The V-Squad Finale

Here is the final of the 3 training clips for Vioxx salespersons. The first and second clips are also available.

Be The Power:
2 efficacy
2 GI risk (and ZERO cardiovascular risk)

How 'bout a nice dose of data? Oh, this clip is SO rich!

More From the V-Squad

The Superhero team of Merck sales reps continued to work hard to push Vioxx. The ending of this clip is definitely a cliffhanger, so be sure to tune in for the finale tomorrow! See clip 1 in my most recent post.

Meet the V-Squad

How did Merck go about training reps to sell Vioxx? Here's part one of three. Thanks to an anonymous reader for sending me along this trilogy. Part 2 is great and part 3 is outrageously funny. Well, I mean except for the part (not included in the videos) where people were dropping dead from taking this newer, "safer" painkiller. Parts 2 and 3 coming soon.



Go to vioxxdocuments.com for more such goodies.

Investigative Journalism Par Excellence

I am a little late in reporting this story, but there is a must-read post from Jonathan Leo over at Chemical Imbalance that I must bring to your attention. Many bloggers have chimed in about the radio program The Infinite Mind broadcast about SSRIs. Most writers have focused, understandably, on the myriad unreported conflicts of interest of the guests on the show. But the conflicts of interest are not the most important part of this saga -- the terribly misleading information on the program, which aired on National Public Radio outlets, is the main problem.

Leo compares the data on SSRIs and suicide to the blatantly false statements made by the The Infinite Mind commentators. He notes, for example, that it is utter BS to state that nobody committed suicide in antidepressant trials submitted to the FDA -- in children there were no suicides, but among adults there certainly were. And kids who dropped out of the studies due to poor response or side effects, well, who knows what happened to them?

Leo also notes that the commentators were dead wrong about their alleged evidence linking decreased prescriptions of SSRIs to an increase in suicides. I also noted the same problem. He then proceeds to make point after point about the commentators overstating the efficacy of antidepressants.

As I've written before, conflicts of interest are important. But rather than just noting that people have conflicts, it is important to show the data -- are people with conflicts of interest misstating the evidence in a manner that reflects the conflict of interest? In the case of The Infinite Mind, the answer is a clear yes. Leo's post is quite lengthy, but well worth the time.

Update (08-31-08): My mistake. I had earlier called the program All in The Mind, which is vastly incorrect. The program was The Infinite Mind (as has been corrected above). This post has absolutely nothing to do with All in The Mind, which is a program which airs on Australia's Radio National. In fact, I've listened to a couple of All in the Mind broadcasts previously and found them to be well-done. Thanks to a commenter for catching my error.

SSRI Doesn't Work? Try Zyprexa

...So said Lilly sales reps who pushed the drug in Alaska. I did a little reading on the topic from the new Zyprexa document set from the recent Alaska case, but was scooped by Furious Seasons, where it was written that:

Lilly was using cases of patients--apparently with bipolar disorder, likely type 2--who ran into problems on SSRIs such as agitation to create a scenario for selling doctors on using Zyprexa in these patients.

Snippets from sales call notes are then added to strongly support this assertion. Well worth a read. Especially the clincher that involves the old-fashioned trick of bribing docs with candy to get them to write Zyprexa scripts. If I get a little spare time, I hope to wrangle through the new Zyprexa docs and spread the word about whatever horrors lie therein.

Sowing the Seeds of Vioxx

A new article in the Annals of Internal Medicine lays bare how research was commandeered by marketing in the promotion of Vioxx, Merck’s former all-star painkiller and personkiller. The article is based on a chunk of internal Merck documents revealed during legal proceedings (not unlike the infamous Zyprexa documents). Merck set up the study known as ADVANTAGE, in which 2785 arthritis patients were given Vioxx and 2772 arthritis patients took naproxen. Physicians across the nation were recruited to enroll patients to participate in the study, which was intiated during the FDA approval process for Vioxx.

The study, however, was conceived and conducted by Merck’s marketing department. Why? As Vioxx was about to come to market, Merck needed to develop a need for their product. By hiring physicians to participate as “investigators” on this trial, Merck was exposing its product to an important group of potential customers. To quote Merck:

The objectives were to provide product trial among a key physician group to accelerate uptake of VIOXX as the second entrant in a highly competitive new class and gather data important to this customer group. The trial was designed and executed in the spirit of the Merck marketing principles.

