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Okay, maybe it's a cloying move by Pfizer to protest the absurdity of government oversight. But it's also kind of funny.
The world's largest drug company is advising US physicians who visit its exhibit booth at the ongoing ASCO meeting that they will have to swipe their registration cards if they want a freebie latte, reports Reuters. And oh no, you di'int: MDs from Minnesota and Vermont can't have one at all, thanks to their state laws that prohibit all swag—no matter how trivial.
Moreover, if you do accept a latte from Pfizer, the company may provide your name to US regulators and post the fact that you received caffeinated remuneration at its disclosure website. God knows, you could end up scribbling scores of prescriptions for Aromasin during your 20-minute Pfizer-propagated caffeine buzz.
At least the oversight measures are keeping somebody employed...and amused.
ASCO = American Society of Clinical Oncology.
"angry latte" by Chris Barkeley at Flickr.
06/10/10 addendum: It's hard to keep up, but Vermont recently amended its existing, relevant law to allow the "provision of coffee and other snacks or refreshments at a booth at a conference or seminar." The bill became effective on March 27th (without the governor's signature, according to the FDA Law Blog).
Successful whistleblowers in qui tam suits against pharma weren't in it for the money. At least that's what they say in hindsight, according to a newly published interview study of 26 such "relators" in the NEJM. (Did anybody expect them to admit otherwise?) The semi-structured study was conducted by investigators at Harvard and the University of Melbourne, one of whom (Kesselbaum) has served as an expert witness in litigation against Merck.*
The 26 interviewed relators, who received a median of $3 million ($100,000-$42 million), were reportedly motivated by their senses of justice, altruism, or integrity, according to the study. In other cases, whistleblowing was viewed as a way to avert possible future accusations of engaging in illegal activity (eg, off-label promotion). They also cited heavy personal and professional costs during the qui tam investigation and litigation.
However, one sentence in the NEJM article, in particular, suggests that whistleblowers are at least initially motivated by the prospect of a financial windfall and don't accurately anticipate the direct and indirect costs of the qui tam process. In a concluding statement to the section, "Settlement and Life Afterward," the authors report the relators' advice to would-be whistleblowers:
Some offered strategic suggestions, such as hiring an experienced personal attorney, and many suggested a need to mentally prepare for a process more protracted, stressful, and conflict-ridden, and less financially rewarding, than prospective whistle-blowers might expect.
The authors also note that if the Justice Department decides to intervene in whistleblowers' qui tam suits, almost all result in settlements or judgments against the pharma defendant. So once the DoJ picks up a case, it's highly unlikely that the whistleblower would decide to back out, whatever the upfront headaches.
* Related to the alleged improper promotion of Vioxx.
Image of Saint Sebastian by Guido Reni from Wikipedia.
Addendum: In a highly revealing statement, one interviewee "likened his large settlement to 'hitting the lottery,'" which, as we all know, has the sole upfront cost of forking over a buck or two for a ticket.
Yesterday the Council of Medical Specialty Societies, a nonprofit umbrella group of 32 medical groups, announced its guidelines for interacting with industry. There's nothing particularly new here to shake up the established movement that emphasizes independence from pharma influence and the full disclosure of industry ties. For instance (yawn), the code stresses a distinction between certified continuing medical education (CME) activities and non-CME activities and prohibits ghostwritten articles in society journals.
In its entirety, the code, currently endorsed by 13 member societies,* addresses charitable contributions, corporate sponsorships, educational grants, exhibits and advertising, licensing, research grants, and editorial standards for society journals. The other 19 member societies, including CMSS President James Scully's American Psychiatric Association, have until the end of the year to sign on.
* American Academy of Family Physicians (AAFP)
American Academy of Neurology (AAN)
American Academy of Ophthalmology (AAO)
American Academy of Pediatrics (AAP)
American College of Cardiology (ACC)
Accreditation Council for Continuing Medical Education (ACCME)
American College of Emergency Physicians (ACEP)
American College of Obstetricians and Gynecologists (ACOG)
American College of Physicians (ACP)
American College of Preventive Medicine (ACPM)
American College of Radiology (ACR)
American Society for Radiation Oncology (ASTRO)
American Society of Clinical Oncology (ASCO)
Like GSK, Lilly, and Merck, Pfizer has begun to publicly disclose its payments to US docs for their advising and speaker services, as of yesterday.* However, unlike the other companies, Pfizer is revealing how much money it has given to fund US-based clinical trials (ie, research grants).
