Eli Lilly CEO on “America’s Growing Innovation Gap”

In “America’s Growing Innovation Gap”, WSJ, July 9, 2010, Eli Lilly CEO John C. Lechleiter, Ph.D. writes that:

“…the most important elements are the seeds of innovation, which equate to talented people and their ideas.”

He then suggests these people are “highly skilled immigrants” abroad.

In my own circle of friends, I know American pharma industry cast-offs who are both brilliant and talented. One with dual MS degrees in mathematics and computer science from a major university, one a skilled bioinformaticist I've had teach my healthcare informatics students as guest lecturer, one a brilliant programmer who could be considered the grandfather of computer image manipulation, another with years of expertise in pharma knowledge discovery.

Then there's me – former Director of a Merck R&D support group and of The Merck Index - with degrees in medicine and post-doctoral specialization in biomedical informatics and information science, plus I'm an extra-class amateur radio licensee who understands complex technology at a level far beyond that of the usual pharmaceutical company worker.

Yet no donuts for us. In recent years the pharmaceutical industry won’t grant any of us the courtesy even of an interview.

However, in Mar. 2009 as I documented here, I did receive an email solicitation from Lilly that read as follows ("sic's" are mine):

“Your Help Is Requested for a Eli Lilly Career Opportunity! (sic) I am a member of the Staffing Team at Eli Lilly. I were referred to me (sic) as person who specializes in pharmaceutical based informatics. I wanted to reach out to me (sic), to see if you maybe able (sic) to recommend anyone that could qualify for the below position (sic)."

I was not exactly inspired by this solicitation, perhaps written by one of the "highly skilled immigrants" Lechleiter covets.

Nor was I inspired by the earlier solicitation I documented at my Jan. 2009 post "What, Me Worry? Lilly Fined Over Zyprexa, Should Be Fined For eRecruitment Inanity As Well?"

I suggest if Mr. Lechleiter wishes to close America’s purported "innovation gap", he spend some time away from the executive castle and perhaps review some resumes – and the job solicitations his company proffers – in his HR department.

A cause of the "innovation gap" may be leadership xenophilia, at the expense of the American born-and-raised scientists the pharma industry is so fond of discarding.

-- SS

Leaders of Discredited Financial Rating Agencies as Leaders of Health Care

This is the latest in our informal series on the cross-linkages between the thinking and leadership that lead to the global financial collapse/ great recession and that current in health care.  Last month, a US Senate sub-committee held hearings on the role of the rating agencies, actually for-profit corporations that evaluated securities, including derivatives, in the collapse. 

The Fundamentally Conflicted Rating Agencies

To briefly provide some background, these agencies were hired by the firms that created these securities to evaluate them.  Because the securities were complex, they were hard for investors to evaluate.  Investors had become used to using the rating agencies' evaluations as benchmarks for the quality and riskiness of complex securities.  Many did not seem to realize that the agencies themselves were for-profit corporations, or subsidiaries thereof, which made more money the more securities they rated.  The rating agencies gave many of their highest ratings (AAA) to securities that later failed.  (See an informal video discussion by corporate governance expert Robert A G Monks here.)

Some key quotes from the news coverage follow.

Former credit rating agency officials said on Friday that the quest for market share fueled a drive for short-term profits, sacrificing credit quality in the process.

Eric Kolchinsky, who was in charge of the Moody's (MCO.N) unit that rated subprime CDOs, or collateralized debt obligations, said that people 'across the financial food chain, from the mortgage broker to the CDO banker, were compensated based on quantity rather than quality,' according to testimony prepared for a Senate panel.

'The situation was no different at the rating agencies.'

from Reuters

Former Moody’s Investors Service and Standard & Poor’s employees said they were excluded from assessing mortgage bonds if they questioned Wall Street’s conclusions and that credit-rating companies focused on protecting business at the expense of accurate grading.

Richard Michalek, a former managing director in Moody’s structured products derivatives group, told the Senate Permanent Subcommittee on Investigations at a hearing today that managers said he was 'not welcome on deals' involving certain banks.

Eric Kolchinsky, who led the Moody’s group that rated collateralized debt obligations made up of mortgage bonds, said he was berated by his boss when the company lost business after implementing more conservative ratings.

S&P wrongly concluded that its increasing profits amid an inflated U.S. housing market was based on 'superior management skill and insight,' said Frank Raiter, a former managing director at the company. In reality, regulators had made the firm part of 'an oligopoly' by requiring investors to hold assets it rated, Raiter said.

per Bloomberg

The documents show, sometimes in excruciating detail, the conflicts of interest that many claim lie at the heart of the ratings business model and the concerns of employees about what was happening inside the companies well before the crisis broke.

One employee at Standard & Poor's, the world's largest rating agency, said its handling of awkward questions in the summer of 2007 made it 'sound like the Nixon White House'.

And,

As one Moody's managing director wrote to his superiors in 2007, the company's errors, made it look 'either incompetent at credit analysis, or like we sold our soul to the devil for revenue, or a little bit of both'.

per the Financial Times

The two companies targeted by these hearings were Moodys, and Standard & Poors (a subsidiary of McGraw-Hill Inc).

Overlaps with Health Care Leadership: Moody's Corporation

Perusal of the roster of the Moody's board of directors in 2008, per that year's proxy statement, reveals the following overlaps with health care leadership, of its 8 directors.

Connie Mack - is also on the boards of EXACT Sciences Corporation (a biotechnology company), and Genzyme.  He is the chair of the H. Lee Moffitt Cancer Center.

Henry A McKinnell Jr - was chairman of the board and CEO from 2001-06 of Pfizer Inc.

Basil L Anderson - is a member of the board of directors of Becton Dickinson.

Overlaps with Health Care Leadership: McGraw-Hill Inc

Via the company's 2008 proxy statement, of 12 directors:

Sir Winfried Bischoff - is a director of Eli Lilly and Company.

Linda Koch Lorimer - is Vice President and Secretary of Yale University, and a Director of Yale-New Haven Hospital.

Kurt L Schmoke - is a Trustee of the Howard Hughes Medical Institute

Sidney Taurel - was chairman and CEO of Eli Lilly and Company.

Summary

So, in summary, the 20 board members of one for-profit "ratings agency," and of the corporation of which the other major "ratings agency" was a subsidiary, served on the boards of 2 biotechnology corporations (EXACT Sciences Corporation and Genzyme), one medical device company (Becton-Dickinson), one pharmaceutical company (Eli Lilly) , 2 major academic medical centers (Moffitt Cancer Center and Yale-New Haven), and one medical research institution (Howard Hughes).  Two were recent former CEOs and chairmen of the boards of 2 of the world's largest pharmaceutical companies (Pfizer and Eli Lilly). 

Most of these health care organizations have been involved with cases we have discussed on Health Care Renewal (see links above).

Given the serious concerns about the conflicts of interest that became the core of these corporations' business models, and their central role in the global financial collapse, one has to wonder why so many of the directors who presided over them still have such influential positions in health care organizations?

As we have pointed out, as the world economy was driven to near ruin by "masters of the universe," some of the same also became leaders of academia and academic medicine in their spare time. Maybe this made sense 10 or 20 years ago, but why does it still make sense? On the other hand, now that we understand how bad the leadership of finance really was, it is a little easier to understand why the leadership of health care has become so bad. It seems reasonable to hypothesize that some of the problems of academia, and particularly the problems of medical academia, may have been at least enabled by leadership more used to working in an increasingly amoral marketplace than to upholding the academic mission. The failures of the leadership and governance of finance thus suggest we need to re-examine the leadership of health care.

Quintiles to More Heavily Directly Invest in the Drugs Which it Evaluates - But Not to Worry, Says an Expert?

The Associated Press just reported on the latest trend in commercially sponsored clinical research, direct investment by contract research organizations (CROs) in the development of specific drugs by particular pharmaceutical or biotechnology companies. Here is the background in the article:

Pharmaceutical companies previously did all their own research and testing and submitted the results to the Food and Drug Administration for approval to put a medication on the market.

Since the 1990s or so, Big Pharma has farmed out more and more of that testing to companies like Quintiles Transnational Corp., which grew quickly to meet the demand.

Now Quintiles is branching out...

