Source: http://www.fdalawblog.net/fda_law_blog_hyman_phelps/biosimilars/page/2/
Timestamp: 2017-03-29 21:02:02
Document Index: 362309730

Matched Legal Cases: ['§ 7002', '§ 7002', '§ 7002', '§ 505', '§ 7002', '§ 351', '§ 505', '§ 351', '§ 505', '§ 505', '§ 7002', '§ 271', '§ 262', '§ 262', '§ 262', '§ 262', '§ 271', '§ 351', '§ 262', '§ 351', 'art 15', '§ 351', '§ 351', '§ 351', '§ 505', '§ 314', '§ 351', '§ 351', '§ 351', '§ 351', '§ 262', '§ 262', '§ 351', '§ 351', '§ 262']

FDA Law Blog: Biosimilars FDA Law Blog
Amgen Asks the Supreme Court to Reject Challenge to Ruling that Notice of Commercial Marketing is Mandatory, But Asks for Review of Patent Dance Ruling Just in Case
On March 21, 2016, Amgen filed a brief opposing Sandoz’s request that the Supreme Court overturn last year’s Federal Circuit ruling that the Biologics Price Competition and Innovation Act’s ("BPCIA's") notice of commercial marketing provision is mandatory and can only be given after FDA licensure of a biosimilar (see our previous posts here, here and here). But Amgen also filed a certiorari cross-petition, asking that, should the Court decide to review the commercial marketing ruling, it should also review and overturn the Federal Circuit’s ruling that the patent dance information exchange procedures of the BPCIA are optional. The case involves the first and only approved US biosimilar product, Sandoz’s filgrastim product Zarxio, which referenced Amgen’s filgrastim product Neupogen in order to be approved.
Amgen’s reply brief asserts that the Supreme Court should reject the Sandoz certiorari request for three reasons. First, Amgen argues that the only issue that Sandoz can appeal based on the record was correctly decided below - the Federal Circuit’s unanimous holding that notice of commercial marketing can only be given post-licensure. Second, Amgen contends that Sandoz’s requests concerning a private right of action and the availability of injunctive relief are moot based on the facts in the case because the issues were not decided by the Federal Circuit. Third, Amgen posits that Supreme Court review would be premature, noting that BPCIA issues are currently being litigated in seven pending cases, including in a case that the Federal Circuit will hear on April 4, 2016.
On the notice of commercial marketing issue, Amgen’s main argument continues to be that the BPCIA’s language is clear (“The subsection (k) applicant shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product licensed under subsection (k)” (emphasis in original)) and that the Federal Circuit correctly applied principles of statutory construction in holding that the notice is mandatory. Amgen also asserts that the Federal Circuit holding is not in conflict with either the statute or any Supreme Court ruling, and thus is not an appropriate case for review. Amgen goes on to say that “Sandoz offers a raft of policy arguments for why [mandatory notice] is supposedly a bad or unfair rule, arguments that are wrong on their merits but that in any event cannot overcome the statute’s text.” Amgen also contends that “requiring that a [biosimilar] be licensed before notice of commercial marketing ensures the existence of a fully crystallized controversy regarding the need for injunctive relief” and “provides a defined statutory window during which the court and the parties can fairly assess the parties’ rights prior to the launch of the biosimilar product.”
Amgen devotes a couple of pages of its brief to distinguishing between marketing exclusivity and data exclusivity, saying that the BPCIA does not protect brand name products from competition and pointing to the example of Teva’s filgrastim product Granix, which was approved under a BLA and competes with Amgen’s Neupogen. In addition, addressing the Sandoz contention that notice after approval makes no sense because approval is public, Amgen points out that commercial marketing cannot be presumed to occur 180 days after approval, and therefore mandatory notice after approval serves a purpose in helping a reference product sponsor determine when and whether to file a lawsuit.
Amgen’s second basis for asking the Supreme Court to reject Sandoz’s request is based largely on procedural matters and state law. One major point made by Amgen is that Sandoz did provide Amgen with notice of commercial marketing, so the issue of what might happen if Sandoz had not done so is moot.
Regarding the third basis, arguing that the Supreme Court should wait for further lower court decisions before taking a BPCIA appeal, Amgen states that there are seven BPCIA lawsuits pending in the lower courts. Amgen also argues a lack of urgency, given that only one biosimilar (Zarxio) has been approved by FDA and that the 15% discount off of the Neupogen wholesale price that Sandoz is offering demonstrates that waiting will have a minimal impact on consumer costs.
