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)

Pfizer CEO Now Acknowledges "We Need to be Straight with People"

Even the CEO of the world's largest pharmaceutical company is now conceding that unethical behavior by large health care corporations has lead to trouble.  As reported by The Day (New London, CT, US): 

Three months after his company paid the largest criminal fine in U.S. history, Pfizer Inc. chief executive Jeffrey B. Kindler called on government and business leaders Tuesday to face up to the 'real and legitimate anger' of citizens fed up with ethics breaches.

'If we fail to change, the future will not be pretty - for business or for society as a whole,' Kindler said in a keynote address to the Boston College Chief Executives' Club at the Boston Harbor Hotel. 'People have had enough, and the backlash is real.'

Kindler told the luncheon meeting of about 250 chief executives in the Boston area that a recent survey found two-thirds of the American people now have less trust in corporations than they did a year ago - and the decline in their faith in government and public officials has been even more drastic.

'When the majority don't trust you, they will find a way to force you to change,' he said. These changes, he added, could include limits on businesses' licenses to operate and might affect private-sector innovation.

Pfizer, he acknowledged, has had ethical lapses as well, capped by the $2.3 billion in fines imposed in September for the company's illegal marketing of various drugs. The company's $1.2 billion criminal fine was the largest corporate penalty in U.S. history.
'It was a real blow to our employees,' Kindler said. 'It did not reflect the company we all knew.'

The government of Switzerland also fined Pfizer and two other firms a total of $5.7 million Tuesday for alleged price-fixing of erectile dysfunction drugs.

Mr Kindler also pledged there would be some changes:

Kindler said he understood those in the audience who might wonder, in the wake of Pfizer's own ethical problems, 'Who are you to talk about trust?'

But he said Pfizer has changed. Golf trips, fancy dinners and tchotchkes left for doctors are now out, and there are fewer company sales representatives in the waiting rooms. Results of clinical trials are now posted for all to see.

Also, according to a Boston Herald article:

'We need to be straight with people,' said Kindler at a Boston College Chief Executives’ Club lunch.

'It’s up to us to earn back the trust we’ve lost,' Kindler said.

Already, the company is much more transparent with its operations, he said. It has begun disclosing a number of its business relationships on its Web site and has ceased the high-priced wooing of the doctors who might prescribe its products.

Let me applaud Mr Kindler's declaration that we "need to be straight with people," and in the spirit of constructive criticism, give him some unsolicited advice about ways the company could be more "straight."

First, he might start by admitting the scope of past problems.  As we posted previously,  the $2.3 billion settlement alluded to above was  the company's fourth major settlement of charges of unethical marketing behavior since 2002, and also as alluded to above, it is not the company's most recent ethical problem.  For a catalog of Pfizer's ethical pfailures, see this link. 

Second, he might acknowledge some responsibility for past problems, or indicate that someone will be held accountable for them.  Note that according to the biographical statement in the 2009 Pfizer proxy, Mr Kindler has held leadership positions at the company since 2002. 

Third, he might consider a more vigorous transparency effort, starting with the company's relationships with physicians, and other health care professionals and academics.  The company has pledged to put some sort of information about payments to such people online, but not until 2010.  Maybe that schedule could be sped up.  Furthermore, it is not clear how much information will be disclosed, but the company ought to consider making it clear what payments are for, what division of the company (e.g., research and development, or marketing or public relations) made the payments, and how the payments were linked to particular Pfizer products.

Fourth, he might make a more vigorous effort to disclose the results of all clinical research sponsored by Pfizer.  In the past, Pfizer has allegedly been a party to suppression of results of clinical research that turned out not to favor its products (e.g., see this post).  It is true that Pfizer pledged to post the results of at least some unpublished studies on ClinicalStudyResults.org, but the completeness of its reporting is questionable.  But a report by the German Institute for Quality and Efficiency in Health Care suggested that through this year Pfizer has been dragging its feet about disclosing results that may not make its products look good.  Consequently, the Institute is now calling for compulsory disclosure of the results of all clinical trials. 

I do hope that Mr Kindler and Pfizer management are serious about their commitment to "earn back the trust we've lost."  If so, more power to them.

