Tuesday, June 26, 2007
Monday, June 25, 2007
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."
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.
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.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.
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 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.
Friday, June 22, 2007
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.
Thursday, June 21, 2007
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.But the controversy is even more pointed than that, this week, Diedtra Henderson wrote in the Boston Globe,
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.'
It actually gets worse than that. According to the New York Times,
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.
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.A quick internet search did reveal that both Dr Hussain and Dr Scher did have conflicts of interest.
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....
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.
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.
Tuesday, June 19, 2007
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.
Sunday, June 17, 2007
Officials in Nigeria have brought criminal charges against pharmaceutical giant Pfizer for the company's alleged role in the deaths of children who received an unapproved drug during a meningitis epidemic.
Authorities in Kano, the country's largest state, filed eight charges this month related to the 1996 clinical trial, including counts of criminal conspiracy and voluntarily causing grievous harm. They also filed a civil lawsuit seeking more than $2 billion in damages and restitution from Pfizer, the world's largest drug company.
This story first came into public view due to the Post's reporting in 2000. At that time, the Post noted,
The experiments raise questions about corporate ethics and profits on a frontier of globalization where drug companies wield enormous influence, and where doctors paid by U.S.-based corporations sometimes perform experiments on ill-informed patients in authoritarian societies.
A Nigerian physician who said he was present during the Kano experiment, for instance, felt it was "a bad thing," but he did not object because Pfizer's test appeared to have backing from the government. 'I could not protest,' said the physician, Amir Imam Yola. 'The system you have in America and the system we have here, there is a wide gap. Freedom of speech is still not here.'
At the time, Nigeria was run by a military government that had one of the world's worst human rights and corruption records.
Fast forward to 2007, and here is the report that sailed in barely over the radar,
via the Chosun Ilbo news service out of South Korea,
The CEO of pharma giant Pfizer, Jeffrey Kindler plans to visit North Korea. According to Pfizer’s Korean subsidiary on Tuesday, Kindler will arrive in South Korea for a two-day visit on Wednesday and plans to go to a hospital in the inter-Korean Kaesong Industrial Complex in the North.
The CEO plans to visit the hospital in the Kaesong Industrial Complex with 40 executives on Thursday if he gets approval from the North Korean government through the South Korean Unification Ministry.
A Pfizer’s spokesman said Kindler was invited by Kim Dong-keun, the chairman of the Kaesong Industrial Complex committee. The CEO will inspect medical services in the industrial complex but has no plans to invest in or support North Korea.
North Korea, of course, has been branded part of the"axis of evil" by US President George W Bush for allegations of state sponsorship of terrorism.
The point of the visit by the CEO and 40 executives of Pfizer to a North Korean hospital is not clear. It seems that Pfizer's international operations have a curious affinity for dictatorial governments not known for protecting human rights, to put it very politely.
And pharmaceutical companies wonder why the public views them as "shifty?" Memo to the CEO, if you do not want your company to be viewed as shifty, avoid appearing too friendly to military dictatorships or governments labelled as supporting terrorism by the US government.
The troubles continue. The hospital regained notoriety after a patient who was left to writhe in pain on the Emergency Department floor eventually died. As the Los Angeles Times recapped the story (re-ordered to make it chronological),
[Edith Isabel] Rodriguez a California native, was poor and uninsured. She reportedly had a history of narcotics use and lived with various relatives.
A security videotape showing the woman writhing for 45 minutes on the floor of the emergency room lobby....
[In response to] 911 calls from Rodriguez's boyfriend and a female bystander. One dispatcher curtly told the bystander that the situation was not an emergency; the other said there was nothing she could do because Rodriguez was already in a hospital.
[A] video show[ed]... her extended time on the floor and a janitor cleaning around her.
She died of a perforated bowel, which probably developed in the last 24 hours of her life, according to a coroner's report.
Meanwhile, the Times also reported that
In new signs of turmoil at Martin Luther King Jr.-Harbor Hospital, officials said Tuesday the chief medical officer had been replaced and more than 40% of licensed vocational nurses and nursing assistants recently failed initial skills tests.
