Richard Epstein, a professor at the New York University and University of Chicago law schools, just authored a report on the perils of conflict of interest rules. In his blog, "The Libertarian," he summarized his beliefs that strict conflict of interest (COI) rules and restrictions on pharmaceutical marketing "spell lower rates of innovation and slower dissemination of new products."
Prof Epstein is extremely prominent. The Manhattan Institute, of which he is a fellow, claimed, "Professor Epstein's influence is profound: he is one of the three most cited law professors in the United States and the most cited professor writing largely in private law." Thus, it is disturbing that it appears that his objections are based on a series of logical fallacies. (Note that we critiqued a defense of certain conflicts of interest he made in 2007 here on similar grounds.)
Ad Hominem: Enemies of Capitalism
Prof Epstein implied that the people who advocate strong conflict of interest rules are enemies of capitalism and free markets. For example, he wrote, "most of the modern critics of the drug and medical device industries start with the assumption that the profit-motive alone is sufficient to distort the behavior of all scientists and researchers." Later, "the people who line up most strongly against drug and device companies often treat the phrase 'market forces' as though it embodies the worst things in life." How he was able to read the minds of those who disagree with him is unclear. Attacking proponents of strict COI regulation as anti-capitalists (and by implication, socialists or communists) appears to be an ad hominem fallacy.
Burden of Proof: Ignoring Evidence of Harms of COI, Asserting Evidence of Benefits
Prof Epstein argued that COIs rarely if ever leads to bad effects: "the number of instances of serious abuses of power in the drug and device industry, like in medical research itself, is small, relative to the huge number of interactions that have taken place." Thus, he ignored evidence that commercially funded research may be biased in favor of the sponsors' products.(1-4) On the other hand, he implied that financial relationships among physicians and researchers and commercial firms that sell health care products and services are necessary for "rapid development and deployment of new pharmaceuticals and medical devices," and for "innovation" in the field, but provided no evidence for these points. Thus, while ignoring evidence of the possible harms of COIs, he failed to provide evidence for their benefits. By placing the burden of proof on those who disagree with him, while avoiding it himself, he invoked the burden of proof (or appeal to ignorance) fallacy.
Appeal to Common Practice: Scientists Wearing Multiple Hats
Prof Epstein asserted that strict COI rules would disturb what is now common practice. They would threaten how "the best research scientists in universities ... wear multiple hats. In addition to researching within the academy, they also offer consulting services to drug companies, or start businesses of their own." Academics may currently behave in this way, but that does not mean this behavior is optimal in any sense. Thus, Epstein employed the fallacy of the appeal to common practice.
Slippery Slope: Silencing Communication and Collaboration
Prof Epstein asserted that strict rules on COI would "prohibit the collaborative efforts that have long characterized standard practices [in research]." Specifically, he asserted the rules could stipulate that "no scientist who sits on any Food and Drug Administration (“FDA”) review committee, or any hospital conflict of interest committee, should be allowed to have connections with the pharmaceutical industry." Also, "collaborations between government and industry scientists on research projects of common interests should either be totally eliminated or heavily regulated." Finally, he asserted, "free interchange of information within and across firm boundaries is best calculated to allow the sharing and coordination of vital information," but "strong conflict of interest regulation poses real threats to these dynamic interactions."
Yet rules about conflicts of interest generally refer to those generated by financial relationships, most often payments by commercial firms to academics, researchers or physicians. Payments are not necessary for collaboration. Researchers can communicate, share information, even work together without one party paying the other. Warning of such dire consequences of regulations that have nothing directly to do with communication or collaboration amount to the slippery slope fallacy.
Appeal to Authority: the "Most Gifted Members of the Academy"
Prof Epstein noted above that it was the best researchers who consult for commercial firms or start their own firms. Later, he stated, "the ablest scientists often have the most extensive outside practices." In complaining about rules that limit the pay of faculty members for services on boards of directors of for-profit health care companies, he asked, "why crimp the behavior of the most gifted members of the academy who can also make major contributions to industry?" Thus he seemed to agree with the arguments made by representatives of pharmaceutical and device companies that the doctors who they pay to speak, consult, or do research are the best and the brightest. However, there is considerable evidence (e.g., see posts here and here), that such "key opinion leaders" or "thought leaders" are chosen because of their sympathy to the companies and their products, and their malleability. In addition, there is evidence that medical schools now put more emphasis on ability to attract external funding than any other faculty characteristic in decisions about payment, promotion, and retention (see post here). Prof Epstein's invocation of the need to honor the best and the brightest appears to be a variant on the appeal to authority fallacy.
Summary
So here we have another example, by " one of the nation's most prolific legal thinkers, (according to the Manhattan Institute) of a defense of the prevalent conflicts of interest that affect academic physicians and clinical researchers. Like many previous such defenses, it seemed to be mainly based on logical fallacies.
Also, like many previous such defenses, it was made by someone with a history of his own financial relationships with health care corporations. To his credit, Prof Epstein did disclose, "over the years, I have worked extensively with various groups in the pharmaceutical industry, but have done no such work in the past few years." On the other hand, he did not disclose his previous relationships with eSapience, a company which once claimed it "shapes the debate on issues that intersect law, economics, and policy." (See post here.)
The currently prevalent relationships with health care corporations among academic physicians, researchers, and other decision makers and influencers in health care have been lucrative for them. I have yet to see a coherent, logical argument that these relationships are good for patients, medical education, biomedical or clinical science, or public health made by anyone who does not have such relationships.
By the way, Prof Epstein also complained about overly rigorous regulation of pharmaceutical marketing in the same blog post, but since this really seems to be a distinct topic, I will not discuss his arguments here.
References
1. Bekelman JE et al. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA 2003; 289: 454-465. Link here.
2. Lexchin J et al. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. Brit Med J 2003; 326: 1167. Link here.
3. Jorgenson AW et al. Cochrane reviews compared with industry supported meta-analyses and other meta-analyses of the same drugs: systematic review. Brit Med J 2006; 333: 782. Link here.
4. McGauran N et al. Reporting bias in medical research - a narrative review. Trials 2010; 11: 37. Link here.
Showing posts with label pharmaceuticals. Show all posts
Showing posts with label pharmaceuticals. Show all posts
Thursday, November 4, 2010
Friday, October 8, 2010
Another Wheel Already Invented (in 1988) - the WHO Ethical Criteria for Medicinal Drug Promotion
At the 2010 Gezonde Scepsis (Healthy Skepticism) "Selling Sickness" conference, I was made aware of another wheel invented a long time ago, the 1988 WHO Ethical Criteria for Medicinal Drug Promotion, a document about which few now seem to be aware. Were this code to have been widely followed, it might have prevented some of the problems afflicting the pharmaceutical industry today.
Some relevant quotes follow:
Drug Promotion
Note that these provisions would seem to prohibit promotional efforts begun before a drug is legally approved (e.g., ghost-writing as in this case), the use of "key opinion leaders" without full disclosure of their role as marketers of drugs, suppression of clinical research sponsored by pharmaceutical companies whose results did not support these companies' marketing interests, e.g. studies which failed to show efficacy of their products, nearly all kinds of payments to physicians, and nearly all pharmaceutical sponsored continuing medical education.
Medical Representatives
Note that these provisions appear to prohibit the current cheer leader/ ex-athlete model of the drug representative, and to prohibit many of the current activities of such representative, including providing gifts, meals, travel to meetings, honoraria, etc (e.g., see posts here and here).
If only these standards had gotten some traction, think of the trouble that could have been averted. On the other hand, it is obvious that such traction would have threatened some peoples' lucrative incomes and power, who may have worked hard to make sure it did not happen.
Some relevant quotes follow:
Drug Promotion
6. In this context, 'promotion' refers to all informational and persuasive activities by manufacturers and distributors, the effect of which is to induce the prescription, supply, purchase and/or use of medicinal drugs.
7. Active promotion within a country should take place only with respect to drugs legally available in the country. Promotion should be in keeping with national health policies and in compliance with national regulations, as well as with voluntary standards where they exist. All promotion-making claims concerning medicinal drugs should be reliable, accurate, truthful, informative, balanced, up-to-date, capable of substantiation and in good taste. They should not contain misleading or unverifiable statements or omissions likely to induce medically unjustifiable drug use or to give rise to undue risks. The word 'safe' should only be used if properly qualified. Comparison of products should be factual, fair and capable of substantiation. Promotional material should not be designed so as to disguise its real nature.
8. Scientific data in the public domain should be made available to prescribers and any other person entitled to receive it, on request, as appropriate to their requirements. Promotion in the form of financial or material benefits should not be offered to or sought by health care practitioners to influence them in the prescription of drugs.
9. Scientific and educational activities should not be deliberately used for promotional purposes.
Note that these provisions would seem to prohibit promotional efforts begun before a drug is legally approved (e.g., ghost-writing as in this case), the use of "key opinion leaders" without full disclosure of their role as marketers of drugs, suppression of clinical research sponsored by pharmaceutical companies whose results did not support these companies' marketing interests, e.g. studies which failed to show efficacy of their products, nearly all kinds of payments to physicians, and nearly all pharmaceutical sponsored continuing medical education.
Medical Representatives
17. Medical representatives should have an appropriate educational background. They should be adequately trained. They should possess sufficient medical and technical knowledge and integrity to present information on products and carry out other promotional activities in an accurate and responsible manner. Employers are responsible for the basic and continuing training of their representatives. Such training should include instruction regarding appropriate ethical conduct taking into consideration the WHO criteria. In this context, exposure of medical representatives and trainees to feed-back from the medical and allied professions and from independent members of the public, particularly regarding risks, can be salutary.
18. Medical representatives should make available to prescribers and dispensers complete and unbiased information for each product discussed, such as an approved scientific data sheet or other source of information with similar content.
19. Employers should be responsible for the statements and activities of their medical representatives. Medical representatives should not offer inducements to prescribers and dispensers. Prescribers and dispensers should not solicit such inducements. In order to avoid over-promotion, the main part of the remuneration of medical representatives should not be directly related to the volume of sales they generate.
Note that these provisions appear to prohibit the current cheer leader/ ex-athlete model of the drug representative, and to prohibit many of the current activities of such representative, including providing gifts, meals, travel to meetings, honoraria, etc (e.g., see posts here and here).
If only these standards had gotten some traction, think of the trouble that could have been averted. On the other hand, it is obvious that such traction would have threatened some peoples' lucrative incomes and power, who may have worked hard to make sure it did not happen.
Wednesday, September 29, 2010
That Wheel Was Already Invented: the UN Special Rapporteur's Guidelines for Pharmaceutical Companies
For five years now, we have been writing about concentration and abuse of power in health care, and on specific tactics used predominantly by large health care organizations that threaten the values that physicians and other health care professionals once swore to uphold.
Pharmaceutical companies may not have been the worst offenders when it came to threatening these values, but they have not been laggards. Specific issues we have discussed included (in a peculiar order that I will explain in a minute): failure of the companies' boards of directors to be accountable for misbehavior by its management, sometimes associated with conflicts of interest affecting these board members (e.g., this recent case); outright crime and corruption (e.g., this case); use of key opinion leaders paid by the company to market products cloaked in the mantle of academia; payments made by the companies to patient advocacy groups (e.g., this one), medical societies, and academic institutions that induce institutional conflicts of interest, and enlist these well-reputed organizations as stealth marketers; ridiculously high prices charged for particular medicines, often to particularly vulnerable patients (e.g., this case); suppression and manipulation of clinical research evaluating the companies' products; and deceptive drug marketing practices.
Many other bloggers have written about these issues. Some of them have been widely taken up in the mainstream media. A few have even made it into the medical and health care literature.
But those of us who bring them up have been attacked as a tiny group of pharmascolds (e.g., here), who get in the way of the needed innovation and scientific advances that the pharmaceutical industry generously brings to the public. Despite such attacks, it may be that our concerns are somewhat more universal, although those with vested interests in maintaining the status quo might not want that publicized too much.
A new issue of PLoS Medicine included several articles on drug companies' responsibilities for human rights. One was by a former United Nations Special Rapporteur on the right to the highest attainable standard of health. I, and I suspect most of even our Health Care Renewal readers were not familiar with that office. I also confess to being unaware that he had published a report to the UN General Assembly entitled Human Rights Guidelines for Pharmaceutical Companies in Relation to Access to Medicines, which included 47 specific guidelines.
Amazingly enough, it turns out that some of these guidelines seemed to directly address the issues raised above, to wit:
Board of Directors' Accountability
Anti-Corruption
Disclosure of Financial Support
Drug Pricing
Suppression and Manipulation of Clinical Research
Deceptive Drug Marketing
Needless to say, I can see no evidence that any big pharmaceutical companies are trying to adhere to any of these guidelines. Somehow I suspect that those who are supporting the vested interests of big pharmaceutical corporations may not all have that much respect for the United Nations. However, I think that the Special Rapporteur's guidelines lend more credibility to the argument that we need better leadership of health care organizations, and specifically that such organizations should follow clear ethical precepts, and their leadership should be held accountable when they do not.
So the next time someone calls you a "pharmascold," you can say, "yeah, yeah, so is the UN Special Rapporteur."
Pharmaceutical companies may not have been the worst offenders when it came to threatening these values, but they have not been laggards. Specific issues we have discussed included (in a peculiar order that I will explain in a minute): failure of the companies' boards of directors to be accountable for misbehavior by its management, sometimes associated with conflicts of interest affecting these board members (e.g., this recent case); outright crime and corruption (e.g., this case); use of key opinion leaders paid by the company to market products cloaked in the mantle of academia; payments made by the companies to patient advocacy groups (e.g., this one), medical societies, and academic institutions that induce institutional conflicts of interest, and enlist these well-reputed organizations as stealth marketers; ridiculously high prices charged for particular medicines, often to particularly vulnerable patients (e.g., this case); suppression and manipulation of clinical research evaluating the companies' products; and deceptive drug marketing practices.
Many other bloggers have written about these issues. Some of them have been widely taken up in the mainstream media. A few have even made it into the medical and health care literature.
But those of us who bring them up have been attacked as a tiny group of pharmascolds (e.g., here), who get in the way of the needed innovation and scientific advances that the pharmaceutical industry generously brings to the public. Despite such attacks, it may be that our concerns are somewhat more universal, although those with vested interests in maintaining the status quo might not want that publicized too much.
A new issue of PLoS Medicine included several articles on drug companies' responsibilities for human rights. One was by a former United Nations Special Rapporteur on the right to the highest attainable standard of health. I, and I suspect most of even our Health Care Renewal readers were not familiar with that office. I also confess to being unaware that he had published a report to the UN General Assembly entitled Human Rights Guidelines for Pharmaceutical Companies in Relation to Access to Medicines, which included 47 specific guidelines.
Amazingly enough, it turns out that some of these guidelines seemed to directly address the issues raised above, to wit:
Board of Directors' Accountability
11. The company should have a governance system that includes direct board level responsibility and accountability for its access to medicines policy.
Anti-Corruption
15. A company should publicly adopt effective anti-corruption policies and measures, and comply with relevant national law implementing the United Nations Convention against Corruption.
Disclosure of Financial Support
18. The company should annually disclose its financial and other support to key opinion leaders, patient associations, political parties and candidates, trade associations, academic departments, research centres and others, through which it seeks to influence public policy and national, regional and international law and practice. The disclosure should extend to amounts, beneficiaries and channels by which the support is provided.
