well worth reading…

Posted on Wednesday 20 August 2014

This is not really a blog post – more like a library of selected readings. Over the last year, there has been a dialog about the use of maintenance antipsychotic medication in the long term treatment of schizophrenic patients scattered around in various publications that hinges on an article published in JAMA Psychiatry last summer. It’s a Dutch Study that followed patients with First Episode Schizophrenic illness for 7 years. First the abstract of the article and an excerpt from the accompanying editorial [both behind a paywall]:
Long-term Follow-up of a 2-Year Randomized Clinical Trial
by Lex Wunderink, MD, PhD; Roeline M. Nieboer, MA; Durk Wiersma, PhD; Sjoerd Sytema, PhD; and Fokko J. Nienhuis, MA
JAMA Psychiatry. 2013 70[9]:913-920.

Importance: Short-term outcome studies of antipsychotic dose reduction discontinuation strategies in patients with remitted first-episode psychosis [FEP] showed higher relapse rates but no other disadvantages compared with maintenance treatment; however, long-term effects on recovery have not been studied before.
Objective: To compare rates of recovery in patients with remitted FEP after 7 years of follow-up of a dose reduction discontinuation [DR] vs maintenance treatment [MT] trial.
Design: Seven-year follow-up of a 2-year open randomized clinical trial comparing MT and DR.
Setting: One hundred twenty-eight patients participating in the original trial were recruited from 257 patients with FEP referred from October 2001 to December 2002 to 7 mental health care services in a 3.2 million–population catchment area. Of these, 111 patients refused to participate and 18 patients did not experience remission.
Participants: After 7 years, 103 patients [80.5%] of 128 patients who were included in the original trial were located and consented to follow-up assessment.
Intervention: After 6 months of remission, patients were randomly assigned to DR strategy or MT for 18 months. After the trial, treatment was at the discretion of the clinician.
Main Outcomes and Measures: Primary outcome was rate of recovery, defined as meeting the criteria of symptomatic and functional remission. Determinants of recovery were examined using logistic regression analysis; the treatment strategy [MT or DR] was controlled for baseline parameters.
Results: The DR patients experienced twice the recovery rate of the MT patients [40.4% vs 17.6%]. Logistic regression showed an odds ratio of 3.49 [P = .01]. Better DR recovery rates were related to higher functional remission rates in the DR group but were not related to symptomatic remission rates.
Conclusions and Relevance: Dose reduction/discontinuation of antipsychotics during the early stages of remitted FEP shows superior long-term recovery rates compared with the rates achieved with MT. To our knowledge, this is the first study showing long-term gains of an early-course DR strategy in patients with remitted FEP. Additional studies are necessary before these results are incorporated into general practice.
By Patrick McGorry; Mario Alvarez-Jimenez; and Eoin Killackey
JAMA Psychiatry. 2013 70[9]:898-899.

…It now seems probable for patients who achieve clinical remission from FEP that as many as 40% can achieve a good longterm recovery with use of no or low-dose antipsychotic medication. It is important to identify these patients at an early stage. Combining DR strategies with proactive psychosocial recovery interventions maximizing early functional recovery, delivered in specialized, optimistic systems of early psychosis care, is likely to further increase the percentage of full functional recovery. Physical health would also be expected to improve through reduction of antipsychotic load and greater levels of social inclusion and employment.

The crude use of antipsychotic medications, the delay in building evidence to guide their use, the ideological storms that continue to distort the discussion, and the tendency of human beings to seek either/or solutions to problems have combined to cause us to pose the wrong questions. In moving to a more personalized or stratified medicine,we first need to identify the probably very small number of patients who may be able to recover from FEP with intensive psychosocial interventions alone.  For everyone else, we need to determine which medication, for how long, in what minimal dose, and what range of intensive psychosocial interventions will be needed to help them get well, stay well, and lead fulfilling and productive lives. These factors have rarely been the goal in the real world of clinical psychiatry — something we must finally address now that we are armed with stronger evidence to counter poor practice. Antipsychotic load is a key concept that takes us beyond polarized views stoked by alarmists on the one hand and hard neurobiological reductionists on the other…
At the time of publication, there were two commentaries, one in Medscape and a blog post by Tom Insel MD, Director of the National Institute of Mental Health [The remainder of these references are available online]:
Sandra Steingard MD, Medical Director at the Howard Center in Burlington Vermont and blogger on Robert Whitaker’s Mad in America, wrote a piece in the Washington Post later last year that discussed the findings of Wunderlink et al and some of her experience in her clinic.
The first response article came from E. Fuller Torrey MD, founder of the Treatment Advocacy Center and Associate Director of the Stanley Medical Research Institute. [To read some of the articles cited below, you will need to register on the Psychiatric Times site. It's free and in-so-far as I can see, painless].
And was followed by one from Joseph M. Pierre, M.D., Co-Chief of the Schizophrenia Treatment Unit at the VA Greater Los Angeles Healthcare Center and Clinical Professor of Psychiatry at UCLA.
While I have thoughts of my own about some of the issues mentioned in these articles, I’ll save them for later. I thought this was a conversation that needed to be collected in a single place. There is no disagreement that it is desirable to use the lowest effective dose of medications. In my day in this particular arena, that was what I was taught and practiced. The "medication for life" injunction certainly has its proponents, but is hardly a specialty-wide injunction. But previously, the central reason was preventing harm – avoiding the specter of Tardive Dyskinesia. The study by Wunderlink et al and some others suggests something further, that patients who can be maintained on either low dose or no medications are able to achieve a better functional recovery. Many of us have felt that intuitively, but this study adds the weight of a controlled trial. While there’s no clear consensus in this discussion, this is a high level dialog of pros and cons among experts of the hands-on variety, well worth reading…

Update: Here’s a critical analysis of the Wunderlink et al study written by George Dawson shortly after it was published:
Mickey @ 5:06 PM
Filed under: politics
intent to mislead…