The disclosures came as the Los Angeles County Board of Supervisors, grappling with federal findings that the hospital continues to endanger patients, bluntly discussed preparations for possible closure of the public facility.
The people more directly involved in the case of Ms Rodriguez were treated more leniently, also according to the Times,
Six staff members at Martin Luther King Jr.-Harbor Hospital — including a nurse and two nursing assistants — saw or walked past a dying woman writhing on the floor of the emergency room lobby last month but did not help her, according to a report made public Friday.
Their discipline: a letter outlining how they should behave in the future.
The six are in addition to two others whose roles have already been made public by The Times: a contract janitor who cleaned the floor around the woman as she vomited blood and a triage nurse who oversaw the whole episode and pointedly refused requests to intervene.
The janitor was counseled verbally; the triage nurse was placed on leave and later resigned, the report said.
What we said last year about what was then King-Drew still seems relevant. A few lessons from this sorry story: in health care, it is often the whole institution and its most vulnerable constituencies that suffer for the mistakes made by top managers; and that bad managers can hide for a long time behind institutions that enjoy a favorable reputation. And to make an addendum, although we have been writing a lot lately about the shenanigans of pharmaceutical management, mismanagement, conflicts of interest, and corruption seem to afflict the leadership of all kinds of health care organization.
ADDENDUM (21 June, 2007) - See this post on The Health Care blog on King-Harbor's plight.
Thursday, June 14, 2007
Tuesday, June 12, 2007
The drug maker Bristol-Myers Squibb pleaded guilty on Monday to making false statements to a federal agency, ending an unusual criminal case involving its blockbuster blood-thinning drug Plavix.
The case involved accusations that the company had entered a secret deal to head off generic competition to Plavix, its biggest-selling product. The investigation began last summer with a search of the company’s Manhattan headquarters by federal agents and it led to the dismissal of the chief executive, Peter R. Dolan.
But the investigation ended with relatively minor charges against the company. During a 30-minute hearing in federal court here, Judge Ricardo M. Urbina fined Bristol-Myers $1 million. The sentence had been worked out beforehand in an agreement between the company and the Justice Department’s antitrust division.
While the company pleaded guilty to making false statements, after the hearing it issued a statement saying that it was merely taking responsibility for the actions of one former executive.
The accusations involved statements reportedly made by Dr. Andrew Bodnar, a former executive of Bristol-Myers. Dr. Bodnar, an adviser to Mr. Dolan, had been given an important assignment last year — settle a patent dispute with the Canadian generic drug maker Apotex.
During settlement negotiations in May 2006, Dr. Bodnar reportedly suggested that Bristol-Myers would not market its own generic version of Plavix.
Under an existing consent decree with the Federal Trade Commission, any such settlement agreement by Bristol-Myers had to be cleared by the agency. But an agreement by Bristol-Myers not to sell its own generic was never disclosed to the F.T.C....
Neither Dr. Bodnar, who is no longer with the company, nor Mr. Dolan has been charged with any wrongdoing.
A Department of Justice press release did state,
According to the two-count criminal charge filed today in the U.S. District Court in Washington, D.C., in 2006, BMS and another company, Apotex Inc., were engaged in litigation over the validity of the patent for Plavix and were negotiating a settlement of that litigation. At the time, BMS was subject to a separate consent decree – for unrelated conduct – with the Federal Trade Commission (FTC) that required BMS to submit any proposed patent settlements for review and approval by the FTC. The FTC warned BMS that it would not approve a settlement of the Plavix litigation if BMS agreed not to launch its own generic version of Plavix that would compete against Apotex for generic sales. After nevertheless entering into such an agreement, BMS concealed it from and then lied about its existence to the FTC. The Department charged BMS with filing two false statements to the FTC as part of its effort to hide part of its agreement with Apotex.
'BMS is charged with both lying to the federal government and with taking steps to conceal its false statement – both serious felonies,' said Thomas O. Barnett, Assistant Attorney General in charge of the Department’s Antitrust Division. 'The seriousness of the offenses is compounded by the fact that BMS’ obstructive conduct occurred in connection with the FTC’s review of a proposed patent settlement affecting the cost of a lifesaving drug sold to tens of millions of Americans.'