19. When providing any financial or other support, the company should require all recipients to publicly disclose such support on all appropriate occasions.
Drug Pricing
33. When formulating and implementing its access to medicines policy, the company should consider all the arrangements at its disposal with a view to ensuring that its medicines are affordable to as many people as possible. In keeping with Guideline 5, the company should give particular attention to ensuring its medicines are accessible to disadvantaged individuals, communities and populations, including those living in poverty and the very poorest in all markets. The arrangements should include, for example, differential pricing between countries, differential pricing within countries, commercial voluntary licences, not-for-profit voluntary licences, donation programmes, and public private partnerships.
34. The arrangements should take into account a country’s stage of economic development, as well as the differential purchasing power of populations within a country. The same medicine, for example, may be priced and packaged differently for the private and public sectors within the same country.
35. The arrangements should extend to all medicines manufactured by the company, including those for non-communicable conditions, such as heart disease and diabetes.
Suppression and Manipulation of Clinical Research
39. The company should take effective measures to ensure that all information bearing upon the safety, efficacy and possible side effects of a medicine are easily accessible to individuals so they can make informed decisions about its possible use.
Deceptive Drug Marketing
41. The company should publicly disclose its promotional and marketing policies and activities, including costs.
Needless to say, I can see no evidence that any big pharmaceutical companies are trying to adhere to any of these guidelines. Somehow I suspect that those who are supporting the vested interests of big pharmaceutical corporations may not all have that much respect for the United Nations. However, I think that the Special Rapporteur's guidelines lend more credibility to the argument that we need better leadership of health care organizations, and specifically that such organizations should follow clear ethical precepts, and their leadership should be held accountable when they do not.
So the next time someone calls you a "pharmascold," you can say, "yeah, yeah, so is the UN Special Rapporteur."
Monday, August 30, 2010
"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
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
Wednesday, June 30, 2010
BLOGSCAN - Deceptive Pharmaceutical Marketing
Perhaps in honor of the recently concluded meeting organized by Dr Adriene Fugh-Berman and her colleagues at PharmedOut.org on the pharmaceutical industry and its influence on continuing medical education, three significant posts appeared this week about deceptive pharmaceutical marketing practices.
On the Health Business Blog, David Williams analyzed how a former pharmaceutical and biotechnology executive spun the Vioxx case, blaming it all on the public's risk aversion.
On the Hooked: Ethics, Medicine and Pharma Blog, Dr Howard Brody summarized two significant articles by Kalman Applbaum on complex psychological campaigns, really versions of disinformation campaigns, used to to market pharmaceuticals.
On the Carlat Psychiatry Blog, Dr Daniel Carlat published a letter about life at a medical school department lead by Dr Charles Nemeroff, one of the "key opinion leaders" most lavishly paid by pharmaceutical companies to help them market questionable drugs for questionable reasons, and giving observations on Dr Nemeroff's new career.
On the Health Business Blog, David Williams analyzed how a former pharmaceutical and biotechnology executive spun the Vioxx case, blaming it all on the public's risk aversion.
On the Hooked: Ethics, Medicine and Pharma Blog, Dr Howard Brody summarized two significant articles by Kalman Applbaum on complex psychological campaigns, really versions of disinformation campaigns, used to to market pharmaceuticals.
On the Carlat Psychiatry Blog, Dr Daniel Carlat published a letter about life at a medical school department lead by Dr Charles Nemeroff, one of the "key opinion leaders" most lavishly paid by pharmaceutical companies to help them market questionable drugs for questionable reasons, and giving observations on Dr Nemeroff's new career.
Tuesday, March 23, 2010
Members of the Board of Now Bankrupt Lehman Brothers as Leaders of Health Care?
In our own Providence Journal, Michael Hiltzik commented about the Valukas report on the fall of the once proud Lehman Brothers. He asserted that one of the lessons learned from the case is the "folly of relying on self-discipline and self-regulation in the financial markets," particularly given the irresponsibility of the top leaders of financial corporations. In particular,
It also should not make us confident that health care, and academic medicine, in the US and elsewhere, are in good hands. Hiltzik declined to name the members of the Lehman board, or identify the other organizations that they lead. One can find a list of the directors who presided over the demise of Lehman in the company's 2008 proxy statement. It turns out that while they were presiding over Lehman's collapse, they also were presiding over the direction of some major health care organizations, to wit:
So, collectively, the confidence uninspiring members of the board of the now defunct Lehman Brothers also were on the boards of two major US and one major Israeli university that include well-known medical schools, one major health care related charity, one major British multi-national pharmaceutical company, a prestigious academic medical center, a large public for-profit US company with major health care interests, and a small, privately held biotechnology company.
We have another vivid illustration in the aftermath of the global economic collapse, and in an ongoing health care crisis, how some of the problems of health care, and academic medicine in particular, may have been at least enabled by leadership more used to working in an increasingly amoral marketplace than to upholding the academic mission. All health care organizations, for-profit and not-for-profit, those in the US and those in other countries, need leaders who value their health care and academic missions more than simply the money they may bring in.
I’d love to hear an argument for allowing any of Lehman’s independent directors, who seem seldom to have asked a penetrating question, ever to serve on a corporate board again.
As I write, those 10 directors, who pulled down better than $100,000 cash a year to sit jointly in the driver’s seat for Lehman’s race to disaster, still boast at least 15 company directorships among them. Does this make you confident that corporate America is in good hands? Me neither.
It also should not make us confident that health care, and academic medicine, in the US and elsewhere, are in good hands. Hiltzik declined to name the members of the Lehman board, or identify the other organizations that they lead. One can find a list of the directors who presided over the demise of Lehman in the company's 2008 proxy statement. It turns out that while they were presiding over Lehman's collapse, they also were presiding over the direction of some major health care organizations, to wit:
MICHAEL L. AINSLIE Director since 1996
Trustee of Vanderbilt University [including the School of Medicine]
JOHN F. AKERS Director since 1996
ROGER S. BERLIND Director since 1985
MARSHA JOHNSON EVANS Director since 2004
Ms. Evans served as President and Chief Executive Officer of the American Red Cross from August 2002 to December 2005.
RICHARD S. FULD, JR. Director since 1990
serves on the Board of Trustees of ... New York-Presbyterian Hospital
SIR CHRISTOPHER GENT Director since 2003
Non-Executive Chairman of GlaxoSmithKline plc.
JERRY A. GRUNDHOFER
Mr. Grundhofer is a director of Ecolab, Inc ["As a leader in infection prevention, Ecolab provides products, tools, training and service to healthcare facilities to help prevent the spread of healthcare acquired infections.]
ROLAND A. HERNANDEZ Director since 2005
HENRY KAUFMAN Director since 1995
a Member of the Board of Trustees of New York University [including the School of Medicine]
a Member of the Board of Governors of Tel-Aviv University [including the Sackler Faculty of Medicine]
JOHN D. MACOMBER Director since 1994
[Also, a member of the board of directors of Warren Pharmaceuticals, "a privately held biotech company, incorporated in 2001 for the purpose of developing proprietary tissue-protective technologies."
So, collectively, the confidence uninspiring members of the board of the now defunct Lehman Brothers also were on the boards of two major US and one major Israeli university that include well-known medical schools, one major health care related charity, one major British multi-national pharmaceutical company, a prestigious academic medical center, a large public for-profit US company with major health care interests, and a small, privately held biotechnology company.
We have another vivid illustration in the aftermath of the global economic collapse, and in an ongoing health care crisis, how some of the problems of health care, and academic medicine in particular, may have been at least enabled by leadership more used to working in an increasingly amoral marketplace than to upholding the academic mission. All health care organizations, for-profit and not-for-profit, those in the US and those in other countries, need leaders who value their health care and academic missions more than simply the money they may bring in.
