revoke their patent…

Posted on Monday 20 October 2014

Pharmalot: WSJ
By Ed Silverman
October 20, 2013

Responding to the ongoing controversy over the prices for new hepatitis C treatments, U.S. Sen. Bernard Sanders [I-Vt.] will probably hold a hearing – possibly before the year ends – to examine how the cost is affecting the U.S. Department of Veterans Affairs, according to his spokesman. Sanders is chairman of the Senate Committee on Veterans’ Affairs.

His interest in a hearing comes as the expense of these medicines helps fuel a national debate over the rising cost of prescription drugs. New hepatitis C treatments, in particular, have caused a ruckus, because they promise cure rates exceeding 90%, which is prompting a sudden surge in prescribing – and subsequent concerns over the effect on insurance budgets. For the past several months, pharmacy benefit managers and state Medicaid programs have complained that the cost of Sovaldi, a treatment sold by Gilead Sciences, may become unsustainable. Sovaldi costs $1,000 a pill, or $84,000, for a 12- week regimen. Gilead maintains the treatment is a cheaper alternative to older forms of care that may be less successful and involve costly hospitalization.

Federal programs may feel the pinch, as well. A recent forecast from the Veterans Department indicated that Sovaldi will cost the department about $1.3 billion over the next two years. And that’s after a discount the VA receives that brings the cost per pill down to about $543, according to department documents provided earlier this year to the U.S. Senate Committee on Veterans’ Affairs. A Veterans Affairs spokeswoman writes us that the department added Sovaldi to its national formulary, or list of drugs for which coverage is provided, last March. As of October 1, more than 5,300 veterans have received treatment with Sovaldi, she writes, adding that about 225 patients are started on the treatment each week.

And so, Sanders “is interested [in holding a hearing,] among other reasons, because of the impact on the VA,” his spokesman tells us. The timing for a hearing, however, remains uncertain. The spokesman says a hearing may occur following the upcoming midterm elections on Nov. 4, “but it’s really up in the air.” This is not the first time Congress has responded to concerns over the cost of hepatitis C medicines. Last July, two members of the U.S. Senate Finance Committee asked Gilead to provide financial information about the $11 billion deal in which it acquired the treatment, R&D costs and subsequent pricing forecasts. A committee spokesman tells us the probe remains under way, but could not offer an update.

We asked Gilead, which has more recently received FDA approval to sell a newer, fixed-dose combination treatment called Harvoni that includes Sovaldi and another compound, for comment and will update you accordingly. [UPDATE: A A Gilead spokeswoman later sent us this note: "We are not aware of a hearing but we are cooperating with the Committee and responding to their questions."] This is the second time in recent weeks that Sanders has indicated concerns about prescription drug costs. Earlier this month, he was one of two members of Congress who launched an investigation into generic drugs and asked 14 drug makers to provide data on what was called the “escalating prices they have been charging” for some medicines.
This is off the beaten path for me, but I guess some things are so absurd that they pull us in from far and wide. Gilead’s pricing of their Sovaldi at $1000/pill for a course of treatment recommended to go for three months at one pill a day is too outrageous to even contemplate. I would suggest that the FDA take it off the market and that their patent be revoked. Gilead is holding people with a potentially fatal disease hostage, using our patent laws to support a prohibitive monopoly. This one should be heard by the Supreme Court – conduct unbecoming a company in the health care industry…
Mickey @ 9:48 PM
Filed under: OPINION
commonsense…

Posted on Monday 20 October 2014

Some things are just so sensible that they need no comment. Here’s one now:
Mental health civil wars leave patients in desperate lurch
Psychology Today: Saving Normal
by Allen J. Frances, M.D.
October 20, 2014
Mickey @ 3:43 PM
Filed under: OPINION
rather than micromanage…

Posted on Monday 20 October 2014

APA has a role in shaping what future psychiatric practice looks like,” Schatzberg stated. “More needs to be done now if we are to have new treatments in the next decade for patients with psychiatric disorders.
Alan Schatzberg in APF Convenes Unique Pipeline Summit, April 2012
PsychiatricNews
October 17, 2014

As development of drugs to treat psychiatric disorders lags behind that of drugs for other illnesses, a recent study published in Psychiatric Services in Advance sheds light on why the pipeline for psychotropic medicines is nearly empty.

Researchers from Brandeis University and Truven Health Analytics led an investigation of the current state of psychotropic drugs in the pipeline and potential barriers that may keep these drugs from reaching distribution in the United States… The analysis showed that the pipeline for psychotropic drug development — 99 clinical trials were included — is limited, with little product innovation evident. Most of the examined drugs were a combination of existing of U.S. Food and Drug Administration-approved medicines or individually approved medicines that were being tested for new indications or delivery-system approaches [such as an injectable version that is similar to an approved oral form]. Only three drugs differed substantially from existing drugs…

In an interview with Psychiatric News, Alan Schatzberg, M.D., a professor of psychiatry at Stanford University and former APA president, said that the departure by pharmaceutical companies to develop innovative psychotropic medicines could result in serious problems for the field of psychiatry, especially for patients. “There is a number of initiatives by various organizations to help with this problem, including the European College of Neuropsychopharmacology, which is working with companies to provide investigators with compounds that have been shelved, and NIMH’s Research Domain Criteria [RDoC], which promotes research on specific [and new] biological targets," he said. Schatzberg emphasized that it will take a concerted effort on the parts of governmental agencies, industry, as well as APA to advocate for investment and innovative psychiatric drug development. “Silence will not be helpful to our patients,” he concluded…
Since it became apparent in the summer of 2011 that the pharmaceutical industry was abandoning CNS drug development, there has been a frantic level of activity in the halls of psychiatry. For the previous two decades, organized and academic psychiatry had occupied itself with brain research and testing, commenting on, [and promoting] the CNS drugs that flowed from the industrial pipeline. After a period of panic and attempts to re-engage PHARMA, two threads emerged: changing the role of psychiatrists [the sequel I…] coming from the APA leadership; and relocating CNS drug development and research to various public institutions, shepherded by NIMH Director, Tom Insel. Over the last several years, in a series of blog posts Dr. Insel has described a number of strategies including the NIMH RDoC [Research Domain Criteria] and many others now under a Translational Science umbrella in the NIH. If you check out the links, most will be familiar to anyone who periodically checks in with Dr. Insel’s blog:
Translational Science started its life as a concept meant to focus research on current medical needs and speed the research findings from the "bench to the bedside." The problem that there were scant findings to translate didn’t seem to matter, and the term appears to have morphed into meaning "anything that people think is a good idea" – a politically correct tag like "evidence-based medicine." Among the NCATS strategies, one stands out as a new addition – the IDG Project, AKA, Illuminating the Druggable Genome [an tongue-twister for the ages]:
Med Check
PsychiatricNews
by Vabren Watts
October 17, 2014

According to the National Institutes of Health [NIH], as many as 3,000 genes express proteins whose molecular actions could be altered by medicines, yet only 10 percent of these “druggable genes” are targeted by drugs that have been approved by the Food and Drug Administration [FDA].

