AbbVie to FDA: Clinical Support Needed For All Reference Product Approved Indications to Support Interchangeability Designation for Biosimilars

and Carolina M. Wirth

On December 16, 2015, AbbVie, Inc. (AbbVie) submitted another Citizen Petition (Petition) to the Food and Drug Administration (FDA) relating to the Biologics Price Competition and Innovation Act (BPCIA) (Docket No. FDA-2015-P-4935).1 The Petition focuses on the standard to be used to determine whether a biosimilar product may be designated as interchangeable with a reference product under Public Health Service Act (PHS Act) §351(k)(4).2 An interchangeable biological product is a product that has established biosimilarity to an FDA-approved reference product and meets additional standards. Such a product may be substituted for the reference product by a pharmacist without the intervention of the health care provider who prescribed the reference product.3 AbbVie takes the position that interchangeability must be established for every condition of use for which the reference product is licensed, regardless of whether the biosimilar applicant intends to label its product for every such condition. AbbVie asks the FDA to “clarify that the statutory standards for establishing interchangeability differ in both kind and scope from the standard for establishing biosimilarity.” Petition at 1. Finally, AbbVie requests that the FDA convene a Part 15 hearing to receive public comment and then issue guidance on the issue.

AbbVie’s Petition was filed only a few weeks after Amgen Inc.’s filing of biosimilar applications in the United States and Europe for a follow-on biologic of AbbVie’s blockbuster drug Humira®.4 According to press releases, Amgen’s applications for ABP 501 include data based on studies in patients with moderate-to-severe rheumatoid arthritis and moderate-to-severe plaque psoriasis as well as “[d]ata to support the switching of patients from Humira to ABP 501.”5 Use of the term “switching” in the press releases suggests some attempt by Amgen to demonstrate interchangeability of ABP 501 and Humira®, even though the submitted clinical data relates to only two of the nine indications for which Humira® is approved.

AbbVie also included in the Petition a 505(q) certification, which requires the FDA to respond within 150 days of receiving a Citizen Petition when the petition requests that the FDA take any form of action related to a pending application, including those submitted under section 351 of the PHS Act. While AbbVie’s Petition does not directly involve a particular product, it will be interesting to see if the FDA reviews the Petition under this expedited schedule given Amgen’s pending abbreviated Biologic License Application (aBLA) under the BPCIA.

Summary of AbbVie’s Citizen Petition

AbbVie’s Petition leads with a discussion of two key differences between biological products and small molecule drugs as supporting a heightened standard for interchangeability. The first is that “biological products present significant risks of immunogenicity, affecting both patient safety and product efficacy. Petition at 2. The second is that “one biological product cannot be the ‘same as’ another,” based on the nature of the manufacturing process for these products. Id. at 3.

AbbVie then focuses on the practical implications of these differences with respect to the interchangeability of biologic products: “[t]he real-world effect of an interchangeability determination for a biological product is intended to mirror the real-world effect of a therapeutic equivalence rating for a generic small molecule drug.” Id. at 4. Therapeutic equivalency ratings were established to encourage the safe substitution of equivalent small molecule drug products by pharmacists. AbbVie asserts that the statute is clear—“[i]nterchangeability determinations for biological products under the PHS Act likewise are intended to guide substitution by dispensing pharmacists.” Id.

Red_and_blue_pillBecause of the differences between biological products and small molecule drugs, AbbVie discusses why such interchangeability by pharmacists could be concerning. Id. at 5. Immunogenicity, a known issue for biological products with both product-specific factors and patient-specific factors, can lead to lack of effectiveness and serious side effects. AbbVie notes that “[f]or patients with serious, chronic diseases, immunogenicity can be particularly devastating – active ingredient can no longer be used by the patient. Immunogenicity can thus eliminate treatment options for patients.” Id. at 6. AbbVie also notes that immunogenicity can be exacerbated by switching biological therapies, potentially leading to “loss of tolerance or efficacy when switching even between highly similar molecules.” Id. at 7. AbbVie points out that, unlike small molecule drugs, biosimilar products are unlikely to be identical to a reference product and that the FDA’s view on the matter appears to be that the biosimilar products have “sufficient similarity to rely on the safety and efficacy findings made with respect to the reference product.” Id. at 9. As such, “[t]hat 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.

