Comment on: Safety and efficacy of a nepafenac punctal plug delivery system in controlling postoperative ocular pain and inflammation after cataract surgery

Abstract

We have read the article by Donnenfeld et al. regarding nepafenac sustained-delivery punctal plugs with great interest.1 The authors present promising results and significant efficacy of the alternative drug delivery system, to be used after cataract surgery instead of topical treatment. Because the outcomes in contemporary cataract surgery partially depend on patient compliance, new therapeutic approaches, such as the one presented in this study, represent an appealing alternative. In the study, patients were randomized after cataract surgery to receive a nepafenac intracanalicular insert or a placebo. Other anti-inflammatory treatment was not permitted preoperatively, intraoperatively, or postoperatively, as stated by the authors. This part of the study design raises some concerns. Routine anti-inflammatory management after cataract surgery, including corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs), was not administered in the placebo arm; therefore, the patients in this group were exposed to a higher risk for adverse events.3 Such concerns were confirmed by the results of the study. More patients in the placebo group experienced pain at both day 3 (62% in the placebo group vs 31% in the treatment group) and day 7 (69% in the placebo group vs 33% in the treatment group), and worse visual acuity at day 7.1 The rescue medication protocol appears to provide a safety net for alarming levels of inflammation or pain. However, the same therapeutic hypothesis could be tested in a different research model. We believe that using a noninferiority study design could be beneficial. Since the 1990s, placebo-controlled trials have become ethically controversial if a standard treatment exists.2 A noninferiority trial aims to show that an experimental treatment is not worse than the accepted one.3 The new treatment might be safer, have better secondary endpoints, be easier to administer, or simply be less expensive. In ophthalmology, noninferiority trials are commonly applied for analyzing outcomes of age-related macular degeneration therapy and glaucoma treatment with prostaglandins. We believe that comparing the efficacy of the nepafenac insert with the accepted topical anti-inflammatory treatment is a good alternative in studies such as this one. Patients in the placebo group had worse outcomes, at least short term, and this could have been prevented with a noninferiority study design, while still offering the possibility of robust scientific scrutiny of the proposed treatment.