Eli Lilly: Our Drug Failed, So it Has Serious Potential

These folks at Lilly must think we are exceptionally stupid. As in can't tie our own shoes. A study in the Journal of Psychiatric Research recently found that their experimental antidepressant LY2216684 was no better than placebo. Here are a couple of quotes from the abstract:

LY2216684 did not show statistically significant improvement from baseline compared to placebo in the primary analysis of the Hamilton depression rating scale (HAM-D17) total score. Escitalopram demonstrated significant improvement compared to placebo on the HAM-D17 total score, suggesting adequate assay sensitivity.

On the primary outcome measure, the experimental drug failed whereas Lexapro worked to some extent. I know what you're thinking - "the sample size was probably too small to find a significant effect." Um, you're wrong. How about 269 people on the Lilly drug, 138 on placebo, and 62 on Lexapro.

But wait, here comes the good news...

Both LY2216684 and escitalopram showed statistically significant improvement from baseline on the patient-rated QIDS-SR total score compared to placebo... The results of this initial investigation of LY2216684’s efficacy suggest that it may have antidepressant potential.

The good news for Lilly is that most people who claim to "read journal articles" really just browse the abstract without actually looking at the full text of the paper. For the select few who have nothing better to do than read Lilly propaganda, take a look at Table 2. A total of 12 secondary outcome measures are listed. The Lilly drug beat placebo on... ONE of them. Lilly doesn't say much about how much better their drug was than placebo on the QIDS-SR measure beside throwing around that often meaningless term of "statistically significant." People on the drug improved by 10.2 points whereas placebo patients improved 8.3 points. So about a 20% difference. If you bother to calculate an effect size, it is d = .24, which is quite small and clinically insignificant. So on the ONE measure where the drug was better than placebo, it was by a small margin, and it missed the mark on 11 other secondary measures as well as on the primary outcome measure. But "it may have antidepressant potential." Hell yes, I've never been so exited about a new drug.

By the way, Lilly is apparently trying this wonder drug out in at least five trials. The journal in which this article appeared has published other dubious Eli Lilly research in the past. The editorial review process is clearly working wonders over at the Journal of Psychiatric Research. Sad, really. The journal publishes some really good work, but then runs this kind of junk as well.

Depression Self-Report Sidebar: The self-reported measure on which the drug had an advantage, the Quick Inventory of Depressive Symptoms (QIDS) - it's really awesome, according to Lilly. Remember, it's the only measure on which their experimental failure drug had an advantage over placebo. So the authors wrote "Self-reported depression symptoms, such as those obtained by the QIDS-SR, may be more sensitive than clinician-administered scales for signal detection in clinical studies of depression."

What does Bristol-Myers Squibb think? In three trials of Abilify for depression, self-reports of depression were unfavorable. So the publications for these studies made sure to downplay these depression self-reports by saying that these measures were not sensitive, that they weren't picking up improvements in depression.

So if a self-report provided positive results, then BAM, it's an awesome measure of depression. But if it provided negative results, then it's a horrendously inaccurate measure and should never have been used in the first place.

Citation below. Yes, one of the authors' last names is Kielbasa.

Dubé, S., Dellva, M., Jones, M., Kielbasa, W., Padich, R., Saha, A., & Rao, P. (2010). A study of the effects of LY2216684, a selective norepinephrine reuptake inhibitor, in the treatment of major depression Journal of Psychiatric Research, 44 (6), 356-363 DOI: 10.1016/j.jpsychires.2009.09.013

Zyprexa: Lilly Admits Guilt, But Also Blame Physicians

In February 2007, I wrote a post in which I described evidence that Lilly's antipsychotic olanzapine (Zyprexa) was marketed off-label for dementia. The evidence I discussed was based on documents generously and bravely hosted at Furious Seasons. At the time, I was careful to avoid labeling the practices as illegal -- they were definitely unethical but I couldn't really say for sure what if a law was broken. However, a law firm known to represent Lilly was regularly visiting my website at the time, which made me think that Lilly was seriously concerned about legal troubles. I suppose they had good reason to be worried.

