Annie medicine…

Posted on Thursday 21 April 2016

Annie [above left on the day she arrived] was a retirement present from my practice partners [2003]. Her first friend, Studly, [above middle] lives down the road, but eats and sleeps here [going home for the odd holiday]. Woofie, above right, showed up after a year or so as a stray, taking up full time residence after being shot in the chest [mistaken for a Coyote we think]. Annie has an electric fence encircling about an acre of our property because she is just not highway·savvy, while the other two are free range denizens of the hood. Annie waits patiently at the edge of her domain while the boys go on their morning and evening walk-abouts.

Thirteen years have passed, and things are a little different now. Annie has bilateral hip arthritis, and [untreated] lays around moping. But she can return to her old frisky self with a single dose of aspirin a day. It’s remarkably effective, but getting her to take it is another matter entirely. She often turns her nose up at the liver flavored Nutri·Vet doggie aspirin, even when sealed inside of a Greenie [a pill pocket designed for such purposes]. So over time, we’ve learned that:
  1. if: we don’t feed the dogs automatically in the morning
  2. and if: we wait until Annie starts lobbying to be fed [by head butting my leg]
  3. and if: she hasn’t seen me preparing the aspirin bomb [broken up pill sealed in the Greenie]
  4. and if: we give her the bomb slightly reluctantly as a treat in response to her demands
  5. then: she sucks it down with relish
  6. and then: we feed the dogs
Any break in the chain, and we’re in a forced drugging situation [not conducive to good inter·species relations]. forced drugging is okay for a one shot heartworm pill or maybe a short course of medication like antibiotics for a discrete illness, but not for everyday meds. So every morning, the background issue around here is "Has Annie been bombed?"


Little question that this is a story about how old people spend their time and about my lifelong attachment to dogs, but I have another agenda in the telling. In medical school and during the first part of an Internal Medicine residency, I think I had an algorithmic view of medications. This medicine is for these things. And that medicine is for those things. This is the dose for this med, etc. But then then came the clinical part of my Fellowship with our Rheumatology Group. Since many of those diseases are of unknown etiology, and the treatments are often empirical, things were very different:
    em·pir·i·cal  /ëm-pir-i-kãl/
      adjective: empirical
      based on, concerned with, or verifiable by observation or experience rather than theory or pure logic…
At first I thought I’d fallen in with a bunch of lunatics. On rounds, we’d spend forever retaking the history and repeating the exam. Then we’d retire to the ward conference room and have a long discussion about treatment, and about what parameters we’d follow to judge the effect of the treatment, whatever it was [and sometimes it was nothing, as in benign neglect]. I was used to the  speed-dial ER mindset, and this seemed like a lesson in what it was like to have OCD in a war zone. Every treatment was a therapeutic trial [emphasis on every]. With every medication trial, we were seeking a therapeutic window in terms of dose. But after a time, I came around to see the wisdom in that way of thinking. We were using medications on the toxic end of the spectrum with crippling chronic diseases and the only solid proof was in the unique response in any given patient. It was a good lesson for all of medical practice. I never got over that way of thinking [and never plan to]. When I got to psychiatry, it was a natural fit [unknown etiology, significant toxicities, chronic course, proof in individual results, benign neglect option, etc].

Back to Annie. This aspirin choice came after trials with several other anti·inflammatories [GI problems] and some concoction being pushed by our vet called Zoom [poor results]. With the aspirin, ½ an adult aspirin worked [~160 mg]; a baby aspirin didn’t [~80 mg]; so on to the 120 mg doggie aspirin which also worked – at least for now.


While this little tale of Annie’s treatment has an obvious moral-to-the-story, its moral only really works in a Marcus Welby, M.D. world [Marcus Welby was a long-running television program about a doctor who devoted 24/7 attention to the patient of the week, with no other apparent cases or duties] – a world in which every case is an Annie. In case it’s not clear, my topics here are modern medical practice and treatment guidelines – obviously too big for a single post [maybe too big for a single blog]. But here’s a viewpoint piece from the JAMA that frames some of the issues:
by Donald M. Berwick MD
JAMA. 2016 315[13]:1329-1330.

Constant conflict roils the health care landscape, including issues related to the Affordable Care Act, electronic health records, payment changes, and consolidation of hospitals and health plans. The morale of physicians and other clinicians is in jeopardy. One foundational cause of the discord is an epic collision of 2 eras with incompatible beliefs.

Era 1
Era 1 was the ascendancy of the profession, with roots millennia deep—back to Hippocrates. Its norms include these: the profession of medicine is noble; it has special knowledge, inaccessible to laity; it is beneficent; and it will self-regulate. In return, society conceded to the medical profession a privilege most other work groups do not get: the authority to judge the quality of its own work. However, the idealism of era 1 was shaken when researchers examining the system of care found problems, such as enormous unexplained variation in practice, rates of injury from errors in care high enough to make health care a public health menace, indignities, injustice related to race and social class, and profiteering. They also reported that some of the soaring costs of care were wasteful — not producing better outcomes. These findings made a pure reliance on trusted professionalism seem naive. If medical professionals were scientific, why was there so much variation? If they were beneficent, how could they permit so much harm? If they self-regulate, how could they waste so much?

Era 2
The inconsistency helped birth era 2, which dominates the present. Exponents of era 1 believe in professional trust and prerogative; those of era 2 believe in accountability, scrutiny, measurement, incentives, and markets. The machinery of era 2 is the manipulation of contingencies: rewards, punishments, and pay for performance. The collision of norms from these 2 eras—between the romance of professional autonomy on the one hand, and the various tools of external accountability on the other—leads to discomfort and self-protective reactions. Physicians, other clinicians, and many health care managers feel angry, misunderstood, and over controlled. Payers, governments, and consumer groups feel suspicious, resisted, and often helpless. Champions of era 1 circle the wagons to defend professional prerogatives. Champions of era 2 invest in more and more ravenous inspection and control…
I was trained in an Era 1 world, one where medical morality and standards were meant to be an inside job. And whether by design or good fortune, I spent my practicing years in a domain that was close enough to welby-esque for this discussion – as a sole practitioner, on no provider panels, with time enough to practice Annie medicine. So I have a big bias on both of these topics [modern medical practice and treatment guidelines]. But as my daughter, a practicing child psychologist, puts it, "Dad, you could never get away with the way you did it now!" While I expect she’s probably right, that doesn’t change what I think one bit. I still think the Annie model of  personalized  individualized medicine is the right way to do things.