The NIH recently announced the launch of Illuminating the Druggable Genome [IDG], a three-year pilot project to explore poorly understood genes that have the potential to be modified by medicines. The IDG will target understudied genes of four important protein families that may be affected by medications — nuclear receptors, ion channels, protein kinases, and G-protein coupled receptors.

“We have a gap in the drug-development pipeline between what gene activities we know could be modified by medication and what currently is targeted,” said James Anderson, M.D., Ph.D., director of the NIH Division of Program Coordination, Planning, and Strategic Initiatives. “By focusing on understudied genes, we hope to find potential targets for medications to treat or cure some of our most burdensome diseases — and then share what we learn so that all can build on this knowledge.”

Primary funding for pilot awards is coming from the NIH Common Fund, which supports high-impact pioneering research in all divisions of NIH. Institutions granted awards will thoroughly investigate potential gene targets and share what they learn on a public resource that will help the larger scientific community build on the findings through basic research and clinical translation.
… and from the NCATS:

Results from the Human Genome Project revealed that the human genome contains 20,000 to 25,000 genes. A gene contains [encodes] the information that each cell uses to make [express] a protein, which is essential for the body to function properly. Abnormal protein expression is associated with many human diseases, which makes proteins key targets for therapeutic agents…

Approximately 3,000 genes are considered part of the “druggable genome”, a set of genes encoding proteins that scientists can or predict they can modulate using experimental small molecule compounds. Yet, only about 10 percent of these genes encode proteins that have been targeted successfully by an approved drug. Therefore, a large number of proteins remain for scientists to explore as potential therapeutic targets. The vast majority of the druggable genome encodes four key protein families: G-protein-coupled receptors, nuclear receptors, ion channels and kinases…

By expanding the potential therapeutic space through the IDG program, NIH is clearing a path for more efficient disease-related research and more effective treatments for patients.
There’s an unexamined inertia of motion in this narrative. The system apparently requires an endless influx of new drugs, and widespread panic ensued when that flow was interrupted, evoking these radical efforts to restore it. In fact, the majority of that stream of CNS medications for the two decades after 1987 [Prozac] wasn’t really new – but rather a set of variations on themes from the 1950s windfall of psychotropic drugs, engineered to be better tolerated. We didn’t hear much about the old-ness of these drugs, at least not in the foreground, until the supply was exhausted. Then we heard of little else, and the gears started whirring overtime for new, novel, innovative strategies to find new targets for CNS drug development.

I did notice along the way that the last new better drug became the next old obsolete drug with some regularity. And with that came the illusion that the drugs were improving [I would now see it as more determined by patent life and advertising]. And in those salad days, psychiatry had developed a sizable commentator class – a group of academics who commented on the drugs, talked about what was coming next, wrote about the neurobiology of this or the psychobiology of that regularly. In my mind, I called it future-think, with the good stuff always lying just around the corner, but it never occurred to me that a house of cards might tumble if the march of the new ever came to an end. So now we’re illuminating the druggable genome, repurposing existing drugs, building neuro-chips for in vitro assays, and revising diagnoses to fit drug effects [RDoC] in an attempt to revitalize the previous flow of new treatments.

There was another quote in that article about the 2012 Pipeline Summit that has also stayed with me:

“There are huge unmet clinical needs in mental disorders and addiction. There should be tremendous interest in this area, but there is not.”
Jeffrey Lieberman in APF Convenes Unique Pipeline Summit, April 2012

I thought that was an incredibly naive comment. One could say that about a million things in medicine. The comment implies that "if you need it, it will come". Most scientific discovery doesn’t work that way. It’s closer to, "don’t push the river, it runs by itself." There are places where mounting a huge effort in science speeds up the process, but those are areas where there’s a clear direction, and the task is working out the practical details [Manhattan Project, NASA, Salk Vaccine, DARPA, etc]. Their quest for genuinely new psychopharmacology starts from near zero. And the pharmaceutical industry has a tremendous interest; has been at it for years; and just couldn’t find a thread to pull that lead them anywhere. So whether you agree that new symptomatic CNS drugs are a critical national priority or not, the likelihood of locating them [if they indeed exist] may not be enhanced by NCATS, the RDoC, or any other directed research under NIH/NIMH martial law. In fact, this forced march might squeeze out the guy who would notice something odd on a dirty petri dish [Alexander Fleming Discovers Penicillin].

There’s little to assure us that these efforts are not motivated by some desperate attempt to revitalize and perpetuate the KOL/PHARMA Camelot that has long past its prime – another grant-driven effort that will attract the same tired researchers who have haunted the grant-recipient rolls for several decades with little to show for the dollars spent. Frances Collins [Dr. Genome] and Tom Insel [Dr. Clinical Neuroscience] have their fingerprints all over these programs. Isn’t it about time for them to pass the reins to some new blood whose leadership styles are less controlling and who have a better eye for picking independent and creative scientists to follow and support [rather than direct and micromanage]?
Mickey @ 1:39 PM
Filed under: OPINION
get here however you can!…

Posted on Saturday 18 October 2014

"We look forward to welcoming you to sunny San Diego for AACAP’s 61st Annual Meeting!

Gabrielle Carlson, MD, AACAP’s Program Chair, welcomes you to San Diego from the USS Midway, the site of the Welcome Reception on Wednesday, October 22. All are invited to attend!"


