1 Boring Old Man

In the Field of Dreams, James Earl Jones reminds of those recurrent seasons that help us mark the passage of time. For him it was baseball season. For many, it’s Christmas, or hunting season, or even Spring. Something that just shows up year after year – the rhythm of life. Then again, for some of us, it’s something else – something forgotten that makes its presence known whether we want to acknowledge it or not:

April is the cruellest month, breeding
Lilacs out of the dead land, mixing
Memory and desire, stirring
Dull roots with spring rain…

• What the Tamiflu saga tells us about drug trials and big pharma
  The Guardian
  by Ben Goldacre
  April 9, 2014

  Today we found out that Tamiflu doesn’t work so well after all. Roche, the drug company behind it, withheld vital information on its clinical trials for half a decade, but the Cochrane Collaboration, a global not-for-profit organisation of 14,000 academics, finally obtained all the information. Putting the evidence together, it has found that Tamiflu has little or no impact on complications of flu infection, such as pneumonia.

  That is a scandal because the UK government spent £0.5bn stockpiling this drug in the hope that it would help prevent serious side-effects from flu infection. But the bigger scandal is that Roche broke no law by withholding vital information on how well its drug works. In fact, the methods and results of clinical trials on the drugs we use today are still routinely and legally being withheld from doctors, researchers and patients. It is simple bad luck for Roche that Tamiflu became, arbitrarily, the poster child for the missing-data story.

  And it is a great poster child. The battle over Tamiflu perfectly illustrates the need for full transparency around clinical trials, the importance of access to obscure documentation, and the failure of the regulatory system. Crucially, it is also an illustration of how science, at its best, is built on transparency and openness to criticism, because the saga of the Cochrane Tamiflu review began with a simple online comment… [click here to continue]

• The Tamiflu trials
  by Fiona Godkee
• Neuraminidase inhibitors for influenza
  by Harlan M Krumholz
• Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments
  by Tom Jefferson, Mark Jones, Peter Doshi, Elizabeth A Spencer, Igho Onakpoya, and Carl J Heneghan
• Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments
  by Carl J Heneghan, Igho Onakpoya, Matthew Thompson, Helen D Cohen, Elizabeth A Spencer,Mark Jones, and Tom Jefferson

hat tip to Jamzo…     

A commenter recently mentioned she noticed a change in psychiatry [for the worse] around 1994. I said maybe a little earlier, but agreed that it was in the right ball park. Looking at these graphs, it looks as if the guesses were on the money [pun intended]. The bottom graph shows a five fold increase in the rate of spending from 1993 to 2001 and the upper graph shows the resulting three and a half fold increase in the drug share of overall spending. Looking at the last five years on the graph, it looks as if we’ve settled into a new equalibrium – a stability in a new system. From a cost perspective, these numbers will probably even fall as the drugs go generic and cost much less. But that doesn’t fix a thing because from the perspective of our system of delivering care, the damage has been done and is likely to be self perpetuating.

A friend of a friend called yesterday with a very sticky child custody problem. In trying to get the family the help they needed, I called a child advocacy lawyer I know in Atlanta  who mercifully agreed to try to help this woman through the thorniest mess I’ve heard in a long time. In talking to the lawyer, I said that if the child needed psychiatric care or evaluation and I could help her find someone suitable, to let me know. I was actually thinking of a psychologist who has spent her career amid the impossible situations that custody cases can be. But my lawyer friend understood my phrase "psychiatric care" as meaning "psychiatrist" and said, "Oh I doubt we’ll need a psychiatrist. They’re for medicines and …" adding "and they’re more expensive." I guess that’s the sad-but-true reputation of psychiatry these days, something that’s hard to add to the graph, but implied.

A message from Carl Elliott:

In early December, we delivered a petition signed by over 3,500 of you to Minnesota Governor Mark Dayton, calling for an investigation of the death of Dan Markingson in a University of Minnesota psychiatric research study. That same week, the Faculty Senate at the university also overwhelmingly approved a resolution calling for an investigation.