Posted on Tuesday 19 August 2014

I never thought of myself as a "learned intermediary" – someone who is a go-between between patients and the pharmaceutical industry. I think of myself as someone who needs to know a lot about the drugs I prescribe – gathered from the literature, colleagues, and patients. In fact, I resent being seen that way by industry. No matter how hard they push this point, I’m not their "vendor," I’m a doctor who sees sick people. But I could rant on about that topic for hours, and there are other points to be made. So how did I get this designation – learned intermediary?
Learned intermediary is a defense doctrine used in the legal system of the United States. This doctrine states that a manufacturer of a product has fulfilled his duty of care when he provides all of the necessary information to a "learned intermediary" who then interacts with the consumer of a product. This doctrine is primarily used by pharmaceutical and medical device manufacturers in defense of tort suits. In a clear majority of states, the courts have accepted this as a liability shield for pharmaceutical companies. Wikipedia
For example, we just learned that Roche just won the appeal of a judgement against Accutane® based on such an argument. The appeal court ruled that Roche had informed the doctor of the possible adverse effect and that ended their obligation. It’s now an essential piece in the lawsuits against Eli Lilly in Cymbalta® withdrawal cases [see Antidepressant discontinuation syndrome] where it was rejected in an attempt to have the suit dismissed:
2013 class action lawsuit
In 2013, a proposed class action lawsuit, Jennifer L Saavedra v. Eli Lilly and Company, was brought against Eli Lilly claiming that the Cymbalta label omitted important information about "brain zaps" and other symptoms upon cessation. Eli Lilly moved for dismissal per the "learned intermediary doctrine" as the doctors prescribing the drug were warned of the potential problems and are an intermediary medical judgement between Lilly and patients; in December 2013 Lilly’s motion to dismiss was denied. Wikipedia
The number of suits around this issue of the Discontinuation Syndrome with Cymbalta® are definitely on the rise [they prefer the term Discontinuation Syndrome rather than Withdrawal because the patients aren't drug-seeking]:
Salient News
by Stoff
August 15, 2014

Pharmaceutical giant Eli Lilly and Company is facing a growing number of lawsuits charging the company with misleading patients about the risk and severity of the withdrawal effects of its antidepressant, Cymbalta.  Cymbalta, which lost its patent protection last year, was Lilly’s top selling drug in 2013, earning $5 billion, according to the website FiercePharma.

In an August 14 press release, the law firm Baum, Hedlund, Aristei & Goldman reports that nearly two dozen Cymbalta withdrawal lawsuits were recently filed in federal courts across the nation, adding to 7 suits filed in 2013, and a class action lawsuit filed in 2012. Plaintiffs in those suits claim they endured serious withdrawal symptoms, lasting in many cases for months, when they tried to stop taking the drug, and allege that Eli Lilly failed to warn them even though it knew, from its own published research, that severe withdrawal effects were commonplace and lasting.

Central to the charges is the Cymbalta drug label itself, which states that the risk of withdrawal effects is “greater than or equal to 1%.” In 2005, a study designed, conducted and funded by Lilly, and published in the Journal of Affective Disorders, found that up to 51% of users experienced discontinuation symptoms, which were severe in 10 – 17% of cases. In over 50% of the patients, withdrawal reactions had not resolved by the end of the study’s two week withdrawal period.

Cymbalta’s withdrawal effects include severe nausea, vomiting, dizziness, headaches, vertigo, nightmares, and electric-shock-like sensations in the brain. In a declaration filed in, Harvard Medical School psychiatrist Joseph Glenmullen, author of two books on antidepressant side effects, says that the true incidence of withdrawal reactions may be as high as 78%.

Plaintiffs in the lawsuits allege that Cymbalta’s label misled them by suggesting that the risk of withdrawal effects was in the range of 1% and that the effects were generally short-term. The Cymbalta label makes no reference to the findings of Lilly’s study, instead referring to “spontaneous reports of adverse events” that are “generally self-limiting.”
hat tip to Bob Fiddaman…  
ProzacWhen I read this, I had a déjà vu moment. I was reminded of the early days of Prozac® [also from Eli Lilly]. Package inserts aren’t my primary resource when a new drug shows up, but I’ve always read the PDR [Physician's Desk Reference] which is essentially a book of package labels for all of our drugs. Over my fifty years in medicine, the PDR has gotten much thicker and the print has gotten much smaller, so I have one of those plastic wallet card magnifiers as an always-around book-mark stuck in my copy. Whenever I learn of a new drug I might prescribe, I always check the PDR [package label] for adverse events and drug interactions. I can’t find the original Prozac® label, but I remember reading about the sexual side effects back in the day. And what it said and what turned out to be true weren’t even in the same state, much less the same county. I sure was no "learned intermediary" in that instance. It’s the first time I can recall feeling like I was being gamed about a drug. I feel the same thing reading this final label for Cymbalta® before it went off-patent this year…
    5.6 Discontinuation of Treatment with Cvmbalta

    Discontinuation symptoms have been systematically evaluated in patients taking duloxetine. Following abrupt or tapered discontinuation in placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, paresthesia, fatigue, vomiting, irritability, insomnia, diarrhea, anxiety, and hyperhidrosis.

    During marketing of other SSRIs and SNRIs [serotonin and norepinephrine reuptake inhibitors], there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances [e.g., paresthesias such as electric shock sensations], anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.

    Patients should be monitored for these symptoms when discontinuing treatment with Cvmbalta. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

… but even moreso when I saw that it says essentially the exact same thing in the original label at the time of FDA Approval on 08/03/2004 [except that it says "2% or greater" instead of "1% or greater" - go figure]. Here’s the 2005 study referred to above:
by Perahia DG11, Kajdasz DK1, Desaiah D1, Haddad PM2.
[all either Lilly employees1 or on their paid  advisory board2]
Journal of Affective Disorders. 2005 89[1-3]:207-212.
[submitted 01/10/2005]

BACKGROUND: Discontinuation symptoms are common following antidepressant treatment. This report characterizes symptoms following duloxetine discontinuation.
METHODS: Data were obtained from 9 clinical trials assessing the efficacy and safety of duloxetine in the treatment of major depressive disorder [MDD].
RESULTS: In a pooled analysis of 6 short-term treatment trials, in which treatment was stopped abruptly, discontinuation-emergent adverse events [DEAEs] were reported by 44.3% and 22.9% of duloxetine- and placebo-treated patients, respectively [p<0.05]. Among duloxetine-treated patients reporting at least 1 DEAE, the mean number of symptoms was 2.4. DEAEs reported significantly more frequently on abrupt discontinuation of duloxetine compared with placebo were dizziness [12.4%], nausea [5.9%], headache [5.3%], paresthesia [2.9%], vomiting [2.4%], irritability [2.4%], and nightmares [2.0%]. Dizziness was also the most frequently reported DEAE in the analyses of 3 long-term duloxetine studies. Across the short- and long-term data sets, 45.1% of DEAEs had resolved in the duloxetine-treated populations by the end of the respective studies, and the majority of these [65.0%] resolved within 7 days. Most patients rated the severity of their symptoms as mild or moderate. A higher proportion of patients reporting DEAEs were seen with 120 mg/day duloxetine compared with lower doses. For doses between 40 and 120 mg/day duloxetine the proportion of patients reporting at least one DEAE differed significantly from placebo. Extended treatment with duloxetine beyond 8-9 weeks did not appear to be associated with an increased incidence or severity of DEAEs.
CONCLUSIONS: Abrupt discontinuation of duloxetine is associated with a DEAE profile similar to that seen with other selective serotonin reuptake inhibitor [SSRI] and selective serotonin and norepinephrine reuptake inhibitor [SNRI] antidepressants. It is recommended that, whenever possible, clinicians gradually reduce the dose no less than 2 weeks before discontinuation of duloxetine treatment.
LIMITATIONS: The main limitation is the use of spontaneously reported DEAEs.
There were only 5 months between the FDA Approval of Cymbalta® and the submission of this Lilly-funded article. So they had to know about the frequency of discontinuation symptoms back then. After all, it was their own trials being reviewed. And this study is not mentioned in any of the label revisions along the ten years of patent protection. Surely they weren’t counting on all doctors to be subscribers to the Journal of Affective Disorders. And I hardly think that the blurb in that package insert comes close to alerting us "learned intermediaries" to the true incidence of discontinuation symptoms. Cymbalta® appeared after I retired and it’s not available in the charity clinic where I work, so I’ve never prescribed it or even looked it up in the PDR. It has only just gone off-patent. But it’s easy to see why the motion to dismiss the class action suit was denied. I had no idea that the withdrawal symptoms were so frequent until I started writing this post.

