The Biggest Chantix News: Pfizer's $12.3 Million Buys No News

By now most of you have heard about this recent study linking the use of Pfizer's anti-smoking drug Chantix with a small increase in heart attacks and arrhythmias. The meta-analysis of 14 double-blind controlled trials indicates that in patients without a history of heart disease, Chantix increases the rate of serious cardiac events from 0.82% of those assigned to placebo to 1.06% of those on Chantix. This is not a huge increase, but considering the millions of people who are prescribed the drug yearly, it could amount to a large public health problem.

Another piece of big news (to those of us who follow the world of industry-supported CME) is the fact the Pfizer-funded smoking cessation program, CS2day (Cease Smoking Today) doesn't mention the study on its website. Recall that CS2day was announced with much fanfare in 2008, when Dr. George Mejicano convinced Pfizer to pay $12.3 million for a national CME program to educate doctors about how to help patients quit smoking (see the Medical Meetings article here). The program was quickly criticized for not disclosing Chantix's many side effects in one of its CME programs.

Given that this new meta-analysis is hitting most major news outlets, you would think that the multi-million dollar CME website could find a writer to post something about the study. But apparently this is something Pfizer would prefer that physicians not get continually medically educated about.

File under: CME programs that are noncompliant with AMA's new ethical guidelines.

Apres le Deluge: The CEJA Spin Cycle Begins

When the AMA adopted the 5^th version of the CEJA report on industry-funded CME, it seemed clear that this was an ominous and very bad sign for the future of industry-funded CME. I already posted my take on the report here (short version: say goodbye to most industry CME). Now we are beginning to see how industry supporters are responding. Basically, they are saying, or maybe just desperately hoping, "Feh! It's no big deal."

 

They were singing a different tune before the vote. As was true for the prior CEJA CME reports, MECCs (medical education communication companies) and their supporters maligned the document. The Alliance for CME, the main trade organization for MECCs, had released this statement recommending that many sentences in the recommendations be stricken—essentially any sentence that challenged the status quo.  

ACRE, a relatively new organization composed of physicians who  vigorously defend financial relationships with drug companies issued what amounted to a white paper calling for the rejection of the report. ACRE found so many things wrong with CEJA 5.0 that its critique ran three pages longer than the report itself.

A couple of weeks before the vote, Medical Meetings magazine published an editorial by columnist and MECC owner Stephen Lewis angrily attacking CEJA as being an “oxymoron” because it “seems to have forgotten the critical link that exists between ethics and evidence.”

And five days before the vote, Thomas Sullivan, the owner of the MECC Rockpointe, who writes the influential pro-industy blog Policy and Medicine, reviewed and agreed with the Alliance for CME’s position that the CEJA report be canned.

So much for the run up. Now that the report has been adopted, industry advocates appear to be quickly distancing themselves from these prior alarmist views about CEJA.

Two days after the vote, Thomas Sullivan was almost celebrating. Headlined “AMA CEJA 2011: AMA House of Delegates Approves Report – Now Emphasis on Value of CME in Patient Care,” his post was nonchalant. Far from seeing this as a threat to industry funding, Sullivan now argued that the report “merely reflects an alignment of AMA policies on CME with the ACCME, HHS OIG, and the PhRMA and AdvaMed Code of Ethics.  Commercial support of CME will still remain a valuable resource for CME providers to help keep physicians up to date on the latest breakthroughs and treatments.”

Medical Marketing & Media, a publication financially dependent on pro-industry stakeholders, published an article that appeared to be journalistic coverage of the decision but which was essentially an editorial saying "don't worry, be happy." The article emphasized that CEJA 5.0 does not call for an “all out ban” on industry funding, but instead “places the moral onus on physician presenters to disclose to learners their financial interests in the topic they are speaking about.”

Derek Warnick, an industry CME director and blogger, responded with an entertaining and thoughtful post in which he concludes that “If I had to guess (OK, I don’t HAVE to guess, but I’m going to anyway), I would say that CME providers may be asked to provide a little more documentation about faculty selection and conflict resolution processes, but I don’t anticipate any major shake-ups.” 

