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Geographic atrophy (GA) secondary to age-related macular degeneration is a common cause of blindness worldwide. Given the recent approval of the first therapy for GA, pegcetacoplan, we critically appraise methodological aspects of the phase 3 clinical trials published so far in this disease in relation to their design, analysis and interpretation. We reviewed some of the key attributes of all phase 3 clinical trials in GA available in the main public registry of clinical trials as of 20 May 2023. The topics discussed included types of endpoints, eligibility criteria, p-value and effect size, study power and sample size, the intention to treat principle, missing data, consistency of results, efficacy–safety balance and application of results. Five phase 3 clinical trials have reported results, either partially or completely: GATHER1, DERBY/OAKS, CHROMA/SPECTRI, SEATTLE and GATE. Although there are many similarities between these trials in terms of endpoints or broad eligibility criteria, they differ in several aspects (metric of the primary endpoint, sample size, type of adverse events, etc.) that can influence the results, which are discussed. Readers should understand key methodological aspects of clinical trials to improve their interpretation. On the other hand, authors should adhere to clinical trial reporting guidelines to communicate what was done and how it was done.

proteoglycan content was found decreased by histomorphometry (score decline-64%) and biochemical analysis of GAG (-75%) and total collagen (-30%) content. Gene expression of catabolic enzymes (MMP13, MMP1, MMP2), and genes involved in inflammatory response (IL8, CCL2, CCL4 CXCL2) was significantly increased (>4-fold) and genes related to ECM formation (COL2A1, COMP, Aggrecan, COL8A1, COL11A1) were decreased (<-4-fold). Whereas histological and biochemical characteristics of the TNF-alpha induced model match with observations known from human OA cartilage, gene expression analysis revealed contrary gene expression pattern related to ECM formation (COL2A1, COL11A1, COMP) and to hypertrophic bone formation (COL10A1). The addition of TGF-b1 and PRP during TNF-alpha stimulation led to reduced GAG loss (both 40%) whereas IL1b enhanced the GAG loss by further 10% demonstrating responsiveness of the model to test substances. Conclusions: The use of porcine chondrocytes in micromasses and the addition of TNF-alpha resulted in the induction of some typical features of OA such as extensive ECM loss and induction of genes related to catabolic activity and inflammatory response. In contrast to human OA, ECM formation was inhibited, which might be a consequence of the exclusive use of TNF-alpha, which is only one of many impacting factors in OA. Although not all characteristics of human OA could be demonstrated, the presented test system was suitable to detect effects of test substances. TNF-alpha induced porcine micromasses can be a useful supplement to existing preclinical tests in OA and an alternative to the use of human tissue in vitro.