{"attribution":{"source":"legal.exploreworldai.com","canonical":"https://legal.exploreworldai.com/api/public/v1/judgment-text?id=us:ca1-25-1268-2026-10-09","cite_as":"NovaCopilot, legal.exploreworldai.com (https://legal.exploreworldai.com/api/public/v1/judgment-text?id=us:ca1-25-1268-2026-10-09)","license":"https://legal.exploreworldai.com/revision","version":"legal-2026-10-27","fingerprint":"ewai:us:b5945d","proof":"sha256:a0ffd96de6d521b0ae4bc02215e796328956a27af12227e4e6e4cf88371fd62a","jurisdiction":"us","lang":"en","publisher":"NovaCopilot by ExploreWorld Legal","terms":"https://legal.exploreworldai.com/om"},"brand_source":"Source: NovaCopilot","item":{"schema_version":"1.0.0","id":"us:ca1-25-1268-2026-10-09","jurisdiction":"us","lang":"en","brand_source":"Source: NovaCopilot","brand":{"product":"NovaCopilot","platform":"ExploreWorldAI","infrastructure":"ExploreWorld Legal","infrastructure_url":"legal.exploreworldai.com","legal_entity":"Valkiv Ventures AB","permanent_url":"https://legal.exploreworldai.com/novacopilot","source":"Source: NovaCopilot","powered_by":"Powered by NovaCopilot","license":"https://legal.exploreworldai.com/licensvillkor"},"sections":[{"title":"United States Court of Appeals","paragraphs":[]},{"title":"For the First Circuit","paragraphs":[]},{"title":"No. 25-1268","paragraphs":[]},{"title":"ELISSA E. WARNER, as Personal Representative of the Estate of","paragraphs":["para_5","para_6","para_7","para_8","para_9","para_10","para_11"]},{"title":"APPEAL FROM THE UNITED STATES DISTRICT COURT","paragraphs":[]},{"title":"FOR THE DISTRICT OF MASSACHUSETTS","paragraphs":["para_14"]},{"title":"Before","paragraphs":["para_16","para_17","para_18"]},{"title":"Vazquez, and Hagens Berman Sobol Shapiro LLP were on brief, for","paragraphs":["para_20","para_21"]},{"title":"Durant, Johannah Cassel-Walker, and Hogan Lovells US LLP were on","paragraphs":["para_23"]},{"title":"October 9, 2026","paragraphs":["para_25"]},{"title":"KAYATTA, Circuit Judge. This appeal arises out of a","paragraphs":["para_27","para_28","para_29"]},{"title":"Lucas Warner, who had a history of seizures and cerebrovascular","paragraphs":["para_31","para_32"]},{"title":"Elissa Warner,1 challenged under state law the adequacy of the","paragraphs":["para_34"]},{"title":"Administration (FDA, or the \"agency\"). The district court","paragraphs":["para_36"]},{"title":"Federal Food, Drug, and Cosmetic Act (FDCA), 21 U.S.C. §§ 301","paragraphs":["para_38","para_39","para_40","para_41"]},{"title":"We affirm the district court's dismissal of Warner's","paragraphs":["para_43","para_44"]},{"title":"1 For consistency with the proceedings below, we refer to","paragraphs":[]},{"title":"Lucas Warner as \"Lucas\" and his mother as \"Warner.\"","paragraphs":["para_47","para_48","para_49"]},{"title":"We begin with the regulatory framework underpinning this","paragraphs":["para_51","para_52","para_53","para_54","para_55","para_56","para_57"]},{"title":"(citation modified); 21 U.S.C § 355(b)(1). Prior to marketing a","paragraphs":["para_59","para_60","para_61","para_62"]},{"title":"Aimovig is a biologic product. Biologic","paragraphs":["para_64","para_65","para_66","para_67"]},{"title":"Amgen Inc., 582 U.S. 1, 6 (2017); see also 42 U.S.C. § 262(i)(1)","paragraphs":[]},{"title":"(defining \"biological product\"). 2 Like other drugs, biologic","paragraphs":[]},{"title":"2 The parties use the term \"biologic product,\" whereas the","paragraphs":["para_71","para_72","para_73","para_74","para_75","para_76","para_77","para_78","para_79"]},{"title":"Notwithstanding the differing regulatory authorities for","paragraphs":["para_81","para_82","para_83","para_84","para_85","para_86","para_87"]},{"title":"C.F.R. § 601.2(a). And they cannot market the drug until the FDA","paragraphs":["para_89"]},{"title":"U.S.C. § 262(i)(1); 21 C.F.R. § 601.2(a). For purposes of this","paragraphs":["para_91","para_92"]},{"title":"3 See Frequently Asked Questions About Therapeutic","paragraphs":["para_94","para_95","para_96","para_97","para_98","para_99","para_100","para_101","para_102"]},{"title":"34, 35–36 (1st Cir. 2015) (explaining that \"[t]he FDA will not","paragraphs":["para_104","para_105","para_106","para_107","para_108","para_109"]},{"title":"The FDA's process for reviewing a BLA submission and","paragraphs":["para_111"]},{"title":"(1) an FDA review committee that \"[p]articipates in the labeling","paragraphs":["para_113","para_114","para_115"]},{"title":"(3) a clinical reviewer who \"[e]nsures [the] accuracy of","paragraphs":["para_117","para_118","para_119","para_120","para_121","para_122","para_123"]},{"title":"(6) an advertising and promotional labeling branch reviewer who","paragraphs":["para_125","para_126","para_127"]},{"title":"(8) a non-clinical toxicologist reviewer. FDA Ctr. for Biologics","paragraphs":[]},{"title":"Evaluation & Rsch., SOPP 8412: Review of Product Labeling 5–6","paragraphs":["para_130","para_131","para_132","para_133","para_134","para_135","para_136","para_137","para_138"]},{"title":"Pursuant to FDA regulations, the contents of a drug label","paragraphs":["para_140"]},{"title":"(1) prominent \"boxed\" warnings about risks","paragraphs":["para_142"]},{"title":"(2) contraindications describing any","paragraphs":["para_144","para_145","para_146"]},{"title":"(3) warnings and precautions about other","paragraphs":["para_148"]},{"title":"(4) any adverse reactions for which there is","paragraphs":["para_150","para_151","para_152"]},{"title":"Merck Sharp & Dohme Corp. v. Albrecht, 587 U.S. 299, 304 (2019)","paragraphs":[]},{"title":"(quoting 21 C.F.R § 201.57(c)). The order in which these","paragraphs":["para_155","para_156","para_157","para_158","para_159","para_160","para_161","para_162","para_163","para_164"]},{"title":"In re Zofran (Ondansetron) Prods. Liab. Litig., 57 F.4th 327, 330","paragraphs":[]},{"title":"(1st Cir. 2023) (quoting Supplemental Applications Proposing","paragraphs":[]},{"title":"Labeling Changes for Approved Drugs, Biologics, and Medical","paragraphs":[]},{"title":"Devices, 73 Fed. Reg. at 49605-06). The agency's final","paragraphs":["para_169","para_170"]},{"title":"(citation modified), such as \"theoretical hazards not","paragraphs":["para_172","para_173"]},{"title":"Content and Format of Labeling for Human Prescription Drug and","paragraphs":[]},{"title":"Biological Products, 71 Fed. Reg. 3922, 3935 (Jan. 24, 2006)","paragraphs":["para_176"]},{"title":"Only after this \"onerous and lengthy\" process is","paragraphs":["para_178","para_179","para_180","para_181","para_182","para_183","para_184","para_185"]},{"title":"After the FDA has approved a label, the manufacturer","paragraphs":["para_187","para_188"]},{"title":"(Trastuzumab) Mktg. & Sales Prac. Litig., 960 F.3d 1210, 1236 (10th","paragraphs":[]},{"title":"Cir. 2020); 21 C.F.R. § 601.12(f)(1)–(3) (describing the pathways","paragraphs":["para_191"]},{"title":"The so-called Changes Being Effected (CBE) regulations