Badly-designed EHR forces mother to decide on sick child's gender

As a medical informaticist who studies the gaps between business computing and clinical computing, and laments the problems caused by the leadership of the latter by representatives of the former, this story speaks for itself:

This story, related by a pediatric specialist, exemplifies the gap between the expertise and thinking of business computing specialists and healthcare informatics specialists:

‘Mother referred for delivery and management of a fetus in utero with diagnosis of hypoplastic left heart – baby born, middle of night, terribly sick, unexpectedly more wrong than expected, and with truly ambiguous genitalia. Can’t get an xray, prostaglandin-E (a lifesaving medication used in babies born with functionally absent, or obstructed, blood flow out of the heart), or any medical test, until there is a “Medical Record Number” in the computer. Can’t get one of those until we tell the computer whether the baby is a boy or a girl. And there is no way to bypass that and get on with delivering emergency care. (Almost unimaginable - ed.)

Not the way one wants to break the news of an intersex (gender not definite) problem to a new young mom, of a very sick baby…. So I ran back to Labor & Delivery, sat down face to face with the mom, still groggy from meds and caesarian section surgery – and said something like, “Your baby is very sick, and we don’t know precisely why. And we can’t tell for sure right now whether your baby is a boy or a girl. In order to get x-rays and medications, we need to tell our computer whether your baby is a boy or a girl. Which do you want the baby to be?

The 18 year old new mom looked me right in the eye, nodded her understanding, and said, “I want a girl.” So I said, “OK, she’s a girl. I’ll come back and talk to you as soon as we get her stabilized.”'

Postscript: We did get her stabilized, and she was a genetic girl, but she died waiting for a heart transplant that never came. And that mom spend nearly every waking minute with the baby for the whole 3 months we all waited for the heart transplant that never came. Truly an amazing person, that mother. All children should be so lucky.

Never since have I ever designed a database with gender as a binary part of the primary key. Out in the business world, people are still doing that. And I’m sure some of those people are still trying to sell their business stuff to healthcare. Babies aren’t the only ones who might need a bypass (intersex is actually quite common), and consider the roadside bomb victims in Iraq – or any other explosive, burning trauma – is gender your first concern?

(My response is that anyone with even a smidgen of pediatric healthcare knowledge knows that gender can be one of “M”, “F”, or “unknown.” Apparently, the designers of the system did not envision such knowledge as important for informing system design .)

-- SS

Did the New England Journal of Medicine Really Commit "Journalistic Malpractice"? And Who Says So?

The publication of a meta-analysis which suggested that rosiglitazone (Avandia, made by GlaxoSmithKline [GSK]) may increase cardiac risk has created quite a kerfuffle. (See our posts here and here. The meta-analysis is Nissen SE, Wolski K. Effects of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356, online here)

There have been several attempts to discredit the Nissen and Wolski article, most prominently in a commentary by Dr Scott Gottlieb in the Wall Street Journal (original version, requiring a subscription here). Yesterday, MedInformaticsMD posted about how the commentary, which blasted the New England Journal of Medicine for political bias, seemed designed to distract attention from problems in how pharmaceutical (and biotechnology) manufacturers dominate clinical research on their own products, and market the results of that research to patients and physicians.

Given the influential placement of this commentary, I thought it worthwhile to examine its specific criticisms of the New England Journal.

Dr Gottlieb started by faulting the journal because, he claimed, it " it rushed onto its Web site a limited and flawed analysis of safety concerns around the diabetes drug Avandia." Then, he claimed "the NEJM study doesn't add much new insight ... because of its own limitations." Furthermore, he charged, "NEJM editors gave short shrift to the study's flaws." Then he noted that the study "contained a number of serious limitations." Later, he decried, "he way data was misused by NEJM....," and that "these shortcomings didn't stop NEJM from spinning the preliminary data...."

So what were the limits of the analysis, how was it flawed, what were its shortcomings, and how was the data misused? After repetitively asserting that the study was imperfect, Dr Gottlieb actually only cited two specific problems with it, in a single sentence.

The authors of the NEJM study based their conclusions that Avandia caused a higher heart risk on just a handful of cardiac events, none of which they could go back and verify, because, unlike the FDA, the authors didn't have access to confidential patient records.

That was it, his whole discussion of the terrible flaws and shortcomings of the Nissen and Wolski meta-analysis, the data which the NEJM so grievously misused.

Yet these are flaws and shortcomings of the existing publicly available data from clinical trials of Avandia, not of how Nissen and Wolski combined that data in their meta-analysis.

The number of events observed in individual clinical trials depended on the size and duration of these previous studies. Similarly, if there were problems in how the original trials categorized cardiac events, the meta-analysis could not solve them.

It actually is not hard to criticize the available clinical research data on the adverse effects of rosiglitazone. It suffers from problems common in the literature on adverse effects of drugs and devices. The publicly available clinical studies were mostly too small, and of too short duration to have much statistical power to find any but the most common adverse effects. Instead, the studies, in the case of rosiglitazone, all sponsored by the drug's manufacturer, were seemingly designed to focus on possible good effects of the drug, not to find problems with it.

Nissen and Wolski's meta-analysis could not solve these problems. It did accomplish two things. First, it brought out from the internet's shadows clinical trial data which is only publicly available on GSK's rather obscure web-site. Second, Nissen and Wolski wrote the first published attempt to combine this obscure data with that from the few published trials to provide a better estimate than those previously available, however imperfect, of the cardiac adverse effects of rosiglitazone.

So why didn't Gottlieb criticize GSK for funding only relatively small, short studies that individually revealed little about the downside of its drug, and then releasing their results late, and only onto an obscure web-site forced into being by lawsuits against the company? Why didn't he criticize the company for not doing a big, definitive study in a timely manner?

(There is an ongoing study, RECORD, which will not be done until 2009 that may be of sufficient size and duration to eventually tell us more about the cardiac effects, good or bad, of rosiglitazone. See: Home PD, Pocock SJ, Beck-Nielse H et al. Rosiglitazone evaluated for cardiac outcomes and regulation of glycaemia in diabetes [RECORD]: study design and protocol. Diabetologica 2005; 48: 1726-1735.)

I can't answer those questions. But note that Dr Gottlieb, like others who have written to defend business as usual in the pharmaceutical industry (see most recent post here), has more relationships with that industry than were revealed by his one-sentence biography at the end of the WSJ article (" Dr. Gottlieb, a physician, is resident fellow at the American Enterprise Institute and was Deputy Commissioner of the FDA from 2005 to 2007.")

Just before he took that job, the Seattle Times reported, "Only a month ago, Dr. Scott Gottlieb was a Wall Street insider, promoting hot biotech stocks to investors." In fact, "Until last month, Gottlieb was editor of a popular biotechnology investor newsletter, Forbes / Gottlieb Medical Technology Investor. Forbes touted Gottlieb's stock-picking success on its Web site in mid-May...." Also, "he also has consulted for, and written positively about, a major matchmaking firm that links doctors with Wall Street investors, the Gerson Lehrman Group in New York."

A few months later, the Boston Globe reported that as FDA Deputy Commissioner, Dr Gottlieb had to recuse himself from discussions about dealing with an avian flu epidemic

because his past consulting work for [large public relations firm] Manning Selvage & Lee involved companies whose products would be used to combat a flu pandemic. Gottlieb's former clients include Roche -- manufacturer of the highly sought antiviral Tamiflu -- and Sanofi-Aventis, parent company of the nation's sole flu vaccine manufacturer.

Manning Selvage & Lee paid Gottlieb a $12,500 monthly retainer for nine months for business development projects that included eight companies. Other firms regulated by the FDA he was involved with include Inamed Corp., one of two companies seeking to return silicone gel implants to the market. He also did private consulting work for VaxGen Inc., a California firm that won a $878 million federal contract to supply 75 million doses of anthrax vaccine for the nation's protective stockpile. The $9,000 he accepted from VaxGen for consulting work between May and July prevents him from doing FDA work related to that company until August 2006.

