Monday, April 30, 2007

Educational DTC Drug Advertisements: "Minky Viagra Noni Noni Boo-Boo Plats"

We have posted before (most recently here) about the need to be very skeptical about direct-to-consumer (DTC) pharmaceutical advertising. On the other hand, DTC proponents often claim that the ads are valuable because they are educational. However, Alex Berenson just reported in the New York Times on television ads by Pfizer Inc for Viagra now being aired in Canada,

The ads feature middle-aged men and women talking in a made-up language, save for one word.

'Viagra spanglecheff?' says a man to a friend at a bowling alley.

'Spanglecheff?' his friend asks.

'Minky Viagra noni noni boo-boo plats!' the first man replies, with a grin that suggests he is not talking about the drug’s side effects. The ads end with the slogan, 'The International Language of Viagra.'

I cannot wait to hear from Pfizer how complete gibberish is educational. But maybe to a drug marketer, it is.

Knocking the Moose Off the Table: the Downfall of a Hypocritical Health Care Leader

A story that got prominent coverage over the last few days says something about the leadership of health care organizations, as long as one puts the information in a new sequence. So, starting with an article in the New York Times,
Mr. [Randall L] Tobias, 65, is a former chairman and chief executive of Eli Lilly & Company and of AT&T International. He served as the chairman of the board of Duke University from 1997 to 2000.
And per the Boston Globe,
Business Week called him one of nation's top 25 managers in 1997. His book, 'Put the Moose on the Table,' which advocates addressing difficult issues in a forthright manner, became a best seller.
Note that in the book, Tobias listed his "prerequesites for leadership," starting with "(1) inspires confidence, trust, and consistently displays the highest ethical standards...."

Back to the Times,
President Bush nominated him in July 2003 to lead a $15 billion program to fight AIDS worldwide.

At the time, some AIDS experts said Mr. Tobias did not have much experience with AIDS or Africa.

Then, as director of United States Foreign Assistance, he held the rank of ambassador.

In January 2006, Mr. Bush said he would nominate Mr. Tobias to be the administrator of the Agency for International Development. That position gave him the rank of deputy secretary of state.
The policies Mr Tobias pursued were often controversial. From the Boston Globe,
Bush persuaded Tobias to take charge of his five-year global AIDS initiative known as PEPFAR, or the President's Emergency Plan for AIDS Relief, which is now on track to spend $18 billion. During his tenure, AIDS treatment, care, and prevention programs were started, but there were also bruising battles with activists over policies relating to generic drugs and abstinence-only initiatives, as well as charges of favoritism in giving grants to evangelical Christian groups with little experience in Africa.

But [Harvard Professor Jim Yong] Kim, who formerly was director of HIV/AIDS programs at the World Health Organization, said that some of Tobias's policy decisions also had negative impacts on the fight against AIDS. 'I completely disagreed with their all-out attacks against making generic drugs more available' by refusing to use the WHO's system for testing the efficacy of medicines, he said.

Michael Weinstein , president of AIDS Healthcare Foundation , a Los Angeles-based group with extensive experience in treating AIDS patients, said that Tobias's policy to test all generic medicine through the US Food and Drug Administration 'meant that fewer people received drugs.'

[Furthermore,] The Bush administration's policy requires that groups receiving US money 'have a policy explicitly opposing prostitution and sex trafficking.' That policy, said [Center for Health and Gender Equity Executive Director Jodi] Jacobson and others, has led to the closure of numerous programs that had been teaching job skills to sex workers, forcing many prostitutes out of brothels and into the street.
Why was Tobias in the news lately? Back to the Times,
The head of the Agency for International Development, Randall L. Tobias, resigned abruptly on Friday for what he said were “personal reasons,” but an administration official said Mr. Tobias’s name had come up in an investigation of a suspected Washington prostitution ring.

On Friday night, ABC News said Mr. Tobias had confirmed on Thursday that he was a customer of an escort service.

A woman from Vallejo, Calif., Deborah J. Palfrey, has pleaded not guilty to charges that she operated a call-girl service in Washington, and has threatened on her Web site to sell her client list to raise money for her defense.

Mr. Tobias told ABC that he used the service for massages, not sex, according to the network’s Web site.
And back to the Globe,
Randall L. Tobias , the Bush administration official responsible for foreign assistance who resigned late Friday because of his use of an escort service allegedly involved in prostitution, was ridiculed as a hypocrite yesterday because he supported US policies that forced overseas organizations not to help prostitutes.

'I think it is somewhat ironic and hypocritical that he would patronize an escort service while he was denying funding to organizations who want to help prostitutes, and supporting a policy that obviously forbids fraternizing with prostitutes,' said Jodi Jacobson....
I am afraid that this case illustrates the psychology of all too many of the leaders of health care organizations. Tobias' downfall is ironic precisely because he failed to follow the rules that he, himself, set out, both in his leadership of the AIDS effort and in his best-selling management book. Too many health care (and other) leaders seem to think that they are not subject to the rules that apply to the ordinary folk, and that what they say need not be what they do. Thus the title and subject matter of Mr Tobias book now seem like something of a sick joke.

As F Scott Fitzgerald said, "the very rich are different from you and me."

As long as health care leaders feel no need to be do what they say and say what they do, and think they are above the common folk and that the rules do not apply to them, health care will be run for the leaders' benefit.

The need for representative, transparent, and accountable health care leadership has never been greater.

Data About Zyprexa's Adverse Effects Still Lost in the (Legal) Fog

We have posted (most recently here , here, here, and here) about allegations in a New York Times series that Eli Lilly and Company had used questionable marketing tactics to promote its atypical anti-psychotic drug Zyprexa (olanzapine), and especially that the company had suppressed information suggesting that the drug had more adverse effects than previously reported, and then how the company tried to restrict publication of the internal memos on which these allegations were based.

Last week, Alex Berenson in the NY Times reported again concerning the continuing controversy about whether Eli Lilly & Co suppressed data about the adverse effects of Zyprexa. Now the US Food and Drug Administration (FDA) seems also to have doubts about whether Lilly provided it was accurate data.

Per the Berenson article,
The Food and Drug Administration is examining whether Eli Lilly & Company provided it with accurate data about the side effects of the antipsychotic drug Zyprexa, a potent medicine that has been linked to weight gain and diabetes.

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

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

The F.D.A. confirmed its inquiry in response to questions from The New York Times. The agency said it had not yet decided whether to take any action against Lilly.

'The F.D.A. continues to explore the concerns raised recently regarding information provided to the F.D.A. on Zyprexa’s safety,' Dr. Mitchell Mathis, a deputy director in the psychiatry division of the agency’s center for drug evaluation and research, said.

The Zyprexa document that has aroused the most interest at the F.D.A. is a Feb. 21, 2000, paper in which Lilly scientists discussed whether Zyprexa’s label should be changed to alert doctors of the risk of hyperglycemia, or high blood sugar, associated with the drug.

The paper showed that 154 of 4,234 patients, or 3.6 percent, who took Zyprexa in clinical trials developed high blood sugar. Only 1.1 percent of patients who took a placebo developed the condition.

Doctors have said that difference is worrisome because most patients in the clinical trials were taking Zyprexa for only a few weeks or months.

The data that Lilly provided to the F.D.A. was notably different from the results discussed in the February 2000 paper, with the gap between the two patient groups much narrower. The company told the agency that patients taking Zyprexa developed high blood sugar at a 3.1 percent rate, while those taking the placebo had a 2.5 percent rate.

[Lilly spokesman] Mr. [Phil] Belt said that after the February 2000 paper, Lilly performed a final quality check of the data and discovered that some patients had been incorrectly included in the analysis, while others had been excluded.

'The original data referred to in the memo was a preliminary analysis, not the final accurate analysis that was provided to the F.D.A., and is therefore very misleading,' he said.
The rebuttal by Lilly mirrors that found in a press release of December 21, 2006. The Lilly press release does not provide further explain what precisely was wrong with the data that apparently showed an excess of hyperglycemia associated with Zyprexa, or how the errors were rectified. Nor did it explain why the company produced the internal 2000 document detailing data that was so quickly proven to be preliminary and error ridden. The latter document may be in the cache of more than 300 documents that is still publicly available (here), but I cannot readily determine which one it is.

