Charles Nemeroff, Consultant Extraordinaire

The key opinion leader of key opinion leaders. Or Boss of Bosses, if you prefer. In any case, take a peek at the following from Charles Nemeroff's page on the University of Miami's website. Seems like something must have happened in 2006 to slow down Chuck's momentum...

What? This is old news? Yeah, I know. But I just hadn't written much about our friends in the world of drug sales/"academics" lately, so I just had to do this.

Pharmaceutical and Clinical Research Company Scientific Advisory Boards

Abbott Laboratories
- Consultant, Abbott Laboratories, Diagnostics Division, 1986-1992.
- Research and Education Advisory Board for Psychiatry
- Member, 1990 - 2006
- Executive Board, 1991 - 1993, 2003 - 2006
-Antidepressant Advisory Board, 1991 - 1992

ACADIA Pharmaceuticals Clinical Advisory Board
- Member, 2000 - 2006.

AstraZeneca Pharmaceuticals
- Psychiatry Advisory Board, 1997 - 2001.
- Chairman, 1999 - 2002.
- Neuroscience Scientific Advisory Board, 1999 - present.

Bristol-Myers-Squibb
- Antipsychotic Advisory Board, 2003 - 2006.
- Antidepressant Advisory Board, 2003 - 2006.
- EMSAM Advisory Board - Chairman, 2005-2006.

Cephalon Pharmaceuticals
- Scientific Advisory Board, 2002

Comprehensive Neuroscience, Inc.
- Scientific Advisory Board, 1999 - 2004.

Corcept
- Scientific Advisory Board, 2001 - 2006

Cyberonics
- Scientific Advisory Board, 2002 - 2006.
- Chair, Mechanism of Action Board, 2003 - 2006.

Cypress Biosciences, Inc.
- Board of Directors, 2001 - 2004
- Consultant, 2004 - 2006

Eli Lilly and Company
- Psychiatry Advisory Board, 1990 - 2000.
- Bipolar Advisory Board, 1998 - 1999.
- Consultant, 2002 - 2003.
- Global Neuroscience Advisory Board, 2005 - 2006.

Forest Laboratories
- Citalopram Clinical Advisory Board, 1997 - 2002.
- Psychiatry Scientific Advisory Board, Chairman, 1999 – 2008.

GlaxoSmithKline Advisory Board of Psychiatrists
- Chairman, 1991 - 2004.

Janssen Pharmaceuticals
- Mood Disorders Advisory Board, Member and Chairman, 1998 - 2004.
- Topiramate Advisory Board, Member and Chairman, 1999 - 2001.
- Antipsychotic Advisory Board, Member, 1999 - present.

Johnson & Johnson Scientific Advisory Board, 2007- present.

Lundbeck
- Consultant, 2006

Merck Sharp & Dohme Research Laboratories
- Consultant, Neuroscience Research Center, 1994.
- Mood Disorders Advisory Board, 1999 - 2003.

Merck-MedCo Mental Health Advisory Board
- Member, 1996 – 1998

Mt. Cook Pharma
- Board of Directors, 2007 - Present

Neurocrine Biosciences
- Scientific Advisory Board, 1994 - 2004.

Neuronetics
- Scientific Advisory Board, 2006

Novadel Pharma
- Board of Directors, 2003 - present
- Chair, Scientific Advisory Committee
- Member, Compensation Committee
- Member, Nominating Committee

Novartis Pharmaceutical Company
- Bipolar Advisory Board Chairman, 2001 - 2003.
- Pediatric Bipolar Advisory Board, 2002 - 2003.
- Antidepressant Advisory Board, 2006.

Organon Pharmaceuticals Psychiatry Advisory Board
- Member, 1997 - 2004.

Otsuka Psychiatry Advisory Board
- Chairman, 2003 - 2006.

PharmaNeuroboost
- Scientific Advisory Board, 2006 – present.

Pfizer Pharmaceuticals
- Clinical Neuroscience Advisory Board, 2004 - 2006.
- Chair, Antipsychotic Advisory Board, 2004 - 2006.

Quintiles Scientific Advisory Board, 2004 - present

Revaax
- Stockholder

Roche Laboratories, a Division of Hoffman-LaRoche, Inc.
- Mania Advisory Board, 1993.
- Pharmocogenomics Advisory Board, 2006

Sanofi/Synthelabo
- Psychiatry Advisory Board, 2002 - 2005.

SciRex
- Scientific Advisory Board, 1999 - 2003.

Solvay Pharmaceuticals Psychiatry Advisory Board
- Member, 1991 - 1999.
- Chairman, 1991 - 1999.
- Antipsychotic Advisory Board, 2005 - 2006.

Somerset Pharmaceuticals Psychiatry Advisory Board
- Chair, 2000 - 2004.

Vela Pharmaceuticals
- Scientific Advisory Board, 2001 - 2002.

Wyeth-Ayerst Psychiatric Advisory Board
- Chairman and Member, 1995 - 2002.

Wanted: Drug Pimp/Key Opinion Leader

Daniel Carlat from the Carlat Psychiatry Blog received an invitation to the key opinion leader club from the good people at Schering-Plough. The company wanted him to read their slides to other physicians in order to promote their brand spanikn' new antipsychotic/mood stabilizer Saphris (asenapine). Because, of course, if he reads the slides, they are more credible than if read by one of those sleazy drug reps; it's so much more classy and believable if an "independent" psychiatrist reads the company's marketing copy.