provide an","paragraphs":["para_193","para_194","para_195","para_196","para_197","para_198"]},{"title":"21 C.F.R. § 601.12(f)(2)(i)(A)–(E). Upon making such a labeling","paragraphs":["para_200"]},{"title":"FDA and may immediately begin using the revised label even as the","paragraphs":[]},{"title":"4 Though the regulations are largely analogous, the district","paragraphs":["para_203","para_204","para_205","para_206","para_207","para_208","para_209","para_210"]},{"title":"With this regulatory framework in mind, we turn to the","paragraphs":["para_212","para_213","para_214","para_215"]},{"title":"Aimovig is the proprietary name for the biologic drug","paragraphs":["para_217","para_218","para_219"]},{"title":"Aimovig aims to prevent migraines by inhibiting CGRP's ability to","paragraphs":["para_221","para_222","para_223"]},{"title":"Amgen submitted a biologics license application for","paragraphs":[]},{"title":"Aimovig on May 17, 2017. Aimovig received FDA approval exactly","paragraphs":["para_226","para_227","para_228","para_229"]},{"title":"See 21 C.F.R. § 201.57(c)(2)–(18) (listing all 17 possible","paragraphs":["para_231","para_232","para_233","para_234","para_235","para_236","para_237"]},{"title":"Warner criticizes that description because it failed to disclose","paragraphs":["para_239","para_240","para_241","para_242"]},{"title":"Knowing of these undisclosed exclusions would have been","paragraphs":["para_244","para_245","para_246","para_247","para_248","para_249"]},{"title":"Lucas underwent an embolization7 to help treat his AVM and migraine","paragraphs":[]},{"title":"6 An arteriovenous malformation is an \"improper or abnormal","paragraphs":["para_252","para_253"]},{"title":"2006). With an AVM, \"blood is shunted from arterioles to venules","paragraphs":["para_255"]},{"title":"7 An embolization is the \"[t]herapeutic introduction of","paragraphs":["para_257","para_258","para_259","para_260","para_261","para_262","para_263","para_264"]},{"title":"In June 2018, unaware that persons with any history of","paragraphs":["para_266"]},{"title":"Aimovig clinical trials, Lucas's doctor prescribed him Aimovig to","paragraphs":["para_268"]},{"title":"2018, at age twenty-three. Less than 48 hours later, Lucas","paragraphs":["para_270","para_271","para_272","para_273","para_274","para_275","para_276"]},{"title":"He was left \"cognitively severely impaired,\" forcing him to","paragraphs":["para_278","para_279"]},{"title":"Lucas's condition worsened, and he suffered repetitive seizures","paragraphs":[]},{"title":"8 The blood-brain barrier is \"a selective mechanism\" that","paragraphs":["para_282","para_283"]},{"title":"Stedman's Medical Dictionary, supra, at 205; see also In re Vertex","paragraphs":[]},{"title":"Pharms. Inc., Sec. Litig., 357 F. Supp. 2d 343, 345 (D. Mass. 2005)","paragraphs":[]},{"title":"(\"The blood-brain barrier is a selective filter that regulates the","paragraphs":["para_287","para_288","para_289","para_290","para_291","para_292"]},{"title":"Lucas died on November 17, 2020. His death certificate","paragraphs":["para_294","para_295","para_296","para_297"]},{"title":"Warner filed a wrongful death complaint against Amgen in","paragraphs":[]},{"title":"Massachusetts state court, alleging that her son died from medical","paragraphs":["para_300","para_301","para_302","para_303","para_304","para_305"]},{"title":"Lucas.\"","paragraphs":[]},{"title":"Amgen removed the suit to the U.S. District Court for","paragraphs":["para_308","para_309"]},{"title":"9 Hypoxia involves the \"[d]ecrease below normal levels of","paragraphs":["para_311"]},{"title":"Stedman's Medical Dictionary, supra, at 939. \"Refractory\"","paragraphs":["para_313"]},{"title":"Refractory, Stedman's Medical Dictionary, supra, at 1664. And","paragraphs":["para_315","para_316","para_317"]},{"title":"Civil Procedure 12(b)(6), contending (among other things) that","paragraphs":["para_319","para_320","para_321","para_322","para_323","para_324","para_325"]},{"title":"Warner introduced a new contention. In addition to critiquing","paragraphs":[]},{"title":"Amgen's efforts to secure FDA approval of the label in the first","paragraphs":["para_328","para_329","para_330","para_331","para_332","para_333"]},{"title":"Following argument, the court requested that Warner file a","paragraphs":["para_335","para_336"]},{"title":"With her supplemental brief, Warner submitted nine","paragraphs":["para_338","para_339","para_340","para_341","para_342"]},{"title":"Warner argued that these articles \"establishe[d] a reasonable","paragraphs":["para_344","para_345"]},{"title":"FDA prior to Aimovig's approval.\" Warner also requested leave to","paragraphs":["para_347","para_348","para_349","para_350"]},{"title":"Aimovig, that were not previously submitted to the FDA.\"","paragraphs":[]},{"title":"After reviewing Warner's submissions, the court","paragraphs":["para_353","para_354"]},{"title":"CGRP-blocking drug to an adverse event or risk\" that would have","paragraphs":["para_356","para_357"]},{"title":"The court further surmised that because the FDA had \"reviewed 'the","paragraphs":["para_359"]},{"title":"CGRP antagonism,\" it was \"not plausible that articles bearing on","paragraphs":["para_361","para_362","para_363","para_364"]},{"title":"FDA disclosing that patients like Lucas had been excluded from","paragraphs":[]},{"title":"Aimovig's trials, the court found that \"the FDA was aware that","paragraphs":["para_367","para_368","para_369","para_370","para_371","para_372","para_373","para_374","para_375","para_376"]},{"title":"This court \"review[s] the grant of a motion to dismiss","paragraphs":["para_378","para_379","para_380"]},{"title":"(1st Cir. 2025)). To survive dismissal for failure to state a","paragraphs":["para_382","para_383","para_384","para_385","para_386"]},{"title":"We are mindful that this plausibility requirement does not \"impose","paragraphs":["para_388","para_389"]},{"title":"556 U.S. at 678. As such, \"[t]he relevant inquiry focuses on the","paragraphs":["para_391","para_392","para_393","para_394"]},{"title":"On appeal, Amgen does not contend that Warner's","paragraphs":["para_396","para_397","para_398","para_399","para_400"]},{"title":"619 (2011) (referring to preemption as an affirmative defense);","paragraphs":["para_402"]},{"title":"2018) (\"FDCA preemption, like all federal preemption, is an","paragraphs":["para_404"]},{"title":"When an order of dismissal under Rule 12(b)(6) is","paragraphs":["para_406","para_407","para_408","para_409","para_410","para_411","para_412","para_413"]},{"title":"1098 (9th Cir. 2025) (\"Under Rule 12(b)(6), only when the plaintiff","paragraphs":["para_415","para_416","para_417","para_418","para_419"]},{"title":"This appeal does not call on us to apply a statutory","paragraphs":["para_421"]},{"title":"2006 (2026) (reviewing an express preemption clause contained in","paragraphs":[]},{"title":"7 U.S.C. § 136v(b)). Rather, Amgen's FDCA preemption defense","paragraphs":["para_424","para_425","para_426","para_427","para_428","para_429"]},{"title":"Impossibility preemption \"is a demanding defense.