Now Durham, N.C.-based Quintiles is the world's biggest contract research organization, and more than ever, it's using its deep pockets to entwine itself with the pharmaceutical companies, fronting them cash and services for a piece of the profits once a drug is approved.

Quintiles, which was created in 1982, upped the ante last month, saying it wants to invest even more in potential drugs as pharmaceutical companies grapple with the down economy. Quintiles is hoping its new investments will produce enormous payoffs in the future,....

Quintiles' decision to become more aggressive in taking investment risks comes at a time it's betting drug makers can use the resources it can offer, both cash and services.

'They're both currency for managing risk and having skin in the game,' said Ron Wooten, a Quintiles executive vice president who heads the company's capital investment group.

Controversy over creating the drug investment unit in 2000 was key in pushing Quintiles founder Dennis Gilling and several private-equity firms to buy out shareholders for $1.75 billion and take the company private again in 2003. Wall Street analysts complained they couldn't estimate what the drug investments were worth, prompting Gilling and others to decide the company's stock was undervalued.

The private company no longer publishes its profits. It claims revenues of about $3 billion a year. That's also about what Quintiles has invested in other drug companies.

Furthermore,

Quintiles appears to be uniquely positioned to both invest in and test potential medications. None of the half-dozen major shareholder-owned contract research organizations will have a drug-investment division after Wilmington, N.C.-based Pharmaceutical Product Development Inc. spins off its unit in a few months, Coldwell said.

The payoffs for the risk of developing a drug can be huge.

In 2002, Quintiles took a chance on Eli Lilly and Co.'s antidepressant Cymbalta. Quintiles said it invested $125 million in cash, then spent another $400 million on a sales force of more than 550 after the product launch. Cymbalta is now Lilly's second-biggest drug. Quintiles said it's brought in more than $700 million so far for a stream of royalties lasting to 2012.

Japan's Eisai Co. is hoping Quintiles' money and experience helps it double the number of potential treatments it can put through testing simultaneously

The article raised a concern that "the buffer between drug makers and testers are again blurred."

But not to worry.... Here is the response from Quintiles,

Wooten, the Quintiles executive, doesn't see his company's increased interest in bringing drugs to the market affecting its testing objectivity. Instead Quintiles is the outsider turning a hard eye on which pharmaceuticals will become profitable.

'It allows you to really get to the essence of the data that you're looking at instead of what you hope it says,' he said. There isn't 'the natural bias that you would have with your own babies.'

Furthermore, the AP reporter got reassurances from a noted academic expert in the area,

The FDA preserves the integrity of testing in a landscape already pockmarked with potential conflicts of interest that include company-sponsored academic research and investigators testing drugs while owning shares in companies that own the drug, said Kenneth Getz, a senior fellow at Tufts University's Center for the Study of Drug Development.

The FDA's view is that any company with a financial stake in a potential drug will face similar scrutiny from the agency.

'It's assumed,' FDA spokeswoman Karen Riley wrote in an e-mail, 'that drug/device/biologic companies who sponsor trials of pending products have a conflict because they will gain if the product is approved.'

Besides, pharmaceutical companies have navigated the tricky territory that comes with testing, Getz said. So have the companies like Quintiles that have taken on the outsourced work, he said.

'These potential conflicts of interest are ever-present, and the real question is how do companies manage these potential conflicts effectively,' he said. 'These are massive, massive companies that have thousands of staff that are not generally aware of a conflict of interest at a corporate level. They are paid to do a quality job that meets internal and regulatory guidelines or they are not going to keep their jobs.'

Here on Health Care Renewal, we have discussed how the conflicts of interest that are now pervasive in health care can adversely affect clinical care, teaching, and research.  We have looked at how clinical research sponsors, who have a vested interest in having the results favor the products and services they sell, may manipulate the design, implementation, analysis, and dissemination of research, and when all else fails, suppress unfavorable results.  We have also looked at problems with the ethics and quality of research done by contract research organizations, who are, after all, paid by companies again with vested interests in selling particular products or services.

Given all that, one may argue that having contract research organizations invest in particular drugs or devices which they are also evaluating through clinical research may not make things much worse.  However, at the least, it seems to me that it further obfuscates conflicts of interest that may lead to biased research results, dishonoring the patients who volunteered for the trials, and biasing the information on which patients and physicians make decisions.

Finally, I should note how Quintiles new investments in specific drugs was defended in the article.  The article quoted Quintiles executive vice president Ron Wooten suggesting that Quintiles might be able to be objective in making the original decision to invest in a drug. He conveniently did not address what might happen after the investment was made, when Quintiles was performing, analyzing, and reporting clinical research on a drug or device in which it had invested.

The article also quoted Kenneth Getz, the Senior Fellow at Tufts, who seemed unconcerned about the issue.  What the article did not mention is that the Tufts Center for the Study of Drug Development, at which Mr Getz is based,

receives unrestricted grants from pharmaceutical and biotechnology firms, as well as companies that provide related services to the research-based industry (e.g., contract research, consulting, and technology firms). These grants represent approximately 40% of Tufts CSDD’s operating expenses.

per the Center's web-site. Another page on the web-site lists Mr Getz's qualifications,

Kenneth A. Getz is a senior research fellow at the Tufts CSDD. Considered an expert on the investigative site and CRO markets, R& D management, ECT solutions adoption and clinical research volunteerism,....

Mr. Getz is the founder and chairman of CISCRP ....

He holds an MBA from the J.L. Kellogg Graduate School of Management at Northwestern University and a bachelor's degree, Phi Beta Kappa, from Brandeis University. Mr. Getz worked for over seven years in management consulting, where he assisted biopharmaceutical companies in planning and implementing drug development strategies. He is also the founder and former CEO of CenterWatch.

Note that Mr Getz seems to have no training in biomedical science, medicine, or health care.  Furthermore, CISCRP (the Center for Information and Study on Clinical Research Participation), has an advisory board (see their web-site here) that includes representatives of pharmaceutical companies (Vertex Pharmaceuticals, Biogen Idec, and Roche), and contract research organizations, (PPD Inc, and particularly, in this case, Quintiles). The vast list of the Center's "supporters" include a catalog of drug and biotechnology companies (including Abbott Vascular, Amgen, AstraZeneca, Biogen Idec, Daiichi Sankyo Pharmaceutical Development, Eli Lilly, Forest Laboratories, Genentech, Genzyme, GlaxoSmithKline, Janssen, Johnson and Johnson, Merck, Novo Nordisk, Novartis, Ortho-McNeil, Pfizer, Roche, Sankyo, Sanofi-Aventis, Serono, Shire, Takeda, and Wyeth), and contract research organizations, (including Covance, Parexel, PPDI, and notably again, Quintiles.)

So the other lesson from this bit of news is how the information the public, health care professionals, and policy makers  receive about health care policy is frequently shaped by people with horses in the race, but that such influences are rarely disclosed.  This article included an interview with a single apparently academic expert who provided reassurance that the conflicts of interest discussed in the article were not really so worrisome.  This expert, however, failed to disclose his own extensive, albeit somewhat indirect ties to a variety of corporations that might benefit from the conflicts discussed as the main topic of the article, including corporations that were directly involved in them (Quintiles and Eli Lilly).  Maybe because the reporter thought that the expert was unbiased, there was no attempt to find a contrasting opinion.

So I say again, again, again, health care professionals, policy  makers, and people in general need to be extremely skeptical of most of the apparently unbiased pronouncements made about medical and health care policy issues in the media.  It would be a small step toward a more transparent discussion if those who expressed opinions would also fully disclose in detail their relevant conflicts of interest.

Pharmacy Benefit Managers as Pharmaceutical Marketers

We posted a number of times about questionable practices Eli Lilly used to market its atypical anti-psychotic drug Zyprexa (olanzapine). A post from 2007, with links backward, is here, and our most recent post is here. The company remains entangled in litigation over its marketing of this drug. That litigation has lead to the release of numerous internal documents that provide quite a view of Lilly's marketing practices. Bloomberg continued its reporting on these documents, with its latest effort here via the Boston Globe, describing yet another surprising way this drug was sold:

A unit of CVS Caremark Corp. used its access to doctors to market Eli Lilly & Co.'s Zyprexa antipsychotic while it was under contract to bargain with the drug maker on behalf of health insurers, internal Lilly files disclosed in a multibillion-dollar lawsuit by insurers show.

