Bad Apple or Bad Orchard? - A Narrative of Alleged Individual Research Misconduct that Sidestepped the Pharmaceutical Corporate Context

anechoic effect clinical research integrity clinical trials New York University Pfizer pharmaceuticals

Bad Apple or Bad Orchard? - A Narrative of Alleged Individual Research Misconduct that Sidestepped the Pharmaceutical Corporate Context

Unknown 7/08/2016 Komentar

Tales of medical research misconduct seem increasingly prevalent in the media, and are getting increasing attention.    They often may present a simple narrative, like this recent story in the New York Times, "An NYU Study Gone Wrong, and a Top Researcher Dismissed."

The Narrative Arc

A Renowned Researcher

The researcher in question was one Dr Alexander Neumeister.  Oddly enough, the article provided very little information about his background, but made it clear he was at New York University, and was a "top researcher."

The Potentially Ground-Breaking Studies

The NY Times article noted that the studies were of "an experimental, mind-altering drug."  In particular,

In one of the shuttered studies, people with a diagnosis of post-traumatic stress caused by childhood abuse took a relatively untested drug intended to mimic the effects of marijuana, to see if it relieved symptoms.

The study was ground-breaking, in that

It’s a critical time for two important but still controversial areas of psychiatry: the search for a blood test or other biological sign of post-traumatic stress disorder, which has so far come up empty, and the use of recreational drugs like ecstasy and marijuana to treat it.

The drug was not identified, but the article noted that it was

a drug intended to produce some of marijuana's effects, made by Pfizer

and was thus like the drug in "a French trial," that caused six patients to be "hospitalized with severe neurologic problems."

The study was apparently a small short-term randomized controlled trial

Some participants took the drug over a seven-day period; others took a placebo pill. The N.Y.U. team performed scans on each person to see whether brain activation patterns correlated with symptom relief.

The study called for recruiting 50 people with a PTSD diagnosis, according to study documents.

Research Misconduct Discovered

Initially, apparently,

Dr. Charles Marmar, the chairman of the psychiatry department at N.Y.U., said that people working with Dr. Neumeister had reported concerns about the lab’s compliance with research standards.

This led to

The federal inspection, from July 16 to Aug. 5 last year, found that the research team had failed to assess at least three subjects 24 hours after they had taken the experimental drug, contrary to study protocol, according to the F.D.A. letter. In several instances, the agency found, Dr. Neumeister had falsified documents by signing a fellow investigator’s name on reports. 'However, in fact, you or another study employee actually conducted these study procedures,' not the colleague, the F.D.A. concluded.

In summary

The violations 'jeopardize subject safety and welfare, and raise concerns about the validity and integrity of the data collected at your site,' the F.D.A. said in a letter

Note that the article did not explain why the FDA was called upon to investigate this problem.



Aggrieved Research Subjects

The article focused on one Ms Diane Ruffcorn, who "writes a popular Facebook blog on trauma,"

'I think their intent was good, and they were considerate to me,' said one of those subjects, Diane Ruffcorn, 40, of Seattle, who said she was sexually abused as a child. 'But what concerned me, I was given this drug, and all these tests, and then it was goodbye, I was on my own. There was no follow-up.'

After the trial, she was concerned because

Ms. Ruffcorn said she had several odd symptoms after the trial, including a hyper, wired sensation that occurred without the usual memories of abuse.  For months, she tried to find out whether those reactions were tied to the experimental drug, but because the study was shut down and the data belonged to Pfizer, the N.Y.U. doctors could not tell her whether she had taken the drug or placebo.

However,

Earlier this month, after much persistence, she found out that she’d taken the placebo. 'It was a big relief,' she said.

Note that the article did not explain why Pfizer owned the data, and would not reveal it. 

The Researcher Punished

The researcher did not agree that things were so bad,

Georges Lederman, a lawyer for Dr. Neumeister, said there may have been protocol violations, 'but N.Y.U. has taken the position that those violations were more egregious than we believe they actually were.' The issues could have been easily remedied, he said, and noted that they did not cause the sponsor of the research, the pharmaceutical giant Pfizer, to shut it down.

Note that the article did not explain why Pfizer was empowered to shut such a study down.

In any case,

Dr. Neumeister and N.Y.U. continue to disagree over the seriousness of the research violations, both sides said. But the university has tossed out all of the data as unreliable, and tracked down the study participants to check on their health, Dr. Marmar said.

And apparently Dr Neumeister quit, or was fired, although the article only said NYU "parted ways with a top researcher."

Summary

So, in summary, the story was that a prominent researcher was doing cutting edge research at a big university, but people onsite noted some problems, the government was called in to investigate, the investigation found problems, the research was stopped, and the researcher lost his job.  However, while the article mentioned that Pfizer sponsored the study, Pfizer had control of the study's data, and Pfizer had the power to shut the study down, the article did not comment on whether the involvement of Pfizer could have had any relationship to the narrative of alleged individual researcher misconduct.

Research Misconduct as a Problem with Bad Apples

Thus, in my humble opinion, this story followed the usual narrative arc of research misconduct stories: an individual scientist over-reaches, possibly in pursuit of fame and money, is discovered and punished, and things get back to normal.  The implication is that research misconduct is a bad-apple problem, although fueled by a hyper competitive research environment.  For example, last week the (UK) Times Higher Education Suppplement published an article entitled, "Is There a Problem with Research Integrity," that opened,

For many academics today, research is not about pushing intellectual boundaries. It is not about investigating a fascinating issue so much as it is about churning out publications, demonstrating impact and generating revenue in order to meet the performance targets upon which institutional reputation and individual careers depend.

The temptation to cut corners is immense. Tricks include getting your name on a paper that you contributed little towards, or “salami-slicing” the same research across several publications. More seriously, some researchers falsify – misrepresent – their data, or even fabricate them entirely. Some universities tacitly encourage such behaviour and the boundary between academic integrity and malpractice is becoming blurred.

The current case seems to be on of attempted falsification, misrepresentation of research data.

Notice the use of the pronoun "you," emphasizing that research misconduct is about individual misconduct.  Similarly, tha THE article included commentaries by various individuals.  One was by a "research integrity expert," who began,

Having positive and preferably spectacular research findings is wonderful. It helps you to get a publication in a journal with a high impact factor, which will be cited often and may attract a lot of media attention. This is not only a pleasant ego boost but may also be instrumental in getting your next grant or strengthening your academic position. So, in an ever more competitive and metrics-driven scientific environment, it is tempting to make such results occur by any means necessary.

All this is true as far as it goes.  But in my humble opinion, the usual research misconduct narrative is vastly oversimplified, as is the case reported by the New York Times.

We have been writing for years about massive problems with manipulation of clinical research to increase the likelihood that the results would satisfy vested interests, and suppression of research whose results remain unsatisfactory after such manipulation.  The vested interests are most commonly pharmaceutical, biotechnology or device companies and those working with them.  Such suppression and manipulation may make treatments that do not work look efficacious, and treatments that are dangerous look safe, and may lead to excess costs, and worse, harms to patients.  This kind of research misconduct may be facilitated by individual researchers seeking fame and fortune, but is hardly an individual sport.

Focusing on individual research misconduct thus leaves the larger problem of vested interests dominating clinical research anechoic.

Looking carefully at the NYU/ Neumeister case as reported, and a little research on the web suggests that there may be more involved than just the conduct of one researcher.  But that could only be confirmed, or refuted, by investigation beyond what this humble blogger can do.

A Pharmaceutical Company Sponsored, Likely Pharmaceutical Company Designed, Phase II Drug Study Gone Wrong

The NY Times article acknowledged, almost parenthetically, that the study on which the article was focused was sponsored by Pfizer, although it first did so in the context of Dr Neumeister's lawyer arguing that the problems with the study were not that serious:

[he] noted that they did not cause the sponsor of the research, the pharmaceutical giant Pfizer, to shut it down.

Later, the article stated,

Pfizer said that N.Y.U. was responsible for conducting the trial,

but noted

the company had previously tested the same drug, known as an F.A.A.H. inhibitor, for osteoarthritic pain, without significant side effects. 'The safety profile we observed does not preclude future development of our compound,' a Pfizer spokesman said by email.

So this was not a case of a company funding a study merely to advance medical science.  The implication was that the company was testing its own compound in hopes of seeking approval from the US Food and Drug Administration. That must be why it was the FDA that investigated the research misconduct, particularly to the extent that the conduct of the research violated a "protocol" to which the FDA was apprently privy.

More evidence that the study was under the control of Pfizer, rather than of Dr Neumeister, could be inferred from the problems Ms Ruffcorn had in determining whether she had taken the drug or placebo.

For months, she tried to find out whether those reactions were tied to the experimental drug, but because the study was shut down and the data belonged to Pfizer, the N.Y.U. doctors could not tell her whether she’d taken the drug or a placebo.

