title: Generalization and extrapolation of treatment effects from clinical studies in rheumatoid arthritis.
abstract: OBJECTIVE
  Pragmatic clinical trials have been proposed as a solution for nongeneralizability of randomized clinical trial (RCT) results. We investigated whether treatment effects of pragmatic clinical trials are indeed generalizable to clinical practice and how efficacy estimates from published RCTs can be translated to daily practice populations.
  
  
  METHODS
  Data from pragmatic clinical trials of the Utrecht Rheumatoid Arthritis Cohort and the observational Nijmegen Early Rheumatoid Arthritis inception cohort were used. The treatment effects of methotrexate and hydroxychloroquine as opposed to the pyramid approach were compared between the trials and observational study using a modified comprehensive cohort design analysis. The changes from baseline in disease activity (Disease Activity Score in 28 joints [DAS28]) and functional disability (Health Assessment Questionnaire [HAQ]) and European League Against Rheumatism (EULAR) response at 6 months were studied. The influence of population and treatment characteristics on the American College of Rheumatology 50% improvement criteria response compared with control therapy also at 6 months from RCTs was assessed using the relative risk (RR) and risk difference (RD).
  
  
  RESULTS
  The DAS28 and HAQ generally improved more in patients in the pragmatic trials than in daily practice. However, using EULAR response as outcome, the treatment effect was not found to be different. In published RCT data, higher glucocorticoid use, disease duration, and cotreatment with disease-modifying antirheumatic drugs increased the RR. Use of glucocorticoids increased the RD, and higher values of baseline DAS28 and HAQ decreased the RR and RD.
  
  
  CONCLUSIONS
  Pragmatic clinical trials might be directly generalizable only regarding relative treatment response. In extrapolating published RCT results to daily practice, population characteristics associated with disease severity, disease duration, and treatment history or cotreatment need to be taken into account.
authors.affiliation: University Medical Center, Utrecht, The Netherlands.
authors.forename: Sandhya C
authors.initials: SC
authors.lastname: Nair
authors.forename: Wietske
authors.initials: W
authors.lastname: Kievit
authors.forename: Rosan W
authors.initials: RW
authors.lastname: Janse
authors.forename: Johannes W J
authors.initials: JW
authors.lastname: Bijlsma
authors.forename: Jaap
authors.initials: J
authors.lastname: Fransen
authors.forename: Floris P J
authors.initials: FP
authors.lastname: Lafeber
authors.forename: Paco M J
authors.initials: PM
authors.lastname: Welsing
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine / Q000627:therapeutic use; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D008962:Models, Theoretical; D064887:Observational Studies as Topic; D064792:Pragmatic Clinical Trials as Topic; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D006886:Hydroxychloroquine; D008727:Methotrexate