But I absolutely can’t argue with Dr. Berwick’s point about the pollyanna idealism and the dark side of Era 1. I wouldn’t even argue that it was those other doctors who didn’t do it right. Medical Care isn’t the Wild West. It’s an essential profession that needs oversight and discipline – not cowboys and entrepreneurs. And I realize that because of my own experience, what I see in modern medical practice and in treatment guidelines is the pollyanna idealism and the dark side of Era 2. But unfortunately, there’s plenty to see.

So I guess this post is my COI declaration for my future comments about modern medical practice and treatment guidelines
Mickey @ 12:23 PM

brexit?…

Posted on Tuesday 19 April 2016

Boston Globe
By John R. Bolton
April 19, 2016

Americans generally still see the EU as an economic union. Until relatively recently, many still called it “the Common Market,” though Europeans themselves had long ago discarded that outmoded term. In economic theory, a continental free-trade zone is hard to argue against; indeed, its commercial appeal was what initially persuaded the UK and others to join. But the EU is not now, hasn’t been for years, and for many never was, intended to be “merely” a free-trade area.

Instead, from its inception, the EU [and predecessors like the European Coal and Steel Community] was always primarily about reconfiguring political power. EU acolytes believe that the very concept of the nation-state brought war and misery to Europe for centuries. Their answer was straightforward: Eliminate European nation-states, a goal embodied in the 1957 Treaty of Rome’s pledge of “ever closer union.” Although Brits generally understood this phrase as merely aspirational, it was gospel for the EU’s altar boys.

Brexit, therefore, highlights for America a central issue in the international sphere: “Who governs?” [As the title of Robert Dahl’s classic study asked.] Today, the United States stands on the slippery slope of “sovereignty sharing,” a concept central to what its EU devotees call “the European project.” At the turn of the millennium, the consensus in academia held that the global nature of so many problems [climate change, for example] meant it was only a matter of time before national sovereignty would be relegated to museums. Although this supranational euphoria has subsided somewhat, Britain’s referendum would constitute a true counterrevolution.

Americans, therefore, should hardly be surprised so many Britons resent distant and unaccountable EU governance. On this side of the Atlantic, we readily understand that sovereignty resides constitutionally in “we, the people,” not in the federal government. At a time of dwindling confidence that we have control over our own government, the idea of sharing sovereignty internationally, thereby diluting it even further, is decidedly as unattractive here as in Britain.

Britain’s debate is full of specious charges and countercharges, such as the argument that Brexit would endanger British and European security. This is false. Europe’s security rests with NATO, not the EU, and NATO has one thing the EU never will: the United States. Nor will Britain simply be cast adrift if it leaves the EU. Economic common sense will persuade all concerned to mitigate the consequences of the split and maintain the benefits of free economic intercourse. If European states, upset with Brexit, try “beggar thy neighbor” policies in response, they will deserve what they get.
What I learned living in the UK for three years is that two things were not to ever be understood by yours truly – British Politics and Cricket. And since I was there, they’ve added the European Union to the mix, so now I double-dog don’t understand. So Obama is headed to London, and he wants the UK to stay in the EU whereas John Bolton, despised by me from his Bush UN Ambassador days as a noted neoconservative opposed to the UN, is fanning Brexit [BRitish EXIT] flames on the side of the Queen. Who can sort this out? Well, the British people will soon have the chance to vote. The "INs" are in the lead, but the polls have gone back and forth.

As much as I hate one issue politics, in this case, I’m guilty. I wonder how this effects the issue of Data Transparency. Is the European Medicines Agency a part of the European Union? I think so. What will happen to their coming policies? Is the Transatlantic Trade and Investment Partnership partly to blame for of all this turmoil? Will Data Transparency gains be consumed by this unrest? I have no real feel about any of this, except that it seems really important, and that it has a lot to do with the power of multinational corporations over elected governments.
Mickey @ 7:20 AM

any lengths…

Posted on Monday 18 April 2016

Other than the official logos [upper left hand corner], all I can find about the Transatlantic Trade and Investment Partnership is mass protest and dire warnings – from all over Europe. They refer to it as a Trojan Horse Treaty and guess who the bad guys are – it’s US Again! In the American News, it’s barely mentioned, but in Europe, a whole lot of people are spitting mad…
EUROPE’S elite were facing the wrath of the Dutch people once more tonight as support surged for a SECOND referendum on a controversial EU deal in a matter of weeks.
Express
by Nick Gutteridge
April 16, 2016

The Dutch people are plotting a second EU referendum

Brussels bureaucrats are facing the humiliating prospect of having to justify their flagship TTIP trans-Atlantic trade deal to the Dutch public less than a month after being sent packing over a land grab plot with Ukraine. Anger has been growing across Europe over the hated commercial stitch-up with America, which opponents say will only benefit big business and pave the way for the privatisation of public services including our NHS. And now, much like with the Ukraine treaty, the Dutch public is leading the way in opposing a deal which has already been rubber stamped behind doors by unelected eurocrats. 

More than 100,000 people have signed a petition ordering the Dutch government to hold referendum on the issue in the last few days alone. If it reaches 300,000, humiliated ministers will have no choice but to prepare a public vote.

Such a move would be another crushing blow for the beleaguered EU, which is coming apart at the seams amid an unprecedented outburst of people power. Spurred on by new online movements pro-democracy campaigners are finally fighting back against the Brussels machine, with the historic Dutch referendum earlier this month signalling a landmark victory for freedom and the right to self-determination. Now the rebellious Dutch have TTIP – which stands for the TransAtlantic Trade and Investment Partnership – firmly in their sights…
It gets the old 60s juices flowing – "power to the people!" "stand up to the Man!" "we shall overcome!" etc. Problem is that I don’t really even know what’s being protested. The Wikipedia version of the Transatlantic Trade and Investment Partnership is a little help, but barely. I first came onto whatever all of this is about a couple of years ago. I had begun to wonder how the Pharmaceutical Companies had gotten the right to treat the Clinical Trial Data as a proprietary piece of intellectual property, a secret. And was getting all wound up to repeal the proprietary data act…! What I discovered after spending a lot of time writing people to get the facts was that there weren’t any [facts] and there was nothing resembling a proprietary data act. They weren’t granted that right, they just took it.