In the spirited video from the deck of the USS Midway, Gabrielle Carlson sporting a sailor’s cap, welcomes us to the AACAP Annual Meeting, ending with the words, "Get here however you can!" You may not recognize her name right off. Here’s a reminder:

Is it fair to haunt Dr. Carlson with her being an author on the by-line of the infamous Paxil Study 329 report in the Journal of the American Academy of Child and Adolescent Psychiatry back in 2001? She is, after all, a valued academic at Stony Brook, decorated for her research contributions in psychopharmacology. She’s obviously right-thinking on some areas of the issue of over medicating children. In a recent Commentary, she decries the overmedication with Atypical Antipsychotics…
The Dramatic Rise in Neuroleptic Use In Children:
Why Do We Do It and What Does It Buy Us?
Theories from Inpatient Data 1988-2010
by Gabrielle A. Carlson, MD
JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY 2013 23[3]:144-147.

…It is ironic that the most noxious and impairing behavior, namely explosive outbursts in children, has no ‘‘home’’ in the DSM no- sology. Recognizing that explosions can occur in many conditions, neither intermittent explosive disorder nor, if it is accepted into DSM-V, DMDD, allows the diagnosis if the explosions are ‘‘better explained by’’ another condition. There is not even a consistent way in which one can find information about rage outbursts. In PubMed, there are almost completely different databases for terms like rages, rage outbursts, anger outbursts, rage attacks, explosive outbursts, and meltdowns. Irritability, the term that seems increasingly to be adopted, like aggression, may sub- sume these behaviors, but is not synonymous. Therefore, we speculate that the behavior that most drives the most use of AAPs does not even have a label that can be consistently used, and will certainly, without a "home," never be an indication for FDA approval….

In conclusion, the meteoric rise in the use of AAPs in children with ADHD and ODD reflects the fact that the traditional evidence-based treatments (stimulants and parent training/behavior modification) are either unsupported by providers and insurance (at least in terms of the intensity they require) or that these treatments are insufficient, because of the severity of the conditions being treated.

AAPs may be expensive, and clearly have important adverse effects. The question is whether society (and insurance companies) want to support the alternatives. If they do not, I feel that the rhetoric is disingenuous. I, for one, would be grateful if the AAPs could compensate for what we have lost in terms of other treatments, and were as powerful as the media imply.
… blaming the Managed Care payers for not supporting more appropriate treatments. Good for her.

However, I not only think that haunting these authors is justified, but is actually an imperative. Twenty of the twenty-two authors of Study 329 are still alive, six are in significant leadership positions in the American Academy of Child and Adolescent Psychiatry, and others dot the by-lines of other ghost-written industry-funded experimercials like this one. Gabrielle Carlson is AACAP’s Program Chair welcoming the attendees to the meeting. It is likely that many of the named authors were on the by-line of that article only because they were site primary investigators for the clinical trial itself and little involved in the writing or the extensive data manipulation involved in creating this masterpiece of deceit – now a monument to an era yet to be fully acknowledged.

In the case of Dr. Carlson, Stony Brook was in the group of sites added to Paxil Study 329 late because of slow recruitment and accounted for only 11 subjects in the trial. She’s not mentioned in any of the subpoenaed documents that I know of. Apparently it was simply a source of revenue for Stony Book, and another paper to add to her CV. But that’s the whole point. Other than the two SKB/GSK employees who directed the show creating the paper with ghost-writer Sally Laden, the actual non-involvement was true for the twenty academic authors whose names were on that author‘s list. They lent their academic credentials and the reputations of their institutions to the paper, a ticket insuring that it would be accepted in a prestigious journal and read by colleagues who respected those honorifics, without really participating in its creation. But even worse, in the decade during which the paper has been universally vilified, not one of those authors has come forward and said a word. They continue to occupy high places, adding an obvious irony to Carlson’s comment, "Get here however you can!"

Sure, Managed Care bureaucrats have pushed atypical antipsychotics over more intensive and expensive interventions [keeping the cost of medical care down]. Of course the Pharmaceutical Industry has promoted antidepressant medications for treatment of adolescent depression [in the business of selling FDA approved drugs]. Yes the professional organizations have created guidelines that recommend these practices [evidence-based medicine from peer-reviewed journals]. But without those names on the by-line certifying the articles, the papers wouldn’t have been published that allowed those things to happen. And when the authors sit in silence in their own careers even after it becomes clear, as in this case, that they lent their names, positions, and institutions to a fictional publication, they are the main force in the center of perpetuating what’s wrong.

So, is it fair to haunt Dr. Carlson with her being an author on the by-line of the infamous Paxil Study 329 report in the Journal of the American Academy of Child and Adolescent Psychiatry back in 2001? Of course it is. The whole profession and the patients we serve are haunted by publications like Paxil Study 329, and will continue to be haunted until  these authors, this journal, this organization, and this profession wakes up and starts talking and making needed changes…
Mickey @ 1:48 PM
Filed under: OPINION
the best presentation money could buy…

Posted on Friday 17 October 2014

WebMD
October 17, 2014

A black box warning about suicide risks should remain on the anti-smoking drug Chantix® until it can be reevaluated using findings from thorough scientific studies, a U.S. Food and Drug Administration panel of experts said Thursday. Chantix® has carried the FDA’s strongest warning label since 2009 after it was linked to violent or suicidal behavior among some patients taking the drug.

Pfizer asked the FDA to drop the boxed warning, citing recent studies suggesting that patients taking Chantix® were not at increased risk for psychiatric problems, the Associated Press reported. However, the 11-member FDA advisory panel voted to retain the black box warning on Chantix®. One member voting in favor of removing the warning and six favored slight changes to the label. The FDA does not have to follow the advice of its expert panels, but typically does.
Pharmalot
by Ed Silverman
October 17, 2014


“I think Pfizer took quite a chance trying to get the box deleted. They obviously wouldn’t have done it if they thought they could convince people, but they failed completely,” says Diana Zuckerman, the president of the National Center for Health Research, a non-profit advocacy group.

“They had the best presentation money could buy – very good analyses and complicated statistics to prove their point. And the company trotted out these studies and tried to make a very strong case for why the Black Box should be deleted, but only one person voted their way."

“Pfizer took a big chance, but I think they did so because they were afraid the next study wouldn’t be so favorable and maybe they could get rid of the Black Box warning now. Remember, if it were removed, it would be hard to get it reinstated later, even if a post-marketing study showed risk.”