Monday, March 15, 2010
Abbott's TriCor Fails To Beat A Sugar Pill in Diabetics - And In Pharma's Current Death Spiral, Forget About a Drug That Will
In numerous national publications today, we are once again reminded that lowering the risk of diabetics for vascular events (MI/heart attack, CVA/stroke etc.) and death is far more complex than lowering measures such as cholesterol and blood pressure.
Note these articles:
There is a meta-issue I wish to bring up:
It's clear there are many phenomena going on in diabetes and other metabolic disorders that we simply do not understand.
Note these articles:
Abbott's TriCor Fails To Beat A Sugar Pilland
March 14, 2010 - 9:58 am
Matthew Herper
Forbes.com
ATLANTA -- A popular triglyceride-lowering drug that has been taken by millions of Americans failed to prevent heart disease in a big federal study being presented today.
The drug, TriCor from Abbott Laboratories, has been used for over a quarter of a century to lower levels of fatty particles in the blood called triglycerides. The presumption has been that doing so would prevent heart attacks or heart-related deaths. TriCor has annual sales of more than $1 billion.
But the new study being presented at the American College of Cardiology meeting casts doubt on this. In the study, funded by the National Heart, Lung and Blood Institute, 5,500 patients with diabetes got either TriCor or a placebo. After five years, there was no difference in the rate of heart attacks, strokes and deaths in the patients who got Tricor versus those who took a sugar pill.
Search for Better Diabetes Therapy Falls Short
Mar. 14, 2010, 9:39 P.M. ET
Ron Winslow
Wall Street Journal
Current Treatments, While Effective, Failed to Also Help Prevent Heart Attacks and Stroke
ATLANTA—New strategies to prevent and treat diabetes and heart disease failed to improve care in two major studies, frustrating researchers' efforts to find more-effective approaches to the world's burgeoning diabetes epidemic.
The studies are among the first large trials to test whether treatments recommended for diabetes patients also reduce the risk of heart attacks and strokes. Diabetics are between two and four times as likely to die of cardiovascular causes as nondiabetics. The lack of data on whether strategies to treat diabetes actually lower heart risk is of growing concern to physicians, researchers and regulators.
One new study, called Accord, found that treating blood pressure to lower levels than recommended in current practice doesn't further reduce risk of death, heart attack and stroke among people with diabetes. The same study also found that the drug Tricor, marketed by Abbott Laboratories, failed to prevent such events even though it lowered levels of blood fats called triglycerides that are associated with high diabetes risk.
In the other report, dubbed Navigator, a diabetes drug called Starlix failed to prevent people at high risk of diabetes from progressing to the disease. The blood-pressure medicine Diovan did modestly reduce risk of developing diabetes in the same study, but neither drug significantly cut the risk of heart-related deaths, heart attacks and strokes. Both pills in this study are sold by Novartis SA of Switzerland.
There is a meta-issue I wish to bring up:
It's clear there are many phenomena going on in diabetes and other metabolic disorders that we simply do not understand.
It's also very likely that there are new drugs, yet undiscovered, that could be developed and that would improve mortality and morbidity.
It's too bad the pharmaceutical industry is now largely run by dyscompetents, incompetents, and other management charlatans, not to mention those responsible for questionable or outright criminal behaviors (such as here, here).
This privileged class has apparently so demoralized pharma rank and file including the very soul of drug discovery (chemists) - based for example on "layoff thread" comments on a very popular blog for medicinal, synthetic and other chemists such as here - that these new drugs are increasingly unlikely to be developed at all.
The industry in its current anti-intellectual, "lay them off and watch the stock price rise", short-term narrow-minded idiocy-driven death spiral is basically good for nothing except money games.
Pity.
Thursday, February 25, 2010
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:
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:
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:
So,
Finally, Dr Krumholz concludes with some solutions with which I heartily agree:
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.
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.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.
'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,' ....
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.Policy Implications
This type of behavior is eroding the public trust in the pharmaceutical industry.
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.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.
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.
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.
Thursday, February 11, 2010
Merck Settles Another Vioxx Case
All the shenanigans that went on in the course of Merck's marketing of the now withdrawn Cox-2 inhibitor non-steroidal anti-inflammatory drug Vioxx have provided grist for the Health Care Renewal mill since 2005. For example, see these posts:
- here about ghost-writing of a Vioxx research publication;
- here, and here about allegations that Merck executives tried to intimidate Vioxx critics;
- here about how advocates of an extreme laissez faire approach to regulation of health care corporations used illogical arguments about the Vioxx case;
- here about how an apparently major clinical trial of Vioxx turned out to be a "seeding trial," that is, a study really meant to recruit supposed physician-researchers as prescribers; and
- here about how one once prominent Vioxx researcher pleaded guilty to fraud in connection with his research on other drugs.
Thus, the Vioxx case provides a good lesson about some of the tactics used to deceptively and unethically promote health care products (pharmaceuticals in this case).
Merck just announced just the latest settlement of Vioxx related legal actions, as reported by Business Week:
Also,
One notable attribute of the current Vioxx settlement is that it does mandate some changes in Merck's governance and leadership meant to prevent future cases similar to this one. These include developing leadership structures and changing the company's code of conduct to emphasize the need for "truthful" communication, and the need to refrain from "inappropriately" influencing research.
On Health Care Renewal we have discussed numerous examples of deceptive practices by health care organizations, often affecting marketing, and of manipulation and suppression of research. It is a small step forward for one company to commit to honest communications and to not manipulate research. A better code of conduct may at least be a start towards an organizational ethics policy, which in turn may have the potential to actually improve behavior.
On the other hand, typical settlements that involve only monetary damages paid by the organization seem to have little deterrent effect on future bad behavior. Usually, the companies involved only need to pay fines, and no individual who performed, directed or approved unethical or illegal acts suffers 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. Until the people who approve, direct, and perform unethical or illegal acts pay some penalties, expect such acts to continue, at best deterred only slightly by written policies that condemn them. I again suggest that to truly reform health care, we need rigorous regulation of health care organizations that has the power to deter unethical behavior that may risk patients' health
- here about ghost-writing of a Vioxx research publication;
- here, and here about allegations that Merck executives tried to intimidate Vioxx critics;
- here about how advocates of an extreme laissez faire approach to regulation of health care corporations used illogical arguments about the Vioxx case;
- here about how an apparently major clinical trial of Vioxx turned out to be a "seeding trial," that is, a study really meant to recruit supposed physician-researchers as prescribers; and
- here about how one once prominent Vioxx researcher pleaded guilty to fraud in connection with his research on other drugs.
Thus, the Vioxx case provides a good lesson about some of the tactics used to deceptively and unethically promote health care products (pharmaceuticals in this case).
Merck just announced just the latest settlement of Vioxx related legal actions, as reported by Business Week:
Merck & Co. agreed to settle shareholder lawsuits over the withdrawn Vioxx painkiller by strengthening its drug-safety procedures, appointing a new chief medical officer and paying $12.2 million in legal fees.
Merck would appoint one committee to address risks that require immediate action and another to monitor the safety of drugs, the company said in a regulatory filing. Merck would also amend its code of conduct to promote scientific and academic integrity as well 'honest communication' with doctors.
'In all research endeavors that are sponsored by Merck, we will refrain from attempting to influence inappropriately the results and conclusions of such research,' according to the amended code. 'We strive for all communications with the medical community to be accurate, truthful and consistent with labeling.'
Also,
The company will be required to make corporate governance changes and “supplement existing policies and procedures,” ... [a Merck spokesperson] said.
Merck would submit results of clinical trials to a public registry, with its compliance overseen by an independent third party.Note that this settlement is only of one type of lawsuit, as described in a Wall Street Journal article,
The chief medical officer will have an 'executive voice' on product safety issues independent of Merck Research Laboratories.
