European Medicines Agency: a timeline…

Posted on Friday 24 October 2014

I was getting ready to write some things about a few new developments in the saga of the European Medicines Agency’s Data Transparency policy, and it occurred to me that the story has gone on so long and become so convoluted that I ought to do a rough timeline. I’d like to say it was for the reader who hasn’t followed the story closely, but the truth is that I’ve followed it closely and there are so many twists and turns that I needed to clarify the sequence of things for myself. It certainly has been a chess game – moves and counter moves, gambits and sacrifices, and it’s still not over. So here’s a rough intro starting with the opening moves through the announcement of their policy three weeks ago with some brief comments, a few posts, and the key links – just hitting the high points:

JUL·2012 The European Medicines Agency announced that they would release their data on approved drugs. It was the first real breakthrough in Data Transparency that I knew about, and it was pretty exciting. Shortly thereafter, GSK finally posted the long overdue data from PAXIL Study 329 [from the NY settlement in 2004].
  • any news is good news…
  • EU agency lifts lid on drug data secrets
  • EMA To Make Clinical Trial Data Available

  • FEB·2013 The centerpiece of this campaign was Tamiflu, a drug stockpiled in case of an epidemic/pandemic. The Cochrane Collaboration questioned its efficacy and wanted to do a meta-analysis on all the trials. The campaign involved Ben Goldacre’s AllTrials, Fiona Godlee and the BMJ, Tom Jefferson and Peter Doshi of the Cochrane group, and many others. Roche finally began releasing the unpublished data.
  • good news…
  • Roche Peels Back The Curtain On Clinical Trial Data

  • APR·2013 Two American companies filed suits contesting the EMA’s plan to release their data, InterMune and AbbVie. The EU court ordered the EMA to temporarily halt its releasing data. It was a decided setback.
  • what don’t they understand about the word “All”?…
  • European Medicines Agency receives interim decisions of the General Court of the EU on access to clinical and non-clinical information
  • EMA Ordered Not To Release Trial Data, For Now
  • Transparency Interrupted: The Curtailment of the European Medicines Agency’s Policy on Access to Documents

  • JUN·2013 A leaked joint memo from the EFPIA [European Federation of Pharmaceutical Industries and Associations] and PhRMA [Pharmaceutical Research and Manufacturers of America] describes an extensive campaign to oppose the EMA’s Data Transparency efforts.
  • a closing argument…
  • Big pharma mobilising patients in battle over drugs trials data
  • Exclusive: The Devil is in the Details

  • SEP·2013 At a meeting in Brussels organized by the PhRMA/EFPIA to clear the air, the air was hardly cleared. AbbVie’s lawyer, Neal Parker, made the case against Data Transparency to the horror of the regulators in attendance. It’s a bit of must watch video [@19:/00].
  • a deal-breaker?…
  • Industry and drug regulators disagree on which data should remain confidential

  • DEC·2013 The European Court lifted the hold on Data Release and asked the companies for justification for their claims. The EMA’s response is in the post.
    another patch of blue…

    APR·2014 After negotiation with the EMA, AbbVie withdrew its suit having extracted some concessions on redaction. The naive among us thought it was now something of a downhill run. The wary were on edge.
  • a sunny day…
  • European drug trial secrecy case hit by delay
  • AbbVie Drops EU Court Bid to Block Clinical-Trial Data Release
  • UPDATE 1-AbbVie drops legal action in EU drug secrecy case

  • MAY·2014 The sunny days didn’t last very long. The EMA released a draft of their policy that was dramatically restrictive. Redacted and abbreviated data would be released with a screen-only interface. There was a universal outcry and the European Ombudsman initiated an investigation.
  • the U-Turn…
  • EMA’s data sharing policy—towards peeping tom based medicine?
  • EMA policy on publication of and access to clinical-trial data
  • Ombudsman concerned about change of policy at Medicines Agency as regards clinical trial data transparency

  • JUN·2014 And as we closed in on the date the policy was to be announced, another U-turn. They dropped the screen-only interface part and reassured us that their commitment to data transparency was unwavering. But the wariness had, by this time, spread throughout the land.
  • out of the shadows…
  • European Ombudsman reaction to EMA’s 12 June 2014 statement issued after its Management Board meeting
  • EMA’s double U-turn on its peeping tom policy for data release?
  • Is the EMA Making Too Many Compromises on Transparency?
  • EMA has reversed its on-screen restrictions following researcher and citizen protest

