Call for a National Institute for Effective Medicine

It's still dark and overcast here in LA, but "it never rains in Southern California...."

An op-ed again in the Los Angeles Times by Shannon Brownlee called for the creation of a US national Institute for Effective Medicine. Brownlee wrote,

With two-thirds of clinical trials and three-quarters of the papers published in the top medical journals commercially funded, the drug industry has gained unprecedented leverage over what doctors and patients know — and don't know — about drugs.
Researchers scoff at the notion that that their scientific integrity is for sale. Certainly most researchers aren't corrupt, but their institutions are guilty of allowing the drug industry to manipulate medical science.
Meanwhile, industry-funded research is failing to provide the clinically useful answers physicians and patients need in order to pick the best treatment. Which drug is right for which patient? What are the risks? Are the added benefits of a new, expensive drug worth the cost? If not, should insurance companies and Medicare be paying for them?
What's needed is a new Institute for Effective Medicine, which would need to be modeled on the Federal Reserve Board or the Securities and Exchange Commission to protect it from political pressure. Its mission would be threefold. It would serve as a new, independent source of research dollars for medicine. It would provide independent evaluation of data generated by industry. And it would oversee the creation of clinical practice guidelines, a manual of proven "best practices" for physicians devised entirely without industry influence.
If insurance companies and the federal government set aside just one-half of 1% of their current annual spending on prescription drugs, they could endow a new institute with roughly half-a-billion dollars. Doctors, employers and insurers all have a stake in this — but not as much as patients do. Americans spend a staggering $200 billion a year on prescription drugs, and that figure is going up about 12% annually, faster than any other healthcare cost. With studies like the NIH's, physicians could prescribe on the basis of solid science, while private insurers and Medicare would have the data they need to rein in costs without sacrificing healthcare quality.
Congress may be reluctant to fund a new agency — particularly one the drug industry may hate— but an Institute for Effective Medicine would be worth its freight in better healthcare and lower costs.

It sounds like an idea worthy of serious discussion.

Financial Ties Between the US Veterans Affairs Department and a Company Lead by the VA's Former Secretary

Reporting from cool and cloudy Los Angeles, about a story reported locally with wider implications....

Early this week, the Los Angeles Times examined the financial ties between former US Veterans Affairs (VA) Secretary Anthony J. Principi and a company that does medical exams on veterans under contract with the VA.

In 1996, Principi, then a partner in a San Diego law firm, chaired a congressional task force on veterans issues. According to the Times, "his panel recommended having a standardized, comprehensive physical exam for outgoing military personnel." In 1998, QTC Management Inc. began doing disability exams for the VA. Its work was criticized as being overly expensive at the time. In 1999, Principi joined the company as CEO. In 2000, Principi was nominated to be VA secretary. During his confirmation hearings, he said he had "terminated all relationships with QTC and waived any and all future rights and benefits that could flow from [his] relationship with that organization."

After he became VA Secretary, Principi formed a task force to assess the processing of veteran's claims. According to the Times, "the panel lauded QTC's performance and recommended that the medical exam program continue or expand. Principi said he had nothing to do with that review or the recommendation. The head of the panel later was appointed top deputy to Principi. The favorable Principi task force report was cited as justification for language inserted into the2003 VA budget authorizing continuation and expansion of the program."

"The VA awarded a new contract to QTC after giving rival contactors 30 days to submit proposals. No other bids were submitted. Some competitors said they learned of the new contract only after it was awarded." Later, "the VA has made multiple amendments to two successive QTC contracts, increasing the number of approved sites for the exams and thereby adding to the contract's value."

After Principi left his position at the VA, he returned to QTC, becoming chairman of its board.

Yesterday, the Los Angeles Times also reported that Democratic members of the House Veterans Affairs Committee have called for an investigation of these financial arrangements, and the head of the American Federation of Government Employees union called Principi's actions, "conflict of interest in its most extreme form." Today, the Times reported that Rep. Harvey Waxman (D - California) is seeking all documents relating to communications between the VA and QTC.

Although it may be too early to be definitive about all the details of this case, this is a reminder that conflicts of interest in health care may not be limited to physicians getting hand-outs from pharmaceutical and device companies. Conflicts may affect leaders of all sorts of health care organizations as well as physicians, and the effects of such conflicts may be proportional to the influence of such leaders.

"An Imbalance of Power Between Company Owners and Managers": The Case of Pfizer Inc.

The New York Times published two stories about the battle over the management of Pfizer Inc. , the world's largest drug company. (Pfizer and the Proxy Adviser, and Investors vs. Pfizer: Guess Who Has the Guns?)

The background is that a coalition of Pfizer investors is upset over the lavish compensation of Pfizer CEO Hank McKinnell, who the Times reported has received $65 million in pay since he was hired in 2001, and is scheduled to collect on a $83 million pension. Over the time McKinnell has been in power, Pfizer has suffered a 46% decline in market value. So the angry investors are waging a campaign to dethrone those who sit on the Pfizer Board of Directors' compensation committee, which sets McKinnell's pay. (See this link for its membership.)

Per the Times (Investors vs. Pfizer), "The Pfizer battle, experts say, illustrates an imbalance of power between company owners and managers that is prevalent today. 'The management has these unlimited resources to fight back, and the shareholders are pretty much powerless,' said John C. Bogle, founder of the Vanguard Group. 'The thing has gotten so out of hand that words almost fail me. The shareholders should not tolerate it.'"

There are several illustrations of this imbalance of power.

The Relationship Between Pfizer and Proxy Governance Inc.

The Times' first article discusses the complex relationships between Pfizer and a firm called Proxy Governance Inc. This is the newest of three firms which provides advice to institutional shareholders, banks, mutual fund companies, and the like, about how to vote their proxies (which in many cases they vote on behalf of individual shareholders). Proxy Governance is the only one of the three major such companies to support the current members of the Pfizer Compensation Committee. The Times reported that Pfizer CEO McKinnell wrote a memo in 2004 "urging corporations to buy and promote Proxy Governance's services just as the firm was opening for business, raising questions about whether the advisory firm's Pfizer recommendation reflects an unbiased point of view or a relationship with the company and its top executive." McKinnell also serves as Chairman of the Business Roundtable, and wrote the memo in that capacity. The founder of Proxy Governance said that the memo had no bearing on the firm's opinions about Pfizer. The Times also noted that "William C Steere Jr., Pfizer's chairman emeritus and one of its directors, is a member of Proxy Governance's policy council. The firm said that he did not participate in any matters involving Pfizer." "In addition, the Business Roundtable, headed by Mr McKinnell, was Proxy Governance's first subscriber, buying about 160 subscriptions to its service for its members." Finally, "James P. Melican, Proxy Governance's chairman until recently, represented the Business Roundtable in a private meeting with Cynthia A. Glassman, an S.E.C. commissioner, in October 2003, as the firm was being created." The Times report thus raises questions whether Pfizer secured support for its incumbent directors through conflicts of interest affecting Proxy Governance and its leadership.

The Relationship Between Pfizer and Institutional Shareholders

The Times also reported that Pfizer has complex relationships with its institutional shareholders. Recall that these companies hold considerable number of Pfizer shares on behalf of individual stock holders, or pension owners. The Times quoted Mr. Bogle again, "ownership of American corporations ... has moved from a diffuse group of individual shareholders into a handful of powerful financial institutions such as mutual funds and banks." He said it "is a clear conflict of interest they face in managing the retirement plan assets of the very corporations whose shares they own and collectively control."

So, per the Times, "conflicts of interest are not always evident, of course, but the potential for them arises at five investment firms among the top 10 holders of Pfizer chares. These are companies that earn money from Pfizer by managing some part of its pension plan, retirement savings plans or employee 401(k) accounts. And Pfizer directors serve on the boards of three investment firms that hold enough of Pfizer stock for their customers to be among the company's top 20 shareholders."

Specifically,

• "Pfizer's top shareholder is Barclays Global Investors, holding 4.54 percent of the stock outstanding. It also manages three funds offered to Pfizer employees in various 401(k) plans and provides investment management services to Pfizer's pension, from which it generated $2.65 million in 2004...."
• "Fidelity Management and Research, which holds 1.62 percent of Pfizer's shares for its customers, also manages several funds offered in Pfizer 401(k) and savings plans."
• "Dodge & Cox, holder of almost 1.3 percent of Pfizer's shares, manages a stock fund offered to Pfizer employees in various 401(k) plans and provides investment management services to Pfizer's pension, for which it uearned $1.06 million in 2004."
• "Northern Trust, holder of 1.35 percent of Pfizer's shares, made approximately $2 million as trustee of the company's pension and savings plan. It also manages an index fund for Pfizer employees in Puerto Rico."
• "J.P. Morgan Chase, holder of 1.26 percent of Pfizer shares, generated $750,000 in fees from the drug company's pension plan."
• "TIAA-CREF, the money management firm that counts [Pfizer director Stanley O.] Ikenberry as president of its board of overseers, also voted alongside Pfizer's board last year."
• "Other Pfizer directors also serve on boards of financial service firms, such as Goldman Sachs, a holder of 0.82 percent of the company's shares; J. P. Morgan Chase; and trust units of Deutsche Bank, which holds 1.36 percent."

