BLOGSCAN - Conflicts of Interest and the Study of Teen-Age Suicide Rates

A population-based study that showed an increase in suicide rates among teen-agers occurred the year after the US Food and Drug Administration (FDA) put a "black-box" warning on selective serotonin reuptake inhibitor (SSRI) antidepressants got a lot of press, with some reports making a causal connection between the warning and the rate increase. On the GoozNews blog, Merrill Goozner critiqued the study, noting that the absolute increase in the suicide rate was small, and certainly could have been due to events from 2003 and 2004 other than the FDA warning. He also noted that the authors of the study had some relevant conflicts of interest. The latter issue was discussed in more detail on the PharmaLot blog, where Ed Silverman criticized main-stream media coverage of this story for failing to note these conflicts.

BLOGSCAN - Pfizer's Zombie Computers

On BrandweekNRX, Dr Peter Rost posted the latest flash about Pfizer Inc: apparently the company has not responded to warnings that many of its in-house computers have become zombies, or bots, and now spew out spam, including spam mentioning Pfizer's famous product, Viagra.

Why "Resident Duty Hour Reform" Did Not Improve Patient Mortality

Soon after a heart-felt post on the Over My Med Body Blog described how it feels to be a sleep-deprived sub-intern, two major studies in JAMA brought media attention to the question of interns' and residents' work hours.(1-2)

These two studies were interpreted by their authors as meaning that reductions in work hours did not clearly do harm.

As MedInformaticsMD noted in a an earlier post, however, a major limitation of the two studies was that they only assessed mortality. While mortality is obviously an extremely important outcome of hospitalization, it is not the only one. Fatigue is likely to cause many errors that lead to bad outcomes short of mortality. Yet the current studies were not designed to determine if the reduction in work hours could have improved patient outcomes other than survival.

Another issue is the nature of the 2003 work hour limitations:

No more than 80 hours per week, with 1 day in 7 free of all duties, averaged over 4 weeks; no more than 24 continuous hours with an additional 6 hours for education and transfer of care; in-house call no more frequently than every third night, and at least 10 hours of rest between duty periods.

Consider the lot of house-staff under these new rules. It is still perfectly legal for house-staff to:

• Work continuously for 30 hours (24 "work" hours plus 6 hours for "education and transfer of care")
• Work continuously for 30 hours, get 10 hours off, and then work for another 30 hours (see above, plus provision of "at least 10 hours of rest between duty periods)
• Work 24 days during a four-week, 28 day period

My still vivid memories of internship and residency were of being pretty fuzzy after working more than 16 hours, and of being a walking zombie after working for more than 24 hours.

And, as noted in the discussion section of the two articles, there is some evidence that limiting shifts to 16 hours might be better justified than allowing 24 or 30 hour shifts.

Yet the reformed rules still allow 24 hours of continuous, intense work, and then another 6 hours of "education" and for hand-off. Then imagine, after such a 30-hour experience, having all of 10 hours to sleep, eat, catch up on life, before it starts all over again....

So another obvious explanation for the failure of these two studies to find much effect of house-staff work hour reforms were that these reforms were woefully insufficient to prevent major sleep-deprivation and fatigue.

Another question is whether the reforms shifted work to those better able to perform it, or merely re-arrange the deck chairs? So who did the work that would have previously been done by house staff working more hours than are now allowed?

My guess is that most teaching hospitals did not rush out to hire more people to take on this responsibility. After all, the house-staff work hour reforms amounted to an "unfunded mandate." Nobody gave the hospitals more money after the reforms went into effect to hire people to do this work. (If I am wrong about this, someone please correct me.)

One possibility is that the same house-staff did the same amount of work, just in fewer hours, i.e., that the reforms resulted in greater intensity of work for house-staff on clinical rotations, and most likely less opportunity to sleep even a few hours when on-call. Another possibility is that the work was given to house-staff who previously were on lighter or elective rotations.

If the reforms did not lessen the overall workload of house-staff, it is doubtful that house-staff as a group are any less fatigued on average after the reforms.

Another possibility is that the work was given to already over-worked and increasingly scarce nurses, and to the faculty in charge of teaching the house-staff, thus reducing the time available to supervise house-staff and teach. These changes could have adverse effects on quality of care that might offset any small improvements made by slightly reducing house-staff fatigue and sleeplessness.

Because of extreme sleep deprivation and fatigue, my internship year was the worst year of my life so far. One reason I went into academic medicine was the hope that I could help reform the system to make it more humane for house-staff, and hence provide them better education, and patients better quality of care.

The gradual introduction of "night-float" systems into many internal and family medicine residencies did substantially reduce sleep deprivation and fatigue, although the work load shifts they caused lessened the possibility that house-staff would have any rotations that were not intense.

However, I am afraid there are still far to many "opportunities" for house-staff to be over-worked and sleep deprived.

In a two-trillion dollar plus US health care system, there ought to be some money to pay for the work that would allow house-staff to get sufficient sleep. But unless the money is forced to follow the mandate, to quote Over My Med Body,

interns on little sleep who’ve admitted patients all night, who are writing orders at 2 or 3 in the morning is, in the best of worlds, sub-optimal, and in the worst of worlds, dangerous.

ADDENDUM (6 September, 2007) - See also comments on the Medical Humanities Blog.

References

1. Volpp KG, Rosen AK, Rosenbaum PR, Romano PS, Even-Shosan O et al. Mortality among hospitalized Medicare beneficiaires in the first 2 years following ACGME resident duty hour reform. JAMA 2007; 298: 975-983. (link here)

2. Volpp KG, Rosen AK, Rosenbaum PR, Romano PS, Even-Shosan O et al. Mortality among patients in VA hospitals in the first 2 years following ACGME resident duty hour reform. JAMA 2007; 298: 984.992. (link here)

Why Might Switching Statins Be Bad for You?

At the risk of being thought redundant, I am going to take on a topic already covered today in the health care blogsphere, mainly because I think there is even more that can be added to the discussion.

There has been some media attention to this poster describing an observational study sponsored by Pfizer Inc., and authored mainly by Pfizer employees, presented at the European Society of Cardiology Congress 2007 [Phillips B, Roberts C, Rudolph AE, Morant S, Aziz F, O'Regan CP. Switching statins: the impact on patient outcomes. Br J Cardiol, in press.] AP coverage is here, and Pfizer's press release is here.

The poster described an observational study that used data from a primary-care data-base. The study compared a cohort of patients who were switched from atorvastatin (Lipitor) to simvastatin to a cohort who remained on atorvastatin. Patients who were switched were more likely to die or sustain major cardiovascular events, even controlling for certain patient characteristics.

The study's media coverage reiterated the authors' conclusion that it is bad to switch patients from Lipitor, a more expensive, brand-name statin, to generic simvastatin. For instance, a Reuters article stated, "switching was associated with a 30 percent increase in the relative risk of major cardiovascular events, including heart attacks, strokes and death."

But the study's observational design allowed for other interpretations.

Dr Peter Rost, writing on the BrandweekNRX blog, fumed, "Lies, damned lies, observational trials. And the morons who write about them." Rost noted that people may switch from one statin to another because the first drug failed to lower their cholesterol. Such people may be resistant to statin treatment, and hence more likely to have a bad outcome for that reason, not because of the switch itself.

A Wall Street Journal Health blog post interviewed Dr Mark Fendrick, who also suggested that people may resent switching drugs for economic reasons, and hence be less likely to comply with their new prescriptions.

I can think of two more plausible reasons that people who switch may have worse results than those who don't, regardless of the particular drugs involved. First, people switched because of side-effects of the first drug may be more prone to have side-effects on the second drug, and thus fail to take it, or a sufficient dose. Second, people switched because they were non-compliant with the first drug may not be complaint with the second drug too.

Thus, there are many reasons that the data from this study could simply indicate that people switched from one drug to another are more likely to have bad outcomes than people who stay on the first drug they are given.

To really test the hypothesis that switching from Lipitor to simvastatin produces worse results than staying on Lipitor would require a randomized, controlled trial.

But isn't it odd that the investigators didn't compare the results of people who switched from Lipitor to simvastatin to people who switched from say, simvastatin to Lipitor, or from Lipitor to a third drug? One wonders whether their failure to consider alternative explanations of their data had something to do with the economic interests of their employer?

