Source: http://www.fdalawblog.net/fda_law_blog_hyman_phelps/hatchwaxman/
Timestamp: 2014-10-21 15:08:10
Document Index: 722738378

Matched Legal Cases: ['§ 505', '§ 355', '§ 271', '§ 505', '§ 505', '§ 505', '§ 505', '§ 505', '§ 505', '§ 505', '§ 505', '§ 505', '§ 505', '§ 505', '§ 505', '§ 505', '§ 505', '§ 505', '§505', '§505', '§505', '§ 524', '§ 529', '§ 505', '§ 529', '§ 524', '§ 505', '§ 314', '§ 156', '§ 156', '§ 156', '§ 505', '§ 505', '§ 505', '§ 505', '§ 505', '§ 351', '§ 505', '§ 301', '§ 505', '§ 505', '§ 505', '§ 505', '§ 505']

By Kurt R. Karst – For several months now we have been monitoring an appeal to the U.S. Court of Appeals for the Federal Circuit concerning a patent – U.S. Patent No. 6,878,703 (“the ‘703 patent”) – listed in the Orange Book for Daiichi Sankyo Inc.’s (“Daiichi”) BENICAR (olmesartan medoxomil) Tablets (NDA 021286). We were waiting for the case to ripen into a blog post. That happened earlier this week, just not in the way we expected it to happen. But before we get there, some background on the BENICAR case.
The ‘703 patent, which Daiichi statutorily disclaimed, is a 180-day exclusivity-bearing patent, and therefore, remains listed in the Orange Book, but with a “Patent Delist Request Flag.” This flag is described by FDA in an Orange Book data file as follows:
Sponsor has requested patent be delisted. This patent has remained listed because, under Section 505(j)(5)(D)(i) of the Act, a first applicant may retain eligibility for 180-day exclusivity based on a paragraph IV certification to this patent for a certain period. Applicants under Section 505(b)(2) are not required to certify to patents where this flag is set to Y. Format is Y or null.
The first ANDA applicant’s eligibility for 180-day exclusivity for Olmesartan Medoxomil Tablets – here subject to the post-Medicare Modernization Act (“MMA”) version of the statute – is apparently serving as an obstacle to Apotex, Inc. (“Apotex”), which has an ANDA pending at FDA that is not yet tentatively approved. In November 2012, Apotex filed a Complaint for Declaratory Judgment in the U.S. District Court for the Northern District of Illinois in an effort to obtain a court decision triggering the 75-day statutory period under FDC Act § 505(j)(5)(D)(i)(I)(bb) and that would ultimately result in a forfeiture of 180-day exclusivity eligibility. Daiichi filed a Motion to Dismiss the Apotex Complaint, as did non-party/proposed intervenor-defendant Mylan (here). Earlier this year, the District Court issued a Memorandum Opinion granting Daiichi’s Motion to Dismiss, saying that “[t]he mere fact that the FDA has failed for some reason to delist Patent ‘703, despite Daiichi’s request, does not create a case or controversy by which Apotex may seek a declaratory judgment regarding a nonexistent patent.” Apotex appealed the District Court decision to the Federal Circuit with the following statement of the issue in the case:
Whether the district court legally erred in concluding that a patentee’s disclaimer of a patent that continues to have an exclusionary effect by virtue of the patentee’s listing of that patent in the FDA Orange Book deprives the court of subject matter jurisdiction to decide Apotex’s civil action to obtain patent certainty under 21 U.S.C. § 355(j)(5)(C) and 35 U.S.C. § 271(e)(5), where the requisites of the statutes were satisfied and where, unless Apotex can obtain the declaratory judgment sought in this action, final FDA approval of its [ANDA] will be delayed by at least 180 days.
Daiichi’s brief is on file, as well as a brief from cross-appellant Mylan challenging the District Court’s denial of the company’s motions to intervene and dismiss the Apotex Complaint. Recently, Apotex filed its Response and Reply Brief. The BENICAR case above serves as an interesting counterpoint to a Memorandum Opinion and Order issued earlier this week by the U.S. District Court for the Eastern District of Virginia. In that case, the court denied a Motion to Dismiss filed by patent owner Ferring B.V. (“Ferring”) seeking dismissal of a Complaint for Declaratory Judgment of Patent Unenforceability filed by ANDA applicant Glenmark Generics Ltd. (“Glenmark”) (Opposition and Reply briefs available here and here). The drug at issue in that case is DDAVP (desmopressin acetate) Tablets, 0.1 mg and 0.2 mg, which FDA approved under NDA 019955 on September 6, 1995. (A hat tip to the folks at Sterne, Kessler, Goldstein & Fox PLLC who represent Glenmark and who alerted us to the DDAVP decision.)
Unlike BENICAR, DDAVP is a pre-MMA drug insofar as 180-day exclusivity is concerned. And in that pre-MMA world, which continues to generate interesting controversies (see our previous post here), a subsequent ANDA sponsor that certifies to a newly listed patent cannot be approved until the first-filer’s exclusivity is over, or is otherwise lost because of, for example, a final court decision. That’s because under the pre-MMA statute 180-day exclusivity is patent-by-patent and can result in multiple rounds of exclusivity. In the case of DDAVP, the listing of U.S. Patent No. 7,022,340 (“the ‘340 patent”) in the Orange Book for NDA 019955, and the subsequent Paragraph IV certification to that ‘340 patent by an unknown first-filer, has given rise to a new period of 180-day exclusivity eligibility. That unknown first-filer’s period of exclusivity is blocking subsequent ANDA applicant Glenmark from obtaining final approval of its ANDA 201831 that FDA tentatively approved in Decemner 2013. So in an attempt to relieve the bottleneck created by the fist-filer’s 180-day exclusivity eligibility, Glenmark initiated litigation. As with the ‘703 patent listed in the Orange Book for BENICAR, the ‘340 patent listed in the Orange Book for DDAVP has been statutorily disclaimed an is identified with a “Patent Delist Request Flag.” But unlike the Illinois District Court in the BENICAR case, the Virginia District Court in the DDAVP case ruled in its October 14, 2014 decision that notwithstanding the patent delisting, there remains a case or controversy by which Glenmark may seek a declaratory judgment regarding the disclaimed and now nonexistent patent. Specifically, wrote the Virginia District Court:
Ferring held an exclusive license to the ‘340 patent that is listed in connection with Sanofi’s NDA for DDAVP Tablets. The Federal Circuit has consistently held that “the alleged action taken (giving rise to the injury-in-fact) [is] [the] listing [of] particular patents in the Orange Book.” Teva Pharms., USA, Inc. v. Eisai Co. Ltd., 620 F.3d 1341, 1346-47 (citing Caraco, 527 F.3d at 1292; and Janssen Pharmaceutica, N.V. v. Apotex, Inc., 540 F.3d 1353, 1359-60 (Fed. Cir. 2008). The same logic applies here. That is, “‘but-for’ the [] list[ing] [of the ‘340] patent in the Orange Book, FDA approval of [Glenmark’s] drug would not have been independently delayed by the patent.” Id. The statutory disclaimer and request to delist the patent from the Orange Book does not obscure the traceability of Glenmark’s injury to Ferring. In other words, the statutory disclaimer of the ‘340 patent, that Glenmark admits renders the patent legally nonexistent, does not eliminate the patent from obstructing the FDA’s approval of Glenmark’s ANDA. The ‘340 patent remains the critical factor in the FDA’s approval process. . . .