Pfizer is not flinching. “The completion of our currently ongoing safety study will represent one more step forward in the process of accurately characterizing the neuropsychiatric safety of this important medication,” says Steven Romano, a Pfizer senior VP who heads the medicines development group.
I’ll be brief since I expect it will be all over the evening news tonight. This is one of those situations where I wonder why physicians are even in the loop. While quitting smoking is obviously an important preventive medicine maneuver, how would any single physician have any knowledge about whether a given patient should take Chantix®?

But there’s something else to say. Pfizer’s sales of Chantix® are down. They obviously think it has something to do with the Black Box warning in the labeling. So they are spending tons of money trying to get the label removed – thinking more patients will "ask their doctor if…" and that more doctors will not be afraid to prescribe it. It’s a sign of their inflated sense that they can influence and control the world if they just play their cards right. It doesn’t occur to them that maybe their sales are down because Chantix® is only for the hardy. If you’ve prescribed it yourself, you know that it does exactly what that Black Box label says it does, and maybe more often than the label suggests. They can’t change that with a label eraser or even a piece of Robert Gibbons statistical sleight of hand [see way past time…].

It is what it is…
Mickey @ 4:16 PM
Filed under: OPINION
more Wagner et al

Posted on Friday 17 October 2014

I know I sometimes get kind of hung up on numbers, and it just happened. I was looking at Wagner et al in the last post because it was ghost-written, but I did read the abstract and something stuck with me. It’s highlighted in red below, "[effect size=2.9]". The effect size is a measure of the strength of an effect and is the simplest of calculations: it’s the difference in the means of the two groups divided by the standard deviation. Besides being an index of the strength of an effect, it also normalizes things so different studies can be compared. The usual range is 0.25 = weak, 0.50 = moderate, and 0.75 = strong. So what’s with effect size=2.9? It doesn’t make any sense. So I went back and pulled the whole paper to calculate it myself. Curious George, I guess…
by Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, Heydorn WE.
American Journal of Psychiatry. 2004 161[6]:1079-1083.

OBJECTIVE: Open-label trials with the selective serotonin reuptake inhibitor citalopram suggest that this agent is effective and safe for the treatment of depressive symptoms in children and adolescents. The current study investigated the efficacy and safety of citalopram compared with placebo in the treatment of pediatric patients with major depression.
METHOD: An 8-week, randomized, double-blind, placebo-controlled study compared the safety and efficacy of citalopram with placebo in the treatment of children [ages 7-11] and adolescents [ages 12-17] with major depressive disorder. Diagnosis was established with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. Patients [N=174] were treated initially with placebo or 20 mg/day of citalopram, with an option to increase the dose to 40 mg/day at week 4 if clinically indicated. The primary outcome measure was score on the Children’s Depression Rating Scale-Revised; the response criterion was defined as a score of < 28.
RESULTS: The overall mean citalopram dose was approximately 24 mg/day. Mean Children’s Depression Rating Scale-Revised scores decreased significantly more from baseline in the citalopram treatment group than in the placebo treatment group, beginning at week 1 and continuing at every observation point to the end of the study [effect size=2.9]. The difference in response rate at week 8 between placebo [24%] and citalopram [36%] also was statistically significant. Citalopram treatment was well tolerated. Rates of discontinuation due to adverse events were comparable in the placebo and citalopram groups [5.9% versus 5.6%, respectively]. Rhinitis, nausea, and abdominal pain were the only adverse events to occur with a frequency exceeding 10% in either treatment group.
CONCLUSIONS: In this population of children and adolescents, treatment with citalopram reduced depressive symptoms to a significantly greater extent than placebo treatment and was well tolerated.

Well, they give us the mean CDRS-R scores at the baseline and the standard deviations…
… Mean Children’s Depression Rating Scale Revised scores at baseline were 58.8 [SD=10.9] and 57.8 [SD=11.1] in the citalopram and placebo groups, respectively, indicative of moderately severe illness.
And they show us that there’s about a 5 point difference at week 8 on the graph, but they didn’t give us either the Means or the Standard Deviations at week 8 anywhere that I could find. Since the Formula is Effect Size = [Difference in the Means] ÷ [Standard Deviation], we could work backwards as in 2.9 = 5 ÷ [Standard Deviation] which comes out with a Standard Deviation = 1.72. Given they started with a Standard Deviation = ~11, 1.72 has to be wrong. As I scratched my head in confusion and pondered, I noticed these references below the abstract on PubMed:
These were comments on the article in the AJP. I wasn’t the first to wonder about that effect size. Commenter Andres Martin had named it the big bang [a bit of AJP humor]. In their response to comments, Wagner et al said:
Dr. Martin and colleagues inquire about the value of 2.9, which was calculated as the quotient of the least square mean, divided by the common standard error of the mean for each treatment group. With Cohen’s method, the effect size was 0.32.
I have no clue where that first part came from, but the effect size=0.32 is more like it – in the weak-to-moderate range. But then there were those other numbers:
… Citalopram treatment showed statistically significant improvement compared with placebo on the Children’s Depression Rating Scale — Revised as early as week 1 [F=6.58, df=l,150, p<0.05], which persisted throughout the study. At week 8, the effect size on the primary outcome measure, Children’s Depression Rating Scale-Revised [last observation carried forward], was 2.9. Additionally, at endpoint more citalopram-treated patients [36%] met the prospectively defined criterion for response than did placebo-treated patients [24%], a difference that was statistically significant [x²=4.178, df=l, p<0.05]. The proportion of patients with a CGI improvement rating <2 at week 8 was 47% for the citalopram group and 45% for the placebo group [last observation carried forward values]. For the CGI severity rating, baseline values were 4.4 for the citalopram group and 4.3 for the placebo group, and endpoint values [last observation carried forward] were 3.1 for the citalopram group and 3.3 for the placebo group.
They report 36% responders to Citalopram as opposed to 24% to Placebo. The NNT [Number needed to Treat] would be 1 ÷ [0.36 - 0.24] or NNT = 8.3. In prose, that translates to, "You have to treat 8 people with Citalopram before you get one that does better than they would’ve done on a Placebo" – which is lousy. And for the chi square, I got [x²=2.852, df=l, p=0.0912] with the Yates correction and [x²=3.439, df=l, p<0.0637] uncorrected. But there was also the CGI [Clinical Global Impressions] result which is the observation of improvement: Placebo 45%, Citalopram 47%. And the severity: Placebo 4.3, Citalopram 4.4 before, and Placebo 3.3, Citalopram 3.1 at 8 weeks. That’s no difference at all. So the subjects showed no overall observed improvement with Citalopram. My Conclusion: A weak at best and clinically insignificant signal. In their response to criticisms, Wagner et al said:
We believe that the results of our study, which demonstrated a significant difference between citalopram and placebo beginning at week 1, is clinically meaningful, particularly at a time when there have been so few antidepressants shown to have superiority to placebo for depressed children.

