In early October 2023 it was announced that the U.S. Food and Drug Administration (FDA) had designated Pfizer’s product Abrilada (adalimumab-afzb) as an interchangeable biosimilar to Humira (adalimumab). Abrilada had previously received FDA approval as a biosimilar to Humira in 2019.
The approval was based on the review of a comprehensive data package which demonstrated biosimilarity of Abrilada to the reference product. That first application included results from a clinical comparative study (REFLECTIONS B538-02) which found no clinically meaningful differences in efficacy, safety or immunogenicity compared to the reference product.
This recent interchangeable designation, which applies to all approved indications of Abrilada, is based on data from the additional Phase 3 REFLECTIONS B538-12 study which demonstrated the safety and efficacy of switching patients between the two products multiple times.
In the case of Abrilada, it is the second biosimilar designated interchangeable with Humira, the other being Cyltezo (adalimumab-adbm) from Boehringer Ingelheim and the fifth biosimilar overall to be deemed interchangeable.
In the United States, the specific biosimilar legislation “The Biologics Price Competition and Innovation Act (BPCI ACT, 2009)” established an abbreviated approval pathway for biological products effectively creating two “stages”: “biosimilar” and “interchangeable biosimilar”. Not all biosimilars are immediately designated as interchangeable.
An interchangeable designation is granted by the FDA to biosimilars that meet additional data requirements demonstrating that patients who alternate between the reference product and the biosimilar have the same clinical result as patients who are being treated with the reference product alone.
It is a common misconception however that an “interchangeable” biosimilar is superior to a “biosimilar”. The FDA states “Both biosimilars and interchangeable biosimilars are as safe and effective as the original biologic they were compared to” (1). The interchangeable designation demonstrates that specific “switching studies” have been performed to provide evidence that there are no higher rates of problems or adverse events or decreased efficacy.
In the US legislation, designation of an interchangeable status allows that the biosimilar may be substituted at the pharmacy level for the reference product without the intervention of the prescribing healthcare provider, depending on state pharmacy laws.
The United States is unique in instituting a separate legal definition of an interchangeable biosimilar. Other countries have different attitudes. In the European Union (EU) for example, where biosimilars were introduced much earlier than in the US, the decision of allowing substitution at the pharmacy level lies with each member state and the biosimilar regulations do not legislate for it.
The European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) issued a joint statement in April 2023 (2) confirming that biosimilar medicines approved in the EU are interchangeable with their reference medicine or with an equivalent biosimilar.
In other countries, such as Japan, interchangeability is automatically applied when the biosimilar is approved.
Since the development of the original biosimilar regulatory pathways in the mid 2000s, many products have been examined and scores approved, re-enforcing the credibility of the scientific basis behind the concept of “biosimilarity”.
The regulatory landscape continues to develop and evolve, building on nearly twenty years of experience allowing guidelines to be refined and updated as necessary. However, the essential premise of demonstrating biosimilarity, prior to safety, efficacy and immunogenicity assessment, through initial extensive structural and biological characterization and comparability against the reference product remains true.
The analytical tools we now have to assist us in these tasks are multiple and any good biosimilarity study will require the judicious choice of orthogonal techniques to interrogate the molecular structure of the complex biologic.
![Biosimilar_studies_1_2_3-V2[1]](data:image/svg+xml;base64,PHN2ZyB2aWV3Qm94PSIwIDAgODk1IDczNyIgd2lkdGg9Ijg5NSIgaGVpZ2h0PSI3MzciIHhtbG5zPSJodHRwOi8vd3d3LnczLm9yZy8yMDAwL3N2ZyI+PC9zdmc+ "Biosimilar_studies_1_2_3-V2[1]")
An overview of global Biosimilar regulations and the pros and cons of various methods which can be used to examine both novel and biosimilar primary and higher order structure will be outlined in an upcoming Masterclass.