Yet four months later, we still have seen no results. The president of the university, Eric Kaler, has indicated publicly that any review he commissions will not include an investigation of Dan Markingson’s death. Governor Dayton has not even acknowledged our petition.

In the meantime, evidence is accumulating that Dan Markingson was not the only patient who died or was seriously injured in psychiatric research studies at the university. Two investigative news reports have appeared with evidence of misconduct involving other patients. A confidential letter has emerged indicating that the Institutional Review Board was aware of ethical problems with psychiatric research at the University in 2009, and that it was concerned enough to request an external investigation. And for over six months, the university has stonewalled our open records requests for reports of deaths and serious injuries in psychiatric research studies.

You can find more information about these issues at:

www.danmarkingson.com

So we need your help. We are organizing a series of actions beginning this week with a call-in campaign to Governor Mark Dayton and University of Minnesota Board of Regents Chairman Richard Beeson. We are asking you to make a phone call as soon as possible to the offices of Dayton and Beeson and leave a message asking for action. Here are phone numbers [and if you need it, a suggested script for your call.]

Please make your voice heard. And let us know that you called by leaving a comment at www.danmarkingson.com.

Thanks,

Carl Elliott

Richard Beeson
Office of the University of Minnesota Board of Regents
Phone: 612-625-6300

Gov. Mark Dayton

Phone 651-201-3437
Toll Free: 800-657-3717

Dan Markingson died by his own hand, a victim of an illness that dates to antiquity. He became a part of a study he should never have been enrolled in – a study that had no medical indication but was rather an experimercial. He was put on a maintenance dose of a blinded medication that wasn’t working. He languished in a treatment facility that did not adjust his treatment to his illness for six months as part of a legal double bind. And not long after hearing that his commitment was to be extended, he killed himself in a bizarre way – consistent with his untreated illness. All of that in a Trial that shouldn’t have been.

The kind of paranoid psychosis Dan had is a big time illness – it can be a lethal illness. Dan’s lethality was there the day he was admitted. He could have succumbed with the best of treatment, but we’ll never know because he didn’t get it. This may even be a case where, in spite of the dominant view of these medications, he may well have been grossly undermedicated, at least early on. But we don’t know that either. All we know is that he was adjudicated to a treatment he never received. Rather, he became a pawn in a marketing chess game.

Arkansas AG asks state Supreme Court to reconsider its tossing of $1.2B Johnson & Johnson fine

The Associated Press

By Andrew Demillo

April 7, 2014

Arkansas Attorney General Dustin McDaniel asked the state Supreme Court on Monday to reconsider its decision tossing out a $1.2 billion judgment against drugmaker Johnson & Johnson, saying justices did "significant harm" to the state and broke from 170 years of precedent. McDaniel filed a petition for rehearing over the high court’s decision last month that the state misapplied the Medicaid fraud law in its lawsuit against New Jersey-based Johnson & Johnson and its subsidiary Janssen Pharmaceutical Inc. over the marketing of the antispyschotic drug Risperdal. McDaniel said last week that he would ask the court to revisit the ruling. "The court’s rejection of the state [Medicaid fraud] case does significant harm to the state and its citizens," McDaniel wrote in the filing. "It deprives the state of a critical tool to protect the integrity of the Arkansas Medicaid program and the vulnerable poor, sick and elderly who depend on Medicaid as a literal lifeline."

McDaniel said justices broke with years of precedent by ruling on grounds not previously raised in filings. Justices ruled that the state Code Revision Commission "substantively altered" the meaning of the Medicaid fraud law when it was codified and that it was originally intended to regulate health facilities. The commission is responsible for making technical corrections to state code. McDaniel noted that the 1993 law remained unchanged for 21 years despite other amendments and attempted amendments by the Legislature over the years. "By improperly transforming a well understood and accepted interpretation of the law, this court has arrogated to itself powers not conferred by the Arkansas Constitution or the General Assembly," he wrote.

