UCB Settles, Pleads Guilty

Tromp, tromp, tromp.... the legal settlements keep marching along.  This latest story was reported by Reuters and Bloomberg.  The basics were, per Reuters:

The American unit of Belgian pharmaceutical company UCB SA (UCB.BR) pleaded guilty on Thursday and will pay $34.4 million to settle criminal and civil charges that it illegally promoted a drug for migraines.

The company pleaded guilty to one count of promoting the epilepsy treatment drug, Keppra, in the United States in 2004 for migraine treatment without the necessary approval from the Food and Drug Administration, the U.S. Department of Justice said.

One atypical element here is that the company actually pleaded guilty to a crime.

Another slightly off-key note came from the description of the activities constituting the illegal marketing, per Reuters:

The company was accused of promoting Keppra with posters that claimed it was safe and effective for migraines and cited studies that it also claimed were independent -- but in fact were sponsored by UCB, according to the Justice Department.

In those posters, UCB failed to disclose that its own trials had failed to demonstrate the drug was effective for migraines or that it had backed the studies, the agency said.

Furthermore, per Bloomberg,

UCB’s marketing included sponsorship of doctor-paid 'studies,' posters, publications and oral presentations about the supposed benefits of using Keppra to treat migraines. Prosecutors said UCB failed to disclose that a 2000 study showed that Keppra was not effective in preventing migraine.

So the company did not deny accusations of deceptive marketing, and the suppression of a clinical study that failed to conform to marketing objectives.

But most of the rest followed the usual routine.

The settlement involved some sort of promises of better corporate behavior in the future, per Reuters:

As part of the settlement, the company agreed to implement procedures and reviews to avoid and detect any future similar conduct. As a result, UCB will not face probation, according to the plea agreement filed in court.

The penalty for the company was a fine that appeared to be big:

UCB will pay about $8.6 million in criminal fines and forfeiture and another $25.8 million to settle parallel civil allegations involving false claims submitted to U.S. federal healthcare programs, according to the plea agreement.

However, it was a pittance compared to the revenues generate by the product whose marketing was illegal, per Bloomberg:

Keppra, with 942 million euros ($1.37 billion) in sales last year, is the company’s top-selling drug, according to data compiled by Bloomberg.

The spokesperson for the government basically said, "that ought to teach them," again per Bloomberg,

'UCB put its pursuit of profits ahead of its obligations to patients,' Ronald C. Machen Jr., U.S. attorney for the District of Columbia, said in an e-mailed statement. 'Today’s guilty plea and UCB’s $34 million payout should remind drug companies that try to cleverly design off-label marketing schemes that we will not allow them to compromise patient safety.'

However, the company's leaders did not seem the least bit fazed, or contrite for that matter, per Reuters,

'We are pleased to have resolved this matter and look forward to continuing to work with the many organizations with whom we partner to advance our mission of transforming the lives of people living with severe diseases,' said Greg Duncan, UCB's president for North American Operations.

The contrast between the crime his company admitted, involving deceptive marketing and the suppression and a study that failed to fit marketing objectives, and the high minded mission seemed to cause Mr Duncan no cognitive dissonance. Or perhaps "transforming the lives of people" was meant more ironically?

Left unsaid in the brief news reports was whether any individual who authorized, directed, or implemented the bad behavior, including, in this case, the deceptive marketing and suppression of clinical research, would pay any sort of penalty. It seems safe to assume that no one will go to jail, pay a fine, lose a job, or even be demoted.  Why the US Department of Justice thought that a small fine and no individual penalties would change corporate behavior, when the profits to be made are so large, in the absence of even a little bit of contrition by corporate leaders, was not exactly clear.

So on and on the march goes. The parade of settlements, sometimes even involving guilty pleas of criminal convictions, now indicates how low the ethical standards of health care organizations have fallen. However, the lack of any consequences to individuals suggests that they have no incentive to rise.

Again, despite promises of tougher treatment of individuals involved in health care corporate misbehavior from the government (see posts here and here), the same old script plays out again and again.