Carlat posted the documents used in the attempt to recruit him (cover letter, speaker bureau arrangement, pimp, er, speaker fees) Everyone should read them. Speakers are only allowed to rake in $170,000 of dirty money through this program. I suppose anything more would make them look like shameless drug pimps. But if you were to take, say, $50k for your "educational" services, that would be totally acceptable, right? I hereby nominate anyone who accepts Schering-Plough's generous offer for the much coveted Golden Goblet Award.

What's the deal with this Saphris drug, anyway? One neuropsychologist reviewed the data and found that it promises to be yet another also-ran atypical antipsychotic, at best. Some have also raised questions of whether the drug deserved FDA approval at all. Get ready for some ghostwritten articles that present the evidence surrounding Saphris in a ridiculously biased manner, for key opinion leaders to travel to conferences extolling its virtues, and for the rest of the usual marketing tricks.

Key Opinion Leader Syndrome

I ran across a rather hilarious article from Medical Hypotheses, in which David Healy described "Krapelin-Fraud Syndrome", which I have also dubbed "Key Opinion Leader Syndrome." See below for the diagnostic criteria.

In line with current neo-Kraepelinian thinking, we put forward operational criteria for this new disorder for provisional inclusion in ICD-XI or DSM-V. An affected subject should meet at least 2 of criteria A–D and 2 more from criteria E–J. Fulfillment of all criteria A–D in the absence of any other features of the disorder will make the diagnosis, although this may represent a syndromal variant.
(A) A pervasive pattern of travelling to scientific conferences and talking about research data that he has had no involvement in generating.
(B) Episodic logosagnosia.
(C) Unusual abilities to compartmentalise information.
(D) Will have a significant number of ‘‘ghost-written” articles.
(E) Actively seeks admiration by peers and subordinates.
(F) An exaggerated sense of own talents, which can be inferred from expectations of recognition as an expert in the absence of commensurate achievements. Happy in the role of opinion leader.
(G) Has a sense of entitlement, i.e. unreasonable expectations of favorable treatment from symposium and congress organisers.
(H) Liable to profound dysphoria if not involved with the ‘‘academic action”.
(I) May be unreasonably envious of the scientific achievements of others and is liable to denigrate these. Would also be unhappy if his colleagues had appeared on ‘‘educational” videos and he had not.
(J) Is unaware of the disorder quality of the syndrome.

Two case studies are included, one of which reads in part:

One of the striking features of his lecturing is the dissociation between his reputation as a critical and skeptical lecturer when dealing with topics on the main programme of the meeting and the extent to which he may be prepared to offer apparently enthusiastic and uncritical endorsement for a compound in a satellite symposium. Very frequently this uncritical endorsement will involve the recycling of outdated ideas, which it is difficult to believe that either B or indeed many of his audience can conceivably believe and which indeed he may contradict within the hour at another symposium.

Hmmmm. Enthusiastic and uncritical endorsement of [insert product name here]. That reminds me of a post or two I've written... I made a rough list of symptoms for KOL Syndrome in July 2008. Different symptoms, but same idea.

Leading Psychiatrist Slammed in Leading Journal

In the latest American Journal of Psychiatry appears a review of Allison Bass's book Side Effects. As many of my readers undoubtedly recall, the book details the saga of the antidepressant drug paroxetine (Paxil) and the troubled line of "research" used to support its use in children (among other points). The reviewer clearly liked the book, which is not necessarily newsworthy. What is notable is that a book review appearing in perhaps the world's leading psychiatry journal slams a leading member of the psychiatry profession. The reviewer, Dr. Spencer Eth, writes the following:

More recently, psychiatrists have been greeted in the morning with front-page newspaper exposés of huge sums being directed by these same drug companies to the physician leaders of our field. In Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial, journalist Alison Bass has written the powerful story of a leading medication, its manufacturer, and a favored psychiatrist, whose driving force was profit not treatment.

Ouch. Though not naming the psychiatrist directly, it is clearly a reference to Martin Keller, bigwig at Brown University, whose work on one particular study regarding Paxil was the subject of a lengthy prior post. For the collection of my posts related to Dr. Keller, please click here.

Back to the review...

This well-told cautionary lacks the excitement of a novel but instead informs the reader with an actual case study with the real names of psychiatrists we know. We can see exactly how corporate greed, drug-company-sponsored clinical research, and mental health care become a toxic mix that inevitably damages our patients’ well being, our colleagues’ reputations, and our profession’s good name.

It was a refreshing surprise to see Martin Keller's goose get cooked in this review. I don't mean to sound vindictive or meanspirited. Keller has done a lot of work over the course of his career, much of which likely has some redeeming value. That being said, there can be little doubt that some of his "science" is quite dubious. And for a major psychiatry journal to run anything, even a book review, that directly goes after a "key opinion leader" who appears quite culpable in performing bad science -- that's a good sign.

The Budget Crisis, Universities, and Key Opinion Leaders

Everyone knows that state budgets across the United States are in a crunch. All state-supported universities are looking for sources of income outside of taxpayer funds. As state legislatures look to cut money, many state universities are in for a big budget hit. So if the state is going to pony up less money, how can a university survive...?

Perhaps by seeking to entice industry funding. Set up a few clinical trials and see what happens. There is nothing inherently wrong about university faculty working on industry-sponsored research. In an ideal world, all goes according to plan and all benefit from such collaboration. Universities love industry collaboration because it brings in good money. Researchers like to collaborate with industry for some altruistic motives, such as receiving funding to work on investigating treatments that might hopefully bring about better lives for people struggling with various ailments. Because receiving funding makes the university
administration happy, it also makes life at a university medical center much more pleasant for those who bring in the bucks.

