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(FDA) implementation of the Biologics Price Competition and Innovation Act of 2009, the agency published draft guidance on biosimilar interchangeability in January 2017 [1-2].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.

Pharmacokinetics 1 V13K15

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 AUCtau and Cmax 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 Cmax and AUCtauin 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
  • Cmax and AUCtauas 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.

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
Alternative designs for clinical switching studies

Endpoints to assess interchangeability for biosimilars

Challenges in implementing trials to prove interchangeability

Interchangeability for biosimilars

1.  GaBI Online - Generics and Biosimilars Initiative. FDA issues draft guidance on biosimilar interchangeability []. Mol, Belgium: Pro Pharma Communications International; [cited 2018 May 11]. Available from:
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:
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 []. Mol, Belgium: Pro Pharma Communications International; [cited 2018 May 11]. Available from:

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