Tweaking Medical Information, Courtesy of CME Zone

If I ever decide to chuck all this idealistic stuff and start taking Pharma money, I know exactly which ghost-writer I will hire first to create my million dollar CME programs: the genius who wrote a hopelessly biased tract for CME Zone called "Recognition and Treatment of Anxiety Disorders in the Primary Care Setting." I have never seen information more artfully tweaked in favor of a sponsor's drug.

You can access this article here, but you will first have to register at http://www.cmezone.com/. I believe this was originally published in CNS News (November 2006), and is now being emailed to various physicians as a free CME activity.

To get a feel for how very good the ghost-writer is, you have to know that the generally accepted first-line treatment for anxiety disorders is one of the antidepressants, either one of the SSRIs or the SNRIs. The sponsor of this article, Schwarz Pharma, unfortunately does not market one of these first-line treatments, being saddled instead with Niravam, which is alprazolam orally disintegrating tablet. It's a fancy version of that old standby, Xanax.

Our ghost-writer starts the article with the usual information about how common anxiety is, and how important it is for primary care doctors to seek it out. This lays the groundwork for the crucial treatment section.

The "Treatment of Anxiety Disorders" section opens with Table 4, above. What's the first medication you see? Alprazolam. So what? There's nothing tricky here, it's simply an alphabetical listing of medications. Well...it is unless you consider the two major classes of medications for anxiety to be "antidepressants" and "benzodiazepines." If they had used this classification, the first drug listed would have been clomipramine, followed by escitalopram, and so on. Alprazolam would have been lost in the middle of the chart somewhere.

But this is minor stuff; it gets more interesting. Under "pharmacotherapy," the first paragraph is a glowing tribute to the power of benzodiazepines. Sentence number one:

"Benzodiazepines have been used extensively for the treatment of anxiety disorders since the 1960s; newer benzodiazepine formulations, such as extended release tablets and orally disintegrating tablets, offer alternative dosing and delivery options."

Thus, our ghost mentions the sponsor's drug right away. Next on the agenda: address the concern that patients can become addicted to benzos. Our ghost quickly describes two studies showing that most patients don't get addicted. Whew! I was beginning to worry that I might have to start my anxious patients on SSRIs after all.

Later, ghost covers both buspirone and SSRIs/SNRIs tepidly.

Buspirone: "Buspirone has been demonstrated to have efficacy in the treatment of GAD, but not in other anxiety disorders or depression." Later we hear about a head-to-head between alprazolam and buspirone in which alprazolam worked more quickly and produced fewer side effects.

SSRIs and SNRIs: One mechanical statement of efficacy ("...most agents in this class now have FDA approval for several anxiety disorders") followed by two gory paragraphs about how awful SSRIs are when it comes to drug-drug interactions (Niravam doesn't share this liability, of course).

There are many more instances of the Power of the Tweak, but I'll let you discover the rest. I wouldn't want to deprive you of your own thrill of discovery!

The Journal of Abilify Psychiatry: A CME Activity

I just received the latest Supplement of the Journal of Clinical Psychiatry.

The Journal of Clinical Psychiatry, which is published by Physicians Postgraduate Press, Inc., and is edited by Alan J.
Gelenberg, has developed a reputation for publishing CME supplements which are biased in favor of the sponsoring drug company.

Thus, the current supplement, paid for by Bristol-Myers Squibb, reads like an advertisement for Abilify.

The supplement is titled "Translating the Psychopharmacology of Antipsychotics to Individualized Treatment for Severe Mental Illness: A Roadmap." Sounds promising to me, though rather vague.

The issue is billed as being the result of an "Expert Consensus Survey." This means that BMS paid a third party for-profit company, Comprehensive Neuroscience, Inc., to cherry-pick experts and to send them a list of questions about their favorite antipsychotics in various clinical situations. The responses were tabulated into a series of charts that form the backbone of this supplement.

To understand why BMS would choose this method of CME promotion, you have to understand the context. Their antipsychotic, Abilify (aripiprazole), was not included in the influential CATIE trial, because it was approved after the trial was completed. Thus, while Eli Lilly (Zyprexa), AstraZeneca (Seroquel), and Pfizer (Geodon) have been able to tweak CATIE results to their advantage, Abilify has little in the way of head-to-head science to back up claims of advantage over competitors. Commissioning an "Expert Survey" allows BMS to round up key opinion leaders who they already know have positive opinions about Abilify, choose questions about topics that will tend to play up Abilify's advantages, and then publish the pre-planned answers.

Let's look at the results of this novel form of drug comparison research.

The supplement highlights the results of 17 questions. Eight of these were questions about general strategies, and nine were quite specific, asking which of a list of specific antipsychotics the experts would favor in given situations. How do the experts rank Abilify in these nine questions comparing it with its direct competitors?

--In seven of these comparisons, Abilify is ranked number one (see page 30 of the supplement).
--In one comparison, Abilify is ranked number two (page 21).
--In one comparison, Abilify is ranked number three (page 26).