But how do things really work? Sometimes, they go well. But there are also nondisclosure agreements, in which an "independent" academic researcher gives away any right to discuss the data from clinical trials that he/she is working on unless approval is given by industry. As Graham Emslie, key opinion leader in the field of child psychiatry, can attest to, there are certainly many cases where negative results were found for a drug, but the negative data were buried to avoid any untoward publicity. Academics often farm out their writing of joint work with industry to ghostwriters who spin the final product to pimp a product rather than accurately describe the results. As regular readers know, this is just the tip of the iceberg.

If academics are willing to be oversee industry-sponsored research, have substantial input into writing the final presentation of the results, and actually review the data from these joint ventures with industry, then academic-industry collaboration can be fruitful. However, if academics are simply used to recruit patients for clinical trials, stamp their names on papers consisting of data with which they are entirely unfamiliar, and are complicit in hiding negative data, then the current sad state of affairs will continue unabated.

Given the current financial situation, universities will be encouraging faculty very strongly to get external funding for their work, and we can only hope that academics will behave responsibly when such collaborations occur.

KOL Continues to Vanish

Charles Nemeroff, about whom I have written much, continues to disappear. His latest vanishing act: From a psychiatric research gathering in Berlin in late November 2008. Their website now reads: "Dr. Charles B. Nemeroff (Atlanta, the USA) called his participation off in the congress and its scientific contributions." We can only hope that they had another key opinion leader of his stature to replace him.

Back story.

The Incredible Vanishing Key Opinion Leader

Charles Nemeroff, former chair of psychiatry at Emory University and key opinion leader extraordinaire has vanished. Not quite vanished from the face of the Earth, but from Medscape CME and now from a Georgia mental health commission. Nemeroff was found to have not disclosed a whole boatload of money he received from Big (and little) Pharma according to an investigation by Senator Charles Grassley. For example, it appears that Nemeroff received about $20,000 in cash from GlaxoSmithKline in one month in exchange for promoting GSK products to his peers.

I have previously written about a number of, um, "interesting" behaviors on the part of Nemeroff, which I recommend you read in order to understand that Nemeroff has, on several occasions, engaged in behavior that certainly appears to have placed the causes of his corporate sponsors over science. Not good for an "independent" researcher.

And now, it seems that Chuck Nemeroff is vanishing. Dr. Bernard Carroll noted that Nemeroff's continuing medical education offerings had vanished from Medscape and offered the following:

Well, good for Medscape. They came in for their share of criticism, here and here, a while back. Now they deserve credit for displaying ethical standards. Meanwhile, we are waiting for another company called CME Outfitters to get the message. Dr. Nemeroff is slated to moderate a raft of new programs for this company in the coming weeks, sponsored by corporations like Pfizer, AstraZeneca, and Ortho-McNeil Janssen. CME Outfitters' logo, after all, is Education with Integrity. Sooner or later the pharmaceutical corporations, like the CME companies, will understand that they are not helping themselves by trotting out a shopworn and sleazy KOL figurehead like Nemeroff for their marketing efforts. And other KOLs who up to now were willing to "wet their beaks" in these CME forums controlled by the Boss of Bosses Nemeroff will now be leery of associating with him.

Well, CME Outfitters is still rolling with Nemeroff. For example, he has an upcoming program called "Atypical Antipsychotics in Major Depressive Disorder: When Current Treatments Are Not Enough," which is a scary thought given that he appears to have been pulling data from thin air for a prior CME exercise in which he pimped risperidone as a treatment for refractory depression. Specifically, Nemeroff's presentation claimed that risperidone improved sexual function in a clinical trial, when the published article based on the trial's results said no such thing. In addition, Nemeroff's claim that risperidone had shown efficacy in a short-term study versus placebo for depression was also unsupported. So I'm thinking the upcoming program on antipsychotics for depression might be a fantastic example of marketing beating the crap out of science.

Georgia appointed a commission to address several issues within the public mental health system. They have completed a report. Interestingly...

The final version also does not contain the name of commission member Charles Nemeroff, an Emory psychiatry professor who has been a subject of a U.S. Senate Finance Committee investigation into whether drug company money paid to doctors and academics compromises medical research and scholarship. Nemeroff, an internationally known expert on depression, did not attend recent commission meetings.

But Nemeroff was appointed to the commission with some fanfare. The press release listing Nemeroff's accomplishments is pretty lengthy. The Georgia state legislator who appointed Dr. Nemeroff said, "I am confident that Charles will be an asset to this commission and will serve as a strong advocate for the people of Georgia being served [by] our mental health systems"

Yet Nemeroff was not on the final report. If it weren't for his work on CME Outfitters, I would be worried that we might need to file a missing persons report for Dr. Nemeroff.

Update (12-18-08): The Wall Street Journal Health Blog has two interesting posts on Dr. Nemeroff (1, 2). Read them and feel free to file them under "bizarre."

Key Opinion Leader With A Very Short Fuse

Psychiatrist Joe "Short Fuse" Biederman of Harvard University is really in hot water now. The sordid details can be seen in a fantastic article by Gardiner Harris of the New York Times. Here's just one snippet:

In a November 1999 e-mail message, John Bruins, a Johnson & Johnson marketing executive, begs his supervisors to approve a $3,000 check to Dr. Biederman as payment for a lecture he gave at the University of Connecticut. “Dr. Biederman is not someone to jerk around,” Mr. Bruins wrote. “He is a very proud national figure in child psych and has a very short fuse.” Mr. Bruins wrote that Dr. Biederman was furious after Johnson & Johnson rejected a request that Dr. Biederman had made for a $280,000 research grant. “I have never seen someone so angry,” Mr. Bruins wrote. “Since that time, our business became non-existant (sic) within his area of control.”

Mr. Bruins concluded that unless Dr. Biederman received a check soon, “I am truly afraid of the consequences.”