Finding that it may appropriately exercise jurisdiction over the matter, the Court now finds no persuasive reason to decline to do so. Exercising jurisdiction in this matter will not merely serve a useful purpose in settling the legal relations at issue and affording relief from the underlying controversy, but is essential to doing so. There exists a legitimate dispute over the continued listing of the ‘340 patent in the Orange Book that the Court may resolve through “specific relief... of a conclusive character. ” MedImmune, 549 U.S. at 127 (citations and internal quotation marks omitted). Such relief is appropriately sought under the Declaratory Judgment Act.
The DDVAP case may be headed on to the Federal Circuit for another look, though a decision in the BENICAR case could resolve this Hatch-Waxman declaratory judgment issue sooner rather than later. Posted at 08:21 PM in Hatch-Waxman, Prescription Drugs and Biologics | Permalink
By Kurt R. Karst – In recent comments submitted to FDA, the American Academy of Pediatrics (“AAP”) is taking a stand against the relief requested in a June 2014 Citizen Petition (Docket No. FDA-2014-P-0830) submitted on behalf of Merz North America. The petition calls into question the long-held belief that FDA’s issuance of a Pediatric Written Request (“PWR”) is a condition precedent to the Agency awarding a period of 6-month pediatric exclusivity pursuant to the Best Pharmaceuticals for Children Act (“BPCA”) (FDC Act § 505A). According to the AAP, Congress never intended for certain provisions of the BPCA “to be an end-run around the requirement for exclusivity to be granted on the basis of a written request.”
As we previoulsy reported, FDA approved the Merz (formerly Shionogi) drug CUVPOSA (glycopyrrolate) Oral Solution on July 28, 2010 under NDA No. 022571 for a pediatric-only indication: to reduce chronic severe drooling in pediatric patients (aged 3-16) with neurologic conditions associated with problem drooling (e.g., cerebral palsy). FDA awarded periods of 3-year new clinical investigation exclusivity and 7-year orphan drug exclusivity, but not 6-month pediatric exclusivity. That’s because the NDA sponsor never obtained a PWR from FDA. But a PWR should not have been necessary says Merz, because the company’s “predecessor fulfilled the requirements for six-month pediatric exclusivity pursuant to FFDCA § 505A(h) as it existed at the time [FDA] approved Cuvposa in 2010. The pediatric studies were performed as required under a provision of law and regulations (i.e., for NDA approval), and thus satisfied the requirements for pediatric exclusivity under § 505A(h) without a formal written request from FDA.”
In 2010, FDC Act § 505A(h), which concerns the relationship between the BPCA and the Pediatric Research Equity Act (“PREA”) (FDC Act § 505B) under which FDA can require sponsors to conduct pediatric testing for on-label uses, stated:
That provision, originally added to the statute in 1997 at FDC Act § 505A(i) with the enactment of the FDA Modernization Act (“FDAMA”), and moved to FDC Act § 505A(i) with the enactment of the 2007 FDA Amendments Act (“FDAAA”), was changed in 2012 with the enactment of the FDA Safety and Innovation Act (“FDASIA”) to state:
Exclusivity under this section shall only be granted for the completion of a study or studies that are the subject of a written request and for which reports are submitted and accepted in accordance with subsection (d)(3). Written requests under this section may consist of a study or studies required under section 355c of this title [FDC Act § 505B].
Merz says that the difference between the 2007 and 2012 versions of FDC Act § 505A(h) is significant for two reasons: “First, it includes language referencing written requests which was not present in that particular subsection when Cuvposa was approved,” and “[s]econd, it facially narrows the relationship between studies conducted for pediatric exclusivity and for other required purposes.” Continuing on with the second point, the petition says that the 2010 version of FDC Act § 505A(h) “broadly referenced pediatric studies conducted as required by another provision of law or regulation,” but that the 2012 version of FDC Act § 505A(h) “only references PREA studies by name as being eligible for pediatric exclusivity.” The upshot of the differences in the statutory text, says Merz, is that for CUVPOSA to have been eligible for pediatric exclusivity under FDC Act § 505A(h) as it existed in 2010, two requirements must have been met: (1) the pediatric studies performed must have been “required by a provision of law (including a regulation);” and (2) the studies must have met the pediatric exclusivity requirements, including completeness and timeliness. And both of these elements were met, argues the company:
Cuvposa met the first hurdle for receiving pediatric exclusivity under § 505A(h) because the sponsor was required to complete pediatric studies for NDA approval under both the FFDCA and the regulations. . . . Cuvposa also cleared the second hurdle for pediatric exclusivity under § 505A(h) — that the studies meet the “completeness, timeliness, and other requirements” for exclusivity. The completeness requirement was certainly met because, if not, then the NDA would not have been approved. The timeliness factor is not relevant here, because the studies were completed as required for NDA approval. As far as any of the “other requirements” — a written request, internal review of the request, and internal review of the completed studies — none of these were required for Cuvposa to be eligible for exclusivity under § 505A(h).
In its comments to FDA, the AAP says there is no reason to believe that Congress ever intended to award pediatric exclusivity under the circumstances in which a company was seeking approval for pediatric-only use of a drug: To argue that Congress intended to allow for the awarding of pediatric exclusivity under §505A(i)/§505A(h) for studies submitted in accordance with a pediatric-only new drug application under §505(b)(1), requires one to also argue that Congress also intended pediatric exclusivity to be an incentive for the development of new pediatric-only therapies. There is no factual basis to make this claim and no record to indicate this is what Congress intended. While improving incentives for the development of first-in-pediatrics therapies is a worthy goal, the goals of the Pediatric Rule, BPCA, and PREA is and always has been to ensure that drugs developed for adults are studied in children and to provide incentives for completing additional FDA-requested studies in children.
Indeed, says the AAP, if that was the case, then Congress would not have pursued legislation to expand the existing Tropical Disease Priority Review Voucher program set forth at FDC Act § 524 (as added by FDAAA) to create the Rare Pediatric Disease Priority Review Voucher under FDC Act § 529 (as added by FDASIA) (see our previous post here). Morover, says the AAP, removing the PWR element as a condition to obtaining pediatric exclusivity could be dangerous:
The written request is and always has been an essential element of the pediatric exclusivity program. Six months of exclusivity is a powerful incentive for manufacturers but it does not come without a cost to society. Tying this incentive to the fulfillment of a written request allows the FDA to ensure that the data generated by trials involving children are maximized, that product sponsors are meeting the objectives and timeframes agreed to in the written request, and that data and labeling generated by such trials are available to the public. It would be a dangerous precedent to allow the awarding of exclusivity without a written request. The written request is in essence a contract between the FDA and the sponsor to conduct specific pediatric studies in return for a generous incentive. Allowing the awarding of exclusivity without a written request would not appropriately serve the interests of child health.
