already gone?…

Posted on Thursday 7 April 2016

"Over the pa$t two decade$, largely becau$e of a few widely publicized epi$ode$ of unacceptable behavior by the pharmaceutical and biotechnology indu$try, many medical journal editor$ [including me] have made it harder and harder for people who have received indu$try payment$ or item$ of financial value to write editorial$ or review article$. The concern ha$ been that $uch people have been bought by the drug companie$. Having received indu$try money, the argument goe$, even an acknowledged world expert can no longer provide untainted advice. But i$ thi$ divide between academic re$earcher$ and indu$try in our be$t intere$t? I think not – and I am not alone. The National Center for Advancing Tran$lational $cience$ of the National In$titute$ of Health, the Pre$ident’$ Council of Advi$or$ on $cience and Technology, the World Economic Forum, the Gate$ Foundation, the Wellcome Tru$t, and the Food and Drug Admini$tration are but a few of the in$titution$ encouraging greater interaction between academic$ and indu$try, to provide tangible value for patient$. $imply put, in no area of medicine are our diagno$tic$ and therapeutic$ $o good that we can call a halt to improvement, and true improvement can come only through collaboration. How can the divide be bridged? And why do medical journal editor$ remain concerned about author$ with pharma and biotech a$$ociation$? The rea$on$ are complex. Thi$ week we begin a $erie$ of three article$ by Li$a Ro$enbaum examining the current $tate of affair$."
by Jeffrey M. Drazen, MD, Editor
NEJM 2015 372:1853-1854.

I added back in what I think Editor Jeffrey Drazen is leaving out of his argument in this current campaign. I’m not as unsympathetic to some of his argument as one might think. Thirty-five years ago, I was in an academic department under a Chairman who had shown a surprising amount of skill in his thirty year tenure financing a growing department in a place where there really wasn’t anything to start with. But by the time I came along, he had run out of tricks. We had virtually no institutional support, which is pretty much the rule in medical academic departments. He’d always maximally utilized Federal Grant support. Resident and faculty salaries came from City/County, State, VAH, and private hospital placements. And he had done well with private donations. But it was all drying up at an almost palpable rate. Increasingly, my job was juggling the training needs of our residents with literally selling their services to earn their pay.

After I left, it was obvious that the post-DSM-III medical psychiatry was a more lucrative enterprise and that they were no longer operating on a shoestring, and I wasn’t so naive that I didn’t know how they brought it off. I guess I assumed that they were doing Clinical Trials and drug research to bring in the needed funding. I don’t recall thinking about it very much beyond that. So when I became reacquainted with such matters a quarter of a century later, I wasn’t surprised about the unrestricted institutional grants or the clinical trials. Their new money had to be coming from some place. But I was oblivious to the direct payment to faculty by industry in the form of Grants, Advisory Committees, or Speakers Bureaus. And that’s what Drazen is talking about, "academician$ who are receiving per$onal money from the pharmaceutical companie$". He’s implying that they can render editorial or review article opinions unbiased by the fact that they are being paid in some form or another by the manufacturer of the drugs being reviewed. It’s not the dialog between academia and industry that’s in question, it’s the money. And his opening sentence …

    "Over the pa$t two decade$, largely becau$e of a few widely publicized epi$ode$ of unacceptable behavior by the pharmaceutical and biotechnology indu$try, many medical journal editor$ [including me] have made it harder and harder for people who have received indu$try payment$ or item$ of financial value to write editorial$ or review article$.
… is like calling Europe’s Black Death epidemic "a few widely publicized cases of Pasteurella pestis."

I thought it was just psychiatry for a while, selling out to industry justified by dire straights. But it’s increasingly apparent that it’s all of medicine that’s playing with the same fire that has been so disastrous for my own specialty. And Jeffrey Drazen, editor of the New England Journal of Medicine is taking a lead in not just condoning it, but telling us it’s a good idea. After suggesting that experts who have personal financial Conflicts of Interest can write unbiased editorials and review articles [an obvious impossibility], he follows up a few months later with an attack on people who re-analyze data they think has been jury-rigged, calling  them  us "data parasites." And then later, he puts a cherry on top of this Sundae by dismissing confrontations about articles reporting drug trial results in his journal with protocol violations [How did NEJM respond when we tried to correct 20 misreported trials?].

I suppose that we should’ve expected this when the New England Journal of Medicine fired Jerome Kassirer and hired Jeffry Drazen in 1999 over these self-same issues. But it’s a bitter pill to swallow following editors like Arnold Relman, Jerome Kassier, and Marcia Angell [see a narrative…] who were champions in Medicine’s navigation between the Scylla of Managed Care and Charybdis of Industrial Conflicts of Interest – trying to preserve some semblence of a medical ethic. In my last post, I said "he has to go" but should’ve added "before the New England Journal of Medicine goes with him." But maybe that’s my naïveté once again in failing to accept that the New England Journal of Medicine may already be gone…
Mickey @ 12:49 PM

a must read…

Posted on Tuesday 5 April 2016

Amid Public Feuds, A Venerated Medical Journal Finds Itself Under Attack
by Charles Ornstein
April 5, 2016

The New England Journal of Medicine is arguably the best-known and most venerated medical journal in the world. Studies featured in its pages are cited more often, on average, than those of any of its peers. And the careers of young researchers can take off if their work is deemed worthy of appearing in it.

Jeffrey Drazen MDBut following a series of well-publicized feuds with prominent medical researchers and former editors of the Journal, some are questioning whether the publication is slipping in relevancy and reputation. The Journal and its top editor, critics say, have resisted correcting errors and lag behind others in an industry-wide push for more openness in medical research. And dissent has been dismissed with a paternalistic arrogance, they say.

In a widely derided editorial earlier this year, Dr. Jeffrey M. Drazen, the Journal’s editor-in-chief, and a deputy used the term “research parasites” to describe researchers who seek others’ data to analyze or replicate their studies, which many say is a crucial step in the scientific process. And last year, the Journal ran a controversial series saying concerns about conflicts of interest in medicine are oversimplified and overblown.

