Genzyme's "Remarkable Business'Strategy" and Contaminated Drugs

In June, 2009, an article in the Boston Globe described how the Boston area based biotechnology company Genzyme sold some astonishlingly expensive drugs, using

a remarkable business strategy: In countries from Colombia to Taiwan to Libya, the Cambridge firm has compiled an extraordinary track record of searching out patients like Tania, providing desperately needed treatment, and then successfully pressing their governments, even poor ones, to pay full price for the most expensive drugs in the world.

The article focused on how Genzyme marketed Cerezyme for Gaucher's disease.

When Genzyme Corp. first introduced a bioengineered drug for Gaucher (pronounced GO-shay) disease in the 1990s, the very idea seemed almost absurd to most people in the pharmaceutical industry. It was expensive to manufacture, there were vanishingly few known patients, and it wasn't clear how you could sell enough of it to recoup research costs, never mind make a profit.

Genzyme's solution, elegant in its way, was to set a price high enough to earn a substantial profit no matter how small its pool of patients. Then the company surprised the medical world - and its investors on Wall Street - by showing that American health insurers could be persuaded to pay the six-figure price tag. And with the only effective treatment for Gaucher disease, Genzyme never needed to lower the price, even as production efficiencies raised profit margins on the drug to as much as 90 percent.

The drug started to bring in tens of millions of dollars a year, then hundreds of millions. Today this one drug, prescribed for about 5,000 patients, has transformed Genzyme and its chief executive, Henri Termeer, into one of the great success stories of biotechnology, fueling its expansion into a $16 billion company with offices and factories worldwide.

By the early 2000s, Genzyme had reached most of the known Gaucher patients in the United States, so it had begun pushing outward to new markets. Genzyme created divisions within the company to find overseas patients; it hired experts to cajole balky governments into paying for the patients' Cerezyme doses. Some of the company's successes were extraordinary: hundreds of patients in Brazil. Patients in Taiwan, Kuwait, and Bulgaria. The government of Libya's Colonel Moammar Khadafy pays for Cerezyme for a handful of patients.

As it notched these successes, the company stayed largely under the radar of public health activists who were pushing drugmakers to discount AIDS drugs and other lifesaving medications whose retail prices were financially out of reach to many governments.

Biotechnology drugs like Genzyme's, though crushingly expensive for each patient, were so rarely prescribed that they did not attract the same attention, and Genzyme followed an extremely disciplined 'one price' strategy: find patients; donate the drug at first if necessary, but press constantly to be paid full retail price.

The "one price" for Cerezyme in Costa Rica was $160,000 per year of therapy.

I thought about posting about this story when it came out, focusing, of course, on the amazing price of Cerezyme. However, then I wondered: while the price of Cerezyme seemed extremely high, could anyone say that it was outrageously and unfairly high? After all, the drug was expensive to develop and produce, could not be sold in volume, and provided apparently very effective treatment for an otherwise untreatable disease. So I put the article in a file, and did not post about it.

Then a few days later, another story ran in the Globe, this time about problems in the Genzyme plant that produces Cerezyme:

n an unprecedented move for Genzyme Corp., the state’s largest biotechnology company has halted production of two drugs for rare genetic disorders after a virus was discovered in production equipment at its Allston plant.

The drugs are used by 8,000 people worldwide and cost about $200,000 per patient annually. While the virus has the ability to taint the drugs, it is not considered harmful to humans, officials said. The manufacturing plant will remain shut through July while it is decontaminated as a precaution.

Shipments of the drugs, Cerezyme and Fabrazyme, have been put on hold while the US Food and Drug Administration seeks assurance from the company that none of its inventory is compromised. Genzyme officials believe the inventory was not affected.

The current supply will need to be rationed, Genzyme said.

My first thought was that if Genzyme can charge so much for Cerezyme, at least it ought to be able to afford a pristine production process. On the other hand, I also realized that manufacturing processes in biotechnology are complex and difficult, perfection is not always possible, and the contamination in question did not appear harmful. So I put this article in the file too, and did not post about it either.

Four days ago, the Boston Globe published yet again about troubles in same manufacturing plant.

Genzyme Corp., the Cambridge biotechnology giant that has spent five months scrambling to regain its footing after detecting a virus at its Allston plant, is facing a new contamination problem: bits of steel, rubber, and fiber found in drugs made by the company and shipped from the same site.

Federal regulators yesterday warned doctors to look for foreign particles in five Genzyme drugs used to treat rare genetic disorders, including two - Cerezyme and Fabrazyme - that have been rationed because of the viral contamination detected in the Allston Landing plant last summer. The five drugs represent roughly half of Genzyme’s $4.6 billion in annual sales.

Particles are believed to have been found in less than 1 percent of the Genzyme drugs based on product lots examined, according to a statement from the Food and Drug Administration. The FDA warned physicians, however, to carefully examine vials of the products and filter them before they are given to patients - steps that are considered standard procedure within the industry. If they find particles, the FDA asked for the vials to be returned to the manufacturer. The agency warned that ingesting the particles could have effects that include allergic reactions and blood clotting.

FDA inspectors arrived at the Allston plant last month to begin an investigation into Genzyme’s production operations.

In addition, a New York Times article noted:

'Biological manufacturing is extremely complex and prone to problems,' including contamination, said Jean-Jacques Bienaime, chief executive of BioMarin Pharmaceuticals, a biotech company that also makes drugs for rare diseases, including one it co-developed with Genzyme. Mr. Bienaime said his company always maintained at least a year’s worth of inventory in case of a production outage.

But Genzyme did not have such an inventory of Cerezyme and Fabrazyme.

Finally, today the In Vivo blog posted a discussion of Genzyme's production woes which suggested that the two different types of contamination at the plant, and the failure of the company to reliably ship pure, unadulterated drug to patients were not simply the results of bad luck or failure to attain unattainable perfection.

Friday's announcement that bits of rubber and other detritus were found in vials of five different drugs manufactured at Genzyme's beleaguered Allston Landing plant was worthy of the satirical publication "The Onion"--except that it was true.

The picture grew murkier over the weekend, with the arrival of another Form 483 missive from FDA about ongoing manufacturing issues and a complete response for Lumizyme, Genzyme's enzyme replacement therapy for Pompe disease has been subject of more regulatory twists and turns than the plot of a Dan Brown novel.

The origin of the problem goes back three years, to the original approval of Myozyme, basically the same drug as Lumizyme only manufactured on a much smaller scale, at a 160-liter scale facility in Framingham. Genzyme underestimated the demand for the drug, and plans to shore up capacity with a 4000-liter facility in Belgium were put in place. Only as a stop gap, the company also decided to devote 1/6th of its manufacturing capacity at Allston to the making of the drug.

And that decision has proved problematic. The stress of running an aging plant full tilt meant there was no time for necessary facility upgrades that might threaten the inventory of drugs manufactured at Allston, among them Cerezyme for Gaucher disease and Fabrazyme for Fabry disease. Genzyme CEO Henri Termeer admitted as much in the Nov. 16 investor call, noting '"the introduction of the production of Myozyme in Allston was a very significant factor in the complications we have experienced there.'

Too bad that realization didn't happen one year ago. That's when regulators started sending warning letters outlining concerns related to what sound like bread-and-butter manufacturing issues: microbial monitoring, equipment maintenance, and process controls.

What's most amazing is that problems are ongoing. Recall that six-week interlude this summer when the firm took the entire plant offline to sterilize it after discovering yet another unrelated problem--several bioreactors contaminated with a non-lethal to humans but problematic Vesivirus.

On the company's Nov. 16 call to investors, management confirmed that the latest 483 letter relates not to a new problem created by Genzyme's decontamination efforts but arising because of 'an older piece of equipment'. As Genzyme's EVP of Therapeutics, Biosurgery, and Corporate Operations said during a Q&Asession with analysts, '"There was a number of issues there that they [regulators] highlighted and many of which we were very aware of and working to address.'

Management's solution? Take the plant off line again for a few weeks to, as Meeker puts it, 'allow us to move more quickly to address those issues.' Does everyone feel better now?

In some strange way, the very minor nature of these gaffes is the most damning element of the story. It throws management's judgment into question and again casts doubt on the ability of the current team to resolve a situation that should never have escalated to this level.