Furthermore, since Dr Gottlieb left the FDA, Bench International boasted, "Bench International Places Eminent Regulatory Advisor Scott Gottlieb, M.D., as Senior Counsel to Novartis." Its text stated that Dr Gottlieb was to assume "a senior-level regulatory advisory position for Novartis Pharmaceuticals Corporation [NYSE: NVS]. Under an exclusive consulting agreement, Scott Gottlieb, M.D., will provide advisory services to Novartis on matters of global regulatory policy and strategy."

So once again, a strident but weakly supported attack on those who would dare criticize an expensive product of a big pharmaceutical company turns out to have been written by someone with extensive, and current financial ties to the pharmaceutical industry.

The pharmaceutical industry is now often regarded by the public as "shifty." A first step to regain public trust would be for people who work for the industry to make that fact clear when they speak publicly in its favor.

ADDENDUM (30 May, 2007) - PharmaLot also noticed Dr Gottlieb's ties to Novartis.

Drug Makers Finance Nurses as On-Site, Chart-Reviewing Drug Reps

You read the title correctly.

Drug Makers Finance Nurses as On-Site, Chart-Reviewing Drug Reps

The Wall Street Journal in its free article here used the title "Drug Makers Finance Nurses for U.K. Doctors", however I believe my title captures the essence of this article more accurately.

Excerpts:

Drug companies are paying for nurses to study patient charts to identify people with chronic illnesses. The nurses, who come from nursing contractors, then recommend which patients should be called in for a check-up and perhaps prescribed new treatment -- sometimes a medicine made by the company funding the nurses. The work is part of what the industry calls "disease-management programs," which the companies say improve care for people with illnesses like diabetes, asthma or heart disease.

The risk, however, is that companies use the programs as a back door for marketing their pills. The programs also raise concerns about patient privacy.

I would agree with that assessment. It's incredible that drug companies sponsor nursing contractors to send nurses into clinician offices for chart reviews and involvement in the clinical decisionmaking process. If that is not the poster definition for "appearance of conflict of interest" if not conflict outright, I don't know what is. Clinicians are also to blame for allowing this.

Are some clinicians themselves accepting pharma money for permitting this "service" on their premises? Want to place bets?

Of course, another paragraph brings a familiar name to the forefront (I am increasingly losing pride in having that company's name on my CV):

Last fall, the Association of the British Pharmaceutical Industry, a trade group, temporarily suspended the United Kingdom subsidiary of Merck & Co. from the trade group after finding that the company had used a program for patients with high blood pressure to promote its drug Cozaar ... In the program that resulted in Merck's recent temporary suspension, the company had been paying for nurses to review patients with high blood pressure in doctors' offices across Britain since 2004. In March 2006, a Merck sales representative filed a complaint with the Prescription Medicines Code of Practice Authority, a U.K. watchdog, alleging that the company was trying to use the program to promote its drug Cozaar. The watchdog body found that Merck had instructed its sales reps to offer the program to doctors who were big prescribers of Cozaar, making the program a reward for high prescribers of the drug. The group suspended Merck for three months and forced it to write a letter to doctors in the program alerting them to the violation and apologizing. The company said in a statement at the time that it took the breach "very seriously," and that it "is working hard on corrective actions."

"Corrective actions" include what, exactly, I ask?

Some clinicians resist:

Jim Kennedy, a physician from Middlesex, England, says he's turned down offers from drug sales representatives to send special nurse teams to his practice. There is a "perceived or real risk of the pharmaceutical companies' interests taking precedence over the patients' interests," says Dr. Kennedy, who is also the spokesman for the Royal College of General Practitioners, a professional group. He says many doctors in his group share his concern.

This "service" is spreading:

While company-sponsored nurse teams are most common in Britain, the practice is growing in other countries that also pay for medical care including Belgium, Germany and Ireland, says Hywell Evans, head of the European unit of Quintiles Transnational Corp., a company based in Research Triangle Park, N.C., that provides nurses and other services to drug companies.

The article goes on to describe how patient record privacy is supposedly protected in these programs, which gives me little confidence that there are no abuses in this regard.

Read the whole article. However, I believe what we are seeing is an increasingly complete takeover of clinical medicine by industry. This also helps me understand the huge resources diverted to drug marketing strategy. It must take a lot of MBA's to come up with these schemes, and bureacracy and support staff to maintain them.

-- SS

BLOGSCAN - The Hazards of Whistle-Blowing

On the Scientific Misconduct Blog, Aubrey Blumsohn addresses how health care whistle-blowers often end up themselves having bad health outcomes.

Journalistic Malpractice, or Pharmaceutical Malpractice?

In today's Wall Street Journal, Scott Gottlieb of the American Enterprise Institute has a piece entitled "Journalistic Malpractice" that accuses medical journals such as the NEJM of an ideological agenda and demonization of the pharmaceutical industry. The piece can be read in its entirety at the AEI website at this link.

The "money quote" is this:

At what cost do political machinations of the medical journals come? When editors pursue a political agenda, it's public health that pays a price ... There is a problem when some journals let antipathy for business interests and left-leaning views interfere with the medical decisions that they make, bending standards or stepping outside their mandate, using their prestige and influence in ways that distort medical facts in the aim of influencing political outcomes.

I have written a letter to the editor to the WSJ in reply. As its chances for publication are slim (the WSJ published my letter to the editor regarding electronic medical information privacy in Dec. 2006 and will be unlikely to take another one so soon), I have reproduced my response below:

May 29, 2007

Re: "Journalistic Malpractice" (WSJ, Tue May 29, 2007, p. A15)

Dear WSJ,

In “Journalistic Malpractice” (WSJ, Tue May 29, 2007, p. A15), Scott Gottlieb writes that medical journals such as the NEJM are pursuing a political agenda of left-leaning views and seems to imply some journals are demonizing the pharmaceutical industry.

I think he’s missed the root cause of the attacks on the pharmaceutical industry almost entirely.

The root cause is not primarily the result of an ideological or anti-capitalist agenda; after all, both the left and the right and everyone in between get ill, and stand to benefit from pharmaceutical innovation.

The cause of the attacks from venerable journals such as the NEJM is not ideology, but mistrust . The pharmaceutical industry has taken societal trust - a must for any industry to be successful - and blown it out of the water. In fact, the public mistrust of the pharmaceutical industry has been well-earned.

As many print and web-based writers including the Foundation for Integrity and Responsibility in Medicine (FIRM) have increasingly and repeatedly pointed out in websites such as FIRM's Healthcare Renewal ( http://hcrenewal.blogspot.com ), where I occasionally write on medical informatics-related topics, pharma has regularized some highly questionable practices.

It is an industry that hires ghost writers to “pave the road” for new or existing drugs with what amounts to scientific spin doctoring. It bribes clinicians with gifts and perks. It advertises its wares shamelessly, as if it were selling lingerie. It presents data “with the best foot put forward” until forced not to, and has done this in some exceptionally socially-tender areas, such as antidepressants in children regarding suicidal ideation. It is an industry that hires MBA-credentialed senior executives who never took care of a patient in their lives (one of the largest pharma's CEOs was actually general counsel at McDonald’s and was president of the company’s smaller brand, Boston Market), leading to clinician and patient disgust and distrust. Its websites promise employees wonderful careers helping people, and then the industry lays off thousands of such professionals in a heartbeat due to a slight tick in stock market valuations. It is an industry where R&D may be controlled by non-medical personnel who often have more power to control internal information flow and availability than senior scientific leadership. (I've seen IT departments effectively running R&D through rationing of critical drug discovery tools.)

In effect, pharma is an industry that socially acts like a bull in a china shop. My only surprise is that the medical journals are not even more hostile than they already are -- and that may have to do with "money issues" as in the preceding paragraph.

Put bluntly, the pharmaceutical industry has lost the public trust. It is said that self-improvement cannot come before one has insight into one’s faults.

Blaming medical journals for journalistic malpractice while the pharmaceutical industry commits social, medical and scientific malpractice is mistaking a symptom for its causative and far more society-damaging disease.

