BLOGSCAN - Pfizer Exclusive Clinical Research Contract Story Based on a Misinterpretation

Last week we ran a "Blogscan" summary about a story that Pfizer Inc would be demanding that sites performing clinical trials for the company not perform trials for other companies. Now, this post on the PharmaLot blog asserts that this story was based on a misinterpretation of a Pfizer executive's remarks. The executive stated "we would never do exclusive deals," and "it's not our policy, now or in the future." So all the blogs that picked this one up, including Health Care Renewal, stand corrected.

BLOGSCAN - More Conflicted Members on FDA Advisory Panels

On GoozNews, Merrill Goozner posted about the US Food and Drug Administration (FDA) advisory board convened to discuss a prosthetic spinal disc manufactured by Medtronic. Two members of the panel have financial links to Medtronic competitors, while one has links to Medtronic. Goozner wondered whether this will remind congress of importance of restricting conflicts of interest affecting these groups that have such influence over the approval of drugs and devices in the US.

"Paying for Access" to Academic and Health Care Leaders at the Tamaya Sustainability Operations Summit

The New York Times just reported on a conference for "university, school, and hospital officials" with an interesting feature. Potential vendors to these institutions were charged very pricy registration fees that guaranteed them one-on-one access to particular officials. In the words of the Times reporter Alan Finder,

The setting for a conference of university, school and hospital officials could not have been more luxurious: a resort in the high desert north of Albuquerque, with a championship golf course, swimming pools, a spa and views of distant mountain peaks.

And for companies wanting to do business with the 200 or so officials attending the gathering, the Sustainable Operations Summit, there was an added benefit.

For $18,500, a vendor was guaranteed 15 one-on-one sales meetings with officials at the conference, held here in June. A company that sent two representatives paid $25,500, with each promised 15 private sessions. The university officials and others who were attending were told flatly that they were required to go to the meetings.

'We’re just organizing an opportunity and a format to encourage discussion and relationships among people,' said Craig Lehmann, a co-founder of the company that organized the event.

CraigMichaels Inc., ... created the sustainability summit. CraigMichaels essentially borrowed the format, which is used by a number of companies promoting conferences that link corporate executives with companies wanting to sell them goods and services, and expanded it to universities and schools.

A year ago, the online publication Inside Higher Ed raised questions about the ethics of the format. But the company has continued its conferences, and many university officials still attend.

The sustainability conference here at the Hyatt Regency Tamaya Resort & Spa, where Al Gore was one of the featured speakers, mixed university, school district and hospital officials who paid roughly $1,000 for three days.

The company gave conflicting accounts of how many half-hour meetings with businesses each official had to attend. Mr. Lehmann, the company president, said at least five were required. Michael P. Owens, the company’s director of production, said there was no minimum number, although people were asked to attend more than one or two.

Each participant was asked beforehand to select at least 10 companies out of the 29 at the event with which he or she would be willing to meet. Vendors were asked to do the same, and CraigMichaels officials then matched them up.

The company’s employees, dressed in blue polo shirts with a CraigMichaels logo and communicating with each other via tiny microphones and earpieces, made sure with a gentle insistence that attendees kept their appointments with the companies, which were promoting solar power or environmentally sensitive roofing, lighting, and heating and cooling systems.

'Why would you let a third party trade on your name and your office?' said Barmak Nassirian, an associate executive director of the American Association of Collegiate Registrars and Admissions Officers. 'I really would have to question if it’s ever appropriate for a third party to charge a fee for an appointment with me.'

Richard A. Hesel, a principal of the Art & Science Group, a marketing consultant to colleges, put it more bluntly: 'This is a form of trying to buy influence. People are paying for access.'

But Susan Jurow, a senior vice president of the National Association of College and University Business Officers, said she did not see a problem, so long as university officials paid to attend the events.

All of the university officials interviewed at the environmental conference saw it that way, too. 'It doesn’t bother me,' said Lisa Glover Henderson, director of energy initiatives at the University of Rochester. 'That’s part of the world we live in today. I don’t think there is a conflict.'

Although the Times article did not describe how many attendees were from health care organizations or had links to academic medicine, its web-site included a link to participant testimonials that included glowing words from an official of Boston University, whose Medical Campus includes the School of Medicine, and School of Public Health, and Presbyterian Healthcare Services, based in Alberquerque, NM. The senior vice president for hospital strategy and national facilities for the large not-for-profit managed care organization Kaiser-Permante delivered a talk, according to the organization's newsletter.

This story seems similar to that of the HRDI scandal (see post here). Once again, representatives of commercial firms that might want to do business with health care organizations (and universities and local governments) get enhanced access to officials who might be able to make purchasing decisions for a hefty fee. As Richard A Hesel said above, it appears to be "paying for access." There may be less polite words for it, but words more fraught with legal meanings.

As an aside, I can't figure out why the university, health care, and government officials would want to attend, given that attendance requires one-on-one sessions with prospective vendors, although maybe the setting was so luxurious that the $1000 registration fee seemed a bargain. But clearly there is reason to think that companies which paid for their representatives to meet academic and health care officials at this luxurious setting may have an inside track on selling goods and services to their organizations, regardless of the price or quality of those goods and services.

The impression created by this story is of academic and health care leaders who are part of a "power elite," attuned to luxuriating with their prospective vendors, but perhaps not to maximizing the resources needed for their missions of discovering and disseminating knowledge and caring for the sick.

Naming a Public Health School After A Health Insurance Company

Sometimes, you just can't make this stuff up. The Des Moines (Iowa) Register reported,

The University of Iowa is considering naming its College of Public Health after the Wellmark Foundation, the charitable arm of Iowa's largest health insurance company, Wellmark Blue Cross and Blue Shield, in exchange for a $15 million gift from the foundation.

Part of the proposed $15 million gift would supplement $20.7 million in state money being put toward a new $44.7 million building to house the public health college. The rest would provide endowed professorships and scholarships at the college.


But the Wellmark deal, if approved, would make the U of I the only public university in the state - and one of few in the country - to give a major academic unit a corporate name.

The Board of Regents would make the final decision on whether to rename the College of Public Health.

The faculty of the college overwhelmingly approved a resolution Thursday that expresses appreciation for Wellmark's offer but says the faculty does not want the college named after Wellmark. 'We did not think being named after an insurance company was in our best interest,' said James Merchant, the U of I's dean of public health.

Professors who attended a faculty meeting last week voiced concerns about whether the Wellmark name would be appear to be a conflict of interest for a college that researches health-related issues, Fuortes said.

As best as I can tell, Wellmark Inc, is a for-profit Blue Cross/ Blue Shield licensed insurance company, albeit a mutual company that is supposed to be owned by the policy holders.

The Wellmark School of Public Health: it has a certain hollow ring to it, doesn't it?

It does seem that naming a school of public health for a for-profit health insurance corporation makes the institutional conflict of interest a bit more in your face. Whether it is more important than, say, having the university president sit on a for-profit health insurance company's board of directors (e.g., see this post), is open to question. But give the majority of University of Iowa faculty extra credit for recognizing the problem that a Wellmark School of Public Health would create.

And give the University of Iowa administration special points off for devising a new and very public sort of institutional conflict of interest affecting health care.

ADDENDUM (9 July, 2007): Wellmark Foundation just withdrew the offer, citing lack of "unwavering support from both the College and University administrative leadership," according to the Des Moines Register.

BLOGSCAN - The Tenth Anniversary of the Case of Dr David Kern

On the Scientific Misconduct Blog, Dr Aubrey Blumsohn continues to mark the tenth anniversary of the "Dr David Kern affair," one of the most important cases of attempted suppression of research of the late twentieth century. We only posted a bit about this case, for example, here, partly because I am still a Brown University faculty member, albeit a voluntary one, and have never completely lost hope that the Brown University administration will someday see fit to revisit this case. After all, the University mission statement once included, "discovering, communicating, and preserving knowledge and understanding in a spirit of free inquiry." But that may simply demonstrate that even after seeing Dr Kern, who was formerly my direct supervisor, lose his job because he dared to present a case report of a new disease that offended the company at whose plants the disease was occurring, and after blogging on Health Care Renewal for several years, I am still hopelessly naive. Maybe Dr Blumsohn's recognition of the anniversary of this important case will get it the attention it deserves.

BLOGSCAN - Why Not Make Pharma Payments to Physicians Public?