The subsidiary of CVS, the largest US drugstore chain, touted Zyprexa starting in 2003, according to e-mails made public by lawyers suing Lilly for overpayment. CVS's AdvancePCS, a pharmacy benefit manager, or PBM, offered to send 120,000 letters to doctors promoting the drug, Lilly's top-seller with $4.7 billion in sales last year, according to a confidential 2004 proposal. The CVS unit said it would charge $5 per letter.

AdvancePCS, acquired by Woonsocket, R.I.-based CVS in 2007, said in the documents that the direct-mail campaign was 'designed to influence key prescribers' as part of a 'tactical plan for Zyprexa.'

Furthermore,

In AdvancePCS's 2004 pitch to Lilly offering to send out letters promoting Zyprexa, Kevin Aholt, the company's assistant vice president in charge of strategic alliances, said he could target physicians based 'on the most recent AdvancePCS claims data,' according to the unsealed documents.

Aholt also said that one of the 'key issues' in the market for antipsychotic drugs was finding ways to 'accelerate the growth of new patient starts,' according to the proposal.

Also,

Steven Fuchs, an official at the PBM, asked Lilly officials in an April 2004 e-mail whether he should include information about Zyprexa's ability to calm agitated patients in the next round of letters to doctors.

'Would a discussion of that be something you would want to include?' Fuchs asked, according to the document.

Lilly marketing executive Scott Dell responded in an e-mail that officials at the drug maker had discussed asking AdvancePCS to include material highlighting 'the new bipolar maintenance indication for Zyprexa.'

AdvancePCS was not the only pharmacy benefits manager (PBM) that offered to help sell Zyprexa.

CVS rival Express Scripts Inc. also sent out Zyprexa marketing letters, according to the unsealed documents and also isn't named as a defendant in the suits.

So here we have at least two pharmacy benefit managers (PBMs) offering to help market a particular drug, for money, of course. What is the problem here?

CVS's contracts with insurers and pensions meanwhile place it in an adversarial posture with Lilly, requiring it to use its buying power as leverage in drug-price negotiations.

'The problem is that PBMs are negotiating these hidden deals while at the same time telling employers that they represent them at the negotiating table,' said Gerry Purcell, a former PBM executive who advises companies on their drug plans. 'These documents will add fuel to the perception that the companies and the PBMs are in cahoots with each other.'

Also,

While PBMs negotiate on behalf of insurers, most states don't designate them as agents of the benefit plans, said Robert Garis, a pharmacy professor at Creighton University in Omaha who studies the industry. As a result, they aren't legally required to act only in the best interest of their clients, he said. Maine is one of a few states that have specified PBMs as fiduciaries, or agents, he noted.

'The companies have gotten around that by adding language to their contracts that exclude them from having to meet those fiduciary duties,' Garis said.

Apparently, in this case, one PBM said it disclosed its relationship to the drug company to physicians, but it is not clear whether it was disclosed to the health care insurers and managed care organizations which paid the PBM to reduce the costs of drugs:

CVS, which isn't a defendant in the Lilly suit, said that it tells doctors when it has 'financial relationships' with drug makers and that they are free to opt out of mailings.

'To engage in a point/counterpoint in a media outlet rather than in court would not be productive,' said Lilly spokeswoman Marni Lemons.

Lemons declined to answer specific queries about the CVS or Express Scripts letters, whether Lilly paid for the practice, or other questions raised by the unsealed documents....

CVS said in its e-mailed statement that it has 'no active educational programs' related to Zyprexa.

'CVS Caremark discloses to its PBM clients that it may have financial relationships with pharmaceutical manufacturers in connection with these educational programs,' said Christine Cramer, a spokeswoman for the chain. 'CVS Caremark's PBM clients are aware of these programs and have the opportunity to opt out.'

Maria Palumbo, a spokeswoman for Express Scripts, didn't respond to eight telephone and e-mail requests seeking comment.

CVS covers 82 million people, with a market share of 12 percent, and is the largest pharmacy benefit manager, according to Atlantic Information Services. Express Scripts, which covers 55 million people, is the fifth largest. PBMs process about 75 percent of the retail prescriptions written annually in the United States, according to the insurance plans.

The insurance plans sued the drug maker in 2005, contending it used researchers, pharmacy benefit managers, advocacy groups, and public agencies to promote Zyprexa.

Whether or not the PBMs disclosed their relationships to the pharmaceutical company to everyone who might be interested, it does seem that having PBMs who are supposed to help insurers and managed care organizations control drug costs be paid by pharmaceutical companies to market drugs is yet another new species of institutional conflict of interest. Like the many other conflicts of interest, individual and institutional, we have discussed, this one appears to be mutually advantageous to the parties involved. However, it could have adverse consequences for physicians, patients, and the health care system. If the organizations that are supposed to be controlling drug costs are also promoting expensive drugs, the likely result would be excess prescription of expensive drugs to patients who may not derive benefits from the drugs outweighing their harms.

This is another reminder how much we need more sunshine shone on the multitudinous conflicts of interest affecting just about every type of actor within the current US health care system.

A Handbook for Ghost-Writing

We posted a number of times about questionable practices Eli Lilly used to market its atypical anti-psychotic drug Zyprexa (olanzapine). A post from 2007, with links backward, is here, and our most recent post is here. The company remains entangled in litigation over its marketing of this drug. That litigation has lead to the release of numerous internal documents that provide quite a view of Lilly's marketing practices. In particular, a Bloomberg news article discussed how the company used ghost-writers:

Ensuring that medical journal articles presented Zyprexa study results in a positive light was one way for Lilly to reach its sales goal, company officials said in its plan, according to the documents.

To do that, Lilly officials hired ghostwriters to prepare submissions to journals such as Progress in Neurology and Psychiatry, according to the unsealed documents.

The article then described how Lilly marketers set up a ghost-written article.

'The paper for the Progress in Neurology and Psychiatry supplement has been completed and sent to the journal for peer review,' Kerrie Mitchell, an employee of the public relations agency Cohn & Wolfe, wrote in a Feb. 23, 2001, e-mail to Michael Sale, a Lilly marketing official. The message was among the unsealed files.

'We ‘ghost’ wrote this article and then worked with author Dr. Haddad to work up the final copy,' Mitchell said in the e- mail. Eric Litchfield, a spokesman for Cohn & Wolfe, didn’t immediately return a call seeking comment.

Peter Haddad, a researcher at Greater Manchester West Mental Health NHS Foundation Trust in the U.K., was listed as the article’s lead author. Haddad didn’t respond to requests for comment.

The global Lilly team approved a draft of Haddad’s ghost- written paper in 2000, according to the unsealed documents.

Lilly marketers, rather than articles' putative authors, sometimes exerted pressure to get ghost-written articles published. For example,

Lilly officials e-mailed journal editors to complain about delays in publishing favorable Zyprexa articles, according to the unsealed documents.

In one instance, Lilly employees contacted the Journal of Clinical Epidemiology about delays of an article criticizing a previously published piece linking Zyprexa, as well as the class of atypical antipsychotics, to diabetes.

After Suraja Roychowdhury, Lilly’s senior scientific communications coordinator, wrote to the journal in November 2002, its editor, Andre Knottnerus, replied in an e-mail that it was 'a bit strange to be contacted via the Lilly product team. Dr. Buse and coauthors can contact us directly next time.'

Knottnerus was referring to the manuscript’s lead author, John Buse, a former president of the American Diabetes Association. A copy of the Nov. 22, 2002, e-mail was included in the unsealed documents.

Patrizia Cavazzoni, a Lilly staffer who co-wrote the article, e-mailed Buse on Jan. 9, 2003, seeking permission to send a separate e-mail asking to expedite publication. She also asked Buse if he would prefer 'to send it in your name?'

It isn’t clear from the e-mail chain whether the e-mail was sent by Buse or Cavazzoni.

Finally, Lilly developed a handbook for ghost-writers:

To ensure that ghostwritten Zyprexa articles met Lilly’s standards, company officials issued a guide to preparing them, according to the unsealed files.

The guide, 'Medical Press: Pre-Launch Feature Outline,' was undated. It’s unclear from the documents which teams in Lilly’s top 10 markets for the drug received it.

