Understandably, the regulatory emphasis during late 2020 was on the review of vaccine candidates to address the worldwide Covid-19 pandemic. Certainly, this task was a priority for the UK Medicines and Healthcare products Regulatory Agency (MHRA), who performed it with speed and efficiency culminating in the authorization of the Pfizer/BioNTech mRNA vaccine product on the 2nd and the Oxford University/AstraZeneca product on the 29th December. However, this groundbreaking news may have somewhat overshadowed an earlier announcement by them of a new draft guidance entitled “Consultation document: MHRA guidance on the licensing of biosimilar products, 7 October 2020” (1). Although the 6-week consultation period has now expired, I thought that it would be useful to look at this to remind ourselves of the intended changes and consider any potential impact on our analytical strategies for biosimilar testing.
With the Brexit transition period ending on 31st December 2020, the MHRA is once again responsible for evaluating biopharmaceutical products for marketing in the UK and have published a short statement on the guidance to be used for Marketing Applications from 1st January 2021 (2) which is based on current European Medicines Agency (EMA) guidance. However, they have taken an opportunity to propose some changes, or perhaps more of an evolution, to the approach to the licensing of biosimilars which diverges from the EMA’s CHMP guideline in some respects.
The proposal derives from the cumulation of MHRA’s extensive experience accrued in the review of biosimilar applications since the first was approved in 2006 - experience which is encapsulated in a September 2020 review paper of 20 EU biosimilar applications covering 6 complex reference products up to the end of 2019 (3). This paper questions whether clinical efficacy trials are still necessary given their limitations as an effective discriminating tool and argues that except in exceptional cases, biosimilarity can be demonstrated by analytical testing and pharmacokinetic (PK) trials.
The proposed draft guidance is based on current EMA guidance, with additional details regarding UK reference standards, the lack of requirement for in vivo animal studies and changes in the requirements for a comparative efficacy trial. It is this last point which is of importance to analytical scientists working with biosimilars- it signals the shift away from conducting biosimilarity assessments which include clinical comparability trials in favour of robust and extensive physicochemical and biological testing data together with pharmacokinetic studies. In most cases, comparative efficacy trials will not be required.
In essence, the MHRA supports the use of in-depth scientific knowledge of the Reference Product (RP), gained using state-of-the-art analytical techniques to interrogate structure and biological activity. These techniques are then utilized in comparative assessment of the biosimilar candidates, together with a pivotal comparative PK trial with no requirement for comparative efficacy/safety trials. The paper concludes that “extensive comparative analytical studies, together with an abbreviated clinical package…………, is sufficient to assess biosimilarity in most cases”.
An important central premise for omitting an efficacy trial is that extensive quality data should be generated, initially for the reference product and then in comparison studies with appropriate numbers of batches of biosimilar. This highlights the importance of detecting and defining the ranges of Critical Quality Attributes of the molecule at both an analytical and in-vitro functional level.
For we analytical scientists, the spotlight is once again turned towards the choice of analytical methods to perform both the detailed interrogation of the RP and the comparability exercise with the biosimilar. As the authority has extensive experience with modern analytical characterization methods it is certainly expecting the “big guns” to be used during this exercise. The new guidance makes this clear, stating: “……..comprehensive analysis of the proposed biosimilar and RP, using state-of-the-art methods with suitable sensitivity and orthogonal methods to determine not only similarities but also potential differences”.
Comprehensive analytical testing of batches of RP followed by comparative testing with biosimilar candidates has always been a pivotal initial step in the development of biosimilars and will of course continue to be so, particularly as comprehensive data derived from orthogonal techniques are expected. A plethora of methods for primary and higher order (glyco)protein structure characterization of the protein and carbohydrate moieties using both simple and highly sophisticated analytical techniques can be utilized to interrogate the structure of the RP and perform subsequent comparative testing. Many suitable protein characterization techniques are mentioned in a table here: https://biopharmaspec.com/protein-characterization-services.
Most guidelines require, in addition to functional testing, determination of physicochemical and biophysical properties, purity, impurities and quality according to ICH Topic Q6B. The skill of the analytical testing lab is in designing an appropriate program of testing and this undoubtedly comes from a combination of experience, understanding of the regulatory requirements and understanding of the strengths and weaknesses of the analytical methods themselves.
In real life, given the sensitivity of modern analytical techniques, some differences are bound to be observed. For example, a frequent observed difference between the biosimilar and the RP in glycosylated proteins (mAbs) is the fucose, galactose and/or sialic acid content of the glycan. There are also often differences observed related to the age of batches used, e.g. increase in deamidation, oxidation, fragmentation etc., and/or differences in C/N terminal sequences. Knowing this, the guidelines state: “It is not expected that all quality attributes of the biosimilar are identical to the RP” but that “any differences detected in the quality attributes have to be appropriately justified with regard to their potential impact on safety and efficacy”.
This proposed new guidance has the potential to accelerate the speed and reduce the cost of licensing of biosimilar products for the UK market. However, as development is generally a global activity and clinical comparability studies are necessary elsewhere, it is unlikely to have a broader impact at present. It will be interesting to see if other regulatory bodies adopt a similar attitude in future. Nevertheless, the emphasis on analytical characterization highlights the importance of using the correct combination of analytical techniques, coupled with experienced interpretation of the findings to assess observed differences for further study using appropriate discriminating methods.
Dr. Fiona Greer is an independent consultant with extensive technical experience and industry knowledge built up over 40 years of supporting drug development and, in particular, biosimilar projects.
1. Consultation document: MHRA guidance on the licensing of biosimilar products, 7 October 2020. https://www.gov.uk/government/consultations/mhra-draft-guidance-on-the-licensing-of-biosimilar-products/consultation-document-mhra-guidance-on-the-licensing-of-biosimilar-products
3. Bielsky, M-C. et al (2020) Streamlined approval of biosimilars: moving on from the confirmatory efficacy trial. Drug Discovery Today 25, 11, 1910-1918. https://www.sciencedirect.com/science/article/pii/S1359644620303433