Two years ago, I had some communication with Trudo Lemmens, a Canadian Law Professor who pointed me to the [weak] legal basis they had rolled out to defend this right-they-really-didn’t-have. It came from a self-serving reading of some trade agreements [see except where necessary to protect the public…, spellbound…, non-negotiable…, tomorrow…]. But in communication with Lemmens, he mentioned that there were some Trade Agreements up ahead that might actually turn that right-they-really-didn’t-have into a right-they-really-did-have and throw a monkey wrench into our hopes for a rational Data Transparency plan – particularly since it’s the EMA [European Medicines Agency] that’s been so rational about this issue. It’s TTIP he was referring to. And now it’s upon us, coming up for a vote by the Council of the European Union on May 26th.

All of those people are marching because TTIP threatens the "social" part of their "social democracies" – something like the "privatization" of the Reagan years  decimated  eradicated our social services here. It seems as if TTIP threatens to export our Corporate Capitalist Greed to Europe, at least that’s how they see it in the streets. If that’s the case, power to the people! I had hoped to report on the specifics of how it might impact of the move for Data Transparency, but alas. I’ve heard from only one of the people I wrote who might actually be able to clarify that point, but he was hurrying off to Brussels to enter the fray. If I find out anything, it’ll be here as soon as I know it. But the one thing I think we can be assured of. The ferocity with which the Pharmaceutical Industry has fought back against letting us see their raw data speaks volumes. They’ll go to any lengths to protect their right to spin [and distort] their results…
Mickey @ 7:48 PM

ttip: the capitalist manifesto?…

Posted on Sunday 17 April 2016

I’ve been looking around for something that explains TTIP without talking about what a really bad idea it is, and I can’t find anything. This link arrived in the comments and is typical of what I found on my own, only it’s clearer. I guess it’s telling that I can’t find a pro-TTP article. Here’s an older link from AllTrials, one from the European Initiative against TTIP and CETA, and one about why they’re in a hurry:
Have you heard about TTIP? If your answer is no, don’t get too worried; you’re not meant to have
The Independent
by Lee Williams
6 October 2015

The Transatlantic Trade and Investment Partnership is a series of trade negotiations being carried out mostly in secret between the EU and US. As a bi-lateral trade agreement, TTIP is about reducing the regulatory barriers to trade for big business, things like food safety law, environmental legislation, banking regulations and the sovereign powers of individual nations. It is, as John Hilary, Executive Director of campaign group War on Want, said: “An assault on European and US societies by transnational corporations.”

Since before TTIP negotiations began last February, the process has been secretive and undemocratic. This secrecy is on-going, with nearly all information on negotiations coming from leaked documents and Freedom of Information requests. But worryingly, the covert nature of the talks may well be the least of our problems. Here are six other reasons why we should be scared of TTIP, very scared indeed:
  1. The NHS
    Public services, especially the NHS, are in the firing line. One of the main aims of TTIP is to open up Europe’s public health, education and water services to US companies. This could essentially mean the privatisation of the NHS. The European Commission has claimed that public services will be kept out of TTIP. However, according to the Huffington Post, the UK Trade Minister Lord Livingston has admitted that talks about the NHS were still on the table.
  2. Food and environmental safety
    TTIP’s ‘regulatory convergence’ agenda will seek to bring EU standards on food safety and the environment closer to those of the US. But US regulations are much less strict, with 70 per cent of all processed foods sold in US supermarkets now containing genetically modified ingredients. By contrast, the EU allows virtually no GM foods. The US also has far laxer restrictions on the use of pesticides. It also uses growth hormones in its beef which are restricted in Europe due to links to cancer. US farmers have tried to have these restrictions lifted repeatedly in the past through the World Trade Organisation and it is likely that they will use TTIP to do so again. The same goes for the environment, where the EU’s REACH regulations are far tougher on potentially toxic substances. In Europe a company has to prove a substance is safe before it can be used; in the US the opposite is true: any substance can be used until it is proven unsafe. As an example, the EU currently bans 1,200 substances from use in cosmetics; the US just 12.
  3. Banking regulations
    TTIP cuts both ways. The UK, under the influence of the all-powerful City of London, is thought to be seeking a loosening of US banking regulations. America’s financial rules are tougher than ours. They were put into place after the financial crisis to directly curb the powers of bankers and avoid a similar crisis happening again. TTIP, it is feared, will remove those restrictions, effectively handing all those powers back to the bankers.
  4. Privacy
    Remember ACTA (the Anti-Counterfeiting Trade Agreement)? It was thrown out by a massive majority in the European Parliament in 2012 after a huge public backlash against what was rightly seen as an attack on individual privacy where internet service providers would be required to monitor people’s online activity.  Well, it’s feared that TTIP could be bringing back ACTA’s central elements, proving that if the democratic approach doesn’t work, there’s always the back door. An easing of data privacy laws and a restriction of public access to pharmaceutical companies’ clinical trials are also thought to be on the cards.
  5. Jobs
    The EU has admitted that TTIP will probably cause unemployment as jobs switch to the US, where labour standards and trade union rights are lower. It has even advised EU members to draw on European support funds to compensate for the expected unemployment. Examples from other similar bi-lateral trade agreements around the world support the case for job losses.  The North American Free Trade Agreement (NAFTA) between the US, Canada and Mexico caused the loss of one million US jobs over 12 years, instead of the hundreds of thousands of extra that were promised.
  6. Democracy
    TTIP’s biggest threat to society is its inherent assault on democracy. One of the main aims of TTIP is the introduction of Investor-State Dispute Settlements (ISDS), which allow companies to sue governments if those governments’ policies cause a loss of profits. In effect it means unelected transnational corporations can dictate the policies of democratically elected governments.

    ISDSs are already in place in other bi-lateral trade agreements around the world and have led to such injustices as in Germany where Swedish energy company Vattenfall is suing the German government for billions of dollars over its decision to phase out nuclear power plants in the wake of the Fukushima disaster in Japan. Here we see a public health policy put into place by a democratically elected government being threatened by an energy giant because of a potential loss of profit. Nothing could be more cynically anti-democratic.