This story, which has gotten little attention so far in the press, seems to suggest the operation of "defining deviancy down" as applied to dishonest conduct by leaders of health care organizations. Even though it would seem that lying to federal investigators is really a "serious felony," such dishonesty in the health care context seems to generate little overt outrage. This lack of outrage in this particular circumstance is even harder to understand given that BMS is a repeat white collar offender. The company agreed to a deferred prosecution agreement in an unrelated case only two years ago (see post here.) The company reportedly agreed to settle charges it had engaged in deceptive marketing practics in another unrelated case one year ago (see post here.)
Nonetheless, multiple stories of deceptive, dishonest, and sometimes felonious health care leadership cannot help but continue to erode the trust of the public and physicians in the leadership of large health care organizations. And these stories are a likely cause of the pharmaceutical industry's "shifty," reputation in particular (see post here).
Monday, June 11, 2007
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?
Regarding the second question, keep in mind that the main achievement of the Nissen and Wolski meta-analysis [Nissen SE, Wolski K. Effects of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356, online here] was to be the first published article to combine data from all relevant clinical trials of rosiglitazone completed to date. Although two major trials of Avandia had been published, its manufacturer, GlaxoSmithKline, had performed many other smaller trials of the drug, most of which have not been published to date. They did eventually appear on a web-site run by GSK. However, this web-site was relatively obscure, and it was not created voluntarily, but in response to a settlement of legal action that alleged GSK had suppressed clinical research about its antidepresant paroxetine (Paxil). (See Steinbrook R. Registration of clinical trials - voluntary of mandatory. N Engl J Med 2004; 351: 1820-1822, link here and our post here). Nissen and Wolski found it, compiled the results of trials on Avandia, and combined their results with those of the few published trials in their meta-analysis.
It is to the credit of Nissen and Wolski to figure out how to do this. It is not to the credit of GSK that they sat on the data from these trials, only put it on this web-site when compelled to do so, did not make any effort to publicize the web-site, and did not publish a meta-analysis done by company scientists that showed qualitatively similar results to that done by Nissen and Wolski (see post here).
However, the spin cycle now in progress does little to answer these questions. Instead, it seems to obfuscate them. The latest revolutions in the cycle are...
GSK published a full-page advertisement in major newspapers including a letter to Avandia patients. The relevant parts of the letter are:
We at GlaxoSmithKline are proud to be the makers of Avandia. As leaders in diabetes, we understand that managing your type 2 diabetes is not easy. We also understand the confusion and concern you may have experienced following recent press coverage about the safety of Avandia. GlaxoSmithKline stands firmly behind Avandia.
Avandia is the most widely studied medicine for type 2 diabetes. GlaxoSmithKline has conducted an unprecendented number of clinical trials in order to continuously monitor the safety of Avandia, including its impact on the cardiovascular system. The response to this commitment from well-informed experts and researchers has been encouraging.
Like any medication, Avandia is not appropriate for all patients. Your doctor is the best resource for information about your health and is in the best position to determine if Avandia is right for you.
Be asssured, GSK gives you all our full commitment to providing you and your doctor with the facts about the safety of Avandia.
The letter obviously contains no specifics. It provides no new information about the benefits and harms of Avandia. It appears that the last sentence in the second paragraph was meant to be key, "the response to this commitment from well-informed experts and researchers has been encouraging." What it means, however, is completely obscure.
So all GSK seems to have done with the letter is provide vaguely soothing words without meaningful specifics.
Meanwhile, the Financial Times reported on the words of the GSK CEO, Jean-Pierre Garnier (via MSN Money here).
Jean-Pierre Garnier, chief executive of GlaxoSmithKline, the UK-based pharmaceutical group, on Wednesday lashed out at a leading medical journal for 'mixing science with politics' in publishing articles attacking its diabetes drug Avandia.
