FDA: September 2010 Archives

Today's report

that Amgen and JNJ are recalling vials of Epogen and Procrit, respectively, because of internal glass flakes prompts a search at this blog for their causes. The incident appears to be a longstanding plague of storing and delivering parenteral solutions, with Baxter (most recently) recalling glass vials of Hylenex in May for a similar problem.

The phenomenon, known as glass delamination, is an apparently well-described, but not well-understood, event in the industry. In a recently published series of experiments on glass vials, Lilly employees remind us that glass is not an inert substance and that several factors—including sterilization (ie, autoclaving), glass makeup, solution properties (eg, pH changes), and mechanical energy (eg, shaking)—can erode the silica framework and contribute to the instability of glass. The authors emphasize that the generation of visible flakes is not a herald sign of glass instability but a late manifestation. "The stage for delamination is set well before flakes are observed," they write. They further conclude that prevention is problematic.

Because the vial interior is compromised so early in the shelf life of the product, few options exist for the prevention of delamination. The [chemical vapor deposition] coating of SiO2 offers some protection against the formation of visible flakes. Materials substitution using plastic vials is also an alternative; however, there are other challenges incurred with such a change. Lyophilization [ie, freeze drying the liquid drug] is also a viable alternative. Although the liquid does have contact with the glass prior to processing, the time that the liquid resides in the glass vial is much less than would be encountered with a liquid formulation.

Electron micrograph of delamination of internal glass-vial surface from Iacocca et al (2010).

• In an opening statement, Rep. Michael Burgess (R-TX), a physician, reveals that the FDA took pictures of the concerning conditions at Wright County Egg. Inexplicably FDA Commissioner Margaret Hamburg and no USDA representatives will be testifying before today's Subcommittee hearing.
• Rep. Henry Waxman (D-CA)—whose bald head is the shape of a perfect egg—cites stonewalling of a new food-safety bill by Senator Tom Coburn (R-OK), another physician turned Congressman.
• Rep. Bruce Braley (D-IA), with a farming background, expresses shock and disgust at the FDA-reported conditions at Wright County Egg and promotes the new food-safety bill. Despite a large, historical consumption of eggs by his family and fellow Iowans, he denies throwing eggs at Halloween, when questioned by another Subcommittee member.
• Rep. Diana DeGette (D-CO) highlights advantages of the pending food-safety bill, which she says would facilitate the FDA's investigation of food contamination.
• Rep. Donna Christensen (D-Virgin Islands) also touts the advantages of the pending food-safety bill.
• Rep. Edward Markey (D-MA) rhymes "eggs over easy" with "should not make you queasy" and likens the reported conditions at Wright County Egg with those described in Sinclair Lewis's The Jungle. He then chastises Senate Republicans, and specifically Coburn, for stalling the pending food-safety bill. Generally he incorporates way too many groan-inducing egg-related phrases (eg, "egg shells," "hard boiled") into his scolding opening statement.
• Burgess objects to defend Senator Coburn and identifies Senator Harry Reid (D-NV) as blocking the food-safety bill, although the objection is not entered into the record, under the direction of Subcommittee Chairman Rep. Bart Stupak (D-MI).

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The first testifying panel is sworn in and seated.