It's also too bad that the media coverage of this study did not initially consider that there may be interpretations of its results other than those provided by its commercially sponsored study investigators.

Metric myopia: does reducing exploitation of medical trainees have 'little effect' on patients?

In "On Sleep Deprivation and Medical Education" Roy Poses wrote that:

It's a sad testimony to our training system that the experience described [overwork, sleep deprivation, psychological abuse, etc.] is little different from the one I went through just about 30 years ago.

Now here come studies that may be used to justify a continuation of such abuses:

Limited effect in reduced hours for MDs in training (link to article)
By Kathy Matheson
Associated Press

Cutting the grueling work hours of doctors-in-training had little effect on reducing patient deaths, according to two large studies.

Death rates dropped in one group of patients in veterans' hospitals but not in three others, researchers reported.

The results come from the most comprehensive national look at work-hour restrictions, which were implemented four years ago to reduce medical errors by tired physicians.

"We were a little surprised," said Kevin Volpp, the studies' lead author and a physician at the Philadelphia Veterans Affairs Medical Center. "We thought that mortality outcomes would improve more consistently."

The studies are in today's Journal of the American Medical Association.

The new work-hour rules limit doctors-in-training to 80-hour weeks. Critics feared they would hurt continuity of care for patients and create a shift-work mentality among doctors. Others supported the limits, saying they might lead to fewer deaths from mistakes.

Before the rules, medical residents often worked 100-hour weeks, with some shifts lasting 36 hours straight. The new limits are still roughly double what other full-time jobs require, but advocates say long hours for doctors-in-training are seen as a traditional trial-by-fire approach that give them needed, intensive experience.

The two studies included 318,000 VA patients and more than 8.5 million Medicare patients at hospitals nationwide. The researchers looked at deaths that occurred within 30 days of hospital admission in the years before and after the rules went into effect in 2003. They compared death rates among hospitals with a large number of residents and hospitals with few residents.

Here is my response, in the form of an Op Ed that is unlikely to be published:

To: inquirer.letters@phillynews.com
Date: 09/05/2007 10:55AM
cc: volpp70@mail.med.upenn.edu
Subject: Re: Limited effect in reduced hours for MDs in training

Sept. 5, 2007

Re: Limited effect in reduced hours for MDs in training

Dear Inquirer,

While I am relieved to see studies showing that “cutting the grueling work hours of doctors-in-training” did not increase patient deaths, I suggest that these studies reflect the old adage about “lies, damn lies, and statistics.”

An endpoint of “patient mortality” seems disingenuous. These studies will undoubtedly be used by reactive forces who wish to profit from the cheap labor provided by medical trainees. The medical “scut work” performed by these trainees, and the cost of labor required to replace it, would be considerable to any hospital.

In fact, non-fatal errors, not mortality rates alone, need a much more careful examination. Patient morbidity and related factors such as severity of illness, length of stay, and number of procedures and treatments required (especially in helping a patient recover from a medical error) need evaluation. Unpleasant but non-fatal adverse events are likely far more common than premature patient death due to errors of omission and commission by exhausted medical trainees on sleepless multi-day shifts.

Let me provide some personal examples.

I have personally seen overtired surgical residents make such errors as falling asleep at the operating table due to exhaustion while holding a large clamp retractor on the aorta, during a procedure to bypass blockages in the major arteries of the leg. This resulted in an aortic tear, massive bleeding, blood transfusions, and an extra-long hospital stay for monitoring. The patient survived.

In another case, I witnessed an exhausted surgical resident insert a long hollow spear too deep. The spear was used to make a canal under the skin for an artificial blood vessel, but was inserted under an anatomic landmark instead of above it, thereby piercing the patient’s abdomen and damaging their intestines. This required major exploratory abdominal surgery and prolonged the patient’s stay a month. The patient also survived.

In medicine, I observed overtired residents making subtle errors such as ordering an intravenous bag of saline mixed with insulin for an out-of-control diabetic patient. With no glucose (sugar) in the infusion, the patient was found comatose several hours later with a blood sugar of about 8 (yes, eight). A rapid infusion of a large amount of high-sugar liquid brought the patient back to consciousness. There were no apparent consequences, but this patient could have suffered major injury.

I’ve observed exhausted interns administer too much narcotic to a jaundiced elderly patient with liver disease, causing them to become unconscious and their blood pressure to fall precipitously, requiring rapid infusion of a narcotic blocker to avoid death. Again, the patient survived.

Need I go on? I am only one observer to the mayhem caused by exhaustion and exploitation of medical trainees. Many others have similar stories they have been disincented to share via the culture of medicine.

There is also the question of physician morale, which affects trainee interaction with patients – probably for the remainder of their career. Being broke, exhausted and abused by comfortable attending physicians does not make for the best long-term empathy and bedside manner. In my own medical internship at MCP [The Medical College of Pennsylvania in Philadelphia, now closed -- ed.], I was often times so tired that I could barely function. As an honors student, this certainly had nothing to do with ability.

Further, I experienced a level of abuse not uncommon in medical training programs. As an example, I was required by an attending to perform a pelvic exam and pap smear on any woman admitted for any reason at night to the medical service who had not had one in the prior year, “or else.” Performing pelvic exams at 3 AM on unfortunate patients with normal minds but severe physical deformities, admitted from Inglis House [a Philadelphia-area facility for people of normal mentation but with severe physical disability- ed.] for urinary tract infection or other non-gynecologic problems, was not my idea of humanistic medicine.

In another splendid example of the non-fatal but very real detrimental effects of cost-cutting, during my internship at MCP I rotated through the Philadelphia VA Hospital, the home of the studies’ lead author, for several months. An intern (one year out of medical school), a medical student, and two or three nurses covered perhaps fifty sick veterans. Many times in the middle of the night, veterans needed an IV replaced.

This task was the job of the intern. As it happened, the Philadelphia VA had only one length of intravenous catheter and it was quite rigid. Interns would often have to stick patients multiple times and waste many of these IV starters before a reliable IV could be placed in a fragile vein of an elderly vet. Being exhausted did not help the odds at all of this often tricky process. (I was so infuriated I put in an employee suggestion for change. Many months after I left the organization I was actually awarded a prize of $200 from the VA for my suggestion to get a larger variety of IV starters in different lengths.) [doing so saved them money -- ed.]

In conclusion, medical errors and the non-fatal “salvage” efforts they necessitate are a somewhat “taboo” subject. Reducing trainee abuses, especially exploitative work hours, are one effort at improving a patient’s chances of the shortest possible hospital stay and minimal discomfort. However, there are major financial incentives to continue the abuse and severe lack of a service mentality. Perhaps recent announcements by payers that “salvage care” due to medical errors will not be reimbursed will help even the financial balance sheet.

Significant work needs to be done to measure nonfatal morbidity-related issues resulting from cavalier practices in medical training. Mortality alone is a vastly inadequate statistic that can lead to further justification for abuses by reactionary forces in healthcare and those with financial conflict of interest.

One obstacle to performing such studies in any detail is the backwardness of Clinical Information Technology in healthcare organizations. We can judge the quality of our high tech manufacturing by internal QA records, but often cannot easily judge the quality of care delivered in acute settings at a fine level of “granularity.” Many of the causes for this Information Technology problem, another “taboo” subject related to inappropriate leadership structures for electronic medical records projects, are outlined in my web site “Sociotechnologic issues in clinical computing: Common examples of healthcare IT failure” at this link.

If my op ed is published, even in abbreviated form, it will be a miracle.

I note that one study did show this:

One study examined VA patients treated for a heart attack, stroke, gastrointestinal bleeding, or congestive heart failure. It found that two years after the [trainee work hour restriction] rules were implemented, mortality improved by 11 to 14 percent in major teaching hospitals, compared with hospitals with few residents.

It seems that less-tired residents may actually save lives, especially when compared to non-teaching hospitals where physicians can be scarce as hen's teeth, especially at night. One can only wonder what changes there were in morbidity-related issues.