“They basically have a view that … they don’t need to change or adapt. It’s their way or the highway,” said Dr. Eric Topol, director of the Scripps Translational Science Institute and chief academic officer at Scripps Health in La Jolla, California…
We are warned that the weakest way to attack an argument we disagree with is to disparage the author of that idea. So avoid ad hominem attacks –  to the man. But in this case, things are different. The argument is actually with the man himself. I’ve tried to keep up with Dr. Drazen’s many splendored bad ideas and arrogance. Ornstein does a better job than I could of cataloging the facts in the case [did I mention that it’s a must-read]. But over and above Dr. Jeffrey Drazen’s bad ideas, and his barely veiled nasty temperament, he’s just not New England Journal of Medicine Editor material. He’s been there for a long time, but now he’s let the cat out of the bag. He needs to go. That’s simply that…
Mickey @ 9:16 PM

a sacred clown…

Posted on Tuesday 5 April 2016

Retraction Watch
by Ivan Oransky
March 16th, 2016

John Ioannidis is perhaps best known for a 2005 paper “Why Most Published Research Findings Are False” … Earlier this month, he published a heartfelt and provocative essay in the the Journal of Clinical Epidemiology titled “Evidence-Based Medicine Has Been Hijacked: A Report to David Sackett.” In it, he carries on a conversation begun in 2004 with Sackett, who died last May and was widely considered the father of evidence-based medicine…

Retraction Watch: You write that as evidence-based medicine “became more influential, it was also hijacked to serve agendas different from what it originally aimed for.” Can you elaborate?
John Ioannidis: As I describe in the paper, “evidence-based medicine” has become a very common term that is misused and abused by eminence-based experts and conflicted stakeholders who want to support their views and their products, without caring much about the integrity, transparency, and unbiasedness of science…

Retraction Watch: You also write that evidence-based medicine “still remains an unmet goal, worthy to be attained.” Can you explain further?
John Ioannidis: The commentary that I wrote gives a personal confession perspective on whether evidence-based medicine currently fulfills the wonderful definition that David Sackett came up with: “integrating individual clinical expertise with the best external evidence”. This is a goal that is clearly worthy to be attained, but, in my view, I don’t see that this has happened yet. Each of us may ponder whether the goal has been attained. I suspect that many/most will agree that we still have a lot of work to do.

Retraction Watch: You describe yourself as a “failure.” What do you mean?
John Ioannidis: Well, I still know next to nothing, even though I am always struggling to obtain more solid evidence and even though I always want to learn more. If you add what are probably over a thousand rejections [of papers, grant proposals, nominations, and other sorrowful academic paraphernalia] during my career to-date, I think I can qualify for a solid failure. Nevertheless, I still greatly enjoy my work in science and in evidence-based medicine.

Retraction Watch: You say that your first grant, which you applied for 17 years ago, was “not even rejected.” Tell us about that grant.
John Ioannidis: It was a randomized controlled trial of antibiotics versus placebo for acute sinusitis. Hundreds of millions of people were treated with antibiotics without good evidence back then, and hundreds of millions of people continue to be treated with antibiotics even nowadays even though most of them would not need antibiotics. I sent in the application to a public funding agency, but have not heard back yet. Probably they felt that requesting funding for a randomized trial and not going to the industry for such funds was a joke. Many public funding agencies are accustomed to funding only research that clearly has no direct relevance to important, real-life questions, so perhaps they didn’t know where to place my application….
Most cultures have some figure who stands outside the mainstream and is allowed to say the things the rest of us can’t get away with saying. In Medieval Times, it was the Court Jester, or the Royal Fool. In our Southwestern Native American culture, they were the Pueblo and other Sacred Clowns. In classic Greek Tragedy, it was often the chorus. Such figures can be sarcastic, even openly hostile, iconoclastic, and  can generally deliver the cold hard truth [in a light-hearted way]. I think of John Ioannidis as occupying such a place in Medicine.

I know that my eyes roll when people start sprinkling terms like evidence-based medicine, best practices, clinical guidelines, etc. in their articles and presentations. I realize that those are important concepts, but they’re so frequently co-opted by other motives that my eye-rolling has almost become an involuntary reflex. But it’s his joke about public funding going to "only research that clearly has no direct relevance to important, real-life questions," that has my attention right now. As much as  we  I complain about the self-serving nature of PHARMA-funded medication research, who else is funding Clinical Trials of drugs? or simple practical studies like do antibiotics help sinus infections? I’m afraid the answer is  almost  nobody.

One place where I frequently find myself thinking about this is the RCTs done on psychiatric medications. The mandate of the FDA is primarily focused on safety, and efficacy is in the mix as a minimal standard, a 1962 afterthought: two statistically significant RCTs out of however-many-they-want-to-do, which can lead to something like the "me too" parade I was describing in the the pipeline paradigm… As I understand it, the lite efficacy testing is there to eliminate snake oil [eg inert medicinal products, the patent medicines of yore], not to inform judgements about prescribing. This is a chart the Atypicals in Schizophrenia by year of introduction, with the effect sizes from a meta-analysis added in…

… hardly representing a progression of increasing efficacy [level, or drifting south?]. One might suspect an incremental safety factor or side effect profile, but that’s not there either. The antidepressant data is harder to gather, but it looks like it degrades by perhaps even more with successive molecules [still work in progress]. The FDA just does what it’s mandated to do – two significant studies and a safety certification, usually based on short term exposure. Reform suggestions often hover around approving only drugs that offer improvement over existing drugs – but in practice that becomes the fuzziest of calls. Others suggest independent, longer running RCTs. That would just be wonderful, except these studies cost a mint, and there’s just no funding source. Sacred Clown Ioannidis’ speaks the truth. Non-industry funding goes to sexier stuff rather than such routine [but vital] independent comparisons.

