Recently in FDA Category

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:

1. Can injected botulinum toxin migrate sufficiently, especially when used for spasticity, to cause paralysis of respiratory muscles?
2. Can injected botulinum toxin cause seizures?
3. 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).

While plowing through Novartis's newly released financial report for 2009, I found this quiet gem: the "dossier" for Gilenia, the proposed trade name for fingolimod or FTY720, was submitted to the FDA and the European Medicines Agency in December. Now by "dossier," I assume that the company means its new drug application for the investigational compound; certainly the media are reasonably interpreting dossier as NDA.

This under-the-radar news of the NDA submission comes as a surprise—not because the fingolimod NDA was submitted (that was actually expected back in December), but because the news was provided so sotto voce.* I merely stumbled across the information while I was looking for more dirt on the company's recent Trileptal plea agreement.

And just in case I missed news of the NDA submission back in December (despite blogging semi-feverishly about the race between Novartis and Merck Serono to market the first-ever disease-modifying pill for multiple sclerosis), I rechecked the Google news archives. Nope, nothing.**

So the question is: Why no big announcement of the Gilenia NDA submission, Novartis? In typical fashion, Merck Serono trumpeted the submission of its NDA for the fast-track approval of oral cladribine in September.

Perhaps the answer has something to do with the FDA's December announcement that it refused to file Merck Serono's cladribine NDA. But I have to admit: I'm kind of flummoxed.

* Not to mention, a month after it happened.

** Although, last week, both Dow Jones and Reuters reported Novartis's NDA submission of fingolimod. I am mentally flaggellating myself for missing these reports.

While the FDA and Allergan remain at an impasse on how to disseminate off-label safety information for Botox, the American Academy of Neurology (AAN) just published its recommendations for use of the toxin in children with spasticity due to cerebral palsy (CP).*

On the basis of 14 20 controlled studies (N = 573) in which botulinum toxin A was assessed in children with CP-related limb spasticity, the AAN recommends injections for localized arm or leg spasticity "that warrants treatment." Although, the Academy writes, "There is insufficient evidence to support or refute the use of [botulinum toxin A] to improve motor function in this population."

In its safety assessment, the AAN found the most common treatment-related adverse events to be localized pain, excessive weakness, unsteadiness, increased falls, and fatigue. A few patients experienced urinary incontinence (n = 5) or dysphagia (n = 2). All adverse events were transient and did not require hospitalization or cause death—despite the fact that, last year, the FDA announced postmarketing reports of toxin spread, which compromised breathing and possibly led to death. The agency continues to investigate these cases.

According to lead author of the AAN guidelines, Mauricio Delgado, CP is the most common cause of spasticity in children, and most children with CP have spasticity. In Western nations, the prevalence of CP among 8-year-olds is 0.36%.

* An unapproved use.

In the neck-and-neck race to market the first-ever disease-modifying pill for multiple sclerosis, both Novartis and Merck Serono scored by getting their respective pivotal trials of fingolimod and cladribine published in the venerable NEJM this week. (For background, start at last year's No. 8 story.)

And because I like to make comparative tables, here's another one providing the salient features of the 3 studies—all of which enrolled patients with relapsing-remitting MS.

Study Features	FREEDOMS	TRANSFORMS	CLARITY
Phase	3	2	3
Drug	Fingolimod 0.5 or 1.25 mg/d	Fingolimod 0.5 or 1.25 mg/d	Cladribine 3.5 or 5.25 mg/kg*
Comparator drug	Placebo	IM interferon-beta 1a 30 µg/wk	Placebo
Duration	24 months	12 months	96 weeks
Enrollees	1272	1292	1326
Completers	1033 (81%)	1153 (89%)	1184 (89%)
Annualized relapse rate (primary outcome)	55% or 60% ↓	39% or 51% ↓	54% or 58% ↓
Major secondary outcomes	26% or 31% ↓ disability progression; significant ↓ MRI lesions	No difference in disability progression	~30% higher relapse-free rate; significantly ↓ 3-month disability progression and MRI lesion burden
Notable drug-related adverse events	Bradycardia, AV block, macular edema, high liver enzymes, mild HTN	Fatal infections,** nonfatal herpes, bradycardia, AV block, HTN, macular edema, skin cancer, high liver enzymes	Lymphocytopenia, herpes zoster

* 2-4 "short" courses for the first 48 weeks, then 2 short courses starting at weeks 48 and 52 (total treatment, 8-20 days/year).
** Two in high-dose group: disseminated primary varicella zoster and herpes encephalitis.

