Recently in FDA Category

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)

Released yesterday, the FDA's inspection report of facilities at Wright Company and Quality Egg, ground zero for the recent egg-borne salmonella outbreak, is either an outing of a filthy outlier in the business of mass agriculture or a revelation of the filthy business of mass agriculture. How much chicken shit is acceptable in and around hen houses is virtually unknowable for the 99% of Americans who don't farm. But 4-to-8-feet piles seem excessive.

According to the FDA, the laying facilities in north-central Iowa, managed by Austin "Jack" DeCoster's son, Peter, were plagued with the following:

• Massive and escalating amounts of chicken excrement.

Inspectors reported that "outside access to the manure pits...had been pushed out by the weight of the manure, leaving open access to wildlife or domesticated animals." Manure, aka "dark liquid," was also observed to be seeping through the concrete foundation of the outside of the laying houses. Uncaged birds were seen using the piled-up manure to access laying areas.

• Standing water near manure pits.
• Live rodents, namely mice, who evidently had free access into and out of the laying houses.
• And lots and lots of flies and maggots. "The live flies were on and around egg belts, feed, shell eggs and walkways in different sections of each egg laying area," the inspectors wrote. "In addition, live and dead maggots too numerous to count were observed on the manure pit floor..."

Most important, perhaps, was the fact that the FDA found evidence of Salmonella enteritidis in multiple locations, including in manure and chicken feed.

The FDA's inspection took place from August 12 to August 30, longer than 2 weeks. Given the duration of the inspection (and the possibility that facility managers knew that the FDA was coming), it seems that officers at Wright County and Quality Egg actually had the opportunity to clean up their facilities. If so, the conditions of these businesses may have been, in reality, considerably worse.

Nearly 8 months after the FDA refused to file Merck Serono's application for oral cladribine as an MS treatment, the company says the drug has now received priority review.* Merck Serono resubmitted its application to the agency in June. Related coverage from the WSJ indicates that the company expects an FDA decision in the fourth quarter, although the goal for a priority review is a bit longer, at 6 months.

With cladribine, Merck Serono has been in a nose-to-nose horse race with Novartis, which is developing fingolimod (Gilenia). One of these companies is very likely to be the first to offer an FDA-approved, orally administered disease-modifying drug for the relapsing-remitting form of the disease. (Current, approved, disease-modifying medications for RRMS, like interferon beta, are injected subcutaneously or intramuscularly.)

According to the WSJ and Reuters, oral cladribine for RRMS was approved in Russia earlier this month and is awaiting a nod in Europe. 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 include opportunistic infections, and analysts have speculated that the FDA will institute some kind of access-limiting REMS program for the drug, if/once it is approved.

A new survey analysis indicates that US neurologists are considerably more aware of cladribine than fingolimod—probably because the former has been available as an injectable anticancer drug since the Stone Age (ie, the early 1990s), and fingolimod is a new molecular entity (NME).

MS = multiple sclerosis; REMS = Risk Evaluation and Mitigation Strategies.

* According to the FDA, a "Priority Review designation is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists. A Priority Review means that the time it takes FDA to review a new drug application is reduced. The goal for completing a Priority Review is six months."

The original source of Baxter's contaminated heparin, which killed scores of Americans in 2007 and 2008, has still not been identified, according to letters sent between the FDA and Congressmen Joe Barton (R-TX), who is investigating the matter. The heparin, which was intentionally spiked with oversulfated chondroitin sulfate (OCSC), was traced early to Baxter's Chinese supplier of crude heparin, Changzhou SPL, but the FDA has apparently not been able to get beyond the company to implicate any of Changzhou's suppliers. (A colorful expose by the WSJ in 2008 about the unregulated production of raw heparin in China showed just how hard it might be to identify the perpetrator.)

According to the agency's response letter of June 16, officials of China's State Food and Drug Administration (SFDA) have stifled the FDA's investigation beyond Changzhou SPL, and "repeated" follow-up requests to the SFDA have yielded only "general information." The latest from Chinese officials to the agency: There have been no breakthroughs in the case. However, Congressman Barton, in his latest volley with the FDA, suggests that the US agency has been lax in its follow-up and specifically in its investigation of several suspect Chinese firms, including transparently bogus "front companies." (For more on these suspect firms, read the letter.)

In its efforts to protect the American public, the FDA posted testing methods for OSCS and initiated a "sampling program" to examine products on entry to the country. In addition, specific Chinese firms, like Changzhou, have been given an "import alert" status, in which products can be confiscated without inspection.

Leading the search for a synthetic version of heparin, which would entirely circumvent any reliance on the crude harvesting process (in China or elsewhere), are investigators at Rensselaer.

SPL = Scientific Protein Labs.

