Biosimilars 101:Commonly asked questions

It’s been less than three years since the first biosimilar launched in the U.S., yet analysts are reporting that the worldwide biosimilar market will reach $90 billion over the next 10 years. Since 2015, the FDA has approved nine for use in the United States – and many more are in the late stage pipeline. Mandates to decrease healthcare costs and increase access to lifesaving drugs are expected to continue to drive demand for biosimilars. Here, we answer some of the most common questions about this new class of medications – and about the abbreviated FDA pathway for bringing these new therapies to market.

Q: What’s the difference between a biologic and a biosimilar?

A: Biologics are protein-based therapeutic products, produced using living organisms. Most biologics are very large, complex molecules or mixtures of molecules, and many are produced using recombinant DNA technology. Unlike drugs, biologics do not have well-defined chemical structures that can be exactly replicated. Biosimilars are highly similar to – but not identical to – the biologic reference product they emulate. Biosimilars have no clinically meaningful difference with the reference product in terms of safety, purity or potency.

Q: Is a biosimilar the same as a generic biologic?

A: Biosimilars are not generic versions of biologics. Generics are made by mixing together known chemicals and reagents in a series of controlled and predictable chemical reactions, so the chemical structure will be identical to the reference product. In contrast, biosimilars are highly similar, but not identical to their reference products, because the reference biologic is made from a living organism.

Q: What are the FDA regulatory requirements for biosimilars?

A: The FDA’s abbreviated pathway for biosimilars allows biosimilar developers to rely on previously established scientific knowledge about the biologic reference product. The goal of the abbreviated pathway is to save time by avoiding the unnecessary duplication of clinical and non-clinical testing that the biologic reference product has already conducted.

Biosimilars are approved under the BLA 351(k) application pathway. Unlike the 351(a) application (approval pathway for new biologics), the goal of a 351(k) application is not to establish safety and efficacy, per se, because the reference product manufacturer has already done that. Rather, the purpose of the 351(k) application is to produce patient results similar to the reference product.

Q: What is extrapolation and what role does extrapolation play in biosimilar approval?

A: Extrapolation allows a biosimilar candidate to potentially be approved for use in indications approved for the reference product, even if those indications were not studied as part of the clinical development program for a biosimilar.

An example of extrapolation of data is the introduction of a new subcutaneous formulation of an IV applied product. Although the formulation and bioavailability of the subcutaneous product will be different, one clinical study is usually sufficient to grant several, if not all, clinical indications approved for the IV product.

However, extrapolation is not automatic. Scientific justification for extrapolation of claims of safety and efficacy for the tested and extrapolated indications must address whether the mechanism of action is expected to differ across indications; whether the product’s PK/PD and biodistribution is expected to vary across patient populations; whether the product’s immunogenicity is expected to vary in different patient populations; and whether there are differences in toxicity in different indications and patient populations.

Q: What evidence does the FDA require to demonstrate biosimilarity?

A: The 351(k) application relies on previous findings that prove that the FDA-approved reference product is safe and effective. However, the application should also contain analytical, animal and clinical data demonstrating biosimilarity to the reference product. The applicant must also provide evidence that the biosimilar product uses the same mechanism of action as the reference product; that the condition(s) of use proposed in labeling have been previously approved for the reference product; and that it has the same route of administration, dosage form and strength as the reference product. The applicant must also prove that the facility in which the biosimilar will be manufactured, processed, packed, or held meets regulatory standards.

Q: Does the FDA require developers of biosimilars to perform phase III safety studies to prove biosimilarity?

A: Demonstrating similarity through analytical characterization is often more valuable than clinical studies, and serves as the foundation of a biosimilar development program. FDA guidance states that clinical studies just confirm the similarity and sometimes aren’t needed. However, to date, in the US, there has not been a 351(k) biosimilar application submitted without clinical studies.

Q: Does FDA limit the number of biosimilars that can be approved for a specific reference product?

A: No – the FDA has not provided any guidance limiting biosimilar development in this way.

To learn more background about biosimilars, and to get insights about how to steer a biosimilar to regulatory success, check out a replay of our biosimilars webinar, which is available on-demand, thanks to FierceMarkets.