What's the take-home?

Although trial-to-trial comparisons are problematic, both drugs appear to have comparable and significant efficacy. Novartis, developer of fingolimod, has an edge owing to its phase 2 study with the standard MS treatment of interferon beta.

But the uptake of these drugs, once they are approved (and I predict they will be...eventually), will likely depend on their safety profiles. Fingolimod, in particular, is associated with some wicked side effects.

AV = atrioventricular; CLARITY = Cladribine Tablets Treating Multiple Sclerosis Orally; FREEDOMS = FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; HTN = hypertension; TRANSFORMS = Trial Assessing Injectable Interferon Versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis.

Yesterday, James Beck over at the Drug and Device Law blog provided an update on Allergan v the United States of America et al—last year's No. 5 story at this-here Pathophilia blog. I completely missed it, but 4 days ago the government responded to Allergan's "free-speech" complaint of last year with its own "45-page whopper" (Beck's words) of a motion to dismiss or for summary judgment.

Plowing through the document, my non-legal mind distills the government's 2 basic counterarguments to Allergan "free-speech" complaint to the following.

1. The argument for dismissal: The case isn't "ripe"—meaning, Allergan hasn't said anything yet to potentially violate the law. Of course, this argument highlights the double bind in which the FDA has put the company. Allergan has been asked by the agency to publish safety information about the off-label use of Botox for spasticity; but Allergan logically fears that if it does so, it will run afoul of federal law that prohibits drug promotion for off-label purposes. Allergan's fear is justified by text in the government's own motion, which reads, "advertisements for prescription drugs may not 'recommend or suggest' the drug for unapproved uses."

But the government allows itself a little wiggle room, by also stating, "It is critical to understand, however, that not all speech or actions by a manufacturer regarding an unapproved use is taken by the FDA to be evidence of intended use." However, I find the government's extended argument confusing: "Absent promotion, the dissemination of safety information relating to an unapproved use would not establish that the use is an intended use, and therefore would not trigger either the new drug approval process or the misbranding provisions of the FDCA [Food, Drug, and Cosmetics Act]."

The crux of the issue seems to be whether safety information regarding the off-label use of a drug, on its face, promotes a drug for that off-label use. The government says not necessarily. (In other words, "Hey, trust us. We won't prosecute you for something we ask you to do...unless we decide you've gone too far."). But again, how can a company know when off-label safety information constitutes illegal promotion before it potentially breaks the law?

2. The argument for summary judgment: Allergan's suit is a "frontal assault" (not a full-frontal assault?) on the 1962 Harris-Kefauver Amendment to the FDCA, which requires that a company prove the efficacy of a prescription drug for a particular indication before it can be promoted and sold in interstate commerce. The government lays out a series of contradictory (at least to me) arguments, while invoking a couple of metaphors from Greek mythology (to Beck's amusement).

Essentially the government claims a) current regulatory laws restricting commercial speech are Constitutional, and 2) if it prevailed, Allergan's complaint would allow the promotion of drugs for unapproved uses, thus placing the public health in jeopardy. Beck parses out the government's arguments in reader-friendly bulleted fashion and provides pointed commentary (like a parsimonious "Wow").

But what gets me (again) are the government's incongruous or ambiguous statements, which (as Beck points out) emphasize the vagueness of regulations that restrict the speech of a drug company—and specifically, 21 § CFR 201.128 regarding intended uses. The government writes stuff like...

The Act and regulations leave ample room for Allergan to disseminate truthful, non-promotional information about dangers associated with unapproved uses of Botox, above and beyond the information that FDA has already directed Allergan to provide. [emphasis added]

Okay, the issue again: How do we distinguish between promotional and nonpromotional information?

Well, try this head-spinner on intended uses:

When a manufacturer engages in speech such as advertising or promotional labeling that expressly or implicitly promotes a particular use, FDA treats such speech as evidence that the use is intended. [emphasis added]

Oy.

Beck's even more impressed with the vagueness of this statement.

In practice, FDA usually does not treat an unapproved use as an intended use solely because the manufacturer knows that the unapproved use is taking place.