Thus we are in an evidence limbo. The very limited evidence that has appeared in public is insufficient to judge whether there was good reason to think in the year 2000 that Zyprexa caused hyperglycemia and diabetes, and whether Eli Lilly withheld data that would have been supported this conclusion.

Apparently evidence sufficient to clear up this conclusion exists. But it remains in the hands of Eli Lilly, which so far has not seen fit to release it. Instead, apparently Lilly is continuing to persue a legal case against the people who first released its documents to the public, thus ensuring that the evidence remains obscure. As reported by Nature this month [Giles J. Court case to reclaim confidential data. Nature 2007; 446: 838-9],
A public-health expert in the United States is facing a potential jail term or a hefty fine after distributing documents that contain safety data on a blockbuster drug. The material came to light during initial negotiations in an ongoing lawsuit over the drug, and its manufacturer says that the information should have remained confidential.

The case, which could result in charges of contempt being levelled against the expert, shines light on the murky debates that go on between lawyers before drug liability cases get to court.

The latest incident centres around David Egilman from Brown University in Providence, Rhode Island, who is a frequent critic of the pharmaceutical industry....

Egilman had access to 15 million pages of confidential documents containing clinical-trial data and details of marketing plans that Lilly had released to lawyers during pre-trial negotiations, known as the discovery phase. But because the cases were settled before they reached court, the material was bound by confidentiality agreements.

[An] attorney, James Gottstein of Anchorage, Alaska, subpoenaed Egilman for the Zyprexa documents and then forwarded them on to the [NY Times] reporter [Alex Berenson].

Although Egilman was subpoenaed to release the documents, he and Gottstein could face jail terms or be required to contribute to Lilly's legal bills if the contempt proceedings proceed and are upheld.
Thus, the evidence that would allow physicians (and patients) to decide whether Eli Lilly suppressed data about adverse effects of Zyprexa remains tied up in legal proceedings. The company has not made any effort to make any of this evidence public. Of course, continuing to suppress evidence about the suppression of research evidence can only raise further suspicion that the latter (and first-order) suppression of evidence did, in fact, occur.

And pharmaceutical executives seem to always be baffled about why the public may not trust them?

If Lilly wants to be better trusted, company executives should try a big dose of transparency. Why not clear up the fog, and fully release the February, 2000, document, and details of why its data was erroneous, how it was corrected, and how the corrections turned out?

Meanwhile, maybe the FDA will be able to figure it out for us.

NOTE: See further discussion of the latest wrinkles in the Zyprexa case here on the Clinical Psychology and Psychiatry blog.

NOTE (May 1, 2007): See this post on Furious Seasons which links to the February, 2000 document in question above. On quick review of this document, I found that it did summarize data that the rate of "treatment-emergent" hyperglycemia in the (apparently pooled) group of patients who were given Zyprexa in multiple clinical trials was 3.6%, versus the rate in the (apparently pooled) placebo group of 1.05%. However, the document did not give much explanation about where this data came from, how the trials were done, or how the data were pooled.

Friday, April 27, 2007

Deja Vu All Over Again

In my Jan 2007 post "Leadership Position in Health Informatics: MD's Need Not Apply?" I noted an ad seeking an informatics leader that spcifically excuded physicians. I wrote:

My colleague Roy Poses writes about deliberate malfeasance in the healthcare sector. I write about overconfidence and recklessness in management circles in the same sector, focusing on healthcare IT. This overconfidence is an equally expensive and damaging phenomenon that, like Roy's "anechoic effect", has unfortunately been an area where substantive, critical discussion is taboo. This taboo comes, I might add, at the expense of patients.

In this example, one can only scratch one's head at a management ideology that, in essence, operates on the principle that in managing technology investments of hundreds of millions of dollars and a major cultural shift to electronic medical records, a difficult shift that has often proven perilous, there's such a thing as too much talent within an organization.

... I finally reached the recruiter yesterday, and the the response I received was unexpected and disappointing: "the organization was looking for a nurse and they would not even talk to a physician."

I make that same observation today on this ad posted on the American Medical Informatics Association job board:

[Name] Health System is one of the nation’s largest private health systems. We offer outstanding career opportunities in an environment focused on excellence.

Director Clinical Informatics

[We are] actively recruiting for a Director for our Clinical Informatics team. Qualified candidates will:

• Be licensed or eligible for licensure to practice as a Registered Nurse
• Possess a Master’s degree, preferably in Informatics
• Candidates will have leadership experience in Informatics or related computer science/technology field
Nursing leadership experience preferred
• Have demonstrated innovative and strategic thinking skills

The reason I entitled this post "Deja Vu All Over Again" is that I held that exact role in the past at the very same organization a number of years ago!

It was not an easy position even for an MD with formal postdoctoral informatics education and significant experience in challenging environments (e.g., manager of medical programs and medical review officer in country's third-largest public transit agency) to hold.

I sincerely believe blanket exclusions of MD's from Director of Informatics roles via such ads is a strategic error for any healthcare organization, and its rationale (cost savings, winner of position already known, anti-clinician bias in the IT organization, or whatever creative rationalizations the organization can come up with) severely flawed at best.

It's quite sad to see a major healthcare provider continue to fail to adhere to "best practice" in healthcare IT management, that is, find a leader based on qualifications and experience, without excluding any medical stakeholder group from the applicant pool.

As I'd written in my prior post, this exclusion is anything but "above-board, state-of-the-art strategic and tactical planning for major healthcare informatics activities in a large healthcare system."

I find the continual repitition of mistakes in health IT leadership and strategy by healthcare organizations a true example of Einstein's principle:

Insanity is doing the same thing over and over again and expecting different results.

-- SS

Monday, April 23, 2007

The Haunted Medical Literature: Moffatt and Elliott on Ghost-Writing

We posted quite a bit back in 2005 about ghost-writing (see post here with links backward).

Back then it became evident that a particularly pernicious type of ghost-writing was much more prevalent than anyone seemed to realize.

This sort of ghost-writing has several important elements.
  • Commissioned by Those With Vested Interests - The writing is commissioned by an organization with a vested, usually commercial interest, e.g., a pharmaceutical company.
  • Directed to Support Vested Interests - The ghost-writer, perhaps a free-lancing medical writer or employee of a medical communication company, writes an article meant to support that organization's interest, often by setting the stage for the organization's new products. For example, a pharmaceutical company about to market a new drug may commission articles that makes the condition for which the drug is used seem particularly common or important, or which emphasizes the negative aspects of current treatments.
  • Fronted by an "Expert" - Finally, an expert, often a well-known academic, agrees to become the article's ostensible first author.

Another article in the journal Perspectives in Biology and Medicine's 2007 "medicine and industry" issue addressed the importance of this sort of ghost-writing. [Moffatt B, Elliott C. Ghost marketing: pharmaceutical companies and ghostwritten journal articles. Perspectives Biol Medicine 2007; 50: 18-31.] It made two important assertions.

Ghost-Writing Is Common

Moffatt and Elliott concluded that ghost-writing practice is common, perhaps accounting for as many as 10% of journal articles. Moreover, stealth marketing campaigns that emphasize ghost-writing may create a bolus of articles that may be enough to dominate the literature on particular topics. Moffatt and Elliott summarized some of the known campaigns, including those sponsored by Pfizer Inc to support Zoloft, by Wyeth to support Fen-Phen, and by Parke-Davis (later merged into Pfizer Inc) to support Neurontin. It is particularly worrisome that the clinical literature on a particular topic may be dominated by the products of organized stealth marketing efforts.

Ghost-Writing Is Wrong

The arguments are strong and straight-forward.

First of all, and most importantly, it is harmful to the public health. Although relatively little is known about the details of corporate ghostwriting, the glimpses that we get of it through anonymous surveys and lawsuits suggest that the reason pharmaceutical companies go through the trouble and expense of shaping medical opinion about the safety and efficacy of their products is that it is highly profitable. Marketing campaigns seek to influence the prescribing practices of doctors. Ghostwritten articles may mislead doctors about the actual risks and benefits associated with medical treatments. Medical misinformation of this sort has the risk of harming a large number of people. The potential for harm is amplified by the fact that ghostwritten articles usually bear the name of a highly respected researcher who appears to have no financial stake in the issue at hand.