Note that the "data belonged to Pfizer," not to NYU or Dr Neumeister.

In fact, in perhaps the only critical look given to this story, in a post on Neuroskeptic, 

I believe the compound in question is PF-04457845.

I believe this because ClinicalTrials.gov lists a trial of PF-04457845 for PTSD, a trial which was recently terminated. NYU was one of the research sites. I also think that this trial is the fateful one, as it matches the NYT’s description of that study. Interestingly, ClinicalTrials.gov says that the trial was stopped 'based on Pfizer portfolio prioritization and not due to safety and/or efficacy concern or change in benefit:risk assessment of PF-04457845'.

So given that the study was a small randomized controlled trials of patients, not of healthy volunteers, it appeared to be a Pfizer sponsored, Pfizer designed, Pfizer controlled Phase II study being done in the hope of eventually marketing PF-04457845.

As noted in an article about agreements between academia and industry on the conduct of randomized controlled trials(1),

Many randomized clinical trials (RCTs) are designed and sponsored by for-profit companies. Companies typically contract academic investigators to identify, recruit, and manage patients. Clinical research under these circumstances is a business transaction that bears the potential for conflicts of interest, including those regarding the publication of trial results

It also appears that Pfizer was spending a more than tiny sum on this work.   A Politico article from 2014 revealed that Dr Neumeister at that time had a $1.7 million grant from Pfizer, presumably for this particular study.  Thus this drug trial was likely providing NYU with more than negligible monetary support, most likely including salary support for Dr Neumeister.

Dr Neumeister apparently has had some previous involvement with pharmaceutical companies, and with Pfizer specifically.  A search of the ProPublica Dollars for Docs 2009-13 database revealed that Dr Neumeister received consulting, travel funds and a more than $227,000 grant from Eli Lilly.  Dr Neumeister apparently is currently on the advisory board for Fiorello Pharmaceuticals.  In a 2015 article in the Journal of Clinical Psychiatry(2), Dr Neumeister acknowledged that he "has received consulting fees from Pfizer."

Conclusion

So it seems that in this case a study which may not have been conducted according to research standards was likely a pharmaceutical sponsored, designed, and controlled Phase II trial done as part of an effort to seek approval for a new drug.  Hence this case was not only about allegations of individual research misconduct, but about yet more problems with the implementation of commercially controlled human experiments designed to ultimately further marketing as well as science.  Yet none of the public discussion so far of this case was about whether Pfizer had any responsibilities to assure the quality of the research in which it was so involved, much less whether interactions between the company, the university which was being funded by the company, and the researcher employed by the university but whose salary was probably partially underwritten by the company might have affected how the study was implemented.

There may be many problems with individual misconduct affecting clinical research.  But failure to consider how this research is now mainly conducted within a commercial milieu seems to be missing the elephant in the room.  If we cannot plainly discuss research misconduct as part of the larger picture of health care dysfunction, we will not be able to do much about it.  True health care reform would help end the taboo on discussion about how powerful organizations and their wealthy and powerful leaders distort health care.  

ADDENDUM (11 July, 2016) - This post was re-published on the Naked Capitalism blog. 

References

1. Kasenda B, von Elm E, You JJ, Blumie A et al. Agreements between Industry and Academia on Publication Rights: A Retrospective Study of Protocols and Publications of Randomized Clinical Trials. PLoS Med 13(6): e1002046. doi:10.1371/journal.pmed.1002046. Link here.

2.  Mota N, Sumner JA, Lowe SR, Neumeister A et al. The rs1049353 Polymorphism in the CNR1 Gene Interacts With Childhood Abuse to Predict Posttraumatic Threat Symptoms. J Clin Psychiatr 2015; 76(12):e1622–e1623. Link here.

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CORRUPTION OF CLINICAL TRIALS REPORTS: A PROPOSAL

Bernard Carroll citalopram clinical trials Eric Topol escitalopram FDA Forest Pharmaceuticals Jay Amsterdam Jon Jureidini Leemon McHenry Lisa Cosgrove Lundbeck Underwriters Laboratory vortioxetine

CORRUPTION OF CLINICAL TRIALS REPORTS: A PROPOSAL

Unknown 6/22/2016 Komentar

CORRUPTION OF CLINICAL TRIALS REPORTS:

A PROPOSAL

There is a disconnection between the FDA’s drug approval process and the reports we see in medical journals. Pharmaceutical corporations exploit this gap through adulterated, self-serving analyses, and the FDA sits on its hands. I suggest we need a new mechanism to fix the problem – by independent analyses of clinical trials data.

When they analyze and publish their clinical trials in medical journals, pharmaceutical corporations have free rein to shape the analyses. The FDA conducts independent analyses of the data submitted by the corporations, and it may deny or delay approval. But the FDA does not challenge the reports that flood our medical journals, both before and after FDA approval. It is no secret that these publications are routinely biased for marketing effect, but the FDA averts its gaze. That failure of the FDA – a posture known as enforcement discretion – has been well documented. The question is why? At the same time, exposing the biases has been difficult for outsiders because the data are considered proprietary secrets.

A Case Study

Now, a detailed example of deliberate corporate bias has finally been documented, through materials released in litigation. This exposé was reported by Drs. Jon Jureidini, Jay Amsterdam, and Leemon McHenry. Their findings were recently published, and their article is freely available on-line. This example concerned a clinical trial of an antidepressant drug in children and adolescents. The drug, citalopram, was already approved for use in adults, and its off-label use in children would spread if there was published supportive evidence. An Investigational New Drug (IND) protocol and plan of analysis were filed by Forest Laboratories with the FDA in 1999. The trial was completed in 2002, and the results were publishedin American Journal of Psychiatry in 2004 – but the FDA did not accept the results as sufficient to approve this drug for use in children or adolescent patients. By that time the patent on citalopram had expired and Forest Laboratories introduced a virtual twin drug, escitalopram (single active enantiomer). That more expensive version of citalopram was heavily promoted, and it was approved in 2009 for use in children, but even then the FDA specifically noted that safety and efficacy were not established in children under age 12. Since then, new analyses suggest that most antidepressant drugs have little evidence of efficacy even in older children.

Tricks of the Trade

In service of a positive report, the statistical analyses performed by Forest Laboratories deviated from the IND plan of analysis, and negative results were edited out. The biases now documented by Dr. Jureidini and his colleagues for that 2004 sponsored reportin American Journal of Psychiatry included:

·       Inflating the main measure of the drug's effect by reporting an incorrect and clearly exaggerated effect size. On being challenged, the authors later explained their misinformed computation without actually acknowledging the error.

·    Failure to report secondary measures of response because they were negative. Those measures had been stipulated in the IND protocol to serve as cross-checks on the main result. These negative findings were airbrushed out of the publication by corporate marketing.

·    Unplanned, new secondary measures of response were inserted ex post facto because they were positive (that is a real no-no).

·    Violations of the IND protocol were not reported and were then fudged (patients who had properly been excluded per protocol were put back in for analysis, which made a nonsignificant primary outcome analysis turn positive).

·    Adverse events were analyzed and summarized in a misleading way.

·    The finding that the drug had no effect on depression in children under age 12 was not reported, even though an age-effect interaction analysis had been specifically projected in the IND protocol. This strategic omission left the impression that off label use of citalopram in younger children could be clinically reasonable.

·    The corporation knew that another, unpublished, trial in children, conducted by their European partner Lundbeck was negative, and that it raised concerns about suicide risk, but that information was withheld. The authors later were challengedin the journal about this concealment. Their responsewas utterly disingenuous.

·    The published article failed to acknowledge that it was authored by a non-medical ghostwriter, who took direction from marketing executives – the 2004 publication was a marketing product purporting to be an objective scientific report.

·    Academic authors were recruited only after the manuscript was written, reviewed, and approved in-house – these nominal academic authors were signed on to front for the corporate narrative.

·    The perfunctory role of the academic (ahem) authors is clear from the fact that they failed to recognize the wildly inflated effect size claimed for the drug – something that was instantly obvious to several groups of competent readers.

The Payoff

These changes created the appearance of a positive result, and the publication drew wide attention. According to Thomson Reuters Web of Science, it has been cited over 160 times, placing it in the top 5% of cited articles in clinical medicine from 2004. This early publication gave plausible justification for off-label use of citalopram/escitalopram in children, even with FDA approval having been denied, and even though the trial was actually negative. The FDA has reported that between 2005 and 2010 well over 750,000 patients up to age 17 received escitalopram, including almost 160,000 under age 12. Thus, the sleight of hand about failure to show even fudged efficacy in younger children is especially deplorable. Internal memoranda reproduced in the exposé by Dr. Jureidini and his colleagues give a clear picture of the corporate manipulation of the scientific publication process. Now we know – in black and white – just how bad the bias can be. This kind of data manipulation, with ad hoc cherry picking and moving of goalposts, is unacceptable, but it is entrenched. Indeed, it is business as usual – and the FDA looks away.