-- SS

Addendum: I am informed of the following via "Integrity in Science Watch - May 29, 2007" (link) in its "Cheers and Jeers" section:

Jeer: To the Wall Street Journal for failing to tell readers of an op-ed by Scott Gottlieb, former FDA deputy commissioner now at the American Enterprise Institute, that AEI takes financial contributions from the drug industry and former Merck chief executive Raymond V. Gilmartin sits on its board. The op-ed accused the New England Journal of Medicine of "journalistic malpractice" in publishing a study that suggested the diabetes drug Avandia, made by GlaxoSmithKline, increased the risk of heart attacks.

I am a Medical Informaticist who got laid off by Merck under Gilmartin's watch during the "Equinox" mass layoff of 4,400 people in Nov. 2003 (they name the layoffs...) This was after helping fill a huge gap in flow of scientific articles to Merck scientists from a constant 100K/year from 1989 to 2000, to over 1,000,000 per year by 2004, and ending rationing of essential drug research informatics tools due to (non-scientist) IT personnel's control of the budget. I accomplished those feats through aggressive challenging of the "IT-department-controls-research" status quo, probably making me a prime layoff target.

I received a special benefit: I gained experience in how to lay off people, because as a manager I was made to take the layoff training in the days before they laid us off. Good industry social graces indeed.

With regard to my post above and the "Cheers and Jeers" item, I say this:

"I rest my case."

-- SS

"That Just Doesn't Happen" - the Ketek Trial Debacle

We previously posted (also here and here) about the ill-fated clinical trial, study 3014, of the antibiotic telithromycin (Ketek) made by Sanofi-Aventis, run by Pharmaceutical Product Development Inc. (PPD). Problems with the trial included fabrication of data at one clinical site, and allegations of manipulation of data at another. The physician in charge of the first site was convicted of mail fraud, and the physician in charge of the second had his license suspended. Although the results of this trial were never published, it still crept into the clinical literature: it was cited in a review article in the New England Journal of Medicine.

The St Petersburg (FL) Times just reported on more details about how the trial was conducted. First, some background...

Aventis devised Study 3014, a clinical drug trial involving 1,800 private physicians and thousands of their patients nationwide.

As is common practice in the industry, Aventis opted to have a third party conduct the study. It paid PPD Inc., one of the world's biggest contract research organizations, some $20-million for the work.

The drugmaker was offering doctors $400 per patient to test Ketek, its new antibiotic for persistent colds and coughs.

Then, here is how things worked at Study 3014's highest patient-volume site:

Anne Kirkman Campbell, a family practice doctor in Gadsden, Ala., signed up 400 patients, more than any other doctor in the country.

Ann Marie Cisneros had worked for PPD for three years when she was sent to check up on Campbell in early 2002. The doctor had recruited more than 1 percent of Gadsden's adult population for the Ketek study.

Cisneros noticed that none of the doctor's staff would look her in the eye. Combing patient files, Cisneros found that the doctor had enrolled her entire staff and several family members in the study.

Patient consent forms had been signed every few minutes and at times when the office was closed. Medical records had been edited, with notations of 'sinusitis' and 'bronchitis' added so patients would qualify for the trial.

'It appeared the patient was coming into the office for one condition and the doctor was writing in something else later,' Cisneros said. 'That's how Dr. Campbell ended up with 407 people.'

By comparison, another local doctor found only 12 patients who met the study criteria.

The Ketek study was demanding; it required that patients come in for three office visits and blood draws over five months. But not a single one of Campbell's patients had dropped out.

'That just doesn't happen, period,' said Cisneros, noting that even small studies experience dropouts.

The doctor didn't appreciate the scrutiny. She told Cisneros that she wouldn't have enrolled so many patients had she known it would trigger an audit.

'That's just scary,' Cisneros said. 'Dr. Campbell didn't get away with it because she hadn't learned the system.'

But the response to Cisneros' findings was at best, lackadaisical...

Certain she had found fraud, Cisneros called her manager at PPD. She also took the unusual step of contacting a consulting partner responsible for ensuring patient safety in clinical trials. Copernicus Group IRB, also paid by the drug company, had access to trial subjects' names and phone numbers. Monitors like Cisneros usually had limited identifying information.

'I wanted them to call some patients and see if they'd really agreed to be in the study,' said Cisneros, who suspected patients were enrolled without their knowledge. 'But the woman at Copernicus said, 'Let's see what Aventis does about this.' '

Spokeswomen for Copernicus and PPD declined to comment.

After Cisneros returned to PPD, she and her bosses had a teleconference with the drugmaker. She said her concerns about the doctor's conduct, including the likelihood that consent forms had been forged, were ignored.

'I walked away from that meeting very frustrated,' Cisneros said. 'I'd never seen a sponsor so lackadaisical about a site.'

A spokeswoman said the Paris-based drugmaker, which has since become Sanofi-Aventis, knew of 'deviations' at Campbell's site but didn't know they amounted to fraud until a subsequent FDA investigation.

'We were aware of issues at that site and had gone in to try to rectify them,' said spokeswoman Lisa Kennedy. 'We strongly object to any characterization of wrongful conduct by Aventis.'

Later, "the U.S. Attorney's Office in Birmingham indicted Dr. Campbell on 21 counts of fraud. She pleaded guilty to one count of mail fraud and was sentenced to 57 months in prison." Dr Campbell, interviewed from prison, charged that Sanofi was part of the problem with the trial.

'They seemed to want to rush you through everything,' said Campbell, who had performed a half-dozen clinical trials for other drugmakers. 'They didn't care how you did it. They wanted the trial over so they could get the data to the FDA.'

Despite Campbell's 'deviations' during the Ketek trial, once it was over Aventis hired her for a second study that spring. The drugmaker also flew Campbell to a conference in San Diego that summer so she could learn how to market Ketek to other physicians.

In the fall of 2002, when the FDA called to schedule a routine audit, Campbell said, Aventis told her to delay the agent for a week.

'Then they flew in two doctors to prep me and four to six girls to go through my files,' said Campbell, who said the drug company's representatives suggested appropriate responses to the FDA's queries.

Sanofi-Aventis' spokeswoman said it is normal for a drug company to help a doctor prepare for a site inspection. She said Campbell was advised to answer the FDA's questions truthfully. The drugmaker ended its relationship with the doctor after the FDA initiated its criminal investigation, she added.

Campbell said she was amazed when the court said the drugmaker was a victim of her fraud and ordered her to pay $925,000 restitution. In a court filing last year, Campbell appealed the restitution order.

Aventis 'had been made aware of the fraud at my site by PPD,' she argued. 'At NO TIME did they (Aventis) attempt to stop my participation.'

Late last month, Campbell's motion was denied.

In any event, data from Dr Campbell's questionable site was just dumped into the hopper with all the other study data. Then it was up to the FDA...

Cisneros, who left PPD for a higher-paying job at a competing company, assumed someone in a position of authority would alert the FDA about Campbell.

But the Ketek study continued uninterrupted. In July 2002, the drugmaker submitted the trial results to the FDA -- including data from all 407 patients at Campbell's site.

While the FDA's drug approval division reviewed the Ketek data, its inspectors were conducting routine audits of the biggest study sites. Their first stop was Campbell's office, where they found such flagrant violations that they immediately called in the agency's criminal division.

FDA investigators visited nine other high-enrolling sites and discovered serious problems at every one. One doctor, whose medical license was on probation at the time of the study, was arrested for cocaine and gun possession soon after. FDA agents referred Campbell and three other doctors for criminal investigation and recommended expanding the inspections to additional sites.

But even as the FDA's Office of Criminal Investigation uncovered widespread problems, the agency's drug approval division proceeded to review the Ketek data.

In addition to its internal review, the FDA often has an outside, advisory group of experts evaluate trial data and recommend whether a drug should be approved. [Dr David] Ross, the FDA scientist, said he expected the Ketek advisory group would be told of concerns about the data's validity in light of the ongoing criminal investigations. He said he was appalled when his boss, Dr. Mark Goldberger, told him not to raise the issue with the outside experts.

'In general, I don't believe spending time on (data integrity) issues in front of the AC (Advisory Committee) will be productive,' Goldberger wrote in an e-mail a few days before the January 2003 meeting.

