The University of Minnesota, Where Nothing Can Go Wrong, Go Wrong, Go Wrong...

As noted on the Periodic Table blog, the administration of the University of Minnesota continues to believe all is well with its clinical research activities.  A recent internal review said there was nothing more to investigate about the unfortunate death of a psychiatric patient years before. So should we all be relieved?

It will take an extensive review of the case to ultimately suggest we should not at all be relieved.  The case raised important concerns about the validity of clinical research, and whether it violates the trust of its patient-subjects.  These concerns had not been addressed before the university's most recent review, and thus seem even more pointed after its recent non-investigation.

Background: the Untimely Death of Dan Markingson

In May, 2008, the (Minnesota) Pioneer Press ran a series of articles about the untimely death of Dan Markingson which occurred while he was enrolled in a randomized trial sponsored by AstraZeneca (the CAFE study) at a site at the University of Minnesota.  The first article in the series made the following major points:

Mr Markingson had given his consent to be enrolled despite evidence that he was actively psychotic

He started having visions of killing his mother in the storm. Markingson was taken Nov. 12, 2003, to Regions Hospital in St. Paul, but it had no open psychiatric beds. He was then transferred to the University of Minnesota Medical Center, Fairview.

Weiss said discussions about research started right away at the hospital. Markingson was placed in Fairview's Station 12, a new unit at the time created to treat psychotic patients and screen them for research. Olson and Dr. Charles Schulz, head of the U's psychiatry department, helped launch the unit in part to enhance the hospital's startup schizophrenia program and meet the U's mandate to bring in more research dollars.

Olson first recommended on Nov. 14 that a Dakota County District Court commit Markingson to the state treatment center in Anoka because he was not fit to make decisions about his care. He wrote to the court that Markingson was convinced his delusions were real and that he wasn't mentally ill.

The doctor changed his opinion about the commitment in less than a week, telling the court Markingson had started to acknowledge the need for help.

Reversals by patients are common, Olson explained in an interview with the Pioneer Press last month. Schizophrenics often arrive for treatment with delusions and denial but change their outlook while hospitalized.

A judge agreed Nov. 20 with Olson's new recommendation, requiring Markingson to follow the doctor's treatment plan. The next day, Markingson signed a consent form to be part of a national anti-psychotic drug study, Comparison of Atypicals for First Episode, or CAFE.

His mother's multiple complaints that while in the study, Markingson was not getting better and not getting proper treatment were ignored

Weiss' letters to Olson and Schulz, who was a co-investigator in the study, urged them to consider different treatment options for her son, which would have disqualified him from the study. But the doctors were unconvinced by her pleas.

In particular, she wrote with strange prescience,

'Do we have to wait until he kills himself or someone else,' she asked three weeks before his suicide, 'before anyone does anything.'

There was evidence that Markingson was not getting optimal treatment

In retrospect, it was not even clear that Markingson was taking his study medications prior to his suicide:

An autopsy showed no medication in Markingson's bloodstream, and a coroner's photo showed a sealed bottle of his medication. Had he been taking his drugs?

Study officials could have been fooled. They only counted drugs left in pill bottles instead of testing blood levels in patients.

Suggestions that financial conflicts of interest influenced trial investigators' actions

The initial news article raised questions whether the study investigator had been unduly influenced to keep Markingson in the study by financial concerns:

CAFE was an early opportunity at the U for Olson to add research experience to his academic credentials. The U had recruited him in 2001 for his expertise in schizophrenia.

It was a slow start. Olson recruited one patient in 2002, and CAFE study leaders considered dropping him altogether, according to monthly recruiting summaries. Olson and the university had been dropped from a previous study because of low recruiting numbers, the doctor later said in his court deposition.

Exchanges between local and national study officials made it clear that there was pressure for results and a 'risk' that the study would be shut down if it didn't recruit enough patients.

Note that:

As Subject 13, Markingson was worth $15,000 to the U, with some of that going to Olson's salary and the psychiatry department. Switching or adding medications could have disqualified Markingson and halted payments to Olson and the department from AstraZeneca.

Overall, the study offered $327,000 to the U and an opportunity to raise the profile of its schizophrenia program.

An accompanying Pioneer Press article indicated that both Dr Olson, and the Chair of Psychiatry, Dr S Charles Schulz, were receiving considerable financial support from AstraZeneca and other pharmaceutical companies at the time of the study.

Olson received $220,000 from six companies since 2002, including $149,000 from AstraZeneca, according to the state records. Schulz received $562,000, including $112,000 as a researcher and consultant to AstraZeneca.

Olson said his AstraZeneca money went straight to the U but did support his salary. Markingson's full participation in the yearlong study meant up to $15,000 for the university.

Did the lawsuit's results indicate nothing was wrong?

Mr Markingson's mother sued the University of Minnesota and AstraZeneca, but (per the first Pioneer Press article),

The lawsuit ended this year after a judge ruled that the university had statutory immunity from such lawsuits and that AstraZeneca shouldn't stand trial because there was no convincing proof that its drug caused Markingson's death. Weiss settled with Olson, the only defendant left. She said she was granted $75,000, which went entirely toward legal bills.

Note that the results did not address the university's or its administration's role.

Dr Carl Elliott Takes Another Look

Thus the case appeared to end, with no real reconsideration of how medical schools' dependence on commercial funding of clinical studies, and how individual faculty members' financial relationships with drug, device, and biotechnology firms may affect research done on human beings.

However, in September, 2010, Mother Jones published an article by Dr Carl Elliott, a University of Minnesota bioethicist, which raised further questions about the case.

I talked to several university colleagues and administrators, trying to learn what had happened. Many of them dismissed the story as slanted and incomplete. Yet the more I examined the medical and court records, the more I became convinced that the problem was worse than the Pioneer Press had reported. The danger lies not just in the particular circumstances that led to Dan's death, but in a system of clinical research that has been thoroughly co-opted by market forces, so that many studies have become little more than covert instruments for promoting drugs

Major design defects of the CAFE study:

It barred subjects from being taken off their assigned drug; it didn't allow them to be switched to another drug if their assigned drug was not working; and it restricted the number of additional drugs subjects could be given to manage side effects and symptoms such as depression, anxiety, or agitation. Like many clinical trials, the study was also randomized and double-blinded: Subjects were assigned a drug randomly by a computer, and neither the subjects nor the researchers knew which drug it was. These restrictions meant that subjects in the CAFE study had fewer therapeutic options than they would have had outside the study.

In fact, the CAFE study also contained a serious oversight that, if corrected, would have prevented patients like Dan from being enrolled. Like other patients with schizophrenia, patients experiencing their first psychotic episode are at higher risk of killing themselves or other people. For this reason, most studies of antipsychotic drugs specifically bar researchers from recruiting patients at risk of violence or suicide, for fear that they might kill themselves or someone else during the study. Conveniently, however, the CAFE study only prohibited patients at risk of suicide, not homicide. This meant that Dan—who had threatened to slit his mother's throat, but had not threatened to harm himself—was a legitimate target for recruitment.

As Dr Elliott noted, this appeared to be yet another example of manipulation of clinical research designed to make the sponsors' products look better, a topic we have frequently discussed on Health Care Renewal:

A 2006 study in The American Journal of Psychiatry, which looked at 32 head-to-head trials of atypicals, found that 90 percent of them came out positively for whichever company had designed and financed the trial. This startling result was not a matter of selective publication. The companies had simply designed the studies in a way that virtually ensured their own drugs would come out ahead—for instance, by dosing the competing drugs too low to be effective, or so high that they would produce damaging side effects. Much of this manipulation came from biased statistical analyses and rigged trial designs of such complexity that outside reviewers were unable to spot them. As Dr. Richard Smith, the former editor of the British Medical Journal, has pointed out, 'The companies seem to get the results they want not by fiddling the results, which would be far too crude and possibly detectable by peer review, but rather by asking the 'right' questions.'