That final comment is pretty bizarre, given that by the time it was written, Dr. Wagner herself had authored three previous articles claiming the effectiveness of SSRIs in youth [collusion with fiction…].

I finally located this study [CIT-MD-18] under Lexapro in Drugs@FDA. The answer to Psycritic’s original point is pretty complicated. They allowed this study [Wagner et al] to count in the Lexapro application for the pediatric MDD Approval because it is a racemic mixture. Wagner et al and one Lexapro trial were used for approval in adolescents, but it was only Lexapro that was approved. The NDA found the CDRS-R difference significant [p=0.038] but not the CGI [no mention of 'responders']. The bottom line is that this [shaky] clinical trial was essential to the pediatric approval.

How was that for a wild goose chase? Actually, I kind of enjoyed it. I had originally just looked at the graph in Wagner et all and assumed it was a positive study. Coming back to it after seeing that [effect size=2.9] value and realizing how shaky it really was was a good reminder that with these clinical trials, "all that glitters is not gold." It was only a positive study by the letter of the law, not by direct observation [CGI].

This actually mirrors my own experience. When I first started volunteering after retirement, I worked in a Child and Adolescent clinic for a while. I tried SSRIs in a few depressed adolescents [actually Celexa®] without any luck. Then I had a case of Akathisia [unknown to me at the time], and that was the end of that little experiment. Actually, it was that case that got me looking at the psychopharmacology literature and ultimately lead to this blog. I looked at it initially to "catch up," but ended up "catching on." I did use SSRIs in a few adolescents with OCD-like symptoms [compulsive "cutting"] with notable success – though after the Akathisia case, I saw them frequently [and worried]. I actually stopped working in that clinic because I was being pressured to prescribe more. In those several years, I never saw a depressed adolescent who was just "depressed." They were all cases with complex family and interpersonal issues – way more psycho·social than bio·
Mickey @ 10:28 AM
Filed under: OPINION
collusion with fiction…

Posted on Thursday 16 October 2014

After the last post [a betrayal…], Psycritic commented that Celexa® had also been approved for adolescent depression by the FDA [I had said "Only Prozac®"]. I had a vague memory that something had happened, but was confused, so I took a look in Drugs @ FDA and got more confused. Then I tried Google and found a 2011 Canadian review of Celexa/Lexapro in adolescents that was illuminating. The part that got my attention was towards the end:
by Carlo Carandang, Rekha Jabbal, Angela MacBride, and Dean Elbe
Journal of the Canadian Academy of Child and Adolescent Psychiatry. 2011 20[4]: 315–324.

FDA Approval Process & Legal Action
While only one RCT for escitalopram was statistically superior to placebo on the primary outcome measure, according to Forest Laboratories, Inc. [US manufacturer of Lexapro] the FDA decision to approve escitalopram was based on two RCTs – the escitalopram RCT with positive results and an earlier trial with citalopram. “Escitalopram is the only active enantiomer of the racemic drug citalopram, so we considered it reasonable to [deem] the positive citalopram study along with the positive escitalopram study as sufficient evidence to support the approval,” said Karen Mahoney, an FDA spokesperson. A 2002 application for a pediatric indication for citalopram had previously been rejected by the FDA, and the US patent for citalopram expired in 2003.

The FDA approval decision for escitalopram came shortly after filing of a federal civil suit alleging Forest Laboratories, Inc. had illegally marketed escitalopram and citalopram for off-label use in children and adolescents from 1998 to 2005. The suit also alleged the company suppressed publication of a negative citalopram trial, and reports of increased suicidality in pediatric patients. This lawsuit was joined with another lawsuit regarding another Forest Laboratories, Inc. product levothyroxine, and was eventually settled in September 2010 for the sum of $149 million.

The citalopram trial [Wagner et al., 2004] that formed part of the basis for escitalopram FDA approval was alleged to have been written and submitted by a medical “ghost-writer” on behalf of Forest Laboratories, Inc. In April 2009, one month after the FDA approval for escitalopram in adolescents was granted, Forest Laboratories, Inc. admitted that a medical communications company, Prescott Medical Communications Group was not acknowledged as a contributor to the article at the time of publication. This practice is not allowed by the American Journal of Psychiatry, and an editor’s note regarding correction of this matter was published in August 2009…

At this point, I will admit that I had lost interest in my initial quest [FDA Approval of Celexa/Lexapro] because I’d run across something that was far more interesting. So let’s start over. The new topic is the 2009 Editor’s Note in the American Journal of Psychiatry about their earlier 2004 article on Celexa:

Editors’ Note

The article "A Randomized, Placebo-Controlled Trial of Cilalopram for the Treatment of Major Depression in Children and Adolescents," published in the June 2004 issue of The American Journal of Psychiatry [vol. 161, pp 1079-1083] is alleged by the United States Department of Justice in an ongoing suit to have been written and submitted to the Journal by a commercial medical writer on behalf of Forest Laboratories, Inc.

We requested responses from Drs. Karen Dineen Wagner, Adelaide S. Robb, and Robert L Findling [authors in their role as investigators in the clinical trial at their respective universities], Dr. William E. Heydom [the senior Forest laboratories study director], and Forest laboratories. Drs. Wagner, Robb, and Findling reported that they had received an initial draft from Dr. Heydom to which they contributed through several drafts, This paper was submitted as a Brief Report, which the Journal’s editors requested be resubmitted as a full-length Article. Drs. Wagner, Robb, and Findling report that they contributed with Dr. Heydorn to the resubmission and that they were not aware that Dr. Heydorn was working with a commercial writer. Dr. Heydorn did not respond to our request for comment.

