Concepts of biosimilars

Biosimilar development, under EMA and FDA regulations, focuses on the totality of the evidence of an all-encompassing comparability exercise. In order to receive the biosimilar regulatory designation, the proposed product must pass non-clinical analytical, pharmacological as well as confirmatory clinical studies to remove in a step-wise approach the uncertainty of comparability and subsequently to demonstrate biosimilarity to a reference product. The development of a biosimilar can take 8–10 years at an estimated cost of $100–200 million (in contrast, these values for a generic drug are 3-5 years and $1-5 million, respectively).^1-3

Biosimilar development steps (please click on different steps for more explanation). Adapted from Wolff-Holz E, et al. ESMO Open 2018;3(6):e000420; Mihalcik L, et al. Regul Toxicol Pharmacol 2021;122:104912.

Biosimilar products are modeled after a product with an established risk-benefit profile, thoroughly studied in large nonclinical and clinical study programs. There is usually a wealth of information available for these reference products, including years of commercial use in large and diverse patient populations.^2,3

The focus of biosimilar development is not to establish a risk-benefit profile, but to demonstrate similarity to a reference product. This starts with thorough biochemical characterization of both the proposed biosimilar and the reference product.^2,3

Healthcare authorities require that the biochemical fingerprint of critical and non-critical product quality attributes (CQA) must be defined for each biologic with standardized, so called “state of the art” analytical methods and replicated in a biosimilar. The extent of variation in each of the CQA must be characterized for the originator molecule and systematically matched as closely as possible, ensuring that the biosimilar is reverse engineered to meet similar specifications.^2,4,5

Replicating highly complex biologics has been made possible due to enormous analytical advances, reducing the need for extensive clinical evaluation. Therefore, the clinical program of a biosimilar aims to confirm that proteins with highly similar structures and biochemical pactivity have similar pharmacokinetic (PK) and pharmacodynamic (PD) profiles.²

The phase I and phase III clinical studies are designed to demonstrate equivalence in PK parameters and in efficacy endpoints and to compare safety and immunogenicity profiles between a biosimilar and its reference product. A phase 2 dose finding study is not required as the same, well-established dosing is used for the biosimilar and the reference product. An equivalence study design is used which aims to prove that differences in response between the biosimilar and reference product are clinically unimportant – i.e. neither the biosimilar nor the originator is superior or inferior to the other. Endpoints and equivalence margins are predefined and endorsed by the regulators scientific advice.⁵

Similar to the reference product, ongoing pharmacovigilance activities will further evaluate effectiveness and safety profiles of biosimilars post approval.^2,3

When similarity of a biosimilar to a reference biologic has been comprehensively shown in a key indication, extrapolation of efficacy and safety data to other indication(s) of the reference product may be possible. The European regulatory agency (EMA) and the US FDA require an acceptable scientific justification to extrapolate clinical data from one indication to another.^7,8

Requirements of reasonable scientific justification for extrapolation include: 1) the principle of similar mechanism of action by understanding the mode of action of the reference product in different indications, 2) similar pharmacokinetic profiles across indications, 3) using a sensitive patient population for clinical studies to detect clinically meaningful differences in efficacy and safety profiles, in particular excluding risk of increased immunogenicity.^7,8

FDA. Biosimilar product Regulatory Review and Approval. Available from: https://www.fda.gov/files/drugs/published/Biosimilar-Product-Regulatory-Review-and-Approval.pdf, accessed Feb 2025.

As an example, the pharmacological activity of TNF alpha inhibition with anti-TNFs is well established for different indications of chronic immune mediated inflammatory diseases. To date there are 17 anti-TNF biosimilars approved by the European Medicines Agency. While most confirmatory phase 3 equivalence studies of biosimilars were performed in RA as the sensitive patient population, they are widely used across different indications.^9,10

Post-marketing surveillance shows that until August 2020, the highest patient exposure of biosimilars in Europe was with anti-TNFs. There were no biosimilar-specific adverse effects, and no product was withdrawn for safety reasons.¹⁰

Interchangeability refers to exchanging one medicine for another that is expected to achieve the same clinical efficacy with the same/a comparable safety profile. For biosimilars this means that switching between a biosimilar and its licensed reference product or another biosimilar can be done without concerns of efficacy, tolerability or immunogenicity.¹¹

In clinical practice, the replacing of a reference product with a biosimilar, a biosimilar with a reference product, or one biosimilar with another is known as switching, if mandated by the physician. In contrast, the practice of dispensing one medicine instead of another medicine without consulting the prescriber refers to auto-substitution.¹¹

From a regulatory viewpoint, the definitions and legal status of the term interchangeability vary across the jurisdictions of EMA and US FDA:

For the EMA, the term interchangeability is a scientific rationale and should not be equated to the term auto-substitution. It acknowledges that interchangeable use of biosimilars is already practiced in many European Member States. In September 2022, the EMA released a joint position statement to harmonize the EU approach with the aim to bring more clarity for healthcare providers and to help more patients to have access to biological medicines across the EU.¹²

The EMA considers that once a biosimilar is approved in the EU, it is interchangeable, which means the biosimilar can be used instead of its reference product (or vice versa) or one biosimilar can be replaced with another biosimilar of the same reference product without patients experiencing any changes in the clinical effect. No additional systematic switch studies are needed to support the interchangeability. Decisions regarding substitution (the practice of dispensing one medicine instead of another medicine without consulting the prescriber), are not within the remit of the EMA and are managed by individual European member states.¹²

By the US FDA, the term interchangeability is a regulatory designation. It is the legal justification that a reference product can be substituted with an interchangeable biosimilar at the pharmacy without the intervention of the prescribing healthcare professional.^11,13 It only permits a biosimilar to be automatically substituted for its licensed reference product, not other biosimilars of the same reference product.^14,15

In 2019, the FDA released guidance to industry on considerations to demonstrate interchangeability of a biosimilar with its reference product. At that time, the FDA had a very strong position that data from “switching studies” must be required to assess the risk, in terms of safety and diminished efficacy when switching between reference product and the biosimilar product. Since then, the scientific approach to when a switching study, or studies, may be needed to support a demonstration of interchangeability has evolved. The FDA acknowledges that 10 years valuable experience, reviewing both biosimilar and interchangeable biosimilar medications, showed that biosimilars and interchangeable biosimilars meet the same high standard of biosimilarity for FDA approval and both are as safe and effective as the reference product. Hence, the FDA is in the process of updating its guidance to the pharmaceutical industry on interchangeable biosimilars, with recommendation of fewer tests to demonstrate interchangeability. The US regulatory agency also recently released a list of “9 Things to Know About Biosimilars and Interchangeable Biosimilars”.^13,14,16