Extrapolation Framework Can Guide Off-Label Determinations for Biosimilars, Study Argues

In clinical practice, biologics are routinely used for medically accepted off-label indications, and these uses are typically curated by guidelines. A newly published study, led by Edward Li, PharmD, MPH, BCOP, argues that the FDA’s framework for granting the extrapolation of indications for biosimilars can be used by clinicians and payers to determine appropriate off-label uses of biosimilars.

The study’s authors conducted a literature review to gather and interpret data in the context of the FDA’s extrapolation framework to ascertain whether biosimilars could be used in off-label indications with scientific justification. Briefing documents—submitted by product developers to the FDA’s advisory committees—were reviewed to determine if differences in mechanisms of action, pharmacokinetics and biodistribution, immunogenicity, and toxicity across on-label indications would affect the evaluation of 2 biosimilars, infliximab-dyyb (Inflectra) and filgrastim-sndz (Zarxio) for the off-label indications of immune-mediated colitis and myelodysplastic syndromes, respectively.

Data collected, the authors reported, were intended to answer 2 questions. First, what are known to be the differences (if any) between the on-label indications and off-label indications for the reference product? Second, how does the totality of the evidence with the biosimilar affect the differences (if any) of the reference product?

In the case of reference infliximab, published case studies show that infliximab has been used successfully to treat severe immune-related colitis (an off-label use). There is no evidence to suggest that using biosimilar infliximab would produce different clinical result in patients with immune-mediated colitis based on the similar mechanism of action.

“The totality of the evidence with the biosimilar makes the case that infliximab-dyyb is an appropriate option in this setting,” wrote the authors.

In the case of filgrastim, National Comprehensive Cancer Network guidelines support the use of reference filgrastim in myelodysplastic syndromes. Because Zarxio is expected to stimulate the production of mature neutrophils to the same degree as the reference product, clinicians and payers may consider the use of Zarxio for symptomatic anemia associated with myelodysplastic syndromes to be scientifically justified.

The authors concluded that, in some cases, using biosimilars for off-label indications is scientifically justified.

“Coverage policy decisions are based on a review of the level of evidence supporting an indication, and decision makers recognize compendia and professional society guidelines in their evaluation of the evidence,” the authors added, and noted that it is incumbent upon compendia curators to conduct formal assessments of biosimilars’ off-label indications using the FDA’s framework for extrapolation.