On December 16, 2015, AbbVie submitted a citizen petition regarding the requirements necessary to show interchangeability of a biosimilar product. This petition follow’s AbbVie previous citizen petition and supplement regarding biosimilar labeling, as discussed in the following: The Name Game: AbbVie’s Citizen Petition Regarding Biosimilar Labeling and The Name Game Continues: AbbVie Files Supplemental Citizen Petition Raising Additional Concerns Regarding Biosimilar Labeling. AbbVie’s citizen petition follows the FDA’s approval of the first biosimilar, Zarxio®, in March 2015. See FDA Approves First Biosimilar: Sandoz’s Zarxio®. However, Zarxio® was not approved as an interchangeable product. Id. To date, no biosimilar has received approval as interchangeable with its reference product.
In its citizen petition, AbbVie proposes that the FDA require that applicants seeking interchangeability meet the requirements of “Safety Standards for Determining Interchangeability” set forth in section 351(k)(4) of the Public Health Service Act as amended by the BPCIA for every condition of use for which the reference product is licensed. AbbVie Citizen Petition at 1. AbbVie believes that these requirements should be met for each condition of use regardless whether the biosimilar applicant is seeking licensure or intends to labels its product for every such use. Id. AbbVie also requests that the FDA convene a Part 15 hearing to gain input from the public on the requirements for interchangeability. Id. at 1–2.
I. Summary of AbbVie’s Arguments
AbbVie argues that although the biosimilar designation is similar to the therapeutic equivalence ratings assigned to generic small molecule drugs, biosimilars are different from small molecule drugs in important ways. Id. at 2. Unlike small molecule drugs, AbbVie asserts that “biological products present significant risks of immunogenicity, affecting both patient safety and product efficacy.” Id. AbbVie cites to two FDA statements, one in 2007 and the other in 2015, that acknowledge potential risks of immunogenicity. Id. at 2–3. AbbVie next asserts that it is impossible for one biological product to be the same as another. Id. at 3. This is because, unlike small molecule drugs, which can be scientifically guaranteed to have structural identity, there are no assurances that two biological products are structurally identical because such identity cannot yet be demonstrated. Id. AbbVie contends that these facts “lead to the conclusion that FDA should not find a biosimilar biological product interchangeable with a reference product unless the agency has found the two products interchangeable for every condition of use for which the reference product is licensed, regardless of how the interchangeable biological product is labeled.” Id. (emphasis in original). AbbVie believes that the FDA should clarify the statutory standard for establishing interchangeability and specify that it differs from the standard for establishing biosimilarity. Id. Further, a hearing should be convened pursuant to 21 C.F.R. Part 15 to “consider the complexities of interchangeability” and the “implications of interchangeability decisions in a multi-source product environment where multiple biosimilar biological products may have been found interchangeable with a single reference product, but not each other.” Id.
II. Biosimilar Interchangeability Decisions Are Intended to Mimic Therapeutic Equivalence Ratings for Small Molecule Drugs
AbbVie asserts that the real-world effect of an interchangeable designation for a biosimilar product is intended to mimic that of the therapeutic equivalence rating for a generic small molecule drug. Id. at 4. A designation of interchangeability for biosimilars is akin to an “A” rating for a small molecule drug, denoting therapeutic equivalence. Id. These designations are supposed to guide pharmacists’ substitutions of generic or interchangeable products. Id. The statutory language supports this by defining “interchangeable” as meaning “that the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” Id. quoting 42 U.S.C. § 262(i)(3).
III. Biological Products Are Fundamentally Different From Small Molecule Drugs
Next, AbbVie argues that biological products are fundamentally different from small molecule drugs because they are more likely to be immunogenic and biosimilars cannot be shown to be the same as their reference products. Id. at 5. AbbVie emphasizes the risks involved should a biological product cause an immunogenic response, including loss of efficacy and neutralization of the body’s own naturally occurring proteins. Id. at 6. These effects are highly variable and unpredictable and can lead to sometimes-fatal side effects in patients. Id. According to AbbVie, immunogenicity can result from product-specific factors and patient-specific factors, either of which can be exacerbated by switching between biological therapies. Id. As evidence of problems caused by switching biological therapies, AbbVie cites to the impact of switching patients whose Crohn’s diseases symptoms were well controlled with infliximab to adalimumab, which in some patients caused loss of tolerance and efficacy within one year when compared to patients who remained on infliximab. Id. at 7.
Additionally, AbbVie argues that biosimilar products cannot be proven to be the same as their reference products, unlike small molecule drugs, which can be proven to be structurally identical. Id. at 8. In fact, the nature of protein products makes it scientifically challenging to compare one protein to another to establish safety and efficacy. Id. at 9. Further, it is unlikely that a biosimilar could be demonstrated to be identical to a reference product. Id. AbbVie concludes, “that biosimilar and reference products are similar, but not identical, means one may not presume biosimilar and reference will have the same clinical effect in each condition of use approved for the reference product.” Id.