I will probably be challenged for providing anecdotal evidence in my Op Ed. However, there is a principle from an unlikely source that should be considered when ignoring anecdotal evidence that many people can identify with:

Ignoring all Anecdotal Evidence
Example: I always get hives immediately after eating strawberries. But without a scientifically controlled experiment, it's not reliable data. So I continue to eat strawberries every day, since I can't tell if they cause hives.

I note that the studies' author is an Assistant Professor of Medicine and an Assistant Professor of Health Care Systems at the Wharton School. Perhaps he can undertake a study of the non-fatal consequences of the work hours of medical trainees that in other cognition-critical professions would probably be considered criminal.

Finally, the blog by "Panda Bear MD" is an excellent site for reading about the challenges of medical training in more depth.

-- SS

BLOGSCAN - To Get CME Credit, Read a "Ridiculous Text"

On the Carlat Psychiatry Blog, this post detailed the disdain for which a noted psychiatrist expressed for a ghost-written, medical education and communication company organized, pharmaceutical company sponsored CME publication which ostensibly was derived from a panel discussion in which that psychiatrist participated. His most pithy comments I will not print in this family-oriented blog ;-) Yet physicians can still get CME credit in part for reading what he called a “ridiculous text… parts of it were inaccurate, simplistic, and [contained] over-generalizations.”

BLOGSCAN - A Less Honorable Career Choice than Stone-Masonry

One of my favorite lines from the original Star Trek was by "Bones," the physician, when asked to patch up an alien, silicon-based creature, "I'm a doctor, not a stone-mason." Of course, there is nothing dishonorable about being a stone-mason. But on the Hooked: Ethics, Medicine, and Pharma blog, Howard Brody notes an outraged article by a physician about medicine's current relationship with the pharmaceutical industry. After noting multiple anecdotes of physicians' grubbing goodies from drug reps, he concluded, "we are physicians, not ...." The final word, of course, was a less honorable career option than stone-masonry.

A Bit of Representativeness, Accountability and Transparency in Academic Governance Threatened

In the opinion section of the Wall Street Journal (and available free here from OpinionJournal) was an interesting article about the governance of US higher education, with some lessons for academic health care.

The story is about Dartmouth College, an Ivy League school, and home of a small, but distinguished medical school. Dartmouth has an unusual way of picking the members of its board of trustees.

It is one of a few schools in the U.S. that allow alumni to elect leaders directly. Eight of the 18 members of Dartmouth's governing Board of Trustees are chosen by the popular vote of some 66,500 graduates. (The other seats are reserved mostly for major donors, along with ex officio positions for the governor of New Hampshire and the college president.) This arrangement has been in place since 1891.

Recently, this has lead to an interesting change in the membership of the board.

Until recently, though, Dartmouth's elections have been indifferent affairs, with the alumni choosing from a largely homogeneous slate handpicked by a committee closely aligned with the administration. In 2004, things got--interesting. Mr. [Thurman J] Rodgers [Founder and CEO of Cypress Semiconductor Corp] bypassed the official nomination channels and was named to the ballot by collecting alumni signatures; he needed 500 and ended up acquiring more than 15 times that. He was dissatisfied with the college's direction and resolved to either 'do something or stop griping about it.' He was elected by 54% of the voters.

Since Mr Rogers' election, three more candidates have been elected to the board after nomination by alumni petition.

Mr. Rodgers's candidacy was followed by two further elections, in which petition candidates--Peter Robinson, a fellow at the Hoover Institution, and Todd Zywicki, a professor of law at George Mason University--were also elected.

Earlier this year another petition trustee, Stephen Smith of the University of Virginia Law School, was elected with 55% of the voters.

All petition candidates were known as dissidents or reformers. As Rogers put it, they are "independent people willing to challenge the status quo."

Thus, the composition of Dartmouth's board of trustees is very different from that of most major American universities. Most university boards pick their new members themselves. Some do allow for alumni membership of a few members, but the candidates for such positions are generally hand-picked by the board or an administration committee, and rarely advertise their policy positions. Thus, the key governing bodies of most US institutions of higher education, and hence the key governing bodies to which most US medical schools (other than the Dartmouth Medical School) report are self-elected.

The atypical members of the Dartmouth board have tried to reform how the institution runs. For example, Mr Rodgers' "first priority was to improve its 'very poor record of freedom of speech.' Soon enough, the college president, James Wright, overturned a speech code. The Foundation for Individual Rights in Education, a watchdog group, elevated Dartmouth's rating from 'red' to its highest, 'green,' one of only seven schools in the country with that status. 'We made progress, and I was feeling pretty good,' Mr. Rodgers says."

This was notable because, as we have discussed on Health Care Renewal, academic institutions, and academic medicine in particular, have not always had stellar records of defending their students' and faculties' right to say or write controversial things, especially those that offend vested interests. In particular, academic medical institutions have:

• Gone along with attempts to suppress medical research that offended vested interests. (See posts here and here.)
• Allowed research contracts with commercial sponsors that allowed those sponsors to control the dissemination of research results (See post here.)

But the popularly elected alumni board members soon ran into opposition.

Perhaps sensing that a critical mass was building, Dartmouth's establishment then tried to skew the petition trustee process. The details are complex and tedious, but last autumn they cooked up a new alumni constitution that would have 'reformed' the way trustees were elected. In practice, it would have stacked the odds, like those in a casino, in favor of the house.

The measure needed two-thirds of alumni approval to pass, and in an election with the highest turnout in Dartmouth's history, it was voted down by 51%. 'It lost big time,' Mr. Rodgers says.

After the election of the fourth alumni reform trustee, things got worse,

A former trustee, and a current chair of Dartmouth's $1.3 billion capital campaign, publicly charged that the petition process had initiated a 'downward death spiral' in which a 'radical minority cabal' was attempting to hijack the Board of Trustees. That was among the more charitable commentaries.

And,

One of the main criticisms leveled at the petition trustee process is that it is polarizing, divisive and somehow detrimental to the college. Mr. Rodgers replies, 'If 'divisive' means there are issues and we debate the issues and move forward according to a consensus, then divisive equals democracy, and democracy is good. The alternative, which I fear is what the administration and [Board of Trustees Chairman] Ed Haldeman are after right now, is a politburo--one-party rule.'

And so, after losing four consecutive democratic contests, the Dartmouth administration has evidently decided to do away with democracy altogether. 'Now I'm working on the existence question,' Mr. Rodgers notes mordantly.

Though he cannot say for sure--'I'll be kept in the dark until a couple of days before the meeting on what they're planning on doing'--a five-member subcommittee, which conducts its business in secret and includes the chair and the president, has embarked on a 'governance review' that will consolidate power. 'It looks like they're just going to abandon, or make ineffectual, the ability of alumni to elect half the trustees at Dartmouth,' Mr. Rodgers says.

He believes that the model is the Harvard Corporation, where a small group 'makes all the decisions. They elect themselves in secret. They elect themselves in secret for a life term. How's that for democracy?'

Rogers noted the likely consequences of the "reform" that would prevent the popular election of any more reform candidates,

The alternative remedy, he continues, is poor corporate governance, for one. 'This is committees working in secret, which is a very bad way to run any organization.' Besides transparency, it may also present conflicts of interest, in which the college president would dominate those who ultimately evaluate his performance.

By the way, what does Rogers expect will happen after the publication of the WSJ article?

Mr. Rodgers expects to be 'severely criticized, unfairly and personally,' for talking to The Journal. He may even be removed from his post entirely.

It is upsetting that the representativeness, accountability, and transparency that partially characterizes Darthmouth's governance model is under threat.

The troubles at Dartmouth, however, should also underline how little representativeness, accountability, and transparency characterize the government of any US university or medical school. As noted earlier, most university boards of trustees elect themselves. The reasons particular people are chosen for board service, and their positions on policy issues relevant to their institutions are generally unknown. The boards' deliberations are generally secret.

If any university faculty members, alumni/ae, or students in the audience can tell me their universities operate differently, I would love to hear about it. (And if those universities include medical schools, I would be happy to publicize their better governance models.)

Meanwhile, it is reasonable to hypothesize that the mismanagement and mission-hostile management that too often is found at US (and other countries') academic medical institutions is due in part to institutional governance that is unrepresentative, unaccountable, and opaque.