I can now officially say that the off-label marketing of Zyprexa for dementia was criminal. Lilly just admitted to committing a crime in the off-label marketing of the drug for dementia and settled legal charges for a cool $1.4 billion. And there are more cases still on the books.

For a really interesting take on this situation, listen to New York Times reporter Gardiner Harris. You can find his talk embedded in the New York Times story from January 14, 2009, which is linked here. The plea agreement in the latest case is available here.

It is important to remember that pimping Zyprexa for dementia is far from a victimless crime. Antipsychotics, including Zyprexa, have been linked to an increased rate of death in elderly patients and have also been shown to be of little to no more benefit than a placebo in reducing dementia-related symptoms (1, 2). For a disturbing account of the widespread inappropriate use of such medications, read this post and weep.

This is truly a case where lust for profits likely led to the early demise of who-knows-how-many patients. And we're just talking about dementia, not the other cases where Lilly went berzerk with marketing Zyprexa (1, 2).

Blame the Physicians Too: While much of the blame for the overuse of antipsychotics in the elderly can be placed on corporations such as Lilly, it is also true that Lilly does not directly administer the drugs. Physicians need to understand that prescribing drugs which have been found to offer little benefit but are linked to killing patients -- how is that legitimately practicing medicine? First, do no harm?? Yes, I know that dementia is a hell of a difficult condition to handle. But does that mean we should be doling out ineffective and potentially deadly treatments to "manage" persons with dementia. Yes, reps from Lilly (and likely others) wined and dined physicians, "educating" them about the benefits of Zyprexa and other antipsychotics. That's their job -- to positively spin their products. No different than a used car salesperson except that drug reps are typically much better looking.

Doctors need to use critical thinking skills -- you don't just listen to a drug rep or skim a drug-company provided journal article reprint then jump on the Zyprexa bandwagon. How about learning how to evaluate evidence so that junky marketing disguised as science does not persuade you to write inappropriate scripts? Yes, we can be outraged that Lilly and others pimp ineffective and dangerous treatments, but the physicians are the most important link. If they cannot be better educated to understand clinical trial results, and cannot take time to critically review the scientific literature, then this pattern will repeat itself over and over again. It takes tricky pharmaceutical marketing in combination with an audience that is unwilling to think critically for this type of tragedy to occur. And occur again, it will.

Unfortunately, the published scientific literature is quite biased, as negative studies tend to vanish rather than grace the pages of our journals. But it's still a much better idea for prescribers to actually read journals and critically examine their findings, as opposed to relying on marketing alone. Better yet would be for research data on medications (negative and positive) to be available for all to see.

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.

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.

In the Name of Science and Charity

Philip Dawdy at Furious Seasons has noted that Eli Lilly released a short report in which they describe the funding they provided to a variety of organizations. All in the name of science and charity, of course. Beneficiaries of Lilly's largess include:

• The American Psychiatric Association
• Massachusetts General Hospital's Psychiatry Department
• National Alliance for the Mentally Ill
  
• Medscape
• American Academy of Child and Adolescent Psychiatry
• Center for Medical Knowledge
• Continuing Medical Education, LLC
  
• Institute for Continuing Healthcare Education
• Johns Hopkins University School of Medicine
• Postgraduate Institute for Medicine
• University of California -- Irvine

These were just some of the big recipients. The report itself is well worth checking out. One will note that Lilly is kindly funding a lot of "education" about fibromyalgia just as they try to move Cymbalta for all things pain-related. The amount of "education" regarding bipolar disorder is also instructive. Um, Viva Zyprexa?

Read some of the details at Furious Seasons and read Lilly's report as well. To Lilly's credit, at least they are making an attempt at disclosure; their industry colleagues are more than welcome to follow suit. Remember that the figures from Lilly's report are from the first quarter of 2008 only.

What Tangled Webs We Weave...

Roy Poses of Health Care Renewal did some digging and turned up gold. One really has to wonder whom some of our "leaders" in healthcare truly pledge their allegiance. Read the paragraph below and tell me that this does anything other than make you curse under your breath (or aloud):

So a director of Eli Lilly that was accused of responsibility for the company's poor performance, poor performance which presumably included its mis-marketing of Zyprexa, also turns out to be responsible for the management of the University of Texas Southwestern Medical Center, currently under fire for maintaining an "A-list" of favored patients, and letting its top executives live the high life on donated funds, practices that go against its mission.