  • JUL·2014 Then, at the 11th hour of announcing their definitive policy, they postponed the release until their October 2nd Board Meeting to get the "wording" right. The Defcon Level rose to wariness²
  • a long hot summer…
  • Management Board delays formal adoption of EMA publication of clinical trial data policy to October 2014
  • Pardon the Delay: EMA Postpones Trial Data Disclosure Policy, Again

  • SEP·2014 And while we waited, the other shoe dropped. The new EU President, Jean-Claude Juncker, moved the EMA from the directorate general for health and consumers [DG SANCO] to the directorate general for the internal market, industry, and entrepreneurship [DG ENTR] – reversing the decision of his predecessor. The Defcon Level rose above wariness³ [a major setback]
  • abuzz over there…
  • The European Commission and pharmaceutical policy: A victory for profits over public health?
  • Prescrire and the British Medical Journal send a letter to Jean-Claude Juncker, President of the European Commission
  • letter from the European Public Health Alliance 

  • OCT·2014 When the EMA policy was finally released, it was an certainly better than what had preceeded it [which was nothing], but it was nowhere close to where they started in July 2012. Even more disappointing, it didn’t fully clarify several points eg what does a CSR actually contain? the access to the IPD was postponed, etc. I suppose it could’ve been worse, but it had promised to be so much more…
  • beyond the blind…
  • Publication of clinical reports
  • EMA Remains Under Fire for its Policy on Disclosing Clinical Trial Data
  • EMA’s release of regulatory data — trust but verify
  • Mickey @ 6:00 PM
    Filed under: OPINION
    sign up…

    Posted on Thursday 23 October 2014

    from AllTrials

    Dear Friends

    We have a chance to get the most influential health body in the world – the World Health Organisation [WHO] – to say something strong on the need for the results of all clinical trials to be publicly reported. Following all of our pressure, the WHO has decided it needs to say something about this and is seeking comments on its draft policy. We have to grab this fantastic opportunity with both hands.

    We all have to tell the WHO that this is a very welcome move and that it must take this opportunity to set a strong global standard for clinical trial reporting by:

    1. Calling for the results of all past clinical trials to be reported, as well as all future clinical trials.
    2. Requiring results to be reported within in 12 months, rather than permitting delays of 18-30 months. The USA’s FDA Amendment Act, the newly adopted EU Clinical Trials Regulation and pharmaceutical companies including GSK and LEO Pharma all agree that 12 months is enough time to report results.
    3. Encouraging researchers to put results on publicly accessible registers, in useful, standardised formats.

    Email your comments to before Saturday, 15 November 2015. Please remember to include your name and contact details as the WHO will not consider anonymous comments.

    You can read the full AllTrials response to the WHO policy here. Feel free to add any of our words to your own comment.

    We know the WHO is going to face resistance from some sectors who say the draft statement goes too far. We can’t let the WHO only hear from those opposed to greater transparency.

    Please write to them today.

    Best wishes

    If you didn’t get this email, it probably means you haven’t signed the AllTrials petition. After you sign up for AllTrials, then respond to the WHO after reading their draft if you can think of ways to strengthen it. They’re right. It is a real opportunity…
    Mickey @ 4:18 PM
    Filed under: OPINION
    blow ye winds…

    Posted on Thursday 23 October 2014

    Well, the Clinical Trial Cops look to be getting Smart®-er [and you’ve just got to admire yankee ingenuity]. Smart® is a device that takes the "non" out of non-compliance. Your study medicine has a little additive. So you take your pill and push a button, and after 20-30 minutes, it alerts you to blow into the machine. The additive has by then been absorbed and can be detected in your expired breath. If it’s there when you blow, this little machine takes a digital photo and sends it to an online database for facial recognition software to authenticate that the real subject took the pill. Check it out [how it works]! And the company [Xhale] has big plans for use beyond just Clinical Trials as you might imagine. How did I find this peculiar little piece of equipment? Creative use of the Physician Payments Sunshine Act Database. I just looked up a KOL [Alan Schatzberg] and found what he’s investing in. Voila` – Xhale!