This was likely what was going on with the CAFE study:

Although the documents unsealed in the Seroquel litigation do not specifically mention the CAFE study in which Dan was enrolled, they do suggest that AstraZeneca planned to establish Seroquel as the "atypical of choice in first-episode schizophrenia,' according to a 2000 'Seroquel Strate'y Summary.' A later document titled 'Seroquel PR Plan 2001' discusses the agenda for an advisory panel meeting in Hawaii. Among the potential topics were the marketing of Seroquel to first-episode patients, adolescents, and the elderly. The document refers to these populations as "vulnerable patient groups."

Even more alarming are internal documents suggesting that AstraZeneca was designing clinical trials as a covert method of marketing Seroquel. In 1997, when Dr. Andrew Goudie, a psychopharmacologist at the University of Liverpool, asked AstraZeneca to fund a research study he was planning, a company official replied that 'R&D is no longer responsible for Seroquel research—it is now the responsibility of Sales and Marketing.' The official also noted that funding decisions would depend on whether the study was likely to show a 'competitive advantage for Seroquel.'

Were study subjects protected?
So, as Dr Elliott wrote,

Many clinical studies place human subjects at risk—at a minimum, the risk of mild discomfort, and at worst, the risk of serious pain and death. Bioethicists and regulators spend a lot of time and energy debating the degree of risk that ought to be permitted in a study, how those risks should be presented to subjects, and the way those risks should be balanced against the potential benefits a subject might receive. What is simply assumed, without much consideration at all, is that the research is being conducted to produce scientific knowledge. This assumption is codified in a number of foundational ethics documents, such as the Nuremberg Code, which was instituted following Nazi experiments on concentration camp victims. The Nuremberg Code stipulates that an 'experiment should be such as to yield fruitful results for the good of society,' and 'the degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.'

But what if a research study is not really aimed at producing genuine scientific knowledge at all? The documents emerging in litigation suggest that pharmaceutical companies are designing, analyzing, and publishing trials primarily as a way of positioning their drugs in the marketplace. This raises a question unconsidered in any current code of research ethics. How much risk to human subjects is justified in a study whose principal aim is to 'generate commercially attractive messages'?

Conflicts of interest
Of course, university faculty pushed to bring in more external funds to support their careers (see this post) by university leaders with their eyes on the bottom line may not be too critical of the intricate designs of the studies they need to do to continue their academic careers, and whether such studies are really meant to promote science and improve patient care, or position products in the marketplace, especially when the same companies are paying them as consultants, speakers, etc.

In fact, Dr Elliott found reasons to make such concerns specific to the case of Mr Markingson's untimely death:

Olson had another financial reason to maintain good relations with AstraZeneca. According to a disclosure statement for a 2006 conference, he was a member of the AstraZeneca 'speaker's bureau,' giving paid talks for the company. He had similar arrangements with Eli Lilly and Janssen, the makers of the other atypicals being tested in the CAFE study, as well as Bristol-Myers Squibb and Pfizer. In addition, Olson was working as a paid consultant for Lilly, Janssen, Bristol-Myers Squibb, and Pfizer.

Bioethicists Demand an Investigation

So eight University of Minnesota bioethicists, including Dr Elliott, wrote a letter to the University administration demanding an investigation, as reported in December, 2010, by the Minneapolis- St Paul Star-Tribune,

In a letter to the board Monday, the professors questioned whether U psychiatrists lacked ethical judgment in enrolling the victim, Dan Markingson, a schizophrenic who may have lacked the wherewithal to consent to research. They also questioned whether financial incentives from AstraZeneca, the drugmaker funding the study, presented conflicts for the researchers, Dr. Stephen Olson and Dr. S. Charles Schulz.

At the time, the administration promised a serious response:

U leaders will take the letter seriously and take the protection of human research subjects seriously, said the U's general counsel, Mark Rotenberg.

But then almost immediately indicated its bias:

'The fact that this is tragic doesn't mean the treating physicians did anything wrong,' he said.

What, Us Worry?

It did not take long for Mark Rotenberg to decide that there was nothing more to worry about. As reported in February, 2011, by the Pioneer Press:

in a Monday letter to Elliott and colleagues, the chairman of the U's board of regents wrote 'we do not believe further university resources should be expended re-reviewing a matter such as this, which has already received such exhaustive analysis by independent authoritative bodies.'

'Our general counsel has provided us with the extensive reviews of this case that were performed over the years by a number of independent experts and governmental units,' chairman Clyde Allen Jr. said in the letter. 'Each and every one of these reviews resulted in the same conclusion: there was no improper or inappropriate care provided to Mr. Markingson, nor is there evidence of misconduct or violation of applicable laws or regulations.'

Of course, since Mr Rotenberg is responsible for, among other things, reducing the university's legal liability, one could see how he might not want to delve further into this case.  As we noted earlier, it is not clear that previous "exhaustive" investigations asked the questions that needed to be asked, or had access to all the relevant data.  The issues are not whether their was criminal conduct, or even civil liability, but whether the university is presiding over good science and protection of research subjects?

So we should be worried, of course, that commercial firms sponsor research on human beings mainly to serve marketing objectives, and that university faculty and administrators go along, allowing their formerly prestigious universities' names to be added to the research in exchange for the money they so much want to keep themselves living in the style to which they are accustomed. We ought to be particularly worried when these universities seem to forget about their mission to find and disseminate new knowledge in favor of defending the work that continues to bring in the money.

Thus, physicians, researchers, patients, and the public ought to be very skeptical about clinical research sponsored by commercial firms with vested interests in the research turning out a particular way, and even about research not sponsored by such firms, but done by researchers who have personal financial ties to such firms. Worse, patients ought to be extremely skeptical about the motives of researchers who want to enroll them in trials when the researchers have financial ties to commercial firms whose products could be promoted through such trials, and especially when such firms are sponsoring the trials.

As a long-time advocate for evidence-based medicine, whose advancement depends on the continuing creation of valid research evidence from clinical research, it is heart-breaking to have to make these recommendations, but they will be necessary until there is better assurance that clinical research is being done to advance science and patient care, not the commercial interests of the sponsors and the researchers.

Until academic medicine becomes more open about how and why it is doing clinical research, such skepticism is warranted.

However, I will end with a ray of hope. If the administrators and faculty do not get it, the student journalists do. Read these words in an editorial in the Minnesota Daily:

Of course, the University has maintained neither it nor anyone involved in the case did anything wrong, an odd claim to make after the Minnesota Legislature unanimously passed a law that prohibits exactly what happened and named the law after Markingson.

The University seems to think that because it was not held liable in court for Markingson’s death, it did nothing wrong. This is false; it is a cynical excuse to keep corporate drug money flowing into the University.

The regents’ decision fundamentally undermines our mission: Supposedly, the University is 'dedicated to … the search for truth.' But the letter makes it clear that corporate research cash is more important to the University than patient safety and transparency.

Refusing to set up an independent investigation is a willfully ignorant attempt to sweep the Markingson case under the rug and damages the integrity of the entire University.

Perhaps it is time for the state legislature to take another look at this issue.

True health care reform would separate clinical research, that is, research done on human beings, from the commercial interests of health care corporations and the people who work for them.

ADDENDUM (18 March, 2011) - See this post by Naomi Freundlich on the Health Beat blog.

The University of Minnesota, Where Nothing Can Go Wrong, Go Wrong, Go Wrong...