CymbaltaThis learned intermediary thing is yet another loophole the drug companies use to increase their sales, like so many others. They minimize or even hide the adverse events that might put a damper on their enthusiastic ad campaigns. That labeling commentary for Cymbalta® seems to me to be written with intent to mislead doctors by not highlighting the frequency. It’s certainly not something planned to make me a more learned intermediary. I expect them to accentuate the positive but I’m surprised that they eliminate the negative so regularly. I used to think that the idea that they just figure losing suits after the fact for withholding adverse events into the "cost of doing business" was perhaps an over-blown charge. But it now seems inescapable that it’s regular and by design. Their losses don’t come close to equaling the gain of a true blockbuster. And thinking back on things, I used to learn a lot about the efficacy and liability of drugs from the review articles that pepper our literature. But in modern times, review articles, at least in psychiatry, seem more often  infomercial-like than comprehensive discussions.

ZyprexaIn the case of Eli Lilly’s Prozac®, the incidence of sexual side effects was minimized. With Lilly’s Zyprexa®, the tendency for significant weight gain and Diabetes was downplayed. Comes now Lilly’s Cymbalta®, and we find yet another inconvenient [secret] truth, a regular Withdrawal Syndrome now increasingly moving into the light of day as the drug goes off-patent. What has this learned intermediary gleaned from Eli Lilly? They specialize in deceit when it comes to reporting the adverse effects of their psychiatric drugs. That’s what…
Mickey @ 2:06 PM
Filed under: politics
only that – tools…

Posted on Sunday 17 August 2014

I was in a Clinical Trial frame of mind after my last post, and I happened to run across a CD that I had gotten with a FOIA [Freedom of Information Act] request a few years ago when I was looking at Paxil Study 329. It’s the data from the original Paxil NDA [New Drug Application] in 1992. I’d never looked at it because it wouldn’t load. But that was several computers ago, and when I put it in the drive this time, it loaded just fine. It’s 500+ pages, but as I scanned through it, I thought I’d post some of its contents, mainly to illustrate some of the quirks in an actual Clinical Trial. They submitted 17 trials in their application. 11 were single site, 6 week, RCTs with placebo controls. Of these, 6 were identical trials that also had an Active Comparator [Imipramine]. The HAM-D scores for the placebo controlled trials are summarized in the figure below.
These are all the ITT [Intent to Treat] populations with a LOCF [Last Observation Carried Forward] correction for drop-outs and missing values. The outcomes are expressed as Cohen’s d [Effect Size] which is the Difference in the Means divided by the Group Standard Deviation – to allow comparison across studies. As a rough gauge, 0.25 is a slight effect, 0.50 is a moderate effect, and 0.75 is a strong effect. Studies with a 95% CI bar that does not cross zero are significant at p < 0.05.

Just scanning the figure, it looks okay. 7/11 of the Paroxetine trials are in the moderate range and are statistically significant. By FDA standards, this passes the efficacy requirements with flying colors. It looks to leave Imipramine in the dust with only 2/6 studies in the moderate range and statistically significant. However, the Paroxetine/Imipramine difference is an illusion. The only statistically significant differences in those 6 identical studies are the two marked with asterisks, one favoring each drug. And the weighted composites [in red] are likewise not significantly different. The unmentioned 6 trials were either uncontrolled or failed trials with recruitment/drop-out problems. The values shown above for the 5/6 of the trials against Imipramine are from only 4 weeks because by the time the planned 6 week period came around, there had been too many drop-outs to make valid calculations. The overall dropout rate by 6 weeks for the 11 trials was ~50%.

Finally, if you look at the breadth of the 95% Confidence Intervals in the figure, there was a lot of variability and many subjects that would fall out of the clinically effective therapeutic range.

These problems of drop-outs, missing data, wide variability among the subjects in a given study or between separate studies, not really knowing if the patients are help-seeking or paid recruits, etc. are part and parcel of most clinical trials whether run in an academic center, by a large Clinical Research Organization, or by a small center like those in Carl Elliot’s recent piece [under some of the rocks…]. Human beings don’t have uniform illnesses, don’t have the genetic uniformity of cloned white mice, aren’t confined to wire cages on a strictly controlled diet. So even in the most pristine and unbiased of trials there’s an intrinsic heterogeneity that transcends the clean demographic tables found in the published articles. And in psychiatry, the subjectivity of the symptoms just adds to the confusion.

The main charge of the FDA is safety, adverse events, and I didn’t look at that part of this NDA [maybe another time]. Proof of efficacy was added in 1962 by the Kefauver-Harris Amendment to keep the ineffective patent medicines out of our pharmacopoeia. The efficacy criteria are minimal – two well conducted studies demonstrated efficacy. This Paroxetine submission easily achieves that requirement. It seems that the drug, Paroxetine, does have antidepressant properties, but that’s all it means. Leaving aside the crucial issue of harms for the moment, that’s what the FDA is for – certifying that the drug does what its sponsor says it does, that it’s not snake oil or some inert substance of no therapeutic value. How well it does it or how often or in whom or when indicated are another matter.