The pact, which is pending final court approval, would resolve state and federal shareholder 'derivative' complaints (which are brought by shareholders on behalf of a company) alleging that current and former Merck officers and directors breached their fiduciary duties in handling Vioxx.Merck had already settled thousands of lawsuits,
Since the Vioxx controversy erupted, about 27,000 personal-injury lawsuits have been filed, the company says. Merck has been challenging all of the cases and settled many of them. Most notably, it agreed to a pay $4.85 billion to settle personal-injury claims of more than 40,000 people. In another settlement, the company will pay $80 million to resolve 190 claims filed by drug-benefit plans seeking to recover costs of paying for Vioxx use.Merck has lots of other legal actions to go through,
The Vioxx litigation remains far from over. The U.S. Supreme Court is weighing a separate shareholder case, seeking billions of dollars in damages from the company. Merck disclosed last year the U.S. Attorney's office in Boston was conducting a grand-jury investigation of Merck's handling of Vioxx. The claims of some 310 plaintiff groups are outstanding in courts in the U.S., according to the securities filing. There are also cases overseas, including Australia and Turkey.So the parade of legal actions and settlements thereof continues. We believe that the scope of this parade provides some sort of index of bad behavior by the health care organizations needing to make such settlements. Most of these legal results are reported on in the business media, and rarely appear in any medical, health care research, or health policy journals. I submit that were health care professionals, health care researchers, and health policy makers more systematically aware of these cases, they might realize that unethical and sometimes illegal behavior, often generated by bad leadership unrestrained by poor organizational governance, is a major cause of the current, seemingly intractable health care crisis.
One notable attribute of the current Vioxx settlement is that it does mandate some changes in Merck's governance and leadership meant to prevent future cases similar to this one. These include developing leadership structures and changing the company's code of conduct to emphasize the need for "truthful" communication, and the need to refrain from "inappropriately" influencing research.
On Health Care Renewal we have discussed numerous examples of deceptive practices by health care organizations, often affecting marketing, and of manipulation and suppression of research. It is a small step forward for one company to commit to honest communications and to not manipulate research. A better code of conduct may at least be a start towards an organizational ethics policy, which in turn may have the potential to actually improve behavior.
On the other hand, typical settlements that involve only monetary damages paid by the organization seem to have little deterrent effect on future bad behavior. Usually, the companies involved only need to pay fines, and no individual who performed, directed or approved unethical or illegal acts suffers 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. Until the people who approve, direct, and perform unethical or illegal acts pay some penalties, expect such acts to continue, at best deterred only slightly by written policies that condemn them. I again suggest that to truly reform health care, we need rigorous regulation of health care organizations that has the power to deter unethical behavior that may risk patients' health
Tuesday, February 9, 2010
Green Ketchup for Novartis?
We recently commented on the challenges facing the large, Swiss based multinational pharmaceutical company Novartis. From Business Week came an interview with the new CEO of Novartis, in which he revealed why he thinks he is especially qualified for the job:
The reason for citing Jiminez's responsibility for green ketchup was more obscure. According to the authoritative medical journal, Woman's Day magazine, Heinz's green ketchup was one of the "7 Biggest Food Product Duds," in the US, and was discontinued in 2006.
As we have discussed before, the current culture of US and global business includes the belief that someone trained in finance or marketing is the most suitable leader of every type of organization. Such leadership has lead the US biggest automobile manufacturer into bankruptcy. We have discussed numerous examples of leaders of health care organizations with no health background or experience who seem to be most expert at making sure their compensation is hugely larger than that of most of their employees.
We hope Novartis does not end up trying to sell the pharmaceutical equivalent of green ketchup.
I say again, to really reform health care, we need to have leaders of health care organizations who actually understand health care and share its values.
Joe Jimenez says that more than 20 years selling Clorox (CLX) bleach and Heinz ketchup taught him to make decisions quickly. Now, as CEO of Novartis (NVS), Europe's second-largest drugmaker, he'll try to prove that speed can also make a difference in the pharmaceutical business.Further explanation of why supervising the selling of cleaning or food products would be good experience for the chief executive of a pharmaceutical company, which faces technical, regulatory, and clinical issues very different from the challenges of selling bleach or ketchup, was not forthcoming.
Jimenez, an American with degrees from Stanford and the University of California at Berkeley, believes his consumer-products background will help. He started his career at Clorox, the world's largest maker of bleach, ran two divisions of ConAgra Foods (CAG), and oversaw H.J. Heinz' (HNZ) European operations. With consumer packaged goods, 'Decisions have to be made quickly because the market moves quickly,' he says. But pharmaceutical businesses have long development lead times, which 'tends to slow decision-making in areas where it doesn't need to.'
Jimenez oversaw the introduction of kid-friendly green ketchup when he was Heinz' North America chief executive,....
The reason for citing Jiminez's responsibility for green ketchup was more obscure. According to the authoritative medical journal, Woman's Day magazine, Heinz's green ketchup was one of the "7 Biggest Food Product Duds," in the US, and was discontinued in 2006.
As we have discussed before, the current culture of US and global business includes the belief that someone trained in finance or marketing is the most suitable leader of every type of organization. Such leadership has lead the US biggest automobile manufacturer into bankruptcy. We have discussed numerous examples of leaders of health care organizations with no health background or experience who seem to be most expert at making sure their compensation is hugely larger than that of most of their employees.
We hope Novartis does not end up trying to sell the pharmaceutical equivalent of green ketchup.
I say again, to really reform health care, we need to have leaders of health care organizations who actually understand health care and share its values.
Friday, February 5, 2010
More Settlements: Christ Hospital, Teva Pharmaceutical Industries
For the end of the week, a round-up of the latest legal settlements involving large health care organizations, in alphabetical order....
Christ Hospital (Cincinnati, Ohio)
As reported by the Business Courier of Cincinnati:
Teva Pharmaceutical Industries
As reported by Reuters,
The march of settlements continues. To repeat, seemingly ad infinitum, these are just the latest in a now long parade of settlements that serve as reminders of poor behavior by myriad health care organizations. As we have previously noted, these settlements seem to have little deterrent effect on future bad behavior. Usually, the companies involved only need to pay fines, 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. Until the people who approve, direct, and perform unethical or illegal acts pay some penalties, expect such acts to continue. I again suggest that to truly reform health care, we need rigorous regulation of health care organizations that has the power to deter unethical behavior that may risk patients' health.
Christ Hospital (Cincinnati, Ohio)
As reported by the Business Courier of Cincinnati:
Christ Hospital and the federal government have reached a settlement agreement on a whistleblower lawsuit that accused the hospital of defrauding federal health-care programs.
The suit alleged that Christ Hospital and the Ohio Heart Health Center cardiology practice, which Christ Hospital has since bought, 'devised a scheme that provided cardiologists improper financial incentives in exchange for generating revenue for the hospital,' according to the U.S. Department of Justice.
Potential liability was reported to be as high as $424 million across the Health Alliance and its former members in an October 2007 document from VMG Health, a consultant hired as part of the separation of Christ Hospital from the Health Alliance.
Christ faced potential liability of as much as $123 million in the case, according to the report, and the St. Luke Hospitals, which also left the Health Alliance, faced exposure of $51 million.
The focus of the suit is an outpatient cardiology testing unit within Christ Hospital known as the Heart Station, where patients receive non-invasive heart procedures such as electrocardiograms, echocardiograms and stress tests.
The action was originally filed in the U.S. District Court in Cincinnati under the whistleblower provisions of the False Claims Act by Dr. Harry Fry, a cardiologist who had provided services to Christ Hospital and Ohio Heart.