As his company's share price continued to fall, Mr Garnier told the Financial Times in an interview that New England Journal of Medicine papers raising safety concerns with Avandia were 'smearing the drug' as they 'pick and choose their numbers as they are trying to make a case the FDA [the drugs regulator] is not doing its job'.
Similarly, during the Congressional hearings last week, the New York Times reported that
Representative Darrell Issa, Republican of California, said the committee was coming dangerously close to 'politicizing science.' And he closely questioned Dr. Steven E. Nissen, a cardiologist at the Cleveland Clinic whose May 21 article in The New England Journal of Medicine questioned the safety of Avandia.
'This does look like in fact that this was a political concoction to anecdotally go after a company, and I object to it,' Mr. Issa said.
I suppose Rep Issa could have objected that the Congressional hearings in which he was participating were "politicizing science," but how a meta-analysis focused on particular adverse effects of a popular drug might be political is beyond me.
But it is one way to distract from the content of the article and the substantive clinical and policy issues it raises.
Note the similarity between the opinions of Rep. Issa and GSK CEO Garnier.
Furthermore, a commentary in the Washington Times by Peter J Pitts and Robert Goldberg took another swipe at Dr Steve Nissen. After starting out by charging that Nissen "positioned himself as the nation's de facto drug regulatory czar." The writers sarcastically labelled him as the "Patron Saint of Drug Safety," and "Saint Steven the Pure." They then went on to chastise Nissen for his involvement in two commercially sponsored studies, one on a drug "designed to reduce the level of fatty plaque deposits (atherosclerosis) in a person's arteries, sponsored by Atherogenics, the other on "a synethetic version of good cholesterol," sponsored by Esperion. Neither trial was apparently sucessful.
Nissen had not hidden the fact that he did commercially sponsored research. The relevance of his role in research on cholesterol lowering drugs to his meta-analysis of Avandia is unclear.
Pitts and Goldberg listed their primary affiliation as the Center for Medicine in the Public Interest. Pitts is its President, and chief blogger on the CMPI site DrugWonks. However, Pitts' day job is to be Senior Vice President for Global Health Affairs at the big public relations firm Manning, Selvage and Lee. Manning, Selvege and Lee has many big pharmaceutical accounts, as listed on the CommuniqueLive.com site. As Senior Vice President for Global Health Affairs, Pitts is presumably responsible for all these accounts. Thus, his livelihood seems to depend largely on his ability to convey the pharmaceutical industry's point of view. Pitts seems to be continuing in his role as a stealth health policy advocate which we first discussed in this post here.
And where else have we heard Nissen sarcastically derided as a would be saint? The Cleveland Plain Dealer reminded us,
Sen. Sherrod Brown and other lawmakers are questioning conflict-of-interest policies at the Food and Drug Administration, where an agency official with ties to the drug industry attacked industry watchdog Dr. Steven Nissen of the Cleveland Clinic.
FDA communications consultant Douglas Arbesfeld recently sent journalists a flaming e-mail about Nissen, who was the co-author of a study in the New England Journal of Medicine that raises safety questions about the diabetes drug Avandia.
The e-mail referred to Nissen as 'St. Steven' and included an anonymous blog item that accused the doctor of criticizing manufacturers that don't support drug trials at the Clinic, according to ABC News online.
Brown and four other lawmakers said in a letter Thursday to FDA Commissioner Andrew von Eschenbach that Arbesfeld 'may be using his position with the FDA to settle old scores with Dr. Nissen.'
It noted that Nissen and Arbesfeld had been adversaries in an earlier controversy over the safety of a Johnson & Johnson heart drug. Arbesfeld was a spokesman for Johnson & Johnson at the time.
The lawmakers said Arbesfeld's e-mail may give the impression the government encourages smear campaigns against independent scientists. Their letter asks the commissioner to explain policies on hiring from drug companies and potential conflicts of interest.
An FDA spokeswoman did not respond to requests for comment Friday.
Disputing whether Dr Steven Nissen is a saint, sinner, or something else only seems to distract from the substantive questions I raised above. It is interesting that the "Saint Steven" references were made nearly simultaneously by the Vice President in charge of health care (mainly pharmaceutical) accounts of a large public relations firm and a FDA spokesperson with many previous ties to the pharmaceutical industry.
