Ethics: January 2010 Archives
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:
- Can injected botulinum toxin migrate sufficiently, especially when used for spasticity, to cause paralysis of respiratory muscles?
- Can injected botulinum toxin cause seizures?
- 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).
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."