Posted at 07:29 PM in Hatch-Waxman, Prescription Drugs and Biologics | Permalink
By Kurt R. Karst – Last Friday morning (October 10th) something interesting popped up out of the blue on FDA’s “What’s New Related to Drugs” webpage: the final version of FDA’s “Guidance for Industry – New Chemical Entity Exclusivity Determinations for Certain Fixed-Combination Drug Products.” But both the timing and content of the final guidance might mean FDA is in store for some controversy in the not too distant future. FDA published a draft version of the guidance in February 2014 (see our previous post here) saying that the Agency would reinterpret the NCE exclusivity provisions of the FDC Act to award NCE exclusivity for a newly approved Fixed-Dose Combination Drug (“FDC”) containing an NCE and a previously approved drug. The draft guidance states, however, that if the Agency’s new interpretation is adopted, it will apply only prospectively: “If the new interpretation is adopted, FDA intends to apply the new interpretation prospectively. Therefore, this guidance does not apply to fixed-combination drug products that were approved prior to adopting the new interpretation.” About a dozen comments were submitted to FDA. Most of the comments applauded FDA’s proposal and urged the Agency to finalize the guidance promptly. FDA proposed the reinterpretation after having received three Citizen Petitions in 2013 requesting that FDA interpret the law to award NCE exclusivity for approved FDCs containing an NCE and a previously-approved drug – specifically STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) Tablets (Docket No. FDA-2013-P-0058); PREPOPIK (sodium picosulfate, magnesium oxide and citric acid) for Oral Solution (Docket No. FDA-2013-P-0119); and NATAZIA (estradiol valerate and estradiol valerate/dienogest) Tablets (Docket No. FDA-2013-P-0471). However, on the same day FDA posted the draft guidance on the Agency’s website, FDA issued a Consolidated Response denying the three petitions and saying that although FDA would reinterpret the law, that reinterpretation would not apply to previously-approved FDCs. That move prompted two of the petitioners to each submit a Petition for Reconsideration (with respect to STRIBILD and PREPOPIK) (see our previous posts here and here). Along the way, another company entered the fray (or what we dubbed the “NCE for FDC Club”). Specifically, Pfizer Inc. submitted a Citizen Petition petition (Docket No. FDA-2014-P-0737) to FDA saying that FDA erred in not granting NCE exclusivity with respect to Wyeth Pharmaceuticals, Inc.’s DUAVEE (conjugated estrogens/bazedoxifene) Tablets (see our previous post here).
Based on that statement, we knew that denials of the STRIBILD and PREPOPIK Petitions for Reconsideration, as well as a denial of the DUAVEE Citizen Petition, would be coming soon. Indeed, just a few hours later, those petition denials (here and here) appeared on Regulations.gov. FDA’s denial of the STRIBILD and PREPOPIK Petitions for Reconsideration notes that “[s]imultaneously with this response, the Agency will issue the Exclusivity Guidance in final form and apply its new interpretation of the relevant statutory and regulatory provisions to fixed-combinations approved from this day forward.” FDA’s statements “from this day forward” in the petition denial and “from the date of this guidance’s publication” in the final guidance document caught our attention. Presumably FDA intends to grant NCE exclusivity for FDCs approved beginning on October 10th (like AKYNZEO and HARVONI). But does the appearance of the final guidance on FDA’s website constitute publication? Or is such a guidance document “published” only once a Federal Register notice announcing the guidance is issued? The answer to that question could generate some controversy. And even if that’s a non-issue, we may still see some controversy over FDA’s decision not to apply the Agency’s reinterpretation to previously approved FDCs. We’ll be keeping an eye on the court dockets.
Posted at 07:46 PM in Hatch-Waxman, Prescription Drugs and Biologics | Permalink
Flare Up: Takeda Challenges FDA Approval of 505(b)(2) Application for Colchicine Capsules
By Kurt R. Karst – Colchicine is one of those drugs that has a long and storied history at FDA. It’s an old drug (about 200 years old) that was marketed for decades without FDA approval. Then, in 2009, FDA approved Mutual Pharmaceutical Company, Inc.’s (and now Takeda Pharmaceuticals U.S.A., Inc.’s (“Takeda”)) 505(b)(2) application (NDA No. 022352) for COLCRYS (colchicine) Capsules, 0.6 mg, to prevent gout, treat gout flares, and treat Familial Mediterranean Fever (“FMF”) and granted periods of 3-year new clinical investigation exclusivity (related to the gout approvals) and a period of 7-year orphan druig exclusivity (related to FMF). Soon after the NDA approval, there was litigation to stem the flow of unapproved colchicine (see our previous posts here and here). And about a year after NDA approval, FDA ordered companies marketing unapproved single-ingredient oral colchicine to remove their products from the market. Companies that wanted to market generic or follow-on versions of single-ingredient oral colchicine then began to consider their options: submit an ANDA or a 505(b)(2) application. And while those decisions were being made, the citizen petition process was initiated, with no less than two petitions: Docket Nos. FDA-2010-P-0614 and FDA-2012-P-1018. Now the storied history of colchicine is about to get longer . . . . Earlier this week, Takeda filed a Complaint in the U.S. District Court for the District of Columbia challenging FDA’s September 26, 2014 approval (here and here) of a 505(b)(2) application (NDA No. 204820) submitted by Hikma Pharmaceuticals LLC (“Hikma”) and its U.S. partner West-Ward Pharmaceutical Corp. (“West-Ward”) for MITIGARE (colchicine) Capsules, 0.6 mg, for prophylaxis of gout flares. Although there are several patents listed in the Orange Book for COLCRYS, this is the first opportunity Takeda has had to challenge MITIGARE. Apparently Hikma was able to avoid identifying COLCRYS as a listed drug in its 505(b)(2) application by virtue of relying on information not containd in (or related to) the COLCRYS NDA approval, and therefore avoid certifying to Orange Book-listed patents for COLCRYS.
Takeda alleges in its October 6, 2014 Complaint that FDA’s approval of MITIGARE violates the FDC Act and the Administrative Procedure Act (“APA”) in several respects:
First, FDA acted arbitrarily and capriciously in approving Hikma’s Section 505(b)(2) application for Mitigare without requiring the label to contain critical safety information that FDA previously stated was necessary for single-ingredient oral colchicine products. Second, FDA’s approval of Hikma’s application for Mitigare was unlawful, arbitrary and capricious because, as approved, Mitigare is not safe in light of the defects in its label. And third, FDA’s failure to require Hikma to reference Takeda’s own colchicine drug, Colcrys®, in its application interfered with Takeda’s rights to participate in the administrative process, including the Paragraph IV certification process under the Hatch-Waxman Act and the Citizen Petition process. As a result, FDA’s decision is unlawful, arbitrary, capricious, an abuse of discretion, and otherwise violates the Administrative Procedure Act (the “APA”).
Takeda’s Complaint fills in some of the details of the allegations. For example, Takeda, citing to one of the FDA petition responses concerning colchicine (i.e., FDA-2010-P-0614), says that “[e]ven though Mitigare is indicated only for prophylaxis, FDA has clearly stated that the labeling for a prophylaxis product must disclose the dosage for treatment of an acute gout flare due to the risk of cumulative toxicity,” but that the MITIGARE labeling omits that low-dose regimen information, as well as “specific dose adjustments to avoid potentially fatal drug-drug interaction.” Having omitted this information, “Hikma was able to avoid referencing Colcrys® and certifying to the Colcrys® patents,” alleges Takeda. Takeda also alleges that MITIGARE fails to meet the statutory standard required for FDA approval because the labeling omits certain safety information. Takeda is seeking declaratory and injunctive relief. Specifically, Takeda wants the court to declare that FDA’s approval of MITIGARE violated the APA and the FDC Act, that FDA’s refusal to require the MITIGARE 505(b)(2) application to reference COLCRYS as a listed drug violated the APA and the FDC Act, and that FDA’s actions, findings, and conclusions in approving MITIGARE were arbitrary, capricious, an abuse of discretion, and without factual basis. In addition, Takeda wants temporary, preliminary and permanent injunctive relief requiring FDA to rescind or stay FDA’s approval of MITIGARE. A redacted version of Takeda’s memorandum in support of the company’s Motion for a Temporary Restraining Order and Preliminary Injunction should be available soon, and will be included as an update to this post. UPDATES:
A redacted version of Takeda's brief accompanying its Motion for Temporary Restraining Order and Preliminary Injunction filed in the DC District Court was made available on October 8th.
