title: Biosimilar erythropoiesis-stimulating agents and the risk of developing anti-drug antibodies-a systematic review.
abstract: OBJECTIVE
  We systematically reviewed published observational studies and randomized controlled trials (RCT) reports of clinical trials on erythropoiesis-stimulating agents (ESA's). Only studies evaluating the risk of developing anti-drug antibodies (ADA) of both original and biosimilar drugs were chosen.
  
  
  METHODS
  Databases including PubMed, EMBASE and Cochrane Library were searched up to 17 March 2015. Two reviewers independently assessed the relevant studies for risk of bias.
  
  
  RESULTS
  Twenty-one publications were included. The overall prevalence of ADA in the studies was about 0.2 to 0.5 %. Most studies were not designed to monitor the development of ADA and often the study duration was too short (less than 6 months) and the patient population too small. Moreover, in many studies, the assays used only determined the presence of ADA and did not measure therapy failure due to ADA. In one RCT, as many as 13 cases (4 %) of ADA were identified.
  
  
  CONCLUSIONS
  ADA development seems to be low in short-term studies with ESA. None of the efficacy and safety issues for ESA biosimilars were judged to be adequately addressed in the evaluated literature, with respect to ADA formation, due to the study design and the assay method used.
authors.affiliation: Department of Learning, Informatics, Management and Ethics (LIME), Karolinska Institutet Stockholm, Stockholm, Sweden.
authors.forename: Marianne Heibert
authors.initials: MH
authors.lastname: Arnlind
authors.affiliation: Swedish Council on Health Technology Assessment, Box 3657, 103 59, Stockholm, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Fryklund
authors.affiliation: Swedish Council on Health Technology Assessment, Box 3657, 103 59, Stockholm, Sweden.|Sweden and Department of Medicine, Clinical Pharmacology Unit, Karolinska Institut, L7:03, Karolinska University Hospital, 171 76, Stockholm, Sweden.
authors.forename: Sigurd
authors.initials: S
authors.lastname: Vitols
authors.affiliation: Swedish Council on Health Technology Assessment, Box 3657, 103 59, Stockholm, Sweden. goran.bertilsson@sbu.se.|SBU, Box 6183, 102 33, Stockholm, Sweden. goran.bertilsson@sbu.se.
authors.forename: Göran
authors.identifier: http://orcid.org/0000-0002-5660-7376
authors.initials: G
authors.lastname: Bertilsson
mesh_terms: D000740:Anemia / Q000188:drug therapy; D000906:Antibodies / Q000276:immunology*; D059451:Biosimilar Pharmaceuticals / Q000627:therapeutic use; D006397:Hematinics / Q000276:immunology* / Q000627:therapeutic use; D006801:Humans; D064887:Observational Studies as Topic; D016032:Randomized Controlled Trials as Topic; D012306:Risk
chemical_list: D000906:Antibodies; D059451:Biosimilar Pharmaceuticals; D006397:Hematinics
keywords: Antibodies; Biosimilar; Efficacy; Erythropoiesis-stimulating agents; Systematic review