On the Hooked: Ethics, Medicine, and Pharma blog, Howard Brody wonders why if pharma argues that payments to physicians are "all about education," then why they would object to making all such payments public?

BLOGSCAN - A "Quickie" Web-Site for Cymbalta

On PharmaLot, this post describes a web-site that suddenly appeared with favorable information about the drug Cymbalta (duloxetine, manufactured by Eli Lilly). Based on rumors that the site was run by NovaQuest, a subsidiary of contract research organization (CRO) Quintiles Transnational, blogger Ed Silverman sent an enquiry to NovaQuest. The response was that the site had been taken down, but did not address who put it up in the first place. Are such "quickie" unattributed web-sites the latest form of stealth marketing?

BLOGSCAN - Data from Key ADHD Study Destroyed

On the Scientific Misconduct Blog, Dr Aubrey Blumsohn posted about the intriguing Gillberg affair. After a key article on attention deficit hyperactivity disorder (ADHD) was challenged, researchers destroyed the study's data rather than letting it be subject to an outside review (although they claimed that letting outsiders review the data would violate confidentiality assurances given subjects.) The principal investigator eventually was convicted of criminal charges in Sweden. Yet these shaky underpinnings of the popular ADHD diagnosis are not well known, and the journal in whom the key article reporting the study appeared has not been willing to publicly retract or qualify it.

Teaching Businesspeople How to Do What They Ethically Ought to Do

Our local Providence Journal just ran a commentary by Mary Gentile on teaching ethics to business students that seems particularly relevant to Health Care Renewal, since businesspeople, not health care professionals, now run most large health care organizations (see recent post here).

THE FALLOUT from 34 MBA students at Duke University having been caught cheating on an exam recently has put business education in the limelight once again. Business education hasn’t received this much attention since Enron and WorldCom.

But the criticism and rebuttals have focused once more on whether business ethics can or should be taught. Instead, we should focus on teaching business students who already recognize right from wrong how to act on those values in the business world.

Business-ethics courses spend a lot of time teaching ethical theories and analyzing those big, thorny ethical dilemmas....

Rather than viewing ethics courses as a way to 'fix' unethical students, let’s focus on the majority of students who want to act on their values but are not at all convinced that it’s feasible to do so. In their survey of MBA students several years ago, the Aspen Institute found that the majority believed that they would be asked to do things in their careers that would conflict with their values; that this conflict would be stressful for them; and that they didn’t feel equipped to deal with that choice when it arose. These are not students who don’t recognize ethical choices. They are not even people who don’t want to do the ethical thing. In many cases, they simply don’t know how to do it effectively.

For some, 'effectiveness' may mean that they are not systematically disadvantaged for taking their stand. In the case of those MBAs who cheated on their exam, often the excuse is: 'Everyone is doing it so why should I be disadvantaged in the grading curve by not cheating?'

And for others 'effectiveness' may mean doing the 'right' thing in such a way that it makes a positive difference; that is, they don’t want to take a stand (and perhaps take a hit) against 'cooking the books' if someone else is just going to walk in and do it anyway. For both of these groups, ethics discussions need to be less about what’s right and more about how to change the system, whether that means building a coalition of peers or convincing one’s boss (or professor) that there is a better approach.

And some just don’t have any idea what to say when the boss tells them to adjust their financial analysis before sending it to the client, or when team mates ask them to shift reported expenses from one quarter to the next in order to improve the numbers. They know it doesn’t feel right but it seems to be the norm and they don’t have a script at the ready to use, to slow down the action, to open the conversation, to make room for others to express their concerns, too, if they share them.

In research we conducted for a new curriculum, 'Giving Voice to Values,' sponsored by the Aspen Institute and the Yale School of Management, we have learned five important things:

• Many ethical choices are not really 'dilemmas.' That is, many times the 'right' decision is rather clear.

• Pretty much everybody has stories of times when they have, in fact, voiced and acted on their values, as well as stories of times when they have not. That is, we all have the ability to do both; most of the time, we are not talking about 'good' people or 'bad' people.

• We can learn to voice our values more frequently and effectively if we understand the different factors that enable each of us to do so. That is, for some it may be fear of punishment and for others it may be the chance to make a positive difference. And we are more effective when we build on our individual strengths and 'enablers' than when we focus on our weaknesses.

• Too often, classroom discussions of ethics spend more time analyzing what the 'right' thing to do is and what the rationalizations are for not doing it, than they do on crafting potential action plans and 'scripts' to respond to those rationalizations. This time allocation should be balanced, if not reversed.

• Instead of asking 'what would you do?' ethical-case discussions should ask the question 'what if I were going to act on my values? What would I do and say? To whom? How? In what sequence?'

In my humble opinion, the key point is that most people know what they ought to do in an ethical sense, but don't know how to go about actually doing it.

The commentary does beg the question about why it is hard for people to do what they ought to do. Clearly, in many organizational cultures, there are incentives and pressures pushing people to do what they ought not to do.

However, at least making people aware of these incentives and pressures, and giving them some suggestions to cope with them would be a step in the right direction.

Let's see if any business schools take this advice.

Parenthetically, I should note that there are few, at best, courses for medical students that address the sort of ethical issues that we discuss on Health Care Renewal. I would suspect that none of them are focused on teaching medical student how to do what they ought to do.

But teaching physicians in training not only how to turn down the free coffee mug with the company logo, but to challenge a culture that that emphasizes bringing in external funding over all else, might go a long way to renewing health care.

More Than Half of WellPoint's Policy Revocation Decisions Erroneous

We have posted previously about how US managed care organizations and health insurance companies like to publicize their warm and fuzzy qualities, while their track records often suggest that they place profits ahead of concerns about patients' welfare. For example, see this post on the continuing investigation of how Blue Cross in California, a subsidiary of for-profit WellPoint Inc., revoked individuals' health care policies after they made their first major claims.

Now Lisa Girion, writing in the Los Angeles Times, has reported:

BC Life & Health revoked 1,880 individual health insurance policies in California in 2004 and 2005, and a state agency that examined a sampling says it found that more than half the cases it reviewed were improperly handled.

The Department of Insurance said it studied 83 sample cases and issued citations in 49 of them, alleging 67 violations of fair-claims handling laws.

In one case, the department contended that BC Life, a Blue Cross company, told a policyholder in a letter that it rescinded coverage because of an undisclosed medical condition, even though the condition was clearly stated on the individual's application.

In another case, the department alleged that BC Life improperly rescinded a policy after miscalculating the period of time between treatment and the effective date of coverage. BC Life declined to reinstate coverage even after the department brought the error to its attention, according to a report issued by the agency.

The 67 citations could lead to fines of as much as $10,000 per sustained infraction, as well as follow-up examinations.

The report was posted on the department's website last week with little fanfare, even though it had been highly anticipated by consumer advocates and lawyers for policyholders who were suing BC Life and other insurers, challenging the rescissions as unfair and illegal.

The Department of Insurance launched an investigation last year when John Garamendi, now lieutenant governor, was the commissioner. The report marks one of the first occasions on which Insurance Commissioner Steve Poizner, who took office in January, has publicly weighed in on a health insurance issue.

'A rescission can be a financial death sentence when you're ill,' Poizner said in an e-mail. 'In my view, even one improper rescission is one too many. When it comes to rescissions, we are acutely aware that these are people's lives. They're not just numbers to us.'

Asked to comment on the report, a spokeswoman for Indianapolis-based WellPoint Inc., which owns BC Life, noted that the majority of the citations were for 'technical violations of the claims-handling processes' ....

The investigation by the Department of Insurance is separate from the investigation by the Department of Managed Health Care to which our blog post above referred.

That post noted how the insurance company's cancellation practices seemed to conflict with its public promises to improve "the lives of the people we serve."

So this post will note how the recent findings by the Department of Insurance contradict one of the prime rationales for handing control of health care to managers and executives, instead of health care professionals. That rationale, of course, was to bring efficient, competent, rational management to a field often deemed sloppy and wasteful. This was one reason that health care economists and other policy wonks, Stanford Professor Alain Enthoven in particular, wanted to break up the supposed "physicians guild" in the 1980s.

Since then, I know of few efforts to actually determine whether businesspeople's management of health care has met any standards of efficiency or competence. The report by the California Department of Insurance, showing an error rate greater than 50% for health insurance policy revocation decisions, suggests that the notion that businesspeople can run health care competently and efficiently is ridiculous.

But we know that putting businesspeople in control of health care has not restrained cost growth, another rationale for breaking up the guild.