Usually. [shudder] 

But all of this legal maneuvering between Allergan and the FDA may be moot (or "moo," as Joey on "Friends" would say*), according to the government's motion. In August 2008, Allergan submitted a supplemental biologics license application (sBLA) for the use of Botox in upper-limb spasticity after stroke—one of the off-label indications at issue. However, in May 2009, the FDA declined to approve the drug for the new indication, citing application deficiencies. Then 4 months later, Allergan resubmitted its sBLA. The "goal date" for the FDA's decision, per the motion, is April Fool's Day.

So is the government saying, "Wait. Give us time to approve Botox for spasticity, and this whole free-speech mess we've created will go away"?

N.B. A motion hearing in Allergan v the United States of America et al (09-cv-1879) is still scheduled for March 2nd, in the US District Court for the District of Columbia.

* Which is just about the only funny thing that was said on "Friends."

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."

No. 8: The Approval Race for an MS Pill

In 2009, Novartis and Merck Serono became the main contenders to market the first-ever pill for relapsing-remitting multiple sclerosis (RRMS).

Aaaaand they're off. Quickly way out, in the middle of the track, Merck Serono takes the early lead.

In January, Merck Serono described favorable 2-year data from an extension phase of its placebo-controlled phase 3 study (CLARITY) of an oral form of cladribine.*

He's challenged on the outside by Novartis, as they race into the turn.

Several months later, Novartis announced positive data from its phase 3 study, in which the novel oral agent, fingolimod, outperformed the standard treatment (not placebo) of IM interferon beta (Avonex; Biogen Idec).

Novartis moving up on Merck Serono as they round the turn.

In August, the FDA announced the approval of Novartis's copycat version of Betaseron (interferon beta-1b; Bayer Schering) for RRMS. Approval came by way of an intricate manufacturing deal with Bayer Schering that began 2 years ago and was apparently intended to prime Novartis's sales team in the MS market.

In the stretch. It's Merck Serono still in front. Merck Serono by a length and a half.

In October, Merck Serono announced its NDA submission for the fast-track approval of oral cladribine for RRMS.

But here comes Novartis on the outside. Novartis comin' after him.

The same day, Novartis announced positive data from its 2-year placebo-controlled phase 3 study of fingolimod in more than 4000 individuals with RRMS (FREEDOMS).

Also getting involved is Teva and Biogen Idec, and looking for a hole on the inside is sanofi-aventis. 

Other novel oral compounds in late-stage development for MS include Teva's laquinimod, Biogen Idec's dimethyl fumarate, and teriflunomide from sanofi-aventis.

Oh, going down now, going down, Merck Serono. Merck Serono takes a spill.

In December, the FDA announced that it refused to file Merck Serono's NDA for oral cladribine, probably on the basis of an incomplete application. The company said that it would request a meeting with the FDA to understand any deficiencies in its application.

Novartis had previously announced that it would file its NDA for fingolimod by the end of the year, but it doesn't look like that's going to happen.

The race isn't over.

CLARITY = Cladribine Tablets Treatment MS Orally; FREEDOMS = FTY740 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; NDA = new drug application.

* Cladribine, a purine analog, has been marketed as the injectable Leustatin [Ortho-Biotech] since 1993 for hairy cell leukemia.

No. 9: Belimumab Buzz

There were few notable FDA approvals for "new molecular entities" (NMEs) in 2009:

• Urolic (febuxostat; Takeda) is the first new treatment for gout in more than 40 years. (But come on: it's gout.)
• Simponi (galimumab; Centacor/Ortho Biotech) is yet another TNF inhibitor for rheumatoid arthritis.
• Effient (prasugrel; Lilly) is an antiplatelet therapy poised to take market share away from chemically related Plavix (clodigrel; BMS/sanofi-aventis)—but only in the setting of angioplasty and stent placement.
• Sabril (vigabratin; Lundbeck) is the first anticonvulsant approved for the treatment of infantile spasms, a rare and devastating form of pediatric epilepsy.

And there were drugs approved for even rarer disorders: Ilaris (canakinumab; Novartis), for the cryptic cryopyrin-associated periodic syndromes; and Kalbitor (ecallantide; Dyax) for hereditary angioedema. Add to those: approvals for yet another statin, another fluoroquinolone, another antidiabetic agent...and you get the idea of the ho-hum-ness of 2009.

In pharma, expectations currently run low for groundbreaking treatments, whether for rare or common disorders. One exception, however, may be Benlysta (belimumab). The human monoclonal antibody, codeveloped by Human Genome Sciences and GSK, inhibits the activity of B-lymphocyte stimulator (BLys), which otherwise promotes the survival of antibody-producing B cells. The drug's mechanism of action supports its use in autoimmune disorders, like systemic lupus erythematosus (SLE).