The drugmaker said in a statement Monday that it didn’t violate the Medicaid fraud law. "After a thorough review of the case, the Arkansas Supreme Court agreed with our position. We believe that the record speaks for itself and are prepared to vigorously defend our position," the company said. Risperdal was introduced in 1994 as a "second-generation" antipsychotic drug, and it earned Johnson & Johnson billions of dollars in sales before generic versions became available. The drug is used to treat schizophrenia, bipolar disorder and irritability in autism patients. An Arkansas jury found the New Jersey-based companies liable in 2012. Pulaski County Circuit Judge Tim Fox then ordered the companies to pay $5,000 for each of the 240,000 Risperdal prescriptions for which Arkansas’ Medicaid program paid during a 3 1/2-year span.

After their settlement in Texas, J&J lost a number of similar suits – Louisiana, South Carolina, Arkansas. Having sat through the Texas trial, it’s hard for me to imagine how they could win. The off-label marketing, hiding side effects, giving out perks, etc. It was just rampant. I think they settled in Texas because they could tell [as could everyone in the courtroom] that if they let the trial proceed, they stood the chance of getting massacred. But in the other suits, they went to the end – losing the verdicts. Now, they’re neutralizing their losses one at a time on technicalities. 

If Glaxo’s CEO wants to be Mr. Clean, he needs to pick up a broom

Fierce PharmaMarketing

By Tracy Staton

April 7, 2014

GlaxoSmithKline [$GSK] says it’s rolling out sales and marketing reforms around the world. Apparently, the changes come none too soon. The British drugmaker opened another bribery investigation, this time in Iraq, to check out allegations that it paid government-employed physicians to promote its products. And Glaxo hasn’t yet finished working through the scandalous Chinese bribery allegations that kicked off an industry-wide corruption crackdown.

So, CEO Andrew Witty and his team sound a bit … conflicted. On the one hand, Witty sounds the perfectly contrite corporate leader. He apologized for the marketing allegations that ended with a $3 billion Department of Justice settlements. He’s promised good behavior and touted those worldwide sales reforms. But on the other, the company is digging into at least two sets of corruption accusations, and faces related repercussions at home and in the U.S. Two bribery probes in two different geographic divisions? That’s a systemic problem.

When the Chinese bribery scandal hit, Glaxo’s U.K. headquarters was quick to say that head-office executives didn’t know about any malfeasance in its China subsidiary. That may be so. But if HQ didn’t know, that means HQ was either turning a blind eye or failing to pay enough attention. Either way, that’s not a good thing for a company trying to clean up its image.

If Witty really wants to reform GSK, then he and his top managers need to move beyond plausible deniability. They can’t just launch new quota-free sales-rep compensation and promise to stop paying speaking fees to doctors in the U.S. and beyond. Painful follow-through has to happen.

We need to see Glaxo execs take out their brooms, and move into global operations to sweep out misbehavior. If they don’t, whistleblowers and government investigators will. And that makes all those the sales-and-marketing changes look like little more than window-dressing.

Undisclosed Financial Ties Prompt Reproval of Doctor

New York Times

By MELODY PETERSEN

August 3, 2003

Two scientists are raising concerns about an article in a medical journal that described experimental treatments for depression because an author did not disclose his significant financial ties to three therapies that he mentioned favorably. The executive editor of the journal said it had not required disclosure of the potential conflicts, but was considering changing its policy in light of the criticism. The ties between pharmaceutical companies and researchers have come under increasing scrutiny in recent years.

The lead author of the article, Dr. Charles B. Nemeroff, chairman of the department of psychiatry and behavioral sciences at the Emory School of Medicine in Atlanta, said he would have reported the conflicts of interest, which include owning the patent on a treatment he mentioned, if the journal had asked him to. ”I have always been totally compliant, probably gone overboard, with disclosure,” Dr. Nemeroff said. ”If there is a fault here, it is with the journal’s policy.”

