The agency received 52 comments on the draft guidance, which was first released in January 2017 [2]. Many of these comments came from big pharma companies, including AbbVie, Amgen, Boehringer Ingelheim, Genentech, Johnson & Johnson, Pfizer, Merck, Sandoz and more.

Many comments concentrated on the issues of switching studies and FDA’s requirements for interchangeability. But other issues raised included naming and labelling, definitions, extrapolation and exclusivity. This first article covers comments on efficacy endpoints and analysis and interchangeability. The next two articles cover comments on extrapolation, immunogenicity, different presentations, definitions, exclusivity, switching and labelling and naming.

1. Efficacy endpoints and analysis
Comments from AbbVie included that ‘the endpoints and statistical methods FDA recommends for use in assessing interchangeability are insufficient to ensure patient safety’. They added that ‘to comply with the “same clinical result” and “alternating or switching” requirements, the guidance should call for a statistically robust analysis of efficacy endpoints and a comprehensive assessment of potential immunogenicity risks associated with alternating or switching’. In addition, ‘to ensure that an interchangeable biological product can be expected to produce the same clinical result as its reference product in “any given patient”, the guidance should call for individual‐level bioequivalence assessments’.

Comments from Johnson & Johnson concluded that the ‘any given patient’ standard meant that ‘a proposed interchangeable product be assessed in each condition of use of the reference product’. The company questioned the logic of only giving direct measures of immunogenicity secondary importance when assessing immunogenicity in switching studies.

Merck supports FDA’s approach ‘that PK testing should be used for the primary endpoint analysis, as well as potentially PD [pharmacodynamics] testing, and safety, immunogenicity and efficacy should be descriptively analyzed as secondary endpoints’. However, it also recognizes ‘that flexibility is needed, as in some circumstances it may be more appropriate, depending on the molecule, to use testing other than PK [pharmacokinetics] or PD for the primary endpoint analysis’. The company also questioned how the ‘any given patient’ requirement ‘may be met’ and asked ‘how FDA interprets’ this and ‘whether the Agency sees an association between this requirement and BE [bioequivalence] testing’.

Sandoz pointed out that ‘immunogenic events with significant safety sequelae may occur without impacting PK or PD’. They added that ‘it is also possible that changes may be detected in PK or PD that are not linked in any manner to immunogenicity but to changes in the underlying disease or concomitant medication’. To avoid this confounding factor, the company recommends to ‘conduct the switching studies in healthy subjects’.

2. Interchangeability
AbbVie highlighted the need for ‘robust postmarketing data’ … ‘to establish interchangeability’. They added that the ‘the final guidance should recommend labelling to address situations where multiple biosimilar products are found interchangeable with the same reference product’.

In its comments, Amgen requested that ‘FDA make clear that an interchangeability designation does not confer a relationship between two biologics[al], that are each designated as interchangeable to the same reference product’.

Sandoz commented that FDA should clarify that ‘interchangeability is a requirement for additional data and does not represent a higher standard for the product itself’. They added that ‘any suggestion that a biosimilar is somehow less safe and effective before it is designated as an interchangeable biologic[al] is clearly an inappropriate conclusion since it is the very same product (molecule and formulation)’. The company also states that the agency’s requirements for interchangeability ‘significantly exceed the Agency’s requirements for evaluation of post-approval manufacturing changes that often lead to changes in critical quality attributes’. Sandoz believes that ‘biosimilars seeking an interchangeability designation should not be subjected to rigorous requirements that go beyond those required for process changes for reference products’.

Pfizer was also concerned about any perception that biosimilars were somehow of lower quality than interchangeable biologicals. They commented that ‘the FDA should ensure guidance does not promote inaccurate perceptions of the quality, safety and effectiveness of interchangeable products versus biosimilars’.

Related articles
Physician associations comment on FDA’s interchangeability guidance

Comments on switching in FDA’s interchangeability guidance from Big Pharma

Comments on extrapolation in FDA’s interchangeability guidance from big pharma

Comments on FDA’s interchangeability guidance

References
1. GaBI Online - Generics and Biosimilars Initiative. FDA extends comment period for interchangeability guidance [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Jun 9]. Available from: www.gabionline.net/Guidelines/FDA-extends-comment-period-for-interchangeability-guidance
2. GaBI Online - Generics and Biosimilars Initiative. FDA issues draft guidance on biosimilar interchangeability [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Jun 9]. Available from: www.gabionline.net/Guidelines/FDA-issues-draft-guidance-on-biosimilar-interchangeability

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