A Forest laboratory official in a letter of April 17, 2009, acknowledged that: "Forest retained a medical communications company to assist with preparation of the manuscript, a practice we understand to be common among pharmaceutical companies. Following discussion with the article’s named authors, the medical communications company created an initial draft of the manuscript. Over the course of time, however, from the initial draft to the final publication, the manuscript went through multiple iterations with the input of the named authors, as well as others who reviewed and commented on the manuscript; throughout this process, the medical communications company continued to provide copy editing, formatting, referencing and other editorial support. Hie manuscript was then submitted to AJP by Dr. Wagner, who, along with the other named authors, maintained control over the final content of the manuscript."

We are satisfied that the named contributors of this article satisfy the criteria for authorship as set forth in the "Uniform Requirements for Manuscripts Submitted to Biomedical Journals" from the International Committee of Medical Journal Editors. However, the Journal’s Instructions to the Authors in 2004 and our policy today do not allow contributions by unnamed writers to the preparation of a paper. Thus, the editorial contributions of Prescott Medical Communications Croup should have been acknowledged in the published article as required at the time the article was published.

Furthermore, Forest Laboratories failed to disclose to the Journal that it was aware of data from a study by Lundbeck that showed increased suicidality in children and adolescents who were treated with citalopram. Authors and sponsors are expected to disclose the existence of all data that affects the interpretation of their study. This note will appear in Medline and other databases as a Comment on the paper.

The official complaint [United States and Christopher R. Gobble v. Forest Laboratories Inc. and Forest Pharmaceuticals Inc. Civil Action No. 03-10395-NMG] is posted at …

Robert Freedman, M.D.
Editor-in-Chief

Michael D. Roy
Editorial Director
American Journal of Psychiatry. 2009 166[8]:942-943.

I’d never seen this before. It’s like a picture window into how much competition there was for the adolescent depression market, and how corrupt the whole enterprise had become. While we can respect Editor Robert Freedman for publishing this Editor’s Note, his certification of authorship is, of course, a sham – as is Dr. Wagner’s claim that she knew nothing of the ghost authoring. In the first place, the paper was presented to her already drafted. Whether it was written by Forest senior study director Dr. William Heydorn or someone else, it certainly wasn’t Wagner’s or her co-investigator’s work. And since she was in the author role in multiple other ghost-written trial reports at that time, her claim of naïveté about hired professional writers holds no water. She was everywhere in those days – Paxil, Prozac, Zoloft, Celexa – an author on each of these of ghost-written journal articles – all four claiming efficacy and safety in depressed adolescents for their respective drug:

Paradoxically, Karen Wagner and some of her co-authors in these studies were later on the ACNP [American College of Neuropsychopharmacology] Task Force convened to report on these questions after the Black Box Warning was added by the FDA in 2004:
And this kind of hyperbole was standard fare whenever ghost-writing was exposed:
    A Forest laboratory official in a letter of April 17, 2009, acknowledged that: "Forest retained a medical communications company to assist with preparation of the manuscript, a practice we understand to be common among pharmaceutical companies. Following discussion with the article’s named authors, the medical communications company created an initial draft of the manuscript. Over the course of time, however, from the initial draft to the final publication, the manuscript went through multiple iterations with the input of the named authors, as well as others who reviewed and commented on the manuscript; throughout this process, the medical communications company continued to provide copy editing, formatting, referencing and other editorial support. The manuscript was then submitted to AJP by Dr. Wagner, who, along with the other named authors, maintained control over the final content of the manuscript."

It’s time to stop arguing with such nonsense as if it might be credible. By now, we all know what happened in these trials. The contract CRO organized and ran the trials. The sponsoring/funding pharmaceutical company analyzed and manipulated the data, then turned it over to the contract medical writers. The named authors may or may not have done some editing along the way after it was written, but their main function was to provide the academic credentials needed for a ticket into the peer-reviewed medical journals or a poster at a meeting. These heavily worked-over studies regularly amplified efficacy while downplaying adverse events. When the FDA finally added the black box warning, it put a glitch in their profit projections, so the involved industries set about publicly debunking the FDA warnings in their now decade-long campaign [as described in a betrayal…].

As for the specific suit that brought this particular bit of ghost-writing into the public eye? The case against Forest Laboratories ultimately settled [see September 15, 2010: Drug Maker Forest Pleads Guilty: Will Pay More Than $313 Million to Resolve Criminal Charges and False Claims Act Allegations]. But even in this instance where the ghost-writing was exposed and admitted, the American Journal of Psychiatry, official journal of the American Psychiatric Association, chose to collude with the fiction that the academics on the by-line were genuine authors, and the journal left the study in place.

The American Psychiatric Association seems to be poised to engineer yet another identity shift in psychiatry [the prequel…, anything but over…, the sequel I…], apparently intending to proceed without acknowledging the misadventures of the last makeover, without participating in the reform efforts like Data Transparency or revised Conflict of Interest policies, without correcting or at least flagging the large fiction sections of our journal libraries. The American Academy of Child and Adolescent Psychiatry meeting in San Diego next week appears to be moving along the same silent path. Beside the obvious moral and ethical tangles involved, it seems to me that there’s an enduring liability being assumed by the professional organizations, the academic community, and our peer reviewed journals when they incorporate this attitude of denial and rationalization. The active participants in the deceit and corruption that accompanied the industrial invasion of academic and organized psychiatry actually represented only a segment of psychiatrists, albeit a segment in high places. Many of their names are already on this page, most are cataloged throughout this blog. And while too many in the specialty followed their lead, it was also the only major highway open to traffic, and it’s easy to forget how little many of us knew of this before the last six or seven years. That’s not intended as an excuse, but rather a commentary on the state of play.

If our professional organizations, our academic departments, and our peer reviewed journals continue to leave this big piece of history and its published record unexamined and uncorrected, the specialty of psychiatry incorporates it as its own rather than seeing it as the foreign body it deserves to be. And any of our current leaders who participate in this strained policy of rationalization and denial might just as well have been among the ranks of the worst of the KOLs, the guest authors, or on the advisory boards and the speaker’s bureau payroll – complicit in creating and perpetuating a fiction in a space reserved for scientific and therapeutic intention…
Mickey @ 1:00 PM
Filed under: OPINION
a betrayal…

Posted on Wednesday 15 October 2014

New York Times
by Robert Gibbons and J. John Mann
October 7, 2014

The changes in treatment and attitude brought on by Prozac prompted two colliding points of view. One was that antidepressants were overprescribed and people were encouraged to turn to a pill to solve all their problems. Another viewpoint was that major depression was one of the most debilitating illnesses in the world and was mostly untreated or undertreated, and even though we were now prescribing a lot of antidepressants there were still too many people with moderate to severe depression that remained untreated.

