defined previously. While encounters for suicide attempts can be identified in administrative databases using external cause of injury codes [E-codes], they are known to be incompletely captured in commercial plan databases. Our preliminary analysis found that E-code completeness varied across study sites, treatment settings, and years. Therefore, instead of deliberate self harm E-codes, we used poisoning by psychotropic agents [international classification of diseases, ninth revision, clinical modification [ICD-9] code 969], a more reliable proxy for population level suicide attempts. Poisoning by drugs or toxic substances is the most common method of suicide attempt leading to hospital admission and emergency room treatments. 35 36 Non-fatal poisoning by psychotropic drugs [predominantly tranquilizers] has a positive predictive value of 79.7% for suicide attempts [sensitivity was 38.3% and specificity was 99.3%], outperforming other types of injuries or poisonings..

… it is disturbing that after the health advisories, warnings, and media reports about the relation between antidepressant use and suicidality in young people, we found substantial reductions in antidepressant treatment and simultaneous, small but meaningful increases in suicide attempts. It is essential to monitor and reduce possible unintended effects of FDA warnings and media reporting.

The 1991 FDA hearing about SSRIs and suicidality was principally focused on Prozac and pitted case reports against the Clinical Trial data. My recollection is that the general thought was that this was seen as a campaign initiated by the Scientologists and it didn’t have a major impact at the time. But the second time around over a decade later was another matter. It was at what we might now call the apogee of the Age of Pharmacology [in that day still a rising star]. This time, the focus was on children and adolescents; there was a damning FDA meta-analysis; and many more cases. The Black Box Warning was born:

The war on the Black Box Warning began immediately, and has been unrelenting for the decade that followed – saying that the analyses showing increased suicidality were wrong or that the Black Box Warning and the publicity caused doctors and patients to withhold needed treatment leading suicide attempts to actually increase. If there is a single consistent point from all this flap, it was a consensus that the rate of prescribing antidepressants to children and adolescents has fallen as a result after the warning.

Identification of hospitalizations for intentional self-harm when E-codes are incompletely recorded

by Amanda R. Patrick, Matthew Miller, Catherine W. Barber, Philip S. Wang, Claire F. Canning and Sebastian Schneeweiss

Pharmacoepidemiology and Drug Safety. 2010 19:1263–1275.

Context: Suicidal behavior has gained attention as an adverse outcome of prescription drug use. Hospitalizations for intentional self-harm, including suicide, can be identified in administrative claims databases using external cause of injury codes [E-codes]. However, rates of E-code completeness in US government and commercial claims databases are low due to issues with hospital billing software.

Objective: To develop an algorithm to identify intentional self-harm hospitalizations using recorded injury and psychiatric diagnosis codes in the absence of E-code reporting.

Methods: We sampled hospitalizations with an injury diagnosis [ICD-9 800–995] from two databases with high rates of E-coding completeness: 1999–2001 British Columbia, Canada data and the 2004 US Nationwide Inpatient Sample. Our gold standard for intentional self-harm was a diagnosis of E950-E958. We constructed algorithms to identify these hospitalizations using information on type of injury and presence of specific psychiatric diagnoses.

Results: The algorithm that identified intentional self-harm hospitalizations with high sensitivity and specificity was a diagnosis of poisoning, toxic effects, open wound to elbow, wrist, or forearm, or asphyxiation; plus a diagnosis of depression, mania, personality disorder, psychotic disorder, or adjustment reaction. This had a sensitivity of 63%, specificity of 99% and positive predictive value [PPV] of 86% in the Canadian database. Values in the US data were 74, 98, and 73%. PPV was highest [80%] in patients under 25 and lowest those over 65 [44%].

Conclusions: The proposed algorithm may be useful for researchers attempting to study intentional self-harm in claims databases with incomplete E-code reporting, especially among younger populations.

Letter to the Editor

How complete are E-codes in commercial plan claims databases?

by Christine Y. Lu, Christine Stewart, Ameena T. Ahmed, Brian K. Ahmedani, Karen Coleman, Laurel A. Copeland. Enid M. Hunkeler, Matthew D. Lakoma, Jeanne M. Madden, Robert B. Penfold, Donna Rusinak, Fang Zhang, and Stephen B. Soumerai

Pharmacoepidemiology and Drug Safety. 2014 23[2]:218-220.

