Much of the groundwork for establishing equivalence is established in the pharmacokinetic evaluation. Further studies add less and less to the body of evidence for biosimilar approval, UK regulators write.
Comparative biosimilar efficacy trials are unnecessary to demonstrate that drug candidates are equivalent to reference products (RPs), authors of an analysis argue in a new paper. The group from the UK’s Medicines and Healthcare Products Regulatory Agency contends that, except in extreme cases, analytical testing and a pharmacokinetic trial are sufficient to demonstrate biosimilarity.
They propose a streamlined approval process for biosimilars to accelerate patient access, in which “efficacy trials are reserved for exceptional circumstances.”
“Little Additional Evidence of Biosimilarity”
The approval processes for biosimilars in the United States and Europe do require extensive analytical testing to determine similarity, followed by in-human pharmacokinetic (PK) and pharmacodynamic investigatory studies and efficacy, safety, and immunogenicity trials. However, “the discriminatory power of these studies decreases in this order,” the authors contend.
“In 2020, it is increasingly questioned whether clinical efficacy trials of biosimilars are still necessary. Revisiting the requirement for efficacy trials appears timely because significant technological advances have been made over the past 10 years and considerable scientific and regulatory experience has been accrued since the first biosimilar was licensed in 2006,” they wrote in a prepublication draft for Drug Discovery Today.
The authors note limitations of comparative efficacy trials, such as limited statistical power to detect small treatment effects or differences in safety and immunogenicity. They said that to detect all clinically relevant differences between biosimilar and originator, “up to a few thousand” patients would be required, whereas most comparative efficacy studies for approved biosimilars have enrolled between 350 and 900 patients. Enrolling sufficient numbers of patients is especially challenging for orphan drug or pediatric indication trials, which the authors said leads to underpowered studies and difficulty drawing conclusions.
In addition to these limitations, the authors argue that clinically meaningful differences in efficacy, safety, or immunogenicity between a biosimilar candidate and its RP “would be unlikely once analytical and PK comparability has been shown.” Therefore, they claim that comparative efficacy trials are “neither an effective discriminating tool for the comparison between biosimilar and RP, nor an efficient use of limited resources.”
To determine whether differences found in comparative efficacy trials changed the course of biosimilar approvals, the authors analyzed 20 complex biosimilars related to 6 reference products approved in the European Union as of the end of 2019. Regarding that analysis, the authors wrote, “we have not found any publicly available results of an efficacy trial being the critical reason for not submitting a marketing authorization application for a biosimilar candidate.” They added that differences detected in clinical trials “did not, on their own, preclude the approval of the biosimilar.”
Need for Comparative Efficacy Trials?
The authors suggest that in-depth knowledge of “crucial aspects of efficacy, safety, and immunogenicity of the RP that emerged during clinical development” can help predict potential issues with a biosimilar. Additionally, they said that technological advances have allowed analytical tools to detect small, potentially clinically relevant differences between reference products and candidate biosimilars.
They also argue that differences between biosimilar and RP that might affect immunogenicity are better detected via analytical tests, “which are more sensitive than the evaluation of the human immune response because of multiple confounding patient- and disease-related factors.”
A Streamlined Approval Process
Multiple batches of RP are evaluated to establish a baseline range within which the biosimilar candidate must fall as evidence of equivalency. The authors write that the variability of the reference product range “is unlikely to be of clinical relevance” and neither should there be a concern if the biosimilar candidate falls within that range.
“Therefore, we contend that, in most cases, an efficacy trial is no longer required to establish biosimilarity once comparability has been demonstrated through the analytical and clinical PK studies,” they wrote.
Their proposed approval process would use in-depth understanding of the RP and advanced analytical testing to minimize clinically relevant differences between RP and biosimilar. They acknowledged this would require extensive knowledge of the RP’s mechanism(s) of action; physicochemical and functional properties likely to be clinically relevant; PK, efficacy, safety, and immunogenicity profiles; and impact of antidrug antibodies on pharmacokinetics.
The authors also recommended extensive quality data must be generated for both the reference product and its biosimilar candidates, with analysis of multiple batches of the originator biologic over months to years to take into account manufacturing variability, and comparison of each batch of biosimilar to the reference product.
The authors still consider a confirmatory PK trial necessary for comparing bioavailability between biosimilar and reference product, as the 2 products by definition will not be identical. Importantly, they argue that the PK trial “provides some safety and immunogenicity information from exposure in humans.”
Regarding safety, they said robust pharmacovigilance will be required; however, they reiterated that safety issues not identified via analytical or PK testing are unlikely, saying “more than a decade of clinical experience indicates that a new safety signal solely identified with a biosimilar is extremely unlikely unless there are additional factors unrelated to the active molecule itself (eg, different excipient or device).”
The authors claim this expedited approach to biosimilar approvals “provides a streamlined pathway for expediting approval of biosimilars, thereby promoting wider patient access to these crucial therapies.”
For more recent opinion on FDA biosimilar guidelines, click here.
Bielsky M, Cook A, Wallington A, et al. Streamlined approval of biosimilars: moving on from the confirmatory efficacy trial. Drug Discovery Today. 2020. doi:10.1016/j.drudis.2020.09.006