Cephalon Sparlon Additional Pre-Approval Safety Study Recommended To Assess Skin Reaction Risk

FDA’s Psychopharmacologic Drugs Advisory Committee rules safety for modafinil product in children with attention deficit/hyperactivity disorder has not been adequately demonstrated.

Cephalon should conduct a 3,000-patient safety study of Sparlon in children with attention deficit/hyperactivity disorder to rule out a higher risk of serious skin reactions, FDA's Psychopharmacologic Drugs Advisory Committee concluded at its March 23 meeting.

"I am leaning towards recommending additional safety testing," Committee Chair Wayne Goodman (McKnight Brain Institute) said. "I don't want to do an experiment in the post-marketing arena."

Committee member Andrew Leon (Cornell University) agreed, saying "I don't feel comfortable in saying it is safe without more data."

The committee voted 12 to 1 that the Cephalon had not presented sufficient safety information for use of Sparlon (modafinil) in children with ADHD. The committee voted unanimously that the drug is efficacious in ADHD.

[Editor's note: To ¹ watch a webcast or order a video/DVD of this meeting, visit FDAAdvisoryCommittee.com.]

"The case for safety has not been sufficiently made," committee member Barbara Wells (University of Mississippi) declared.

The committee discussion focused on one case of suspected Stevens Johnson Syndrome seen in the modafinil clinical trials for ADHD. There were also four cases of suspected SJS from post-marketing data in 3 mil. adult patients. Stevens Johnson Syndrome is a potentially fatal skin reaction that occurs in about one in a million people.

There is "reasonable suspicion that this was a case of SJS related to medication exposure," committee member Daniel Pine (National Institute of Mental Health) said.

Pine said he would be satisfied if the company conducted an open-label 3,000 patient study which treated ADHD children for one month.

FDA Psychiatry Products Division Director Thomas Laughren suggested the figure of 3,000 patients to see if the rate of SJS is higher than the one in 1,000 patients suggested by the clinical trial data.

The study could try to answer the question "is this some wild weird fluke or is that the true rate," FDA Office of Medical Policy Director Robert Temple remarked.

Interestingly, the only person to vote for the adequate safety of Sparlon in ADHD was the committee consulting dermatologist Michael Bigby (Beth Israel Deaconess Medical Center) who convinced the committee that the risk of SJS with modafinil could not be ruled out.

"Given the description, nobody could say it wasn't a case of SJS," Bigby said.

SJS was one risk cited in a clinical review by Psychiatric Product Division Medical Officer Glenn Mannheim that recommended a non-approval action for Sparlon. The FDA division, however, made the drug "approvable" in October with requests for further information (² (Also see "Sparlon Risk Management Plan For Serious Skin Reactions To Be Discussed By Committee" - Pink Sheet, 22 Mar, 2006.)).

A dermatological consultant for Cephalon tried to cast doubt on the whether the SJS case was genuine.

"What I have seen so far has not convinced me" that it is SJS, Neil Shear (University of Pennsylvania) said, noting that the case looked more like erythema multiforme with a viral etiology.

While a safety study showing no additional cases of SJS could cap the rate of risk of the condition, FDA indicated that the drug still would be considered to have a one in a thousand potential risk, which would likely require a black box warning.

The committee voted against the demonstrated safety of the drug even though modafinil has been marketed in the U.S. since 1999 as Provigil for adults with excessive sleepiness associated with narcolepsy, obstructive sleep apnea and shift work sleep disorder.

Committee members pointed out that the dose being proposed by Cephalon for ADHD patients is higher than the one used in adults and the product's safety has not been previously demonstrated in the younger age group.

The committee only briefly touched on issues related to how the drug fits in with other safety concerns currently dogging ADHD drugs, such as suicidality, psychosis, aggression and cardiovascular risks. The committee agreed that the safety data for modafinil in ADHD were not sufficient to distinguish the drug from other ADHD medications with regard to those risks.

FDA's Pediatric Advisory Committee agreed at a meeting the day before the Sparlon meeting that all ADHD drugs should carry warnings on the risk of various psychiatric and cardiovascular events but that a black box warning on those risks is not warranted (³ (Also see "ADHD Black Box Warning On Psychiatric/Cardiac Events Is Unnecessary, Pediatric Committee Says" - Pink Sheet, 22 Mar, 2006.)).

-Danielle Foullon