In its cross-petition on the patent dance provisions, Amgen asks that, should the Supreme court decide to review the notice of commercial marketing issue, that the Court also take under review the Federal Circuit’s ruling that the patent dance is a voluntary proceeding. Amgen argues that the two issues are “inextricably intertwined” and that the Federal Circuit ruling is incorrect under Supreme Court precedent on statutory interpretation. Regarding the latter point, Amgen’s basic contention is that the word “shall” employed in the patent dance provisions of the BPCIA is a mandatory word, just as it is in the notice of commercial marketing provisions. Sandoz’s response to Amgen’s cross-petition is due on April 22nd. Meanwhile, interest in the case form third parties remains high, including amicus briefs from Hospira, Apotex and the Biosimilars Council.
Posted at 10:26 PM in Biosimilars, Prescription Drugs and Biologics | Permalink
FDA’s BPCIA “Deemed to be a License” Guidance Provides Practical Help with Development, But Limits Exclusivity
By James C. Shehan & Kurt R. Karst –
On March 10, 2016, FDA released a draft guidance interpreting the “deemed to be a license” provision of the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”). This provision, at BPCIA § 7002(e)(4), is one of a broader series of transition provisions in BPCIA § 7002(e), and, as FDA notes in the draft guidance, is “[t]he linchpin of the transition scheme described in section 7002(e).” The “deemed to be a license” provision, which FDA notes Congress was silent on implementation when it passed the BPCIA, transitions certain products that FDA has historically regulated as drugs into biologics on March 23, 2020. (Shortly thereafter, FDA archly quotes a Supreme Court opinion for the proposition that the Affordable Care Act – of which the BPCIA is part – “contains more than a few examples of inartful drafting.”) Specifically, BPCIA § 7002(e) states:
The draft guidance deals with four major topics: (1) what happens to approved applications for such transitional products on March 23, 2020; (2) what happens to pending applications on that date; (3) how sponsors of pending applications should prepare for the effects of the transition; and (4) how exclusivity will be affected by the transition. FDA’s position on the last topic is sure to generate the most commentary and controversy, because FDA proposes to interpret the law such that transitional products get less exclusivity than either traditional drugs or biologics. Some background on these transition products and the BPCIA is necessary to understand the guidance. Although most products that fit the statutory definition of “biologic” have been licensed and regulated by FDA under Section 351 of the Public Health Service Act (“PHS Act”), some protein products historically have been approved and regulated as drugs under FDC Act § 505. The draft guidance provides examples of such products, including insulins, hyaluronidases, thyrotropin alfas and human growth hormones. Although such products seem to fit the pre-enactment definition of biologic, the BPCIA removed any doubt, amending the definition of “biologic” in the PHS Act to include “protein[s] (except any chemically synthesized polypeptide).” The BPCIA also requires, with certain exceptions, that a marketing application for a biologic be submitted as a BLA and not as an NDA. And lastly, BPCIA § 7002(e)(4) provides that, on March 23, 2020, a marketing application for a biologic that has been approved as an NDA shall be “deemed to be a license” for a biologic under PHS Act § 351; that is, NDAs for transitional products become BLAs. Regarding approved applications, FDA simply states that, on March 23, 2020, applications for biologics approved under FDC Act § 505 “will no longer exist” as NDAs or ANDAs and “will be replaced by approved” Section 351(a) “full” BLAs or Section 351(k) “abbreviated” BLAs (“ABLAs”), “as appropriate.” In a footnote, FDA states that the Agency intends to provide further guidance on the issue of which transitional products will become Section 351(a) full BLAs and which will become Section 351(k) ABLAs. This further guidance will also address issues such as user fees and BLA numbers. FDA also states that these products will be removed from the Orange Book, but the Agency is silent as to whether they will then appear in one of the two lists that comprise the Purple Book.
Regarding pending applications, the draft guidance interprets the statute rather strictly. FDA states that the BPCIA “does not provide a mechanism to transition an approved application under section 505 to an approved BLA under the PHS Act prior to March 23, 2020, or after March 23, 2020. Therefore, FDA “will not approve” any pending or tentatively approved application for a transitional product. FDA recommends that such an application be “withdrawn and resubmitted under section 351(a) or 351(k).”