The lawsuit alleges that, between at least 1999 and 2004, cardiologists were allocated time at the Heart Station based on the number of coronary arterial bypass graph procedures and catheter lab revenues they or their group generated for Christ the previous year.
Many of the procedures were billed to federal benefit programs, including Medicare and Medicaid, according to the government. It’s against federal law to exchange financial incentives for patient referrals.
Teva Pharmaceutical Industries
As reported by Reuters,
Generic drugmaker Teva Pharmaceutical Industries Ltd ... said on Friday it plans to settle lawsuits alleging it caused governments to pay inflated prices for its drugs under Medicaid and other programs.
Teva, which denies the charges, said it will record a charge of about $315 million in its fourth quarter, 2009. The charge includes the settlement in principle and a reserve for the remaining drug pricing lawsuits to which Teva is a party.
Israel-based Teva is one of a number of drug companies named in civil lawsuits that relate to drug price reporting by manufacturers in about 15 states. The cases are pending....
The march of settlements continues. To repeat, seemingly ad infinitum, these are just the latest in a now long parade of settlements that serve as reminders of poor behavior by myriad health care organizations. As we have previously noted, these settlements seem to have little deterrent effect on future bad behavior. Usually, the companies involved only need to pay fines, 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. Until the people who approve, direct, and perform unethical or illegal acts pay some penalties, expect such acts to continue. I again suggest that to truly reform health care, we need rigorous regulation of health care organizations that has the power to deter unethical behavior that may risk patients' health.
Monday, January 18, 2010
Not Just an American Disease
We have written about attacks on rigorous evidence-based medicine, and particularly on comparative effectiveness research from those with vested interests in having clinical research come out a certain way (e.g., see this most recent relevant post). Those who see such research primarily as a marketing opportunity tend to be offended by the notion of rigorous, unbiased research that may not be so easily turned to marketing purposes. Since I, like the other current Health Care Renewal bloggers, am based in the US, we tend to focus on local examples. But it turns out that the American malady described above has spread to Germany.
From the Science blog, ScienceInsider:
And it turns out that the American-based pharmaceutical industry has jumped right in.
Parenthetically, "innovation" seems to be a favorite term that those with vested interests in selling products or services use to describe those products, sometimes in the absence of any data that shows them to be superior to the alternatives in terms of important clinical outcomes, that is, outcomes that patients may care about. "Innovative" was also how complex financial products which contributed to the global economic meltdown were described by those who stood to make money selling, or sometimes simultaneously short-selling them, - but maybe that's guilt by association.
I hope the Germans are able to preserve their stake in honest, comparisons of tests and treatments that are not influenced by those with vested interests in selling those tests and treatments.
From the Science blog, ScienceInsider:
A long-running feud between pharmaceutical companies and the German institute that evaluates the effectiveness of medical treatments could cost the institute director his job. Although the post is supposed to be apolitical, members of Germany’s new coalition government have called for Peter Sawicki, founding director of the Institute for Quality and Efficiency in Health Care (known by its German acronym IQWiG, pronounced ICK-vig), to be replaced with someone who is friendlier to the pharmaceutical industry. The institute’s board of directors are expected to decide on 20 January whether Sawicki, a clinical researcher and diabetes expert, will be replaced when his contract runs out later this year.
Sawicki’s supporters say the move would endanger the institute’s reputation for impartial and rigorous science, and earlier this month a petition signed by 600 doctors and clinical researchers called on the health minister and the board to keep Sawicki on. Gerd Antes, director of the German Cochrane Centre in Freiburg, a not-for-profit organization that analyzes health care effects, says that replacing Sawicki would significantly undermine IQWiG and its work. Antes views the anti-Sawicki push as 'part of the political game to soften and to weaken rigorous procedures for new drugs and medical devices in Germany.'
And it turns out that the American-based pharmaceutical industry has jumped right in.
Big pharma’s attacks have even come from outside Germany. In March 2009, the Pharmaceutical Research and Manufacturers of America petitioned the Obama Administration to put Germany on a trade and intellectual property 'priority watch list' chiefly because of IQWiG’s influence on the German drug market. The petition complained that the institute has 'inadequately taken into account the value of innovative pharmaceuticals,' among other complaints. The Obama Administration declined to put Germany on its watch list.
Parenthetically, "innovation" seems to be a favorite term that those with vested interests in selling products or services use to describe those products, sometimes in the absence of any data that shows them to be superior to the alternatives in terms of important clinical outcomes, that is, outcomes that patients may care about. "Innovative" was also how complex financial products which contributed to the global economic meltdown were described by those who stood to make money selling, or sometimes simultaneously short-selling them, - but maybe that's guilt by association.
I hope the Germans are able to preserve their stake in honest, comparisons of tests and treatments that are not influenced by those with vested interests in selling those tests and treatments.
Friday, January 8, 2010
Abbott Laboratories Settles
Another day, another settlement, this time,as reported by Reuters:
While each new entry in the ongoing march of settlements merits a few lines in the business media,separately, or in the aggregate these settlements rarely get noticed by health services or health policy research, or receive attention in health policy circles. Nor do the contrasts between the conduct revealed by such settlements and the rosy public relations of the settling companies attract much attention. For example, Abbott Laboratories proclaims its "promise,"
New York Attorney General Andrew Cuomo said Abbott Laboratories (ABT.N) and French drugmaker Fournier have agreed to pay $22.5 million to settle a multistate lawsuit that accused them of conspiring to block generic forms of their TriCor treatment for triglycerides.The ongoing march of legal settlements of charges of various kinds of wrongdoing by diverse health care organizations is a reminder of the pervasiveness of bad conduct by such organizations. We have commented repeatedly (see some posts here) such settlements, including the "corporate integrity agreements" now frequently attached to them, seem to have done little to deter bad behavior. Usually, the companies involved only need to pay fines, 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.
The drugmakers will pay the money to New York, 22 other states and the District of Columbia, Cuomo said in a news release on Thursday. About $4.5 million goes to New York.
The lawsuit, filed in Delaware federal court in March 2008, alleged Abbott and Fournier schemed to block generics when competitors started to develop versions of TriCor, used to treat a type of blood fat that increases the risk of heart disease.
Cuomo said Abbott and Fournier made minor changes to TriCor that provided no clinical benefit, but were meant to prevent pharmacists from dispensing less-expensive generic versions of TriCor.
The states alleged the drugmakers also thwarted generic competition by filing baseless patent-infringement suits against generic drugmakers, thereby securing a monopoly for blockbuster TriCor.
While each new entry in the ongoing march of settlements merits a few lines in the business media,separately, or in the aggregate these settlements rarely get noticed by health services or health policy research, or receive attention in health policy circles. Nor do the contrasts between the conduct revealed by such settlements and the rosy public relations of the settling companies attract much attention. For example, Abbott Laboratories proclaims its "promise,"
We are here for the people we serve in their pursuit of healthy lives. This has been the way of Abbott for more than a century - passionately and thoughtfully translating science into lasting contributions to health.The settlement of allegations about a scheme to maintain a monopoly on a profitable drug raise doubts about the company's committment to "earn the trust of those we serve" through "behavior characterized by honesty, fairness and integrity." Whether the disconnect between this settlement and the "Abbott Promise" will affect the stratospheric earnings of Abbott executives (for example, in 2008, the total compensation of Abbott CEO Miles D White was $28,335,494 per the company's 2009 proxy statement) is a question that could be put to the company's Board of Directors. Perhaps our readers at Yale University might want to ask Dr Robert J Alpern, Dean of the Yale School of Medicine, who just joined the Abbott Board of Directors in 2008 about that.
Our products encircle life, from newborns to aging adults, from nutrition and diagnostics through medical care and pharmaceutical therapy.