When I found this disc, I was initially curious because it came from several decades ago. It would be surprising to find single site trials these days. It’s hard to recruit the number of subjects needed to show differences [called power] at a single site. Nowadays, the trials use multiple sites to achieve the necessary power [and they're a lot faster]. This study is from a time before the meteoric rise of the Clinical Research Organizations, so these trials were at the smaller clinical research centers of the time or academic institutions. I expected [and found] that the NDA would show why Clinical Trials are really not some bottom line knowledge [beyond…], just a piece of data among the many other things that go into a clinical recommendation. Talking about them, people like to use the word confounders. and RTCs always have confounders like in this study.

As Dr. Carroll said in a recent comment:
    When David Healy critiques “the notion that clinical trials provide a higher form of knowledge than knowledge borne in a clinical encounter – the realm of the experiential and the singular…” he draws from the distinction between disease and illness. Clinical trials deal with operationally defined diseases, whereas treating clinicians deal with singular illnesses. As you say, relevant factors that operate in the singular illness may not be considered in the clinical trials – age; co-morbidity; concurrently required medications; insight; capacity for a treatment alliance; duration of required treatment; family stress; economic stress; and many others. So, the knowledge gained in clinical trials is needed but is not necessarily generalizable to or determinative in the management of an individual patient. So, it’s not a question of a higher form of knowledge so much as it is addressing a different question
There are two always-available criticisms of physicians’ decisions: "That’s just what you think! What’s your evidence base?" and "You’re just following a guideline by rote and not seeing the person in front of you!" At one time or another, each of those negative epithets might well be accurate – sometimes both apply. But somewhere in recent times, the battle cry of evidence based medicine has shifted the balance and fostered the notion that the guidelines derived from groups dictate the best course for an individual case - implying a uniformity among people and a strict objectivity to medical care that is illusory. Randomized Clinical Trials, Rating Scales, Statistical Significance, FDA Approval, Expert Opinions, and all the other ways we try to extract objective markers from subjective phenomena are vital tools in the medical toolbox, but only that – tools…
Mickey @ 10:00 PM
Filed under: politics
the beginning of an end…

Posted on Friday 15 August 2014

Finally wading through my emails for the 10 days I was gone, I ran across this:

August 8, 2014

Thank you for your email of 20 May 2014 and the EMA request for information (reference number 3644) of 10 June 2014 concerning the draft policy on proactive publication of and access to clinical trial data. Your email and your request for information have been received and your comm

Yours sincerely

Guido Rasi
Executive Director
European Medicines Agency

Having had some experience with the screen-only interface proposed for the EMA Data Transparency, we were among the throng that complained about their proposed use of such a system. We had written:

… In writing about your proposal [the U-Turn…], I made the analogy, "It’s like going to sea to see the world in a submarine looking through a periscope." If anything, that’s an understatement. Trying to review the CRFs in the single window interface is beyond difficult. In our case, there are 275 subjects with the CRFs averaging over 200 pages each [more than 55,000 pages]. The data tables are equally voluminous making computation and extraction of data very difficult. I don’t know what process suggested that you change your policy, but it makes data analysis extremely awkward. I would suggest you have one of your own scientists try it out to see how really obstructionistic this policy is going to be. Please consider going back to the plan of access originally described…

As you may recall, the promise of the EMA [European Medicines Agency] to release all of the data for clinical trials hit a snag with add-on restrictions [see also Welcome to Troy, Ombudsman concerned about change of policy at Medicines Agency as regards clinical trial data transparency, EMA policy on publication of and access to clinical-trial data, the U-Turn…]. There was much wailing and gnashing of teeth [the end game…, to be continued…, a decision to reconsider…, a crushing setback…, oh how we’ve missed our Pharmalot!…]. And then they recanted! [awaiting further information…, some further information…, out of the shadows…]. And then, as they say above, they put off their decision until October 2, 2014.

Is there something that brings this to mind other than getting a belated response from Dr. Rasi? It’s my ongoing suspicion that the tenacles of PHARMA are never still. We may be waiting expectantly, but you can count on the fact that the PhRMA/EFPIA lawyers are burning the candle at both ends in this lull:
In the illusion of evidence… and beyond…, I was echoing Dr. Healy’s point that Clinical Trial Data Transparency is just a starting place, not a destination. The escalation of Clinical Trials, Algorithms, and Treatment Guidelines to the level of Dogma is also a big problem – perpetuating somebody’s silly fantasy that a group mean in a controlled trial can direct treatment for individual patients. That said, insisting that the data from Clinical Trials is freely available for independent analysis is of vital importance to insure accurate baseline efficacy and adverse event data as a drug enters the real arena of clinical medicine. This coming EMA policy is going to be the linchpin for establishing integrity in Clinical Trials if properly implemented – the beginning of an end to the untenable notion that patient data is the proprietary property of trial sponsors…
Mickey @ 8:54 PM
Filed under: OPINION
rarely, if ever, available…

Posted on Friday 15 August 2014

But our discussions of mental illness rarely focus on this inconvenient truth: these illnesses are currently just as fatal as the “big killers.” We must continue to invest in research to develop new and more effective treatments for people with depression and other mental illnesses. The goal must be a future in which no lives are lost as a result of suicide.

“It’s very important that we stop seeing these illnesses as false and stop blaming patients and see them for what they are — which are medical conditions, genetic conditions, brain disorders that require appropriate diagnosis, treatment, care, and support,”
APA President Paul Summergrad, M.D., on NBC Nightly News

I sincerely doubt that there will come a time when some pill will come along that will quickly whisk away the kind of profound depression that Robin Williams was apparently suffering. He was no stranger to feel better pills, and chose not to take them – to his credit.  There were a myriad of risk factors we know about: waning celebrity; financial problems; a cancelled tv series; the diagnosis of Parkinson’s Disease [which can be associated with Depression over and above as a stressor]. He was sleeping 18 hours a day and had no appetite. In his last picture, his weight loss is obvious.

I don’t want to pile on with after the fact analysis. There’s plenty enough of that coming from everywhere. But there is one thing that needs saying. A mainstay of treatment for patients with this kind of profound depression is hospitalization. And one of the reasons is protection from suicide. This is the kind of depressive illness that got lost in the 1980 DSM-III Revision that lumped it in with the more usual depressive illnesses – once called neurotic depression. Independent of one’s theories about the etiology or nosological preferences, impulsive suicide is a constant risk in such severe depressions, so protective hospitalization is a big part of any rational treatment plan – or at least it was. Managed Care and the psychopharmacological revolution have essentially eliminated the kind of mental hospitalization such patients need. It’s a paradox that with all the modern talk about depression, this kind of depression with delusional hopelessness and unbearable pain has gotten lost in the shuffle.