    Oh yeah, Waiting to Xhale:
      SMART® products have not been cleared for sale or use within the United States. The company is neither soliciting nor accepting any orders for the products. All benefits and claims made are concerning future generations of the product line, which are still under development.
    Mickey @ 2:29 PM
    Filed under: OPINION
    restoring pharma II…

    Posted on Thursday 23 October 2014

    My interest in this article [restoring pharma I…] has a personal component. I’m not being coy when I say that I was stunned when Senator Grassley revealed what I would now call the Academic·Psychiatry·PHARMA·Alliance and all the corruption among, around, and in-between. I have figured out some of the reasons – medical school to internal medicine residency to NIH fellowship to Air Force overseas to psychiatry residency to academic psychiatry means that I was mid forties before I ever had the kind of office that a drug rep might visit [and they hardly haunt the offices of psychoanalytic psychotherapists who work with no office staff and rarely writes prescriptions]. So that Pie Chart showing that PHARMA spends $25 B/year on targeting me is still an eye opener:
    by Mark Kessel
    Nature Biotechnology 2014 32[10]:983–990.

    But more than that, Kessel’s opening sentence was what I recalled from the Internal Medicine days…
    It wasn’t that long ago that the pharmaceutical industry was considered among the most respected industries and Merck the most admired corporation in the United States.
    and when I woke up forty years later, this is what I found:
    This is in sharp contrast to consumer attitudes today, when the industry’s reputation is not much better than that of the financial sector or tobacco companies. Why has an industry in the business of developing lifesaving drugs garnered such a negative reputation, and how should it go about fixing it?
    Washington Irving’s Rip Van Winkle slept through the whole American Revolution. I guess I’d done some power sleeping of my own, because we now see PHARMA as among the greediest and most unscrupulous of the lot – from Paxil Study 329 to Gilead’s pricing of Sovaldi and the table from the paper in the last post in which the word criminal appears much too often. Kessel’s analysis of the reason for the change is detailed and contains a lot of food for thought. It’s there for all to read, but here’s where he starts:
    Big pharma and big business: To some extent, reputational decline can be attributed simply to the fact that many pharma companies are large multinational corporations that are now facing strategic issues that require an adjustment to the traditional business model. The increasing price and cost pressure, patent expirations on blockbuster drugs leading to aggressive generic competition, public policy and changes in how consumers access medicine are leading to erosion of profit margins. Big pharma, like other industries, is not immune from the pressure of having to meet Wall Street quarterly earnings expectations; indeed, today’s companies are measured on how well their stock performs and boards of directors incentivize management accordingly to meet Wall Street’s demands. The needs of patients are secondary.
    As I read through the various factors and forces he describes, I thought they could apply to PHARMA, or the Insurance and Managed Care industry, or the Hospital Corporations, or for that matter Medicine [eg the collection of physicians] and the other medical professional groups. There’s an erosion in the overall ethic and morality in all of the elements of medicine – PHARMA just seems to have jumped into the lead and made it all the way over to the dark side, becoming its own caricature.

    Kessel makes an eloquent plea for the value of corporate reputation, and outlines changes that would, indeed, improve both the company’s image and function. But I expect most of the multinational PHARMAs already have a "workgroup" "tasked" with the same thing. GSK has Sir Andrew Witty out front carrying a banner of reform while his Chinese division is bribing physicians to prescribe their drugs. Alex Gorsky of Johnson & Johnson masterminded Risperdal®’s meteoric rise, and now an army of lawyers works to keep him out of a courtroom as they try to cut their losses in the aftermath. In the legal actions, PHARMA settles the government suits rather than allowing them to go to a jury, and later "denies any wrong-doing" – no matter what they admit in the settlement agreements. In the Civil suits, they play the legal chess in the appeal courts when they lose – much like the culture of jail-house lawyers inhabiting our crime dramas.

    Whether cynicism or pragmatism, I doubt Kessel’s good advice will change the directions of PHARMA:
    According to Alexander Brigham and Stefan Linssen of the consulting firm Ethisphere Institute, over the past three decades, the percentage of a company’s value attributable to tangible assets has dropped from 90% to just 25%. Other estimates also suggest that it is the intangible assets of a company [including reputation] that currently represent as much as 40–60% of a corporation’s market capitalization. Thus, a company’s reputation is among its most valuable assets.

    My read is that these major pharmaceutical corporations have completed the move from being drug·discovery and drug·manufacturing companies, part of the legitimate health care effort, to being drug·selling cash·cows in the business of "doing business" [in the Bernie Maddof/Enron tradition]. I would suspect any moves they made in the reform arena would be called "brand·building" in their meetings – illusions they definitely know how to create [that should probably be followed with mumbles like at the end of the DTC ads as we watch the cured patients and colorful butterflies]. Meanwhile, here‘s the Forbes’ version of a PHARMA argument lest you’re hoping for anything but the business of "doing business."

