Michael Fitzpatrick, M.S.W., executive director of the National Alliance
on Mental Illness, describes the upcoming "report card" that will
grade all state mental health systems. See
The Psychopharmacologic Drugs Advisory Committee (PDAC) of the Food and
Drug Administration (FDA) recommended last month that the agency approve a new
drug application for a methylphenidate skin patch.
The approval advice was qualified, however, by the committee's
recommendation that the drug be relegated to "second-line"
status—to be used only after patients with
attention-deficit/hyperactivity disorder (ADHD) have responded well to oral
The PDAC members, said committee chair Wayne Goodman, M.D., a professor of
psychiatry at the University of Florida, were concerned in particular about
skin reactions in persons wearing the new methylphenidate patch.
"Given the uncertain knowledge regarding the risks of
sensitization," Goodman said, oral forms should be tried before the
methylphenidate patch is prescribed.
The committee recommended that language be used that mirrors wording in the
label for ziprasidone (Geodon), which urges physicians to consider other
antipsychotics before prescribing ziprasidone due to concern that ziprasidone
slows down steps in the heart's conduction cycle (resulting in a prolonged
However, PDAC members voted 11-1 to reject a proposal to restrict
prescribing of the patch to "those patients who are unable to take oral
The methylphenidate transdermal system (MTS) was developed by Noven
Pharmaceuticals and will be marketed jointly by Noven and Shire
Pharmaceuticals under the proposed trade name Daytrana. The MTS is indicated
for treatment of ADHD in children and adults. After a daylong public advisory
committee hearing, the FDA indicated it hoped to make a final decision on the
product near the beginning of 2006. (No decision had been made as this issue
of Psychiatric News went to press.)
The PDAC's concerns were not surprising, given the overall negative tenor
of the briefing documents posted on the agency's Web site the day before the
hearing. The FDA's internal review of the application was capped by a"
not approvable" recommendation by FDA medical and safety clinical
reviewer Robert Levin, M.D.
Levin wrote in his review of the companies' clinical-trials data,"
Treatment with MTS was associated with a high incidence of insomnia,
anorexia or decreased appetite, headache, and gastrointestinal symptoms
including vomiting, nausea, and upper abdominal pain."
In addition, Levin wrote, "these adverse events were significantly
more common in the MTS group than in the active comparator group (McNeil's
Concerta brand of extended-release methylphenidate) and the placebo
Pharmaceutical industry analysts who spoke with Psychiatric News
said that officials at Noven and Shire seemed to be taken off guard by the
latest negative review. Noven had originally submitted the application in June
2002. After the FDA issued a "not approvable" letter in April
2003, Noven and Shire proposed conducting further laboratory and clinical
trials to answer the FDA's concerns. The companies resubmitted the amended
application on June 28, 2005, with the new data included.
In a phase-III clinical trial conducted by Noven/Shire, 270 patients were
randomized to the MTS patch, the Concerta brand of extended-release oral
methylphenidate, or placebo. Insomnia occurred in 13 percent of those on the
patch compared with 8 percent on extended-release oral methylphenidate and 5
percent taking placebo. With the MTS patch, 26 percent of patients had
decreased appetite compared with 19 percent of those on extended-release oral
methylphenidate and 5 percent of those on placebo. These differences are
Noven and Shire argued that the rates of adverse effects on MTS were
similar to those reported with other methylphenidate products. Indeed,
decreased appetite, anorexia and potential weight loss, headache, and
gastrointestinal symptoms have been associated with methylphenidate for more
than 50 years.
FDA's Levin had no problems with the drug's efficacy, however. He wrote in
his review that the new clinical data confirmed a statistically significant
reduction in ADHD symptoms measured on standardized scales. In the new data (a
phase-III trial), for example, total ADHD Rating Scale-IV scores fell an
average 24.2 points for those wearing the MTS patch, compared with a 22-point
reduction for those taking extended-release oral methylphenidate. Compared
with placebo, MTS patients saw a 13.9 point drop in total score compared with
11.3 points for those taking the oral formulation.
What created the biggest surprise, however, were Levin's comments at the
public advisory meeting, during which he reversed his own recommendation.
Shortly into the meeting, Levin told panel members he was recommending
approval of the application.
"One of the main reasons for changing my recommendation," Levin
told PDAC members, "is that there are more data now available."
His thinking on the approval changed, he added, because "it is clear
that almost all, if not all, of these adverse events—other than
skin-sensitization events—are consistent with those" known to be
associated with other forms of methylphenidate.
While there were differences numerically between the occurrence of adverse
events in the three groups, Levin said at the hearing, "it was not a
statistical difference. Upon further review, I don't think it's a widely
different range of adverse events."
FDA's briefing documents on the methylphenidate patch approval
application are posted at<www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4195B-index-with-disclaimer.htm>.▪