In June, Robin Williams checked in to the Hazelden Rehabilitation facility. not because of a relapse, but for a "tune up" of his sobriety. Maybe people do that, but I’ve never heard of such a thing. My guess is that he was looking for help in the only way he knew how, but that’s not what he needed. This kind of Depression is uncommon, but in a modern world, the "diagnosis, treatment, care, and support"  that Dr. Summergrad mentions are rarely, if ever, available for these particular patients…


"…the pain of severe depression is quite unimaginable to those who have not suffered it, and it kills in many instances because its anguish can no longer be borne. The prevention of many suicides will continue to be hindered until there is a general awareness of the nature of this pain. Through the healing process of time — and through medical intervention or hospitalization in many cases — most people survive depression, which may be its only blessing; but to the tragic legion who are compelled to destroy themselves there should be no more reproof attached than to the victims of terminal cancer."
Mickey @ 9:08 AM
Filed under: politics
into the Boston Harbor…

Posted on Friday 15 August 2014

Pharmalot: WSJ
By Ed Silverman
Aug 14, 2014

The U.K. agency that evaluates the cost effectiveness of prescription drugs has recommended the government pay for the controversial Sovaldi hepatitis C treatment, although not for all patients. The move, which still requires a final endorsement, comes as the medicine causes a ruckus in the U.S. The price tag – $84,000 for a 12-week regimen – has insurers and state Medicaid directors worried that the Gilead Sciences medication will become a budget buster and helped to fuel a national debate over the rising cost of prescription drugs.

Generally, the U.K.’s National Institute for Health and Care Excellence causes a ruckus of its own by declining to recommend coverage for medications. Consequently, the agency has often butted heads with drug makers and patient groups over its decisions. Last week, for instance, NICE and Roche battled over the cost of a cancer drug, although in a rare development, patient groups sided with the agency. NICE, in fact, sent mixed signals two months ago about its Sovaldi decision. The agency asked Gilead to supply additional data about certain patient populations and maintained there were “substantial uncertainties in the evidence” that the drug maker provided to win a coverage recommendation. The request for more data prompted speculation that NICE may not recommend coverage.

After reviewing the data, though, NICE agrees that Sovaldi is an effective improvement over existing treatments. The Gilead drug, by the way, can cure nine of 10 patients. The decision was likely helped by the lower price tag in the U.K. Gilead is selling its drug for about $56,000, according to a NICE spokesman. “It’s a lot cheaper here,” he tells us. The agency is recommending Sovaldi, plus interferon and ribavirin, for adults with genotype 1, which is the most common form of hepatitis C, and accounts for 46% of all cases in the U.K., a NICE spokesman says. The recommendation also extends to patients with genotype 3, which accounts for 43% of hepatitis C sufferers…
Pharmalot: WSJ
By Ed Silverman
Aug 7, 2014

“We have set three basic pricing tiers [based on a country’s per capita income and hepatitis C prevalence] that serve as the starting point for negotiations with national governments. The tiers are low-income, low middle-income and upper-middle income,” Gregg Alton, a Gilead executive vice president for corporate and medical affairs, tells the paper. Such decisions, however, have further fed a controversy in the U.S., where Sovaldi costs $84,000 for the same 12-week regimen and has become a proxy for a growing national debate over the rising cost of prescription drugs…
In the US, Sovaldi® costs $1000/day [total $84,000/patient]. Now we learn that in the UK, it will cost $56,000/patient [~$667/day]. And in India and Egypt, it’s being offered at $900/patient [~$11/day].  We once knew what to do about situations like this one:

Boston Tea Party, 1773
Mickey @ 6:36 AM
Filed under: politics
under some of the rocks…

Posted on Thursday 14 August 2014

I started writing about these topics a few years ago because I was stunned by the deceptive presentation methods in clinical trial reporting. And then I discovered that if a trial didn’t come out like they wanted and couldn’t be doctored, they just didn’t publish it. The more I looked, the worse things got. I kept running across the term CRO, one that I’d never heard before, and asked a more knowledgeable colleague what it meant. Looking into that arena lead me to a whole new level of deception. It has been a disillusioning journey, I must admit. Back in the day, there weren’t so many resources for chasing things down: Carlat, Soulful Sepulcher, Healthcare Renewal. Now there are many more, thankfully. But Dr. Roy Poses blog at Healthcare Renewal remains the gold standard when it comes to the big picture. This take on the recent article by Carl Elliot in Matter is up to his usual level and worth a full read for its editorial perspective:
Healthcare Renewal
by Roy Poses
August 13, 2014

Dr Carl Elliott seems to be one of the few people willing to investigate how modern medical research may threaten vulnerable research subjects.  His book, White Coat, Black Hat, opened with a chapter on vulnerable "guinea pigs," people willing to be clinical research subjects for money.  Such people may be desperate for money, and further may be homeless, and have psychiatric problems, including psychosis or drug or alcohol problems.  Dr Elliott just wrote another important article on the plight of vulnerable research subjects…
In Carl Elliot’s article [The Best-Selling, Billion-Dollar Pills Tested on Homeless People], he talks about making a personal hegira into the Clinical Research Center world, and he actually visited South Coast Clinical Trials, home to The Clinical Trials Guru. I first ran across South Coast back in 2011 [the clinical research industry: the CRCs…] directed by a post on Soulful Sepulcher [still active on Twitter]. In my recent take on Carl’s articles [some system…, the illusion of evidence…], I posted one of South Coast‘s many videos of their research subjects. Here‘s another oldie from South Coast, their discussion about the case of Dan Markingson, Carl Elliot’s major focus. And speaking of University of Minnesota’s bioethicist Carl Elliot, here’s his recent blog about another old friend I was also introduced to by Soulful Sepulcher some time back [selling seroquel II: into the fray…]:
Fear and Loathing in Bioethics
by Carl Elliot
August 11, 2014

Illinois has suspended the medical license of Dr. Michael Reinstein, aka The Clozaril King.  Reinstein "received ‘illegal direct and indirect remuneration’ from the maker of generic clozapine; did not consider alternative treatments for his patients; and disregarded patients’ well-being because of potentially life-threatening side effects of the drug."  