We advise caution in applying the claim-based algorithm developed by Callahan et alet al. method uses external cause of injury codes [E-codes] in combination with diagnosis codes for poisoning derived from the International Classification of Diseases, ninth revision, Clinical Modification [ICD-9-CM] coding scheme to identify hospitalizations for suicide attempts. In recent years, there has been considerable concern that suicidal behavior is a potential adverse outcome of prescription drug use such as antidepressant and anticonvulsant agents. Nonfatal, deliberate self-harms resulting in emergency department treatments and hospitalizations can be identified in administrative databases using E-codes. These codes are part of the ICD-9-CM and are used to provide information about the cause and intent of an injury or poisoning. E-coding is mandatory in about half of US states, and the completeness of E-codes in state hospital discharge databases typically exceeds 90%. As part of a study of effects of safety warnings on antidepressant use and suicidality in youth, we assessed the completeness of E-codes in commercial health plan databases.

METHODS: Our analysis included 10 geographically distinct healthcare organizations in the Mental Health Research Network [MHRN] within the Health Maintenance Organization Research Network [HMORN]. The health plans had a combined population of nine million enrollees in 2010. This analysis was part of a longitudinal study of effects of Food and Drug Administration warnings for antidepressants and suicidality in youth that was approved by the institutional review board of each participating organization…

We calculated the completeness of E-codes, defined as the proportion of encounters with an injury/poisoning ICD-9-CM code that had a valid E-code indicating the cause for the encounter. As in prior research, we identified hospitalizations and emergency department visits with a primary or secondary diagnosis of injury/poisoning. We focused on injuries that are likely methods of deliberate self-harm: open wound injuries, superficial injuries, and poisonings. Because E-code collection and reporting requirements vary temporally and by region, we assessed E-code completeness rates from 2000 to 2010 by MHRN site and care setting. A V-code [supplemental information about factors influencing health service use] was introduced in 2005 indicating suicidal ideation [ICD-9: V62.84]. In a sensitivity analysis, we calculated E-code completeness, while also including V62.84 that could be used in place of E-codes to identify a suicidal related encounter.

RESULTS: Figure 1 presents E-code completeness rates in emergency department and hospital settings over time. E-code completeness varied widely across study sites [e.g., ranging from 7% to 92% in the emergency department setting in 2010], across treatment settings [e.g., ranging from 7% to 56% at one study site in 2010], and across years [e.g., ranging from 36% in 2000 to 92% in 2010 at one study site]. Only two sites had consistent, reasonable levels of E-code recording over this period [ranging from 65% to 82%]. Our investigation indicates that the suicidal ideation code did not substitute or compensate for lack of E-codes with injury/poisoning diagnoses.

^{Proportion of injury and poisoning encounters that had a valid E-code in [A] emergency rooms and [B] hospitals by study site [2000–2010]}

COMMENT: In our analysis of VDW data from 10 MHRN sites between 2000 and 2010, we found that E-code completeness varied across study sites, across treatment settings, and across years of observation. There are several possible reasons for the low rates of and/or variability in E-code completeness observed: E-codes have no relevance for payments; not all diagnosis codes are transformed into the VDW from source data; and recording practice for E-codes may vary across sites, possibly because of state regulations, health plan policies, or the clinical software used. The incompleteness we observed in this study limits the usefulness of the available E-coded data. Other studies also found high missingness of E-codes in hospital and emergency department settings.

Despite the high positive predictive value of 85% reported by Callahan et al. there are two issues relating to the use of the algorithm: [i] the completeness of E-codes in the dataset and [ii] the dependence on valid E-coded data.

We agree with Callahan et al. that it is important to develop and use alternative diagnosis codes that can identify suicide attempts. In the absence of complete E-codes, Patrick et al. developed and tested algorithms for identifying hospitalizations for deliberate self-harm in a population aged 10 years and over. This study used the US National Inpatient Sample data and data from British Columbia; both data sources had E-code completeness rates above 85 %. The gold standard for deliberate self-harm was defined as hospitalizations with a diagnosis of E950-958. Patrick et al. found that an algorithm combining diagnoses for psychiatric disorders [including depression] and injury/poisoning can produce a positive predictive value as high as 87.8% for identifying hospitalizations for deliberate self-harm [with specificity of 99.4% and sensitivity of 57.3%].