\"","paragraphs":[]},{"title":"Wyeth, 555 U.S. at 573. As a general matter, there is a","paragraphs":["para_432","para_433","para_434","para_435","para_436","para_437","para_438"]},{"title":"Warner claims in support of her complaint that it would","paragraphs":["para_440","para_441","para_442","para_443","para_444","para_445","para_446"]},{"title":"We begin with what the parties call Warner's","paragraphs":["para_448","para_449","para_450","para_451","para_452","para_453","para_454","para_455"]},{"title":"We see two flaws in this argument, one legal and one","paragraphs":["para_457","para_458","para_459","para_460","para_461","para_462","para_463","para_464","para_465","para_466","para_467","para_468","para_469","para_470"]},{"title":"Indeed, the Supreme Court itself has recognized that prescription","paragraphs":["para_472","para_473"]},{"title":"570 U.S. at 492–93 (citing Wyeth, 555 U.S. 555, and PLIVA, 564","paragraphs":[]},{"title":"U.S. 604). That puzzlement arises in part due to the lack of","paragraphs":["para_476"]},{"title":"FDCA's treatment of prescription drugs includes neither an express","paragraphs":["para_478","para_479","para_480"]},{"title":"Id. at 493. This lack of clarity leaves courts to \"divine","paragraphs":[]},{"title":"Congress' will from the duties the statute imposes.\" Id. So we","paragraphs":["para_483","para_484"]},{"title":"We start with Wyeth. If Warner were correct that a","paragraphs":["para_486","para_487","para_488","para_489","para_490","para_491","para_492","para_493","para_494","para_495","para_496","para_497","para_498"]},{"title":"(\"There is, however . . . the 'changes being effected' (CBE)","paragraphs":["para_500"]},{"title":"This suggestion grew stronger yet with the Court's","paragraphs":["para_502","para_503","para_504"]},{"title":"619–21. In so holding, the Court explained that \"[t]he question","paragraphs":["para_506","para_507"]},{"title":"In that context, where state law required a stronger label, \"[t]he","paragraphs":["para_509","para_510"]},{"title":"Id. at 624. Because requesting that the FDA take action was simply","paragraphs":["para_512","para_513","para_514"]},{"title":"Court found such a claim to be preempted. Id. at 620-21; see also","paragraphs":["para_516","para_517","para_518"]},{"title":"Government's special permission and assistance, which is dependent","paragraphs":["para_520","para_521","para_522"]},{"title":"As we subsequently stated in Celexa, the PLIVA Court","paragraphs":["para_524","para_525","para_526","para_527","para_528"]},{"title":"Wyeth can use the CBE process \"to unilaterally strengthen its","paragraphs":["para_530","para_531"]},{"title":"And then more recently in Albrecht, the Supreme Court again turned","paragraphs":["para_533"]},{"title":"FDA for a labeling change, but rather to the CBE regulation","paragraphs":["para_535","para_536","para_537","para_538","para_539","para_540","para_541","para_542"]},{"title":"And while the foregoing cases all apply this principle","paragraphs":["para_544","para_545","para_546","para_547","para_548","para_549","para_550"]},{"title":"10 This is not to say that a manufacturer remains free to","paragraphs":["para_552","para_553","para_554","para_555","para_556"]},{"title":"The FDCA prohibits manufacturers from obscuring information from","paragraphs":["para_558","para_559","para_560","para_561","para_562"]},{"title":"Johnson & Johnson Consumer Inc., 184 F.4th 130, 141 (2d Cir. 2026)","paragraphs":[]},{"title":"(\"The misbranding provision . . . prohibits not only affirmative","paragraphs":["para_565","para_566"]},{"title":"2002) (describing misdemeanor and felony misbranding provisions","paragraphs":["para_568"]},{"title":"And, as we will explain, information not submitted to the FDA","paragraphs":["para_570","para_571","para_572","para_573","para_574"]},{"title":"Adding belt to suspenders, the record in this case makes","paragraphs":["para_576","para_577","para_578","para_579","para_580","para_581","para_582"]},{"title":"Products (DNP) expressly mentioned those exclusions. The DNP","paragraphs":["para_584","para_585","para_586","para_587","para_588"]},{"title":"Indeed, Aimovig's DNP reviewer initially proposed adding","paragraphs":["para_590","para_591"]},{"title":"That recommendation was rejected after further internal review, as","paragraphs":["para_593","para_594","para_595","para_596","para_597","para_598","para_599","para_600","para_601"]},{"title":"Ultimately, the final label as approved by the FDA","paragraphs":["para_603","para_604","para_605","para_606","para_607","para_608"]},{"title":"12 months prior to screening\" had been excluded from Aimovig's","paragraphs":["para_610","para_611","para_612","para_613"]},{"title":"Bearing in mind the FDA's knowledge of the clinical trial","paragraphs":["para_615","para_616"]},{"title":"11 Warner would have us discount the FDA's consideration of","paragraphs":["para_618"]},{"title":"Warner's view, the FDA trained its attention more (but not","paragraphs":["para_620","para_621","para_622"]},{"title":"FDA's review. But there was good reason for the FDA to home in","paragraphs":["para_624","para_625","para_626","para_627","para_628","para_629","para_630","para_631","para_632","para_633","para_634","para_635","para_636","para_637","para_638","para_639","para_640","para_641","para_642","para_643","para_644","para_645","para_646","para_647","para_648","para_649","para_650","para_651","para_652","para_653","para_654","para_655","para_656"]},{"title":"In sum, we conclude that the district court correctly","paragraphs":["para_658","para_659","para_660","para_661","para_662","para_663","para_664","para_665"]},{"title":"We turn next to the district court's denial of Warner's","paragraphs":["para_667","para_668","para_669","para_670"]},{"title":"The district court determined that Amgen could not have revised","paragraphs":["para_672","para_673","para_674","para_675","para_676","para_677","para_678"]},{"title":"D'Agostino v. ev3, Inc., 845 F.3d 1, 6 (1st Cir. 2016) (quoting","paragraphs":["para_680"]},{"title":"1996)); see also Fed. R. Civ. P. 15(a). We therefore review the","paragraphs":["para_682","para_683","para_684","para_685","para_686"]},{"title":"Warner's proposed amendment to the complaint would have","paragraphs":["para_688","para_689"]},{"title":"Amgen could have unilaterally changed Aimovig's approved label to","paragraphs":["para_691","para_692","para_693","para_694","para_695","para_696","para_697","para_698","para_699","para_700","para_701"]},{"title":"The Supreme Court has considered several times how the","paragraphs":["para_703","para_704","para_705","para_706","para_707"]},{"title":"Keeping in mind that we are reviewing the viability of","paragraphs":["para_709","para_710","para_711","para_712","para_713","para_714"]},{"title":"Colonial Mortg. Bankers