A Telephone Conference is set for October 9th at 1:00 PM before Judge Ketanji Brown Jackson (DC District Court).
On October 3, 2014, Takeda filed a patent infringement lawsuit against West-Ward in the U.S. District Court for the District of Delaware: Takeda Pharmaceuticals U.S.A., Inc. v. West-Ward Pharmaceutical Corporation et al, Case No. 1:14-cv-01268-SLR. A telephonic hearing on Takeda's Motion for Temporary Restraining Order and Preliminary Injunction in that case was held on October 8th.
October 9, 2014: "Minute Entry for proceedings held before Judge Ketanji Brown Jackson: Telephone Conference held on 10/9/2014 discussions re: Temporary Restraining Order. Government Brief due by 10/17/2014; Intervenor Brief, if any, shall be filed by 10/17/14; Responses due by 10/20/2014. Preliminary Injunction Hearing set for 10/21/2014 @ 2:30 PM in Courtroom 17 before Judge Ketanji Brown Jackson. Motion to Intervene GRANTED for reasons stated on the record." Posted at 07:42 PM in Hatch-Waxman, Prescription Drugs and Biologics | Permalink
“Wildcard Exclusivity” Returns: PCAST Recommends Consideration of a Tradable Voucher to Reward Successful Antibiotic Development By Kurt R. Karst – As most folks know by now, earlier this month the President’s Council of Advisors on Science and Technology (“PCAST”) released a report to the President titled “Combating Antibiotic Resistant Bacteria.” The report is part of a broader initiative announced by The White House to address the growing challenges posed by antibiotic resistance that includes a National Strategy on Combating Antibiotic Resistant Bacteria and a Presidential Executive Order. Of particular interest to us are the various “push” and “pull” mechanisms the PCAST report considers to incentivize the development of antibiotics – and especially the “push” mechanism described in the report as “[t]radable vouchers to extend patent life or market exclusivity of another drug.” This is longhand for “wildcard exclusivity.” And although it is not a new concept, there seems to be a growing chorus of support for wildcard exclusivity that may mean it will gain traction among legislators and find its way into the FDC Act. By way of background, traditional research and development incentives can be divided into two main types: “push” and “pull” methods. “Push” incentives tend to focus on removing barriers to product development, and include tax credits and grants. “Pull” incentives tend to focus on the promise of financial reward after a product has been developed, and include monetary prizes, intellectual property extensions, tradable vouchers, and non-patent marketing exclusivities. The FDC Act is chock-full of “pull” incentives. Indeed, several have been created in the past decade, including a 5-year marketing exclusivity add-on pursuant to the Generating Antibiotic Incentives Now Act (“GAIN Act”) (FDC Act § 505E) for a drug product designated by FDA as a Qualified Infectious Disease Product (see our previous post here), and tradable vouchers under the Rare Pediatric Disease Priority Review Voucher (FDC Act § 529) and Tropical Disease Priority Review Voucher (FDC Act § 524) programs (see our previous posts here and here). But existing incentives – and in particular GAIN Act exclusivity – are not enough when it comes to antibiotics, says PCAST:
Such a voucher could be very valuable, providing a powerful incentive to potential innovators. For a mature blockbuster drug with $4 billion in annual sales, a three-month extension would yield $1 billion in additional sales – corresponding to profits of $800 million, assuming margins on a mature drug of 80%. Such an incentive might elicit considerable interest from the venture capital community in launching biotechnology companies focused on new antibiotic development. There are several advantages to this approach, says PCAST, including that “[i]t would leave innovation decisions up to the free market,” “would not require direct appropriation from the Federal discretionary budget,” and that “[t]he overall cost of incentivizing antibiotic development would be spread across many different drugs, with the cost of any given three-month extension being limited.” But as the PCAST report also notes, “[t]he key issue with this approach is that it would delay the transition of other drugs to generic status.” Such delay could raise significant opposition from an array of stakeholders, including patients, public health advocates, generic drug manufacturers. “Public health advocates, for example, may ask why patients taking a statin drug (or their insurers) should bear the financial burden of incentivizing antibiotic development.” Moreover, “the total social cost of this approach is likely to be larger than some other solutions because antibiotic developers will require a fraction of the value of the tradable vouchers,” says PCAST. The concept of wildcard exclusivity is not new. It has cropped up from time to time over the years. We’ve seen it discussed in reports and in the published literature generally, and specifically in the context of providing an incentive for antibiotic and cancer drug development (see here, here, here, and here). It’s also a concept that Congress debated including in the law a decade ago in the context of bioterrorism countermeasure development (see here at pages 17-18). That effort drew sharp criticism from the Generic Pharmaceutical Association (see here). Congress may once again be poised to consider wildcard exclusivity. Indeed, the topic was discussed on Capitol Hill just a day after the release of the PCAST report when the Subcommittee on Health of the House Committee on Energy and Commerce held a hearing as part of the broader 21st Century Cures Initiative, titled “Examining Ways to Combat Antibiotic Resistance and Foster New Drug Development.” A 21st Century Cures Initiative bill is expected to be dropped in January 2015 and may incorporate some of the “push” and “pull” incentives laid out in the PCAST report. That bill could ultimately be wrapped into a broader FDA bill that reauthorizes and amends several of the user fee acts. Posted at 06:54 PM in Drug Development, Hatch-Waxman, Prescription Drugs and Biologics | Permalink
Thanks to everyone who participated in our “30 for 30” Hatch-Waxman Trivia! Based on the corrrespondence we received since posting the trivia questions earlier this week, FDA Law Blog readers enjoyed the trip down memory lane. . . and were entertained along the way. We know you are chomping at the bit to see the answers, so without further ado, we give you the answers to each of the trivia questions. Q1: What U.S. Senator is a musician, songwriter and producer, a member of ASCAP, and whose works have been recorded by Gladys Knight, Donny Osmond and Brooks and Dunn, among others?
Ronald Reaganwas inBrother Rat (1938)withEddie Albertwas inThe Big Picture (1989)withKevin Bacon
Henry Waxman was inMoveOn: The Movie (2009) withMoby was inCome Together: A Night for John Lennon's Words and Music (2001) withKevin Bacon
Orrin G. Hatch was inTraffic (2000) withJohn Slattery was inThe 60th Primetime Emmy Awards (2008) withKevin Bacon
FDC Act § 505(j)(5)(B)(iv), as enacted states: If the application contains a certification described in subclause (IV) of paragraph (2)(A)(vii) and is for a drug for which a previous application has been submitted under this subsection continuing such a certification, the application shall be made effective not earlier than one hundred and eighty days after-
Q8: What is the significant difference between ANDA No. 076933 and ANDA No. 076934? (The answer is neither “1,” nor the drug name.) A. ANDAs with a number less than or equal to 076933 are pre-MMA applications, and ANDAs with a number equal to or greater than 076934 are post-MMA applications.