In the context of our longitudinal study on the impact of Food and Drug Administration warnings on antidepressant use and subsequent suicidality in youth, using Patrick’s algorithm may introduce ascertainment bias because rates of depression diagnosis declined subsequent substantially after the warnings.

1. Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs.
   by Libby AM, Brent DA, Morrato EH, Orton HD, Allen R, Valuck RJ.
   American Journal of Psychiatry. 2007 164[6]:884-891.
   [full text online]
2. Persisting decline in depression treatment after FDA warnings.
   Libby AM, Orton HD, Valuck RJ.
   Archives of General Psychiatry. 2009 66[6]:633-639.
   [full text online]

A diagnosis of “poisoning by psychotropic agents” alone outperformed other injury/poisoning types; its positive predictive value was 79.7% with specificity of 99.3% and sensitivity of 38.3%.

While psychotropic drug poisoning underestimates rates of suicide attempts because of its low sensitivity, it can be useful for detecting suicide attempts in study settings that have low or inconsistent E-code rates over time. Such consistency is required for longitudinal analyses of trends in deliberate self-harms.

In summary, our analysis confirmed that E-codes were substantially incomplete in commercial insurance claims databases. We observed that E-code completeness varied widely across MHRN sites, across treatment settings, and over time. Completeness improved at some sites and deteriorated at other sites. Psychotropic drug poisonings may be useful for identifying deliberate self-harm requiring hospitalization in commercial plan databases when E-codes are missing…

I’m about to hit the road to visit an old friend on the other end of the South for a few days and will be out of pocket, but I didn’t want to take off without linking to this article about the BMJ study at hand [Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study].

Did the FDA antidepressants warnings increased suicidality?

PLoS Blogs

By Adrian Preda M.D.

June 21, 2014

A new study just published in the BMJ makes this very point [Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study]

The title makes two claims:

1. That the  2003 black box  US Food and Drug Administration warning about possible increased risk of suicidality with antidepressants lead to a change in antidepressant prescriptions.
2. Further, that there were changes in suicidal behavior following the said US FDAwarning.

While the title does not indicate the direction of the changes, the study conclusions carry little ambiguity:

Safety warnings about antidepressants and widespread media coverage decreased antidepressant use, and there were simultaneous increases in suicide attempts among young people.

This is obviously a big claim, with far reaching implications spreading from the level of primary care physicians who might consider changing their antidepressant prescription practices to the level of policy makers deciding on guidelines about antidepressants approvals and reimbursement. In this post we will discuss some of the study limitations that, for unclear reasons, seem to have been all but ignored by the over-excited welcome that study received in the mainstream media. Our goal here is to not discuss subtle academic limitations but rather obvious limitations which could have been picked even by a casual yet critical reader of the paper. We will then cursorily survey the media presentations of the paper and assess the quality of their review in terms of balance and fair criticism. Let’s start with some of the study most overt shortcomings:

1. The title is not entirely informative. The study reviews US data however the title seems to indicate world-wide findings.
2. The study uses a quasi-experimental design assessing changes in outcomes after the FDA  warnings, controlling for pre-existing trends. However the reliability of the controls is not entirely convincing.
3. Not much is known about the relationship (if any) between the individuals entered in the study because they were prescribed antidepressants and the individuals who took psychotropic overdoses.
4. The study uses psychotropic drug poising data as a proxy for suicide but is that a good proxi?
5. The study does not address the possibility that suicide has been on the raise for reasons having nothing to do with antidepressant prescriptions (such as the recent years economic crisis).

Big media enthusiastic welcomes

First the Washington Post (Dennis) reports:

As a result [of the FDA warnings] antidepressant prescriptions fell sharply for adolescents age 10 to 17 and for young adults age 18 to 29. At the same time, researchers found that the number of suicide attempts rose by more that 20 percent in adolescents and by more than a third in young adults.

Comment from a non-study affiliated expert? YES

How many limitations are discussed? NONE

According to NBC News (Raymond) :

New research finds the warning backfired, causing an increase in suicide attempts by teens and young adults. After the FDA advisories and final black box warning that was issued in October 2004 and the media coverage surrounding this issue, the use of antidepressants in young people dropped by up to 31 percent.