How Industry Views the Research It Sponsors

We have posted frequently about threats to the integrity of the clinical evidence-based, and to the practice of evidence-based medicine.  In particular, we have discussed how research may be manipulated in favor of vested interests, or suppressed when the results do not favor such interests.

Last week, the British Medical Journal electronically published a set of guidelines for how industry sponsored clinical research ought to be published, sponsored by the International Society for Medical Publication Professionals.  The authors came from pharmaceutical companies (Johnson & Johnson, AstraZeneca, Pfizer and Cephalon), medical device companies (LifeScan), and medical publishing and medical education and communication companies (John Wiley & Sons, Excerpta Medica, Field Advantage Medical Communications, PharmaWrite, and Knowledgepoint 360 Group).  [Graf C, Battisti WP, Bruce-Winkler V et al. Good publication practice for communicating company sponsored medical research: the GPP2 guidelines.  Brit Med J 2009; 339:b4430.  Link here.]

These guidelines are remarkable for the questions they raise about how people from industry view clinical research and how it should be reported in medical journals. 

Who's in Charge?

Nowhere does the article acknowledge that any one person has overall responsibility for a research project.  Clinical research projects funded by the US National Institutes of Health, Agency for Healthcare Quality and Research, and other federal agencies must have "principal investigators," who are the people who take overall scientific responsibility for the project.  The Graf et al article does not use this or an equivalent term.   There is no sense that they expect anyone to be in completely in charge of industry sponsored research. 

Particularly confusing is the following passage:

Before writing begins one author (a lead author, who may also be guarantor) should take the lead for writing and managing each publication or presentation. One author (identified as guarantor) should take overall responsibility for the integrity of a study and its report.

Here are some questions it raises.  If the guarantor could be chosen only when writing a paper is contemplated, which presumably could be years after the study that the paper would report was designed and implemented, who then would have been responsible for study "integrity" before the guarantor was chosen? Who would chose the guarantor for a particular paper? If a study generates more than one paper, could they each have a guarantor, and then how could they share responsibility for study "integrity?"  If the guarantor and lead author of a paper are different people, how would they share responsibilities, what would happen if they were not to agree, and who would be finally accountable?

So the guidelines seem to completely diffuse accountability for research projects, and the reports written about them.

Who is an Author?

In my experience with US federally and foundation funded research, research papers are written by the investigators, the people who actually did the research project.  However, in the guidelines by Graf et al, the concept of authorship is also ambiguous.  They suggest that "recognised criteria should be used to determine which of the contributors to an article should be identified as authors."  This is already confusing, since how could one be a "contributor" to an article without authoring it?  A later discussion of "contributors" as "investigators, sponsor employees, and individuals contracted by the sponsor" was not very helpful.  Why should a "sponsor employee" who was not an "investigator" be a "contributor" or an "author," whatever the distinction is between them? 

So the guidelines blur distinctions among people who do research, and people employed by companies that may have vested interests in the research favoring their products or services.

What do Professional Medical Writers Do?

There has been considerable recent controversy, not directly acknowledged by Graf et al, about the role of professional medical writers in the reporting of research and the writing of ostensibly scholarly medical publications, particularly in cases where the writers were paid by and reported to corporate sponsors, but were not recognized as such in the publications they wrote (a type of ghost-writing).  The guidelines by Graf et al do not clearly explain what the roles of professional medical writers ought to be:

Professional medical writers must be directed by the lead author from the earliest possible stage (for example, when the outline is written), and all authors must be aware of the medical writer’s involvement. The medical writer should remain in frequent contact with the authors throughout development of the article or presentation. The authors must critically review and comment on the outline and drafts, approve the final version of the article or presentation before it is submitted to the journal or congress, approve changes made during the peer review process, and approve the final version before it is published or accepted for presentation.

Note that this would not prevent a professional medical writer from writing an initial outline, the first draft, and all subsequent drafts. including the final draft of a paper. (The role of an "author" above might be restricted to simply commenting on and accepting the outline and all drafts.) Thus, the "authors" could function as distant editors, and the professional writer would assume authorship, as most people would define it. (Merriam-Webster: "1. one that originates or creates 2. the writer of a literary work.")