A: Then-Representative Albert Gore, Jr. (D-TN). See The Push to Protect Patents on Drugs; The Drug Industry Nearly Won Last Year, but Then the Political Winds Changed. (Science 1983: Vol. 222 no. 4624 pp. 593-595). Q11: Donald Hare, R.Ph., who has since retired from FDA, is sometimes referred to as the Father of the Orange Book. To whom does the distinction of Mother of the Orange Book – or at least Mother-in-Law – belong?
A: A period of GAIN exclusivity expiring on August 6, 2024 is listed for NDA No. 206334 for ORBACTIV (oritavancin diphosphate) Lyophilized Powder Injection. This is the latest of the few periods of GAIN exclusivity FDA has granted. The other GAIN Act approvals are NDA Nos. 205435 and 205346 for SIVEXTRO (tedizolid phosphate) (GAIN exclusivity expiring on June 20, 2024), and NDA No. 021883 for DALVANCE (dalbavancin HCl) (GAIN exclusivity expiring on May 23, 2024). Q13: When were Reference Listed Drug (“RLD”) designations added to the Orange Book?
A: An electronic Orange Book search function was added to FDA’s website on October 31, 1997. Beginning in 1998, current patent listings for approved drug products could be obtained from the electronic Orange Book through a search by active ingredient, proprietary name, application holder, or application number. Since February 2005 (25th Edition), FDA has provided daily electronic Orange Book product updates, and made the volume available in a downloadable PDF format. Q15: What is the “Blue Book”?
Q16: Prior to FDA’s formal creation of Orange Book patent listing forms (Form FDA 3542a and Form FDA 3542) in 2003, did FDA offer any informal guidance to NDA sponsors on patent listing? A: Yes. FDA provided a Patent Submission Sample Format to sponsors who requested it. Q17: Can you identify 10 types of non-patent marketing exclusivities (or non-patent exclusivity extensions) recognized by the FDC Act?
A: Gary P. Jordan is the the first assistant U.S. attorney who prosecuted a case arising from the so-called “generic drug scandal.” Q23: Who is Marion J. Finkel?
A: Marion J. Finkel is credited with developing the framework for the so-called “paper NDA,” which is a predecessor to the 505(b)(2) NDA. Q24: What is the only instance in which a court has ordered FDA to approve an ANDA during another sponsor’s period of 180-day exclusivity? A: In Watson Laboratories, Inc. v. Sebelius, et al., Case No. 12-1344 (ABJ) (D.D.C. Oct. 22, 2012), which concerned 180-day exclusivity for generic ACTOS (pioglitazone) under the pre-MMA statute, the district court overruled FDA’s determination that Watson was not eligible to share in 180-day exclusivity because the company was not the first (or among the first) to amend its pending ANDA to convert a patent certification to Paragraph IV. Instead, the district court ruled that Watson was entitled to share in another applicant’s 180-day exclusivity period, because FDA’s long-standing interpretation of the FDC Act was contrary to the terms of the statute, and ordered the Agency to approve Watson’s ANDA. FDA appealed the decision to the U.S. Court of Appeals for the District of Columbia Circuit (Docket Nos. 12-5332 & 12-5342), where a motion for vacatur (based on mootness) was ultimately granted. Q25: What is the only instance in whch FDA was faced with a leap year NCE NDA approval?
A: FDA approved PRISTIQ (desvenlafaxine) Extended-Release Tablets under NDA No. 021992 in a leap year, on February 29, 2008, and granted NCE exclusivity expiring in a non-leap year, on March 1, 2013. FDA added a note to the Orange Book stating: “Applications referencing NDA 021992 Pristiq (Desvenlafaxine Succinate) and challenging the listed patent may be received by the Agency beginning on Feb 29, 2012, four years from the NDA approval date” (see our previous post here). Q26: FDA’s regulation at 21 C.F.R. § 314.94(a)(12)(viii) states, in relevant part, “an applicant who has submitted a paragraph IV patent certification may not change it to a paragraph III certification if a patent infringement suit has been filed against another paragraph IV applicant unless the agency has determined that no applicant is entitled to 180-day exclusivity or the patent expires before the lawsuit is resolved or expires after the suit is resolved but before the end of the 180-day exclusivity period.” What is the status of this regulation?
A: On May 10, 2010, the U.S. Court of Appeals for the Federal Circuit issued its decision in PhotoCure v. Kappos, 603 F.3d 1372 (Fed. Cir. 2010) (and in a second case, Ortho-McNeil Pharm., Inc. v. Lupin Pharms., Inc., 603 F.3d 1377 (Fed. Cir. 2010)) concerning the proper interpretation of 35 U.S.C. § 156(a)(5)(A), which states that the term of a patent claiming a drug shall be extended from the original expiration date of the patent if, among other things, “the permission for the commercial marketing or use of the product . . . is the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred.” For several years, the PTO interpreted the term “product” in 35 U.S.C. § 156(a)(5)(A) to mean “active moiety” rather than “active ingredient.” The Federal Circuit’s PhotoCure and Ortho-McNeil decisions say that the an “active ingredient” interpretation of the statute should be applied for PTE purposes. Q29: What is the connection between the drugs INDOCIN (indomethacin) and CAPOZIDE (captopril and hydrochlorothiazide), U.S. Patent Nos. 3,849,549 (INDOCIN) and 4,217,347 (CAPOZIDE), and Title II of the Hatch-Waxman Amendments?
A: Both drugs and both patents were cited in a March 25, 1985 letter from Reps. Henry Waxman and Robert Kastenmeier (D-WI) to the PTO Commissioner as examples of drug products covered by a patent that the Congressmen did not believe should be granted a PTE because the drugs contain an active ingredient previously approved by FDA. Q30: What patent concerning what drug led to a change in the PTE statute at 35 U.S.C. § 156 involving the deadline for submitting a PTE application to PTO?
Posted at 10:08 PM in Hatch-Waxman, Prescription Drugs and Biologics | Permalink
By Kurt R. Karst – It’s difficult to believe that almost 30 years have passed since President Ronald Reagan signed into law the Drug Price Competition and Patent Term Restoration Act of 1984 on September 24, 1984. So much in Hatch-Waxman law (or Waxman-Hatch law if you are a food and drug attorney “of a certain age”) – and the world – has changed since that signing in the Rose Garden. President Reagan is no longer with us; Representative Henry Waxman (D-CA), now 74 years old, is retiring after the conclusion of the 113th Congress; Senator Orrin Hatch (R-UT), now 80 years old, is still going strong, but announced that he plans to retire in 2018. If you’re a regular reader of this blog, then you know that we have more than a passing interest in the Hatch-Waxman Amendments. It’s a bit of an obsession. And we also have a thing for anniversaries. Over the past couple of years we’ve celebrated the 30th Anniversary of the Orphan Drug Act (see our post here), and the 75th Anniversary of the enactment of the FDC Act (see our post here). This blogger also authored an article for the William Mitchell Law Review’s Hatch-Waxman 30th Anniversary issue providing the first ever analysis of FDA’s nearly 30-year track record of responding to ANDA suitability petitions (see our post here). Five years ago we celebrated the 25th Anniversary of the Hatch-Waxman Amendments with a trivia contest (see our post here). We came up with a mere 20 questions for FDA Law Blog readers to answer. It’s five years later and once again we’ve decided to challenge FDA Law Blog readers with Hatch-Waxman trivia. This time we’re going “30 for 30.” We had to dig deep . . . real deep . . . to come up with new trivia. We hope you enjoy it! We’ll reveal the answers in a separate post later this week.