As noted on the Periodic Table blog, the administration of the University of Minnesota continues to believe all is well with its clinical research activities.  A recent internal review said there was nothing more to investigate about the unfortunate death of a psychiatric patient years before. So should we all be relieved?

It will take an extensive review of the case to ultimately suggest we should not at all be relieved.  The case raised important concerns about the validity of clinical research, and whether it violates the trust of its patient-subjects.  These concerns had not been addressed before the university's most recent review, and thus seem even more pointed after its recent non-investigation.

Background: the Untimely Death of Dan Markingson

In May, 2008, the (Minnesota) Pioneer Press ran a series of articles about the untimely death of Dan Markingson which occurred while he was enrolled in a randomized trial sponsored by AstraZeneca (the CAFE study) at a site at the University of Minnesota.  The first article in the series made the following major points:

Mr Markingson had given his consent to be enrolled despite evidence that he was actively psychotic

He started having visions of killing his mother in the storm. Markingson was taken Nov. 12, 2003, to Regions Hospital in St. Paul, but it had no open psychiatric beds. He was then transferred to the University of Minnesota Medical Center, Fairview.

Weiss said discussions about research started right away at the hospital. Markingson was placed in Fairview's Station 12, a new unit at the time created to treat psychotic patients and screen them for research. Olson and Dr. Charles Schulz, head of the U's psychiatry department, helped launch the unit in part to enhance the hospital's startup schizophrenia program and meet the U's mandate to bring in more research dollars.

Olson first recommended on Nov. 14 that a Dakota County District Court commit Markingson to the state treatment center in Anoka because he was not fit to make decisions about his care. He wrote to the court that Markingson was convinced his delusions were real and that he wasn't mentally ill.

The doctor changed his opinion about the commitment in less than a week, telling the court Markingson had started to acknowledge the need for help.

Reversals by patients are common, Olson explained in an interview with the Pioneer Press last month. Schizophrenics often arrive for treatment with delusions and denial but change their outlook while hospitalized.

A judge agreed Nov. 20 with Olson's new recommendation, requiring Markingson to follow the doctor's treatment plan. The next day, Markingson signed a consent form to be part of a national anti-psychotic drug study, Comparison of Atypicals for First Episode, or CAFE.

His mother's multiple complaints that while in the study, Markingson was not getting better and not getting proper treatment were ignored

Weiss' letters to Olson and Schulz, who was a co-investigator in the study, urged them to consider different treatment options for her son, which would have disqualified him from the study. But the doctors were unconvinced by her pleas.

In particular, she wrote with strange prescience,

'Do we have to wait until he kills himself or someone else,' she asked three weeks before his suicide, 'before anyone does anything.'

There was evidence that Markingson was not getting optimal treatment

In retrospect, it was not even clear that Markingson was taking his study medications prior to his suicide:

An autopsy showed no medication in Markingson's bloodstream, and a coroner's photo showed a sealed bottle of his medication. Had he been taking his drugs?

Study officials could have been fooled. They only counted drugs left in pill bottles instead of testing blood levels in patients.

Suggestions that financial conflicts of interest influenced trial investigators' actions

The initial news article raised questions whether the study investigator had been unduly influenced to keep Markingson in the study by financial concerns:

CAFE was an early opportunity at the U for Olson to add research experience to his academic credentials. The U had recruited him in 2001 for his expertise in schizophrenia.

It was a slow start. Olson recruited one patient in 2002, and CAFE study leaders considered dropping him altogether, according to monthly recruiting summaries. Olson and the university had been dropped from a previous study because of low recruiting numbers, the doctor later said in his court deposition.

Exchanges between local and national study officials made it clear that there was pressure for results and a 'risk' that the study would be shut down if it didn't recruit enough patients.

Note that:

As Subject 13, Markingson was worth $15,000 to the U, with some of that going to Olson's salary and the psychiatry department. Switching or adding medications could have disqualified Markingson and halted payments to Olson and the department from AstraZeneca.

Overall, the study offered $327,000 to the U and an opportunity to raise the profile of its schizophrenia program.

An accompanying Pioneer Press article indicated that both Dr Olson, and the Chair of Psychiatry, Dr S Charles Schulz, were receiving considerable financial support from AstraZeneca and other pharmaceutical companies at the time of the study.

Olson received $220,000 from six companies since 2002, including $149,000 from AstraZeneca, according to the state records. Schulz received $562,000, including $112,000 as a researcher and consultant to AstraZeneca.

Olson said his AstraZeneca money went straight to the U but did support his salary. Markingson's full participation in the yearlong study meant up to $15,000 for the university.

Did the lawsuit's results indicate nothing was wrong?

Mr Markingson's mother sued the University of Minnesota and AstraZeneca, but (per the first Pioneer Press article),

The lawsuit ended this year after a judge ruled that the university had statutory immunity from such lawsuits and that AstraZeneca shouldn't stand trial because there was no convincing proof that its drug caused Markingson's death. Weiss settled with Olson, the only defendant left. She said she was granted $75,000, which went entirely toward legal bills.

Note that the results did not address the university's or its administration's role.

Dr Carl Elliott Takes Another Look

Thus the case appeared to end, with no real reconsideration of how medical schools' dependence on commercial funding of clinical studies, and how individual faculty members' financial relationships with drug, device, and biotechnology firms may affect research done on human beings.

However, in September, 2010, Mother Jones published an article by Dr Carl Elliott, a University of Minnesota bioethicist, which raised further questions about the case.

I talked to several university colleagues and administrators, trying to learn what had happened. Many of them dismissed the story as slanted and incomplete. Yet the more I examined the medical and court records, the more I became convinced that the problem was worse than the Pioneer Press had reported. The danger lies not just in the particular circumstances that led to Dan's death, but in a system of clinical research that has been thoroughly co-opted by market forces, so that many studies have become little more than covert instruments for promoting drugs

Major design defects of the CAFE study:

It barred subjects from being taken off their assigned drug; it didn't allow them to be switched to another drug if their assigned drug was not working; and it restricted the number of additional drugs subjects could be given to manage side effects and symptoms such as depression, anxiety, or agitation. Like many clinical trials, the study was also randomized and double-blinded: Subjects were assigned a drug randomly by a computer, and neither the subjects nor the researchers knew which drug it was. These restrictions meant that subjects in the CAFE study had fewer therapeutic options than they would have had outside the study.

In fact, the CAFE study also contained a serious oversight that, if corrected, would have prevented patients like Dan from being enrolled. Like other patients with schizophrenia, patients experiencing their first psychotic episode are at higher risk of killing themselves or other people. For this reason, most studies of antipsychotic drugs specifically bar researchers from recruiting patients at risk of violence or suicide, for fear that they might kill themselves or someone else during the study. Conveniently, however, the CAFE study only prohibited patients at risk of suicide, not homicide. This meant that Dan—who had threatened to slit his mother's throat, but had not threatened to harm himself—was a legitimate target for recruitment.

As Dr Elliott noted, this appeared to be yet another example of manipulation of clinical research designed to make the sponsors' products look better, a topic we have frequently discussed on Health Care Renewal:

A 2006 study in The American Journal of Psychiatry, which looked at 32 head-to-head trials of atypicals, found that 90 percent of them came out positively for whichever company had designed and financed the trial. This startling result was not a matter of selective publication. The companies had simply designed the studies in a way that virtually ensured their own drugs would come out ahead—for instance, by dosing the competing drugs too low to be effective, or so high that they would produce damaging side effects. Much of this manipulation came from biased statistical analyses and rigged trial designs of such complexity that outside reviewers were unable to spot them. As Dr. Richard Smith, the former editor of the British Medical Journal, has pointed out, 'The companies seem to get the results they want not by fiddling the results, which would be far too crude and possibly detectable by peer review, but rather by asking the 'right' questions.'