Meanwhile, the only person whose opinion anyone cares about has remained silent. That would be Murray Kopelow, the director of ACCME. If you email ACCME for his response (as I did) you will receive the following official statement: “We are currently reviewing the CEJA Recommendations and the Board of Directors will be deciding on any next steps.” The next board meeting is July 21 in Chicago, so we will probably not get any response until they publish their Executive Summary of that meeting, probably a month or so after it occurs. 

Meanwhile--into the void--let the spinning continue. 

AMA Votes to Discourage Commercial Support of CME

Something huge happened yesterday at the American Medical Association House of Delegates meeting in Chicago. Although the meaning of what happened will be spun throughout the blogosphere, twittersphere, and schmuckosphere, the bottom line is that the AMA just voted most commercial funding of CME out of existence.

Specifically, the delegates voted to approve a report of the AMA ethics committee that calls for a near elimination of industry support for CME. The report is entitled "Financial Relationships with Industry in Continuing Medical Education," and can be read in its entirely here.

It is a 12 page report, and CME geeks like me will want to pore over every word, but the essence is found on page 8 under "Recommendations." The third paragraph makes the intent of the AMA explicit:

"CME that is independent of funding or in-kind support from sources that have financial interests in physicians‘ recommendations promotes confidence in the independence and  integrity of professional education, as does CME in which organizers, teachers, and others  involved in educating physicians do not have financial relationships with industry that could influence their participation. When possible, CME should be provided without such support or the participation of individuals who have financial interests in the educational subject matter." (emphasis added)

What this means is that the AMA now expects that most CME courses will meet two criteria:

1. No commercial support for the activity.

2. Faculty teaching the CME should have no financial relationships (such as being on speakers' bureaus) with drug or device companies.

The report does allow for some exceptions to these criteria: "At times it may be impossible to avoid a financial interest or extraordinarily difficult or even  impossible to mitigate its potential impact on an educational activity." They cite examples such as courses involving the use of very expensive material, such as cadavers or sophisticated equipment. Also, they allow that in some remote parts of the country it may be acceptable to take industry money to fly out experts to teach doctors. However, in that same "exception section," they reiterate that: "For the most part, accepting support from a company or permitting participation by an individual when there is an irreducible financial interest would not be ethically acceptable."

What happens next? Since the AMA literally defines "AMA PRA Category 1 Credit" for the ACCME, any company that deviates from the recommendations of this report will be non-compliant with ACCME's criteria for CME. ACCME itself will have to revise its Standards for Commercial Support to clarify that in most cases, commercial support is no longer allowed.

None of this will happen overnight, of course. But you can bet that medical societies and medical education companies that are dependent on commercial support are, even as you read this, holding emergency conference calls with their attorneys to figure out what they need to do next. 

We have finally entered the era of post-deception medical education. Congratulations to the AMA.

Unhinged in The New York Review of Books

The July 14, 2011 issue of The New York Review of Books includes the second of a two-part review of several new books on the topic of psychiatry, including my book Unhinged. Review author Marcia Angell, Senior Lecturer in Social Medicine at Harvard Medical School and former Editor in Chief of The New England Journal of Medicine, calls Unhinged “absorbing” in her article “The Illusions of Psychiatry,” where she also explores Irving Kirsch’s The Emperor’s New Drugs, Robert Whitaker’s Anatomy of an Epidemic, and the DSM-5.
Read the review here: www.nybooks.com/articles/archives/2011/jul/14/illusions-of-psychiatry

Horizant: The Second Coming of Gabapentin

by Steve Balt

In keeping with the religious notion of reincarnation, apparently some drugs are destined to be reborn, redesigned, and re-packaged for brand new indications.  I've written about Contrave and Silenor for instance—two drugs with generic counterparts that have been re-tweaked and renamed for newer (and larger) markets.