So the spin cycle revolves merrily on about the Avandia case, throwing off obfuscation after obfuscation that distract from the central issues of the case. But maybe if the pharmaceutical industry really wants to avoid being labelled "shifty," (see post here) it could damp down the enthusiasm of its advocates for endlessly spinning this case, and address the real substantive issues: what are the harms and benefits of Avandia? were data about the drug suppressed, and if so, how can we prevent this from happening in the future.
ADDENDUM (14 June, 2007) - To those visiting via links from Clinical Psychology and Psychiatry, KevinMD, Notes from Dr RW, PharmaGossip, Retired Doc's Thoughts, and Question Authority with Dr Peter Rost: We thank those bloggers for their kind words. Welcome to Health Care Renewal. Our goal is to discuss threats to physicians' and other health care professionals' core values, especially those due to concentration and abuse of power. We do end up talking a lot about questionable practices by the pharmaceutical industry and its leaders, but there are many things to question about the management and operations of other health care organizations. Please have a look, and feel free to comment.
Friday, June 08, 2007
This reminds me of my earlier post here about another organization in California that spent that level of cash and had little to show for it except perhaps controversy. From that story:
Internal documents show the [UC Davis clinical IT] project -- with the final bill estimated to be anywhere from $75 million to $100 million -- is two years behind schedule and up to a fifth of the budget went to an outside consulting firm whose expense reports are now the subject of an internal UC audit.
Now we have this in Pennsylvania:
... [Lancaster General Hospital] plans to invest $60 million to $100 million in electronic medical records, another step toward transparency. Marion A. McGowan, executive vice president and chief operating officer of Lancaster General, said electronic medical records are a vital step toward giving patients more control over their care. Primary care physicians would be able to access the information during office visits, and the patients themselves can see their information from their home computers.
The other myth I keep seeing is how EMR's and PHR's ("personal health records") will "empower patients" and "give them control over their care." I've seen no evidence of that and do not understand the arguments behind this claim, but such statements do have "punch" and make a great marketing and "selling point" - which brings up another issue:
I am becoming increasingly concerned about whether the push for national-scale EMR's has created a "gold rush" where prospectors of varied honesty and ability have set out to 'strike it rich' -- by sucking every dollar they can out of an already strained healthcare system under pressure to 'revolutionize care' through computerization.
It seems like health IT is entering a a "pre-Flexner report medicine" or perhaps "Roaring 20's" phase. The UK's CfH national EMR initiative seems to be a few years closer to the "Great Depression" than ours; e.g., see "£20bn NHS computer system doomed to fail ". I am concerned we could be headed down the same path.
At the same time, I see schizophrenic articles such as this ("Hospitals oppose plan for uniform reporting") where the senior vice president for policy and regulatory services at the Hospital and Healthsystem Association of Pennsylvania, an organization representing hospitals, claims that "[computer reporting on hospital infections] is very costly", in fact too costly for small hospitals to implement for participation in a single statewide system.
As a physician from Philadelphia whose father died of a hospital-acquired infection, a medical informatics specialist, and a staunch advocate of clinical data initiatives to improve quality of care, I am highly troubled by such statements. Such a central state infection rate reporting system could be implemented, for example, by just a few competent IT people and accessed by hospitals via the Web on commodity PC's, transcribed from paper by hospitals if they have to. In fact the hardest part would be development of a standard, agreed-upon state dataset and data definitions, not technology costs.
Such technology is, in fact, dirt cheap in 2007.
I think it more likely that hospitals and their cost-cutting management fear what an integrated, consistent reporting system might make them do - clean up their dirt, literally.
Reducing infection rates is the expensive issue, requiring better facilities management, enforcement of handwashing, etc., but ultimately the benefits outweigh the financial and human costs by several orders of magnitude.
Hence, resistance to such simple technology as a central infection registry at a time when we can send megabytes of information around the world effortlessly in seconds, and when powerful PC's and web technology are commodities, is absurdist at best.