A Specific Proposal

Our primary defense against such perversions of scientific reporting is fidelity to the registered IND protocol and plan of statistical analysis. The solution is not hard to see: We need independent analyses of clinical trials because we cannot trust the corporate analyses. In effect, we need something like the Underwriters Laboratory to verify the statistical analyses of clinical trials. Nobody takes the manufacturing corporation’s word for it concerning the safety and performance of X-ray machines or cardiac defibrillators. Why treat the statistical analysis of drug trials any differently? It’s highly technical work.

Who should assume that responsibility? Why not the FDA? After all, they alone see all the data. My specific proposal is for Congress to mandate that the FDA analyze all clinical trials data strictly according to the registered protocols and analysis plans. That requirement should apply to new drugs or to approved drugs being tested for new indications. It should apply also to publications reporting new trials of approved drugs. Corporations and investigators should be prohibited from publishing their own in-house statistical analyses unless verified by FDA oversight.

Why Bother?

There are three good reasons for prohibiting in-house corporate analyses of clinical trials data. First, as the present example illustrates, the inherent conflict of interest is simply too great to be ignored. Second, when corporate statisticians who answer to marketing executives get “creative” in the ways exposed here, then the conditions for valid statistical analyses no longer apply – the statisticians are then on a fishing expedition and they are no longer testing the defined study question with fidelity to the methods specified in the IND protocol. In that case, any nominally significant statistical findings are just exploratory, not actionable – not good enough to justify off-label use of the drug, especially when properly evaluated alternatives are available.

Third, there can be no justification for treating the production of influential publications in medical journals any differently than we treat the production of potent drugs. Our FDA continuously inspects production facilities for evidence of physical adulteration, even as far away as China. They now need to monitor the adulteration of clinical trials reports in medical journals. The harms of adulterated analyses can be just as serious as the harms of adulterated products.

Push Back from Pharma?

We can expect the pharmaceutical industry to mount a First Amendment challenge to this proposal. It will fail, because the public health is too important. Just as there is no First Amendment right to shout fire in a crowded theater, so also corporations have no First Amendment right to say a drug is safe and effective when they know it isn’t. That is a betrayal of patients.

The corporations will also claim piously that their publications undergo peer review. Sadly, that is no barrier to this pervasive corporate bias because the peer reviewers for medical journals don’t see all the real data – they see only the data the corporation wants them to see. Only the FDA sees all the data. We can no longer cling to the myth of informed and unbiased peer review of clinical trials reports. The corporations rely on that myth as a fig leaf to support their First Amendment claims and to defend their practice of in-house statistical analyses. Moreover, medical journals also are subject to bias and conflict of interest. We could note that the Associate Editor of American Journal of Psychiatry in 2004 was also a major U.S. key opinion leader for Forest Laboratories. According to one of the released depositions, he was instrumental in securing acceptance of the report by the journal.

Business as Usual?

The present example is not an isolated case. Dr. Jureidini and his co-authors described several similar, recent examples. One of those was the reanalysis by Jureidini and others of an infamous trial of paroxetine for pediatric depression. And still, fresh exposés keep appearing. The latest is from Lisa Cosgrove at the University of Massachusetts in Boston and her colleagues, involving “ghost management of the information delivery process” for another new antidepressant drug, vortioxetine – available on-line here. (What is it with the antidepressants, anyway?) On this Health Care Renewal blog, Roy Poses has called attention to these issues. As recently as June 8, 2016 he discussedthe Transparency International report on corruption in the pharmaceutical sector.

Eric Topol, who helped to expose the Vioxx scandal, made similar points recently in a BMJ commentary: “The bad science in clinical trials has been well documented and includes selective publication of positive results, data dredging, P hacking, HARKing, and changing the outcomes that were prespecified at the beginning of the study…. Furthermore, the disparity between what appears in peer reviewed journals and what has been filed with regulatory agencies is long standing and unacceptable.”

It’s No Time for Old Solutions 

As the eye-popping numbers of children treated with escitalopram show, even off-label use of an undistinguished drug in a niche population can be highly profitable. That is why I am proposing that the statistical analysis of clinical trials data can no longer be entrusted to pharmaceutical corporations, on account of their massive inherent conflict of interest. Open access to patient level data, as well as pre-registration of protocols and of data analysis plans, have been actively promoted for some years now to clean up the corporate bias in clinical trials. These are positive developments, but they will not close the disconnection highlighted just above by Dr. Topol. The once idealistic world of clinical trials has changed irreversibly in the past 30 years. As one observer has noted, “… in the course of time the coordinated actions of industry, government, and the biomedical research community have degraded the basic rules of empirical science…” We would do well to acknowledge this fact, and to recognize with Abramson and Starfield that “The first step is to give up the illusion that the primary purpose of modern medical research is to improve Americans’ health most effectively and efficiently. In our opinion, the primary purpose of commercially funded clinical research is to maximize financial return on investment, not health.”

When corporations are involved, there is no point in prolonging the myth of noble and dispassionate clinical scientists searching for truth in clinical trials. It’s over. We would do better to stop pretending that corporate articles in medical journals are anything but marketing messages disguised with the fig leafs of coöpted academic authors and of so-called peer review. The case study reported out by Drs. John Jureidini, Jay Amsterdam, and Leemon McHenry shows us the real face of business as usual in commercial clinical trials. That being the case, it makes no sense to expect corporations and academic key opinion leaders suddenly to reform their biased and conflicted behavior. Only a structural change from the outside like I propose here has any chance of succeeding. The statistical analysis of clinical trials is too important to be entrusted to the sponsoring corporations.

It is time for Congress to grasp this nettle. The time for enforcement discretion is past, and we need Congress either to direct the FDA to act or to create a new mechanism of oversight. To do nothing would be unthinkable.

Bernard J. Carroll

Professor and Chairman Emeritus,

Department of Psychiatry, 

Duke University Medical Center.

E-mail: bcarroll40@comcast.net

The writer is a former chairman of the Psychopharmacologic Drugs Advisory Committee, Food and Drug Administration, U.S Public Health Service.

Acknowledgment: Several colleagues commented and made suggestions on drafts of this post – in particular John M. Nardo, MD, Donald F. Klein, M.D., and Patrick Skerrett from STAT News.

Update 06-23-2016:  This post was cross-posted on Naked Capitalism, where some interesting comments can be found.

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How Managerialists Turned Housestaff Training into a Zero-Sum Game: the Continuing Saga of the FIRST and iCompare Studies

academic medical centers amphetamines clinical trials generic managers managerialism medical ethics post-graduate medical education resident sleep deprivation

How Managerialists Turned Housestaff Training into a Zero-Sum Game: the Continuing Saga of the FIRST and iCompare Studies

Unknown 12/23/2015 Komentar

A ongoing controversy about two controlled trials (FIRST and iCompare) meant to test the bizarre hypothesis that sleep depriving medical housestaff (that is, physicians in training) would improve health care provided new evidence that academic medicine has been captured by managerialists.  

Background: the Controversy about the FIRST and iCompare Housestaff Sleep Deprivation Trials

In early December, 2015 we posted about two clinical trials, FIRST and iCompare, designed to test the hypothesis that  increasing housestaff sleep deprivation would improve care continuity, and thus somehow improve housestaff their performance and their patients' outcomes.  Not only did the studies' hypothesis seem strange, but the studies seemed to violate fundamental rules of research ethics.  Study investigators proceeded without obtaining formal informed consent from their house staff or patient research subjects, and did not allow any research subjects to opt out without penalty (e.g., house staff would have to quit their programs and find new ones to opt out).  Finally, after Public Citizen and the American Medical Student Association (AMSA) complained about the studies, study defenders based their arguments on logical fallacies.

Why would distinguished medical educators behave so strangely?  I hypothesized that medical educators could not imagine a way to improve care continuity without worsening trainees' sleep deprivation because all logical methods to do so would cost money.  However, the managerialist executives to whom medical educators are now beholden shrink from increasing costs, other than their and their cronies' own compensation.

Two Psychiatric Residents Write about the Zero-Sum Game of Housestaff Training

Of course, the controversy, and particularly the complaints from AMSA and Public Citizen have been largely anechoic.  But recently, the Washington Post published a commentary by two psychiatric residents on these issues.  The authors, Jeffrey Clark and David Harari, confirmed many of my concerns about the sleep deprivation trials.  They personally verified that the studies were done without informed consent from the research subjects.

The two of us and our patients were not provided informed consent before being enrolled in the iCompare trial.

The also confirmed that the trial investigators assumed they were working in a zero-sum framework.

