BioRationality: Removing the Misconceptions Surrounding Interchangeability

The US is the only country in the world that has 2 classes of biosimilars: “biosimilars” and “interchangeable biosimilars.” The second status qualification requires extensive switching and alternating clinical efficacy studies for most cases, none of which have ever failed. Still, hundreds of millions of dollars are spent by biosimilar manufacturers to secure interchangeable status even if the product is not dispensed at the pharmacy level—where this designation may have meant value—leaving this status to mislead decision-makers that some biosimilars are better than others. Some stakeholders, including the developers and their associations, are working hard to remove this unique status of biosimilars in the US. Still, these efforts fail because they misunderstand the line between legislation and scientific rationale.

For a biosimilar to be considered interchangeable, it must satisfy 3 conditions. First, it must be an FDA-approved biosimilar; second, it must produce the same clinical outcome as the reference product in any given patient for any given indications; and third, if the biosimilar medication is given more than once to the same patient, either switching from the reference product or alternating with the reference product, it must produce the same efficacy and have no greater risk of adverse events as when the reference product is used alone (with no switching or alternating).

In addition, the FDA requires robust postmarket safety monitoring for interchangeable biosimilars. A biosimilar product that receives the first interchangeable designation has exclusivity for an entire year. It is possible that multiple interchangeable biosimilars could share a period of initial interchangeable exclusivity if they are approved on the same day. Although the FDA does not require interchangeable biosimilars to seek licensures for all indications for which the reference product is licensed, it is recommended.

There is a need to remove misconceptions about interchangeable biosimilars. First, it applies to substitution at the dispensing level, eliminating most biological drugs. Second, it does not prevent a developer from requesting an interchangeable status regardless. In all instances, to secure an interchangeable status, the developer must make a particular filing after the approval as a biosimilar or simultaneously to the first application. Thirdly, to date, the FDA has approved 49 biosimilars representing 15 molecules out of more than 200 available choices and 10 interchangeable biosimilars with 5 molecular entities (2 insulin glargine, 3 adalimumab, 2 ranibizumab, 1 ustekinumab, and 2 denosumab). Although most of these medications are dispensed at the pharmacy level, ranibizumab is administered intravitreally at the clinic under a physician's supervision.

The FDA has recently changed the labeling of biosimilars, removing the term “interchangeable” from the label with the following justification: “Because interchangeability pertains to pharmacy-level substitution, it is more appropriate to include information about interchangeability in the Purple Book, which may be easier to use as a pharmaceutical reference, rather than in product labeling, which is prescriber-focused” And: “Prescribers can prescribe both biosimilar and interchangeable biosimilar products in place of the reference product with equal confidence that they are as safe and effective as their reference products”

The biosimilar stakeholders have taken an active role, wherein a deluge of peer-reviewed publications shows that the test for interchangeability never fails. PubMed reports over 400 such papers, while the number of papers on biosimilars exceeds 6000. A recent paper reports that as of 31 December 2023, 31 observational studies that included a total of 6081 patients who underwent switching and alternating showed no impact on the safety and efficacy; the same journal has published around 300 articles on “interchangeable biosimilars.” While such findings should bring confidence in biosimilars, these do little to achieve the goal of getting more biosimilars to patients.

A common misconception is that such studies can convince the FDA to remove the interchangeable status of biosimilars, not realizing that the FDA does have the power to change the clauses in the Biologics Price Competition and Innovation Act. The interchangeable status is a legislative authorization that requires Congressional action. The focus of the interchangeability studies should be to convince the FDA that clinical efficacy testing should be waived, an action that is within the powers of the FDA. An argument is that if the intensive interchangeability studies do not fail, then the chance of a single study failing should have been called out in these papers. To support the argument, they should have cited the weakness of the study power, the heterogeneity of the test population, and the robustness of analytical and clinical pharmacology comparisons that are robust to efficacy testing.

Also missing in these papers, written mainly by the biosimilar industry authors, is the status of pending bills in the Senate to remove interchangeability and other hurdles in adopting biosimilars. Even the FDA has refused to accept the 2025 budget, suggesting the removal of interchangeability and preferring a legislative change.

As the biosimilar industry writers have gained much support from prestigious journals, it is time that they bring rational solutions—it is not up to the FDA when it comes to removing interchangeability; they are better advised to engage in dialog with the US Senate and work with the FDA to remove clinical efficacy testing.