In 2009, ProPublica and the Chicago Tribune detailed how he had prescribed more of the antipsychotic clozapine to patients in Medicaid’s Illinois program in 2007 than all doctors in the Medicaid programs of Texas, Florida and North Carolina combined. Autopsy and court records showed that, by 2009, at least three patients under Reinstein’s care had died of clozapine intoxication.
Dr. Michael Reinstein was even more than the Clozaril King, he was also the psychiatrist for a Clinical Research Center next door in Chicago. I ran across this bit of information trying to run down where the Lurasidone [Latuda®] trials were conducted by looking at Google™ Maps, Street View [see hiding uptown]. Uptown Research is a CRC like South Coast, only in Chicago rather than California. They were also involved in some of the Seroquel® clinical trials:


Charles Ornstein at ProPublica has long been on the trail of Dr. Michael Reinstein:
ProPublica
by Charles Ornstein
Aug 11, 2014

Illinois medical regulators have indefinitely suspended the medical license of psychiatrist Michael Reinstein, who prescribed more of the most powerful and riskiest antipsychotic drug clozapine than any other doctor in the country. The decision by Illinois’ Department of Financial and Professional Regulation, signed Friday, suspends Reinstein’s license for a minimum of three years, at which time he can apply to have it reinstated.

The state’s medical disciplinary board recommended the sanction in May after determining that Reinstein, 71, received "illegal direct and indirect remuneration" from the maker of generic clozapine; did not consider alternative treatments for his patients; and disregarded patients’ well-being because of potentially life-threatening side effects of the drug. Reinstein’s motion for a rehearing was denied Friday, making the matter public.

Clozapine is approved to treat patients who don’t respond to other medications. But it can have dangerous side effects, including seizures, inflammation of the heart muscle, and a drop in white blood cells. The drug is considered particularly dangerous for elderly patients…

In 2009, ProPublica and the Chicago Tribune detailed how he had prescribed more of the antipsychotic clozapine to patients in Medicaid’s Illinois program in 2007 than all doctors in the Medicaid programs of Texas, Florida and North Carolina combined. Autopsy and court records showed that, by 2009, at least three patients under Reinstein’s care had died of clozapine intoxication. At that time, Reinstein defended his prescription record, arguing that clozapine is effective and underprescribed.

Last year, as part of an investigation into Medicare’s failure to monitor problem prescribers, ProPublica reported that Reinstein prescribed even more clozapine in Medicare’s prescription drug program for seniors and the disabled. We found that the program continued to let him prescribe even after the U.S. Department of Justice accused him of fraud and Illinois’ Medicaid program suspended payments to him…

I came back Monday from a vacation trip with friends where I spent little time thinking about contemporary matters medical. When I got back Monday night, I was out of the rhythm of keeping up with the things I usually follow. What I always find when I’ve taken a break is that I feel anew the same kind of outrage I felt five or six years ago when I first began to understand how the pharmaceutical-academic psychiatry alliance had become so widely corrupting. Obviously it’s a much bigger problem than simply psychiatry, but it appears my specialty was especially vulnerable [and had some people in high places who dove in head first]. It always takes me a few days to recover my composure and get back into the state of play, rather than this just rant on and on about the myriad of absurdities like those mentioned above.

I remain awed by the tenacity of the people who have dogged this problem for years – people like Drs. Bernard Carroll and Bob Rubin, Jon Juriedini and Healthy Skepticism, David Healy and Rxisk, Stephany of Soulful Sepulcher, Danny Carlat, Dr. Poses of Healthcare Renewal, Ed Silverman of Pharmalot, Joe Friday at Pharmagossip, Carl Elliot of Fear and Loathing in Bioethics, Ben Goldacre of AllTrials, the volunteers of the Cochrane Collaboration – and the growing number of others who’ve taken up the task of shining spotlights into the dark corners of the medical industries. What’s missing, by my read, are strong stands by the various medical professional organizations and particularly their sponsored academic journals. Dr. Fiona Godlee of the British Medical Journal stands tall as an exception to the laissez-faire attitude of journal editorial staffs elsewhere.

On my trip, I returned to the Museum of Civil War Medicine in Frederick Maryland that I mentioned last Fall [in the museum…], this time with four other doctors and our wives – people we were stationed with in the early 1970s that we spend a week with every summer. In the Fall, I was impressed with the advances in medicine in the Civil War – triage, ambulances, hospitals, nursing care, anesthesia and early amputation to prevent gangrene. This time through, I found myself thinking about what was missing. About the only medication in the displayed pharmacy kits that would pass muster was opium. Everything else was either in the toxic poison or inert patent medicine category. Those were the days before Pasteur and Lister so antiseptic techniques were unknown, much less antibiotics. The real killers in the Civil War were the infectious diseases that swept through the camps in waves, killing many more than the enemy’s bullets. On the nearby battlefield at Antietam where 23,000 soldiers became military casualties in a single day, there was an unfinished stone with a small embedded brick cross among the cannons and heroic granite sculptures of soldiers. It marked the spot where Clara Barton [later founder of the American Red Cross] narrowly escaped a miniball that killed the fallen soldier she was tending to. The chief of nursing there was Dorthea Dix, the crusader for moral treatment of the mentally ill.

As we walked around the museum, I realized that among the ten of us seventy-somethings, there were any number of artificial joints, stents, lumbar fusions, early detected cancers with successful treatment, and I expect that the dopp kits back at our B&B held a number of pill bottles with medication that actually helped with something or another. I think I need periodic reminders of the advances and successes of modern medicine to counter the cloud that sometimes forms looking at the dark places under some of the rocks that dot the medical landscape…
Mickey @ 5:22 AM
Filed under: politics
shame…

Posted on Wednesday 13 August 2014

Pharmalot: WSJ
By Ed Silverman
Aug 7, 2014

India has become the latest country where the Sovaldi hepatitis C treatment will be offered for $900 per patient. The move, which was reported by The Times of India, comes a few weeks after the manufacturer, Gilead Sciences GILD +0.66%, is making the medication available for the same price in Egypt. The pricing reflects an effort by Gilead to forestall the sort of criticism the pharmaceutical industry has often encountered when selling life-saving medicines in poorer countries, which have often complained bitterly that many of its citizens have been unable to afford some treatments. An advocacy group last year formally opposed a patent for Sovaldi in India, claiming the treatment is based on “old science” and, therefore, does not deserve patent protection. An Indian generic drug maker made a similar point recently in asking Indian officials to deny the patent. If they prevail, generic alternatives could become available at low prices.

“We have set three basic pricing tiers [based on a country’s per capita income and hepatitis C prevalence] that serve as the starting point for negotiations with national governments. The tiers are low-income, low middle-income and upper-middle income,” Gregg Alton, a Gilead executive vice president for corporate and medical affairs, tells the paper. Such decisions, however, have further fed a controversy in the U.S., where Sovaldi costs $84,000 for the same 12-week regimen and has become a proxy for a growing national debate over the rising cost of prescription drugs.