In early April, the FDA granted its approval to yet another "new" agent (that's "new" with an asterisk, mind you), Horizant, developed by GlaxoSmithKline (GSK) and Xenoport.  Horizant is a name-brand version of gabapentin, also known as Neurontin.  But instead of simply re-labeling gabapentin and introducing it with a new name, GSK made some subtle changes to gabapentin that may provide advantages over the already-available alternative.  But the question is: at what cost?  And for what, exactly?

Gabapentin was first approved in 1994 and is marketed as Neurontin.  It's approved for the treatment of partial seizures and post-herpetic neuralgia (although its manufacturer, Pfizer, got into some serious trouble for extensive off-label marketing of this compound—seems to happen a lot these days).  Gabapentin is actually quite widely used by neurologists and psychiatrists, not just for seizures, but also for  chronic pain syndromes, anxiety, mood stabilization (where it's not particularly effective), and even for alcohol dependence.

Gabapentin's bioavailability—the proportion of drug that enters the bloodstream when taken as an oral dose—is rather low (and, paradoxically, decreases as the dose is increased) and the duration of its action is quite short, which means that users need to take this drug three or four times daily.  The key advantage of Horizant is that it is a "pro-drug."  Technically it's gabapentin enacarbil, and the "enacarbil" refers to a molecule added to the drug which allows it to be absorbed along the entire GI tract, resulting in greater blood levels for a longer period of time.

Interestingly, in early 2010 the FDA rejected Horizant's first request for approval, citing a small but significant risk of cancer.  They relented, however, and approved it this year after "reconsidering the risks and benefits."  (Specifically, GSK argued that the large number of pancreatic tumors found in rats taking Horizant may have occurred spontaneously, and human data don't show a compelling link between cancer and gabapentin use.)

So who might use Horizant?  Well, GSK and Xenoport probably hope that anyone who currently uses Neurontin (and there are a lot of them) is a potential patient.  Officially, though, Horizant was approved only for the treatment of restless legs syndrome (RLS).

Now, RLS is one of those "diseases that may not be diseases"—or "diseases that you didn't know you had."  (See the articles here and here for accusations of "disease mongering" by GSK [Hey! GSK! Coincidence? I

don't think so!] when it introduced Requip, the first "treatment" for RLS.)  In particular, whenever you see a headline like "Disease X may affect 7-10% of the population" when, in fact, no one had even heard of Disease X ten years ago, you have to be somewhat suspect.

Nevertheless, like much else in psychiatry, there may be some reality to RLS; it may in fact be a true pathophysiological entity that responds to medication, and some people report an excellent response to
treatment.  (Whether it afflicts 10% of the population is another story.)  Current treatment strategies involve dopamine replacement, in the form of Requip (ropinirole) or Mirapex (pramipexole) so maybe dopamine insufficiency is part of the process.

However, the symptoms of RLS are rather nonspecific: "an urge to move the limbs, which improves with activity and worsens with rest."  That's about it.  Which leads to yet another problem (a problem that GSK and Xenoport don't see as a problem, that's for sure): with such vague and common symptoms (who among us hasn't felt somewhat restless at times, with interrupted sleep?), a lot of people might get diagnosed with RLS when their symptoms are actually due to something else.

A while back, a fellow blogger directed me to the RLS "patient page" on the National Institutes of Health (NIH) web site, where RLS was—and still is—referred to as "akathisia."  However, these may be two entirely different things.  Akathisia (from the Greek for "not sitting still") has long been recognized as a  side effect of some—perhaps most—psychiatric medications, from antipsychotics to antidepressants.  It is often described as an "inner restlessness," a "need to keep moving."  Sometimes it's associated with extreme emotional distress.  In terms of severity, it can range from a mild nuisance to—in some cases—aggressive tendencies.  (Indeed, the psychiatrist David Healy has even linked psychotropic-induced akathisia to suicide attempts and violent behavior.)