So I get to say twice in two days,,,, pervasive bad behavior by large health care organizations has got to be a major cause of our ongoing health care dysfunction.


So, to really deter bad behavior, those who authorized, directed or implemented bad behavior must be held accountable. As long as they are not, expect the bad behavior to continue.

Guidant (Boston Scientific) Gets Probation

The latest in the parade of legal settlements by health care corporations involves a new wrinkle. 

We have been writing about the case of Guidant Corporation's faulty implantable cardiac defibrillators (ICDs) in 2005, almost since the start of the Health Care Renewal blog.  A quick summary, via the Minneapolis Star-Tribune, is:

In 2005 Minneapolis Heart Institute doctors Barry Maron and Robert Hauser went public with concerns about a Guidant defibrillator called the Ventak Prizm 2 after a 21-year-old patient died when his defibrillator short-circuited and failed to revive him after he went into sudden cardiac arrest.

Guidant had known about the short-circuiting issue since 2002 and had made two attempts to fix the device, according to court documents. The company did not alert the FDA -- even though federal law requires manufacturers to report changes that may pose a health risk to patients.

In early 2004, Guidant discovered a similar short-circuiting problem in different defibrillator models called Contak Renewal 1 and 2. The company ordered its factory to stop making and shipping the models, but potentially faulty products on hospital shelves continued to be implanted in thousands of patients.

Although engineers at Guidant had recommended recalling the Contak Renewal devices, upper management rejected the proposal, court documents state. Instead, Guidant issued the 'least aggressive' form of communication, called a product update, in which sales representatives were told to tell doctors that 'nothing was broken' with the device.

Maron and Hauser met with top Guidant officials in May 2005 and urged the company to communicate the problem to doctors, but Guidant refused. The doctors then went to the New York Times, which published an article indicating that the company had known for three years that the Ventak Prizm model could short-circuit, but did not communicate that to doctors.

In June 2005, Guidant issued a public missive detailing safety issues with the defibrillators, which were later recalled by the FDA.

A longer version from a series of Health Care Renewal posts can be found here.

In 2010, Guidant, now a subsidiary of Boston Scientific, agreed to a settlement which would involve guilty pleas to misdemeanors and payment of a large ($296 million) fine, but the settlement was rejected by a federal judge who found it to be too lenient (see post here). Now the judge has approved a new version, again per the Star-Tribune,

In what is believed to be the largest criminal penalty ever imposed in a medical device case, a federal judge on Wednesday approved an agreement calling for Guidant Corp. to pay $296 million for concealing safety information about several of its heart devices.

The denouement in U.S. District Court in St. Paul ended a difficult chapter for one of the biggest players in Minnesota's signature medical technology industry. Thirteen patient deaths have been associated with faulty devices made by Arden Hills-based Guidant, which is now part of Boston Scientific Corp. The controversy lingered for almost six years and raised questions about how safety issues involving medical devices are communicated to the Food and Drug Administration, doctors and patients.

Last April, U.S. District Judge Donovan Frank rejected a previous $296 million settlement between the Department of Justice and the company. This time that fine remained intact, but Frank also called for Boston Scientific to serve three years' probation.


Boston Scientific will be required to make quarterly reports to the U.S. Probation Office regarding safety and compliance issues, as well as submit to regular, unannounced inspections of its records. Frank also called upon Boston Scientific to continue charitable programs intended to raise awareness about heart disease.

'I believe this serves not only the interests of the community and the interests of justice, but respect for the law and corporate responsibility,' Frank said.

The new wrinkle is, of course, probation. I have not previously heard of a US health care corporation put on probation in a criminal settlement. Presumably, the idea is that probation will involve court supervision of the company that might be less lenient than US Department of Justice oversight via a corporate integrity agreement.

So this is a small step forward, but once again, the extent that this settlement will deter future bad behavior seems small. Once again, although the fine imposed seems large, it is small compared to the money to be made by selling these very expensive devices. Moreover, the cost of the fine can be diffused over the entire company, and ultimately over all its employees, its stockholders, and its customers.