Second, ghostwritten journal articles always contain undisclosed conflicts of interest. The failure to disclose conflicts occurs on many levels. The "named author" fails to disclose that he or she has received payment for agreeing to publish the paper under his or her name. The MECC fails to disclose that it has received a substantial amount of money to prepare the article and find a 'named author.' And the sponsoring company fails to disclose that it has a direct financial stake in the drug or product in question.
Furthermore, Moffatt and Elliott argue that ghost-writing undermines science.

Ghostwritten articles are useful as marketing tools precisely because they appear to come from a disinterested source. In fact, the entire program of ghostwriting is designed to give articles written by people with a direct financial interest in promoting a product the appearance of disinterestedness.

The harm done by ghostwriting is compounded by the fact that the system of scientific communication is a key aspect of scientific objectivity. One approach to scientific objectivity holds that science is objective because of its procedures. According to this view, the foundation of scientific objectivity rests in the way scientists communicate and contest results. Helen Longino (2001) argues that scientific communities are objective insofar as their communication procedures are open and contestable. But ghostwritten papers conceal the interests of authors and sponsors in a way that makes it difficult to assess and contest the scientific data, which undermines the objectivity of science itself.

Ghost-writing appears to be yet another of the common practices in the contemporary health care arena that ought to create outrage, but have attracted little notice, yet another example of the anechoic effect.

Honest medical scientists ought to be outraged that their field has been contaminated by ghost-written articles meant to sell products. Physicians ought to be even more outraged that the clinical data on which they ought to be basing decisions for individual patients has been likewise contaminated.

WHAT IS TO BE DONE? - Moffatt and Elliott do make some recommendations:

First, universities need to treat the practice of signing on to ghostwritten journal articles as a case of academic misconduct. They need to institute rules to prevent faculty members from lending their names to papers they did not write, and when they discover cases where faculty members have engaged in the practice, they need to have mechanisms in place to sanction them.

Second, lawyers should start naming ghostwriters and sham authors as defendants in litigation against the pharmaceutical industry. As things stand now, only pharmaceutical companies are financially punished for fraud, and since their pockets are so deep, the threat of litigation is not sufficient to deter them from commissioning ghosted articles. But the threat of litigation would probably deter those with more limited financial resources. Litigation could serve as a dramatic way of making ghostwriters, sham authors, and medical communications companies directly culpable for the harm caused by their fraudulent activity.

Third, there needs to be a standing committee, task force, or office with an established institutional home whose job is to gather information about potential cases of ghostwriting, to sanction authors who have been determined to participate in ghostwriting, and to disseminate information about ghostwritten papers to the public. One major difficulty in identifying ghostwritten articles is the fact that journal editors are often reluctant to identify suspected or known ghostwriters publicly. A committee to counter ghostwriting could be housed in a professional body or in a governmental institution, such as the Office of Research Integrity (ORI). Alternatively, it could be hosted in a university or a watchdog organization.

Finally, there needs to be an effective strategy for identifying and discouraging ghostwriting. To achieve this end, we propose an amnesty program where people who report their own involvement in the production of ghostwritten journal articles are offered immunity from sanction in exchange for a detailed description of their involvement. People involved with the production of ghostwritten articles but who have not reported their involvement, on the other hand, would, if discovered, receive sanctions. In the case of academic sham authors, for example, such sanctions might include restrictions on receiving federal funds for research and the forwarding of the academic misconduct case to the university of the researcher in question. The benefit of the amnesty approach is that it would offer incentives for authors to come forward and would identify previously ghostwritten papers, while also discouraging the production of ghostwritten papers in the future.

I would urge practicing physicians and physician-scientists to support these recommendations.

Otherwise, the continued production of ghost-written pseudoevidence will continue to undermine science and delude practitioners.

New book: Analysis of the Commodification & Ownership of Life

In the past, Healthcare Renewal posts have focused on ethical issues related to healthcare management, the pharmaceutical industry, and other traditional biomedical sectors.

On a somewhat different note, a new book has appeared that describes numerous unpleasant interactions between academics and indigenous people (people who through geography and culture have remained relatively isolated and have not generally mated with other populations).

A number of academic-led and/or big-company-funded research projects have arisen to study the genome of the world's indigenous peoples, in the hopes of identifying rare genes that confer immunity or susceptibility to certain diseases, better understanding genetic mechanisms of disease, shedding light on migrations of people throughout the ages, and other lofty goals.

Project examples include the now-defunct Human Genome Diversity Project ("an international project that seeks to understand the diversity and unity of the entire human species") and the Genographic Project ("a landmark study of the human journey").

Unfortunately, while the researchers and companies involved in these projects have made and published promises that the cultural and property rights of the indigenous peoples studied would be respected, both at the individual and group levels, these promises have not been kept. It seems scientific arrogance, paternalism and moral relativity have created quite a number of unpleasant interactions between sponsors and subjects of these studies.

This seems yet another playing field for people in biomedicine who cannot seem to understand the world does not revolve around them.

Pacific Genes and Life Patents, Pacific Experiences & Analysis of the Commodification & Ownership of Life" is a new book edited by Aroha Te Pareake Mead, Faculty of Commerce & Administration, Victoria University of Wellington, New Zealand, and Steven Ratuva on this subject. It is available as a PDF (11 MB) via this link.

As a result of my past interest in this topic, I received the link to the book as well as the following from Aroha Mead:

For several years, indigenous groups have taken issue with scientists studying their DNA. When National Geographic began collecting DNA samples for The Genographic Project , the Maori of New Zealand along with Alaska natives feared that DNA evidence would invalidate their history and break family ties. Aroha Mead and Dr. Steven Ratuva have put together a volume of essays, entitled Pacific Genes & Life Patents , that examine how Pacific Indigenous communities have been affected by genetic research and products, and patents on life forms. The book is available for free online from the following website: (Publications), (Latest Publications).

The editors and authors of Pacific Genes & Life Patents present articles, case studies, and other information which show that “outsiders” are predominantly interested in harvesting genetic information for profit without any regard for Pacific cultural values and norms.

From the Preface:

As a region, the Pacific has experienced more than its fare share of external experimental research that has resulted in the commodification and misappropriation of important components of their ancestral inheritance. For others, it might be difficult to understand how a plant could be regarded as a living ancestor, or that human blood retains its life spirit even after it has been collected for medical research and synthesized and isolated for specific DNA qualities. Such values are still very much a part of the daily lives and analysis of Pacific communities.

More at ABC Science Online , March 20, 2007

In the past, I'd worked on the Yale-Saudi collaboration in clinical genetics, along with one of the principal researchers of the Human Genome Diversity Project. The HGDP project during that time period was being subjected to objections by many of its intended subjects. The principals promised to respect indigenous peoples' rights, and I believed that at the time.

Unfortunately, the underhanded attempts of the HDGP project leader I was working with to misappropriate my own intellectual property, a computer program I authored, while at the same time promising to respect the right of indigenous peoples, struck significant doubt in my mind (see this story from Yale, about halfway through where I document the actions of this Human Genome Diversity Project principal investigator at Yale, a participant in a series of rather revealing ethical lapses at that university).

I emailed Aroha Mead to let her know I supported her book, and gave her a link to the above story, an earlier version of which I had forwarded some years ago. I also agreed with her that it was unwise to trust researchers such as in the Human Genome Diversity Project. As I do not generally write such things behind people's backs, I cc'd my email to the International Executive Committee Members of the HGDP as listed on their web page.

I received this condescening, dismissive, paternalistic reponse from one of them at Stanford:

If you are able to say in English what your complaint is and against whom you are complaining, and on whose behalf you are complaining, in one or two paragraphs, you might find that people are willing to read it. As it is your message is so hidden and confused that it is not interpretable.

This person clearly did not have time of day to read my email, nor my Yale web story. I simply replied that:

If you find my several-page web story "confusing and not interpretable", one can only imagine how you would find Aroha Mead's book "Pacific Genes & Life Patents."