Oddly enough, Zyprexa was at the bottom or near the bottom in all of these rankings, even though some of these same experts have written elsewhere that Zyprexa was the most effective of all newer atypicals in the CATIE trial.

Why did Abilify come out on top? Because of the types of questions these experts were asked. Most questions asked which antipsychotic the experts would choose in patients who were overweight, had cardiac disease, or who had diabetes. This is a great way to stack the deck in favor of Abilify.

The expert panel's rankings would surely have been in favor of Zyprexa if they had been asked to choose an antipsychotic based on efficacy alone. Abilify would have ranked very low indeed if they had been asked to choose a treatment for patients who suffered insomnia, anxiety, or agitation. These are all important clinical questions in the field, but were not asked because the answers would not have promoted Abilify.

Shame on Journal of Clinical Psychiatry for publishing such pseudoscience.

Tired of Being Depressed? Shire's Solution: Call it ADHD

Suddenly, a third of my patients with depression have ADHD, according to promotions by Shire. In a coordinated series of journal ads, CME newsletters, and a specially prepared "depressionandadhd.com" website, psychiatrists are being encouraged to further expand the diagnostic territory treatable by Shire's products (which include Adderall XR, Vyvanse, and Daytrana).

While I was aware and increasingly annoyed by this latest promotional gimmick, I thank psychiatrist Paul Natvig for alerting me to a rankly deceptive advertisement in the current issue of Psychiatric News.

"Could it be ADHD?", asks a male model with a 5-day beard and an insouciant pout reminiscent of Tom Cruise in one of his rare blue moments. "ADHD was diagnosed in 1 out of 5 men with depression*" continues the ad, referencing a 1996 study published in an obscure journal, Psychiatric Research (Alpert J et al., 1996;62:213-219). The problem is that if you actually read the paper, you find that only about 1/9 depressed men, or 11%, actually met criteria for current ADHD. In order to arrive at the more alarmist 1/5 figure, Shire included "sub-threshold" ADHD in the total.

And what about the really astounding claim that "32% of adults with a depressive disorder" have ADHD? This is a figure pulled from the National Comorbidity Survey Replication, the controversial study that concluded that half of all Americans eventually develop a psychiatric disorder. This study sent lay interviewers to interview a sample of about 9000 people in the U.S., and they used a checklist to diagnose DSM-IV disorders. But since the interviewers were not clinicians, they were unable to accurately determine the clinical importance of the symptoms reported by the sample. The study tried to correct for this problem by having clinicians interview a subset of the sample, but many believe that the final reported prevalence rates were still vastly inflated.

The fact is that if you are hell-bent on finding "ADHD" in patients with major depression, you can. Patients with depression typically have symptoms such as distractibility, poor focus, and difficulty finishing tasks, all of which intersect precisely with ADHD criteria. Shire is hoping that we will start to put our depressed patients on stimulants. In my practice, this rarely helps. Such patients often develop insomnia and agitation, and sometimes paranoia.

On the plus side, Shire's stockholders develop lucrative portfolios, greater self esteem, and meals out more often. Maybe my depressed patients should just skip the stimulants and contact their brokers to buy some shares.

Vyvanse Watch

Vyvanse (lisdexamfetamine dimesylate) was approved by the FDA in February for the treatment of ADHD in children, and is finally available in pharmacies. Tonight, Shire is presenting its official introduction of Vyvanse to physicians in a live webcast called "ADHD Thursday Night Live."

I don't know a huge amount about Vyvanse yet. I do know that Vyvanse is the molecule dextroamphetamine (trade names Dexedrine and Dextrostat) attached to the amino acid lysine. Shire cleverly calls it "lisdexamfetamine," presumably on the theory that using an "f" instead of "ph" in the chemical name will make it less obvious that Vyvanse is simply a fancified version of good old Dexedrine, a mainstay of ADHD treatment of decades.

At any rate, Vyvanse is an inactive “pro-drug” which has no pharmacologic effect until after it is absorbed through the GI tract into the bloodstream, when liver and gut enzymes cleave off the lysine portion and produce the active drug d-amphetamine. The requirement that lysine be lopped off delays the peak concentration of d-amphetamine, but not by very much. To give you a sense of the scale that we are talking about, Dexedrine, which is pure dexamfetamine (I'm using Shire's Newspell here) reaches its peak concentration at 3 hours after administration (see Dexedrine prescribing information, accessed at http://www.fda.gov/cder/foi/label/2006/ 017078s040lbl.pdf). Vyvanse reaches its peak concentration at 3.5 hours, a delay of 30 minutes. While classified as a Schedule II controlled substance like existing stimulants, Vyvanse produces no high if snorted, and a 100 mg dose made drug abusers less buzzed than a 40 mg dose of Dexedrine. However, at 150 mg of Vyvanse there were no differences between the two on the “drug likeability scale.” (See the manufacturer’s Web site at http://www.vyvanse.com/.)