And reading Health Care Renewal ought to provide convincing evidence that businesspeople's management of health care has too often put their own financial fortunes ahead of the needs of patients, and sometimes has been frankly corrupt.

So now that the guild has been broken up, what now, Professor Enthoven?

BLOGSCAN - FDA Official's Disappearing Calendars

On the Clinical Psychology and Psychiatry blog is a post about how top US Food and Drug Administration (FDA) officials kept their official calendars almost blank for almost seven years, apparently concealing how often they met with pharmaceutical company executives. It was explained as just an "administrative oversight." Not much transparency, but ah well, good enough for government work, I guess.

BLOGSCAN- Pfizer to Demand Clinical Trials Sites Only Do Pfizer Trials

On PharmaLot is a post on the new proposal by Pfizer Inc to demand that any site that performs clinical trials sponsored by the company not perform trials sponsored by any other company. This appears to take the commercialization of clinical research to a new level. The company did not address the ethics of this stance, or how it might impact trial participants.

Selling OTC Pharmaceuticals Door-to-Door: A New Stealth Marketing Variant?

A few weeks ago, Brandweek ran a story about a new pharmaceutical marketing idea from Johnson and Johnson:

Johnson & Johnson wants to turn Girl Scout troops into 'drug dealers' —but it's all for a good cause.

The drug giant said it will launch a promotion this month, in which churches, charities and nonprofit groups—such as the Girl Scouts—will be encouraged to sell J&J's painkillers and cough medicine to their friends and neighbors. For every purchase of a J&J brand, including Tylenol, Sudafed, BenGay and Motrin, J&J will donate 8% of the sale to the community group.

It includes all the OTC brands that New Brunswick, N.J.-based J&J acquired from Pfizer in December, such as Benadryl and Listerine.

Here's how it works: The volunteer persuades a neighbor to buy their regular over-the-counter medicine from J&J as part of the fund-raiser. The consumer then goes to Ucareorg.com to punch in the code for their specific fundraising group. After that, any product they buy will benefit the community group. (Info is at Ucare's Web site.)
'We're always looking for new, creative, breakthrough ways of getting to our consumer base,' said Eric Bruno, vp-marketing at McNeil Consumer Healthcare, Fort Washington, Pa., the unit that handles J&J's nonprescription drug brands. 'This program does specifically highlight an increasing trend of wanting to more proactively engage consumers to participate with our brands, versus our brands just speaking to consumers.'

The story got some play on local television stations, e.g., here, and on the PharmaGossip blog. The reaction by Johnson & Johnson was striking, as recounted by Jim Edwards on the BrandweekNRX blog.

To my surprise, McNeil was furious, and I got an earful from one of their PR people about a day after it came out. 'We're not trying to turn Girl Scouts into drug dealers,' they fumed. 'We demand a correction.'

After some back and forth Brandweek declined to run a correction on the ground that the matter was more about tone than fact. No one really thinks J&J/McNeil is trying to get girl scouts to deal drugs. It was a journalistic turn of phrase. And besides, despite that one line the entire rest of the story was told straight.

We offered to publish a letter to the editor from McNeil, but they declined.I figured the matter would end there ... but then Pharmagossip produced an item (which has since moved off his frontpage so I can't reproduce it here for you but Jack Friday kindly provided the link in a comment below) ... and then Tampa Bay News 10 did this item ... and (9 News Now in Virginia did this (including that fancy logo at the top)...

Which explains why McNeil was so pissed at me.

For the record: J&J is not literally trying to turn literal girl scouts into literal drug dealers. The program, which does involve the distribution of pharmaceuticals, is open to any charitable group, including the girl scouts, who want to participate. I only wrote that "girl scout" line because the girl scouts and their cookies are the most famous nonprofit group who sell things to raise money.

Guys, you can put your website back up now.

I thought it was telling just how strongly the company reacted. But the flap over the turn of phrase used on Brandweek seems to have distracted from the very serious questions raised by the original article.

The pharmaceutical company was trying to involve not-for-profit organizations in their marketing. It would try to induce people volunteering for these organizations to get others "to buy their regular over-the-counter medicine from J&J as part of the fund-raiser." Thus, it would tie J&J to the reputation of the not-for-profits who sign up, and would benefit from sympathy towards the volunteers who go door to door.

Thus, it appears to be another way for a pharmaceutical company to turn people and organizations with exemplary reputations into part-time pharmaceutical marketers, perhaps without making it clear how this benefits the pharmaceutical company as well the not-for-profits. This appears to be a new variant on stealth marketing.

Certainly the idea was not to turn Girl Scouts into "drug dealers" in the colloquial sense. But would it be good for the Girls Scouts, or similar organizations to turn their volunteers and members into drug marketers? And would it be good for society?

A US Senate Committee on Financial Relationships Among Drug Companies and Physicians

We have often discussed, recently here, physicians' and health care academics' financial relationships with drug, biotechnology, and device companies.

Last week, the US Senate Special Committee on Aging held hearings about financial relationships between pharmaceutical companies and doctors. Those testifying included Dr Jerome Kassirer, Professor, Tufts University and author of "On the Take: How Medicine's Complicity with Big Business Can Endanger Your Health," Marjorie Powell, Senior Assistant General Counsel for the Pharmaceutical Research and Manufacturers of America (PhRMA), Dr Greg Rosenthal, an ophthalmologist, and Dr Robert Sade, chair of the American Medical Association's Council on Ethical and Judicial Affairs. The hearings did not get a lot of coverage, but I could piece together some of the testimony from articles in the Milwaukee Journal-Sentinel, New York Times, and United Press International. The results are striking:

Senator Herb Kohl (D-Wisconsin): "Gifts and payments can compromise physicians' medical judgment," Kohl said. "Efforts are needed to curb this." While such practices "are not illegal, they need to be disclosed." [UPI]

Dr Jerome Kassirer: "Doctors are human; they respond to financial incentives." And, "financial connections have a negative influence on the quality of care," but "the response to this has been inadequate." [UPI] So, "these marketing efforts are thinly disguised bribes." [MJS]

Senator Claire McCaskill (D-Missouri): "We must acknowledge that a lot of what goes on between the pharmaceutical industry and physicians is lobbying and that's not patient first." [MJS]

Dr Greg Rosenthal said drug companies are exerting increasing control over what research to conduct and what results to report. [MJS]

Dr Robert Sade: Interaction between doctors and drug companies "is necessary to the free flow of valid scientific information," The AMA has "continually revised" codes on such interactions stating that any gifts changing hands must "mainly benefit the patient and be of modest value," with no strings attached, he said. [UPI]

Marjorie Powell: "testified that doctors' prescribing decisions are largely based on what drugs health insurers list on their formularies, not on the promotional activities of drug companies, which she said are geared mainly to 'making sure doctors know a drug is available and how to use and not to use it.' [UPI]

"'Doctors are trained professionals; they know how to evaluate the information they receive,' she said." [UPI]

"She added that free drug samples given to doctors should not be disclosed as 'gifts,' calling them 'tools' for physicians and needed by patients who are uninsured and otherwise can't afford them." [UPI]

"Powell argued that drug companies, reacting to public pressure, have already pared down their extravagant wooing of doctors that went on in the past." [UPI]

Finally, Ms Powell "is not in favor of full disclosure and a national registry now. She said the industry follows its own code of ethics, and both the Federal Drug Administration and Department of Health and Human Services play a role in regulation." [MJS] Furthermore, "Ms. Powell told the committee that similar state efforts had become enmeshed in difficult details — like deciding whether free drug samples should be classified as gifts. 'There are those kinds of complexities that would make a registry very difficult,' she said." [NYT]

How fascinating. Kudos for Jerry Kassirer for his blunt assessment. On the other hand, note that Dr Sade of the AMA side-stepped the issue: no one seems to challenge the necessity for the free flow of scientific information. But what does such information exchange have to do with pharmaceutical companies giving gifts and making payments to physicians. Finally, is Ms Powell serious in her contention that drug company marketing has no effect on physicians? If so, why in the world would the companies pay such vast sums to support their marketing efforts to physicians?

We have called before for full and detailed disclosure of all conflicts of interest affecting anyone with decision making authority in health care. A federal registry of all pharmaceutical payments to physicians would be a step in that direction. But why not have a registry of all payments to all health care academics, all health care academic leaders, all health care not-for-profits, and all individuals who lead any kind of health care organizations? Why not have a registry of payments by biotechnology companies, device companies, managed care organizations and insurance companies, health care information technology companies, etc, etc? Maybe the magnitude of such disclosures would suggest that conflicts of interest are so pervasive that we will need not just to disclose, but to ban them. But that would be a very uncomfortable idea to all the people and organizations who are currently benefiting from them.