The primer provided a how-to for writing articles, such as instructing the author to use Zyprexa’s generic name, olanzapine, instead of its brand moniker, according to the documents. Scientists in medical research traditionally refer to a drug’s chemical name.

The guide also offered tips on how to find authors by identifying a 'key opinion leader' and providing them either an outline of the article or a finished copy. Authors could include a study investigator, an advisory board member or “Lilly-friendly” doctor, according to the documents.

A sample article laid out how a Lilly employee may find a doctor to ghostwrite a submission that would 'prepare the market' for the launch of an intramuscular injectable version of the drug. It also offered an outline for the contents of the article, beginning with background on another drug, droperidol, which had been withdrawn from several countries.

The article, with the suggested title 'Filling the Droperidol Gap,' noted that an anti-anxiety drug could be used, before going on to say, 'more advanced IM treatments may soon be available to provide a superior alternative.' The article explained that injectable Zyprexa had just received approval from the FDA, and recounted its clinical trial history.

'The anticipated forthcoming availability of atypical antipsychotics in an IM formulation could be a major step forward in the treatment of acute agitation associated with schizophrenia,' the sample article concluded.

We addressed ghost-writing frequently when we started Health Care Renewal, and have returned to the topic periodically (see these more recent links, from 2008, here and here). The most striking feature of this newest case is the use of a "ghost-writers' handbook" denoting how systematized the practice has become. With each new case, it becomes clearer how common the practice may be. Since the parties involved seem ashamed enough of the practice to try to keep it well hidden, it may be that ghost-writing is even more common than we now realize.

Nonetheless, while the practice may be common, and mutually advantageous for ghost-writers, the academics who front for them, and the marketers who hire them all, as we and others have said before, ghost-writing is dangerous to health. It deludes physicians and patients into thinking health care products are more beneficial and less risky than they really are. Ghost-writing also undermines science by shifting the agenda away from interesting and important questions to questions whose answers may mainly benefit vested interests. Finally, on a personal note, ghost-writing demoralizes honest academics who must run their own studies, write their own papers, and manage the logistics of paper submission in competition with fake authors backed by corporate money and corporate staff. Scientists and academics who allow and front for ghost-writers ought to be ashamed of themselves.

See also comments in the Clinical Psychology and Psychiatry blog, and discussion of some of the other recent revelations about Zyprexa marketing in the Hooked: Ethics, Medicine and Pharma blog.

ADDENDUM (14 June, 2009) - Also see comments by Prof Margaret Soltan on the University Diary blog on the "Stockholm Syndrome" as manifested by "key opinion leaders" in the pay of health care corporations.

ADDENDUM (15 June, 2009) - Furthermore, see comments by Dr Howard Brody in the Hooked: Ethics, Medicine and Pharma Blog.

Lilly: "I were referred to me as person who specializes in pharmaceutical based informatics and wanted to reach out to me."

At "What, Me Worry? Lilly Fined Over Zyprexa, Should Be Fined For eRecruitment Inanity As Well?", I wrote about a very bizarre eRecruiting message I received from Eli Lilly:

In just about the most bizarre and inane recruiting email I think I've ever received, this unsolicited gem came in to my professional email account. This is at least the second time I received this identical message in the past few weeks.

It began with "Dear MD." Click on the above link to see that solicitation.

I didn't think it could get much worse than that.

I was wrong.

This just in, exactly as received (emphases mine):

From: Hank Gehron
Sent: Tue, 3 Mar 2009 7:45 am
Subject: Your Help Is Requested for a Eli Lilly Career Opportunity! (Discovery Informatics Director at Indianapolis)

I am a member of the Staffing Team at Eli Lilly. I were referred to me as person who specializes in pharmaceutical based informatics. I wanted to reach out to me, to see if you maybe able to recommend anyone that could qualify for the below position.

[Perhaps I should recommend my grade school English teacher to go over this solicitation with a big red marking pencil? - ed.]

For more than 130 years, Eli Lilly and Company has been dedicated to meeting the health care needs of people in the United States and around the world. We address these needs primarily by developing innovative medicines-investing a higher percentage of our sales in research and development than any other major pharmaceutical company. If you are interested in being considered for employment with a "Best in Class" Pharmaceutical company, please review the following opportunity.

Please feel free to call me with any questions; or perhaps you may know of someone that could qualify.

Your consideration is most appreciated.

Hank Gehron, MBA, SPHR
Lilly Talent Acquisition Team / RightThing Recruiting Process Outsourcing
work. 610-263-3030 Ext. 4450, Country Code 001
blackberry. 610-836-1856
hank.gehron@rightthinginc.com

Then there are the "requirements":

MINIMUM REQUIREMENTS:
M.S. or Ph.D. in Biology, Chemistry, or related Computational sciences
Minimum of 8-10 years experience in biotech or pharma industry
Minimum of 3-5 years managing/leading Informatics teams
Strong understanding of genomic, proteomic, expression, and imaging platforms.
Experience in the specifications, design, development, and deployment of bioinformatics, chemo-informatics, and translational informatics tools and analysis to support research portfolio.

Note no call for formal medical or medical informatics training, as this position is not really "Discovery Informatics" (which would encompass medical informatics), it is primarily bioinformatics or "gene stuff." I commented on that field at "Has Bioinformatics Hit a Hard Wall of Stagnation?" here.

I will not comment further, only asking a simple question:

Is this a company you would want to work for or that inspires confidence in its ability to produce safe medicines?

What? Me worry about talking good with grammar?

-- SS

Who Supports Fibromyalgia Patient Advocacy?

The Associated Press just published a story on the marketing of drugs for fibromyalgia, which provided a window into relationships among pharmaceutical companies and not-for-profit disease advocacy groups. One example was the National Fibromyalgia Association:

The drug industry's grants also help fill out the budgets of nonprofit disease advocacy groups, which pay for educational programs and patient outreach and also fund some research.

'If we have a situation where we don't have that funding, medical education is going to come to a screeching halt, and it will impact the kind of care that patients will get,' said Lynne Matallana, president of the National Fibromyalgia Association.

Matallana founded the group in 1997 after she was diagnosed with fibromyalgia. A former advertising executive, Matallana said she visited 37 doctors before learning there was a name for the crushing pain she felt all over her body.

A decade later, her patient advocacy group is a $1.5 million-a-year operation that has successfully lobbied Congress for more research funding for fibromyalgia. Forty percent of the group's budget comes from corporate donations, such as the funds distributed by Pfizer and Eli Lilly.

Pfizer gave $2.2 million and Lilly gave $3.9 million in grants and donations related to fibromyalgia in the first three quarters of last year, the AP found. Those funds represented 4 percent of Pfizer's giving and about 9 percent of Eli Lilly's.

Another example was the National Fibromyalgia Research Association:

Dr. Daniel Clauw of the University of Michigan said pharmaceutical industry market research shows roughly half are undiagnosed. People with fibromyalgia experience widespread muscle pain and other symptoms including fatigue, headache and depression.

Research by the University of Michigan's Clauw suggests people with fibromyalgia experience pain differently because of abnormalities in their nervous system. Brain scans show unusual activity when the patients experience even minor pain, though there is no abnormality common to all.

Clauw's work, however, illustrates the knotty issues of drug company funding. He has done paid consulting work for the drugmakers, and he's received research funding from the National Fibromyalgia Research Association, which receives money from the drugmakers.

By the way, the National Fibromyalgia Association's list of sponsors includes quite a few pharmaceutical companies in addition to Pfizer and Lilly:

Acorda Therapeutics
Cause Marketing, LLC
Citrucel
Cuddle Ewe
Eli Lilly
Fibronol
Forest Laboratories, Inc.
Ortho McNeil Pharmaceutical, Inc.
Pacific Life
Pfizer
Wyeth

The National Fibromyalgia Research Association's web-site is not so forthcoming, although I did find an acknowledgement that Lilly supported one NRFA conference in 2007 in the amount of $46,500.

This case illustrates the willingness of pharmaceutical companies (and likely other health care corporations) to support what appear to be grass-roots, not-for-profit disease advocacy groups when doing so coincides with corporate marketing objectives. Such "astroturf" organizations may help raise the profile of diseases for which the corporations market products, thus also helping to increase the market for these products, and may help further corporate health policy objectives.

With health care in flux due to new leadership in the US, and the global financial meltdown, look for stealth marketing and stealth health policy advocacy to increase.

