Variation in Endpoints in FDA Medication Approvals: A Review of Acute and Preventive Migraine Medications.

Abstract

To assess the characteristics and extent of variation of the endpoints used in trials supporting the US Food and Drug Administration (FDA) approval of medications treating migraine. Using the Drugs@FDA online database, we identified novel prescription medications approved by the FDA between January 2001 and September 2022, for migraine with or without aura, for both acute and preventive treatment, and for episodic and chronic presentations. For each medication, we used the most recent FDA-approved labeling to identify indication, mechanism of action, mode of administration, manufacturer, approval year, number of pivotal trials, trial design, and primary endpoints. Sixteen FDA-approved medications for the acute or preventive treatment of migraine were supported by 45 pivotal trials. There were 5 primary endpoint types: (1) change in mean monthly migraine days from baseline; (2) change in mean monthly migraine attacks from baseline; (3) change in mean monthly headache days from baseline; (4) mild to no pain After 2 hours; (5) pain free at 2 hours. There were 3 combinations of coprimary endpoints: (1) Headache Pain Free at 2 Hours and Most Bothersome Symptom Free at 2 Hours; (2) Pain Free at 2 Hours and Sustained Pain Free from 2-24 Hours Postdose; (3) Pain Free at 2 Hours and 2-24 Hours Sustained Pain Free and 2-Hour Pain Relief. Of the 8 preventive migraine medications, the timing of endpoint measurement included the full double-blind period, segments of the double-blind period, and the final month of the double-blind period. Migraine medication trial endpoints were inconsistent within the same indication (episodic or chronic), mechanistic class, and route of administration, frustrating direct comparison among these medications. Furthermore, inconsistent definitions for the indications "episodic" and "chronic" migraine were also observed. Consistent endpoint selection for medications approved for preventive and acute migraine treatment would enhance the ability of patients, physicians, and payers to make informed choices among these medications.