BLOGSCAN - "Payola" for Vermont Physicians

A post on the Clinical Psychology and Psychiatry blog summarizes the latest data from Vermont on the financial relationships between pharmaceutical companies and physicians in the state. The physicians who got the most money, or what the blogger dubbed "payola," from drug companies were psychiatrists, and then endocrinologists. A study of the relationships among such payments and Vermont physicians' prescribing practices is pending.

Yet Another Species of Health Care Conflicts of Interest: Contract Research Organizations Which Invest in Biotechnology Companies

The St. Petersburg (Florida) Times has an interesting story about the relationships between contract research organizations (CROs) and biotechnology and pharmaceutical companies.

Like many startup businesses, Accentia BioPharmaceuticals of Tampa was long on dreams but short on cash.

It held the license to an experimental sinus drug that looked like a potential blockbuster. But the company needed serious bucks to get the product to market.

Accentia found an investor in PPD Inc., a company that specializes in running the studies that must be conducted before regulators can approve a drug.

A year after recruiting PPD as an investor, Accentia went looking for someone to run the all-important trials proving the safety and effectiveness of its sinus drug.

Guess who got the job.

Now PPD is not only the second-biggest investor in Accentia, it also is handling the final preapproval studies of Accentia's new drug, SinuNase.

If the PPD-run trials result in the drug being approved by the Food and Drug Administration, financially strapped Accentia will be on its way to tapping a billion-dollar market of folks with chronic sinusitis. And PPD will get 14 percent of the royalties.

Is that a conflict of interest?

The FDA doesn't think so.

The agency requires doctors to disclose any financial interest in drugs they are testing on patients, but it doesn't even gather such information from companies like PPD.

Charged with protecting the public, the FDA gets most of its drug approval budget from pharmaceutical companies. Increasingly, those companies have been foisting off the drudgery of running drug trials onto companies like PPD, which are called contract research organizations.

But now, instead of just being paid to conduct a study, some CROs are taking a stake in a trial's success. This does not concern the FDA's senior adviser for clinical science, Dr. David LePay.

'We assume CROs have a financial interest in the compounds they're testing,' he said.

As proof the system is working, LePay noted how rarely the government finds fraud in clinical trials: 'We only find it in 1 to 2 percent of inspections.'

Others say those numbers prove something altogether different: that the regulators' focus is on approving, not challenging clinical studies.

'The FDA does not have the resources to inspect all clinical trial sites or even a major fraction of them,' said Dr. David Ross, who was with the agency's drug review office for a decade. 'And if you don't look for fraud, you won't find it.'

We should note that Pharmaceutical Product Development Inc (PPDI) was the CRO that ran a very questionable trial of the drug Ketek (see our most recent post here).

It turns out that PPDI's involvement with Accentia is not an isolated occurrence.

Most preapproval drug testing used to be done in academic institutions, directly under the control of the drug companies. Now most trials are performed in regular doctors' offices around the globe, and contract research organizations handle a major chunk of the work. As hired hands for the pharmaceutical industry, last year the companies generated some $15-billion in revenue.

Head and shoulders above the competition in terms of size are PPD and its chief rival, Quintiles Transnational Inc. Together their more than 25, 000 employees oversee thousands of clinical trials in more than 50 countries.

The two companies have distinguished themselves by offering clients a particularly attractive feature: money.

PPD, with $1.3-billion in revenue last year, has made four investments, including the one with Accentia. Through these "compound partnering" alliances, PPD said that last year it reaped $94-million in related clinical trial business. The company declined to comment for this story.

Quintiles, with $2-billion in revenue last year, started investing in up-and-coming drugs in 1999. Last year the investment division, called NovaQuest, teamed with a giant $5.8-billion venture fund to give it access to additional capital to invest. To date, NovaQuest has committed $2-billion to dozens of partnerships, including 26 deals with small biotechs.

Not surprisingly, CRO executives think that they can have such relationships without generating conflicts of interest.

Ron Wooten, the 49-year-old president of NovaQuest, said his company deals with the same potential conflicts of interest a drug company has when it oversees trials of compounds it owns.

'You manage that conflict by having fire walls around all information and strict confidentiality across all functions,' he said. 'Nobody on my staff talks to operations about there being higher stakes in a program when we have an investment. That never happens.'

But not all agree.

Arthur Caplan, professor of bioethics at the University of Pennsylvania, said federal regulators need to pay more attention to contract research organizations. Even if they don't invest in a drug under review, the companies have an incentive to get patients enrolled and tests completed fast, he said. Timely, trouble-free trials are the ticket to the next contract.

'CROs stay in business by hitting the numbers,' Caplan said.

And when a trial monitor has a financial interest in a drug study's outcome, as PPD does with SinuNase: 'That's a big ethical no-no,' Caplan said. 'They should never be reviewing anything in which they have a direct financial interest.'

Furthermore,

Dr. Marcia Angell, senior lecturer at Harvard Medical School, doesn't buy it. She said having drug companies or their proxies in charge of drug trials means the entire system is corrupt, 'from stem to stern.'

'It's a house of cards built on a fundamental conflict of interest,' said Angell, former editor of the New England Journal of Medicine and author of The Truth About the Drug Companies: How They Deceive Us and What to Do About It.

'The problem is that drug companies have inordinate influence over the evaluation of their own products. That, on the face of it, doesn't make sense.'

We have posted before about major problems with how CROs conduct research. Other than the story of how PPDI ran trials of Ketek, there were, for example, the disastrous trial of TGN 1412 run by Parexel International (see most recent blog post here), and the clinical trials by SFBC International (now Pharmanet) that infected multiple participants with tuberculosis (most recent blog post here).

The St Petersburg Times seems to have uncovered yet another species of conflict of interest affecting health care, and particularly affecting clinical research. In a way, this is akin to the conflicts that occur when academic researchers who are paid part time, usually as consultants or members of speakers' bureaus, by a given drug, biotechnology, or device company also conduct human research on that company's products. The concern is that their financial arrangements will influence how they design, carry out, and disseminate this research. The potential research biases induced by such arrangements ought to be clearly disclosed to the humans who volunteer to participate as research subjects.

Similarly, the potential research biases induced when a contract research organization has an ownership interest in the drug, biotechnology, or device company whose products it is supposedly dispassionately evaluating ought to be clearly disclosed to the human subjects of such research.

Finally, this is a reminder that patients and physicians ought to be highly skeptical about the results of clinical research carried out by people and organizations which may have financial relationships with the companies that produce the products their research is supposed to to evaluate.

And it is another reminder that for the good of research subjects, of clinical science, and of patients in general, we ought to consider how to make sure that all human research is done by people who do not have conflicts of interest, especially those that link the researchers to the manufacturers of the products or the providers of the services their research is meant to evaluate.

The Ongoing NIH Conflicts of Interest Story: The Case of the "Footloose and Fancy-Free" Institute Director

My apologies for being off the air. I was on the road, and then my lap-top decided it no longer wanted to communicate with the internet. Of course, while I was incommunicado, health care's problems continued.

For example, a while back we posted quite a bit (recently here) about conflicts of interest affecting top US National Institutes of Health (NIH) officials. In 2005, the NIH director reinstated strict rules about conflicts of interest.

Yet last week the Washington Post reported that the issue has not gone away. The most recent story was about "David Schwartz, a physician and researcher recruited from Duke University to great fanfare in 2005 as chief of the National Institute of Environmental Health Sciences...." "Schwartz, an expert in environmentally related lung diseases, was hired in 2005 just three months after [NIH Director Elias] Zerhouni imposed strict new conflict-of-interest rules in the aftermath of a scandal involving agency scientists who failed to disclose lucrative consulting deals with pharmaceutical companies." "In an internal NIH investigation he "was found to have spent modest amounts of institute money for personal purposes but was cleared of other allegations of wrongdoing...." However,

several members of Congress have demanded more details, saying they have evidence that the NIH report is incomplete. And scores of e-mails reviewed by The Post confirm that ethics officials in NIH and in the Health and Human Services secretary's office have grown increasingly frustrated with Schwartz's repeated insensitivity to conflict-of-interest rules.