We already know that extended shifts are dangerous. While many people rightfully suspect that current duty-hour limits aren’t improving outcomes, these studies err in assuming that the dangers of sleep deprivation must be traded for the dangers of shared patient care. Such a zero-sum framework won’t help us improve patient care or ensure the well-being of resident physicians.

To elaborate, the big problem with the duty hour restrictions is that while limiting the consecutive hours interns were supposed to work, this was not accompanied by any diminution of the total workload of housestaff at any one institution.

The standards published in 2011 by the Accreditation Council for Graduate Medical Education still allow hospitals to put residents through blistering 80-hour work weeks, while setting maximum shift lengths of only 16 hours for interns and 24 hours for more senior residents. Interns simply work shorter but more-frequent shifts. Doctors hand off patients to each other more regularly but without the training needed to manage these transitions effectively. And, by and large, hospitals have not responded to the changes with larger workforces, leaving residents no choice but to compress their daily work into shorter time periods.

It appears that housestaff were formerly sleep deprived not by their own choice, but because they were required to accomplish enormous amounts of work.  The new duty-hour limits rearrangde their work into shorter shifts, without diminishing their total responsibilities.  This does not seem like much of an improvement.  The FIRST and iCompare trials were designed to test whether removing the new duty-hour limits, and thus increase sleep deprivation, would somehow help, which ignores the reason  the new duty-hour restrictions were enacted.  But simply shortening shifts accomplishes little as long as total workload remains the same.

Stimulants, An Even Worse Solution

So Clark and Harari confirmed my concerns about the FIRST and iCompare trials.  But they added a new and in some ways even more dire concern.  They uncovered an even more troubling response by medical academics to the zero-sum game which the managerialists ensure they are playing.

Adequate sleep is a fundamental physiological need. No amount of caffeine, prescription stimulants (as some physician leaders have advocated for) or 'alertness management strategies' can adequately compensate for acute and chronic sleep deprivation.

In an aside, Clark and Harari suggested the medical educators were advocating that housestaff use prescription stimulants to counteract the effects of sleep deprivation.  This seems astonishing.

Yet a brief search revealed many informal accounts of medical students and housestaff using psychoactive prescription drugs to increase wakefulness.  For example, see an account of a medical student using Focalin (dexmethylphenidate) here.  Surveys, for example by Shy et al of emergency residents, suggest that use of stimulants by housetaff is rare,(1), but survey respondents may be unwilling to admit to such behavior, and emergency medicine residents may work shorter shifts than medicine and surgery residents.

Also, there is some other evidence that medical educators may encourage use of stimulants.  At least one 2014 guest poster on the KevinMD blog stated

at one medical university, it is common knowledge among the student body that struggling individuals are encouraged to see a physician about their 'possible ADD,' or attention deficit disorder.

Furthermore, in 2009, Rose and Curry writing in the Mayo Clinic Proceedings (2) noted that 

extending the use of drug therapy to include resident with no identified sleep disorder to improve concentration and learning, improve wakefulness, enhance performance, and promote high-quality patient care (especially at night) raises a variety of concerns

without explaining who came up with that idea in the first place.  However, in a response to a letter challenging their commentary, they denied (3) that they were advocating for such drug use, but never made clear who else was.

As we have noted, stimulants used for attention deficit and hyperactivity disorder (ADHD) are  amphetamines or relatives of amphetamines, and have dangerous adverse effects.  Encouraging, even subliminally, medical trainees to use such dangerous drugs to try to compensate for underfunding of training programs seems unethical, as the above letter writer pointed out.(3)  That medical educators would resort to such an extreme solution suggests how they are now boxed in. 

Conclusion: the Problem is Managerialism   

While the ongoing trials of housestaff sleep deprivation have been largely anechoic, the recent Washington Post commentary by Clark and Harari make questions about why in the world medical academics would have set up such trials and continue to defend them even more stark.

But it seems that medical academics are boxed in, playing a zero-sum game.  They may know that there housestaff are overworked and sleep deprived, a situation that endangers the housestaff and their patients.  Yet every reasonable way one could imagined improving the situation would require spending more money, most likely to hire more people to spread the workload.  Yet spending more money may be an anathema to the generic managers to whom medical academics report.  Spending more money would decrease revenue, and for many managerialist managers, increasing revenue, not patient outcomes or physician performance, is the prime directive.    


We have frequently posted about what we have called generic management, the manager's coup d'etat, and mission-hostile management. Managerialism wraps these concepts up into a single package.  The idea is that all organizations, including health care organizations, ought to be run people with generic management training and background, not necessarily by people with specific backgrounds or training in the organizations' areas of operation.  Thus, for example, hospitals ought to be run by MBAs, not doctors, nurses, or public health experts.  Furthermore, all organizations ought to be run according to the same basic principles of business management.  These principles in turn ought to be based on current neoliberal dogma, with the prime directive that short-term revenue is the primary goal.

To conclude, as I did on my first post on the sleep deprivation studies....  I hope that the two studies create the degree of controversy they deserve, and that the federal government promptly starts investigating honestly and thoroughly.  I further hope that this unseemly episode causes medical educators to rethink the cozy or at least conflict averse relationships they have with their managerialist leaders.

True health care reform would restore health care leadership that understands health care and medicine, upholds the health care mission, is accountable for its actions, and is transparent, ethical and honest.



References

1.  Shy BD, Portelli I, Nelson LS. Emergency medicine residents' use of psychostimulants and sedatives to aid in shift work. Am J Emerg Med 2011; 29: 1034-36. Link here.

2.  Rose SH, Curry TB.  Fatigue, countermeasures and performance enhancement in resident physicians.  Mayo Clin Proc 2009; 84:  955-57.  Link here.


3.  Paparodis R. Fatigue, countermeasures and performance enhancement in resident physicians.  Mayo Clin Proc 2010; 85: 300 - 303.  Link here.

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Drinking the Managerialists' Kool-Aid? - Why Did Medical Educators Launch Trials of Increased Sleep Deprivation of Physician Trainees Apparently in Violation of the Nuremberg Code?

clinical trials informed consent logical fallacies managerialism medical ethics nuremberg code resident sleep deprivation

Drinking the Managerialists' Kool-Aid? - Why Did Medical Educators Launch Trials of Increased Sleep Deprivation of Physician Trainees Apparently in Violation of the Nuremberg Code?

Unknown 12/04/2015 Komentar

It all seemed so bizarre.  In 2014, with little fanfare, two large trials that imposed longer work hours and sleep deprivation on physician-trainees (interns and residents), ostensibly to combat the problem of excess hand-offs of patients among physicians.  Both trials involved multiple academic medical centers, including some of the most prestigious in the US.  Within a year, the American Medical Student Association (AMSA) and Public Citizen called for a federal investigation of the trials, calling them "highly unethical."

This unprecented conflict between prestigious academic medical institutions and the largest organization of medical students and a respected watchdog group suggests either the former have serious ethical problems, or the latter have gone a little crazy.  The minimal media attention to the dispute did not explain what is going on.  My suspicion is that these events open a window on how respected medical academics are now in the thrall of the managerialist leaders of health care.

Background of the Studies

My Personal Experience on the Medical Housestaff

Let me start by disclosing the axe I am grinding.  I was an internal medicine intern from 1978-79 in a program known to be very arduous.  For much of the year, I worked up to 36 consecutive hours every fourth night, often without more than a few hours of sleep.  My on call shifts were extremely busy, involving admission of usually 4-5 complex and acutely ill patients, handling exacerbations and emergencies affecting my own patients already in the hospital, and three other interns' patients for about 12-15 hours of the shift.  The workload was augmented by a hefty amount of "scut," that is, tasks that either did not involve direct patient care, or could easily have been done by someone who was not a physician, e.g., paperwork and phone calls, other bureaucratic tasks, drawing blood, starting IVs, and even transporting patients.  As the shift dragged on into the evening, I knew my mind was getting fuzzier and my coordination was getting clumsier.

The notion that working 36 hours straight was educational, was good for my patients, or was good for me seemed nonsensical.  One reason I went into medical education was to improve the experience for future trainees.

Addressing Housestaff Sleep Deprivation

I was hardly the only person who thought the work requirements imposed on medical housestaff were nonsensical.  The first notable improvement was the advent of night float systems that allowed on-call housestaff to get at least some sleep.  Eventually, in part after the infamous "Libby Zion case," (see NY Times retrospective here,)  teaching hospitals were required to limit work hours.  In 2003, Accreditation Council for Graduate Medical Education limited the total work week to 80 hours, required one day off a week, and required call schedules no more frequent than every third night.  (Note that my old program fulfilled all but the first.)  In 2011, the rules were tightened further, limiting interns to shifts no longer than 16 hours.

