Insufficient Substantial Evidence of Effectiveness for Cataplexy Indication
Severity: criticalThe NDA submission does not provide substantial evidence of effectiveness to support the approval of pitolisant for the treatment of cataplexy in adult patients with narcolepsy. Analyses of HARMONY I were deemed inadequate due to issues with secondary endpoint analysis, post-hoc subgroup definition, and handling of missing data. While HARMONY CTP was viewed as positive, it had significant weaknesses (small size, conducted exclusively in Eastern Europe, generalizability concerns) and could not, by itself, provide sufficient evidence. A second confirmatory trial is required.
Recommended response: Conduct a new, adequate, and well-controlled randomized, double-blind, placebo-controlled, fixed-dose trial for cataplexy, enrolling a meaningful fraction of U.S. patients, to substantiate the results of HARMONY CTP.
Cited: FDA has concluded that your NDA submission does not provide substantial evidence of effectiveness to support the approval of pitolisant for treatment of cataplexy in adult patients with narcolepsy.
Labeling Comments Reserved Pending Clinical Resolution
Severity: minorThe FDA reserves comment on the proposed labeling until NDA 211150/Original 2 is otherwise adequate. If labeling is revised, the response must include updated content in Structured Product Labeling (SPL) format.
Recommended response: Prepare to revise and resubmit labeling in SPL format once clinical deficiencies are addressed and the application is otherwise adequate.
Cited: If you revise labeling, your response must include updated content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format as described at FDA.gov.
Comprehensive Safety Update Required Upon Resubmission
Severity: majorUpon responding to the deficiencies, a comprehensive safety update is required as described at 21 CFR 314.50(d)(5)(vi)(b). This includes detailing significant changes in safety profile, presenting new safety data from all studies/trials (for proposed and other indications), tabulating combined new and original data, comparing frequencies, providing case report forms and narratives for deaths/discontinuations/serious adverse events, describing changes in common adverse events, providing updated exposure information, and summarizing worldwide safety experience with English translations of foreign labeling.
Recommended response: Compile and analyze all new safety data, prepare detailed reports, narratives, and updated tabulations as per 21 CFR 314.50(d)(5)(vi)(b) for inclusion in the resubmission.
Cited: When you respond to the above deficiencies, include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b).
