Issues Impacting Adverse Event Frequency and Severity: Differences Between Randomized Phase 2 and Phase 3 Clinical...

Area of Science:

• Clinical trial methodology
• Pharmacovigilance
• Neurology

Background:

• Lasmiditan, a 5-HT1F agonist, demonstrated efficacy in Phase 2 and 3 trials for migraine treatment.
• Higher frequencies and severity of treatment-emergent adverse events (AEs) were observed in the Phase 2 lasmiditan trials compared to Phase 3.

Purpose of the Study:

• To investigate the factors contributing to the disparities in adverse event (AE) reporting between Phase 2 and Phase 3 lasmiditan clinical trials.
• To identify methodological and procedural differences that may explain the varying AE profiles observed.

Main Methods:

• A hybrid approach combining a review of primary trial documents (protocols, informed consents, data collection forms) and study reports.
• Post hoc analyses of individual patient data from both Phase 2 and Phase 3 lasmiditan trials.

Main Results:

• The incidence of any AE in Phase 2 was 72-86% (26% severe) versus 36-43% (2% severe) in Phase 3 for lasmiditan 100 and 200 mg.
• Central Nervous System (CNS)-related AEs were most common across all studies.
• Differences in AE reporting were linked to informed consent wording, paper vs. electronic diaries, AE translation (e.g., 'Schwindel'), and stricter exclusion criteria for dizziness in Phase 3.

Conclusions:

• Informed consent language, AE data collection methods, translation accuracy, and patient selection criteria significantly impact the reported frequency and severity of AEs in clinical trials.
• These methodological variations can lead to apparent differences in drug safety profiles between trial phases.
• Careful consideration of these factors is crucial for accurate interpretation of clinical trial safety data.