I think the response I received is a "poster example" of the arrogance, lack of values and lack of humility in a significant sector of the biomedical community, especially at major universities and the corporate sector. The abuses that then affect patients, ethical scientists and clinicians, and others (such as the indigenous peoples whose voices are heard in this new book) are the result.

Here is a more detailed book description:

Hand off Our Genes, Say Pacific Islanders

Pacific Islanders are demanding the power to restrict patenting of their human, plant and animal genes, even if they run foul of international patent laws.

A new book documents 16 'acrimonious' encounters between scientific researchers and indigenous communities and calls for Pacific states to take a united approach to gaining control over such patents in the region.

"Researchers are harvesting and patenting the Pacific region's genetic resources by simply gathering and taking ownership over almost everything in their path," says co-editor of the book, Aroha Mead of the Victoria University of Wellington in New Zealand.

She says lack of regulation and a lack of knowledge about the latest genetic technologies and intellectual patent law has made the region a major target for commercial gene hunters.

The book, Pacific Genes & Life Patents , is published by international indigenous activist group Call of the Earth and the United Nations University in Tokyo.

The book says a major problem is that communities involved in research often don't give informed consent.

It documents an early example in which the US government filed patents on material taken from the Hagahai tribe in Papua New Guinea and the Solomon Islands in the early 1990s.

As a result, says the book, Hagahai immune cells can be bought today from the American Type Culture Collection for U$216, despite subsequent objections from those involved that they had not been informed.

The book documents other cases in which researchers gained consent from people who were not representative of their community. This resulted in conflicts within the community and the community's eventual withdrawal from the research.

Culture clash

Scientific research and patenting can often offend deeply held cultural values, says co-editor Dr Steven Ratuva, of the University of the South Pacific in Fiji.

He says patents on genes in medicinal plants conflict with the traditional view that such plants are common property, available for everyone.

While fair compensation for exploiting indigenous knowledge can be important, there are other issues at stake, says Ratuva.

"It's not only a matter of money," he says. "There are certain aspects of the culture which a lot of communities think cannot be bought or sold.

"Plants and animals are not seen as mere physical or biological entities but also as embodiment of ancestral spirits," says Ratuva.

He says recognition of local people's world view, even if it appears absurd to outsiders, must be part of the process in working out any patent or bioprospecting agreements.

Vetting patents

The book renews calls for a Regional Pacific Intellectual Property Office to vet patent applications and make sure they conform with Pacific Island cultural values.

Leaders at the intergovernmental Pacific Islands Forum say they also want such a regional office.

Mead says Pacific states should also pass laws to either prevent or significantly reduce patents on life.

But Professor Brad Sherman, director of the Australian Centre for Intellectual Property in Agriculture , says such laws would contravene current World Trade Organization (WTO) rules on intellectual property relating to plants and animals.

"It's at odds with the trend on intellectual property across the world over the last decade which has seen any prohibitions on patenting of life being removed from the laws," he says.

Economic sanctions?

Any countries that contravene the WTO rules would run the risk of economic sanctions, says Sherman, based at the University of Queensland .

He says in his experience bioprospectors are often public sector researchers, who are under pressure to generate income from patenting.

And he says tough gene patent laws would not stop such researchers from taking material out of the Pacific region and patenting it elsewhere.

Mead is aware going against the tide won't be easy but is committed.

"Patents are out of control and a growing number of sectors of society are indicating that limits do need to be drawn," she says.

-- SS

Kassirer on: Who Really Controls Medical Professional Organizations?

The journal Perspectives in Biology and Medicine's first issue of 2007 was about "medicine and industry." Since many of my colleagues are returning from the US American College of Physicians meeting and others are getting ready for the Society of General Internal Medicine meeting, I thought starting with the first topical article in the issue, by Jerome P Kassirer, entitled "Professional societies and industry support: what is the quid pro quo?" would be apt. [Perspectives Biol Med 2007; 50: 7-17.]

When I was researching my article based on physicians' thoughts about what was going wrong with health care [ Poses RM. A cautionary tale: the dysfunction of American health care. Eur J Int Med 2003: 14: 123-130 here] I found many cases of large health care organizations acting against physicians' core values, and of ill-informed, conflicted, and even corrupt leadership of such organizations. I was struck by how rarely physicians and other health care professionals caught up in these cases could find useful allies to defend their values, and particularly how rarely their medical associations and societies provided any useful support.

Dr Kassirer explained why this may be so. From his introduction,

Professional societies see themselves in noble perspectives. Their mission statements are nearly all the same: they tout their intentions to support research, improve care, advocate for patients, educate physicians, and foster communications. They implement these goals with numerous activities, including continuing medical education (CME) programs, clinical practice guidelines, informational brochures and Web sites, and grants to investigators. Some run gigantic annual meetings attended by tens of thousands of participants from all over the world. They give travel awards to promising investigators and achievement awards to leaders in their field who have distinguished themselves in science or practice. Undoubtedly they accomplish a great deal of good. Yet the growing support that nearly all of them solicit and receive, often millions of dollars each year, from the pharmaceutical, device, and biotechnology industries can threaten the very goals they espouse.

Kassirer went on to catalog cases in which medical societies' noble goals seemed compromised by conflicts of interest. They included:

  • Society sponsorship of practice guidelines that supported the vested interests of the societies' commercial sponsors. Examples included: 1) an Endocrine Society guideline favoring aggressive testing for and treatment of androgen deficiency in older men, written by a panel with financial ties to the manufacturer of testosterone; and 2) the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition's guideline that recommended Propulsid for reflux in children after the drug's manufacturer donated almost half a million dollars to the society. (Another more recent example is the National Kidney Foundation's Amgen supported guidelines on the use of epoetin in anemia due to chronic renal failure, see post here.)
  • Society sponsored educational materials that supported the vested interests of the societies' commercial sponsors. An example was a booklet on nocturnal gastroesophageal reflux produced by the American Gastroinestinal Association, underwritten by a drug company (Wyeth) that makes a proton pump inhibitor (PPI) drug, written by a panel all of whom had financial relationships with producers of PPIs, supposedly in response to a survey suggested and underwritten again by Wyeth.
  • Society meetings "conflating informational material with commercial messages." Examples included intermixing scientific presentations and industry sponsored talks during meeting sessions, and allowing commercial logos on the society's newsletter.

Kassirer noted the various types of conflicts of interest that can affect medical societies. These included not only the sorts of conflicts implied above, but also:

  • Society officers or board members who have financial relationships (e.g., consulting arrangements) with commercial firms
  • Editors of society medical journals who have such relationships
  • Society managers who know their financial position will be enhanced by industry funding of the society.

I should note that this list may not be exhaustive. There are a larger set of conflicts that can afflict societies' medical journals. Journals may have institutional conflicts of interest due to support from commercial sources in the form of "unrestricted" educational grants. Journals also get substantial revenue from pharmaceutical/ biotechnology/ device company advertising, (see relevant post here) commercial support for special supplements, and bulk purchases of reprints. Furthermore, associate editors, members of editorial boards, and reviewers can all have significant financial ties to commercial firms.

It is also possible that the full-time staff of medical societies have individual financial relationships which may cause conflicts of interest. I am unaware of any public discussion of this issue.

The broad implication, that various health care corporations, particularly pharmaceutical, biotechnology, and device manufacturers, may exert major influence over physicians professional societies and academic health care associations is very troubling. If physicians and other health care professionals do not control their own professional organizations, we have fallen into a sorry state.

WHAT IS TO BE DONE? - Kassirer closed with some concrete recommendations:

Restore professionalism to the organizations.

  • Appoint as officers only those physicians who have no financial conflicts of interest.
  • Restore a professional environment to medical meetings by gradually reducing the circus-like atmosphere of the exhibit halls, discontinuing the support of the industry-sponsored symposia, and insuring that scientific programs are not intermixed with industry-sponsored talks that can be mistaken for unbiased science.
  • Rein in management's enthusiasm for financial support from industry.

Preserve and protect the integrity of medical information.

