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Challenges in implementing trials to prove interchangeability

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In the US, a legal framework for approving biosimilars 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 As part of the Food and Drug Administration’s (FDA) implementation of the BPCI Act the agency published draft guidance on biosimilar interchangeability in January 2017 [1].

In his presentation, Dr Daniel F Alvarez discussed challenges in implementing clinical trials that support interchangeability based on the current draft FDA guidance [2].

With respect to clinical study design the guidance recommends that a study is carried out in patients and that pharmacokinetic endpoints are used as the primary outcome. The guidance also recommends the number of switches to be carried out and the lengths of the periods to be used.

BPCI Act	FDA guidance
To meet the additional standard of interchangeability, an applicant must provide sufficient information to demonstrate biosimilarity and also to demonstrate that the biological product can be expected to produce the same clinical result as the reference product in any given patient	Generally, the data and information to support a showing under the ‘can be expected to produce the same clinical result as the reference product in any given patient’ standard will likely not involve additional clinical studies other than those necessary to support other elements of demonstrating interchangeability
If the biological product is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch	Switching study in patients expected for products intended to be administered more than once Primary endpoints should be pharmacokinetic /pharmacodynamic (PK/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’ Efficacy endpoints can be supportive; at therapeutic doses many clinical efficacy outcomes would only be sensitive to large changes in exposure or immunogenicity Assessment of safety/immunogenicity expected Clinical implications of multiple switching Increase in immunogenicity due to switching Tolerability, adherence Container closure system and/or delivery device considerations

Clinical concerns related to multiple switches include the possible development of immunogenicity, as well as worse safety, tolerability and/or adherence. In fact, the general position of FDA, as outlined in its draft guidance, is that there may be ‘subtle differences’ between a reference product and an interchangeable biological that upon repeated switching may elicit a new and unique immune response.

Increased immunogenicity could potentially:

Have an effect on PK (decrease) and ultimately efficacy (decreased)
Cause neutralization of biosimilars and endogenous proteins
Cause hypersensitivity, other immune-safety events

However, despite these concerns, single switch studies, i.e. switch in one direction (originator to biosimilar), have not raised any concern [3-5]; and multiple switching studies have also shown no apparent effect on efficacy, safety or immunogenicity [5, 6]. In addition, a review of switching data for biosimilars ‘found no evidence from clinical trial data or post-marketing surveillance data that switching to and from different biopharmaceuticals leads to safety concerns’ [7]. In addition, in Europe more than 10 years of post-marketing data on biosimilars has also raised no safety concerns.

Although FDA strongly recommends that studies should be conducted in patients to mimic real-life use, it is not clear what exactly this means in terms of the type of study design to be used. Several possible designs for switching studies of biosimilars have been suggested [8].

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

Use of PK as an endpoint for clinical switching studies

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 4]. Available from: www.gabionline.net/Guidelines/FDA-issues-draft-guidance-on-biosimilar-interchangeability
2. Alvarez DF. Interchangeability. DIA Biosimilars Conference; 24-25 October 2017; Bethesda, Maryland, USA.
3. GaBI Online - Generics and Biosimilars Initiative. Etanercept switching study investigates non-mandatory transitioning [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 May 4]. Available from: www.gabionline.net/Biosimilars/Research/Etanercept-switching-study-investigates-non-mandatory-transitioning
4. GaBI Online - Generics and Biosimilars Initiative. Positive phase III switching results for Celltrion’s infliximab biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 May 4]. Available from: www.gabionline.net/Biosimilars/Research/Positive-phase-III-switching-results-for-Celltrion-s-infliximab-biosimilar
5. GaBI Online - Generics and Biosimilars Initiative. NOR-SWITCH study finds biosimilar infliximab not inferior to originator [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 May 4]. Available from: www.gabionline.net/Biosimilars/Research/NOR-SWITCH-study-finds-biosimilar-infliximab-not-inferior-to-originator
6. GaBI Online - Generics and Biosimilars Initiative. Positive results for etanercept and bevacizumab biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 May 4]. Available from: www.gabionline.net/Biosimilars/Research/Positive-results-for-etanercept-and-bevacizumab-biosimilars
7. Ebbers HC, Muenzberg M, Schellekens H. The safety of switching between therapeutic proteins. Expert Opin Biol Ther. 2012;12(11):1473-85.
8. GaBI Online - Generics and Biosimilars Initiative. Interchangeability and switching study designs for biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 May 4]. Available from: www.gabionline.net/Reports/Interchangeability-and-switching-study-designs-for-biosimilars

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