We have mostly short-term RCTs done either for FDA approval or for a bit of indication creep  with their heavy dose of COI and bias. And no amount of re-analysis or meta-analysis of these early-on RCTs can really get at what we want to know – efficacy and side effects over time in the real world without the spin and sin. Managed Care isn’t any more interested in paying for ongoing research than anyone else, so MD visits remain limited in time and frequency hindering our personal learning from our own patients. It’s easy to hatch "on site" research fantasies, but "translating" such things into a workable reality is quite another matter. Thus Sackett’s evidence-based medicine can downgrade to a trope, or a cliché, or even a trick rather than “integrating individual clinical expertise with the best external evidence.”

Actually, things overall are improving. The prosecutions are down, the data transparency movement is on the move, and the public seems more aware. But bringing honesty to trial reporting isn’t going to change the fact that we have mostly short-term front loaded trials and little else. Somewhere down this road, we need to move beyond approval into clinical usage with our RCTs. Until then, the message of Sacred Clown John Ioannidis will have to keep echoing until someone hears it. Stripped of its misuses, evidence-based medicine is a term that actually means something…
Mickey @ 8:33 PM

a couple of points…

Posted on Sunday 3 April 2016

The residue of undue influence we call Conflict of Interest spreads like jungle vines in an deserted temple, and the longer the absence, the harder the restoration. In a recent [silly] JAMA Viewpoint article,
by Anne R. Cappola and Garret A.
September 24, 2015
we were told Conflict of Interest was a pejorative term and should be changed to Confluence of Interest [in a bid to suggest something like synergy]. While our collective eyes rolled at the time [see a creative rationalization…,, selective inattention… have no place…], there’s a way in which the term is appropriate – as in a confluence of rivers, where contamination is guaranteed. And to push my analogy, the further you go downstream, the more muddied the distinctions.

In following the Brintellix® for Cognitive Dysfuntion in Major Depressive Disorder story [a parable…], I ran into a examples where the COI laden literature is what seems headed downstream – into the future. Both of the supporting studies and a pre-emptory review article are available full text on-line – industry funded, industry designed, industry written, authors industry tainted or employed:

On the other hand, a well researched critique of the literature about Brintellix® and its approval are behind a $41 pay wall in an otherwise inaccessible journal [to have made it available Open Access would have cost ~$3000]:
by Lisa Cosgrove, Steven Vannoy, Barbara Mintzes, and Allen Shaughnessy
Accountability in Research. 2016 Feb 18. [Epub ahead of print]

The relationships among academe, publishing, and industry can facilitate commercial bias in how drug efficacy and safety data are obtained, interpreted, and presented to regulatory bodies and prescribers. Through a critique of published and unpublished trials submitted to the Federal Drug Administration [FDA] and the European Medicines Agency [EMA] for approval of a new antidepressant, vortioxetine, we present a case study of the "ghost management" of the information delivery process. We argue that currently accepted practices undermine regulatory safeguards aimed at protecting the public from unsafe or ineffective medicines. The economies of influence that may intentionally and unintentionally produce evidence-biased-rather than evidence-based-medicine are identified. This is not a simple story of author financial conflicts of interest, but rather a complex tale of "ghost management" of the entire process of bringing a drug to market. This case study shows how weak regulatory policies allow for design choices and reporting strategies that can make marginal products look novel, more effective, and safer than they are, and how the selective and imbalanced reporting of clinical trial data in medical journals results in the marketing of expensive "me-too" drugs with questionable risk/benefit profiles. We offer solutions for neutralizing these economies of influence.
POINT 1: The Literature is what persists
In medicine, the thing that lasts is the published academic literature. Blog posts and press releases will evaporate sooner or later. So what will be available long term full text on-line will be those industry funded, industry designed, industry written, industry authored articles. In time, Cosgrove et al will require an archeologist to locate after a few years. It’s already hard enough. It’s because the industry funded ghosted studies come from deep pockets for whom the online fee is nothing, and because they’re in high impact journals. The critiques are hard to get published, usually unfunded, and there’s no loose petty cash to pay the Open Access fees. That’s one of the reasons for RIAT [Restoring Invisible and Abandoned Trials], to keep the other side of the story in The Literature [downstream]…

So what’s being passed to the future is the COI laden story, not the balancing independent, unfunded critique. Sooner or later, I’ll review their whole paper, but right now I wanted to focus on one particular piece of it. In looking over a new article, many of us reflexively look at the Conflict of Interest declarations and the funding to see if a clinical trial is industry funded and authored. A few years ago, we checked to see if the academic authors had COI and if it was ghost written. But they tightened the rules, and it hasn’t much mattered. The COI is now quickly apparent as well as the whatever-they-call the ghost-writer. Often they don’t even bother to have an academic author these days, just employees. And it doesn’t seem to make any difference except to cut down on the sponsors publication costs [which makes one wonder why an academician-free article is even in an academic journal anyway?]. We’ve apparently gotten enured to what was once taboo.

But Cosgrove et al added something that hasn’t occurred to me, and I haven’t noticed before. In looking at the COI, they went beyond the listed authors:
    Below is a summary of the industry-publishing relationships of the eight published studies submitted to the FDA and one additional study submitted to the EMA that was published…
    1. In eleven of the thirteen publications, the majority of authors were employees of the manufacturer, and in four of the thirteen published studies, all authors were company employees.
    2. In all of the trial reports, the authors explicitly thank an employee of the manufacturer for “assistance in the preparation and writing” of the manuscript or note that assistance with preparing and writing the article was provided by an employee.
    3. In nine of the thirteen published articles, the following issue was disclosed:
      [the manufacturer] was involved in the study design, in the collection, analysis and interpretation of data, and in the writing of the report.
    4. The thirteen published studies were published in seven academic journals. The editors of five of these journals had financial ties to vortioxetine’s manufacturer…

POINT 2: The Editors control The Literature
It’s number 4. They looked into the financial conflicts of interest of the Journal Editors. Of course we should’ve been doing that all along. It’s the Journal Editors that control the gateway into The Literature. It was Editor Myna Dulcan who opened the door to Paxil Study 329 and it is Editor Andres Martin who has kept it there for 15 years. It’s Jeffrey Drazen who wants to relax COI restrictions at the NEJM and thinks people who want to check articles are "parasites." If there’s any place where COI is a more important parameter, I don’t know where that might be. I would’ve naively assumed they didn’t have COI. Silly me.