This was likely what was going on with the CAFE study:

Although the documents unsealed in the Seroquel litigation do not specifically mention the CAFE study in which Dan was enrolled, they do suggest that AstraZeneca planned to establish Seroquel as the "atypical of choice in first-episode schizophrenia,' according to a 2000 'Seroquel Strate'y Summary.' A later document titled 'Seroquel PR Plan 2001' discusses the agenda for an advisory panel meeting in Hawaii. Among the potential topics were the marketing of Seroquel to first-episode patients, adolescents, and the elderly. The document refers to these populations as "vulnerable patient groups."

Even more alarming are internal documents suggesting that AstraZeneca was designing clinical trials as a covert method of marketing Seroquel. In 1997, when Dr. Andrew Goudie, a psychopharmacologist at the University of Liverpool, asked AstraZeneca to fund a research study he was planning, a company official replied that 'R&D is no longer responsible for Seroquel research—it is now the responsibility of Sales and Marketing.' The official also noted that funding decisions would depend on whether the study was likely to show a 'competitive advantage for Seroquel.'

Were study subjects protected?
So, as Dr Elliott wrote,

Many clinical studies place human subjects at risk—at a minimum, the risk of mild discomfort, and at worst, the risk of serious pain and death. Bioethicists and regulators spend a lot of time and energy debating the degree of risk that ought to be permitted in a study, how those risks should be presented to subjects, and the way those risks should be balanced against the potential benefits a subject might receive. What is simply assumed, without much consideration at all, is that the research is being conducted to produce scientific knowledge. This assumption is codified in a number of foundational ethics documents, such as the Nuremberg Code, which was instituted following Nazi experiments on concentration camp victims. The Nuremberg Code stipulates that an 'experiment should be such as to yield fruitful results for the good of society,' and 'the degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.'

But what if a research study is not really aimed at producing genuine scientific knowledge at all? The documents emerging in litigation suggest that pharmaceutical companies are designing, analyzing, and publishing trials primarily as a way of positioning their drugs in the marketplace. This raises a question unconsidered in any current code of research ethics. How much risk to human subjects is justified in a study whose principal aim is to 'generate commercially attractive messages'?

Conflicts of interest
Of course, university faculty pushed to bring in more external funds to support their careers (see this post) by university leaders with their eyes on the bottom line may not be too critical of the intricate designs of the studies they need to do to continue their academic careers, and whether such studies are really meant to promote science and improve patient care, or position products in the marketplace, especially when the same companies are paying them as consultants, speakers, etc.

In fact, Dr Elliott found reasons to make such concerns specific to the case of Mr Markingson's untimely death:

Olson had another financial reason to maintain good relations with AstraZeneca. According to a disclosure statement for a 2006 conference, he was a member of the AstraZeneca 'speaker's bureau,' giving paid talks for the company. He had similar arrangements with Eli Lilly and Janssen, the makers of the other atypicals being tested in the CAFE study, as well as Bristol-Myers Squibb and Pfizer. In addition, Olson was working as a paid consultant for Lilly, Janssen, Bristol-Myers Squibb, and Pfizer.

Bioethicists Demand an Investigation

So eight University of Minnesota bioethicists, including Dr Elliott, wrote a letter to the University administration demanding an investigation, as reported in December, 2010, by the Minneapolis- St Paul Star-Tribune,

In a letter to the board Monday, the professors questioned whether U psychiatrists lacked ethical judgment in enrolling the victim, Dan Markingson, a schizophrenic who may have lacked the wherewithal to consent to research. They also questioned whether financial incentives from AstraZeneca, the drugmaker funding the study, presented conflicts for the researchers, Dr. Stephen Olson and Dr. S. Charles Schulz.

At the time, the administration promised a serious response:

U leaders will take the letter seriously and take the protection of human research subjects seriously, said the U's general counsel, Mark Rotenberg.

But then almost immediately indicated its bias:

'The fact that this is tragic doesn't mean the treating physicians did anything wrong,' he said.

What, Us Worry?

It did not take long for Mark Rotenberg to decide that there was nothing more to worry about. As reported in February, 2011, by the Pioneer Press:

in a Monday letter to Elliott and colleagues, the chairman of the U's board of regents wrote 'we do not believe further university resources should be expended re-reviewing a matter such as this, which has already received such exhaustive analysis by independent authoritative bodies.'

'Our general counsel has provided us with the extensive reviews of this case that were performed over the years by a number of independent experts and governmental units,' chairman Clyde Allen Jr. said in the letter. 'Each and every one of these reviews resulted in the same conclusion: there was no improper or inappropriate care provided to Mr. Markingson, nor is there evidence of misconduct or violation of applicable laws or regulations.'

Of course, since Mr Rotenberg is responsible for, among other things, reducing the university's legal liability, one could see how he might not want to delve further into this case.  As we noted earlier, it is not clear that previous "exhaustive" investigations asked the questions that needed to be asked, or had access to all the relevant data.  The issues are not whether their was criminal conduct, or even civil liability, but whether the university is presiding over good science and protection of research subjects?

So we should be worried, of course, that commercial firms sponsor research on human beings mainly to serve marketing objectives, and that university faculty and administrators go along, allowing their formerly prestigious universities' names to be added to the research in exchange for the money they so much want to keep themselves living in the style to which they are accustomed. We ought to be particularly worried when these universities seem to forget about their mission to find and disseminate new knowledge in favor of defending the work that continues to bring in the money.

Thus, physicians, researchers, patients, and the public ought to be very skeptical about clinical research sponsored by commercial firms with vested interests in the research turning out a particular way, and even about research not sponsored by such firms, but done by researchers who have personal financial ties to such firms. Worse, patients ought to be extremely skeptical about the motives of researchers who want to enroll them in trials when the researchers have financial ties to commercial firms whose products could be promoted through such trials, and especially when such firms are sponsoring the trials.

As a long-time advocate for evidence-based medicine, whose advancement depends on the continuing creation of valid research evidence from clinical research, it is heart-breaking to have to make these recommendations, but they will be necessary until there is better assurance that clinical research is being done to advance science and patient care, not the commercial interests of the sponsors and the researchers.

Until academic medicine becomes more open about how and why it is doing clinical research, such skepticism is warranted.

However, I will end with a ray of hope. If the administrators and faculty do not get it, the student journalists do. Read these words in an editorial in the Minnesota Daily:

Of course, the University has maintained neither it nor anyone involved in the case did anything wrong, an odd claim to make after the Minnesota Legislature unanimously passed a law that prohibits exactly what happened and named the law after Markingson.

The University seems to think that because it was not held liable in court for Markingson’s death, it did nothing wrong. This is false; it is a cynical excuse to keep corporate drug money flowing into the University.

The regents’ decision fundamentally undermines our mission: Supposedly, the University is 'dedicated to … the search for truth.' But the letter makes it clear that corporate research cash is more important to the University than patient safety and transparency.

Refusing to set up an independent investigation is a willfully ignorant attempt to sweep the Markingson case under the rug and damages the integrity of the entire University.

Perhaps it is time for the state legislature to take another look at this issue.

True health care reform would separate clinical research, that is, research done on human beings, from the commercial interests of health care corporations and the people who work for them.

ADDENDUM (18 March, 2011) - See this post by Naomi Freundlich on the Health Beat blog.

St Jude Medical Settles Again

Here we go again to kick off the week, legal settlements, cardiac devices, alleged kickbacks, manipulated research, as reported by Bloomberg:

Another Legal Settlement by St Jude Medical

St. Jude Medical Inc. agreed to pay $16 million to settle a U.S. government probe of claims the company paid kickbacks to doctors who implanted its heart devices in patients.