Other snippets from a Merck marketing memo, with pithy commentary added free of charge:

• "...the trial was targeted to a select group of critical customers.” So the main qualification to be a “research investigator” in this trial was to be a customer that Merck wanted to win over.

• “The sales force nominated potential investigators and completed intake forms, allowing a very large number of sites to be evaluated and enrolled and ensuring equal distribution of investigators across the business groups.” Again, the sales force chose the physicians, apparently based on how easily they could be swayed to prescribe Vioxx as a result of participating in this study.

• “An analysis performed at 6 months post launch demonstrated a significantly higher level of prescribing for VIOXX among primary care ADVANTAGE investigators compared to a control group of VIOXX 99 prescribers (see attached). Feedback from the field has been overwhelmingly positive about their ability to access key customers and the influence that being involved in the trial has had on their perceptions of VIOXX and Merck.” The program apparently had its desired results – more docs prescribing Vioxx as a result of their participation in Merck marketing-designed “research.” As for the patients dying due to taking Vioxx, well, what’s a little collateral damage when there are quarterly sales goals to be met?

The name for such an exercise in marketing is a “seeding trial,” referring to a company planting seeds in physicians to use their product under the guise of research.

II. What about getting the results out?

According to Merck: “Preparations are now underway for analysis and publication of the data, which will utilize key investigators as authors and advisors.” Turns out that worked pretty well – as the lead author on the main ADVANTAGE publication told the New York Times that “Merck designed the trial, paid for the trial, ran the trial. Merck came to me after the study was completed and said, “We want your help to work on the paper. The initial paper was written at Merck, and then it was sent to me for editing.” – it was sent to him to place a veneer of academic credibility on Merck’s marketing-run trial.

Even Merck’s head of research said that trials such as ADVANTAGE are “intellectually redundant” – as they tend to focus on results that are already well-established, such as showing Vioxx to be somewhat easier on the gastrointestinal tract that naproxen.

Harold Sox and Drummond Rennie, also writing in the Annals of Internal Medicine, in a critique of Vioxx’s marketing wrote:

This practice—a seeding trial—is marketing in the guise of science. The apparent purpose is to test a hypothesis. The true purpose is to get physicians in the habit of prescribing a new drug. Why would a drug company go to the expense and bother of conducting a trial involving hundreds of practitioners— each recruiting a few patients—when a study based at a few large medical centers could accomplish the same scientific purposes much more efficiently? The main point of the seeding trial is not to get high-quality scientific information: It is to change the prescribing habits of large numbers of physicians. A secondary purpose is to transform physicians into advocates for the sponsor’s drug. The company flatters a physician by selecting him because he is “an opinion leader” and incorporates him in the research team with the title of “investigator.” Then, it pays him good money: a consulting fee to advise the company on the drug’s use and another fee for each patient he enrolls. The physician becomes invested in the drug’s future and praises its good features to patients and colleagues. Unwittingly, the physician joins the sponsor’s marketing team. Why do companies pursue this expensive tactic? Because it works.

This is hardly the biggest problem with Vioxx, as its tendency to kill people en masse via heart problems is obviously a far more important issue. And we all know at this point that Merck made sure to underplay the risks of Vioxx, and that the medical community was also asleep at the wheel when it came examining published studies on the risks of Vioxx. Nonetheless, using the guise of science to recruit naive (or greedy) physicians to serve as Vioxx pushers is contemptible.

Merck was out pushing how wonderfully safe and well-tolerated was via a “study” designed solely to turn “investigators” into top Vioxx prescribers, while at the same time, more and more people were meeting an early end due to this purportedly safe new drug.

For more hot Vioxx action, check out this site.

Update (8-19-08): Check out an interview with Dr. Kevin Hill, lead author of the investigation of the ADVANTAGE trial, over at the Carlat Psychiatry Blog. As always, Pharmalot also has a good post on the topic.

Don't Call it a Comeback

I've received a couple of nastygrams from readers asking when the *&^% I plan to return to blogging. If all goes well, I plan to return to writing more regularly soon.

