something essential betrayed…

Posted on Tuesday 2 April 2013

Since my earliest days writing about Pharma and the state of modern psychiatry, I’ve used some version of the image on the left below to convey my beef about the state of play – most recently a few days ago talking about Dr. David Healy’s Not So Bad Pharma post [see least-squares-mean patients…]. It’s meant to convey that diagnosis is controlled by the APA’s DSM-IV/5; effective treatment is certified by Pharma·directed CRO·run clinical trials; and treatment is directed by managed care. The computer originally represented Dr. Madhukar Trivedi’s aborted IMPACTS study using computer directed algorithms, but could represent any algorithm create by the APA/Pharma/Managed·Care trio. The point is that a patient is reduced to symptoms [Sx] and the system spits out a treatment [Rx]. There’s no doctor in the loop, at least no personal doctor to have independent thoughts – AKA clinical judgement:

I advertised that "My next post will attempt to summarize the first two installments" of Dr. Healy’s current series [Not So Bad Pharma and April Fool in Harlow]. That wasn’t completely accurate. Healy’s right there on the Internet for all to read, but I do want to comment on some of what he has to say. In Not So Bad Pharma, he gives Ben Goldacre his due as an expert on Evidence-Based Medicine and Clinical Trials who points out the many ways that Pharma and the article authors [whoever they are] distort the data, including furloughing about half [or more] of the trials they do. Healy certainly has no objection to data transparency, having called for it himself for years. He summarizes Goldacre’s position, "The big picture – RCTs are critical to good medicine and everything would be fine if only companies didn’t ‘game’ them." But adds, "The central problem is the premium Ben puts on controlled trials not found in other books."

I’m going to give my version of one of Dr. Healy’s points using the right-hand version of my image above. The main controlling force of the schematic is the randomized clinical trial. What if through data transparency we have all the raw data from the trial [and that’s a big ‘if’]? The clinical trial still determines what happens, and in most cases it is still in the hands of Pharma. They design the trial, pick the parameters, etc. The clinical trial is still king. That was never intended. Here are two versions of that story. One from Dr. Healy’s post:
    For drugs, the criterion is two positive trials. These regulations were not designed to have anything to do with the practice of medicine, they regulate adverts… Introducing trials into the regulatory apparatus has created a mess.  What’s been captured is the production of evidence and the more books like Bad Pharma fetish clinical trials the more captured medicine becomes…
And the other is from a comment by Dr. Bernard Carroll, another long-time watchdog of published clinical trials:
    First, the FDA does not exist to regulate the practice of medicine. It was chartered by Congress to regulate the claims made by manufacturers about the efficacy and safety of their products. The practice of medicine is regulated by the states. Thus, FDA approval of a product for a given indication is just a permit, not a mandate to use that product in clinical practice. Deference to the regulator is the responsibility of corporations, not of clinicians. Clinicians work from a different evidence base.
    Second, clinical trials are not coterminous with clinical practice. Clinical practice must take account of multiple casewise variables that are excluded from clinical trials. Clinical practice occurs over time spans that clinical trials usually cannot match. Clinical practitioners have an ongoing commitment to care for their patients while the academic and commercial CROs that conduct clinical trials do not. Clinical trials in psychiatry nowadays recruit subjects [symptomatic volunteers] whereas clinical practitioners manage patients actively seeking help through clinical referral channels. In some areas of psychiatry like depression and anxiety disorders, the pretend patients and the real patients are different. Just look at the creep of placebo response rates to north of 50% in recent years. Just look at the reported 85% rate of response to placebo in pretend patients with [ahem] psychotic depression in the FDA-monitored trials of mifepristone sponsored by Corcept Therapeutics…
So in Dr. Healy’s version, Pharma loves people talking about evidence based medicine and randomized clinical trials because that means they still have control of the evidence base. And I would add that even if Pharma were to play it totally straight, clinical trial methodology permits a claim of efficacy at very weak, perhaps clinically irrelevant, levels.

Another of Dr. Healy’s points is, by the way, they’re not going to play it totally straight. With great fanfare, GSK has pole vaulted from goat of 2012 [after their well-deserved $3 B fine] to a position rivaling Pope Francis for humility and cooperation, even signing the AllTrials petition – except they aren’t going to do it and it’s a trick. They’re going for data transparency through a glass darkly by adding riders up front. They’ll have a board of who-knows-who to decide who gets to see their data and what data they get to see. Not only does the firewall stay up, but by controlling the form of the data, they get to do the same thing they did in Paxil Study 329 – shape what the data says. In the terms from the long gone 1960s, Dr. Healy thinks that industry will co-opt Goldacre’s AllTrials, turning his campaign to their advantage just as they’ve co-opted evidence based medicine and randomized clinical trials.

I hope Ben Goldacre hears that point loud and clear, because I’ve been worried about the exact same thing as this saga plays out. I’m not sure GSK should’ve been allowed to sign that AllTrials petition prior to spelling out in minute detail what they mean by data transparency. I anticipate that data transparency GSK-style will be like data transparency Roche-style in the Tamiflu story – bait and switch. They will try to use Goldacre’s campaign to their own advantage and continue to keep playing the game until they win. In Ingmar Bergman’s classic, The Seventh Seal, about his chess game with Death, the Knight says, "As long as I resist you, I live":

The pharmaceutical industry has turned every single reform movement to their advantage so far, and one can begin to think of them having an inevitable advantage – something like that of Death in the movie. The truth is the opposite. It’s GSK that’s fighting for its life as defined by the kind of blockbuster profits they’ve come to require. The stakes for GSK and Andrew Witty are higher than most of us can ever imagine. Sir Andrew Witty can’t ride on being a Knight forever. He’s the one saying, "As long as I resist you, I live," and David Healy is onto him. I hope Goldacre, Godlee, Doshi, Jefferson, et al are as well.

There’s much more in these two posts, including a takedown of my own favorite data-transparency flim-flam man, Robert Gibbons, author of the meta-analysis from outer space that has been such a preoccupation of my own [in April Fool in Harlow][[an anatomy of a deceit… et al]. In the second part of Not So Bad Pharma, Healy synopsizes the points he makes in Pharmageddon. He’s accused of being a cryptic writer at times. In this instance, I don’t think that’s the case. Some of his points are counter-intuitive and require more than just reading, they require something like study. That’s the reason I haven’t synopsized them here. I haven’t digested them myself enough to comment, though I’m beginning to understand his idea about how making drugs prescription-only was part of the problem. This version is a simple statement of the point:

    A second set of bolts put in place in 1962 was prescription-only status for medicines [Dance of the Sugar Plum Fairies]. The idea that drugs should be prescription-only fits Ben’s worldview – no matter how health literate you are doctors have spent more time being educated in these things than you and they’re here to manage you.

    But prescription-only was a mechanism designed to control addicts and it makes doctors rather than their patients the consumers of medicines. And pharmaceutical companies bring more money to bear on influencing this small band of consumers – $50,000 per annum per doctor – than other companies bring to bear on influencing an entire population. When they slip on the Ring of Prescription Privileges, doctors become visible to Eye of Sauron and shrivel.

    The hazards of thalidomide came to light in Germany because it was over-the-counter there and doctors didn’t make a living out it. Ditto with tobacco and alcohol.

    In contrast, the significant hazards of prescription drugs now take 15 – 20 years to be accepted. The combination of trials and prescription-only status has fashioned doctors into a risk-laundering service for companies. Bad Pharma mentions nothing about this.