Medical reviews face criticism over lapses

The Wall Street Journal

By David Armstrong

July 19, 2006

Charles Nemeroff, one of the nation’s most prominent psychiatrists, edits the journal Neuropsychopharmacology, which this month favorably reviewed a controversial new treatment for depression. But Tuesday, the journal said it plans to publish a correction because it failed to cite the ties of the article’s eight academic authors to the company that makes the treatment, including the article’s lead author: Dr. Nemeroff.

The journal’s nondisclosure of the financial ties of its own editor as well as those of the other authors highlights the failure of many respected medical journals to identify relationships between academic researchers and medical companies that may benefit from positive research reports. A spate of recent lapses is prompting calls for more journals to ban offending authors from publication. In addition, medical schools are being urged to regulate relationships between their researchers and industry more closely…

I was a retired person before I was capable of believing that Doctors, Academic Department Chairmen, and Pharmaceutical Companies named after long-dead men with handle-bar mustaches were capable of the kind of deceit we’ve all seen in recent decades – but our naivety has given way to, at the least, a careful suspiciousness, even paranoia about such matters. And GSK has placed itself in a goldfish bowl that’s going to be hard to escape.

Biologism in Psychiatry: A Young Man’s Experience of Being Diagnosed with “Pediatric Bipolar Disorder”

by Peter Parry

Journal of Clinical Medicine. 2014 3:334-347.

[full text online]

Pediatric bipolar disorder is a diagnosis that arose in the mid 1990s in the USA and has mostly remained confined to that nation. In this article a young American man (under a pseudonym) describes his experience of having the diagnosis throughout his adolescent years. His story was conveyed via correspondence and a meeting with the author, an Australian child psychiatrist. The young American’s story reveals several issues that afflict contemporary psychiatry, particularly in the USA, where social and economic factors have contributed to the rise of a dominant biomedical paradigm—or “biologism”. This focus on the “bio” to the relative exclusion of the “psychosocial” in both diagnosis and treatment can have serious consequences as this young man’s story attests. The author explores aspects of his tale to analyze how the pediatric bipolar disorder “epidemic” arose and became emblematic of a dominant biologism. This narrative points to the need, depending on the service and country, to return to or retain/improve a balanced biopsychosocial perspective in child and adolescent mental health. Child psychiatry needs to advocate for health systems that support deeper listening to our patients. Then we can explore with them the full range of contextual factors that contribute to symptoms of individual and family distress.

3.5 Projective Identification and “Munchausen’s by Proxy”

It is traditional wisdom in child psychiatry that parents often project unresolved issues onto their offspring. The children may identify and act out accordingly. Some extreme versions of this can lead to “Munchausen’s syndrome by proxy”, where a parent , through having an ill child, vicariously gains desired attention from respected medical experts for unmet and disavowed dependency needs. It appears that once Adam left the home his mother produced spurious medical symptoms and diagnoses for herself, in other words her own likely case of Munchausen’s disorder.

An early critique of PBD noted that not only could parents have a psychological investment in the PBD diagnosis, but so too could a range of others including the pharmaceutical industry, academic child psychiatry, schools and cons umer advocacy groups. The authors speculated whether PBD may be a “variant on Munchausen’s syndrome”.

This is not to say that there need be any negligence or mal-intent at all. Factors operate at systemic and subconscious levels. Adam’s mother, his doctors and others no doubt acted with Adam’s best interests in mind. A dominant paradigm is hard to see when you’re living and working within it.

"But the patients that come to me, and the families in tears and despair with these type of problems, I in good faith cannot tell them, ‘Come back in ten years until we have all the data in hand.’ I still need to use medicines that I am assuming that if they work in adults, with appropriate care and supervision, may also work in children."