So now it is time to discuss Genzyme's production woes on Health Care Renewal.  For $160,000 a year, it seems reasonable to expect that patients could expect a reasonably well-thought out, conservatively planned production process that would be able to reliably produce sufficient quantities of pure, unadulterated drug.  Instead, Genzyme's "remarkable business strategy" did not seem to include adequate maintenance of production facilities with adequate capacities, or even keeping an adequate reserve supply of product in anticipation that over-working a single aging facility with aging equipment might lead to something breaking down. 

By the way, for overseeing this "remarkable business strategy," Genzyme paid its CEO, Henri A Termeer, $13,773,782 in total compensation last year (per the 2009 proxy statement).  Presumably mainly from the stock and option awards he has accumulated over the year, Mr Termeer now owns 4,080,387 shares of Genzyme stock, 1.5% of total outstanding shares.  For that money, patients, share-holders, and line employees ought to expect "remarkable business strategies" that include attention to such basics as good maintenance of production facilities. 

Maybe the company's well compensated (more than $400,000 a year) directors should have been more vigilant about overseeing the management's "remarkable business strategy."  The board  included Gail K Boudreaux, an Executive Vice President of UnitedHealth Group, Charles L Cooney PhD, the Haslam Professor of Chemical and Biochemical Engineering at the Massachusetts Institute of Technology, and Dr Victor J Dzau, Chancellor of Health Affairs at Duke University and CEO of Duke University Health Systems, who seemingly have some relevant expertise, although the board also included Richard F Syron PhD, the former CEO of the Federal Home Loan Mortgage Corporation, (Freddie Mac), who resigned in 2008 after the failure of the company which was later bailed out by the US government.   

So once again we see how leaders of health care organizations, in this case perhaps blinded by the prodigious amounts of money they were making, failed to exercise rigorous oversight over how their company produced its product.  The actual production part of biotechnology may seem far less glamorous than other aspects of the company.  Yet, if a drug company cannot reliably produce pure, unadulterated drugs, all its advanced research, cutting edge finance, and glitzy marketing may be for nought. 

This case is another argument for finding health care corporate leaders who remember that long term success comes from putting patients, not dollars, not glitz,  first. 

Seeking NIH to fund studies on medical ethics, conflicts of interest in medicine and research, and prescribing behavior

Adriane Fugh-Berman MD is principal investigator (PI) of the PharmedOut project. PharmedOut is an independent, publicly funded Georgetown University Medical Center project that educates physicians about industry influence on prescribing. project that empowers physicians to identify and counter inappropriate pharmaceutical promotion practices. PharmedOut promotes evidence-based medicine by providing news, resources, and links to pharma-free CME courses.

PharmedOut is requesting that the U.S. NIH (National Institutes of Health) fund more research into ethics, conflicts of interest, and prescribing behavior. One hundred researchers, clinicians, and ethicists have signed a letter sponsored by PharmedOut asking NIH to fund research on medical ethics, conflicts of interest, and industry influence on prescribing behavior. Stimulus funds have increased the NIH budget by ten billion dollars, but NIH has no mechanism for funding research on how commercial interests affect the choice of medical therapeutics.

Signers include Virginia Barbour MD, Chief Editor of PLoS Medicine, Jerome Kassirer, MD, former editor in chief of the New England Journal of Medicine, Jerry Avorn MD, the Harvard physician who invented academic detailing, Kay Dickersin PhD, Director of the U.S. Cochrane Center, and Susan Wood, PhD, former head of the FDA Office of Women’s Health Research, who resigned over political influence regarding FDA decisions on the emergency contraceptive Plan B. Institutional signers include the Public Library of Science, the American Medical Student Association, the National Physicians Alliance, Consumers Union, the Center for Science in the Public Interest, and the National Women’s Health Network.

The letter, sent to NIH today, is available at http://www.pharmedout.org/NIHLetter.pdf (PDF) and below:

Nov. 17, 2009

From: Adriane Fugh-Berman MD
Department of Physiology and Biophysics
Georgetown University Medical Center
Box 571460
Washington DC 20057-1460
Phone: (202) 687-7845
Fax: (202) 687-7407
ajf29 AT georgetown DOT edu

To: Francis S. Collins, MD, PhD
Director
National Institutes of Health
9000 Rockville Pike
Bethesda, MD 20892

Dear Dr. Collins,

We are writing to ask NIH to fund studies on medical ethics, conflicts of interest in medicine and research, and prescribing behavior. NIH funds a substantial portion of the generation and dissemination of evidence, but the uptake of that evidence and its translation into clinical practice is strongly affected by the complex web of relationships that exists among industry, academicians, medical educators and clinicians.

There is growing evidence that each strand of this web is compromised by ethical lapses and financial conflicts of interest. The recent disclosure of ghostwritten articles, physician payoffs, and the use of academic opinion leaders to increase markets for FDA-regulated products indicate that ethical lapses may permeate biomedical research. A PLoS Medicine editorial in September called ghostwriting “The dirty little secret of medical publishing” and notes “the systematic manipulation and abuse of scholarly publishing by the pharmaceutical industry and its commercial partners in their attempt to influence the health care decisions of physicians and the general public.” [1] An October 1 editorial in the Boston Globe called for a ban on industry speaker fees to physicians. [2] Last month, a commentary in JAMA called for physicians to pay for continuing medical education (CME), [3] citing a recent Institute of Medicine report [4] that criticized physicians’ reliance on industry-funded education.

A stated goal of the NIH is to “exemplify and promote the highest level of scientific integrity, public accountability, and social responsibility in the conduct of science.” Could the muted effect that large, definitive NIH studies, including the WHI, ALLHAT, and CATIE, have had on clinical practice be due to commercial influences? To what extent have ghostwritten articles corrupted the medical and scientific literature? The extent to which industry influences the interpretation of science is unknown.

Dr. Elias Zerhouni, in the September 17th issue of Nature, commenting on Senator Grassley’s investigation of academic medical centers, said “People flouted the rules, didn’t disclose, and did it for years on end, repeatedly.” [5]

In your role as the director of “the steward of medical and behavioral research for the Nation,” we ask that you acknowledge the research gap on the effect of conflicts of interest and commercial influence on medical decisionmaking and set in motion a process that leads to recognition of the importance of funding studies on research ethics, the beliefs and behaviors of researchers and clinicians, and the effects of industry-academic relationships on the generation and dissemination of medical knowledge.

Between bench and bedside lies a path treacherous with ethical quandaries. NIH is the best place to launch and support a scientifically rigorous inquiry into the state of research ethics, industry-academic relationships, and the effect of these relationships on human health. There is currently no identifiable mechanism through which NIH would fund this research.

Your leadership regarding the importance of this issue as one the NIH needs to direct resources towards is essential. We hope to discuss these issues in a face-to-face meeting.

Sincerely,

Adriane Fugh-Berman, MD
Associate Professor, Georgetown University Medical Center
Director, PharmedOut

ajf29 AT georgetown DOT edu
http://pharmedout.org

[and others whose signatures can be seen at the PDF - ed.]

[1] Ghostwriting: The Dirty Little Secret of Medical Publishing That Just Got Bigger. PLoS Medicine, September 8, 2009. http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000156

[2] Keep Doctors Independent; Ban Fees From Drug Makers. Boston Globe, October 1, 2009. http://www.boston.com/bostonglobe/editorial_opinion/editorials/articles/2009/10/01/keep_doctors_independent_ban_fees_from_drug_makers/

[3] Campbell EG, Rosenthal M. Reform of Continuing Medical Education: Investments in Physician Human Capital. JAMA. 2009;302(16):1807-1808.
http://jama.ama-assn.org/cgi/content/full/302/16/1807?home

[4] Institute of Medicine. Conflict of Interest in Medical Research, Education, and Practice. Washington, DC: National Academies Press; April 28, 2009. http://www.iom.edu/CMS/3740/47464/65721.aspx

[5] Wadman M. The Senator’s sleuth. Nature. 2009 Sept;461(17):330-4.

This letter caught my eye, and I expressed support as follows, adding an additional angle to Dr. Fugh-Berman's letter:

Dear Dr. Fugh-Berman,

As a blogger at Healthcare Renewal, I will enthusiastically sign on to and endorse your letter calling on NIH to fund more research into ethics, conflicts of interest, and prescribing. I also wish to add an extended point:

The issues of ethics and conflict of interest also affect healthcare information technology (HIT), and ultimately physician practice. HIT applications are experimental medical devices now being pushed upon physicians via the Office of the National Coordinator and HHS. These medical devices are soon to undergo regulation as such in the EU (pdf report from the Swedish Medical Products Agency here), Canada, the U.S. and other countries as well.

