FDA Gives Thumbs Up To Kiddie Bipolar: Is KOL Syndrome Next?

Philip Dawdy at Furious Seasons noted that the FDA has officially approved the existence of child bipolar disorder. Prior to it being included in the DSM, and with considerable controversy in the professional community, the FDA jumps on board. Nice. Thanks to Philip for chasing down the FDA's official view.

A few questions for consideration by the FDA (and others) that I mentioned a few months ago:

1. Does child bipolar really exist in substantial quantity?
2. Does treatment help kids with this "disorder"?
3. Why would a leading "expert" in child "bipolar disorder" say that up to 75% of children who are "bipolar" become suicidal without citing any supporting evidence?

Joe Biederman must be proud -- the FDA will now help him and his posse save countless lives through the administration of treatments (like, say, Seroquel) for "child bipolar" that lack any sort of substantive evidence base. But who cares -- even without professional consensus or any sort of official word from the FDA, the treatment of child bipolar has already flown the coop in a big way. Realistically, I suppose that the FDA's view is irrelevant -- drug marketers and key opinion leaders wield more influence than anyone at FDA when it comes to how physicians view psychiatric diagnoses.

KOL Syndrome: On a related note, perhaps the FDA (or the DSM-V committee) can approve KOL Syndrome as a disorder. That would be Key Opinion Leader Syndrome. For case examples, please see here, here, here, here, here, and here. The prevalence of KOL Syndrome seems to be increasing and seems related to the widespread adoption of irrational prescribing as well as information laundering. Symptoms include:

• Providing false "education" to physicians as a service to your corporate clients
• Calling one or more of one's own articles "commercial pieces of crap," then recanting
  
• Hiding blatant conflicts of interest
  
• Writing misleading review articles that falsely tout the efficacy of one or more drugs,
• Magically converting results that show a product is a dud into results showing that a product is safe and effective
• Making a boatload of money through ties to various drug or medical device companies, then claiming that such corporate ties have absolutely no influence on your professional judgment
• As an author, calling a study's results positive, then calling these same results negative a few years later without noticing the contradiction.
• Giving tasty sound bites in press releases about the wonders of various medications in one's capacity as an "independent" scientist
  

Back to kiddie bipolar: Do some adolescents have bipolar disorder? Sure. Five-year-olds? That's where I start getting suspicious...

Also see an excellent post from John Grohol at Psych Central on youth bipolar and some of the logical problems regarding how its treatment is advocated. And Furious Seasons also notes that the FDA database raises questions about two of the drugs touted as safe and effective for kiddie bipolar.

Iloperidone: Vanda Shareholder Train Wreck

Many months back, when shares of Vanda Pharmaceuticals were going for 29 bucks, I warned y'all: Their main product, iloperidone, showed all the signs of being a dud. It has been in the clinical trials stage of development for about a decade and it had yet to receive FDA approval. Um, if a drug was of significant benefit, do you really think it would have been in late-stage development for 10 years? In December 2006, I wrote:

As for iloperidone, one article forecasted that it would hit the market in 2001! Further digging indicated that Titan, which holds the license for iloperidone (to some extent, anyway), was in a spot of trouble for allegedly hiding the drug’s side effect profile. In 1997, according to a report filed with the SEC, “the Company does not have the funds necessary to complete the clinical development of Iloperidone and is currently pursuing several financing alternatives including corporate partnering arrangements and off balance sheet financing to complete development of Iloperidone.” I assume this is where Vanda got involved. I could find not a single published trial of ilopderidone in either PubMed or Clinicaltrials.gov. If anybody can direct me to clinical trials data for this product, I’d love to see it! So this drug has been in the clinical trials phase of development for nearly a decade, and there is no published data to show its efficacy. I’m not impressed.

My personal opinion is that you are better off burning your money than investing in Vanda after the huge jump earlier this week.

Now, according to Reuters, Vanda received a not approvable letter from the FDA "over concerns of efficacy" regarding iloperidone in the treatment of schizophrenia. Ouch. This after the drug was ludicrously named "Fiapta," then "Fanapta." Hello?? Vanda shares can now be had at about a dollar per share -- down about 95% from when I initially warned everyone to steer clear of the company's stock.

There is always a chance that the FDA has a change of heart; it's possibly even worth buying at this point, as even obvious dogs have their day on the market occasionally, such as Corcept Therapeutics. I have no faith that any of Vanda's products are worth anything clinically, but I think they might be able to BS enough analysts and investors to help drive up the price up a few bucks per share. Note that this is not official investment advice.