During the second half of 2009, the world's biggest drug firm shelled out $19.8 million to 4500 health care professionals ($4400, on average, per HCP) and $15.3 million to 250 academic or other research groups ($61,200, on average, per group). Pfizer provides a friendly graph (below) and also notes that it invests about $7 billion in R&D and spends about $1.3 billion to bring a drug to market.
Individual Pfizer payments are available here, with a database that is browsable and searchable. However, the payment information, like that from other companies, is not easily downloadable, as yesterday's NYT notes.
According to a Pfizer spokesperson, also by way of the NYT, the disclosures (or at least most of them) are mandated by an "integrity agreement" between Pfizer and the federal government. The agreement was struck as part of a settlement in re Pfizer's off-label promotion of drugs (like Wyeth's Neurontin [gabapentin]).
HCP = health care professional (including nurse practitioners and PAs).
* "Meals, business travel expenses and educational items that are greater than or equal to $25 in value, and where the aggregate amount paid to an individual health care professional is greater than or equal to $500 in a calendar year."
This week, the ACC, as an arena for impassioned conflict, didn't stand solely for the Atlantic Coast Conference. A heated confrontation also occurred at the annual meeting of the American College of Cardiology, where Duke physician Robert Harrington debated the Cleveland Clinic's attention-loving Steve Nissen on the issue of physicians' relationships with industry.
Both cardiologists acknowledged historical examples of the marketing influence that pharma and the medical-device industry have had on professional education and, potentially, medical practice. But Harrington painted a more complex picture, in which physicians and medical journal publishers have been complicit in allowing this influence to happen. While Harrington advocated that ongoing relationships with commercial entities are "critical," he urged clear "firewalls" between physicians (particularly academic physicians) and industry and full access to data from industry-funded research. Harrington also correctly stressed that potential conflicts of interest go beyond money; "scientific hubris" is also in the mix.
And speaking of hubris...
Nissen conversely argued that industry funding to sponsors of continuing medical education (CME) and professional medical societies must cease. He cited a Merck-funded CME program at the ACC's Cardiosource web site, "Optimizing Patient Outcomes in Acute Heart Failure Syndromes: Strategies to Preserve Cardiorenal Function," which was sponsored by an accredited* medical-education communications company (Med-IQ) and the ACC.** Without citing specific examples of undue industry influence in the program, Nissen argued that Merck's reason for sponsoring the program was due to the fact that the company had a novel compound, rolofylline, in development that addressed the condition in question. Nissen called the CME program a "market preparation business activity" and an ultimate "misuse of medical information," primarily because the drug died in phase 3 development. But Nissen failed to acknowledge the obvious follow-up question: How could Merck influence cardiac practice with this particular CME program if rolofylline can never be prescribed?
Using an even more tenuous example, Nissen implied that the American Heart Association had backed away from a study that linked soft-drink consumption with cardiac risk factors and an NEJM-advocated soft-drink tax, on the basis of the AHA's alleged marketing relationship with Coca-Cola. As evidence, Nissen offered up the red-dress logo for The Heart Truth educational campaign, which has been prominently displayed on cans of Diet Coke. Nissed charged that the logo comes from the AHA.
However, on this very circumstantial point, Nissen appears to be wrong in his facts. According to MedPage Today, the logo belongs to the National Heart, Lung, and Blood Institute. Moreover, both the AHA and the NHLBI deny that any money has been exchanged between Coca-Cola and their organizations to produce the campaign. The Heart Truth program is solely funded by government entities, according to an NHLBI spokesperson.
Those physicians who argue that ties between industry and medical practice should be severed may have some valid points, but Steve Nissen didn't deliver their perspective in any compelling fashion in this debate. Like in the recent b-ball champ-ship, the hands-down ACC winner here was (the guy from) Duke.
N.B.--Audio portions of the debate are provided by MedPage Today.
* Nissen called the Accreditation Council for CME, the organization that accredits other organizations to sponsor certified CME, "absolutely pathetic" and a "toothless watchdog."
