Selecting Vehicle Comparators in Dry Eye Disease Clinical Trials: Implications for Efficacy and Safety Assessment and Regulatory Outcomes.

INTRODUCTION: Clinical trials evaluating investigational drugs for dry eye disease (DED) frequently employ vehicle comparators that include excipients (polymers, cyclodextrins, and oil-in-water emulsions) known to have palliative effects. When a saline-based vehicle without any palliative excipient is used as the comparator, the investigational drug only needs to show superiority over a minimally active control to achieve the trial's primary endpoint. Lifitegrast 5% received US Food and Drug Administration approval based on comparisons with its saline-based vehicle. This study evaluated the efficacy and safety outcomes of lifitegrast 5% compared with an investigational drug vehicle containing a palliative excipient. METHODS: Stage 2 of a 42-day randomized, double-masked, multicenter phase 1/2a study tested investigational drugs, their cyclodextrin-containing vehicles, and lifitegrast 5% administered bilaterally twice daily in patients with DED. The present post hoc analysis compared the lifitegrast group with one of the cyclodextrin-containing vehicle groups. Mixed-model repeated-measures analysis was used to evaluate changes from baseline in efficacy variables at day 42. RESULTS: There were no significant differences in symptom and sign improvement between the lifitegrast group (N = 50) and the cyclodextrin-containing vehicle group (N = 49). Changes from baseline in visual analog scale symptom scores, Ocular Surface Disease Index scores, Schirmer scores, corneal and conjunctival staining scores, and tear break-up time were comparable between groups (all P values > 0.05). Treatment-related adverse events were more frequent in the lifitegrast group. CONCLUSIONS: This study found no evidence of superiority of lifitegrast 5% to a vehicle containing cyclodextrin. Use of a saline-based vehicle as the control in registration studies sets a low bar for approval and makes it challenging to judge whether a drug provides benefits beyond current artificial tears. To provide evidence of added therapeutic benefit, comparators that are not treatments for DED should include palliative excipient(s) similar to those found in artificial tears. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04030962.