The accord resolves a five-year investigation of St. Jude’s marketing practices for defibrillators and pacemakers.

This was not even the first recent settlement by this particular company:

In June, St. Jude agreed to pay the federal government $3.7 million to resolve a separate whistleblower case over claims that it made illegal payments to hospitals in Kentucky and Ohio that used the company’s heart devices.

Our relevant post about that previous settlement was here.

Kickbacks, Manipulated Research

The $16 million settlement stemmed from a case filed by Charles Donigian, a former St. Jude technician from St. Louis, who accused the company of using kickbacks to market products.

The kickbacks, which ranged as high as $2,000 per patient, came in the form of 'sham fees' for phony clinical-research studies on the devices, Donigian said in his suit.

There was slightly more detail in a report in TheHeart.org:

According to the DoJ, the company used postmarketing studies and a registry as vehicles to reward physicians participating in those studies to implant the devices. 'In each case, St Jude paid each participating physician a fee that ranged up to $2000 per patient,' a statement from US Attorney Carmen M Ortiz notes. 'The United States alleges that St Jude solicited physicians for the studies in order to retain their business and/or convert their business from a competitor's product.'

The statement also observes: 'Although St Jude collected data and information from participating physicians, it knowingly and intentionally used the studies and registry as a means of increasing its device sales by paying certain physicians to select St Jude pacemakers and ICDs for their patients.'

Summary

It all is getting so old, isn't it? Yet another pharmaceutical, biotechnology or device company settles a case alleging payments to physicians to induce them to use its products. The twist here is that the form of the payment allegedly also manipulated the clinical research process.

There have been other cases of manipulation or suppression of research about cardiac devices. For example, see our recent post about how Guidant, now a subsidiary of Boston Scientific, was put on probation for its actions in another such case.

The allegations amounted to serious external threats to physicians' professionalism: payments to promote use of health care products whether or not their implantation was in patients' best interests, and manipulation of clinical research that could have further corrupted the clinical evidence base, and presumably could have broken the trust of clinical research subjects. Left unsaid in the brief articles is how willingly the physicians gave in to these threats to their professionalism for the dollars involved.

Yet despite the apparently corrosive quality of the bad behavior, the penalties to the company were trivial. Per St Jude Medical's most recent financial profile, its yearly revenue was over $4.5 billion.  Two settlements totaling less than $20 million amount to a relatively small cost of doing business.  And note that St Jude Medical is not admitting it did anything wrong.  Per TheHeart.org, its statement was:

We are pleased to have reached a settlement agreement with the DoJ that fully resolves the postmarket-study matter in Boston. The company maintains that its postmarket studies and registries are legitimate clinical studies designed to gather important scientific data, and St Jude Medical does not admit liability or wrongdoing by entering into this agreement. The company entered into a settlement agreement to avoid the potential costs and risks associated with litigation. This settlement brings the previously reported postmarket-study investigation to a close.

So it all gets so tiresome. The continuing march of legal settlements like this do provide evidence of how professionalism and evidence-based medical practice are under threat. However, as we have said ad infinitum, such settlements are likely to do nothing to alleviate that threat.

To repeat the conclusion of our last post about St Jude Medical, the usual sorts of legal settlements we have described do not seem to be an effective way to deter future unethical behavior. Even large fines (and the one described above would be peanuts to a large health care corporation) can be regarded just as a cost of doing business. Furthermore, the fine's impact may be diffused over the whole company, and ultimately comes out of the pockets of stockholders, employees, and customers alike. It provides no negative incentives for those who authorized, directed, or implemented the behavior in question. My refrain has been: we will not deter unethical behavior by health care organizations until the people who authorize, direct or implement bad behavior fear some meaningfully negative consequences. Real health care reform needs to make health care leaders accountable, and especially accountable for the bad behavior that helped make them rich.

St Jude Medical Settles Again

Here we go again to kick off the week, legal settlements, cardiac devices, alleged kickbacks, manipulated research, as reported by Bloomberg:

Another Legal Settlement by St Jude Medical

St. Jude Medical Inc. agreed to pay $16 million to settle a U.S. government probe of claims the company paid kickbacks to doctors who implanted its heart devices in patients.

The accord resolves a five-year investigation of St. Jude’s marketing practices for defibrillators and pacemakers.

This was not even the first recent settlement by this particular company:

In June, St. Jude agreed to pay the federal government $3.7 million to resolve a separate whistleblower case over claims that it made illegal payments to hospitals in Kentucky and Ohio that used the company’s heart devices.

Our relevant post about that previous settlement was here.

Kickbacks, Manipulated Research

The $16 million settlement stemmed from a case filed by Charles Donigian, a former St. Jude technician from St. Louis, who accused the company of using kickbacks to market products.

The kickbacks, which ranged as high as $2,000 per patient, came in the form of 'sham fees' for phony clinical-research studies on the devices, Donigian said in his suit.

There was slightly more detail in a report in TheHeart.org:

According to the DoJ, the company used postmarketing studies and a registry as vehicles to reward physicians participating in those studies to implant the devices. 'In each case, St Jude paid each participating physician a fee that ranged up to $2000 per patient,' a statement from US Attorney Carmen M Ortiz notes. 'The United States alleges that St Jude solicited physicians for the studies in order to retain their business and/or convert their business from a competitor's product.'

The statement also observes: 'Although St Jude collected data and information from participating physicians, it knowingly and intentionally used the studies and registry as a means of increasing its device sales by paying certain physicians to select St Jude pacemakers and ICDs for their patients.'

Summary

It all is getting so old, isn't it? Yet another pharmaceutical, biotechnology or device company settles a case alleging payments to physicians to induce them to use its products. The twist here is that the form of the payment allegedly also manipulated the clinical research process.

There have been other cases of manipulation or suppression of research about cardiac devices. For example, see our recent post about how Guidant, now a subsidiary of Boston Scientific, was put on probation for its actions in another such case.

The allegations amounted to serious external threats to physicians' professionalism: payments to promote use of health care products whether or not their implantation was in patients' best interests, and manipulation of clinical research that could have further corrupted the clinical evidence base, and presumably could have broken the trust of clinical research subjects. Left unsaid in the brief articles is how willingly the physicians gave in to these threats to their professionalism for the dollars involved.

Yet despite the apparently corrosive quality of the bad behavior, the penalties to the company were trivial. Per St Jude Medical's most recent financial profile, its yearly revenue was over $4.5 billion.  Two settlements totaling less than $20 million amount to a relatively small cost of doing business.  And note that St Jude Medical is not admitting it did anything wrong.  Per TheHeart.org, its statement was:

We are pleased to have reached a settlement agreement with the DoJ that fully resolves the postmarket-study matter in Boston. The company maintains that its postmarket studies and registries are legitimate clinical studies designed to gather important scientific data, and St Jude Medical does not admit liability or wrongdoing by entering into this agreement. The company entered into a settlement agreement to avoid the potential costs and risks associated with litigation. This settlement brings the previously reported postmarket-study investigation to a close.

So it all gets so tiresome. The continuing march of legal settlements like this do provide evidence of how professionalism and evidence-based medical practice are under threat. However, as we have said ad infinitum, such settlements are likely to do nothing to alleviate that threat.

To repeat the conclusion of our last post about St Jude Medical, the usual sorts of legal settlements we have described do not seem to be an effective way to deter future unethical behavior. Even large fines (and the one described above would be peanuts to a large health care corporation) can be regarded just as a cost of doing business. Furthermore, the fine's impact may be diffused over the whole company, and ultimately comes out of the pockets of stockholders, employees, and customers alike. It provides no negative incentives for those who authorized, directed, or implemented the behavior in question. My refrain has been: we will not deter unethical behavior by health care organizations until the people who authorize, direct or implement bad behavior fear some meaningfully negative consequences. Real health care reform needs to make health care leaders accountable, and especially accountable for the bad behavior that helped make them rich.