This is not to say that there need be any negligence or mal-intent at all. Factors operate at systemic and subconscious levels. Adam’s mother, his doctors and others no doubt acted with Adam’s best interests in mind. A dominant paradigm is hard to see when you’re living and working within it.

In the Fall of 2012, having had a chance to look at the raw numbers for the first time, I sent a series of posts to the Ethics Committee of the American Academy of Child and Adolescent Psychiatry along with a request that they consider retracting their article. I had written Dr. Andres Martin the year before [letter], but he hadn’t responded. Here’s my 2012 letter:

I thought this letter had a chance of being well received. The 329 data was now public and I’d done my homework, The $3 B suit had just been settled by GSK. I used my long name and spell checked it several times. Looking back, rereading it, the "familiarize yourself with this story" part was a little cheesy, but otherwise not bad for a non-English Major. The letter was received warmly by the President of the AACAP, the President Elect, and the Chair of the Ethics Committee who assigned a member of the Committee to work with me, presumabely to present it at the meeting coming up in several months. We had several amicable exchanges. I sent her Alison Bass’s book. All very civilized.

AACAP COUNCIL

Tuesday, January 22, 2013 • 12:00–1:00 pm EDT/11:00 a.m. – 12:00 p.m. CDT

Conference Call Minutes

Council members in attendance: Martin J. Drell, M.D., President; Paramjit T. Joshi, M.D., President-Elect; David R. DeMaso, M.D., Secretary; Steven P. Cuffe, M.D., Treasurer; Louis J. Kraus, M.D., Assembly Chair; Laurence L. Greenhill, M.D., Steven Adelsheim, M.D., Mark Borer, M.D., Stephen Cozza, M.D., Deborah Deas, M.D., Joan Luby, M.D., Neal D. Ryan, M.D., Jennifer S. Saul, M.D., Margaret L. Stuber, M.D., Sourav Sengupta, M.D., M.P.H., Marika Wrzosek, M.D.

Council members absent: Warren Y.K. Ng, M.D., Harsh K. Trivedi, M.D.

Others participating: Andrés Martin, M.D. Staff: Heidi B. Fordi, Mary Billingsley, Jill Brafford, Larry Burner, Yoshie Davison, Colleen Dougherty, Genifer Goldsmith, Rob Grant, Earl Magee, Kristin Kroeger Ptakowski

Study 329: Andrés Martin, M.D., M.P.H

As an author of the JAACAP article, Keller et al 2001, Neal Ryan recused himself from this conversation. Dr. Martin briefly summarized the situation regarding Study 329. He and the JAACAP Action Editors [AEs] reviewed this issue over the past 6 months, and shared a letter outlining the situation, steps taken, and their determinations, with Academy leadership. In short, Study 329 and the article published in JAACAP about it, Keller et al 2001, was mentioned in a federal lawsuit against GlaxoSmithKline [GSK], but none of the criminal charges related to the article itself. This is the 4th time the Journal has conducted an inquiry into the circumstances surrounding Study 329 and Keller et al 2001 since its publication, and it has again been determined that while the article is not perfect, the ethical concerns raised by the GSK lawsuit are not substantiated. The AEs consulted with many individuals in making their determination, including several lawyers and editors of other academic journals, and have decided not to take any action against the paper. Both the Academy and the Journal received inquiries from the press about the situation and what was to be done, and Dr. Martin and the AEs believe that there is little to gain in responding and that doing so would simply ‘fuel the fire.’