Q8: What is the significant difference between ANDA No. 076933 and ANDA No. 076934? (The answer is neither “1,” nor the drug name.) Q9: What pharmaceutical industry trade organization executive referred to the pre-Hatch-Waxman hurdles to generic competition of post-1962 drugs as an “iron curtain”?
Q16: Prior to FDA’s formal creation of Orange Book patent listing forms (Form FDA 3542a and Form FDA 3542) in 2003, did FDA offer any informal guidance to NDA sponsors on patent listing? Q17: Can you identify 10 types of non-patent marketing exclusivities (or non-patent exclusivity extensions) recognized by the FDC Act?
Q24: What is the only instance in which a court has ordered FDA to approve an ANDA during another sponsor’s period of 180-day exclusivity? Q25: What is the only instance in whch FDA was faced with a leap year NCE NDA approval?
Posted at 06:41 AM in Hatch-Waxman, Prescription Drugs and Biologics | Permalink
By Kurt R. Karst – There have been rumors floating around Washington, DC for a few months that efforts were afoot to introduce legislation to amend the FDC Act to address the availability of products subject to a restricted distribution program to generic drug and biosimilar manufacturers for purposes of conducting studies necessary to pursue approval of a marketing application. Those rumors turned into reality with the September 18th introduction of H.R. 5657, the Fair Access for Safe and Timely Generics Act of 2014 (“FAST Generics Act”). Introduced in the U.S. House of Representatives by Congressmen Steve Stivers (R-OH) and Peter Welch (D-VT), the bill would “increase consumer access to generic drugs, boost market competition and ultimately save consumers money,” according to a press release announcing the introduction of the FAST Generics Act. The Generic Pharmaceutical Association, which sponsored a paper published in July 2014 on restricted distribution programs and generic drug competition, applauded the introduction of the bill in a press release.
In case you’re not familiar with the topic of the FAST Generics Act, the issue concerns drug and biological products covered by restricted distribution programs – either under a Risk Evaluation and Mitigation Strategies (“REMS”) program with Elements To Assure Safe Use (“ETASU”) under FDC Act § 505-1, or under a restricted distribution program adopted and implemented by a brand-name manufacturer. In most cases, in order for a generic drug (or biosimilar) manufacturer to submit a marketing application to FDA, the company must first conduct studies comparing its proposed product to the brand-name reference product. In order to do so, the generic drug manufacturer must first obtain reference product sample. Normally drug product sample is easily obtained through various market channels. Products under a restricted distribution program, however, are tightly controlled (often because of a safety concern) and are not readily available. If a generic drug sponsor is unable to obtain sample for equivalence testing, then it is unable to seek marketing approval from FDA.
Current law states that “[n]o holder of an approved covered application shall use any element to assure safe use required by [FDA] under [FDC Act § 505-1(f)] to block or delay approval of an application under section 505(b)(2) or (j) or to prevent application of such element under [FDC Act § 505-1(i)(1)(B)] to a drug that is the subject of an [ANDA].” In June 2009, Dr. Reddy’s Laboratories, Inc. submitted a Citizen Petition (Docket No. FDA-2009-P-0266) to FDA requesting that the Agency “establish procedures to facilitate the availability of generic versions of drug products subject to a [REMS] and enforce the FDC Act to prevent companies from using REMS to block or delay generic competition.” FDA responded to the petition in August 2013 saying, among other things, that decisions to take enforcement action are made at the Agency’s discretion on a case-by-case basis and that FDA “agrees that issues related to ensuring that marketplace actions are fair and do not block market competition would be best addressed by the FTC,” to which FDA has been referring complaints related to restricted distribution programs. In 2012, as Congress was considering legislation that was ultimately enacted as the FDA Safety and Innovation Act (“FDASIA”), there was a push to amend the law to address REMS and generic competition. Specifically Section 1131 of Senate-passed S. 3187 would have amended FDC Act § 505-1 to state that:
Notwithstanding any other provision of law, if a drug is a covered drug, no elements to ensure safe use shall prohibit, or be construed or applied to prohibit, supply of such drug to any eligible drug developer for the purpose of conducting testing necessary to support an application under [FDC Act § (b)(2) or § 505(j) or PHS Act § 351(k)] if the Secretary has issued a written notice described in paragraph (2), and the eligible drug developer has agreed to comply with the terms of the notice.
That provision was not enacted as part of FDASIA. As one legislative bulletin issued at the time stated, “[s]ome controversy surrounded this provision since it could have [led] to the FDA forcing drug sales between brand and generic manufacturers.” In addition, then-FTC Commissioner J. Thomas Rosch objected to including the provision in FDASIA. Referring to both REMS legislation advocated by FTC staff that would “give the FTC jurisdiction to challenge the refusal of a pioneer drug company to provide product samples to generic manufacturers if the FDA determined that the generic company’s protocols were safe,” and to the REMS provisions in S. 3187, Commissioner Rosch commented that “[n]either proposal should be tacked on to other legislation on the Senate floor and should instead be considered by the Help Committee on their own merits” (see our previous post here). Meanwhile, issues concerning ETASU REMS, restricted distribution programs, and generic competition were being debated in court in the context of antitrust law (see our previous posts here, here, and here). None of the earlier court challenges resulted in a decision, because the cases were settled. Earlier this year, however, Mylan Pharmaceuticals Inc. filed a lawsuit alleging that Celgene Corporation violated federal and state antitrust laws by preventing generic competition for Celgene’s drug products THALOMID (thalidomide) Capsules and REVLIMID (lenalidomide) Capsules (see our previous post here). That case is still pending, with a Motion to Dismiss filed by Celgene (Opposition and Reply briefs are available here and here).
The 17-page FAST Generics Act would amend the FDC Act to add Section 505-2, titled “Competitive Access to Covered Products for Development Purposes.” Proposed FDC Act § 505-2 would add several provisions, including:
(b) COMPETITIVE ACCESS TO COVERED PRODUCTS AS A CONDITION ON APPROVAL OR LICENSING.—As a condition of approval or licensure, or continuation or renewal of approval or licensure, of a covered product under section 505 of this Act or section 351 of the Public Health Service Act, respectively, the Secretary shall require that the covered product’s license holder not adopt, impose, or enforce any condition relating to the sale, resale, or distribution of the covered product, including any condition adopted, imposed, or enforced as an aspect of a risk evaluation and mitigation strategy approved by the Secretary, that restricts or has the effect of restricting the supply of such covered product to an eligible product developer for development or testing purposes. (c) COMPETITIVE ACCESS TO COVERED PRODUCTS OTHER THAN REMS PRODUCTS FOR DEVELOPMENT PURPOSES.—No license holder shall adopt, impose, or enforce any condition relating to the sale, resale, or distribution of a covered product that interferes with or restricts access to reasonable quantities of a covered product by an eligible product developer for development and testing purposes, at commercially reasonable, market-based prices, from the license holder or from any wholesaler or specialty distributor authorized by the license holder to commercially distribute or sell the covered product unless the license holder generally adopts, imposes, or enforces lawful conditions relating to the sale, resale, or distribution of a covered product, with respect to other buyers of the covered product.