Study highlights 'lurking question' of measuring EHR effectiveness: The science in Medical Informatics is dead

The science in Medical Informatics is dead.

I'm not going to even use academic fabric softener in my assertion, e.g., "may be", "appears to be", or "is it?" (as a question) dead.

It's dead.

When HIT experts recommend changing the study goalposts when existing studies don't give results they'd like to see, rather than first and foremost critically and rigorously examining why we're seeing unexpected results, science is dead.

Study highlights 'lurking question' of measuring EHR effectiveness

December 22, 2010 | Molly Merrill, Associate Editor

WASHINGTON – Hospitals' use of electronic health records has had just a limited effect on improving the quality of medical care nationwide, according to a study by the nonprofit RAND Corporation.

The study, published online by the American Journal of Managed Care, is part of a growing body of evidence suggesting that new methods should be developed to measure the impact of health information technology on the quality of hospital care.

[In other words, we're not getting the results we thought and hoped we'd get with "Clinical IT 1.0", so let's alter the study methodologies and endpoints --- rather than using the results we have to identify the causes and improve the technology to see if we can do better with "Clinical IT 2.0."

Further, it's not as if there's no other data on why health IT might not work as hoped - ed.]

Most of the current knowledge about the relationship between health IT and quality comes from a few hospitals that may not be representative, such as large teaching hospitals or medical centers that were among the first to adopt electronic health records.

[This implies "other" "representative" hospitals are either not doing it right, or the technology is ill suited for them and may never work. Which is it? We really need to know before we proceed with hundreds of billions more in this "Grand Experiment" - ed.]

The RAND study is one of the first to look at a broad set of hospitals to examine the impact that adopting electronic health records has had on the quality of care.

The research included 2,021 hospitals – about half the non-federal acute care hospitals nationally. Researchers determined whether each hospital had EHRs and then examined performance across 17 measures of quality for three common illnesses – heart failure, heart attack and pneumonia. The period studied spanned from 2003 to 2007.

The number of hospitals using either a basic or advanced electronic health records rose sharply during the period, from 24 percent in 2003 to nearly 38 percent in 2006.

[How many billions of dollars diverted from patient care needs does that represent? - ed.]

Researchers found that the quality of care provided for the three illnesses generally improved among all types of hospitals studied from 2004 to 2007. The largest increase in quality was seen among patients treated for heart failure at hospitals that maintained basic electronic health records throughout the study period.

However, quality scores improved no faster at hospitals that had newly adopted a basic electronic health record than in hospitals that did not adopt the technology.

[In other words, the improvements or lack thereof had little to do with electronic vs. paper record keeping - ed.]

In addition, at hospitals with newly adopted advanced electronic health records, quality scores for heart attack and heart failure improved significantly less than at hospitals that did not have electronic health records.

[In other words, the clinical IT was probably impairing doctors compared to simpler paper methods and good HIM personnel - ed.]

EHRs had no impact on the quality of care for patients treated for pneumonia.

Researchers say the mixed results may be attributable to the complex nature of healthcare.

[That is likely true, but maybe the mixed results are also -- and even more likely in major part -- due to poorly designed and/or poorly implemented IT - ed.]

Focusing attention on adopting EHRs may divert staff from focusing on other quality improvement efforts.

[That speaks to poor EHR overkill, poor usability, unfitness for purpose, and other issues that may or may not be remediable in short or even long term - ed.]

In addition, performance on existing hospital quality measures may be reaching a ceiling where further improvements in quality are unlikely.

[That speaks to a low ROI or even negative for the hundreds of billions of dollars being diverted to the IT sector - ed.]

"The lurking question has been whether we are examining the right measures to truly test the effectiveness of health information technology," said Spencer S. Jones, the study's lead author and an information scientist at RAND. "Our existing tools are probably not the ones we need going forward to adequately track the nation's investment in health information technology."

["Probably" not the ones we need? How can the authors know this? This is not science, it is speculation. Further, I'd say the scientific imperative before we design "the right measures" to "truly" test the effectiveness of HIT is to understand why the measures we're using now are not showing the desired results, because perhaps they are perfectly adequate and are revealing crucial flaws, overestimations and false assumptions that need to be dealt with, now, not after another round of billions is spent - ed.]

New performance measures that focus on areas where EHRs are expected to improve care should be developed and tested, according to researchers.

[In pharma clinical trials, this is akin to what is known as "changing the study methodologies and endpoints" - a form of manipulating clinical research, usually with the true ultimate endpoint of money - ed.]

For example, EHRs are expected to lower the risk of adverse drug interactions, but existing quality measures do not examine the issue.

[I believe the studies that have been done of CPOE have not been consistently supportive, and in fact show CPOE might create new med errors - ed.]

"With the federal government making such a large investment in this technology, we need to develop a new set of quality measures that can be used to establish the impact of electronic health records on quality," Jones said.

[This is truly putting the cart before the horse as I wrote here. The studies showing the benefit should have long preceded the "large investments" that were decided upon - ed.]

Support for the study was provided by RAND COMPARE (Comprehensive Assessment of Reform Efforts). RAND developed COMPARE to provide objective facts and analysis to inform the dialogue about health policy options. COMPARE is funded by a consortium of individuals, corporations, corporate foundations, private foundations and health system stakeholders.

Other authors of the study are John L. Adams, Eric C. Schneider, Jeanne S. Ringel and Elizabeth A. McGlynn.

The overarching assumption is that the metrics are wrong, not the quality and fitness for purpose of the technology, the 'wrongness' of which is painfully obvious from the aforementioned other literature, e.g., link, link, link, and the many posts at this blog referring to other literature. Are the authors unaware, one might ask? I know they are not. (Or - blinded? That is, could there be external pressures affecting the thought processes? The arguments might not unreasonably be construed to be skewed from that perspective.)

Recognizing the atrocious user experience and mission hostile nature of the technology (link), how disruptive it is (link, link), how poorly implemented it is often by domain amateurs to support financial battles of the payers, not cognitive processes of clinicians, I am amazed there's any signs of improvement at all, not outright deterioration. (That there is not outright deterioration of care displays if anything the results of the hard mental labor and ingenuity of clinicians to work around the technology's deficits.)

I note that the last time RAND looked at such matters there were problems with pro-health IT bias, among other issues (see my Feb. 2009 post "Heartland Institute Research & Commentary: Health Information Technology").

Carl Sagan wrote that science is a candle in the dark in a demon haunted world.

It seems the demons are winning.

-- SS

Study highlights 'lurking question' of measuring EHR effectiveness: The science in Medical Informatics is dead

The science in Medical Informatics is dead.

I'm not going to even use academic fabric softener in my assertion, e.g., "may be", "appears to be", or "is it?" (as a question) dead.

It's dead.

When HIT experts recommend changing the study goalposts when existing studies don't give results they'd like to see, rather than first and foremost critically and rigorously examining why we're seeing unexpected results, science is dead.

Study highlights 'lurking question' of measuring EHR effectiveness

December 22, 2010 | Molly Merrill, Associate Editor

WASHINGTON – Hospitals' use of electronic health records has had just a limited effect on improving the quality of medical care nationwide, according to a study by the nonprofit RAND Corporation.

The study, published online by the American Journal of Managed Care, is part of a growing body of evidence suggesting that new methods should be developed to measure the impact of health information technology on the quality of hospital care.