The FDA recently said that at the time of the advisory meeting it had only preliminary information on problems with the Ketek study and wished to avoid 'compromising the ongoing investigations.'

But Ross said his bosses had plenty of options. 'They could have told the committee what they knew in closed session. Or they could have postponed the meeting,' he said. 'I felt like I was being told to hide things.'

The FDA's advisory committee recommended approving Ketek. After delaying its decision to get anecdotal information on Ketek's safety record overseas, the FDA approved the drug on April 1, 2004.

Last week, there was quite a brouhaha about a new meta-analysis that suggested that rosiglitazone (Avandia, GlaxoSmithKline) had more cardiovascular risks than heretofore believed (see posts here and here, and for just a taste of the bit of the brouhaha related to Health Care Renewal, see this post on In the Pipeline, this post on the Pharma Marketing Blog, and this post on the Pharma Blogsphere.)

That meta-analysis included the results of multiple unpublished clinical trials. These results, in turn, were only made available because GSK had been forced to set up a web-based clinical trials registry by a 2004 settlement of a lawsuit brought by Eliot Spitzer, who charged that GSK had suppressed clinical research about its antidepresant paroxetine (Paxil). (See Steinbrook R. Registration of clinical trials - voluntary of mandatory. N Engl J Med 2004; 351: 1820-1822, link here and our post here.)

Both the Avandia and Paxil cases underlined, in my humble opinion, how pharmaceutical (and other) companies that sponsor clinical trials have often tried to keep the results of these trials secret. Such attempted suppression of research both breaks promises made to the human subjects of clinical research that their participation would go to advance science and improve health care. Such attempted suppression also denies patients and doctors important evidence relevant to decisions about health care interventions, and hence may lead to bad decisions that harm patients.

The Ketek case underlines, in my humble opinion, how pharmaceutical (and other) companies that sponsor clinical research may be at best sloppy in how they let their clinical trials be conducted. Such sloppy science also breaks promises made to human subjects of clinical research that their participation would go to advance science and improve health care. Sloppy trials that produce dubious data will do neither. Furthermore, sloppy science that produces dubious results provides patients and doctors pseudoevidence rather than the best possible evidence relevant to decisions about health care interventions, and hence may also lead to bad decisions that harm patients.

So if pharmaceutical and other health care companies do not want to be regarded by the public as "shifty," maybe they ought to think about making sure that the clinical trials they sponsor are done honestly and well, and that their data results are quickly and accurately released. Or maybe they ought to get out of the business of sponsoring such trials entirely.

Hat-tip to PharmaGossip.

BLOGSCAN - Did Pfizer "Pre-Market" Maraviroc?

Question Authority with Dr Peter Rost has put a series of posts (here, here, and here) about allegations of questionable marketing practices by the world's largest drug company, Pfizer Inc. In particular, Pfizer is alleged to have started to market maraviroc, a treatment for HIV infection, in the US before FDA approval.

Expanded Avandia Story Now Echoes Familiar Themes

The story about the possible cardiovascular adverse effects of rosiglitazone (Avandia, made by GlaxoSmithKline [GSK]) just continues to get more interesting, now that more reporters are digging around about it. In particular, today Stephanie Saul and Gardiner Harris wrote in the New York Times that the US Food and Drug Administration (FDA) had been warned in 2000, seven years ago, about possible cardiovascular side effects of Avandia.

A leading diabetes doctor sent the Food and Drug Administration a letter seven years ago that warned of the heart risks of the drug Avandia.

The documents, found in a reporter’s search of the F.D.A.’s database, indicate that the agency had been warned of safety concerns with the Type 2 diabetes treatment Avandia, and that the drug’s maker, GlaxoSmithKline, was seeking to minimize Avandia’s risks....

The letter in 2000 to the F.D.A. was written by Dr. John B. Buse, chief of endocrinology at the University of North Carolina in Chapel Hill, who is about to become the president of the American Diabetes Association. His letter from seven years ago sounded an alarm about Avandia, citing 'a worrisome trend in cardiovascular deaths and severe adverse events' among patients using the drug.

In his letter to the agency, dated March 15, 2000, Dr. Buse was highly critical of the drug maker’s marketing of Avandia, accusing the company of 'pervasive and systemic' efforts to play down the drug’s risks and overstate its benefits.
Dr. Buse said that he does not generally prescribe Avandia to patients. He has been an outspoken critic of the drug in medical education meetings, some of them sponsored by Takeda and Eli Lilly, which jointly market a competing drug, Actos.

He was also an investigator in a study comparing Avandia with Actos, sponsored by Eli Lilly, that showed Actos had better effects on cholesterol than Avandia.

Dr. Buse said yesterday that he wrote the letter in 2000 in response to an F.D.A. petition filed by Dr. Sidney Wolfe, a consumer activist, who had asked the agency to place warning labels on Rezulin, Avandia and Actos.

Dr. Wolfe’s Health Research Group, a part of Public Citizen, has long warned patients not to use any of those drugs. At the time, the F.D.A. was considering removing Rezulin from the market, and Dr. Buse objected. Rezulin was made by Parke-Davis, a division of the Warner Lambert Company.

'The way I felt about it, after several years of clinical availability of Rezulin, we kind of understood the problems with it,' he said, 'and we didn’t understand the problems of Actos and Avandia.'

Dr. Buse analyzed data submitted to the F.D.A. in support of Actos and Avandia and came to the conclusion that there was a 'hint, a whisper' of cardiac-related deaths with Avandia as well as evidence of negative effects on cholesterol.

Referring to Avandia by its generic name, rosiglitazone, and to Rezulin as troglitazone, Dr. Buse wrote in the letter, 'I do not believe that rosiglitazone will be proven safer than troglitazone in clinical use under current labeling of the two products.' He added: 'In fact, rosiglitazone may be associated with less beneficial cardiac effects or even adverse cardiac outcomes.'

In the 2000 letter, Dr. Buse asked the agency to call for head-to-head studies of all the drugs.

Yesterday, he said, 'I would say that in the last several years, there has not been a study that’s made me feel better about this.'

The Times reporters also uncovered evidence that GSK had been warned about over-zealous marketing of Avandia that played down its possible side effects.

The F.D.A. was conducting its own investigation of Avandia marketing and found that company representatives were denying the existence of changes on the drug’s label that the F.D.A. had already ordered, which were meant to flag Avandia’s risks to the heart and liver.

The agency sent the drug maker a warning letter in July 2001, citing misleading statements made by company representatives at a recent meeting of the American Academy of Clinical Endocrinologists, where the agency had sent undercover investigators. The F.D.A’s letter criticized company posters displayed at the meeting, saying they did not carry adequate warnings.

It was the third time that the agency had chastised the company about its promotion of Avandia. Because of the repeated warnings, the agency demanded that the company send out a letter to doctors specifically warning them of the risks. The company subsequently sent out that 'Dear Doctor' letter on Sept. 6, 2001.

One wonders in retrospect whether the unfortunate timing of that letter, just before the attacks on the World Trade Center in New York, diverted attention from it.

In any event, this story has acquired even more elements that ought to be familiar to readers of Health Care Renewal. First the story seemed to be about how the designs of clinical studies of rosiglitazone make them less likely to find clear evidence of cardiovascular risk, how failure of the results of some of these studies to be published lessened attention to then, and how the published reports of the bigger studies were written to divert attention from cardiovascular risk.

Now there are new, but familiar elements:

• Early warnings from at least one whistle-blower were apparently ignored.
• The pharmaceutical promoted the drug enthusiastically, apparently again in a way designed to distract attention from particular adverse effects.
• Just to muddy the water, the whistle-blower had financial relationships to manufacturers of competing drugs, possibly leading to questions about whether his whistle-blowing may have been influenced by them.

So let me reiterate some implications.

Failing to Disclose Clinical Research Results Violates the Trust of the Research Subjects

People who perform clinical research, that is studies of real, live people, especially experimental studies, that is, randomized controlled clinical trials have an obligation to their study subjects to make the results of these studies as widely available as possible. Otherwise, they have violated the trust of their study subjects, who participated under the assumption that their efforts were going to advance science and health care.