Caring is central to the work we do and defines our responsibility to those we serve:
We advance leading-edge science and technologies that hold the potential for significant improvements to health and to the practice of health care.
We value our diversity - that of our products, technologies, markets and people - and believe that diverse perspectives combined with shared goals inspire new ideas and better ways of addressing changing health needs.
We focus on exceptional performance, a hallmark of Abbott people - worldwide - demanding of ourselves and each other because our work impacts people's lives.
We strive to earn the trust of those we serve by committing to the highest standards of quality, excellence in personal relationships, and behavior characterized by honesty, fairness and integrity.
We sustain success - for our business and the people we serve - by staying true to key tenets upon which our company was founded over a century ago: innovative care and a desire to make a meaningful difference in all that we do.
The promise of our company is in the promise that our work holds for health and life.
Monday, December 21, 2009
Addressing Drug, Biotechnology, and Device Companies' Payments to Physicians: the Thai National Health Assembly
We have frequently discussed how financial relationships among physicians, other health care professionals, and health care academics, on one hand, and drug, biotechnology, medical device and other health care corporations may have adverse effects on patient care and medical teaching and research. A first step towards addressing these relationships would be their full disclosure. Here in the US, Senators Grassley (R-Iowa) and Kohl (D-Wisconsin) have been pushing for a Physician Payments Sunshine Act which would require all such companies to disclose all such payments. Whether it will become law, as part of health care reform legislation or independently, is now anyone's guess.
Since we are based in the US, we tend to discuss such issues from a US viewpoint. Just to show that these problems are global, and that some countries may have more fruitful approaches to them than others, see a recent article from the Bangkok Post on the run up to the Thai National Health Assembly:
At the close of the Assembly, the Bangkok Post reported:
One would think that having a National Health Assembly would orient health policy more towards the issues concerning people and patients rather than those pushed by health care corporate CEOs (as we discussed here). Of course, here in the US, we have nothing that resembles the Thai National Health Assembly. Maybe if we did, legislation like the Sunshine Act would get a more favorable reception.
Since we are based in the US, we tend to discuss such issues from a US viewpoint. Just to show that these problems are global, and that some countries may have more fruitful approaches to them than others, see a recent article from the Bangkok Post on the run up to the Thai National Health Assembly:
Over-prescription of pills and medicines by doctors under pressure from pharmaceutical companies is being condemned by senior doctors ahead of a national health assembly on the issue this week.
In some cases, drug sales representatives were criticised for wearing 'inappropriate outfits' and offering gifts to secure orders.
Doctors say they are quite prepared to join any public sector moves to end unethical drug promotion to protect patients and cap soaring national health care costs and irrational drug use.
At a forum on ethical criteria for promoting medicines, physician Prasert Palittapongarnpim, of Chiang Rai's Prachanukroh Hospital, said big pharmaceutical firms use many different methods to encourage doctors to prescribe their drugs.
They range from small gifts and stationery to lucrative luncheon lectures, seminar sponsorships and overseas trips.
Dr Prasert said he was once offered a huge sum of cash by a drug salesperson to change his drug order.
Some senior doctors also tell their medical students to buy drugs of smaller dosages so they can increase the size of their orders.
At the close of the Assembly, the Bangkok Post reported:
Curbing the influence of pharmaceutical firms on doctors topped the agenda of the three-day National Health Assembly which ended yesterday.
A better regulation was needed to govern the promotional activities and the sale of medicine to solve the problem of unnecessary and excess drug prescription by physicians, the annual health forum was told.
Unethical sales of drugs were among 11 health-related issues discussed during the second National Health Assembly (NHA2009).
Suwit Wibulpolprasert, the assembly's chairman, said the problem of over-prescription was rampant and worrying.
There are doctors who only place orders with a firm offering them lucrative inducement packages in return, such as overseas trips and expensive gifts.
'We need to have a regulation which would require these drug firms' sponsorship to doctors to be made public,' said Dr Suwit. He said a group of experts were working on a bill to prevent a conflict of interest between doctors and pharmaceutical companies. When ready, it would be submitted to the national drug system development panel, chaired by the prime minister, for consideration.
Dr Suwit has recommended that an independent body be set up to monitor and report the unethical behaviour of doctors and concerned agencies until the enforcement of the new law.
One would think that having a National Health Assembly would orient health policy more towards the issues concerning people and patients rather than those pushed by health care corporate CEOs (as we discussed here). Of course, here in the US, we have nothing that resembles the Thai National Health Assembly. Maybe if we did, legislation like the Sunshine Act would get a more favorable reception.
Wednesday, December 9, 2009
More Air Into the Health Care Bubble: the $30,000 a Month Cancer Drug
Over four years ago, we posted about the stratospheric prices of new drugs that seemed disproportionate to manufacturing and development costs on one hand, and the value of the drugs for patients on the other. For example, back then we noted that thalidomide, a very old drug that notoriously was found to cause birth defects when it was given to preganant women, but that then showed promise as an anti-cancer drug, was being marketed in the US for $29 per capsule (approximately $25,000 a year), while a generic form sold in Brazil for $0.07 per capsule.
That was then, and this is now. This week, the New York Times reported on a $30,000+ per month cancer drug.
So what could be the rationale for this breathtaking price?
Drug Effectiveness
Could it be that the drug is extremely effective? Not according to the NY Times:
A PubMed search revealed no sign that this trial had been publsiehd, and no publications reporting any controlled trials of this drug.
So at best, this drug at best may temporarily shrink tumors, although that assertion is based on evidence that has not yet been published or subject to peer-review. It does not seem that the tremendous price of the drug could be justified by tremendous benefits to patients.
Research, Development and Manufacturing
So, perhaps the drug was very difficult and expensive to create, manufacture and develop? That does not seem to be the case, either.
Folotyn's generic name is pralatrexate. As the name suggests, it is a chemical compound very similar to the much older anti-cancer drug methotrexate. [See O'Connor OA. Pralatrexate: an emerging new agent with activity in T-cell lymphoma. Curr Opin Oncol 2006; 18: 591-597.] It was first developed not by Allos Therapeutics, but by Memorial Sloan-Kettering Cancer Center, Southern Research Institute, and Stanford Research Institute. The Allos Therapeutics 2008 annual report noted that the company's total research and development expenses for the drug from 1992 through 2008 were $26.8 million (so much for the urban myth that the average drug costs $1 billion to develop.) Based on the estimate that the drug would cost roughly $30,000/ month from the NY Times, the company could recover all the development costs of this drug after 893 patient-months of use.
Allos Therapeutics does not actually make pralotrexate, but outsources its production, according to the company's . The firm's total yearly manufacturing costs (for several experimental drugs as well as pralotrexate) in 2008 were $6.7 million.
So it does not seem that the tremendous price of the drug could be attributed to the costs of discovering, developing, or manufacturing it.
So where would the money go?
General and Administrative Costs, Executive and Board Compensation
Allos Therapeutics seems to spend a disproportionate amount of money on marketing, general and administrative costs. According to the 2008 report, "marketing, general and administrative expenses include costs for pre-marketing activities, corporate development, executive administration, corporate offices and related infrastructure." In 2008, these expenses were $23 million, in one year, almost as much as the company spent over 16 years to research and develop Folotyn.
Allos Therapeutics has enriched its corporate insiders. According to the company's 2009 proxy statement, in 2008, CEO Paul L Berns received $2,091,600 in total compensation; Chief Commercial Officer James V Caruso received $1,259,700; and Chief Medical Officer Pablo J Cagnoni received $1,408,700. The total compensation of the five highest paid executives of the company in 2008, $5,945,500, was over 10% of the entire company's budget, $53,639,000.