    There are around 500 similar cases of businesses versus nations going on around the world at the moment and they are all taking place before ‘arbitration tribunals’ made up of corporate lawyers appointed on an ad hoc basis, which according to War on Want’s John Hilary, are “little more than kangaroo courts” with “a vested interest in ruling in favour of business.”
So I don’t know about you, but I’m scared. I would vote against TTIP, except… hang on a minute… I can’t. Like you, I have no say whatsoever in whether TTIP goes through or not.  All I can do is tell as many people about it as possible, as I hope, will you. We may be forced to accept an attack on democracy but we can at least fight against the conspiracy of silence.
hat tip to berit bryn jensen…  

Mickey @ 2:22 PM

uh oh…

Posted on Saturday 16 April 2016

I’m not sure what all this means, but I’m pretty sure it’s not good news, a decided blow to Data Transparency. I’ve e-mailed everyone I know who might be able to clarify…
Trade Secrets Directive opens the way for shady TTIP negotiations
epha
14 April 2016

Brussels, 14 April 2016. The European Parliament approved today a new Directive on Trade Secrets, a position that would signal that trade secrets outweigh the public interest. The impact will be negative for health, by declaring information on safety of medicines commercially confidential and to be kept secret from patients, regulators and the public. The Trade Secrets Law would gag journalists and whistle-blowers, undermining freedom of expression and preventing vital information reaching the media and public. With regard to public health, the new rules would erect a barrier to public access to data on the safety and efficacy of medicines.

As a result, Europe could soon be stripped of its hard-won global leader position on clinical trials transparency. The proposals for the Trade Secrets Directive are clearly intended to increase commercial confidentiality in the interest of drug makers who seek to keep clinical trials results secret, and would weaken patient safety protection and halt further research and independent analyses. The worrying lack of legal guarantees preventing companies from abusing the concept of trade secrets opens the way for unethical repetition of clinical trials on people, and the injection of public resources spent on therapies that are no better than existing treatments, do not work, or do more harm than good.
    “This vote weakens recent efforts by European Institutions to increase sharing and transparency of essential health data. Clinical trials data transparency is key for patient safety, for access to affordable medicines, for public health research and innovation.” stated Nina Renshaw, Secretary General of the European Public Health Alliance. “Today’s vote is clearly designed to undermine the Clinical Trials Regulation, on which the ink is barely dry, which was huge progress for patient safety and access to medicines, but has always been opposed by the pharmaceutical industry which prefers to conduct trials in secrecy. It also seems to be aiming at smoothing the way for the pharmaceutical industry in the EU-US TTIP negotiations, and would lower transparency requirements in the EU to be closer in line with much weaker rules in the US.
Today’s vote creates dangerous uncertainty around the issue of trade secrets, particularly for medicines. It opens the way for pharmaceutical companies to use and abuse this Trade Secrets Directive, leaving only rulings from the European Court of Justice to determine the outcome and judgement of future litigations on a case-by-case basis. The Council of the EU will vote on this Directive on 26 May -a vote that will likely be in line with the Parliament’s stance…
Intellectual Property Watch
by Dugie Standeford
14/04/2016

Rejecting calls for a vote to be delayed until the European Commission proposes tougher whistle-blower protections, the European Parliament on 14 April approved by 503-131 new rules giving companies redress for theft or misuse of trade secrets. Debate on the trade secrets directive showed sharp divisions among lawmakers, heightened by the recent “Panama Papers” and other leaks, over whether the legislation will help businesses safeguard their innovative ideas or lead to increased corporate secrecy…
Mickey @ 2:57 PM

i wonder

Posted on Saturday 16 April 2016

by David Beiser, Milkie Vu, and Robert Gibbons
Psychiatric Services. Published online: April 15, 2016

Objective: Computerized adaptive testing [CAT] provides improved precision and decreased test burden compared with traditional, fixed-length tests. Concerns have been raised regarding reliability of CAT-based measurements because the items administered vary both between and within individuals over time. The study measured test-retest reliability of the CAT Depression Inventory [CAT-DI] for assessment of depression in a screening setting where most scores fall in the normal range.
Methods: A random sample of adults [N=101] at an academic emergency department [ED] was screened twice with the CAT-DI during their visit. Test-retest scores, bias, and reliability were assessed.
Results: Fourteen percent of patients scored in the mild range for depression, 4% in the moderate range, and 3% in the severe range. Test-retest scores were without significant bias and had excellent reliability [r=.92].
Conclusions: The CAT-DI provided reliable screening results among ED patients. Concerns about whether changes in item presentation during repeat testing would affect test-retest reliability were not supported.
This story is so convoluted that it can’t be quickly summarized so I won’t even try [see why…, when…, what…, why again…, open letter to the APA…]. I’ll stick to just this article:
Patients who had a critical illness, were age 17 or younger, were non–English speaking, were without decisional capacity, or had a behavioral health–related chief complaint were excluded. After written consent was obtained, the CAT-DI was administered twice by research assistants using tablet computers. The second test was administered within one to three minutes following the end of the first test.
They’re screening people in the Emergency Department Waiting Room who have come for some other reason than their mental health for depression:
Depression is associated with increased mortality, adverse health outcomes, and increased overall treatment-related costs. The emergency department [ED] is an important safety net for patients with behavioral health problems and thus may be an ideal setting to diagnose and initiate treatment for patients with depression. Current estimates suggest that between 8% and 32% of ED patients present with depression. However, conducting the detailed assessments of depression severity required to initiate treatment is often infeasible in the ED because of high patient volumes and limited access to behavioral health expertise. Therefore, any strategy that reduces the burden of empirically based assessment of depression has the potential to improve outcomes…
So based on this 93 second assessment [average time to take a CAT-DI test on a computer tablet], we’re going to prescribe an antidepressant medication? See, I can’t even talk about this without getting sarcastic. Let me start over. There’s a whole line of thinking that conceptualizes depression as if it’s an epidemic medical disease. The logic begins with some allusion to the prevalence in the population and the notion that it is rapidly increasing, then progresses to some kind of estimate of the cost in lost productivity and things like over-use of medical services etc. The end point of this logic train is that we need early detection, rapid treatment [antidepressants], and better drugs than the ones we currently have.