It makes no ethical sense to think that because a drug (or other) company pays for a clinical study, i.e., a study of real people, it owns the data from the study, and has no obligation to see that the results of the study are made public. (The exception would be if the subjects were told plainly the study was done for marketing or other commercial purposes, that is, to benefit the company, not science or health care. One suspects that if patients were told this, they would demand such high fees for participating that the conduct of such studies would be prohibitively expensive.)

It is very worrisome that at least one high FDA official was quoted as seemingly disturbed by the wider distribution of the results of clinical trials. The New York Times reported yesterday,

Some experts also believe that releasing the results of hundreds of studies involving drugs or medical devices might create confusion and anxiety for patients who are typically not well prepared to understand the studies or to put them in context.

'I would be very concerned about wholesale posting of thousands of clinical trials leading to mass confusion,' said Dr. Steven Galson, the director for the Center for Drug Evaluation and Research at the F.D.A.

Recently, a report issued by the Institute of Medicine, a part of the National Academy of Sciences, recommended that the F.D.A. release all summaries of study data it had collected in the process of approving new drugs as well as all post-marketing studies of those products.

The F.D.A. rejected the first recommendation as overly burdensome and Dr. Galson, the director of the F.D.A.’s drug evaluation and research, said that the agency already released much of this information. 'It is not that we are philosophically opposed to it, but the work would be enormous, he said.

There is an argument for making sure that clinical trial results are disclosed in a clear, non confusing way. That may take some work and cost some money. But failing to disclose the results because of worries about "confusion," again, violates the trust of the study subjects.

Patients and Physicians Need to be Very Skeptical About Drug and Device Marketing

Once again, it appears that a drug company was pushing one its products beyond what the clinical research evidence supported. In this day and age, patients and physicians should be extremely skeptical of any and all marketing claims by drug, device, and biotechnology companies (and all other health care organizations, for that matter). Instead, we ought to be looking at the biomedical science and clinical research evidence.

Pervasive Conflicts of Interest in Health Care Make Figuring Out What is Best for Patients Even Harder

This story is muddied by the apparent conflicts of interest of the major players, even the "good guys." Dr Buse, the apparent whistle-blower about the hazards of Avandia, had financial ties that may have made him more critical of that drug. Thus, his warning message may have not been so easy to interpret. Even Dr Steve Nissen, who dug out and meta-analyzed the data about Avandia, has been criticized for his conflicts of interest, per this report by Michelle Fay Cortez for Bloomberg,

While drugmakers pay for much of the research that Nissen conducts, the nonprofit Cleveland Clinic provides his salary -- one bit of data that the doctor won't disclose. To distance himself from industry, Nissen set up a separate foundation to receive consulting income and speaker fees.

The arrangement hasn't shielded Nissen from criticism that he sometimes goes too far to promote medicines that he studied for drugmakers.

Sales of Crestor [rosuvastatin, made by AstraZeneca] swelled after a study from Nissen showed the cholesterol medication reversed signs of heart disease in some patients. He praised the drug from the podium of a medical meeting in March 2006, saying the study showed 'unequivocal' evidence that disease retreated with high-dose Crestor therapy.

He took over as president of the meeting sponsor, the American College of Cardiology, the same evening. Crestor sales have climbed at least 50 percent in every quarter since then, rising 62 percent to $628 million in the first three months of 2007.

His handling of the Crestor study casts doubt on Nissen's status as a public-health defender, says Sidney Wolfe, the director of Public Citizen's Health Research Group in Washington. Nissen wouldn't have been so bullish if he hadn't received the research grant, Wolfe says.

'This paper, and the way it was played, is an example of what happens with financial conflicts of interest,' Wolfe says. 'If he had not been an investigator for the study, I don't think he would have put quite the same spin on the results.'

So the Avandia story turns into another 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.

Oh, and finally,

Failing to Disclose Research Results Is Bad for Patients

According to the evidence-based medicine paradigm, patients and physicians should together make decisions about health care interventions based on a critical review of the best available evidence from clinical research, combined with the physicians' knowledge of the clinical context and biology, with consideration of the patient's values. Hiding relevant evidence (because a sponsoring company feels it owns the evidence and the evidence is not favorable to that company's products) distorts this decision making process, creates pseudo-evidence, and will lead to patients not getting the best tests and treatments for them. That is bad for patients.

ADDENDUM: See also comments on GoozNews, Retired Doc's Thoughts, PharmaGossip, and again PharmaGossip, PharmaLot, and again Pharmalot.

"Medical Leaders Double as Corporate Directors"

We have posted about some examples of top leaders of US academic medicine who are also on the boards of directors of large for-profit health care corporations.

I may be blowing my own horn a bit here, but the Internal Medicine News included a story, entitled, "Medical Leaders Double as Corporate Directors," on our abstract on this topic presented at the annual meeting of the Society of General Internal Medicine. It opened thus,

If accepting free pens or lunches from industry represents a potential conflict of interest for physicians, what do you call it when a medical school dean is also the corporate director of a large, for-profit health care company?

Exactly.

We found that of 125 medical schools, 65 (52%) had at least one faculty member or academic leader who was also on the board of directors of a large US public for-profit health care corporation. Furthermore, "7 [schools] reported to university presidents who also were directors of health care corporations, 11 reported to vice presidents for health affairs who were corporate directors, and 5 were lead by deans who also were health care corporate directors. Also, 11 schools had academic medical center CEOs who were corporate directors, and 22 schools had at least one [such] top leader who also was a director of a health care corporation." My summary was,

The bottom line is that a substantial portion of medical schools are led or influenced by people who are also obligated to have ‘unyielding loyalty’ to stockholders of forprofit health care corporations.

The report also featured some rather pessimistic comments by Nicole Lurie,

There are a lot of factors at play, including how aware you are of the potential
conflict and how much transparency protects you from acting in a conflicted way if you are conflicted.

Many physicians in practice don’t perceive a conflict at all. The first thing is to
open yourself up, look at yourself, and examine the issue. Then you have to think,
if these relationships exist, are there things you can do to make them work, because
I don’t think as a matter of public policy that we’re going to succeed in obliterating all these relationships.

Maybe if these relationships were made considerably more public there would be more support for their elimination.

DREAM Turns to Nightmare: Avandia and Cardiovascular Risks

The just released meta-analysis published in the New England Journal of Medicine that suggests that rosiglitazone (Avandia, by GlaxoSmithKline) is associated with increased cardiovascular risks [Nissen SE, Wolski K. Effects of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356, online here] has received a tremendous amount of media attention. So let me just summarize the story in a chronological way to emphasize some particular issues, based on Anna Wilde Mathews reporting today in the Wall Street Journal.

Dr. Nissen began following Avandia closely and was struck last year by the results of two major trials of the drug, published in the New England Journal of Medicine and the Lancet. The two studies showed the drug was effective in controlling blood sugar, but Dr. Nissen thought they held signs of cardiovascular problems.

The two trials were DREAM [The DREAM Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006; 368: 1096-1105.] and ADOPT. In DREAM, patients with glucose metabolism abnormalities who had not developed diabetes were randomized to get rosiglitazone or placebo, and followed for three years. The outcome of interest was the development of diabetes as defined by elevated blood sugar or abnormal results on a glucose tolerance test (or death). As Nissen noted in a letter to Lancet [Nissen SE. The DREAM trial. Lancet 2006; 368: 2049.], patients who received rosiglitazone were numerically more likely to have cardiovascular events, including heart failure, myocardial infarction [heart attack], stroke, angina, receipt of revascularization, or cardiac death, than were those who received placebo. The differences in rates, however, did not reach statistical significance, and hence could have been due to chance alone.

In ADOPT [Kahn SE, Haffner SM, Heiase MA et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355: 2427-2443.], patients with type 2 diabetes were randomized to rosiglitazone, metformin, or glyburide and followed for four years. The outcome of interest was increasing blood sugars leading to the use of another glucose lowering drug. Patients who received rosiglitazone were numerically more likely to have a cardiovascular adverse event, including myocardial infarction, congestive heart failure, and stroke.

