title: Tocilizumab in rheumatoid arthritis: a case study of safety evaluations of a large postmarketing data set from multiple data sources.
abstract: OBJECTIVE
  To evaluate the magnitude of serious adverse events (SAEs) observed in postmarketing reports of tocilizumab (TCZ) for rheumatoid arthritis (RA) in relation to SAEs observed in TCZ clinical trials and external epidemiology data.
  
  
  METHODS
  A total of 64,000 patient-years (PY) of TCZ exposure was needed to determine, with 90% power, whether rates of SAEs of interest (eg, death, hepatic, gastrointestinal, and cardiovascular) were ≥50% higher (agreed with the Food and Drug Administration) than expected. Reporting rates were calculated for spontaneously reported SAEs, open-label or unblinded postmarketing clinical trials (phase 3b/4), and a Japanese postmarketing surveillance program in the global postmarketing safety database. Event rates were calculated for the registrational placebo-controlled trials and long-term extension data. External comparators for anti-tumor necrosis factor (aTNF)-treated RA patients were derived from a US-based health care insurance claims database or published literature.
  
  
  RESULTS
  The global postmarketing safety database provided 65,099 PY of TCZ exposure; the aTNF external comparator population provided 53,360 PY. Spontaneous reporting rates per 100 PY (95% confidence interval) were 8.3 (8.1, 8.5) SAEs, 0.39 (0.34, 0.44) deaths, 0.06 (0.04, 0.08) serious hepatic events, 0.15 (0.12, 0.18) serious gastrointestinal events, 0.09 (0.07, 0.12) serious myocardial infarctions, 0.15 (0.12, 0.18) serious strokes, and 0.07 (0.05, 0.09) cardiac deaths in the global postmarketing safety database. These were of similar magnitude to corresponding rates from registrational clinical trials, the aTNF external comparator population, and published literature.
  
  
  CONCLUSIONS
  SAE rates observed among postmarketing TCZ users were similar to those of various comparison populations. Predetermined design of studies to compare postmarketing AEs using multiple data sources is a useful strategy that can be applied to other medications.
authors.affiliation: Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL. Electronic address: jcurtis@uab.edu.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Curtis
authors.affiliation: RTI Health Solutions, Barcelona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Perez-Gutthann
authors.affiliation: Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Samy
authors.initials: S
authors.lastname: Suissa
authors.affiliation: Genentech, South San Francisco, CA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Napalkov
authors.affiliation: Genentech, South San Francisco, CA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Singh
authors.affiliation: Roche Products Ltd., Welwyn Garden City, UK.
authors.forename: Liz
authors.initials: L
authors.lastname: Thompson
authors.affiliation: Genentech, South San Francisco, CA; Roche Products Ltd., Welwyn Garden City, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Porter-Brown
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects* / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000401:mortality; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000453:epidemiology; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D005060:Europe; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D007564:Japan; D008297:Male; D008875:Middle Aged; D011358:Product Surveillance, Postmarketing / Q000706:statistics & numerical data*; D015996:Survival Rate; D014481:United States
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C502936:tocilizumab
keywords: Postmarketing; Rheumatoid arthritis; Serious adverse events; Tocilizumab