Recognizing the potential “significant impact” of such a policy on development programs, FDA later in the guidance offers sponsors more detailed advice. The soundest and most basic piece of advice is that sponsors developing transitional products should evaluate whether a planned 505 submission would allow adequate time for approval of an NDA or ANDA prior to March 23, 2020, considering, among other things, “whether the submission may require a second cycle of review and, for certain types of applications, whether unexpired patents or exclusivity may delay final approval.” FDA recommends that sponsors of full NDAs consider submitting a full BLA instead. Noting that the PHS Act has no analogy to a Section 505(b)(2) NDA, FDA recommends that sponsors of these applications for transitional products consider submitting them as full BLAs or treat them as biosimilars and submit ABLAs.
Regarding the existing exclusivity of transitional products, FDA, with very little preamble, states that “any unexpired period of exclusivity” for a transitional product, “e.g., 5-year exclusivity, 3-year exclusivity, or pediatric exclusivity … would cease to have any effect, and any patents listed in the Orange Book would no longer be relevant for purposes of determining the timing of approval of a 505(b)(2) application (or ANDA).” A single sentence provides the rationale for this decision: “the exclusivity provisions of the FD&C Act serve to limit the submission or approval of applications under section 505 of the FD&C Act, but not under section 351 of the PHS Act.” FDA makes one crucial exception: because orphan drug exclusivity is available to both drugs and biologics, “any unexpired period of orphan drug exclusivity would continue to apply to the drug for the protected use after March 23, 2020.” FDA is silent with respect to the applicability of previously earned pediatric exclusivity to extend a period of orphan drug exclusivity for a transitioned product, but it would seem to make sense to apply pediatric exclusivity for such a product given that the BPCIA, at Section 7002(m), attaches pediatric exclusivity to orphan drug exclusivity.
Turning to the question of whether transitional products will be eligible for biologics exclusivity come March 23, 2020, FDA explains that the BPCIA grants such exclusivity to products “first licensed under” PHS Act § 351(a). Because transitional products are only “deemed” to be licensed under Section 351(a), FDA does not regard them as eligible for exclusivity. In support of this determination, FDA states that “[n]othing in the [BPCIA] suggests that Congress intended to grant biological products approved under [FDC Act § 505] – some of which were approved decades ago – a period of exclusivity upon being deemed to have a license under the PHS Act that would impede biosimilar or interchangeable product competition in several product classes until the year 2032.” FDA’s statement implies that the Agency’s only option was to grant all transitional products 12 years of exclusivity starting on March 23, 2020. But it seems that same statutory language relied upon by the Agency could support a number of alternative positions on transitional product exclusivity, including awarding a 12 year period from the date of FDC Act § 505 approval. It remains to be seen whether interested parties, perhaps including Congress, will support those alternatives. In 2015, Congress did express some interest in the BPCIA’s transition provisions. Specifically, the “Generic Complex Drugs Safety and Effectiveness for Patients Act of 2015” (H.R. 1576) would have the Government Accountability Office study some of the unique challenges presented by FDA’s evaluation of generic versions of complex drug products in the context of BPCIA § 7002(e) (see our previous post here).
Posted at 01:30 AM in Biosimilars, Prescription Drugs and Biologics | Permalink
If I Keep Asking You to Dance, Perhaps You’ll Say Yes? Amgen Files a Third Patent Dance Lawsuit Against Sandoz By James C. Shehan –
More than one commentator predicted that the Federal Circuit’s decision in Amgen v. Sandoz interpreting the patent dance provisions of the Biologics Price Competition Innovation Act ("BPCIA") would be a fertile source of new litigation rather than a definitive decision laying out clear rules for industry to follow. But to our knowledge no one predicted that Amgen and Sandoz would themselves engage in multiple additional patent dance lawsuits, which is exactly what is occurring now after Amgen filed two suits against Sandoz on February 26th (complaint here) and March 4th (complaint here). The first case involves an etanercept biosimilar to Amgen’s Enbrel and the second a pegfilgrastim biosimilar to Amgen’s Neulasta. Of perhaps great significance is that the first case is a patent infringement case and the second is not – it solely asks the court to interpret the BPCIA. The second case may therefore result in a court ruling on a point contested by Amgen and Sandoz – whether a decision by a reference product sponsor such as Amgen to not bring a patent infringement lawsuit within 30 days of a breakdown in patent dance proceedings will trigger 35 U.S.C. § 271(e)(6)(B) and therefore limit the reference product sponsor to the sole and exclusive remedy of a reasonable royalty in case of a later finding of infringement.