Pushback Against Duty Hour Restrictions

Yet soon after the pushback began.  A 2014 MedPage today article that described the two studies noted,

The rule change elicited mixed reactions from residents and program directors of residency programs, who worried that increased hand-offs led to worse patient care and shorter hours reduced education opportunities. 

I agree that the increasing number of hand-offs could be problematic, and discuss that below.  On the other hand, the notion that sleep deprived housestaff could learn anything useful while in that condition seems bizarre.  There is plenty of evidence about the adverse cognitive effects of sleep deprivation, including affects on learning.  (See, for example, Durmer et al.)(1)

A brief discussion of one of the two trials, the iCOMPARE trial, put it this way:

Policy limiting duty hours in graduate medical education training programs has become a central point of debate amongst stakeholders. Evidence from human chronobiology and sleep science argues for shorter shifts, because fatigue leads to errors. Evidence from operations research argues for more continuity because patient handoffs also lead to errors, and may reduce the effectiveness of education necessary to produce independent clinicians for the nation’s future.

Poorly Conceived Study Question

The two controversial trials were thus designed to answer the question of whether allowing increased consecutive duty hours would lead to better hand-offs and better outcomes.   This question seems poorly conceived, and was not clearly justified.

The trials were apparently based on the idea that housestaff training programs can exist in only two possible states: allowing longer duty hours with fewer and better done hand-offs, or allowing shorter duty hours with more and badly done hand-offs.  Therefore, the only choice seems to be to maintain the current system (tighter duty hour restrictions) or go back to the old system (more relaxed restrictions).

However, these are not the only possible alternatives.  One can easily think of other choices.

Oddly, the spotty materials about the iCOMPARE trial available online did not include any consideration of why the more restrictive duty hour regulations may have led to bad handoffs.  Perhaps the current problem with hand-offs, while it may be real, may have not come about only due to a decrease in the consecutive hours housestaff were allowed to work.  Perhaps it came about because the consecutive hours regulation was imposed on the closed systems of housestaff training programs in which the clinical and non-clinical responsibilities of the housestaff were fixed.  So, cutting consecutive work hours without decreasing the number of patients that need to be managed, or the housestaff's total workload, including "scut," may have pushed individual residents to try to do more work in less time.  This could have had various detrimental effects, including increased numbers of hand-offs occurring under too much time pressure. 

That hypothesis suggests that measures other than allowing more consecutive work hours could address any unintended effects on hand-offs of the mandated consecutive work hour reduction.  It seems plausible that shorter duty hours combined with measures to decrease total housestaff workload, starting with offloading "scut" work, could produce as good or better results than simply going back to the old system.  

Nonetheless, the two trails were set up as if the only alternative to the current situation is to return to the old situation (longer work hours allowed).  Thus it seems that the reasoning underlying the trials was based on a false dilemma.     

Summary of the Studies' Methods

This apparently badly conceived study question led to trials whose design and implementation raised further concerns.  Per the 2014 Medpage article:

The Comparative Effectiveness of Models Optimizing Patient Safety and Resident Education (iCOMPARE) will compare the current duty-hour regimen (16-hour maximum continuous work period for interns) to what the trial calls a 'more flexible regimen' that eliminates the 16-hour cap.

A total of 59 residency programs are enrolled, including academic and community-based programs.

The 12-month study, led by investigators from the University of Pennsylvania, Johns Hopkins University, and Brigham and Women's Hospital, states that its goal is 'to provide evidence to help policymakers evaluate whether the current duty-hour standards should be changed.'

Measured outcomes will include 'patient safety and trainee education,' with data from Medicare claims, exam scores, and participant surveys.

The study comes on the heels of a similar year-long, randomized trial for surgical interns (Flexibility In duty hour Requirements for Surgical Trainees, or FIRST), which began in July 2014 and is currently underway.

Also

The programs in iCOMPARE's intervention arm will adhere to three rules, which are consistent with the ACGME's July 2003 duty hour regulations:
An 80-hour weekly limit
1 day off in 7
In-house call no more frequent than every 3 nights, averaged over 4 weeks

The Protest

In November, 2015, the complaints about the two trials were announced by AMSA and Public Citizen.  The main issues were summarized in a Huffington Post article by Dr Michael Carome of Public Citizen.   First he stated that on its face, making house staff work long hours, as they are in the intervention group, is dangerous.

The iCOMPARE and FIRST trials have allowed first-year medical residents to work shifts lasting 28 consecutive hours or more -- nearly twice the current maximum number of hours allowed by the Accreditation Council for Graduate Medical Education (ACGME) for such residents. The ACGME's awareness of the known harms to both residents and patients caused by excessively long work hours led the organization in 2011 to tighten restrictions on resident physicians' work hours, including limiting shifts for first-year residents to a maximum of 16 hours.

Substantial evidence shows that sleep deprivation due to excessively long work shifts increases the risk of motor vehicle accidents, needle-stick injuries and exposure to blood-borne pathogens, , and depression in medical residents. It also exposes their patients to an increased risk of medical errors, sometimes leading to patient injuries and deaths

The last statement cited seven references. I should note here that I could not find in the current media reports, or in the spotty documentation of the ICompare trial avaiable online any engagement with the evidence that sleep deprivation is bad for trainee physicians (and everyone else).

The next important point is that the housestaff who were research subjects of the trial, and their patients who also were at least indirectly research subjects did not give their informed consent for participation in the trial.

Among the many disturbing aspects of the trials is the researchers' failure to seek the voluntary informed consent of either the resident doctors or their patients who are forced to be part of these experiments.

According to a recent media report, the University of Pennsylvania's IRB -- the designated lead IRB that reviewed and approved the iCOMPARE trial -- incorrectly found that the trial involves only 'minimal' risk and therefore waived the requirements for obtaining informed consent for all subjects.

For the FIRST trial, the administrator of the IRB at Northwestern University, the lead institution for that trial, shockingly determined that the trial was not even 'research with human subjects' and, therefore, that IRB review and approval were not required. As a result, there was no opportunity for the IRB to discuss the risks of the research and the need for obtaining the voluntary informed consent of both the general surgery residents and their patients. This determination represents a colossal failure of Northwestern University's human subjects protection system. This same failure presumably occurred at many of the other institutions that participated in the FIRST trial.

An article in the business section of the Chicago Tribune added that Public Citizen claimed the failure to obtain informed consent was all the more serious because the house staff and patients were exposed to danger contingent on their trial participation.

It claimed the 'highly unethical' experiments, including the other led by the University of Pennsylvania and Johns Hopkins University, exposed doctors to an increased risk of making serious medical errors and suffering personal injury.

'Substantial evidence shows that sleep deprivation due to excessively long work shifts increases the risk of motor vehicle accidents, needle-stick injuries and exposure to blood-borne pathogens and depression in medical students,' according to the complaint. For patients, the long hours could lead to increased medical errors and death, the complaint said.

Furthermore, the trials apparently did not include mechanisms for house staff to refuse participation, or to stop participating.  An article in Medscape quoted Dr Karl Bilimoria, a professor of surgery at Northwestern who led the surgical trial,

Dr Bilimoria said that for first-year general surgery residents assigned extended hours at intervention-arm hospitals, the trial was no secret. 'They were told, because they had to monitor their hours,' he said. 'Residents knew which arm of the trial they were in.'

'This has been very public.'

Asked whether this process amounted to informed consent, he replied that if residents strongly disagreed with the prospect of longer hours, 'they could choose to work elsewhere.'

The news coverage of the controversy included several statements that the trials were particularly and severely unethical.  For example, a BMJ news article quoted

Charles Czeisler, professor of medicine and director of sleep medicine at Harvard Medical School [who] told the BMJ, 'I was shocked when I heard about this study assigning resident physicians to work marathon shifts.'  Czeisler said that even as little as one week of sleep deprivation was knwon to cause serious harms.

In Modern Healthcare,

Other ethics researchers found it difficult to understand how such a trial could be approved by an institutional review board.

'Because you're looking at deaths of patients as the major outcome, that makes it much more difficult ethically to support because patients may be harmed,' said Dr. Robert Klitzman, director of the master of bioethics program at Columbia University. 'If you find that twice as many patients died under anything but the current system, you could say they died unnecessarily.'

Apparent Violations of the Nuremberg Code

 [Photograph: Defendants in the dock at Nuremberg trials.  Link here.]

In fact, in my humble opinion, the two trials appeared to violate several major components of the Nuremberg Code, the set of principles for ethical research that was developed after Nazi atrocities visited in the course of supposed medical experiments were revealed during the Nuremberg Trials.  These principles include,

1. The voluntary consent of the human subject is absolutely essential.

This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved, as to enable him to make an understanding and enlightened decision. This latter element requires that, before the acceptance of an affirmative decision by the experimental subject, there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person, which may possibly come from his participation in the experiment.