Zyprexa Marketing: We Don't Need No Stinkin' Diagnosis and Hiding Risks

From an excellent piece at Bloomberg:

"The doctor's thinking that he does not see a schizophrenic or bipolar patient,'' [Zyprexa brand manager] Bandick said in a December 2000 internal e- mail to the marketing department. "But he probably does see patients with symptoms of behavior, mood and thought disturbances,'' he wrote. "Even if the doctor does not have diagnosis, he should treat anyway.''

Adding more fuel to the fire I discussed in February 2007:

The document discussed in this post is called the “Zyprexa Primary Care Presentation”. It appears to be a transcript of a speech Mike Bandick, the Zyprexa Brand Manager, gave at the Eli Lilly National Sales Meeting on March 13, 2001.

It is important to note that Zyprexa is only FDA-approved for use in schizophrenia and bipolar disorder. The document appears to indicate that Bandick was encouraging salespeople to market Zyprexa for treating more than just these two conditions.

Bandick said:

We intend, quite simply, to redefine the way PCPs treat mood, thought and behavioral disturbances. We will continue to focus on symptoms and behaviors that PCPs see every day.

Later he said, referencing Zyprexa:

Broad symptom efficacy in mood, thought, and behavioral disturbances.

It seems curious that Lilly states they did not market Zyprexa for off-label purposes, yet the term “Mood, thought, and behavioral disturbances” seems a fair amount broader than schizophrenia and bipolar disorder. In addition, schizophrenia and bipolar disorder (especially bipolar I, which is the much more severe form of bipolar in comparison to bipolar II) are uncommon disorders. It is highly unlikely that primary care physicians would see patients with such conditions “every day.” However, it is certainly possible that a PCP may run across individuals who are manifesting much less severe “disturbances”, and it may well have been that it was this group, the patients who exhibited mild “mood, thought, or behavioral” symptoms, for whom Zyprexa was being marketed.

But don't worry -- Lilly will tell you that they don't promote off-label. Do keep in mind that I'm not singling out Lilly, as this kind of thing seems to be par for the course.

As for risks of Zyprexa, well, according to Bloomberg...

Lilly added a warning to its packaging in October 2007 saying that more than half of patients in 13 studies gained an average of 12 pounds after taking the drug for less than a year. It said Zyprexa was more associated with higher blood sugar levels, a risk factor for diabetes, than similar medications.

Before the October 2007 label change, Lilly didn't instruct its sales force to say Zyprexa's diabetes rates were higher, former marketing director David Noesges said in a January deposition.

"We will NOT proactively address the diabetes concern,'' the Zyprexa sales force was advised in 2002, the documents show. "The competition wins if we are distracted into talking about diabetes."

The Bloomberg article is a must-read.

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.

Cymbalta: Good For Whatever Ails You

I don't have time to write much on the topic, suffice to say that John Russell of the Indianapolis Star raises some good questions about Cymbalta, Eli Lilly's antidepressant/antianxiety/analgesic/good for whatever ails you pill.  He calls it a Swiss Army Knife, which is ironic given that Lilly gave out Swiss Army Knives as part of its Viva Zyprexa campaign, likely as a reminder that Zyprexa (much like Cymbalta) was a broad spectrum psychotropic that could be used to treat, um, a lot of things.  Despite Cymbalta being touted as a cure for both depression and all sorts of different types of physical pain, once again it appears that the science has failed to live up to the marketing, at least for treating pain in depressed patients. Russell's article asks whether it is reasonable to expect that one drug could really work for so many different conditions.  It's well worth a read.

Hat Tip: Furious Seasons and an anonymous reader.

Conflicts, Bad Science, and Corlux: Part Two

The blogosphere has been abuzz with discussion of psychiatrist Alan Schatzberg's dual roles as a tycoon and an allegedly "objective scientist."  But wait... there's more.  Schatzberg is deeply involved with Corcept Therapeutics, a company that has repeatedly found that mifepristone (Corlux/RU-486) is a dud for psychotic depression.  Yet Corcept has continually attempted to spin the results as positive, in a manner that should be obvious to anyone who passed an introductory research methods or statistics course.  Schatzberg has millions of dollars in Corcept shares and should Corcept actually turn out to possess even minimal efficacy for psychotic depression, Schatzberg stands to profit quite handsomely.  