For myself, I cringe when I hear the term evidence based medicine these days. When somebody uses it and you argue  with anything they say, it’s like talking about Women’s Rights to a Taliban soldier [who is armed]. It reminds me of how I felt about all those patriotic magnets stuck all over cars in the early part of our Invasion of Iraq. I felt that the genuine patriotism of Americans, a feeling I share, was being misappropriated – and that there was nothing I could say that didn’t sound like treason. If evidence based medicine meant what it means to me fifty years after starting medical school, I’d have it tattooed on my forehead. But that’s not what it means these days. It means that if you can’t prove it with a randomized clinical trial, it doesn’t exist. That is wrong, and as Healy points out, a central piece of the problem. It’s the same kind of perversion as those magnets – something essential betrayed…
    April 2, 2013 | 10:18 AM

    Interesting read. I agree with your summary and Dr. Healy’s points on EBM/RCTs in the field of psychiatry. However, I’m not so sure its generalizable to other disciplines of medicine.

    As a family doctor, I try to use the best evidence for treating my patients and avoid harms. For many things, as John Ioannidis has written ( ebm helps us avoid unnecessary medications and treatments.

    Their is a separate issue of pharma marketing peddling the doctors the consumer, who may not be aware of all the ebm. The best example are billions made on brand name PPIs and Statins, when ebm shows that generics are just as good.

    If we want to extend David Healy’s insights into the problems with RCTs and EBM from psychiatry to general medicine, then one actually has to study the history of RCTs and EBM in general medicine to make sure the same points apply.

    I suspect that Healy hasnt gotten more traction from others in the field, because they disagree with this point. I think Dr. Healy misunderstands their criticism as a rejection of his ideas.

    Just my thoughts….

    annie UK
    April 2, 2013 | 12:52 PM

    I really think that Dr. Mickey should take Alltrials off his lovely blog because Alltrials are playing right into the hands of GSK and their transparency of joining, produced by Ben Goldacre and is not actually a good thing to promote at the moment………
    Dr. Mickey, this is a personal, private note.
    Please take Alltrials off your lovely blog……it is actually playing into the hands of the likes of GSK and think what this is doing……….please take it off………think….please……

    April 2, 2013 | 2:03 PM

    Was the introduction to this post influenced by my April Fool’s comment?

    Dr. Mickey, I’m glad you elucidated Dr. Healy’s arguments about requiring prescriptions for medications. I couldn’t follow that before. But he’s write — the prescription process is risk-laundering for pharma.

    HOWEVER, doctors do have the responsibility to know as much as possible about the treatments they prescribe. Misinformation from pharma is no excuse. Everybody is exposed to advertising and has to exercise critical judgment; doctors, with their pretensions to greater analytical ability, are no exception!

    If a doctor has doubts about a treatment, he or she shouldn’t be prescribing it. I know of psychiatrists — admittedly, exceptions — who don’t prescribe SSRIs because they were suspicious of the marketing.

    The way things go, you can be sure any drug that’s advertised, or has any effort put into marketing, is probably not that great. Because, if it were, it wouldn’t need to be hawked! Its effectiveness would speak for itself.

    Remember that the next time you see an Abilify commercial….

    April 2, 2013 | 2:04 PM

    Darn, I mean Healy is RIGHT.

    April 2, 2013 | 2:07 PM

    Holy Crap!

    “fits Ben’s worldview – no matter how health literate you are doctors have spent more time being educated in these things than you and they’re here to manage you.”

    Whatever the validity of some of Healey’s points, this statement is deeply disturbing. 

    Goldacre is not calling for fundamental restructuring of the regulatory system. Healy is and thinks that Goldacre’s approach actually cements the current system more in place. In some ways Healey seems to want to open source the entire enterprise top to bottom. I’m not sure Goldacre would disagree. Healey believes that Goldacre cannonizes the RCT in ways that can be destructive. He believes Goldacre gives short shrift to morbidity from meds, and interprets Goldacre as being too dismissive of some forms of data mining. All fair enough. 

    But other than by simple dint of Goldacre being a physician and not having called for the abolition of the prescription-only status of medications: 1BOM, or anybody else for that matter, point to ONE direct quote from ANYWHERE  that supports  the statement up top?