Want the full story? Head over to Health Care Renewal and check it out. You'll also find some background material there -- by the time you're done reading it all, you are guaranteed to have smoke coming from your ears. File under outrageous.

Blast From the Past: Suicide Data Regarding Prozac Buried

This post will document plainly how Lilly and/or the National Institute of Mental Health and/or key opinion leader(s) made data on Prozac and suicide vanish. Poof! A study known as Study X065, published with Graham Emslie as the lead author, differs notably from the FDA report on the data from the same study. In the published paper, there is no mention of suicidal ideation whatsoever. None. However, according to the FDA report...

You can read it on page 19 of the report. It is clearly referencing the X065 study. Yet even a passing mention of suicide is not provided in the published paper. Regarding a different medication, the lead investigator for the X065 study, Graham Emslie, was asked at one point why he was not sharing data showing that Paxil/Seroxat was not an effective treatment for child/adolescent depression. He responded as follows:

I couldn’t talk about it because it was proprietary.

In other words, GSK owned the data, so he could not mention the negative information unless he had their permission. In my humble opinion, this gives the impression of Emslie not being a scientist, but rather a sock puppet for the drug industry. Back to the X065 study. Why wouldn't Emslie, lead author of the study insist that the suicide attempt data be included in the X065 study publication? NIMH theoretically owned the data, as they funded the study, so why wouldn't they make sure to publish such important information? It's one thing to exclude data from two patients on Prozac who had, say, treatment-emergent flatulence, but it is quite another to exclude data on a much more troubling treatment-emergent event such as suicide attempts.

I'm not the first to notice this issue. It was previously mentioned by Jonathan Leo in a letter to the editor in Psychiatric Times. When I see this incidence of hiding suicide data and I think about NIMH's poor attempts at journalism regarding the SSRI-suicide issue, it raises my suspicions regarding whose agenda is being served at the agency.

Whose Opinion Matters? Also of note, yet frequently not mentioned by the SSRI's are terrific for kids crowd is that depression measures completed by the children and adolescents in this study showed no significant improvement versus a placebo. This has nearly always been the case in studies examining SSRIs for child and adolescent depression. Measures rated by clinicians have occasionally found an advantage for SSRIs in youth depression, yet almost never have such effects extended to the youths' perceptions of their depression. Call me crazy, but if we're going to say a treatment is effective for depression, yet the people who are depressed say it does not relieve their depression, shouldn't that raise some suspicion? The authors, however, try to squirm out of this difficult position with the following sentences:

Furthermore, self-reported depressive symptom measurements also showed improvement in both groups, but the between-group differences were not significant. However, given the wide variability of initial child self-reports, these findings are difficult to interpret.

Oh, I get it. When a significant advantage is shown on a measure rated by clinicians, it is not difficult to interpret, but when a drug is not shown more effective than a placebo, well, who knows what that might mean? A very nice attempt at obfuscation on the part of the authors. You'd think this was a drug company funded study -- it hid negative data and obfuscated negative findings -- yet the good old NIMH, with our tax dollars, was behind this work.

But worry not, my friends, the study X065 conclusion, as published in the flagship journal of psychiatry (Archives of General Psychiatry) reads as follows:

These data indicate that fluoxetine 20 mg/d is safe and effective in children and adolescents.

Back to Graham Emslie. He admits to helping to keep GSK's secret that Paxil was not an effective treatment for youth depression and he was the lead investigator on a study in which two suicide attempts appear to have been deep-sixed. His interpretations of research regarding Effexor for (you guessed it) youth depression also seem overly positive, and it seems that he helped to keep data on Effexor for youth depression buried for several years. But, worry not, according to his website, he is "is known internationally for his work in the treatment of pediatric depression." Indeed. I'm comforted to know that we can expect this high caliber of work from high-ranking academic psychiatrists.

Will the Antipsychotic Coverup Continue?