As I have said before, I do not have a problem with pharmaceutical and other health care corporations marketing their products, and expressing their views on policy. I do have a problem with corporate marketing or policy advocacy is disguised as grass-roots, not-for-profit education and advocacy.

What, Me Worry? Lilly Fined Over Zyprexa, Should Be Fined For eRecruitment Inanity As Well?

In a story of a type all too familiar to HC Renewal readers, Eli Lilly & Co. on Thursday reached a deal to pay $1.4 billion and plead guilty to a federal misdemeanor charge over promoting an antipsychotic drug to treat dementia when it wasn't approved to do so. This involved promotion for use in the elderly including nursing home patients. "5 at 5" (for "5 mg at 5 PM to keep the sundowning at bay") was the sales pitch.

Lilly will take a reputational hit as a result, although like the Ford Pinto (a.k.a. "the barbecue that seats four") this minor cost of doing business (and the patient harm done) is, in the calculus of modern business, outweighed by the margins they attained for this activity.

Zyprexa's brought in more than $37 billion in sales for Eli Lilly since its U.S. approval in 1996, according to calculations made by The Wall Street Journal.

Here's my take on this from an entirely different angle. Perhaps the following email helps explain why the company lacked people on board who might have prevented this debacle.

In just about the most bizarre and inane recruiting email I think I've ever received, this unsolicited gem came in to my professional email account. This is at least the second time I received this identical message in the past few weeks:

To: (MedInformaticsMD)
From: Candidate Care [candidatecare@rightthinginc.com]
Date: 01/16/2009 06:34AM
Subject: Job Opportunity - Lilly

Dear MD,

I am a member of the Staffing Team at Lilly and I am writing to express my interest in your background and skills in regards to a position with our company.

At Lilly , we are looking for candidates who meet a specific and unique skill set. I feel that you may be this type of candidate and would like to discuss this opportunity with you further, and I encourage you to visit our website at https://jobs.lilly.com/index.cfm for more information. Lilly offers very competitive salary and benefit packages, commensurate with skills and experience.

Once you are at this website please select the category and what type of work you might be interested in. You can then select the position of interest and review the specific information about your potential new career

Applying online for this position would be a great first step. Shortly after you apply, someone from our staffing team will contact you to discuss next steps and provide you with more information.

Thank you for your time. I will monitor our database for your submittal and ensure you are contacted soon after.

Sincerely,

Lilly , Talent Acquisition Team

Please do not reply to this email

Problems I see:

1. Dear "MD"

Dear MD? How so very personalized and suggestive that this company values people. Perhaps, as in the recent U.S presidential election, it could simply address potential candidates as "that one?"

2. "I am a member of the Staffing Team at Lilly and I am writing to express my interest in your background and skills in regards to a position with our company"

"I" am a member? Who are you? What is your name? Are you with RightThingInc.Com (apparently some sort of eRecruitment outsourcing company -ed.) or Lilly? What do you mean by "A position?"

I'm listening, but ...

3. "At Lilly , we are looking for candidates who meet a specific and unique skill set. I feel that you may be this type of candidate and would like to discuss this opportunity with you further."

What specific and unique skill set? What "opportunity?" The link that was sent seems to be some sort of tracked hyperlink that merely sends me to Lilly's general eRecruiting site and search tools. If you mouse over the deceptive "https://jobs.lilly.com/index.cfm" hyperlink in the email it appears to contain some type of unmentioned, embedded tracking data for purposes unknown:

http://www.netrecruit.net/cgi-bin/CloakTrkr.pl?_siteGuid=spartner
&_smhid=2000961039010&_isa=Recruiter&_isaID=69481630
&oemID=RTI_1084&_redirencoded=https%3A%2F%2Fjobs.lilly.com
%2Findex.cfm&_txt=https%3A%2F%2Fjobs.lilly.com%2Findex.cfm

4. "Once you are at this website please select the category and what type of work you might be interested in. You can then select the position of interest and review the specific information about your potential new career."

Select "the" position of interest? The position of interest to whom? Them, or me? Is this a guessing game of some type? Find the hidden treasure? What the hell are they talking about? Did the person who wrote this speak English? Did they have a brain?

5. "Applying online for this position would be a great first step. Shortly after you apply, someone from our staffing team will contact you to discuss next steps ..."

Oh, really? How about if I apply for CEO? For Janitor? (or, how about Chief Corporate Honesty Officer?)

6. "Thank you for your time. I will monitor our database for your submittal and ensure you are contacted soon after." -- Lilly, Talent Acquisition Team

And who, exactly, are you, Mr. or Ms. T. A. Team? Perhaps your name is "HAL?"

7. "Please do not reply to this email"

Consider this post my reply.

HAL, will I also have to take some moronic online personality assessment test? And by the way, could you please open the pod bay doors?

Seriously, I've been involved in recruitment and hiring in both industry (hospital, pharma) and academia. This Lilly email has truly hit a new low for inanity, misuse of information technology, and more seriously the utter destruction of my ability to take a company that would issue such a message, or hire a contractor who did so, seriously.

I'm sure many smart and competent people of integrity would feel likewise.

It's likely hard to get good talent to prevent debacles over drugs when you present your company to the world in this manner.

What, me worry? Zyprexa is good for 'dem gorked out old fogies!

Additional thought: speaking of talent management, was anyone dismissed over the push to market Zyprexa for off-label use in dementia? If not, why not?

-- SS

BLOGSCAN - Duplicate Publication about an SSRI

On the Clinical Psychology and Psychiatry Blog, the anonymous blogger described an interesting example of apparent dual publication on a selective serotonin reuptake inhibitor (SSRI) anti-depressant drug, duloxetine (Cymbalta, manufactured by Eli Lilly). Important aspects of the story include how both articles draw conclusions that go well beyond the (same) data in their enthusiasm for the drug in question, and how the second article incorporated an author not found in the first, an author who also happened to be the co-editor in chief of the journal in which the second article appeared, and the leader of an important medical society. This author has been the subject of previous posts (like this one), on Health Care Renewal.

More Questions About Conflicts of Interest and "Surviving Sepsis"

Two years ago, we posted about questions whether the "Surviving Sepsis" campaign was driven by marketing as well as science. Then, we discussed a commentary in the New England Journal of Medicine which asserted that the campaign was part of an effort by Eli Lilly & Co to market Xigris (recombinant human activated protein C, or rhAPC, also known as drotrecogin alfa [activated]) for the treatment of sepsis.(1)

The Wall Street Journal just published an article questioning another aspect of that campaign. In 2001 a clinical trial in the New England Journal of Medicine by Rivers et al reported favorable results for early goal-directed therapy in the treatment of sepsis.(2) This therapy incorporated continuous monitoring of oxygen in the blood using a special central venous catheter capable of measuring oxygen saturation. The WSJ article first raised concerns that some of the patients initially entered into the study were excluded after randomization.

The medical-journal article analyzed 263. But it also said that 288 patients were 'evaluated,' of whom 25 'were excluded or did not consent to participate.'

Dr. Rivers, in an April interview describing how he proceeded, said 'all 288 are randomized' -- that is, placed into either the standard-therapy group or the other group -- 'and then some are excluded because they're not considered severe septic shock.'

But once patients are randomly placed in a group, they must be included in a final analysis, according to a fundamental principle of medical research. Twenty-five were not, the medical-journal article makes clear.

Further muddying the waters, Dr. Rivers, despite having said all 288 patients were 'randomized," stated in a later email that 'there were absolutely no patients pulled out before the analysis.'

The result appears to be a lack of clarity about exactly how this seminal study was done.

Hospital statisticians who worked on it had concerns about the data and recalculated the results with all 288 patients, according to people familiar with the events. When they did, these people say, the death-rate gap wasn't statistically significant.

Statisticians were especially concerned when they noticed that a relatively high proportion of the other 25 -- those not included in the final analysis -- were either conventional-therapy patients who survived or patients on aggressive therapy who died, say the people familiar with the events.

In 2005, a medical resident at Henry Ford doing follow-up research complained to senior hospital officials about the data in Dr. Rivers's study. The hospital convened a panel of inquiry, which concluded the issues had been satisfactorily resolved, hospital officials say.