The U.S. price tag has prompted objections from insurers, state Medicaid programs and politicians, among others, who complain the cost for Sovaldi will bust budgets as more hepatitis C sufferers are diagnosed and seek treatment. Gilead and its supporters say this argument is, effectively, short sighted by noting that Sovaldi can cure nine of 10 patients, many of whom would require more expensive treatment over a protracted period. In other words, society saves money in the long run…
There is nothing that Gilead will ever do or say that will justify the US price tag on Sovaldi®. And they’re not alone. AbbVie’s Humira® is another example of similar price gouging. The Atypical Antipsychotics and many new cancer drugs are in the same class. These PHARMA Companies are using the patent laws not for their intended purpose. There’s no "free market enterprise" or "supply and demand" in these enterprises. It’s simply a predatory monopoly feeding on a captive audience – and in the case of Sovaldi®, a captive audience with lives on the line. After decades of jury-rigged clinical trials and false advertising campaigns, when PHARMA finally comes up with something that might actually work as advertised, they feel entitled to break the bank. Shame on them…
 
Mickey @ 11:00 PM
Filed under: politics
a more legitimate science…

Posted on Wednesday 13 August 2014

You’ll never know more about a disease than with those first cases in medical school. The first autopsy, the first case in the clinic, the first hospitalized patient. It’s all so new and things fall on a mind eager to see the things learned in the basic sciences manifested in a real patient. In those days, one believes everything you read in journals, textbooks, hear from valued teachers. It’s a time where one is desperate for anchors. This article is by a second year medical student, however it unfortunately veers off the track.
New York Times: Opinion
By EDWARD LARKIN and IRENE HURFORD
AUG 12, 2014

Edward Larkin is a second-year medical student at the University of Pennsylvania, where Irene Hurford is an assistant professor in the department of psychiatry.  

A few months ago, a patient came to our hospital, seeking help. One of us, Edward, was on the team that treated him. He was pleasant, if slightly withdrawn, and cogent. He was a college graduate in his 20s and had recently been fired from his job as a high school math teacher, because of unexpected absences. He had come to believe that government agents were conspiring against him, and he had taken to living out of a truck and sleeping in different parking lots. By the time he came to us, he was exhausted. A diagnosis became clear: he had schizophrenia. We admitted him to the hospital, and after a few days, with his symptoms under control, we released him. Unfortunately, we prescribed a medication for him that could cause significant, permanent harm, instead of an equally effective drug with milder side effects — all because he was uninsured.

Schizophrenia, which affects 1 percent of the population and emerges in the late teens to early 20s, is deeply misunderstood. People who suffer from it are often suspected of being dangerous, but this is not usually the case, and antipsychotic drugs are very effective. Our patient was exactly the kind of person who, with the right treatment, could have weakened the stigma surrounding schizophrenia. Antipsychotic drugs fall into two classes: the older ones, like Haldol, and newer ones, like Abilify and Latuda. Both classes are equally effective at treating some of the worst symptoms of schizophrenia, specifically the hallucinations, delusions and paranoia that cause social alienation. [They’re not effective for treating “negative symptoms,” like low motivation].

But the older drugs can cause a multitude of serious side effects, including a potentially devastating one called tardive dyskinesia. This condition involves unsettling, animalistic smacking and wagging of the lips and tongue. At its extreme, it can affect the entire body. It occurs in 20 percent or more of patients who take the drugs long-term, and it tends to start so mildly that patients can’t identify it in time to stop taking the drugs. It is often irreversible.

The newer drugs have lower rates of tardive dyskinesia [estimates vary, but most likely less than half or one-third the risk], although they can cause weight gain and predisposition to diabetes, among other side effects. The newest among them, however, have decreased these risks, too. And a 2006 study showed that patients were more likely to keep taking the new drugs than the older ones.
    Note from 1boringoldman: This 2006 study is from a proprietary Insurance Claims database with the following financing and ghost? authorship: "This study was supported by AstraZeneca Pharmaceuticals LP. The authors would like to acknowledge the assistance of Anusha Bolonna, PhD [PAREXEL MMS], who provided medical writing assistance on behalf of AstraZeneca."  [The article itself makes multiple pair-wise comparisons with no overall ANOVA to justify them, nor did it provide enough information to allow me to accurately estimate the overall ANOVA's significance].
As a result, most psychiatrists prefer the newer drugs, especially for younger people, and they should have been the clear choice for our patient. He didn’t have the luxury of choice, however, because he was uninsured, and he was explicit about the fact that he didn’t have much money to spend on medications. So we had to prescribe him Haldol, which costs about $20 per month, instead of one of the newer drugs, which can cost more than $600 per month. These issues will be amplified as progress is made in discovering the mechanisms of psychiatric disease, as it likely will be, thanks to the billions of dollars that are now going to neuroscience research. We can already see the results of that kind of investment in oncology, where extravagantly expensive specialty drugs are coming on the market. But as we make much-needed progress and develop new, expensive treatments that are clearly superior to old, cheap ones, we have to ask: Will those with the most to gain still receive a lower standard of care?
Good for our young medical student taking the position as a patient advocate. But the point he’s making about the drugs is unfortunately one fostered by PHARMA propaganda and filled with curve balls. First off, the study he quotes in Psychiatry Research is refuted by the NIMH and even by a more cogent prospective study conducted by AstraZeneca itself [kept hidden because of its outcome] in addition to having a flawed analysis:
[CATIENIMH on top, AstraZeneca's unpublished Study 15 below].
 
Perhaps an even greater omission from this article is that it fails to recognize that its logic is the logic of TMAP [the Texas Medical Algorithm Project] which was the source of numerous charges against J&J/Janssen resulting in one $158 M settlement and many other court battles. It remains a major PHARMA scam still largely unprosecuted.

So while his point holds that we aren’t taking good-enough care of Schizophrenic patients, it’s not our using the older medications that’s the problem [in fact, there are generic Atypicals now as available as the first generation antipsychotics]. Our failure is in offering little more than medications to his young patient and vague hopes for some future breakthrough medication that will fix everything.