** Notably the program included faculty from Duke (acknowledged by Nissen) and the Cleveland Clinic (not acknowledged by Nissen).
Image of The Heart Truth campaign logo from the NHLBI web site.
Addendum
: The AHA sponsors the trademarked Go Red for Women campaign, which is supported by Macy's and Merck, according to the campaign web site. The campaign's logo (left), while incorporating a red dress, is distinct from The Heart Truth's logo. Both red-dress logos are trademarked by the DHHS.03/19/10 addendum: Christopher Cannon, Harvard cardiologist and Cardiosource Editor-in-Chief, reviewed the Merck-sponsored CME program that was criticized by Dr. Nissen and provided a lengthy comment at MedPage Today. Among 5 talks, according to Cannon, 4 did not mention Merck's (now defunct) drug in development, rolofylline. The talks covered the pathophysiology and epidemiology of the condition in question, possible interventions, and clinical development. Last a case was presented "where the drug is not mentioned." Cannon counted 130 slides in the CME program, 8 (6%) of which concerned the funder's drug in development. Cannon concluded, "This is I believe a fair balanced program and it does not meet the charaterization [sic] stated by Dr. Nissen."
Pharma's financial layout in 2009 for DTC ads remained, for all practical purposes, stable, when compared with 2008's numbers. According to the latest Nielson data, by way of MM&M, a total of $4.5 billion was shelled out by drug companies for ads on TV (64%), in magazines (28%), in newspapers (4%), on the web (3%), and on the radio (1%).
Here's Ye Microsofte Pie for the graphically impressed (dollar amounts are in millions).
For those who blame DTC advertising on the high cost of healthcare generally and that of drugs specifically, keep in mind that changes in DTC spending don't parallel the ever-increasing costs for drugs, outpatient care, and inpatient care.
Also costs for prescription drugs account for only about 12% of the overall healthcare spend (and are arguably one of the most cost-effective aspects of healthcare). In 2006, the spend on outpatient care was $850 billion (~41% of overall costs), and that on inpatient care was $458 billion (~22%), according to the McKinsey Global Institute.
Last year, the Congressional Budget Office reminded us that pharma invests relatively heavily in sales-rep detailing: $12 billion in 2008. The CBO's number for DTC ad spending in 2008 was $4.7 billion.
HT for lead: Pharmalot
In Orange County, California, opening statements began yesterday in a multi-plaintiff civil case against Allergan, maker of Botox. The plaintiffs, including the mother of a deceased 7-year-old Texas girl with cerebral palsy, argue that off-label use of the company's drug caused severe adverse reactions including death. Trial coverage is provided in frustratingly nonlinear stories from ABC News and the LA Times.
Piecing together the information, the case against Allergan appears to rest on these issues:
- Can injected botulinum toxin migrate sufficiently, especially when used for spasticity, to cause paralysis of respiratory muscles?
- Can injected botulinum toxin cause seizures?
- Did Allergan promote the off-label use of Botox for pediatric spasticity?
Related to the third issue is whether Allergan promoted the off-label use of Botox a) at particularly high doses and b) despite being aware of the related dangers.
For its part, Allergan is claiming that Botox did not cause the death of the 7-year-old girl, Kristen Spears, who received a series of 7 Botox treatments, beginning at the age of 6 years, for muscle spasticity in her legs, groin, and chest. Spears's mother alleges that these treatments led to the girl's clinical deterioration. Already underweight and with a baseline seizure disorder, Kristen allegedly experienced more severe seizures and swallowing difficulties after her treatments began. The latter problem, along with breathing problems, led to 10 hospitalizations. Kristen died of respiratory failure and pneumonia in November 2007, reports the LA Times.
Apparently on the basis of Kristen's case and others, the FDA announced last year that it had received postmarketing reports of toxin spread, when the drug was used to treat spasticity in children or adults. The reported symptoms were essentially those of botulism: dysphagia and respiratory compromise. Consequently the agency required makers of botulinum toxin products to add a black-box warning to their drug labels, advising of the risk of toxin spread.