At this point, there are a slew of lawsuits facing manufacturers of atypical antipsychotics, from individual suits ranging to suits brought by state governments. Allegations of fraudulent marketing, kickbacks, and hiding research results are among the claims made in such suits. For example, Arkansas recently filed a lawsuit. Read it here and read my take here.

The most important thing that could come from these suits in the long run is not the money that various drug companies may have to shell out in fines. No, the important piece is the information, the internal documents that I am nearly certain document numerous instances demonstrating bad science, covering up negative data, and detailing ludicrous marketing campaigns. Check out the documents on Zyprexa over at Furious Seasons and you'll get a taste for what I mean. I've written about them on a few occasions (1, 2, 3) as have others, with one monster post from Furious Seasons serving as an excellent example. If such documents from all companies who have engaged in such ethically dubious practices were to become public information, the PR hit would be enormous. Hell, the media may even wake up and run numerous stories on this issue. Imagine: 60 Minutes, Panorama, NPR, Frontline, Now, and other news programs hitting this one hard on multiple occasions. And the complicity of academic psychiatry makes the story yet more fascinating.

As I mentioned recently:

Without academics pimping these treatments well beyond what was scientifically justifiable, these medications would never have achieved such huge success, but now this rather dangerous group of medicines is used for virtually every psychiatric disorder under the sun. These uses include "bipolar disorder" in infants, ADHD, and dementia. Let's put the most vulnerable individuals on the riskiest treatments despite no clear evidence that they work particularly well. There is indeed some evidence for the efficacy of these medications in the short-term treatment of schizophrenia and bipolar disorder, and in a small number of trials, even some long-term evidence of efficacy. But their indiscriminant use across the board for virtually every condition brings great shame upon psychiatry as a profession, on Big Pharma for its slick marketing strategies (1, 2), and most especially upon academic psychiatry for its morally bankrupt role as a group of salespeople who have misrepresented scientific findings to help promote drugs (1, 2, 3, 4, 5, 6, 7, 8).

But such hopes may well be fleeting. The various offending companies may just decide to settle these cases, which nearly always means that they get to keep their dirty laundry private. Here is a sad possibility mentioned by Furious Seasons:

Risperdal goes off patent in about one month--except for some extra and short-lived pediatric indications--so I'm not sure that Janssen/J&J has a huge incentive to fight Arkansas and the other states that are suing it in order to protect what is soon to be a generic product. It's likely much cheaper for the companies to settle the case (liability insurance will cover much of the cost), write an agreement in which they admit no fault and manage to deep six any documents and other evidence of bad behavior, and move onto Invega.

Zyprexa goes off-patent in 2011 and Seroquel is off-patent the same year as well (not sure about patents on Seroquel XR), so one wonders how much incentive those companies have to fight the state suits, or whether they will just settle the cases and move onto whatever is next for them.

Maybe I am a bit too cynical, but it wouldn't shock me if that's how things played out. After all, Lilly has already settled about $1.3 billion in lawsuits over Zyprexa. Why stop now?

Unfortunately, his prognostication is likely correct. Of course, if some insider at AstraZeneca, Janssen, Bristol-Myers Squibb, or Lilly (or Pfizer --though it seems Geodon has not received much legal attention) decides to leak aforementioned documents, then we're on to something. Consider this an open call to the insiders at said companies. Email me or Peter Rost or Philip Dawdy or Ed Silverman or Jack Friday (Pharmagossip). We're all currently accepting insider documents regarding such matters...

The Slap Heard 'Round the World: Atypical Antipsychotics for Alzheimer's

Atypical antipsychotics just got slapped hard. A new study in the Archives of General Psychiatry delivered sizable blow to these medications by finding that they yielded no clinical benefit over "watchful waiting" (placebo) in treating dementia, while all atypical antipsychotics studies were associated with higher costs.