    No, as most of us have long preached, rapidly escalating fines and criminal prosecution of the actual people involved is the only real recourse for the moment. But, like Kessel, I can have my fantasies. The most disillusioning piece of this story is the complicity of physicians that are apparently easily "hired on." Medicine, unlike the pharmaceutical industry, does have an intrinsic ethic, a traditional morality to draw on. Without the complicity of physicians, this whole game is dead in its tracks. If there’s a place to make a dent in this madness, it’s in aiming for a time when an accurate Physician Payments Sunshine Act Database is every bit the Hall of Shame it’s intended to be…
    Mickey @ 1:19 PM
    Filed under: OPINION
    restoring pharma I…

    Posted on Wednesday 22 October 2014

    I want to say some things about this article later…
    by Mark Kessel
    Nature Biotechnology 2014 32[10]:983–990.
    … but first, here’s a graphic and table to ponder:

    Date Pharma Fine [$M] Infringement

    02/2014 Endo
    193 criminal and civil liabilities arising from Endo’s marketing of the prescription drug Lidoderm [lido-caine]. As part of the agreement, Endo admitted that it intended that Lidoderm be used for unapproved indications and that it promoted Lidoderm to healthcare providers this way.
    11/2013 J&J 2,200 criminal and civil allegations relating to illegal promotion of the prescription drugs Risperdal [risperidone], invega [paliperidone] and Natrecor [Nesiritide] for uses not approved as safe and effective by the FDA, the targeting of elderly dementia patients in nursing homes, and the payout of kickbacks to physicians and to the nation’s largest long-term care pharmacy provider, Omnicare.
    12/2012 Amgen 762 criminal and civil charges that the company illegally introduced and promoted several drugs, including Aranesp [darbepoetin alfa], a drug to treat anemia. Amgen pleaded guilty to illegally selling Aranesp to be used at doses that the FDA had explicitly rejected, and for an off-label treatment that FDA had never approved.
    Sanofi 109 Allegations that company gave doctors free units of Hyalgan [hyaluronate injection to relieve knee pain] to encourage sales, lowered the effective price by promising doctors free samples, while at the same time obtaining inflated prices for the drug from government programs by submitting false price reports.
    10/2012 Boehringer Ingelheim 95 Allegations that company promoted several drugs including Aggrenox [aspirin/dipyridamole], Atrovent [ipratropium], Combivent [Ipratropium/albuterol] and Micardis [telmisartan] for nonmedical ly accepted uses.
    07/2012 GSK 3,000 Civil and criminal liabilities regarding misbranding of Paxil for treating depression in patients under 18, even though the drug had never been approved for that age group as well as failure to disclose safety information about Avandia to the FDA.
    05/2012 Abbott 1,500 illegal promotion of Depakote [divalproex] in indications for which it had never been approved: schizophrenia and control of aggression and agitation in elderly dementia patients.
    11/2011 Merck 950 illegal promotion of Vioxx as a treatment for rheumatoid arthritis before it had been approved for that use and misrepresentation of the drug’s heart safety to increase sales.
    04/2010 Astra-Zeneca
    520 Allegations of illegal promotion of Seroquel [quetiapine] for a variety of unapproved uses, such as aggression, sleeplessness, anxiety and depression. The company paid the fine but denied the allegations.
    09/2009 Pfizer 2,300 Misbranding Bextra with "the intent to defraud or mislead," promoting the drug to treat acute pain at dosages the FDA had previously deemed dangerously high. Bextra was pulled from the market in 2005 due to safety concerns. The government alleged that Pfizer also promoted three other drugs illegally: Geodon [ziprasidone], Zyvox [linezolid]and Lyrica [pregabalin].
    01/2009 Eli Lilly 1,420 Off-label promotion of Zyprexa [olanzapine] to elderly populations to treat dementia. The US government also alleged that Lilly targeted primary care physicians to promote Zyprexa for unapproved uses and "trained its sales force to disregard the law."
    Mickey @ 12:30 PM
    Filed under: OPINION
    a clarification…

    Posted on Tuesday 21 October 2014

    "I venture to suggest that most practicing psychiatrists, if pressed, would choose to replace or discard any existing treatment or intervention save one: the power to impose a treatment or intervention."