They are used in patient care without patient consent. Their use holds significant potential to monitor and enforce practices deemed appropriate by whomever has the most influence on the bodies controlling the use of these technologies and the data they generate.

From that perspective, and from the perspective of the 2009 National Research Council report that calls for accelerating interdisciplinary research in biomedical informatics, computer science, social science [i.e., the social and ethical implications of health IT], and health care engineering as a sine qua non of health IT success, I believe it is time for NIH to take a leadership role in regulating these devices, conflicts of interest in the health IT industry, and the ethics of their use.

I perhaps should have written "I believe it is time for NIH to take a leadership role in sponsoring research on regulating these devices, conflicts of interest in the health IT industry, and the ethics of their use", rather than calling on NIH to be a regulator. However, until the regulatory affairs concerning health IT are in order, I felt the stronger statement appropriate.

-- SS

Merck Seeks Medical Informatics Dud On The Cheap @ $30/hr

At the post "Medical Informatics, Pharma, Health IT, and Golden Advice That Sits Sadly Unused" and other posts I lamented the fact that the pharma sector (in deep decline due to scientific mediocrity, ill-qualified leadership, public image tarnished by scandal, and other reasons), as well as the Healthcare IT industry (now also racked by similar issues and undergoing a Senate investigation while its products are being found to show little benefit) neglected a scientific discipline that might actually help them achieve the goals of better products, better patient care, and stronger profits.

At that post I specifically wrote about pharma that:

... In recent correspondences with colleagues I was reminded of a letter I wrote seven years ago that was published in Bio-IT World, a journal about biomedicine focusing mainly on pharma, bioinformatics and related fields.

As the sole formally-trained Medical Informatics specialist at Merck, I wrote:

Medical Informatics MIA [Missing in Action - ed.]
Bio-IT World
August 13, 2002

Dear Bio-IT World:

I enjoyed reading the article "Informatics Moves to the Head of the Class" (June Bio·IT World). Thank you for spotlighting the National Library of Medicine (NLM) training programs in medical informatics and bioinformatics, of which I am a graduate (Yale, 1994).

Bioinformatics appears to receive more media attention and offer more status, career opportunities, and compensation than the less-prestigious medical informatics.

This disparity, however, may impede the development of next-generation medicines. Bioinformatics discoveries may be more likely to result in new medicines, for example via pharmacogenomics, when they are coupled with large-scale, concurrent, ongoing clinical data collection. At the same time, applied medical informatics, as a distinct specialty, is essential to the success of extensive clinical data collection efforts, especially at the point of care.

Hospital and provider MIS personnel are best equipped for implementing business-oriented IT, not clinical IT. Implementing clinical IT in patient-care settings constitutes one of the core competencies of applied medical informaticists.

Informatics specialists with a bioinformatics focus — even those coming from the new joint programs — usually are not proficient in hospital business and management issues that impede adoption of clinical IT in patient care settings. Such organizational and territorial issues are in no small way responsible for the low utilization of clinical IT in patient care settings.

It will be important for medical informaticists focused in the clinical domain and bioinformaticists specializing in the molecular domain to collaborate with other specialists in order to best integrate clinical and genomic data.

[note: I was directed to add the "with other specialists" phrase by internal reviewers at Merck; it was not in my original piece. My intent was that bioinformatics and medical informatics specialists collaborate with each other - ed.]

Further information on these issues can be found in the book Organizational Aspects of Health Informatics: Managing Technological Change, by Nancy M. Lorenzi and Robert T. Riley (Springer-Verlag, 1995). Various publications from the medical informatics community, such as the American Medical Informatics Association (www.amia.org) and the International Medical Informatics Association (www.imia.org), are also useful.

Scot Silverstein, MD
Director, Published Information Resources & The Merck Index
Merck Research Laboratories

I was also responsible for the entry of the term "Medical Informatics" into the controlled vocabulary pool used for various purposes at Merck.

After a mere seven years, it looks like someone there has realized the need for Medical Informatics expertise.

Unfortunately, consistent with prior posts including an Open Letter to Merck CEO Richard Clark on informatics, and the observation that bioinformatics has probably hit a hard wall of stagnation due to disciplinary insularity and resultant inadequate collaboration with its medical counterpart, it's clear pharma hasn't yet fully received the message -- in line with this medieval drawing.

I wad directed to this job posting for a one-year Medical Informatics temp position:

Nov. 2, 2009

Position : SCIENTIST –Pharma ("Medical Informatics Scientist"
Location: Boston, MA
Length: 1 YEAR
Rate: $38/hr Max

[Thirty-eight dollars per hour, max? Holy cow - ed.]

Client needs an innovative, talented, agile leader in the field of Medical Informatics --with experience connecting genomic analyses/information with patient medical records -- to help position Merck in the rapidly evolving space of personalized medicine. --solid experience in statistics, bioinformatics, medical informatics, and programming -- 3+ yrs of experience developing and using text analytics and NLP for extraction of information from medical records. -- 5+ yrs of people and project management experience -- solid biology background including experience with oncology vocabularies/ontologies -- experience with genomic data analysis (gene expression, genotyping, sequencing), biomarkers, and pharmacogenetics applied to clinical samples -- 5+ yrs of scientific programming experience -- comfortable working with physicians and IT groups [a "medical informatics" leader would be far more than "comfortable" in such settings - ed.] -- familiar with drug discovery and development process.

*Responsibilities:*

Actual Job Title: "Medical Informatics Scientist" Helps develop and implement Merck's medical informatics strategy, supporting personalized medicine initiatives at Merck. Merck's Partnership with the Moffitt Cancer Research Center will be the main starting point. Collaborates with Merck Therapeutic Areas, and Merck and Moffitt IT groups to prototype medical informatics solutions for collaborative implementation. Provides flexible scripts, prototype data pipelines, DB design, mockups, product management, including requirements for software design and development. Leads collaboration with knowledge management area and leading academic labs to develop/refine text- based natural language processing (NLP) methods for standardizing medical informatics data, defining vocabularies, and building pipelines.

Please send the updated resume of the consultant along with the rate,
location and contact information. Please make sure the Consultant's skills
match the requirement. After reviewing the resume I will contact you if I
need more information.

Thanks,

Anand Bandarupally
Nihaki Systems Inc
346 Georges Road, Suite # 1, Dayton, NJ 08810.

That's a very tall order.

$38 per hour max - as a temp without benefits - probably works out to something like two thirds of that per hour after health insurance, taxes, etc. Not to mention the expense of the Boston area.

So, a "talented, agile leader in Medical Informatics" - who has made the sacrifice to invest time and energy into training in the field - is worth about $30 per hour to a major pharma.

This eyebrow-raising absurdity should really alarm the stockholders, Moffatt Cancer Center leaders, the Boards of both Merck and Moffatt, the leadership of the Medical Informatics community, and anyone with an interest in the development of new medicines and the economic stability that results from success in that domain.

Also, in my view anyone with significant skills who takes such a position at that type of compensation is doing the profession of Medical Informatics a disservice, by further lowering the "comps" for the field, that is, the benchmark data and formulas that HR recruiters use to gauge professional salary ranges. (One might wonder who in fact came up with this penurious figure to begin with).

Put simply, it seems Merck seeks a Medical Informatics dud who will work for peanuts, and probably provide results to match in "building pipelines" of new and safer drugs.

-- SS

The Editorial that Wasn't: Evidence for Systematic Research Manipulation Undetectable by Critical Review

Woe to those of us who have been advocates for evidence-based medicine.  A short description of the evidence-based medicine is medicine whose practice is informed by critical, rigorous review of the best available evidence from clinical research as revealed by systematic search of the published research literature, as well as by the clinician's understanding of biology and the medical and biopsychosocial context, and by the patient's own values.

Evidence-based medicine is based on some key assumptions.  One is that a systematic review will reveal all the results of research studies that are relevant to the issue at hand.  A second is that while the research studies may be flawed and imperfect, they are reported honestly.

Unfortunately, as we have repeatedly discussed, there is more and more evidence that a systematic review will not reveal all relevant results, because research studies may be suppressed, perhaps often, when their results are unfavorable to vested interests.  (Look here for further discussion.)  There is also considerable anecdotal evidence that the design, implementation, and analysis of research studies may be manipulated to make the results more likely to favor vested interests.  (Look here for further discussion.)