• 30-year-old Californian Sarah Lewis describes her experience of being infected recently with Salmonella enteritidis, which necessitated 2 hospitalizations and resulted in a Clostridium difficile infection (due to antibiotic treatment). She presumably acquired S. enteritidis, as did her sister, by eating a dessert custard at a graduation banquet in May. The custard was made with unpasteurized eggs. She reports that her family owns a retail butcher shop and later describes how the butcher shop is regulated by state and county authorities (although the meat in the shop is USDA inspected). This aspect of her history is used by the Subcommittee to highlight her familiarity with the food business, the importance of food-industry standards, and the benefits of food regulations.
• 77-year-old Coloradan Carol Lobato describes her "septic shock" after eating at an upscale game restaurant in June (later revealed to be The Fort in Morrison, CO). Treated for rheumatoid arthritis, Lobato developed salmonella septicemia. The FDA identified the eggs in the "rattlesnake cake" [!] appetizer that she and others ate at the restaurant as the source of her illness. The DNA fingerprint of bacteria isolated from Lobato matched that of S. enteritidis cultured from Wright County Egg. Lobato reveals that she grew up on an Iowa farm, an experience that included the raising of "free range" chickens. She urges the Congressional panel to pass food-safety legislation that rewards companies for doing "the right thing" and punishes those that don't.
• Stupak asks the salmonella victims to review the photos of conditions at Wright County Egg, which are included in a binder in front of them. Lobato calls the photos "deplorable." Lewis calls the photos "appalling."
• After gently questioning the victims, Burgess attempts to enter a statement defending Senator Coburn, which results in a contentious exchange between Burgess and Stupak.
• While Braley questions the victims, background squabbling (presumably between Burgess and Stupak) is heard. Braley later cites a salmonella outbreak associated with duck eggs in the 1920s and 30s, which prompted (he claims) Americans to switch to the consumption of chicken eggs.
• Rep. Bob Latta (R-OH) asks Lobato to explain rattlesnake cake (sort of like a crab cake, it turns out). The contaminated raw egg that Lobato ate was likely contained in the sauce or "relish" that was served with the cake.
• When questioning the salmonella victims, DeGette implies that current, pending "bipartison" legislation would facilitate the tracing of the origin of food-borne illnesses and necessary recalls.

The panel is dismissed. 

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• Burgess asks Stupak for 30 seconds of time (presumably to read his defense of Senator Coburn), and Stupak denies Burgess the time. Burgess complains that Stupak silenced his mike and calls this act "censorship." Stupak chides Burgess for trying to "backdoor" his defense of Coburn. Stupak ultimately calls the next panel of witnessess, including the DeCosters.