In the Enbrel case, Amgen alleges infringement of five patents covering the active ingredient, its method of manufacture, and certain therapeutic uses. According to the Amgen complaint, in October 2015, Sandoz gave Amgen its ABLA and information about the manufacturing processes for its Enbrel biosimilar. In December, Amgen provided Sandoz with a list of patents for which it believes that infringement claims could reasonably be asserted. At this point, Sandoz apparently decided to exit the dance floor. On January 27th, Sandoz sent Amgen an 86 page letter in which Sandoz agreed with the Amgen patent list and provided more information about its manufacturing processes for its biosimilar. But Amgen states that Sandoz also declared in that letter that it was “waiving” its right to receive the next documents in the patent dance, a detailed statement from Amgen under 42 U.S.C. § 262(l)(3)(C) of the grounds for infringement. Sandoz also informed Amgen that further “negotiations were unnecessary” and that Amgen under 42 U.S.C. § 262(l)(6) should file a patent infringement suit within 30 days.
Amgen protested by letter Sandoz’s exit from the dance and invoked its right under 42 U.S.C. § 262(l)(9) to seek a declaratory judgment of infringement. According to Amgen, Sandoz replied by confirming its refusal to further negotiate and stating that it “wished for patent litigation to begin as soon as possible." The eagerness exhibited in this “see you in court” statement may hearken back to Sandoz’s attempt a couple of years ago to get a judicial declaration of invalidity for two of the patents that Amgen is now asserting, an attempt that ended with the Federal Circuit dismissing the case as premature (see our post here and the decision here) In contrast to the Enbrel case, Amgen’s lawsuit against Sandoz over the Neulasta biosimilar does not allege patent infringement. Rather, it asks the court to declare that Sandoz failed to comply with the mandatory patent dance information exchanges, declare that this failure means that there can be no “immediate patent infringement action” under 42 U.S.C. § 262(l)(6), and declare that Amgen may get injunctive relief and lost profits damages in case infringement is later found, The interactions between the parties leading up to the Neulasta lawsuit are quite similar to those in the Enbrel lawsuit. In November 2015, Sandoz gave Amgen its ABLA and information about the manufacturing processes for its Neulasta biosimilar. In January 2016, Amgen provided Sandoz with a list of two patents that Amgen believed Sandoz’s biosimilar would infringe. Then on February 2, 2016, Sandoz told Amgen why the two patents were invalid, unenforceable and/or not infringed, and also told Amgen that it would no longer follow the patent dance. As in the Enbrel case, Sandoz declared that it was waiving its right to receive Amgen’s detailed statement of the grounds for infringement, informed Amgen that further “negotiations were unnecessary” and admonished Amgen to file a patent infringement suit within 30 days. Sandoz added that “[o]therwise, the penalty for an untimely suit—that the ‘sole and exclusive remedy’ for any infringement be limited to a ‘reasonable royalty’—applies. See 35 U.S.C. § 271(e)(6)(B).” Note that the reasonable royalty point does not appear in Amgen’s complaint in the Enbrel lawsuit, so it is unknown whether Sandoz asserted it there as well. What can be gleaned from these multiple battles? As for Sandoz, it may be that, at least in the case of older biologics lacking exclusivity, Sandoz has decided that beginning and then abandoning the patent dance is a good strategy. As for Amgen, it seems committed to litigating to defend its biologics products but there is no indication of why it did not bring a patent infringement lawsuit over the Neulasta patents but did over the Enbrel patents. In any event, a court ruling over whether reasonable royalties are the sole remedy if a patent infringement case is not brought is likely to be at least an unintended consequence of that decision. And for both parties, it seems that there are many more turns ahead in their BPCIA patent dance saga. And finally we wonder whether, having been jilted three times now, does Amgen feel like a shy but determined teenager who keeps on pursuing the same potential partner despite multiple rejections, hopeful that one day he or she will own the dance floor as completely as Tony Manero, Alex Owens or Ren McCormack?
