The Sandoz Perspective on Biosimilar Interchangeability: A Designation Unique to the United States

The FDA recently issued its final guidance on demonstrating interchangeability of a biosimilar medicine with a reference product. While we applaud the FDA for providing regulatory clarity, we should first examine the concept of interchangeability and whether it is necessary.

Interchangeability is a regulatory designation unique to the United States that is defined in the Biologics Price Competition and Innovation Act (BPCIA), the legislation establishing biosimilar and interchangeable biologic pathways. According to FDA guidance, drug sponsors must provide additional and different clinical information to obtain an interchangeability designation for approved biosimilar medicines.

An interchangeability designation enables pharmacists to offer patients a potentially more affordable — and equally safe and effective — biosimilar medicine option at the counter without contacting the prescribing physician first. However, the additional research burden and costs for a biosimilar drug to be considered interchangeable by the FDA are substantial.

In addition, the very creation of an interchangeable designation has unintentionally led to yet another barrier for biosimilar adoption in the United States by inadvertently suggesting that it denotes a higher quality standard than biosimilarity because it requires more data.

This suggestion is simply not true, because the FDA requires the same quality standards for biosimilars and interchangeable biologics, and there is no scientific basis for creating a separate category.

A molecule approved as a biosimilar medicine is not altered in any way before conducting the clinical study required by the FDA to obtain an interchangeability designation. As a result, there is no difference in quality between a biosimilar and interchangeable biologic. This point must be emphasized to healthcare professionals and to patients to counter misconceptions that interchangeability is a higher quality standard.

The requirement for additional and different data is based on a belief that subtle structural differences may exist between a biosimilar and its reference biologic that are only clinically relevant when "switching interchangeably," or switching multiple times back and forth between reference biologic and a biosimilar. This is, however, a purely hypothetical argument that lacks any supportive data.

Advanced analytics are accepted by the scientific community to provide power to detect subtle differences in structure when evaluating biosimilarity. There is no reason to disregard this capability when considering interchangeability and to instead require a clinical study.

While we believe that the concept of interchangeability as a distinct category has no scientific basis, we do acknowledge the reality that interchangeability is incorporated into the BPCIA and needs to be addressed as a practical matter.

With that in mind, we are pleased to see the FDA has become more flexible in its willingness to accept reference product material sourced from outside of the United States. However, sponsors must provide the FDA with convincing data to support such a request, and this may prove exceedingly difficult owing to the requirement to prove the absence of "subtle differences." We are also glad to see that the requirement for a unique statistical evaluation of human factor studies was removed from the guidance, and that human factor studies will instead be conducted in a manner consistent with that required for other drugs.

There are still a few unknowns to the guidance remaining, and the central requirement to obtain interchangeability remains unchanged, requiring sponsors to conduct an extensive, comparative pharmacokinetic (PK) study using multiple switches followed by an extended follow-up period — criteria not mandated for PK studies of novel drugs, including originator biologics. This requirement is technically challenging and increases research and development expenses, as sponsors must enroll a large number of patients to account for relatively higher dropout rates in studies of such a long duration.

Given the extended time necessary to do the additional required study and the reality that some may not prescribe or be willing to take a biosimilar unless it has an interchangeability designation, Sandoz is concerned that the separate regulatory designation of "interchangeability" will delay patient access to these therapeutic options.

Sandoz was the first to bring biosimilars to US patients, and is the only US success story to date with a biosimilar surpassing its reference biologic in market share. With Zarxio, which does not have an interchangeability designation, we have proven that biosimilars create early and expanded patient access to life-changing biologics while increasing healthcare savings and fueling innovation.

Biosimilars can help provide millions of patients more affordable and accessible treatments. They create the potential to save the US healthcare system $54 billion over 10 years. While scientifically questionable, it remains to be seen if the regulatory distinction of interchangeability will bring any benefit to patients, or if it will instead be a barrier to access these more affordable therapeutic options.