In its guidance on pharmacology data for biosimilarity, the FDA states that clinical pharmacology data is ‘a critical part of demonstrating biosimilarity’ and outlines three key concepts that the agency believes are ‘especially relevant to the stepwise development of proposed biosimilar products’ [2]:

• pharmacokinetic (PK) and pharmacodynamics (PDs) response assessment
• evaluation of residual uncertainty
• assumptions about analytical quality and similarity

When assessing uncertainty Dr Lynch points to the following as important considerations:

• Failure to meet predefined acceptance criteria on a statistical test does not necessarily preclude determination of ‘highly similar’
• When differences are observed:

–     Do orthogonal methods corroborate an impact on function?

• Understanding of structure‐function relationship

–     Refine manufacturing control strategy to ensure lots meet acceptable limits?
–     Is the difference clinically meaningful?

• Understanding criticality of the attribute
• Sensitivity of non‐clinical and clinical studies to address residual uncertainty

In its guidance on Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product [3], FDA highlights the importance of functional assays in the assessment of uncertainty by stating that ‘functional assays are also critical tools for evaluating the integrity of the higher order structures’. 

In particular Dr Lynch points to the following:

• Additional structure–function relationship studies, can help confirm attribute criticality or address ‘gaps’ in knowledge regarding critical quality attribute (CQA) potential to impact clinically meaningful outcomes, e.g. impact on potency, PK/PD, immunogenicity, safety
• Assessment of variant impact on in vitro bioactivity
• Assessment of variant impact on FcRn binding (to provide additional understanding of impact on PK)
• Functional assays can help address residual uncertainty due to minor differences in structure

Disclaimer
Dr Patrick Lynch, Product Quality Reviewer at the US Food and Drug Administration (FDA), stated that his presentation reflects the views of the author and should not be construed to represent FDA’s views or policies.

Related articles
Lot selection and handling for biosimilarity

Ranking and evaluation of quality attributes for biosimilarity

Analytical consideration in demonstrating similarity for biosimilars

Analytical similarity for biosimilars

References
1.  Lynch P. Expectations and approaches for demonstrating analytical similarity. DIA Biosimilars Conference; 24–25 October 2017; Bethesda, Maryland, USA.
2.  GaBI Online - Generics and Biosimilars Initiative. FDA issues final guidance on pharmacology data for biosimilarity [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Sep 7]. Available from: www.gabionline.net/Guidelines/FDA-issues-final-guidance-on-pharmacology-data-for-biosimilarity
3.  GaBI Online - Generics and Biosimilars Initiative. FDA finalizes biosimilars guidelines [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Sep 7]. Available from: www.gabionline.net/Guidelines/FDA-finalizes-biosimilars-guidelines

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