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Role of efficacy trials in biosimilar assessments questioned Posted 30/10/2020

In recent years, the role of the comparative efficacy trial in biosimilar assessments has been brought into question. This is explored in a recent article published by Bielsky and colleagues [1].

Authors Bielsky et al. carried out a detailed review of European Union (EU) applications for all 20 complex biosimilars that were related to six reference products (the monoclonal antibodies: infliximab, rituximab, adalimumab, bevacizumab, and trastuzumab; and a fusion protein, etanercept). All of these were approved in the EU prior to 2019 and do not have known pharmacodynamic (PD) markers.

Biosimilar product quality
Clinical differences
The data showed that there were some frequent notable differences between biosimilars and their reference products. For example:
• an increase in high molecular weight species, particles or aggregates – which can increase immunogenicity
• an increase in methionine oxidation – which can decrease binding to the neonatal Fc receptor (FcRn) and, hence, increase drug clearance
• differences in C-terminallysine truncation – which are not considered to have any impact.

Where such differences were minor, they were assessed as unlikely to have clinical impact. Other differences, such as in the level of acidic/basic species, were generally evaluated by additional tests to find out if they had any effect on biological activity.

Glycosylation differences
The data revealed that the most frequent differences of note were:
• increases in afucosylated glycans – which might increase affinity for Fc-gamma receptor (FcγR) IIIa and resultantly increase antibody-dependent cell-mediated cytotoxicity (ADCC)
• increases in sialylated glycans – which could decrease affinity for FcγRIIIa and resultantly decrease ADCC
• increases in galactosylated glycans – which might increase binding to complement component C1q and resultantly increase complement-dependent cytotoxicity (CDC)
• increases in high mannose glycans – which can increase drug clearance via a mannose receptor-mediated mechanism
• the elimination of non-human glycan structures when the biosimilar is produced in Chinese hamster ovary (CHO) mammalian cell lines rather than in SP2/0 murine lines – which can decrease immunogenicity

Overall, it was also observed that there are multiple examples of biosimilars with differences in afucosylation and FcγR binding. In addition, there were differences in the level of high mannose glycans observed in several biosimilars, but the pivotal pharmacokinetic (PK) trials for some biosimilars enabled the conclusion that they did not affect exposure to them.

Biosimilar PK trial results
The investigation showed that, generally, pivotal PK trials were conducted in healthy volunteers (except in the case of rituximab). Here, it was found that the standard design was a parallel 3-arm trial that compared the biosimilar to EU and US reference products. In some cases, the first PK trial failed to show comparability, but this was seen in a second attempt. It was especially relevant to show PK comparability when the biosimilar formulation is different to that of the reference, or when quality differences had been detected. These trials also provided information on safety and immunogenicity.

Efficacy trial results
It was seen that, generally, efficacy trials were conducted for a single indication with 350‒900 patients. Overall, these showed similar efficacy (within predefined margins) except for in the trastuzumab biosimilars. However, there were efficacy issues concerning infliximab Flixabi, rituximab Rixathon and adalimumab Halimatoz but none of these precluded the products being established as biosimilars.

Conclusions
Importantly, the review did not find any circumstances where efficacy trials added important information to definitively establish biosimilarity and any differences that were uncovered were discarded. As such, the report notes that in most cases, efficacy trials are not required once comparability has been demonstrated through other means.

In light of these results, the authors explained the rationale for allowing biosimilar applications without comparative efficacy trials [2]. In addition, they have created a blueprint for how biosimilar applications can be carried out without efficacy trials [3]. This could provide a streamlined assessment and facilitate global access to more affordable medicines.

Conflict of interest
The authors of the paper [1] did not provide the conflict of interest statement.

The authors disclaim that the publication reflects the views of the individual authors and should not be understood to represent official views or policies of the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Related articles
Biosimilar assessments: do we need efficacy trials?

Clinical development challenges for biosimilar orphan drugs

References
1. Bielsky M-C, Cook A, Wallington A, et al. Streamlined approval of biosimilars: moving on from the confirmatory efficacy trial. Drug Discov Today. 2020. In press. doi.org/10.1016/j.drudis.2020.09.006
2. GaBI Online - Generics and Biosimilars Initiative. Rationale for biosimilar assessment without efficacy trials [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Oct 30]. Available from: www.gabionline.net/Biosimilars/Research/Rationale-for-biosimilar-assessment-without-efficacy-trials 
3. GaBI Online - Generics and Biosimilars Initiative. A blueprint for biosimilar assessment without efficacy trials [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Oct 30]. Available from: www.gabionline.net/Biosimilars/Research/A-blueprint-for-biosimilar-assessment-without-efficacy-trials 

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