=====================

• Three of the 4 panel members, including Austin "Jack" DeCoster, owner of Wright County Egg, name their counsel.
• Jack DeCoster reads his opening statement. The beginning of his statement is interrupted by 2 banner-waving protestors, who chant on their escorted way out of the hearing room, "All eggs kill." Jack's statement does not appear to stray appreciably from his written testimony submitted to the Subcommittee.
• Peter DeCoster, son of Jack, defends the managment and oversight of Wright County Egg, particularly as it relates to the control of "SE." He implicates meat and bone meal as the source of S. enteritidis in his eggs.
• Orland Bethel, president of Hillandale Farms of Iowa, does not have an opening statement.
• In his opening statement, Duane Mangskau, production representative of Hillandale Farms, expresses "shock" at the FDA allegation that 7 people acquired salmonella from their eggs after eating at a Mexican restaurant.
• Stupak asks Bethel about an August 21st e-mail from Mangskau. Bethel takes the Fifth. Stupak then questions Jack DeCoster about why this outbreak occurred, if he cleaned up his operations as stated. DeCoster senior appears slightly stunned or confused when attempting to explain a photo of dead chickens in his laying facility. Peter interrupts in an attempt to answer this and other questions directed to his father. Peter claims that piled-up manure at Wright County Egg, which is shown in a photograph pushing out a large access door, was cleaned up the day that the photo was taken.
• Burgess questions Bethel about an e-mail in which Bethel allegedly expressed a desire to dissociate from the DeCosters' operations. Bethel "respectively" declines to answer the question. Burgess then asks Peter DeCoster when and why he started testing for S. enteritidis, although it is not required by law. Burgess also asks DeCoster junior to explain what he did to address the positive S. enteritidis results. Peter cites vaccinations and methods to control molting.
• Stupak dismisses Bethel from the panel.
• Waxman asks DeCoster senior about his 30-year problem with S. enteritidis-infected eggs, including in Maine and Maryland. Waxman asks DeCoster to reconcile his claim of cleaning up his operations with the recent FDA-inspection report. "Does this sound like a clean facility to you?" Waxman asks. Again Peter attempts to intercept the question, but to no avail. DeCoster senior cites hiring some kind of fly and/or rodent expert more than 1 year ago. Waxman suggests that the DeCosters may want to fire this so-called expert. Peter DeCoster attempts to explain "excaped" chickens at his facilties. Waxman attempts to redirect DeCoster to explain how they've cleaned up their facilities. Peter objects that he's not being given enough time to respond to Waxman's questions. Waxman then asks Jack to respond, who begins to explain (in rambling fashion) what some company supervisor does to inspect and clean the hen houses each day. Waxman interrupts (because his time is nearly up) and expresses outrage that the DeCosters are attempting to implicate the bone-meal feed as the source of the S. enteritidis, given the FDA-documented conditions of their facilities.
• Latta asks Peter DeCoster about his manure-management plan and any inspections conducted by the state's Department of Natural Resources (DNR). Peter explains a manure-removal procedure of every other year ("we was going with," he explains) to every year.
• Braley asks the panel to respond to how this egg recall has adversely affected the industry and the livelihood of egg producers. They all respond that they feel bad. Iowan Braley also wants to know from Jack why the DeCoster name is appearing again in another recall of S. enteritidis-infected eggs. Jack rambles on about what he remembers from a Maryland-based egg recall years ago and chews up Bailey's time.
• Rep. John Dingell (D-MI), who's 7 years older than Jack DeCoster and appears 7 times as sharp, grills Peter on the FDA-reported conditions at the DeCoster facilities. Dingell also asks Peter to describe the steps that are being taken to improve conditions at his egg farms. In his responses, Peter divulges that the family also leases hog facilities.
• DeGette makes the point that DeCosters' facilities and the Peanut Corp. of America, both of which have been implicated in recent salmonella outbreaks, were inspected by a third-party auditor, AIB, and received "superior" ratings right before the outbreaks. Peter informs DeGette that AIB's inspection was of DeCosters' processing facilities, not their hen houses.
• Rep. Mike Doyle (D-PA) asks Mangskau to clarify the relationship between Hillendale and Wright County and to explain what Hillendale is doing to ensure the safety of its eggs. Mangskau explains that Hillendale will no longer take chickens from Wright County and reiterates that Hillendale has severed its marketing relationship with Wright County.

The panel is dismissed.

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• The third panel consists solely of Joshua Sharfstein, Principal Deputy Commissioner of the FDA. Sharfstein explains the FDA's recommendations for reducing the risk of egg-borne salmonella outbreaks and events of its most recent trace-back investigation, which led to Wright County and Hillendale. Sharfstein cites "significant" problems with pest control, manure management, and cross contamination at the DeCosters' facilities. He also implicates multiple probable sources of S. enteritidis contamination at Wright County Egg. He promotes new food-safety legislation, which would "strengthen" FDA's enforcement and recall capacities.
• Stupak explains the "Final Rule" of the Egg Safety Action Plan, implemented in July 2009, that applies to egg farms with more than 3000 hens. Sharfstein explains that the Egg Safety Action Plan should improve the safety of eggs.
• Burgess, through his questioning of Sharfstein, clarifies that the FDA wasn't prohibited from inspecting egg facilities, but that the new rule now provides standards by which the FDA can inspect egg facilities. Burgess also asks why communication between the USDA (which was grading DeCosters' eggs) and the FDA was apparently lacking. Burgess tries to identify what's new in the pending bill, other than the ability to mandate recalls. Burgess also stresses the fact that the bill won't necessarily improve communication between the 2 government agencies. Sharfstein says that there will be "enhanced" criminal penalties under the new bill. Sharfstein looks confused when Burgess asks about the difference between external and internal S. enteritidis contamination of eggs.
• Waxman asks Sharstein to explain how the "Egg Rule" will improve the safety of eggs. Sharfstein explains that the Egg Rule provides certain standards or benchmarks for FDA inspections. Also new legislation will aid the FDA in its food inspections, Sharfstein argues, and provide the agency with mandatory-recall powers and stronger "teeth" with respect to civil and criminal penalities. Sharfstein concludes, "We need this bill," to prevent another salmonella outbreak.
• Under questioning from DeGette, Sharfstein stresses that the FDA "does not agree with this conclusion" that the source of S. enteritidis at Wright County Egg is the chicken feed, as maintained by the DeCosters. DeGette also helps Sharfstein promote the "trace-back" provisions of the new bill.
• Braley maintains that the cost of the new food-safety bill, which he implies would reduce hospitalizations and fatalities, would be borne by food manufacturers.
• Under questioning from Markey, Sharfstein says that FDA will use information from OSHA and the USDA to prioritize inspections of the highest-risk facilities. Sharfstein clarifies that new legislation will give the FDA of new "tools" to fortify its inspections.