ACTION: IF COUNCIL MEMBERS RECEIVE ANY INQUIRIES ABOUT STUDY 329, PLEASE DIRECT THESE TO ANDRÉS MARTIN.

hat tip to 1boringyoungman…

Journal Article Didn’t Mislead, Drug Company Asserts

Chronicle of Higher Education

October 1, 2012

[full text on-line]

To the Editor:

As counsel for GlaxoSmithKline LLC in its recently concluded settlement with the United States government, I write to correct some significant factual inaccuracies in "Academic Researchers Escape Scrutiny in Glaxo Fraud Settlement" [The Chronicle, August 6]. The piece focuses on a peer-reviewed journal article published in 2001 in the Journal of the American Academy of Child and Adolescent Psychiatry reporting the results of a clinical trial sponsored by Glaxo­SmithKline [Study 329] of Paxil® [paroxetine hydrochloride] for the treatment of major depressive disorder in adolescents [the article was "Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial," by M.B. Keller et al., in the July 2001 issue]. Unfortunately, your piece incorrectly states that, as part of its government settlement, GlaxoSmithKline admitted that the journal article "was part of the fraud" and "constituted scientific fraud." In fact, GlaxoSmithKline made no such admission and vigorously disputes that the journal article was false, misleading, or fraudulent.

As part of its settlement with the government, GlaxoSmithKline pleaded guilty to a misdemeanor violation of federal law related to the marketing of Paxil for use by patients under 18, an unapproved, "off label" use for Paxil. While the law permits physicians to prescribe medications for such off-label uses, manufacturers are not permitted to market them for such purposes. The charging document filed by the United States, known as an information, contains many allegations that are either inaccurate or incomplete, that tell only part of the story, and that draw unwarranted conclusions from disputed facts. Throughout the investigation, the settlement process, and the guilty-plea proceeding, GlaxoSmithKline made clear to the government and to the court that it did not agree with all of the factual allegations made in the information. In particular, GlaxoSmithKline has consistently denied and disputed the allegations that the journal article was false or misleading. Nothing in the settlement or the guilty plea has changed Glaxo­SmithKline’s position on the journal article. Most important, Glaxo­SmithKline did not admit and has not admitted that the journal article was part of any fraud or that it was false or misleading.

Your piece also incorrectly states that the journal article "was actually written by Glaxo-hired authors to overstate the benefits and understate the risks of a highly profitable Glaxo drug." While GlaxoSmithKline did hire a medical writer to provide editorial assistance to the clinical investigators, a fact that the journal article itself acknowledged, control over the contents of the manuscript remained at all times with the clinical-investigator authors who provided substantial comments on and input into the manuscript. GlaxoSmithKline believed then and continues to believe that the journal article reflects the honestly held views of the clinical-investigator authors.

Thomas H. Lee II
Philadelphia

---

Editor’s note: The federal "criminal information" document in the Paxil case repeatedly describes the journal article as "false and misleading." It also notes that GlaxoSmithKline distributed the article to its marketing department and its sales representatives, who used it to promote the use of the drug for children and adolescents. In addition, the criminal information says that a contractor hired by Glaxo­SmithKline wrote the first draft of the article and incorporated changes made in the article by researchers and another GlaxoSmithKline employee. The plea agreement between GlaxoSmithKline and the U.S. Department of Justice states that GlaxoSmithKline "expressly and unequivocally admits that it committed the crimes charged in the information, and is in fact guilty of those offenses."

I’m not so grandiose as to think that my letter was the impetus for all that wheeling and dealing, for the GSK Chronicle letter, for the AACAP to go silent and dig in its heels even further. Because the call for retraction was coming from everywhere at that time [and ever since]. And I have no notion of the potential legal ramifications of JAACAP retraction the article. But I do feel sorry for the members of the AACAP Ethics Committee. It must be mighty disillusioning to be preparing to debate a thorny ethical issue like this one and to essentially be taken off the case and have its domain simplified down to "the ethical concerns raised by the GSK lawsuit are not substantiated" by a decree from above. What’s an Ethics Committee for if it’s not to deal with such matters?

It’s soon going to be the law in Europe that drug clinical trials are publicly registered and results reported. MEPs have today voted by a huge majority to adopt the Clinical Trials Regulation, 547 in favour and 17 against.