And instead of seeing movement toward representativeness, accountability, and transparency, at one of the few schools that has a somewhat better governance model, we see moves by the administration in the wrong direction.

Conflicted View on the Pitfalls of Government-Sponsored Comparative Effectiveness Research

Many have raised concerns that physicians too often favor the latest, most expensive, most high-technology, and sometimes most invasive treatments, contributing to the high costs and often bad outcomes of health care. One solution would be better research comparing the various possible treatments for particular problems. Yet some worry that this approach, too, has its problems.

The Wall Street Journal just printed a commentary warning about the dangers of government-sponsored studies comparing treatment effectiveness, written by Dr Scott Gottlieb, described as "a physician and resident fellow at the American Enterprise Institute, ... a former senior official at the Food and Drug Administration and the Centers for Medicare and Medicaid Services."

Dr Gottlieb raised some good points about pitfalls to be expected when comparing alternative treatments. These include:

• The need to do very large (and hence expensive) studies to have sufficient statistical power to determine if the treatments really are different, "detecting small clinical differences between two active drugs, such as whether one pill lowers blood pressure more than another, requires very large studies...."
• The tendency of investigators not to share results, making them harder to verify.
• The danger that results that fit preconceived notions will be too readily accepted.
• The danger that government-funded studies might be influenced by the government's need to control medical costs, and thus favor cheaper treatments. "Medicare is no ordinary payer: It dictates decisions made in the private market. So as the government begins tying its own payment decisions to the results of its own studies, there's a great temptation to selectively interpret data and arbitrarily release results. Clearly, this obvious conflict of interest demands even more outside scrutiny and transparency than has been the usual fare when it comes to government research."

Of course, these also are pitfalls of studies comparing active treatment to placebo, and of studies funded by not-for-profit organizations or commercial firms.

In fact, Dr Gottlieb's essay seemed to do its best to raise suspicions about government-funded comparative effectiveness research while neglecting that the alternatives may be worse.

The evidence-based medicine paradigm, to which I obviously subscribe, suggests that physicians should make decisions about treatment based on a critical review of the best available evidence from clinical research, informed by their knowledge of biology and the medical context, and taking into account patients' preferences and values.

Where can physicians get the best available evidence from clinical research now, in the absence of many government-funded studies of comparative effectiveness? In most cases, the best they can do is to look at results of studies sponsored by the manufacturers of the drugs and devices they evaluated, often compared to placebo.

Dr Gottlieb used a few examples of government-sponsored comparative studies to illustrate their potential problems. But most of these problems have affected commercially sponsored studies even more severely.

Dr Gottlieb asserted that early results of the Women's Health Initiative "were rushed to print with a cleverly orchestrated PR blitz." Yet pharmaceutical, biotechnology, and device companies make huge marketing efforts to rapidly publicize results of the trials they sponsor that are favorable to their products. (This is so glaringly obvious that it needs no web-link.)

Dr Gottlieb accused the researchers who ran the Women's Health Initiative of refusing "to share bottom-line results, even with outside academics or the companies that manufactured the drugs." Well, at least the researchers had their own data. There have been noteworthy cases of researchers running commercially sponsored studies who were unable to access the data they collected, which were kept secret by the commercial sponsor. See, in particular, the case of Dr Aubrey Blumsohn, who was unable to analyze the data he collected in a trial of Actonel because the company's sponsor, Proctor & Gamble, refused to let him have it. (See this link on Dr Blumsohn's blog for numerous posts, and our most recent posts here and here.) And we have posted about a New England Journal of Medicine study(1) which showed that US medical schools are often quite willing to let commercial research sponsors maintain control of the data collected by academic researchers.

Dr Gottlieb worried that studies funded by the government might be biased to favor less expensive drugs. Yet there is copious evidence that commercially sponsored studies favor their sponsors' projects.(2-3)

Dr Gottlieb worried that government-funded comparative effectiveness studies might be too small to generate precise enough results. Yet there is considerable evidence that the design and implementation of commercially-funded are often manipulated to increase the likelihood that the studies' results will favor the sponsors' products. (4-6)

Finally, and most ironically, Dr Gottlieb worried that Medicare sponsorship of studies would constitute a conflict of interest. We have posted before about previous commentaries by Dr Gottlieb in which he failed to reveal his past ties to industry, including his past consulting work for a large public relations firm that has many pharmaceutical companies as clients, and a firm that recruits physicians to advise about particular health care related investments. Dr Gottlieb also failed to reveal his apparent current role as a "counsel" to a major pharmaceutical company.

Most recently, Dr Gottlieb was just appointed to the board of directors for a biotechnology firm, Molecular Insight Pharmaceuticals. Thus he now has responsibility to the share-holders of this firm to maximize its profits, profits which presumably would be at risk if a government-sponsored comparative effectiveness study were to find that one of its products were not as good as expected.

I would be more inclined to credit the comments of people who have financial ties to health care corporations if they revealed these ties when making public comments. It amounts to stealth health policy advocacy for someone with multiple ties to the pharmaceutical and biotechnology industries to write in the guise of a think-tank intellectual.

ADDENDUM (4 September, 2007) - See also Aubrey Blumsohn's comments on the Scientific Misconduct Blog here.

References

1. Mello MM, Clarridge BR, Studdert DM. Academic medical centers' standards for clinical-trial agreements with industry. N Engl J Med 2005; 352: 21. (available here)

2. Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA 2003; 289: 454-465.

3. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. Brit Med J 2003; 326: 1167-1170.

4. Bero LA, Rennie D. Influences on the quality of published drug studies. Int J Technol Assess 1996; 12:209-237.

5. Brophy JM. Selling safety - lessons from muraglitazar. JAMA 2005; 294:2633-5.

6. Smith R. Medical journals are an extension of the marketing arm of pharmaceutical companies. PloS Medicine 2005; 2: 364-366.

On Sleep Deprivation and Medical Education

On the Over My Med Body Blog, see this eloquent rant about what it is like to begin a sub-internship. A sub-internship is an experience for (usually fourth year) medical students during which they function like interns, and hence functions as an introduction to the world of post-graduate medical training. Sub-interns, and later interns and residents are up at all hours of the night, taking care of often severly ill patients, with little experience and less sleep. Yes, they do have various forms of back-up, from sub-specialty fellows to seasoned faculty. But nothing can make up for the cloud of cotton wool that fills one's head after being up all night.

It's a sad testimony to our training system that the experience described is little different from the one I went through just about 30 years ago.

But now the intrepid blogger of Over My Med Body may be getting an inkling why doctors who have had years of training like this can get so upset when their dedication, knowledge, or work habits are questioned by some "suit" with a six-, seven-, or eight-figure income, a "suit" who is comfortably in bed every night of the week, and who never has to handle an emergency, much less a patient throwing up blood, hallucinating, and febrile at three in the morning.

But perhaps some of the money going to pay for those "suits'" fancy salaries could be used to pay for more hands on care givers in teaching hospitals, alleviating the need for those sub-interns, interns, and residents to work so many hours straight.

BLOGSCAN - Make a Drug An "Orpha," Raise the Price 20x

On the Health Business Blog, David Williams posts about how Questor Pharmaceuticals got an "orphan drug" status for its formulation of ACTH (adrenocorticotrophic hormone) to treat a form of seizures that occur in early childhood. After doing so, the company will increase the price of the drug, which has been on the market a long time, 20x, that is, 2000%. Somehow methinks that this was not what the orphan drug law was meant to do.

Nissen and Califf on the Avandia Case, and the Evils of Suppressing Data from Clinical Research

We have posted quite a bit about the controversy sparked by a meta-analysis of the cardiovascular adverse effects of rosiglitazone (Avandia, by GlaxoSmithKline) by Nissen and Wolski. (For example, see this post.)

Medscape just published a conversation between Dr Robert Califf and Dr Steven Nissen. (Nissen, who wrote the controversial meta-analysis, is at the Cleveland Clinic, while Califf is at Duke.) Much of the discussion addressed technical and methodologic aspects of the Avandia controversy. But I was struck by what the two had to say about suppression of clinical research.

