SILVER SPRING, MD – A Food and Drug Administration advisory panel has backed the approval of infliximab to treat ulcerative colitis in children and adolescents.
The FDA’s Gastrointestinal Drugs Advisory Committee unanimously voted July 21 that the risk-benefit profile of infliximab supported this indication. The panel based its vote on results of an open label pediatric study and extrapolation of efficacy data in adult studies to pediatric patients.
All but one panelist voted that safety concerns remained that still had not been adequately addressed, particularly with longterm treatment. Panelists were most concerned about the unclear risk of immunogenicity associated with treatment and the risk of malignancies, notably, a safety signal for hepatosplenic T-cell lymphoma (HSTCL).
Infliximab, a tumor necrosis factor blocker marketed as Remicade by Centocor Ortho Biotech, was previously approved by the FDA for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adults with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.
The manufacturer had proposed that this indication be expanded to include pediatric patients, citing an open label, single arm, 54-week study of 60 pediatric patients (median age 14.5 years) with moderate to severe ulcerative colitis, and two adult studies. In the pediatric study, 73% (44 patients) at week 8 had a clinical response to infliximab, given at a dose of 5 mg/kg intravenously at weeks 0, 2 and 6. Responders were then randomized to one of two maintenance doses.
Over an average of 38 weeks of follow-up, 23% of the patients had serious adverse events, including infection (12%), anemia (1.7%), and neutropenia (1.7%). There were no cases of tuberculosis or malignancies, which have been reported in children treated with TNF-blockers.
HSTCL has been reported in people treated with infliximab who also have been treated or were currently undergoing treatment with a thiopurine (azathioprine and mercaptopurine), according to the manufacturer.
As of April 2008, 48 malignancies in children and adolescents treated with infliximab or other TNF antagonists have been reported to the FDA’s adverse event reporting system, of which 25 were in pediatric patients with Crohn’s disease (21) or ulcerative colitis (4). Among these 25 cases were 10 reports of HSTCL. There are no known cases of HSTCL in patients treated with a TNF antagonist without a history of previous or concomitant thiopurine treatment, according to the FDA.
Panelists stressed the importance of following patients closely for malignancies and other risks associated with infliximab treatment and informing patients and their parents about the possible serious risks of treatment.
Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although occasionally a panelist may be given a waiver. At this meeting two panelists were granted a waiver because of their expertise and the "paucity" of physicians on the committee with knowledge of the subject, according to the disclosure forms posted by the FDA before the meeting.