Since no individual will pay a penalty, and since it is likely some individuals made themselves rich or richer from the company's actions, it is likely that other individuals in the future will authorize, direct, and implement similar bad behavior to fatten their bonuses and total compensation.

Last June, we noted that some government officials were starting to talk tough about imposing penalties on individuals for misbehavior by health care corporations. In fact, in 1943, the US Supreme Court found that corporate leaders could be held responsible for corporate bad behavior, the so-called Responsible Corporate Officers doctrine. However, the laissez faire malaise that apparently infected most government officials starting in the 1980s seemed to prevent anyone from invoking this doctrine during the last 30 years of health care dysfunction. That malaise still seems to be rendering US federal law enforcement effete, at least when applied to wrong-doing by big, powerful, rich health care corporations.

So like Cassandra, fated to have her predictions always ignored, I repeat: When it comes to health care's leadership, society seems to have acceded to defining deviancy down. Until we start holding health care leaders to high standards, expect their organizations not to uphold high standards.  Further, expect organizations that did not uphold high standards in one instance to fail to uphold them in other instances.  If we really want high quality accessible, reasonably priced health care, we need true health care reform that reduces concentration of power in large organizations, and makes health care organizations' leadership accountable, ethical, and transparent. That will not be easy.

Forest Pharmaceuticals Pleads Guilty to Obstruction of Justice, No Individual Pays Any Penalty

The parade of legal settlements marches on.  The latest story is about Forest Laboratories and its marketing of Celexa (citalopram ) and Levothyroid (l-thyroxin).  Here is the most complete version, courtesy of Natasha Singer reporting for the New York Times. First, the lead sentence:

A unit of Forest Laboratories, the maker of the antidepressant Celexa, agreed on Wednesday to pay more than $313 million to settle criminal and civil complaints, including a claim that it had illegally promoted the drug for use in children.

Here are the charges:

Among the criminal charges was one that the subsidiary, Forest Pharmaceuticals, marketed Celexa, which was approved only for adult depression, to treat children and adolescents. The government also claimed that, in conjunction with the company’s off-label promotion, Forest publicized the positive results of a study on Celexa in adolescents while failing to tell doctors about a similar study that had negative results.

'Forest Pharmaceuticals deliberately chose to pursue corporate profits over its obligations to the F.D.A. and the American public,' Carmen Ortiz, the United States attorney for the District of Massachusetts, said in a statement Wednesday.

In addition, federal prosecutors accused Forest of paying doctors to induce them to prescribe Celexa and another antidepressant, Lexapro. The remuneration included 'cash payments disguised as grants or consulting fees, expensive meals and lavish entertainment, and other valuable goods and services,' the government said in its civil complaint.

Among the items that Forest sales representatives gave to doctors from 1998 to 2005, the complaint said, were tickets to St. Louis Cardinal games, which were to be 'leveraged and sold as a reward for prescriptions'; a $1,000 gift certificate to Alain Ducasse, a gourmet French restaurant, for a high-prescribing child psychiatrist; a deep-sea fishing trip off Cape Cod for a doctor and his three sons; $400 in Broadway theater tickets for a doctor and his wife; and Red Sox tickets worth $2,276 to be used for doctors in the Boston area.

So we not just off-label marketing, but suppression of clinical research (of course, a study whose results were not favorable to the product being marketed), and payments to doctors as an "inducement to prescribe."

But wait, there is more:

As part of the criminal settlement, Forest Pharmaceuticals, which is based in St. Louis, agreed to plead guilty to one felony count of obstructing justice, acknowledging that employees had lied to F.D.A. officials during a plant inspection in 2003.

The company also agreed to plead guilty to two misdemeanors, one of which covers the company’s misbranding of Celexa by marketing the antidepressant for use in children from 1998 to 2002.

The other misdemeanor covers the illegal distribution from 2001 to 2003 of an unapproved drug, Levothroid, to treat a thyroid hormone deficiency. Such thyroid pills, made by various drug makers, had been sold in the United States since the 1950s without F.D.A. approval. But in 2001, the agency told drug makers that they needed to reduce their distribution of such medications until the companies obtained agency approval to market the pills.

