Biosimilars are biological products that are highly similar to an already approved biologic medicine (referred to as a reference product), with no clinically meaningful differences in terms of safety, purity, and potency. These medicines provide cost-effective alternatives to biologic medicines and are increasingly being used to treat various diseases, from cancer to autoimmune diseases. One of the most critical and scientifically complex aspects of biosimilar development is the concept of “extrapolation”.

Extrapolation allows a biosimilar to be approved for use in multiple clinical indications of the reference product without the need for conducting clinical trials for each one. This not only speeds up the availability of the drug but also significantly reduces development costs. However, to ensure patient safety and efficacy, the process of extrapolation requires rigorous scientific justification and regulatory scrutiny.

Understanding Biosimilars ¹

Before diving into extrapolation, it's important to understand what makes biosimilars different from small-molecule drugs or generic medicines. Traditional small-molecule drugs are chemically synthesized and have simple structures. Because of their simplicity, generic versions of these drugs can be easily created and shown to be identical to the original.

Biosimilars, on the other hand, are much more complex. They are derived from living cells, and their large molecular structure and production process can lead to inherent variability. Despite this variability, biosimilars must still demonstrate that they are “highly similar” to the reference product. The key is ensuring that any minor differences in the molecular structure do not affect the biosimilar's clinical performance.

What Is Extrapolation? ^2,3

Extrapolation refers to the regulatory approval of a biosimilar for use in clinical indications that were not directly tested in clinical trials, based on the “totality-of-evidence” gathered from analytical, preclinical, and clinical data. This approach is grounded in the understanding that the biological mechanism of action, pharmacokinetics (PK), and pharmacodynamics (PD) are likely to be similar across different conditions.

If a biosimilar is tested and proven effective for treating one form of arthritis, extrapolation might allow it to be approved for use in treating another type of arthritis (perhaps psoriatic arthritis), assuming the drug's mechanism of action is the same across both conditions.

In case of Samsung Bioepis, EPYSQLI™ (SB12), a biosimilar to Soliris⁴ (eculizumab) was approved by the European Commission (EC) in May 2023 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) based on the totality-of-the-evidence including analytical, non-clinical, and clinical data in healthy subjects and PNH patients.⁵ In March 2024, EC adopted an additional indication of atypical hemolytic uremic syndrome (aHUS) for SB12 based on the principle of extrapolation, also supported by the totality-of-the-evidence.

The Scientific Rationale Behind Extrapolation ⁶ 

The foundation of extrapolation lies in robust analytical and preclinical data. Analytical studies are used to demonstrate the high similarity between the biosimilar and the reference product at a molecular level. These studies typically include comparing the structure, function, and biological activity of the two products.

Next, preclinical studies assess the pharmacokinetics (how the drug moves through the body) and pharmacodynamics (how the drug affects the body) of the biosimilar. If these studies demonstrate that the biosimilar behaves similarly to the reference product, it becomes possible to assume that it will work similarly across different patient populations or diseases.

Finally, limited clinical studies, usually in a single disease state, are conducted to confirm that the biosimilar has similar efficacy and safety to the reference product. When all this evidence is combined, regulators may allow extrapolation to other conditions for which the reference product is already approved.

Regulatory Considerations

Regulatory agencies like the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have established stringent guidelines for the extrapolation process. These guidelines emphasize the need for a "totality-of-evidence," meaning that extrapolation is only allowed when there is strong scientific data supporting the biosimilar's similarity to the reference product. Regulatory bodies assess the mode of action, safety profile, and disease pathology before granting approval.

Biosimilar extrapolation is a scientifically robust process that leverages the totality of evidence to increase access to life-saving biologics while ensuring safety and efficacy. It represents a major advancement in modern medicine, offering a pathway to more affordable treatments without compromising on quality. Through careful regulation and thorough scientific evaluation, biosimilars can play a vital role in the future of healthcare, offering more treatment options for patients worldwide with fraction of the cost.