Cymbalta Smacked Via Excellent Letter to Editor

Eli Lilly/Boehringer Ingelheim published a study claiming that duloxetine (Cymbalta) was an effective treatment for pain in depressed patients. Nothing new – they’ve run several such studies. The results were published in the Journal of Clinical Psychiatry in November 2007. Three wise readers (Jay Griffith, Joseph Hasley, and Daniel Severn) noted serious issues with the study and submitted a letter to the editor, which was then published in the June 2008 issue. It was noted that the patients were unclearly described: What kind of pain were they experiencing? The study also noted that patients weren’t taking pain-relieving medications for six months prior to the start of the study, at least not on a “regular basis,” a term that was not defined in the paper. Don't most patients who experience serious pain take analgesic medication at least somewhat regularly? Finally, and most importantly, the difference between Cymbalta and placebo was “statistically significant,” but more importantly (and ignored by the study authors), the difference was small. On an 11-point rating scale, the average difference in pain ratings favored Cymbalta by less than a point. Griffith and colleagues note, accurately, that the small advantage for Cymbalta “is not robust from the standpoint of clinical practice.” I’m always glad to see that there are a few readers of medical journals who are willing to take the time to pen a good letter to the editor in which the massive inadequacies of a study are noted. If we’re going to have evidence based medicine, we might want to make sure the evidence is of somewhat palatable quality, eh?

The kicker is that the lead author of the Cymbalta study, Stephan Brecht of Boehringer Ingelheim opted not to offer a response to Griffith et al.’s letter. So I suppose Brecht is conceding that the patient population was poorly defined and that Cymbalta’s advantage over placebo was meager. So this kinda runs counter to the conclusions of the study, which claimed in part that duloxetine is an effective painkiller. Not a big surprise, given that a prior analysis also cried foul about Cymbalta’s claim to successfully treat pain in depression.

Yet Cymbalta continues to fly off pharmacy shelves. Are physicians really this poorly trained at understanding scientific literature? “Gee, the ads say that Depression Hurts and the rep handed me these journal reprints that prove it's a painkiller, so now I’m writing Cymbalta scripts like there’s no tomorrow!”

For failing to note that Cymbalta's effects over placebo were small, and for refusing to reply to the concerns about their study, I hereby nominate the authors of the November 2007 Cymbalta study (especially the lead author) for a Golden Goblet Award. Your dedication to obfuscation is notable -- keep up the bad work.

Welcome Back, Jim Edwards!

I was always a big fan of Jim Edwards' work at BrandweekNRX. While I also enjoyed Peter Rost's writings at the aforementioned blog, the blogosphere certainly took a hit without Jim's insightful writings. The good news: Jim is back! His blog can be read at: http://jimedwardsnrx.wordpress.com. I was flattered that he picked up my piece on the sexual side effects of SSRIs for one of his first posts upon his return.

While Jim's return is a welcome addition to the world of healthcare blogging, the mysterious disappearance of the funniest pharma parody site of all time, Pharma Giles, is still a mystery...

Round Up The Usual Suspects

Senator Grassley's investigation of the connections between Big Pharma and psychiatry continues to target individuals who have been featured on this blog. The latest, according to Pharmalot: Martin Keller of Brown University. Those of you who have any familiarity with GlaxoSmithKline's work with Paxil in youth will recall that Keller was the "lead author", using the term as loosely as possible, of the infamous Study 329 paper which claimed inaccurately that Paxil was safe and effective in treating depression. Recently, a team of researchers published a bombshell of a paper that pointed out in detail how the Study 329 manuscript was doctored to paint an unrealistically favorable picture of the study's findings.

A recent transcript became available in which Keller discussed his role in "authoring" the Study 329 paper (pgs. 242-266 in particular). The CliffsNotes version: Keller claimed on one hand that he couldn't recall what happened and on the other hand said that he always played a key role in developing the main points to be communicated in every manuscript on which he was lead author. If we take Keller at his word, that he really developed the main ideas for the paper, then he was either a) negligent of the actual study data or b) actively participating in covering up the unfavorable results from the study. I noted earlier that Keller indicated earlier that he did not seem particularly familiar with the actual study data, so I suppose option A may be more likely. In any case, being the lead author on a study that claims a drug is safe and effective when the study data show that the drug is dangerous and ineffective -- that's nothing to brag about.

An interesting coincidence: There is a new Dean of Medicine (Edward J. Wing) at Brown University. Aubrey Blumsohn of the Scientific Misconduct Blog wrote a letter to the incoming Dean. So far, Blumsohn says he has received no reply. Blumsohn expressed concerns with Keller and with the handling of David Kern, a Brown University faculty member who was canned for apparently nefarious reasons. My bet: Nothing will change. Keller brings in a boatload of money to the university and is hence highly valued by the administration. He is also a "big name" in psychiatry, though between Study 329 and ARISE-RD, another strange study in which Keller seems to have designed a study after it was already completed, his standing is certainly not spotless. Let me be clear: I'm not advocating that the new Dean do anything in particular. I'm not calling for Keller to be canned or anything of the like. However, if I were a Dean (God forbid), then I would be concerned about well-documented issues with one of my big-name faculty, particularly because these issues go to the heart of scientific integrity.