Posted at 01:05 PM in Biosimilars, Prescription Drugs and Biologics | Permalink
Sandoz Petitions High Court to Review the Federal Circuit’s Decision on the BPCIA’s 180-Day Notice of Commercial Marketing Provision By Kurt R. Karst – Whether notice of commercial marketing given before FDA approval can be effective and whether, in any event, treating [Public Health Service Act (“PHS Act”) § 351(l)(8)(A) (42 U.S.C. § 262(l)(8)(A))] as a standalone requirement and creating an injunctive remedy that delays all biosimilars by 180 days after approval is improper.
Those are the questions presented by Sandoz Inc. (“Sandoz’s”) in a Petition for Writ of Certiorari submitted to the U.S. Supreme Court earlier this week on the last possible day permitted for such a petition. The highly anticipated petition is the first time – but certainly won’t be the last time – the Supreme Court has been asked to take up an issue raised by the text of the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”). The Sandoz Petition appeals one aspect of a highly fractured July 21, 2015 opinion handed down by the U.S. Court of Appeals for the Federal Circuit in a dispute between Amgen Inc. (“Amgen’s”) and Sandoz over Sandoz’s ZARXIO (filgrastim-sndz), a biosimilar version of Amgen’s NEUPOGEN (filgrastim) (see our previous post here). FDA licensed ZARXIO on March 6, 2015 under BLA 125553. The provision at issue – PHS Act § 351(l)(8)(A) – states that a biosimilar (or subsection (k) “applicant shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product licensed under subsection (k).” A 2-1 panel majority of the Federal Circuit ruled that licensure of a biosimilar application is required before an “operative notice” of commercial marketing can be given. Specifically, in overturning a lower court decision on this issue, the Federal Circuit stated:
In a dissenting opinion, Judge Chen found the 180-day notice of commercial marketing provision to be optional, just like the BPCIA’s so-called “patent dance” provisions (which were also ruled on in the Federal Circuit’s opinion). The importance of final resolution of the meaning of the BPCIA’s 180-day notice of commercial marketing provision – either in the context of Sandoz’s Petition, if it is granted, or in another case that could ultimately reach the Supreme Court (there are at least three similar lawsuits pending around the country, including this one) – cannot be understated. The Federal Circuit's ruling on the notice of commercial marketing provision, if it is upheld, could have everlasting effect on the biosimilars industry (more so that the Court's ruling on the optional nature of the statute’s patent dance provisions). And reference product sponsors may find (and argue for) new ways to apply it, perhaps in the context of supplemental applications submitted to FDA seeking changes to a licensed Section 351(k) biosimilar product. Such supplemental applications may seek changes to the manufacturing process of a biosimilar product, or to add into labeling an indication previously omitted because of unexpired patent or non-patent exclusivity (e.g., orphan drug exclusivity) protections on the reference product. Why not argue for a 180-day notice in those situations as well?
Posted at 08:13 AM in Biosimilars, Prescription Drugs and Biologics | Permalink
Any Given Patient for Any Given Indication: AbbVie Petitions FDA on Interchangeable Biosimilars
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—
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.
Posted at 06:42 PM in Biosimilars, Prescription Drugs and Biologics | Permalink
Posted at 09:26 PM in Biosimilars | Permalink
Using Bad Names: FTC Says FDA’s Naming Proposal for Biologics will Impede Competition from Biosimilars
On October 27th, the FTC submitted comments objecting to the FDA’s draft guidance on Nonproprietary Naming of Biological Products. In the comments and an accompanying press release, the FTC asserts that the proposal may reduce price competition in biologic drug markets, create unnecessary costs and impede efforts to harmonize names globally. The FTC therefore asks FDA to reconsider its proposal and suggests alternatives with less impact on competition.
In its draft guidance (see our post here), FDA proposes adding a new, random suffix to the name of every approved biologic. FDA’s rationale for the proposal is that, with the advent of biosimilars, it will improve pharmacovigilance and prevent inadvertent substitution of non-interchangeable biologics.
In its comments, the FTC proceeds very quickly to its rationale – biologics are expensive, prices are increasing rapidly, and without biosimilars, “patients have no other alternative” (sic). Biosimilars would reduce prices and increase patient access. The FTC analysis has four parts. First, the agency cites “standard economic logic” for the proposition that perceived product differentiation dampens price competition. Next, the FTC states the naming proposal may increase product differentiation because “physicians may mistakenly believe that different suffixes indicate clinically meaningful differences between a biologic and its biosimilar.” In the third part of the analysis, the FTC states that a single European example involving Hospira’s Retacrit epoetin zeta biosimilar “suggests” that biosimilars with distinct nonproprietary names are less commercially successful than those with the same nonproprietary names. In the fourth part of its analysis, the FTC assets that the FDA proposal will create for pharmacists unnecessary “coding and system inefficiencies” and costs and will undermine global harmonization efforts.