I hope this article comes to us as an anachronism past it’s prime. It started in 2002 when Dr. Gibbons, a statistician at the University of Chicago, got an NIMH Grant to develop computerized screening instruments [what!…]. That same year, Dr. David Kupfer et al published A Research Agenda for the DSM-V, laying out a plan for a biologically-based medical psychiatry, the dream of many since the 1980 DSM-III. And 2002 was also the year Tom Insel was appointed head of the NIMH [Psychiatry as a Clinical Neuroscience Discipline]. Robert Gibbons part in this story has been a dogged determination to undermine the Black Box warning on the antidepressants and an equally persistent campaign to advance this screening instrument. The CAT-DI tools were developed with NIMH funds and then turned into a for-profit enterprise in concert with David Kupfer, his wife Elizabeth Frank, and others on the sly [When is Disclosure Not Disclosure?]. So there’s an attempt to capitalize on this screening instrument.

If this article is about evaluating the test-retest reliability of his CAT-DI instrument, and using the ER patients was a way to get a spread out cohort for that test, it didn’t come out so well. Only 2/5 in the severe range and 2/5 in the moderate range were reliable – that’s 4/10 in the ranges that mattered:

But beyond being a weak test [… Not Ready for Prime Time], the gross improprieties in its development, and the obvious profit motives involved, I wonder about the whole idea of screening people for depression. The questions asked on any such instrument that would register significant depression aren’t subtle. If a person is answering them honestly enough to generate a high score, they’re not trying to hide being depressed, so it’s going to show to anyone who is engaged and looking. 

Actually, saying I wonder is ingenuous. I can’t find a way to exactly say why, but my reaction to this screening for depression business is overwhelmingly negative, and more visceral than cognitive. It just feels like yet another step down a bad road – the movement to mechanize patient contact, to objectify the obvious. When I’m handed a PHQ9 in my own physician’s office, I cringe. I’m on Medicare, and apparently he can charge more for a visit if he screens for depression. I’m glad to increase his revenue. He’s a good doctor. But I have to suppress an urge to fill it out as if I’m a homicidal ax murderer just to see if it gets read. If your doctor can’t detect severe depression just by looking, go find a real doctor…
Mickey @ 1:00 PM

cartesian dualism in appalachia…

Posted on Tuesday 12 April 2016

The ever-sensible British Neuroscientist we know as Neuroskeptic has a particularly sensible blog post up [How To Avoid Neurohype], tied to his equally sensible Daily Dot commentary [Why we’re living in an era of neuroscience hype].
In my view, it’s this sense of “hard” vs. “soft” truth that lies at the root of the craze for neurobullshit. We seem prone to a mind-brain dualism, thinking that the mind is something soft, malleable, and mysterious, whereas the brain is a hard, biological thing open to scientific probing. Therefore, we feel that if we can reframe a “mind” problem as a “brain” problem, then by doing so we’re already halfway to finding a solution. [In fact, the hard/soft, brain/mind fallacy dates back to Greek philosophy, and is known as Cartesian Dualism.]

Really, the human brain is no harder or easier to understand than the human mind, because they are ultimately the same thing. So, while it is possible in principle to reframe a “mind” issue as a “brain” issue, it’s often not useful to do so… Why is there so much neurobullshit around today? I think the answer is that neuroscience really has made great advances in the past few decades, and these advances have been very visible…

Ultimately, modern neurohype is driven by the appeal of “hard” or scientific approaches to problems, combined with the modern buzz surrounding brain science. The result is that neuroscience [or something resembling it] has become a selling point — a shiny new coat of paint, both for products and for ideas. Today, while we really do know more about the brain than ever before, our understanding is still very limited. Neuroscience is not yet advanced enough to tell us the answer to life, the universe, and everything.
How does the ever-sensible British Neuroscientist we know as Neuroskeptic stay so ever-sensible? It’s because he really is a Skeptic and knows what that means. But in this case, I don’t think he pushes his observation far enough. His point has more ramifications than he credits. If I go to the Dermatologist having noticed a new skin growth and it turns out to be a skin cancer, I’m not the agent of my illness. I’m its victim. And if I’m going to get any help, it’s coming from medical treatment, not my own efforts. However, for many presenting with mental symptoms, the afflicted often has plenty of agency in their creation and maintenance. Or maybe life has thrown one of its curve-balls. Or a jillion other things.

I had left general psychiatry for a particularly specialized niche, and on returning twenty-five years later, there was a distinct change in the way patients presented. It was a surprise that took some getting used to. Some announced their diagnosis [bipolar, ocd, dissociative disorder]. Many presented their emotional complaint as if it were a disease [depression, anxiety]. And I was supposed to do something with that pronouncement with no further information, as if "I have depression" lead to some specific treatment. Even harder for me was "My antidepressant isn’t working anymore,!" "My depression is coming back," or "I have a chemical imbalance."  I had no illusion that I was going to do in-depth case studies in a general charity clinic, but I didn’t anticipate hearing something equivalent to "I found a new mole." And often, taking a real history was hard work. "What’s that got to do with…?"

Many of the patients, even here in the Appalachian Mountains, had adopted this medical model [in the scorned usage]. At first I thought it was something learned from their doctors or the tv ads, but it was more than that. It was something they had maybe initially picked up that way, but it was maintained by many because… [don’t know the because]. And it’s in the culture now "My neighbor, see she’s bipolar and…". The responsibility for improvement was jettisoned to some external locus of control – a new variant of an old psychological defense mechanism. It was enough of a change that I had to relearn how to interview certain people to get the necessary information. There are a lot of things you can do to help people even in the direst of circumstances, but you can’t do them if you don’t know what they are. And you can’t know that without their allowing you to join in a "look around."

So "Therefore, we feel that if we can reframe a ‘mind’ problem as a ‘brain’ problem, then by doing so we’re already halfway to finding a solution" is not just what neuroscientists or some psychiatrists do. Patients do it too. Sometimes it’s a burden handed to patients by their psychiatrists or GPs. And sometimes it’s a thing that patients pick up and carry to extremes – going on a search for an elusive chemical cure instead of making changes in their lives or situations that would make for a more fulfilling visit to our planet. And occasionally, it becomes a place where patients can hide for a very long time to their detriment.