A third claim intruded into this debate, namely that the efficacy of antidepressant medications is overstated and the best evidence of effectiveness was in only the most severely ill patients. In an effort to shed light on this question, we obtained much of the world’s complete longitudinal data on randomized controlled trials of the antidepressants fluoxetine [Prozac] and venlafaxine [Effexor] in depressed patients conducted by Lilly, Wyeth and the National Institute of Mental Health. We included studies regardless of whether they demonstrated the medications were effective in order to get the clearest picture possible of the efficacy of these widely used antidepressants.

From the statistical model that synthesized these data across all studies separately for each age category, we computed estimated response and remission rates. We found an improvement in depression regardless of age in both medications relative to a placebo pill. Interestingly, the greatest benefit in terms of response and remission rates was seen in children, followed by adults, and then by more modest effects in the elderly. There was no evidence that severity of depression made a difference to how well the antidepressant medication worked. Based on these findings we concluded that antidepressants work across the lifespan, in patients with moderate or severe depression.
In a recent blog post, I reviewed Dr. Gibbons’ most recent paper, yet another assault on the Black Box Warning, this time using commercial databases [gibbons everlasting...] and cataloged his many previous attempts to cast doubt on the 2004 FDA Black Box Warning. He has made similar attempts to debunk the warnings on Neurontin® and Chantix® [very monotonous…].. This recent NYT comment is based on his 2012 articles with the same intent. I had offered a strong criticism at the time of those 2012 articles [an anatomy of a deceit 1… etc.], as did many others. But in gibbons everlasting…, I left out something important, something mentioned by Dr. Bernard Carroll both in his comment here and to the New York Times. So I thought I’d just run it around again:
by Gibbons RD, Coca Perraillon M, Hur K, Conti RM, Valuck RJ, and Brent DA
Pharmacoepidemiologic Drug Safety. 2014 Sep 29. doi: 10.1002/pds.3713. [Epub ahead of print]

PURPOSE: In the 2004, FDA placed a black box warning on antidepressants for risk of suicidal thoughts and behavior in children and adolescents. The purpose of this paper is to examine the risk of suicide attempt and self-inflicted injury in depressed children ages 5-17 treated with antidepressants in two large observational datasets taking account time-varying confounding.
METHODS: We analyzed two large US medical claims databases (MarketScan and LifeLink) containing 221,028 youth (ages 5-17) with new episodes of depression, with and without antidepressant treatment during the period of 2004-2009. Subjects were followed for up to 180 days. Marginal structural models were used to adjust for time-dependent confounding.
RESULTS: For both datasets, significantly increased risk of suicide attempts and self-inflicted injury were seen during antidepressant treatment episodes in the unadjusted and simple covariate adjusted analyses. Marginal structural models revealed that the majority of the association is produced by dynamic confounding in the treatment selection process; estimated odds ratios were close to 1.0 consistent with the unadjusted and simple covariate adjusted association being a product of chance alone.
CONCLUSIONS: Our analysis suggests antidepressant treatment selection is a product of both static and dynamic patient characteristics. Lack of adjustment for treatment selection based on dynamic patient characteristics can lead to the appearance of an association between antidepressant treatment and suicide attempts and self-inflicted injury among youths in unadjusted and simple covariate adjusted analyses. Marginal structural models can be used to adjust for static and dynamic treatment selection processes such as that likely encountered in observational studies of associations between antidepressant treatment selection, suicide and related behaviors in youth.
In gibbons everlasting… I listed Dr. Gibbons previous articles on this topic since the Black Box Warning was issued by the FDA in 2004. While the FDA meta-analysis supported the case that suicidality is an uncommon but dangerous side effect of the use of SSRIs in adolescents, it was the case reports heard by the panel that lead them to append the warning. Dr. Gibbons statistical analyses have chased disproving the warning all over the map – from multi-country comparisons, the CDC statistics, proprietary databases, VAH statistics, drug company clinical trials, etc. always chasing the same hypothesis, the same one recently espoused by Lu et al [all databases are not created equal…]:
    The Hypothesis [my version]:
    The Black Box Warning is wrong. It scared doctors who prescribe fewer antidepressants to adolescents, depriving them of needed treatment, thereby increasing the incidence of suicidality.
In his previous outings, over the last decade, Gibbons has stuck to attempts at using population meta-analyses to show that antidepressants don’t increase the incidence of suicidality. His articles are difficult because they can’t be vetted [not enough information] and they involve complicated statistical analyses that he describes, but does not show. They are invariable followed by media reports, The ones mentioned in the NYT above were followed by a media blitz [the campaign…]. Invariably he finds no evidence of suicidality in adolescence on SSRIs. There are several points to make about these papers:
  1. There is no strong evidence that SSRIs are even effective in adolescent depression. Only Prozac was approved, and that was early on before these questions were raised. So the notion that effective treatment is being withheld is unsubstantiatable.
  2. This syndrome is not common, but once you see it, you have no question of causality [at least I didn't]. It’s not a population study thing, it’s a case report thing. And there are plenty of cases of completed suicides among those reports. I don’t even treat adolescents, but I personally know of several such cases. The cases are substantiatable.
Now to the most recent paper and Dr. Carroll’s point. After a decade of trying to prove it doesn’t happen, in this new study, it seems that it does happen after all:
    "For both datasets, significantly increased risk of suicide attempts and self-inflicted injury were seen during antidepressant treatment episodes in the unadjusted and simple covariate adjusted analyses."
And then Dr. Gibbons undoes it with some kind of factor analysis that is opaquely described and unintelligible to any physician no matter how statistically sophisticated. Carroll calls it "voodoo statistical hand waving," but even that is forgiving because Gibbons’ presentation is effete and insulting to the reader. So the question really comes down to Why do these recurrent articles against the Black Box Warning keep coming? with each study more questionable and convoluted than the last. They are presented as being in the service of child advocacy – hardly likely. One hint about their persistence is in looking at the authorship:
by Nemeroff CB, Kalali A, Keller MB, Charney DS, Lenderts SE, Cascade EF, Stephenson H, and Schatzberg AF.
Archives of General Psychiatry. 2007 64[4]:466-72.
Three authors on Senator Grassley’s list, chairmen who lost their chairs in the following years; four customers of Sally Laden, notorious ghost-writer; and the medical director and emplyees of Quintiles, a major CRO. Then:
News coverage of FDA warnings on pediatric antidepressant use and suicidality
by Barry CL and Busch SH.
Pediatrics. 2010 125[1]:88-95.
These studies were financed by the National Bureau of Economic Research, a think tank founded by a member of the Eli Lilly Board at the time [see pretty loud coi…, the NBER study, and tortured numbers…]. Then there are the numerous studies of Dr. Gibbons who has testified for Pfizer in the cases involving SSRIs, Chantix, and Neurontin. Throw in the recent study by Lu et al [see all databases are not created equal…], employed by Harvard’s Managed Care conglomerate. There are others, but nowhere among them are the expected child psychiatrists or psychologists. This is pretty much an industry effort all the way through.