An article by Vedula et al just published in the renowned New England Journal of Medicine suggests that such manipulation might be systemic, and that the reporting of manipulated studies may not clearly show what manipulation was done. (1)

To summarize, the authors got access through legal proceedings to internal study protocols and research reports from clinical trials sponsored by Parke-Davis (later merged into Pfizer Inc) of gabapentin (Neurontin) for a variety of clinical problems other than seizures.  Gabapentin was originally marketed as an anti-seizure drug, but Pfizer later "admitted guilt for off-label marketing."  (We discussed the stealth marketing campaign for Neurontin here.)  Vedula et al compared the primary outcome variables specified in the original research protocols, internal research reports, and any publications of the trials' results.  They identified 21 trials, 13 of which were published.  For 12 of the 13, the authors had access to the internal protocol, report, or both.  The main results were:

For 8 of the 12 published trials, there was a disagreement between the definition of the primary outcome in the protocol and that in the published report.... Sources of disagreement included the introduction of an entirely new primary outcome in the published report (in the case of 6 trials); failure to distinguish between primary and secondary outcomes in the published report, even though the protocol did distinguish between them (2 trials); relegation of a primary outcome in the protocol to a secondary outcome in the published report (2 trials); and failure to include in the published report one or more primary outcomes specified in the protocol (5 trials).

Furthermore, it appeared that failure of published articles to clearly and fully report results in terms of the original, pre-specified primary outcome variables occurred when these comparisons were not favorable to gabapentin. As the authors summarized:

Thus, trials with findings that were not statistically significant (P≥0.05) for the protocol-defined primary outcome, according to the internal documents, either were not published in full or were published with a changed primary outcome.

As shown in Figure 3, all the changes that took place between what was specified in the protocol, what was known before publication (as presented in the internal company research reports), and what was reported to the public led to a more favorable presentation in the medical literature of gabapentin's efficacy for unapproved indications.

They concluded:

We are concerned that the reporting practices observed in our analysis do not meet the ethical standards for clinical research or maintain the integrity of scientific knowledge. Fair and honest treatment of patients enrolled in clinical trials of any kind requires full, open, and unbiased reporting. Journal publication, a formalized platform for scientific discourse and dissemination of knowledge, should not be used as a marketing tool for off-label drug use.

Reporting biases such as those we describe here increase the likelihood that interventions will appear to be effective when they are not. Such biases can lead to the omission of negative findings in systematic reviews of intervention effectiveness and in evidence-based guidelines. For example, the 2005 Cochrane systematic review regarding the effectiveness of gabapentin for acute and chronic pain concluded that it is effective on the basis of published findings and should now be updated with the inclusion of unpublished information made available through litigation.

I believe that the article by Vedula et al is particularly important because it shows what appears to be systematic manipulation of the analysis and reporting of multiple clinical trials of the same drug (but for different indications) that had the effect of making the drug appear efficacious when it likely was not. Furthermore, the manipulation was concealed. The published research articles did not completely describe what the intended primary efficacy outcome variables were, did not provide results in terms of these variables, and instead provided results only in terms of variables that were chosen post-hoc as new primary outcome variables.

To address that latter point, I independently reviewed three of the research publications cited by Vedula et al.(2,3,4) All three were noted to have reported significant results favoring gabapentin in terms of a primary efficacy outcome variable that was not identified as such in the corresponding studies' original research protocols or reports (see the supplementary data provided with the New England Journal article.) Per my review, none of the three published articles offered any hint that what they reported as primary outcome variables were not the variables originally chosen in that capacity, nor did they identify what those original primary outcome variables were, or how comparisons made using them turned out.

The implications of the article by Vedula et al are very important. Hence, I was surprised that the article appeared without an accompanying editorial to discuss these implications, and that its publication did not generate much media interest.

So that gives me an opportunity to comment further.

One could start with the implications for evidence-based medicine. As noted above, a short description of the evidence-based medicine is medicine whose practice is informed by critical, rigorous review of the best available evidence from clinical research as revealed by systematic search of the published research literature, as well as by the clinician's understanding of biology and the medical and biopsychosocial context, and by the patient's own values. Evidence-based medicine depends on critical, rigorous review, but the review process is generally done under the assumptions that research publications honestly describe what was done and what its results were. The review process was never designed to detect dishonest reporting or find information that was deliberately concealed. Manipulation of research (design, analysis, and implementation), concealment of that manipulation, and outright suppression of research threaten the foundations of evidence-based medicine. Yet the article by Vedula et al is part of a growing body of evidence that such manipulation, concealment and suppression are widespread, and done to serve vested interests, often commercial.

That is a huge problem for proponents of evidence-based medicine, but also for physicians who want their practices to be based on science, for patients who want their care to be based on science, and for all those in society who see the advancement of medical science as a way to improve peoples' lives.

As senior author Professor Kay Dickersin noted in an interview with Bloomberg "The trouble is, as a scientist, the publication has always been held up to me as the truth. It's the scientific record. What this study indicated is we can't believe that record."

Furthermore, to be a bit more concrete, most physicians, patients, and policy makers depend on what appears to be honest clinical research to make decisions about individual care and health policy. Deliberate and deceitful manipulation of clinical research to favor sponsors' products has likely lead to excessive use of and payments for drugs and devices that are less effective than advertised, if not useless or dangerous. Thus, it is likely that such manipulation is partially responsible for ever increasing health costs and poor health outcomes.

Finally, we need to start thinking about how we can detect and compensate for manipulation of clinical research in the past, and deter such manipulation in the future. One possible deterrent would be, as was noted by Vedula et al, detailed clinical trials registries that contain complete information about trial protocols.  For this to be effective, there need to be mechanisms to assure compliance, and penalties for non-compliance.  Moreover, since clinical research is now global, the registries must have global scope, and enforced assurance of compliance must also be global.

Registries might decrease future manipulation and suppression of research.   No one has suggested, as far as I know, a systematic way to detect and correct for previous manipulation. It would require a major, global investigative effort to uncover manipulation, and it would be a major scientific and policy endeavor to reveal most suppressed research and correct most manipulations.

However, before anything is done, patients, physicians and policy makers must acknowledge and understand the problem.  Yet it seems that even discussing these may be topics that are very uncomfortable for some of us. The longer we shrink from addressing them, however, the worse will be the results for patients, physicians, science and society.

References


1. Vedula SS, Bero L, Scherer RW, Dickersin K. Outcome reporting in industry-sponsored tirals of gabapentin for off-label use. N Engl J Med 2009; 361: 1963-1971. Link here.


2. Mathew NT, Rapoport A, Saper J et al. Efficacy of gabapentin in migraine prophylaxis. Headache 2001; 41: 119-128. Link here.


3. Vieta E, Goikolea JM, Martinea-Aran A et al. A double-blind, randomized, placebo-controlled, prophylaxis study of adjunctive gabapentin for bipolar disorder. J Clin Psychiatr 2006; 67: 473-477.  Link here.


4. Caraceni A, Zecca E, Bonezzi C et al. Gabapentin for neuropathic cancer pain: a randomized controlled trial from the gabapentin cancer pain study group. J Clin Oncol 2004; 22: 2909-2917. Link here.

Omnicare, IVAX Settle

Settlements and kickbacks and corporate integrity agreements, oh my (to the tune of "lions and tigers and bears, oh my")

To quote the BusinessWeek version of the story:

A $112 million settlement involving alleged drug kickbacks that the Justice Dept. announced with the nation's largest nursing home pharmacy and a generic drug manufacturer on Nov. 3 is part of a wide-ranging investigation of suspected Medicaid fraud by the pharmaceutical industry.

Under Tuesday's settlement, Omnicare will pay $98 million plus interest to the federal government and a number of state Medicaid programs to settle allegations that it participated in kickback schemes with IVAX, J&J [Johnson & Johnson], and two nursing home chains. IVAX, a subsidiary of Israel's Teva Pharmaceutical Industries (TEVA), agreed to pay $14 million plus interest.

Omnicare and IVAX entered 'corporate integrity agreements' to establish new training and policies to prevent future problems. Neither company admitted any wrongdoing.

Here are some details of the alleged wrong-doing:

Omnicare is a publicly traded pharmacy benefit manager for long-term care facilities that operates in 47 states, the District of Columbia, and Canada. It had revenues of $6.3 billion in 2008.