One thing I found that was a surprise to me. While there are times when the long term use of medication is indicated, it seemed like everybody was on medications chronically. At first I thought it was something symbolic or perhaps magical. But it turned out that a lot of people thought that the medicine was treating the underlying problem which would progress if they stopped it. And the withdrawal syndromes reinforce that notion. Once people get such an idea, one has to walk softly in trying to dispel it and stop unnecessary medications or the patient will think you’re trying to take something vital away from them and move on to somebody who will just keep on refilling the Rx…
Mickey @ 6:46 PM

the making of « wolf alert! wolf alert!… » part 3

Posted on Monday 11 April 2016

In a psychotherapy career, you learn some odd things – things you didn’t even know were there to learn. One important one is that we all do wrong and hurtful things that cause trouble in both our own lives and the lives of people around us. And if you look hard enough in the mirror, you see your own blemishes and it’s important to address them too. As a therapist, often the most difficult task is helping people look at their own shortcomings constructively, and coming to grips with the negative things they’ve done themselves. It’s not a question of getting "off the hook," it’s about cleaning up your own act going forward. In the Twelve Step programs, it’s occupies a number of their steps. But it’s a piece of any recovery enterprise – and you don’t get there by sweeping things under the rug.

My complaint about the Institute of Medicine Reports and the International Committee of Medical Journal Editors article is that they never say why Data Transparency is such a hot-potato issue. Why are we even talikng about this? Yet we all know the answer. The pharmaceutical industry, the third party payers, and a way-too-big segment of the medical profession has behaved very badly and the clinical trials of medications sits in the middle of that bad behavior. There has been corruption small and large, and a solid piece of re·form is vitally needed. That’s why this is on the front burner – the sins of our fathers [and our father’s children AKA ourselves].

I think of Jeffrey Drazen, editor of the world’s first line medical periodical, the New England Journal of Medicine, as a wolf in sheep’s clothing. In spite of having his name on the three documents laying out a plan for Data Transparency, he uses his influential editorial page as a bully pulpit for only one side of the conflict. The month after the first IOM report in 2014 he wrote:
by Jeffrey M. Drazen, M.D.
New England Journal of Medicine. 2014 370:662

… I am especially eager to receive feedback from the biomedical community about one issue in particular of the many considered in the report. At the completion of a research study or clinical trial, a first report is often published. Usually, this report contains the key findings of the study but only a small fraction of the data that were gathered to answer the scientific or clinical question at hand. To what extent and for how long should the investigators who performed the research have exclusive access to the data that directly support the published material? And should the full study data set be subject to the same timetable? Open-data advocates argue that all the study data should be available to anyone at the time the first report is published or even earlier. Others argue that to maintain an incentive for researchers to pursue clinical investigations and to give those who gathered the data a chance to prepare and publish further reports, there should be a period of some specified length during which the data gatherers would have exclusive access to the information…

The month after the second IOM report in 2015 he wrote:
by Jeffrey M. Drazen, M.D.
New England Journal of Medicine. 2015 372:201-202.

… With whom will data be shared? When they register a trial, investigators will need to indicate whether their data can be shared with any interested party without a formal agreement regarding the use of the data, only with interested parties willing to enter into a data-sharing agreement, or only with interested parties who bring a specific analysis proposal to a third party for approval. It is possible that investigators could choose to share their data with different groups at various times. For example, data might be shared for the first year of availability only with parties who specify their analysis plan but be shared more widely thereafter…
And who will ever forget this one in the summer of 2015?
by Jeffrey M. Drazen, M.D.
New England Journal of Medicine. 2015 372:1853-1854.
May 7, 2015

Over the past two decades, largely because of a few widely publicized episodes of unacceptable behavior by the pharmaceutical and biotechnology industry, many medical journal editors [including me] have made it harder and harder for people who have received industry payments or items of financial value to write editorials or review articles. The concern has been that such people have been bought by the drug companies. Having received industry money, the argument goes, even an acknowledged world expert can no longer provide untainted advice. But is this divide between academic researchers and industry in our best interest? I think not — and I am not alone. The National Center for Advancing Translational Sciences of the National Institutes of Health, the President’s Council of Advisors on Science and Technology, the World Economic Forum, the Gates Foundation, the Wellcome Trust, and the Food and Drug Administration are but a few of the institutions encouraging greater interaction between academics and industry, to provide tangible value for patients. Simply put, in no area of medicine are our diagnostics and therapeutics so 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 editors remain concerned about authors with pharma and biotech associations? The reasons are complex. This week we begin a series of three articles by Lisa Rosenbaum examining the current state of affairs…
In the month of the publication of the ICMJE report in 2016 he wrote:
by Dan L. Longo, M.D., and Jeffrey M. Drazen, M.D.
New England Journal of Medicine. 2016; 374:276-277.

… However, many of us who have actually conducted clinical research, managed clinical studies and data collection and analysis, and curated data sets have concerns about the details. The first concern is that someone not involved in the generation and collection of the data may not understand the choices made in defining the parameters. Special problems arise if data are to be combined from independent studies and considered comparable. How heterogeneous were the study populations? Were the eligibility criteria the same? Can it be assumed that the differences in study populations, data collection and analysis, and treatments, both protocol-specified and unspecified, can be ignored? A second concern held by some is that a new class of research person will emerge — people who had nothing to do with the design and execution of the study but use another group’s data for their own ends, possibly stealing from the research productivity planned by the data gatherers, or even use the data to try to disprove what the original investigators had posited. There is concern among some front-line researchers that the system will be taken over by what some researchers have characterized as “research parasites”…
There’s more, but that’s enough for my point. He never talks about why we are clamoring for Data Transparency [widespread corruption in Clinical Trial reporting]. He never gives examples of the dangers of these distorted reports that have already happened. Yet he often brings up hypothetical problems that might happen with Data Transparency. And he uses the industry spin term, Data Sharing, as if the whole point is industry’s magnanimus sharing for new discovery rather the truth – that we want to check their work for the kind of distortions we’ve lived with for several decades.

So Drazen is a prominent and influential member of the Committees setting the policy for Data Transparency going forward who hardly represents a neutral position. And it’s not like the industry side isn’t represented. For example, the IOM Activity Sponsors:

Activity Sponsors

• Bayer
    
• Sanofi
• Takeda

It would be foolish not to be concerned that by the time Data Transparency becomes a reality, it will be severely eroded and become as much a failed reform as previous attempts. For example, the Clinical Trials.gov Results Database has been around for years, but industry and academia just ignored it even when it was required. We need a solid policy with teeth in it, and Jeffrey Drazen is not the guy for that kind of work. I started with comments about the need to look in the mirror as part of any recovery. He’s advocating just the opposite, ignorng the very problems that we’re trying to solve.

