AbbVie, Inc., a biopharmaceutical company, has submitted a citizen petition to the FDA regarding determinations of interchangeability under the BPCIA. An interchangeable biological product is biosimilar to a reference product and meets additional, heightened standards for interchangeability. While biosimilars are required to be highly similar to an FDA-approved reference product, an interchangeable biological product is expected to produce the same clinical result as the reference product in any given patient. A determination of interchangeability is significant because an interchangeable biological product may be substituted for a reference product by a pharmacist without requiring permission from the physician who prescribed the reference product. While the FDA approved the first biosimilar biological product in early 2015, it has yet to issue a decision that one biological product is “interchangeable” with another.
AbbVie’s petition makes three main points. First, in assessing interchangeability, the FDA should ensure that applicants meet the “Safety Standards for Determining Interchangeability” set forth in PHSA section 351(k)(4) “with respect to each condition of use for which the reference product is licensed, regardless of whether the applicant intends to label its product for every such condition of use.” AbbVie notes that generic small molecule drugs are the “same” as their reference listed drug counterparts, meaning that they will be therapeutically equivalent to the reference drug for any condition of use for which the reference drug is labeled. Pharmacists may substitute a generic drug without considering the condition of use for which the reference drug was prescribed.
State laws governing pharmacy substitution of biologics typically function in the same way, directing the pharmacist to dispense an interchangeable biological product when one has been approved by the FDA, regardless of whether the product to be substituted is labeled for the prescribed use in question. Because state laws effectively treat interchangeable biologics as functionally the same as generic small molecule drugs, AbbVie argues that the FDA needs to ensure that biological products listed as substitutable are, in fact, interchangeable for all the indications and conditions of use of the reference product. It supports its argument with, among other things, the statutory text, which permits an interchangeability determination only if the proposed interchangeable product and the reference product “can be expected to produce the same clinical result as the reference product in any given patient.”
Second, AbbVie requests that the FDA “clarify that the statutory standards for establishing interchangeability differ in both kind and scope from the standard for establishing biosimilarity.” In order to establish interchangeability, an applicant must show, for each condition of use, that (1) the biological product is biosimilar to its reference product and (2) “can be expected to produce the same clinical result as the reference product in any given patient,” and further (3) in the case of a biological product administered more than once to a patient, “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.” According to AbbVie, this high standard requires “an unprecedented level of certainty,” which cannot be presently met with analytical testing alone. Rather, a demonstration of interchangeability will require clinical testing. As AbbVie points out, the Center for Drug Evaluation and Research has indicated that it intends to issue guidance on considerations in demonstrating interchangeability, but has yet to do so. AbbVie suggest that any FDA guidance on interchangeability should address the “real-world possibility that different interchangeable biological products corresponding to a single reference product will be substituted and switched over the course of a single patient’s treatment.” As such, all biological products that have been found to be interchangeable with a single reference product must be interchangeable with one another. As a public health matter, because many patients receive biological products for long-term therapies, the FDA should set “the standard for interchangeability determinations for chronic therapies.”
Third, AbbVie requests that the FDA convene a part 15 hearing on interchangeability to obtain public input on issues including “the implications of interchangeability determinations in a multi-source product environment where multiple biological products have been found interchangeable with a single reference product, but not each other…” The FDA should then issue guidance or regulations addressing this issue. AbbVie points to the 2010 and 2012 public meetings to discuss the implementation of the BPCIA, and notes that “questions regarding the BPCIA’s interchangeability provisions were largely left for another day.”