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Meta-Analysis Confirms Bioequivalence of Adalimumab, Infliximab, Etanercept Biosimilars


An analysis of 25 studies found adalimumab, infliximab, and etanercept biosimilars were considered just as safe, effective, and tolerable compared with their originators in the treatment of rheumatoid arthritis.

A systematic review and meta-analysis assessing adalimumab, infliximab, and etanercept biosimilars in the treatment of rheumatoid arthritis (RA) confirmed that the biosimilars were clinically equivalent to their reference products.

The review was published in JAMA Network Open and assessed the efficacy, safety, and immunogenicity profiles associated with adalimumab, etanercept, and infliximab biosimilars by compiling data from multiple randomized clinical trials (RCTs) compared biosimilars to their originators.

It is the largest systematic review to adequately assess the equivalence of biosimilars and reference products in RA populations, according to the authors. Four other reviews have been published; however, they ignored the equivalence or noninferiority design of the primary studies.

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

About 20 million people around the world have RA. However, the high cost of originator medications like Humira (reference adalimumab), Remicade (reference infliximab), and Enbrel (etanercept) can present access barriers for many patients with RA. Although the promise of biosimilars is to lower drug costs for patients and payers without compromising clinical outcomes, there remains a lack of adequate systemic reviews demonstrating the equivalence of these drugs in the treatment of RA.

In the United States, the FDA has approved 9 adalimumab biosimilars, 2 etanercept biosimilars, and 4 infliximab biosimilars. However, only 1 adalimumab biosimilar and 3 infliximab biosimilars have launches thus far. To contrast, in the European Union, patients with RA have access to 10 adalimumab biosimilars, 3 etanercept biosimilars, and 4 infliximab biosimilars.

The researchers conducted the meta-analysis using 4 databases and searched for data published up until September 2021. To be included, the studies needed to be head-to-head RCTs involving adalimumab, etanercept, or infliximab biosimilars in patients with RA. The authors used prespecified margins from the American College of Rheumatology (ACR20; at least 20% improvement in the core set measures) as well as Health Assessment Questionnaire-Disability Index (HAQ-DI) scores during the assessment.

In total, 25 trials were included the analysis, containing data on 10,642 randomized patients with moderate-to-severe RA. The tested biosimilars met equivalence with the originators in terms of ACR20 response in 24 studies including 10,259 patients (risk ratio, 1.01; 95% CI, 0.98-1.04). Changes in HAQ-DI scores from baseline were comparable with the reference products in 14 studies with 5579 patients (standardized mean difference, -0.04; 95% CI, -11.0 to 0.02).

Conducting a trial sequential analysis revealed evidence for equivalence for ACR20 since 2017 and HAQ-DI since 2016. Overall, the data showed that biosimilars were considered just as safe, effective, and tolerable compared with their originators.

The review had some limitations, including that it did not include information on all reference biologics and relevant biosimilars for RA treatment, suggesting that the analysis may have limited generalizability beyond biosimilars for Humira, Remicade, and Enbrel. Additionally, the authors prespecified subgroup analyses had few available trials, the safety data was sparse for some outcomes, and clinical outcomes associated with switching from a reference biologic to a biosimilar were not included.

“Additional meta-analyses considering each reference molecule separately are warranted as more trials are performed and published, especially for etanercept biosimilars…. The association of switching with clinical response and safety outcomes should be a topic of additional systematic reviews,” the researchers noted.

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