The criminal charges accused Forest of making a deliberate decision to continue distributing the drug in quantities exceeding the F.D.A.’s directive. After the agency sent a warning letter to Forest, the company directed employees to work until 1 a.m. to continue shipping as much Levothroid as possible, according to the criminal complaint.

So there was also obstruction of justice in the form of lying to the FDA, and selling drugs that the FDA had ordered not to be sold.

So what are the penalties?

The criminal settlement calls for the company to pay a $150 million fine and to forfeit an additional $14 million in assets. Forest will also pay more than $88 million to the federal government and more than $60 million to the states to resolve a civil complaint that its actions caused false claims to be submitted to federal health care programs. In addition, two whistle-blowers will split $14 million from the federal share of the settlement.

Forest has also entered into a five-year corporate integrity agreement, requiring an independent expert to review the company’s compliance with drug marketing regulations.

So here we go again. A large drug company was up to no good, suppressing research, paying doctors for their prescriptions, lying to the FDA, and disobeying its orders.

The penalty seemed large, over $300 million. However, Celexa was a big revenue generator at the time the events above occurred, topping $1 billion in revenue first in 2002 (per Forbes here). Furthermore, as noted by Ed Silverman on Pharmalot, it seems no individual will suffer any negative consequences for authorizing, directing, or implementing the conduct described above. Finally, as best I can tell, despite the fact that a Forest subsidiary will plead guilty to a felony, the company is not going to be barred from doing business with the government. 

So, despite pleading guilty to a felony and three misdemeanors, neither Forest as a company nor any individual working for the company will really suffer very much.  On the other hand, the leaders of Forest have been doing very well.  The company's CEO, Howard Solomon, was number 18 on Wall Street Journal list of the 25 highest paid CEOs over the last decade.  His total realized compensation was over $385 million over the last 10 years.  According to the company's 2010 proxy statement, his total compensation in 2009 was $8,267,236.  The four other highest paid executives made from just over $2.5 million to $5.3 million.

So here we go again.  Another large health care organization has been found to have done wrong, but the only penalty is a fine that whose impact will be diffused across the whole company, and ultimately be paid by its employees, its customers, including patients, and its stockholders.  Meanwhile, the people who authorized, directed, or implemented the wrong doing apparently will pay nothing and receive no negative incentives.  Furthermore, the top leaders of the company, whose huge compensation in the past was increased by the results of the wrong doing, will continue to prosper.

As we have said again and again,  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.

By the way, the current case offers an avenue for those who do not like what Forest did to ask those who are supposed to be ultimately responsible for its behavior how this was allowed to happen.  The board of directors of the company is supposed to be ultimately accountable for the company's actions.  As we have noted before, these directors are supposed to "demonstrate unyielding loyalty to the company's shareholders." [Per Monks RAG, Minow N. Corporate Governance, 3rd edition. Malden, MA: Blackwell Publishing, 2004. P.200.]

The current directors of Forest Laboratories, according to the company's 2010 proxy statement, include Dr Nesli Basgoz, "Associate Chief for Clinical Affairs, Division of Infectious Diseases, Massachusetts General Hospital (MGH)," and "Associate Professor of Medicine at Harvard Medical School."  Also, it includes Dr Lester B Salans, "Clinical Professor" at Mount Sinai Medical School, not to mention Dr Peter J Zimetbaum, "Director of Clinical Cardiology" at Beth Israel Deaconess Medical Center in Boston (BIDMC), and "Associate Professor of Medicine at Harvard Medical School."   Maybe some enterprising student journalist will get to ask the good doctors how they let things at Forest get so ethically out of hand.

"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.

Bring Back the DSI*? - the Avandia Case as Spy Novel

Starting in 2007, we posted quite a bit about the "Avandia case," which centered on whether Avandia (rosiglitazone, by GlaxoSmithKline), a glucose lowering drug for type 2 diabetes, presented excess cardiovascular risks, and how evidence about these risks was handled. 