So, while I believe that the idea of RIAT [Restoring Invisible and Abandoned Trials] remains a good solution for articles that are found to be questionable, there are lots of articles that can be identified almost from the get-go as in need of a strong counterpoint which is one part of what Cosgrove et al did in their article. So for POINT 1, we need more of those, but we also need some way to give people access to them – whether that means publishing in an Open Access journal, establishing journals for that specific purpose, or raising some money to give authors of those articles scholarships to pay Open Access fees. Contemporary criticism needs to travel alongside questionable literature as it rides into the future. And as for POINT 2, point taken!  In any article that appears to be COI-laden, we need to make the COI declaration of the Editor[s] a public part of any critique…
Mickey @ 9:35 PM

a pipeline rejig…

Posted on Saturday 2 April 2016

In the course of reading about the FDA’s rejection of Lundbeck/Takeda‘s bid for a Cognitive Dysfunction in MDD for Brintellix® [still going strong?…], I ran across another article in FiercePharma, the one that got me thinking about the pipeline in general [the pipeline paradigm…]. It’s about another Lundbeck drug – an Atypical Antipsychotic [Lu AF35700] – note the date. If I read this right, they’ve completed three Phase 1 Clinical Trials,
been granted Fast-Track status by the FDA [November 2015], and are off and running with a Phase III Clinical Trial,
By Nick Paul Taylor
March 17, 2016

Lundbeck has started the first of several planned Phase III trials of its candidate against treatment-resistant schizophrenia, Lu AF35700. The candidate is a key component of the turnaround strategy initiated by Kåre Schultz, who has shed other pipeline prospects in order to up Lundbeck’s bet on Lu AF35700 since taking over as CEO last year.

Copenhagen, Denmark-based Lundbeck is kicking off the pivotal trial program of the experimental drug with a Phase III study that will recruit 1,000 patients across 15 countries. In the study, Lundbeck will administer one of two doses of Lu AF35700 to patients with treatment-resistant schizophrenia. If the drug works as Lundbeck hopes, participants’ scores on the Positive and Negative Syndrome Scale [PANSS] will improve following 10 weeks of treatment. The primary PANSS endpoint is being supplemented with Clinical Global Impression – Severity of Illness scores and Personal and Social Performance Scale data.

Lundbeck expects to be running the study for the next three years, during which time it will roll out additional trials with a view to gathering data on more than 2,000 people with treatment-resistant schizophrenia. The size of the bet is proportional to Lundbeck’s assessment of the scale of the unmet need and opportunity associated with treatment-resistant schizophrenia. "Today there is only one therapy approved for patients with treatment-resistant schizophrenia, and its use is severely limited by its problematic safety profile," Lundbeck R&D Chief Anders Gersel Pedersen said in a statement…

The drug they’re looking to compete with is Clozaril, based on the fact that Lu AF35700 has a strong D1 receptor binding like Clozaril, but a weaker D2 binding. Surely I’ve missed something here because the only study I see in Schizophrenia is the 3 week safety study – nothing that even determines that the drug has antipsychotic properties that I could find [?]:
By Nick Paul Taylor
August 20, 2015

Lundbeck  has initiated a rejig of its pipeline, taking an ax to undisclosed early-stage assets in order to funnel cash into what it sees as its most promising candidates. The schizophrenia drug Lu AF35700 is among the beneficiaries of the reshuffle, with Lundbeck using its reorganized balance sheet to advance the therapy through development unpartnered.

Copenhagen, Denmark-based Lundbeck unveiled the tweaks to its R&D priorities alongside sweeping changes to its operations, which will see it shed 1,000 jobs in an attempt to become profitable. The commercial operation is expected to bear the brunt of the cuts but R&D will be affected, too, with recently-appointed CEO Kåre Schultz committing to dropping certain early-stage assets. Trimming the pipeline will allow Lundbeck top focus its cash on programs in which it thinks it has the clearest understanding of the underlying science, such as the schizophrenia drug Lu Af35700.

"35700 is an antipsychotic with a profile that is somewhat different than most drugs available. What we see is that many of the drugs that are available on the market today are predominantly driving effects through D2," Lundbeck R&D chief Anders Gersel Pedersen said on a conference call. 35700, like clozapine, has a strong binding affinity to the D1 receptor. Lundbeck hopes to differentiate its pipeline candidate from clozapine through its side effect profile, giving patients who are resistant to D2-targeted drugs a treatment option that doesn’t cause weight gain and metabolic disturbances. Lundbeck’s belief in this hypothesis has led it to conclude Lu Af35700 is among its most promising early-stage assets. "We have to put our bets where we think we have the best ability to translate science into products," Pederson said…
While this post is a little bit about Lu AF35700, I’ll have to admit it’s also about something else. When the announcement that the FDA had turned down that sNDA for Brintellix®, I was intrigued by the number of sites Google found echo-ing the announcement. They were mostly business/investor sites and they had a surprising amount of sophisticated science thrown in. I started looking at what else was on those sites, and was frankly amazed. I’ve spent the last several days bouncing from place to place in that domain that was, for me, new territory. One thing I learned was that if you want to know about what’s in the pipeline and what’s up with clinical trials, that’s the place to look – not in the medical universe [unless you consider that the medical universe].