Bernard Carroll has the next chapter in this interesting saga, dealing particularly with Stanford University's claim that Schatzberg was not involved in "managing or conducting any human subjects research" using Corlux.  Such a claim is essentially saying that because of his financial connections with Corcept, Schatzberg avoided tight involvement with the studies of the drug so that he could avoid a conflict of interest.  Dr. Carroll, however, notes that it seems very likely Schatzberg was indeed involved in Corlux research.

There is reason to believe that Dr. Schatzberg had a key role in Stanford’s clinical trials of Corcept’s drug reported in 2001, 2002, and 2006. He was a co-author on all three publications, and there was no disclaimer about his role until 2006. This disclaimer is hardly credible. As Principal Investigator on the NIH grants, Dr. Schatzberg was expected to supervise the junior faculty and research staff at Stanford who recruited, assessed, and treated patients in the studies of RU 486. He was responsible for the choice of outcome measures, about which questions have been raised. He was responsible for the quality of the reported data analyses, which were, frankly, inexpert, when they were provided at all. Above all, he was responsible for the tone of the NIH-supported Stanford publications that claimed Corcept’s drug is effective.

That's just a tidbit -- there is much more to the story, and it should be read immediately at Health Care Renewal.  Keep in mind that Schatzberg is the president of the American Psychiatric Association.  You may then choose to giggle or cry -- your choice.  

Conflicts, Bad Science, and Corlux

Recently, the watchful eyes of Charles Grassley have been peering into the bank accounts of big name psychiatrists. Melissa DelBello and Joe Biederman (1, 2) from the Wonderful World of Child Bipolar were first, and now Alan Schatzberg has been hit. Schatzberg is the Chair of Psychiatry at Stanford University. He is also the President of the American Psychiatric Association. In other words, he's kind of a big deal.

Pharmalot hits the details, but the gist is that Schatzberg is deeply involved at Corcept Therapeutics, a company for which he is chair of the scientific advisory board and holds a large amount of stock. According to Grassley, he did not disclose some of his stock sale profits or the magnitude of his multimillion dollar stock holdings in the company. Additionally, Schatzberg allegedly underreported income received from other drug companies. It appears that Schatzberg was not really required to disclose some of this information, so according to my brief review of the information, it is quite possible that he has broken no rules. Now, whether the rules need to be changed is a different story. No offense to Grassley, but I was well ahead of him on part of this story, noting in April 2007 that Schatzberg had a mega-conflict of interest going with Corcept. I also noted previously that Schatzberg was on the Zyprexa bandwagon, helping to "educate" fellow physicians about the Lilly wonder drug.

The Real Problem: But amidst all this discussion of conflicts of interest, I am afraid that we are getting a bit diverted from the main problem, that of shoddy science. It is admittedly interesting noting that Schatzberg is somehow supposed to be an independent, disinterested scientist while standing to make an absolute truckload of money if his sponsored product succeeds. But it runs deeper. While Schatzberg is a bigwig at Corcept, let's review how Corcept's main product mifepristone (RU-486; yes, the abortion pill) has done.

Mifepristone (aka Corlux) is intended to work as a treatment for psychotic depression. One main problem: It doesn't relieve depressive symptoms. In multiple trials, it has failed to demonstrate antidepressant properties. The CEO of Corcept and another member of their scientific advisory board have previously tried to spin away such inconvenient data by painting negative results as positive. To give Corcept credit, their scientists are consistent spinmeisters, seemingly always able to dredge a positive from obviously negative findings. Schatzberg has been an author on a couple Corlux-related papers that were shredded by independent analysts, who found statistical problems and overly optimistic interpretations of the study results. As the senior member of the Scientific Advisory Board, I assume that Schatzberg had some input on the other study reports that also overstated the efficacy of Corlux.

Could his millions of dollars in Corcept holdings bias Schatzberg, either subconsciously or overtly? You be the judge. But remember that this is not just about conflicts of interest -- this is about science. There is hard evidence that the research on Corlux, which is tightly linked to Schatzberg, has been misinterpreted for the sake of marketing. Conflicts of interest sometimes lead to bad science, but rather than focus just on conflicts of interest, we need to dig a layer deeper and see the poor science -- the shoddy evidence that is used as the foundation for "evidence based medicine" in many cases.