According to the settlement, Omnicare allegedly received $8 million in payments from IVAX in 2000-04 to buy $50 million in generic drugs and recommend that physicians prescribe them to their nursing home patients. Omnicare entered the contract even though its outside counsel repeatedly warned it might violate the federal anti-kickback law, the government alleged in its complaint, filed in March. Omnicare also took payments from New Brunswick (N.J.)-based J&J from 1999 to 2004 to aggressively persuade doctors to prescribe Risperdal, an anti-psychotic drug, and discourage use of alternative medications, according to the settlement.

In addition, Omnicare allegedly paid $50 million to nursing home chains Mariner Health Care and SavaSeniorCare in 2004 to keep referring their Medicaid and Medicare patients to Omnicare for pharmacy services.

It is noteworthy that these activities went on despite repeated advice of at least one attorney:

According to the government's complaint, Omnicare again ignored its outside counsel's advice that the payment was illegal.

The activities also went on despite Omnicare's participation in a previous corporate integrity agreement.

This isn't the first time Omnicare has had to settle civil fraud complaints filed by the government. In 2006, Omnicare agreed to pay $102 million to settle Medicaid fraud cases in 43 states, without admitting wrongdoing, including a $52.5 million settlement with Michigan. One complaint accused Omnicare of switching two drugs from tablet to capsule form to boost Medicaid payments. Omnicare had to enter a five-year corporate integrity agreement.

As I have written again and again regarding many other cases that resulted in legal settlements or guilty pleas, the companies involved only need to pay fines, and no individual who performed, directed or approved unethical or illegal acts will suffer any negative consequences. I submit once again that such fines are viewed merely as costs of doing business by the affected companies, and do not deter future bad behavior.

For once, the coverage of this case included some opinions similar to mine:

The Office of Inspector General of the Health & Human Services Dept. has the authority to bar health-care companies from participating in the Medicaid, Medicare, and other federal health programs as a penalty for violating anti-fraud laws. That's a severe sanction given the huge size of those programs. The settlements with Omnicare and IVAX left open the possibility of exclusion.

Some experts say Omnicare should be barred as a repeat offender, to send a strong message to other pharmaceutical industry players that fraud will no longer be tolerated. 'If the government were really serious, they'd give Omnicare the death sentence,' said Erik Gordon, a business professor at the University of Michigan who follows the pharmaceutical industry. 'Then all the other players would say this isn't just the cost of doing business, this is a bet-the-company thing.'

West declined to comment on whether the Justice Dept. will recommended the exclusion of the two companies, saying only that his office works closely with the OIG's office on appropriate penalties.

[Patrick] Burns, with Taxpayers Against Fraud, said the government has been hesitant to exclude health-care companies for fraud, fearing it will be seen as overzealous. But he believes that's the wrong attitude. 'Doing business with the U.S. government is a privilege, not a right,' he said. 'I think Omnicare has abused the privilege.'

Finally, note that the description of this case suggested that the kickbacks had effects on physicians' prescribing and hence the use of specific drugs. The Justice Department's filing alleged that in return for the payment from IVAX, Omnicare tried to get physicians to prescribe that company's products, and that in return for the payment from J&J, Omnicare pushed them to prescribe the atypical anti-psychotic Risperdal. Thus the activities that went on this case could have lead to the use of inappropriate, useless or even harmful drugs by certain patients.

I submit that would-be health care reformers who want to improve care, reduce costs and improve access should advocate for real negative consequences for people who implement, direct or approve the various versions of fraud, kickbacks, and miscellaneous corruption and malfeasance we have discussed on Health Care Renewal.

By the way, it appears one of the members of Omnicare's Board of Directors is also a leader in academic health care.  She is Andrea R. Lindell, DNSc, RN, who is also Dean of the College of Nursing at the University of Cincinnati.  One would think that someone who thus boasts "the success of our students, faculty, staff and alumni who work together to promote excellence in education, research, service and practice" needs to keep a closer eye on the ethical aspects of her company's management.

Suppression of Clinical Trials of Sumatriptan

Correspondence to the Lancet two weeks ago revealed another instance in which clinical research studies that failed to provide results favorable to a sponsor's product were suppressed. [Tfeft-Hansen  PC. Unpublished clinical trials of sumatriptan. Lancet 2009; 374: 1501-2.  Link here.]

Sumatriptan, sold as Imitrex by GlaxoSmithKline, and now available generically, is a commonly used treatment for acute migraine headaches.  A Cochrane review from 2003 concluded that multiple clinical trials versus placebo showed that the drug is a safe and effective treatment of acute migraine [link here.]  A comparison of multiple guidelines for headache treatment noted considerable variability in how guidelines were developed, but that a number recommended sumatriptan as a first-line agent based apparently mainly on trials against placebo, while noting a lack of head-to-head comparisons among sumatriptan (and other triptans) and older, simpler treatments, like non-steroidal anti-inflammatory drugs (NSAIDs).  [Schuurmans A, van Weel C. Pharmacologic treatment of migraine: comparison of guidelines. Can Fam Physician 2005; 51: 838-843.  Link here.]

Tfelt-Hansen had written a review of treatment of migraine with a combination of ergotamine and caffeine, which included a single trial comparing that combination to sumatriptan.  He noted that the results of this trial appeared on "the homepage of the Swedish Medical Agency," but were not published in a peer-reviewed journal.  The trial suggested that sumatriptan was inferior to the combination. 

Tfelt-Hansen looked up this trial in the GlaxoSmithKline trial register.  Recall that this database was the source of information on unpublished trials of Avandia (rosiglitazone, GSK) that Dr Steven Nissen and colleagues meta-analyzed to suggest that Avandia may produce adverse cardiovascular effects (see post here).   Recall also that the registry was created as part of a settlement of a lawsuit by then New York Attorney General Elliot Spitzer that accused GSK of concealing clinical research unfavorable to its drug paroxetine (Paxil, GSK).  [Steinbrook R. Registration of clinical trials - voluntary or mandatory? N Engl J Med 2004; 351:1820-1822.  Link here.]

Tfelt-Hansen's main finding was that there were six trials comparing sumatriptan to other treatments, including paracetamol (acetaminophen) plus metaclopamide (2 trials), buclizine chloride, paracetamol and codeine (2 trials), ergotamine tartrate, cyclizine HCl, caffeine (1 trial), and ergotamine tartrate plus caffeine (1 trial).  In 3 trials, sumatriptan treated patients were not significantly more likely to have relief of their headaches within 2 hours.  In 1 trial, there was a non-significant trend favoring sumatriptan.  In two trials, sumatriptan was superior to the comparison.  In 4 trials, the rate of relief after sumatriptan treatment was 50% or less. 

Tfelt-Hansen concluded:

It is easy to understand why these RCTs were never published when sumatriptan was introduced: in only one of the oral trials did more than 50% of patients have headache relief (the primary efficacy measure) after sumatriptan 100 mg for the first attack treated (table), and in the RCT with rectal sumatriptan, the drug was found inferior to ergotamine. These findings would at the time have spoiled the very positive picture of sumatriptan as a new wonder drug for migraine.

Of course, this points out that health care corporations may regard clinical trials more as marketing tools than as science. We have discussed numerous instances in which trials that did not show commercial sponsors' products in a favorable light were suppressed by these sponsors.

Individual trials only at best produce approximations of the truth about the drugs or devices they compare. Trials may be positive due to chance alone when the test or treatment under study actually has no good effects. Post-hoc suppression of "negative" trials therefore may exaggerate the benefits (and safety) of tests or treatments. Physicians and patients who try to uphold the ideals of evidence-based medicine, and base decisions on the best possible evidence can be misled when evidence unfavorable to vested interests is systematically suppressed. Suppression of evidence unfavorable to vested interests may lead to excess use of tests and treatments that really are less beneficial or more risky than the published evidence suggested, and to willingness to pay exaggerated prices for such tests and treatments. Thus suppression of evidence can lead to excess costs and bad outcomes.

Also, as we have said before, suppression of results of clinical research that are unfavorable to the vested interests of research sponsors violates the trust of research subjects.  Research subjects are often assured that their participation is for the benefit of science and health care.  Suppressing results unfavorable to vested interests distorts science and makes health care more dysfunctional.

Evidence that is purposefully suppressed is by definition hard to find. Nonetheless, we have seen several recent examples in which suppressed evidence was later revealed, and when combined with existing evidence, showed that previously hyped treatments were really not as safe and effective as was thought.  In particular, the suppression by various drug companies of evidence unfavorable to new anti-depressants they were marketing has generated some discussion (see post here).