Over the past 2 weeks in my private practice office I have received 9 different mailings from Shire about Vyvanse, an average of about one every other day, but I expect the pace to pick up significantly. Today, my Vyvanse mailing invited me to a "virtual roundtable series" to "provide feedback on various support materials that Shire provides physicians to help them better understand...Vyvanse." In other words, Shire has invited me and thousands of other physicians to be marketing consultants. No compensation was mentioned, but I was provided with the following number to register: 1-800-635-8730, program 2595. Readers are invited to do their own research on this opportunity.

I'll keep you updated on future promotionals as they flood into my office. This should be interesting, as Shire is the most aggressive pharmaceutical marketer I've ever seen, and they are not shy about using CME programs to promote their products.

Dr. Carlat and Pharma Marketing Blog go Podcastic

John Mack of Pharma Marketing Blog just posted his interview with me about the "CME Laundromat" here. Thank you, John. Since I know that many listeners of his excellent series of interviews are employees of the pharmaceutical industry, I look forward to productive, spirited, or even nasty debate in response to the program!

Biased Education: A Summer's Cornucopia with CME, LLC

I've been on vacation in New Hampshire for the past week, giving me an opportunity to appreciate summer's bounty. Now, getting back to business, I realize that the cornucopia doesn't end at a dinner table overlooking a New England lake. Throughout the world of commercial CME, there is enough pro-sponsor bias to leave us all sated, whether we are on vacation or not.

The first course of what will undoubtedly be a long summer feast of bias is provided to us by one of the largest medical education communication companies, named, aptly enough, CME, LLC. This is the dominant provider of commercial CME in psychiatry, publisher of Psychiatric Times and sponsor of the well-attended U.S. Psychiatric Congress, heavily subsidized by industry-supported symposia.

Recently, perusing the web, I came across one of their programs entitled "Bipolar University," a "lifelong learning initiative" set up in response to the "pressing need to educate clinicians about bipolar disorder."

Navigating to "educational components," I clicked on the first of several offerings listed, "CME Articles with Interactive Case Studies." I chose the first article, "A Case-Based Guide to Using Treatment Guidelines in Bipolar Disorder," by Trisha Suppes, MD, PhD and Deborah Kelly, MA. I invite you to visit this activity now, which will require a free registration process. You'll see that the point of the lesson is to teach us how to apply the Texas Implementation of Medical Algorithms (TIMA) to the treatment of bipolar disorder. For those who have not heard about TIMA, it is an updated version of TMAP, the Texas Medication Algorithm Project, originally developed in 1997 with funding from both the Robert Wood Johnson Foundation and several pharmaceutical companies.

You can already see that something fishy is going on here, because an article ostensibly about the general topic of treatment guidelines is actually an exposition of one particular, industry-friendly guideline.

At any rate, the article itself is a discussion of TIMA's recommended treatments for both bipolar mania and bipolar depression, illustrated by two case examples. In the first case, we hear about a 35 year old woman who presents with mixed mania, and is treated with valproic acid and risperidone to good effect.

The second case is where things get more interesting, and where our summertime feast of CME bias really begins. This is a 30 year old man with bipolar disorder, already on lithium monotherapy, who presents with symptoms of major depression. The patient is started on Lamictal, which is TIMA's first line recommendation for treating bipolar depression. However, unfortunately for GlaxoSmithKline (maker of Lamictal), the patient suffers unspecified "side effects" on Lamictal, and is therefore switched to AtraZeneca's Seroquel, and gets better.

Oh, did I forget to mention that this article was funded by AstraZeneca, and that Seroquel was just approved by the FDA for the treatment of bipolar depression, and that AstraZeneca is in the midst of a major marketing campaign to encourage its use for this indication?

Now, let's conduct an autopsy of exactly how this CME article is biased in favor of the sponsor's drug. Case studies are a favorite technique used by medical education communication companies, because they are a way of spotlighting a particular product without appearing biased. Thus, apart from the case studies, this article is a fairly objective, if bland presentation of industry-supported treatment guidelines. The first case study endorses valproic acid and Risperdal, neither of which are in direct commercial competition with Seroquel, since Depakote is available generically and risperidone is a lame duck for Janssen, on the verge of going generic and being vigorously supplanted by Janssen's "new" Invega.

No, the money for AstraZeneca is in getting Seroquel prescribed in favor of arch-rival Lamictal, which is itself being vigorously promoted in a series of GSK-funded CME programs (see my review of one here). The second case study takes place in a bizarre parallel universe in which patients have more side effects on Lamictal than on Seroquel, exactly the reverse of what we psychiatrists commonly see here on Earth. Unrealistic, perhaps, but it serves the sponsor well, telling the story of a patient who likes Seroquel. We don't hear anything about Seroquel's famous side effect of sedation, because that would reflect poorly on the company footing the bill.

Aah, the feasts of summer. Now I have to sit back to build up an appetite for my next course. Luckily, the menu offers of plethora of choices.