 

The history since inception in 1962 is for the Clinical Trial reforms to end up leaking like a sieve, and this is exactly how it happens. Not with a bang, but a whimper…
Mickey @ 6:23 PM

the making of « wolf alert! wolf alert!… » part 2

Posted on Monday 11 April 2016

I hope I got across in the making of « wolf alert! wolf alert!… » part 1 that I think ClinicalTrials.gov is a good idea, and that putting it in the center of a system aiming towards appropriate Data Transparency is a good idea too, but that it needs some heavy tweaking before it will actually work. First, obviously, it needs to be used in a timely manner and that usage enforced. That part seems easy. No registration, no consideration for publication or regulatory approval. No Results posting, no consideration for publication or regulatory approval. No exceptions. Next, the a priori Protocol and Statistical Analysis Plan must be declared [in ClinicalTrials.gov] before the study starts and those results shown in the Results Database. If some investigator or sponsor wants to switch or add outcomes or methodologies in the published version, that’s their prerogative, but only if they also show us the results of their original plans. They can make their case in the paper, not behind closed doors. No exceptions.  At least that’s what I think. There are many opinions about whether the investigators should be held to their original choice of outcome variables and statistical methods. But there’s no controversy in my mind about secrecy. We need to hear what they thought a priori no matter what they decide after the study was underway or post hoc. No exceptions.

And now for a slight change in direction, what about the actual, rather than the summary data? Here’s what others think: From the National Academy’s Institute of Medicine COMMITTEE ON STRATEGIES FOR RESPONSIBLE SHARING OF CLINICAL TRIAL DATA come two very long policy documents…
and the International Committee of Medical Journal Editors, adds a more forgiving single pager…
The first two are tomes. I scanned them and I doubt they are much read; however, the one from ICMJE is short and a definite must read document. Here’s the central message:
by Darren B. Taichman, Joyce Backus, Christopher Baethge, Howard Bauchner, Peter W. de Leeuw, Jeffrey M. Drazen, John Fletcher, Frank A. Frizelle, Trish Groves, Abraham Haileamlak, Astrid James, Christine Laine, Larry Peiperl, Anja Pinborg, Peush Sahni, Sinan Wu
PLOS. Published on January 20, 2016

Note: This editorial is being published simultaneously in Annals of Internal Medicine, British Medical Journal, Canadian Medical Association Journal, Chinese Medical Journal, Deutsches Ärzteblatt (German Medical Journal), Ethiopian Journal of Health Sciences, JAMA (Journal of the American Medical Association), Nederlands Tijdschrift voor Geneeskunde (The Dutch Medical Journal), New England Journal of Medicine, New Zealand Medical Journal, PLOS Medicine, Revista Médica de Chile, The Lancet, and Ugeskrift for Laeger (Danish Medical Journal).

… As a condition of consideration for publication of a clinical trial report in our member journals, the ICMJE proposes to require authors to share with others the deidentified individual-patient data [IPD] underlying the results presented in the article [including tables, figures, and appendices or supplementary material] no later than 6 months after publication. The data underlying the results are defined as the IPD required to reproduce the article’s findings, including necessary metadata. This requirement will go into effect for clinical trials that begin to enroll participants beginning 1 year after the ICMJE adopts its data-sharing requirements.

Enabling responsible data sharing is a major endeavor that will affect the fabric of how clinical trials are planned and conducted and how their data are used. By changing the requirements of the manuscripts we will consider for publication in our journals, editors can help foster this endeavor. As editors, our direct influence is logically, and practically, limited to those data underpinning the results and analyses we publish in our journals.

The ICMJE also proposes to require that authors include a plan for data sharing as a component of clinical trial registration. This plan must include where the researchers will house the data and, if not in a public repository, the mechanism by which they will provide others access to the data, as well as other data-sharing plan elements outlined in the 2015 Institute of Medicine Report [e.g., whether data will be freely available to anyone upon request or only after application to and approval by a learned intermediary, whether a data use agreement will be required] [1]. ClinicalTrials.gov has added an element to its registration platform to collect data-sharing plans. We encourage other trial registries to similarly incorporate mechanisms for the registration of data-sharing plans. Trialists who want to publish in ICMJE member journals [or nonmember journals that choose to follow these recommendations] should choose a registry that includes a data-sharing plan element as a specified registry item or allows for its entry as a free-text statement in a miscellaneous registry field. As a condition of consideration for publication in our member journals, authors will be required to include a description of the data-sharing plan in the submitted manuscript. Authors may choose to share the deidentified IPD underlying the results presented in the article under less restrictive, but not more restrictive, conditions than were indicated in the registered data-sharing plan…

Data sharing is a shared responsibility. Editors of individual journals can help foster data sharing by changing the requirements of the manuscripts they will consider for publication in their journals. Funders and sponsors of clinical trials are in a position to support and ensure adherence to IPD sharing obligations. If journal editors become aware that IPD sharing obligations are not being met, they may choose to request additional information; to publish an expression of concern; to notify the sponsors, funders, or institutions; or in certain cases, to retract the publication…
I don’t personally think the behavior of the sponsors of Clinical Trials have earned the right to get as much consideration as they’re being given in these reports. The scientific misbehavior in Clinical Trial reporting, particularly in psychiatry, has been rampant rather than subtle, so I would’ve stonewalled for more ease of access. That being said, if this plan is put into action and actually enforced, it will do. But the enforcement paragraph is too weak as it stands. How about, if they don’t comply, publish a retraction notice and annotate ClinicalTrials.gov? How about, if they don’t live up to their agreement, put sponsor and authors on a no further acceptance until… list? So I’ve pushed the wolf in sheep’s clothing down one more rung. I promise  the making of « wolf alert! wolf alert!… » part 3 will have no more introductory remarks…
Mickey @ 2:13 PM

the making of « wolf alert! wolf alert!… » part 1

Posted on Sunday 10 April 2016

Usually when I write a blog post, I know what I want to say. I don’t like it when others wander around, so I try not to do it myself. But that’s not what happened with wolf alert! wolf alert!…. A coauthor on the Paxil Study 329 article had forwarded the PLOS article. It was a short simple piece, but I thought it might be a springboard to contrast the  approach to Data Transparency between the European Medicines Agency [EMA] and the more chaotic efforts here in the US. I particularly wanted to say something about the notion that ClinicalTrials.gov site and its Results Database were resources. They may become that, but they sure aren’t right now. I wanted to mention two things: that they’re frequently not current with missing results and they’re not checked for completeness even if present. Then I wanted to talk about the advantages of the EMA plan to release all the information submitted for approval. A short post about a simple little article.

