Alternative designs for clinical switching studies

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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 As part of the Food and Drug Administration’s (FDA) implementation of the BPCI Act, the agency published draft guidance on biosimilar interchangeability in January 2017 [2].

Clinical Trials 2 V13K29

According to Dr Alvarez, statistical design alternatives for pharmokinetic (PK) endpoints could include [1]:

  • Use of wider margins for high variability drugs
    • High variability expected for certain compounds
  • Non-inferiority designs
    • Follows BPCI Act intent (assesses not increase risk with switching)
    • Compatible with scientific plausibility - addresses FDA concern regarding potential increase of clinically important immunogenicity leading to PK
      • No better efficacy expected
    • Allows more reasonable sample sizes
  • Asymmetric margins for drugs at the plateau (or near) or the dose response curve
    • Similar FDA guidance for efficacy testing in clinical comparative studies based on clinical significance

As far as review of biosimilars for establishing interchangeability, FDA has said that it will use a flexible approach, reviewing each product on a case-by-case basis [2]. The principles of totality-of-evidence and clinical significance should be followed, as is done in the evaluation of biosimilarity [3]. According to Dr Alvarez, PK and immunogenicity assessments are important pieces, but not absolute ones. He adds that it is important to follow the intent of the BPCI Act and ensure that there are no deleterious effects on efficacy and safety.

Dr Alvarez concludes that ‘in most cases a PK non-inferiority design should be appropriate’. This, he says, aligns with the intent of the BPCI Act and with biological plausibility, as well as allowing for more reasonable sample sizes. He adds that ‘case-by-case, totality-of-evidence and clinical significance are key principles that should be followed’.

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.

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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 []. Mol, Belgium: Pro Pharma Communications International; [cited 2018 May 25]. Available from:
3.  GaBI Online - Generics and Biosimilars Initiative. Assessment of biosimilarity under the BPCI Act []. Mol, Belgium: Pro Pharma Communications International; [cited 2018 May 25]. Available from:

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