Psychiatrists really don't know exactly what causes akathisia, and disagree on how to treat it.  It may have something to do with dopamine blockade, or something completely independent.  Treatment might consist of benzodiazepines (like Ativan or Valium), beta blockers (like propranolol), or discontinuing the drug that caused it in the first place.

Unlike RLS, which seems to bother people most when they are lying down (hence its tendency to disrupt sleep), drug-induced akathisia is worse when people are awake and moving around.  Sounds like a simple distinction.  But nothing is quite this simple, particularly when psychiatric drugs—and real people—are involved.   In fact, many psychiatric meds can cause other motor side effects, too, involving (theoretically) yet other neural pathways, such as "parkinsonian" side effects like rigidity and tremor.  In fact, some antipsychotic drug trials show "restlessness" and "akathisia" as entirely separate side effects (and when I've tried to ask experts to explain the difference, I have never received a straightforward answer.)

So what does this all mean for Horizant?  It's likely that GSK/Xenoport hope to capitalize on the nonspecificity of symptoms, the tremendous diagnostic overlap, and the fact that motor side effects, in general, are common side effects of antipsychotics (one of the most widely prescribed drug classes worldwide).  In other words, they know that there are a lot of people out there with "restless legs" for all kinds of reasons, and lots of psychiatrists who will misdiagnose akathisia as RLS and prescribe Horizant for this purpose.  Sound fishy?  You be the judge.  Remember, there is this pesky little thing called "return on investment."

What it means for patients and doctors is less clear.  A new agent with apparently better availability and kinetics than gabapentin is now available, but it's approved for the treatment of something that may or may not exist (in most patients).  It also may or may not be more effective than gabapentin itself, but it will most certainly have a heftier price tag.  Ah, the wheels of psychopharmacology keep turning…

Steve Balt is psychiatrist at North Bay Psychiatric Associates in San Rafael, California and writes his own blog: Thought Broadcast.

A Review of QuantiaMD: Good Content, Murky Firewalls, and Hypo-Disclosure

There are a number of new and rapidly growing physician social networking sites, and two of the largest are Sermo and QuantiaMD. They both offer tempting packages of free information to doctors, including CME. When stuff is free to you, someone else is paying for it. That "someone" has a stake in the content, and the art of operating an ethical educational website hinges on creating a good firewall between product promotion and educational content.

In the spirit of full disclosure, I have an iron in this fire, since I own a for-profit publishing company (called, amazingly enough, Carlat Publishing LLC) and I have chosen a business model relying exclusively on users paying for content. That way, my readers know that there is no hidden promotional agenda. I don't have to deal with firewalls, because there is nothing to wall off. I hope  that this leads to high quality, trustworthy content; I know for a fact that it is a hard way to make money. After 8 years in business, my company's gross annual income from two newsletters and some joint sponsorship arrangements is slightly over $500,000--which is probably what Medscape charges for a single sponsored web-page. Am I bitter? You bet.

At any rate, when a new medical education website comes on the scene, I give it a close look, both to check on the competition and to provide fodder for this blog.

QuantiaMD was founded in 2003, and describes itself as "an online physician-to-physician learning collaborative where 1 in 6 U.S. physicians engage, share, and learn from experts and each other, free of charge."

The site specializes in short video powerpoint presentations--some are CME accredited, others are not. The quality is usually good. They get top academics as well as just very good doctors to give  mini-talks. There's plenty to learn on QuantiaMD.

Since there are no drug company ads on the site, at first I couldn't figure out how they were able to fund a site with so many bells and whistles. On their FAQ page, they explain their income like this:

"QuantiaMD generates revenue through sponsored content that is delivered to physicians as short, interactive, educational presentations narrated by medical experts. This content is always accompanied by sponsors’ logos, and the decision to view is at the physician’s discretion, with no associated penalties or rewards. QuantiaMD proprietary technology ensures that physicians will only be offered sponsored content that aligns with their specialty. Sponsors do not, in any way, influence the non-sponsored content that QuantiaMD members experience."

