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).
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.
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.
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)