Extrapolation in Practice: Lessons from 10 Years with Biosimilar Filgrastim

Abstract

Biosimilar filgrastim (Sandoz) was approved in Europe in 2009 and, in 2015, was the first biosimilar approved in the USA. These authorizations were based on the "totality of evidence" concept, an approach that considers data from structural and functional characterization and comparability analysis and non-clinical and clinical studies. For biosimilar filgrastim, phase III confirmatory clinical studies were performed in the most sensitive population, patients with breast cancer undergoing myelosuppressive chemotherapy. In Europe and the USA, approval was granted for all indications of the reference biologic. Hence, stem cell mobilization and severe chronic neutropenia indications were approved on the basis of extrapolation, with no clinical data available at the time of market authorization in the EU. Although extrapolation is well-accepted in biologic development and regulatory contexts, it remains a misunderstood part of the biosimilarity concept in the medical community. Since approval, more than a decade of obtained clinical experience supports the totality of evidence and reassures clinicians regarding the efficacy and safety of biosimilar filgrastim. This includes real-world data from MONITOR-GCSF, a multicenter, prospective, observational study describing treatment patterns and clinical outcomes of patients with cancer (n = 1447) receiving biosimilar filgrastim for the prophylaxis of chemotherapy-induced neutropenia in solid tumors and hematological malignancies. Evidence is also available from unrelated healthy donors and those with severe chronic neutropenia. Together, the experience from a decade of use of biosimilar filgrastim includes over 24 million patient-days of exposure, which can help reassure oncologists that extrapolation is based on strong scientific evidence and works in practice.

Clinical and Regulatory Concerns of Biosimilars: A Review of Literature

“…Extrapolation is a rationale scientific principle used to describe the process when the proposed biosimilar receives all the approved indications of the originator, while performing comparative clinical studies of just one or two indications [ 60 , 61 ]. This rationale is acquired in phase three confirmatory clinical trials, although the results from each investigational phase impact the extrapolation of indications [ 61 ]. Still, limitations exist if particular indications are under patent protection [ 61 , 62 ].…”

“…This rationale is acquired in phase three confirmatory clinical trials, although the results from each investigational phase impact the extrapolation of indications [ 61 ]. Still, limitations exist if particular indications are under patent protection [ 61 , 62 ]. The integral key to comprehending extrapolation lies in the fact that the structure determines the clinical performance of the medicine [ 61 ].…”

“…Still, limitations exist if particular indications are under patent protection [ 61 , 62 ]. The integral key to comprehending extrapolation lies in the fact that the structure determines the clinical performance of the medicine [ 61 ]. Currently, this concept of transferring the safety and efficacy data from one indication to the other is not very clear to regulators and clinicians.…”

“…Currently, this concept of transferring the safety and efficacy data from one indication to the other is not very clear to regulators and clinicians. Whether the proposed biosimilar will be able to receive all the other indications from the originator, while performing a clinical trial for one indication, depends on several factors: mechanism of action, posology, pharmacokinetics, and population type [ 61 , 62 ].…”

Validation of Nivestym compared to Neupogen: An NMDP analysis

“…This is in line with other studies comparing other filgrastim biosimilars. 2 The first biosimilar to be approved, Zarxio was tested in a phase III trial of patients receiving chemotherapy for breast cancer. 3 Based on the equivalence shown in that study, approval was granted across all indications of filgrastim.…”