The panel did a 'thorough investigation' and 'unanimously supported the conclusions,' the hospital said, adding that Dr. Rivers is 'an outstanding clinical investigator whom we support.'

The hospital declined to make the panel's report available. The medical resident who complained, Michael Donnino, declined to discuss the issue of the other 25 patients not included in the final analysis.

Dr. Rivers said that 'randomization was valid,' that 'all patients enrolled in the [early goal-directed therapy] study were appropriately selected, randomized and examined statistically,' and that 'there are no scientific integrity issues in the study.'

I should note that ideally randomized controlled trials should account for all patients randomized, and attribute their results to the group in which they were randomized, even if they did not complete the treatment to which they were randomized. Eliminating patients after randomization could bias the results of analysis, especially if patients particularly likely to have good or bad outcomes were selectively eliminated from one group or the other. The WSJ article raises questions about the occurrence of such bias, but does not prove it occurred.

Further complicating things, the WSJ article suggested that the authors of the article also had undisclosed conflicts of interest.

At the time the study at Henry Ford Hospital was published, in late 2001, the hospital was the owner of patents on the catheter used in the new treatment. Dr. Rivers had transferred the rights to the institution.

The New England Journal of Medicine didn't mention the patents when publishing the study. According to its editor, its policy at the time was to ask only whether an investigator had financial ties to companies involved, and Dr. Rivers said, correctly, that he had none.

Since the publication, catheter maker Edwards Lifesciences has made various payments to Dr. Rivers and his hospital. Such arrangements aren't unusual in medicine, but their existence can raise doubts about findings.

Dr. Rivers and the hospital over the years have received at least $404,000 from Edwards, the Irvine, Calif., company says.

For instance, Edwards paid $150,000 between 2001 and 2003 to Henry Ford Hospital for what Edwards terms 'nonexclusive patent rights [and] ongoing research' into blood oxygen and the mechanism of shock. Dr. Rivers, in an interview, described this as 'money I've gotten from the catheter...all for research.'

In addition, Edwards said, it has paid Dr. Rivers $158,000 to make speeches about his research, $20,000 to reimburse him for patent legal fees, $36,000 in reimbursed expenses and $40,000 in consulting fees.

Edwards Lifesciences said medical evidence has 'demonstrated that early goal-directed therapy yields significant reductions in sepsis-related mortality, lower organ failure rates and/or reduced health-care costs, particularly due to reduced stays.' In recent articles he has written, Dr. Rivers has disclosed receiving support from Edwards.

Also, Edwards Lifesciences was, along with Eli Lilly, a major sponsor of the Surviving Sepsis campaign.

In 2002, critical-care doctors from several specialties joined together to recommend treatments, calling themselves the Surviving Sepsis Campaign. Leading it were R. Phillip Dellinger of Cooper University Hospital in Camden, N.J., and Mitchell M. Levy of Brown University Medical School. Both, plus four others in the group, received consulting fees, honoraria or research-grant support from catheter maker Edwards.

Edwards helped pay for overseas meetings of the group in 2002 and 2004, which cost $861,000 in all. Surviving Sepsis endorsed Dr. Rivers's protocol as well as a drug made by another funder of the conferences, Eli Lilly & Co. Edwards said such support is 'routinely given to advance science and treatments for the benefit of patients.'

Finally, Dr Rivers also has also recently disclosed that he has been receiving money from Eli Lilly, for example, in a 2006 article, "Dr. Rivers has done consultant work for Biosite, Inc., Chiron, the Lilly Corporation, and Edwards Lifesciences over the last year."(3)

So, for an interval summary, recent guidelines promulgated by the "Surviving Sepsis" campaign include fairly enthusiastic endorsements for use of Xigris, made by Eli Lilly & Co, and early goal directed therapy, which requires use of a specific catheter made by Edwards Lifesciences (and other companies). These guidelines were based on research sponsored by these two companies which the guidelines touted as more definitive than it now appears to be. Furthermore, there is a web of financial links, that now appears increasingly complex, tying together these two companies, some researchers involved in these studies, their institutions, and the guideline writing process. These apparent conflicts of interest have raised questions about the integrity of the research on which the guidelines were based, and bias influencing the writing and deployment of the guidelines.

So it is becoming more difficult to determine the extent that marketing considerations influenced the "Surviving Sepsis" campaign, and some of the medical research on which its guidelines were based. Thus, the issue of how best to manage sepsis, already a complex one, now becomes more complex and less clear.

The larger lessons, again, are that there is a growing and ever more pervasive web of financial ties among academic medicine and commercial firms that make drugs and devices and provide various health care services. The resulting conflicts of interest suggest patients, physicians and policy-makers should be ever more skeptical about seemingly authoritative medical research, and medical education, practice guidelines, and health care policy based on this research.

To make better decisions for individual patients, and better policies for populations, people, patients, physicians and policy-makers at least need clearer and more detailed information about all conflicts that may affect the evidence and opinions that influence their decisions. But might it not be simpler and ultimately better for people, patients, physicians and policy-makers to eliminate some of these conflicts so that we can begin to believe that researchers and academics are paid only to take care of patients, and create and disseminate new knowledge?


References

1. Eichacker PQ, Natanson C, Danner RL. Surviving sepsis - practice guidelines, marketing campaigns, and Eli Lilly. N Engl J Med 2006; 335: 1640-1642. Link here.

2. Rivers E, Nguyen B, Havstad S et al for the Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-1377. Link here.

3. Rivers EP. Early goal-directed therapy in severe sepsis and septic shock: converting science to reality. Chest 2006;129:217-218. Link here.

Another Former "Dr Drug Rep" Outs Himself

I found this a little belatedly, but then again, it is from a slightly obscure source (at least, if one lives on the East Coast of the US).

The Willamette Weekly ran a profile of Dr Erick Turner, the author of a systematic review that showed incorporating the results of unpublished trials of selective serotonin reuptake inhibitor (SSRI) anti-depressants into the review produces much less optimistic results about these drugs than simply attending to the published trials. [Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008; 358: 252-60. Link here.] What is notable in the Willamette Weekly article is the account of how Dr Turner was once also a "Dr Drug Rep." (see our post here, and the Carlat Psychiatry Blog, written by the original former "Dr Drug Rep," Dr Daniel Carlat, here.)

... for 18 months, Turner pimped for antidepressants. He wouldn’t put it that way, of course, as many doctors do the same thing. But starting in 2004, Turner, who is the medical director of the Mood Disorders Program at the Portland VA and has worked at the Food and Drug Administration and the National Institute of Mental Health, became a speaker for Eli Lilly, one of the world’s largest pharmaceutical companies.

It’s not unusual in pharmaceutical marketing for doctors to be hired as 'consultants'—or members of a company’s 'speakers' bureau' in industry parlance—and then hit the road doing 'doctor talks.' These are typically lunches or dinners where area M.D.s are invited by a company to eat and drink while listening to a respected physician describe the benefits of a particular drug.

Lilly approached Turner around the time the FDA was set to approve a new Lilly antidepressant named Cymbalta. He was an especially good catch for the company because, in addition to his academic appointment at OHSU, Turner had spent seven years as a researcher at the prestigious National Institute of Mental Health and another three years as a clinical trials reviewer at the FDA.

'They’re using your reputation and political capital, as it were, as sort of a frontman for the drug,' says Turner, 54.

After training in Indianapolis in the summer of 2004, Lilly sent Turner out into the field in the Northwest, receiving anywhere from $500 to $750 per talk. He says he did about 12 talks for Lilly over the next 18 months.

He says his motivation wasn’t so much the money—he netted less than $10,000—as it was his desire to keep up his reputation as an expert on clinical trials.

Dr Turner discussed the positive incentives to do drug company talks.

'In the beginning, I think I got narcissistic gratification,' he says. 'They fly you somewhere else in the country and pick you up in a limo, and you stay in a nice hotel you could never afford otherwise.'

But Dr Turner soon realized that his talks were really not under his own control.

Turner found he could say only what Lilly allowed him to say. He could use only Lilly’s overhead slides of results from clinical trials of the drug. He couldn’t offer his own expertise as a researcher and former FDA reviewer to his fellow doctors.

'I began to feel straitjacketed,' he says.

Those feelings inspired Dr Turner to rebel, and to gather the data that lead to his NEJM article.