Schwartz allegedly had several kinds of conflicts of interest. One kind involved his personal investments. Schwartz reportedly did not see that his personal investments should not be limited by any petty federal rules and regulations.

In one exchange, when officials learned that Schwartz had not fully divested all his biotechnology and drug company stocks as required, Schwartz wrote to the NIH ethics office that the divestiture 'seems totally unreasonable. . . . I'm simply not willing to limit my investments in this way.'

The ethics officer, who later complained that she had 'lost patience . . . a long time ago' with Schwartz, responded, 'It may appear to be unreasonable, but it is the law.'

Another kind of conflict of interest involved Schwartz's activities as a paid expert witness.

Also raising alarms were Schwartz's growing commitments to give expert testimony in multimillion-dollar asbestos injury cases -- of concern because he might be perceived as profiting personally from his status as head of the nation's premier environmental toxicology program.

Schwartz said he earned about $150,000 from asbestos-related expert testimony and clinical exams from mid-2005 through fiscal 2006.

A third kind of conflict of interested involved Schwartz's position at Duke University.

Schwartz brought more than a dozen Duke researchers to his federal lab, despite a requirement that he recuse himself from matters involving Duke. He also overspent his lab budget by millions of dollars. Those actions led agency officials to take the extremely unusual step of banning Schwartz from his own lab for nearly three months, putting it into receivership and sending the researchers back to Duke in what one official called a 'de-Duking' process.

The lab was recently placed under the budgetary control of another NIH institute to prevent further problems....

And in March, Schwartz -- who had retained his faculty status at Duke, a few miles from the institute's headquarters in Research Triangle Park, N.C. -- separated himself from the university.

All this has attracted the attention of Congress.

Last Thursday, Sen. Chuck E. Grassley (R-Iowa), ranking minority member of the Finance Committee, which has been investigating Schwartz for months, sent an eight-page letter to NIH Director Elias A. Zerhouni with a host of new questions to be answered by July 10.

'The National Institutes of Health conducts important research for the public good, and individuals who hold high-level positions there ought to understand that they hold the public trust and demonstrate respect for it with their actions,' Grassley said.

Schwartz denied any wrong-doing.

In a telephone interview yesterday, Schwartz said he made mistakes, which he blamed on "misunderstandings" about institute rules and "poor communication," for which he said he takes "full responsibility."

Schwartz denied any deception on his part, however, and said he has taken corrective actions to prevent future problems.

The Post found that Schwartz's actions were taking their toll on those he supervises.

In interviews this week, various current and former NIEHS employees called Schwartz 'brilliant' and an 'excellent scientist' but also 'patriarchal,' and 'footloose and fancy-free with the rules.'

Since his arrival, three top institute officials have left, and many employees have expressed dismay at Schwartz's leadership.

'Morale is just horrible,' one said speaking on the condition of anonymity for fear of retribution.

This story seems significant first because it demonstrates that there are continuing conflict of interest problems at the NIH, even after the rules were stiffened in 2005. Such conflicts should be of particular concern because the NIH is one of the world's foremost biomedical research organizations. Having conflicted people in its top leadership positions, particularly as full Institute directors, raises concerns about whether their actions are meant to serve science and the public, or their private financial interests.

This story also seems significant because it shows how multi-faceted conflicts of interest may be. Schwartz's conflicts included not only his pharmaceutical and biotechnology company stock-holdings, but his role as an expert witness, and his continuing relationship with a university that gets millions of dollars in NIH funding. Clearly, solving the conflict of interest problems at the NIH is goint to require ongoing vigilance.

Finally, at the end of the story is a reminder that conflicted leaders tend to demoralize their subordinates, an effect that is particularly important given the pervasive nature of conflicts of interest in health care.

BLOGSCAN - Dodgy marketing of Pfizer Anti-Viral Drugs

On Question Authority with Dr Peter Rost there have been a series of posts, (the most recent one is here), about allegations that Pfizer Inc started marketing its new antiviral drug for HIV, maraviroc, before the drug received US Food and Drug Administration (FDA) approval. Now Pharmalot has a post picking up the maraviroc story, and looking at related allegations that Pfizer improperly marketed its old antiviral drug Viracept (nelfinivir).

Smokescreen - Will Tobacco Company's New Research Program Create New Conflicts of Interest?

Writing in the Wall Street Journal, Anna Wilde Mathews and Vanessa O'Connell highlighted the increasing involvement of tobacco company Philip Morris (subsidiary of Altria Group Inc) in health and medical research. First, the company has been building a big research facility in a biotechnology research park.

At a research park that's home to several biotech companies, a $350 million facility under construction will soon house hundreds of researchers. But instead of testing lifesaving medicines, these scientists will be focused on a product that kills an estimated 438,000 Americans a year.

The facility, due to open in August, is owned by Philip Morris USA, the nation's biggest tobacco company. The Altria Group Inc. unit is preparing for a tectonic change -- regulation of tobacco by the Food and Drug Administration.

The bills also dangle a potentially lucrative opportunity. They say that if a new kind of cigarette can be scientifically proven to 'significantly reduce harm' to smokers -- and its availability would also benefit the health of 'the population as a whole' -- the cigarette's marketing claims may win approval from the FDA.

Philip Morris, which is working on a slew of new products it hopes might qualify for FDA-approved health claims, acknowledges it must transform itself into a credible player in the expected scientific debates at the FDA. So the company is trying to emulate an industry already under the agency's purview -- the drug companies.

The company has a number of highly engineered products in the works, all of which are designed to possibly reduce tobacco's dangers.

Analysts say the effort is consuming about half of the estimated $200 million Philip Morris spends on research and development each year. Philip Morris scientists are conducting human studies, presenting results at research conferences and publishing findings in scientific journals such as the Journal of Clinical Pharmacology.

To staff its 450,000-square-foot research center, its biggest investment in two decades, Philip Morris is trying to recruit dozens of physicians, biochemists, and other scientists.

Although the article did not identify the location of the new Philip Morris facility, the Richmond, VA dateline of the article suggests that it is in the Virginia Biotechnology Research Park, whose web-site boasts of hosting the new Philip Morris Research and Technology Center. The research park was "originally created as a partnership of Virginia Commonwealth University, the city of Richmond and the commonwealth of Virginia."

The WSJ article also suggested that Philip Morris is getting more involved with academic researchers, and that other tobacco companies are following its lead.

And in the same way that pharmaceutical companies pay top researchers to lead drug studies and speak about their findings to regulators and other scientists, the tobacco maker is trying to forge relationships with outside experts who might support Philip Morris's research efforts.

While they have been reaching out to outside scientists and medical researchers who can review their own reduced-harm product research, Philip Morris's rivals haven't done as much to ready themselves for regulation.

Also, Philip Morris is working more with outside research organizations.

One of the company's efforts -- hiring the Life Sciences Research Office in Bethesda, Md. -- has already sparked controversy. A nonprofit founded to conduct research for the Army, it has done work under contract for the FDA, as well as such projects as weighing the evidence of walnuts' health benefits for a group of walnut growers.

In 2004, Life Sciences began a Philip Morris project that focused on reviewing research from tobacco companies and others related to potential reduced-risk products, with the goal of figuring out what evidence was needed to prove reduced-risk claims. The nonprofit says it reached out to about 1,000 scientists and organizations, seeking recommendations on what questions to address and who might serve on panels that would conduct the review. It also invited scientists to submit research and participate in meetings.

Earlier this month, two University of California-San Francisco researchers published a paper in Tobacco Control, an antitobacco journal, accusing Life Sciences of downplaying or concealing its 'true level of involvement' with the tobacco giant. It warned that Life Sciences may not be fully independent, saying that some members of the nonprofit's outside panels have had financial relationships with tobacco companies.

The concern is that Philip Morris' research effort will generate a whole new set of possible conflicts of interest. The company already apparently has some sort of indirect relationship, through the Virginia Biotechnology Research Park, with Virginia Commonwealth University, which includes the VCU Medical Center. The Medical Center claims on a page on its web-site dedicated to the park that "the park works hand-in-hand with VCU, other academic institutions, businesses, and government and not-for-profit organizations to facilitate technology transfer and business development." It is hard to tell whether this relationship could be sufficient to constitute an institutional conflict of interest for VCU.