(d) COMPETITIVE ACCESS TO REMS PRODUCTSFOR DEVELOPMENT PURPOSES.—
(1) PROHIBITED USE OF REMS TO RESTRICTACCESS.—With respect to a REMS product, no aspect of a risk evaluation and mitigation strategy under section 505–1 shall prohibit or restrict, or be construed or applied to prohibit or restrict, the supply of such REMS product to an eligible product developer for development and testing purposes, at commercially reasonable, market-based prices, from the REMS product’s license holder or from any wholesaler or specialty distributor authorized by the license holder to commercially distribute or sell the REMS product.
(2) SINGLE, SHARED SYSTEM OF ELEMENTS TO ASSURE SAFE USE.—With respect to a REMS product, no license holder shall take any step that impedes—
(A) the prompt development of a single, shared system of elements to assure safe use under section 505–1; or
(B) the entry on commercially reasonable terms of an eligible product developer into a previously approved system of elements to assure safe use.
(e) PROCEDURES FOR OBTAINING ACCESS TO COVERED PRODUCTS.—
(1) COMPETITIVE ACCESS.—Notwithstanding any other provision of law, in the case of an eligible product developer that has an authorization to obtain a covered product in effect . . . , no license holder shall adopt, impose, or enforce any other condition relating to the sale, resale, or distribution of such covered product that interferes with or restricts access to reasonable quantities of the covered product by the eligible product developer for development and testing purposes, at commercially reasonable, market-based prices, from the license holder or from any wholesaler or specialty distributor authorized by the license holder to commercially distribute or sell the covered product, unless the license holder generally adopts, imposes, or enforces lawful conditions relating to the sale, resale, or distribution of a covered product, with respect to other buyers of the covered product.
A violation of a requirement or prohibition in any of the above-proposed sections would be treated, in the case of a REMS product, as a violation of the product’s REMS, and would be a prohibited act under proposed FDC Act § 301(ddd). Also, an “eligible product developer” (i.e., a person seeking to develop an ANDA, 505(b)(2) application, or a BLA) that has authorization for access to a covered product from FDA and that is aggrieved by a violation of one of the above-proposed sections “by a license holder or any wholesaler or specialty distributor authorized by the license holder to commercially distribute or sell the covered product[,] may sue such license holder for injunctive relief and treble damages (including costs and interest of the kind described in section 4(a) of the Clayton Act (15 U.S.C. 15(a)).”
In addition to laying out the procedures for an interested party to obtain an authorization to procure a covered product, the FAST Generics Act would give FDA the authority to prohibit, limit, or otherwise suspend a transfer of a covered product to an eligible product developer because such transfer would present an imminent hazard to the public health, and would shield NDA and BLA holders from liability for any claim arising out of an eligible product developer’s development or testing activities conducted under proposed FDC Act § 505-2, “including a claim arising out of a failure of the eligible drug developer to follow adequate safeguards to assure safe use of the covered product.”
Finally, the bill would require various reports from FDA and from the FTC on the implementation of proposed FDC Act § 505-2, and would amend FDC Act § 505-1(i)(1)(B) concerning waiver of the single, shared REMS requirement (see our previous post here). If enacted, the bill would apply to all NDAs and BLAs, regardless of whether or not those applications were approved before, on, or after the date of enactment of the FAST Generics Act. Posted at 09:09 PM in Biosimilars, Hatch-Waxman, Prescription Drugs and Biologics | Permalink
By Kurt R. Karst – There are mortal sins and there are venial sins. In the latest guidance documents FDA announced (here and here) earlier this week – a final guidance on ANDA Refuse-to-Receive (“RTR”) standards and a draft guidance on ANDA RTR for lack of proper justification of impurity limits – FDA focuses on the mortal sins of ANDA submission that will generally result in the Office of Generic Drugs (“OGD”) refusing to accept an ANDA for review. Indeed, the phrase “FDA will refuse-to-receive an ANDA” (followed by or preceded by some example) appears not less than 24 times in FDA’s final ANDA RTR standards guidance. Both ANDA RTR guidances were issued on the eve of a September 17th public meeting on implementation of the Generic Drug User Fee Amendments of 2012 (“GDUFA”). FDA requested comment at the meeting on the ANDA RTR impurity limits draft guidance and other recent guidances on GDUFA implementation (see our previous posts here, here, and here). FDA also solicited comment on “GDUFA Implementation Related to Generic Drug Exclusivity” and “GDUFA Implementation and Potential First Generics.” Although very few comments (see here) were submitted to FDA in response to the Agency’s solitation, we understand that the public meeting was well attended and included statements from an array of generic drug industry stakeholders, including the Generic Pharmaceutical Association (see here and here). The September 17th public meeting follows a solitication from FDA earlier this year seeking input and suggestions on ways to improve the quality of ANDAs and on how to best communicate those suggestions to the generic drug industry (see our previous post here). About a dozen comments have been submitted to the docket FDA established for that solicitation.
FDA’s ANDA RTR standards guidance finalizes a draft version of the guidance released in October 2013. In addition to providing greater clarity around major deficiencies (i.e., mortal sins) that will generally result in an RTR decision and minor deficiencies (i.e., venial sins) that can be easily corrected, the guidance makes several important changes to the draft version. Bob Pollock from Lachman Consultants covers those changes in his recent post. In the ANDA RTR impurity limits draft guidance – a guidance FDA presumably issued in draft form and separate from the ANDA RTR standards guidance because the issue was not addressed in the draft ANDA RTR standards guidance – FDA lays out serious deficiencies in impurity information that could cause FDA to RTR an ANDA. The deficiencies described in the draft guidance include: “(1) Failing to justify proposed limits for specified identified impurities in drug substances and drug products that are above qualification thresholds; (2) failing to justify proposed limits for specified unidentified impurities that are above identification thresholds; and (3) proposing limits for unspecified impurities (e.g., any unknown impurity) above identification thresholds.” As Bob Pollock notes, the position FDA takes in the draft guidance “is consistent with past Guidance issued by OGD on the requirements for justification of impurity limits, but, in the past, OGD has not stated that if such justification is lacking, they will issue an RTR letter rather than handling the issue as a review issue.” This is an important observation, because it shows that OGD is making an effort to clarify the sometimes fuzzy line between what constitutes a deficiency for ANDA RTR purposes, and what is properly an ANDA review issue (and not an RTR issue). Indeed, we’re likely to see more follow-on, issue-specific guidances like the ANDA RTR impurity limits draft guidance as the new ANDA filing and review groups within OGD hash things out and establish brighter lines between ANDA filing and review issues. FDA says as much in the notice announcing the ANDA RTR impurity limits draft guidance: “FDA intends to develop additional guidance documents further clarifying the enhanced refusal to receive standards.”
Posted at 07:43 PM in Hatch-Waxman, Prescription Drugs and Biologics | Permalink
By Kurt R. Karst – In the 2003 movie “Freaky Friday,” based on the novel of the same name by Mary Rodgers, teenager Anna Coleman (played by Lindsay Lohan) and her mother, Tess Coleman (played by Jamie Lee Curtis), have their souls switched due to an enchanted Chinese fortune cookie. The food and drug law version of “Freaky Friday” played out last Friday when FDA first found itself on the losing end of a court battle over orphan drug exclusivity (see our post here), and then, hours later, switched places and found itself on the winning end of another court battle over generic versions of Hospira, Inc.’s (“Hospira’s”) PRECEDEX (dexmedetomidine HCl) Injection. In a Memorandum Opinion and Order granting Motions for Summary Judgment filed by FDA, Mylan, and Par, and denying Hospira’s Motion for Summary Judgment, Judge George Jarros Hazel of the U.S. District Court for the District of Maryland found FDA’s August 18, 2014 Letter Decision permitting the approval of ANDAs for generic PRECEDEX not arbitrary, capricious, or otherwise not in accordance with law, but rather, a decision based on a reasonable and sound interpretation of the FDC Act. In addition, Judge Hazel found that FDA’s Letter Decsion “was entirely consistent with the FDA’s established practice of approving generic drugs and therefore did not effect a change to settled law.” As such, the district court said that no new “rule” was created by FDA’s decision and that FDA was not required to follow the Administrative Procedure Act’s (“APA”) formal rulemaking procedures.