Comment from a non-study affiliated expert? NO

How many limitations are discussed? NONE

Reuters (Seaman) reports that:

Antidepressant use decreased by 31 percent among adolescents, about 24 percent among young adults and about 15 percent among adults after the warnings were issued. At the same time, there were increases in the number of adolescents and young adults receiving medical attention for overdosing on psychiatric medicines, which the authors say is an accurate way to measure suicide attempts. Those poisoning increased by about 22 percent among adolescents and about 34 percent among young adults after the warnings. That translates to two additional poisoning per 100,000 adolescents and four more poisoning per 1,000 young adults, the researchers write.

Comment from a non-study affiliated expert? YES

How many limitations are discussed? ONE (limitation #5)

According to USA TODAY (Painter):

Warnings that antidepressant medications might prompt suicidal thinking in some young people may have backfired, resulting in more suicide attempts, new research suggests.

Comment from a non-study affiliated expert? YES

How many limitations are discussed? NONE

Forbes (DiSalvo) reports:

Antidepressant use fell 31 percent among adolescents and 24 percent among young adults after the FDA warnings, according to the study. Suicide attempts increased by almost 22 percent among adolescents and 33 percent among young adults in the same time period. Suicide attempts tracked in the study were largely the result of drug overdoses.

Comment from a non-study affiliated expert? NO

How many limitations are discussed? NONE

NPR (Stein) also reports on the story:

Antidepressant use nationally fell 31 percent among adolescents and 24 percent among young adults, the researchers reported. Suicide attempts increased by almost 22 percent among adolescents and 33 percent among young adults.

Comment from a non-study affiliated expert? YES

How many limitations are discussed? ONE (limitation #5)

Finally, the Boston Globe (Freyer) concludes that

instead of declining as hoped, suicide attempts over the next six years showed a “small but meaningful” uptick among people ages 10 to 29, according to a study published Wednesday in the journal BMJ. That increase followed a substantial drop in the use of antidepressants.

Comment from a non-study affiliated expert? YES

How many limitations are discussed? NONE

Final conclusions

Somewhat paradoxically, a study that tongue-in-cheek points to the media’s uncritical coverage of medical news as a possible contributor to a public health issue receives an almost universal and equally uncritical acclaim from the same media that it rightfully criticizes. In a past analysis of medical news reporting I stated that

In closing: my hope is that members of the media who cover [medical] debate[s] will realize that “first do no harm” is not only the duty of physicians; it is also the responsibility of anyone trusted with giving health information to the public at large.

More than 2 years later I found that this conclusion still stands…

Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. [see peaks and valleys…, watchful waiting…]
  by Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Erkens JA, Herings RM, Mann JJ.
  American Journal of Psychiatry. 2007 Sep;164[9]:1356-63.

But I’m done with the science of this article and defer to people with more wisdom and talent on the methods of analysis. I want to talk about something else related – Big Data [see two points…]. It’s all the rage now and deserves our attention. Essentially, it comes from places like Google, Amazon, the NSA. It’s a way of thinking about the huge databases being amassed everywhere. The book is about how people are learning how to query and correlate these huge datasets without worrying so much about missing data and unequal sample sizes. We don’t think about it, but a lot of our science is based on looking at a small sample, then extrapolating to the general population – so we’re super precise and use our statistical tests and our rational brains. Big Data people don’t worry about that so much. They have huge data [like approximating all of it]. And they don’t care if the correlations don’t make sense [as in the most accurate index for following the spread of flu is an algorithm that queries Google searches]. It’s the fact that they correlate that matters. And this study [Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study] is Big Data. They have an impressive dataset:

Study cohorts included adolescents [around 1.1 million], young adults [around 1.4 million], and adults [around 5 million].

The Clinical Trial era has already confronted us and our patients with the problem of small differences in medication effect and reams of treatment guidelines that may or may not be meaningful. We’d best anticipate that studies like this one are just harbingers of what’s going to happen when these vast datasets gathered by electronic medical records, HMOs, prescriptions, pharmacies, scanners, screenings, etc multiply exponentially in the coming years. I expect some good things will emerge, but the possibilities for confusion, error, and deceit will likely grow in parallel. In psychiatry, we already have studies ongoing like iSpot and EMBARC that hope to pick your antidepressant based on some collection of other measurable parameters [don’t hold your breath]. Add to that the dream of adjusting your medication dose based on your weekly iPhone CAT-D App via a brief chat on the cloud with your tele-psychiatrist. Maybe your Google searches can get in the mix as well [I wish I were exaggerating].

