title: Safety monitoring of ophthalmic biologics: a systematic review of pre- and postmarketing safety data.
abstract: OBJECTIVE
  The present study evaluates the safety of the biologics approved for the treatment of ocular diseases.
  
  
  METHODS
  The European medicines agency Website was searched to identify biologics with approved ophthalmologic therapeutic indications. A systematic search was performed using MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL) and the International Clinical Trials Registry Platform up to December 2013. Pre-marketing, phase III randomized controlled trials (RCT), postmarketing clinical trials, observational longitudinal studies, and case reports involving adverse events (AE) were included. Methodological quality was assessed by Downs & Black checklist. All European spontaneous reports of AE included in the Eudravigilance up to December 2013 were also considered. AE were classified as ocular (related and non-related with the injection procedure) and non-ocular (related or non-related with vascular endothelial growth factor inhibition). Incidences of all reported AEs were estimated.
  
  
  RESULTS
  Pegaptanib, ranibizumab, and aflibercept were identified as ophthalmic biologics. Fourteen premarketing RCT, 7 postmarketing clinical trials, 31 observational studies, along with 31 case reports and 7,720 spontaneous reports were identified and included in this study. Both in pre- and postmarketing settings, ocular AEs were more frequent than non-ocular AEs. Premarketing safety data inform the most common AEs. Postmarketing studies suggest an increased number of events such as retinal pigmented epithelium tears (0.6%-24%), thromboembolic events (0.8%-5%), and mortality (2.8%-4%).
  
  
  CONCLUSIONS
  This study highlights the need to properly evaluate the risk for rare, serious, and long-term AEs, such as thromboembolic events, since they can lead to imbalances in the benefit-risk ratio of biologics in ophthalmology.
authors: 1 Centre for Health Assessment and Drug Research (CHAD), Association for Innovation and Biomedical Research on Light and Image (AIBILI) , Coimbra, Portugal .
authors: Ana
authors: A
authors: Penedones
authors: Diogo
authors: D
authors: Mendes
authors: Carlos
authors: C
authors: Alves
authors: Francisco
authors: F
authors: Batel Marques
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use; D052157:Aptamers, Nucleotide / Q000009:adverse effects / Q000627:therapeutic use; D001688:Biological Products / Q000009:adverse effects* / Q000627:therapeutic use; D005128:Eye Diseases / Q000188:drug therapy*; D006801:Humans; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor / Q000009:adverse effects / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000627:therapeutic use; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000473:pathology; D013923:Thromboembolism / Q000139:chemically induced / Q000453:epidemiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D052157:Aptamers, Nucleotide; D001688:Biological Products; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; C495058:pegaptanib; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab