Authors Bielsky et al., based at UK’s Medicines and Healthcare products Regulatory Agency (MHRA), carried out a detailed review of EU applications of complex biosimilars. This revealed that efficacy trials fail to add information that will definitively establish biosimilarity [2]. As such, they argue that, in most cases, efficacy trials are not required once comparability has been demonstrated through other means.

Current biosimilarity assessments
The authors highlight aspects of current biosimilarity assessments that form a rationale for allowing applications without comparative efficacy trials. These are outlined as follows:

In-depth clinical knowledge of reference product and high-performance analysis
Bielsky et al. highlight that an in-depth knowledge of the reference product is required to enable a biosimilarity assessment to be conducted. This includes knowledge of the reference product’s efficacy, which can usually be derived from its mechanism of action (MoA), of which there can be multiple for complex biologicals. Its safety profile can also be predicted from exaggerated adverse effects. There are other adverse effects related to injection of the product that must be addressed. Post-licencing experience can outline important aspects of safety, efficacy and immunogenicity that may have emerged during clinical development.

To confirm biosimilarity, comparative studies are carried out that are based on scientific evidence. The methods used can detect small differences in the physiochemical characteristics, target/receptor binding and numerous bioactivities of the biosimilar and reference.

It is noted that, knowledge of reference product MoA(s) will highlight which physiochemical and functional properties may relate to clinical outcomes. This information is of use in the biosimilar assessment. Today, improved analytical methods mean that certain important factors in the production of biosimilars are more easily controlled. As such, these properties of biosimilar candidates and reference products can now be better aligned.

With this in mind, it is noted that, if a biosimilar’s analytical profile is highly similar to its reference product, then the pharmacokinetic (PK), efficacy, safety and immunogenicity should not be different. Assuming that binding and functional assays cover all possible MoAs, then efficacy trials in patients are not expected to show differences that have not already been detected through analytical tests. Similarly, chemical and post-translational modification differences are detected through tests that are more sensitive than evaluating the human immune response.

The authors note that, overall, some analytical differences are always observed in comparability studies. Those that lie outside the reference’s range are not acceptable if related to clinical efficacy and safety. However, in some cases, in vivo non-clinical studies may be used to evaluate impact. When all aspects are considered, some differences are accepted if there is enough evidence to show that efficacy and safety are not impacted.

Confirmatory biosimilar pharmacokinetic trials
The article outlines that PK comparability can generally be determined through analytical comparability. However, as reference product and biosimilar formulations can differ, a pivotal PK trial is considered necessary to allow the bioavailability of the formulated products to be compared. This is of notable importance if there are alterations to drug delivery method or excipient and, even if intravenous administration occurs, this can lead to physiochemical differences. In these cases, the pivotal PK comparison can help determine the relevance of such differences. In addition, these trials also supply some safety and immunogenicity data.

Today’s robust pharmacovigilance
For effective pharmacovigilance, biosimilars must be fully traceable. In recent years traceability has improved, with clear identification of brand and batch number. In addition, some complex biosimilars have been required to participate in drug registries. These have been able to provide reassurance about rare events and the safety of switching between a biosimilar and reference product.

A blueprint for biosimilar assessment without efficacy trials
The above information form the basis of the authors rationale for allowing biosimilar applications without efficacy trials. In light of this, the authors have created a blueprint for a regulator approach that reduces the need for clinical efficacy trials [3]. It is hoped that this can make biosimilar assessment more efficient and improve access to 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?

Optimizing the benefits of biosimilars for society

Considerations for real-world research on biosimilars

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. Role of efficacy trials in biosimilar assessments questioned [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Nov 6]. Available from: www.gabionline.net/Biosimilars/Research/Role-of-efficacy-trials-in-biosimilar-assessments-questioned 
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 Nov 6]. Available from: www.gabionline.net/Biosimilars/Research/A-blueprint-for-biosimilar-assessment-without-efficacy-trials 

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