Summary

The Nissen and Wolski meta-analysis [Nissen SE, Wolski K. Effects of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356, online here] was to be the first published article to combine data from all relevant clinical trials of rosiglitazone then available.  Although two major trials of Avandia had been published, its manufacturer, GlaxoSmithKline, had performed many other smaller trials of the drug which remained unpublished.  These results eventually appeared on a web-site run by GSK. However, this web-site was relatively obscure.  It had not been created voluntarily, but in response to a settlement of legal action that alleged GSK had suppressed clinical research about its antidepresant paroxetine (Paxil). (See Steinbrook R. Registration of clinical trials - voluntary of mandatory. N Engl J Med 2004; 351: 1820-1822, link here and our post here).

Nissen and Wolski found the site, compiled the results of trials on Avandia it contained, and combined their results with those of the few published trials in their meta-analysis. It is to the credit of Nissen and Wolski that they were able to figure out how to do this. It is not to the credit of GSK that they sat on the data from these trials, only put it on this web-site when compelled to do so, did not make any effort to publicize the web-site, and did not publish a meta-analysis done by company scientists that showed qualitatively similar results to that eventually done by Nissen and Wolski (see post here).
 
I originally thought the case raised 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?
 
But the immediate response to the Nissen and Wolski meta-analysis was a spin cycle that seemed to obfuscate these questions, and the answers to him (see posts here, here, here, and here)
 
A Reconsideration
 
In the last few weeks, several articles about Avandia have appeared in the media, and in medical journals, that reconsider the issues, and in particular, the "Avandia Spin Cycle."  First was a commentary in the European Heart Journal by Dr Steven E Nissen, the first author of the meta-analysis [Nissen SE. The rise and fall of rosiglitazone. Eur Heart J 2010: published online here.]  Dr Nissen provided a narrative history of the Avandia case from his viewpoint, and summarized it thus:

What were the key mistakes and lessons learned from the rosiglitazone affair?

1. The FDA rushed to approve rosiglitazone because of hepatotoxicity concerns about troglitazone, resulting in failure to consider the ‘signals’ suggesting cardiovascular toxicity.
2. An early critic of rosiglitazone was intimidated by company representatives and effectively silenced, a process antithetical to the principals of open scientific discourse.
3. Although early warnings were issued for the risk of heart failure, these warnings went largely unheeded in the face of aggressive marketing and promotion suggesting cardiovascular benefits.
4. No well-designed cardiovascular outcome trials were ever conducted for rosiglitazone, despite evidence suggesting increased cardiovascular risks. The only cardiovascular outcome trial was an open label study driven by a soft endpoint (hospitalization) with low adherence to randomized medications, seriously underpowered, and not completed until 10 years following launch.
5. Although both the FDA and the company were aware of evidence of an increased risk of adverse cardiovascular outcomes, certainly by 2005, neither warned physicians nor the public.
6. When a meta-analysis of rosiglitazone was eventually submitted for publication, the company subverted the editorial review process by stealing a copy of the manuscript and used this advance knowledge inappropriately to unblind an ongoing randomized trial.
7. Approval of diabetes drugs based exclusively upon their glycaemic effects has been short-sighted and scientifically unwise. Drugs that lower blood sugar may have other adverse effects that overcome any inherent benefits.
8. The failure of  50 other PPARs, many for adverse cardiovascular effects, went largely unreported because of negative publication bias. Such knowledge might have warned the medical community about the potential risk of these agents.

Meanwhile, the New York Times published conclusions of some internal US Food and Drug Administration (FDA) reports, and of an investigation by the US Senate Finance Committee. FDA safety officials suggested that Avandia should be taken off the market. Some key points from the Senate investigation were:

The bipartisan multiyear Senate investigation — whose results are expected to be released publicly on Monday but which were also obtained by The Times — sharply criticizes GlaxoSmithKline, saying it failed to warn patients years earlier that Avandia was potentially deadly.

'Instead, G.S.K. executives attempted to intimidate independent physicians, focused on strategies to minimize or misrepresent findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that a competing drug might reduce cardiovascular risk,' ....

In combination, the Nissen commentary, and the Senate report nicely summarized what I called the "Avandia spin cycle" above.  It appears that research was suppressed, marketing was deceptive, and critics and whistleblowers were intimidated. 