Summary
The Times articles suggest that conflicts of interest may affect the management and governance of Pfizer, and may help to support the lavish compensation of Pfizer's CEO while the financial performance of the company lags. None of these articles dealt with Pfizer's main business, selling pharmaceuticals, the quality of its products, how it markets them, or the research it performs. But these articles do raise questions, once again, about the priorities of the leadership of large health care organizations, and whether the interests of the top (hired) managers are put before those of others, including share-holders on one hand, and patients and physicians on the other. In a time when health care is decreasingly affordable and accessible, while the leaders of health care organizations become increasingly wealthy, such questions need to be raised.

More About UMDNJ Leaders Feathering Their Own Nests

Has it really been almost three weeks since we posted about the University of Medicine and Dentistry of New Jersey (UMDNJ)? UMDNJ now is operating under a federal deferred prosecution agreement with the supervision of a federal monitor (see most recent posts here and here.) We had previously discussed allegations that UMDNJ had offered no-bid contracts, at times requiring no work, to the politically connected; had paid for lobbyists and made political contributions, even though UMDNJ is a state institution; and seemed to be run by political bosses rather than health care professionals. (See post here, with links to previous posts.)

There are yet more revelations about how UMDNJ leaders feathered their own nests.

Some concern one New Jersey State Senator Wayne R Bryant (Democrat - Camden County). According to the Philadelphia Inquirer, "in 2003, the college's School of Osteopathic Medicine in Stratford created a program-support coordinator job for Bryant. Investigators are looking into allegations that Bryant improperly used his position as Chairman of the Senate's budget committee to direct millions in state funds to the school." Furthermore, "legislative sources say that as the state budget was finalized last June, Bryant steered a last-minute $2.7 million to the Stratford school for debt service. In addition, Bryant also paved the way to increase a state allocation to UMDNJ's Robert Wood Johnson Medical School in Camden, for a total of $7.8 million, as well as a $5 million appropriation for the Newark campus' Neurosciences Institute...."

Others arise out of more findings by the federal monitor who is now overseeing UMDNJ. According to the indefatigable Newark Star-Ledger, the monitor's latest report has more about Dr R Michael Gallagher, the former Dean of the School of Osteopathic Medicine (mentioned above). "Investigators concluded that the osteopathic school near Camden systematically falsified profit and loss statements - at Gallagher's direction - to show the headache center [which Gallagher ran] was making money, thus making Gallagher, whose salary is $381,854, eligible for the annual bonus." Also, the investigators reported that Gallagher "submitted travel expenses to the university for reimbursement that had already been picked up by drug companies." The report also included a variety of lavish expenses for which Gallagher was reimbursed by UMDNJ, such as an expensive leather computer case for his wife, a night at the Waldorf for Gallagher and his wife, and the now familiar meals at exepnsive restaurants and country clubs.

Also according to the Star-Ledger, the monitor alleged UMDNJ Trustee Donald Bradley, who is also Newark City Council President, pushed UMDNJ to "further his political activities." He persuaded UMDNJ to underwrite a gala affair entitled "Keep the Dream Alive." It cost over $22,000, including $2550 for a martini bar and ice sculptures. "The event apparently violated state policy, which prohibits publicly funded institutions from holding receptions honoring any state employee - which would have included the UMDNJ staffers who were celebrated at the event - or expenses for alcoholic beverages...." Bradly also applied pressure to secure jobs for favored people at UMDNJ. "Bradley would often personally accompany people he recommended for jobs on interviews. Among those were his daughter-in-law, who was hired and subsequently fired." Finally, the monitor questioned "whether Bradley forced UMDNJ to sublet medical office space it leases at 194 Clinton Avenue in Newark to Chandrakant Patel, a physician and contributor to Bradley who operated Universal Industrial Clinic until he lost his medical license." "Top [UMDNJ] administrators were told they should provide physicians and medical imaging equipment to enable Patel to establish a federally qualified health clinic at the site. According to the report, the city council president told one that if she assisted in the effort, he could make 'go away' a separate city lawsuit against UMDNJ...." "UMDNJ has never tried to collect $75,000 in real estate taxes Patel was obligated to pay under the token lease...." The University was never even paid its symbolic lease payment. "It is owed $3 by Patel."

UMDNJ has unfortunately become a prime example of how the leadership can bring a once respected health care organization low by putting their own interests ahead of the institution's mission. At least we can hope that the ongoing clean-up will provide a model for how to clean up other errant health care organizations. Once again, my sympathy is with the dedicated UMDNJ staff who have tried to soldier on through all of this, and of course with the patients who still need to go to UMDNJ for their health care.

Financial Ties of the Members of the Tysbari Advisory Panel

The Boston Globe reported that a new law designed to "limit industry influence" on the US Food and Drug Administration (FDA) have not had much effect. The law requires disclosure of financial ties to relevant organizations by participants on the FDA's advisory panels, but allows the FDA to seek waivers to let those with such ties serve on these panels.

The news article focused on ties affecting an advisory panel that recommended that Tysbari, a drug for multiple sclerosis, made by Biogen Idec and Elan, be allowed back on the market. Five of 12 had relevant financial relationships. It quoted Dr Karl Kieburtz, the chairman, who is a consultant to Biogen Idec, "All behavior is guided by conscious and unconscious motives. Consciously, I'm not aware of of any swaying of my decision-making based on the fact I did consulting for Biogen Idec within the last year." Kieburtz noted that he received no more than $12,000 for consulting, which was not related to Tysbari or multiple sclerosis, and he gave the payments to his institution, the University of Rochester, or charity. Another member of the panel, Dr Steven DeKosky, "said he didn't know he had a conflict until he filled out the FDA's disclosure forms in which he had to list all the work he'd done recently for industry." DeKosky "disclosed he'd received less than $10,001 as an industry sponsored speaker and was paid less than $10,001 by Pfizer Inc. as a visiting professor. Until the FDA issued his waver, DeKoskey said he did not know that a rival MS drug is made by a company that has a financial agreement with Pfizer." The article also reported that "other Tysbari advisers reached by the Boston Globe who received FDA waivers said drug industry funding did not influence their votes."

The FDA's stance was that trying to get the most expert to serve on the panels requires recruiting "scientists with drug industry sponsorship. Barring those researchers would result in smaller panels with less expertise."

However, Merrill Goozner, director of th Integrity in Science Project for the Center for Science in the Public Interest, (and author of the blog, GoozNews), thinks that the FDA should issue no waivers, "Period. End of story. Get rid of scientists with conflicts from serving on the FDA advisory panels."

A while back we posted on an article in JAMA (Brennan TA et al. Health industry practices that create conflicts of interest: a policy proposal for academic medical centers. JAMA 2006; 295: 429-433.) that argued that practicing physicians should be barred from receiving even gifts of trivial value (the proverbial pen or coffee mug with the company logo on it) because

social science research demonstrates than the impulse to reciprocate for even small gifts is a powerful influence on people's behavior. Individuals receiving gifts are often unable to remain objective.

If there is concern that getting a coffee mug with a company logo might affect a practicing physician's decision making, there surely ought to be a concern that getting $10,000 for consulting, giving a talk, or being a visiting professor, even if that money ultimately goes to one's employer, may affect the decision-making of a member of an influential national committee. As both a recent NY Times op-ed, and the JAMA article argued, the effects of gifts or other payments may not be conscious, so the recipients may not honestly be conscious of their effects. (Dr Kieburtz seemed to acknowledge that possibility above.) Thus, that their recipients deny that the gifts had conscious effects is of little comfort.

Thus, if the goal is unbiased decision making, Merrill Goozner's "just say no" approach to panel members with conflicts of interest seems justified.

(Full disclosure: I own more than $10,000 worth of stock in Elan.)

Financial Relationships Among Authors of the Psychiatric Diagnostic and Statistical Manual and Pharmaceutical Companies

A new study about conflicts of interest affecting the writing of important medical texts has been widely reported in the media, although the study is not yet available (as far as I can tell, on the web).

Based on New York Times and Washington Post reports, the study was a cross-sectional study of the prevalence of financial links to pharmaceutical companies among the authors of the latest (1994) full edition of the American Psychiatric Association's Diagnostic and Statistical Manual (DSM). This text is the authoritative guide to the definitions of psychiatric diseases. Apparently, the investigators searched through publicly available data, including "legal files, patent records, conflicts-of-interest databases and journal articles," covering 1989 to 2004, according to the Times. From these records, they were not able to determine the time course of the authors financial connections to the drug companies.

They found that 95/170, 56% of authors had some financial relationship to at least one pharmaceutical company from 1989 to 2004. They found higher prevalences of such relationships among authors "who worked on sections of the manual devoted to severe mental illnesses, like schizophrenia...," according to the Times.