The company's efforts to build relationships with outside experts "who might support Philip Morris' research efforts" based on an attempt to "emulate" pharmaceutical companies suggest the possibility of new conflicts of interest affecting academic who consult for the tobacco company, and new institutional conflicts of interest affecting their parent instutions who receive grant money from the company. (We posted on Philip Morris' large grant to the University of Virginia, not to be confused with Virginia Commonwealth University, here.)

Finally, the company's relationship with at least one not-for-profit research organization also suggests the possibility of new conflicts of interest affecting other such organizations.

All these conflicts of interest are even more concerning than parallel conflicts of interest having to do with pharmaceutical, biotechnology, and device companies. At least all of those companies make products meant to ameliorate, control or cure disease. When physicians, academic researchers, or health care institutions take their money, doubts are raised whether their opinions and research are influenced by the commercial vested interests that fund them. Such doubts make it harder for patients and physicians to weigh the possible benefits and harms of medical interventions. That isn't good for health care.

Tobacco, of course, is cause of, not a treatment for disease. When physicians, academic researchers, or health care institutions take tobacco money, doubts will be raised whether their opinions and research are influenced by their tobacco company funding meant to obscure the risks of tobacco products. Since their are no benefits of tobacco that could counter-balance these risks, the result may be more people smoking more, thus more tobacco produced disease. For academics and health care professionals, and their organizations to thus promote disease would violate their core principles, and would be the opposite of the dictum "first, do no harm." Cloaking research meant to market more cigarettes in academic respectability could be very bad for health care.

Hear No Evil? - Conflicts of Interest Affecting Research on Hearing Loss

The Wall Street Journal today carries a report on research on occupational hearing loss carried out by Prof William W Clark of the Department of Otolaryngology of the Washington University School of Medicine. Prof Clark has studied hearing loss in a variety of occupational settings, often finding little evidence for this problem. For example, he has studied fire fighters.

Thousands of firefighters ... have sued the maker of the sirens, contending they caused hearing loss.

A study ... [Dr Clark] published in 2005 concluded that 'firefighters are not at risk for occupational noise-induced hearing loss, even though they work nonstandard shifts and are occasionally exposed to high levels of noise.'

The siren manufacturer, Federal Signal Corp., told a court the study 'directly refutes plaintiffs' argument that siren noise exposure causes hearing loss in firefighters.'

What the study didn't mention was that Dr. Clark was a paid expert for the company helping it with its litigation at the same time as he was doing his research. Not only that, but the company gathered data that were the basis of the study.

Readers of Dr. Clark's study, which ran in Ear & Hearing Journal, were told only that the researcher 'has provided consulting services for manufacturers of emergency firefighting equipment.' There was no mention that such a manufacturer was being sued for causing hearing loss.

Dr Clark has also studies hearing loss in railroad workers.

Union Pacific railroad ... was defending a slew of suits claiming trainmen were losing their hearing from noise.

In 1989, ... [Dr Clark] published a peer-reviewed article concluding that 'trainmen are not typically exposed to hazardous occupational noise.'

After its publication, cases began to be settled on less-generous terms, according to affidavits from rail workers and the railroad. They were settled for 80% less, on average, than before the Clark study appeared.

The journal that published the trainmen report, called Laryngoscope, didn't disclose that Dr. Clark was consulting for Union Pacific. Dr. Clark says it didn't require such disclosure. Laryngoscope says it doesn't know what its disclosure policy was in the late '80s.

[Dr Clark] also ran a 'hearing hotline' for Union Pacific workers that, among other things, counseled them on results of their hearing tests.

To run the railroad's hearing hotline, Union Pacific paid $850,000 to a partnership of Dr. Clark and his co-author of the railroad hearing-loss study, according to a deposition Dr. Clark gave in Cook County, Ill., Circuit Court.

Dr Clark also studied hearing loss in miners.

In 1997, the U.S. Mine Safety and Health Administration was considering tougher noise guidelines. An industry group called the National Mining Association hired Dr. Clark to do a critical analysis of another federal body's noise data. He testified before the mine agency against tougher guidelines.

Two years later, Dr. Clark published a study concluding that miners did not have significant occupational hearing loss. The study was done "at the request of the National Mining Association," he acknowledged in the article. He didn't mention that the association had paid him as a consultant.

This is a reminder that conflicts of interest affecting medical researchers are not limited to those due to their financial relationships with pharmaceutical, biotechnology, and device manufacturers. In this case, the conflicts were generated by financial relationships a medical researcher had with a manufacturer of sirens, a railroad, and a mining trade association.

In all cases, though, such conflicts throw doubt on the interpretation of the resulting research. One wonders whether conclusions of research studies done by researchers with conflicts, particularly conflicts that are not clearly disclosed, may have been influenced by the relevant financial relationships, and thus to what extent the research should not be trusted. The questions raised by such conflicts are almost impossible to answer unless one can find clearly unconflicted research that addressed the same question.

This just expands the rationale for what we have said before: pervasive conflicts of interest in health care make figuring out what is best for patients even harder. And this just strengthens our previous argument that physicians, other health care professionals, and leaders of health care organizations should rid themselves of conflicts of interest that might influence their professional, academic, or research work on behalf of patients or public health.

The Provenge Brawl: Two Wrongs Do Not Make a Right

The controversy, to use a polite word, over how the US Food and Drug Administration (FDA) has handled a proposed immunotherapy treatment for prostate cancer, Provenge (?Sipuleucel-T?, manufactured by Dendreon) has been striking. To start, let me quote from an article in the Philadelphia Inquirer,

In a small study, the median survival of men treated with Provenge was 26 months, just 4.5 months more than patients receiving a placebo. A survival edge in a second small study could have been by chance. And Provenge did not achieve one of its primary goals of delaying disease progression.

Yet the 4.5-month survival benefit was almost double that of Taxotere, a treatment with tough side effects that is the only other option for advanced, progressing cancer.
The FDA's expert advisory panel voted unanimously that Provenge is safe but voted only 13-4 that it was effective.

Prostate cancer activists have raised questions about two of the negative voters - academic medical oncologists Maha Hussain and Howard Scher. Both were granted conflict-of-interest waivers and have been members of an FDA advisory committee that evaluates conventional cancer drugs.

In an unusual move, both wrote letters to top FDA officials complaining about the advisory committee that recommended approval of Provenge.

Yesterday about 100 activists from 19 organizations rallied in Washington. The activists are petitioning Congress - and pressuring the FDA - to approve marketing of the promising prostate cancer "vaccine," while its manufacturer, Dendreon Corp., completes a 500-patient study.

Afterward, six of them met with FDA Commissioner Andrew von Eschenbach - who himself has been treated for prostate cancer.

The FDA's delay, the activists believe, could add years more to Provenge's long development odyssey.

'You're talking a minimum of two more years,' declared rally leader Thomas Farrington, founder of the Prostate Health Education Network, aimed at African American and other men at high risk of the disease. 'Since prostate cancer kills 27,000 men a year, you're talking 54,000 deaths.'

But the controversy is even more pointed than that, this week, Diedtra Henderson wrote in the Boston Globe,

When federal regulators delayed approving a promising new prostate cancer therapy, patients and the drug’s advocates reacted with more than disappointment.

They took a page from the playbook of AIDS activists and took to the streets and to the Internet, mounting an unusually intense lobbying campaign to pressure the Food and Drug Administration to reverse its stance on Provenge, the experimental cancer drug.

Blogs and websites are uniting disappointed cancer patients and disillusioned investors who put money on Seattle-based Dendreon Corp.’s Provenge, believing it could rally the body’s immune system to combat cancer.

Some, however, question whether some Provenge advocates are too aggressive. Some patient advocates say the FDA should be guided only by science.

'Do people in this country really want drugs to be approved by riot?'’ asked Abx bey Meyers, president of the National Organization for Rare Disorders. 'Every other patient organization is going to go down there and have a March on Washington and use political pressure to get their drug approved. That’s not what the American people want.'

Dr. Howard I. Scher, a Memorial Sloan-Kettering Cancer Center researcher whose image is featured on Vestal’s MySpace page and who was pilloried on the InvestorVillage website, received additional security during a recent cancer conference after receiving e-mails from Provenge supporters that he considered threatening.

Paul Goldberg, editor of The Cancer Letter, a weekly newsletter that reprinted letters from Scher and other Provenge skeptics, received a spate of irate e-mail messages, including one that said: 'I hope the entire male staff at the Cancer Letter is diagnosed with Prostate Cancer.'

Another Provenge supporter told him about her idea to create 'it squads,' people assigned to chat up FDA advisers during meeting breaks, Goldberg said.