     Look at Dr. Carroll’s comment in an earlier related thread:
    “Do we say, in effect, “Trust me because I am a doctor?” Yes.”
    And, Dr. Shorter’s comment right after:
    “Dr Carroll is saying that years of clinical judgment and experience acquired at the bedside are at least as valid as the knowledge acquired in these RCTs, and that off-label prescribing represents — if I may extend his argument a bit — a further exercise in the art of medicine.”
    Please look at the link to check that I am not misrepresenting them (not I mention they are informative in their own right). 

    Who is more saying that “no matter how health literate you are doctors have spent more time being educated in these things than you and they’re here to manage you.”?

    Again, point to ONE direct quote from Goldacre. 

    I am not actually convinced that Drs. Carroll or Shorter are truly saying that, but to present that as the worldview of Dr. Goldacre, of all people, seems to me deeply disingenuous.

    1BOM, I truly hope that you do not leave this statement about “Ben’s Worldview” from Healey’s unchallenged. 

    How would have treated a statement like this about Goldacre had it come from anyone but Healey? How about if it had come from Pharma?

    P.S. when you have the chance please release one of my earlier comments from hold purgatory (it contained too many links).

    Bernard Carroll
    April 2, 2013 | 2:50 PM

    Annonymous, you left out the part about the physician’s reciprocal obligation to put the interest of the patient first and to eliminate conflicts of interest. That is the Hippocratic stance. Within that framework, patients are relieved to feel able to trust their physicians. Also within that framework of management and advice, patients retain autonomy over accepting what the physicians recommend. I hope you don’t have a problem with that.

    April 2, 2013 | 4:09 PM

    I had a discussion with a psychiatrist about “evidence based medicine” once.

    I had told him it it was used by another physician as a derogatory term for pseudoscience. He scoffed at it and asked why would anyone say that?

    It’s not really very complicated at all. So I tried to explain.

    Evidence Based Medicine is supposed to be Empirical Evidence.

    Empirical evidence is a scientific term for where you make an Objective Observation, but you don’t know why it it has been observed. An example would be a blood pressure medicine that lowers dangerously high blood-pressure though an unknown mechanism. Objective observations are made with an instrument, in this case a Sphygmomanometer.

    The rest of medicine doesn’t need exclusively Empirical Evidence, because they know what causes some illnesses, the why and how of what they observed is explained. So, medicine uses science, not purely empirical evidence. Thus only psychiatry uses “Evidence Based Medicine”.

    Except, Evidence Based Medicine is not actually Empirical evidence. There are no instruments used to make objective observations. Observations like depression, anxiety, and psychosis are subjective. The symptoms and their rating scales are subjective, as are Disorders these symptoms supposedly create. In other words, these subjective observations do not actually qualify as a scientific observation, empirical or otherwise.

    Science was created to offer an alternative to subjective conjecture, thus science requires objective observations and a scientific process.

    My opinion of why psychiatry uses this is pure conjecture though.
    I imagined Evidence Based Medicine was like a legacy of Freud’s fault. He didn’t understand enough about science to recognize that observations had to be objective – yet he wanted science to be a part of the field. Not surprisingly, this problem never went away in field that was always exclusively subjective.

    April 2, 2013 | 4:12 PM

    I had (and have) questions about the details of clinical decision making, but don’t really have a problem with the first part of the statement I quoted. Definitely don’t have a problem with the second. I am sorry if it appears that I was trying to caricature your statement, it was more that I was trying to focus on whether emphasis on trial data privileges somewhat black box of physician expert opinion more or less than an emphasis on individual experience. When I included the link to the 2 comments and said I thought they were informative I meant that in a good way.

    I think it is fair to say that the “art” of medicine presents somewhat more of a black box and asks for possibly more trust in somewhat fuzzier pattern recognition. Does not mean that is wrong.

    I was trying to emphasize the point it is absurd to in any way imply that Goldacre’s worldview is one where expert pattern recognition should be reverenced over that which an educated populace can derive from open access to, and educated analysis, of data.