Corp., 324 F.3d 12, 16 (1st Cir. 2003)","paragraphs":["para_716","para_717","para_718","para_719","para_720","para_721","para_722"]},{"title":"First, the parties appear to agree that Warner must","paragraphs":["para_724","para_725","para_726","para_727","para_728","para_729","para_730","para_731"]},{"title":"The requirement that the information be \"newly acquired\" preserves","paragraphs":["para_733","para_734","para_735","para_736","para_737"]},{"title":"Second, Warner must plausibly allege facts showing that","paragraphs":["para_739","para_740","para_741","para_742","para_743"]},{"title":"Third, because Warner argues that Amgen should have","paragraphs":["para_745","para_746","para_747"]},{"title":"12 By \"available\" information we refer to information that","paragraphs":["para_749","para_750","para_751","para_752","para_753","para_754","para_755"]},{"title":"(emphasis added), or \"some basis to believe there is a causal","paragraphs":["para_757","para_758"]},{"title":"If Warner successfully makes the three foregoing","paragraphs":["para_760","para_761","para_762","para_763","para_764"]},{"title":"Zofran, 57 F.4th at 342. With that framework in mind, we next","paragraphs":["para_766","para_767"]},{"title":"We begin with the threshold issue of determining whether","paragraphs":["para_769","para_770","para_771","para_772","para_773","para_774","para_775","para_776","para_777","para_778","para_779","para_780","para_781","para_782","para_783","para_784","para_785","para_786","para_787","para_788","para_789","para_790"]},{"title":"In support of her motion for leave to amend her","paragraphs":["para_792","para_793","para_794","para_795","para_796","para_797"]},{"title":"13 Vasodilatory refers to dilation of the blood vessels. See","paragraphs":["para_799","para_800","para_801","para_802"]},{"title":"Turning to the nine articles submitted by Warner, we","paragraphs":["para_804","para_805","para_806","para_807"]},{"title":"Meanwhile, the Szeto literature review references CGRP only in","paragraphs":["para_809","para_810","para_811","para_812","para_813","para_814","para_815","para_816","para_817"]},{"title":"Without more, we do not consider these articles newly acquired","paragraphs":["para_819"]},{"title":"14 See Jing-Jing Zhao et al., Remote Ischemic","paragraphs":[]},{"title":"Postconditioning for Ischemic Stroke: A Systematic Review and","paragraphs":["para_822","para_823"]},{"title":"15 See Vivian Szeto et al., The Role of KATP Channels in","paragraphs":[]},{"title":"Cerebral Ischemic Stroke and Diabetes, 39 Acta Pharmacologica","paragraphs":["para_826","para_827"]},{"title":"That leaves us with seven articles. We can also dispose","paragraphs":["para_829","para_830","para_831","para_832","para_833","para_834","para_835","para_836","para_837","para_838"]},{"title":"This leaves us with six articles, including the 2018 Guo","paragraphs":["para_840","para_841","para_842","para_843"]},{"title":"16 See Stelios Kokkoris et al., Role of Calcitonin Gene-","paragraphs":[]},{"title":"Related Peptide in Cerebral Vasospasm, and As a Therapeutic","paragraphs":[]},{"title":"Approach to Subarachnoid Hemorrhage, 3 Frontiers Endocrinology 135","paragraphs":["para_847"]},{"title":"17 A subarachnoid hemorrhage is a bleed within the","paragraphs":["para_849","para_850"]},{"title":"Hemorrhage, Stedman's Medical Dictionary, supra, at 873; Arachnoid","paragraphs":["para_852"]},{"title":"18 See Zheng Guo et al., Independent Roles of CGRP in","paragraphs":[]},{"title":"Cardioprotection and Hemodynamic Regulation in Ischemic","paragraphs":["para_855","para_856","para_857"]},{"title":"CBE procedure to change the warnings or precautions on a label","paragraphs":["para_859"]},{"title":"21 C.F.R. § 201.57(c). Warner does not address how the study's","paragraphs":["para_861","para_862","para_863","para_864","para_865"]},{"title":"The 2018 Basalay literature review 19 discusses the","paragraphs":["para_867","para_868","para_869","para_870","para_871"]},{"title":"19 See Marina V. Basalay et al., Neural Mechanisms in Remote","paragraphs":[]},{"title":"Ischaemic Conditioning in the Heart and Brain: Mechanistic and","paragraphs":["para_874"]},{"title":"20 Ischemia is the \"[l]ocal loss of blood supply due to a","paragraphs":["para_876"]},{"title":"Stedman's Medical Dictionary, supra, at 1001. As the district","paragraphs":["para_878","para_879","para_880"]},{"title":"(i.e., restoration of blood flow to the tissue or organ), to","paragraphs":["para_882","para_883","para_884","para_885","para_886"]},{"title":"Neurology Products and the Division of Cardiovascular and Renal","paragraphs":[]},{"title":"Products. Indeed, the DNP noted that \"[t]here are numerous","paragraphs":["para_889","para_890","para_891","para_892","para_893","para_894","para_895","para_896","para_897","para_898","para_899","para_900"]},{"title":"The 2007 Rehni study21 presents a close call. This study","paragraphs":["para_902","para_903","para_904"]},{"title":"21 See Ashish K. Rehni et al., Possible Involvement of","paragraphs":[]},{"title":"Insulin, Endogenous Opioids and Calcitonin Gene-Related Peptide in","paragraphs":[]},{"title":"Remote Ischaemic Preconditioning of Brain, 127 Pharm. Soc'y of","paragraphs":["para_908"]},{"title":"22 Rehni noted that cerebral ischemia in particular \" has been","paragraphs":["para_910","para_911"]},{"title":"Basalay review, the FDA was well-aware of the \"theoretical concern\"","paragraphs":["para_913","para_914"]},{"title":"Rehni study -- at least on this record -- arguably took a step","paragraphs":["para_916","para_917","para_918","para_919","para_920","para_921","para_922","para_923","para_924","para_925","para_926"]},{"title":"That leaves three articles concerning the interactions","paragraphs":["para_928"]},{"title":"However, \"remote mesenteric ischaemic preconditioning has been","paragraphs":["para_930","para_931","para_932"]},{"title":"23 As further defined by the Sorby-Adams literature review","paragraphs":["para_934","para_935","para_936","para_937","para_938","para_939","para_940","para_941"]},{"title":"Liu study,24 researchers placed rats under stroke conditions and","paragraphs":["para_943"]},{"title":"The findings suggest that the effects of blood-brain barrier","paragraphs":["para_945","para_946","para_947","para_948","para_949","para_950","para_951","para_952"]},{"title":"The second of these articles is the 2017 Sorby-Adams","paragraphs":["para_954","para_955","para_956","para_957"]},{"title":"Disruption and Development of Cerebral Oedema Following Acute","paragraphs":["para_959","para_960"]},{"title":"24 See Zhen Liu et al., Calcitonin Gene-Related Peptide","paragraphs":[]},{"title":"Prevents Blood-Brain Barrier Injury and Brain Edema Induced by","paragraphs":[]},{"title":"Focal Cerebral Ischemia Reperfusion, 171 Regul. Peptides 19","paragraphs":["para_964","para_965","para_966","para_967","para_968","para_969","para_970","para_971","para_972","para_973","para_974","para_975","para_976","para_977","para_978","para_979","para_980","para_981"]},{"title":"The