The first alternative proposed by the FTC is to simply rely on trade names to distinguish products. In support, the agency cites a Pfizer statement that brand names are cited in about 99 percent of adverse event reports. The second alternative proposed by the FTC is for healthcare professionals to rely on the FDA Purple Book (see our post here) for information about biologic products, just as they currently use the FDA Orange Book for small molecule drugs.
The FTC position has a few potential holes that may lead FDA to discount it. For one, the data cited by the FTC to support the proposition that physicians will believe that different suffixes indicate clinically meaningful differences is indirect and limited. For another, there are alternative explanations for the lesser commercial success of Retacrit epoetin zeta, such as differences between epoetin zeta and epoetin alpha, dates of market entry, and the commercial savvy of different manufacturers.
Possible flaws in the FTC’s proposed alternatives have previously been suggested by parties involved in the biosimilar naming debate. For example, it has been pointed out that pharmacists primarily consult the Orange Book to learn the therapeutic equivalence ratings of potentially substitutable drugs, whereas the Purple Book does not contain therapeutic equivalence ratings because that concept does not exist for biologics.
Will the FDA give any more weight to the FTC’s comments than to those of other parties? Stay tuned. Posted at 02:07 PM in Biosimilars | Permalink
You Win Some, You Lose Some: Federal Circuit Denies En Banc Review in BPCIA Dispute & Otsuka Files Suit Over 3-Year Exclusivity
Predicting the future is a tricky business. Predictions don’t often pan out, even when most or all of the indicators prognosticators use say something will (or will not) happen. We have a pretty decent track record of guessing how a case might come out or whether FDA will be challenged over a particular decision. Last week we batted .500 on two previous predictions.
In July, after the U.S. Court of Appeals for the Federal Circuit issued a severely fractured panel opinion in Amgen v. Sandoz concerning various statutory issues under the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), we thought the likelihood that the Federal Circuit would grant petitions for rehearing and/or petitions for rehearing en banc (from both Amgen and Sandoz) was pretty high. After all, we had to chart out the differing Circuit Judge opinions on a couple of the issues at bar (see our previous post here). Moreover, the implications of the Court’s decision, if not altered, are manifold and may very well set the stage for implementation of the BPCIA’s so-called “patent dance” procedures for quite some time. Last Friday, however, the Federal Circuit surprised us when the Court issued an Order denying the Amgen and Sandoz petitions for rehearing and rehearing en banc. We doubt the Federal Circuit’s Order will be the last word in the case. So, we’re going to double down now and predict that the U.S. Supreme Court will be asked by Amgen and/or Sandoz to take up an appeal of the Federal Circuit’s decision. There’s simply too much at stake here for the budding biosimilar industry (and for the future of the BPCIA) for a party not to take this dispute to the next level. We’ll know in the coming months if our prediction is correct. Of course, if neither Sandoz nor Amgen go further (or the issues are otherwise deemed moot in the case), both of the primary issues in the case – whether or not the “patent dance” is mandatory, and when a biosimilar applicant can provide notice of commercial marketing – may still reach the U.S. Supreme Court though a future dispute (perhaps here or here).
We hit the nail on the head with our second prediction when Otsuka Pharmaceutical Development & Commercialization, Inc. and Otsuka Pharmaceuticals Co., Ltd. (collectively “Otsuka”) filed a Complaint in the U.S. District Court for the District of Columbia last week challenging FDA’s October 5, 2015 denial of a Citizen Petition (Docket No. FDA-2015-P-2482) and approval of Alkermes plc’s (“Alkermes”) 505(b)(2) NDA 207533 for ARISTADA (aripiprazole lauroxil) Extended-elease Injectable Suspension in light of unexpired 3-year new clinical investigation applicable to Otsuka’s ABILIFY MAINTENA (aripiprazole) for Extended-release Injectable Suspension, for Intramuscular Injection 300 mg/vial and 400 mg/vial, approved under NDA 202971. ARISTADA is a prodrug of N-hydroxymethyl aripiprazole (and which N-hydroxymethyl aripiprazole is a prodrug of aripiprazole) that FDA approved for the treatment of schizophrenia (the same use for which ABILIFY is approved).