The Post reported that "Darrel Regier, director of the association's division of research, said that concerns over disclosure are a relatively recent phenomenon, which may be why the last edition, published in 1994, did not note them. Regier and John Kane, an expert on schizophrenia who worked on the last edition, agreed with the need for transparency but said financial ties with industry should not undermine public confidence in the conclusions of its experts. Kane has been a consultant to drug companies including Abbott Laboratories, Eli Lilly, Janssen and Pfizer Inc. 'It shouldn't be assumed there is a true conflict of interest,' said Kane, who said his panel's conclusions were driven only by science. 'To me, a conflict of interest implies that someone's judgment is going to be influenced by this relationship, and that is not necessarily the case....'

Furthermore, again per the Post, "at least one psychiatrist who worked on the current manual criticized the analysis. Nancy Andreasen of the University of Iowa, who headed the schizophrenia team, called the new analysis "very flawed" because it did not distinguish researchers who had ties to industry while serving on the panel from those who formed such ties afterward."

In summary, Sheldon Krinsky, a study author, said, "When someone is establishing a clinical guideline for the bible of psychiatric diagnosis, I would argue they should have no affiliation with the drug companies in those areas where the companies could benefit from those decisions."

There is reason to be concerned that the data in this study may have reflected financial relationships that did not occur at the time the authors worked on the manual. Yet no better data about the time course of these relationships may have been available from public sources. In retrospect, one could criticize the study investigators for not directly querying the DSM authors about their financial relationships. But would all the authors have answered them? And would an academic institutional review board approved such a study?

It may very well be true that DSM authors with financial ties to drug companies honestly believed that these ties did not bias their work. On the other hand, some cognitive psychologists have found that people do not believe that conflicts of interest affect their thinking, yet such effects may occur, but not be consciously acknowledged. A recent op-ed article in the New York Times summarizing this work stated, "research suggests that decision-makers don't realize just how easily and often their objectivity is compromised. The human brain knows many tricks that allow it to consider evidence, weigh facts and still reach precisely the conclusion it favors."

Finally, and again commenting without having seen the actual research paper, in thinking about conflicts of interest, one has to consider all the parties involved. This leads to questions including: Did the editors and publishers of the DSM try to limit the involvement of authors with conflicts? Were the authors under pressure from their academic institutions to develop more financial ties with pharmaceutical companies to help "support their salaries?" Did the pharmaceutical companies develop the ties to the authors because of their work with DSM, or for entirely unrelated reasons?

US Health Insurance: More Market Domination, More CEO Compensation

Among US health insurers, the rich just get richer...

A new report from the American Medical Association documented the increasing consolidation of the US health insurance market, if that is what it should be called. As reported by the Baltimore Sun, "in each of 43 states, a handful of top insurers have gained such a stronghold that their markets are considered 'highly concentrated' under US Department of Justice Guidelines, often far exceeding the thresholds that trigger antitrust concerns. The study also shows that in 166 of 294 metropolitan areas, or 56 percent, a single insurer controls more than half the business in health maintenance organization and preferred provider networks underwriting." Furthermore, "critics say that carriers are not only creating monopolies and oligopolies in many regions, they also control the other side of the equation in what is known as monopsony power. That means in addition to having the most enrollees, they're also the biggest purchasers of health care and can dictate prices and coverage terms." The results is "double-digit premium increases from 2001 and 2004 - peaking with a 13.9 percent jump in 2003 - soaring well above inflation and wages increases." But the federal government so far seems uninterested in addressing this concentration of economic power: "AMA officials say regulators seem uninterested, even though government officials are more than willing to target doctors' groups and hospitals on antitrust matters."

The rising rates insurers and managed care organizations can charge as they increasingly dominate individual markets have helped fuel an even faster rise in the compensation given to their top leaders. The Wall Street Journal reported (available here through the Pittsburgh Post-Gazette) on the stunning good fortune of the CEO of UnitedHealth Group, Dr William McGuire. "He draws $8 million in salary plus bonus, enjoying perks such as personal use of the company jet. He also has amassed one of the largest stock-option fortunes of all time. Unrealized gains on Dr. McGuire's options totaled $1.6 billion, according to UnitedHealth's proxy statement released this month. Even celebrated CEOs such as General Electric Co.'s Jack Welch or International Business Machines Corp.'s Louis Gerstner never were granted so much during their time at the top."

The article reported the company's board's willingness to furnish such largesse. "Dr. McGuire has pursued stock-options wealth tirelessly, as an iron-willed leader surrounded by an admiring board." "'We're so lucky to have Bill,' says Mary Mundinger, a UnitedHealth director who sits on the company's compensation committee. 'He's brilliant.' She says his income gives him extra credibility in health-policy debates because it shows his success. 'He needs to be compensated appropriately so that his business model has believability in the market,' says Ms. Mundinger, who is dean of the nursing school at Columbia University."

We have posted before (here, here, and most recently here) on Dr McGuire's amazingly remunerative career as a hired employee of UnitedHealth. Each post was based on new evidence that suggested his position was even more remunerative than had been heretofore believed. However, his spectacularly lavish compensation stands now in stark contrast to the stated mission of UnitedHealth Group:

UnitedHealth Group is a diversified health and well-being company dedicated to making the health care system work better. The company directs its resources into designing products, providing services and applying technologies that:
- Improve access to health and well-being services;
- Simplify the health care experience;
- Promote quality; and,
- Make health care more affordable.

I do not understand how the company can makes such claims when it has directed $1.6 billion of its resources into Dr McGuire's cache of stock options.

Finally, we have written before about Dean Mary Mundinger of Columbia University's School of Nursing. Her academic writings advocated advanced practice nursing, advocacy that may fit the financial interests of UnitedHealth Group, since advance practice nurses are paid less than doctors. Yet she has not acknowledged her fiduciary duty to UnitedHealth Group as a member of its board of directors in her written academic work. It will be up to the stockholders of UnitedHealth Group to determine if her enthusiastic support of the CEO's huge compensation package is the best fulfillment of that fiduciary duty. One wonders whether she and other directors who also have allegiances to academic organizations and/or who write about health policy (including Donna Shalala, President of the University of Miami, [see post here,] and Gail Wilensky, Senior Fellow at Project HOPE, see list here) may be less inclined to rein in CEO compensation than those with less divided interests. Whose interests their academic and health policy work serves remains equally open to questions. But conflicts of interest inevitably raise such questions.

A Plea for Ethical Behavior Addressed to Health Care Leaders

HealthLeaders Media published a plea for better ethics in the health care business. The author was Fred Goldstein, who described himself as a president of a disease management company, and former hospital administrator, and HMO senior executive. His title was, "'The Word of Those With Whom We Do Business:' The State of Ethics in Healthcare. His introduction included:

IÂ’ve experienced a lot of what is right with the American healthcare system. But I have also seen enough fraud, abuse and unethical behavior to sicken even the heartiest soul. This characteristic of American healthcare is far too prevalent, and it undermines our efforts to control cost, build access and--most importantly--assure quality care.

He then went on to list a variety of examples of unethical behavior, starting with "pharmaceutical companies have paid for and published studies in distinguished professional journals, but left out results that reflected poorly on their products," and ending with "many healthcare executive have enjoyed extraordinary compensation while fraud and abuse occurs, and is even encouraged under their watch."

Most of the examples will be familiar to readers of Health Care Renewal, although Goldstein named no names. He seemed to leave out some particularly egregious examples, especially involving leaders of hospitals and academic medical centers (e.g., UMDNJ operating under a deferred prosecution agreement, see most recent post here), and pharmaceutical companies' extensive efforts to manipulate the clinical evidence base (e.g., see this recent post). He also seemed to bend over backwards to give doctors (an equally bad) time, (e.g., criticizing doctors' failure to practice evidence-based medicine as an ethical flaw, rather than a result of inadequate training, limited resources, and external pressure). But all in all it was a pretty good list of examples.

Goldstein further noted that:

Unethical behavior exists among healthcare organizations and professionals of all types. Organizations that try to do the right thing are often outmanuevered by those that do not. Self-interest is often hidden behind a facade of patient concern.

Worse, these self serving behaviors have become so common that professional outrage has been dulled. But to save healthcare, we can't just take these acts for granted. The prevalence of inappropriate actions in healthcare drives additional margins in the industry's supply, delivery and financing sectors. It is at the root of our cost explosion and our healthcare crisis. And, it is based on an ingrained acceptance of unethical behaviors.

Yet he failed to provide a ringing plea for change:

The recent movement toward transparency and quality reporting will shine a bright light on some of these practices, and should tone down the environment of opportunism. But many of these behaviors have been well known for years. I have little faith that, with so much money at stake, any reforms can be substantial enough to turn around the industry. This is especially true if change does not support and engage much more participation from payers and consumers.

I am not naive and do not expect that a plea for ethics will have much impact.

It's nice to see something about the ethics of health care show up in a place where health care organization leaders might notice it. It's too bad that it contained a list of anecdotes that named no names, pulled its punches, and seemed to bend over backward to give weight to physicians' misdeeds. It's also too bad that its call for solutions was somewhat muted, and did not include health care professionals. But despite these criticisms, or this carping perhaps, Goldstein's piece was a real step forward. I wonder if any health leaders will listen?