A series of documents described the goals behind establishing the Johnson & Johnson Center for the study of pediatric psychopathology, where Dr. Biederman serves as chief. A 2002 annual report for the center said its research must satisfy three criteria: improve psychiatric care for children, have high standards and “move forward the commercial goals of J.& J.,” court documents said.

And from Bloomberg,

Biederman “approached Janssen multiple times to propose the creation of a Janssen-MGH center,” according to an e-mail from a J&J executive. The center would “generate and disseminate data supporting the use” of Risperdal in children, the e-mail said. Pediatric use was approved by U.S. regulators in August 2007.

Wow. And the plot sickens, er, thickens from there. Normally, being caught with one's hands this deep into the cookie jar would lead me to write a much more blistering piece, but the day job shows no signs of abating in its workload. Fortunately, Philip Dawdy is rolling with the story at Furious Seasons (1, 2).

Let's see if Biederman's defenders can defend him in another op-ed as they did a few months ago. Or maybe we can leave Joe to defend himself. Here's what he said a few months ago when facing criticism:

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.

Nope, most of his critics cannot match his credentials of apparently shaking down hundreds of thousands of dollars from Johnson & Johnson. But maybe I just like brownies and he likes hot dogs. Another key opinion leader whose reputation is deservedly shot to shreds. Nemeroff, Biederman, and the list goes on.

A Month in The Life of Chuck "High Life" Nemeroff

The psychiatry world is belatedly exhibiting outrage toward a man whose ability to lure pharma cash seems to know no bounds. He may be the textbook case of a key opinion leader. Of course, I speak of Charles "Bling Bling" Nemeroff. Rather than list the many questionable at best behaviors he has exhibited, each of which has called into question his standing as a scientist as opposed to a blatant drug marketer, I just want to a) direct everyone to a detailed list of his speaking engagements from GlaxoSmithKline and b) discuss a month of living the High Life, Nemeroff Style.

As is well known by now (1, 2), Nemeroff appears to have not been particularly forthcoming about the huge amounts he was making while moonlighting for every drug company on the planet (see below) despite requirements that he do so. According to psychiatrist Danny Carlat:

From 2000 to 2006, GSK paid Nemeroff a total of $960,488. Note that this was not research grant money, or money for Emory's psychiatry department. These were fees that went into his personal bank account, which he earned by either sitting on GSK's Advisory Board, or speaking to doctors about GSK products. His typical fee for a talk was $3500 plus expenses, but sometimes he made more.

Of this $960,488, the total amount he disclosed to Emory [his employer, to whom he was required to report such income] was $34,998.

According to a GSK document hosted by Senator Charles Grassley, Nemeroff took in over $20 grand in one month from speaking engagements for GSK. Not bad work if you can get it, eh? And this month doesn't seem unusual for Nemeroff. These are only his speeches for GSK -- he also gave speeches for several other companies. The document goes on and on -- 39 pages of paid speech listings, nearly all of them featuring Nemeroff. I just picked 03-30-00 to 04-30-00 because they were on the first pages of the document, which covers expenses from 2000 to 2008 for Dr. Bling Bling.

Nemeroff GSK Honoraria from March 30, 2000 to April 30, 2000

Date	Speaking Fee
03/30/2000	$4000
04/12/2000	$2500
04/19/2000	$4000
04/20/2000	$4175 (includes some 'expenses'; I suspect $4000 was the speaking fee)
04/27/2000	$4000
04/30/2000	$2500
TOTAL	$21, 175 (probably $21,000 excluding travel expenses)

Imagine making $20k in a month for basically reading slides a few times that were quite possibly entirely written by a drug company. And many of these talks were accompanied by posh meals, the kind that myself and most of my readers might eat once or twice a year.

Here's a Nemeroff disclosure from a recent journal article:

Dr Nemeroff has received grants from or performed research for the American Foundation for Suicide Prevention, AstraZeneca, Bristol-Myers Squibb, Forest Laboratories, Inc, Janssen Pharmaceutica, NARSAD: TheMental Health Research Association, the National Institute of Mental Health, Pfizer Pharmaceuticals, and Wyeth-Ayerst Laboratories; has been a consultant to Abbott Laboratories, Acadia Pharmaceuticals, Bristol-Myers Squibb, Corcept Therapeutics, Cypress Bioscience, Cyberonics, Eli Lilly and Co, Entrepreneur’s Fund, Forest Laboratories, Inc, GlaxoSmithKline, i3 DLN, Janssen Pharmaceutica, Lundbeck, Otsuka America Pharmaceutical, Inc, Pfizer Pharmaceuticals, Quintiles Transnational, UCB Pharma, and Wyeth-Ayerst Laboratories; has been on the speakers bureau for Abbott Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, and Pfizer Pharmaceuticals; is a stockholder in Acadia Pharmaceuticals, Corcept Therapeutics, Cypress Bioscience, and NovaDel Pharma Inc; is on the board of directors of the American Foundation for Suicide Prevention, the American Psychiatric Institute for Research and Education, the George West Mental Health Foundation, NovaDel Pharma Inc, and the National Foundation for Mental Health; holds patents on a method and devices for transdermal delivery of lithium (US 6,375,990 B1) and on a method to estimate serotonin and norepinephrine transporter occupancy after drug treatment using patient or animal serum (provisional filing April 2001); and holds equity in Reevax, BMC-JR LLC, and CeNeRx.

No, I didn't make that up. As Ed Silverman wrote at Pharmalot, "It also raises a question - when he did find time to do anything else?"

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.

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.

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.