But in its very recent review of published trials, the American Academy of Neurology (AAN) did not find evidence of drug-associated hospitalization or death when botulinum toxin was used to treat limb spasticity in children. All trial-based adverse events—the most common being localized pain, excessive weakness, unsteadiness, increased falls, and fatigue—were transient. Dysphagia was observed in 2 patients among more than 500 children. Seizures or the increased severity of seizures were not reported.*
The plaintiffs also argue that Allergan, in violation of federal law, promoted the off-label use of Botox for pediatric spasticity and specifically in the case of Kristen Spears. The company allegedly paid for the girl's pediatrician, Rolf Habersang, and his nurse practitioner wife to attend sponsored training seminars in 2000 and 2001 and arranged for Dr. Habersang to receive instruction from an Arkansas pediatric neurologist. In depositions, Habersang testified that he learned to use Botox at a dosage of 15 units/kg—a high, but not-unheard-of, dose in the case of CP-related spasticity in kids. The suit also alleges that Allergan sales reps discussed the off-label use of Botox repeatedly with the Habersangs and provided the dosage range of 10-15 units/kg for juvenile spasticity.
While the off-label promotion reportedly took place, the company knew of mounting Botox-related adverse events, the plaintiffs claim. Beginning in 2005, Allergan became aware of European reports of toxin spread that led to aspiration and death, and the company accumulated its own safety database, at least some of which it shared with the FDA. Also according to the plaintiffs, Allergan knew of reports of Botox-related seizures.*
The plaintiffs' allegations of off-label promotion, if true, are at complete odds with Allergan's current stance against the FDA, which requested last year that the company disseminate safety information about the off-label use of Botox. The agency's request led to Allergan's pending federal suit against the government, which seeks "declaratory relief" from the FDA's long-time restrictions against the discussion of off-label uses of prescription drugs.
To confuse matters even further, Allergan's supplemental biologics license application (sBLA) for the use of Botox in upper-limb spasticity after stroke is currently being considered by the FDA. The goal date for the agency's decision is April 1st.
Currently Botox is approved to treat spasticity associated with pediatric CP in more than 60 countries, according to news reports. In the United States, the drug's off-label use for CP-related spasticity is, by and large, considered standard practice.
* Because the effects of botulinum toxin are strictly confined to the neuromuscular junction, it seems highly unlikely that a direct mechanism exists for the drug to cause or exacerbate seizures. However, it is conceivable that the drug, through respiratory compromise, could indirectly precipitate or exacerbate seizures through hypoxic brain damage. The case of Kristen Spears, as reported, is unusual in that she received injections of botulinum toxin in her chest, which could have paralyzed her intercostal muscles.
02/01/10 addendum: The total doses used in the pediatric Botox studies that were assessed by the AAN ranged from 2 to no more than 13 U/kg for upper-extremity spasticity (n = 193; age range, 2.5-10 years) and from 4 to 30 U/kg for lower-extremity spasticity (n = 286; age range, 2-16 years). Ranges of respective per-muscle doses, when provided, were 0.3-4 U/kg and 4-6 U/kg (only 1 lower-extremity study provided these data).
No. 3: The Transparency Movement Takes a Vice-Like Hold
The push to uncover every potentially relevant tie between physicians and commercial interests, every medical writer behind a figurehead author continued with a vengeance in 2009.
In December, Northwestern University became the latest medical school to voluntarily disclose the financial relationships of its faculty with drug or device companies at its web site. The Chicago-based university joined Stanford, which provided similar online information in August, and the Cleveland Clinic, which boarded the disclosure train last year.
A handful of pharma companies, perhaps in an effort to avoid legislated disclosure,* also committed to posting some of their payments to physicians. This year, Eli Lilly, Merck, and GlaxoSmithKline began revealing various forms of compensation to healthcare professionals for a variety of services, like consulting or speaking. And Pfizer promised to disclose comprehensive data (for instance, meals exceeding $25) beginning in the new year.
Caught up in the spirit of transparency—the Accreditation Council for Continuing Medical Education (ACCME), the US organization that accredits other organizations to provide certified CME—released detailed data on 729 accredited providers in August. In an impressive data dump, the ACCME revealed each provider's accreditation status and whether they received commercial support or income from advertising or exhibits (without, however, disclosing dollar amounts). The vast majority (81%) received some type of commercial support.