third of these articles, the 2018 Zhai study,27 was","paragraphs":["para_983","para_984","para_985","para_986","para_987","para_988","para_989","para_990","para_991","para_992","para_993"]},{"title":"27 See Liuyu Zhai et al., Endogenous Calcitonin Gene-Related","paragraphs":[]},{"title":"Peptide Suppresses Ischemic Brain Injuries and Progression of","paragraphs":["para_996","para_997","para_998","para_999","para_1000","para_1001","para_1002","para_1003","para_1004","para_1005","para_1006","para_1007","para_1008","para_1009"]},{"title":"28 The study also found that CGRP-deficient mice had","paragraphs":["para_1011","para_1012","para_1013","para_1014","para_1015"]},{"title":"29 Demyelination is the \"[l]oss of myelin, with preservation","paragraphs":["para_1017"]},{"title":"Dictionary, supra, at 509. The myelin sheath is an \"envelope\"","paragraphs":["para_1019"]},{"title":"Dictionary, supra, at 1758–59, which are the parts of nerve cells","paragraphs":["para_1021","para_1022"]},{"title":"30 An astrocyte is \" [o]ne of the large neuroglia cells of","paragraphs":["para_1024","para_1025","para_1026","para_1027","para_1028","para_1029","para_1030","para_1031","para_1032","para_1033","para_1034"]},{"title":"The district court found that none of these four articles","paragraphs":["para_1036","para_1037","para_1038","para_1039","para_1040","para_1041","para_1042","para_1043"]},{"title":"Warner, 2025 WL 490720, at *10. The district court also concluded","paragraphs":["para_1045","para_1046","para_1047","para_1048","para_1049","para_1050","para_1051","para_1052"]},{"title":"31 Apoptosis is the process of \"[p]rogrammed cell death.\"","paragraphs":["para_1054","para_1055","para_1056","para_1057","para_1058","para_1059"]},{"title":"We are inclined to read the record as the district court","paragraphs":["para_1061","para_1062","para_1063","para_1064","para_1065","para_1066","para_1067"]},{"title":"For example, we are not convinced by the district court's","paragraphs":["para_1069","para_1070"]},{"title":"FDA's review of the \"world's literature\" was limited to \"published","paragraphs":["para_1072","para_1073","para_1074","para_1075","para_1076","para_1077","para_1078","para_1079","para_1080","para_1081","para_1082"]},{"title":"Zhai study, or the Sorby-Adams literature review were brought to","paragraphs":["para_1084","para_1085","para_1086","para_1087"]},{"title":"FDA's world-literature review included studies on CGRP's role in","paragraphs":["para_1089","para_1090","para_1091"]},{"title":"Contrary to Amgen's assertions, the publication dates of","paragraphs":["para_1093"]},{"title":"32 This is not to say that the FDA was not at all aware of","paragraphs":["para_1095","para_1096","para_1097","para_1098","para_1099","para_1100","para_1101"]},{"title":"CGRP outside of its vasodilatory role. Such technical matters","paragraphs":["para_1103","para_1104","para_1105","para_1106"]},{"title":"33 Indeed, as Aimovig had only been studied in healthy","paragraphs":["para_1108","para_1109","para_1110","para_1111","para_1112","para_1113","para_1114","para_1115","para_1116","para_1117","para_1118","para_1119","para_1120","para_1121","para_1122","para_1123"]},{"title":"Wyeth, 555 U.S. at 569 (quoting Supplemental Applications","paragraphs":[]},{"title":"Proposing Labeling Changes for Approved Drugs, Biologics, and","paragraphs":["para_1126"]},{"title":"Nor are we certain that the Zhai study fails to qualify","paragraphs":["para_1128","para_1129","para_1130","para_1131","para_1132","para_1133","para_1134","para_1135","para_1136"]},{"title":"Indeed, the parties agree that \"FDA guidance permits theoretical","paragraphs":["para_1138","para_1139","para_1140","para_1141","para_1142","para_1143","para_1144","para_1145","para_1146"]},{"title":"The FDA also considered rat studies, including a study on diabetic","paragraphs":["para_1148","para_1149","para_1150","para_1151","para_1152"]},{"title":"Viewed together, the Rehni study, the Liu study, the","paragraphs":[]},{"title":"Sorby-Adams literature review, and the Zhai study plausibly","paragraphs":["para_1155","para_1156","para_1157","para_1158","para_1159","para_1160","para_1161","para_1162","para_1163"]},{"title":"Based on the record before us, we cannot say with certitude that","paragraphs":[]},{"title":"Warner has failed to plausibly allege a \"reasonable basis\" to view","paragraphs":["para_1166","para_1167","para_1168"]},{"title":"Zofran, 57 F.4th at 337 (quoting 21 C.F.R. § 314.3(b)); see also","paragraphs":["para_1170","para_1171"]},{"title":"We turn now to the second prong of our CBE inquiry, which","paragraphs":["para_1173","para_1174","para_1175","para_1176"]},{"title":"34 A manufacturer may use the CBE procedure to supplement a","paragraphs":["para_1178","para_1179","para_1180","para_1181","para_1182","para_1183"]},{"title":"(B) To add or strengthen a statement about","paragraphs":["para_1185","para_1186"]},{"title":"(C) To add or strengthen an instruction about","paragraphs":["para_1188","para_1189","para_1190"]},{"title":"(D) To delete false, misleading, or","paragraphs":["para_1192","para_1193","para_1194","para_1195","para_1196","para_1197","para_1198","para_1199","para_1200","para_1201","para_1202","para_1203","para_1204","para_1205","para_1206","para_1207"]},{"title":"Liu, Sorby-Adams, and Zhai articles, we cannot say with certainty","paragraphs":["para_1209","para_1210","para_1211","para_1212"]},{"title":"(E) Any labeling change normally requiring a","paragraphs":["para_1214","para_1215","para_1216","para_1217","para_1218","para_1219","para_1220"]},{"title":"Finally, we turn to the issue of causal association. We","paragraphs":["para_1222","para_1223","para_1224","para_1225"]},{"title":"Both the \"warnings and precautions\" and \"adverse","paragraphs":["para_1227","para_1228","para_1229","para_1230"]},{"title":"C.F.R. § 201.57(c)(6)(i) (emphasis added). On the other hand, to","paragraphs":["para_1232","para_1233","para_1234","para_1235","para_1236","para_1237","para_1238","para_1239"]},{"title":"Proposing Labeling Changes for Approved Drugs, Biologics, and","paragraphs":[]},{"title":"Medical Devices, 73 Fed. Reg. at 49604. Indeed, because","paragraphs":["para_1242","para_1243","para_1244","para_1245"]},{"title":"Because the district court hinged its futility finding","paragraphs":["para_1247","para_1248","para_1249","para_1250","para_1251"]},{"title":"2025 WL 490720, at *9. On appeal, the parties disagree as to the","paragraphs":["para_1253","para_1254","para_1255","para_1256","para_1257","para_1258","para_1259","para_1260","para_1261"]},{"title":"Aimovig's association with damage that Lucas experienced, such as","paragraphs":["para_1263"]},{"title":"35 At oral argument, Amgen contended that Warner's theory was","paragraphs":["para_1265","para_1266","para_1267"]},{"title":"At the motion hearing before the district court, Warner