Note also that David Healy has written an interesting piece on the topic of conflicts of interest and bad science, pointing out that a larger problem is lack of access to company-owned data. Think Paxil and suicide. He concludes:

If I were employed in a company marketing department I would much prefer to have the field think that all that is wrong is that a few corrupt academics fail to declare competing interests than to have the field think that company practices that restrict access to data while still claiming the moral high ground of science are the real source of the problem.

I'd love to know what American Psychiatric Association members think about this. The news had already broken about Schatzberg overstating the efficacy of Corlux before he was elected APA president. Do APA members not care that their president has a documented record of putting product promotion before scientific evidence?

More Than Filling My Shoes

I'll be on hiatus for a while. Too many things to do in too little time. Fortunately, material that is right in the sweet spot for readers of this site can be found at:

• Carlat Psychiatry Blog. His takedown of Medscape is much needed, as is further digging into ye olde coverup of industry cash by child psychiatry key opinion leaders.
• PsychCentral. Who cares about St. John's Wort for ADHD? JAMA seriously published a small trial of SJW versus placebo. I thought JAMA was for higher importance issues -- and so did John Grohol at Psych Central.
• Furious Seasons. Overdiagnosis of ADHD? Not a new complaint, but interesting perspective is provided by a Canadian psychologist who thinks the ADHD label is being passed about unnecessarily in Canada.

I hope to return soon.

Say It Ain't So Joe

It appears that Joe Biederman, King of Child Bipolar, has been caught with his hands in the cookie jar. More specifically, the New York Times and Bloomberg have noted that Biederman has received a great deal of pharma cash (like at least $1.6 million dollars from 2000-2007) and has not been very forthcoming about such funds. How was such undercover money revealed? Courtesy of Charles Grassley, the Iowa Republican Senator whose prior investigation unearthed a similar situation impacting another Bipolar Child Key Opinion Leader, Melissa DelBello from the University of Cincinnati.

Here's one example, from Gardiner Harris and Benedict Carey at the New York Times:

In one example, Dr. Biederman reported no income from Johnson & Johnson for 2001 in a disclosure report filed with the university. When asked to check again, he said he received $3,500. But Johnson & Johnson told Mr. Grassley that it paid him $58,169 in 2001, Mr. Grassley found.

So Biederman is supposed to report outside income to the university, but he didn't. Then, his amended reports were in some instances a wild underestimate of his outside income. So how well is the "honor system" working out for conflicts of interest, anyway? To be fair, Biederman is not alone -- two other Harvard psychiatrists (Timothy Wilens and Thomas Spencer) had similar reporting problems. Indeed, there is nothing to say that Biederman's conflicts of interest are any more noteworthy than those of other "stars" in the academic psychiatry universe.

Worry not, Biederman is still interested in saving lives. He is recruiting 4 to 6 year olds with "bipolar disorder" for a Seroquel trial.

For some reason, I thought Biederman's prior comments were worth repeating here. From the Boston Globe:

Biederman dismisses most critics, saying that they cannot match his scientific credentials as co author of 30 scientific papers a year and director of a major research program at the psychiatry department that is top-ranked in the "US News & World Report" ratings.

"The critics 'are not on the same level. We are not debating as to whether [a critic] likes brownies and I like hot dogs. In medicine and science, not all opinions are created equal,' said Biederman, a native of Czechoslovakia who came to Mass. General in 1979 after medical training in Argentina and Israel. He now lives in Brookline.

You tell 'em, Joe! I suppose those who dare critique his conflicts of interest are "not on the same level" as him. Some say that we shouldn't be concerned about conflicts of interest, that we should just look at the quality of a person's work, regardless of financial conflicts. Well, Biederman is the undisputed King of Bipolar in kids, and I'm still awaiting any impressive outcome dataon the "bipolar" kids being treated with antipsychotics. Especially the young kids. 4 year olds on Seroquel -- I'm glad I'm not on Joe's level. Are we better off now that the diagnosis of bipolar has run rampant in kids?

Also see and Furious Seasons and Pharmalot.

Update: Also read the Carlat Psychiatry Blog post on the topic.