Warnings Against Antidepressants For Teens May Have Backfired

New England Public Radio

by Rob Stein

June 18, 2014

… “I think there were a lot of mistakes made in terms of how this risk was communicated to the public, which led a lot of parents to be terrified to have their children on these medications — and they took them off and there was a lot of untreated, serious depression,” says Robert Gibbons, a University of Chicago biostatistician who advised the FDA on the issue…

• Reuters
• Forbes
• USA TODAY
• Washington Post
• CBS News
• Daily Mail
• BBC News
• Toronto Star
• Boston Globe
• FiercePharma

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf [available on request from the corresponding author] and declare that all authors have support from the National Institute of Mental Health for the submitted work… Other authors [including Christine Lu] declared no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.

• The relationship between antidepressant medication use and rate of suicide.
  by Gibbons RD, Hur K, Bhaumik DK, Mann JJ.
  Arch Gen Psychiatry. 2005 Feb;62(2):165-72.
• The relationship between antidepressant prescription rates and rate of early adolescent suicide.
  by Gibbons RD, Hur K, Bhaumik DK, Mann JJ.
  Am J Psychiatry. 2006 Nov;163(11):1898-904.
• Association of suicide and antidepressant prescription rates in Japan, 1999-2003.
  by Nakagawa A, Grunebaum MF, Ellis SP, Oquendo MA, Kashima H, Gibbons RD, Mann JJ.
  J Clin Psychiatry. 2007 Jun;68(6):908-16.
• Relationship between antidepressants and suicide attempts: an analysis of the Veterans Health Administration data sets.
  by Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Mann JJ.
  Am J Psychiatry. 2007 Jul;164(7):1044-9.
• Impact of Publicity Concerning Pediatric Suicidality Data on Physician Practice Patterns in the United States
  by Charles B. Nemeroff, Amir Kalali, Martin B. Keller, Dennis S. Charney, Susan E. Lenderts, Elisa F. Cascade, Hugo Stephenson, and Alan F. Schatzberg
  Archives of General Psychiatry. 2007 64(4):466-472.
• Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents.
  by Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Erkens JA, Herings RM, Mann JJ.
  Am J Psychiatry. 2007 Sep;164(9):1356-63.
• The role of randomized trials in testing interventions for the prevention of youth suicide.
  by Brown CH, Wyman PA, Brinales JM, Gibbons RD.
  Int Rev Psychiatry. 2007 Dec;19(6):617-31.
• Mixed-effects Poisson regression analysis of adverse event reports: the relationship between antidepressants and suicide.
  by Gibbons RD, Segawa E, Karabatsos G, Amatya AK, Bhaumik DK, Brown CH, Kapur K, Marcus SM, Hur K, Mann JJ.
  Stat Med. 2008 May 20;27(11):1814-33.
• News coverage of FDA warnings on pediatric antidepressant use and suicidality
  by Barry CL and Busch SH.
  Pediatrics. 2010 125[1]:88-95.
• Strategies for quantifying the relationship between medications and suicidal behaviour: what has been learned?
  by Gibbons RD, Mann JJ.
  Drug Saf. 2011 May 1;34(5):375-95.
• Suicidal Thoughts and Behavior With Antidepressant Treatment: Reanalysis of the Randomized Placebo-Controlled Studies of Fluoxetine and Venlafaxine
  by Robert D. Gibbons, PhD; C. Hendricks Brown, PhD; Kwan Hur, PhD; John M. Davis, MD; J. John Mann, MD
  Arch Gen Psychiatry. 2012;69(6):580-587.

Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study

by Christine Y Lu, Fang Zhang, Matthew D Lakoma, Jeanne M Madden, Donna Rusinak, Robert B Penfold, Gregory Simon, Brian K Ahmedani, Gregory Clarke, Enid M Hunkeler, Beth Waitzfelder, Ashli Owen-Smith, Marsha A Raebel, Rebecca Rossom, Karen J Coleman, Laurel A Copeland, and Stephen B Soumerai

British Medical Journal. 2014 348:g3596.

