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Use of PK as an endpoint for clinical switching studies

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As part of the Food and Drug Administration’s (FDA) implementation of the Biologics Price Competition and Innovation Act of 2009, the agency published draft guidance on biosimilar interchangeability in January 2017 [1-2]. Based on this guidance, the clinical study design primary endpoints should be pharmacokinetic (PK)/pharmacodynamic (PD) ‘because these assessments are generally most likely to be sensitive to changes in immunogenicity and/or exposure that may arise as a result of alternating or switching’. PK can be used as a surrogate endpoint to detect the impact of clinically important immunogenicity that can affect efficacy/safety.

In his presentation, Dr Daniel F Alvarez discussed why PK and PD endpoints are necessary for switching studies for biosimilars [1].

Margins exist (‘borrowed’ from small molecule PK therapeutic equivalence guidance [3]) – ‘90% confidence interval for the geometric mean ratio of AUC_tau and C_max between the proposed interchangeable product and the reference product should be within 80−125%’.

But the question Dr Alvarez asks is: ‘Are we trying to assess PK similarity again?’ This is already established during biosimilar development. Therefore, the goal of a clinical switching study should be to assess the multiple switch strategy:

Lower exposure: Could be related to switching
Higher exposure: In most cases would not be related to switching per se

Study challenges that biosimilar makers face when using PK endpoints include:

Limited data exist for C_max and AUC_tauin patients
- Clearance fluctuates over time
Sample size will be too large for certain products
Very high %CV of PK parameters in patients
- Subcutaneous administered drugs
  For example: Adalimumab 50% CV for both (higher than healthy volunteers)
- Affected by concomitant medications, immunogenicity, albumin levels

C_max and AUC_tauas co-primary endpoints
- Degree of correlation between these parameters influences sample size
Need for intensive PK sampling
- Could affect study enrolment and dropout rates
- Adds operational challenges

Dr Alvarez concludes that PK endpoints bring new challenges, especially for subcutaneous drugs with high PK variability.

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.

Endpoints to assess interchangeability for biosimilars

Challenges in implementing trials to prove interchangeability

Interchangeability for biosimilars

References
1. 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 11]. Available from: www.gabionline.net/Guidelines/FDA-issues-draft-guidance-on-biosimilar-interchangeability
2. 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 11]. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf
3. Alvarez DF. Interchangeability. DIA Biosimilars Conference; 24-25 October 2017; Bethesda, Maryland, USA.
4. GaBI Online - Generics and Biosimilars Initiative. Glossary of key terms [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 May 11]. Available from: www.gabionline.net/Biosimilars/General/Glossary-of-key-terms

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