Clarifying the Extrapolation of Indications in Biosimilars

In 2017, the European Society for Medical Oncology (ESMO) published its position paper on biosimilars for oncology prescribers. Since the paper's publication, both the FDA and the European Medicines Agency (EMA) have approved biosimilar versions of monoclonal antibodies to treat multiple cancer types, but misconceptions about biosimilars are still prevalent.

An editorial recently published in The BMJ discusses addresses 1 of the most commonly misunderstood biosimilar concepts: extrapolation. The authors define extrapolation as “the authorization of a biosimilar medicine for clinical indications of the reference medicine without the need to conduct clinical trials of the biosimilar medicine in those indications.” The crucial part in understanding the concept is to first acknowledge that extrapolation is a well-established regulatory and scientific principle that has been used well before the arrival of biosimilar medicines.

As an example, the authors explain that the principle of extrapolation is also applied after major changes in the manufacturing process of a biologic. When this kind of change takes place, the manufacturer is required by regulatory agencies to conduct a comprehensive comparability exercise to establish that the pre-manufacturing change and post-manufacturing change products are sufficiently similar. Clinical data are usually studied in 1 indication and extrapolated to the other indications, while taking into account all data generated by the comparability exercise.

The authors note that potential confusion around extrapolation may come about from the term itself. When utilized in mathematical terms, "extrapolation" refers to the projection of unknown values from trends in known data. However, when the term is applied to biosimilar medicines, extrapolation is based on the knowledge that the biosimilar medicine is similar to the reference in all critical quality attributes. In fact, Health Canada previously acknowledged the confusion around the terminology and consequently removed the term “extrapolation” from its biosimilar guidance in 2016.

The authors say that it is important to understand that extrapolation is undertaken from the reference to the biosimilar medicine—molecule to molecule—rather than from 1 indication in which the biosimilar medicine has been studied to other indications. Furthermore, each extrapolated indication needs to be scientifically justified and assessed by regulators.

“From regulatory and scientific viewpoints, the active substance of a biosimilar is just another version of the active substance of the reference medicine,” said the authors.

Reference

Krendyukov A, Schiestl M. Extrapolation concept at work with biosimilar: a decade of experience in oncology. Published February 6, 2018. Br Med J. doi:10.1136/ esmoopen-2017-000319.