This parade of examples suggests that stronger measures are needed to assure that clinical research is not suppressed due to the vested interests of research sponsors.  One seemingly radical, but increasingly plausible approach would ban corporations that sell health care products or services from influencing clinical research done to evaluate those products.  Would be health care reformers who really want to improve outcomes, improve access and decrease costs might want to think about how to make the evidence available about the outcomes of health care interventions more honest.

Boston Scientific to Plead Guilty (of Suppressing Information about Failure-Prone Defibrillators)

In the early days of Health Care Renewal (2005-2006) we posted several times about allegations that Guidant hid information about defects in the implantable cardiac defibrillators (ICDs) the company manufactured.  As we noted in early 2005 here, Guidant executives allegedly knew that ICDs made from 2000-2002 were at risk for short-circuiting and failing, thus making them unable to deliver potentially life saving electrical shocks meant to prevent cardiac arrests, but the company only revealed the problem in 2005.  By failing to notify physicians and the public, Guidant executives let expensive and profitable, but potentially useless devices to continue to be implanted, potentially increasing the risk of sudden death for the patients who received them.  Then here we noted reports that Guidant continued to ship failure-prone devices even after it had designed and started to manufacture new ICDs that were supposed to be less likely to fail.  By June, 2005 we posted that Guidant had recalled thousands of ICDs, including models that were previously not identified as likely to fail.  Later that year, the case rated an article by Robert Steinbrook in the New England Journal of Medicine.  Towards the end of 2005, we noted that Eliot Spitzer had sued Guidant for fraud.  At the end of the year, more information appeared, suggesting that Guidant knew the ICDs were flawed, but continued to sell them.  Still more appeared early in 2006.  Then the business media became interested in the bidding war between Johnson and Johnson and Boston Scientific for Guidant, provoking a bit more interest in the tale of the suppression of data about the flawed ICDs.

And then there was silence.  The story of the suppressed information about the defective defibrillators became old news, as did the story of the merger between Boston Scientific and Guidant.  The story vanished, nothing more happened, until last week

A lone echo from this story from what now seems long ago was heard, as reported by Bloomberg,

Boston Scientific Corp. agreed to pay $296 million to settle a U.S. Justice Department investigation into its Guidant unit’s handling of heart devices and restated third-quarter results to show a loss.

Guidant will plead to two criminal misdemeanors for failing to properly alert the U.S. Food and Drug Administration about problems with some of its implantable defibrillators, Boston Scientific said today in a statement. The probe concerned product advisories sent by Guidant before its acquisition by Boston Scientific in April 2006, the parent company said.

So even though Boston Scientific's now subsidiary Guidant will plead guilty to a crime involving suppression of information about the flaws in its defibrillators, the current CEO of Boston Scientific denied anyone did anything wrong:

'Guidant and its employees acted in good faith and believed they complied with applicable laws and regulations,' Boston Scientific Chief Executive Officer Ray Elliott said in the company’s statement. 'We elected to resolve this matter so we could put it behind us and devote our full energies and resources to developing our innovative technologies.'

I guess it's not hard to put a little matter of criminal conduct behind a big health care corporation and its leaders when the only downside of pleading guilty is a fine paid seven years after the criminal conduct occurred.  Moreover, that fine that will come out of the company treasury, and its impact will thus be spread among stock-holders, employees, and customers, not targeted at those who performed, directed or approved the acts that lead to the guilty plea.

Although the Bloomberg report was more detailed than others I found, none mentioned that the information that was concealed back in the day was about the failure of an expensive device that was supposed to be life-saving, and whose failure might doom some of its recipients to an early death.  Anyone reading these late 2009 articles would get a sense that Guidant personnel were guilty of some technical reporting violations, not of withholding information that supposed life-saving treatments might be useless.

As in the case of many other cases that resulted in legal settlements or guilty pleas, the company involved only needs to pay a fine, and no individual who performed, directed or approved unethical or illegal acts will suffer any negative consequences.  I submit once again that such fines are viewed merely as costs of doing business by the affected companies, and do not deter future bad behavior.

In this vein, note that in 2005, Boston Scientific agreed to a $74 million settlement of charges that it knowingly sold a defective coronary artery stent system (see post here), which did not deter the company from merging with Guidant. 

This case also demonstrates how the anechoic effect continues.  Bad behavior by large health care organizations still gets little notice, and when it is noticed, its real clinical and human effects are discounted. 

Real health care reform would address how leaders of health care organizations can continue to act with impunity even when their actions can lead to sickness, disability, and death. 

Academic Freedom and ED EHR's Down Under: Another Update and a Welcome Development

In "Academic Freedom and ED EHR's Down Under: An Update" I wrote about the disputed essay on electronic health record (EHR) problems in the Australian state of New South Wales (NSW) by medical informatics professor Dr. Jon Patrick, Health Information Technologies Research Laboratory (HITRL), University of Sydney.

The essay was entitled "A Critical Essay on the Deployment of an ED Clinical Information System ‐ Systemic Failure or Bad Luck?"

I am happy to report that an updated version of the essay, version 5, is now available from Dr. Patrick's university web site at http://www.it.usyd.edu.au/~hitru/index.php?option=com_content&task=view&id=91&Itemid=146 . It can be downloaded from the icon at Item 6.

This is a welcome development.

The essay is now labeled as an Op-Ed (Opinion Editorial).

-- SS

The Kelo Case Redux Once More: Pfizer Pulls Out and the "Carefully Formulated" Development Plan Collapses

Four years ago we posted (here, here and here) about the controversial US Supreme Court decision in the Kelo case. Most discussion of the case at the time focused on individual property rights vs the power of the government to promote economic development, but the case had an important health care angle.

Briefly, the case centered on the taking of private property, including a house owned by Susette Kelo, by a not-for-profit organization, the New London (Connecticut) Development Corporation (NLDC) given the power of eminent domain by the New London city government. While the ostensible rationale for the taking was economic development, the action appeared to have been at the behest of Pfizer Inc, the world's largest pharmaceutical company, which had built a research and development facility in the city, and wanted a suitably upscale and sanitized environment for its workers.

As we previously posted, the NLDC's leadership had multiple conflicts of interest that involved ties to Pfizer. One board member was a Pfizer vice-president. The board president was married to another Pfizer vice-president. Pfizer wanted the part of New London that included Kelo's house made more attractive to complement its new research facility. The husband of the NLDC president had said, "Pfizer wants a nice place to operate. We don't want to be surrounded by tenements."

Kelo's and other property owners' protest of the taking went all the way to the US Supreme Court. As we posted here, the Court decided against the property owners by a 5-4 vote. Justice John Paul Stevens wrote for the majority that the city's "determination that the area was sufficiently distressed to justify a program of economic rejuvenation is entitled to our deference. The city has carefully formulated an economic development plan that it believes will provide appreciable benefits to the community, including - but by no means limited to - jobs and increased revenues." This majority opinion is important, because the Fifth Amendment to the US Constitution provides "nor shall private property be taken for public use without just compensation." Many had interpreted this provision to mean that eminent domain could only be used to take property for public use, e.g., to build a road or a public school, but not for private purposes, like building upscale waterfront developments.

Two months ago, we posted on how the supposedly "carefully formulated" development plan had fallen apart.  The land on which the Kelo house stood had never been developed, and remained a weedy lot.
 
This week, the (New London) Day reported:

Eight years after opening its state-of-the-art global research-and-development headquarters in New London, Pfizer Inc. announced Monday it will close the nearly $300 million complex within the next two years and consolidate local operations into its Groton campus.

Why did Pfizer decide to close the facility?

Pfizer earlier this year said nearly 20,000 jobs would be cut as a result of its merger with the New Jersey-based Wyeth. The company said Monday that about 15 percent of its overall R&D work force would be cut as part of that downsizing.

The result apparently will be the complete dissolution of the "carefully formulated" development plan.

The announced closing of the New London site came as a blow to a city that had counted on Pfizer to help revive its fortunes.

The loss of Pfizer as a keystone business in New London could put in further jeopardy the Fort Trumbull development that started in conjunction with Pfizer's move into the city but has left little but flattened buildings and eminent-domain angst in its wake.