Okay, so they charge drug companies for a portion of its content, which should be clearly labeled as sponsored, and this money allows them to create unbiased content in the rest of the site. Sort of like Medscape without the ads.

But when you get on the site, it's far from clear where the sponsored content begins and ends. Navigating to the psychiatry section, the first thing you see is the "Expert Practice Series in Enhancing Psychiatric Care," and the featured presentations are on bipolar disorder. I watched some of them, and they were useful, by and large, and not clearly biased in favor of any particular bipolar medication. But I was perplexed that there were no industry disclosures listed in this section, although virtually all their featured experts have extensive industry relationships (Dr. Charles Nemeroff, for example, is one of the presenters).

In an email to QuantaMD's communication manager, Ross Homer, I asked him about this omission. He promptly responded:

"Thank you for your message. In terms of industry disclosures, I was aware that these need to accompany accredited content for CMEs, but I was not familiar with the need for these with unaccredited content. However, if this is an issue, I’d be grateful to hear more about your thoughts on this (and please excuse my naiveté) to direct how we incorporate industry disclosures moving forward. In terms of this TRD program, neither the Program nor the series had any direction or influence from a commercial entity. Both were conceived from our Primary Mental Health Interest Group, which was itself created to help address the problem that a great many of our PCP members told us they were struggling with: whether, how and when to diagnose, treat or refer their patients with mental health disorders.  In general, all commercial content on QuantiaMD is clearly marked and opt out. All non-commercial content, like the TRD series, is developed by independent subject matter experts with the support of our internal editorial team. This content is developed in response to the measured needs and suggestions of our clinician community."

Ross was right. There is no need for disclosure if by "need" you mean a regulatory mandate. But I encouraged him to go the extra mile:

"Ross, I agree with everything you have to say below. But if I were you I would put that very same explanation on your Interest Group page (or a link to an explanation, like "Where are the industry disclosures?"). The mental health experts on your site are well known in the psychiatric community for their close ties to the pharmaceutical industry, so I'm sure I'm not the only doctor with the same question. You might also explain how these doctors are getting paid (presumably directly by QuantiaMD, out of funds obtained via pharma ads and CME sponsorship), because in these days of cynicism every doctor realizes that no high quality information is free, and if they are not paying for it someone else is. Inquiring minds might be eased by Quantia's acknowledgment that it's important to follow the money trail if we want to trust the objectivity of your education."

Ross responded diplomatically: "Thank you for this insight. As we grow as a physician community and begin to do more promotion of our programs to the outside world, input like this is very helpful. We truly believe in the value of our content and don’t feel that we have anything to hide in terms of our business model, but it is important that we provide as much information as necessary so that everyone else we speak with about what we are doing feels comfortable as well."

This email exchange was on March 9, and since then there was been no discernible "QuantiaMD Spring" of increased transparency. There are still no industry disclosures in the Expert Practice Series, nor does the site print an explanation of why. 

Meanwhile, as I dug a bit deeper into the other sections of the site, I was disheartened to find that the CME activities I sampled were biased in favor of the commercial interests of the sponsors, if subtly so. For instance, PriCara, a Division of Ortho-McNeil-Janssen Pharmaceuticals, supports QuantiaMD's CME lectures on the management of chronic pain. PriCara markets the Fentanyl patch. One of the presentations, "Managing Chronic Pain with Opioids in a Primary Care Setting," reassures doctors that a positive opiate screen "does not diagnose drug addiction, physical dependence, or impairment." And on the final slide, one of the four "Take Home Messages" was that "the prevalence of 'true' addiction in patients treated long-term with opioids is unknown but appears low in a community sample." I'm certain that this is a debatable assertion among chronic pain experts, and that a "fair balanced" program would have better covered the range of views. Overall, the program portrays chronic opioid use as something that can be easily managed and for  which the dangers of addiction are low. That's music to the ears of the Fentanyl Patch people who paid for this "CM-Ad."