Dr. Nissen wrote to GlaxoSmithKline in early January, asking for more data. The company offered to collaborate with him, but said it wanted to crunch the numbers itself. Dr. Nissen countered that the Cleveland Clinic needed full access to all the raw information and the right to publish as it pleased. Talks over the matter were inconclusive.

In mid-April, he found online the 1999 FDA document detailing the agency's original review of the drug. Then, in a Google search, Dr. Nissen found the online database of Glaxo study results. Many of the trial summaries included heart-attack data.

Dr Nissen and statistician Kathy Wolski used the on-line data in a meta-analysis of 42 trials of rosiglitazone. The meta-analysis suggested that the drug was associated with a higher risk of myocardial infarctin (odds ratio 1.43) and death from cardiovascular causes (1.64) than alternative treatments.

Because Avandia is now so widely used, Nissen's and Wolski's study has gotten a lot of press and caused a lot of consternation. Let me note at this point that Dr Nissen and Ms Wolski should be commended for being alert to the data on adverse effects found in the DREAM and ADOPT trials, and then being diligent in their search for more data. Nonetheless, the first big question is why Avandia become so popular in the first place?

When I have taught evidence-based medicine using the venerable "Users' Guides" approach, we came back to the key question to be answered when deciding about what therapy to use: do the benefits of therapy outweigh the potential harms?

A commentary published electronically that accompanied the Nissen and Wolski meta-analysis [Psaty BM, Furberg CD. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; 356, available here] suggested:

Physicians who chose to prescribe rosiglitazone perhaps focused on the single dimension of glycemic control. The underlying assumption represents a kind of linear 'physiological' argument: high levels of glycated hemoglobin increase risk, so a reduction in glycated hemoglobin will automatically translate into improved health outcomes for patients. This perspective ignores the many actions of the genes activated by PPAR-{gamma} agonists, only some of which are currently known. Many physicians did not require proof of health benefits as a criterion for selecting rosiglitazone as a therapy for type 2 diabetes.

Had practicing physicians required this higher standard, they would have been at a loss for evidence from large, long-term trials. Rosiglitazone was approved on the basis of short-term studies of the surrogate end point of glycemic control.

So it appears that the first lesson from this case reiterates the approach used in the "Users Guides." Only use treatments whose benefits to patients outweigh their potential harms, based on a critical review of the best available evidence. When several treatments are available, pick the one whose benefit/harm ratio is superior for the particular patient.

The consternation currently being caused by the results of the meta-analysis by Nissen and Wolski indicates how far many of us have departed from these principles.

But it gets worse,

Dr. Nissen made another discovery in scrolling through the Web site. The company itself had done a meta-analysis similar to the one he was attempting, and quietly posted the result. The analysis, which didn't appear to include the two big trials published last year, tied the drug to a 31% higher risk of events involving an obstruction of blood flow, such as heart attacks. The rate for people taking Avandia was 1.99%, compared with 1.51% for other patients.

So,

One issue coming under congressional scrutiny is whether the Food and Drug Administration should have acted faster to alert the public about possible risk from Avandia. Glaxo performed its own meta-analysis, which also showed a potential danger. It shared an early version of it with the FDA in September 2005 and a more complete one in August 2006. The findings weren't reflected on the U.S. label, which is supposed to give a comprehensive review of the drug's risks.

Robert Meyer, head of the FDA office that oversees diabetes drugs, said the agency is still working on its analysis. 'We have other data that suggests we can't make a definitive conclusion at this point,' said Dr. Meyer, although he called the meta-analyses 'a signal of concern.'

So some people did spot the problems, but did not publicize or act on them. Thus, the next big question is if both GSK and the FDA had data suggesting rosiglitazone may be associated with increased cardiovascular risks (and again, in the absence of any data that the drug has clinical benefits that could outweigh these risks), why didn't they act on, or at least publicize this data?

Well, there is one obvious explanation why GSK may have not been in a hurry to act.

Glaxo rang up more than $3 billion in world-wide sales of Avandia last year. Its share price fell more than 7% after the New England Journal of Medicine released the analysis by prominent cardiologist Steven Nissen of the Cleveland Clinic, who helped raise early safety concerns about Vioxx.

But the FDA does not have to worry about sales or share prices. Its job is supposed to be to protect the public's health and safety. Why didn't it act?

Has its funding by users' fees made FDA officials feel they are responsible first to the drug, device, and biotechnology companies that pay these fees? (See, for example, Furberg CD, Levin AA, Gross PA et al. The FDA and drug safety: a proposal for sweeping changes. Arch Intern Med 2006; 166: 1938-1942.)

Has its dependence on advisory panels often populated by people who have financial arrangements with drug, device and biotechnology companies made it more used to these companies' interests than any others? (See this post and its links.)

We can hope that the Avandia story will mark the tipping point on the way to reinvigorated FDA that sees itself as responsible first and foremost to the public, not specific commercial interests.

See also comments on GoozNews, and on PharmaGossip.

WHAT IS TO BE DONE?

American citizens might advocate these suggested ways to reinvigorate the FDA to their members of congress:

1. End financing by "user fees" that incorrectly suggest that the FDA's clients are drug and device manufacturers, not the public at large.

2. Ban people with conflicts of interest from FDA advisory panels.

3. Make the FDA explicitly responsible for safety of drugs that are on the market, and give it the resources and tools to uphold that responsibility.

4. Require that drugs and devices demonstrate clinical benefits to patients, not just improvement in laboratory test results, prior to marketing.

"FDA’s Conflicted Conflict-of-Interest Guards"

In Sunday's Providence Journal was an op-ed on defenses of conflicts of interest on US Food and Drug Administration (FDA) advisory panels made by people who turned out to have their own conflicts. The article summarized issues raised by three such defenses published in the Wall Street Journal, Boston Globe, and Providence Journal. The issues raised will be familiar to those who read our previous posts (re the Wall Street Journal article here and here, re the Boston Globe article here, and re the Providence Journal article here.) And they should be since I am tooting my own horn a bit here - I am the author of the latest Pro Jo op-ed. So to summarize my main points very quickly:

• Although the FDA has moved to more stringently restrict conflicts of interest affecting members of its advisory panels, these conflicts have had prominent public defenders
• The defenders' arguments were often based on exaggeration and logical fallacies
• The three most prominent examples of such defenses were written by people with financial ties to the pharmaceutical, biotechnology and/or public relations industry, suggesting that the conflicted have trouble making good arguments in defense of conflicts of interest.

Thus, "these defenses of conflicts of interest are reminders that we all need to be more skeptical of private interests underlying health-policy advocacy."

BLOGSCAN - Why Did Pfizer CFO Suddenly Depart?

On Question Authority with Dr Peter Rost is this post which speculates whether the sudden departure of the Chief Financial Officer (CFO) of Pfizer Inc was related to multiple allegations posted last week on the same blog about funny financial and other activities at Pfizer's Indian subsidiary. A more conventional explanation of the staff changes is here at PharmaLot.

The Senate Finance Committee Report on Pharmaceutical Companies and Continuing Medical Education

Last month, an important report by the US Senate Finance Committee on pharmaceutical sponsorship of continuing medical education (CME) was released, but received almost no coverage. The only media coverage I could find was here on MeetingsNet.com. The report itself is here.

The report was based on responses to questions made by 23 major US pharmaceutical manufacturers, and by the Accreditation Council for Continuing Medical Education (ACCME). Given the lack of coverage of this report so far, I will summarize the major points, using quotes from the report itself.

Pharmaceutical Involvement in CME

Pharmaceutical manufacturers fund educational programs that physicians and other health care workers attend, including programs used to fulfill their licensure requirements. These educational grants have become a well-established tool that all of the major pharmaceutical manufacturers use to disseminate information to the medical community. Drug companies routinely fund educational grants to support programs that favorably discuss the companies’ newer and more lucrative products, thereby encouraging physicians to prescribe those products and, ultimately, driving sales.

All of the 23 pharmaceutical companies surveyed funded educational grants. Most of the companies spent tens of millions of dollars annually to fund thousands of educational grants and educational programs. Educational grant budgets reported by individual companies for 2004 ranged from less than $2 million to $117 million. In 2004, total expenditures by commercial sponsors to support CME exceeded $1 billion.

