Side-Effect Concerns Delay Approval of ADHD Drug

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 Original article: page 1).

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 acceptable.

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 adults.”

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>.▪