Olanzapine (Zyprexa) did particularly poorly. Patients taking Zyprexa had higher costs, yet their activities of daily living (personal care, doing chores, household activities, etc.) score was significantly worse than patients taking placebo. Patients taking risperidone (Risperdal) and quetiapine (Seroquel) also scored worse than patients receiving placebo on this measure, though Zyprexa patients had the lowest overall scores. In addition, Zyprexa patients were rated as significantly more dependent by their caregivers than patients taking placebo. Here's what the authors said:

The secondary finding that patients taking olanzapine scored worse on the activities of daily living measure than patients treated with watchful waiting most likely represents the greater level or combination of sedation, gait disturbances, and behaviorally inhibiting adverse effects with this drug.

Ouch. You may recall that this class of medications was marketed off-label for dementia. For example, see a prior post, complete with links to documentaton of how Lilly pushed Zyprexa for dementia/Alzheimer's. Let's not forget that antipsychotic meds are linked to that teeny little side effect known as death in older patients with dementia as well.

Let's see if I have this straight: A large number of dementia patients are placed on expensive drugs that have scant evidence of efficacy, and are linked to an increased rate of death. Uh, does this strike anybody else as W-R-O-N-G?

What Do Academics Say? Surely, academic psychiatrists are aware of the fact that atypical antipsychotics are poorly supported in treating dementia. After all, they are highly educated, objective scientists and they will pass along the objective evidence to the world. That's why they write things like this in the journal Current Psychiatry:

SGAs [atypical antipsychotics] remain the first therapeutic option for psychosis and agitation in Alzheimer’s patients.

Phew, good thing people can turn to objective, unbiased scientists for a realistic appraisal of the research literature, right? I think a Golden Goblet nomination can safely be issued to the authors of the above piece in Current Psychiatry -- you really should read my earlier post on the topic -- the article is mind-bogglingly bad.

Lilly Updates Label: A Little Too Late

The good news is that Lilly has updated its warnings for Zyprexa (olanzapine) and Symbyax (olanzapine/fluoxetine combo). Here's a bit from the PR release:

Specifically, the changes include new warnings for weight gain and hyperlipidemia (elevation of triglycerides and cholesterol) and updated information in the warning for hyperglycemia (elevated blood sugar), including additional language on a greater association of increases in glucose levels with olanzapine than with some other atypical antipsychotics.

Here's the tragicomic part:

"Today's communication is part of Lilly's historical and ongoing commitment to inform doctors and patients about updated prescribing information," said Sara Corya, M.D., global medical director, Lilly.

AND

"Lilly continues to recommend that clinicians consult expert guidelines for treating people with antipsychotics, particularly the monitoring of lipids and blood glucose, regardless of the medication prescribed," Dr. Corya said. "Over the last several years, the company has been actively informing healthcare professionals about these recommendations."

Yes, Lilly is all about honestly sharing information. Please read my prior post on the incredible shifting Zyprexa glucose data here. Read a whale of a great post from Furious Seasons on how Lilly tried to play weight gain on Zyprexa off as a benefit of treatment (!) here. Interesting questions about Lilly's handling of the glucose discussion can also be seen here. If you have some time to burn, look through the above posts, then tell me Lilly has a "historical and ongoing commitment" to sharing data openly and honestly.

As for the expert guidelines, yeah -- great idea! Like TMAP -- read my postabout how the research supporting said guidelines for treating bipolar disorder is flimsy at best, yet these "expert guidelines" are oft-cited as a great example of the good that comes from expert guidelines. Oh, and did I mention that the "expert guidelines" are often authored with the help of industry?

Here's the bad news. Really bad news. Philip Dawdy has posted an interview with the mother of a man who took Zyprexa, apparently piled on the pounds, and then allegedly died of "profound hyperglycemia." It is a sad, sad story and well worth your time to read it.

While you're there, look around the Furious Seasons blog and ask yourself, "Is there anywhere else where I can find this type of mental health coverage?" I bet you'll say no. If you want continuing coverage of these issues, I suggest that you contribute whatever you can to Philip Dawdy, author of Furious Seasons.

You REALLY Don't Wanna Publish That, Right?

Due to a lot of hits on a post from March over the past few days, I am providing a link to it since it is apparently becoming a hot commodity. The post is about Zyprexa, and the email of one Lilly employee in which different ways to suppress the study's results were discussed. Naughty. Very naughty.