‘‘The idea of a ‘hit squad’ is really unpleasant,’’ he said. ‘‘The idea of a committee member getting threats, being approached on the way to the restroom, at coffee breaks — this is about science.

‘‘Or it should be about science. That’s how patient interests are protected.’’

And Adam Feuerstein, a senior writer for TheStreet.com, received at least 100 e-mails, some of them anti-Semitic, after writing about Provenge and suggesting that investors ‘‘ditch Dendreon’’ stock.

It actually gets worse than that. According to the New York Times,

Two prominent prostate cancer experts have been threatened for opposing approval of a controversial new drug and are being protected by bodyguards as they attend the nation’s largest cancer conference here.

The experts, Dr. Howard Scher of Memorial Sloan-Kettering Cancer Center and Dr. Maha Hussain of the University of Michigan, received e-mail and other threats, according to spokeswomen for Sloan-Kettering and for the cancer conference.

When he gave a talk at the conference on Sunday, Dr. Scher was accompanied by three men wearing suits and earphones, but not conference name badges, which attendees must wear.

A spokeswoman for the oncology association said it had been working with the two doctors and was increasing security at the conference.

Christine Hickey, a spokeswoman for Sloan-Kettering, said Dr. Scher had received e-mail messages and phone calls, including one e-mail entitled 'our murder.' A copy of his biographical page on the Sloan-Kettering website was vandalized.

It is not known who sent the threats. However, it is clear that the doctors’ public stance against the drug, Provenge, has inflamed the passions of some men with prostate cancer and patient advocates, who say the drug would offer hope to desperate patients with few or no alternatives.

'ntimidation or harassment is going to make qualified people think twice about serving in national positions,' Dr. Hussain said....

A quick internet search did reveal that both Dr Hussain and Dr Scher did have conflicts of interest.

Dr Hussain acknowledged receiving consulting and lecture fees and holding stock in Sanofi (the forerunner of Sanofi-Aventis) in 2004 [Petrylak DP, Tangen CM, Hussain MHA et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: 1513-1520]; receiving research funding from Bristol-Myers-Squibb in 2005 [Hussain M, Bhandari MS. Epothilones and the next generation of phase III trials for prostate cancer. Brit J Urol 2005; 96: 296-302.]; owning stock in AstraZeneca in 2006 [Hussain M, Tangen CM, Higano C et al. Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metatstatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol 2006; 24: 3984-3990.]; and receiving research funding from Genentech in 2007 [Hussain MHA, MacVicar CR, Petrylak DP et al. Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute Trial. J Clin Oncol 2007; 24: 2218-2224.]

Dr Scher acknowledged research funding from AstaZeneca, Bristol-Myers-Squibb, Novartis Pharmaceuticals, and Millenium Pharmaceuticals; consulting fees from Bristol-Myers-Squibb, Conforma Therapeutics, Genentech, Novartis, ProQuest Investments, and Wyeth-Ayerst Pharmaceuticals; membership in the speaker's bureau for AstraZeneca; and stock holdings or option holdings in Cell Therapeutics, Vidamed, ProQuest, Conforma, and Genta [Shaffer DR, Scher HI. Prostate cancer: a dynamic illness with shifting targets. Lancet Oncology 2003; 4: 407-413.]

But while we're on the topic of conflicts of interest, the Boston Globe article also noted,

Dendreon is among the drug industry sponsors that have provided funding for a patient advocacy group that [Thomas] Farrington founded.

What a mess.

On one hand, this appears to be yet another in our series of stories about FDA advisory panels that include members with conflicts of interests (see recent post here). The presence of such conflicts naturally raise questions about whether the actions of the panels are influenced by their members financial entanglements, thus challenging the validity of the whole process. In my humble opinion, I think that to restore integrity in its advisory panels and its operations in general, the FDA should not allow people with conflicts of interest to serve on these panels.

On the other hand, the advisory panel's decision unleashed far more than scientific or clinical criticism, or concerns about how its members' conflicts may have affected its decision. It unleashed not just political pressure, but apparently threats of intimidation by "hit squads" and ominous emails, to the extent that the conflicted panel members felt they needed bodyguards. Intimidation of this nature is plain wrong, and surely will not lead to a climate in which policy makers will make the best decisions for patients and the public at large. Such threats deserve investigation, and anyone who was waving the bloody shirt in a way that might have inspired people to make such threats ought to be ashamed. Two wrongs here surely do not make a right.

Did Conflicts of Interest Affect a Review of Anti-Coagulants to Treat Blood Clots?

In an article published last week on Medscape [Cundiff DK. Evidence-based medicine and the Cochrane Collaboration on Trial. Medscape Gen Med 2007; 9(2):56, link here] are allegations that conflicts of interest affected the Cochrane Collaboration review of the use of anti-coagulants for pulmonary embolism and deep venous thrombosis. Here are the main points of the article:

In 2001, I volunteered to help conduct a review for the Cochrane Collaboration of the evidence base for the use of anticoagulants (warfarin [Coumadin] and heparins) for blood clots in the lungs (pulmonary emboli, or PE) and legs (deep venous thromboses, or DVT), as recently affected Vice President Dick Cheney. Dr. Juliet Manyemba, a physician from England, and John Pezzullo, PhD, a retired biostatistician formally from Georgetown University School of Medicine, were my coauthors. I disclosed to the Cochrane editor that my research interest in anticoagulants for DVT and PE originated because of a malpractice case against me concerning a DVT patient that resulted in the loss of my medical license.

Warfarin, heparin, and other anticoagulant drugs have been used to treat blood clots since the 1940s based on unscientific anecdotal evidence and observational studies with historical controls. Subsequently, countless RCTs involving blood thinners for venous thromboembolism (VTE) patients have included no un-anticoagulated control subjects. According to anticoagulation researchers contracted or employed by drug companies, the rationale is that it would be "unethical" not to give anticoagulants to clinical research subjects with blood clots in their legs or lungs. After reading over 1000 studies on the topic, I found 1 randomized and properly controlled trial of DVT patients. Patients in the study received either standard treatment (warfarin and heparin) or phenylbutazone (an anti-inflammatory drug like aspirin). From this single well-designed study of anticoagulants came a startling result: The anticoagulants did not prevent deaths.

Cochrane archivists turned up 2 other RCTs of anticoagulation therapy in DVT patients. Neither trial found any benefit due to anticoagulants. Summing the results of the 3 trials, 66 DVT patients received anticoagulants and 6 of them died; 60 DVT patients did not receive anticoagulants, and 1 of them died. None of the 3 trials had been referenced in any journal articles or reviews of anticoagulant therapy that I read.

Although these 3 trials show a trend suggesting that warfarin and heparin do harm, there were too few patients to show with statistical significance that anticoagulants increase deaths. But they contain enough subjects to show that anticoagulants do not reduce mortality. Based on the complication rate of anticoagulation for DVT or PE in much larger observational studies, anticoagulants kill 1000-4000 Americans with VTE each year due to internal bleeding, mostly in the brain.

The Cochrane peer reviewers (at least 4 out of 7 of which had undisclosed financial ties to the drug companies that make anticoagulants) delayed four years over releasing this review for publication. When the only 3 RCTs discovered showed no benefit and possible harm from anticoagulants, the editor and peer reviewers directed us to include 8 additional lines of evidence supporting anticoagulation from about 50 other studies in the medical literature. When my critique of those 8 lines of evidence showed that they were all faulty, the peer reviewers did not rebut a single point. Instead, the editor demanded that we delete the additional lines of evidence from the review, because they were not from RCTs.

When the author of one of the randomized trials discovered by the Cochrane archivists refused to cooperate and clarify to us his method of randomizing patients in his study, the Cochrane editor and/or peer reviewers invented a reason to disqualify the trial from inclusion in our review. The editor told us to accept the edits or the review wouldn't be published. The 'authors' conclusions,' written into our article by the Cochrane editor and peer reviewers, were these: 'The limited evidence from randomized controlled trials of anticoagulants versus nonsteroidal anti-inflammatory drugs or placebo is inconclusive regarding the efficacy and safety of anticoagulants in venous thromboembolism (DVT and PE) treatment. The use of anticoagulants is widely accepted in clinical practice, so a further randomized trial comparing anticoagulants to placebo could not ethically be carried out.'