Paxil, Lies, and the Lying Researchers Who Tell Them

A bombshell has just appeared in the International Journal of Risk & Safety in Medicine. The subject of the paper is Paxil study 329, which examined the effects of the antidepressant paroxetine in adolescents. The study findings were published in the Journal of the American Academy of Child and Adolescent Psychiatry in 2001. These new findings show that I was wrong about Paxil Study 329. You know, the one that I said overstated the efficacy of Paxil and understated its risks. The one that I claimed was ghostwritten. Turns out that due to legal action, several documents were made available that shed more light on the study. The authors (Jureidini, McHenry, and Mansfield) of the new investigation have a few enlightening points. Let's look at the claims and you can then see how wrong I was, for which I sincerely apologize. The story is actually worse than I had imagined. Here's what I said then:

Article [quote from the study publication]: Paroxetine is generally well-tolerated and effective for major depression in adolescents (p. 762).

Data on effectiveness: On the primary outcome variables (Hamilton Rating Scale for Depression [HAM-D] mean change and HAM-D final score < 8 and/or improved by 50% or more), paroxetine was not statistically superior to placebo. On four of eight measures, paroxetine was superior to placebo. Note, however, that its superiority was always by a small to moderate (at best) margin. On the whole, the most accurate take is that paroxetine was either no better or slightly better than a placebo.

I went on to bemoan how the authors took differences either based on arbitrary cutoff scores or from measures that assessed something other than depression to make illegitimate claims that paroxetine was effective. Based upon newly available data from the study, here's what happened.

• The protocol for the study (i.e., the document laying out what was going to happen in the study) called for eight outcome measurements. To quote Jureidini et al: "There was no significant difference between the paroxetine and placebo groups on any of the eight pre-specified outcome measures." So I was wrong. Paxil was not better on 4 of 8 measures -- it was better on ZERO of eight measures. My sincerest apologies.
• Another quote from Jureidini and friends: "Overall four of the eight negative outcome measures specified in the protocol were replaced with four positive ones, many other negative measures having been tested and rejected along the way."

Let's break this thing down for a minute. The authors planned to look eight different ways for Paxil to beat placebo. They went zero for eight. So, rather than declaring defeat, the authors then went digging to find some way in which Paxil was better than a placebo. Devising various cutoff scores on various measures on which victory could be declared, as well as examining individual items from various measures rather than entire rating scales, the authors were able to grasp and pull out a couple of small victories. In the published version of the paper, there is no hint that such data dredging occurred. Change the endpoints until you find one that works out, then declare victory.

How About Safety?

I was incensed about the coverage of safety, particularly the magical writing that stated that a placebo can make you suicidal, but Paxil could not. I wrote:

It gets even more bizarre. Remember those 10 people who had serious adverse psychiatric events while taking paroxetine? Well, the researchers concluded that none of the adverse psychiatric events were caused by paroxetine. Interestingly, the one person who became “labile” [i.e., suicidal] on placebo – that event was attributed to placebo. In this magical study, a drug cannot make you suicidal but a placebo can. In a later document, Keller and colleagues said that “acute psychosocial stressors, medication noncompliance, and/or untreated comorbid disorders were judged by the investigators to account for the adverse effects in all 10 patients.” This sounds to me as if the investigators had concluded beforehand that paroxetine is incapable of making participants worse and they just had to drum up some other explanation as to why these serious events were occurring.

Turns out I missed a couple things. Based on looking at an internal document and doing some calculations, Jureidini et al. found that serious adverse events were significantly more likely to occur in patients taking paroxetine (12%) vs. placebo (2%). Likewise, adverse events requiring hospitalization were significantly disadvantageous to paroxetine (6.5% vs. 0%). Severe nervous system side effects -- same story (18% vs. 4.6%). The authors of Study 329 did not conduct analyses to see whether the aforementioned side effects occurred more commonly on drug vs. placebo.

Funny how they had time to dredge through every conceivable efficacy outcome but couldn't see whether the difference in severe adverse events was statistically significant.

One quote from the discussion section of the paper sums it all up:

There was no significant efficacy difference between paroxetine and placebo on the two primary outcomes or six secondary outcomes in the original protocol. At least 19 additional outcomes were tested. Study 329 was positive on 4 of 27 known outcomes (15%). There was a significantly higher rate of SAEs with paroxetine than with placebo. Consequently, study 329 was negative for efficacy and positive forharm.

But the authors concluded infamously that "Paroxetine is generally well-tolerated and effective for major depression in adolescents."

Enter Ghostwriters. Documentary evidence as shown on indicated that the first draft of the study was ghostwritten. This leaves two roles for the so-called academic authors of this paper:

• They were willing co-conspirators who committed scientific fraud.
• They were dupes, who dishonestly represented that they had a major role in the analysis of data and writing of the study, when in fact GSK operatives were working behind the scenes to manufacture these dubious results.

Remember, this study was published in 2001, and there has still been no apology for the fictional portrayal of its results, wherein a drug that was ineffective and unsafe was portrayed as safe and effective. Physicians who saw the authorship line likely thought "Gee, this is a who's who among academic child psychiatrists -- I can trust that they provided some oversight to make sure GSK didn't twist the results." But they were wrong.

By the way, Martin Keller, the lead "independent academic" author of this tragedy of a study said, when asked about what it means to be a key opinion leader in psychiatry:

You’re respected for being an honorable person and therefore when you give an opinion about something, people tend to listen and say – These individuals gave their opinions; it’s worth considering.

So is completely misrepresenting the data from a study "honorable"? Is Keller's opinion "worth considering?" As you know if you've read this blog for long, such behavior is, sadly, not a fluke occurrence. Many others who should be providing leadership are leading us on a race to the scientific and ethical bottom. What will Brown University, home of Keller, do? Universities don't seem to care at all about scientific fraud, provided that the perpetrators of bad science are bringing home the bacon.