The two trials did not get true informed consent from the housestaff subjects. As trainees required to complete housestaff training to become surgeons or internists, informing housestaff that their program would be participating in the trial, and their only option if they did not want to participate would be to seek another program surely seems like any consent they provided was given under duress.  Furthermore, it is not clear that they were ever informed of "all the inconveniences and hazards reasonably to be expected; and the effects upon" their "health or person[s]."

2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methds or means of study, and not random and unncessary in nature.

Again, if the major rationale for doing the trials was to mitigate the postulated effects of increasing hand-offs, there are many other ways one could try to do this which do not involve increasing duty hours and sleep deprivation.

3.  The experiment should be designed based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study, that the anticipated results will justify the performance of the experiment.

Again, there is a considerable body of research that sleep deprivation is harmful to patient and humans in general.  Thus, the science suggests that increasing sleep deprivation will have unfavorable results, and thus the performance of a trial of increasing sleep deprivation  seems unjustified.

9. During the course of the experiment, the human subject should be at liberty to bring the experiment to an end, if he has reached the physical or mental state, where continuation of the experiment seemed to him to be impossible.

Again, the housestaff could not easily opt out of further participation. At best, to do so, as one of the investigators said, they would have to quit their training programs, which could jeopardize their careers and entail major financial costs.

The Rebuttal

The main arguments of the trial proponents in response to the complaints seemed weak, and often appeared to be based on logical fallacies.

The ACGME and the IRBs Approved the Trials - Appeals to Authority

In the Chicago Tribune article:

But Northwestern said the council [ACGME] granted a waiver for the longer hours and helped fund the study.

'It was done with their approval,' Dr Karl Bilimoria, principal investigator for the trial ... said.

An article from the Milwaukee Journal Sentinel and MedPage Today  quoted Dr Thomas Nasca, CEO of the ACGME,

He said institutional review boards at all the participating hospital reviewed the trial protocols and determined the patients did not need to be informed.

These arguments amount to assertions that the trials must have been ethical because external authorities said they were.  Thus they appear to be based on logical fallacies, appeals to authority. 

The Arguments and Evidence Supporting Duty Hour Restrictions are Weak - Burden of Proof

In an unfortunately misnamed ModernHealthcare article (it refers to medical students rather than housestaff) , Dr Bilimoria was again quoted,

The key piece is that we just have never had prospective, randomized high-level evidence to inform our decisionmaking....

Similarly, in a Medscape article  Dr Nasca, the ACGME CEO,

calls resident scheduling rules a work in progress, especially because only very small, single-institution studies have examined the effect of long hours on residents and patients.

On the other hand, there are no big randomized trials to suggest that longer duty hours or increased sleep deprivation is advantageous.  However, there are huge numbers of studies that show that sleep deprivation is bad for patients and people in non-medical settings, as well as medical trainees.

In any case, the supporters of the trials seem to be arguing that the burden of proof should be on those who want to limit duty hours, while it seems more reasonable that to justify a trial of increased sleep deprivation, the burden of proof was on those who proposed the trial.  Thus, this appears to be a version of the burden of proof logical fallacy.

Increased Hand-Offs are Bad, and the Only Alternative to Having Them is to Increase Duty Hours - False Dilemma

In trying to defend their work the advocates for these trials further corroborated my concerns above that the trials were conceived without any consideration that measures other than increasing duty hours (and consequent sleep deprivation) was the only possible alternative to the current situation.   For example, in the Modern Healthcare article.

'There's always a trade-off,' [senior RAND natural scientist Dr Mark] Friedberg said, noting the increased number of patient hand-offs that occur with shorter hours. These hand-offs reduce consistency of care and open patients up to more mistakes and miscommunication among providers. 'It's not clear-cut. That's why you have to do the science,' he said.

However, he did not argue that increased hand-offs are so bad that a trial of increasing duty hours and sleep deprivation to achieve fewer hand-offs could be justified.  He also did not consider whether there might be some way to mitigate the effect of increased hand-offs without causing sleep deprivation.

Similarly a New Haven Register article quoted Dr Thomas Balcezak, chief medical officer for Yale-New Haven, saying

one issue is that there are 'more handoffs between caregivers' when residents work shorter hours. 'There’s always a risk that important information could fall through the cracks' because of 'a lack of consistency or continuity.'

Again, that seems to be at best a theory, but not evidence based argument. Besides, the article quoted Dr Carome of Public Citizen on just one of many other possible approaches to mitigate the effects of increased hand-offs,

hospitals could overcome that problem by hiring doctors to work overlapping shifts.

There is no evidence that the people who were so concerned about hand-offs thought of any alternative ways to mitigate any problems the duty hour restrictions could have created.  This corroborates my concerns that the trials were fundamentally based on a logical fallacy, the false dilemma.

Managerialism and Tunnel Vision

So why would medical educators at some of the most prestigious US teaching hospitals launch trials to see if increasing housestaff sleep deprivation might benefit them and their patients, mandate partcipation of housestaff and patients in these trials without obtaining informed consent or allowing these subjects to opt out of the trials, thus seemingly violating the Nuremberg Code, and then defend their actions with logical fallacies?

I do not think they have gone mad.  I do suspect they are in the thrall of their managerialist hospital executives.

Recently we discussed the rise of managerialism in the leadership of health care organizations. Managerialism, which wraps up what we have called generic management, the manager's coup d'etat, and aspects of mission-hostile management into a very troubling but coherent package, was first  described for a medical audience in 2015 by Komesaroff in an article in the Medical Journal of Australia(2):

The particular system of beliefs and practices defining the roles and powers of managers in our present context is what is referred to as managerialism. This is defined by two basic tenets: (i) that all social organisations must conform to a single structure [defined by management theory and dogma]; and (ii) that the sole regulatory principle is the market. Both ideas have far-reaching implications. The claim that every organisation — whether it is a mining company, a hospital, a school, a professional association or a charity — must be structured according to a single model, conforming to a single set of legislative requirements, not so long ago would have seemed bizarre, but is now largely taken for granted. The principle of the market has become the solitary, or dominant, criterion for decision making, and other criteria, such as loyalty, trust, care and a commitment to critical reflection, have become displaced and devalued. Indeed, the latter are viewed as quaint anachronisms with less importance and meaning than formal procedures or standards that can be readily linked to key performance indicators, budget end points, efficiency markers and externally imposed targets.

Many of the prestigious teaching hospitals/ acacemic medical centers/ hospital systems participating in the two controversial trials may be led in the managerialist tradition.  We have shown numerous examples of such leadership that may put short term revenue and the continuing enrichment of top managers ahead of all other concerns, including good patient care and the integrity of academics, has been frankly mission hostile, and jump on the latest management bandwagons as solutions all problems.

I postulate that housestaff directors at such institutions tremble at the idea of challenging such leaders.  Yet to improve the handoff problem, teaching programs might have to do things that cost money.  Spending money that does not lead to immediate increases in revenue, and boosts in management pay, could be an anathema to managerialists.  Also, to improve the hand-off problem, programs might have to challenge management dogma, such as the worship of badly designed, time wasting electronic health records.  So I suspect the leaders of the two studies consciously or unconsciously eschewed trial designs that could assess any educational alternative that might have made management uncomfortable.  Thus boxed in, they wound up with an apparently indefensibly unethical research project.

I hope that the two studies create the degree of controversy they deserve, and that the federal government promptly starts investigating honestly and thoroughly.  I further hope that this unseemly episode causes medical educators to rethink the cozy or at least conflict averse relationships they have with their managerialist leaders.

True health care reform would restore health care leadership that understands health care and medicine, upholds the health care mission, is accountable for its actions, and is transparent, ethical and honest.

ADDENDUM (5 December, 2015) - This post was republished on the Naked Capitalism blog. 

References

1.  Durmer JS, Dinges DF.  Neurocognitive consequences of sleep deprivation.  Sem Neurology 2005.  25. 117-129.  Link here.

 2.  Komesaroff PA, Kerridge IH, Isaacs D, Brooks PM.  The scourge of managerialism and the Royal Australasian College of Physicians.  Med J Aust 2015; 202: 519- 521.  Link here.

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Entresto: Blockbuster, or Just Over Hyped? - Whatever, It Will Cost $4500 a Year

CHF clinical trials Entresto evidence-based medicine manipulating clinical research Novartis sacubitril

Entresto: Blockbuster, or Just Over Hyped? - Whatever, It Will Cost $4500 a Year

Unknown 7/30/2015 Komentar

The newest drug for congestive heart failure, Entresto, a fixed combination of valsartan and sacubitril, has just hit the market at an elevated price.  Like other drugs recently introduced as blockbusters, the high price does not seem clearly justified by clinical evidence about the drug's benefits and harms.  


