Therapeutic Equivalence of Biosimilar and Reference Biologic Drugs in Rheumatoid Arthritis

Abstract

ImportanceBiosimilar drugs are potentially lower-cost versions of biologics that may improve access to therapy. However, there is a lack of adequate systematic reviews demonstrating equivalence between these drugs for the treatment of rheumatoid arthritis (RA).ObjectivesTo assess the efficacy, safety, and immunogenicity associated with biosimilars of adalimumab, etanercept, and infliximab compared with their reference biologics in patients with RA.Data SourcesMEDLINE via PubMed, Embase, Cochrane Central Register of Controlled Trials, and LILACS databases were searched from inception to September 2021.Study SelectionHead-to-head randomized clinical trials (RCTs) of biosimilars of adalimumab, etanercept, and infliximab and their biologic reference drugs for RA were assessed.Data Extraction and SynthesisTwo authors independently abstracted all data. Meta-analysis was conducted with bayesian random effects using relative risks (RRs) for binary outcomes and standardized mean differences (SMDs) for continuous outcomes, with 95% credible intervals (CrIs) and trial sequential analysis. Specific domains were assessed for the risk of bias in equivalence and noninferiority trials. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline.Main Outcomes and MeasuresEquivalence was tested using prespecified margins for the American College of Rheumatology criteria, with at least 20% improvement in the core set measures (ACR20) (ie, RR, 0.94 to 1.06), and for the Health Assessment Questionnaire–Disability Index (HAQ-DI) (ie, SMD, −0.22 to 0.22). Secondary outcomes included 14 items measuring safety and immunogenicity.ResultsA total of 25 head-to-head trials provided data on 10 642 randomized patients with moderate to severe RA. Biosimilars met equivalence with reference biologics in terms of ACR20 response (24 RCTs with 10 259 patients; RR, 1.01; 95% CrI, 0.98 to 1.04; τ2 = 0.000) and change of HAQ-DI scores (14 RCTs with 5579 patients; SMD, −0.04; 95% CrI, −0.11 to 0.02; τ2 = 0.002) considering prespecified margins of equivalence. Trial sequential analysis found evidence for equivalence for ACR20 since 2017 and HAQ-DI since 2016. Overall, biosimilars were associated with similar safety and immunogenicity profiles compared with reference biologics.Conclusion and RelevanceIn this systematic review and meta-analysis, biosimilars of adalimumab, infliximab, and etanercept were associated with clinically equivalent treatment effects compared with their reference biologics for the treatment of RA.

Consensus-Based Overarching Principles and Recommendations on the Use of Biosimilars in the Treatment of Inflammatory Arthritis in the Gulf Region

“…As mentioned earlier, the comparative pharmacokinetic, pharmacodynamic, efficacy, safety, and immunogenicity data are stringently reviewed and approved by regulatory agencies [ 12 – 14 ]. Since the approval of the first biosimilar in 2006, evidence from both clinical studies and real-world experience have validated the comparability between biosimilars and reference products and have shown no significant differences in physiochemical properties and post-translational modifications or impurities [ 12 , 14 , 51 – 53 ]. Therefore, approved biosimilars can be utilized as a more affordable treatment alternative to their respective reference products [ 12 , 26 , 36 ].…”

“…Neutralizing antibodies are typically detected within 6 months of exposure to a biologic agent and can negate drug efficacy. Over the past 17 years since the first approval of a biosimilar, studies have demonstrated no clinically significant differences in the formation of antibodies between biosimilars and reference products [ 14 , 53 , 54 ]. Therefore, antidrug antibodies to biosimilars do not need to be routinely measured in clinical practice [ 12 ].…”

“…Biosimilars are drugs that are highly similar to reference products in terms of physiochemical properties, quality, safety, and efficacy profiles [ 13 , 14 ]. Biosimilars do not have a similar patent protection as the reference products [ 15 ], thereby limiting the market exclusivity of biosimilars.…”

“…Biosimilars do not have a similar patent protection as the reference products [ 15 ], thereby limiting the market exclusivity of biosimilars. By promoting competition in a multi-source market [ 16 , 17 ], they can reduce the financial burden on healthcare, and prevent the underutilization of medication while still being safe and effective in managing rheumatic disease [ 12 , 14 , 17 – 19 ]. The US Food and Drug Administration (FDA) describes a biosimilar as a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product in terms of the safety, purity, and potency [ 20 ].…”

Clinical Benefit, Price, and Uptake for Cancer Biosimilars vs Reference Drugs in China

“…As of December 2022, the EMA, FDA, and PMDA had approved more than 90, 40, and 32 biosimilars, respectively. Several studies have shown that biosimilars are equivalent to reference drugs, with varying degrees of price reduction . However, it was reported that biosimilars are still confronted with serious challenges to their use, including patent litigation, exclusivity protection, anticompetitive behavior, and interchangeability requirements, which have limited the use of biosimilars (eTable 1 in Supplement 1).…”