Pharmaceutical Funded CME is Self- Not Government Regulated

ACCME is the primary accrediting body for CME for physicians. Many of the manufacturers’ responses indicated that the manufacturers rely on grant recipients’ accreditation by ACCME and the recipients’ promise to comply with ACCME’s Standards for Commercial Support as safeguards that the educational grants will be used for legitimate purposes. A primary principle of ACCME’s standards is that CME programs must be independent and the commercial sponsor must not control program content.

The FDC Act imposes limits on how manufacturers may advertise their products and forbids them from marketing or promoting their drugs for uses that have not been approved by the FDA. However, these marketing restrictions and the prohibition on off-label promotion apply only to entities involved in the manufacture or sale of the drugs. The FDA lacks jurisdiction over favorable discussions of a product, including a product’s off-label uses, by individuals or in settings independent from the manufacturer. Thus, the FDA does not claim jurisdiction over academic discussions or exchanges of scientific thought regarding off-label uses, except where attributable to the manufacturer.

In 1997, the FDA released guidelines for companies involved in industry-supported educational activities. The guidelines expressed the FDA’s intention not to regulate CME as long as it is independent from the companies whose products are discussed. The FDA advised that educational providers should maintain control over the content of their programs, disclose company funding of programs and connections to speakers, and discuss all relevant treatments for a condition, rather than focusing entirely on the newest medication or on one particular company’s product(s). Beyond this guidance, the FDA does little to ensure that educational grants are used for bona fide educational purposes. Nor does the FDA have a system in place to monitor educational programs.

CME Is Often Not Independent of Pharmaceutical Sponsors

ACCME reported that it reviewed 76 accredited CME providers for compliance with the ACCME Standards. Eighteen [24%] of these CME providers were found to be in non-compliance with at least one element of the ACCME standards. Examples from ACCME’s written findings of non-compliance include:
• 'The provider does not ensure that decisions regarding the planning and implementation of CME activities are made independent of commercial interests. A commercial interest influenced where and how many presentations were scheduled for three years of a CME activity.'
• 'The provider does not ensure that decisions regarding the planning and implementation of CME activities are made independent of commercial interests. Evidence from one activity reviewed indicates that a commercial interest was involved in the selection of faculty and other activities that interfered with
independence.'
• 'The provider does not ensure that a mechanism(s) has been implemented to identify and resolve all conflicts of interest prior to education activities being delivered to the learner.'
• 'The provider does not demonstrate appropriate management of commercial support. . . . Written agreements for commercial support were signed after the CME activity. However, the ACCME Standards for Commercial Support require written
agreements to include the terms and conditions to which both provider and supporter agree to abide. Therefore, it is the expectation of ACCME that agreements are signed prior to the activity taking place.'
• 'The provider does not demonstrate appropriate management of commercial promotion associated with educational activities. One commercially supported activity contains recurring use of one company’s product trade name at the exclusion of other products.'
• 'The provider does not demonstrate that the content and format of educational activities is without commercial bias. One activity reviewed promotes the proprietary business interests of a commercial interest.'

Company Procedures Have Improved, But Maybe Not Enough

The pharmaceutical industry is paying increased attention to educational grants and its compliance with fraud and abuse laws. The Committee staff’s review suggests that, in recent years, the major drug companies have limited the direct involvement of field sales representatives and sales and marketing departments in the educational grant-making process. Until a few years ago, it was common industry practice for the drug companies’ marketing departments to be responsible for awarding educational grants and for grant funding to come directly from the marketing budget, often from the specific product budget for a particular sales team. While many companies still allow marketing personnel to offer input, the
grant-making authority has largely been removed from the marketing department and placed with medical affairs departments, medical education departments, or general business units.

The responses to the Committee’s inquiry showed that the companies have undertaken some efforts to train employees in complying with corporate policies.

While the fact that corporate headquarters now espouse a commitment to compliance is certainly promising, it does not guarantee that all the company’s agents, operating in a highly competitive marketplace and an industry in which employees’ compensation is often tied to sales volumes, will put those policies into practice.

Continuing medical education has developed into a multi-billion dollar a year industry, much of which is funded by pharmaceutical manufacturers. It seems unlikely that this sophisticated industry would spend such large sums on an enterprise but for the expectation that the expenditures will be recouped by increased sales.

Corporate policies still allow this industry to walk a fine line between violating rules prohibiting off-label promotion and awarding grant money in a manner likely to increase sales of their products, including sales for off-label uses. The opportunity for abuse remains, particularly in the following four areas: (1) kickbacks; (2) veiled advertising; (3) bias in clinical protocols; and (4) off-label promotion.

It is difficult to quantify the risk of kickbacks related to industry-sponsored education where companies overpay high-prescribing physicians as ‘‘consultants’’ or ‘‘speakers’’ for minimal work to develop educational material or teach at educational programs.

Educational grants are often used to sponsor programs to teach physicians about treatment options for particular diseases. The information presented often encourages physicians to change their prescribing practices to favor certain drugs. When the favorable message is delivered in the context of education—even if corporate sponsorship is disclosed—there is an imprimatur of credibility and independence.

As with educational grants, commercial funding of clinical protocol development raises concerns about the introduction of commercial bias—favoring products marketed by the companies that helped fund the program.

The off-label promotion risk of educational grants appears to pose the greatest threat to the Federal health care programs and beneficiaries, but it is also the most difficult to demonstrate conclusively.

The report suggests that the current voluntary system of regulation has not been sufficient to guarantee that continuing medical education activities are strictly educational, and are not allowed to become instruments of stealth marketing. On Health Care Renewal, we have discussed several instances in which CME activities were turned into marketing. (For example, see this post on the stealth marketing of Neurontin.) The (almost) new Senate Finance Committee report is a reminder that physicians need to be very skeptical about the independence of commercially financed CME, even when the sponsorship is by a supposedly "unrestricted" educational grant.

Finally, the fact that this post on Health Care Renewal seems to be the longest discussion of this report available publicly to date, more than a month after its release, suggests that the anechoic effect continues. Or, as Aubrey Blumsohn recently suggested, criticism of the effects of vested interests in health care is just not done because it is considered incivility.

Hat tip to the Center for Science in the Public Interest's Integrity in Science Watch newsletter.

Son of the "Drug Secrets" Story: Restricting Access to Clinical Research Abstracts

The Wall Street Journal just reported a most unusual phenomenon,

Before a big meeting of doctors, a handful of pharmaceutical stocks move in mysterious ways. With an annual gathering of cancer specialists coming June 1, the action already has begun.

Shares of ImClone Systems have tumbled more than 9% since Tuesday on heavy volume after embargoed data from an important cancer trial was released to 24,000 physicians expected to attend the conference of one of the largest oncology groups, the American Society of Clinical Oncology, or ASCO. Shares of Regeneron Pharmaceuticals have fallen almost 15% since and Genentech is down 3%, while Onyx Pharmaceuticals is up almost 10%, as investors pass around abstracts, or summaries, of data to be released as part of the ASCO meeting.

'Oncology stocks consistently have shown unexplained volatility around the time ASCO releases data on embargo to its members,' says Steven Harr, an analyst at Morgan Stanley.

In fact, a number of analysts and investors have urged ASCO officials to stop sending the summaries to doctors before the conference, or make them available to everyone, in order to give investors an equal opportunity.

'We have pointed out the volatility to ASCO in multiple communications over the past several years,' says Dr. Harr, who also is a physician.

But the oncology group says that while it has tweaked the way it shares the data ahead of the meeting, it doesn't have plans to stop releasing the summaries beforehand. Officials say they have tried waiting until the conference to release the data but its members were inconvenienced, noting that ASCO serves its members, doctors and cancer patients, not Wall Street.

Officials say the abstracts, which can be submitted as much as six months in advance of the meeting, only go to ASCO members, and that they come in a shrink-wrap package that has written instructions that the recipient can't "publish the information or provide it to others or use it for trading purposes," says Kristin Ludwig, senior director of communications and patient information for ASCO.