You can refer back to our previous post for the details on FDA’s (rather lengthy and complex) decision that Otsuka is challenging. In the end, the dispute concerns the scope of 3-year exclusivity. Otsuka alleges in its Complaint that FDA violated the FDC Act’s 3-year exclusivity provisions (FDC Act § 505(c)(3)E)(iii) and (iv)), the Agency’s regulation governing 3-year exclusivity (21 C.F.R. § 314.108), and the Administrative Procedure Act (“APA”) in approving ARISTADA. According to Otsuka:
The FDA decisions challenged in this case undermine a fundamental aspect of the [FDCA]. . . . Here, FDA disregarded the text and purpose of the exclusivity provisions and, in their place, created a wholly unauthorized new scheme to deny Otsuka exclusivity rights it earned and to approve a so-called new drug that undeniably is not a medical advance; provides no new or additional therapeutic benefit; and, as its own manufacturer has boasted repeatedly, operates in the body exactly as does Otsuka’s drug. Rather than incentivize innovation and new drug development to benefit public health, FDA’s action punishes the innovator and unlawfully rewards a follow-on copycat company that proposes to bring to market a drug that provides no new or additional public health benefit. FDA’s decision inverts the intent of the FDCA by denying Otsuka the protection to which it is legally entitled and rewarding what is, at best, an imitative competitor’s facially clever, but substantively meaningless, chemical trick. Neither law nor sound policy supports this outcome. FDA’s decision should not stand.
Otsuka asks the D.C. District Court to declare, after expedited proceedings (in a Motion to Expedite), that FDA’s denial of Otsuka’s exclusivity rights and ARISTADA approval violated the APA insofar as such alleged violations are arbitrary, capricious, an abuse of discretion, and otherwise not in accordance with law. Otsuka also asks the court to vacate FDA’s ARISTADA approval and “any FDA decisions or actions underlying or supporting or predicated upon that approval,” and that the court declare that Otsuka’s 3-year exclusivity precludes the Agency from granting approval of the ARISTADA NDA until such exclusivity expires in 2017. As one would expect, Alkermes promptly filed a Motion to Intervene in the case.
Posted at 07:18 PM in Biosimilars, Hatch-Waxman, Prescription Drugs and Biologics | Permalink
By Kurt R. Karst – One day in the future, reporting on biosimilar patent dance challenges lodged pursuant to the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) will be considered passé. Such challenges will be as commonplace as Hatch-Waxman Paragraph IV challenges. Indeed, earlier this week, FDA released a report that the Agency has held nearly 90 meetings with more than 50 companies interested in biosimilars, and last week, CDER Director Janet Woodcock testified before a Senate Committee that as of July 31, 2015, 57 proposed biosimilar products were in FDA’s Biosimilar Product Development Program. But we’re not yet even close to that future date. Today, each BPCIA patent dance lawsuit holds the potential to alter the future course of the law. And because of that potential, we try to keep a close eye on the biosimilars scene. BPCIA-related lawsuits come in many flavors, several of which we have not yet even tasted. (Consider, for example, the palate-expanding experience that awaits us when the duo of Amgen and Allergan face off against Roche and Genentech over a biosimilar version of Avastin (bevacizumab) – see here – or when FDA is eventually challenged over the Agency’s implementation of the law.) Initially, there were the declaratory judgment cases filed by biosimilar applicants (see our previous post here). Then there were the challenges alleging that biosimilar applicants violated the BPCIA for failure to participate (or to cooperate) in the patent dance process and for providing inadequate or ineffective notice of commercial marketing (see our previous post here). More recently, there has been a post-patent dance challenge involving a biosimilar version of Amgen’s NEULASTA (pegfilgrastim) – see here – and that also involves an allegation of ineffective notice. For the most part, courts are still working on sorting out the second wave of BPCIA lawsuits involving participation in the patent dance process (PHS Act § 351(l)(2)-(l)(7)) and the timing of 180-day commercial notice (PHS Act § 351(l)(8)). Both issues are in dispute in a recent Complaint filed by Amgen against Hospira concerning a biosimilar version of EPOGEN (epoetin alfa) (BLA 103234). Amgen’s Complaint (Case No. 1:15-cv-00839-RGA) – the first BPCIA-related Complaint filed in the U.S. District Court for the District of Delaware – alleges that Hospira violated PHS Act §§ 351(l)(8)(A), (l)(2)(A), and (l)(4) after Hospira engaged Amgen upon FDA