Not one of the "key opinion leaders" who signed on as an author to this study has said, "Yep, I screwed up. I didn't see the data and I was a dupe." Nobody. Sure, I don't expect that every author of every publication can vouch for the data with 100% certainty. I understand that. But shouldn't the lead author be taking some accountability?

This is a Fluke (?) Some may be saying: "But this is just a fluke occurrence." Is it? I've seen much evidence that data are often selectively reported in a manner like this -- looks like (sadly) it takes a lawsuit for anyone to get a whiff of the bastardization of $science that passes for research these days. If GSK had not been sued, nobody would have ever known that the published data from Study 329 were negative. A reasonably educated person could see that the writeup of the study was a real pimp job -- lots of selling the product based on flimsy evidence, but nobody would have seen the extent of the fraud. Apparently lawyers need to police scientists because scientists are incapable of playing by some very basic rules of science.

See for Yourself. Documents upon which the latest Jureidini et al. paper are based can be found here. Happy digging.

Key Opinion Leaders, Osteoporosis, Vioxx, Psychiatry, Science, and Patients

Remember Richard Eastell? To summarize briefly, he is a professor at Sheffield University who was lead author on a publication that showed positive results for the osteoporosis drug Actonel. One problem: the data did not actually provide good news for Actonel. In a key graph in the published paper, 40% of patient data was missing. Now that's an interesting form of science: Just eliminate the pesky 40% of the data that don't go along with your hypothesis and POOF!, you get exactly the results you are looking for. An excellent writeup of the situation can be seen in Jennifer Washburn's excellent piece in Slate. Making the plot more interesting, Eastell did not have the raw data; Procter & Gamble's (Actonel's sponsor) statisticians were in charge of the analysis. Hence the missing 40% of the data, which helped to cast Actonel in a more positive light. Read more on the topic here. When all data are included, the analysis does not support Actonel's marketing points. Eastell signed off on the original (misleading) paper saying that he had seen all of the data, which was, of course not true.

I noted in October 2006 that Eastell was chairing a session on osteoporosis, one that charged a hefty registration fee. The website promoting the session at the time mentioned: "This course is suitable for pharmaceutical industry personnel from clinical through to marketing disciplines." I suppose that Eastell is a key opinion leader in his field. Being willing to put one's name on a paper where the key graph knocks out 40% of the data is a good step toward becoming an influential academic these days. I suppose Eastell could at least claim ignorance, since he was unfamiliar with the underlying data.

In psychiatry, Charles Nemeroff, a key opinion leader, put his name on a continuing medical education presentation in which the data don't match with the published article that was based on the same data set. In the CME presentation, the medication (risperidone) outperformed placebo, although the published report indicated that risperidone did not beat a placebo, and in the CME presentation, risperidone was claimed to improve sexual functioning, which was never mentioned in the published article.

Eastell and a colleague recently received a roughly $7.5 million grant. Good for them. I've got nothing against the guy personally; I just find it interesting that he is getting rewarded nicely despite the whole Actonel fiasco. And I've only described a wee bit of that strange saga. The Scientific Misconduct Blog has much, much more. Like the part where he told Blumsohn to stop bothering Procter & Gamble about the data because P & G was a good source of income for the university. I've got no problem with excellence being rewarded. Perhaps Eastell has done many excellent things. However, during the P &G/Actonel fiasco, Eastell was willing to let the sponsors push him around, even if science was being bastardized in the process. Their money meant more than good science. And if patients took Actonel thinking that it was more effective than it actually was, who cares -- they're not the ones providing the research funding, right?

Think about this for a second. Many people have been up in arms about the recently unveiled Vioxx ghostwriting scandal. For a fantastic take on the scandal, see Health Care Renewal or Hooked. Briefly, Merck and its associated medical writers wrote manuscripts that said nice things about Vioxx. Then academic authors/key opinion leaders were found to review the papers and stick their names on as lead authors. Mind you, "reviewing" the papers often meant simply meant making minimal edits, if even putting in that much effort. Did they see the data? They saw tables and figures provided by Merck, but did they see the raw data? In most cases, apparently not. Doesn't that make them information launderers? They take industry data, and clean it up with their academic reputation. Oh, Dr. So-and-So is at Sheffield or Emory or Harvard... -- he must have made sure that the sponsoring drug company is portraying the data accurately. A veneer of credibility. And an extra publication for the key opinion leader, which makes the KOL that much more important in the academic world where publication envy runs rampant.

This system is not exactly set up to benefit patient outcomes, is it?

Key Opinion Leader Is Unfairly Disparaged

Or so she said. I've written about key opinion leader, University of Cincinnati child psychiatrist Melissa DelBello a few times (here, here, and here). One key point was she was quoted as saying "Trust me. I don't make much" in regards to income received from AstraZeneca for giving favorable talks for its antipsychotic drug Seroquel. I had missed that in 2007, she claimed she was misquoted in an interesting piece on Inside Higher Ed:

[University of Cincinnati spokesperspon] Puff said that DelBello’s comment in May that she did not “make much” money from drug companies had actually come in response to the reporter’s question “about how much money she was given for making a single, individual presentation. Her comment was misrepresented and then repeated by Sen. Grassley.” Added DelBello: “I was and have been misquoted by the NYT.” (The Times reporter, Gardiner Harris, could not be reached Sunday to respond to the suggestion that he had misrepresented DelBello’s comment.)