I don’t mean to malign the student author here. Maybe I do worry about his supervisor’s mentorship. But my point is rather that he shouldn’t have to be disillusioned about the literature he found [the 2006 study] at this point in his career. Articles like that one – an industry infomercial – continue to do their damage in perpetuity. They just shouldn’t be there in the first place. I hope Edward’s patient advocacy stays with him, but is directed by a more legitimate science…
Mickey @ 9:25 PM
Filed under: politics
beyond…

Posted on Saturday 9 August 2014

In my last post [the illusion of evidence…], I was playing with the phrases evidence of illusion [looking for signs that a scientific paper has used the the techniques of presentation to obscure rather than clarify data] and the illusion of evidence [valuing the mathematical/statistical results of Randomized Clinical Trials over all other sources of information]. I was trying to get at something besides simply the corruption of the Clinical Trial system – but lost track along the way. The corruption theme is so compelling and those two articles in Matter were so powerful, that they carried away my narrative. The thing that got lost, the thing I started off wanting to say, probably deserves its own separate post anyway. In a recent article [unfortunately behind a pay-wall], David Healy makes the point explicitly,
    Today, many argue that the growing crisis in health care stems from conflicts of interest and lack of access to clinical trial data. Our view is that small-print disclosure in academic footnotes and open access to trial data, important though these are, will not solve problems that stem from the notion that clinical trials provide a higher form of knowledge than knowledge borne in a clinical encounter – the realm of the experiential and the singular…
and he illustrates it with a poem:
    This ‘Trust in Numbers’ story was caught wonderfully when it was unfolding, by George Oppen, a New York poet and member of the communist party, in his 1968 volume Of Being Numerous:
      Crusoe we say was rescued.
      So we have chosen.
      Obsessed, bewildered
      By the shipwreck of the singular
      We have chosen the meaning
      Of being numerous.

I envy that eloquence. For many, this point is counter-intuitive and easy to brush off.

beyond corruption…

Even in the best of circumstances – when protocols are followed precisely, diagnosis is rigorously pursued, analyses are pristine, conflict of interest is absent – a Randomized Clinical Trial is time-limited, and constrained by the measurement instruments selected, proxies like the HAM-D scale substituting for depressive affect. In addition, statistical significance or even effect size measurements don’t necessarily parallel clinical changes that make much of a difference. Subtle adverse effects often become apparent in a time-frame that exceeds the trial’s duration. In many cases, the cleanest of clinical trials can only say that the drug may possibly be effective and may possibly be safe.

beyond limitations…

In the case of psychiatry, the limits of the clinical trial are in bas relief. Unpleasant emotions themselves are not pathological – anything but. They are a part of an essential and elaborate warning system similar to physical pain. Among those presenting with emotional difficulties, primary disorders of the emotional system [Manic Depressive Illness, Melancholia, Anxiety disorders, psychosis, etc] are in the minority. In the majority whose emotional discomfort is related to some aspect of their life or personae, the use of emotion altering medications is highly dependent on the specifics. Likewise, the capacity to manage adverse effects, addiction, withdrawal, the downside of psychoactive medications, is as variable as ripples in the stream. A physical analogy might be the use of corticosteroids. For some, short-term use can be therapeutic. For others, it can be the introduction of a medication that can be over-used with disastrous consequences.

beyond groups…

After medical school and an internal medicine residency in a busy charity hospital where everyone was quite ill, I found myself in a military hospital on a base with healthy soldiers and their dependents – a very different place. My head was filled with facts and algorithms galore. But I had much to learn. The majority of patients had symptoms but rarely any of the dire illnesses that populated my mind. And I realized that a lot of my job was informed reassurance – a different role I had to learn to fill. Somewhere along those early days there, I realized that I was thinking in terms of case studies, talking less about diseases. A particular case comes to mind that goes with this topic:

    She had been diagnosed with Idiopathic Thrombocytopenic Purpura, a condition where the platelets, cells involved in clotting, all but disappeared leading to easy bleeding. The wisdom of the time was that taking out the spleen would cure cases in kids under 13, but wasn’t helpful in kids over 13. She was 13 at diagnosis, and a splenectomy had been curative. When I saw her, she was thirty something, mother of two, and had consulted a gynecologist for heavy periods. She was referred because her blood smear showed no platelets and her platelet count was essentially zero. We did the workup and started her on the recommended anti-metabolite. We were rewarded with a rising platelet count. One day, she came in "itching," a sign of liver toxicity  and we watched with dismay as she became jaundiced and quite ill from our treatment. Her platelet count rose to normal, but it took a month for her liver function to return [to our great relief].

    We sent her to the Air Force teaching hospital in Texas. When she returned, she was on another anti-metabolite [cousin to the one we used]. Our consulting hematologist sent us a stack of articles about treatment. Her platelets rose, but the itching returned, along with signs of liver failure. This time we stopped the medication more quickly and she didn’t get quite so sick. One day, I asked her about bleeding, and she said that except for heavy menses, it was no problem. I had been following protocol, and had given her two cases of liver failure chasing an abnormal lab test in an otherwise asymptomatic person, abetted by our best and brightest. We stopped the medications. Depot hormone shots eliminated her periods. And she did fine for the two years I followed her after that.
I know it’s not a Randomized Clinical Trial, but the case has always stuck with me because I was young and wanted to do the right thing, so I checked with the experts and followed recommendations precisely, but I was treating a surrogate, an abnormal lab value, and not attending to the clinical reality of the patient. I have no idea how this patient lived with such a low platelet count and no bleeding problems – but that was the way the case went for years after I stopped assaulting her with chemotherapeutic agents. I could tell such stories for hours – stories where well studied guidelines, clinical trials, or algorithms weren’t right for a given patient. I learned that the case at hand can often end up trumping the group recipe when they are at odds. Clinical medicine mirrors the Zen saying: 
    you can’t get it from books,
    you can’t get it without books.
Without the evidence-base from history, group studies, treatment guidelines, we’re lost at sea. But without careful attention to the individual case in front of  us, we can wander just as far off track. And so to the point being made by Dr. Healy:
    …small-print disclosure in academic footnotes and open access to trial data, important though these are, will not solve problems that stem from the notion that clinical trials provide a higher form of knowledge than knowledge borne in a clinical encounter…

beyond clinical trials…

The necessarily contained environment of a Randomized Clinical Trial is only a distant surrogate to that of the patients encountered in clinical practice, analogous to the relationship between the model airplane and the jumbo jet – a useful step, but hardly the full story. The cogent question is how did it come to be that the clinical trial has been escalated to some kind of gold standard for evidence based medicine rather than what it is – a minimum safety and efficacy requirement for FDA approval.

The point of the push for accurate Randomized Clinical Trials is to give practitioners a clear picture of the safety and efficacy of available medications, not to direct treatment or initiate an ad campaign. The real clinical trial is in the individual patient, and sometimes, the best medicine is in none at all.
    With the patient mentioned above, we saw her frequently. We made sure her husband’s next assignment was to a base stateside with a full hematology department [affiliated with a medical school]. He sold his Porsche and bought a Volvo after we cautioned them about car wrecks. But other than stopping her menstrual periods, it was what’s called benign neglect or watchful waiting.
Mickey @ 6:00 AM
Filed under: politics