Starting with Dr Nissen, edited for clarity:

I believe that if you ask human subjects to participate in an experiment that the results of that experiment belong to the public. That it is not acceptable to do such an experiment and then to deep-six the results. And I want that to be a matter of law. I think if it's not a matter of law, we will continue to see negative publication bias where the studies that get published are the ones that show favorable effects of drugs. Things have gotten out of balance, Rob. We hear about the efficacy of drugs through media, on television, through advertising, detail people, CME, but we need to see all of the data in order for us to make good clinical judgments.

Response by Dr Califf:

I've asked the question: 'Will everyone in the room who's in favor of secret human experimentation please raise your hands?' And so far I haven't really had anyone -- well, maybe one exception, but I don't want to reveal who that was -- say they're in favor of that.

The definition of research ... is something that's done to create generalizable knowledge. And generalizable knowledge to me can't be present if the result is kept from the public if it's negative.

Back to Dr Nissen:

Well, ... [companies] argue that the data is proprietary. And they have gotten a lot of traction in the Congress. The companies have said through their lobbyists and so on that when they spend the money to run a clinical trial that they own those results and they should be free, in a free enterprise system, to do whatever they want with those results. And if they don't like them and they want to put them somewhere other than in the public domain, that should be their right.

And from Dr Califf:

while there are lobbyists arguing that, there are many good people in companies who feel quite differently and would like to have permission, as you say, with regard to their corporate boards, who are always looking after optimal profitability, they'd like to have that happen.

The fiduciary responsibility of the corporate board is to not do things that damage the profitability of the company, and that leads, I think, to a very distorted perspective on the ethics that are involved.

Although in the past the argument has been made about trade secrets and so on and so forth, but when you get into the human experiment arena, if we level the playing field so all companies are working under the same rules, then the best products will win out because the public will have better information and people will make better decisions about what to do.

So let's summarize the main points:

• People participating in clinical experimental research are told that their participation will benefit science and patient care.
• This benefit could only occur if the results of the research are made public, even if they go against the commercial (or idological) interests of the people who paid to have the research done.
• For the financial supporters of research to keep data they do not like secret violates the trust of the research subjects.
• However, if hiding data has no negative consequences, commercial sponsors will continue to hide data unfavorable to their interests.
• Government regulation would be one way to impose negative consequences for hiding data.
• Preventing the suppression of data from clinical research ultimately will favor the products that are actually best for patients, which would be good for patients, and, incidentally, good for companies that make the better products.

Sounds good to me. But will any politician have the courage to advocate the punishment of companies that hide data they don't like?

Another solution would be to ban research on humans done or supported by those who have financial interests in the products or services tested by such research. That would require some massive redirection of the flow of money that supports human research.

I am wondering when some clever attorney will figure out how to sue a company on behalf of a research subject in a trial whose results were suppressed by its commercial sponsor. That particular sledge hammer might prompt some re-thinking of the issue.

BLOGSCAN - Maggie Mahar's Health Beat Blog

Maggie Mahar, author of Money-Driven Medicine, one of the best of the current crop of books about the dysfunctional US health system, now has a blog. It's called Health Beat, and went live August 7, although most posts on it were from yesterday. Maggie had previously guest-blogged on The Health Care Blog. We welcome her feisty voice in the health care blogsphere.

BLOGSCAN - Dilbert in Medicine

On Retired Docs Thoughts, this post takes off with a commentary on the recent New England Journal of Medicine article on the rush to do "quality improvement" without evidence that it works to address the rise of the business culture in health care. The best part was:

Twenty years ago when I began to do some consultative work with the corporate world,I felt rather smug that my field (medicine) was immune to the Dilbert like silliness that seemed to pervade the corporate culture. However,medicine has become more and more corporate and the business school belief that one does not need know a business to run it is increasingly applied to medical practice . The business-speak jargon now echoes through the hospitals and clinics and we talk about vision statements and leveraging this and that and the suits with MBAs are no longer minor distractions but are in control. What the Dilbert cartoons depict are as applicable to much of medicine as they are to the bureaucratic world of big business.

No Confidence Vote for NIEHS Leader

We have posted frequently (e.g., here) about conflict of interest issues affecting the flagship US biomedical research organization, the National Institutes of Health. Most recently, our focus was on happenings at the National Institute of Environmental Health Sciences (NIEHS), whose director was just forced to temporarily step down.

The Scientist (UK) reported more trouble:

More than 100 tenured and tenure-track scientists at the NIH's environmental agency say they no longer have confidence in the leadership of David Schwartz, embattled director of the National Institute of Environmental Health Sciences (NIEHS).

A senior NIEHS researcher, who asked not to be identified, provided to The Scientist the results of a secret ballot held by NIEHS's Assembly of Scientists at the request of assembly members. The group consists of tenured and tenure-track professors at the agency. Out of 146 NIEHS researchers who voted, 91 voted that Schwartz no longer had their support and 99 voted that their morale was negatively affected.

The researcher said that 'the morale is as low as it can go,' at NIEHS. 'We're devastated down here,' the researcher said from the agency's Research Triangle Park, North Carolina headquarters.

The senior researcher who provided the ballot results said that Schwartz diverted money away to his own research program and that the researcher therefore lost funding.

The senior NIEHS researcher interviewed by The Scientist said that ethical problems extend all the way to the top of the NIH hierarchy. 'The things that Dr. Schwartz did, he got approval for,' the researcher said.

This story is not yet over, as a Congressional enquiry is underway.

It is very sad to continue to hear stories like this about an organization that is responsible for so much important science, and which used to have a sterling reputation. This story teaches an important lesson about the demoralizing effect of bad leadership of health care organizations on the people who actually make these organizations run. Maybe some of the recruitment problems that federal health care organizations have had are due to problems with the integrity of their leadership, rather than employees' diminishing prospects of private gain.

BLOGSCAN - An Alternative to the Usual Left- vs Right-Wing Rhetoric on Health Care

On the Hooked: Ethics, Medicine and Pharma blog, this post by Howard Brody covers the debate between Arnold Relman and Richard Epstein as yet another of the unenlightening left wing vs right wing (or "you bloody fascist" vs "you stupid communist") debates that have failed to advance health care much. (See our post here for another example.) But for a more productive discussion, Brody's new suggested reading list looks promising.

BLOGSCAN - New CME Policies Dissected

On the Carlat Psychiatry Blog, this post dissects the new rules for providing continuing medical education (CME). My favorite was the re-definition of "commercial interest" that still does not define a for-profit medical education and communication company (MECC) as "commercial."

BLOGSCAN - More on Collaborating with UnitedHealth for the "Advanced Medical Home"

A number of medical/ health care bloggers have kept at the story of various medical societies' (including the AAFP, AAP, and ACP) questionable collaboration on a pilot project for the "advanced medical home" with UnitedHealth (see our post here). Retired Doc's Thoughts first took it up here, and then here continued to ask tough questions in particular about the ACP's role. The Covert Rationing Blog suggested that the pilot project was just managed care with better makeup, and was echoed by KevinMD. Outside of the blogsphere, however, I can't find any discussion of the issue.

BLOGSCAN - How Aggressive Treatment of Anemia was "Earmarked"

On GoozNews, Merrill Goozner just posted at length about a hidden "earmark" he discovered in the S-CHIP bill, one that would reward dialysis units for very aggressively treating their patients' anemia. There has been a lot written (our meager contributions includes posts here and here) about how the previous dogma that aggressive correction of hemoglobin in patients with chronic renal failure proved to be unreliable, and about how Amgen, maker of products frequently used to effect this correction, e.g., epoetin (Epogen) aggressively marketed its wares. Now Merrill Goozner has disclosed how the "earmark" process seems to have been used to add federal muscle to the push for aggressive treatment of anemia, even if such treatment is not good for patients. How this was orchestrated remains unclear. Stay tuned....

Minnesota Medicaid, Big Pharma and Delusions about Conflict of Interest

Roy Poses posted previously at "US States Using Pharmaceutical Company Funded Program to Influence Physicians' Prescribing " on how Minnesota, and other US states, use a program funded by Eli Lilly & Co which is meant to reduce physicians' supposedly inappropriate use of anti-psychotic medications. Eli Lilly is also the manufacturer of one such medication, olanzapine (Zyprexa). The source article noted that states that use the Lilly program seem to have adopted policies that tend to favor Lilly and its products, and that neither Minnesota nor the other states that use the Lilly program uses prior authorization schemes to limit drug use.