Finally, Dr Harlan Krumholz published a commentary about the thiazolidinedione drugs (a group that includes rosiglirazone) in Circulation Cardiovascular Quality and Outcomes [Krumholz HM. A perspective on the American Heart Association Presidential Commission Advisory on thiazolidenedione drugs. Circ Cardiovasc Qual Outcomes 2010; 3 available online, link here], and an op-ed in Forbes. The latter sums it all up nicely:

I want to believe in America's pharmaceutical companies. I want to believe that people in these companies believe that the best strategy for success is to do what is best for patients. I want to believe that they are interested in scientific truth and eager to know of any safety issues and ready to share that information with the public.

This week I was disappointed again.

Over the years GlaxoSmithKline ( GSK - news - people ) has repeatedly reassured the public about the safety of its blockbuster diabetes drug Avandia. But this weekend the Senate Finance Committee released a report revealing that inside the company Glaxo's own experts and advisors were raising concerns about whether the drug could cause heart problems all along.

The report, based on more than 250,000 internal documents, provides a rare and unsettling glimpse into the decision by company executives to deflect safety issues--even as their own experts agreed with conclusions of outside researchers who were warning the public about possible harms.

The documents reveal that company researchers were deeply concerned about the cardiovascular safety of the drug as far back as 2003. The pages of the Senate report read like a spy novel: Glaxo receiving confidential documents leaked by a sympathetic academic who consulted for the company; the company embarking on a campaign to intimidate critics who warned about potential safety issues with the drug; and executives pulling strings to release data early from a scientific study that was supposedly controlled by an 'independent' committee of researchers.

So,

The story here is less about the drug--the Senate report breaks no new ground about Avandia's safety issues (even among experts there remains some controversy)--and more about the ethical behavior of a company. What is clear: Glaxo failed to disclose its own concerns even as it sought to discredit outside researchers who were raising questions about the drug.


This type of behavior is eroding the public trust in the pharmaceutical industry.

Policy Implications

Finally, Dr Krumholz concludes with some solutions with which I heartily agree:

The fix is simple: Once a drug is approved, all data relevant to drug safety should be placed in the public domain and independent investigators across the country should be able to use it. There should be big financial penalties for withholding relevant information. Drug studies sponsored by industry must be truly independent--outside of company control. Companies should give outside investigators independence over every aspect of the study. There are too many examples of companies wresting control of clinical studies from their consultant investigators for reasons that seem more related to product promotion than clinical science.

And on all sides there should be a commitment to protect against the intimidation of academics who are willing to raise questions about the safety and effectiveness of company products. The free flow of information about the effects of drugs and medical devices will best serve the public's interest.

Here in the US, the debate over health care reform has reached a new phase. Today the President is hosting an attempt to get bipartisan discussion of reform going again. Now that there is a new opportunity for discussion, I submit that would be health care reformers ought to think about the underlying causes of our continuing problems with rising costs, declining access, stagnant quality, and demoralized health care professionals.

One set of causes that is rarely discussed has to do with the distortion of clinical research by commercial research sponsors with vested interests in the results turning out in favor of their products, and the further distortion of clinical discourse and decision making by the deceptive marketing practices of these same organizations. If we started introducing steps like those suggested by Dr Krumholz into health care reform, maybe we really could decrease costs, increase access, improve quality, and renew professionalism.

*Bring Back the DSI?
To lighten things up a bit, and to explain the title...

When I was in school in the 1960s, I first became a fan of the Hardy Boys mysteries, then the slightly more mature Tod Moran series.  While on the Neiuw Amsterdam (the 1938 version) one day out of Kingston, Jamaica, I viewed Dr No, the first James Bond movie, a sophisticated spy thriller, not a spoof like some later entries in the series.  I later read all the classics, like those by Agatha Christie, Earl Stanely Gardner, Rex Stout, Ellery Queen, etc.  So it should be no surprise that I, like many other schoolboys and girls, collaborated to form an amateur detective and intelligence agency.  But this was the sophisticated 1960s, so we called it the Department of Scientific Investigation (DSI).  We skulked around New York City and its suburbs looking for spies, saboteurs, and common criminals.  Luckily, we never really found any.  As more realities intruded, I gave up any ideas about becoming an investigator or intelligence agent (although I still read mysteries, spy novels, and thrillers to this day, but mainly on airplanes.)  Once I became a physicians, those days in the DSI seemed very remote (although the title does now seem like it ought to be part of the NIH ;-) ).