  • Reject restricted grants for activities (guidelines, educational ventures) that have not been previously specified as one of the society's products. Accept unrestricted funds from industry only if they are unencumbered, in other words, requiring no payback.
  • Require that all medical society journal editors who are in a decision-making mode in accepting or rejecting manuscript submissions have no financial conflicts.
  • Protect clinical practice guideline committees from the bias of financial conflicts. As with society leaders and editors, the ideal is to choose those with no financial ties.

Make financial arrangements transparent.

  • Do not provide demographic information of members and conference attendees unless these individuals grant their permission to do so.
  • Insist on review of all new industry support for any possible quid pro quo by a committee of unconflicted society members.
  • Reveal all sources of industry support on the society's Web site, including the amounts given. Identify also the specific purposes and projects for which the funds were employed.

I would urge physicians and other health care professionals who want their societies to represent their core values (and to be available to help members whose values are challenged by external threats) to push their societies' leaders to adapt Kassirer's recommendations at a minimum.

Of course, doing so may make for less lavish meetings, and somewhat higher dues. Wouldn't these costs be worth it to have professional societies that really uphold professional values?

Have we fallen so low that we cannot even control ostensibly our own professional organizations?

Friday, April 20, 2007

That Recent Unpleasantness: The Fall of the Allegheny Health, Education, and Research Foundation

We just posted about an article that described a case illustrating how large health care organizations' interests may conflict with physicians' values [Klasko SK, Ekarius JC. Collision course: the privatization of graduate medical education at one university. Acad Med 2007; 82: 238-244 here] This article also spoke to another issue of interest to Health Care Renewal readers.

The article set the stage for the dispute between the managers of Tenet Healthcare and leaders of the Drexel University College of Medicine by explaining the history of how Drexel University acquired a medical school, thus:

Founded in 1850, the Female Medical College of Pennsylvania was the first American medical school devoted exclusively to the training of female physicians. Later renamed the Woman’s Medical College, the school operated in several hospitals in Philadelphia and moved to its final location in the East Falls section of the city in 1930. Facing financial difficulties, the school voted in 1969 to admit men and to raise the class size to accommodate their presence. As a result of this decision, the name was changed to the Medical College of Pennsylvania (MCP) Medical School and MCP Hospital (MCPH).

In 1987, MCP was acquired by the Allegheny Health, Education, and Research Foundation (Allegheny), a Pittsburgh-based hospital and physician practice organization that was pursuing an aggressive statewide growth strategy. In 1993, Allegheny acquired Philadelphia’s Hahnemann University Hospital, along with its affiliated medical school, nursing school, and school of public health. The two medical schools were merged into MCP–Hahnemann Medical School and made part of the Allegheny University of the Health Sciences in 1995.

By 1998, Allegheny had acquired 14 hospitals and over 300 Philadelphia-area primary care physician practices, along with nearly $1.3 billion in debt and losses of more than $1 million per day. Under the burden of this debt, Allegheny filed for bankruptcy. That year, Tenet Healthcare Corporation bought Allegheny’s Philadelphia assets from bankruptcy. Tenet acquired MCP and Hahnemann hospitals along with six others, all of Allegheny’s physician practices, and the Allegheny University of the Health Sciences. During the bankruptcy proceedings, civic leaders and state officials intervened to find an organization to take responsibility for the educational resources and personnel affected by the sale. Drexel University, a Philadelphia-based Carnegie Foundation–ranked research university, stepped forward to protect the educational programs and nearly 10,000 jobs of the hospitals and health sciences schools.

Admittedly, the focus of the article was on what happened when Tenet decided to close MCP Hospital in 2003.

On the other hand, simply describing what happened to the Allegheny Health, Education, and Research Foundation (AHERF) as a "bankruptcy" seems like describing the US civil war as "the recent unpleasantness," a phrase that used to be heard in polite company in the south of the US.
The long and tortuous story of the rise and fall of AHERF has never appeared in detail in one place in the public domain. I summarized some aspects here (starting on page 5). Certain points must be made:

  • AHERF, one of the largest health care systems of its day, was built by the poster-boy for health care imperial CEOs, Sherif Abdelhak
  • Abdelhak, who started as food services purchasing manager at Allegeheny General Hospital, was repeatedly hailed as a "visionary" (in the March, 1997, ACP Observer) a "genius," and the like. His plans to create a huge integrated health care system were part of the wave of the future. Abdelhak was even invited to give the prestigious John D Cooper lecture at the annual meeting of the American Association of Medical Colleges (AAMC), which was published in Academic Medicine [Abdelhak SS. How one academic health center is successfully facing the future. Acad Med 1996; 71: 329-336.] He proclaimed that "we will need to create new forms of organization that are more flexible, more adaptive, and more agile than ever before." And he announced that "my aim as chief executive has been to unleash the creativity and productive potential of every individual and to provide an environment that encourages teamwork"
  • While Abdelhak was making these grandiose promises, he paid himself and his associates very well. For example, Abdelhak was paid $1.2 million in the mid-1990s, more than three times the average then for a hospital system CEO. He lived in a hospital supplied mansion worth almost $900,000 in 1989. Five of AHERF's top executives were in the top 10 best paid hospital executives in Philadelphia.
  • Although Abdelhak talked of teamwork, he warned the combined faculty of the new Allegheny University of the Health Sciences (AUHS): "Don’t cross me or you will live to regret it."
  • As AHERF was hemorrhaging money, Abdelhak continued to pay himself and his cronies lavishly.
  • After the AHERF bankruptcy, which was at the time the second largest bankruptcy recorded in the US, Abdelhak was charged with numerous felonies involving receiving charitable assets. In a plea bargain, he pleaded no contest to misusing charitable funds, a misdemeanor, and was sentenced to more than 11 months in county prison.

The story of AHERF is not merely that of an unlucky bankruptcy. It shows what can go wrong when health care adopts business practices such as jumping the latest management band-wagons and genuflecting before imperial CEOs.

Parts of the story appeared in a contemporaneous multi-part series in the Pittsburgh Post-Gazette (here). Considerable detail with emphasis on the debt and the bankruptcy, appear in one article written before Abdelhak's guilty plea [Burns LR, Cacciamani J, Clement J, Aquino W. The fall of the house of AHERF: the Allegheny bankruptcy. Health Aff (Millwood) 2000; 19: 7-41.] But again, I have found no single reasonably complete narrative of the case in the public domain. The case almost never has appeared in the scholarly health care and medical literature. (The first article in such a journal that mentioned Abdelhak's jail sentence was one I wrote.) And as best as I can tell, it almost never is taught in medical or public health schools.

Although George Santayana wrote "those who ignore history are bound to repeat it," it seems to be politically incorrect to discuss the history of health care mismanagement. This phenomenon has been dubbed the "anechoic effect" here on Health Care Renewal.

Until we can put an end to the anechoic effect, and freely discuss cases like the fall of AHERF, we are all bound to continue repeating this unfortunate bit of history.

It is too bad that Klasko and Ekarius did not at least allude to what lead to the AHERF bankruptcy.

Closing MCP Hospital: A Case Study How Health Care Organizations' Interests May Conflict with Physicians' Values

Some of the issues on interest to Health Care Renewal readers have been getting a lot more attention in scholarly health care and medical journals. This is a good problem to have, but I am struggling to keep up with the recent relevant publications. It may take me a while to get caught, but I am starting now....

An issue that came up a lot when I interviewed physicians back after the turn of the century about what they thought was wrong with health care [see results in Poses RM. A cautionary tale: the dysfunction of American health care. Eur J Int Med 2003: 14: 123-130 here]. An overriding concern was how health care is increasingly dominated by large organizations whose interests may conflict with physicians' core values.

In the March issue of Academic Medicine appeared an illuminating case report on this topic. [Klasko SK, Ekarius JC. Collision course: the privatization of graduate medical education at one university. Acad Med 2007; 82: 238-244 here]

The case arose when Tenet Healthcare, the owner of MCP Hospital [MCPH], one of Drexel University College of Medicine's [DUCOM] main teaching hospitals, decided to shut it down. The article clearly indicated how the interests of Tenet and its top hospital managers conflicted with the academic mission of the College of Medicine. It also indicated how the funding of US graduate medical education [GME] (that is, the training of interns and residents) is disconnected from the academic needs of the trainees. Some key quotes, (re-ordered), first on the conflict between the hospital's interests and the medical school's mission:

For an investor-owned company, the business mission is clear: maintain and enhance the company’s value to the shareholders. Although it would be naïve to argue that financial pressures have not placed similar pressures on not-for-profit academic institutions, the admonition that we often receive as deans to 'remember our mission' is well stated.