More on Minnesota today.

In "Drugmakers' deep pockets linked to decision-makers", Martiga Lohn today describes the effects of a new Minnesota law: shining of a rare light onto the big money that drug companies spend on members of state advisory panels who help select which drugs are used in Medicaid programs for the poor and disabled.

The article is striking in several respects.

Drugmakers' deep pockets linked to decision-makers

By Martiga Lohn, Associated Press

ST. PAUL, Minn. - A groundbreaking Minnesota law is shining a rare light onto the big money that drug companies spend on members of state advisory panels who help select which drugs are used in Medicaid programs for the poor and disabled.

Those panels, most composed of physicians, hold great sway over the $28 billion spent on drugs each year for Medicaid patients nationwide. Yet only three states - Maine, Vermont and Minnesota - require drug companies to report payments to doctors for lectures, consulting, research and other services.

A review of Minnesota records found that a doctor and a pharmacist on the eight-member state panel simultaneously got big checks - more than $350,000 to one - from drugmakers for speaking about their products.

The online version of the story does not contain a chart in the print version entitled "Tracking Spending on Advisry Panels" that lists the major pharmas and their payments to two people, Dr. John E. Simon and pharmacist Robert Straka.

From 1998-2006 Dr. Simon, a psychiatrist, received $582,469.97 (over $350,000 from 2004-6 alone as a member of the panel) and Mr. Straka $85,807.95 (served on the panel from 2000 to 2006, and collected $78,000 during that time from various drugmakers), according to the article and chart.

Eli Lilly was the largest single contributor, having given psychiatrist Dr. Simon $488,952. Merck and Schering-Plough were the largest "contributors" to Straka, having given $24,623 and $36,745 respectively.

Back to the article:

Both said the money did not influence their work on the panel, and spokesmen for the drug companies said their payments had nothing to do with the members' roles.

Let's put, say, $489 thousand dollars into perspective. What might that amount buy?

Assuming after taxes that a bit over $300,000 were left:

Dutch automaker Spyker makes several different editions of its C8 supercar. The most expensive one is the $326,000 C8 Double 12 S.

Rolls-Royce Phantom: MSRP: $333,350. The 2007 Phantom is a 4-door, up to 5-passenger luxury sedan, available in one trim only, the Sedan. Upon introduction, the Phantom is equipped with a standard 6.75-liter, V12, 453-horsepower engine that achieves 12-mpg in the city and 19-mpg on the highway. A 6-speed automatic transmission with overdrive is standard.

Aston Martin DB9 MSRP $169,750 - $183,250 (Name's Bond. James Bond. why settle for one when $300K+ can buy two!)

For the numismatists among us:

Large One-Cent Pieces, Flowing Hair, Chain Reverse 1793 Periods $304,000
Half-Cent Pieces, Liberty Cap 1796 With pole $303,000
Half Eagles ($5.00 Gold Pieces), Capped Bust 1797 Large eagle $301,000
Silver Dollars, Flowing Hair 1795 $299,000

And for the boaters among us:

30 Express Rampage Sportfishing Yacht $200,000-$300,000

Those who say that this amount of money from pharma "did not influence their work" on such decision-making committees are either in serious denial, deluded or dishonest, in my opinion. It is risible to say that these amounts could not influence decisions - or not be perceived to influence decisions by the reasonable man or woman.

Those who think that payments like this do not present a most disastrous appearance are certainly in denial or deluded about issues of public trust:

The advisory panel's recommendations to the Minnesota Human Services Department are almost always followed. The panel guided $240 million in spending on drugs for 202,000 patients last year - slightly less than a third of all the state's Medicaid patients.

The top drugs for Minnesota Medicaid patients covered by the panel's advice in recent years have been for schizophrenia - Eli Lilly & Co.'s Zyprexa, from 2000 to 2004, and AstraZeneca PLC's Seroquel, in 2005 and 2006.

About a third of the drugs on the state's preferred list are made by companies that paid Simon, Straka or both.

Here's another major part of the problem:

The lack of recorded votes in meeting minutes makes it difficult to track any link between payments and policy.

That is simply incredible. In Minnesota, not only were these activities conducted with little or no public scrutiny before the new law went into effect, but also minutes were not taken to see who was voting for what.

Finally:

... State officials said they would examine the panel's past actions for any bias tied to the payments, and they would start screening appointees to two dozen advisory councils for similar links. They will also require the Drug Formulary Committee to record how members vote.

Other states need to do likewise. Fast.

A List of drug companies' payments to doctors in Minnesota is also available.

-- SS

Why is the NIH Monitoring Its Employees' Communication with Congress?

We have posted quite a bit (recently here) about conflicts of interest affecting top US National Institutes of Health (NIH) officials. In 2005, the NIH director reinstated strict rules about conflicts of interest. Last month, we noted that allegations of conflict of interest at the Institutes continue, most recently involving the head of the National Institute of Environmental Health Sciences (NIEHS), Dr David Schwartz.

The Associated Press (here via the San Diego Union-Tribune) just reported the case's latest ramifications.

First, Dr Schwartz has temporarily stepped down from his position, pending an investigation:

The NIH is beginning its own review of the management and leadership of the institute, NIH director Dr. Elias Zerhouni announced Monday. The embattled director of the institute, Dr. David Schwartz, is stepping aside for the duration of the review.

Meanwhile, the AP reported that the NIH has seemingly gotten very concerned about communication by its employees with the US Congress.

Employees of one of the National Institutes of Health are being asked to report all contacts with Congress – a request that one lawmaker suspects is an attempt to flush out would-be whistle-blowers.

Managers distributed 'record of congressional inquiry' forms to employees of the National Institute of Environmental Health Sciences, one of the 27 institutes and centers that make up the NIH. At least one of those workers reported being made 'nervous' by the form – and forwarded it to congressional investigators probing allegations of conflicts of interest, excessive spending and other management issues at the institute.

The form asks for details of each telephone call from the offices of members of the House or Senate, including on the information sought.

Asking employees to document such contacts is highly irregular.

Logging and reporting such calls is standard procedure in the congressional affairs offices of federal departments and agencies. But the forms don't appear to be something given out to 'regular' employees, said Sen. Charles Grassley. Their distribution came in the midst of multiple and ongoing investigations by Congress, including by the Iowa Republican's staff. Nor do the forms appear to have been distributed elsewhere within NIH.

'Hopefully, the intent of this form was not to discourage or intimidate NIEHS employees from talking to Congress; but I must admit, the timing is curious,' Grassley wrote Zerhouni in a letter, sent late Monday, seeking details of the circumstances of the form's distribution. It is illegal to deny or interfere with a federal employee's right to provide information to Congress.

The letter and NIH review are the latest salvos in an ongoing series of investigations of the institute. Grassley and other lawmakers have relied on federal whistle-blowers in conducting oversight of the institute.

Previously, those whistle-blowers have told Grassley's staff of employee discussions with institute management 'that left them with the impression that there would be retaliation if it was discovered that they had provided information to among others, congressional investigators,' the lawmaker wrote Zerhouni in a July 11 letter.

This case now seems to combine several elements familiar to readers of Health Care Renewal. Initially, it involved allegations of important conflicts of interest affecting the top leadership of an important health care organization. Now, it also involves allegations about intimidation of those attempting to blow the whistle about these conflicts.

The case now reminds me of arguments that I just made at a meeting convened by the International Council on Human Rights Policy about the relationship between corruption and violations of human rights: people involved in activities that might embarass them if reported in the media may often try to silence those who might try to make such reports. And it further reminds of the slogan favored by FIRE in their campaign for individual rights in education:

Sunlight is the best disinfectant.

Hat tip: to Effect Measure. And also see this post on Effect Measure (just up).

US States Using Pharmaceutical Company Funded Program to Influence Physicians' Prescribing

The Pioneer Press just reported on how Minnesota, and other US states, use a program funded by Eli Lilly & Co which is meant to reduce physicians' supposedly inappropriate use of anti-psychotic medications. Eli Lilly is also the manufacturer of one such medication, olanzapine (Zyprexa).