And Lilly is painting David Egilman as the bad guy for his role in disseminating the now-infamous Zyprexa documents? Gimme a friggin' break! Oh, and did I mention the aforementioned post is based on one of those documents?

Atypical Antipsychotics Down Under

Furious Seasons has a roundup of the latest regarding atypicals in Australia. How about a substantial number of deaths related to their use? Add in a substantial number of patients complaining of other side effects and, for good measure, how about Lilly facing legal action over Zyprexa? Crikey.

Let the Lawsuits Fly

From a press release from Prescription Access Litigation...

A U.S. District Court judge today issued a decision allowing to go forward a class action lawsuit that alleged that Eli Lilly & Co. (NYSE: LLY) fraudulently marketed the atypical antipsychotic drug, Zyprexa, for uses not approved by the FDA. Judge Jack B. Weinstein, of the U.S. District Court, Eastern District of NY, denied Eli Lilly’s motion for summary judgment, as well as a summary judgment motion filed by the plaintiffs.

The 14-page order highlighted the importance of the Courts in protecting the public in the arena of prescription drugs. The Judge stated:

"Under the present organization of the pharmaceutical industry, the official federal Food and Drug Administration (FDA), and the plaintiffs' bar, the courts are arguably in the strongest position to effectively enforce appropriate standards protecting the public from fraudulent merchandising of drugs." (Opinion, pp. 3-4)

The entirety of the judge's latest ruling can be seen here. This is a potentially big story, but I have little time to discuss it now. Maybe later...

The Tobacco Connection

Lilly is represented by multiple legal firms, one of which is Covington & Burling. Let's think about it -- Lilly is being sued over Zyprexa for such things as off-label marketing and health risks. Well, C & B knows a little about health risks. They represented Big Tobacco, for which their shining work at helping to conceal the risks associated with smoking and secondhand smoke earned them a stern reprimand from a judge. They are apparently not ashamed of their work with the Tobacco Institute (Big Tobacco's former lobbying group), as it is mentioned on C & B's website. I don't mind looking at their website, as they have visited my site on several occasions.

Below are a few articles you may enjoy regarding Covington & Burling's stalwart representation of Big Tobacco, and how they covertly got involved with the "science" surrounding the health effects of secondhand smoke. I highly advise reading them, then thinking about the current Zyprexa controversy.

• SourceWatch
• Center for Indoor Air Research
• The Latin Project
• Playing with Airline Cabin Science
• More on the "Center for Indoor Air Research"

So, in line with C & B being intimately involved with the Tobacco Institute and Center for Indoor Air Research, I suggest that they set up something similar for Zyprexa. What do you think of the following?

• Center for Diabetes Studies
• Center for Weight Management Research
• Institute for The Appropriate Marketing of Pharmaceuticals
  

The Beehive State Joins the Zyprexa Party

As pointed out by Ed at Pharmalot, Utah is now added to the list of states suing Lilly over its promotion of Zyprexa. Read some of the statements from Attorney General Mark Shurtleff regarding the lawsuit. The lawsuits just keep stacking up.

It must suck to be Lilly these days. The documents that may incriminate Lilly are just hanging out in full public view. Any enterprising attorney general just needs to get their feet wet by looking through a handful of documents (which can be downloaded here and here) and by perhaps taking a peek at a few posts by your humble correspondent and Philip Dawdy, such as the following:

• The Zyprexa Chronicles: Marketing Zyprexa As The New Mood Stabilizer For Bipolar Disorder And Downplaying Diabetes And Weight Gain Concerns
• Zyprexa: Off-Label Promotion?
  
• Zyprexa Off Label Marketing(?): Part 2
  
• Demented Marketing of Zyprexa?

Good thing that Lilly's lawyers are just the right team for the task. More on that in a soon-to-come post...

Lilly and Cash

Pharmalot has a very interesting post regarding how Lilly disseminates cash to various organizations. The largest recent recipient was Massachusetts General Hospital, which by sheer coincidence (?), is where Mauricio Tohen, the lead scientist on the Zyprexa team happens to hang his hat (See update below!). In the first quarter of this year, Lilly doled out over a half million dollars to the National Alliance for the Mentally Ill. This should come as no surprise, given that a few years ago, the head of NAMI was a Lilly executive "on loan" from Lilly. So it comes as no surprise that NAMI often finds itself issuing talking points that coincide nicely with Lilly's goals, such as lobbying against restricting Zyprexa usage. Much more over at Pharmalot and the Wall Street Journal (registration required).