These new antidepressants—which critics argued had turned America into a culture of the quick fix and that proponents praised as lifesavers—didn’t perform very well. Turner knew this. And he decided in 2004, at the very same time he was taking money from Lilly, that it was time to start telling the truth.

'I guess you could say I bit the hand that fed,' says Turner of his revelation.

Turner quit doing doctor talks for the pharmaceutical industry in 2005, convinced he needed to make his case more strongly by collecting reports of pre-approval clinical trials for antidepressants that had not been published.

Note that Dr Turner's account of his career as a pharmaceutical company paid lecturer parallels the account of Dr Daniel Carlat in his "Dr Drug Rep" article, even though the two worked for two different companies.

Both were seduced by their treatment as minor VIPs; initially thought they were selected because of their expertise; and eventually discovered that they were only supposed to deliver the content that the drug company marketers dictated, and specifically could only show the slides that the companies' marketers had prepared for their speakers.

These are only two case reports, they both strongly suggest that physicians who give "drug talks" may be helping companies market their products, rather than imparting their professional wisdom or scientific expertise. Such talks are sales talks, not medical education. Those physicians who give them, and those physicians who attend them, should not pretend otherwise.

Hat tip to Ed Silverman on the PharmaLot blog.

Everything that Rises Must Converge: University of Texas High Living Executives and Eli Lilly's Marketing of Zyprexa

Recently we posted about some dubious practices at the University of Texas Southwestern Medical Center that seemed to contradict this proud academic medical institution's mission. First, there was the case of the "A-list" of local notables who were to have special access, including enhanced access to physicians (see posts here and here). Then, there was the report of how medical center executives seemed to be living the high life funded by charitable donors (see post here).

Also, more than a year ago, we posted about how Eli Lilly and Co. was alleged to have marketed its atypical anti-psychotic Zyprexa (olanzapine) to minimize its major side-effects, including frequent weight gain and the development of diabetes, and how the company was accused of marketing the drug "off-label" for medical problems and in situations for which the drug had not been approved by the US Food and Drug Administration. Since this story has since got a lot of coverage in the media and blogs, we have not returned to it for a while.

Now I have appeared to be guilty of a non sequitur. What is the possible connection between these two issues, other than they both seem to involve questionable decisions by leaders of large health care organizations?

Just wait...

Many media outlets have reported how Eli Lilly is under fire for its marketing of Zyprexa. Last month the NY Times reported on a memo that suggested the company's incoming president "appears to have encouraged Lilly to promote its schizophrenia medicine Zyprexa for a use not approved by federal drug regulators." That article noted that the company is also "under federal criminal investigation for the way it promoted Zyprexa and played down the drug's risks to doctors." Many media outlets reported late last month that the company settled a lawsuit by the state of Alaska that again charged that the company minimized Zyprexa's side-effects (e.g., see the Wall Street Journal here.)

The Wall Street Journal just reported that one large Eli Lilly shareholder was increasingly discontented by the company's current management, presumably at least in part due to how it marketed Zyprexa. Now read closely, and you will see that my hands never leave my arms...

California's public-employee pension fund plans to withhold votes for three Eli Lilly & Co. directors up for re-election next month, citing a lagging stock price and poor corporate governance.

The California Public Employees' Retirement System, or Calpers, said Thursday it will withhold votes for John Lechleiter, a long-time Lilly executive who is set to become chief executive next week. He has been on the drug maker's board since 2005.

In addition, Calpers will withhold votes for directors Alfred Gilman, provost at University of Texas Southwestern Medical Center in Dallas; and Karen Horn, a retired executive with Marsh Inc. Mr. Gilman has been a Lilly director since 1995 and Ms. Horn has been director since 1987.

'It was on their watch that Eli Lilly experienced severe stock underperformance, poor corporate governance practices, and was unresponsive to shareowners,' Russell Read, Calpers' chief investment officer, said in a press release.

Lilly said in a written statement it disagreed with Calpers' assessment of the three directors as unsupportive of and unresponsive to shareholders.

Gotcha...

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.

This seems like a good illustration of how conflicts of interest affecting health care leaders may not be good for any of the organizations to which these leaders simultaneously owe allegiance. An academic medical institutional leader who is also a director of a public for-profit company may not be a particularly good guardian of share-holders' interests. A director of a for-profit health care corporation who also is the leader of an academic medical institution may not be a particularly good guardian of that institution's values.

Of course, conflicts like these benefit the conflicted individual, who gets power and prestige from both allegiances, plus, of course, a lot of money. (Note that according to Eli Lilly's 2008 proxy statement, Dr Gilman got $281,448 total compensation in 2007 to serve as director. In addition, Dr Gilman now owns 17,159 shares of Eli Lilly stock, currently valued at $51.76 per share, see Google Finance, for a total value of $888,150.) The conflicted individual in such a situation might well feel himself or herself to be among the power elite. And the conflicted individual in a case like this might be in a good position to help out his or her buddies in both the corporate and academic medical hierarchies.

But in my humble opinion, such conflicted leaders are not good for patients, for academia, for physicians, or for stock-holders, for that matter.

If we are really worried about the conflicts of interest created when physician trainees get pens or coffee mugs with company logos from drug companies, or practicing physicians get pizza lunches for their office staffs from pharmaceutical representatives, (see post here) then we should really worry when leaders of academic medical institutions serve on the board of directors of large health care corporations.

Variations on a Theme of Sleaze

VARIATIONS ON A THEME OF SLEAZE

A few days ago I posted on corrupt reports in two medical journals, where key opinion leaders (KOLs) and corporate employees misrepresented the potential of Janssen’s atypical antipsychotic (AAP) drug risperidone for depression. One of these reports appeared in a general medical journal, Annals of Internal Medicine (AIM), which confirms the designs of the corporate marketers: by volume, treatment of depression now is centered in primary care. Considering the weak efficacy data, the dubious risk-benefit profile, and the inferiority of AAP drugs to other options, there is no justification for the broad and early adjunctive use of these agents for depression in primary care. The Eli Lilly Company, which markets the combination of olanzapine and fluoxetine in a single pill (Symbyax), has the same objective. Other companies are moving rapidly into this market space.

Combining AAP drugs with antidepressants takes us back to the bad old days of antidepressant-antipsychotic drug combinations like Triavil in the1960s and 1970s, when we learned that depressed patients are especially susceptible to a serious adverse event known as tardive dyskinesia (TD) caused by antipsychotic drugs. While the risk of TD is less than with the early antipsychotic agents, it is still unacceptably high with AAP drugs for patients who are unlikely to show meaningful clinical benefit, as I detailed earlier. In adult patients with schizophrenia the risk of TD with olanzapine treatment is about 2.5% at 1 year. In children and adolescents treated with AAP drugs for 6 months the risk is an alarming 6% (Wonodi I et al Movement Disorders 2007; 22: 1777). In patients with mood disorder, these figures are likely to be higher. And this is before one even begins to factor in the metabolic toxicity of AAP drugs (weight gain, obesity, insulin resistance, and Type II diabetes mellitus)! Patients are not well served when AAP drugs are pushed for treating depression in primary care.

Medical journals are not the only compromised medium. Continuing Medical Education (CME) is a second front in the campaign to expand the AAP drug market. The standard formula calls for corporate sponsorship channeled through an “unrestricted educational grant” to a medical education communications company (MECC). The MECC employs writers to prepare the “educational content,” and academic KOLs are recruited to deliver this content. The KOLs are chosen for their willingness to be “on message” for the corporate sponsor. If they go “off message” they know they will not be invited back. The talk of “unrestricted grants” is window dressing. The MECC also secures the imprimatur of a nationally accredited CME sponsor, typically an academic institution. The sponsor is paid to certify that the CME program meets the standards of the Accreditation Council on Continuing Medical Education (ACCME). Everybody turns a buck: the MECC and its staff are handsomely paid (CME is now a multi-billion dollar business); the KOLs are generously rewarded with honoraria and perquisites; the academic sponsor is well paid by the MECC; the ACCME receives dues from the academic sponsor; the audience obtains free CME credits rather than having to pay for these required educational experiences; and the corporate sponsor gets what it considers value for its marketing dollar.

