By Emily P. Walker, Washington Correspondent, MedPage Today
Published: August 20, 2010
BETHESDA, Md. -- A federal advisory panel voted 20-2 to recommend that the FDA not grant approval for an expanded indication for sodium oxybate (Xyrem) -- also known as GHB -- to treat fibromyalgia.
A number of members on the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committees felt the potential for widespread abuse of the "date rape" drug was too great to warrant expanding the indication to a condition that affects an estimated 2% of the U.S. population.
Sodium oxybate, currently approved at a 500 mg/ml dose for narcolepsy-associated cataplexy and excessive daytime sleepiness, is a central nervous system depressant and carries a boxed warning against its use in combination with other similar drugs.
The label information also warns that sodium oxybate is a drug known to be abused. Sodium oxibate is a sodium salt of y-hydroxybutyrate, or GHB.
"Right now it's viewed as a drug for a very rare condition, and that is not fibromyalgia," said panelist Thomas Kosten, MD, professor of psychiatry and addiction at Baylor College of Medicine in Houston. "We've gone from a micro, tiny population, to something that's going to affect a huge population.
"Should we be giving LSD to people because it improves their psychotherapy? Should we give marijuana to people because it improves their well-being?" Kostan said. "What are we thinking?!"
Other panelists weren't as worried -- or as agitated -- as Kostan over the potential for abuse, but they noted that the drug's maker, Jazz Pharmaceuticals, failed to convincingly prove the drug worked. Others were concerned about the odd dosing mechanism of the drug.
The vote came at the end of an unusually tense joint advisory board meeting during which one panelist sparred with an FDA official; fibromyalgia patients pleaded with the panel to give them access to a drug they said helped save them from lives filled with pain; and drug abuse prevention advocates urged the FDA not to add another indication to sodium oxybate out of fear it will increase the amount of GHB on the streets.
Panelists Question Effectiveness Data
Although narcolepsy is a rare disorder, fibromyalgia effects about five million people, or 2% of the U.S. population, according to FDA staff reviewers in briefing documents prepared for the panel. However, if approved, the sodium oxybate would be used in far fewer patients, Jazz Pharmaceuticals argued, largely because many patients would be scared off by all the safety warnings and by horror stories they've heard about GHB.
The committee examined the company's two randomized, double-blind, phase III trials testing sodium oxybate versus placebo.
In one of the trials, involving 548 patients randomized to placebo or to 4.5 g or 6 g per night of the drug, researchers reported the following improvements relative to baseline:
Pain visual analogue scale (VAS) score: placebo, -18 points; low drug dose, -29 points; high drug dose, -32 points (P<0.001 for both doses)
Fatigue VAS score: placebo, -17 points; low drug dose, -28 points; high drug dose, -30 points (P<0.001 for both doses)
Jenkins Sleep Scale score: placebo, -2.9 points; low drug dose, -6.1 points; high drug dose, -6.2 points (P<0.001 for both doses)
At Friday's meeting, FDA staff said there was no question that the drug was effective, but panelists weren't so sure.
For starters, several panelists rejected the idea that a true placebo could exist in Jazz's trials -- or in any trial testing a "hypnotic sedative." One patient who was enrolled in the Jazz trial told the panel she knew she received the test drug from the onset.
"From the very first dose, I knew this was no placebo," patient Barbara Gehr told the panel. She was bedridden for eight months with pain from fibromyalgia before enrolling in a Jazz sodium oxybate trial.
Patients taking the drug pass out almost immediately, with no time to even "send an e-mail" as another patient put it.
Dosing Raises Red Flags
Panelists were also concerned with the unusual dosing mechanism. The drug has an extremely short half-life, so patients must take one dose at bedtime, and set their alarm clocks to wake up and take a second dose four hours later.
The dosing apparatus also has the potential for confusion, panelists pointed out. Patients must empty a solution into a small cup and mix it with water. Several people in the study accidentally took a double dose.
A pediatrician on the panel said she was concerned that children could accidentally ingest the drug, even though the dosing devices are "childproof." Patients might prepare their second dose and set it next to their bed in order to easily take it in the middle of the night, she suggested.
Panel chairwoman Kathleen O'Neil, associate professor of pediatrics at the University of Oklahoma College of Medicine in Oklahoma City, said she worries a child might walk in and take the drug, "because mommy's out cold." (Fibromyalgia is more common in women).
Public Testimony Also Heated
GHB was sold without a prescription in health food stores until 1990 when it was classified as a controlled substance by the FDA. Despite the classification, emergency room visits for GHB increased 100-fold in the '90s. However, abuse has dramatically decreased since then said Janne Wissel, chief regulatory and compliance officer of Jazz.
A drug addiction physician who testified at the hearing disagreed. Alex Stalcup, MD, medical director of the New Leaf Treatment Center, in Lafayette, Calif., said emergency room data on dramatic decreases can't be trusted because GHB is nearly impossible to detect in a toxicology screen, and thus often isn't fingered as the cause of hospital visits.
Stalcup said he's seen a significant increase in people with GHB dependence, almost all of whom were introduced to GHB via Xyrem.
"GHB use is not down based on our stats; it just remains ignored due to testing difficulties," said Trinka Porrata, director of the drug abuse prevention organization, Project GHB. "I consider it the drug from hell having been a cop for 10 years," said Porrata, who spoke during the public comment portion of the meeting. "Approving this will create a new batch of addicts and deaths."
To counter the potential for abuse, Jazz proposed a stringent risk managment program to prevent sodium oxybate from hitting the street.
As is often the case at FDA advisory committee meetings focusing on a drug with a history of abuse, speakers at the public portion the fell into two camps: Those who focus on the potential for widespread misuse and abuse, such as Porrata and Stalcup, and those who say the drug changed their lives for the better.
In that second camp were testimonies like those of fibromyalgia patient Susan Christ, who enrolled in one of Jazz's sodium oxybate trials after a crippling lack of energy and constant pain left her unable to complete daily tasks. After taking the drug and finally being able to get restorative sleep, she said her life was changed -- finally "full and enriched."
"Sodium oxybate was closest to a cure of anything I've found," she said. "Now that the drug study is concluded, my life has began to collapse a bit."
In a statement released following the committee vote, Bruce Cozadd, chairman and CEO of Jazz expressed disappointment with the recommendation, but said the company plans "to work closely with FDA on the continuing review of our new drug application. We will carefully consider the input of the Committee as we seek to address the needs of fibromyalgia patients for new treatment options in a safe and responsible way."
The FDA is not required to follow the advice of its advisory committees, but it often does.
My oh my, I'm surprised the panelists could even think straight, what with all the wailing and gnashing of teeth from the likes of Trinka Porrata and Thomas Kosten.
Never let objective reasoning get in the way of good ol' hysterical demonisation.