Mr Berns, who has only been with the company since 2006, owned 994,606 shares or equivalent (at a price of $6.62 per share on 4 December, 2009, worth $6,584,292). Mr Caruso owned 272,072 shares or equivalent,and Dr Cagnoni owned 386,245. Although two board members, Stewart Hen and Jonathan S Leff seemed to be serving by virtue of their positions with Warburg Pincus & Co, whose Private Equity VIII LP owns over 29% of Allos Therapeutics stock, Mr Hen and Mr Leff received $120,700 and $119,400 to sit on the board.
These amounts should be considered in light of the fact that the company is comparatively tiny. Its 2008 report disclosed that it only has 81 full-time employees, of whom fully 31 "are involved in marketing, corporate development, finance, administration, and operations." The company has never made money. Its 2008 report noted losses of over $20 million a year in the past five years, and a total loss of over $289 million.
So one wonders if the real reason pralatrexate was priced so high was to justify the millions that top company leaders have reaped from a company that lost money over the 16 years?
Summary
The NY Times reported that people outside of Allos were not pleased with the price of Folotyn:
Furthermore,
If we really want to provide accessible health care of good quality and a reasonable cost, we will need to develop mechanisms to pay more reasonable amounts for health care goods and services. This will require some courage facing down the corporate and organizational insiders who have made themselves very rich from the current craziness.
NOTE (21 December, 2009) - See also comments on the Postscript blog.
That was then, and this is now. This week, the New York Times reported on a $30,000+ per month cancer drug.
A newly approved chemotherapy drug will cost about $30,000 a month, a sign that the prices of cancer medicines are continuing to rise despite growing concern about health care costs.
The price of the new drug, called Folotyn, is at least triple that of other drugs that critics have said are too expensive for the benefits they offer to patients. The colon cancer drug Erbitux, for instance, costs $10,000 a month and the drug Avastin about $8,800 when used to treat lung cancer.
So what could be the rationale for this breathtaking price?
Drug Effectiveness
Could it be that the drug is extremely effective? Not according to the NY Times:
Folotyn has not yet shown an effect on longevity. In the clinical trial that led to approval of the drug, 27 percent of the 109 patients experienced a reduction in tumor size. The reductions lasted a median of 9.4 months.
But considering all the patients in the trial, only 12 percent had a reduction in tumor size that lasted for more than 14 weeks. The trial did not compare Folotyn to another drug or a placebo
A PubMed search revealed no sign that this trial had been publsiehd, and no publications reporting any controlled trials of this drug.
So at best, this drug at best may temporarily shrink tumors, although that assertion is based on evidence that has not yet been published or subject to peer-review. It does not seem that the tremendous price of the drug could be justified by tremendous benefits to patients.
Research, Development and Manufacturing
So, perhaps the drug was very difficult and expensive to create, manufacture and develop? That does not seem to be the case, either.
Folotyn's generic name is pralatrexate. As the name suggests, it is a chemical compound very similar to the much older anti-cancer drug methotrexate. [See O'Connor OA. Pralatrexate: an emerging new agent with activity in T-cell lymphoma. Curr Opin Oncol 2006; 18: 591-597.] It was first developed not by Allos Therapeutics, but by Memorial Sloan-Kettering Cancer Center, Southern Research Institute, and Stanford Research Institute. The Allos Therapeutics 2008 annual report noted that the company's total research and development expenses for the drug from 1992 through 2008 were $26.8 million (so much for the urban myth that the average drug costs $1 billion to develop.) Based on the estimate that the drug would cost roughly $30,000/ month from the NY Times, the company could recover all the development costs of this drug after 893 patient-months of use.
Allos Therapeutics does not actually make pralotrexate, but outsources its production, according to the company's . The firm's total yearly manufacturing costs (for several experimental drugs as well as pralotrexate) in 2008 were $6.7 million.
So it does not seem that the tremendous price of the drug could be attributed to the costs of discovering, developing, or manufacturing it.
So where would the money go?
General and Administrative Costs, Executive and Board Compensation
Allos Therapeutics seems to spend a disproportionate amount of money on marketing, general and administrative costs. According to the 2008 report, "marketing, general and administrative expenses include costs for pre-marketing activities, corporate development, executive administration, corporate offices and related infrastructure." In 2008, these expenses were $23 million, in one year, almost as much as the company spent over 16 years to research and develop Folotyn.
Allos Therapeutics has enriched its corporate insiders. According to the company's 2009 proxy statement, in 2008, CEO Paul L Berns received $2,091,600 in total compensation; Chief Commercial Officer James V Caruso received $1,259,700; and Chief Medical Officer Pablo J Cagnoni received $1,408,700. The total compensation of the five highest paid executives of the company in 2008, $5,945,500, was over 10% of the entire company's budget, $53,639,000.
Mr Berns, who has only been with the company since 2006, owned 994,606 shares or equivalent (at a price of $6.62 per share on 4 December, 2009, worth $6,584,292). Mr Caruso owned 272,072 shares or equivalent,and Dr Cagnoni owned 386,245. Although two board members, Stewart Hen and Jonathan S Leff seemed to be serving by virtue of their positions with Warburg Pincus & Co, whose Private Equity VIII LP owns over 29% of Allos Therapeutics stock, Mr Hen and Mr Leff received $120,700 and $119,400 to sit on the board.
These amounts should be considered in light of the fact that the company is comparatively tiny. Its 2008 report disclosed that it only has 81 full-time employees, of whom fully 31 "are involved in marketing, corporate development, finance, administration, and operations." The company has never made money. Its 2008 report noted losses of over $20 million a year in the past five years, and a total loss of over $289 million.
So one wonders if the real reason pralatrexate was priced so high was to justify the millions that top company leaders have reaped from a company that lost money over the 16 years?
Summary
The NY Times reported that people outside of Allos were not pleased with the price of Folotyn:
Dr. Lee N. Newcomer, senior vice president for oncology at the big insurer UnitedHealthcare, called the price of Folotyn 'unconscionable.' He said that Folotyn alone would cost as much as UnitedHealthcare now typically spends in total to treat a lymphoma patient from diagnosis until death. That median expenditure now, he said, is $87,000 for a little over a year of treatments.
But Dr. Newcomer said insurers would be obligated to pay for Folotyn because there were no alternatives.
Furthermore,
'This drug is not a home run,' Dr. Brad S. Kahl, a lymphoma specialist at the University of Wisconsin, said during a meeting of an advisory committee to the F.D.A. on Sept. 2. 'It’s not even a double. It’s a single.'So the health care bubble continues to inflate. I suggest that the case of the ridiculous pricing of Folotyn shows how this bubble is in part generated by "compensation madness," not only "insiders hijacking established institutions for their personal benefit," but also insiders able to become rich at the expense of even tiny, money-losing corporations. But the bubble is also generated by the amazing acquiescence of those who pay bills at all levels, form the individuals who ultimately fund health care through salary dollars not earned, health insurance premiums, co-pays and the like, and tax payments, through the health care insurers and government agencies who did not balk at paying $25,000 a year for thalidomide in 2005, and seemingly will not balk at paying $30,000+ a year for pralatrexate in 2009.
Saying that even a single was helpful, Dr. Kahl was part of a majority on the panel that recommended approval of the drug, 10 to 4.
But after recently learning what Allos planned to charge for Folotyn, Dr. Kahl said he was 'disappointed' by the 'excessive' price.
'It dampens my enthusiasm for using that drug,' he said. 'It creates these huge ethical quandaries about trying a drug that has a modest benefit for the average patient at enormous expense.'
If we really want to provide accessible health care of good quality and a reasonable cost, we will need to develop mechanisms to pay more reasonable amounts for health care goods and services. This will require some courage facing down the corporate and organizational insiders who have made themselves very rich from the current craziness.
NOTE (21 December, 2009) - See also comments on the Postscript blog.
Monday, November 30, 2009
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:
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:
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:
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:
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.
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.
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