"We've worked very hard to communicate the policies to members," Ms. Ludwig says. She says ASCO will review its policies after the meeting.

The strategy doesn't seem to be working. The summaries were sent out last week, and a broad range of investors say they got their hands on the abstracts this week.

Almost two years ago we posted about the related "drug secrets" controversy. At that time, the issue was researchers involved in particular clinical trials being paid to talk about ongoing clinical trials to investors. Then, and again now, the controversy focused more on the possibility of insider trading than the drawbacks of restricting the distribution of data from clinical research.

In my humble opinion, however, the real concern is how in both contexts information about clinical research was being made available a select group before it was made more generally available. Restricting data from clinical research to a select group, even temporarily, is bad for science, bad for patients and health care, and bad for the patients who participate in clinical research.

It is bad for science, because advancing science requires open discussion of results and methods, and open discussion is not possible when only a few people have the results. It is bad for patients and health care, because restricting the dissemination of information restricts which patients may benefit from it. Finally, it is bad for patients who participate in research, because it may break promises given to the original research subjects that data from their participation would be used to advance science and benefit other patients.

I understand that in the current case, the ASCO members might want to see meeting abstracts before they go to the meeting, if for no other reason, to help them plan which sessions they will attend. But I see no good reason not to make the abstracts available to anyone else who is interested at the same time they go out to he society members (subject to a reasonable fee to cover publication costs). Making the abstracts more widely available would not inconvenience physicians who want to plan their time at the meeting, but it would ensure there would be no "insiders" to trade.

As clinical research has become increasingly commercialized, we risk forgetting what the point of research on patients ought to be. It should not primarily be about marketing drugs or pricing stocks. It should be about advancing science and health care.

See also discussion on GoozNews and on PharmaLot, both focused on the insider trading issue.

ADDENDUM (May 19, 2007): Listen to our brief comments on this issue during a report aired on the NPR Marketplace program May 18 here.

BLOGSCAN - More Strange Deeds by Pfizer's Indian Subsidiary Alleged

On Question Authority with Dr Peter Rost is the second in his series of posts on allegations of questionable practices by the leadership of the Indian subsidiary of Pfizer Inc, the world's largest drug company. This post covers allegations that Pfizer used private investigators to spy on an activist share-holder of Parke-Davis who opposed the merger of that company with Pfizer India. Rost noted that the person in charge of Pfizer's security operations at the time was the current CEO, Jeff Kindler, and speculated whether Pfizer's actions could have violated the US Foreign Corrupt Practices Act.

BLOGSCAN - Did Pfizer Issue a "Veiled Threat" in Response to a Property Tax Hike?

On PharmaLot, see this post on the corporate citizenship, or lack thereof displayed by the leadership of the research facility owned by the world's largest pharmaceutical company, Pfizer Inc, in Groton, Connecticut, USA. It appears that Groton was going to raise taxes on some commercial properties, including Pfizer's. So Pfizer's Senior Vice President in charge of the facility warned, "What is paid to Groton in taxes will come out of some other account, and we are concerned this reduction will hurt this community,” which at least one Groton city council member viewed as a "veiled threat."

Why Did VA Officials Get Bonuses for Questionable Performance?

The US Department of Veterans Affairs (VA) health care system, a national health care system that provides care to many veterans of the armed forces, has been held up lately as a model health care system. For example, after one study showed that diabetes care based on several quantitative measures was better in the VA system than in commercial managed care(1), the VA has been held up as an exemplar of quality improvement.(2)

But lately a bit of tarnish has appeared on its luster. And it appears that an organization that has put a lot of effort into improving performance in clinical care may conceive of performance very differently for top leaders.

Two weeks ago the Associated Press reported (here via the Boston Herald) that VA officials involved in various management blunders had nonetheless received performance bonuses.

Months after a politically embarrassing $1 billion shortfall that put veterans’ health care in peril, Veterans Affairs officials involved in the foul-up got hefty bonuses ranging up to $33,000.

The list of bonuses to senior career officials at the Veterans Affairs Department in 2006, obtained by The Associated Press, documents a generous package of more than $3.8 million in payments by a financially strapped agency straining to help care for thousands of injured veterans returning home from Iraq and Afghanistan.

Among those receiving payments were a deputy assistant secretary and several regional directors who crafted the VA’s flawed budget for 2005 based on misleading accounting. They received performance payments up to $33,000 each, a figure equal to about 20 percent of their annual salaries.

Also receiving a top bonus was the deputy undersecretary for benefits, who helps manage a disability claims system that has a backlog of cases and delays averaging 177 days in getting benefits to injured veterans.

The bonuses were awarded even after government investigators had determined the VA repeatedly miscalculated _ if not deliberately misled taxpayers _ with questionable methods used to justify Bush administration cuts to health care amid a burgeoning Iraq war.

Annual bonuses to senior VA officials now average more than $16,000 _ the most lucrative in government.

But yesterday, the Associated Press followed that up (here via San Diego Union-Tribune) with allegations that many of the VA officials who got bonuses themselves sat on the boards which made decisions about bonuses, which would seemingly lead to major conflicts of interest.

Nearly two dozen officials who received hefty performance bonuses last year at the Veterans Affairs Department also sat on the boards charged with recommending the payments.

Documents obtained by The Associated Press raise questions of conflicts of interest or appearances of conflicts in connection with the bonuses, some of which went to senior officials involved in crafting a budget that came up $1.3 billion short and jeopardized veterans' health care.

The documents show that 21 of 32 officials who were members of VA performance review boards received more than half a million dollars in payments themselves.

Among them: nearly a dozen senior officials who devised the flawed 2005 budget. Also rewarded was the deputy undersecretary for benefits, who manages a system with severe backlogs of veterans waiting for disability benefits.

Deputy undersecretaries who sit on the review boards, which are appointed by VA Secretary Jim Nicholson, also had input on bonus recommendations involving themselves, fellow members and spouses that made questionable performance claims and neglected agency problems.

The VA, which has defended the bonuses as necessary to retain hardworking senior employees, says board members do not participate in bonus decisions that involve themselves or fellow board members. In those cases, recommendations are made by agency heads in consultation with deputy undersecretaries, who usually serve as supervisors to their fellow board members, the agency says.

But government watchdogs were harshly critical, saying the process does little to instill public confidence in the fairness of awards.

In one case, Michael Walcoff, associate deputy undersecretary for field operations who sits on two of the review boards, and his wife, Kimberly, a VA director, received a package of bonuses totaling $42,000.

'This is a scandal in the making,' said Paul C. Light, professor of public service at New York University who specializes in government reform. He said the VA bonuses pointed to possible 'featherbedding' and other favoritism.

Under a federal law passed in 1978 to increase government accountability by tying bonuses more closely to performance, agencies are required to appoint performance review boards yearly to guarantee bonus awards are “fair and credible.”

According to guidance by the U.S. Office of Personnel Management, performance boards must ensure that bonuses are given based not only on individual accomplishments cited by supervisors, but also the department's overall success.

However, 2006 bonus proposals obtained by the AP show that senior officials who received top payments of $33,000 were sometimes credited for achievements that were questionable, if not inaccurate.

The matter has just been referred to an oversight agency, the US Office of Personnel Management, again per the AP via the Boston Herald.

This appears to be another example of how leaders of large health care organizations, whether governmental, commercial, or not-for-profit, are often treated differently from you and me. Not only may the leaders be rewarded for "performance" that often amounts to poor performance, but they may get to decide on their own rewards. And this can happen even in organizations that put a lot of effort into performance improvement on the ground.

Is it any wonder that health care lead by such winds up expensive, inaccessible, and not of the best quality, and why health care professionals are often demoralized?

References
1. Kerr EA, Gerzoff RB, Krein SL et al. Diabetes care quality in the Veterans Affairs health care system and commercial managed care: The TRIAD Study. Ann Intern Med 2004; 141: 272-281. (link here).
2. Kupersmith J, Francis J, Kerr EA et al. Advancing evidence-based care for diabetes: lessons from the Veterans Health Administration. Health Affairs 2007; 26: w156-w168. (link here)