By Kurt R. Karst –
The once nascent biosimilars industry took off in 2015 with the first biosimilar approval (ZARXIO [filgrastim-sndz], which FDA licensed on March 6, 2015 under BLA 125553), myriad court decisions interpreting the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) (see our previous post here), and the release of highly anticipated FDA guidance on Nonproprietary Naming of Biological Products (see our previous post here), as well as other guidance (here, here, here, and here). Congress also entered the mix with the introduction of the Generic Complex Drugs Safety and Effectiveness for Patients Act of 2015 (H.R. 1576) (see our previous post here) and with recent directives included as part of the 2016 Consolidated Appropriations Act (in explanatory statements here, here, and here), including with respect to FDA’s efforts to address biosimilarity and interchangeability:
The agreement acknowledges some progress in FDA’s effort to address issues with products that are biosimilar to and interchangeable with FDA-licensed biological drug products. In August of this year, the FDA issued draft guidance and a proposed rule regarding naming of these products. However, the agreement remains concerned that FDA needs to provide the public with a greater opportunity to review and comment on all regulatory standards for the approval and oversight of biosimilar drugs. Therefore, FDA is directed to provide the Committees with an estimated timeline by which the agency will finalize all pending draft biosimilars guidance documents and regulations. The Committees expect to receive this report no later than 60 days after enactment.
And then there’s the recent gear up for reauthorization of the Biosimilar User Fee Act (“BsUFA”). FDA held a public meeting on that topic on December 18, 2015.
The year that was (2015) also saw an uptick in the number of citizen petitions submitted and responded to by FDA concerning a variety of biosimilar and BPCIA implementation topics. There was the first response to a biosimilars 505(q) Citizen Petition (Docket No. FDA-2014-P-1771) that addresses the sharing of aBLA (or Section 351(k) application) information (see our previous post here). There was also a second Citizen Petition submitted to FDA as a 505(q) petition (Docket No. FDA-2015-P-2000) challenging FDA policies on biosimilar labeling (see our previous post here). As we close out 2015, and as we move into what will likely be a very active 2016 insofar as biosimilars are concerned, AbbVie Inc. (“AbbVie”) has given us fodder for one last post in 2015 about biosimiliars (unless, of course, there’s a surprise decision or announcement later this week).
On December 16, 2015, AbbVie submitted a Citizen Petition (Docket No. FDA-2015-P-4935) to FDA concerning Agency determinations of interchangeability – the step after mere biosimilarity is demonstrated – between a brand-name reference product and its biosimilar (or “biogeneric”) counterpart. AbbVie wants three things from FDA. First, FDA should “ensure that applicants seeking interchangeability determinations 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” (emphasis added). Second, AbbVie requests that FDA “clarify that the statutory standards for establishing interchangeability differ in both kind and scope from the standard for establishing biosimilarity.” Third, FDA should convene a Part 15 hearing to obtain public input on interchangeability, says AbbVie, and then “issue guidance or regulations that address this important public health issue.”
AbbVie’s petition comes on the heels of Amgen Inc.’s (“Amgen”) announcement the of the submission of an aBLA to FDA for a biosimilar version of AbbVie’s blockbuster biological product HUMIRA (adalimumab). According to press reports, Amgen’s aBLA for its product, dubbed ABP 501, includes data and information based on studies in patients with rheumatoid arthritis and plaque psoriasis – just two of the many indications for which HUMIRA is licensed – as well as “[d]ata to support the switching of patients from Humira to ABP 501.” “Switching” is the key word in that quote, as it seems to imply efforts to demonstrate interchangeability between HUMIRA and Amgen’s ABP 501. After all, the BPCIA amended the PHS Act to provide the following at PHS Act § 351(k)(4) concerning interchangeable biological products:
(4) 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.