But I couldn’t seem to finish it. I’d write something  and wander off. Coming back, I’d erase what I wrote and start over. That’s just not my M.O. and I went to bed with it open on my desktop. When I looked at it in the morning, I decided that I might be dawdling because I hadn’t really read the IOM Report, so I started reading. It only took a couple of pages to get to the part where they listed who was on the Committee. And my musing about my dawding came to an end. I finally got to what was bothering me. I dashed off the post [wolf alert! wolf alert!…] having other things to do in the afternoon, and picked it up when I got home later in the evening.

First, the PLOS Medicine article…
PLOS Medicine
National Library of Medicine, National Institutes of Health
by Deborah A. Zarin and Tony Tse
January 19, 2016

A newly published reanalysis, part of the Restoring Invisible and Abandoned Trials [RIAT] initiative, was based on access to original case report forms for 34% of the 275 participants. These highly granular IPD datasets enabled the researchers to recategorize certain adverse events that they determined had been miscategorized originally [e.g., “mood lability” rather than the more serious “suicidality”]. The reanalysis concluded that Study 329 did not show either efficacy or safety.

How Would the Problems of Study 329 Be Addressed by the Current TRS?

It would be an oversimplification to conclude that this reanalysis demonstrates the need to make IPD for all trials available. A more nuanced look at the specific problems is useful. Many of the concerns about Study 329 and the other Paxil studies might have been addressed if current policies regarding registration and results reporting had been in existence. The key issue that specifically required access to IPD was the detection of miscategorization of some adverse events in the original report…

Key Issue   Relevant TRS Component   Comment

    Summary Results Reporting   Results database entries would have provided access to "minimum reporting set" including all prespecified outcome measures and all serious adverse events.
 
Detection of selective reporting bias of efficacy and safety findings in the published results of Study 329, unacknowledged changes in outcome measures, and other issues.   Prospective Registration   Archival registration information would have allowed for the detection of unacknowledged changes in prespecified outcome measures and detection of nonprespecified outcome measures reported as statistically significant.
 
    Summary Results Reporting   Structured reporting devoid of interpretation or conclusions would have made summary data publicly available while avoiding the possibility of spinning the results.
 
Invalid and unacknowledged categorization of certain adverse events, resulting in the underreporting of suicidality   Sharing Highly Granular IPD and Documents [CRFs]   Access to high-granularity IPD enabled the elucidation of data analytic decisions that had not been publicly disclosed; reanalysis was possible with different methods of categorizing adverse events.

It is important to note that this illuminating reanalysis required access to the highly detailed IPD available in the original CRFs, represented by the far-left side of the x-axis in Fig 1. However, recent high-profile proposals for the sharing of IPD might not have added any clarity in the case of the Paxil studies in children beyond what could have been achieved with the optimal use of a registry and results database [i.e., two foundational levels of the pyramid in Fig 2]. The reason is that journal publication serves as the “trigger” for IPD release in many of these proposals, which could not possibly mitigate biases resulting from selective publication in the first place [i.e., IPD from unpublished trials would be exempt from sharing requirements]. In addition, such proposed IPD policies call for the release of only the “coded” or “analyzable” dataset, which would not have allowed for the detection of miscategorization or the recategorization of the adverse events. Finally, such proposals would only require the sharing of a subset of IPD and documents for those aggregate data reported in the publication and not the full dataset, precluding secondary analyses intended to go beyond validation and reproducibility of the original publication.

I hadn’t really said what needed saying about this idea of putting ClinicalTrials.gov at the center of our Clinical Trial system. So I want to redo my points from the last post:
  • the a priori Protocol:
    While the ClinicalTrials.gov write-up for a trial usually contains the PRIMARY and SECONDARY OUTCOME VARIABLES, it doesn’t have the full a priori protocol. It needs to be emphasized that this is a definitive outcome variable declaration and a harbinger of what’s going to be reported in the Results Database on the completion of the study. While some debate whether this declaration is "binding" [whether outcomes can be changed along the way as they were in Paxil Study 329], it’s the only guard we have against someone running every imaginable analysis until they find one they like.
  • the Results Database:
    First, as I mentioned, this is the single most ignored requirement on the planet. And filling it out is no big deal. I would propose that one requirement for any submission to the FDA for approval or perhaps even for publication in a journal is a completed entry in the ClinicalTrials Results Database.
  • the Statistical Analysis Plan:
    My part of the Study 329 RIAT article was primarily the efficacy statistical analysis. And while the point that "The key issue that specifically required access to IPD was the detection of miscategorization of some adverse events in the original report." was indeed the central focus of our reanalysis, there was a less obvious but important finding in the efficacy analysis that required the full IPD to resolve. The original paper skipped the omnibus ANOVA analysis before making pairwise comparisons and there were many other gross statistical issues with the article’s "rogue variables" that didn’t make it into our paper, but were reported here [see study 329 vii – variable variables?… thru study 329 xii – premature hair loss…]. While it didn’t matter in this instance, in many other cases it could be absolutely crucial. If ClinicalTrials.gov is to be the definitive Summary Results Reporting mechanism, the details of the statistical analytic methods need to be specified in the original ClinicalTrials.gov write-up.
Of the many lessons for me in the couple of years we spent on that paper, one of the the biggest was the power of the saying "the devil’s in the details." Some of the things that are crystal clear now in just looking at the summary reports took going over the full IPD over and over to see them the first time. We repeated every analysis using the full complement of raw data, and it took that to locate many of the problems. I heartily agree with these authors that partial data access schemes are not much better than no access at all.

So part of my dawdling had to do with needing to add the things in this list to the paper’s discussion of How Would the Problems of Study 329 Be Addressed by the Current TRS?  But that’s not all. There was something else that had me peppering that last post with pictures of a wolf in sheep’s clothing, and that’s why there’s a the making of « wolf alert! wolf alert!… » part 2 just around the corner. But I wanted to say what I thought before looking at what the Institute of Medicine Committee thought in any detail…

Mickey @ 9:08 AM