The September 5th decision was a turnabout for the court. A couple of weeks ago Judge Hazel issued a Memorandum Opinion and Order granting Hospira’s Motion for Temporary Restraining Order. In doing so, Judge Hazel said that Hospira demonstrated that the company is likely to succeed on the merits regarding its contention that FDA violated FDC Act § 505(j)(2)(A)(viii) concerning labeling carve-outs, and with respect to Hospira’s APA claim (see our previous post here). Backgound on the case and on FDA’s Letter Decision is available here and here. Briefly, FDA ruled that ANDA sponsors could omit (i.e., carve out) from their generic drug labeling information protected by U.S. Patent No. 6,716,867 (“the ‘867 patent”) listed in the Orange Book for PRECEDEX. The ‘867 patent is currently listed in the Orange Book for PRECEDEX with a “U-1472” patent use code defined as: “INTENSIVE CARE UNIT SEDATION, INCLUDING SEDATION OF NON-INTUBATED PATIENTS PRIOR TO AND/OR DURING SURGICAL AND OTHER PROCEDURES.” (The ‘867 patent was previously listed in the Orange Book with a “U-572” patent use code defined as “INTENSIVE CARE UNIT SEDATION.”) Hospira and ANDA sponsor Sandoz, which is eligible for a period of 180-day exclusivity based on a Paragraph IV certification to the ‘867 patent, contended that FDA was prohibited from omitting any labeling information related to the ‘867 patent, because the patent covers both approved uses for PRECEDEX – i.e., (1) sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting, and (2) sedation of non-intubated patients prior to and/or during surgical and other procedures – thereby leaving ANDA sponsors with carved-out labeling without an approved use. Hospira also alleged that FDA violated the APA in announcing a new interpretation of the FDC Act through its Letter Decision. FDA, on the other hand, argued that the Agency’s decision to permit a labeling carve-out of information protected by the ‘867 patent – and to approve two ANDAs (one from Mylan (ANDA No. 202881) and one from Par (ANDA No. 203972) with labeling omitting information protected by the ‘867 patent – was permissible and entirely consistent with previous carve-out decision. According to FDA,
In his September 5, 2014 decision, Judge Hazel agreed with FDA on all counts. With respect to Count I, that FDA violated FDC Act § 505(j)(2)(A)(viii) when the Agency approved ANDAs with labeling omitting information concerning intensive care unit sedation, the court reviewed FDA’s decision under the familiar two-step process of Chevron, U.S.A., Inc. v. Natural Resources Defense Council, Inc., 467 U.S. 837, 842 (1984). Finding that the statute does not address what constitutes “overlap” between an NDA holder’s patent use code and an ANDA sponsor’s carved-out labeling, Judge Hazel proceeded to Chevron Step Two. There, Judge Hazel rejected each of Hospira’s arguments that “it was the FDA’s ‘rule’ that ‘if any indication or indications in the generic’s proposed label overlap[ped] ‘at all’ with the brand’s use code as published in the Orange Book, the FDA must reject a section viii statement.’” That rule, argued Hospira, came from the U.S. Supreme Court in Caraco Pharmaceutical Laboratories, Ltd. v. Novo Nordisk A/S, 132 S. Ct. 1670 (2012)), where the Court noted in dicta that “the FDA will not approve an ANDA if the generic’s proposed carve out label overlaps at all with the brand’s use code.” Judge Hazel cited three reasons, however, for rejecting Hospira’s Caraco argument:
[F]irst, notwithstanding the government’s statement in Caraco, the FDA has been consistent in how it has interpreted section viii; second, Hospira’s reading of the Caraco dicta would turn the holding of Caraco on its head; and, third, there is simply no overlap between the ANDA’s carved-out labels and Precedex®’s use code (original or amended).
The district court also relied on previous FDA ANDA labeling carve-out decisions and said that FDA’s decision on generic PRECEDEX is consistent with them:
FDA’s handling of the approval of generic tramadol and generic oxandrolone is entirely consistent with the way the FDA handled the approval of generic Precedex®. That is, just as the FDA concluded that a labeling carve out was proper for tramadol and oxandrolone notwithstanding the fact that a physician might conceivably use the generic drug for a protected method of use, the FDA, here, concluded that ANDAs for Precedex® may also carve out the protected information (related to use for ICU sedation), and be approved for procedural sedation despite the fact that use for procedural sedation may at times occur in the intensive care unit. Accordingly, the FDA has not been inconsistent with its past practice. To the contrary, the FDA has consistently “approve[d] ANDAs for broad, general indications that may partially overlap with a protected method of use, so long as any express references to the protected use are omitted from the labeling.” That is exactly what the FDA did here. As such, the Court will decline Hospira’s invitation to deny the FDA the heightened level of deference it is afforded under Chevron step two.
Given the court’s decision on Count I, Judge Hazel easily dispensed with Count II (violation of APA rulemaking requirements):
FDA’s August 18, 2014 decision to authorize the approval of a section viii ANDA whose carved out label omits explicit reference to a protected method of use, despite the fact that, in practice, the generic drug might be used for a protected use, was entirely consistent with the FDA’s past practice. . . . Accordingly, the Court finds that the FDA’s August 18, 2014 was entirely consistent with the FDA’s established practice of approving ANDA’s and therefore did not effect a change to settled law. As such, no new “rule” was created by the FDA’s decision and the FDA was therefore not required to follow the formal rulemaking procedures required by the APA when the FDA promulgates a new rule.
During a teleconference in which Judge Hazel announced his Memorandum Opinion and Order, Hospira requested and was denied a Motion for a Stay of the Court’s Order. It was immediately clear what was coming next: an emergency appeal to the U.S. Court of Appeals for the Fourth Circuit (and a busy weekend for all of the parties involved in the litigation). On Saturday morning, Hospira filed an Emergency Motion For Injuction Pending Appeal and a Motion to Expedite the appeal. On Sunday, briefs opposing the Hospira motions were filed by FDA (here), Mylan (here), and Par (here), to which Hospira later replied (here). Sandoz filed a brief in support of Hospira’s efforts. According to Hospira, “ [p]ending the outcome of this appeal, this Court should stay the effectiveness of FDA’s decision, including prohibiting FDA from granting any further generic drug approvals based upon the decision which Hospira challenges in this case, and prohibiting Mylan and Par from the further sale and distribution of their respective generic versions of Hospira’s drug.”
On September 8, 2014, the Fourth Circuit denied Hospira's Emergency Motion For Injuction Pending Appeal and granted the company's Motion to Expedite the appeal. The court tentatively scheduled the appeal for Oral Argument on the afternoon of October 27, 2014.
Posted at 01:02 AM in Hatch-Waxman, Prescription Drugs and Biologics | Permalink