Assessment of Availability, Clinical Testing, and US Food and Drug Administration Review of Biosimilar Biologic Products

This study examines the US Food and Drug Administration's approval process for biosimilar biologic products by evaluating the site and facility inspections, animal and human studies, and comparative efficacy trials conducted to support the applications. Question Ten years after an abbreviated pathway was established for approval of biosimilar biologic products in the US, what biosimilars have been approved, and how extensively were they tested? Findings In this study of 23 biosimilars for 9 reference products approved by the US Food and Drug Administration (FDA), 1 novel and frequent requirement for approval was a year-long comparative efficacy trial that included not only a comparison with the reference product but also a period in which some patients were switched between products. The issues that the FDA identified in biosimilar applications most often required addressing problems in facilities or manufacturing process. Meaning Findings of this study suggest that comparative efficacy trials for biosimilar products are as rigorous as and often larger, longer, and more costly than many pivotal trials for initial approval of new molecular entities, in contrast to trials for most small-molecule generic drugs, which compare plasma concentrations over time in healthy volunteers. Importance Biosimilar biologic products were authorized in 2010, after the US Congress established an expedited pathway for approval of clinically similar versions of approved biologic products. Unlike for most small-molecule generic drugs, approval requirements for a biosimilar included animal studies and a comparative efficacy clinical trial. Objective To analyze the evidence required to support a biosimilarity license application, examine the US Food and Drug Administration (FDA) evaluation process, and estimate the costs of the key clinical trial evidence. Design This study evaluated all biosimilar biologic products approved from January 2010 through October 2019, using the publicly available FDA review documents, disclosures from ClinicalTrials.gov, and the published peer-reviewed literature. The costs of efficacy clinical trials were estimated using licensed proprietary software. Main Outcomes and Measures The following elements of each approved biosimilar were evaluated: the extent of human clinical testing to establish that the biosimilar had no clinically meaningful differences with the reference product, results of comparative animal studies, and FDA-cited application deficiencies. The cited deficiencies included the following categories: (1) facility inspection, (2) manufacturing or product quality, (3) animal studies, (4) laboratory analytical studies, (5) phase 1 and/or immunogenicity studies, and (6) phase 3 comparative efficacy trials. Results As of October 2019, the FDA had approved 23 biosimilar biologics for 9 reference products. The 29 clinical trials that established that the efficacy of the biosimilar products was comparable to that of the reference products enrolled a median (interquartile range [IQR]) of 504 (258-612) patients, had a median (IQR) estimated cost of $20.8 ($13.8-$35.3) million, and had a median (IQR) treatment duration of 52 (28-68) weeks. Substantial deficiencies temporarily halted the review of 9 applications, and the most frequent deficits were failed facilities inspections (n = 5) and manufacturing process quality problems (n = 6). The approved biosimilar submissions included 51 animal studies on species that included mice, rats, rabbits, dogs, and cynomolgus monkeys. Negative outcomes in 2 animal studies were attributed to differences between human and test species. The FDA generally met the standard 12-month review deadlines or stopped the review clock when serious deficiencies were identified. Conclusions and Relevance This study found that most comparative efficacy trials supporting the FDA approval of biosimilars appeared to be as rigorous as and often larger, longer, and more costly than pivotal trials for new molecular entities. Further research is needed into whether less costly comparative efficacy trials could provide adequate evidence of biosimilarity and whether animal studies contribute useful scientific evidence.

Automated summary

This study examined the approval process of biosimilar biologic products by the US FDA and found that most comparative efficacy trials supporting the approval appeared to be as rigorous as pivotal trials for new molecular entities. Biosimilar approval requirements included animal studies and comparative efficacy clinical trials.