On the cusp of the FDA's safety review of Avandia, a couple of indeterminately sized bombshells:

One from Dr. Rosemary Johann-Liang, vis-a-vis Business Week. Johann-Liang, a former manager in the FDA's drug-safety office, said by way of a legal deposition that GSK withheld results of a 2001 Avandia study from the agency. The study reportedly showed that Avandia increased the risk of heart attack.

And another from Gardiner Harris of the NYT, who reported on the buried results of a 1999 GSK-sponsored trial that pitted Avandia against its competitor Actos and an older OAD, glyburide. The results, which have evidently been cloistered at GSK for more than 10 years, were "disastrous," Harris wrote, with respect to Avandia's cardiac risks. According to Harris, Dr. Martin I. Freed, who was in charge of Avandia's development at SmithKline Beechem in 2001 (ie, before the Glaxo merger), wrote that "these data should not see the light of day..."

Unfortunately Harris didn't or wasn't able to track down Freed for the doctor's updated perspective—that is, Harris did not even write something like "Dr. Freed declined to comment" in his NYT report.

According to a 2007 press release from Adnexus Therapeutics (an R&D arm of BMS), Freed was appointed to the newly created role of Chief Medical Officer; however, at the company's web site, Freed is not currently mentioned among the company's current top management.

The 2007 Adnexus press release described Freed's background, including his pharma experience:

Dr. Freed was Vice President of Clinical Development at GlaxoSmithKline. During his tenure he led [the] clinical development of Avandia, a leading drug in the treatment of type 2 diabetes from preclinical to market. Dr. Freed was also involved in the clinical development of drugs across a broad range of therapeutic areas including metabolic diseases, cardiovascular disease and diseases of inflammation, with experiences ranging from Phase 1 through Phase 4 clinical trials. He participated or directed more than 100 clinical and clinical pharmacology studies, involving thousands of patients, for multiple products. Prior to joining Adnexus, Dr. Freed was Chief Medical Officer at a privately-held biotechnology company Vitae Pharmaceuticals, which has programs across a range of therapeutic areas including hypertension, diabetes, cancer and inflammation. A Fellow of the American College of Physicians, Dr. Freed received his Doctor of Medicine from Pennsylvania State University College of Medicine and graduate magna cum laude with a Bachelor of Arts with Distinction in Biology from the University of Delaware. Dr. Freed is Board Certified in Internal Medicine, Nephrology and Clinical Pharmacology. He performed his internal medicine residency and nephrology post-doctoral training at Temple University Hospital and Yale New Haven Hospital, respectively.

Other web-based searches suggest that Freed is now in Wellesley, Mass. It's unclear if the 50-ish doctor is retired or working.

OAD = oral antidiabetic drug. 

In what amounts to the best brief analysis of the Avandia controversy—that is, whether to keep the antidiabetic drug on the market—Daniel Carpenter, professor of government at Harvard, defines the major divisive issues that inform the FDA's upcoming review of the product. His BEST GUEST PHARMA BLOG POST PROBABLY EVER can be found at today's Pharmalot.

The battles, as defined by the prof:

• "The War Over Method"—meaning, should we continue to overwhelmingly favor the results of randomized controlled trials, which have generally downplayed Avandia's cardiac risks, or should we cling to the findings of less rigorous and inherently problematic observational studies (eg, meta-analyses), which emphasize the drug's cardiac risks? Inextricably tied to this debate is the fact that the Avandia RCTs are uniformly funded by GlaxoSmithKline, the maker of Avandia, while the most press-worthy observational studies have been conducted by an attention-loving academic (Steve Nissen) and an FDA maverick (David Graham)—both of whom may have their own axes to grind with GSK and the FDA, respectively.
• A complicating subissue in The War Over Method (although Carpenter defines this as a separate issue) is what to do with a new report from FDA reviewer Thomas Marciniak, who publicly maligned the design and analysis of GSK's RECORD trial (a trial that was intended to assess Avandia's cardiac risks). With his report, Marciniak cast a very long shadow over the integrity of all GSK-sponsored RCTs.
• The third issue that Carpenter defines is Reputation and Power—which, in my mind, is so strong an undercurrent in the Avandia debate that it merits upfront discussion. And while Carpenter primarily directs this topic at the FDA (an emphasis, not coincidentally, that markets his new book, Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA), the issue can also be applied to the motives and integrity of individual parties—like Steve Nissen and David Graham.

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).

From heartwire: Reported ambivalence about enrolling patients in the TIDE trial, a head-to-head study of rosiglitazone (Avandia; GSK) and pioglitazone (Actos; Takeda) in patients with type 2 diabetes, endangers the assessment of vitamin D supplementation.

That's because the GSK-funded and FDA-commissioned trial uses a 2-by-2 factorial design to answer 2 questions.

• Does long-term treatment with rosiglitazone or pioglitazone reduce the risk of vascular events?
• Does even longer-term treatment with vitamin D reduce the risk of death or serious cancer?

