Across Pivotal Trials for Migraine Medications, Primary Endpoints Vary

Medication trial endpoints were inconsistent within the same indication, mechanistic class, and administration route in 16 US FDA-approved drugs for acute or preventative treatment of migraine.

The variation in primary endpoints in pivotal trials for migraine medications makes it difficult to compare trials to one another, according to study findings published in Neurology

There has been an increase in the number of medications approved for acute migraine and migraine prevention. Researchers conducted a study to determine the trial endpoints used to support the US Food and Drug Administration (FDA) approval of migraine medications. 

The researchers identified all over-the-counter and prescription products that were FDA-approved between January 2001 through September 2022. Products with many indications were included in this study, including migraine with or without aura, acute and preventive treatment, and episodic or chronic migraine medications. 

Products that combined a migraine medication with active ingredients approved before 2001 were excluded from this analysis. Secondary endpoints were not considered in this study. The search was limited to pivotal trials leading to FDA approval. Endpoints were categorized based on timing and type of pain. 

Manufacturers may prefer incongruous endpoints to differentiate newer from older products, which can help imply superiority or frustrate cost-effectiveness comparisons.

A total of 16 medications were approved based on 45 pivotal trials. The pivotal trials per medicine ranged from 1 to 8 trials. Among the 8 preventive medications, 3 were indicated for episodic migraine, 1 was for chronic migraine, and 4 were for both indications. 

There were 9 acute medications with no distinction between indications for episodic or chronic migraines, however, the trials only included participants with episodic migraines. 

There were 7 different mechanistic classes for the medications included in this study, with the most common class reported as anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (4 medications) and selective serotonin receptor (5-HT1B/1D) agonists (3 medications).

Among the 45 pivotal trials, 17 studied migraine prevention and 28 studied the effects of acute treatment. 

The researchers found 5 types of primary endpoints across studies:

  • Change in mean monthly migraine days from baseline (6 medications, 12 trials);
  • Mild to no pain after 2 hours (3 medications, 16 trials); 
  • Change in mean monthly headache days from baseline (2 medications, 3 trials);
  • Change in mean monthly migraine attacks from baseline (topiramate, 2 trials);
  • Pain-free at 2 hours (sumatriptan/naproxen, 1 trial). 

Across all studies, there were 3 that used co-primary endpoints: 

  • Headache pain-free at 2 hours and most bothersome symptom-free at 2 hours (4 medications, 7 trials); 
  • Pain-free at 2 hours and sustained pain-free from 2 to 24 hours postdose (sumatriptan/naproxen, 2 trials);
  • Pain-free at 2 hours and 2 to 24 hours sustained pain-free and 2-hour pain relief (diclofenac potassium, 2 trials). 

The timing of data collection for the primary endpoints of the preventive medications varied, with a full-double blind period for 9 trials, a partial double-blind treatment period for 5 trials, and final month of treatment for 3 trials. 

“Manufacturers may prefer incongruous endpoints to differentiate newer from older products, which can help imply superiority or frustrate cost-effectiveness comparisons,” the researchers wrote. 

Study limitations are the inclusion of primary endpoints exclusively and the inability to assess the overall trial design.


Sharpless LK, Kesselheim A, Orr SL, Darrow J. Variation in endpoints in FDA medication approvals: a review of acute and preventive migraine medications. Neurology. Published online July 12, 2023. doi:10.1212/WNL.0000000000207544