Thanks to the Health Care Blog for the tip.

Evidence About How Commercial Firms Control the Research They "Sponsor"

Last week's Journal of the American Medical Association (JAMA) had a short, but very important article on how the commercial sponsors of clinical trials may manipulate how the trials' results are disseminated. [Full citation: Gotzsche PC et al. Constraints on publication rights in industry-initiated clinical trials. JAMA 2006; 295: 1645-46.]

The investigators reviewed the original trial protocols from all "industry-initiated randomized trials that were approved in 1994-1995 by the Scientific-Ethical Committees for Copenhagen and Frederiksberg in Denmark and that resulted in publication." The investigators also reveiwed all resulting trial publications. They similarly reviewed all 2004 protocols (but not publications, as it is too early for their results to be published).

43 of 44 trials from 1994-5 had "multinational pharmaceutical firms as sponsors." For half of the trials, the protocol assured that the sponsor would own the data and/0r would need to approve any manuscript submitted for publication. 41% of trials had other constraints by the sponsors on publication, such as requirements that the sponsor review the manuscript, or that the sponsor's views must be represented in the manuscript. 61% of the 2004 protocols required that the sponsor would own the data and/or would need to approve any manuscript submitted for publication, and 32% had other constraints.

Furthermore, the investigators noted that none of the constraints on publication found in trial protocols in 1994-5 were mentioned in the articles published about the trials. But none of the trial publications "stated that investigators had access to all of the data generated from the trial or had final responsibility for the decision to submit for publication without requiring approval from the sponsor."

We had posted a while back about the study by Mello and colleagues that showed that many US medical schools and academic medical centers would be willing to contractually cede control over aspects of clinical research, and publications resulting from such work to the work's commercial sponsor. That study was of what academic contracting officers said they were willing to do. This new study was of how clinical research was actually designed. It shows that in Denmark most clinical trial protocols as early as 1994 had already ceded substantial control over publication of trial results to commercial sponsors. The studies' nominal "principal investigators" did not have full control over the data they collected, nor over what they could say about it in print. And none of the investigators were apparently able to even publicly acknowledge their lack of such control.

This quantitative study adds to vivid, but case-based data (such as that of the unfortunate case of Aubrey Blumsohn's inability to get the data from his own research from the work's commercial sponsor, as per this post) suggesting that the ostensible sponsors or funders of research increasingly control how the work is done, and how the results are disseminated.

Thus it gets harder and harder to trust that published clinical research studies sponsored by commercial firms are not manipulated by studies' sponsors to produce results favorable to their financial interests. There is more and more reason to be concerned that the altruism of the people who volunteer to participate in human clinical research may be exploited. Patients and physicians need to be increasingly skeptical of the results produced by commercially sponsored research, and applying them to clinical decisions.

If we cannot persuade commercial research sponsors to let researchers do their work unaffected by commercial interests, then the only alternatives may be the heavy hand of government regulation, or even an outright ban on commercial firms having any role in clinical research.

"Mismanagement" in Another Rhode Island Health Care Organization

Here is a local Rhode Island story, reported by the Providence Journal, with all too familiar elements.

Rhode Island's dominant workmens' compensation insurer is Beacon Mutual Insurance Co, a not-for-profit corporation chartered by the state to provide affordable insurance. After a whistle-blower made the first ever call to the company's 1 1/2 year old hot-line last year, the company's auditor began to raise questions about the conduct of a firm, Temporary Manpower Services, owned by Beacon Mutual's former Board Chairman, Sheldon Sollosy. Beacon Mutual then commissioned an outside review. According to the Providence Journal, among its findings were:

• "Beacon executives maintained a VIP list of about a dozen companies, some of which received favorable treatment resulting in lower workmens' comp rates. Beacon's president, Joseph A Solomon, denied the list's existence... but then told another Beacon executive to delete it from his computer."
• Beacon paid some favored insurance agents at a higher rate than called for by their contracts.
• Chairman Sollosy resigned in February after "refusing to provide the insurer with payroll records for the company he owned, Temporary Manpower Services. His refusal, 'ignored' by Beacon management even though it violated Beacon policy, made it imposssible to determine whether Sollosy's company paid the rate it should have."
• " Beacon's president Solomon had granite countertops installed in the kitchen of his East Greenwich house by a company that received undocumented breaks on its workers' comp insurance. An executive of the stone-working company told investigators that the $10,000 Solomon paid for the kitchen work didn't cover the total cost."
• "Solomon and three Beacon insurance agents used Beacon funds to help pay for a trip to the exclusive Carnegie Club at Skibo Castle in the Scottish highlands three years ago. Solomon said in an interview that Beacon spent $19,000 on the trip. "
• Beacon seemed to deal with some other corporations in a particularly favorable way. For example, "he report also questioned Beacon's due diligence in checking the payrolls and job classifications at Lifespan [the state's largest hospital system], by far its largest policyholder, with nearly $5 million in premiums last year. Lifespan's three-year guaranteed rate was 'highly unusual and not customary,' the report said. "
• "The report also explored, but came to no definitive conclusion about, various financial dealings between Beacon and political operative Guy Dufault. Dufault's Cornerstone Communications, a Beacon consultant that occupied a rent-free office in Beacon's Warwick headquarters, charged Beacon $90,000 from 2001 to 2005 for "special projects" that lacked adequate documentation, the report said. "

After the report was released, again per the Journal, RI Governor Donald Carcieri called for a "complete overhaul" of Beacon Mutual's management. "Carcieri said the report was 'replete with examples of mismanagement more than sufficient to justify these actions,' and he was 'particularly concerned' by allegations that Solomon 'attempted to obstruct the board's very own internal audit.' He said the board members who have 'presided over this mismanagement' -- since 1994, in some cases -- should resign voluntarily, regardless of how much they actually knew about the alleged abuses. 'As directors for over a decade, they were either complicit in the abuse or they were incompetent in not stopping it. Either is reason enough for their removal,' Carcieri said."
The next day, the Journal reported that Beacon Mutual's board accepted the resignation of one member, and suspended CEO Joseph A Solomon and the Vice President for Underwriting David Clark. Stay tuned for more developments.
Again, this case has all too familiar elements: a not-for-profit health care corporation whose management seemed to play favorites, grant itself special perks, pay local political figures for undocumented work, and then seek to conceal some of these practices. In little Rhody, this case follows on recent scandals at Roger Williams Medical Center, (see this post and earlier ones) and Rhode Island Blue Cross (see this post and earlier ones) , and the punishment of Brown University and Memorial Hospital of Rhode Island faculty member David Kern for refusing to suppress his research on a new occupational disease (see this post).
This again demonstrates the needs to push health care non-profit corporations to more transparent and accountable governance, and to put mechanisms in place that encourages management to behave ethically.

Leapfrog Over What?

In the US, large employers have become more vocal about the need to control the cost of their employees' health care, for which they pay, and improve its quality. Leading the charge on this one has been the Leapfrog Group, which announces itself as "an initiative driven by organizations that buy health care who are working to initiate breakthrough improvements in the safety, quality and affordability of healthcare for Americans." The Group proclaims that "today, doctors and hospitals are paid without regard to the quality or affordability of the care they provide. This practice discourages efforts to deliver better and more efficient care. Leapfrog and our members are working to create real incentives to improve care through new payment practices. We also encourage consumers to choose high quality health care providers."

In a 2005 article in Health Affairs written by Robert S Galvin (director of corporate health care at General Electric), and Suzanne Delbanco (CEO of the Leapfrog Group), the authors proclaimed, "large employers can play a unique role in theU.S. health care system, using private-sector purchasing approaches to procure health benefits for their employees. Most employers believe that the appropriate use of market forces, such as public disclosure of physician and hospital performance measures, incentives to create price- and quality-sensitive consumers, and rewards for better care, is the optimal way to control costs and improve quality." So, " in 2000 a small group of large employers formed the Leapfrog Group to address these shortcomings in the market. They developed purchasing principles to deliver a new message to health plans and providers about the imperative of swift action to "leapfrog" over the current state of poor value."

The Leapfrog Group describes its members thus "Leapfrog has over 170 members who are made up of Fortune 500 companies and other large private and public organizations that provide health benefits for their employees, retirees and dependents. Together they spend nearly $67 billion each year on health care for 36 million Americans in all 50 states." Perusual of the Leapfrog Group's membership list does include some prominent, large corporations that employ many people, for example, Citigroup Inc, and Qwest Communications International Inc.

(It also includes many health care related companies, including pharmaceutical companies like AstraZeneca, Eli Lilly, GlaxoSmithKline, Merck and Co, and Schering-Plough, and managed care companies, like Aetna Inc, Cigna, HCA, Humana, and UnitedHealthGroup, just to name a few, which may have particular interests in quality and affordability issues beyond those entailed by their status as large employers who pay for their employees' health insurance. But that is for another day.)