    Note the list of people authorized to sign the Commitment form. In addition, the Georgia Advocacy Office has an explanation of the processes involved in any involuntary hospitalization or treatment. The word "psychiatrist" is nowhere found. At least here, the power discussed above hasn’t been around for a long time. All involuntary hospitalization or involuntary medication is decided by a court hearing with full representation. I expect that most States have similar laws, but maybe Georgia is just a very enlightened place…
    Mickey @ 10:00 PM
    Filed under: OPINION

    Posted on Tuesday 21 October 2014

    With the American Academy of Child and Adolescent Psychiatry meeting in San Diego right now, I’m having something of a remembrance of things past period. Of course there’s Paxil Study 329 which stands in my mind as a paradigm for an infamous era, along with a other less well known Clinical Trials suggesting that the SSRIs are effective and safe in the treatment of adolescent depression [ie more Wagner et al]. It remains a major unresolved question in my mind why the Journal of the American Academy of Child and Adolescent Psychiatry is still unwilling to retract Paxil® Study 329, or for that matter, why the American Journal of Psychiatry didn’t [and still doesn’t] retract Wagner et al’s ghost written Citalopram [Celexa®] paper [collusion with fiction…]. And I continue to wonder why journals still publish the stream of papers attempting to discredit the Black Box Warning on these drugs about the uncommon but potentially fatal suicidality that the drugs sometimes cause [a betrayal…]. It’s like the ripples from that period when the pharmaceutical industry, complicit psychiatrists, and journals were publishing fiction-as-fact under the cover of darkness won’t die out.

    There was one issue from that period that remains very sticky – Pediatric Bipolar Disorder. It’s sticky because the patients in question really exist, and the medications in question really work, and the treatment questions are really tricky for anyone who actually sees these cases. And whether these cases represent a distinct group or not is, itself, an open question in my mind. To use Dr. Joseph Biederman’s term, they are children with super angry, grouchy, cranky, irritability. They drive parents, teachers, siblings, psychiatrists, therapists, and themselves crazy. They usually have the clinical findings of ADHD [with a capital H] but there’s no cure with stimulants, and if you give them antipsychotics, they do become more manageable – but... These are among the kids that get drugged, often in response to pleas by parents, caretakers, psychologists, social workers, teachers, etc. – the exasperated people who deal with them. I’ll skip the many diagnoses invented for this maybe-group, except for one – Pediatric Bipolar Disorder.

    When Risperda® was introduced, it came with a study of behavioral treatment for retarded children that was, of course, positive [genuinely positive] [see trial 93: a bad penny…]. Janssen’s application for FDA Approval was turned down. When Dr. Biederman began to say that these kids with super angry, grouchy, cranky, irritability had Pediatric Bipolar Disorder, this study was republished and repurposed under Dr. Biederman’s name [Risperidone for the treatment of affective symptoms in children with disruptive behavior disorder: a post hoc analysis of data from a 6-week, multicenter, randomized, double-blind, parallel-arm study] and the rest is history. Pediatric Bipolar Disorder took off like wildfire and the papers flowed from everywhere [I called it Biedermania].

    I’ve reviewed all of this ad nauseum. And I ended up wondering if Pediatric Bipolar Disorder even exists, or if it does, thinking it’s uncommon. In my opinion, the reason Pediatric Bipolar Disorder caught on was that Child Psychiatrists and Pediatricians who were seeing these extremely difficult kids were previously guiltily treating them with antipsychotics for behavior control [unable to place them in the tough love token economy environments of the past], and that the diagnosis of a disease treated with a medicine for that disease took away the guilt. I was volunteering in a child clinic for a time, and I ultimately quit working there because of this very issue. The pressure to medicate with antipsychotics was overwhelming because there were no rational alternatives, and that’s just not my cup of tea. It’s simply a do no harm thing for me. But I felt some empathy for my colleagues who were and are in that double bind, and couldn’t just say, "No thanks."

    So back to the ripples. Looking over the faculty at AACAP, Drs. Biederman and Wozniak who were the Pediatric Bipolar Disorder gurus are not listed at all on the faculty of the American Academy of Child and Adolescent Psychiatry meeting today in San Diego, though they’re still publishing regularly about the condition they popularized. And the ripples are still reverberating in the halls of the AACAP:

    I wish I knew the contents of numbers 1 and 3, just wondering what they’re saying about Pediatric Bipolar Disorder and the use of the SSRIs in depressed adolescents. But that roster is not intended to be an indictment of the AACAP. Compared to my remembrance of things past, it’s a remarkable improvement. Even the topics are more benign and rational. But they’re all ripples nevertheless. It’s time for the ripples from that time in our history to stop…

    Mickey @ 4:47 PM
    Filed under: OPINION
    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

    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
    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
    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