One of the nation's largest drug companies is helping Minnesota cut costs and reduce questionable prescriptions of psychiatric drugs to poor and disabled residents.

Officials with the Minnesota Department of Human Services defended the program, which is funded by Lilly but run by an independent contractor, Comprehensive NeuroScience. State officials believe CNS has saved money for Minnesota's fee-for-service health plans, but more important, it has corrected some questionable prescriptions of expensive and powerful psychiatric drugs.

'Cost is an issue, certainly, but what is most important is that we get the right health care for patients,' said Brian Osberg, assistant commissioner of the human services department.

Twenty states have contracts with CNS, which identifies doctors who are prescribing psychiatric drugs outside of recommended guidelines for safety and effectiveness. A common problem is patients taking two or three antipsychotic drugs at once, despite an increased risk of side effects and no evidence that patients benefit by taking multiple drugs.

The states then send warning letters to doctors, who can decide whether to alter their prescriptions.

The article noted that states that use the Lilly program seem to have adopted policies that tend to favor Lilly and its products. In particular, neither Minnesota nor the other states that use the Lilly program uses prior authorization schemes to control drug use.

Opponents believe states are paying Lilly back for this help by keeping its drugs off prior-authorization lists. Such lists prohibit doctors from prescribing drugs without first gaining permission from the state.

Lilly is the manufacturer of Zyprexa, a top-selling antipsychotic drug. Minnesota's fee-for-service health plans spent more than $28 million on Zyprexa in 2005, and $103 million on antipsychotics in general. That more than doubled the 2000 total of $43 million for the plans, which cover 200,000 poor and disabled Minnesotans.

While other states have used prior authorization to curb these soaring costs, Minnesota has not. In fact, none of the states with Lilly partnerships use prior authorization to manage antipsychotic drugs.

Wisconsin had a contract with Lilly until last year, when the state's Medicaid agency placed antipsychotic drugs, including Zyprexa, on the prior authorization list. State officials were informed shortly thereafter that Lilly was canceling the program.

A Lilly spokeswoman acknowledged that the company is trying to discourage states from using prior authorization.

Furthermore, another of Minnesota's policies seems to tilt toward Zyprexa.

In February, Minnesota encouraged patients to split cheaper double-strength pills instead of taking multiple smaller-dose pills, which can save money for the state at the expense of drugmakers.

The 'dose optimization' strategy was required for Abilify, Geodon and Seroquel - which are competing antipsychotic drugs - but not for Zyprexa.

'Pure coincidence that dose optimization and tablet splitting are utilized exclusively for Eli Lilly's competitors?' asked Ben Hansen, who has sued to expose Michigan's partnership with Lilly. 'I don't think so.'

Human services officials replied that there was no financial benefit to placing Zyprexa on the pill-splitting list.

The program has its local critics:

If the state 'asks Eli Lilly to help decide how to buy prescription drugs, or even General Motors to help decide how to buy a car, I guess I'm going to be concerned about that,' said Ronald Hadsall, assistant dean of the University of Minnesota College of Pharmacy. 'That just smacks of conflict to me.'

A state's program to make physician prescribing more appropriate already threatens physician autonomy, but could be justified if physicians' relevant current prescribing is clearly not in patients' best interests, and if the program would clearly suggest prescribing more in patients' interests. However, the threat to autonomy cannot be justified for the sake of a program supported by a single drug company which seems to tilt the playing field in that company's favor. The state's use of this program seems to be participation in a stealth marketing scheme, made worse by its association with the aura of government power

Hat tip to Kaiser Daily Health Policy Reports.

More Details and Concerns About the Death of a Gene-Therapy Patient

Details continue to come out about the death of a woman who was participating in a gene-therapy trial of an agent made by Targeted Genetics meant to treat joint symptoms of rheumatoid arthritis. We posted about the case here and here.

Almost two weeks ago, the Seattle Times reported on the company's response to initial news stories about the case.

Chief Executive H. Stewart Parker said in an interview that the company has always applied 'the highest rigor in clinical trials' and that it behaved properly.

The company said it reported the incident to the FDA 'within 24 hours' of determining that the patient's illness was possibly related to the drug. A chronology released by the company shows that occurred 18 days after the patient was injected, in the wake of her admission to a hospital.

Staff at the hospital where Mohr was being treated was the first to alert the FDA, Parker confirmed in the interview.

Targeted Genetics said the patient received a second dose of the arthritis therapy on July 2. On July 10, the company learned that she and another patient suffered nausea, fever and vomiting. The other patient recovered, but Mohr was hospitalized on July 13. The clinical investigator thought it unlikely that the symptoms of both patients were related to the drug, the company said in a statement.

On July 17, the investigator told the company that Mohr's condition 'was deteriorating,' but that it was unrelated to the therapy. The next day, Targeted Genetics notified the chairman of the independent data safety-monitoring board that supervised the study, and on July 19 determined that the incident was possibly related to the therapy.

On July 20, the company informed the FDA.

Last week, the Washington Post reported more details about the demise of the patient.

The 36-year-old Illinois woman who died last month after being treated with an experimental gene therapy was infected with a fungus that usually causes only a mild illness. But the infection spun out of control and ravaged her organs, suggesting that her immune system was seriously impaired, said a doctor who is part of the medical investigation.

The woman's body was also teeming with a cold-sore virus that the body normally keeps in check, another indication of a faltering immune system. And because of a tear inside her abdomen -- perhaps caused by infection, perhaps by injury -- she had an internal blood clot the size of a watermelon.

The picture will be complicated, however, because Mohr was also taking conventional immune-suppressing drugs for her arthritis. One of those in particular, adalimumab, whose brand name is Humira, is known to make patients susceptible to histoplasmosis, the kind of fungal infection that Mohr had. Inexplicably, Mohr suddenly became ill in July even though she had been taking that drug for years and the fungus that causes histoplasmosis is ubiquitous in the area where she lived.

Meanwhile, a columnist in the Seattle Post-Intelligencer wondered about the implications of the case.

Those tragedies reflect one of the more troubling regulatory failures in the U.S. health care system: the inability to develop sensible and enforceable rules to oversee a growing biotech industry that is using humans to test what it hopes will become the next big moneymaker -- all without having much of a clue as to gene therapy's long- or short-term impacts.

When a federal committee charged with reviewing gene therapy trials evaluated Targeted Genetics' arthritis study in 2003, members openly questioned its justification, as it involved patients who were not very ill and evidence from animal studies didn't seem all that promising. They also worried it could trigger dangerous immune responses and questioned the informed consent documents' clarity. But as they have no binding authority or enforcement powers, Targeted Genetics was free to continue as it saw fit.

But this isn't simply about regulatory failure. It's also about how profit motives embedded in the clinical trial process can undermine patient safety. Pharmaceuticals had the fifth-most profitable return on revenues of any industry in 2006; the top five drug companies took home close to $30 billion in profits. Such companies as Targeted Genetics hope gene therapy and other biotech products will help them tap into and expand those markets. To be sure, Targeted Genetics CEO H. Stewart Parker told the P-I in 2005 that arthritis treatment could be 'a $7 billion market ... by 2011' and that the gene therapy used in the clinical trial that may have led to Mohr's death might help the company capture '15 percent to 40 percent of that opportunity.'

Time is money; in the rush to get products to market, patient safety can inadvertently take a backseat. And the fact that Targeted Genetics doesn't currently have any products on the market suggests that it has a significant financial incentive to stop hemorrhaging cash -- financial reports indicate it has lost $8 million this year alone -- and do everything possible to quickly get its products out of the clinical trial phase.

Time will tell whether gene-therapy caused this death. It very well may not have.

However, in my humble opinion, the most troubling aspect of this case so far is how people involved with this trial seem to have believed that their new treatment was safe in the absence of much evidence one way or the other. In particular, they seemed to persist in their disbelief that the new treatment could have had anything to do with the patient's unexplained rapidly deteriorating condition. Why were they so confident that their new treatment could not have been responsible?

This treatment was not merely new, it was a new variant on a broad class of new treatments, genes delivered by viruses, which are not yet in clinical use because no treatment in this class has been proven safe and effective. Furthermore, a few previous attempts at gene-therapy have produced very bad results, most notably in the unfortunate case of Jesse Gelsinger. Thus, one would expect that people setting up a new trial of gene-therapy would be properly cautious, and concerned that the new treatment might have unanticipated kinds of risks.