[full text on-line]

Objective To investigate if the widely publicized warnings in 2003 from the US Food and Drug Administration about a possible increased risk of suicidality with antidepressant use in young people were associated with changes in antidepressant use, suicide attempts, and completed suicides among young people.

Design Quasi-experimental study assessing changes in outcomes after the warnings, controlling for pre-existing trends.

Setting Automated healthcare claims data [2000-10] derived from the virtual data warehouse of 11 health plans in the US Mental Health Research Network.

Participants Study cohorts included adolescents [around 1.1 million], young adults [around 1.4 million], and adults [around 5 million].

Main outcome measures Rates of antidepressant dispensings, psychotropic drug poisonings [a validated proxy for suicide attempts], and completed suicides.

Results Trends in antidepressant use and poisonings changed abruptly after the warnings. In the second year after the warnings, relative changes in antidepressant use were −31.0% [95% confidence interval −33.0% to −29.0%] among adolescents, −24.3% [−25.4% to −23.2%] among young adults, and −14.5% [−16.0% to −12.9%] among adults. These reflected absolute reductions of 696, 1216, and 1621 dispensings per 100 000 people among adolescents, young adults, and adults, respectively. Simultaneously, there were significant, relative increases in psychotropic drug poisonings in adolescents [21.7%, 95% confidence interval 4.9% to 38.5%] and young adults [33.7%, 26.9% to 40.4%] but not among adults [5.2%, −6.5% to 16.9%]. These reflected absolute increases of 2 and 4 poisonings per 100 000 people among adolescents and young adults, respectively [approximately 77 additional poisonings in our cohort of 2.5 million young people]. Completed suicides did not change for any age group.

Conclusions Safety warnings about antidepressants and widespread media coverage decreased antidepressant use, and there were simultaneous increases in suicide attempts among young people. It is essential to monitor and reduce possible unintended consequences of FDA warnings and media reporting.

 

Merck Seeks Sanctions Against Expert Witness for Talking to a Journalist

Pharmalot

By Ed Silverman

Jun 16, 2014

A federal judge may sanction a physician who served as an expert witness in the ongoing litigation over the Vioxx painkiller for describing confidential documents to The Wall Street Journal. Earlier this month, U.S. District Court Judge Eldon Fallon issued a restraining order saying David Egilman, who is a Brown University clinical professor of family medicine, “may have acted in derogation of his responsibilities.” Egilman was an expert witness with access to documents in litigation over the Merck pill that took place in various courts around the country. Vioxx was withdrawn a decade ago over links to heart attacks and strokes. Fallon, who presides over Vioxx litigation that was consolidated in federal court in New Orleans, had issued an order in 2005 that marked swaths of documents as confidential. Much of the documentation was filed as evidence in litigation in both state and federal courts.

Three months ago, though, a Kentucky state judge permitted Egilman to challenge the confidentiality of the documents, since he had standing as an expert witness which gave him previous access to the materials. As we noted at the time, the judge wrote that “important public policy questions regarding consumer protection and public health have been raised. The public has an interest in evaluating Dr. Egilman’s opinions and the documents on which they were based.” Egilman was a paid expert witness for plaintiffs in a lawsuit that had been filed by the Kentucky Attorney General, who alleged Merck violated consumer protection laws by failing to disclose to doctors and patients that taking Vioxx significantly raised the risk of a heart attack. The lawsuit was settled last November for $23 million, although the drug maker did not admit to any wrongdoing.

Egilman maintains that some documents demonstrated a failure to properly inform research subjects of side effects and risks, and thus he believes the information should be publicly available. “In general, there’s information on the toxicity of the drug that’s not been previously published by Merck and there is information that Merck published that misrepresents the health effects of the drug,” he told us three months ago, which prompted the drug maker to complain to the federal judge. At the time, he added that, in his role as an expert witness, he reviewed raw study data, company emails and internal analyses that “provide new information on the health hazards of the drug and evidence of fraud in the conduct of the studies. I’ve been able to see documents few others have”…

At Merck’s Urging, a Federal Judge Threatens to Sanction a Lone Professor for Trying to Reveal Evidence about Vioxx