Eventually, I found Quantia's explicitly "sponsored content". Within psychiatry, they seem to have worked out a lucrative deal with Pfizer, with Geodon pushed by both Charles Bowden: 

 

and by Prakash Masand:

Dr. Bowden may want to review UT Health Sciences Center's policy on relationships with industry, which states that "Clinicians should not deliver talks that support a drug or device manufactured or marketed by the sponsoring company." I don't know if this Quantia gig runs afoul of that guidance, but it's certainly treading the line. Dr. Masand's employer Duke also frowns on promotional speaking, but its policy reads less strict than UT's.

To sum up, QuantiaMD is a mixed bag of great unbiased content mixed with promotional brand messaging. Figuring out where the honest education ends and the promotion begins is a challenge. The cynic in me suspects that this opacity is purposeful, and is done to ramp up sponsorship fees. Drug companies love promotion that does not look like promotion, and are willing to pay a premium for it.

I give QuantiaMD kudos for trying to create a useful website with minimal commercial content, and they succeed much better than some of their competitors, such as Medscape. But there's still that familiar sneaky hidden agenda feel to their site. Is it possible to create a large, robust, technologically sophisticated medical education site paid for exclusively by physician users? I pray that the answer is yes.

APA Joins Vanda in Running Misleading Fanapt Ad

Makers of atypical antipsychotics are desperately trying to differentiate their products from their competitors. This explains the deceptive insert from Vanda Pharmaceuticals that was bagged with the latest version of the APA's newspaper, Psychiatric News.

The insert is a 5 X 8 inch 4 page booklet. The front cover is below:

Evidently appealing to the scratch-ticket set among psychiatrists, Vanda drew cartoons of three different brain receptors: 5-HT2A (serotonin 2A), D2 (dopamine 2), and D3 (dopamine 3). The quiz question is: "The blocking of which of these receptors distinguishes atypical antipsychotics from conventional agents?"

Most psychiatrists presumably know that all atypical antipsychotics are mixed D2/5HT2A antagonists, whereas conventional antipsychotics block D2 but not 5-HT2A. Nobody outside of biochemistry labs knows what "D3" does, so that's certainly not the answer. As you can see, I vigorously scratched off 5-HT2A, which is the right answer. I scratched off the other two just to see what was underneath (honestly, I scratched those  after 5-HT2A!)

Anyway, after uncovering the green and blue arrows, I was instructed to "continue on to learn about the receptor binding of one specific atypical antipsychotic agent." So I turned the page:

 

Here you read what is (to the uninitiated) a bunch gobbledygook about binding affinities, cholinergic receptors, etc.... For the well trained psychiatrists, however, this is, well, a bunch of gobbledygook about binding affinities and receptors. Vanda is boasting about Fanapt's "distinct" receptor profile, but in the fine print, they admit that "The clinical significance of the receptor-binding affinity of FANAPT is unknown."

You can say that again. In fact, Fanapt touts its low affinity for H1 (histamine) receptors, implying that it won't cause sedation and weight gain. Unfortunately, in the real (clinical) world, "somnolence" is one of Fanapt's prominent side effects (package insert), and it caused significantly more weight gain than Geodon in head to head trials--6.2 pounds vs. Geodon's 2.4 pounds after 4 weeks of treatment (see abstract here).

Vanda doesn't highlight the fact that Fanapt causes a potentially dangerous EKG change called QT widening, and that one of its receptor binding properties causes so much dizziness upon standing up that patients have to increase the dose very gradually to prevent fainting. Yes, you can find this information in the insert, but you'll have to look for it.

This is deceptive advertising, because the underlying message is "Fanapt is better than other antipsychotics because it's biochemically special," but the reality is that the biochemistry of Fanapt is not clearly related to its side effects, it is no more effective than any other antipsychotic, and it costs over $600/month.

My beef isn't just with Vanda's sleezy ad, but also with the APA, which made the wrong decision to grab the large amount of money that such special inserts cost. It is the responsibility of the editors to screen such ads and to reject them when they are misleading.