However, after reading Dr Krumholz's article above, maybe we need to resurrect the DSI.  At least, maybe we health professionals ought to consider how we can become better and more organized watchdogs for the kind of problems revealed in the Avandia case, and in many other cases discussed on Health Care Renewal.

But if any of my old DSI colleagues want to set up a reunion, it would be fine with me. 

ADDENDUM (25 February, 2010) - see also comments by Dr Howard Brody on the Hooked: Ethics, Medicine and Pharma blog.

Deja Vu All Over Again - Sheffield Researcher Under Threat for Trying to Present Data that Offends Research Sponsor

It's deja vu all over again.  A case reported (so far only) in the UK Times Higher Education Supplement of a biomedical researcher apparently threatened because she tried to present data that did favor a particular commercial health care product. Here is the summary:

An academic has risked the wrath of her university by submitting results to a forthcoming conference without permission.

The University of Sheffield has claimed that the submission has been made in breach of a contract it has with a pharmaceutical company, which funds work in the scholar's field.

Guirong Jiang, a research radiologist who has worked at Sheffield for 13 years, is due to face a disciplinary hearing over her actions this week.

Her findings - submitted to a symposium of the European Calcified Tissue Society (ECTS), to be held in Glasgow in June - add to the debate over what some have claimed is a distortion in the field of osteoporosis caused by the over-diagnosis of vertebral fractures.

Here are more particulars:

Sheffield has censured her for making the submission without the consent of her supervisor, Richard Eastell, head of Sheffield's Academic Unit of Bone Metabolism.

It said her actions breached the terms of a 2007 contract the unit has with pharmaceutical manufacturer Sanofi-Aventis to conduct studies relating to the osteoporosis treatment risedronate, which is sold as the drug Actonel.

It also said Dr Jiang failed to follow 'reasonable requests' to withdraw the submission.

Dr Jiang said she believed her results should be published as they had not been reflected in the unit's previous output.

She added that last December she was informed that her contract would not be renewed when it came to an end this March, which she said had prompted her to throw caution to the wind and publish without permission.

She has queried whether her work is bound by Sheffield's Sanofi-Aventis contract, which stipulates that the company must be allowed to review manuscripts and abstracts prior to publication.

She pointed out that the work was carried out in 2002 when the unit's risedronate work was funded by Procter & Gamble in partnership with Aventis. Dr Jiang added that she had not seen or signed the full Sanofi-Aventis contract.

Dr Jiang is still under threat:

The disciplinary hearing, scheduled to take place on 18 February, will consider the allegation that Dr Jiang 'acted inappropriately in making a direct submission of an abstract to a journal outside unit protocol and in contravention of the terms of the research contract'.

It will also consider the charge that she 'failed to follow a request by her head of unit and head of department to rectify her actions', which 'aggravated a situation which otherwise could have been quickly resolved'.

A long time ago, in a galaxy far, far away, academics had the expectation that they could publish or present their research without first acquiring the express approval of their academic superiors (at least as long as their work was original, the research project was under their control, and that they had properly protected the rights of any human subjects). Furthermore, in at least the US, academics are citizens who expect to have free speech.

But as academic institutions became more enamored of and dependent on "external funding," faculty were increasingly pressured to do only sponsored research. The growing dependence on sponsored research allowed the sponsors to try to get more control over how research was done.

In the 1990s, there were several important cases in North America in which academic researchers tried to present or publish results that clashed with their research sponsors' vested interests. Doing so resulted in lesser or greater threats to the faculty. Two of the classic cases of research suppression in the 1990's demonstrated this issue.


