Meta-Analysis Confirms Clinical Equivalence Between RA Biosimilars, Originators

Biosimilars referencing Humira (adalimumab), Remicade (infliximab), and Enbrel (etanercept) were found to have comparable safety and efficacy compared with their originator products in the treatment of rheumatoid arthritis (RA), according to a recent meta-analysis and systematic review.

The review, published in JAMA Network Open, sought to fill the gap of systematic reviews for demonstrating equivalence between RA biosimilars and originators. Previous reviews provide only qualitative summaries, which may not be sufficient for providers looking to use the data in decision-making. Also, the few reviews that use quantitative evidence did not use appropriate equivalence testing methods, leading to indefinite conclusions.

Biosimilars are biologic drugs that have no clinically

meaningful differences from their reference biologics.

“As opposed to previous reviews, our review shows up-to-date conclusive evidence on the equivalence between biosimilars and their reference biologics….. Overall, our results are in line with the conclusions that both biosimilars and reference biologics are equally valuable for RA treatment,” wrote the authors.

The researchers searched MEDLINE by PubMed, Embase, Cochrane Central Register of Controlled Trials, and LILACS through September 2021 for head-to-head randomized controlled trials (RCTs) assessing adalimumab, etanercept, or infliximab biosimilars and their reference products for RA. Two authors abstracted all data independently. The meta-analysis utilized Bayesian random effects using relative risks (RRs) for binary outcomes and standardized mean differences (SMDs) for continuous outcomes.

Clinical equivalence was tested using prespecified margins outlined by the American College of Rheumatology criteria (at least 20% improvement in the core set measures [ACR20]) as well as the heath Assessment Questionnaire-Disability Index (HAQ-DI). The secondary outcomes were 14 items used to assess safety and immunogenicity.

Overall, 25 trials containing data on 10,642 randomized patients with moderate to severe RA were included in the analysis. The median sample size of the included trials was 426 patients with RA, the median (IQR) baseline age was 53 (51-54) years, and the median percentage of women was 81% (80%-84%). Adalimumab products were assessed in 11 trials (44.0%) and infliximab and etanercept products were evaluated in 7 trials each (28.0%).

Among the trials, 24 had data showing equivalence between biosimilars and reference products in terms of ACR20 response (n = 10,259; RR, 1.01; 95% CI, 0.98-1.04). Additionally, 14 RCTs demonstrated equivalence between products in terms of change of HAQ-DI scores (n = 5579; SMD, –0.04; 95% CI, –0.11 to 0.02).

Biosimilars were associated with similar rates of serious adverse events (AEs), treatment discontinuation, hypersensitivity, and positive neutralizing antibodies (ADAs). However, the risk of treatment emergent AEs (TEAEs)—including risk of injection site reaction and the formation of ADAs—were lower in patients who were treated with a biosimilar than those treated with an originator. Overall, 35.9% of patients using a biosimilar and 39.6% of those receiving the originator experienced at least 1 TEAE. Similarly, 30.0% of patients receiving the biosimilar and 33.5% of patients receiving the originator tested positive for ADAs.

To the authors' knowledge, this is the largest systematic review to assess the equivalence of RA biosimilars and originators. The review had some limitations, including the lack of generalizability outside of the molecules assessed, sparce safety data, and the detection of funnel plot asymmetry for ACR20 and implemented secondary analyses to address potential biases due to the small nature of the studies.

The authors concluded, “Further research is warranted to investigate the best strategies to address publication and small-study bias in meta-analyses involving equivalence or noninferiority trials.”

Reference

Ascef BO, Almeida MO, Medeiros-Ribeiro AC, Oliveira de Andrade DC, Oliveira Junior HA, de Soárez PC. Therapeutic equivalence of biosimilar and reference biologic drugs in rheumatoid arthritis: a systematic review and meta-analysis. JAMA Netw Open. 2023;6(5):e2315872. doi:10.1001/jamanetworkopen.2023.15872