Antipsychotics: Global Buckets of Money

Antipsychotics were the sixth best selling class of medications globally in 2007, according to IMS Health. They raked in a cool $20.7 billion, an increase of 10.7% from 2006. Thank God we are doing a better job of overrecognizing, er, appropriately treating bipolar disorder. Antidepressants were #7, at $19.7 billion, down nearly seven percent. This does not appear to be due to declining prescriptions. Blame generics, not decreased prescriptions for the lower numbers. With Cymbalta, Lilly has shown that new antidepressants don't have to be anything special, so it would behoove other companies to release other run of the mill antidepressants, attach a comical, er, highly educational marketing campaign such as Depression Hurts, then watch the money roll in. Just some free advice.

How about the top 10 drugs? Three of them were antipsychotics. No, I'm not kidding. Most surprisingly, Zyprexa had the best figures worldwide, which was interesting given the flat U.S. sales in 2007. Seroquel outsold Zyprexa in the U.S., but Zyprexa had a better run globally. Who knows what tricks are being used to sell Zyprexa internationally? Never mind, it's not like Lilly would do anything sly to market Zyprexa.

The new era of antipsychotics for everything appears to be in full swing.

BOLDER Update: Lilly Started It

Some of my longstanding readers probably remember that I long ago wrote about a statistical issue in the Seroquel trials for bipolar depression (known by the corny acronym BOLDER). It was just a minor issue, you know, the kind that would make a drug look about 50% more effective than a placebo depending on which type of analysis you chose to use. No biggie.

Lilly Started It: It just so happens that Philip Dawdy (who has apparently been christened as Dr. Dawdy) at Furious Seasons recently had a letter published in the Journal of Clinical Psychopharmacology on this issue of statistics. Dawdy noted that the authors' use of a statistical method known as mixed models repeated measures (MMRM) rather than the more conventional last observation carried forward (LOCF) resulted in a major inflation in effect size. As I mentioned earlier, the choice of methods to calculate the effect size (the magnitude of difference between drug and placebo) had a big impact. Dawdy aptly noted that the authors should have reported the effect sizes calculated by both methods so that readers could note how one method made Seroquel look better than did the other method. To quote Dawdy, "...the authors should also have reported the LOCF effect sizes so that the readers would have been aware of how the method impacted the findings." I was flattered to see that my blog was cited in Dawdy's letter. I heard through the grapevine that another author attempted to cite my blog in a letter to the editor, but that the journal struck the citation to my site in the final version of the published letter. If some of y'all researchers who read this blog wanna cite my site, go ahead.

I'm not saying that Seroquel was a dud, but that it did get a boost from the analysis used in the study. When the authors are playing by a new rule when it comes to calculating the differences between drug and placebo, it would make sense to report the results using both the old rules and new rules. In his response, Michael Thase of the BOLDER team responded that "It is my understanding that mixed model repeated measurement (MMRM) analysis was chosen to compute effect sizes in the BOLDER studies because it would permit direct comparison with the results of the study of the only other treatment approved for bipolar depression, the combination of olanzapine and fluoxetine (OFC). Thus, in plain and simple terms, we were attempting to facilitate an apples to apples comparison between quetiapine monotherapy and OFC." So because Lilly did it, we did it. Um, OK. But is there some kind of law against reporting the results from both the newfangled MMRM analysis and the old-fashioned LOCF analysis? Just wondering. And if Lilly started saying it was okay to market Zyprexa off-label for various conditions, would that mean all antipsychotics could be marketed off-label for all sorts of issues? (Hypothetically speaking, of course.)

Stats: Thase goes on to note that there is some research suggesting that MMRM does not overinflate effect sizes; rather, LOCF underestimates them. I know a bit about stats, but I'm not a statistician. Basically, the differences between the methods boil down to how data is handled for persons who dropped out of a study. The best solution is to try to track down study dropouts and assess how they are functioning, rather than having a statistical model guess at their sense of mental well-being, but this requires extra effort and time, and is sometimes not possible. Basically, the LOCF model makes some assumptions that are quirky at best, while MMRM seems to handle missing data better in many situations. All that being said, in many trials where a drug beats placebo, MMRM appears to generate effect sizes that are higher than LOCF, which then leads us to a question "Geez, have we been underestimating the effects of drugs by 50%?" -- um, that seems a little hard to swallow. I'm not quite ready to buy into that.