The Subcommittee meeting is adjourned by Stupak.

By a length and a half, maybe?

Today the FDA approved fingolimod, trade name Gilenya,* the first orally administered disease-modifying drug for the treatment of relapsing-remitting multiple sclerosis. The pill, at a dosage of 0.5 mg once daily, was approved approximately 9 months after Novartis quietly submitted its NDA to the agency in December and nearly a year after Merck Serono filed its first application for an oral competitor, cladribine.

The final stretch of the approval horse race was significant for a bad stumble taken by Merck Serono, after the FDA refused to file its application in December. Speculation: the submission was incomplete. Merck Serono filed a new application 6 months later, and the company received a priority review from the agency (with an anticipated approval at the end of this year).

But also in June, an FDA panel voted overwhelmingly in favor of fingolimod's approval—at least with respect to its efficacy. Safety issues with Novartis's agent included opportunistic infections, and analysts speculated that the FDA would institute some kind of access-limiting REMS program for the drug—which has evidently come to pass, according to today's Novartis press release.**

A Health Care Provider letter at the Gilenya website describes the risk of initial bradycardia or AV block, and that all patients should be observed for 6 hours after the first dose—a cumbersome recommendation that may deter rapid, practical uptake of the drug. Warnings also exist for lymphopenia (and consequent opportunistic infections), macular edema (0.4%), respiratory compromise, elevation of liver enzymes, and fetal risk. Novartis says it will begin a 5-year global study to monitor safety-related outcomes and establish a voluntary pregnancy registry—much like what exists for Biogen Idec's Tysabri (natalizumab), which is associated with the rare, but deadly, PML.

The anticipated efficacy of Gilenya, provided here in a friendly tabulated format, is a 40% reduction in the annualized relapse rate, when the drug is compared with the standard disease-modifying treatment of Avonex (interferon-beta 1a 30 ug/wk IM).

AV = atrioventricular; NDA = new drug application; PML = progressive multifocal leukoencephalopathy; REMS = Risk Evaluation and Mitigation Strategies.

* Sometime during FDA review, Novartis changed the trade name from Gilenia to Gilenya.

** Although the FDA press release fails to mention a REMS program for Gilenya.

In the ongoing investigation of Wright County Egg, the apparent source of disease-causing bacteria in the recent egg-borne salmonella outbreak, an effort by management to point the finger at an outside feed supplier isn't panning out.

Facilities at Iowa's Wright County Egg, the apparent origin of the recent egg-borne salmonella outbreak, tested positive for the disease-causing bacteria, Salmonella enteritidis, at least as far back as 2 years ago. The revelation is made in a letter sent Tuesday by Congressmen Henry Waxman and Bart Stupak, chairmen of the House Investigations and Oversight Subcommittee, to Austin "Jack" DeCoster, CEO of Wright County Egg. Waxman and Stupak cite 28 sample reports, obtained by unclear means,* that reveal at least 73 instances in which Salmonella serogroup D was detected on chickens, egg belts, or "pit rows" in DeCoster's hen houses. The most recent sample report, dated July 26, 2010, revealed that DeCoster's poultry tested positive for serogroup D and ultimately S. enteritidis.**