notification that the Agency accepted Hospira’s BLA for a biosimilar version of EPOGEN. (The Complaint also alleges infringement of three patents, one of which was included in Amgen’s disclosure under PHS Act § 351(l(3)(A).) These issues, insofar as they concern the mandatory or voluntary nature of the patent dance process and the timing of notice, were tackled by the U.S. Court of Appeals for the Federal Circuit in a July 21, 2015 decision, but the decision has been appealed. According to Amgen, “Hospira has chosen to ignore certain statutory requirements of the BPCIA that Congress put in place to protect innovators such as Amgen. Rather than follow the requirements of the BPCIA, Hospira has selectively decided to comply with certain provisions while refusing to comply with others.” First, Amgen alleges that “[a]lthough Hospira provided a copy of the Hospira BLA to Amgen, it did not provide Amgen with the other information describing the processes used to manufacture the Hospira Epoetin Biosimilar Product as required by § 262(l)(2)(A),” and that Hospira has repeatedly refused to provide information specifically identified by Amgen. None of the correspondence identified in Amgen’s Complaint is attached to the Complaint, so we’re unclear what that information is exactly. Is it information included in a Drug Master File (i.e., a submission of information to FDA to permit the Agency to review such information in support of a third party’s submission without revealing the information to the third party), or in some other submission to FDA? “By unlawfully withholding the information required by 42 U.S.C. § 262, Hospira has thereby frustrated the statutory purpose and deprived Amgen of the opportunity to seek redress for potential infringement. Amgen may therefore seek to assert additional patents following eventual receipt of Hospira’s manufacturing information to be produced in discovery in this action under the Federal Rules,” says Amgen in its Complaint. Notwithstanding the alleged absence of certain information from Hospira, Amgen engaged Hospira in the patent exchange process of the patent dance. But Amgen says that Hospira has failed to cooperate. After accepting Amgen’s patent list provided pursuant to PHS Act § 351(l)(3)(A), “Hospira refused to engage in any of the negotiations required by [PHS Act § 351(l)(4)(A)]” in violation of the statute, according to Amgen. Turning to notice of commercial marketing, Amgen says that the 180-day notice Hospira provided on April 8, 2015 is invalid. The Federal Circuit recently ruled in a severely split decison that valid notice can only be provided on or after FDA licensure of a biosimilar BLA. “Despite its obligation under § 262(l)(8)(A), Hospira provided Amgen with a purported (8)(A) notice on April 8, 2015, before Amgen had provided its initial disclosure of patents under (3)(A) and before Hospira received FDA approval for its Hospira Epoetin Biosimilar Product” (emphasis in original), says Amgen. “In serving a purported ‘notice of commercial marketing’ before its biosimilar product is licensed, Hospira intends to deprive Amgen of the statutory time period for considering the need for and, if appropriate, seeking adjudication of, a potential preliminary injunction motion. Therefore, Hospira intends to continue violating this provision of the BPCIA absent an order of the Court compelling Hospira to comply.”
In addition to patent-specific relief, Amgen has a laundry list of BPCIA-specific relief the company wants from the court. The relief includes: (1) orders “enjoining Hospira from commercially marketing the Hospira Epoetin Biosimilar Product until Amgen is restored to the position it would have been in had Hospira met its obligations under the BPCIA,” “enjoining Hospira from continuing to seek FDA review of its [biosimilar] application and/or compelling Hospira to suspend FDA review of its [biosimilar] application until Hospira has obtained permission from Amgen to use the EPOGEN® (epoetin alfa) license or Hospira has restored to Amgen the benefits afforded to Reference Product Sponsors in the BPCIA,” and “requiring Hospira to provide Amgen ‘such other information that describes the process or processes used to manufacture the biological product that is the subject of’ the Hospira BLA; (2) declarations that Hospira’s April 9, 2015 notice of commercial marketing is ineffective, and that Hospira has violated the BPCIA by failing to provide to Amgen by the statutory deadline certain manufacturing informatin; and (3) an injunction requiring notice of commercial marketing from Hospira to Amgen on or after FDA licensure of Hospira’s EPOGEN biosimilar application and prohibiting Hospira from launching its biosimilar until 180 days after notice is provided. Posted at 05:37 AM in Biosimilars, Prescription Drugs and Biologics | Permalink