In our final draft of the review, we authors said that a placebo-controlled trial would be impractical and suggested a 'noninferiority trial' with anticoagulants vs a nonsteroidal anti-inflammatory drug. One of the peer reviewers, with no conflict of interest that I could find, commented, 'Note that it is ethically possible to conduct a study to determine if anticoagulation therapy is harmful. If nothing else, dose reduction studies could determine if lower doses or weaker therapies (aspirin or NSAIDS?) are equally effective" (ie, a noninferiority trial).'

At the suggestion of Dr. [Kay] Dickersin [the Director of Cochrane's US Center for Clinical Trials], I issued a complaint to the Cochrane Collaboration publication arbitrator in September 2006.

Dr. Dickersin recently told me that she cannot estimate when the Cochrane investigation will be completed. A recent similar investigation took 2 years. The publication arbitrator has resigned, and she has no guarantee of finding a replacement anytime soon.

Medscape General Medicine published my entire review, including the evidence from the 8 lines other than the 3 RCTs included in our Cochrane VTE review.[Cundiff DK. Anticoagulation therapy for venous thromboembolism. MedGenMed. 2004;6(3):5. See link here.] The Medscape VTE review concluded, 'Anticoagulants have not been shown to be efficacious in reducing morbidity or mortality or safe in venous thromboembolism treatment.' Medscape Chief Editor, George Lundberg, MD (former Chief Editor of JAMA), wrote the accompanying editorial, entitled 'Is the Current Standard of Medical Practice for Treating Venous Thromboembolism Simply Wrong?' [MedGenMed. September 9, 2004;6(3):36. See link here.]

While I concur with Dr. Healy that relying solely on evidence-based medicine to determine medical guidelines better suits the needs of governments and insurance companies for cost control than the needs of patients for optimal medical treatment, I agree for a different reason. While evidence-based medicine is absolutely essential to comprehensive healthcare reform, it has been profoundly corrupted by money.

This article has received no attention in the press, as far as I can tell. Note that the main benefit of warfarin after DVT is supposed to be prevention of extension and new clots, not postponement of death. However, Cundiff is certainly correct that the use of warfarin entails the risk of major, sometimes disabling or fatal bleeding, so that mortality should be assessed in any trials of this drug.

Note further that the article did not disclose the identity of the reviewers with alleged conflicts of interest, nor the nature of their alleged conflicts. Nonetheless, add this to other cautionary tales about how financial entanglements can influence the design, execution, and in this case, dissemination and discussion of clinical research.

ADDENDUM (22 June, 2007) - This post on Notes from Dr RW reminds us that blog first posted about this story in 2005.

The Wall Street Journal Gives Avandia a Whirl

We previously have posted quite a bit about what now can be called the Avandia case, which started recently with the publication in the New England Journal of Medicine by Nissen and Wolski of a meta-analysis focused on cardiac adverse effects of rosiglitazone (Avandia, by GlaxoSmithKline) (see post here) More recently, we noted how this case has generated its own spin cycle, spinning off multiple obfuscations which distract from what I at least, in my humble opinion, ought to be the main points for patients and physicians.

Now the Wall Street Journal has published a major editorial which gives it another whirl. Like some previous efforts, it raises methodological questions about the Nissen and Wolski meta-analysis,

Meta-analysis can be a useful contribution to medical knowledge, but it is in no way conclusive.

Several aspects of the Nissen study are particularly troubling. The assertion that Avandia raises the absolute risk for heart attacks by 43% relied on a methodology that excluded data in which there were no reported adverse events, skewing the results.

Besides, the data Dr. Nissen analyzed did not control for cardiac events, so things like indigestion and heartburn may have counted.

It appealed to authority by citing the Lancet,

Even the Lancet, the British medical journal with its own politicization issues, clucked about the NEJM's 'alarmist headlines.'

After denigrating the Nissen and Wolski meta-analysis, it touted GSK's latest clinical trial, which is still ongoing,

GlaxoSmithKline is conducting its own clinical trials, which are more rigorous, to be concluded next year. The interim results showed that Avandia patients had a 7% decrease in heart attacks, and a 17% decline in deaths from cardiac events, though these aren't yet definitive either.

It also praised GSK's transparency,

GlaxoSmithKline was already engaged in extensive postmarket trials before this scandal broke -- beyond those that would be required by Enzi-Kennedy. And Glaxo makes the data from its completed trials transparent on the Internet, where Dr. Nissen acquired it in the first place. So much for Mr. Waxman's repeated claims that Big Pharma is suppressing negative results.

Finally, the WSJ editorial concluded with assertions that the issue is political, not methodological, epidemiological, or clinical,

The larger political context here is the evidence of collusion to gin up one more drug-company "scandal." Dr. Nissen has a reputation as an adversary of the pharmaceutical industry, and was involved in the controversy that led Merck to withdraw Vioxx from the market in late 2004.

At bottom, the Avandia fuss is political, not medical, and it turns on risk itself: how to strike the best balance between patient safety and lifesaving therapies.

An interesting counterpart of the WSJ's arguments appeared in the British Medical Journal two days earlier, but apparently went unnoticed by the WSJ. (See Kazi D. Rosiglitazone and implications for pharmacovigilance: postsurveillance data should be systematically collected and publicly available. Brit Med J 2007; 334: 1233-4. Link is here.)

The WSJ raised doubts about meta-analyses in general, and the Nissen and Wolski article in particular. But the BMJ, while acknowledging meta-analysis is far from perfect, was far more measured,

Meta-analyses have unique strengths and weaknesses and this one is no exception. Its singular strength is the statistical power generated by data on 15 560 patients from published and unpublished trials. However, it includes clinically heterogeneous trials and criteria used by individual trials to classify adverse events are somewhat unclear. Only summary data are available in the public domain—for example, whether or not a person had a myocardial infarction, not when it occurred—which makes time to event analyses impossible. Also, the total number of adverse events was small, so that misclassification of a few events could alter the conclusions.

Although the WSJ seemed to put a lot more faith in the ongoing trial being run by GSK, the BMJ editorial noted that the results available from this trial so far do not undercut concerns about risks of cardiac adverse events due to rosiglitazone,

In response to the concerns raised by this meta-analysis, an unplanned interim analysis of a large, manufacture sponsored, randomised, open label, non-inferiority trial specifically designed to investigate the cardiovascular safety of rosiglitazone was recently released. Compared with patients taking metformin and a sulphonylurea, people taking a regimen that included rosiglitazone had no significant increase in the risk of myocardial infarction (hazard ratio 1.16, 0.75 to 1.81), although they had a significantly increased risk of heart failure (2.24, 1.27 to 3.97). When these new data are added to the trials in the previous meta-analysis, rosiglitazone is associated with an increased risk of myocardial infarction (odds ratio, 1.33; 1.02 to 1.72)

Moreover, even if one wants to entirely discount the Nissen and Wolski meta-analysis, there was another meta-analyis of clinical trials of rosiglitazone, done by GSK itself, which produced similar results, although its results were not quickly made public,

Of note, a similar meta-analysis submitted by the manufacturer to the EMEA and the FDA in August 2006 showed an increased risk in ischaemic events (hazard ratio, 1.31, 1.01 to 1.70)

The WSJ editorial simply ignored GSK's own meta-analysis.

Finally, although the WSJ claimed that GSK made its clinical trial data transparent on the Internet, it failed to mention that it did so only as a consequence of a legal settlement of a case which alleged the company had been less transparent about data about the side-effects of its antidepresant paroxetine (Paxil). (See Steinbrook R. Registration of clinical trials - voluntary of mandatory. N Engl J Med 2004; 351: 1820-1822, link here and our post here).

So the Wall Street Journal's new whirl has kept the Avandia spin cycle merrily revolving. This spin cycle continues to distract from what I think, in my humble opinion, are really the major questions.

The first question is clinical: what are the benefits and harms of rosiglitazone as a treatment of Type 2 diabetes, and therefore for which patients under what circumstances should this drug be used?

The second question is about policy: what barriers, if any, have prevented physicians and patients from getting the best possible answer to the first question, and what can be done about them?

I understand that WSJ editorials may want to protect an important industry that provides the drugs physicians need to help patients from excess political interference, and excess regulation that might decrease its innovation and efficiency. The pharmaceutical industry is very important, and does make major contributions to society.

But that should not blind us to poor industry practices. Continuing defense of poorly done clinical studies, failure to do needed post-marketing studies, and suppression of clinical research only makes the whole industry seem more "shifty," (see post here), and would ultimately only give more ammunition to those who advocate the most radical regulation or even nationalization.