We recognized that Tenet and DUCOM [Drexel Univesity College of Medicine] had very different priorities when it came to the maintenance and growth of GME. ... the residents were viewed as employees by many of the financial operatives at Tenet and were subject to the same actions that would be taken by an investor-owned company that needed to reduce its expenses.

[There is] a common battle that remains under the surface in most GME programs where the hospital entity is not part of the same system as the university entity: Where do we invest our residency resources, and where do we allocate, or reallocate, our cap numbers—in the most academically relevant specialties, or in those specialties that will have the greatest financial benefit to the hospital? This dichotomy quickly came to the fore when hospital and medical school leaders disagreed about who was responsible for making that decision. In the mind of the Hahnemann hospital CEO, the decision was his to make; after all, the residents were his 'employees.' In the mind of the dean’s office, there was a clear academic accountability issue; after all, the residents were 'students.'

The actions of the Tenet leaders in this case appeared in conflict with the academic mission of their own teaching hospitals (and of the medical school).

Then, on the disconnect between the funding of graduate medical education and the academic mission:

Once the political tug of war began over the fate of MCPH, the disconnect between the hospital’s funding source (the CMS [Center for Medicare and Medicaid Services]) and its accrediting body (the ACGME [Accreditation Council for Graduate Medical Education]) became apparent.

In every discussion with Tenet, federal officials, and representatives of the Commonwealth of Pennsylvania, the 'sale' of MCPH was contingent on the flow of funds that followed the residents. The perception that the residents were part of the 'deal' was in large part driven by federal and state public officials and potential hospital purchasers during their discussions with CMS.

For-profit hospital operators continue to act as employers of medical residents across the nation, and there continues to be a disconnect between residency programs’ funding sources and funding recipients (the CMS and hospitals) and between residency programs’ accrediting body and their academic entities (the ACGME and universities). Currently, for example, universities are experiencing increasing pressure from the ACGME and individual resident review committees (RRCs) to increase program directors’ protected time. Unfortunately, many of the academic organizations feeling that pressure do not control the flow of funds from the hospital entities. Residency numbers, physician supply, and service versus education continue to be hotly debated topics in GME programs across the country.

So, at least in some cases when teaching hospitals are administratively distinct from medical schools, the managers of these hospitals may put financial concerns ahead of the academic mission. Furthermore, these managers seem to feel entitled to the federal Medicare money that funds graduate medical education, without feeling accountable for how that money is spent.

Clearly this illustrates how some of the leadership of the large organizations that now dominate health care have interests that may conflict with physicians' values.

The article by Klasko and Ekarius showed how the medical school was able to preserve its residency programs even after the closure of the hospital. But often conflicts between large organizations' interests and physicians' values are often not easily resolved.

Wednesday, April 18, 2007

Can People with Conflicts of Interest Make Clear Arguments Defending Their Conflicts?

Calls to limit conflicts of interest affecting advisory panels for the US Food and Drug Administration (FDA) have inspired some curious apologias for the current practices that result in many conflicted board members.

Yesterday, Dr Thomas P Stossel, identified as a Professor at Harvard Medical School and director of the Translational Medicine Division at Brigham& Women's Hospital wrote about "Drugs and Demagogues" in the Boston Globe. His arguments, in my humble opinion, were weak and beset with logical fallacies.

The Arguments and My Responses

Invalid accusations of conflicts of interest may deprive the government of good advice:

Thucydides noted how some people invoke financial conflicts of interest to discredit worthy opponents: 'If a man gives the best possible advice but under the slightest suspicion of being influenced by his own private profit, we are so embittered by the idea that we do not allow the state to receive the certain benefit of his good advice.'

Although Stossel's use of a historical anecdote is appealing, this argument appears to be based on a false dichotomy: some accusations of conflicts of interest may be invalid, so all such accusations must be invalid. Clearly, the importance of conflicts of interest depend on their nature, and the context.

The scientific evidence shows that conflicts of interest do not adversely affect FDA advisory panel decisions:

The answer is not that financial conflicts of interest provably influence FDA panel recommendations. A study of advisory panel decisions published in The Journal of the American Medical Association found that advisers' financial relationships had no effect on their approval recommendations.

There are multiple problems with this argument. First, Stossel seemed to confuse lack of evidence with evidence of a lack. Stossel asserted that the data from one study did not provide evidence for the influence of conflicts of interest on FDA advisory panel recommendations. Lack of evidence for such influence in one study, however, does not constitute evidence that conflicts of interest have no influence on the panels' recommendations.

Second, Stossel ignored the major weakness of the JAMA study, one that would have made it unlikely that the study would have found a relationship between conflicts of interest and FDA panel recommendations. (Stossel did not identify the study, which was apparently: Lurie P, Almeida CM, Stine N et al. Financial conflict of interest disclosure and voting patterns at Food and Drug Administration advisory committee meetings. JAMA 2006; 295: 1921-1928.) The study was a cross-sectional study that assessed the relationship between the prevalence of members with conflicts on advisory panels and the panels' votes. Since the panels were the unit of analysis, and the study only considered panels that voted on specific drug products, the sample size was very small (76). The study used three different types of analyses, all rather complex. Two types of analyses failed to show relationships between conflicts of interest and voting outcomes. The article noted "both analyses were hampered by small sample sizes." This study was too small to have much statistical power to find a relationship between conflicts of interest and panel recommendations.

Finally, Stossel ignored evidence in the study that went against the thesis of his commentary. Even though the JAMA study was small, one of the three types of analyses did find an effect of conflicts of interest, that "exclusion of advisory committee members or voting consultants with conflicts would have produced absolute vote margins less favorable to the index drug in the majority of meetings...." Stossel completely ignored this finding.

Excluding people with conflicts from FDA advisory panels would exclude the best and the brightest,

Furthermore, medical experts who consult for private companies have the most research agency grant funds. They are the most knowledgeable, inventive, and productive scholars -- which is why corporations want to work with them.

But is this a post hoc fallacy? Do pharmaceutical, biotechnology, and device companies select the best and most accomplished doctors and researchers to consult for them? Or do people who are supported by these companies have more academic success, and hence come to be known as the best and the brightest?

At best, that such companies hire the best and brightest as consultants is a testable hypothesis. Yet even if this is a hypothesis that Dr Stossel favors, it is not a proven fact.

The alternative hypothesis is also tenable. Maybe pharmaceutical, biotechnology, and device companies hire as consultants and fund as researchers the people the companies feel are most likely to help market their products, one way or the other. Since, as we recently posted, the strongest current determinant of success in medical school now appears to be acquisition of external funding, it could be that commercial funding causes faculty members to be successful, rather than successful faculty members are the ones who get commercial funding.

People who do not have conflicts may make terrible recommendations,

Meanwhile, some groups selected for their independence can make terrible recommendations. After having to retract its assertion that certain baby car seats were unsafe, Consumer Reports magazine recently changed its policy of consulting only with experts without commercial ties. The second-best experts do not produce the best results.

This is simply reasoning by anecdote. Furthermore, it seems to again present a false dichotomy: either an expert is perfect, or terrible. Thus, because Consumer Reports made a single error, it must be terrible.

Can Conflicted People Make Clear Arguments in Defense of Their Conflicts?

So Stossel's defense of conflicted FDA panel members seems to be based on a mixture of logical fallacies and poor understanding of existing evidence.

To return to the main issue, conflicts of interest. In the British Journal of Medicine, Joe Collier made the argument that having conflicts of interest leads to conflicted, and hence unclear thinking: "people who have conflicts of interest often find giving clear advice (or opinions) particularly difficult." [See: Collier J. The price of independence. Br Med J 2006; 332: 1447-9. and our relevant post here.] That is an argument against having people with conflicts of interest on FDA panels.