Peer-reviewed medical journals published at least 2 press-worthy studies that outlined the prevalence of industry ties among academic physicians (53%) and the incomplete disclosure practices of orthopedic surgeons specifically (nearly 30% of payments, some of which exceeded $1 million). An example of the exhaustive transparency to be expected in medical journals today: the author disclosures in a highly publicized, company-sponsored study in Alzheimer disease consumed roughly 3 columns of small type in the journal Neurology.
In addition to flushing out the financial ties of physician authors, journal editors launched the age of "ghostbusting." The practice and that of honorary authorship (eg, adding the name of a laboratory head to lend cachet or credibility to an article) were found to be relatively common in the most prestigious medical journals, including The New England Journal of Medicine and the Journal of the American Medical Association, according to survey results presented publicly in September.** For offenders whose work is published in PLoS Medicine, the editors recommended immediate article retraction, lifetime banning of the named author, and a report to the author's institution for investigation. Ouch.
Recently Cochrane reviewers became concerned about the actual involvement of listed authors, the possibility of ghostwriting, and the quality of the data from a 2006 analysis of 10 Roche-sponsored trials of oseltamivir (Tamiflu). The drug company received a very public comeuppance from BMJ editor Fiona Godlee this month, for resisting unconditional access to the trial data (see BMJ Editor Bitch Slaps Roche). Godlee concluded that the joint investigation by the Cochrane reviewers, BMJ editors, and a British TV news station "cast doubt not only on the effectiveness and safety of [Tamiflu] but on the system by which drugs are evaluated, regulated, and promoted."
* Either through the proposed Physician Payments Sunshine Act or healthcare reform bills.
** Nosing in on the ghostbusting movement was Senator Chuck Grassley (IA-R), ranking minority member of the Senate Finance Committee. In November, Grassley sent a letter (personally written by the Senator?) to the deans of 10 medical schools, asking them to respond to 6 essay-type questions regarding their schools' policies on ghostwriting and plagiarism.
No. 5: Allergan Challenges FDA's Speech Restrictions
In what may turn out to be a pivotal case on the rights of commercial speech, Allergan, the maker of Botox (onabotulinumtoxinA), filed a suit against the US government in October. The company seeks declaratory relief from the FDA's long-time restrictions* against the discussion off-label uses of prescription drugs.
Turns out the FDA really brought this trouble on itself by creating a double bind for Allergan and other makers of botulinum toxin. In April, the agency required such companies to add a boxed warning to the drugs' labels and provide other public information regarding the risks of toxin spread when botulinum is used in certain forms of spasticity, like those related to cerebral palsy or after stroke. Problem is: botulinum toxin hasn't been approved for these conditions, and companies are prohibited by law from proactively discussing off-label conditions.
Allergan logically claims that it cannot reasonably abide by the FDA's safety mandate regarding the off-label use of Botox without fear of prosecution. In its complaint, the company argued that much of its proposed speech about the safety of Botox would "fall within the FDA's expansive definition of 'labeling'" and could lead to federal misbranding charges. Discussions about the safety of Botox treatment for spasticity might also be interpreted as promoting Botox for spasticity, and such an interpretation could lead to charges of distributing an unapproved "new drug" in the eyes of the FDA (meaning, an existing drug for a new indication).
Following the logic a step further, Allergan wrote: "Even by filing this complaint and thereby exercising its First Amendment right to petition the Government, Allergan fears that it will run afoul of the FDA's regulatory regime by demonstrating its knowledge that Botox is sold to physicians who use it to treat spasticity and other off-label conditions. On the Government's view, Allergan's possession of this knowledge—and its choice to defend its constitutional rights—violates 21 CFR §201.128 [which relates to the drug maker's knowledge of intended uses] on its face."
Allergan justified its fear of prosecution for the off-label promotion of Botox by acknowledging that the company is the subject of a DoJ investigation in the Northern District of Georgia.
According to the schedule of the US District Court for the District of Columbia, a motion hearing in Allergan v the United States of America (09-cv-1879) will occur March 2, 2010.