The publicized testing records, which are incomplete and heavily redacted, show more than 400 instances in which environmental swabs (ie, "sponges") at DeCoster's egg farms were contaminated with various serogroups of Salmonella—B, CI, C2, D, "untypeable," and polyvalent. Isolates revealing serogroups D, untypeable, and polyvalent, detected on samples by the Veterinary Diagnostic Laboratory at Iowa State University (which were presumably taken as a part of routine surveillance testing performed by the company), were then forwarded for species identification to the NVSL, or the National Veterinary Services Laboratory. However, only about half, or 10, of these NVSL results are included in the publicized testing records. Of the available NVSL reports, 8 (80%) revealed S. enteritidis. (The NVSL is a part of the USDA—a fact that raises questions about the government lab's responsibility for further scrutinizing facilities that repeatedly test positive for infectious pathogens.)

The Subcommittee's information gathering, which is ongoing, is in anticipation of the DeCoster's voluntary appearance before Congressional members on Tuesday, September 21 (Hearing on Salmonella Outbreak and Egg Recall, beginning at 12 noon EDT). "Habitual violator" DeCoster, up until now, has been almost Howard Hughes-like in his ability to avoid direct media scrutiny and public accountability for the recent outbreak, the eyebrow-raising conditions at his egg farms, and several past infractions.

Whether DeCoster's S. entertidis isolates are related to the recent salmonella outbreak is currently unknown (or at least unpublicized). DNA characteristics of DeCoster's bacterial samples, including recent samples detected by the FDA, would have to be compared with those of bacteria cultured from infected individuals. The CDC reports that this egg-borne salmonella outbreak is distinct in that DeCosters' eggs are infected internally—meaning through the infection of his chickens' ovaries.

* Waxman's and Stupak's letter indicates that DeCoster provided, on request, documents to the Subcommittee on September 11, but that these did not contain the "potentially positive Salmonella Enteritidis test reults." The congressmen want to know why these reports weren't provided by DeCoster.

** Serogroup D includes the bacterial species S. enteritidis.

Yesterday the US Court of Appeals of DC granted an emergency motion of stay against Judge Royce Lamberth's August 23 order, which banned research on human embryonic stem cells (hESCs). Wrote the appeals court,

The purpose of this administrative stay is to give the court sufficient opportunity to consider the merits of the [DoJ's] emergency motion for stay and should not be construed in any way as a ruling on the merits of that motion.

The appeals court ordered the appellees (Sherley et al) to file a response to the emergency motion by September 14 and allowed the appellants (Sebelius et al) to file a reply on September 20.

On the basis of the news, NIH officials signaled a tentative OK to restart intramural hESC work and to fast-track pending extramural grants for hESC research.

Background on this story can be found here, here, and here; but in the interest of sheer thoroughness, I recommend coverage of this story by The Great Beyond:

Appeals court temporarily lifts stem cell injunction - September 09, 2010

NIH tells researchers to recommence stem cell work - September 09, 2010

Image of undifferentiated hESCs from http://www.nih.gov/catalyst/2007/07.01.01/page1.html.

According to today's WSJ,* the US Department of Agriculture failed to inform the FDA of deteriorating conditions at Wright County Egg, the presumed center of the recent egg-borne salmonella outbreak. (For background, visit here and here.) While trash and bugs began to pile up at the Iowa plant last spring, blinkered USDA workers continued to ensure that Wright County's eggs were appropriately graded.

*Bleech. I cite the story, despite the fact that it was cowritten by Alicia Mundy, whose work I've found sensationalist and irresponsible.

The reason to care about medical ghostwriting is that it may be used to convey drug-industry messages through credited academic authors. In other words, there is an attempt by industry to influence a physician-reader's prescribing practices under the guise of academic objectiveness (although nobody, to my knowledge, has demonstrated this outcome).