It may also help explain the lack of clarity in Dr Stossel's arguments.

Toward the end of the article, Stossel noted,

I have not participated in FDA panels, but I do have some corporate relationships that could exclude me under the proposed rules.

A little internet-based research revealed Stossel's conflicts of interest.

In a commentary in the New England Journal in which Stossel attacked the rigorous conflicts of interest rules that were once again imposed on the US National Institutes of Health (NIH), Stossel disclosed "having received consulting fees from ZymeQuest, owning stock options in ZymeQuest and Biogen, and having pending and issued patents, owned by Brigham and Women's Hospital, some of which are licensed to ZymeQuest." [Stossel TP. Regulating academic-industrial research relationships - solving problems or stifling progress? N Engl J Med 2005; 353: 1060-1065.]

But in another paean to a laissez-faire approach to conflicts of interest in Perspectives in Biology and Medicine, Stossel also disclosed that he "is a member of the Board of Directors of Zymequest Inc, and the Scientific Leadership Advisory Board of Merck & Co. The author is a founding scientist of Critical Biologics Corporation and a consultant to Boston Scientific, Inc., and Gerson-Lehrman, Inc." [Stossel TP. Regulation of financial conflicts of interest in medical practice and medical research. Perspect Biol Med 2007; 50: 54-71. ] Note that members of boards of directors of for-profit corporations are legally expected to exercise the duty of loyalty, and exhibit "unyielding loyalty" to the corporation's stockholders. [See Monks RAG, Minow N. Corporate Governance, 3rd ed. Malden, MA: Blackwell, 2003.] Such unyielding loyalty may require directors to act in ways that challenge the mission of academic medicine. Furthermore, a 2004 ZymeQuest press release revealed that Stossel has been on its board at least since that year, suggesting that Stossel's disclosures in his 2005 NEJM article were not complete.

So two of the most visible published arguments against more stringent conflict of interest rules for FDA advisory panels were made by people who have relevant conflicts of interest, and seem not always to have disclosed them completely. (See our post on Epstein's article in the Wall Street Journal here and on his conflicts of interest here.) Furthermore, both these commentaries were badly argued, exhibiting misconceptions about relevant data and depending on logical fallacies. These are only anecdotes, but it does seem that the confusion caused by conflicts of interest make it difficult for those with conflicts to make clear arguments that such conflicts are harmless.

I am waiting to see if any individuals without any relevant conflicts will stand up to argue the harmlessness of major conflicts of interest of FDA advisory panel members.

Monday, April 16, 2007

The Butterfly Runs Into Flak: Critically Analyzing Lunesta's Television Ad

National Public Radio's show "All Things Considered" ran a segment last week explaining how direct to consumer (DTC) advertising can make drugs appear better than they may really be.

The show focused on a single television advertisement (with the butterfly) for Lunesta (eszopiclone) marketed by Sepracor for insomnia. The show focused first on the psychology of advertising design, pointing out the following features:

Using Images to "Sell You a Feeling" - The advertisement shows a lovely woman waking up after an apparently restful sleep produced by Lunesta. A former TV producer commented, "and when she wakes up, she's just gorgeous. She sits right up and stretches and looks great. Who wouldn't want that?" Thus, "you remember what you feel longer than what you know." So the image of restful sleep swamps all those facts about adverse effects presented later.

Obscuring the Adverse Effects - A number of tactics are used to make it less likely that the viewer will remember the obligatory recitation of adverse effects. These include

  • Putting the litany in the middle of the advertisement, since it is hardest to remember the middle of a presentation.
  • Reciting facts quickly, and using a more advanced vocabulary than the rest of the advertisement.
  • Presenting the visual images during the recitation that do not correspond to the words spoken, so "when the eye and the ear compete, the eye wins."

The show also featured an analysis by Dr Lisa Schwartz of the claims made in the ad versus a critical reading of the most relevant evidence from clinical research (that is, using the evidence-based medicine approach). Her main points were about how the advertisement:

  • Enlarges the Eligible Population - The ad suggests that the drug is suitable for "millions of Americans who once had trouble turning off their restless minds," that is, a large population of people who have occasional trouble falling asleep. But clinical studies of the drug were limited to defined populations of people who fit the DSM-IV criteria for insomnia, and who reported sleeping less than 6.5 hours a night, and taking >30 minutes to fall asleep for at least a month. Thus the ad appears to be trying to expand the population of patients for whom the drug is marketed well beyond those patients who were in the clinical trials of the drug.
  • Exaggerates Results About Amount of Sleep - The ad suggests that people can sleep all through the night on Lunesta, implying that it leads to eight hours of sleep. Schwartz noted that the largest trial of Lunesta [Krystal AD, Walsh JK, Laska E et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep 2003; 26: 793-799.] only showed that patients given Lunesta slept 37 minutes longer, for an average of 6 hours and 22 minutes, than those given placebo. Thus, Lunesta did not prolong sleep much longer than placebo, and did not on average result in anything close to 8 hours of sleep.
  • Exaggerates Results About Falling Asleep- The ad suggests Lunesta "works quickly." Yet the study results suggest that those taking Lunesta fell asleep only 15 minutes earlier than those taking placebo.
  • Exaggerates Long-Term Usability - The ad suggests that the drug "is approved for long-term use." Yet the longest study of the drug only lasted six months, not what many people would call long-term.

Note that Sepracor said it based the advertising claims on a different smaller, shorter study that assessed patients in a sleep lab. [McCall WV, Erman M, Krystal AD et al. A polysomnographyt study of eszopiclone in elderly patients with insomnia. Curr Med Research Opinion 2006; 22: 1633-1642.] Yet this study only lasted 2 weeks, and it excluded patients with many chronic problems such as sleep apnea, chronic obstructive pulmonary disease, "uncontrolled medical abnormalities or unstable chronic disease, medical or psychiatric disorders," etc. Even so, this study only showed that people feel asleep on average of 11 minutes faster on Lunesta (average sleep latency -40.8 vs -29.6), and slept only 16.2 minutes longer (average change of total sleep time 48.6 vs 32.4 minutes).

The main points are that DTC advertising, rather than being educational, may be psychologically designed to convey positive impressions about the product far beyond the actual words used. Furthermore, the words used are still likely to suggest that the product is much better than what the data from clinical research suggest. In this case, rather than being a wonder drug, Lunesta on average makes people fall asleep a few minutes earlier and sleep a few minutes longer than they would have without it. These small advantages should be weighed against its adverse effects, including strange sleep behaviors which the FDA wants to add to Lunesta's (and other "sleep aids'") labels but which were apparently not in the advertisement.

Patients should be extremely skeptical about DTC advertising, especially about whether the psychological good feelings conveyed by the ads obscure the cold facts about the drug, and whether the facts spoken about the drug exaggerate its benefits and obscure its harms.

Knowing about these issues, physicians need to be appropriately circumspect when patients ask for that wonder drug they saw on TV. Remember that DTC ads are particularly likely to amount to pseudoevidence-based medicine.

Friday, April 13, 2007

A Dire Warning Arrives in the Mail: Evidence or Pseudoevidence?

I get all sorts of letters, but this one was striking. It was in an envelope from /alert Marketing, a company which promises to "target physicians by therapy area or by specialty with the #1 rated M.D./alert mail programs." In the envelope was a "dear healthcare provider" letter from one Dan MacDonald, VP for managed healthcare operations from Forest Pharmaceuticals. The letter contained this dire warning:
certain managed care organizations have instituted initiatives attempting to switch patients from Lexapro .. to a generic SSRI, including citalopram. However, well-controlled Lexapro patients should not be switched, unless switched for a medical circumstance..

Then, in a black box, it stated (the bold font was in the original):

The clinical profile of Lexapro and citalopram are distinct, as illustrated by the following:

- Lexapro is effective in the treatment of major depressive disorder (MD) and generalized anxiety disorder (GAD). In contrast, citalopram is not indicated for GAD, or for any other anxiety disorder. [citations were two the respective drug labels.]

