Application of the FDA Biosimilar Extrapolation Framework to Make Off-Label Determinations.

Abstract

The FDA's extrapolation framework allows for a biosimilar to obtain licensure for indications that were not explicitly studied in the context of a clinical trial by extending conclusions from studies in 1 population to make inferences in other populations. Within routine clinical care, drugs and biologics are routinely used for medically accepted off-label indications. The appropriateness of these products for off-label indications are typically curated by compendia and guidelines, which have established processes and criteria for reviewing and evaluating the evidence to make such determinations. The evidence paradigm for biosimilars is different from originator biologics and is one of comparability to a reference product, not to reestablish clinical benefit. Thus, this paradigm shift can be applied to the exercise of making off-label determinations for biosimilars, and the FDA's framework of extrapolation can be used by clinicians and coverage policy decision makers to determine appropriate off-label indications for biosimilars. To highlight how the FDA's biosimilar extrapolation framework can be used to make off-label policy decisions, using to 2 approved biosimilars for filgrastim and infliximab as case studies. This study describes the FDA extrapolation framework for evaluating whether there are any differences in the mechanism of action, pharmacokinetics/biosdistribution, immunogenicity, and toxicity between on-label and off-label indications. Two case studies are presented that evaluate the biosimilars filgrastim-sndz and infliximab-dyyb for the offlabel indications of treating symptomatic anemia in patients with myelodysplastic syndromes and immune-mediated colitis, respectively. The analytical, nonclinical, and clinical pharmacology, along with clinical studies demonstrating that filgrastim-sndz and infliximab-dyyb are biosimilar to their respective reference products, are reviewed and discussed in context with the extrapolation framework to ascertain whether use of the biosimilar within the off-label indications is scientifically justified. The mechanism of action of filgrastim and infliximab between their FDA-approved and off-label indications are the same. In addition, there is a high degree of similarity with the analytical and nonclinical characteristics of filgrastim-sndz and infliximab-dyyb and their respective reference products. There is no expectation of differences in safety and immunogenicity across the patient populations. Thus, some decision makers may determine that filgrastim-sndz and infliximab-dyyb be used for the off-label indications of treating symptomatic anemia in patients with myelodysplasia and immune-mediated colitis, respectively. In some cases, the use of biosimilars for off-label indications can be scientifically justified. Since coverage policy decisions are intimately tied to compendia and guideline listings, it is incumbent upon these groups to conduct formal assessments of biosimilar off-label indications using the FDA extrapolation framework. No outside funding supported this study. Li discloses that he has received honoraria and/or paid travel expenses as an advisory board and speaker's bureau participant for Pfizer; for speaking on behalf of Mylan and Apobiologix; and for participating on advisory boards for Eli Lilly and Mylan. Lobaina has nothing to disclose. Li was responsible for study design and manuscript revision. Li took the lead in data collection and interpretation and manuscript preparation, along with Lobaina.