So, the unfortunate Kelo case has become a vivid demonstration how badly government does when it partners with businesses and tries to pick corporate winners and losers.  Unfortunately, it seems that much of what passes for US health care policy is such "corporate socialism."  As we said before, instead of trying to pick corporate winners and losers, government would do better to act like a combination of an honest policeman on the beat, deterring and punishing dishonest behavior, and in impartial referee, trying to make sure everyone is playing the game honestly. But no doubt government officials used to mingling with the corporate superclass would not be comfortable in the roles of honest cop or impartial referee.

See also comments on the Volokh Conspiracy blog.  Hat tip to the PharmaLot blog.

Health IT Personnel: Want To Bone Up On Technology? Try This

An interesting article appeared in an IT journal that merits brief mention with respect to electronic health records:

"Want to bone up on wireless tech? Try ham radio"
Computerworld, October 29, 2009

I find it interesting in that in no interaction that I recall with IT personnel, my amateur radio background and the deep understanding of technology it imparted seemed of interest or value to them.

Key point in the article:

"For IT professionals, ham radio can foster skills that are translatable into real-world wireless and wired networking applications."

I would extend this to many other IT-dependent areas.

Unfortunately, many IT personnel - and many so called physician directors of information systems - seem to be "appliance operators", a term hams use to describe people who can push buttons but lack a depth of understanding of what goes on "inside the box". Also expressed in ham radio terms, I have found most IT personnel in hospitals to be at the "CB operator" level of technological understanding, where "computer" equates to "cybernetic miracle," and computerization equates automatically to "improvement."

Breaker, breaker, big buddy!

For IT personnel, studying and then securing a ham radio license and experimenting might give them the technical skills they need to be more fully in control of their systems, rather than the systems being in control of them.

This physician-informaticist diagnosing and treating ailments in an electronic patient, the classic Ten Tec Corsair II amateur radio transceiver.

Such expertise could also help ameliorate the problems noted on this site regarding healthcare IT.

-- SS

(Amateur radio, extra class)

Paging (and Paying) "Dr Coca-Cola"

A few weeks ago, the Los Angeles Times Booster Shots blog announced that "Dr. Coca-Cola will see you now," noting opposition to the recently revealed alliance between the Coca-Cola Company and the American Academy of Family Physicians:

[in] a sharply worded letter sent Wednesday to Dr. Douglas E. Henley, the academy’s chief executive.

'We urge the AAFP to regain its credibility by rejecting the deal with Coca-Cola,' the letter stated. 'If the AAFP declines to do that, we urge your organization to reassert its support for the public health (and its own independence) by supporting a warning label on caloric sugar-sweetened beverages and a federal tax on soft drinks to support health promotion or health insurance programs.'

The letter was signed by 22 doctors, nutritionists and health advocates,

Dr Henley was not moved:

Henley told Food Navigator-USA.com that the academy was aware of the letter. But he stood by the partnership with Coke.

'We will move forward with this commitment together by providing educational materials on sweeteners and how to maintain a healthy, active lifestyle while still enjoying many of the foods and beverages consumers love,' he said in a statement.

Nonetheless, criticism of the deal has continued. A Kansas City Star editorial said:

the Leawood-based American Academy of Family Physicians has set a poor example when it comes to resisting the lure of the soft drink industry.

The academy has accepted a grant from Coca-Cola, reportedly in the neighborhood of $500,000. It will use the money for educational materials about drinks and sweeteners for its consumer Web site, FamilyDoctor.org. Leftover funds will go into the academy’s general budget.

In return, Coca-Cola gets what? Legitimacy, for one thing. Consumers are less likely to consider a product unhealthy if it’s listed as a partner with a leading physicians’ alliance.

In a more shameful scenario, the soft drink manufacturer would succeed in muting the message that the academy puts out to its consumers.

The editorial did not buy Dr Henley's assurances:

Academy leaders say they won’t allow the hefty corporate grant to compromise the organization’s integrity.

'We have total editorial control, as we always have, of FamilyDoctor.org,' said Executive Vice President Douglas Henley.

Henley added, 'I would hope folks won’t rush to judgment but hold us to the content we’re going to put on FamilyDoctor.org.'

But consumers accessing that information will soon be informed that information about soft drinks is being sponsored in part by Coca-Cola, 'a proud partner of FamilyDoctor.org.'

That’s a mixed message, regardless of the content.

Meanwhile, family physician and AAFP member Dr Howard Brody noted on his Hooked: Ethics, Medicine and Pharma blog how AAFP leaders continued to obfuscate:

AAFP President Dr. Lori Heim: obesity is more complex and that 'there's no one evil out there.'

Why does the question of whether it's a good idea for AAFP to take money from Coke so quickly segue into the question of whether Coke is 'evil'? (For our blogger colleague who likes logical fallacies, Roy Poses, this sounds like "straw man." [It sure does - Editor]) Why does it have to be: either they are evil or else it's just fine for us to take their money? What cannot it simply be that they have different interests--they are trying to make a buck selling beverages (some of which I enjoy drinking myself, I am pleased to report, if they don't have calories in them) while AAFP is trying to protect the public interest through credible health education? What part of conflict of interest don't you understand?

Some AAFP members went beyond criticism, as reported by the AP:

Dr. William Walker, public health officer for Contra Costa County near San Francisco, likened the alliance with ads decades ago in which physicians said mild cigarettes are safe,

Walker has been a member of the academy for 25 years but quit last week. He said 20 other doctors who work with his local medical practice also quit because of the Coke deal.

Nonetheless, as Dr Brody later posted,

Sadly, if the responses to this news report from AAFP leadership are accurate, the AAFP still does not get it. '[AAFP CEO Dr. Douglas] Henley said the academy regrets the resignations and hopes other members will not 'rush to judgment' before seeing the new content." News flash: we don't need to see the content to know there's something rotten in Denmark. The deal itself raises concerns about the credibility of anything AAFP posts about diet and obesity from now on.

So here we have the latest variant on institutional conflicts of interest affecting medical associations. We have noted (e.g., here) how professional societies have blithely accepted substantial funding from corporations which sell products physicians may prescribe for or implant in patients. This raises concerns that professional societies have become drug and device marketers. This conflicts with physicians' prime directive, to put the interests of individual patients ahead of their own, and hence to base decisions on which drugs to prescribe, tests to order, and procedures to do on maximizing benefits and minimizing harms for individual patients, not maximizing financial gain for physicians, or their organizations.

Family physicians are a respected source not only of decisions about tests and treatments, but about diet. Having the main family physician organization humming "things go better with Coke" suggests that professional advice could be co-opted by marketing. As Dr Brody noted above, the issue is not whether the product is good or bad, but is whether physicians are giving each patient the best possible advice.

One question implied by the "Dr Coca-Cola" story is why the leadership of the AAFP seems so oblivious to the conflict of interest issues it raises.  As Dr Brody wrote:

What's even more depressing is that with the whole world telling them that they mishandled this affair, the AAFP still seems to think that the problem is someone else's.

I appreciate Dr Brody's depression, but note that this is not the first time that AAFP leadership has seemed tone deaf to the issue of the organization's institutional conflict of interest. In 2005, we posted how the AAFP had banned the "No Free Lunch" organization, which opposes most pharmaceutical marketing to physicians, from appearing in the exhibit hall of its annual meeting. The exhibit hall was otherwise populated by lavish exhibits by pharmaceutical and other health care corporation marketers.

The abstract for a 2006 article in Family Medicine [Standridge JB. Of doctor conventions and drug companies. Fam Med 2006; 38(7):518-20. Link here] began:

Pharmaceutical companies provide the majority of financial support for staging the American Academy of Family Physicians (AAFP) Annual Scientific Assembly. In return they are allowed to dominate the physical and mental environment.

The current web-site for the AAFP Foundation boasts of its corporate partners, which include many of the biggest pharmaceutical and biotechnology companies (at the "Pinnacle" level, Amgen, AstraZeneca, Lilly, Purdue Pharma.

So adding Coca-Cola to the list of corporate sponsors does not seem like such a big step.  In fact, being "Dr Coca-Cola" does not seem intrinsically more questionable than being "Dr Amgen," "Dr AstraZeneca," etc.