- There is clinical evidence for the greater efficacy of Lexapro vs. Celexa

- In a prospective, randomized double-blind trial in MDD patients, Lexapro 20 mg/day was significantly superior to Celexa 40 mg/day in both response (p<0.01)>

- In a pooled analysis of three randomized, double-blind comparison trials, Lexapro 10-20 mg/day led to significantly greater improvement in MADRS scores of severely depressed patients then citalopram 20-40 mg/day at endpoint.(4)

- In the overall population (moderately to severely depressed patients) in the pooled analysis of these same three trials, Lexapro 10-20 mg/day showed a significant improvement in MADRS vs placebo at week 1, whereas citalopram was not significantly different from placebo until week 6.(4)

There is currently no generic equivalent for Lexapro.

And there it was, the dread managed care companies were trying to bludgeon us poor "healthcare providers" into switching patients to less effective medicine. And the warning was in a black box.

Of course, I have not always been a big fan of how many managed care companies have operated. (See, for example, this post.)

But is it really so bad to switch a patient from escitalopram (Lexapro) to citalopram? Let's have a look at the evidence.

First, it is true that citalopram does not have an indication for generalized anxiety disorder. But that is because Forest Pharmaceuticals did not go to the effort to try to secure one before its patent ran out.

Let us then look at References 3 and 4:
3. Moore N, Verdoux H, Fantino B. Prospective, multicentre, randomized double-blind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder. Int Clin Psychopharmacol 2005; 20: 131-137.
4. Gorman JM, Korotzer A, Su G. Efficacy comparison of escitalorpram and citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials. CNS Spectrums 2002; 7(suppl 1): 40-44.

Reference 3 turns out to be a short-term (8 week) trial. Thus the importance of its results are questionable because treating major depression usually involves treatment for considerably longer than 8 weeks. It showed at best a two-point difference on the 60 point MADRS scale in favor of escitalopram, which does not suggest much of an advantage to this non-psychiatrist.

Reference 4 was a pooled analysis. It turns out it was the main focus of a 2004 article which assessed claims of the superiority of escitalopram over citalopram in Sweden. [ Svensson S, Mansfield PR. Escitalopram: superior to citalopram or a chiral chimera? Psychother Psychosom 2004: 73: 10-16.]

The main points made by Svensson and Mansfield were that:
  • Most chiral drugs (like escitalopram) have not proven superior to the racemic mixtures from which they were derived (like citalopram).
  • Escitalopram (Cipralex in Sweden) was heavily promoted by H Lundbeck A/S, its Swedish manufacturer as its patent on citalopram (Cipramil in Sweden) was ready to run out.
  • "The advertisements published so far do not claim less adverse effects but do claim superior efficacy. These efficiacy cliams, however, are not supported by evaluations from the Swedish MPA [Medical Products Agency] and the Institute for Rational Pharmacotherapy (IRP) attached to the Danish Medicines Agency."
  • All the trials and the pooled analysis were sponsored by Lundbeck
  • In the best single analysis from the study by Gorman et al, a pooled analysis most compatible with the intention-to-treat principle, comparing the change in MADRS scores at 8 weeks, there were no significant differences between escitalopram and citalopram.

Thus the claims made in the letter sent to me above based on the study by Gorman et al apparently referred to an analysis that was less compatible with the intention-to-treat principle, or to the one-week results. The intention-to-treat principle is that patients should be analyzed in the groups to which they were initially assigned, even if they drop out of the study. Failing to follow this principle risks biasing the results, since patients who drop out may do so because they did not get good results with the study drug. The one-week results mean little, since, again, depression usually is a problem that lasts much longer than one week.

So in summary the dire warnings sent to many "healthcare providers" about switching from Lexapro to citalopram do not appear to be based on very strong evidence. In fact, it puts enough of a spin on the existing evidence to qualify as an example of pseudoevidence (see post here). But physicians and other health care professionals receive lots of letters, and few have the time to analyze the claims made in each one. However, the pharmaceutical (and biotechnology and device) companies and their marketing and "medical education" company partners appear to have huge resources to devote to spinning the evidence into pseudoevidence to support their products.

If only there were equal resources devoted to a truly evidence-based approach to the relevant clinical research.

Meanwhile, fellow "healthcare providers," be very skeptical of dire but self-serving warnings from pharmaceutical/ biotechnology/ device companies and their marketing and "medical education" allies.

More Unconnected Dots: Pay for Malfeasance, Again?

The bandwagon to subject physicians to "pay for performance" (P4P) just keeps gathering momentum. (See most recent post here.) This movement is supposedly derived from a broader movement for pay for performance in business management.

Yet it seems in many companies, including some in the health care industry, the standards by which performance is measured for top executives are ridiculously low, so low that one pundit wanted the slogan changed to "pay for pulse." His most prominent example of a company that paid for pulse was Pfizer Inc, known as the world's largest drug company.

Last year, we posted about one example in which a subsidiary of the pharmaceutical company Schering-Plough pled guilty to a federal count of conspiracy, yet its CEO never seemed to suffer any sort of financial penalty for the actions leading to this plea. We called it an example of pay for malfeasance.

Now we have a new example. Last week we posted about how subsidiaries of Pfizer Inc, still known as the world's largest pharmaceutical company, pled guilty to one federal offense, entered into a deferred prosecution agreement for another, and agreed to pay an approximately $35 million fine for both.

Fortuituosly, Pfizer Inc has its annual meeting this month, so its 2006 annual proxy statement was recently published. From this statement one can determine (with a certain degree of difficulty) how well the company's top executives are paid, and how well its board members, who have fiduciary responsibility for the company's actions and performance, get paid.

Neither group seemed to have suffered in 2006. Board members who served for all of 2006 received from over $70,000 to more than $100,000 in fees (excluding the chair), and all earned stock awards worth at least $124,300 (see page 21). Thus all board members got more than $197,000.

The 2005 proxy statement revealed that board members who served for the full year got from $63,000 to $86,000 (excluding the chair), and all earned stock awards worth $122,084. Thus their compensation increased modestly from 2005 to 2006.

In 2006, the total compensation of the new Pfizer Inc CEO, Jeffrey B Kindler, was $9,799,234; of David L Shedlarz, Vice Chairman, was $10,275, 470; of John L LaMattina, Senior Vice President, and President, Pfizer Global Research and Development, was $7,019,667; of Ian C Read, Senior Vice President, and President, Worldwide Pharmaceutical Operations, was $4,779, 299; and of Alan G Levine, Senior Vice President and Chief Financial Officer, was $4,766, 299.

Note also that former CEO Henry McKinnell received $19,418,466 in 2006; and outgoing Vice Chairman K Katen received a whopping $28,995,078.

How publicly traded companies must reveal the compensation of top executives changed in 2006, so it would be hard to compared these figures to last year's results.

I suppose it's possible that the Pfizer leadership will be penalized financially in 2007.

But it is hard to believe that the guilty plea and the substance of the deferred prosecution agreement executed in March, 2007 were not anticipated last year. And it is harder still to see how a company whose subsidiaries just pled guilty to "willfully" offering "inflated payments on a contract to induce another party to recommend purchasing or ordering ... [its] drug products" in violation of federal law, and in a deferred prosecution agreement admitted to promoting human growth hormone for unapproved uses, and admitted that this "conduct was unlawful," could justify having paid current top executives total compensation from over $4.5 million to over $10 million.

Maybe the shareholders, who it seems will ultimately pay for the $35 million fine, should ask the board members, who are supposed to have fiduciary duty to protect the stockholders' financial interests, why their hired executives do not seem to be suffering any penalty for presiding over a company whose subsidiaries admitted to committing federal crimes.

Meanwhile, rather than pay for performance, it appears that the reigning compensation philosophy was again pay for malfeasance.

WHAT YOU CAN DO? - If you own stock in a public for-profit health care company that has recently admitted to misconduct or has had to make a huge financial settlement in response to civil litigation (see the Health Care Renewal archives for examples), demand changes in your company's governance such that negative incentives apply to the leaders responsible for these problems.

If you are a physician, demand that P4P must apply to the whole health care system if it is to apply to physicians.

And maybe everyone should write their congresspeople demanding better regulation of the leaders of health care organizations, at least sufficient to hold people responsible for their worst decisions.