Furthermore, while the professional writer could take one the role of authorship, the guidelines do not require him or her to publicly acknowledge this role:

Professional medical writers, depending on the contributions they make, may qualify for authorship. For example, if a medical writer contributed extensive literature searches and summarised the literature discovered, and by doing so helped define the scope of a review article, and if he or she is willing to 'take public responsibility for relevant portions of the content' then he or she may be in a position to meet the remaining ICMJE criteria for authorship.

Presumably, a professional writer could dodge authorship by simply being "unwilling" to take such public responsibility.

So the guidelines apparently condone nearly all functions commonly assumed to be those of an author to be performed by a professional writer paid directly by the sponsor, without the writer being listed as an author.  The guidelines thus appear to condone ghost-writing in its most pernicious form.

Who Owns and Analyzes the Data?

Cases in which various the implementation and analysis of clinical research seems to have been manipulated to favor vested interests have raised concerns about the integrity of the data collected in the course of a research project, and how it is analyzed.  This is what Graf et al say about the ownership and use of the data:

Sponsors have a responsibility to share the data and the analyses with the investigators who participated in the study. Sponsors must provide authors and other contributors (for example, members of a publication steering committee or professional medical writers) with full access to study data and should do so before the manuscript writing process begins or before the first external presentation of the data. Information provided to the authors should include study protocols, statistical analysis plans, statistical reports, data tables, clinical study reports, and results intended for posting on clinical trial results websites. Sufficient time should be allowed for authors and contributors to review and interpret the data provided and to seek further information if they wish (for example, access to raw data tables or the study database).

The guidelines by Graf et al suggest that the company that sponsors the research should own the data. The investigators who collected the data and implemented the research project should not. At best, the company should "share" summaries, analyses, or pieces of the data, but at best investigators could have only "sufficient time" to "seek ... access to raw data tables or the study database."

So the guidelines would allow corporate research sponsors to analyze the data from studies evaluating their own products and services as they see fit, and the scientists who implemented the study and collected the data could only ask for access to it. 

Summary

The guidelines by Graf et al seem based on a very strange conceptualization of clinical research. In their view, no individual may be responsible for a clinical research project. Research data is controlled by the company that paid for the project, not scientists who implemented the research and collected the data. Research papers may be written by anonymous professional writers while the scientists who did the research only need to review and approve what they have written.

So why should anyone give credence to industry sponsored research?

We have discussed numerous instances in which clinical research was manipulated in favor of vested interests, and when clinical research whose results did not favor vested interests was suppressed. In most cases, the vested interests were held by for-profit pharmaceutical, biotechnology or device anufacturers acting as research sponsors. The guidelines by Graf et al seem to have been cleverly written to to employ comforting platitudes while licensing manipulation and suppression.  They should inspire no confidence in the integrity of industry sponsored research.

More Evidence for Suppression of Research: the Case of Lamictal for Depression

We recently discussed the severe challenges to evidence-based medicine presented by manipulation and suppression of clinical research to serve vested interests.  I recently (and unfortunately belatedly) came upon yet another example of suppression of research that was unfavorable to a research sponsor's vested interests, suggesting that such suppression may be more prevalent than heretofore believed. 

This example appeared in the journal Evidence-Based Mental Health [Gahemi SN. The failure to know what isn't known: negative publication bias with lamotrigine and a glimpse inside peer review.  Evidence Based Mental Health 2009; 12: 65-68.  Link here.]

The author was able to use the database of clinical trials provided by GlaxoSmithKline as part of a settlement of a suit by former New York state Attorney General Elliot Spitzer that charged that the company had suppressed information about the selective serotonin reuptake inhibitor paroxetine (Paxil).  His interest was the use of lamotrigine (Lamictal) in depression.  His main findings were:

Of the nine lamotrigine related bipolar disorder studies posted on the website (see table 1), two were positive and published supporting the FDA approved indication for delay of relapse in the long term treatment for bipolar disorder patients. A negative study in rapid cycling bipolar disorder and another in acute bipolar depression were published but both emphasised positive secondary outcomes as opposed to the negative primary outcomes. Five other negative studies involving rapid cycling bipolar disorder, acute bipolar depression and acute mania have not been published and are only available on the GSK website.