argued","paragraphs":["para_1269","para_1270","para_1271","para_1272","para_1273","para_1274","para_1275","para_1276","para_1277","para_1278","para_1279"]},{"title":"2009)). In making that judgment based on the record as it now","paragraphs":["para_1281","para_1282","para_1283"]},{"title":"We are also not convinced by Amgen's argument that the","paragraphs":["para_1285","para_1286","para_1287","para_1288","para_1289","para_1290","para_1291","para_1292","para_1293","para_1294","para_1295","para_1296","para_1297","para_1298","para_1299"]},{"title":"Those regulations define an adverse reaction as an \"undesirable","paragraphs":["para_1301","para_1302","para_1303","para_1304","para_1305","para_1306","para_1307","para_1308"]},{"title":"FDA, Warnings and Precautions, Contraindications, and Boxed","paragraphs":[]},{"title":"Warning Sections of Labeling for Human Prescription Drug and","paragraphs":["para_1311","para_1312"]},{"title":"UDZE].36 That guidance further instructs that the Warnings and","paragraphs":[]},{"title":"Precautions section of a drug label should include \"anticipated\"","paragraphs":["para_1315","para_1316","para_1317","para_1318"]},{"title":"36 These documents, though not binding, accord with our","paragraphs":["para_1320","para_1321","para_1322","para_1323","para_1324","para_1325","para_1326","para_1327","para_1328","para_1329","para_1330","para_1331","para_1332","para_1333","para_1334","para_1335"]},{"title":"In the setting of cerebral ischemia, the four articles","paragraphs":["para_1337"]},{"title":"CGRP antagonism and the dilution of neuroprotective effects from","paragraphs":["para_1339","para_1340","para_1341","para_1342"]},{"title":"Lucas's history would be causally associated with a greater risk","paragraphs":["para_1344","para_1345","para_1346"]},{"title":"Warner argues that her submitted articles \"suggest[] that blocking","paragraphs":[]},{"title":"CGRP could accelerate the death of oxidatively stressed neurons in","paragraphs":["para_1349","para_1350","para_1351","para_1352"]},{"title":"Based on the foregoing and as the record now stands, we","paragraphs":["para_1354","para_1355","para_1356","para_1357","para_1358","para_1359","para_1360","para_1361","para_1362","para_1363"]},{"title":"Even given the foregoing, Amgen would still prevail in","paragraphs":["para_1365","para_1366","para_1367","para_1368","para_1369","para_1370","para_1371"]},{"title":"Nor did the district court. We conclude that Warner's proposed","paragraphs":["para_1373","para_1374","para_1375","para_1376","para_1377","para_1378"]},{"title":"For the foregoing reasons, we reverse the district","paragraphs":["para_1380","para_1381"]},{"title":"Rehni, Liu, Sorby-Adams, and Zhai articles enabled Amgen to use","paragraphs":["para_1383","para_1384","para_1385","para_1386","para_1387","para_1388"]}],"paragraphs":[{"text":"United States Court of Appeals","paragraph_id":"para_1"},{"text":"For the First Circuit","paragraph_id":"para_2"},{"text":"No. 25-1268","paragraph_id":"para_3"},{"text":"ELISSA E. WARNER, as Personal Representative of the Estate of","paragraph_id":"para_4"},{"text":"Decedent Lucas Joseph Warner,","paragraph_id":"para_5"},{"text":"Plaintiff, Appellant,","paragraph_id":"para_6"},{"text":"v.","paragraph_id":"para_7"},{"text":"AMGEN INC.; AMGEN USA INC.,","paragraph_id":"para_8"},{"text":"Defendants, Appellees,","paragraph_id":"para_9"},{"text":"NOVARTIS INSTITUTE FOR BIOMEDICAL RESEARCH, INC.,","paragraph_id":"para_10"},{"text":"Defendant.","paragraph_id":"para_11"},{"text":"APPEAL FROM THE UNITED STATES DISTRICT COURT","paragraph_id":"para_12"},{"text":"FOR THE DISTRICT OF MASSACHUSETTS","paragraph_id":"para_13"},{"text":"[Hon. Julia E. Kobick, U.S. District Judge]","paragraph_id":"para_14"},{"text":"Before","paragraph_id":"para_15"},{"text":"Montecalvo, Lipez, and Kayatta,","paragraph_id":"para_16"},{"text":"Circuit Judges.","paragraph_id":"para_17"},{"text":"Abbye R. K. Ognibene, with whom Thomas M. Sobol, Mark T.","paragraph_id":"para_18"},{"text":"Vazquez, and Hagens Berman Sobol Shapiro LLP were on brief, for","paragraph_id":"para_19"},{"text":"appellant.","paragraph_id":"para_20"},{"text":"Jessica L. Ellsworth, with whom Lauren S. Colton, Maria R.","paragraph_id":"para_21"},{"text":"Durant, Johannah Cassel-Walker, and Hogan Lovells US LLP were on","paragraph_id":"para_22"},{"text":"brief, for appellees.","paragraph_id":"para_23"},{"text":"October 9, 2026","paragraph_id":"para_24"},{"text":"- 3 -","paragraph_id":"para_25"},{"text":"KAYATTA, Circuit Judge. This appeal arises out of a","paragraph_id":"para_26"},{"text":"wrongful death suit concerning the prescription medication","paragraph_id":"para_27"},{"text":"Aimovig, a biologic manufactured by Amgen Inc. and Amgen U.S.A.","paragraph_id":"para_28"},{"text":"Inc. (collectively, \"Amgen\") for the prevention of migraines.","paragraph_id":"para_29"},{"text":"Lucas Warner, who had a history of seizures and cerebrovascular","paragraph_id":"para_30"},{"text":"disease, died at the age of twenty-five from cerebrovascular","paragraph_id":"para_31"},{"text":"complications after taking a single dose of Aimovig. His mother,","paragraph_id":"para_32"},{"text":"Elissa Warner,1 challenged under state law the adequacy of the","paragraph_id":"para_33"},{"text":"drug's label as originally approved by the U.S. Food and Drug","paragraph_id":"para_34"},{"text":"Administration (FDA, or the \"agency\"). The district court","paragraph_id":"para_35"},{"text":"dismissed Warner's complaint, finding her claims preempted by the","paragraph_id":"para_36"},{"text":"Federal Food, Drug, and Cosmetic Act (FDCA), 21 U.S.C. §§ 301","paragraph_id":"para_37"},{"text":"et seq. The court also denied Warner leave to amend her complaint","paragraph_id":"para_38"},{"text":"to include allegations that Amgen should have supplemented its","paragraph_id":"para_39"},{"text":"label after it was initially approved but before Lucas received","paragraph_id":"para_40"},{"text":"the drug, finding that such an amendment would be futile.","paragraph_id":"para_41"},{"text":"We affirm the district court's dismissal of Warner's","paragraph_id":"para_42"},{"text":"original complaint but reverse the court's decision to deny Warner","paragraph_id":"para_43"},{"text":"leave to amend her complaint. Our reasoning follows.","paragraph_id":"para_44"},{"text":"1 For consistency with the proceedings below, we refer to","paragraph_id":"para_45"},{"text":"Lucas Warner as \"Lucas\" and his mother as \"Warner.\"","paragraph_id":"para_46"},{"text":"- 4 -","paragraph_id":"para_47"},{"text":"I.","paragraph_id":"para_48"},{"text":"A.","paragraph_id":"para_49"},{"text":"We begin with the regulatory framework underpinning this","paragraph_id":"para_50"},{"text":"appeal. In 1962, Congress amended the FDCA, \"shift[ing] the","paragraph_id":"para_51"},{"text":"burden of proof\" for drug safety and labeling \"from the FDA to the","paragraph_id":"para_52"},{"text":"manufacturer.