title: Generic immunosuppression in solid organ transplantation: systematic review and meta-analysis.
abstract: OBJECTIVE
  To compare the clinical efficacy and bioequivalence of generic immunosuppressive drugs in patients with solid organ transplants.
  
  
  METHODS
  Systematic review and meta-analysis of all studies comparing generic with innovator immunosuppressive drugs.
  
  
  METHODS
  Medline and Embase from 1980 to September 2014.
  
  
  METHODS
  A literature search was performed for all studies comparing a generic to an innovator immunosuppressive drug in solid organ transplantation. Two reviewers independently extracted data and assessed quality of studies. Meta-analyses of prespecified outcomes were performed when deemed appropriate. Outcomes included patient survival, allograft survival, acute rejection, adverse events and bioequivalence.
  
  
  RESULTS
  1679 citations were screened, of which 50 studies met eligibility criteria (17 randomized trials, 15 non-randomized interventional studies, and 18 observational studies). Generics were compared with Neoral (cyclosporine) (32 studies), Prograf (tacrolimus) (12 studies), and Cellcept (mycophenolate mofetil) (six studies). Pooled analysis of randomized controlled trials in patients with kidney transplants that reported bioequivalence criteria showed that Neoral (two studies) and Prograf (three studies) were not bioequivalent with generic preparations according to criteria of the European Medicines Agency. The single Cellcept trial also did not meet bioequivalence. Acute rejection was rare but did not differ between groups. For Neoral, the pooled Peto odds ratio was 1.23 (95% confidence interval 0.64 to 2.36) for kidney randomized controlled trials and 0.66 (0.40 to 1.08) for observational studies. For kidney observational studies, the pooled Peto odds ratios were 0.98 (0.37 to 2.60) for Prograf and 0.49 (0.09 to 2.56) for Cellcept. Meta-analyses for non-renal solid organ transplants were not performed because of a lack of data.There were insufficient data reported on patient or graft survival. Pooling of results was limited by inconsistent study methods and reporting of outcomes. Many studies did not report standard criteria used to determine bioequivalence. While rates of acute rejection seemed similar and were relatively rare, few studies were designed to properly compare clinical outcomes. Most studies had short follow-up times and included stable patients without a history of rejection.
  
  
  CONCLUSIONS
  High quality data showing bioequivalence and clinical efficacy of generic immunosuppressive drugs in patients with transplants are lacking. Given the serious consequences of rejection and allograft failure, well designed studies on bioequivalence and safety of generic immunosuppression in transplant recipients are needed.
authors.affiliation: Division of Nephrology, Kidney Research Centre, Department of Medicine, University of Ottawa, 501 Smyth Road, Ottawa, Canada, K1H 8L6 Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Canada, K1H 8L6.
authors.forename: Amber O
authors.initials: AO
authors.lastname: Molnar
authors.affiliation: Division of Nephrology, Kidney Research Centre, Department of Medicine, University of Ottawa, 501 Smyth Road, Ottawa, Canada, K1H 8L6 Division of Nephrology, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Canada, K1H 8L1.
authors.forename: Dean
authors.initials: D
authors.lastname: Fergusson
authors.affiliation: Division of Nephrology, Kidney Research Centre, Department of Medicine, University of Ottawa, 501 Smyth Road, Ottawa, Canada, K1H 8L6 Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Canada, K1H 8L6.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Tsampalieros
authors.affiliation: Division of Nephrology, Kidney Research Centre, Department of Medicine, University of Ottawa, 501 Smyth Road, Ottawa, Canada, K1H 8L6 Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Canada, K1H 8L6.
authors.forename: Alexandria
authors.initials: A
authors.lastname: Bennett
authors.affiliation: Division of Nephrology, Kidney Research Centre, Department of Medicine, University of Ottawa, 501 Smyth Road, Ottawa, Canada, K1H 8L6 Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Canada, K1H 8L6.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Fergusson
authors.affiliation: Division of Nephrology, Kidney Research Centre, Department of Medicine, University of Ottawa, 501 Smyth Road, Ottawa, Canada, K1H 8L6.
authors.forename: Timothy
authors.initials: T
authors.lastname: Ramsay
authors.affiliation: Division of Nephrology, Kidney Research Centre, Department of Medicine, University of Ottawa, 501 Smyth Road, Ottawa, Canada, K1H 8L6 gknoll@ottawahospital.on.ca.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Knoll
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D016568:Drugs, Generic / Q000627:therapeutic use*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016377:Organ Transplantation / Q000401:mortality*; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016568:Drugs, Generic; D007166:Immunosuppressive Agents