Having established its position on why biological products raise concerns with regards to interchangeability, AbbVie sets out its position that a biosimilar product may be designated as “interchangeable” only when it is shown to be interchangeable with respect to every reference product condition of use. Pointing to its own Humira®, AbbVie notes that product is approved to treat a wide range of disorders, with each indication having “specific instructions regarding dose, frequency of administration, duration of use, type of therapy (e.g., monotherapy, concomitant, first-line, second-line, etc.) and other relevant clinical considerations.” Id. AbbVie asserts that all of “[t]hese instructions combine to constitute the ‘conditions of use’ for which the product is prescribed, recommended, or suggested within the meaning of both the FDCA [Federal Food, Drug, and Cosmetic Act] and the [PHS Act].” Id.

AbbVie grounds its arguments in public health, statutory interpretation, legislative history, and concerns regarding post interchangeability determination product changes. The public health arguments are largely based on the practical risks that may be associated with interchanging similar but not identical biological products, particularly for all indications for which a reference product may be approved. AbbVie asserts that the plain meaning of section 351(k)(4)(A), buttressed by the language in sections 351(k)(2)(A), (k)(4)(B), and (k)(6), requires that the biosimilar “be expected to produce the same clinical result as the reference product in any patient for whom the reference product is specified—meaning any patient covered by any approved reference product condition of use.” Id. at 12. AbbVie notes changes between earlier and later versions of the biosimilar bills and official correspondence from the Secretary of Health and Human Services on the matter in support of this interpretation as well. Finally, AbbVie indicates that the “FDA will need to consider the impact of changes made to either the reference product or the interchangeable biological product after an interchangeability determination has issued. (e.g., new indications approved for reference product).” Id. at 15. However, similar to the position outlined in the Orange Book regarding therapeutic equivalence ratings for generic drugs, AbbVie suggests that “previously issued interchangeability determination should not be disturbed absent significant scientific questions regarding the continuing validity of the determination following a product change.” Id.

AbbVie provided additional, separate statutory arguments that the standards for interchangeability and biosimilarity are different, asserting that the former has additional requirements over the latter. Pointing to the “same clinical result in any given patient” language of section 351(k)(4)(A)(ii), AbbVie asserts that this assessment regarding any given patient is novel, as “other product approvals, including biosimilar approvals, represent a conclusion that, at a population level, the benefits of the product outweigh the risks of the product when used as labeled.” Id. at 16. Also, according to AbbVie, “(k)(4)(B) requires full evaluation of safety and effectiveness in two new scenarios that were not addressed in either the reference product application or the initial biosimilar application” – evaluating the risks of switching from one product to another and the risks of alternating between products. Id. at 17. AbbVie further alleges that section 351(k)(4)(B) has a higher burden of proof than section 351(k)(4)(A)(ii), requiring a more definitive showing that the risk of switching or alternating between products “is not” greater than use of the reference product alone. AbbVie concludes that the “unprecedented level of certainty” required by the statute will require clinical testing, in line with statements made by FDA officials.

In the final substantive sections of the Petition, AbbVie calls for the issuance of interchangeability guidance and the holding of a Part 15 Hearing to allow the submission of public input.

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1 A copy of AbbVie’s Petition can be downloaded here. Citizen Petitions were previously filed by Amgen regarding the sharing of abbreviated biologic license application (aBLA) information under the BPCIA (Docket No. FDA-2014-P-1771; available here) and by AbbVie challenging FDA policies on biosimilar labeling (Docket No. FDA-2015-P-2000; available here; and Supplement; available here).

2 PHS Act, Section 351(k)(4) sets out the safety standards for determining interchangeability.

Upon review of an application submitted under this subsection or any supplement to such application, the Secretary shall determine the biological product to be interchangeable with the reference product if the Secretary determines that the information submitted in the application (or a supplement to such application) is sufficient to show that—

(A) the biological product—

(i) is biosimilar to the reference product; and

(ii) can be expected to produce the same clinical result as the reference product in any given patient; and

(B) for a biological product that is administered more than once to an individual, 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.

3 42 U.S.C. § 262(i)(3).

4 See prior blog posts on Amgen’s aBLA filing (here) and European filing (here).

5 See press releases by Amgen on its aBLA filing (here) and European filing (here).

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