My concern here is that hospitals would rather make such claims to avoid participation rather than perform the truly expensive physical and process cleanups needed to reduce infections.
It costs little to do little. The ultimate economy in healthcare, after all, is death.
Health IT is an industry that has a bit of a split personality (sorry for all the metaphors today). I believe it needs far more transparency that it has, along with other healthcare sectors (nursing homes and pharma come to mind).
As provocative statement of the day, based on an ever growing number of anecdotes and case examples of health IT difficulties, failures, consultant overuse, etc., I am increasingly of the belief that (at least in public hospitals), strong community, external stakeholder, or other oversight is needed for health IT projects.
I increasingly do not believe most hospitals are competent, disciplined and well-managed enough to accomplish enterprise EMR implementation by themselves without large amounts of overspending, inefficiency, and waste (if not outright failure), and that outside oversight may be essential to ensure these tasks are performed in a manner that makes the best use of limited resources.
Wednesday, June 06, 2007
Let us concentrate on just a few stories. First, on June 5, the Boston Globe focused on Dr Steve Nissen, who was lead author of the meta-analysis about the cardiovascular adverse effects of Avandia that lead off the controversy (see our post here). As Diedtra Henderson reported,
After the Avandia news broke, Robert Goldberg , a conservative pundit and vice president of the Center for Medicine in the Public Interest New York, posted a message on his blog, DrugWonks.com, that said Nissen is campaigning to become FDA commissioner in a way that 'makes him look craven and small.'
Told of Goldberg's blog entry, Nissen asked, 'Who would say such a thing?'
'I'm not running for anything,' Nissen added. 'I've got a great job here, and I'm not going anywhere.'
Goldberg, however, does have more clout than the average blogger. As a senior fellow at New York's Manhattan Institute , he once wrote that a front-runner to become FDA commissioner would so stymie the drug-approval process that the shorthand message to patients would be: 'Drop dead.' The candidate, Dr. Alastair J.J. Wood, foundered in the face of stiff industry opposition.
In an interview, Goldberg said the cardiovascular risks of such drugs as Vioxx have been highlighted by others, but Nissen is 'the most aggressive in promoting himself, whether he is accurately depicting the risks and benefits of products.'
As we have discussed before, the President of the Center for Medicine in the Public Interest, where Goldberg works, and which runs the blog called DrugWonks, is Peter J Pitts, whose day job is to be Senior Vice President for Global Health Affairs at the big public relations firm Manning, Selvage and Lee. Manning, Selvage and Lee has many big pharmaceutical accounts.
FDA spokesman Douglas Arbesfeld , in an e-mail to reporters days after Nissen's Avandia analysis was published by the New England Journal -- derisively dubbed him 'St. Steven ,' and wondered whether his feet were made of clay.
Arbesfeld, responding to a Boston Globe question about the e-mail message, said the correspondence -- sent using his FDA e-mail address -- reflected his personal views and not the agency's.
Douglas Arbesfeld, where have we heard of him before? Before he went to work for the FDA, he was a spokesperson for Johnson & Johnson, whose assignments included arguing with Dr Steve Nissen on the implications of more restrictive labeling for the drug nesiritide (Natrecor, made by Scios, a Johnson & Johnson subsidiary) (see the NY Times here, and our post here); and defending the company's Janssen subsidiary against charges it manipulated the TMAP guidelines in favor of atypical anti-psychotic drugs like its product risperidone, (Risperdal) (see the NY Times here, see our post here). Earlier, he worked for - you guessed it - public relations firm Manning, Selvage and Lee, and before that, pharmaceutical firm Rhone Poulenc Rorer (which merged into Aventis, which in turn merged into Sanofi-Aventis) (from "On the Move," AdWeek, January 11, 1999.)
Then there was this article in the New York Times by Stephanie Saul and Gardiner Harris,
A supervisor in the drug safety office at the agency said in an interview yesterday that she was rebuked last year after calling for a stronger warning label on Avandia and a competing drug, Actos.