Failure to adequately publish these negative studies led to the creation of a clinical impression that lamotrigine is an 'antidepressant,' a view innocently expressed to me as recently as last week by an academic colleague. This mistaken impression occurred partly because the prophylactic benefits of lamotrigine for depressive episodes were confused with a presumed acute benefit. Partly it was due to the publication of one apparently positive study, and the non-publication of several negative studies.

The clinical relevance of the lamotrigine studies is notable: taking the negative outcomes into account, as of now, one might say that this agent is reasonably effective in maintenance treatment of bipolar disorder, particularly in prevention of depression. It is proven ineffective in acute mania, rapid cycling disorder and acute bipolar depression.

Note that Dr Ghaemi and colleagues had published a summary of the suppressed negative articles in Medscape Journal of Medicine in late 2008.  [Ghaemi SN, Shirzadi AA, Filkowski M. Publication bias and the pharmaceutical industry: the case of lamotrigine in bipolar disorder. Medscape J Med 2008; 10(9):211.  Link here.]  That earlier article also documented the group's failed attempts to discover whether negative trials of other drugs for depression had been suppressed.

Dr Ghaemi's newer made some additional important points about suppression of clinical research.  The first is that it is occurring with the acquiescence of government regulators. In particular,

It is worth mentioning that the [US] FDA [Food and Drug Administration] has encouraged this state of affairs, by viewing negative studies as uninformative, due to the possibility of being 'failed' rather than truly negative (ie, the sample may have simply been unresponsive, or dosing might have been too low and so on). Thus drugs could have two positive studies, and 10 or so negative ones (as did a number of selective serotonin reuptake inhibitors),8 and the FDA not only allowed approval but it did not require that the pharmaceutical industry publish its negative results. The pharmaceutical industry did the minimum necessary; the FDA set the minimum far below what should have been the acceptable scientific standard.

Furthermore, even though the FDA is supposed to allow access to information about all studies for drugs for which it provides an indication, in fact it still does not allow access to raw data from industry sponsored studies, which are viewed as confidential and proprietary. Rather, in my experience and those of colleagues who have attempted to access such studies, Freedom of Information Act requests are met with abstracted summary results. While summary results are better than no results, full access to scientific data should be the standard at the FDA.

The second is that medical journal reviewers and editors do not seem enthused about publishing articles about how research has been suppressed (an apparent example of the anechoic effect, or perhaps the anechoic effect squared, i.e., discussion of our failure to discuss research studies whose results did not please their sponsors is simply not done.)

In the course of trying to investigate and publicise these negative findings, we ran into numerous roadblocks, as I discussed in an interview for the Carlat Report last year

Instead of repeating what I have said before about the evils of suppressing clinical research, I will offer some concluding quotes from Dr Ghaemi.

Evidence based medicine—or, more simply put, the science of medicine—cannot be taken seriously, and is certainly not valid, if the evidence base is only partial. The scientific literature currently is like an under cooked meal which we think is ready to eat. We never know whether what we see in the evidence is correct or biased in one direction or the other. Meta-analyses of large published datasets are not as meaningful as they seem when unpublished data languish elsewhere.

Manipulation and suppression of clinical research has likely misled doctors and patients into using and paying too much for minimally effective, ineffective, or even harmful drugs and devices.  Manipulation and suppression of research is thus probably a major reason that health care costs much more than its value and accessibility warrants.  To truly reform health care, we should not let those with vested interests in selling health care products or services control the clinical research that purports to evaluate what they are selling.

Suppression of Clinical Trials of Sumatriptan

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

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

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

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

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

Tfelt-Hansen concluded:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Who Should Sponsor Comparative Effectiveness Research?

We have tried to argue why comparative effectiveness research is a good idea. To cut and paste what I wrote in a previous post,

Physicians spend a lot of time trying to figure out the best treatments for particular patients' problems. Doing so is often hard. In many situations, there are many plausible treatments, but the trick is picking the one most likely to do the most good and least harm for a particular patient. Ideally, this is where evidence based medicine comes in. But the biggest problem with using the EBM approach is that often the best available evidence does not help much. In particular, for many clinical problems, and for many sorts of patients, no one has ever done a good quality study that compares the plausible treatments for those problems and those patients. When the only studies done compared individual treatments to placebos, and when even those were restricted to narrow patient populations unlike those patient usually seen in daily practice, physicians are left juggling oranges, tomatoes, and carburetors.
Comparative effectiveness studies are simply studies that compare plausible treatments that could be used for patients with particular problems, and which are designed to be generalizable to the sorts of patients usually seen in practice. As a physician, I welcome such studies, because they may provide very useful information that could help me select the optimal treatments for individual patients.