    Goldacre seems to believe that it is trials, in various degrees of rigor, that most fundamentally distinguishes the art of medicine practiced by a 20 year veteran, from most (perhaps not all) CAM 20 year veterans practicing their art.

    When physicians venture into territory where their practice largely depends on that art, or perhaps also on n of 1 trials, then what distinguishes them from CAM providers? What tools do they use to minimize confounds such as placebo effects, regression to the mean, observation bias, etc? Can those tools be detailed in such a way they they can be critically assessed for likely effectiveness/drawbacks in a way akin to the way we can discuss the merits and limits of randomization, blinding, …etc?

    I think these would be richer discussions if the Art could be discussed in ways at least somewhat akin to the science. You tried to speak to that some in a response on an earlier thread and I appreciated that.

    I enjoy this blog immensely, but if the Art of medicine is I be privileged (and it should) then its advocates should be discussing how to address its biases when not resorting to larger trials (especially because often they aren’t there). Awareness of bias does not address it. Taking inspiration from larger trials, but not too much mind you (just Ye right amount), is not addressing it.

    Goldacre lays out very clearly what distinguishes the science of medicine from that of CAM.

    It would be an enormous service for people to lay out in close to the same level of detail and clarity what distinguishes the art of medicine from the art of CAM.

    In my view, Goldacre oversells the RCT. However, I don’t believe he oversells the problems that the RCT is designed to address.

    At the very least he shouldn’t be caricatured as having a worldview that is contrary to what seems to be a lot of what drives him.

    The second part of your statement that I left out spoke to something that should be of fundamental importance to all physicians. But, even individuals who share that striving can disagree on how to best compensate for the fallibility of judgment, experience, and external data.

    It was on these later I wa trying to focus.

    It would be ironic if I unfairly characterized your views while ranting on the subject of mischaracteization. Was not my intent and apologize if that is how it came across.

    April 2, 2013 | 4:38 PM

    But the Evidence-Based Medicine diagram you posted is so cute.

    Like those ads on television.
    Easy to understand.
    And so cute.

    What’s next?
    Are we going to criticize the Miss America contest?
    The ‘world peace’ speech?

    Surely, there’s a place for so-called Evidenced-Based Medicine
    It’s cute.

    ‘I can’t believe that!’ said Alice.

    ‘Can’t you?’ the Queen said in a pitying tone. ‘Try again: draw a long breath, and shut your eyes.’

    Alice laughed. ‘There’s no use trying,’ she said: ‘one can’t believe impossible things.’


    April 2, 2013 | 4:40 PM


    Thanks for the sanity.


    April 2, 2013 | 7:56 PM

    “Evidence-based medicine” is another method of risk-laundering for pharma.

    berit bj
    April 3, 2013 | 9:07 AM

    “As long as I resist you, I live.” The quote from Ingmar Bergman’s The Seventh Seal could be a late, repenting Faust, trying to undo the deal his ambitious self made with the Devil.
    The devils today do not come clad in black hoods, black metal, knives, daggers, shearing tools on display, but in suits and ties, white coates, uniforms, ones in a while also in pearls and high heels.
    Growing up is not all fun. It may entail shedding belief in benevolent authorities and the good of good intentions. We are a fallible species, rarely, perhaps never, to be trusted when drawn to power …

    berit bj
    April 3, 2013 | 9:30 AM

    Once in a while… Too often I see my faults afterwards, unlike Knights, like another Faust. Sad.
    I do not forget a documentary about My Lai, a helicopter commander seeing the carnage on the ground, realizing what it was, ordering his crew to fire on American soldiers if they tried to stop him and his crew from rescuing civilians in mortal danger of being massacred by other Americans. The retired commander was intact, a human being, in contrast with one wreck of a man who spoke, shaking, crying, of murders he and his mates committed, shooting defenseless civilians, women, children, elderly – he was seated at a table covered by bottles of prescription drugs. His own young child had recently been shot by stray bullets in a turf war on an American street. Then other wars … and lifesaving resisters…

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