title: Biological drugs for the treatment of rheumatoid arthritis by the subcutaneous route: interpreting efficacy data to assess statistical equivalence.
abstract: BACKGROUND
  No equivalence analysis has yet been conducted on the effectiveness of biologics in rheumatoid arthritis. Equivalence testing has a specific scientific interest, but can also be useful for deciding whether acquisition tenders are feasible for the pharmacological agents being compared.
  
  
  METHODS
  Our search covered the literature up to August 2014. Our methodology was a combination of standard pairwise meta-analysis, Bayesian network meta-analysis and equivalence testing. The agents examined for their potential equivalence were etanercept, adalimumab, golimumab, certolizumab, and tocilizumab, each in combination with methotrexate (MTX). The reference treatment was MTX monotherapy. The endpoint was ACR50 achievement at 12 months. Odds ratio was the outcome measure. The equivalence margins were established by analyzing the statistical power data of the trials.
  
  
  RESULTS
  Our search identified seven randomized controlled trials (2846 patients). No study was retrieved for tocilizumab, and so only four biologics were evaluable. The equivalence range was set at odds ratio from 0.56 to 1.78. There were 10 head-to-head comparisons (4 direct, 6 indirect). Bayesian network meta-analysis estimated the odds ratio (with 90% credible intervals) for each of these comparisons. Between-trial heterogeneity was marked. According to our results, all credible intervals of the 10 comparisons were wide and none of them satisfied the equivalence criterion. A superiority finding was confirmed for the treatment with MTX plus adalimumab or certolizumab in comparison with MTX monotherapy, but not for the other two biologics.
  
  
  CONCLUSIONS
  Our results indicate that these four biologics improved the rates of ACR50 achievement, but there was an evident between-study heterogeneity. The head-to-head indirect comparisons between individual biologics showed no significant difference, but failed to demonstrate the proof of no difference (i.e. equivalence). This body of evidence presently precludes any option of undertaking competitive tenderings for the procurement of these agents.
authors.affiliation: HTA Unit, Area Vasta Centro Toscana, Regional Health System, Via San Salvi 12, 50100 Firenze, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Messori
authors.affiliation: HTA Unit, ESTAV Toscana Centro, Regional Health Service, Firenze, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Fadda
authors.affiliation: HTA Unit, ESTAV Toscana Centro, Regional Health Service, Firenze, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Maratea
authors.affiliation: HTA Unit, ESTAV Toscana Centro, Regional Health Service, Firenze, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Trippoli
authors.affiliation: HTA Unit, ESTAV Toscana Centro, Regional Health Service, Firenze, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Gatto
authors.affiliation: President, SIFACT, Italian Society for Clinical Pharmacy and Therapeutics, Milano, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: De Rosa
authors.affiliation: Department of Pharmaceutical Logistics, ESTAV Toscana Centro, Regional Health Service, Firenze, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Marinai
keywords: adalimumab; biologics; certolizumab; equivalence; etanercept; golimumab; meta-analysis; rheumatoid arthritis; tocilizumab