Healthcare Renewal

by Roy Poses

June 17, 2014

We have written often, and most recently this week, about the limp posture taken by US law enforcement and regulatory agencies in the face of misbehavior by large health care organizations.  At best, official action often results in legal settlements which let companies pay fines, sometimes large, while the individuals who profited most from the alleged wrongdoing do not suffer any negative consequences.  Worse, the legal settlements often allow the companies to continue to deny any culpability, and the legal evidence underlying the settlement, which might let the public at least estimate culpability, is often kept sealed, or confidential.  As Judge Rakoff wrote in turning down such a settlement involving a financial, not health care company, sealing evidence hides "any proven or admitted facts upon which to exercise even a modest degree of independent judgment,"  and prevents courts and presumably anyone else from trying to determine whether the government endorsement of such a settlement serves any public purpose [look here]…

We have long talked about what we have called the anechoic effect, how inconvenient truths that might reflect badly on the current health care status quo and especially those insiders who are making so much money from it are treated as recent unpleasantness that one just should not talk about. The anechoic effect does not arise merely from politeness, or desire not to discomfit the powerful, but from active measures the powerful take to keep dissent down. Here we have an example of a huge drug company, apparently helped by US law enforcement and US courts trying to keep truths about how it marketed a drug out of the public eye, even after so much information suggesting that its marketing was deceptive and unethical, and lead to patients dying has come out.

As we have said endlessly, until health care professionals, policy makers, and the public can obtain and openly discuss information about health care dysfunction, even if that information and its discussion may threaten those who lead health care and make so much money doing so, health care dysfunction will continue. True health care reform would improve transparency and put an end to the anechoic effect.

Lots of reasons. A lot of these are whistle blower suits and the whistle blowers want their money [there’s no appeal to a settlement]. The same holds for the lawyers who take such cases on contingency. Whether it’s civil or criminal, settling avoids the lengthy appeal process and gets the case off the books. They all go out and celebrate, ignoring the fact that they’ve played into the hands of the companies.

Tarasoff v. Regents of the University of California, 17 Cal. 3d 425, 551 P.2d 334, 131 Cal. Rptr. 14 [Cal. 1976], was a case in which the Supreme Court of California held that mental health professionals have a duty to protect individuals who are being threatened with bodily harm by a patient. The original 1974 decision mandated warning the threatened individual, but a 1976 rehearing of the case by the California Supreme Court called for a "duty to protect" the intended victim. The professional may discharge the duty in several ways, including notifying police, warning the intended victim, and/or taking other reasonable steps to protect the threatened individual.

Regulating prescription drugs for patient safety: Does Bill C-17 go far enough?
[see a missing link… ]
International treaties simply require Canada to protect trade secrets and confidential business information without specifying the scope of those types of information. No Canadian court decision indicates that information about the safety or efficacy of a drug is proprietary, and current case law casts doubt on any such assertion. In principle. Health Canada can at present disclose greater amounts of safety and efficacy information. However, to clarify and to overcome manufacturers efforts to resist disclosure. Bill C-17 should explicitly state that the results of clinical trials, including de-identified patient-level data, postmarket studies, and adverse drug reactions reported by drug manufacturers and health care institutions, are not proprietary and therefore should be publicly disclosed…

TRIPS: AGREEMENT ON TRADE-RELATED ASPECTS OF INTELLECTUAL PROPERTY RIGHTS

PART II — Standards concerning the availability, scope and use of Intellectual Property Rights

SECTION 7: PROTECTION OF UNDISCLOSED INFORMATION

Article 39

3. Members, when requiring, as a condition of approving the marketing of pharmaceutical or of agricultural chemical products which utilize new chemical entities, the submission of undisclosed test or other data, the origination of which involves a considerable effort, shall protect such data against unfair commercial use. In addition, Members shall protect such data against disclosure, except where necessary to protect the public, or unless steps are taken to ensure that the data are protected against unfair commercial use.

"… we have to recognize that the pharmaceutical industry has an irreducible conflict of interest in relation to the way it represents its drugs, in science and in marketing. And unless we can resolve this in a way that is more in the public interest and in patients’ interest, I would argue that drug companies should not be allowed to evaluate their own products."