The supervisor, Dr. Rosemary Johann-Liang, said that in March 2006 she approved a recommendation from a safety reviewer at the agency that the drugs be required to carry the strongest warning, a so-called black box warning, because they posed a risk of unusual swelling that could lead to heart failure.
But after officials at the agency who dealt more closely with Glaxo complained, Dr. Johann-Liang said she was ordered to retract her approval of the warning, lost her power to approve such assessments and no longer supervised reviews of the safety of Avandia and Actos.
'This was a very careful review that came to an inescapable conclusion,' Dr. Johann-Liang said in the interview. 'They decided to act like the review never happened and punish me for approving it.'
Senator Charles E. Grassley, Republican of Iowa, has investigated Dr. Johann-Liang’s accusations. Mr. Grassley sent a letter on Monday to the Food and Drug Commissioner Andrew C. von Eschenbach demanding that he investigate the case.
'I hope you recognized what is wrong with this picture,' Mr. Grassley wrote. 'I also sincerely hope that this is not standard practice within the F.D.A.'
A spokeswoman for the agency, Susan Cruzan, said it was investigating the accusations.
Finally, the Associated Press just reported (via the San Diego Union-Tribune here) about today's Congressional hearings by the Committee on Oversight and Government Reform of the US House of Representatives,
Dr. John Buse told lawmakers that after he drew attention in 1999 to heart problems among some patients using Avandia, SmithKline Beecham, which later combined with GlaxoWellcome, warned him that some executives wanted to hold him accountable for a $4 billion drop in the company's stock.
In a letter to SmithKline distributed at the hearing, Buse wrote: 'Please call off the dogs. I cannot remain civilized much longer under this kind of heat.'
Buse, who is head of endocrinology at the University of North Carolina and is set to become president of the American Diabetes Association, said he eventually signed a clarifying statement with the company that was used to ease concerns from investors.
In Buse's letter to the Committee he stated
There was a trend toward increases in serious cardiovascular events and cardiovascular deaths with Avandia as compared to active comparators. Neither was statistically significant. I could not find evidence for such trends with Rezulin and Actos.
I recognized that this was potentially an explosive issue and went to rather extreme ends to make sure that I was not making an error including sharing the results and the slides I was going to present with research scientists from SmithKline Beecham (SKB), the manufacturer of Avandia. Those discussions were cordial and helpful.
Couched with many caveats, I presented the issues outlined at least twice in June of 1999. In the week that ensued, there were a number of phone calls in this regard from SKB. During these calls, it was mentioned on two occasions that there were some in the company who felt that my actions were scurrilous enough to attempt to hold me liable for a loss in market capitalization..... In the end I offered to help the company with further studies and signed a clarifying statement drafted by SKB which was to be used to with the investment community
Is there a pattern here? In one of our earlier posts on the Avandia affair, we noted that the extent that this is a suppression of research case has been overlooked. Many of the clinical trials that Dr Nissen used in his meta-analysis were trials sponsored by GSK which were only made public 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 antidepressant 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.).
The pattern above also seems to be one of attempts to intimidate any one who questions the safety of Avandia. These attempts have gone from verbal ridicule to threats of litigation, and official government action. There also seem to be some interesting linkages among those doing the intimidation to pharmaceutical companies and public relations firms who have them as clients, even if those linkages are not always openly stated.
Of course, intimidating people who blow the whistle about drug safety concerns is bad not only for the whistle-blowers, but for patients and doctors whose decisions about which treatments to give ought to be based on critical review of the best possible clinical evidence, not evidence that is filtered by secrecy and intimidation to only reflect vested interests of the makers of the treatments.
As we have mentioned before, pharmaceutical companies (and other health care corporations) may be regarded by the public as "shifty." If such companies want to regain public trust, they need to call off their dogs, lest nobody can "remain civilized."
ADDENDUM - Pharmalot has links to many documents used in the Congressional hearing here.
"We Really Did Screw Up" - Kaiser Permanente Kidney Transplant Program
Baseline Magazine, May 14, 2007, Deborah Gage and Kim S. Nash
Kaiser opened its transplant center in 2004, but so bungled paperwork and procedures, according to state and federal investigators, that less than two years later, it shut down the facility.
