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…
    August 19, 2014 | 2:33 PM


    When Prozac cam on the scene, my psychiatrist had already bought into “the latest/greatest” meme. I was assured that the dry mouth and weight gain associated with Elavil would be things of the past. In fact, he assured me, Lilly was already pursuing a weight-loss indication for this ‘miracle drug.’! Wow!

    The dry mouth did, indeed, disappear . . . but not the weight. Nor did Prozac provide depression relief to a greater degree than did Elavil. Eventually (time IS the great healer), I chose to forego all anti-depressant treatment. I was fortunate to NOT experience withdrawal symptoms . . . and 15 years later, I do still have ups and downs. Melancholia has receded (again, I thank time and an unstressful life) and I now feel able to fight my demons on my terms (with the aid of a sympathetic and understanding life partner). But between their manipulation of the diabetes (insulin) market and their “misrepresentation” of my “needed” drug–I view Lilly as the most evil of all drug manufacturers

    Allen Jones
    August 19, 2014 | 6:18 PM

    This 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.


    August 19, 2014 | 8:12 PM

    I’d say that the mental health professionals who work for state and local treatment centers cannot afford to be “learned intermediaries” than the teachers and foster parents who recommend children for labeling and drugging.

    Steve Lucas
    August 19, 2014 | 8:29 PM

    First rule of sales management: All salespeople lie. Learn it, make it a part of you and act accordingly.

    Steve Lucas

    August 21, 2014 | 4:49 PM

    As David Healy pointed out, the “learned intermediaries” — doctors — launder the risk for the drug companies so they cannot be sued for failure to warn.


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