Questions Raised by the One Big Published Controlled Trial

Last year, we discussed the hoopla around a study of a new drug for congestive heart failure (CHF),(1) a fixed combination of valsartan and sacubitril. Also, on the now defunct CardioExchange blog, Dr Vinay Prasad discussed the same study (look here, and scroll down.) We both concluded that the (apparently multiply flawed) design of the study left important questions unanswered.

Does Sacubitril Actually Work?

 The PARADIGM-HF study compared patients given valsartan plus sacubitril to patients given enalapril.  Valsartan, an angiotensin receptor blocker (ARB) and enalapril, an angiotensin converting enzyme inhibitor (ACEI) have both been shown separately to improve symptoms and function, decrease morbid events, and extend life for patients with systolic CHF.  However, the PARADIGM-HF study compared a high dose of valsartan, 160 mg twice a day, (plus sacubitril) to a medium dose of enalapril, 10 mg twice a day.  Apparently, no trial comparing just valsartan 160 mg to enalapril 10 mg twice a day has been done.  So it is quite possible that a high dose of valsartan is better than a medium dose of enalapril.  Thus, PARADIGM-HF could not prove that sacubitril has any benefit independent of high dose valsartan.

What are the Adverse Effects of Sacubitril (With or Without Valsartan) Likely to be in Practice?

The PARADIGM-HF design prevented any assessment of the adverse effects of sacubitril independent of those of valsartan.  Furthermore, the trial had an active run-in period which resulted in the exclusion of  patients who failed to tolerate valsartan-sacubitril in a pre-trial run-in period.  This effectively biased downward the prevalence of adverse effects due to the combination reported during the trial.  Finally, the trial, while big, was not big enough to discover rare but severe adverse effects.  Thus, one cannot easily tell how the benefits of valsartan-sacubitril compare to its harms, or how the benefits of sacubitril alone compare to its harms.

How Would Valartan-Sacubitril Work for Patients with Common Diseases in Addition to CHF?

The study excluded patients with common conditions that may afflict CHF patients, including relatively severe coronary artery disease, severe lung disease, ulcers and liver disease.  CHF patients are often elderly and often have other diseases, but how the drug might work for them is unclear.

Other Doubts and Questions

In a recent Medscape post, Dr John Mandrola noted additional problems with the study that raise doubts about its validity.  These included its early termination, the very large number (1000) of study sites raising doubts about quality control of implementation and data collection, and the finding, not emphasized by the authors, that valsartan-sacubril caused an apparent increase in hypotension, a significant issue for CHF patients.

As far as I can tell, there have been no other big trials of sacubitril, with or without valsartan, so there are no other source of clinical research data to address these questions.  As we noted here, one of the most prominent PARADIGM-HF investigators tried to rebut Dr Prasad, but did so mainly by employing logical fallacies.

So in my humble opinion, there is only weak, ambiguous data to show valsartan-sacubitril produces benefits that outweigh its harms for congestive heart failure patients seen in usual clinical practice.

More Enthusiasm and Hype about Entresto

These questions about the one big study of valsartan-sacubitril did not deter the US Food and Drug Administration (FDA) from approving it.  As soon as it was approved, the hype machine started up in a big way.

Per the NY Times,

'This is one of those once-in-a-decade kind of breakthroughs, to get a drug that extends life so substantially,' David Epstein, the head of Novartis’s pharmaceutical division, said in an interview.

Per the Wall Street Journal,

Clyde Yancy, chief of cardiology at Chicago’s Northwestern Memorial Hospital, said that Entresto is 'one of the few times that we have identified a medication that is better than the standard. It’s clearly superior to what we have.'

Per a Medscape news post, Dr Clyde Yancy also said,

A year later, I continue to feel that this is, in fact, a reflection of a new day—for patients and for the opportunity to reenergize the community. It's also a huge endorsement for the importance of science in cardiovascular medicine.

And Dr Milton Packer (who had countered Dr Pradad's critique of PARADIGM-HF with logical fallacies, said,

I think they considered the data to be compelling and strong. And I think that when physicians look at the data, they will be convinced that this drug will become a cornerstone of treatment for heart failure.

The Medscape article did document some doubts.  Dr John G Cleland of Imperial College, London, UK allowed that the active run-in group was among "issues that have yet to be settled," Dr Marriell Jessup who had written a positive editorial in the NEJM when the trial was published(2) allowed that the lack of patients with co-morbities might be a problem.  Finally, Dr Yancy allowed that the early termination might be a problem.   Yet each focused on a single problem with the study, and none of these physicians seemed to acknowledge the totality of the study's problem.  Neither did any of them seemed to let these doubts dampen the enthusiasm, e.g., at the end of the article, quoting Dr Yancy,

Can we change the narrative?  I believe it's time to take the 'failure' out of heart failure and look at what we can do to generate success.

Note that the article disclosed Dr Cleland does research funded by Novartis, maker of Entresto, and Dr Packer is a consultant to Novartis.  Is is possible these commercial relationships tempered any concerns that might have had about the study design. 

I realize that CHF is a miserable problem for patients, and clearly leads to severe symptoms, multiple hospitalization, and sometimes early death.  So I understand why people may be enthusiastic about a new therapy for it, especially if their research or consulting is funded by the drug's manufacturer.  But is it crystal clear the latest innovation is that good?

Billions of Dollars in Play

But never mind those unanswered questions and the multiple problems with the PARADIGM-HF trial, Entresto, the trade name for valsartan-sacubitril will not be cheap.  Per the NY Times,

Novartis said Entresto would cost about $12.50 a day, or about $4,500 for a year....

Novartis wants to convince you that it's not really that expensive

Mr Epstein said the price was 'really quite reasonable,' given that some drugs for other diseases cost many times that amount and confer less benefit.

He is certainly right that some drugs are even more expensive. However, is argument is just an appeal to common practice.  Whether the prices of other drugs are justified by strong evidence about their benefits and harms may not be clear. The benefits conferred by Entresto, and the harms it may cause as we belabored above, are really not that certain either. 

In the financial news, you could almost imagine the salivation.  Per the WSJ,

Wall Street predicts Entresto will be a blockbuster, with Leerink Partners estimating that annual global sales could top $6 billion by 2024.

In Reuters,

Expectations for Entresto have been building since it won early U.S. approval and Novartis set a higher than expected price, with analysts now forecasting $4.7 billion of sales in 2020, according to Thomson Reuters Cortellis.

Chief Executive Joe Jimenez said Entresto sales would take time to ramp up but growth would accelerate in 2016. Reception to the new drug, which Novartis started shipping within 24 hours of U.S. approval this month, has been good and there was little resistance to the $12.50 daily cost.

'The average hospital stay for a heart failure patient in the United States is $11,000,' Jimenez told reporters. 'So we are not receiving pushback on the price because I think this is seen as good value.'

Compared to what? Again, it is not clear that Entresto would be better than generic enalapril dosed at 20 mg/day, which is a lot cheaper than $4,500 a year.  But could it be that visions of billions of dollars have clouded some peoples' thinking, at least people paid by or owning stock in Novartis?

Summary

We have posted frequently about the blockbuster drug Sovaldi promoted as a cure for deadly hepatitis C infections.  Yet while the evidence that Sovaldi and its competitors are really so good, really provide cures, and really will prevent many patients from dire consequences of hepatitis C is not so strong, the US price of these drugs is stratospheric.

Now we have Entresto, whose price is not so stratospheric, but still quite high, and whose benefits compared to its harms are not clearly supported by evidence from clinical research.

 Unfortunately, Entresto (valsartan-sacubitril) is now one of a long line of new drugs that are breathlessly hyped, often by people who should know better, despite weak evidence in their favor.  It is one of a long list of examples of drugs approved based on poorly designed studies whose design flaws seem likely to make their commercial sponsors' products look better.  As a recent post in Health Affairs by Christopher Robertson reminds us, while many industry supporter act like allowing drug and device manufacturers to support (and usually control) most of the clinical research meant to evaluate their own products in inevitable,

When one steps back from our current practices, it should appear rather odd that we rely on companies to test the safety and efficacy of their own products. It would be as if a litigant were allowed to choose and fund its own judge, or an athlete to hire her own referee.

To convince us that we live in the best of all possible worlds, however, the media is full of proclamations that we are in a new era of marvelous medical and health care "innovations" that will bring us all untold benefits.  The notion that physician-industry collaboration is necessary to continue to produce these wondrous "innovations" is a talking point used to counter those who criticize conflicts of interest affecting academic medicine (look here).   Yet the evidence supporting many game-changers and blockbusters is often weak and ambiguous.  This rarely seems to deter the drug, device and biotechnology industry from charging more and more for them.


The sober, evidence-based medicine approach is being lost in all the hoopla and hucksterism.  We are adopting treatments of unproven value, whose benefits may be much less, and harms may be much worse than we imagine, and paying unconscionsable prices for them.  The results for patients and society include our ever rising health care costs, ever challenged access, and no evidence that outcomes are better for patients.