Trouble at the center came to light last May, after the Los Angeles Times and KPIX-TV in San Francisco, which were tipped by a whistle-blower, reported on increasing wait times for Kaiser patients on the national kidney transplant list and other problems.
Few details about the exact nature of Kaiser's information management problems have been reported. However, in an attempt to document Kaiser's missteps, Baseline, for the past five months, has studied audit reports of the federal Centers for Medicare & Medicaid Services and California's Department of Managed Health Care (DMHC), which investigated Kaiser's transplant center, and reviewed court documents filed in cases against Kaiser. Interviews were conducted with key players, including patient Burks; whistle-blower and former employee David Merlin; officials at the United Network for Organ Sharing (UNOS), which oversees national transplant waiting lists; and health-care and information management consultants familiar with medical data governance and public information about Kaiser.
- An assortment of information management problems plagued Kaiser's kidney transplant center:
- During Kaiser's startup, there was no specific procedure established to transfer data on the initial 1,500 patients to UNOS, acknowledge officials from that organization as well as Kaiser.
- Kaiser compiled no master list or database of patient names to check that it had the records of all the patients who had transferred into its kidney program, according to Medicare and DMHC.
- More than 1,000 patient records had missing or incorrect data, such as erroneous Social Security numbers or missing test results, which delayed re-registrations on the national transplant list, according to Medicare. As of September 2005, a year after the facility opened, 330 Kaiser patients, including Burks, were still not credited with wait-list time they had accrued at the University of California, according to UNOS.
- The center, working mainly from paper records gathered from the University of California medical centers, according to Medicare, could take months to collect a missing data point, such as blood-test results, both Medicare and DMHC found.
- The transplant center, meanwhile, had no systematic way to track and analyze patient complaints, both Medicare and DMHC said, which would have alerted Kaiser to trends in problems.
- Kaiser staff worked with "inadequate" written guidance on how to do their jobs, according to DMHC, which also found that most of the center's staff lacked transplant experience. And while Kaiser named a transplant director, it failed to designate a chief executive responsible for the overall management of the center, a Medicare requirement.
In all, Kaiser failed to adhere to five state and 15 federal regulations.
The problems reflected Kaiser's "lack of effective planning," DMHC concluded, which "placed Kaiser patients at risk for disruption in care and potentially life-threatening delays in care."
In 2005, the center's first full year in business, twice the number of patients died waiting for kidneys at Kaiser as received transplants the reverse of regional trends, according to the Scientific Registry of Transplant Recipients (SRTR), a research group in Ann Arbor, Mich., that tracks U.S. transplant data. All 56 patients who received kidneys at Kaiser that year were still alive one year later, a key metric tracked by SRTR. However, Kaiser managed kidney transplants for just 6% of the patients on its waiting list, while UC-San Francisco, for example, transplanted 7% and UC-Davis 27%.... Most companies don't risk harming customers if they mismanage information. But the potential for data management disaster hides in every organization, according to Tom Redman, president of Navesink Consulting Group, which consults with companies about data quality.
... "We did not anticipate how complicated that was," George Halvorson, chairman and chief executive of Kaiser Permanente, told the Commonwealth Club, a current-events discussion group in San Francisco, in March.
A reader at the HIStalk blog asks:
"Core questions remain, including why it wasn't until Kaiser decided to close the center that it put in information technology, such as custom spreadsheets and a virtual private network between it and UC, to help manage patient data. Why, despite Kaiser's pioneering work in electronic medical records since the early 1990s, the new transplant center apparently managed most incoming patient data on paper. Why it didn't use one of the specialized transplant databases available from health-care technology vendors. Why it wasn't until the end that Kaiser developed basic policies and procedures, such as weekly meetings and monthly reports, to ensure data didn't go missing and appropriate parties stayed apprised of Kaiser's progress with patient records."
My remaining question is, who was the "we" who "did not anticipate how complicated that was," what were their backgrounds, and had they ever read my web site on healthcare IT difficulties?