Thus a recent article in the Wall Street Journal (available here from the Pittsburgh Post-Gazette) adds some irony for this Friday. The article is about how "former top executives at many corporations are receiving partial or full lifetime medical coverage on top of pensions valued at millions of dollars." Furthermore, "companies often provide their top executives with more generous health-care plans than other full-time employees get and then continue to provide the richer benefits through retirement." Most of these benefits are not clearly disclosed by the companies' public filings. Two relevant examples:

• "Citigroup Inc. promised to pay the premiums and out-of-pocket expenses for both health and dental care for Chairman Sanford I. Weill and his wife now, and it will continue to provide those benefits for the rest of the Weills' lives, the company's proxy statement says. Citigroup will also continue to pay for any taxes Mr. Weill owes on the imputed income arising from these benefits. A company spokeswoman says the benefit dates back to a 1980s contract and isn't available to other executives."
• "Regular employees who lose their jobs can apply for continued health-care coverage under Cobra, the federally mandated requirement that employers of a certain size allow departed employees to remain in the company health plan for some 18 months. However, the coverage, which can cost more than $1,000 a month, can be too expensive for laid-off workers." However, "Qwest Communications International Inc., pay[s] 100 percent of executives' Cobra costs, according to filings. A Qwest spokesman confirms those details but declines to comment."

Not to be too heavy-handed, but as mentioned above, Citigroup Inc, and Qwest Communications International Inc are both members in good standing of the Leapfrog Group. It looks like some large employers' concerns about controlling the costs of health care do not apply to their top employees. Top executives of such corporations may be well insulated from the sorts of concerns about health care that affect their employees. Yet it is the top executives, not the employees, who are represented in such organizations as the Leapfrog Group. Any changes that the Leapfrog Group manages to make in the provision of health care to their employees are not likely going to affect these top executives. So what is it, again, that the Leapfrog Group wants to leap over?
But as F Scott Fitzgerald said, "the very rich are different from you and me."

Some Themes Emerge from the Problems at the University of California

Several recent reports help our understanding of the recent problems at the University of California - Irvine (UCI) medical center, and more broadly, in the University of California (UC) system. (See recent posts on UC here, and here, and on UCI here.)

The Los Angeles Times reported that "UC Irvine is beginning program-by-program reviews of its medical center, hiring consultants and launching its search for top health care officials, recommendations made by a panel of outside experts that reviewed the university's troubled medical programs." The new Chancellor, Michael V Drake, reiterated, "there was a 'failure of leadership and accountability' and poor oversight." Concretely, UCI is starting searches for a vice chancellor for health affairs and for a health care ombudsman "to make it easier for faculty and staff at the hospital to report problems. An interim ombudsman is working part time."

Perhaps some impetus will be added to these efforts by reports that the US Federal Bureau of Investigation (FBI) is investigating UCI ( also per the LA Times.) Meanwhile, the Ocean County Register published a long review of events at UCI. It first noted, "The residue for UCI is a hospital with a damaged reputation and low morale." David Magnus of the Stanford Center for Biomedical Ethics commented, "When you get that many problems, that speaks to a problem of institutional culture. There needs to be a pretty dramatic overhaul of that culture to proceed in an ethical fashion."

The history leading to the current problems was telling.

Until the early 1990s, UCI Medical Center's primary mission was to be the hospital that served Orange County's neediest residents. That was both a practical and historical remnant of a hospital that was founded in 1912 as Orange County Hospital and Poor Farm.

'Its image remained steeped in its history as Orange County's 'hospital of last resort.' Back then, a dedicated but underappreciated faculty and staff provided care exclusively for the county's poor and underserved in a tired and drab facility.' [said former CEO Ralph Cygan]
The nation's adoption of managed care as a medical-industry standard in the early 1990s threw UCI Medical Center and other hospitals into financial and operating crisis. For a time, UC officials considered leasing or selling UCI Medical Center to a private company.

That plan was abandoned in 1997. But all UC medical centers (including UC San Diego, UC Davis and UCLA) were ordered to bring in more middle-class patients with private insurance, reducing the hospital's reliance on government payouts for indigent patients.

Partly as a way to maintain its role serving the county's poorest residents, UCI worked to develop other ways to bring in more income.

In 1999, UCI spent six months drafting a new strategic plan for the medical school and hospital that sought to increase market share and research funding, and improve medical education, yet also cut costs. The new strategy called for UCI to start investing in "high-profile clinical programs with high potential for market impact, return on investment" and referrals.

Yet, while the hospital has rapidly expanded from a small operation into a giant, multi-tentacled enterprise, questions have arisen about whether oversight has kept up with growth.

Meanwhile, the San Francisco Chronicle reported the assessment of a task force on how UC compensated its leadership across the system. It concluded, "The recent disclosures ... lead (us) to conclude that, at least as regards compensation, neither the executives who lead the university nor the regents who oversee it have done all they could or should to fulfill their respective or shared responsibilities." Former state Assembly Speaker Robert Hertzberg, co-chair of the task force, said, "In this competitive environment where you want to bring in the best and the brightest, there was just a breakdown in terms of full disclosure. But it was a significant breakdown."

Putting this all together, there seem to be some themes:

• A leadership culture that "lacked accountability" seemed to be a problem across the UC system, and at UCI in particular.
• Despite demoralization induced by this leadership culture, faculty, physicians, staff, and students generally tried to do their best in trying circumstance.
• The leadership culture may have to some extent derived from a broad impetus within society to push not-for-profit, academic institutions to "compete."
• Making things better will require major improvements in leaderships' accountabilty and transparency.

These are familiar themes on Health Care Renewal.

New UK Research Integrity Panel Formed in Response to Blumsohn - Procter and Gamble - University of Sheffield Case

A new UK Panel for Research Integrity in Health and Biomedical Sciences has just been launched, per the Guardian. The panel will support the self-regulation of institutions, but will also "support whistleblowers alleging research fraud." The inspiration for the panel partially came from the "example of Aubrey Blumsohn.... "

We had posted a while back, and then more recently here, about the story of Dr Aubrey Blumsohn's dispute with Proctor and Gamble (P&G) and the University of Sheffield in the UK. In summary, Blumsohn and Professor Richard Eastell had done clinical research on the risedronate (Actonel), sponsored by P&G, the drug's manufacturer. P&G refused Blumsohn access to the original data from the study he was ostensibly running, and hired a ghost-writer to write abstracts in his name. Blumsohn protested to Eastell, who advised him not to make waves because P&G "is a good source of income" for the university. When protests to other university officials produced no results, Blumsohn told the story to the press, whereupon the university suspended him.

While announcing the new panel, Professor Michael Farthing, the Principal of St. Georges Medical School of the University of Londong, noted that Blumsohn was a "very sophisticated whistleblower who could not find an ear. Instead of taking it seriously, [the university] suspended him." Farthing also noted that it was "a great embarrassment in the UK" that there was no organization to "audit research misconduct." Furthermore, Professor Sir Ian Kennedy stated, "The UK's research community needs to demonstrate its integrity in the conduct of research. The poor practice and misconduct of a few undermine public confidence and can put volunteers and patients at risk."

Well said. This sounds like a step, albeit perhaps belated, forward. Maybe Dr Blumsohn will yet have a chance to appeal to this panel. Unfortunately, it was constituted too late to prevent the TGN 1412 calamity.

The unfairness of Merck's current problems

I was reading Yahoo finance today and came upon this Reuters article: "Study shows how painkillers raise heart risk." At the top of this article was the banner "Reuters.com: No spin. No agenda. Just the facts. As they happen."

Right, I thought.

However, this banner got me to thinking about the "spin" that has caused a proud pharmaceutical company to suffer the indignity of the VIOXX trial losses and accusations of impropriety, and events such as this, "Merck May Face Criminal Probe in New Jersey."

This is unbelievable.

While I worked at Merck, I can state will full confidence that people there, including the senior Merck Research Labs personnel I worked with, were both ethical and highly concerned about the safety of the products they produced. Dr. Ed Scolnick, for example, then president of Merck Research Labs, was a consummate clinician and scientist, and it was clear to me he would have chewed the head off anyone who dared even think to compromise on patient safety issues. I saw it personally, just with reference to matters of science. Dr. Scolnick had his ways.

Dr. Scolnick commissioned me to establish a web-based worldwide training program in scientific information retrieval, which I did, to bring all Merck scientists to a basic level of competence in information searching. He felt this essential towards good science, and that included safe science.

The issue of VIOXX is one of science, not of malfeasance. While I will not go into the issues of what should have or could have been reported to FDA, for example, I believe honest difference of opinion was involved in decision making, not malfeasance.

The only problem I believe Merck may have had was one of overconfidence, of resting on past laurels. As head of the Merck Research Labs libraries 2000-2003, I noted upon my debut that there were informatics tools (cheminformatics, science literature retrieval, etc.) that were not, in my view, adequately available. CAS SciFinder, for example, critical to basic and preclinical phases of discovery (at least), as well as MDL/Beilstein Crossfire, were not widely available to scientists.

SciFinder and the other computer databases have really gutted the rationale for committing large numbers of transformations to memory. It's important to know what sorts of things can be done, but there's little point in memorizing exactly which reagents do them and what journal they appeared in. You can always look that up, and when you do you'll likely find a dozen alternatives that you didn't even know about.

