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

Area of Science:

• Biosimilarity and extrapolation in pharmaceutical science.
• Regulatory science and policy for biologics.
• Clinical pharmacology and therapeutic applications.

Background:

• The U.S. Food and Drug Administration (FDA) employs an extrapolation framework enabling biosimilar licensure for unstudied indications by extending data from one population to another.
• Off-label use of biologics is common, with compendia and guidelines assessing evidence for appropriateness.
• Biosimilar evidence focuses on comparability to reference products, not re-establishing clinical benefit, necessitating a distinct approach for off-label determinations.

Purpose of the Study:

• To demonstrate the application of the FDA's biosimilar extrapolation framework for off-label policy decisions.
• To utilize two case studies, filgrastim and infliximab biosimilars, to illustrate this process.

Main Methods:

• The study outlines the FDA's extrapolation framework, assessing mechanism of action, pharmacokinetics, immunogenicity, and toxicity for on-label versus off-label indications.
• Case studies of filgrastim-sndz and infliximab-dyyb examine their use for symptomatic anemia in myelodysplastic syndromes and immune-mediated colitis, respectively.
• Analytical, nonclinical, and clinical pharmacology data, alongside clinical studies demonstrating biosimilarity, were reviewed within the extrapolation framework.

Main Results:

• The mechanism of action for filgrastim and infliximab remains consistent between FDA-approved and off-label indications.
• Filgrastim-sndz and infliximab-dyyb exhibit high similarity in analytical and nonclinical characteristics to their reference products.
• No anticipated differences in safety and immunogenicity are expected across patient populations, supporting potential off-label use.

Conclusions:

• Biosimilar use for specific off-label indications can be scientifically justified.
• Compendia and guideline groups should formally assess biosimilar off-label indications using the FDA extrapolation framework to inform coverage policies.