ACCME standards include clear identification of off-label drug use; full and fair disclosure of clinical trial results, warts and all; and clinical guidance to the audience about risks, benefits, and treatment options. It is not an exaggeration to say that these standards are more often honored in the breach than in the observance. That is because CME events have been degraded to little more than thinly veiled advertising, built around promoting a product rather than around education. So corrupted has the process become that the Macy Foundation recently recommended that industry financing of CME be ended, “whether such support is provided directly or indirectly through subsidiary agencies.” See Daniel Carlat for more on this topic. Is this position alarmist? Consider the following examples of corruption in CME.

A widely advertised CME program appeared on-line 6 November 2007, titled Treatment-Refractory Depression: Is there a Role for Atypical Antipsychotics? Note the leading question and the product category focus. The program was developed by the MECC PeerView Institute for Medical Education, and it was sponsored by the Semel Institute for Neuroscience and Human Behavior at UCLA, which certified CME credits. Like the journal articles I discussed last week, this CME program is marked by a concatenation of deceits. The major messages were, augment earlier rather than later; AAP drugs are “an emerging therapeutic option” for augmentation (note the branding language); and AAP drugs are efficacious. None of these messages is based on credible evidence.

The first sleight of hand was the leadoff presentation, which featured the STAR*D study results concerning remission and response rates to adjunctive treatments or switching after various levels of treatment failure. The data naturally suggest unmet needs in treating depression (a favorite theme of marketers). The unspoken implication of this academic veneer is that the later studies described in the CME program were comparable to the STAR*D study in terms of case material, which is not so. Recruitment to STAR*D was explicitly different from recruitment to the usual experimercial sponsored by a drug company, where many cases come from contract research organizations, not from clinical referral streams. Moreover, STAR*D was a purely descriptive study that by design could not identify specific treatment effects.

Charles B. Nemeroff, MD, PhD from Emory University (yes, the same) discussed short term use of AAP drugs. His presentation is a model of being economical with the truth. Dr. Nemeroff has clearly mastered the art of accommodating his many corporate clients. He discussed 4 atypical antipsychotic drugs as augmenting agents for nonresponding depression. When discussing olanzapine he went beyond his short term remit to suggest that long term treatment is efficacious, yet he neglected to address the neurological or metabolic toxicity of long term olanzapine. When discussing risperidone he did not disclose that he was senior author of the major report he described and cited; he neglected to disclose the retractions he and Mark Rapaport from Cedars-Sinai Medical Center had been obliged to publish; he neglected to disclose that treatment with risperidone beyond 6 weeks was no more efficacious than placebo. That aspect was discussed by another speaker, who repeated Dr. Nemeroff’s now-retracted and discredited claims for significant long term preventive efficacy of risperidone in a subgroup of patients. Dr. Nemeroff made further claims about risperidone improving sexual function in patients receiving an SSRI antidepressant but he failed to disclose that beyond 6 weeks risperidone impaired sexual function in women who were receiving the SSRI; he backed up his claims about risperidone and sexual functioning by citing his publication in his own journal Neuropsychopharmacology that contained no data whatsoever on the matter; and he neglected to address the metabolic toxicity of risperidone that the corporation disclosed on ClinicalTrials.gov. He also falsely stated that the short term efficacy of risperidone in nonresponding depression was demonstrated in a controlled study, citing his own open-label study. These problems were called to the attention of the Semel Institute for Neuroscience and Human Behavior at UCLA. In response, the CME program was revised on January 11, 2008. Dr. Nemeroff’s material now contained a different citation that again contained no data concerning sexual side effects. They removed the claim that the short term efficacy of risperidone had been established in a controlled trial (although by then the problematic report of this very issue in AIM had been published for over 2 months). The inadequate discussion of the toxicity of risperidone in Dr. Nemeroff’s trial was unchanged, and another speaker continued to repeat the retracted and discredited claims of Dr. Nemeroff for significant long term preventive efficacy of risperidone in a subgroup of patients. No explanation of the changes made on January 11, 2008 in the on-line materials was provided by UCLA to CME readers who had studied the erroneous and biased material for more than 2 months. Other speakers made passing reference to the metabolic toxicity of AAP drugs but only in a perfunctory way that had no educational value, like what we see in direct-to-consumer advertising. Nobody mentioned the risk of TD.

As the Macy Foundation report makes clear, CME providers are expected to give learners guidance on the risk-benefit balance of new treatments. It is disingenuous of Dr. Nemeroff to talk up risperidone for short term treatment of these difficult depressions by exaggerating the benefit, downplaying the risks, avoiding comparison with alternative treatments, and glossing over the problem of longer term loss of efficacy. These are clear violations of ACCME principles.

When discussing aripiprazole for nonresponding depression, Dr. Nemeroff once again was economical with the truth. Note that Bristol-Myers Squibb, the marketer of aripiprazole, sponsored this PeerView/UCLA program. To document his claims about aripiprazole, Dr. Nemeroff cited one Abstract from the American Psychiatric Association meeting in May 2007. That does not meet ACCME standards of documentation for learners, most of whom would be unable to access the cited Abstract (not that it would tell them much even if they could). For some reason, Dr. Nemeroff did not inform learners that the complete report of the aripiprazole study had appeared in June 2007 (Berman RM et al. J Clin Psychiatry 2007;68: 843-853), fully 5 months before the CME event went on-line. From that readily available report it is clear that the Number Needed to Treat (NNT) for response with aripiprazole is 10, which compares unfavorably with a NNT of 4 for lithium, the best established augmenting option in placebo-controlled trials. A NNT of 10 means a clinician would need to treat 10 patients with aripiprazole before obtaining one remission that would not have occurred anyway with placebo. That does not constitute compelling clinical benefit. Dr. Nemeroff did not candidly discuss these troubling data. Dr Nemeroff provided his CME audience none of the remission or response data from the published aripiprazole study, though these data were readily available. These omissions of published, highly relevant information signify disrespect for his audience by Dr. Nemeroff, incompetence by the MECC, and failure of due diligence by the accrediting institution, UCLA, to ensure that accurate, balanced information and adequate documentation are provided. Likewise, no substantive risk-benefit analysis was provided to guide CME learners, and there was no meaningful discussion by Dr. Nemeroff of the metabolic toxicity of aripiprazole. The published report tells us that 7.1% of patients treated with aripiprazole gained more than 7% body weight, a very significant difference (p < 0.01) from the placebo treated patients (1.2%). Dr. Nemeroff did not share that information with the CME audience. Instead, he slyly minimized the appearance of the problem by showing a mean weight gain of only 2 kg with aripiprazole. In addition, the neuromotor toxicity of aripiprazole was remarkable (23.1% akathisia and 27.5% extrapyramidal symptoms). Dr. Nemeroff gave the CME audience no guidance about that problem or about its unblinding effect in the trial. Why do highly paid KOLs behave in this way? Do they think nobody will notice?

A final insult to CME learners in this program was the disclaimer that “The Semel Institute for Neuroscience and Human Behavior at UCLA is responsible for the selection of this report’s topics, the preparation of editorial content, and the distribution of this report” but “No responsibility is taken for errors or omissions in these reports.” Well, then, who is responsible? Why not UCLA, considering the ACCME standards and the fees UCLA received for sponsoring this CME activity through an “educational grant” from Bristol-Myers Squibb Company? Overall, it is difficult to avoid the impression that this so-called CME activity is a meretricious infomercial for Dr. Nemeroff’s corporate clients rather than a balanced educational event that aims to give practitioners considered guidance on a difficult clinical problem.

Will these revelations slow the marketing-inspired momentum for use of atypical antipsychotic drugs in depression? Not likely. Indeed, a new road show is right now getting under way, bringing the good news about atypical antipsychotic drugs in depression to CME audiences in Miami, San Francisco, Los Angeles, Chicago, Boston, and New York. Why now? Has some new insight been achieved that requires urgent communication to physicians? No. The road show has been launched now because aripiprazole was recently approved by the FDA for the secondary indication of adjunctive treatment in depression. It’s all about marketing. The faculty speakers are the usual suspects – KOLs and KOL wannabes who enjoy cozy or nepotistic relationships with the chairman. The funding is through another “educational grant” from the marketers of aripiprazole. The CME sponsor is an outfit in Texas that knows how the CME game is played. And the chairman of this new enterprise? Why, none other than the compromised Dr. Charles Nemeroff from Emory University. Why are we not surprised?