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. Conclusion: 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.

Comparative efficacy of biological agents in methotrexate-refractory rheumatoid arthritis patients: a Bayesian mixed treatment comparison

“…In an equivalence analysis of seven RCTs, MTX plus adalimumab or certolizumab led to superior ACR 50 responses in comparison with MTX monotherapy, but not for MTX with etanercept or golimumab [37]. Head-to-head indirect comparisons between individual biologics showed no significant difference, but failed to demonstrate equivalence.…”

“…While the effectiveness of biologics in RA patients unresponsive to MTX has been settled in many clinical trials and meta-analyses thereof, therapeutic equivalence and noninferiority continue to be debated. In an equivalence analysis of seven RCTs, MTX plus adalimumab or certolizumab led to superior ACR 50 responses in comparison with MTX monotherapy, but not for MTX with etanercept or golimumab [ 37 ]. Head-to-head indirect comparisons between individual biologics showed no significant difference, but failed to demonstrate equivalence.…”

Cryptotanshinone induces reactive oxygen species‑mediated apoptosis in human rheumatoid arthritis fibroblast‑like synoviocytes

“…Furthermore, accumulating evidence has suggested that RA-FLSs serve crucial roles in the destruction process of the joints and the development of RA (5)(6)(7). RA-FLSs have aggressive properties similar to those exhibited by cancer cells, including hyperproliferation, defective apoptosis and invasiveness (8). Thus, the prevention of RA-FLS proliferation and induction of apoptosis may be an effective therapeutic strategy for the treatment of RA.…”