[In other words, we're not getting the results we thought and hoped we'd get with "Clinical IT 1.0", so let's alter the study methodologies and endpoints --- rather than using the results we have to identify the causes and improve the technology to see if we can do better with "Clinical IT 2.0."

Further, it's not as if there's no other data on why health IT might not work as hoped - ed.]

Most of the current knowledge about the relationship between health IT and quality comes from a few hospitals that may not be representative, such as large teaching hospitals or medical centers that were among the first to adopt electronic health records.

[This implies "other" "representative" hospitals are either not doing it right, or the technology is ill suited for them and may never work. Which is it? We really need to know before we proceed with hundreds of billions more in this "Grand Experiment" - ed.]

The RAND study is one of the first to look at a broad set of hospitals to examine the impact that adopting electronic health records has had on the quality of care.

The research included 2,021 hospitals – about half the non-federal acute care hospitals nationally. Researchers determined whether each hospital had EHRs and then examined performance across 17 measures of quality for three common illnesses – heart failure, heart attack and pneumonia. The period studied spanned from 2003 to 2007.

The number of hospitals using either a basic or advanced electronic health records rose sharply during the period, from 24 percent in 2003 to nearly 38 percent in 2006.

[How many billions of dollars diverted from patient care needs does that represent? - ed.]

Researchers found that the quality of care provided for the three illnesses generally improved among all types of hospitals studied from 2004 to 2007. The largest increase in quality was seen among patients treated for heart failure at hospitals that maintained basic electronic health records throughout the study period.

However, quality scores improved no faster at hospitals that had newly adopted a basic electronic health record than in hospitals that did not adopt the technology.

[In other words, the improvements or lack thereof had little to do with electronic vs. paper record keeping - ed.]

In addition, at hospitals with newly adopted advanced electronic health records, quality scores for heart attack and heart failure improved significantly less than at hospitals that did not have electronic health records.

[In other words, the clinical IT was probably impairing doctors compared to simpler paper methods and good HIM personnel - ed.]

EHRs had no impact on the quality of care for patients treated for pneumonia.

Researchers say the mixed results may be attributable to the complex nature of healthcare.

[That is likely true, but maybe the mixed results are also -- and even more likely in major part -- due to poorly designed and/or poorly implemented IT - ed.]

Focusing attention on adopting EHRs may divert staff from focusing on other quality improvement efforts.

[That speaks to poor EHR overkill, poor usability, unfitness for purpose, and other issues that may or may not be remediable in short or even long term - ed.]

In addition, performance on existing hospital quality measures may be reaching a ceiling where further improvements in quality are unlikely.

[That speaks to a low ROI or even negative for the hundreds of billions of dollars being diverted to the IT sector - ed.]

"The lurking question has been whether we are examining the right measures to truly test the effectiveness of health information technology," said Spencer S. Jones, the study's lead author and an information scientist at RAND. "Our existing tools are probably not the ones we need going forward to adequately track the nation's investment in health information technology."

["Probably" not the ones we need? How can the authors know this? This is not science, it is speculation. Further, I'd say the scientific imperative before we design "the right measures" to "truly" test the effectiveness of HIT is to understand why the measures we're using now are not showing the desired results, because perhaps they are perfectly adequate and are revealing crucial flaws, overestimations and false assumptions that need to be dealt with, now, not after another round of billions is spent - ed.]

New performance measures that focus on areas where EHRs are expected to improve care should be developed and tested, according to researchers.

[In pharma clinical trials, this is akin to what is known as "changing the study methodologies and endpoints" - a form of manipulating clinical research, usually with the true ultimate endpoint of money - ed.]

For example, EHRs are expected to lower the risk of adverse drug interactions, but existing quality measures do not examine the issue.

[I believe the studies that have been done of CPOE have not been consistently supportive, and in fact show CPOE might create new med errors - ed.]

"With the federal government making such a large investment in this technology, we need to develop a new set of quality measures that can be used to establish the impact of electronic health records on quality," Jones said.

[This is truly putting the cart before the horse as I wrote here. The studies showing the benefit should have long preceded the "large investments" that were decided upon - ed.]

Support for the study was provided by RAND COMPARE (Comprehensive Assessment of Reform Efforts). RAND developed COMPARE to provide objective facts and analysis to inform the dialogue about health policy options. COMPARE is funded by a consortium of individuals, corporations, corporate foundations, private foundations and health system stakeholders.

Other authors of the study are John L. Adams, Eric C. Schneider, Jeanne S. Ringel and Elizabeth A. McGlynn.

The overarching assumption is that the metrics are wrong, not the quality and fitness for purpose of the technology, the 'wrongness' of which is painfully obvious from the aforementioned other literature, e.g., link, link, link, and the many posts at this blog referring to other literature. Are the authors unaware, one might ask? I know they are not. (Or - blinded? That is, could there be external pressures affecting the thought processes? The arguments might not unreasonably be construed to be skewed from that perspective.)

Recognizing the atrocious user experience and mission hostile nature of the technology (link), how disruptive it is (link, link), how poorly implemented it is often by domain amateurs to support financial battles of the payers, not cognitive processes of clinicians, I am amazed there's any signs of improvement at all, not outright deterioration. (That there is not outright deterioration of care displays if anything the results of the hard mental labor and ingenuity of clinicians to work around the technology's deficits.)

I note that the last time RAND looked at such matters there were problems with pro-health IT bias, among other issues (see my Feb. 2009 post "Heartland Institute Research & Commentary: Health Information Technology").

Carl Sagan wrote that science is a candle in the dark in a demon haunted world.

It seems the demons are winning.

-- SS

"Trouble Coming Every Day" as Discussed by our Fellow Health Care Skeptics

With apologies to the late Frank Zappa... even though we are going through the dog days of summer, the parade of health care troubles in the news is never ending, so I thought I would recap some of the more interesting issues discussed by some of my fellow health care skeptic bloggers.

We have discussed the ongoing decline of primary care. On DB's Medical Rants, Dr Robert Centor takes on the topic: "The system has, without consciously meaning to, held primary care in contempt." The result is a "quiet rebellion: of primary doctors.

We have discussed whether the currently fashionable idea of "accountable care organizations" (ACOs) might turn out to be a cover for health care oligopolies. See what Paul Levy, CEO of the Beth Israel/ Deaconess Medical Center said about them in his blog, Running a Hospital.

We frequently talk about the manipulation or suppression of clinical research studies by those with vested interests in the results pointing in a particular direction. On the Hooked: Ethics, Medicine and Pharma blog, Dr Howard Brody wondered why the FDA will not even reveal the identities of the clinical researchers who did the studies on which it based its decision to approve the Infuse bone growth enhancement device.

Prof Carl Elliott has done an outstanding job investigating commercially funded and implemented clinical research. Dr Brody reviewed his new book, White Coat, Black Hat.  In the Carlat Psychiatry Blog, Dr Daniel Carlat reviewed Prof Elliott's new article in Mother Jones on how a pharmaceutical company sponsored drug trial went badly awry.

We asked whether the former CEO of a for-profit hospital chain who resigned after the company paid a > $1.7 billion penalty to settle charges of fraud would be a proper candidate to be governor of Florida. After Rick Scott won the Florida Republican primary, Maggie Maher, writing in the Health Beat blog, took on Scott's dubious past as prologue to a worrisome future.

Well I'm about to get sick
From watchin' my TV
Been checkin' out the news
Until my eyeballs fail to see
I mean to say that every day
Is just another rotten mess
And when it's gonna change, my friend
Is anybody's guess

So I'm watchin' and I'm waitin'
Hopin' for the best
Even think I'll go to prayin'
Every time I hear 'em sayin'
That there's no way to delay
That trouble comin' every day
No way to delay
That trouble comin' every day
- Frank Zappa

"Trouble Coming Every Day" as Discussed by our Fellow Health Care Skeptics

With apologies to the late Frank Zappa... even though we are going through the dog days of summer, the parade of health care troubles in the news is never ending, so I thought I would recap some of the more interesting issues discussed by some of my fellow health care skeptic bloggers.