\" Wyeth v. Levine, 555 U.S. 555, 567 (2009). Under","paragraph_id":"para_53"},{"text":"the amended FDCA, a manufacturer seeking FDA approval of a license","paragraph_id":"para_54"},{"text":"to market a drug must \"demonstrate that its drug [is] safe for use","paragraph_id":"para_55"},{"text":"under the conditions prescribed, recommended, or suggested in the","paragraph_id":"para_56"},{"text":"proposed labeling before it [can] distribute the drug.\" Id.","paragraph_id":"para_57"},{"text":"(citation modified); 21 U.S.C § 355(b)(1). Prior to marketing a","paragraph_id":"para_58"},{"text":"pharmaceutical drug, a manufacturer must submit a new drug","paragraph_id":"para_59"},{"text":"application (NDA) that meets the requirements for FDA approval","paragraph_id":"para_60"},{"text":"promulgated under 21 C.F.R. § 314.50(c). See Wyeth, 555 U.S. at","paragraph_id":"para_61"},{"text":"566; 21 C.F.R. § 314.50.","paragraph_id":"para_62"},{"text":"Aimovig is a biologic product. Biologic","paragraph_id":"para_63"},{"text":"products -- which include viruses, vaccines, blood components,","paragraph_id":"para_64"},{"text":"allergenic products, and proteins -- are a \"type of drug,\" though","paragraph_id":"para_65"},{"text":"they are \"derived from natural, biological sources\" rather than","paragraph_id":"para_66"},{"text":"\"synthesized from chemicals\" like typical drugs. Sandoz Inc. v.","paragraph_id":"para_67"},{"text":"Amgen Inc., 582 U.S. 1, 6 (2017); see also 42 U.S.C. § 262(i)(1)","paragraph_id":"para_68"},{"text":"(defining \"biological product\"). 2 Like other drugs, biologic","paragraph_id":"para_69"},{"text":"2 The parties use the term \"biologic product,\" whereas the","paragraph_id":"para_70"},{"text":"statute and regulations refer to \"biological product[s].\" See 42","paragraph_id":"para_71"},{"text":"- 5 -","paragraph_id":"para_72"},{"text":"products are regulated under the FDCA. 42 U.S.C. § 262(j). The","paragraph_id":"para_73"},{"text":"licensing of biologic products is nevertheless governed primarily","paragraph_id":"para_74"},{"text":"by section 351 of the Public Health Service Act (PHSA), 42 U.S.C.","paragraph_id":"para_75"},{"text":"§ 262.3 Thus, rather than submit an NDA to obtain permission to","paragraph_id":"para_76"},{"text":"market a new drug, a biologic manufacturer must instead submit to","paragraph_id":"para_77"},{"text":"the FDA a Biologics License Application (BLA) under the PHSA. 21","paragraph_id":"para_78"},{"text":"C.F.R. § 601.2(a).","paragraph_id":"para_79"},{"text":"Notwithstanding the differing regulatory authorities for","paragraph_id":"para_80"},{"text":"licensing biologics versus other drugs, for our purposes the","paragraph_id":"para_81"},{"text":"approval process and the implications of that process are","paragraph_id":"para_82"},{"text":"materially the same. Compare id., with 21 C.F.R. § 314.50.","paragraph_id":"para_83"},{"text":"Manufacturers submitting a BLA are required, among other things,","paragraph_id":"para_84"},{"text":"to \"submit data derived from nonclinical laboratory and clinical","paragraph_id":"para_85"},{"text":"studies which demonstrate that the manufactured product meets","paragraph_id":"para_86"},{"text":"prescribed requirements of safety, purity, and potency.\" 21","paragraph_id":"para_87"},{"text":"C.F.R. § 601.2(a). And they cannot market the drug until the FDA","paragraph_id":"para_88"},{"text":"approves both the drug and its label. 42 U.S.C. § 262(a); see","paragraph_id":"para_89"},{"text":"U.S.C. § 262(i)(1); 21 C.F.R. § 601.2(a). For purposes of this","paragraph_id":"para_90"},{"text":"appeal, we use the terminology of the parties and refer to Aimovig","paragraph_id":"para_91"},{"text":"as a \"biologic\" or \"biologic product.\"","paragraph_id":"para_92"},{"text":"3 See Frequently Asked Questions About Therapeutic","paragraph_id":"para_93"},{"text":"Biological Products, FDA (May 16, 2024),","paragraph_id":"para_94"},{"text":"https://www.fda.gov/drugs/therapeutic-biologics-applications-","paragraph_id":"para_95"},{"text":"bla/frequently-asked-questions-about-therapeutic-biological-","paragraph_id":"para_96"},{"text":"products [https://perma.cc/64F7-6BSQ] (noting that \"[b]iological","paragraph_id":"para_97"},{"text":"products are a subset of drugs\" that are \"regulated under","paragraph_id":"para_98"},{"text":"provisions of the [FDCA],\" but \"only biological products are","paragraph_id":"para_99"},{"text":"licensed under section 351 of the [PHSA]\").","paragraph_id":"para_100"},{"text":"- 6 -","paragraph_id":"para_101"},{"text":"also In re Celexa & Lexapro Mktg. & Sales Pracs. Litig., 779 F.3d","paragraph_id":"para_102"},{"text":"34, 35–36 (1st Cir. 2015) (explaining that \"[t]he FDA will not","paragraph_id":"para_103"},{"text":"approve a drug,\" and thus the drug cannot be marketed, \"if the NDA","paragraph_id":"para_104"},{"text":"or [supplemental NDA] lacks substantial evidence that the drug","paragraph_id":"para_105"},{"text":"will have the effect it purports or is represented to have,\" but","paragraph_id":"para_106"},{"text":"\"[a]fter approval, the manufacturer may distribute the drug","paragraph_id":"para_107"},{"text":"without violating federal law as long as it uses the FDA-approved","paragraph_id":"para_108"},{"text":"label\" (citation omitted)).","paragraph_id":"para_109"},{"text":"The FDA's process for reviewing a BLA submission and","paragraph_id":"para_110"},{"text":"determining the appropriate content of a biologic's label involves","paragraph_id":"para_111"},{"text":"(1) an FDA review committee that \"[p]articipates in the labeling","paragraph_id":"para_112"},{"text":"review to ensure the content and formatting of the label comply","paragraph_id":"para_113"},{"text":"with requirements per applicable regulations\"; (2) a regulatory","paragraph_id":"para_114"},{"text":"project manager who oversees and coordinates the labeling review;","paragraph_id":"para_115"},{"text":"(3) a clinical reviewer who \"[e]nsures [the] accuracy of","paragraph_id":"para_116"},{"text":"clinically relevant product information in the labeling\"; (4) a","paragraph_id":"para_117"},{"text":"clinical pharmacology reviewer who \"[e]nsures [the] accuracy of","paragraph_id":"para_118"},{"text":"mechanism of action statements, pharmacodynamics,","paragraph_id":"para_119"},{"text":"pharmacokinetics, and information on the impact of age, sex, and","paragraph_id":"para_120"},{"text":"race in the labeling\"; (5) a chemistry manufacturing and control","paragraph_id":"para_121"},{"text":"reviewer who \"[e]nsures [the] accuracy of chemistry and","paragraph_id":"para_122"},{"text":"manufacturing product information provided in the labeling\";","paragraph_id":"para_123"},{"text":"(6) an advertising and promotional labeling branch reviewer who","paragraph_id":"para_124"},{"text":"\"[e]nsures the information in the labeling is not false or","paragraph_id":"para_125"},{"text":"- 7 -","paragraph_id":"para_126"},{"text":"misleading