Because I believe that comparative effectiveness studies could be very useful to improve patient care, it upsets me to see this particular kind of clinical study get caught in political, ideological, and economic battles.

In particular, we have discussed a number of high profile attacks on comparative effectiveness research, which often have featured arguments based on logical fallacies. While some of the people making the attacks have assumed a conservative or libertarian ideological mantle, one wonders whether the attacks were more driven by personal financial interests. For example, see our blog posts here, here, here, and here. On the other hand, we discussed a clear-headed defense of comparative effectiveness research by a well-known economist most would regard as libertarian here.

Comparative effectiveness research has been discussed as an element of health care reform in the US. It turns out that the current version of the health care reform bill in the US Senate has a provision to create a Patient Centered Outcome Research Institute, which presumably would become the major organization which could sponsor comparative effectiveness research.

This institute, however, would not be a government agency (despite the name that makes it sound like it would be part of the National Institutes of Health). Moreover, here is a description of the Board of Governors who would run the institute from the current version of the bill :

BOARD OF GOVERNORS.—
(1) IN GENERAL.—The Institute shall have a Board of Governors, which shall consist of 15 members appointed by the Comptroller General of the United States not later than 6 months after the date of enactment of this section, as follows:
(A) 3 members representing patients and health care consumers.
(B) 3 members representing practicing physicians, including surgeons.
(C) 3 members representing private payers, of whom at least 1 member shall represent health insurance issuers and at least 1 member shall represent employers who self-insure employee benefits.
(D) 3 members representing pharmaceutical, device, and diagnostic manufacturers or developers.
(E) 1 member representing nonprofit organizations involved in health services research.
(F) 1 member representing organizations that focus on quality measurement and improvement or decision support.
(G) 1 member representing independent health services researchers.

Thus, only 3/15 members of the governing board would represent the patients who ultimately reap the benefits or suffer the harms produced by medical diagnosis and treatment. Further, 6/15 members represent for-profit corporations which stand to make more or less money depending on how particular comparative effectiveness studies come out. Also, 3/15 members would be physicians, some of who may get paid more to deliver particular treatments (e.g., procedures) than others (e.g., providing advice about diet and exercise).

We often discuss how clinical research sponsored by organizations with vested interest in the research turning out to favor their products or services may be manipulated to favor these interests, and sometimes suppressed if it does not. In the US, there are few unconflicted sources of sparse funds to support comparative effectiveness research. (The most significant current source is the Agency for Healthcare Research and Quality, AHRQ. For full disclosure, I have been an ad hoc reviewer of grants for that agency.)

The current draft of legislation would create the largest potential sponsor for comparative effectiveness research, but would make that organization report to representatives of for-profit companies whose profits may be affected by the results of such research. In my humble opinion, this is not much of an advance. Comparative effectiveness research controlled by corporations that stand to profit or lose depending on its results will forever be suspect.

If the government is going to support comparative effectiveness research, it ought to make sure such research is not run by people with vested interests in the outcomes coming out a certain way. I may be biased myself, but why not let the research be sponsored by AHRQ, an agency with relevant experience and no axe to grind vis a vis any particular product or service?

The Reappearance of a Ghost of Seasons Past

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. The early posts were here, here, here, and here. In this post, we summarized the case thus:

• Dr Aubrey Blumsohn, a senior lecturer at Sheffield University, and Professor Richard Eastell performed a research project on the effects of the drug risedronate (Actonel, made by Procter & Gamble Pharmaceuticals [P&G]) under a contract between P&G and the University.
• Although the research contract designated Blumsohn and Eastell as "Investigators" under whose direction the project would be carried out, Blumsohn was not given access to the original data collected by the project.
• Despite numerous requests, (like this one), P&G refused access to this data repeatedly.
  Blumsohn was concerned that he and Eastell could be accused of scientific fraud if they continued to make presentations and write articles and abstracts without access to the data which they were supposedly writing about.
• Blumsohn became suspicious that some of the analyses done by P&G could be misleading, especially related to a graph shown to him that omitted 40% of patient data.
• Blumsohn objected to P&G arranging for papers and abstracts to be written by a professional writer, but with Blumsohn listed as first author. Blumsohn was concerned that such ghost-written documents were mainly meant to convey "key messages" in support of P&G's commercial interests.
• Eastell warned Blumsohn not to aggravate P&G, because the company was providing a grant to the University which "is a good source of income."
• After repeated failed attempt to get the data, Blumsohn complained to numerous officials at Sheffield University, including Eastell, medical school Dean Tony Weetman, University Vice-Chancellor Robert Boucher, and the Head of the University's Department of Human Resources, Ms R Valerio.
• Still unable to get the data, he spoke with news reporters about his case. At this point, Sheffield suspended him, but then offered him a severance agreement if he signed a contract binding him not to make any detrimental or derogatory statements about the University and its leaders.

So the case involved suppression and manipulation of research, ghost-writing, institutional conflicts of interest, and attempts to silence a whistle blower. It provides lessons about the downsides of letting commercial firms sponsor and hence control human research designed to evaluate the products or services they sell; and of academic medicine becoming dependent on research money from such firms for such research. Although Health Care Renewal, being US based, most often writes about such issues in the US, this case is a reminder that they are global. (Note that we posted more about this case in 2006, here, here and here, but since then it has not gotten much public attention.)

Last weekend the (UK) Guardian returned to it:

The Guardian has learned that one of Britain's leading bone specialists is facing disciplinary action over accusations that he was involved in 'ghost writing'.

The General Medical Council will call Professor Richard Eastell in front of a fitness to practice committee. Eastell, a bone expert at Sheffield University, has admitted he allowed his name to go forward as first author of a study on an osteoporosis drug even though he did not have access to all the data on which the study's conclusions were based. An employee of Proctor and Gamble, the US company making Actonel, was the only author who had all the figures.

Experts believe the practice is widespread in Britain.

In a letter published in the Journal of Bone and Mineral Research, which carried the original study, he stated: 'In the original paper one of the authors, a statistician working for P&G, Ian Barton, had full access to all the data.' The authors had full access to all the analyses of the data that they requested, he said – but those analyses were carried out by the company.

The letter, published in 2007, also acknowledged flaws in the study. A later independent analysis of the data 'identified some errors and poor practice', he wrote. The study was designed to show the strengths of Actonel which was in fierce competition with a rival bone-strengthening drug called Fosamax, made by Merck.

Eastell's paper concerned a study carried out on behalf of Proctor and Gamble, comparing the bone density of women prescribed Actonel with others who were not. Only the company knew which women were on the drug and which were taking something else.

Eastell's colleague, Dr Aubrey Blumsohn, wanted the codes which would say which of the patients who suffered fractures had been on the drug. The company refused. Blumsohn took his concerns to Eastell, but in a conversation which Blumsohn says he taped , Eastell said he was concerned that persistent requests might damage the relationship they had with the company. Eastell is said to have told him: 'The only thing that we have to watch all the time is our relationship with P&G. Because … we have the big Sheffield Centre Grant [from P&G] which is a good source of income, we have got to really watch it.' .

So, after four years, this case has generated an official hearing of sorts. The hearing is obviously late, and seemingly will only be devoted to only one aspect of this case (ghost writing). However, at least our friends in the UK are doing something. I cannot recall a single case that resulted in any serious consideration of imposing negative consequences on anyone who was accused of suppressing research, manipulating research, endorsing ghost-writing, or intimidating a whistle-blower. In fact, many of the more troubling cases have never resulted in any sort of public discussion either at the institutions at which they occurred, or at any organization with relevant regulatory, or even just moral authority. So the GMC hearing is at least a step forward. Two cheers for the British GMC, and none for US universities, academic medical centers, professional societies, and government regulators.

(If anyone can remind me of a case in which there was a public discussion at the relevant institution, or some public consideration of the case by a regulatory agency, professional society, or some group with moral authority, please remind me of it, and I would be happy to post about it.)