In my humble opinion, it is all too possible, as suggested by the op-ed above, that financial concerns have pushed manufacturers, researchers, and physicians into believing that the new treatments they are developing just have to be safe and effective.

This is another argument that clinical research, that is, experiments on humans to evaluate new tests or treatments should not be designed, implemented, or reported by people who have a financial stake in the success of the product bying evaluated.

Who's responsible for that prescription denial? If an MD has trouble finding out and is insulted in the process, what's a layperson to do?

I pity non-medical laypeople trying to navigate the mess that is called "the healthcare system." I've just had a most spectacular and bizarre encounter myself. The left hand does not know what the right hand is doing, which does not know what the foot is doing ... and the foot despises the body it's supposed to support for good measure.

Over the past few years, I've put on extra pounds. Way too many. My BMI has climbed to unhealthy proportions and I hit the big five-oh in age recently. After using sheer willpower to diet and exercise to drive my weight down 15 lbs. in a month, I had my blood work checked and parameters are decent. However, I need to repeat the weight reduction accomplishment a few more times over before I am back at a desirable BMI. It is not easy.

My personal physician (yes, doctors go to doctors) prescribed Meridia 10 mg daily, an Abbott drug in the Serotonin Reuptake Inhibitor (SSRI) class, and that's where this bizarre encounter with the "non-system" began.

The active ingredient in MERIDIA, sibutramine, works in the area of the brain that signals the sense of fullness (satiety). Meridia does not suppress appetite, which is your signal to start eating.

Meridia blocks the re-uptake of the brain chemicals (serotonin and norepinephrine) which help regulate the sense of fullness. Fullness is your signal to stop eating. Having a sense of fullness, or satiety, means you may feel satisfied with less food.

When I went to my neighborhood pharmacy a.k.a. megastore, I was told my health plan did not cover this medication. I possess a BC/BS PPO and Medco card through my employer, a university. The cost of a month's supply of the medication was approximately $160. The pharmacist suggested I contact Medco to find out why Meridia was not covered.

I did, which started a string of phone calls ending in my being seriously insulted by a service rep at Medco! The account (best as I can recall from memory, as things got convoluted) is as follows:

A Medco representative told me Medco is only a contractor and plan administrator to "my insurer" and does not make such decisions. However, the rep did not know who did.

I next contacted BC/BS. Their rep told me they only covered medical care and not medications, and suggested I call Medco. When I mentioned Medco told me they did not make such decisions, the BC/BS rep had no suggestions.

I called Medco back. The Medco rep this time told me I could appeal the denial and was sending me an appeal form that I should mail back to - Medco. Now, I was really confused.

I inquired why Medco gets an appeal form for denial of coverage if Medco did not make the decision. The rep did not know. I asked for the name of a person at the organization where the form would go. Again, the rep did not know.

I finally called my university's benefits management contact, yet another contractor company (it seems everything is handled by third parties - just a little bit of administrative overhead there?), and that is where this already confusing matter took a very deep turn directly south.

The rep at the university's Benefits Management contractor said that he believed Medco was the responsible party. I informed him Medco said they were not.

In the first actually creative and industrious response from any of these organizations, the rep said he would get a Medco representative on the phone in conference call mode so we might get to the bottom of this.

We got to the bottom all right. The real bottom.

The Medco customer service rep that the University Benefits Management Rep conferenced in was a new individual, not the ones I had spoken to prior. This rep repeated that Medco was just a benefits manager and was not responsible for the denial.

I asked the university's Benefits Management contractor rep if he believed that was the case. He was as confused as I. The Medco rep said I needed to appeal.

I asked the Medco rep for the name or identity of a person or organization where the appeal form would go, so I could contact them directly, as I was a medical doctor with pharma experience as well and wanted to go direct to the source.

The Medco rep replied that "my title would not get me advantage in this matter" or words to that effect.

I again tried to explain that I wished to know exactly who made the appeals decision. The Medco rep started to become patronizing in tone, not letting me get a word in edgewise and calling me "Mr."

I reminded the Medco rep that I was a physician and wished to be addressed more formally, as "Dr." I don't often make this request of anyone, but I was starting to sense something odd here.

The Medco rep again referred to me as "Mr."

I said once again that I wished to be referred to as "Dr."

The Medco rep once again referred to me as "Mr."

I think we went through three cycles of that little skit.

At this point, getting rather angry from this deliberate insult, I asked the Medco rep rather pointedly if her refusal to call me "Dr." was an act of prejudice (my name gives away my religious identity). At that point, the Medco rep hurredly put a supervisor on the phone. I don't think she'd ever been called on such behavior in such un-PC (i.e., unashamedly direct) terms.

The supervisor rapidly answered my question, telling me the University itself was who needed to be contacted. I mentioned to the supervisor that the refusal to call me "Dr." even after I asked for this courtesy was quite disturbing, reflecting at the very least a very bad level of customer service. The supervisor offered agreement.

I emailed the University HR benefits director (finally, a principal, not a contractor!) As it turns out, the University covers drugs, and I was emailed back that "this class of drug is not covered" (I presumed that means the weight reduction class of drugs.) I emailed back a question as to why. I have not yet received a response - and I'm not even going to go there in this posting. (Discrimination against the obese?)

On the other hand, the extremely rude and deliberate refusal of a Medco Customer Service Representative to call me "Dr." even when I asked for this courtesy several times was unbelievable.

I can only wonder what types of attitudes this person held about physicians - and if the company's customer service management or higher shared a similar bias. I also cannot discount other cultural biases. Imagine if the situation occurred in reverse.

I was able to find out very quickly from the Internet and several phone calls to Medco Corporate that the customer service department at Medco reported to the VP of HR. I believe physicians need to start being far more direct and confrontational when they encounter attitudes like this.

In Roy Poses' post "Bling Bling, Political Correctness, and the Anechoic Effect" it was observed that:

In the post-modern academic world, everyone is afraid of saying anything that might be the least bit offensive. (See the web-site of the Foundation for Individual Rights in Education, or FIRE, for some amazing examples.)It seems that that even the most skeptical and iconoclastic health care bloggers may also be fearful of being too politically incorrect.

I agree. And pushback should not just occur after major scandals. After calling the VP's administrative assistant who said she would forward my complaint to the VP if I sent it via email, I passed along details of what occurred as I summarize here (my email was actually a bit more direct):

As former Director of Scientific Information Resources and The Merck Index at Merck & Co. [note - Medco was a Merck subsidiary until a few years ago - ed.], I am familiar with the pharma industry and customer service. I am also a writer for the Foundation for Integrity and Responsibility in Medicine (FIRM) ... The interaction I had this morning (appx. 11:40 AM EST) with one of your customer service reps was so profoundly disturbing I feel you should be aware.

... your service rep was patronizing, would not let me get a word in to clarify my questions, but those were minor issues. When the customer service rep referred to me as "Mr. " I informed her I was an MD and wanted to be addressed as "doctor." The rep deliberately and repeatedly called me "Mr." after being told several times I wished to be addressed more formally. When I expressed my outrage, a supervisor was put on who did help answer my question about my medication coverage. The customer service rep sounded like a minority.

My question to you is: Was this an issue of your customer service rep disrespecting a man of European heritage? Was it religious prejudice, as my name is quite revealing in that regard? Or did it reflect a bias against physicians? Any of these would be a serious matter. I would really like to know why your rep refused to address me formally as I repeatedly requested.

Unsurprisingly, I have not heard back from the Medco VP of HR. I do not expect to. Medco has certainly had more serious fish to fry. Perhaps he will give his service reps some "sensitivity training" - towards physicians.

Finally, I observe that I am a physician and former corporate manager who had the greatest of trouble and frustration trying to navigate the morass of tangled third-parties-for-everything we call a "health care system" over a simple single non life-threatening prescription. I was insulted for my efforts by a pharmacy benefits management company just for good measure.

I can only imagine what Joe and Mary Citizen have to put up with.

(And, I've shelled out the money for the medication, deciding this one was just not worth pursuing further.)

-- SS