A lot of the material on the investor sites came from press releases by the various PHARMA companies, and so they were generally upbeat, like this one for Lu AF35700. I had a few laughs thinking that the investment world was in the same boat we’re in, a target for spin, and in real need of some Data Transparency too. But there were some other things – like this quote about the Brintellix® ruling:
The FDA doesn’t have to follow the advice of its expert review panels, but it usually does. That’s a standard line in stories about advisory committee votes. Unfortunately for Lundbeck and Takeda, their new Brintellix app is one of the unlucky ones.
I doubt most of us would say it that way ["unlucky"]. There was a surprising-to-me absence of attention to the actual medical benefit or risk – mainly comments on success or failure of various gambits. I’m not being hyper-moral here, business sites are about business after all. It was just a bit jarring – as was something else. Much of this literature is about strategies. It reads like a huge chess game with the various moves and gambits cataloged, and sometimes relished. In the case of Lu AF35700, Lundbeck’s new CEO, Kåre Schultz,  is shutting down some of Lundbeck’s R&D, laying off employees, and dropping other candidate drugs to raise the cash for his big bet on Lu AF35700 [AKA rejig]. A 1000 Subject three year International Clinical Trial is apparently going to cost them a mint. Just like the failed bet they made on Brintellix® to be a think-better antidepressant cost them dearly. It’s little surprise they hauled in the uber-KOLs for that FDA hearing.

I hadn’t thought of it before, and maybe it was The Big Short movie that had me in this frame of mind, but a lot of the investing in pharmaceuticals is analogous to the Commodities Market – betting on a future value. Again, the pipeline paradigm, as in being in a position to reap large profits when and if the product flows out into the market. I suppose any business venture is like that, but here, it’s in bas relief because of the long development process, the FDA’s yes/no position, the guaranteed time limited monopoly afforded by the patent/exclusivity laws, and the presence of those pesky middlemen [AKA physicians]. So if Lu AF35700 turns out as they hope [a non-toxic Clozaril], as things now stand, they’ll be able to charge Gilead/Valeant/Shkreli prices – the treatment-resistant Schizophrenia patients are unlikely to have very deep pockets, so I presume they’re aiming at third patry payers.

There’s plenty more to say about the Lu AF35700 study itself, but it’s for another day. I just wanted to report on my visit to other side…
Mickey @ 1:36 PM

the pipeline paradigm…

Posted on Thursday 31 March 2016

It really does sort of look like a pipeline. It’s the SSRis, SNRIs, and Atypicals graphed by the  year of their FDA Approval. The first time I ever heard that term, pipeline, I thought it was a joke of some kind. But I found out it was in wide usage in the business and KOL worlds. I wonder if there was a similar chart for the First Generation Antipsychotics? for Tricyclic Antidepressants? or for the Benzodiazepines? some string of "me too" drugs that stretches all the way back to the 1950s?

I know that when I showed up for a psychiatric residency in 1974, I thought there was sure a lot of chatter about  only a few categories of drugs. In internal medicine, I can’t recall anything similar. Admittedly, I spent those medicine years in public facilities that had more limited formularies, but I doubt that there was anything like what I encountered coming to psychiatry. There was a difference back then. We talked about the differences among ourselves and picked the best choice for the situation. I for one didn’t even know which company made which drug or what was new and what was old. Now, the patients have often already tried many of them, and sometimes made a choice based on what they’ve heard about from somebody or seen on television before they show up ["ask your doctor if kerfunkeltine is right for you"]. In fact, that’s why they’ve come. Here are those drugs labeled:

I may have missed a few or added one or two that ought not be there, but I was aiming for a Gestalt, and I think it comes across. And alongside the flow of new drugs, there were lots of other things for Key Opinion Leaders [KOLs] to talk about: Sequencing; Combining; Augmenting; Indications; Statistics; XRs; StereoIsomers; Genetics; Receptors; Neurotransmitters; etc.

In my own mind, I saw classification like I later learned Karl Jaspers had: Brain Disease, the Major Syndromes [Psychotic Illness]; and Other. The Biological Psychiatrists were focusing on the Major Syndromes with treatment and etiologic research. And there were any number of disciplines and approaches in the fuzzy Other group, presumed to be psychological in origin and treatment. The DSM-III was an attempt to get the theories [specifically psychoanalytic theories] out of diagnosis, which made sense. But it also ablated the border between the Major Syndromes and the fuzzy Other group in the process.

Over time, there was a new boundary: Mainstream Psychiatrists treating with medications and researching the brain, and other disciplines focusing on psychotherapy and matters social. But for my purpose here, that pipeline now emptied onto the entire domain  of mental health treatment. PHARMA and Managed Care institutionalized this new way of looking at things. There were many who didn’t follow along, but were basically working off-the-grid. New Industries rose up [Contract Research Organizations, Medical Writers]. Old Institutions waned [mental hospitals, community mental health] or changed [jails-as-mental-hospitals]. And in the last decade the whole thing has turned into what could only be called one mell-of-a-hess.

I originally constructed that pipeline graph because in spite of all the hoopla about it drying up, it looked to me like it was still dripping. But I didn’t have much success in locating what else is under development [other than the Ketamine dreams]. And as I looked at it, I began to have another thought. It’s obvious that right now, we’re all in a period of paradigm exhaustion in this whole corner of the healthcare world. The focus is on what’s wrong with all the models instead of what each has to offer. The drugs are weak, over-used, more toxic than advertised. CBT’s effectiveness is waning, and no other specific psychotherapy fits the bill. Neuroscience, Genomics, and Technology have let even their biggest cheerleaders down  [Clinical Neuroscience? bah humbug!]. PHARMA is turning off CNS research. Guild Wars are reviving with an old familiar fire-in-the-belly and name calling. Even Managed Care is having trouble showing results.