But I would argue that the issue of medical ghostwriting is irrelevant when pharma-employed scientists are among the credited authors of articles (which are usually reports of pharma-supported studies). In these cases, the potential for commercial influence in the published material is already obvious, regardless of who actually wrote the article.

Nevertheless, the possibility that there are situations in which medical ghostwriting is immaterial is evidently lost on some (nor will it get in the way of a mission to root out ghostwriting, no matter how immaterial). Case in point:

In a 2-part effort to impugn the marketing of the antidiabetes drug Avandia (rosiglitazone), the Senate Committee on Finance sent a letter to FDA Commissioner Margaret Hamburg on July 12, alleging that manufacturer GSK 1) failed to publish negative studies of the drug "in a timely manner" and 2) hired ghostwriters to pen medical articles that were favorable to Avandia. The former charge, the more serious of the two, has received considerable press attention—most notably in a recent NYT article by Gardiner Harris. However, the ghostwriting charge has not, by any means, been ignored.

In a confusing post at the generally anti-pharma (and often sensationalist, IMO) blog Pharmalot, Ed Silverman asked his readers last Thursday, "Did the American Heart Association's Circulation journal publish a ghostwritten article about Avandia?" Silverman's answer, yes, lies in an exchange of letters among the Senate Committee, the FDA Commissioner, and the AHA. But a closer examination of the letters and the published literature reveals a more nuanced answer than what Silverman concluded (and what his blog readers are likely to be receptive to). A closer examination also reveals how deftly and stubbornly the Committee maintained its ghostwriting allegations against the AHA while failing to acknowledge 1) its confusing and/or mistaken evidence and 2) when medical ghostwriting is an important issue.

In its July 12 letter, the Finance Committee provided 2 attachments to substantiate allegations of Avandia-related ghostwriting by GSK. The first attachment, H (pp 58-109 of 158), contained an e-mail from the Avandia Publication Strategy Manager, who presented a draft manuscript to his GSK colleagues. The manuscript, which reviewed 5 modifiable risk factors for cardiovascular disease, was to be credited to University of Texas cardiologist Steven M. Haffner, MD, and "targeted" to the American Journal of Cardiology, an independent peer-reviewed medical journal that is published by Elsevier. The journal is not affiliated with the AHA.

The text of the redacted and "VERY poorly written"* manuscript mentioned rosiglitazone exactly twice (at the end of the article), both times in conjunction with its chief competitor, pioglitazone (Actos). A notable, suggested edit was to use "Avandia references" in the construction of a table detailing the effects of thiazolidinediones on cardiovascular risks.

The Committee's follow-up attachment I (pp 110-158) contained Haffner's "reworked" and highly condensed manuscript, entitled, "Modifying cardiovascular risk in the type 2 diabetes patient." The title page of the review now indicated the authorship of Haffner and nurse Holly B. Cassells, PhD, who is on faculty at the University of the Incarnate Word [?!]. The title page also acknowledged that the paper was "[s]upported by an unrestricted, educational grant from GlaxoSmithKline" (thereby acknowledging the potential for commercial influence in the manuscript). The heavily redacted text in the attachment mentioned rosiglitazone 4 times (by my count) and highlighted a study of the cardiovascular effects of combined therapy with atorvastatin (Lipitor; Pfizer) and rosiglitazone (Cohen et al, 2001). A GSK e-mail suggested that the review article should now be targeted to another non-AHA journal, Clinical Cardiology (published by Wiley).  

In its attachment I to Hamburg, the Committee chased the Haffner review paper with another Haffner-authored article, which was evidently accepted into the journal Circulation, a bona-fide AHA journal. This article, "Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus," described the results of an actual study; in other words, it was not a review article (and it was clearly not the review manuscript previously cited by the Committee in its attachments). The article, published in 2002, had 6 credited authors, 3 of whom (including Martin I. Freed, MD) were acknowledged employees of GSK, and the study's GSK funding was made clear.