The CrossFire Beilstein* database is the world's largest compilation of chemical facts. As the cornerstone database to organic chemistry, the CrossFire Beilstein database is essential for generating new leads, planning synthetic routes (including starting materials and intermediates), determining bioactivity and physical properties and ascertaining the environmental fates of compounds.

I set out to convince my management that additional funds were needed to substantially increase access to these tools, using a detailed and comprehensive department-by-department analysis, testimonial from scientific leaders as to the critical nature of such access, and comparisons to competitors where access was greater. I received only about one third of what I sought from the VP who headed research computing (who had difficulty understanding the ROI), although in the end I obtained a global unlimited license to Beilstein and significant increase to SciFinder with the limited funds.

I believed then, and believe now, that this represented the effect of overconfidence. In the past, Merck's scientists had invented fantastic drugs without such tools. It was thought they could continue to do so. In reality I believe that the "low hanging fruit" were largely picked, and to move beyond them required new informational tools.

One other symptom of overconfidence was in the background of that VP who oversaw research computing. That person had no background in medical science. As I've pointed out in my writings, in biomedical computing a person's skills and abilities should match their position and authority. However, that is a matter of opinion, not of unchallengable fact. This issue culminated in the closure of one of the research libraries last year in the Rahway site in the belief that eJournals were sufficient, something I'd advised against when I was there, and which I found out about from displaced employees.

As an information scientist I had my views, and the decision makers theirs. Again, the VP's making the decisions simply had a different opinion from mine. These decisions were not made in any negative light.

It's likely any perceived problems related to VIOXX clinical trials adverse events were, at worst, due to this issue and nothing more.

I believe it is extremely unfair for issues related to honest opinion, however those opinions were driven, to be spun into stories about unethical practices. Merck's leadership and line personnel were all highly committed to patient safety. The current sad events represent the abuses of the tort system, with which physicians are all too familiar, and represent a severe loss to biomedical science and the innovation that companies like Merck are capable of when not confronted by legal manipulation.

We will all suffer for this.

-- SS

What Did Parexel Tell the Participants in the TGN 1412 Trial?

We previously posted about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG. All six healthy volunteers who got the antibody soon became critically ill. We recently reported an account of an interview with one of the participants which serious questions about whether research subjects were adequately informed about the nature of the trial and its possible risks, and why the investigators continued to administer the drug after the first subjects had begun to experience adverse effects (see post here).

Bloomberg news just reported on the consent form used in the trial, raising even more issue about what the participants were told or understood about what could happen to them. These issues are summarized below.

Risks Not Revealed - Bloomberg showed the form to several medical ethicists. Michael Goodyear stated, "they [the trial investigators] failed to to adequately disclose the degree of uncertainty around a first-in-man trial. The risks were well known. They were not disclosed in the consent form." Arthur Caplan, of the Center for Bioethics at the University of Pennsylvania, said, "they hid the most serious threats with bland language." Parexel countered only by saying that the UK Medicines and Healthcare Products Regulatory Agency (MHRA) "has done an exhaustive inquiry of Parexel and confirmed that the trial was run according to the approved protocol." However, Bloomberg noted "the agency says its investigation didn't include a review of the consent form."

Participants Questions Deflected - Bloomberg reported that study participant Raste Khan claimed that Parexel staff deflected questions, saying "we're in a bit of a push. Can you sign now, and I'll explain it all to you."

Proportion of Patients to Receive Placebo Not Explained - Khan also said, "They didn't tell us how many placebos there were, so I just thought it was 50/50." Caplan called this a "'major' ethical violation to withhold the actual chance of receiving the drug."

Drug Not Described Clearly in Lay Terms - The drug was described as "a 'monoclonal antibody,' which means that it is an antibody (a naturally produced protein) that has been designed by scientists to target a particular type of cell -- in this case, a type of white blood cell called T-cells.'' Caplan retorted, "I've read a lot of consent forms and I don't understand this." Goodyear noted that the consent form never clearly said what the drug would do, specifically never stating that the drug would stimulate the immune system, and suggested that comparing the drug to aspirin and ibuprofen was also misleading.

Adverse Effects Minimized - "Parexel's consent form says the drug, called TGN 1412, was designed to treat arthritis, other inflammatory illnesses and leukemia. The form says that 'no significant side effects had been seen in the animal studies.' "I think it was misleading not to tell participants that that this drug was genetically engineered from hamster cells and that it was designed to alter their immune system,"' commented Goodyear. "Reasonable people would think twice before allowing an experimental drug to change their immune system.''
Furthermore, the form described a cytokine burst as akin to hives. Goodyear responded, "Since monoclonal antibodies are know to cause Cytokine Release syndrome, which can be fatal, and Parexel was not even planning for this, the subjects should have been warned." Parexel's response, again was "the MHRA found no deficiencies during its inspection of Parexel's Phase I unit at Northwick Park Hospital that would have contributed to the adverse reactions experienced by the study volunteers.''

Possible Coercion - "Ethicists say the consent document exploited the participants' need for cash. The first page of the consent document says participants can leave the trial at 'any time without giving a reason and my rights will not be affected.'' On page 9, the document says, 'If you leave the study and exercise your right not to give a reason or are required to leave the study for non-compliance, no payment need be made to you.'
'That's very coercive language,'' says Greg Koski, 56, a physician and former head of the U.S. Office for Human Subject Protection, interviewed by phone April 5. 'It's a bait and switch.'"

Failure to Identify Ethics Committee Which Approved the Trial - " Parexel's TGN 1412 consent form omitted the name and contact information for the Brent Medical Ethics Committee, which approved the consent form and supervised the trial." Caplan noted, "The participant needs to know who to contact. There has to be a source of independent advice. They are defeating the entire purpose of having an ethics committee if you can't find it.'' The MHRA investigation did not cover the role of the ethics committee.

Referral to an Irrelevant Pamphlet - " Parexel's consent form advised subjects to read a pamphlet published by Consumers for Ethical Research, a London-based advocacy group. Naomi Pfeffer, chair of the organization, says the booklet shouldn't be used for healthy volunteers as it was written as advice to sick people considering treatment through a clinical trial."

Revelations about how Parexel failed to inform, or misinformed subjects in the calamitous TGN 1412 trial, coupled with previous reports about how SFBC International, another contract research organization, treated its trial subjects (most recent post here), suggest that commercial contract research organizations need to be much more closely regulated and supervised than they are now. And it may be time to question the whole notion of commercial firms doing clinical trials of drugs and devices.

Addendum (14 April, 2006): The Lancet just published a lead editorial that summarized the TNG 1412 trial, and concluded, "the TGN 1412 events indicate that urgest change is needed in the approval processes and regulation of phase I trials of biologic agents." [Anonymous. Urgent changes needed for authorisation of phase I trials. Lancet 2006; 367: 1214.]

Indictment For Promoting GHB, the "Party Drug"

Newsday reported last week that a New York psychiatrist was indicted for allegedly participating "in a nationwide scheme to promote the prescription drug Xyrem to physicians ... for unapproved medical purposes and to conceal the fact from insurance companies." The indictment further alleged that the physician "conspired with the company that made Xyrem, Orphan Medical Inc, in Minnetonka, Minn., to promote it for unapproved uses including chronic pain and weight loss. Orphan Medical allegedly relied on ... [him] to give lectures promoting Xyrem to physicians and paid him tens of thousand of dollars to do so."

Xyrem is the trade-name for sodium oxybate, better known as gamma hydroxybutyrate, or GHB, which is popularly known as a "party drug" and has been linked to date-rape. It has been approved by the US Food and Drug Administration (FDA) only for a narrowly defined group of patients with cataplexic narcolepsy, under strict conditions (see the relevant FDA site here.)

The physician's attorney said "our client adamantly maintains his innocence and looks forward to his day in court."

Note that Orphan Medical Inc has actually been acquired by Jazz Pharmaceuticals. Newsday noted "although physicians can prescribe drugs for a variety of uses, pharmaceutical companies may only market them for FDA-approved treatments." Yet, the news article was silent about any actions being taken in response to the pharmaceutical company's role in the allegedly "nationawide" "health care fraud and conspiracy." This silence is especially curious because of the singular dangers posed by this particular drug. Stay tuned on this one.

Thanks to for Capsules for the tip.

Hopkins Retreats from Cosmetics Venture

Recently, we posted about Johns Hopkins Medicine's unique collaboration with a cosmetics manufacturer.

After the relationship was publicized and criticized, the Baltimore Sun reported that Johns Hopkins quickly decided to revise it. Johns Hopkins will no longer receive stock or a seat on the board of directors of the cosmetics company. Hopkins asked that company marketers "withdraw all references to JHM (Johns Hopkins Medicine) except for certain limited information - on product packages and in previously printed promotional material - that disclose JHM's consulting role," although so far the Sephora web-site's page for Klinger Advanced Aesthetics Cosmedicine has not been modified (as of April 10, 2006).