UPDATE: I made an error. I thought that Dr. Tohen held an academic appointment at Mass General -- I was mistaken -- he holds no such appointment. I sincerely apologize for the mistake. Mea culpa. Rather than delete the offending text and leave the impression I am trying to cover my mistake, I will leave it above so that my error can be recognized publicly.

Lilly Plays The Heavy

Lilly has apparently threatened to sue the pants off an individual who disseminated some of its documents regarding the Zyprexa debacle. Health Care Renewal indicated (via a Nature article unavailable to most) that David Egilman, who played a role in getting the infamous documents disseminated may face severe legal sanctions. The kind that cost a lot of money.

The irony is that Lilly claims that the documents which paint a rather awful picture of its off-label marketing (here, here, here, and here) are taken out of context, yet they refuse to make any additional information available. If the documents are out of context, why don't you provide some context? Indeed, they are suing those who tried to disseminate information pertaining to the drug. And let's also not forget about the email exchange where a Lilly employee discussed ways in which a study casting dispersions on the "safety" of Zyprexa could get deep-sixed through nefarious means.

Don't Diss Berenson

Drug Wonks has a post saying that Alex Berenson's latest reporting on the Zyprexa scandal is likely erroneous because he is pulling information from just a few Lilly documents. Indeed, it is stated...

Once again, Berenson uses the "one paper out of several thousands of documents" approach to depict Lilly as a criminal corporation.

Further, it is added

On the heels of intense criticism of the NYT coverage of the Duke rape case and the paper's falling earnings, the Berenson reporting is another example of the Times decline.

OK. Here's my challenge. I'd like Drug Wonks or, well, anyone to read the following posts. Read the Lilly documents that are freely available and are linked within said posts. Then talk about how Lilly is a good corporate citizen, and did not promote Zyprexa off-label. Here you go...

• Demented Marketing of Zyprexa?
• Marketing Zyprexa as the New Mood Stabilizer...
• Zyprexa Off-Label Promotion (?)
• Zyprexa Off-Label Marketing (?): Part 2

As for the "well, we haven't seen every single document" argument, please see my earlier post for why I think that argument is weak.

Data Massaging at Lilly?

From the New York Times:

The FDA has questions about a Lilly document from February 2000 in which the company found that patients taking Zyprexa in clinical trials were three and a half times as likely to develop high blood sugar as those who did not take the drug.

That document was not submitted to the agency. But a few months later, Lilly provided data to the FDA that showed almost no difference in blood sugar between patients who took Zyprexa and those who did not.

But worry not, Lilly is claiming the above was just an honest mistake. Kind of a large mistake, eh? After the data were analyzed accurately, then Zyprexa did not appear nearly as risky. Of course, we can be sure Lilly is being honest, just like when they said that they never marketed Zyprexa as a treatment for dementia. Or the time they said that Zyprexa does not cause diabetes. Or maybe when Lilly decided to sell Zyprexa as a "safe, gentle psychotropic." I think you get the point... It is indeed possible that Lilly is being truthful, but I personally doubt it.

On a side note, good to see that Alex Berenson is back to writing about Zyprexa.

Lilly Posts 1Q Earnings

And they're pretty good. Of psych note, Zyprexa sales were up 10% compared to the 1st quarter of '06; Cymbalta sales up 89% from 1Q '06, and Strattera sales down 8% from 1Q '06. Overall, sales were up 14%. Source.

According to Bloomberg, Lilly is planning to ramp up marketing of Cymbalta and Zyprexa. Can you say Viva Zyprexa Strikes Back? How about Anxiety Hurts (1, 2)? I wonder to whom Lilly will market Zyprexa? Seriously -- they've tried primary care, psychiatrists, and likely the geriatric market, so who's next? How about pediatricians? Tantrum = Zyprexa?