This is a strange story about an unlikely collection of people diligently pursuing the debunking of a clear, if uncommon, adverse effect of a class of medications when given to youth – a potentially fatal complication. It proposes to be advocacy for teens being denied effective treatment, yet even the evidence for its effectiveness is decidedly underwhelming. The people producing these studies are not from the community of people actively involved in treating the populations studied, and the evidence they present is at some distance removed from the actual patients [claims databases, population statistics, etc.], invariably connected with some industry [PHARMA, Managed Care, etc.], and generally accompanied by some kind of prominent media coverage like the NYT piece I started with above. The important question is Why? Why do they keep at it? Of course we can’t truly know their motives, but it’s a pretty good guess that it’s not what the articles say. And though unprovable, we can easily hypothesize for ourselves what drives this campaign. Almost anyone reading this could come up with a set of motives, but I want to say a few of them out loud:
  • PHARMA: Depressed adolescents are common – a lucrative market for the sale of antidepressants.
  • PHARMA: The suicidality Adverse Event was downplayed in the original reports – a litigation liability.
  • Managed Care: The cost of delivering care other than drugs to depressed teens would be expensive.
  • Psychiatry: The KOL psychiatrists have based their reason d’etre on the effectiveness of the SSRI drugs, talking about ‘depression’ as if it’s a ‘disease entity’ and the SSRIs as the ‘treatment’ for that ‘disease entity’. They essentially define psychiatry by this disease/treatment dyad. 
In my mind, this is an affront to the biological psychiatrists who have given us effective treatments for the subset of depressed people who have the depressions that fit the disease model – eg Manic Depressive Illness, Melancholia. It is an affront to the psychotherapists from a variety of disciplines who work with adolescents who present with depression. It is an affront to psychiatrists who don’t subscribe to the neoKraepelinian dictum that all mental illness is biological. And it is an affront to the scientists who adhere to the scientific method and use its tools carefully – hypervigilant to the introduction of bias, including their own. But first and foremost, it is a betrayal of the trust of the depressed adolescents, their parents, and the practitioners who treat them…
Mickey @ 2:00 PM
Filed under: OPINION
«evidence-based medicine» some evidence

Posted on Tuesday 14 October 2014

In my medical lifetime, I’ve watched medicine turned into a business enterprise. I was fortunate to be able to hide in the cracks and mostly evade that myself – haunting places like training programs, academia, military service, a solo practice off the grid, a charity clinic. It’s not that I’m averse to systems. I’m just specifically wary of systems for-profit being involved with anything that purports to give care. And I’m wary of systems not-for-profit that are funded as start-ups that are slated to later carry the ball on their own. The best medical system I ever worked in was an overseas military hospital. The worst was everything else. These are all acquired feelings at the end of a career, not something I started with.

The top graph tells the story. The relative cost of medical care in the United States has doubled [since the days I first heard of Managed Care around the late 1970s]. And the reasons are obvious everywhere you turn. Fee churning Emergency Rooms in for-profit Hospital Corporation owned facilities; Direct-to-Consumer ads increasing drug sales six-fold; inflated guidelines fueling unnecessary testing and treatment; controlling Managed Care monitors demanding evidence of efficacy but giving no evidence of their own [efficacy]; abusive pharmaceutical advertising and pricing; the constant whirr of the MRI machines in the background pouring out normal studies. The sick and those of us who treat them are a captive audience with no clear alternatives in sight. We’ve been an easy mark for decades. And it’s as if there’s an inertia from a more benevolent time, memories of a different ethic – something that keeps us naive about the impact that the business·i·fi·ca·tion of medicine has had on our lives and our healthcare. And speaking of evidence, the bottom graph is one of the many that make the same indictment – it hasn’t been worth it.

It’s funny, the cynicism in that last two paragraphs is evanescent. I can get to feeling it in spades, work myself up into a righteous froth – and then watch it evaporate within minutes. It happened today. I hadn’t worked in a couple of weeks – weddings, funerals, other things – but when I went to the clinic today, the cynical gloom lifted and I had fun. Maybe that’s not the right word. I got into the problems that came my way and did what I’ve learned to do. Some might say I wrote too many prescriptions. Others might say I didn’t write near enough. Some would say I didn’t need all those years of training to do what I actually spent my time doing today. Since I don’t get paid, it would be hard to say I didn’t earn my keep. My point is that I felt none of that uncomfortable cynicism I can feel at other times. The Licensed Professional Counselor I worked with and I saw several cases together we pass back and forth in our version of Collaborative Care, the same with the Internist and the Nurse Practitioner.

After work, I came home and saw those graphs up there on my desktop, prepared before I left town for the weekend. They seemed far away from the morning’s activities. It took a bit to recall why I’d hunted them down. I’ll get back to that I’m sure. But right now, I think I’ll just let the good feeling linger…
Mickey @ 8:44 PM
Filed under: OPINION
a thing to share…

Posted on Monday 13 October 2014

from ChopstiX restaurant
Raleigh NC
Mickey @ 7:09 PM
Filed under: OPINION