As I mused about what paradigm is it that’s so exhausted?, I had the thought "you just drew it." I don’t mean the individual drugs, or even their classes. But the idea of a pipeline that would just keep on flowing and bringing the hope of something newer, something better. It was the pipeline that sustained KOL psychiatry. The other disciplines had gained access to third party coverage and practitioners worked to have a connection with a prescriber. Managed Care thrived on the existence of a pipeline of future hope and built a reimburement system around it. Researchers fought to do the Clinical Trials that sustained it. PHARMA milked it for all it was worth. Even the failings of the drugs kept people busy and things moving along. Nobody gave much thought about the fact that there were only two [maybe three] basic themes playing out in these drugs and that the main advantage was that they were better tolerated. The pipeline itself, or what it implied, is the paradigm that lasted for three decades – so long that for many, it’s all they’ve ever known. And when it started running dry, all hell broke loose. The rest of the universe may have already known that the pipeline is the paradigm, but I didn’t…

Mickey @ 3:47 PM

still going strong?…

Posted on Wednesday 30 March 2016

By Tracy Staton
March 29, 2016

The FDA doesn’t have to follow the advice of its expert review panels, but it usually does. That’s a standard line in stories about advisory committee votes. Unfortunately for Lundbeck and Takeda, their new Brintellix app is one of the unlucky ones. The agency issued a complete response letter on new labeling that might have given Brintellix a new edge in the crowded antidepressant field. The claim: Brintellix can give a brainpower boost to depressed patients, whose thinking abilities often suffer. Lundbeck and Takeda had scored study data showing that the novel med can help patients think, pay attention, and make decisions – something no other antidepressant had managed to pull off. And the trial didn’t test Brintellix against a placebo, but head-to-head with Eli Lilly’s rival drug Cymbalta.

When an FDA advisory panel met last month to review those data, they voted 8-2 for an approval. European regulators had already approved a new use for Brintellix, to improve cognitive function in depressed adults. The FDA didn’t agree, and that puts Lundbeck and Takeda’s long-term sales projection – $2 billion – in jeopardy. Lundbeck developed the med, and Takeda has U.S. marketing rights under a marketing deal with the Danish drugmaker…

In any case, the hoped-for cognitive claim will be delayed at best, and with just $94 million in 2015 sales, Brintellix hasn’t lived up to early launch expectations. It faces considerable competition in depression, particularly now that a raft of commonly used meds – including Pfizer’s Zoloft, Eli Lilly’s Prozac and GlaxoSmithKline’s Paxil – are now available in cheap generic versions. And with payers requiring patients to try older, less expensive meds before moving to brands, the marketing task for Brintellix has been heavy. After the panel vote last month, one investment firm pointed out that Brintellix would be "the only product on the market with a leaflet on cognitive effects," Alm. Brand wrote in a note to clients. Focusing label language on improvements in thinking, attention and decision-making "means doctors also will," the firm said…

Meanwhile, Lundbeck has been laying off workers and cutting other costs as part of a plan to save 3 billion kronor, or about $445 million, in annual costs by 2017. Most of the cuts were focused on the company’s HQ in Denmark and commercial operations, mainly in Europe.

Lundbeck stock from Feb 9 to March 30 [between the two FDA hearings]
There’s no problem with Data Transparency on Wall Street. This is just one of the many articles about the FDA’s denying Lundbeck’s play for the cognition indication in depression and there’s data all over the place. I’m pretty sensitive to the fact that a lot of the criticism of these drugs is generic – "drugs are bad!" – and I try to stay out of that sinkhole. My negativity about this submission really was based on the lack of replication in their two studies and their weak effect sizes [more vortioxetine story…], but I did try to look at their underlying metrics. All we have from the other side are the  slides from the NIMH presentation, but I thought they had done their homework. Here are their final two slides:

[click image for the .pdf]

They weren’t impressed. Any comments from the more savvy about quantifying Cognitive Dysfunction in Depression would be welcome. But at least from Wall Street’s perspective, this is being looked at as a delay rather than the end of the story.

During the last month, I’ve talked to a couple of people who mentioned that they’d been started on Brintellix® [given samples]. They both said something like, "It’s a new one. It’s supposed to help you [focus or think] better." or something like that. These were not patients – but the daughter of a friend and a friend of my daughter. I didn’t really register much at the time, but thinking about it now, that had to come from somewhere to the prescribing primary care doctor. I would guess from a detail person [drug rep]. While my anectdote is hardly a scientific survey, it gives me a pause. Whether it’s on a package insert or "a leaflet" doesn’t matter if it’s in the dialog. It’s like the political "talking points" that spread from talk radio host into the general conversation. And the investor guy isn’t wrong when he says, "Focusing label language on improvements in thinking, attention and decision-making ‘means doctors also will,’ the firm said…."

It has been four years since there was a general alarm in the KOL world about the "pipeline" running dry. But from where I sit, it seems like it’s still dripping, and the myths keep spreading. The idea of fixing it with a pill is still going strong…

Addendum: Maybe not. See the next post…
Mickey @ 10:30 PM

a parable…

Posted on Tuesday 29 March 2016

A month ago I ran across a MEDPAGE TODAY article about Vortioxetine [Brintellix®] and a hearing at the FDA [see indications… and more vortioxetine story…]. Brintellix® had been approved by the FDA for use in Major Depressive Disorder in September of 2014. I  had previously run across it through a review article in the Journal of Clinical Psychiatry in December 2014 – a ghost-written garbled affair with multiple KOL guest authors [see the recommendation?…]. It seems that the manufacturers [Takeda and Lundbeck] had been planning for years to try to get it approved for treating the Cognitive Dysfuntion in Major Depressive Disorder. That would be a new category for FDA Approval and would’ve become a strong selling point for this late-coming antidepressant. I found a recent article by Lisa Cosgrove et al who had done a case study of this particular drug and its approval process [Under the Influence: the Interplay among Industry, Publishing, and Drug Regulation] that contained the results of both published and unpublished trials showing that in comparator studies, Brintellix® had uniformly come up short. And I later read a blog on George Dawson’s Real Psychiatry [Vortioxetine] about it.

