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FDA routinely reviews and approves changes to brand biological products that occur when a manufacturing process is changed based on comparability studies. FDA considers the “pre-approval” and the “post-approval” products to be interchangeable, and the label of the product does not change. However, FDA comments and the Agency’s draft guidances on biosimilars suggest FDA may be slow to allow interchangeability for biosimilars. Potential sponsors can still request the interchangeability designation at the initial filing of their biosimilar application, but unlike with manufacturing changes, they can expect that FDA will require a clinical switching study between the originator, a reference study, and the biosimilar.

What is interchangeability?

According to the new law, interchangeability means that the biosimilar can be substituted for its reference originator product without the involvement of the health care provider who wrote the initial prescription - just as is the case today for generic drugs. A physician can always override substitution for any medicine, drug or biologic, by checking the “Do Not Substitute” box that is found on every prescription. FDA can designate the biosimilar as interchangeable with its reference based on any evidence that the Agency considers appropriate to fulfill the law’s requirements.

What does FDA guidance on biosimilars recommend?

FDA has not issued specific recommendations on interchangeability. However, FDA has said that they consider interchangeability a higher standard than biosimilarity, and indicated their preference for a two-step approach by which a company first proves “biosimilarity” before requesting an “interchangeability” designation. Nonetheless, the new law allows sponsors to submit a single application for an interchangeable biosimilar today. Biosimilars are being routinely switched for their reference product in other highly regulated markets and this data may be of value to FDA, or the Agency may wait to address interchangeability after gaining experience with the first biosimilars in the US. FDA may issue additional guidance on interchangeability in the future.

What is the practical approach for determining interchangeability?

No other global regulatory agency makes a distinction between biosimilarity and interchangeability. Given the international experience with interchangeability, a two-step approach to determining “interchangeability” may be unnecessary. Despite FDA’s preference for a two-step approach, FDA is not legally required to approve a product as interchangeable before sponsors seek an interchangeability designation. Thus, lack of specific FDA guidance still allows biosimilar manufacturers to request a biosimilar be designated as interchangeable. Industry will likely propose approaches for interchangeability based on individual product characteristics. Initial approaches will likely include a clinical “switching” study. Therapeutic substitution by physicians may be a more pragmatic approach for near term to increase access and affordability for patients.