In the last post [doing the right thing…], I was praising Canadian Bill C-17 to amend their Food and Drug Act to give the government needed powers to deal with Clinical Trial reporting and drug approval, but I was worried that I couldn’t find the details [that place where the devil lives]. I was helpfully pointed to some articles in the Toronto Star [Mar 10, 2014 Canadian Medical Association Journal says proposed drug recall bill has too many loopholes, May 30, 2014 Federal drug reform law approved for further review]. They, in turn, lead to an article in the Canadian Medical Association Journal published online in March and in print in May called Regulating prescription drugs for patient safety: Does Bill C-17 go far enough? [It is neither abstracted nor available on-line past page 1, so we’re going to have to go with my pulling out key quotes].

• Power to recall drugs: "Bill C-17 empowers the Health Minister to issue a recall, without first entertaining representations from the manufacturer, provided he or she ‘believes that a therapeutic product presents a serious or imminent risk of injury to health.’"
• Power to overcome information asymmetries: Bill C-17 enables Ihe Health Minister to compel manufacturers to provide information about drugs. eg information "about a serious adverse drug reaction that involves a therapeutic product or a medical device incident." "These information-sharing requirements are a major improvement on the status quo."
• Power to enforce conditions on market authorizations and compel changes to product labels: "In 2007, Ihe US Food and Drug Administration (FDA) was granted powers to enforce conditions and to compel changes to a product’s label in light of safety concerns that emerge after market approval. It is imperative that Health Canada be vested with these powers."
• Serious enforcement measures: "Finally, Bill C-17 creates much stronger penal- ties for failure to comply with some of the provi- sions of the Food and Drugs Act and accompa- nying regulations.These include lines of up to $5 million per day during which the offence is committed, and/or imprisonment for the most egregious oflences. "

• Enhance the power of recall and alter the ability to suspend:
• Exempt the Health Minister from liability for drug suspensions and recalls:
• Ensure transparency in clinical trials: "… requiring registration by law, and creating a robust mechanism to enforce that requirement, is an important step toward improving the transparency of the evidence base behind drugs and other therapies, and avoiding potential harm to patients." In addition, making sure that clinical trial data, whether collected before market approval or in postmarket studies, are available for scrutiny by independent researchers is critical to ensuring that treatment and use decisions are evidence-based."
• Enhance transparency in Health Canada’s decision-making: "Bill C-17 should empower Health Canada to publish both positive and negative regulatory decisions. At minimum. Health Canada should publish the rationales lor decisions concerning all drugs approved for sale, drugs refused for reasons of safety or efficacy, and drugs that are suspended or recalled."
• Outline clear limits to the scope of proprietary information: "Meaningful transparency is hard to achieve in practice, in part because manufacturers often claim that the government is obliged to protect information about the safety and efficacy of a drug as "proprietary," either as a "trade secret" or as "confidential business information."" These assertions overstate what the law actually requires and prevent important information about safety and effectiveness from being released." International treaties simply require Canada to protect trade secrets and confidential business information without specifying the scope of those types of information. No Canadian court decision indicates that information about the safety or efficacy of a drug is proprietary, and current case law casts doubt on any such assertion. In principle. Health Canada can at present disclose greater amounts of safety and efficacy information. However, to clarify and to overcome manufacturers’ efforts to resist disclosure, Bill C-17 should explicitly state that the results of clinical trials, including de-identilied patient-level data, poslmarket studies, and adverse drug reactions reported by drug manufacturers and health care institutions, are not proprietary and therefore should be publicly disclosed."
• Do not allow trade to trump patient safety: "Bill C-17 gives the Governor in Council scope to impose stringent rules favouring data protection to the detriment of other powers in the Food and Drugs Act This proposal is fundamentally problematic and must not be enacted."

The amendments to Bill C-17 were introduced by Member of Parliament, Terrence Young and adopted by the House of Commons Standing Committee on Health on June 12. The Bill has now passed Third Reading in the House of Commons and moves to the Senate for consideration. The amendments include the requirement that both positive and negative decisions about drug authorizations be disclosed on a public website; and that clinical trial information be disclosed on a public registry. The amendments also better define the scope of confidential business information [CBI] and allow the Minister to disclose CBI about a product if the Minister believes the product may pose a serious risk to Canadians.