On August 23, the AHA responded to the Committee's charges by sending a letter to Hamburg. Donna K. Arnett, PhD, the chair of the AHA's Scientific Publishing Committee, attempted to clarify the distinction between the 2 articles cited by the Committee in its attachments. Arnett noted correctly that the review article was never published in Circulation and was targeted to at least 2 non-AHA journals.** Arnett concluded,

Since Circulation has never published a review article by Haffner and Cassel[sic] entitled, "Modifying Cardiovascular Risk in the Type 2 Diabetes Patient," as claimed in the letter to you, the letter and its appendices are misleading. We have requested that [the Committee] provide a correction for the record.

But not to let details get in the way of a mission, Ranking Member of the Committee, Senator Chuck Grassley, responded to Hamburg with yet another letter, dated September 1. Grassley disingenuously wrote (or one of his staffers disingenuously ghostwrote),

At the time, it was unclear if the emails about ghostwriting concerned the article that appeared in Circulation, or if they were discussing a separate manuscript.

To which I say: Rubbish. The featured, originally ghostwritten review article by Haffner (and then Haffner and Cassells) was the clear subject of the GSK e-mails.

Then Grassley (or his staffer) added, while completely ignoring the cited review article,

Regardless, my staff has consulted with GSK, and the company confirmed that the manuscript which appeared in Circulation was written for GSK by a medical education company.

To which I say, more or less, to the Committee (and Pharmalot): So what? Given that 3 of the 6 authors of the Circulation article were acknowledged GSK employees and that the study was transparently funded by GSK, the potential for commercial influence is obvious to any physician-reader, regardless of who actually wrote the article.

Now as far as the originally ghostwritten review article is concerned, which Senator Grassley (or his ghostwriting staffer) failed to address in the September 1 rebuttal letter, a quick search of the literature reveals that Cassells and Haffner (credited in that order) finally published, “The metabolic syndrome: risk factors and management,” in the Journal of Cardiovascular Nursing in 2006. This journal is not an AHA journal. Because access to the article requires a subscription, I am (at this time) unable to assess the objectiveness of the article, how closely the article adheres to the attachment I text, or whether commercial support is acknowledged.

* As it was described by GSK's Julia Eastgate, Head of Diabetes Communications, Europe, in her e-mail.

** Silverman called Arnett's letter "sharply worded"; on the contrary, I find Arnett's wording moderate in tone and matter-of-fact. 

In a 3-part criminal and civil agreement with the Department of Justice, Allergan, the maker of Botox, has dropped its free-speech suit against the FDA—which had the potential to be a pivotal case on the rights of commercial free speech. In addition, the company has pleaded guilty to a single misdemeanor "misbranding" charge, stemming from the off-label promotion of Botox during 2000-2005, and will pay $375 million. Last Allergan will fork over another $225 million to resolve civil claims made by the DOJ under the False Claims Act (concerning qui tam or whistleblower complaints). The plea agreement was announced yesterday in a company press release and also by the DOJ.

According to the government, Allergan, during the described time period, "exploited" an approved indication for cervical dystonia (obtained in 2000) to expand the off-label use of Botox for headache. Company reps were also instructed to call on doctors who typically treat off-label conditions (like pediatric spasticity), and Allergan held workshops to inform healthcare providers on how to be reimbused for injecting Botox off label.

The civil settlement resolved 3 qui tam lawsuits, with whistleblowers Dr. Amy Lang (a former Allergan consultant), Charles Rushin (a former Botox sales rep), Cher Beilfuss (a former Regional Healthcare Policy Manager for Allergan), Kathleen O'Conner-Masse (a former Payor Reimbursement Account Manager for Allergan), and Edward Hallivis (a former I-don't-know-what). They will split $37.8 million.

The current, FDA-approved indications for Botox (not Botox Cosmetic) in adults are the following:

• Cervical dystonia
• Primary axillary hyperhidrosis
• Blepharospasm and strabismus
• Upper limb spasticity (approval obtained March 2010)