Quoted by heartwire, US principal investigator Jeffrey Probstfield said, "...I can tell you that probably at least half of the investigators in the US who signed up to do this [trial] find the vitamin D question more compelling and interesting than the rosiglitazone-vs-pioglitazone-vs-placebo issue."

If the trial is sidelined over enrollment problems (because of the controversy about rosiglitazone's safety), GSK is unlikely to support a trial assessing only vitamin D, Probstfield reasonably concluded.

A search of the NIH database reveals that, while there are several other studies assessing the possible health benefits of vitamin D, TIDE is the only trial examining the supplement's death- or cancer-preventing potential.

TIDE = Thiazolidinedione Intervention With Vitamin D Evaluation.

Worries about a rise in Guillain-Barre syndrome during the 2009 H1N1 vaccination campaign were unfounded. Only 35 cases of the acute autoimmune neuropathy were reported to the CDC or the FDA's voluntary reporting system, VAERS, at the end of last year, say researchers at the ongoing annual meeting of the American Academy of Neurology in Toronto.

The 2009 H1N1 (or swine flu) vaccination campaign began in earnest in mid-October of last year, and approximately 100 million vaccinations were administered in the United States. Consequently the rate of GBS associated with vaccination was 3.5 per 10 million. All but 1 case occurred within 6 months of vaccination; 23 cases occurred within 2 weeks of inoculation. The annual background rate of GBS is about 1-4 cases per 100,000. (The 2009 H1N1 vaccine protects against GBS, anyone?)

Original worries about a vaccine-associated increase in GBS stemmed from the observed rise in the condition during the 1976 swine-flu vaccination program.

VAERS = Vaccine Adverse Event Reporting System.

Recently detected DNA fragments of a common pig virus, circovirus type 1 (PCV1), in GSK's Rotarix vaccine have been present since the early development of the vaccine, says the FDA. The agency reported that GSK found the PCV1 DNA fragments in the "working cell bank" and viral "seed" that was used to produce the oral vaccine. Consequently the contaminated Rotarix vaccine was assessed in clinical studies, which were the basis for FDA approval. The detection of PCV1 DNA fragments does not necessarily mean that intact virus was or is present in the vaccine; moreover, the virus itself is not known to cause human disease.

How GSK learned of the presence of PCV1 DNA fragments in Rotarix is somewhat sketchy in detail. According to the FDA, an "independent US academic research team," while assessing a number of vaccines with a "new technology," detected the PCV1 DNA fragments. After finding the DNA fragments in 2 lots of Rotarix vaccine, the researchers alerted GSK on February 9th. Follow-up tests by the company confirmed the presence of the DNA fragments in the 2 tested lots, as well as samples leading back to the seed virus. GSK notified the FDA on March 10th, and the agency, as a precautionary measure, suspended the use of Rotarix yesterday.

The GSK press release provides 2 references on PCV1:

Li L, Kapoor A, Slikas B, et al. Multiple diverse circoviruses infect farm animals and are commonly found in human and chimpanzee feces. J Virol. 2010;84:1674-1682. (From the Blood Systems Research Institute in San Francisco.)

Hatterman K, Roedner C, Schmitt C, Finsterbusch T, Steinfeldt T, Mankertz A. Infection studies on human cell lines with porcine circovirus type 1 and porcine circovirus type 2. Xenotransplantation. 2004;11:284;294. (From the Robert Koch Institut in Berlin.)

Li et al used something called viral metagenomics to identify "circovirus-like" DNA sequences in stool samples of humans and wild chimpanzees. Viral metagenomics is apparently a relative new field, in which researchers attempt to recover viral DNA from environmental samples (as opposed to laboratory cell lines).* In US adults, the detection of circovirus was limited to the discovery of porcine circovirus (which is also found in most US pork products, according to the authors).

Hatterman et al reported on their infection of human cell lines with PCV1, which did not cause "any visible changes," unlike the type 2 PCV strain.

For children who require rotavirus vaccination, the FDA recommends the use of Merck's Rotateq vaccine—which is evidently not contaminated with PCV1 DNA.

* The technique may (may) be the method by which PCV1 DNA fragments were detected in GSK's Rotarix vaccine.

Image of Rotarix administration from Rotarix Prescribing Information.

03/26/10 addendum: Relying on reason and common sense, the European Medicines Agency reported today that it "sees no safety concerns with the Rotarix oral vaccine" and that the DNA of a virus that does not cause human disease "does not present a risk to public health." The EMA stressed that PCV1 is commonly found in meat and other food products.

The agency, however, requested that 1) GSK identify how the DNA fragments got into Rotarix and 2) produce a vaccine that is free of PCV1 DNA. The agency also reported that other GSK vaccines do not contain PCV1 DNA.