A legal framework for approving biosimilars in the US was established in 2009, via the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). As part of the Food and Drug Administration’s (FDA) implementation of the BPCI Act, the agency published draft guidance on biosimilar interchangeability in January 2017 [2-3].

In its guidance FDA suggests that pharmacokinetic (PK) can be used as a surrogate endpoint to detect the impact of clinically important immunogenicity that can affect efficacy/safety. Alternatives to this approach could be to use immunogenicity or safety and efficacy endpoints.

The FDA guidance states that ‘immunogenicity should be descriptively analyzed as a secondary endpoint’, but Dr Alvarez raises the question of why immunogenicity is not measured as a primary endpoint?  The reasons include:

• Unavailability of equivalence margins tied to clinical significance
• Incidence too low for certain compounds not allowing comparisons in a meaningful way
• Improved assays detect antibodies that are not clinically important

Despite these arguments, measurement of immunogenicity is still important as it can detect neutralizing antibodies – the full impact of which is not addressed by PK comparison.

Alternative approaches to allow comparison of immunogenicity could involve measurement of epitope drift/spread and integrated assessment/modelling of antibody data.

Efficacy and safety endpoints are the ultimate goal but the problem is that the endpoints are not sensitive enough. If they were used as primary endpoints it would lead to the requirement for large samples sizes. FDA states that ‘safety, immunogenicity and efficacy should be descriptively analyzed as secondary endpoints’.

Challenges with using efficacy and safety endpoints include:

• Nocebo effect in assessments of efficacy and subjective assessments of efficacy if study is not fully blinded
• Difficult to fully blinded
  • Different formulations, e.g. different pain of injection
  • Different volumes of administration

Dr Alvarez concludes that ‘sponsors should try to propose better immunogenicity measurements and/or biomarkers’.

Disclaimer
Dr Daniel F Alvarez, Senior Director at Pfizer, stated that the views and opinions expressed in his presentation are those of the individual presenter and should not be attributed to DIA, its directors, officers, employees, volunteers, members, chapters, councils, communities or affiliates, or any organization with which the presenter is employed or affiliated, including, without limitation, Pfizer and Hospira.

Related articles
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Use of PK as an endpoint for clinical switching studies

Challenges in implementing trials to prove interchangeability

Interchangeability for biosimilars

References
1.  Alvarez DF. Interchangeability. DIA Biosimilars Conference; 24-25 October 2017; Bethesda, Maryland, USA.
2.  GaBI Online - Generics and Biosimilars Initiative. FDA issues draft guidance on biosimilar interchangeability [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 May 18]. Available from: www.gabionline.net/Guidelines/FDA-issues-draft-guidance-on-biosimilar-interchangeability
3.  U.S. Food and Drug Administration. Considerations in demonstrating interchangeability with a reference product. Guidance for Industry. January 2017 [homepage on the Internet]. [cited 2018 May 18]. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf

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