To that end, favorable data from 2 phase 3 trials of Benlysta (BLISS-52 and BLISS-76) in patients with SLE were reported in July and November. The positive clinical data are notable, because there hasn't been a new treatment for the 1.5 million Americans with lupus in about 30 years, says the Lupus Foundation of America. Even the almighty Rituxan (rituximab; Genentech/Roche) bit the dust this year in phase 3 studies of patients with SLE. And another great hope for SLE, CellCept (mycophenolate mofetil; Roche), died a death of noninferiority after it performed no better than cyclophosphamide for the induction treatment of lupus nephritis.

Excitement over Benlysta should be tempered, however, by the fact that neither phase 3 study has been published in a peer-reviewed journal—yet. Human Genome Sciences indicates that applications for the approval of Benlysta in the United States and Europe will be submitted during the first half of 2010. 

TNF = tumor necrosis factor.

After 13 years as the number-one prescription treatment for Alzheimer disease, Aricept—a branded cholinesterase inhibitor that generated nearly $1.9 billion in US sales this year for its Japan-based developer Eisai and US comarketer Pfizer—is now (officially) available generically in the United States.

Yesterday the FDA announced the approval of a generic formulation of Aricept (or more correctly, donepezil) in orally disintegrating tablets. The generic manufacturer is the privately owned Mutual Pharmaceutical (URL Pharma), which will produce the drug in 5- and 10-mg strengths.

Other branded, FDA-approved treatments for AD include the NMDA-receptor antagonist memantine (Namenda; Forest) in tablets or solution and the cholinesterase inhibitors galantamine (Razadyne; Ortho-McNeil) in extended-release capsules, tablets, or solution and rivastigmine (Exelon Patch; Novartis). The patent for galantamine, originally marketed as Reminyl in the United States, expired in December 2008, and the drug is available generically in its various formulations.

According to the FDA's Orange Book, the following patent and exclusivity expirations apply to Namenda and Exelon*:

Drug	FDA Approval	Patent Expiration	Exclusivity Expiration
Namenda tablets	Oct 16, 2003	Apr 11, 2015	Oct 16, 2008
Namenda solution	Apr 18, 2005	Apr 11, 2015	Oct 16, 2008
Exelon patch	Jul 6, 2007	Aug 14, 2012	Jul 6, 2010

(Differences between a drug's patent and exclusivity are explained by the FDA here.)

On November 24, Eisai announced that the FDA accepted for review its NDA supporting the use of a 23-mg extended-release tablet version of Aricept in AD. The NDA is based on a head-to-head study (N > 1400) between the new formulation and the old Aricept 10-mg tablet. This study, apparently, has not been published yet in a peer-reviewed journal. In its 2009 report, Eisai also reveals that it is developing transdermal patch and jelly formulations of Aricept.

Very recent controlled studies of immediate-release Aricept in patients with amnestic mild cognitive impairment (aMCI) suggest that the drug delays the progression to AD among depressed individuals, but Aricept had only a modest effect on cognition in a more inclusive population with MCI.

NDA = new drug application; NMDA = N-methyl-D-aspartate.

* Rivastigmine is generically available in capsules; however, this formulation is no longer marketed by Novartis. It is also reported that Forest applied for a "patent term restoration" for Namenda, which would extend protection until September 2013.

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism. 

In an effort to market the first FDA-approved oral treatment for multiple sclerosis, Merck Serono may have submitted an incomplete NDA for cladribine. The suggestion is provided by the consistently informative and entertaining* In Vivo Blog.

Although the FDA has not publicly addressed its refusal to file Merck Serono's cladribine NDA, the agency's John Jenkins, director of the Office of New Drugs, provides a hint, according to the blog. Yesterday, during the FDA/CMS Summit, Jenkins addressed the agency's refuse-to-file notifications and a primary reason for drawing them up.

Jenkins implicitly chastised pharma for submitting incomplete NDAs and then providing additional information during the drug-review process—which may require an extension owing to the lack of necessary data.** Jenkins reportedly said that pharma execs who delay the submission of an NDA to ensure its completeness will ultimately save themselves time.

NDA = new drug application; PDUFA = Prescription Drug User Free Act.

* Hey, In Vivo Blog, you can quote the flattery.

** And thereby violates the 6-month "PDUFA clock."