* In the "David Kern case," a textile manufacturer, Microfibres Inc., tried to prevent Dr. David Kern, a general internist and occupational medicine physicians at Memorial Hospital of Rhode Island and faculty member at Brown University, from presenting an abstract that described a case-series of a new pulmonary disease, flock-workers lung, that affected workers at Microfibres Inc. factories. Kern did present the abstract, but under a threat, never carried out, of law-suit, Memorial Hospital of Rhode Island removed Kern as head of the Occupational Medicine program, and refused to renew his contract, even though he was an Associate Professor. Brown University was unable to reverse these moves by the hospital, and Brown officials blamed Kern for signing an agreement to protect trade secrets, even though the agreement was unrelated to the research Kern did on the disease, and his research did not obviously reveal any trade secrets. [1-4]

* In the "Nancy Olivieri case," Apotex, a pharmaceutical company, acted against Dr. Nancy Olivieri for revealing preliminary data from a trial of deferiprone, a chelating agent for the treatment of iron overload in thalassemia, suggesting that the drug was often ineffective in treating iron overload, and appeared to be associated with hepatic fibrosis. Ultimately, a report by the Canadian Association of University Teachers also held that her academic freedom was abridged, in the context of a negotiation between the University of Toronto and Apotex over a large donation, and that the hospital harassed Dr. Olivieri during her dispute with Apotex (link here for report)
 
In the early 21st century, there was a case in the UK with spooky similarites to the present case: at the same university involved in the present case, and with at least one participant in common with that case.  About a year after we started Health Care Renewal, in late 2005, we wrote multiple posts about the complex and unfortunate case of Dr Aubrey Blumsohn's attempts to keep a research project honest. Our most recent summary of the case was here. Dr Blumsohn was also doing clinical research on the drug Actonel, again at the University of Sheffield.  He was denied access to the very data he had collected, and to analyses of the data by Procter and Gamble, the then manufacturer of the drug and sponsor of the research.  Dr Blumsohn found that Procter and Gamble seemed to be arranging for ghost-writers to author abstracts about the research based on these hidden analyses.  After he complained to numerous officials at Sheffield, including Dr Richard Eastell, to no avail, he spoke to the press, and thereafter lost his academic position.  The case was just recapped in an interview of Dr Blumsohn published in the British Medical Journal(5).
 
So we seem to have made little progress.  Most clinical research at academic medical institutions is sponsored by firms that make drugs and devices.  The firms try to secure contracts that give them control over most aspects of the research.  Thus, they can determine how the research is designed, implemented, ana analyzed.  If the resulting manipulation still does not yield results that make the firms' products look good, the sponsors can then just suppress them.  Academics who naively think it is their duty to find and disseminate the truth are in jeopardy when they attempt to present or publish results that challenge their research sponsors' vested interests.
 
Suppression of clinical research, however, is bad for patients and honest health care professionals, since it misleads about the benefits and harms of tests and treatments.  Suppression of clinical research dishonors research subjects who volunteer for studies, often at risk to themselves, thinking they may help to advance science and clinical care.  Suppression of clinical research undermines the fundamental mission of academia: to seek out and disseminate the truth.
 
Those who truly want better health care, here in the US and globally, should advocate for clinical research done without the influence of those with vested interests in how the research comes out. 
 
Thanks to an anonymous Health Care Renewal scout who located the Times article. 
 
References


1. DG Kern, RS Crausman, TH Durand et al. Flock worker's lung: chronic interstitial lung disease in the nylon flocking industry. Ann Intern Med 1998; 129: 261-272. (link here)
2. Shuchman M. Secrecy in science: the flock worker's lung investigation. Ann Intern Med 1998; 129: 341-344. (link here)
3. Marsh DJ. Intimidation of researchers by special interest groups. N Engl J Med 1997; 337: 1317-1318. (link here)
4. Shuchman M. Consequences of blowing the whistle in medical research. Ann Intern Med 2000; 132: 1013-1015. (link here)
5.  Cyer C. Aubrey Blumsohn: academic who took on industry. Brit Med J 2009; 339:b5293. (link here)