We have discussed the ongoing decline of primary care. On DB's Medical Rants, Dr Robert Centor takes on the topic: "The system has, without consciously meaning to, held primary care in contempt." The result is a "quiet rebellion: of primary doctors.

We have discussed whether the currently fashionable idea of "accountable care organizations" (ACOs) might turn out to be a cover for health care oligopolies. See what Paul Levy, CEO of the Beth Israel/ Deaconess Medical Center said about them in his blog, Running a Hospital.

We frequently talk about the manipulation or suppression of clinical research studies by those with vested interests in the results pointing in a particular direction. On the Hooked: Ethics, Medicine and Pharma blog, Dr Howard Brody wondered why the FDA will not even reveal the identities of the clinical researchers who did the studies on which it based its decision to approve the Infuse bone growth enhancement device.

Prof Carl Elliott has done an outstanding job investigating commercially funded and implemented clinical research. Dr Brody reviewed his new book, White Coat, Black Hat.  In the Carlat Psychiatry Blog, Dr Daniel Carlat reviewed Prof Elliott's new article in Mother Jones on how a pharmaceutical company sponsored drug trial went badly awry.

We asked whether the former CEO of a for-profit hospital chain who resigned after the company paid a > $1.7 billion penalty to settle charges of fraud would be a proper candidate to be governor of Florida. After Rick Scott won the Florida Republican primary, Maggie Maher, writing in the Health Beat blog, took on Scott's dubious past as prologue to a worrisome future.

Well I'm about to get sick
From watchin' my TV
Been checkin' out the news
Until my eyeballs fail to see
I mean to say that every day
Is just another rotten mess
And when it's gonna change, my friend
Is anybody's guess

So I'm watchin' and I'm waitin'
Hopin' for the best
Even think I'll go to prayin'
Every time I hear 'em sayin'
That there's no way to delay
That trouble comin' every day
No way to delay
That trouble comin' every day
- Frank Zappa

The Avandia Spin Cycle Continues Even After the FDA Safety Hearings

We have posted multiple times about Avandia (rosiglitazone), GlaxoSmithKline's star-crossed glucose-lowering drug.  While Avandia has received considerable media coverage, we focused on two questions: 1 - what are the benefits and harms of rosiglitazone as a treatment of type 2 diabetes, and therefore for which patients under what circumstances should this drug be used? 2 - what barriers have prevented physicians and patients from getting the best possible answer to the first question, and what can be done about them?  (See recent post here.) 

In particular, the Avandia case has illustrated how those with vested interests in the success of a health care product have done their best to obscure information that might threaten its success, even when doing so obscures the information that physicians and patients need to make the best possible decisions.  At one point, (in 2007, no less) we called this the "Avandia spin cycle."

Avandia once again has been in the news after the US Food and Drug Administration's hearings on the safety of the drug.  These hearings were so well covered in the media that a lengthy summary would be superfluous.  However, their main points demonstrated the persistence of the Avandia spin cycle:
- An FDA reviewer felt that "the company's misreadings of the ... Record trial ... were so profound, he concluded, that they 'suggest serious flaws with trial conduct.'" (per Gardiner Harris writing in the New York Times)
-A former FDA reviewer "withheld from regulators a study showing its Avandia diabetes drug may cause heart attacks." (per Bloomberg News)
- GlaxoSmithKline's forerunner SmithKline Beecham "secretly began a study to find out if its diabetes medicine, Avandia, was safer for the heart than a competing pill, Actos, made by Takeda."  However, "the study also provided clear signs that it [Avandia] was riskier to the heart.  But instead of publishing the results, the company spent the next 11 years trying to cover them up." (per Gardiner Harris writing in the New York Times.
- "Government experts and a panel of medical advisers repeatedly voiced skepticism on Tuesday about the trustworthiness of GlaxoSmithKline, which makes the controversial diabetes drug Avandia." (per Gardiner Harris again writing in the New York Times.)

So the Avandia saga has brought to the front pages the concerns we have had with suppression and manipulation of clinical research, especially when pursued by health care organizations with vested interests in the results of specific research projects coming out a certain way, and how they have been enabled by those with conflicts of interest.  Doctors thus should be worried whether those of us who try to practice evidence-based medicine have been fooled into practicing pseudo-evidence-based-medicine.

Those commenting on the story focused on the need for transparency when clinical research is funded and run by the corporations whose products are being evaluated.
-  "GlaxoSmithKline, the maker of Avandia, can't be trusted to report adverse clinical results fairly.  The company must be watched like a hawk as additional trials that it sponsors go forward."  (NY Times editorial)
-  "What America should demand in return for ... [generous patent] protection is that the FDA be able to make an honest evaluation of the efficacy of drugs.  When drug companies make this impossible by suppressing test results, not only do they violate their fundamental obligation of honesty with the public, their customers and their regulator, but they also break the bargain they have struck in return for the protection of their intellectual capital."  (Former NY Attorney General Eliot Spitzer in Slate.)

Instead, as I have written before, maybe we ought to consider whether those with vested interests in drugs or devices ought to be running clinical research meant to evaluate their own products.

 Ironically, while this discussion of how the Avandia spin cycle first began to revolve were going on, others were still trying to add revolutions (per minute).  In particular, a Reuters story noted:

Three influential groups of doctors who treat diabetes urged patients not to stop taking Avandia, saying on Thursday that while news about the controversial drug may be frightening, it would be worse to suddenly stop taking it.

That is odd, given that Avandia has never been shown to improve clinical outcomes for patients with diabetes, and that there are many other drugs that control blood sugar which appear to be safer. But wait, there is more,

The Endocrine Society, American Diabetes Association and the American Association of Clinical Endocrinologists worried that patients may be afraid to take Avandia.

'Patients should continue taking all currently prescribed medications unless instructed otherwise by their health care provider,' Dr. Robert Vigersky of the Endocrine Society said in a statement.

'Stopping diabetes medications can cause significant harm and result in higher levels of blood glucose that may cause severe short term health problems and could increase the risk of diabetes-related complications in the long term.'

Would not it make more sense to advise patients still on Avandia to consult with their doctors urgently about possible alternatives?  Meanwhile, it does not seem irrational to be afraid of taking Avandia, given the increasing evidence about its harms, and increasing evidence that what we know about its harms may be an under-estimate.

So I wondered why these august medical societies seemed so unaffected about the doubts about Avandia's safety, and about the evidence offered to support its use that the latest news ought to generate. It turns out that all three of the medical societies get financial support from, -- wait for it --, GlaxoSmithKline.

The Endocrine Society lists GSK as one of its Corporate Liaison Board Members. The American Diabetes Association lists GSK as one of its Banting Circle Supporters, that is, those that give at least $1,000,000 a year. The American Association of Clinical Endocrinologists lists GSK as a member of its Corporate AACE Partnership. (I was not able to find out the total amount contributed by GSK to either the Endocrine Society or the AACE.)

So once again, the loudest voices in support of the product come from those used to, and perhaps dependent on financial support from its manufacturer. As a physician, I have been particularly disappointed that our medical societies, whose missions are ostensibly to support our professional values, seem to act more and more like marketers for the companies whose contributions, rather than members' dues increasingly support them.

The cycle keeps spinning.

For further thoughts on the latest in the Avandia case, see this post by Howard Brody on the Hooked: Ethics, Medicine and Pharma blog, and this by Alison Bass on the Alison Bass Blog.