The FDA originally looked unfavorably on approving Brintellix® for Cognitive Dysfuntion in Major Depressive Disorder, seeing it as an example of pseudospecificity. But the manufacturers kept coming. In February 2015, there was a Workshop at the Institute of Medicine entitled Enabling Discovery, Development, and Translation of Treatments for Cognitive Dysfunction in Depression: A Workshop moderated by Tom Insel [NIMH] and Thomas Laughren [formerly FDA’s director of psychiatry products]. After the workshop, the FDA agreed to reconsider, but only in a public hearing with an independent advisory committee. That happened on Feb 3, 2016 [2016 Meeting Materials, Psychopharmacologic Drugs Advisory Committee]. It was an elaborate all day affair with presenters from all parties concerned. At the end of the day, the FDA Advisory Committee voted 8:2 in favor of recommending Approval. When I looked at the papers and the presentations, I disagreed. My reasons are cataloged in my second blog [more vortioxetine story…]:
  • The NIMH presentation was thoughtful and concluded that the psychometrics being used were not a valid sole proxy for a specific Cognitive Dysfuntion designation.
  • They had one positive study [FOCUS]. But the second study [CONNECT] didn’t replicate those results. It was reported as statistically significant, but in my opinion, the statistical analysis was flawed.
  • There’s nothing in my clinical experience or reading that suggests that the affective and cognitive symptoms in depression can be cleanly parsed in this way. Frankly, this felt like a commercially driven ploy.
So I bundled up my findings into a letter [essentially the two blog posts minus the 1boringoldman·isms] and set out to figure out where to send a letter to the FDA that might get read [much thanks to Drs. Lisa Cosgrove, Bernard Carroll, and Erick Turner for their pointers]. I started with the FDA Ombudsman [who knew there was one?]. It didn’t fit their sphere of operations, but they forwarded it to someone at the generic who was extremely helpful – sending it on to the reviewers herself and updating me with an email confirming it had gotten there. I was impressed. So I googled the topic last night, as I had often over the last month, and Bingo!
Mar 28, 2016, 20:02 ET

OSAKA, Japan and VALBY, Denmark, March 28, 2016 /PRNewswire/ — Takeda Pharmaceutical Company Limited [Takeda] and H. Lundbeck A/S [Lundbeck] today announced that the U.S. Food and Drug Administration [FDA] issued a complete response letter [CRL] for the supplemental new drug application [sNDA] to include new data in the clinical trials section of the U.S. label of Brintellix® [vortioxetine] for treating certain aspects of cognitive dysfunction in adults with major depressive disorder [MDD]. The FDA approved Brintellix on September 30, 2013 for the treatment of MDD in adults. The CRL does not apply to the use of Brintellix in MDD.

Takeda and Lundbeck are disappointed with the response given that the U.S. FDA Psychopharmacologic Drugs Advisory Committee [PDAC] voted 8 to 2 that Takeda and Lundbeck presented substantial evidence to support a claim of effectiveness for Brintellix in treating certain aspects of cognitive dysfunction in adults with MDD. However, the companies were pleased that FDA recognized the importance of cognitive dysfunction in MDD and view it as a legitimate target for drug development…
In case you don’t speak FDA-ese, a Complete Response Letter essentially means "No" [see Complete Response Letter Final Rule]. The proceedings are here.

I don’t nor will I ever know if my letter had anything to do with the FDA’s decision. Other than the average expectable "tree" narcissism ["if a tree falls in the forest and no one hears it, does it make a sound?], I’m not sure I care. I had already gotten my reward from hearing the echo. In another way, I’d actually feel even better if the decision came out this way totally based on the FDA’s own evaluation. Takeda and Lundbeck had gone all out and to a lot of expense trying for this indication [6 cognition-specific clinical trials, bringing a lot of big KOL guns to the IOM workshop and earlier hearing, etc]. I could only guess that the 8:2 vote for Approval was in response to their zeal and presentations. But it just wasn’t in the data, and that’s what the FDA is there to evaluate. So good on them. They did the right thing after all. As for my letter…

A Parable: Two years ago, my two closest friends died in the week after Easter, and so they are much in my mind. One was a photographer whose photographic chronicles of the poverty in the Mississippi Delta and in the Appalachian Mountains will never be forgotten. But as gifted as he was with his camera, he sure had his quirks. And he was never happier than when he was talking about the intrinsic evils of politics – any politics. He claimed to have never voted, and delighted in being asked why. "It’s a trick to make you think you matter," he would begin [showing his own Appalachian roots]. This dialog was part tongue in cheek, but part deeply felt. One day, we were all floating in our little lake on a hot summer day, and he started up with his usual exposition on politics. My wife [a prime candidate for an fMRI study to locate the political regions of the cerebral cortex] announced, "Al, you can’t talk about politics anymore. You’re on political restriction. If you’re not going to vote, you have no right to complain." We were surprised at her little speech, as we were all used to Al’s diatribes and knew they would pass shortly. He didn’t say much and we went back to whatever old friends do when they’re cooling off in a lake on a hot summer day. But after that, he started voting – I think every time it came up until he died. I don’t know for sure that those things were 1:1 related, but I’d bet good money they were…
Mickey @ 3:29 PM

more than enough…

Posted on Monday 28 March 2016

This last weekend, I finally saw the film, The Big Short, the Academy Award winning movie about the 2008 financial collapse. I’d spent more time than I’d like to admit looking into the ins and outs of what happened, and when I heard there was a movie, I wondered how they were going to present it. Would it be about Bob and Wendy Graham’s campaign to create the Derivative Market, abetted by Fed Chairman, Alan Greenspan? or about Brooksley Born’s valiant attempts to stop it? or the raters who overvalued the CDOs? or maybe about the visionary Yale economist, Robert Shiller, and his book, Irrational Exuberance that predicted the whole thing? or the simple fact that no market can ever keep growing forever? There were so many angles.

[spoiler alert!] But the way they did it was a surprise to me and just plain brilliant by my estimate. They told the story through the eyes of the few people on the edges of Wall Street who saw it clearly from the start, and when they hit parts where the movie-goer needed a few complicated things explained, they mimicked a technique from antiquity, the Greek Chorus, in the form of a blond in a bubble bath, a player at a roulette table, or an actor stepping out of character and talking directly to the audience – truthsayers on the sidelines. I thought it was one fine piece of film-making!