According to AbbVie, the public health, the text and structure of the BPCIA, and the legislative history of the BPCIA all clearly support – and, in fact, mandate – that before FDA issue a determination of interchangeability with a reference product, the Agency must determine that “the two products [are] interchangeable for every condition of use for which the reference product is licensed” (emphasis in original), and notwithstanding that a biosimilar/interchangeable biological product may not be licensed for all reference product uses (i.e., is “skinny labeled”) because of patent or non-patent exclusivities.
Pointing to state laws enacted over the past few years governing the substitution of biosimilar biological products, AbbVie says that those laws do not differentiate interchangeable biosimilars according to approved use, thereby raising the possibility that a product will be substituted for the reference product for a use for which interchangeability has not been assessed and that could jeopardize patient health:
State laws governing pharmacy substitution of biological products generally direct the pharmacist to dispense a biological product that FDA has found interchangeable with the reference product. Neither 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. The assumption of these state laws is that an interchangeable biological product is functionally the same as a generic drug—it is therapeutically equivalent for all uses.
FDA therefore needs to ensure that biological products listed as substitutable are in fact interchangeable for all indications and conditions of use for which the reference product is labeled and thus might be prescribed. Any other approach risks the possibility that a physician will prescribe the branded product and the pharmacist will dispense a biological product that is not interchangeable for the patient’s condition.
Turning the the text of the statute (and later, to its legislative history), AbbVie focuses on four words at PHS Act § 351(k)(4) (reprinted above) to make its case: “in any given patient.”
Section 351(k)(4)(A) permits an interchangeability determination only if the biological product in question is biosimilar and (separately) “can be expected to produce the same clinical result as the reference product in any given patient.” As the Supreme Court has explained, “the word ‘any’ has an expansive meaning, that is, ‘one or some indiscriminately of whatever kind.’” Further, “given” means “known; stated; [or] specified.” When paired together, the words “any given” take on an extraordinarily broad, idiomatic meaning akin to “every” or “all” (e.g., “on any given Sunday” or “at any given time”). Thus, the plain meaning of “any given patient” in section 351(k)(4)(A) is all known, stated, or specified patients. Further, because it is juxtaposed with “the reference product,” the phrase “any given patient” must be understood to mean all patients for whom the reference product is known, stated, or specified. Under the plain terms of section 351(k)(4)(A), therefore, a biological product can be deemed interchangeable only if it can 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. [(Emphasis in original.)]
AbbVie points to other statutory language – at PHS § § 351(k)(2)(A), (k)(4)(B), and (k)(6) – and to events in 2006-2007, including precursor legislation and FDA statements, to buttress the company’s argument. “This history compels the conclusion that Congress rejected the option for applicants to make selective interchangeability showings,” says AbbVie.
AbbVie’s position raises the possibility that reference product changes after licensure of a interchangeable product, such as the addition of a new reference product indication, could make interchangeability determinations listed in the Purple Book fluid: there one day and gone the next day. But AbbVie takes a page out of the Orange Book to address that situation:
AbbVie believes that a previously issued interchangeability determination should not be disturbed absent significant scientific questions regarding the continuing validity of the determination following a product change. We believe that the Orange Book preface points to a path forward for handling these situations that will respect the law, adequately protect the public health, and minimize disruption to established products and markets. The Orange Book suggests that therapeutic equivalence ratings for generic drugs may be changed, but only “as a result of new information raising a significant question as to bioequivalence.” Applying a similar approach in the BPCIA context, a previously issued interchangeability determination for a biological product would not be altered unless a manufacturing change or a new condition of use raises significant scientific questions (that were not answered satisfactorily) about the continuing validity of the determination. This, AbbVie believes, should be a rare occurrence.
AbbVie makes several other points throughout the 21-page Citizen Petition that make it worth a read and that may garner public comment. Although AbbVie includes in its petition a 505(q) certification – which, if operative, would trigger an FDA response within 150 days – the company notes that it is unlikely to be classified by FDA as such because, to the best of the company’s knowledge, “no applicant has yet submitted to FDA a BLA seeking licensure as an interchangeable biological product.” However, as noted above, that may not be the case given Amgen’s aBLA for ABP 501.