True health care reform would encourage sober discussion of the evidence, of benefits and harms, and of fair pricing, and would challenge the hype, hucksterism, and conflicts of interest that all swirl around modern health care. 



References

1.   McMurray JJV, Packer M, Desai AS et al.  Angiotensin - neprilysin inhibition versus enalapril in heart failure.  N Engl J Med 2014; DOI: 10.1056/NEJMoa1409077  Link here.

2.  Jessup M. Neprilysin inhibition - a novel therapy for heart failure.  N Engl J Med 2014;  DOI: 10.1056/NEJMe1409898.  Link here.

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Two New Independent Reports on the Death of Dan Markingson, But Now What Will Happen?

anechoic effect AstraZeneca atypical anti-psychotics clinical trials conflicts of interest manipulating clinical research research subjects suppression of medical research University of Minnesota

Two New Independent Reports on the Death of Dan Markingson, But Now What Will Happen?

Unknown 3/26/2015 Komentar

Years after his death, there is now a little more clarity about the clinical trial in which Dan Markingson was enrolled when he died.  Whether this clarity will have any impact remains to be seen.

We most recently posted about the aftermath of Mr Markingson's death here, (and see posts in 2013 here, and in 2011 here.)  Very briefly, Mr Markingson was an acutely psychotic patient enrolled in a drug trial sponsored by Astra Zeneca at the University of Minnesota.  His enrollment was said to be voluntary although at the time he enrolled he had been under a stayed order that could have involuntarily committed him to care.  Despite his mother's ongoing and vocal concerns that he was not doing well on the study drug and under the care of trial investigators, he continued in the trial until he died violently by his own hand.  After his death, his mother Mary Weiss, friend Mike Howard, and University of Minnesota bioethics professor Carl Elliott campaigned for a fair review of what actually happened.  University managers not only rebuffed their concerns, but harshly criticized Professor Elliott, and ended up reprimanding him for "unprofessional conduct."

Two New Reports

In the last few weeks, two new independent reports on the case appeared.  Both vindicated the concerns and questions raised by Mary Weiss, Mike Howard, and Prof Elliott.

Association for Accreditation of Human Research Protection

One, called for by the University of Minnesota faculty senate, was by the Association for Accreditation of Human Research Protection,  and said that the university left research subjects "susceptible to risks that otherwise would be avoidable" (see this Minneapolis Star-Tribune article.)  Furthermore, according to a post in the Science Insider blog from the American Association for the Advancement of Science, it said,

[T]he external review team believes the University has not taken an appropriately aggressive and informed approach to protecting subjects and regaining lost trust,

Also, it said the university has been

assuming a defensive posture. In other words, in the context of nearly continuous negative attention, the University has not persuaded its critics (from within and outside the University) that it is interested in more than protecting its reputation and that it is instead open to feedback, able to acknowledge its errors, and will take responsibility for deficiencies and their consequences.

Finally, it noted a "climate of fear" in the Department of Psychiatry.

Office of the Legislative Auditor for the State of Minnesota

The second report, available in full here,was from the Office of the Legislative Auditor for Minnesota.  If anything, it was more damning. Its summary included,

the Markingson case raises serious ethical issues and numerous conflicts of interest, which University leaders have been consistently unwilling to acknowledge. They have repeatedly claimed that clinical research at the University meets the highest ethical standards and dismissed the need for further consideration of the Markingson case by making misleading statements about past reviews. This insular and inaccurate response has seriously harmed the University of Minnesota’s credibility and reputation.

It seemed to affirm in detail nearly all of Weiss', Howard's and Elliott's concerns.  It recommended that the University should suspend new psychiatric drug trials until the problems it identified were remedied (see Star-Tribune article here.)

Vindication, but Will It Lead to Progress?  

Taken together, these reports vindicate the work of Mr Markingson's mother, friend, and academic watchdog Professor Elliott and their supporters.  As the Star-Tribune reported,

'Over the past eleven years the University of Minnesota has made us feel as if we have no voice, no rights and absolutely nothing remotely called justice,' wrote Mike Howard, a close friend to Markingson’s mother, in a letter in the audit. 'This report is the first step toward accountability.'

The Minnesota Post added the response of Professor Elliott and a colleague,

'It’s nice to have an independent confirmation of what we’ve been telling the university for five years, but which they have refused to listen to,' he told MinnPost on Thursday.

Elliott said he is not convinced, however, that Kaler and other university leaders are going to take responsibility for what happened in the Markingson case — or take the necessary steps to fix the problem going forward.

'One of the most worrying findings in the report was the widespread belief on campus that the university leadership doesn’t care about human study subjects,' he said.

Leigh Turner, another U bioethicist who has also been outspoken about the issues raised by the Markingson case, expressed similar concerns. 'Can we expect reform from the very people who have done nothing for the past several years?' he said in a phone interview.

'I hope there’s some change,' he added. 'But the fact that [Markingson died in 2004] and it’s now 2015, I think hope has to be tempered with a dose of realism. There are some very powerful forces interested in minimizing the findings and suggesting that there are only minor things that need to be done.'

It appears there a several major remaining questions.

What Were the Underlying Causes?

Although both reports went into some detail about what happened to Mr Markingson, they seemed not to dwell on why it happened.  They did not seem to address relevant contextual factors, policies, and decisions.  For example, the report by the Office of the Legislative Auditor included,

We understand that the University of Minnesota has been and should continue to be an institution that delivers not only high quality medical care but also engages in cutting edge medical research— research that does pose risks to human subjects. In addition, we do not question the appropriateness of the University obtaining money from pharmaceutical and other medical companies to support that research. However, in every medical research study—whether supported with public or private money—the University must always make the protection of human subjects its paramount responsibility.

However, as we and many others more erudite have discussed frequently, clinical research that evaluates products or services made by the commercial sponsors of the research has proven to be highly susceptible to manipulation by these sponsors to increase the likelihood that the results will serve marketing purposes, and suppression if the manipulation fails to produce the wanted results.  Commercial sponsors often strongly influence the design, implementation, analysis and dissemination of clinical research.  Often their influence is mediated by financial relationships with individual researchers and with academic institutions who seem more and more beholden to outside sponsors, that is, by conflicts of interest.  The report by the Auditor noted pressures, including financial pressures on the physician who ran the study in which Mr Markingson was a subject to enroll more patients and keep them enrolled.  To protect patients better in the future, in my humble opinion the relationships among commercial sponsors, academic medical institutions, and individual researchers need further consideration.  Is the easy money supporting research coming from commercial firms with vested interests in the outcome of that research really worth the risks of biased results, hidden results, and to research subjects?   

Will Anything Change and Will Anyone be Held Accountable?

Once these two reports were delivered, it now seems to be up to university managers to make needed changes.  In general, these are the same managers who are described above as so "defensive," who not only ignored complaints, but appeared to try to silence those who complained.  If they are left in charge, why should we expect them to make any meaningful changes?  Instead, should they  not be held accountable for their actions?  

Will the University Cease Hostilities Against Dr Elliott?

Again, as noted above, university managers did not merely disagree with Professor Elliott.  They disparaged him, appeared to try to intimidate him, and reprimanded him.  It seems at the very least he is owed an apology.  So far, nothing in the news coverage suggests he has or will receive one.

Will Anyone Notice? 

So far, this case has gotten good coverage in Minnesota media.  However, it has largely been ignored in the national media.  Beyond Minnesota, I could only find mention in some blogs, e.g., in PharmaLot by Ed Silverman, and in Forbes by Judy Stone.  I have seen nothing in any US medical or health care journal, although the British Medical Journal did cover it in a news feature.  This case clearly has global implications, and ought to be considered one of the most important cases illustrating the perils of commercially sponsored human research, but it remains proportionately anechoic.

Summary

The latest reports seem only to confirm that clinical research at major academic institutions has gone way off track.  It now seems that in their haste to bring in external funding, university administrators and the academic researchers who are beholden to them have sadly neglected the protection of their own patients.  As we have said ad infinitum, true health care reform would turn leadership of health care organizations over the people who understand and are willing to uphold the mission of health care, and particularly willing to put patients' and the public's health, and the integrity of medical education and research when applicable, ahead of the leaders' personal interests and financial gain.

ADDENDUM (25 March, 2015) - See also numerous posts by Professor Elliott on the Fear and Loathing in Bioethics blog,  by Bill Gleason in the Periodic Table blog,  and by Mickey Nardo on the 1BoringOldMan blog. 

ADDENDUM (30 March, 2015) - Note that after receiving offline comments, I changed the first paragraph to emphasize the clarity is about the trial, rather than the patient's death, and second paragraph to clarify that the order to commit was stayed.

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