IV. A Biosimilar Should Only Be Designated as Interchangeable When It Has Been Shown to Be Interchangeable for Every Reference Product Condition of Use
AbbVie asserts several arguments in support of its proposal that a biosimilar product seeking an interchangeable designation should have to show interchangeability for every reference product condition of use. Id. at 9–15. AbbVie argues that state laws governing pharmacy substitution of biological products direct the pharmacist to dispense a biosimilar product that has been found to be interchangeable with the reference product. Id. at 11. However, “[n]either federal nor state law requires the pharmacist to determine whether the product to be substituted is labeled for (let alone determined to be interchangeable for) the prescribed use in question.” Id. Thus, AbbVie concludes that these laws assume that an interchangeable biosimilar is functionally the same a generic small molecule drug and is therapeutically equivalent for all uses. Id. Because of this, AbbVie argues that the FDA must ensure that biosimilars listed as interchangeable are in actuality interchangeable for all indications and conditions of use for which the reference product is licensed. Id. If the FDA does not take this approach, pharmacists might dispense a biosimilar that is not actually interchangeable for a patient’s condition. Id.
AbbVie alleges that the statutory language supports its position. Id. at 12. Section 351(k)(4)(A) allows an interchangeability designation only if the biosimilar “can be expected to produce the same clinical result as the reference product in any given patient.” Id. (emphasis in original) quoting 42 U.S.C. § 262(k)(4)(A)(ii). “Any” means “one or some indiscriminately of whatever kind” and “given” means “known; stated; [or] specified”; thus, “any given” means “every” or “all.” Id. at 12. Therefore, the plain meaning of “any given patient” is “all known, stated, or specified patients.” Id. Hence, the statutory language requires that a biosimilar can only be deemed interchangeable if it can be expected to produce the same clinical results as the reference product in all conditions of use for which the reference product is approved. Id.
Further, the language of the interchangeability standard set forth in 351(k)(4)(A) is different from the requirements for licensure of a non-interchangeable biosimilar set forth in 351(k)(2)(A). Id. at 13. A biosimilar applicant seeking approval of a non-interchangeable product does not need to show biosimilarity for every reference product condition of use, stating that the applicant must include clinical studies “to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use.” Id. quoting 42 U.S.C. § 262(k)(2)(A)(i)(I)(cc). However, this language is absent from the interchangeability standard, which adds language referring to the same clinical results in any given patient. Id. at 13. Additionally, the language in section 351(k)(4)(B) requires that the applicant seeking an interchangeable determination show the risk to patients of switching between the biosimilar and the reference product without qualifying “use.” Id. AbbVie contends that “[i]t is hard to see how this standard could be met unless the applicant had addressed ‘use’ of the reference product broadly, i.e., in all approved reference product conditions of use.” Id. AbbVie also concludes that this reading of section 351(k)(4) is consistent with section 351(k)(6), which provides a period of exclusivity for the first biosimilar product to be approved as interchangeable as to any condition of use of the reference product. Id.
AbbVie asserts that the legislative history of the BPCIA supports its interpretation of the statute. Id. at 14. Specifically, AbbVie points to several letters stating concerns over the interchangeability determination and potential safety hazards that could be implicated depending on how interchangeability is determined. Id. AbbVie also notes that the version of the legislation that was passed by Congress used the phrase “any given patient” without any language that would permit a selective showing of interchangeability. Id.
AbbVie acknowledges that its proposed requirement to consider all conditions of use approved for the reference product means that the FDA would have to consider changes made to either the reference product or the interchangeable biosimilar after an interchangeability decision has been made. Id. at 15. AbbVie contends that such an issued determination should not be altered unless there are “significant scientific questions regarding the continuing validity of the determination following a product change.” Id. AbbVie believes that this should be “a rare occurrence.” Id.
V. The Statutory Standards for Interchangeability and Biosimilarity Are Different
As touched on above, the statutory requirements for showing biosimilar and interchangeability differ. Id. To show interchangeability, a biosimilar applicant must show for every condition of use licensed for the reference product that the product is biosimilar, is expected to produce the same clinical result as the reference product in any given patient, and, if the product is administered more than once to a patient, that risk in terms of safety and efficacy of switching between the reference product and biosimilar is not greater than simply using the reference product without any switching. Id.
AbbVie argues that interchangeability “must be interpreted to require more than biosimilarity” and notes that section 351(k)(4)(A)(ii) requires that an applicant answer additional scientific questions not required to show biosimilarity. Id. at 16. The first difference is that to be interchangeable, a biosimilar product must have the “same clinical result” as the reference product instead of merely “no clinically meaningful differences.” Id. Further, interchangeability requires a showing that that the same clinical results are achieved for “any given patient,” which is not required to show biosimilarity. Id. Next, there is a distinct interchangeability requirement for a biosimilar product administered more than once to a patient mandating an evaluation of the risks associated with switching. Id. at 16–17. These requirements show that the licensure for interchangeability requires an “unprecedented level of certainty.” Id. at 17. An applicant that meets this exacting requirement benefits from a one-year period of exclusivity as the sole substitutable alternative to the reference product. Id.
VI. FDA Needs to Issue Guidance on Interchangeability and Should Hold a Public Hearing
AbbVie concludes by noting that CDER has failed to issue its promised interchangeability guidance. Id. at 18. AbbVie requests that any such guidance address the possibility of having multiple interchangeable biosimilar products for a single reference product and the implications of switching between those products during a single patient’s treatment. Id. at 19. AbbVie also asserts that given the amount of time since the FDA held public hearings in 2010 and 2012, another Part 15 public hearing should be held regarding the implementation of the interchangeability provisions of the BPCIA. This will allow public input and ensure that interchangeable biosimilars are introduced in a manner that “best serves the public interest and the public health.” Id.
K&L Gates LLP will continue to monitor any developments, including any response the FDA may provide, that arise from this citizen petition.