Puff also said that “the implication of what Sen. Grassley said was that she was disingenuous in what she was paid. She has been completely open in disclosing her payments. She’s made complete disclosures to the university and its IRB. Furthermore, she’s made full disclosure to the Senate Finance Committee.... Additionally, Dr. DelBello has disclosed her funding at all speaking engagements and she’s disclosed in the patient consents of her studies.”

I wonder if she has made disclosures about her company (MSZ Associates) that Senator's Grassley's investigation claims was set up for "personal financial reasons"and well-funded by AstraZeneca. Also, does the above mean that DelBello disclosed that she has personally received hundreds of thousands of dollars from AstraZeneca and other sources in the consent forms for her studies? I have to admit I'm pretty skeptical about that, but I could be wrong. As far as full disclosure to the Senate, Grassley's most recent findings seem to contradict this claim. Hey, maybe Grassley is just making things up, so either DelBello is being unfairly persecuted or her story is simply not adding up.

Why am I making such a big deal about this? Well, such a gigantic hidden conflict of interest doesn't exactly engender my faith, and DelBello is a person who can take at least responsibility for the widespread treatment of children with antipsychotic medications. Due to her research findings that some claim support the use of antipsychotics in kids and her many marketing speeches for AstraZeneca and others, the landscape for badly behaving children is changing, and likely not for the better (1, 2, 3).

Pharmalot reports that the University of Cincinnati is unresponsive to his requests for comment. Perhaps they're going for the time-honored tradition of remaining in silence under the belief that this publicity cannot possibly last much longer.

Bipolar Child Key Opinion Leader: I Get Money

As reported on the Wall Street Journal Health Blog, Dr. Melissa DelBello's tight financial ties to AstraZeneca are again under scrutiny. This should come as no surprise to my readers, as I noted in March that, in 2003-2004, DelBello had been the recipient of $180,000 from AstraZeneca (makers of Seroquel). I gleaned this information from results of an investigation by Senator Charles Grassley. The WSJ Health Blog noted that Grassley's investigation has continued, revealing that:

DelBello, who also has received NIH grants, also reported $100,000 in outside income between 2005 and 2007. But when Grassley asked AstraZeneca directly, the total value of its payments to DelBello during those three years came to $238,000.

So she claimed initially that she received $100k from 2005-2007, but she actually pulled in $238k from a single company and who knows how much from other outside entities. In fact, it is clear that DelBello has received funding from several other corporate interests. To quote her disclosure from a continuing medical education exercise:

Dr. DelBello has disclosed the following relevant financial relationships: AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Pfizer: Consultant; AstraZeneca, GlaxoSmithKline, Pfizer: Speakers’ Bureau; and Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Johnson and Johnson, Pfizer, and Shire: Research Support Recipient.

But wait, there's more! According to Grassley's investigation, DelBello has also established a company for "personal financial purposes." The company is called MSZ Associates and AstraZeneca put $60,000 in the coffers of the company. The address of MSZ Associates, according to Grassley, is the University of Cincinnati Department of Psychiatry (where DelBello works).

Again, as I've said earlier, I don't know Dr. DelBello, but from this information, I do indeed feel comfortable nominating her for a Golden Goblet Award. For background, read here and here. PharmaGossip's interesting visual representation of the situation can be seen here.

This is how one sets out to become a key opinion leader. DelBello quite likely has a mortgage and bills to pay, but is this confluence of commercial and academic interests really the best we can do for our patients?

Being a key opinion leader has one pleasant side effect: You Gets Mad Money.

(Warning: Video contains adult language)

The Lingering Stain of Paxil Study 329

Neal Ryan has an editorial in this month's American Journal of Psychiatry. Dr. Ryan is a noted academic child psychiatrist who played a role in the infamous Paxil Study 329, which obfuscated its own findings that Paxil possessed little if any efficacy relative to a placebo and carried more risk than placebo in terms of suicidal thoughts/attempts, and aggressive behavior.

A summary of the excellent Panorama expose on the study included the following snippet:

Child psychiatrist Dr Neal Ryan of the University of Pittsburgh was paid by GSK as a co-author of Study 329.

In 2002 he also gave a talk on childhood depression at a medical conference sponsored by GSK.

He said that Seroxat could be a suitable treatment for children and later told Panorama reporter Shelley Jofre that it probably lowered rather than raised suicide rates.

In amongst the archive of emails in Malibu, Shelley was surprised to find that her own emails to Dr Ryan from 2002 asking questions about the safety of Seroxat had been forwarded to GSK asking for advice on how to respond to her.

She also found an email from a public relations executive working for GSK which said: "Originally we had planned to do extensive media relations surrounding this study until we actually viewed the results.

"Essentially the study did not really show it was effective in treating adolescent depression, which is not something we want to publicise."

But now Ryan has changed his tune. He writes in the latest American Journal of Psychiatry about a trial of fluoxetine (Prozac) in the treatment of children and adolescents with depression. In the piece, he begins with some background information:

Other, newer antidepressants have at most a single controlled trial showing efficacy in the treatment of major depression in youths, and thus far studies of several antidepressants have not shown statistical superiority to placebo in well-designed trials in this population

He cites one source (Bridge et al., 2007) in support of this statement. I checked his source and it is clear from the table (eTable 1 to be precise) in the source that the single trial showing superiority of drug over placebo is not the Paxil study he coauthored.

Ryan in 2001: Paroxetine is generally well-tolerated and effective for major depression in adolescents (p. 762). Yet he is now saying that antidepressants such as Paxil are not effective in treating depression.

Note that Dr. Ryan does not specifically retract his earlier claims about the efficacy of Paxil, but that his current statement does certainly contradict his prior writing about the wonders of Paxil. Well, to be fair, his statement from 2001 about the efficacy of paroxetine could very well have been ghostwritten, as we now know that the good majority of the paper was written by ghostwriters under the employ of GlaxoSmithKline.