Johns Hopkins has to get some credit for deciding to rapidly retreat from some of the most questionable parts of this relationship, which was criticized for being irrelevant, and possibly at odds with the institution's mission, and for posing a (possibly unique new form of) conflict of interest.

Papers from the Disease-Mongering Conference Now Available

We were happy to announce a while back that the Inaugural Conference on Disease-Mongering would be held in Newcastle, New South Wales, Australia, from 11 to 13 April, 2006.

Now we are also pleased to announce that a list of papers from the conference is available today from PLoS Medicine on the web here, and the links to the papers should go live later today. The papers look interesting, and we hope to report back on them after we have had a chance to read them.

The TGN 1412 Trial "Raises a Number of Big Red Flags"

We previously posted about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG. All six healthy volunteers who got the antibody soon became critically ill (see our most recently here). The International Herald Tribune has done some investigative reporting on this trial.

First, the Tribune confirmed that TeGenero, the manufacturer of TGN 1412, was aware prior to the trial of the possibility that subjects might undergo "cytokine release syndrome" after taking the drug. This syndrome had apparently been observed in some animal testing, although the species of primates tested did not manifest the syndrome. TeGenero, however, felt that this reaction was "not expected," in the human trial.

The Tribune interviewed a survivor of the trial, who stated:

• He believed "he was participating in a fairly standard trial of a painkiller like ibuprofen, for arthritis."
• He said that "the novelty of TGN 1412 never came up in upbeat pre-trial briefing, adding: "I had no idea it altered the immune system.'"
• "At Parexel's orientation meeting there was little time to read the study's 11-page consent form before signing, Rob O. said. Headaches and bruising were listed as potential side effects, as well as the possibility of a severe allergy. But that risk was downplayed."
• Once the trial was underway, the investigators continued to dose subjects even after the first subjects had started to experience adverse effects. "About the time Rob. O's infusion started, at 9:10 am, the first patient had actually passed out in the adjacent room...." charged one of the subjects' attorneys.
• Since the trial, "the companies [TeGenero and Parexel] have been unwilling to meet with the trial subjects or provide more data...."

The Tribune quoted Dr Michael Ehrenstein of University College London, who said that human research on TGN 1412 was "a high risk strategy." Michael Goodyear, described as an oncologist and medical ethicist at Dalhousie University, Halifax, Nova Scotia, Canada, said that the conduct of the trial "raises a number of big red flags."
Nonetheless, Dr Ezekiel Emanuel, Chief of Clinical Bioethics at the US National Institutes of Health (NIH) , said "This is a terrible tragic event but so far I don't see any clear ethical problems." (Note that Emanuel formerly expressed indignation when the NIH made conflict of interest rules more stringent, so that his secretary would no longer be allowed to keep stock holdings in health care companies worth more than US $15,000, as noted in this post.)
In my humble opinion, this newspaper article raises further serious questions about whether research subjects were adequately informed about the nature of the trial and its possible risks, and why the investigators continued to administer the drug after the first subjects had begun to experience adverse effects.
Hopefully, further investigations will afford more transparency, and will lead to improved conduct of trials that put the interests of patients ahead of the imperative to "speed your product through clinical development." (The latter phrase is currently a promise made by Parexel on its web-site.)

Transparency International's New Site on Corruption and Health

Transparency International just put up a new, extensive web-site on corruption and health care. It will take me a while to peruse the whole thing, but a quick skim reveals clear explanations of the major issues, an extensive set of on-line text references, and an interesting set of links. It appears to be a unique resource. Please have a look.

Also, note that Transparency International's site now includes a page for World Health Day 2006, whose slogan is "the cure for corruption in the health care industry starts with transparency" The World Health Day web-page includes a tidy summary of the problem of health care corruption, plus a series of useful recommendations.

Johns Hopkins: The Most Trusted Name in ... Skin Care?

The Baltimore Sun and the Wall Street Journal reported (the latter available here via the Pittsburg Post-Gazette) the latest venture by the revered Johns Hopkins University. They are collaborating with a cosmetic company whose products will be labeled as produced "in consultation with Johns Hopkins Medicine."

The Cosmedicine "premium skin-care line," per the Journal, will be sold by Sephora, a unit of LVMH Moet Hennesy Louis Vuitton, and manufactured by Klinger Advanced Aesthetics, a unit of TrueYou.com Inc. According to Dr Edward Miller, Chief Executive of Johns Hopkins Medicine and Dean of the School of Medicine (and also on the board of directors of Bradmer Pharmaceuticals, a Canadian biotechnology company), "We have been pretty clear about our role. We are reporting on the scientific validity of studies done by outside testing agencies." But, according to the Journal, "Johns Hopkins will also work with Klinger to develop clinical 'best practices for the company's chain of spa-clinics." Their offerings include "'light medical' services, such as Botox and Restylane shots...."

The Cosmedicine web-page proclaims, "Cosmedicine, the only skincare line tested for performance and safety in clinical studies designed and analyzed in consultation with Johns Hopkins Medicine, a world leader in healthcare, education, and research."

The idea of the Johns Hopkins collaboration developed out of Klinger CEO Rich Rakowski's idea of developing products "through the lens of healthy skin and not anti-aging." The company "adopted what he calls a 'healing strategy' for its products." The company decided it wanted to offer products with "measurable" benefits, and then approached Johns Hopkins to help with the measurements. The Journal reported that Professor Frederick Brancati, Chief of the Division of General Internal Medicine, championed the collaboration, but had to work "to overcome significant faculty opposition."

Prof Brancati "and other officials declined to disclose the fees Johns Hopkins Medicine received from Klinger or to estimate how much revenue the venture may one day bring. Klinger, a unit of a publicly traded company, TrueYou.com, Inc., plans to give the institution a yet-to-be-determined equity stake." The Sun also reported that the University will get a "board seat."

According to the Journal, the motivation to work with Klinger was Hopkins' "need for funding the traditional research and teaching mission." Prof Brancati said, "that is what sold it for me and to the leaders of the institution. We have to be innovative and creative" The Sun reported that Brancati "hopes his division might get a six-figure sume from the deal to help fund its mission, which includes care for the poor."

The deal has drawn criticism now that it has been made public.

Product Endorsement (as a Mission Violation) - One issue is that Hopkins' role appears to be close to endorsement of a product. The Journal quoted Prof Arthur L Caplan of the University of Pennsylvania Department of Medical Ethics, "unless you have acute vision and a lot of time to read [the small print], this is going to look like a product endorsement." The Sun quoted Mildren Cho of Stanford Center for Biomedical Ethics, "what is the consumer supposed to take away from the fact that Hopkins' name is attached to this product?" The Sun also quoted Dr Amy Newburger, a practicing dermatologist, "this is a weapon of mass promotion. The university's name is going to be used to promote this [product] ... to the exclusion of other, perhaps more effective products that have not forged a relationship with the university." Unsaid here, but important is that the university appears to be endorsing a product in exchange for money, in apparent contrast with its academic mission to conduct free and honest inquiry. In contrast, the Sun quoted Rakowski, "they are not endorsing this product, nor have I asked them."

Conflict of Interest - Caplan also stated that it would be a conflict of interest to "study what you own." The Sun quoted Dr Marcia Angell, former editor of the New England Journal of Medicine, "you can't evaluate a product that's made by a manufacturer that's hired you. The thing is riddled with conflict of interest." Johns Hopkins Medical Dean Miller countered by saying that the Hopkins scientists who are examining Cosmedicine data do not personally own equity shares in the company that makes the product, although they do received consulting fees of an undisclosed size.

Irrelevance to Mission - Finally, the Sun quoted Dr Peter Lurie of Public Citizen Health Research Group charged, "it's an educational institution that's willing to completely stray from its true function, whic is to do education, research, and provide clinical services."

In my humble opinion, the criticisms are apt. It particularly saddens me that a division of general medicine within a wealthy university, whose budget is $2.4 billion, endowment, $1.695 billion, and hospital and health system revenue, $1.661 billion apparently feels so impoverished that it needs to help sell cosmetics to raise money to support its basic academic mission.

JCAHO Defines (Hospitals' Quality of Care) Deviancy Down

The Los Angeles Times reported how the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) has lowered their quality standards for hospitals. Apparently after getting "better-trained inspectors and switch this year to surprise reviews," JCAHO found they were finding more problems when they inspected hospitals. So, Joseph L Cappiello, Vice President of Accreditation Field Operations for JCAHO, said, "we shouldn't deny accreditation to 10 or 15 or 20% of all hospitals in the United States." Instead, they have increased the allowable number of deficiencies.

US Senator Charles E Grassley (R-Iowa), Chair of the Senate Finance Committee, commented, "goverment investigators have already documented that the Joint Commission misses too many serious problems and rarely drops any hospital's accreditation. This move to weaken standards seems to be going in the opposite direction of what makes sense for quality of care."

We physicians hear more and more about how many errors we allegedly commit, and about how our reimbursements will soon be subject to pay-for-performance (see previous post). Yet while physicians feel ever increasing pressure to increase quality of care, when more stringent hospital inspections find more problems, the hospital inspectors decide that they will make their grading standard more lenient. How curious.