Lehman Brothers - beforeBack when the markets crashed [September 15, 2008], I hadn’t seen it coming. But thinking back on things, like a lot of people, I registered some of the warning signs without realizing what they were warning us about. Some years before, I had needed some money to pay for the last of our two girls’ college costs and had refinanced my house – standard operating procedure in those days. To my surprise, lenders were calling us at home vying to get our loan. It was actually kind of fun. I did a spreadsheet model of all the loan parameters, and my wife spent the days fielding the calls and using my model to compare the offers. But the significance eluded me. In 2004 when we sold our home to move out of the City, I was staggered [pleasantly staggered] by the Lehman Brothers - afterselling price. But I just thought of it as our good fortune, saying, "Boy, this neighborhood has sure come up since we moved here twenty-five years ago." It never dawned on me that the banks were gathering mortgages not as investments, but to use as chips for playing in the huge casino called the Commodities Market [futures] – creating illusions, the inflated values that I had just taken advantage of.

I doubt that many among those of us who follow blogs like this didn’t find ourselves making analogies with the pharmaceutical industry and the Irrational Exuberance [and corruption] in psychopharmacology marketing that has plagued psychiatry  for the last quarter century. I won’t catalog all the obvious things that seemed parallel to me, but I want to mention one conceptual piece – futures. The traditional products traded on the Commodities Market are next season’s soy beans – growers selling their crops in advance to raise the money needed to plant and run their farms – buying and selling future value. The buyers take out insurance to cover their losses in case of a draught etc. With deregulation, that way of buying and selling future value was expanded to encompass almost anything and everything. And what better product than home mortgages – a guaranteed future value. For that matter, what better way to market tepid drugs to a hot market than to present them as on a continuum of future promise?

We’ve lived in a world where "new! improved!…" has been a permanent meme for our toothpaste and wash·day products. And it was easily transported to the psychopharmacology world of the 1980/1990s. The formula seemed to be keeping up an exuberant rhetoric of future-breakthroughs-just-around-the-corner, deceptive presentations maximizing efficacy and minimizing harms in scientific journals, expert testimonials and endorsements from all the right academic places, and questionable marketing techniques. The result has been a couple of decades when the psychiatric drugs have been consistently on top of the sales charts – an almost unimaginable outcome in a rational world. It happened with only two basic drug classes – the SSRIs and the Atypical Antipsychotics. And in spite of the pharmaceutical industry literally shutting down its CNS research several years ago, the so-called empty pipeline continues to produce "new! improved!…" versions of these drugs [see a future blog]. But unlike the mortgage futures market or something like the Madoff Ponzi scheme, it doesn’t seem that this version yet has any built-in ending. So long as the story line of future promise persists and new is still presumed to mean better, the drugs we call me too drugs keep on coming and remain successful.

One of the effective aspects of The Big Short was the subtle way it portrayed the real message of the story, how the Irrational Exuberance of the business end of the housing bubble either lost sight of or didn’t care about its impact on our everyday world [another analogy]. The graphic at the top was a scene of a visit to a defunct neighborhood of unoccupied new houses. And the six million who lost homes were represented by only one man [the insert picture above], but he got the message across in a only few brief appearances. The shots of traders being marched out of Lehman Brothers with boxes of personal items added to that side of the message – participant·victims, many of whom unlikely completely knew what they had been a part of until they entered the ranks of the disillusioned.

If my analogizing the mortgage banking debacle to what happened in our medical world seems forced, I’d suggest looking again. The damage done to patients and the profession may be qualitatively different, but the shared theme of deceit in plain sight would give the right Director in Hollywood way more than enough to work with…
Mickey @ 8:54 PM

a nostalgia break

Posted on Saturday 26 March 2016

When March Madness time comes around, I always remember a time when it wasn’t about Basketball for me – during the decade when I was a Psychiatric Residency Training Director. That may sound like an honorific, but that’s not how it was. I was only a year beyond my own residency and wasn’t exactly recruited, I was conscripted amid a crisis when my predecessor abruptly quit. But "we need you to fill in" lasted for a long time. And during those years, March Madness referred to Match Week – the week in which we found out what residents were or were not coming for next year. A few years ago, I had a nostalgia attack and made a graph of the history of Match Week in psychiatry [fuzzy math…]. As you can see, 1978 wasn’t a time when psychiatry was high on the list – filling only about half the positions offered. So Match Week was a frantic period because there was much ado thereafter with the flow into psychiatry from outside the Match to negotiate.

Also for 1978, it was a circus. It was at the end if Deinstitutionalization, the end of the Community Mental Health Movement, just after the Viet Nam War, and a peak time for the ideological and guild battles in mental health. We often think of the modern era in psychiatry beginning in 1980 with the DSM-III’s publication, and in a way that’s true. But at the same time, it was the end of a whole lot of other things – very loud things. Actually, the graph accurately reflects how it felt through that first post-DSM-III decade. Things just seemed to calm down.

The dip from around 1988 until 2004 spans the period when I started a practice until I retired, so I was otherwise occupied, ergo I know nothing about the why? of the dip. Here are some selections and comparisons from the info about the 2016 match that came out yesterday [this was Match Week], and I added 2016 to the graph above:

The specialty choices of medical students is a broad topic, but it usually reflects something about the state of the specialty. The medical students are influenced a lot by their contact with attending physicians and residents they meet on their clinical rotations. And 2016 looks like business as usual [in fact, I’m a little surprised to see no effect from the turmoil one might’ve predicted from reading our various blogs].

That first year after medical school sets a tone that endures throughout a career, something that persists even as medicine goes through its inevitable cart-wheels, its ups and downs. One of the pleasures of that Residency Training Director decade of my life was watching people literally grow up in such a short period of time. Even tough they’re entering a different world than I did as a medical intern in 1967 or the second time around as a psych resident in 1974, the patients will bring the same turmoil and symptoms they’ve always brought. I guess I’m just taking a nostalgia break from the focus on the contemporary problems that usually haunt these posts, and hoping the class of 2016 can look back in fifty years and feel like I do, that it was a good way to spend the days…

Note: The designation other on the graph is a mixed bag. The majority in that category are from non-US schools, but some are US citizens who went to medical school elsewhere.
Mickey @ 10:40 PM