And in the end of his current editorial, it is stated that:

Dr. Ryan has received research support from NIMH. He reports no other competing interests.

Did Dr. Ryan participate in Paxil Study 329 for free? I would guess that he indeed received funding from GSK for his efforts on the study, but perhaps I'm wrong. But that is actually a peripheral point.

The main point is that Ryan never disavowed the overstatement of efficacy or the minimization of risk that occurred in the published study report of Paxil 329 findings, yet now he pens an editorial in which he states that no antidepressants except Prozac possess any efficacy in treating child/adolescent depression. Either Paxil works or it does not work, and Dr. Ryan cannot have it both ways.

Still waiting for the first key opinion leader to admit frankly that the efficacy claims made in Paxil 329 were inaccurate...

Zyprexa and Key Opinion Leaders

Since the Zyprexa trial is ongoing in Alaska, I thought I should return to the wonderful world of Zyprexa. I encourage readers to follow the Zyprexa coverage at Furious Seasons, Pharmalot, and PharmaGossip. Today, I will discuss the link between key opinion leaders and the marketing of Zyprexa. To preface, a coveted Golden Goblet Nomination could be handed out to several individuals based on their involvement in Zyprexa marketing...

In March 2000, Zyprexa received FDA approval for treatment of manic episodes. One document laid out the multipronged marketing maneuvers that Lilly utilized to move Zyprexa shortly after its approval. Some of the details of this document have been well-covered in a terrific piece of investigative journalism at Furious Seasons. This post will provide some coverage of the link between Zyprexa and the key opinion leaders who helped popularize the drug across the nation.

Once approved for bipolar disorder, Lilly utilized several tactics to market Zyprexa for bipolar disorder, including a satellite conference beamed to about 6000 physicians, and 8000 treatment team members in 1000 facilities. The faculty providing this educational service included many of the big names in academic psychiatry, including Paul Keck, Jan Fawcett, Hagop Akiskal, and Alan Schatzberg.

Alan Schatzberg, you say? Yes, the same Alan Schatzberg who is set to become president of the American Psychiatric Association. Some have been less than pleased with his election as APA president, considering his background as a physician-marketer, a key opinion leader with large conflicts of interest. The same Alan Schatzberg who has been involved in marketing passing itself off as continuing medical education.

Lilly also bankrolled dinner meetings, anticipated to draw 150-400 physicians per sitting. Dr. Schatzberg was also listed as a speaker for such dinners. One mental health service provider was impressed enough with receiving such excellent medical education that you can find it on his CV.

In the document outlining Zypexa's big marketing launch, Paul Keck's name appears in the following contexts:

• Satellite symposium provider
• Trainer of "local speakers." I believe this means he would train local physicians in various markets to then discuss Zyprexa with their colleagues.
• Faculty for bipolar weekend symposia
• Faculty for audio conferences
  
• Faculty for a satellite CME workshop
• Faculty for "dissemination of Bipolar information to 30,000 customers"
• Faculty on a "closed symposium" resulting in a CME newsletter and a CME audiotape, both of which were mailed to 30,000 individuals
• Author of two journal supplement articles

Paul Keck was also a member of a task force chartered by the American Psychiatric Association that served to revise the organization's guidelines to provide a more favorable view of atypical antipsychotics (including Zyprexa) in the treatment of bipolar disorder. No conflict of interest there, eh?

Keck said in a 2002 interview that:

"Often," Keck said, "patients with bipolar disorder require complex treatment regimens to manage all phases of their illness, creating a compliance challenge for patients and a management challenge for clinicians. These studies suggest that physicians may be able to use olanzapine as a foundation to simplify patients’ treatment regimens, and the combination of olanzapine and fluoxetine could be an effective treatment choice

It is likely that Keck was not performing all of his "educational" functions for Lilly in exchange for lollipops. He was likely receiving a healthy dose of cold, hard cash. Yet in the article, nothing is written about his financial links to Lilly. Keck has also appeared in press releases saying nice things about Symbyax (fluoxetine/olanzapine combination).

To be fair, Keck has also stumped for Pfizer's Geodon in press releases. Oh, and he also said nice things about Abilify in a press release. I suppose that if one is going to be a true key opinion leader, a real mover and shaker, one should be prepared to say nice things about whatever new drug is released, since each new drug naturally represents an "important" treatment option. Keck, like Alan Schatzberg and Charles Nemeroff, is also currently listed as a member of the clinical advisory board for Neuroscience CME, a for-profit entity awash in drug industry money. Dr. Daniel Carlat has previously written that the "educational" content produced by this organization is biased, and I find that easy to believe. It's not hard to find examples of poorly done industry-funded CME. In fact, you might be interested in reading about a CME activity in which Nemeroff seems to have pulled data out of thin air.

In sum, the usual fun and games were in play when Zyprexa was initially being pushed for bipolar disorder. Some of the biggest names in psychiatry left their fingerprints all over the marketing of Zyprexa and one of these key opinion leaders recently won the presidential election for the American Psychiatric Association. I suppose, then, that American psychiatrists are generally either unaware of conflicts of interest or don't care about them.

The beautiful thing about being a key opinion leader is that one's name recognition is huge. Among psychiatrists, I bet that Schatzberg's name is better known than that of Bill Clinton, since Schatzberg's byline appears on journal supplements and CME so frequently. That can't hurt when running for president of the national professional organization. I will be very interested to see how Schatzberg handles questions about conflicts of interest and drug industry influence on his profession. Don't be expecting any major efforts at reform in the near future.