Nonetheless, one would think that the latest round of criticism would make the top leaders of this august professional society less comfortable about the organization's financial relationships with pharmaceutical, biotechnology, and now beverage corporations.  I fear, though, that they may live too much in the sort of bubble that now protects top executives of most large health care organizations to really question their corporate ties.  After all, according to the most recent (2007, covering 6/2007-5/2008) US Internal Revenue Service form 990 filed by the AAFP (via Guidestar), its leaders get sufficient compensation to put them into such a bubble.  For example, Dr "Coca-Cola" Hensley received $441,027 regular compensation and $108,930 in benefits and deferred compensation, compared with a median compensation for family physicians in 2008 reported as $159,000 from one survey.  Presumably "voluntary" officers got five- and six-figure "expense accounts and other allowances," maxing out at $195,648 for then President Dr James B King.  It may be hard for leaders who are so comfortably recompensed by the organization to become uncomfortable about the financial relationships that make the largesse they receive seem less of a burden for members who may not be so well-paid.  The leaders' comfort with the current arrangement, however, makes their organization more liable to be viewed as a drug, device, and now beverage marketer rather than a defender of physicians' professionalism.  Maybe the leaders should accept more austere compensation, perhaps similar to what working family doctors get paid, as the price they need to pay to remove questions about their organization's real commitment to professionalism.

Academic Freedom and ED EHR's Down Under: An Update

At the post "Academic Freedom Curtailed?" I wrote:

The essay on Emergency Department electronic health record (EHR) problems in the Australian state of New South Wales (NSW) by medical informatics professor Dr. Jon Patrick, Health Information Technologies Research Laboratory (HITRL), University of Sydney, that I referenced in my posts "The Story of the Deployment of an ED Clinical Information System ‐ Systemic Failure or Bad Luck" and "NSW Nightmare and Overuse of Computers" appears to have been censored. This apparently occurred at the level of the the government.

Professor Patrick has updated his web page that formerly contained a link to his essay on problems with EHR's in that state's EDs.

He advises:

... This document has been temporarily withdrawn by the university following a complaint from NSWHealth. I think the University has acted appropriately by investigating the complaint and I do not yet consider it an act of censorship. I am working through the issues with the University and expect that the essay will be re-published.

I would like to thank all the people who have written to me to offer support and I would encourage you to write to me if you are interested in the matter so that i can demonstrate to the university the importance of this issue to both the Australian and international communities. I do not wish for people to write to anyone else but me. I have no wish to run a public campaign and I am not available for statements to the press about this particular matter. This matter has brought to light many interesting and illuminating things that i will be happy to share in the next version of the Critical Essay.

Jon Patrick 27th October 2009 0930 Eastern Australian Summer time

He then follows up with this:

Update on the withdrawal of "Essay No.6"

It is now two weeks since the original essay was withdrawn. In that time I have been able to establish confidently that NSWHealth phoned my Head of Department and asked him to remove the article without giving a specific complaint. He refused. Subsequently a person from another faculty took up the cause and succeeded in persuading an appropriate person to order withdrawal of the essay. To this time i have not received a specific complaint let alone a written complaint. The Univeristy's Office of General Counsel has studied the essay at my request through my Dean, and found that it is "consistent with the University's Public Comment Policy". I am awaiting further investigations by the University.

Subsequently I have received many messages of support from around the world, and importantly much more information to be included in the essay. I am preparing a much enhanced version.

5th November 2009 1150 Eastern Australian Summer time

I sincerely hope this matter will be resolved in favor of dissemination of the enhanced and updated piece. I think it contains information that is quite valuable to a worldwide audience of clinicians, IT vendors and patients.

I also note that those who aim to suppress a document such as this in the age of informational computing, one product of which is the Internet, should be confined to using only the Commodore PET due to their technological and sociological ineptitude:

State-of-the-art computing for the would-be Health IT article police

-- SS

Addendum

Nov. 10, 2009, evening EST:

The essay in version 5 is once again available as Item 6 at http://www.it.usyd.edu.au/~hitru/index.php?option=com_content&task=view&id=91&Itemid=146 .

-- SS

Is Someone at Jefferson Regional Medical Center Lying About EHR Safety?

This curious story appeared about apparent clinician health IT safety concerns at Jefferson Regional Medical Center near Pittsburgh:

Switch to electronic records alarms Jefferson Regional physicians

By Walter F. Roche Jr.
PITTSBURGH TRIBUNE-REVIEW
Friday, October 30, 2009

Jefferson Regional Medical Center's attempts to convert to electronic medical records have some doctors concerned about patient safety.

In a memo issued this month, the hospital's Health Information Technology Committee announced the 373-bed facility in Jefferson Hills would revert to printed versions of patients' consultant reports "due to patient safety concerns from the majority of physicians."

Jefferson executives downplayed the memo and said they found no evidence that patient safety has been impacted, arguing a small group of physicians expressed concerns and not a majority, as the memo claimed.

"It was a very small number that were concerned. It wasn't the majority," said Dr. Richard F. Collins, Jefferson's vice president for medical affairs. "To this point, we haven't identified any issue of patient safety."

Now, one or the other must be true. Either a majority of physicians expressed concerns, or a small number did. Both cannot be true. Assuming the account in the Pittsburgh Tribune Review is accurate, someone is lying.

I should point out that the numbers ultimately do not matter - patient safety issues should never be determined via a headcount, and in fact hospital governance obligations under the Joint Commission and their own fiduciary responsibilities mandate the utmost conservatism and due diligence on safety concerns.

Perhaps the executives did find "no evidence" of safety issues. Regardless, I raise the following questions:

• How was such a study performed, how were physicians and other clinicians involved in the study, and was it a rigorous study using validated methodologies, or cursory?

• Who is most motivated to find an HIT system "safe", the HIT Committee and clinicians, or the administration?

I have served on HIT Committees; led them, in fact. Those committees "have the pulse" of clinician sentiment, even when they do not conduct formal surveys. In hospitals, the walls have ears, and the clinicians on HIT Committees understand what their colleagues are feeling - usually via direct and sometimes confrontational conversations.

HIT Committees charged with making HIT successful do not generally pull back from HIT projects without very good reason.

On the other hand, hospital executives who have signed off on investments of millions or tens of millions of dollars in IT investments do have a strong motive to ensure all goes well - either in reality or in the narrative they proffer.

This is especially true when conflicts of interest exist.

According to [VP for Medical Affairs] Collins and James Witenske, Jefferson's chief information officer, the transition [to EHR] began about a year ago and was completed in May. The hospital uses a system developed by Siemens, Collins said. He declined to disclose the cost.

I find this an interesting finding. After a short Google search, the following appeared:

Western Pennsylvania Hospital News

20 Years of Hospital Information Technology
by John Fries
(December 2005)

... James Witenske is chief information officer at Jefferson Regional Medical Center, having left Arthur Andersen four years ago to accept the position. Before working at the Big Eight firm, he served as chief information officer at UPMC Health System.

At Jefferson, IT takes place a bit differently that at other healthcare institutions. Where most hospitals have an IT department with staff, Witenske works almost exclusively with outside experts, one of whom is Ron Forys, a Siemens site executive who is based at Jefferson. It’s a complementary relationship – Witenske’s role is strategic and Forys’ is operational. Both are longtime technology professionals who have seen huge changes take place during the past two decades.

The hospital had/has its own vendor representative in a front line role, and apparently shied away from having its own IT staff. A person who comes from a consulting firm uses consultants whose loyalty is to the vendor, not the hospital, one of them as his operations guy.

This raises a number of questions:

• Who paid/pays the Siemens Site Executive? The hospital, the vendor, or both?
• Who did/does the Site Executive report to?
• Did/does not the Site Executive have a conflict of interest with regard to physician opposition to the vendor's system?
• What was/is the financial relationship between hospital executive leadership and the Site Executive? Between hospital executive leadership and the vendor?

These type of arrangements do raise my eyebrows, and the discrepancy between the HIT Committee's memo and the hospital executive's account, both of which cannot be true, could certainly be a symptom of conflicts of interest.

I have noted that a Congressional investigation of the health IT industry is now underway. This would not be a good time for hospital governance to downplay physician concerns about HIT, overruling their own HIT committee. For if a patient is injured or dies as a result of physician HIT concerns that were ignored, the executives could likely find themselves in a very unpleasant situation - and not just from malpractice attorneys.

Collins and other hospital officials who support the conversion say that once adopted and accepted, electronic records will increase patient safety and efficiency, and eliminate "piles of paper."

He apparently forgot the word "perfected." HIT in an experimental medical device. This VP for Medical Affairs makes no mention of the unintended consequences of poorly designed or implemented HIT. He either doesn't know about them (i.e., is dyscompetent regarding HIT) or is suffering the syndrome of inappropriate overconfidence in computers in the face of what seems like his own staff's concerns.

This is typical of the Wild West environment of Health IT.

-- SS