Heightened concern at the U.S. Food and Drug Administration (FDA) over
adverse events potentially associated with medications used to treat
attention-deficit/hyperactivity disorder (ADHD) may have played a role in
derailing final approval for the use of modafinil for ADHD.
Modafinil, which Cephalon hopes to market for ADHD under the name Sparlon,
is currently marketed as Provigil for the treatment of narcolepsy, obstructive
sleep apnea/hypopnea, and shift-work sleep disorder. However, proposed dosing
for Sparlon is significantly higher than that approved for Provigil.
After receiving Cephalon's supplemental new drug application last year and
reviewing clinical-trials data, the FDA expressed concern about the potential
for serious adverse events. The agency asked its Psychopharmacologic Drugs
Advisory Committee (PDAC) to review the Sparlon application and advise the
agency on whether the drug was efficacious and safe in pediatric ADHD.
Members of the PDAC met one day after the FDA's Pediatric Advisory
Committee convened to review the adverse-event profiles of medications
currently approved for the treatment of ADHD (see
The supplemental application for modafinil to treat ADHD was deemed"
approvable" by the FDA on October 20, 2005, after an agency
medical reviewer recommended the application be deemed not approvable because
of safety concerns. In the agency's approvable letter to Cephalon, FDA
officials cited concern over three categories of serious adverse events:
serious and potentially fatal skin reactions (Stevens Johnson syndrome),
psychiatric adverse events (such as agitation, aggression, mania, depression,
and hallucinations), and liver toxicity.
After reviewing the data, PDAC members said that of the 950 subjects in
modafinil pediatric clinical trials, they were most concerned about the one
pediatric patient who developed a blistering rash—something not reported
in adults taking the drug. While that child recovered after modafinil was
stopped, PDAC members said the case suggested modafinil, in the higher doses
used for ADHD, may be too risky to approve without further studies.
PDAC Chair Wayne Goodman, M.D., professor and chair of psychiatry at the
University of Florida, McKnight Brain Institute, said, "I'm leaning
toward recommending additional safety testing. I don't want to do that
experiment in the postmarketing arena."
Fellow committee member Andrew Leon, M.D., a professor of psychiatry at
Weill Medical College of Cornell University, added, "I don't feel
comfortable saying it is safe without more data."
The panelists voted unanimously that the data presented showed modafinil
was effective in the treatment of ADHD. However, on the safety data the panel
voted 12—1 against approval, saying the safety profile was not
The lone PDAC panelist voting in favor of approval, based on the safety
data, was dermatologist Michael Bigby, M.D., of Beth Israel Deaconess Medical
Center. He served as a voting consultant to the committee.
The PDAC panel urged the agency to request a new safety study looking at
modafinil in 3,000 children with ADHD to rule out any greater risk of serious
skin reactions. Thomas Laughren, M.D., the FDA's director of psychiatry
products, recommended the 3,000-child study to determine whether the rate of
Stevens Johnson syndrome is really about 1 in 1,000—as suggested by the
clinical-trials data—or is higher or lower.
Paul Blake, M.D., Cephalon's executive vice president for medical and
regulatory operations, noted surprise during a conference-call briefing
following the meeting. PDAC members, he said, appeared to be "caught up
in heightened concern about safety issues, made more complicated by dealing
with children and adolescents, where the emotions are even higher than with
Analysts who track the pharmaceutical industry, including Morgan Stanley's
Marc Goodman, noted that the drug's final approval for ADHD could be delayed
as much as two years.
More information on the application to market modafinil for ADHD and
the FDA's review are posted at<www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4212B1-index.htm>.▪