Ethics: December 2009 Archives

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."

Fifty-four of 57 Nigerian children died between October 2008 and January 2009 after receiving a liquid acetaminophen preparation that was tainted with diethylene glycol (DEG). Exposure to the branded teething product, My Pikin,* was determined in 96% of the identified cases of unexplained acute renal failure (ARF) in the 57 children, according to a retrospective surveillance study performed by Nigerian officials, the CDC, and the US FDA. Their report is available in the latest issue of the MMWR.

The surveillance study was prompted by clusters of unexplained ARF cases in very young children (≤3 years of age) among hospitals in Lagos, Kadun, and Osun in the fall of last year. Initial reports led to the identification of the DEG-tainted product, a full product recall, and the shutting down of the responsible manufacturer in Lagos, Barewa Pharmaceuticals. Despite a nationwide recall and a press release in November of last year, which resulted in the confiscation of 7616 of 15,000 bottles of the contaminated drug, more than a quarter of the affected children received the product after the recall was announced.

Among children for whom data were available, the median time from drug exposure to ARF was 5.6 days (range, 0-24 days), and the mean time between the onset of ARF and death was 6.8 days (range, 1-19 days). Treatments with dialysis, received by 24 children, and the ethylene-glycol antidote fomepizole, received by 2 children, did not appear to prolong survival.

The MMWR editors report at least 12 episodes of DEG contamination in oral or topical medications during the last 70 years, which have caused at least 450 deaths. (Most of these episodes are described here and here.) The contamination was almost always due to the intentional economic-driven substitution of DEG for the more expensive solvents of glycerin or propylene glycol. (An account of the US deaths that occurred in 1937 due to a DEG-tainted antibiotic solution has been provided in numerous serial posts at this blog [search for "sulfanilamide" or "Massengill," for example], and the deceased are listed on this page.)

Prevention of DEG-contaminated drugs is easy and cheap, according to the editors. "Simple, rapid, and low-cost assays" that use thin-layer chromatography are available to detect and measure DEG at levels of 2% in liquid acetaminophen products and 6% in glycerin, they report.

* DEG accounted for 17%-21% of the My Pikin liquid medication by weight in sampled bottles. According to the MMWR, another contaminated acetaminophen-based syrup, made by a different manufacturer, was discovered to contain 0.5% DEG.

Photo of My Pikin Baby Teething Formula from Vanguard.