* Mandated by the Federal Food, Drug, and Cosmetic Act of 1938. The FDCA dictates that an approved drug is "misbranded," if it is marketed (in interstate commerce) for an unapproved use. The act stipulates that the product's approved label, in this case, does not provide "adequate directions for use."
In the midst of the 2009 pandemic influenza epidemic, BMJ editor Fiona Godlee takes Roche to task for not supplying the necessary data to confirm or refute the benefits of oseltamivir (Tamiflu) in otherwise healthy people with influenza. In one of 2 BMJ editorials, Godlee chides Roche for not supplying unconditional access to raw data from a pooled analysis of 10 company-sponsored trials (Kaiser et al; PubMed link here) to Cochrane reviewers Jefferson et al. Consequently the reviewers were "obliged to disregard" the bulk of these data (8 of the 10 trials) and were unable to verify that oseltamivir prevents lower-respiratory-tract complications (eg, pneumonia) due to influenza.
In their previous 2006 Cochrane review, Jefferson et al had concluded that oseltamivir 150 mg daily prevents such complications on the basis of the Kaiser article. However, the authors were criticized through a public feedback mechanism for using the 10-trial analysis without having access to the raw data. Prompted by this criticism, Jefferson et al then conducted another review, published this week in the BMJ, in which they affirmed their critic's perspective:
Data on the effectiveness of oseltamivir against complications of influenza principally came from one study...This was a meta-analysis of 10 trials containing a mixture of published and unpublished data, two of which are reported in this update and the remainder inaccessible to proper scrutiny, so that we are now obliged to disregard them. The remaining data showed no benefit for oseltamivir against complications.
In her editorial, Godlee asks, "Where does this leave oseltamivir, on which governments around the world have spent billions of pounds?" She, moreover, emphasizes that the Cochrane review data apply only to healthy adults with influenza, but they "say nothing about [oseltamivir's] use in patients judged to be at high risk of complications—pregnant women, children under 5, and those with underlying medical conditions." Even the drug's ability to reduce influenza-related symptoms (which Jefferson et al reconfirmed) are doubted, because there are no head-to-head studies with oseltamivir and NSAIDs, for instance.
In another BMJ editorial (with Cochrane director Mike Clarke), Godlee concludes that the latest Cochrane review and a "linked investigation undertaken jointly by the BMJ and Channel 4 News cast doubt not only on the effectiveness and safety of oseltamivir (Tamiflu) but on the system by which drugs are evaluated, regulated, and promoted." In their investigation, Cochrane reviewers became concerned about the actual involvement of listed authors on the Kaiser analysis, the possibility of ghostwriting, the high rates of influenza in the trials, and the low rates of serious adverse events.
Initial responses from Roche employees, who first declined to provide the data and then offered selected files, were less than satisfactory to the reviewers. The latest response from the company: it is "committed to making the 'full study reports' available on a password protected site soon."
On the basis of this experience, Godlee and Clarke conclude that the current system for reporting drug research "isn't working" and offer a number of potential remedies—including government-mandated access to raw data that are used to license and market a drug (eg, something in the spirit of the FDA Amendments Act of 2007).
News sources are all over this story (eg, Bloomberg), and the BMJ offers full-text access to the following relevant articles, including a response from a Roche employee—who chastises Jefferson et al for enlisting the investigative help of a TV news station.**
- Godlee F. We want raw data, now.
- Godlee F, Clarke M. Why don't we have all the evidence on oseltamivir?
- Smith J, on behalf of Roche. Roche replies to the authors of the Cochrane Review on oseltamivir.
- Cohen D. Complications: tracking down the data on oseltamivir.
- Doshi P. Neuraminidase inhibitors--the story behind the Cochrane review.
- Freemantle N, Calvert M. What can we learn from observational studies of oseltamivir to treat influenza in healthy adults?
- Jefferson T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis.
- Web extra (including the criticism that got the ball rolling).
* And I mean that in the nicest possible way.
** Roche's Smith writes, "It is unclear to us why Dr Jefferson would adopt this approach, particularly given that he was a paid ad hoc consultant to Roche working on flu and oseltamivir between 1997 and 1999. During that period he worked closely with Roche experts, many of whom are still in the company, and he would therefore not have had difficulty in contacting them directly to discuss his requirements."
Photo from Vermin Inc at Flickr.
