California trial will focus on safety of botox as treatment for cerebral palsy

From the Los Angeles Times:

Kristen Spears (pictured) started getting Botox injections at the age of 6 -- not to smooth furrows in her brow, but to calm spasms in her legs.

The girl was born with severe cerebral palsy, and Botox, best known as a face-lift-in-a-syringe, can relax contorted muscles and sometimes help young patients walk without surgery.

Instead, Kristen's mother alleges, an overdose of the drug killed her.

Opening arguments in a negligence lawsuit by Dee Spears against Botox manufacturer Allergan Inc. are set for today in Orange County.

At issue is the safety of the blockbuster drug, especially in the higher dosages that are used to treat children with cerebral palsy.

It is believed to be the first Botox case alleging a fatal reaction to reach trial, and is one of several pending suits related to the drug's cosmetic and non-cosmetic uses.

The trial comes less than a year after federal authorities mandated "black box" labels that warn of potentially serious reactions to Botox. And it opens a window on the Irvine-based drug maker's own records of reported ill effects, showing that the company knew of some serious problems linked to neurotoxins such as Botox as early as 2005.

Allergan declined to comment on the trial. In a court motion, Allergan says that Kristen died of a bacterial infection and that her mother cannot prove Botox killed her.

When the suit was filed, a spokeswoman characterized the drug's safety record as "remarkable." Serious side effects, she said, were rarely reported in more than 15 million treatments over two decades.

In a confidential 2008 report to federal regulators, Allergan said it found that the risk of death among children with cerebral palsy was low and that fatalities often resulted from underlying poor health.

Approved in the United States specifically to treat frown lines, crossed eyes and other conditions, Botox yields $1.3 billion in annual sales. But the drug can be legally prescribed at doctors' discretion for a variety of other purposes, including cerebral palsy. It is also specifically approved for cerebral palsy in many other countries. Its use for that condition alone contributed $47 million to Allergan's bottom line in 2007.

The drug uses botulinum toxin, a powerful poison, to block neural communications, allowing muscles that produce worry lines or gnarled limbs to relax. A few injections smooth wrinkles, while larger doses are required to relax arms and legs.

Kristen died in November 2007 of respiratory failure and pneumonia, according to her death certificate. Experts hired by Dee Spears say Botox weakened muscles that controlled her breathing and swallowing, leading to respiratory failure and pneumonia.

Kristen's death came more than a year before the U.S. Food and Drug Administration ordered the labels warning of the drug's potential to cause botulism symptoms, including "potentially life-threatening swallowing and breathing difficulties and even death."

At the same time, the agency required Allergan to notify physicians that the toxin could spread beyond the injection site and to prepare a patient guide saying that it was not known whether Botox was safe for children or for other patients whose conditions it had not been approved to treat.

Spears alleges that Allergan knew problems had been reported at least two years before Kristen died. What's more, she alleges, Allergan encouraged Kristen's pediatrician to treat cerebral palsy patients with Botox and helped with his training.

"I don't want this to happen to anyone else's child," she said in a statement.

In preparation for the trial, Allergan was required to produce safety assessments of Botox and other confidential internal reports. Portions of some documents were obtained by The Times after Orange County Superior Court Judge Ronald L. Bauer unsealed them.

The documents include a 2005 letter sent by a European health official that alerted Allergan of reports that botulinum toxin had spread beyond the injection site among patients who sought cosmetic treatment. There was at least one similar drug manufactured by another company in the European market, and the letter did not specify which products the reports related to.

Trouble with swallowing and "aspiration have been reported to occur secondary to muscle weakness in the muscle in the neck region," the letter says. "Fatal cases of aspiration have been reported."

In a confidential response dated Sept. 16, 2005, Allergan said its internal database contained 436 "serious adverse event" reports related to Botox.

Of those, 201 were "serious, healthcare professional-confirmed cases with events possibly due to remote spread of the toxin," including 42 after facial wrinkle treatments.

Also in 2005, documents show, Allergan sent a confidential report to the FDA, saying that an analysis identified 38 patients -- 20 children, most of them with cerebral palsy, and 18 adults -- who had suffered seizures after Botox injections.

In May 2007, European regulators asked Allergan and two competitors to add information to labels and warn doctors that the toxin could spread, causing botulism symptoms.

Two months later, on July 16, 2007, consulting firm BioSoteria Inc., in a confidential report to Allergan, identified 207 patients with medical problems, including several deaths, associated with the spread of toxin.

A third of the cases identified by BioSoteria occurred in people treated for wrinkles; the rest were treated for muscle spasms, muscle spasticity and eye problems. Proportionally more problems were reported among children.

Kristen's care proceeded as such reports flowed into Allergan, according to depositions and documents filed in court.

The Amarillo, Texas, pediatrician who treated Kristen said in a deposition that he learned to use Botox on children with cerebral palsy at Allergan-sponsored seminars in 2000 and 2001.

Dr. Rolf Habersang, who is a critical care pediatrician and medical professor at Texas Tech University, and his nurse practitioner wife, Pia, both testified that they believed that Allergan arranged and paid for them to fly to an Irving, Texas, seminar.

Allergan also sent Habersang to Little Rock, Ark., to train with a pediatric neurologist, the Habersangs said.

The doctor testified that he learned to dose children with 15 units of Botox per kilogram of body weight.

That is nearly twice the maximum dosage that Allergan considers safe for children, according to the deposition testimony of Allergan executive and neurologist Mitchell Brin.

But, Brin testified, the company never shared its maximum dosage information with physicians because of a federal ban on marketing for non-approved uses that it believed prohibited such communications.

Still, Allergan's sales agents discussed the use of Botox for juvenile cerebral palsy patients with the Habersangs repeatedly, visiting the practice about 50 times over several years, according to motions and depositions.

One sales agent told the Habersangs that other physicians were using Botox "in the range of 10 to 15" units per kilogram, Pia Habersang said in her deposition.

Allergan said in a court motion that Rolf Habersang was aware of the risks of Botox when he treated Kristen, although Habersang testified that he was unaware of the reports of seizures and breathing, swallowing and other difficulties among pediatric cerebral palsy patients. He said he would have shared such information with parents.

In June 2006, the suit alleges, Kristen's health was stable. Over the next 15 months, the 33-pound girl got seven Botox treatments in her legs, groin and chest.

Kristen's health deteriorated dramatically, the suit alleges.

Already subject to seizures, Kristen got them more frequently, and they got worse, according to one motion.

She was hospitalized 10 times for repeated bouts of breathing and swallowing difficulties and pneumonia, it says.

About six weeks after her last treatment, Kristen stopped breathing.

She died on Nov. 24, 2007, at the age of 7.