The LA Times article did note that JCAHO is paid by the hospitals it inspects, and "owns a consulting business that helps hospitals prepare for its reviews." In a previous post, we also noted reports of other possible conflicts of interest affecting JCAHO. These possible conflicts are important because the federal government has given JCAHO responsibility for most evaluations of hospital quality. Do these possible conflicts of interest have anything to do with what could not be called JCAHO's defining down (hospitals' quality of care) deviancy? Once again, inquiring minds want to know.

Addendum (14 April, 2006): In a letter to the LA Times, Dr Dennis S O'Leary, Presidence of JCAHO, stated that "this article misses the markin in suggesting recent changes ... reflect a relaxation in performance expectations for hospitals." He noted, "the changes in the review threshold are simply designed to assure that the right hospitals are the subject of intensified review. The changes are part of a series of steps being taken to refine the accreditation decision process. Pending their finalization, no adverse decisions for hospitals evaluated in 2006 have yet been rendered. This will begin to happen in May. Because nothing has happened yet, there have been no expressed concerns among accredited organizations about the new process, and the joint commission has received no pressure from any source to make its accreditation process more rigorous."

A Report Leaves Many Questions About TGN 1412 Unanswered

We previously posted about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG,. All six healthy volunteers who got the antibody soon became critically ill.

Our first post noted that little was known about how the trial was designed, and about who had reviewed the ethical aspects of its protocol. A later post summarized questions posed in a BMJ editorial, including how were research subjects recruited and motivated, what were they told about possible risks, why were healthy volunteers rather than patients recruited, and why were all patients given the drug simultaneously? The BMJ editorial, a Lancet editorial, and our first post all called for more openness and transparency in drug research.

Now the UK Medicines and Healthcare Products Regulatory Agency has issued an interim report. (See news articles in the Times [UK], Nature, and the Boston Globe.) Basically, the MHRA "ruled out contamination, overdose, and procedural problems," as per the Globe. But it revealed nothing more about the trial protocol, nor how it was reviewed. For example, the Globe stated that "Parexel spokeswoman Jill Baker said that she couldn't comment on the design of the trial, but it had been approved by health authories and reviewed by an ethics committee in Britain." None of the other news accounts provided any other answers to the questions above.

The main conclusion of the report was that "the drug TGN 1412 caused an unprecedented and unexpected reaction that did not occur in tests on animals," per the Times. This seems to be stating the obvious. The questions remain whether this unprecedented and severe adverse drug reaction could somehow have been anticipated by perusal of animal testing data or understanding of the science behind development of the drug; or whether the adverse drug reaction could have been reduced by a differently designed or implemented trial?

The Telegraph reported that a lawyer for two of the trial participants is not happy. Ms Ann Alexander said "the MHRA's report gives no detailed information about the pre-clinical trials, about which there has been conflicting information since the trial was suspended."

So there is still little transparency to this trial. We still do not know the results of testing the antibody in animals, the design of the trial protocol, the justification for aspects of the trial design, or who reviewed the ethical aspects of the protocol.

This sad case still illustrates how commercially sponsored pharmaceutical research often remains hidden behind the veils of trade secrecy and business confidentiality. If pharmaceutical companies really want patients and physicians to trust them more, they should start making their human research more transparent.

UMDNJ: "A Political Patronage Pit"

We have posted extensively at the troubles at UMDNJ, which now is operating under a federal deferred prosecution agreement with the supervision of a federal monitor (see most recent post here.) We had previously discussed allegations that UMDNJ had offered no-bid contracts, at times requiring no work, to the politically connected; had paid for lobbyists and made political contributions, even though UMDNJ is a state institution; and seemed to be run by political bosses rather than health care professionals. (See post here, with links to previous posts.)

The federal monitor, former federal Judge Herbert J Stern, has issued his first quaterly report, and the findings are stunning. We will summarize them below, as compiled from several news articles listed at the end of the posting.

High Officials Resign After Allegations of Financial Irregularities

The first fall-out from the report were the resignations of R Michael Gallagher, Dean of the UMDNJ School of Osteopathic Medicine, and Robert Saporito, the UMDNJ Senior Vice President for Academic Affairs. UMDNJ's new Interim President, Bruce C. Vladek, is considering barring them from returning to academic positions at the school.

Gallagher's resignation means that all of UMDNJ's medical and osteopathic schools will be operating under interim deans. Gallagher is alleged to have made improper use of his discretionary account to purchase Christmas gifts and a country club membership, and to have his university driver run personal errands for him and his wife.

Saporito was the top academic officer for the university, overseeing all three medical and osteopathic schools, the nursing and dental schools, and three others. Saporito is alleged to have abused his expense account, once by renting an Alfa Romeo for a business trip, and other times for renting local hotel rooms for purported late night meetings

Additional Overbilling Found

UMDNJ has already been charged with $4.9 million worth of Medicare fraud. Last month, the monitor suggested a possible Medicaid scandal worth another $70 million. The report now suggests that UMDNJ received another $51 million from the state to which it was not entitled. The amounts that UMDNJ's University Hospital may now owe could threaten its financial viability.

Job Applicants Ranked by Political Connections

The report also detailed a system to formally rank job applicants for UMDNJ positions by the political clout of their sponsors. Applicants sponsored by powerful politicians received a ranking of "1" on a personnel spreadsheet, while those sponsored by less powerful figures, or none at all, received rankings of "2" or "3." The system began under former UMDNJ President John Petillo, who said that the system was intended as "a courtesy." University employees, however, "saw the ranking system as a codification of what had been going on for decades." The system was in operation for about six months.

Politicians whose sponsorship rated a ranking of "1" included US Congressman Robert Menendez (Democrat - New Jersey), New Jersey State Senator Raymond Lesniak (Democrat - Union), and sometimes Newark Mayor Sharpe James (Democrat). Other political patrons identified included Essex County Chief Executive Joseph DiVincenzo, former chief counsel to the governor Paul Fader, husband to Newark Councilwoman Gayle Chaneyfield-Jenkins, Kevin Jenkings, Essex County Democratic Chairman Philip Thigpen, and Newark Councilman Charles Bell.

Sponsors sometimes accompanied their applicants to interviews. Sometimes human resource administrators hand delivered favaored applications to supervisors.

James did not return a call for comment. Neither did Jenkins or Chaneyfield-Jenkins. Menendez denied ever hearing about the ranking system prior to the public report of it. Lesniak said he only recommended one person to UMDNJ, and not for political reasons. Thigpen did not "recall" anything relevant. DiVincenzo forwarded his daugher's resume, but said she did not apply to the university.

When Interim President Vladek heard about this method of institutionalizing political favors, he said "I couldn't believe it," and "it's one of the more astonishing things I've heard."

Suggestions of Organized Crime Involvement

The most stunning aspect of the report were allegations that now former Vice President for Academic Affairs Saporito, sometimes accompanied by former UMDNJ President Petillo, dined on three occasions with a convicted criminal with ties to organized crime, and charged the meals to the university. Their dinner partner was one Louis Garruto, who was convicted in 1985 of a multi-million dollar fraud against some drug companies. The charges included racketeering and income tax evasion. NorthJersey.com also reported that "in the 1990s Garruto's partner in a firm that did business with Passaic County was James Yacenda, who was linked to the Lucchese crime family by the State Commission on investigation."

Summary

In summary, John Ingelsino, a lawyer working on the investigation, said, "the auditing and compliance were grossly deficient, and that aided in creating an environment where UMDNJ has been used as a political patronage machine." Furthermore, "it was a place that was used, by and large, as a political patronage pit."

The news about UMDNJ gets worse and worse. It has become one of the most striking cases of an academic medical institution run by conflicted leadership, ultimately to the point of corruption. It is now evidenct that the conflicts of health care leaders may involve politics as well as money.

The problems at UMDNJ apparently evolved over decades, yet only were discovered in 2005 after some energetic investigative work by local newspapers. The case at UMDNJ underlies the need to prevent conflicted and corrupt leadership from taking hold of health care organizations, or at least to discover it before decades go by. Yet such institutions still too often lack formal codes of ethics, ombudsmen or chief ethics officers, and methods for physicians, health professionals, and others to complain about unethical practices. Current licensing and accrediting standards do not seem to address these sorts of ethical issues.

As a society, we will not be able to develop the means to persuade health care leaders to be more ethical, however, until physicians, patients, and policy makers are aware of the frequent mismanagement and corruption afflicting the top echelons of health care organizations. For that to happen, cases like that of UMDNJ must be reported beyond their local areas. So, where is the medical journal brave enough to publish even a single news item on this case? So, where is there a medical or health care leader brave enough to even mention the case of UMDNJ in public? We are still waiting.

Sources

Newark Star Ledger: 2 top UMDNJ execs quit as probe widens; UMDNJ may bar two ousted execs; UMDNJ ranked job applicants on political ties; UMDNJ finances in sad shape; how UMDNJ became a 'patronage pit';

New York Times: report finds patronage rife at university

NorthJersey.com: med school executives dined with racketeer

Philadelphia Inquirer: UMDNJ monitor cites 14 inquiries