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Introduction The purpose was to compare two flexible regimens of intravitreal aflibercept (IVT-AFL) with fixed dosing every 8 weeks, beyond the first year of treatment, in patients with diabetic macular edema (DME). VIOLET was a 100-week, randomized, Phase IIIb, non-inferiority study in patients with center-involving DME previously treated with IVT-AFL for ≥ 1 year according to the European label. Methods Patients received an initial dose of IVT-AFL at study baseline and were randomly assigned (1:1:1) to treat-and-extend (T&E), pro re nata (PRN), or fixed regimens. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline (randomization) to Week 52. Results Full analysis set comprised 458 patients (baseline mean BCVA: 72.5, 71.0, and 72.7 letters in the T&E, PRN, and fixed-dose groups, respectively). Patients received a mean (min–max) of 10.0 (2–14; T&E), 11.5 (1–25; PRN), and 12.3 (3–13; fixed) injections over 100 weeks, with 13.3 (4–23), 25.0 (3–29), and 16.1 (5–25) clinic visits, respectively. At Week 52, mean (± standard deviation) BCVA changes from baseline were + 0.5 ± 6.7 (T&E), + 1.7 ± 6.8 (PRN), and + 0.4 ± 6.7 (fixed-dosing) letters (least squares mean difference [95% confidence interval]: T&E 0.01 [− 1.46, 1.47] and PRN 0.95 (− 0.52, 2.42) letters versus fixed dosing; p < 0.0001 for both non-inferiority tests [4-letter margin]). The IVT-AFL safety profile was consistent with previous studies. Conclusion The treatment burden associated with intravitreal injections for DME is lowest with T&E regimens, but there are a range of flexible IVT-AFL dosing regimens, allowing physicians to adopt an individualized treatment plan. Trial Registration ClinicalTrials.gov identifier: NCT02818998. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-022-02119-z.

OBJECTIVES:The systematic synthesis of drug's safety data constitutes a valuable tool in clinical and/or regulatory decisions. This systematic review aims to characterize and review the methodology of the systematic reviews reporting ophthalmic adverse drug reactions. METHODS: This systematic review followed the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-analyses guide. MEDLINE and EMBASE databases were searched, by all Ophthalmology journals. All systematic reviews reporting ophthalmic adverse drug reactions in the last decade were included. Data on methodology were extracted. Methodological quality was assessed through AMSTAR 2 scale. Descriptive analysis was performed. RESULTS: Twenty-one systematic reviews were identified. Almost 60% of the systematic reviews reported non-ophthalmic drugs. Nine (43%) systematic reviews did not follow any recommendation. A search filter was not applied in 48% systematic reviews. Observational data was the source of information most included. The methodological quality was assessed in 57% systematic reviews. A meta-analysis was performed in 57% systematic reviews. The protocol's elaboration, the explanation of the sources of information and the list of excluded articles were the domains less performed in the systematic reviews. CONCLUSIONS: The systematic reviews reporting ophthalmic adverse drug reactions diverged in some methodological aspects. Such issue deserves further investigation since that discrepancies may lead to biased conclusions and, consequently, impact clinical and/or regulatory decisions.