to the target audience(s)\"; (7) a statistician; and","paragraph_id":"para_127"},{"text":"(8) a non-clinical toxicologist reviewer. FDA Ctr. for Biologics","paragraph_id":"para_128"},{"text":"Evaluation & Rsch., SOPP 8412: Review of Product Labeling 5–6","paragraph_id":"para_129"},{"text":"(2026), https://www.fda.gov/media/81790/download [https://perma.","paragraph_id":"para_130"},{"text":"cc/TY7V-H59X]. The review committee is further tasked with","paragraph_id":"para_131"},{"text":"\"[c]omplet[ing] a thorough review of the labeling,\" meeting with","paragraph_id":"para_132"},{"text":"the BLA applicant (in this case, the manufacturer), \"identify[ing]","paragraph_id":"para_133"},{"text":"labeling revisions,\" and \"[s]end[ing] . . . revision requests\" to","paragraph_id":"para_134"},{"text":"the manufacturer. Id. at 8–9. When the manufacturer revises the","paragraph_id":"para_135"},{"text":"draft labeling, the review committee and the regulatory project","paragraph_id":"para_136"},{"text":"manager work together to confirm that the changes are consistent","paragraph_id":"para_137"},{"text":"with the agency's requested revisions. Id. at 9.","paragraph_id":"para_138"},{"text":"Pursuant to FDA regulations, the contents of a drug label","paragraph_id":"para_139"},{"text":"must include, in order (and among other things):","paragraph_id":"para_140"},{"text":"(1) prominent \"boxed\" warnings about risks","paragraph_id":"para_141"},{"text":"that may lead to death or serious injury;","paragraph_id":"para_142"},{"text":"(2) contraindications describing any","paragraph_id":"para_143"},{"text":"situation in which the drug should not be used","paragraph_id":"para_144"},{"text":"because the risk of use outweighs any","paragraph_id":"para_145"},{"text":"therapeutic benefit;","paragraph_id":"para_146"},{"text":"(3) warnings and precautions about other","paragraph_id":"para_147"},{"text":"potential safety hazards; and","paragraph_id":"para_148"},{"text":"(4) any adverse reactions for which there is","paragraph_id":"para_149"},{"text":"some basis to believe a causal relationship","paragraph_id":"para_150"},{"text":"exists between the drug and the occurrence of","paragraph_id":"para_151"},{"text":"the adverse event.","paragraph_id":"para_152"},{"text":"Merck Sharp & Dohme Corp. v. Albrecht, 587 U.S. 299, 304 (2019)","paragraph_id":"para_153"},{"text":"(quoting 21 C.F.R § 201.57(c)). The order in which these","paragraph_id":"para_154"},{"text":"categories must appear is far from random; rather, \"the category","paragraph_id":"para_155"},{"text":"- 8 -","paragraph_id":"para_156"},{"text":"in which a particular risk appears on a drug label is an indicator","paragraph_id":"para_157"},{"text":"of the likelihood and severity of the risk.\" Id. With this","paragraph_id":"para_158"},{"text":"\"hierarchy of label information,\" the FDA assures that \"more","paragraph_id":"para_159"},{"text":"important information\" is not \"overshadowed\" by \"less important","paragraph_id":"para_160"},{"text":"information.\" Id. (citation modified).","paragraph_id":"para_161"},{"text":"In approving the final label for a new drug or biologic,","paragraph_id":"para_162"},{"text":"the FDA aims to warn of risks while at the same time \"prevent[ing]","paragraph_id":"para_163"},{"text":"overwarning, which may deter appropriate use of medical products.\"","paragraph_id":"para_164"},{"text":"In re Zofran (Ondansetron) Prods. Liab. Litig., 57 F.4th 327, 330","paragraph_id":"para_165"},{"text":"(1st Cir. 2023) (quoting Supplemental Applications Proposing","paragraph_id":"para_166"},{"text":"Labeling Changes for Approved Drugs, Biologics, and Medical","paragraph_id":"para_167"},{"text":"Devices, 73 Fed. Reg. at 49605-06). The agency's final","paragraph_id":"para_168"},{"text":"determinations are thus meant to \"guard[] against the exaggeration","paragraph_id":"para_169"},{"text":"of risk, or inclusion of speculative or hypothetical risks,\" id.","paragraph_id":"para_170"},{"text":"(citation modified), such as \"theoretical hazards not","paragraph_id":"para_171"},{"text":"well-grounded in scientific evidence [that] can cause meaningful","paragraph_id":"para_172"},{"text":"risk information to lose its significance,\" Requirements on","paragraph_id":"para_173"},{"text":"Content and Format of Labeling for Human Prescription Drug and","paragraph_id":"para_174"},{"text":"Biological Products, 71 Fed. Reg. 3922, 3935 (Jan. 24, 2006)","paragraph_id":"para_175"},{"text":"(citation modified).","paragraph_id":"para_176"},{"text":"Only after this \"onerous and lengthy\" process is","paragraph_id":"para_177"},{"text":"complete, Mut. Pharm. Co. v. Bartlett, 570 U.S. 472, 476 (2013),","paragraph_id":"para_178"},{"text":"does the agency confirm its acceptance of a BLA or NDA with the","paragraph_id":"para_179"},{"text":"manufacturer. Accordingly, the approval of a BLA \"constitute[s]","paragraph_id":"para_180"},{"text":"- 9 -","paragraph_id":"para_181"},{"text":"a determination that the . . . product meet[s] applicable","paragraph_id":"para_182"},{"text":"requirements to ensure the continued safety, purity, and potency\"","paragraph_id":"para_183"},{"text":"of biologics such that the product may enter the market. 21 C.F.R","paragraph_id":"para_184"},{"text":"§ 601.2(d); see also 42 U.S.C. § 262(a)(2)(C).","paragraph_id":"para_185"},{"text":"After the FDA has approved a label, the manufacturer","paragraph_id":"para_186"},{"text":"must usually obtain permission from the FDA before making any","paragraph_id":"para_187"},{"text":"changes to it. See In re MDL 2700 Genentech Herceptin","paragraph_id":"para_188"},{"text":"(Trastuzumab) Mktg. & Sales Prac. Litig., 960 F.3d 1210, 1236 (10th","paragraph_id":"para_189"},{"text":"Cir. 2020); 21 C.F.R. § 601.12(f)(1)–(3) (describing the pathways","paragraph_id":"para_190"},{"text":"available to manufacturers seeking to amend a biologic label).","paragraph_id":"para_191"},{"text":"The so-called Changes Being Effected (CBE) regulations provide an","paragraph_id":"para_192"},{"text":"exception, applicable to both general pharmaceutical drugs under","paragraph_id":"para_193"},{"text":"21 C.F.R. § 314.70(c)(6) and biologics under 21 C.F.R.","paragraph_id":"para_194"},{"text":"§ 601.12(f)(2).4 Under the CBE procedure, a manufacturer may","paragraph_id":"para_195"},{"text":"without prior permission alter a drug or biologic's approved label","paragraph_id":"para_196"},{"text":"based on \"newly acquired information\" in order to \"accomplish\" one","paragraph_id":"para_197"},{"text":"of five possible labeling objectives provided by the regulations.","paragraph_id":"para_198"},{"text":"21 C.F.R. § 601.12(f)(2)(i)(A)–(E). Upon making such a labeling","paragraph_id":"para_199"},{"text":"change, the manufacturer must submit a supplemental label to the","paragraph_id":"para_200"},{"text":"FDA and may immediately begin using the revised label even as the","paragraph_id":"para_201"},{"text":"4 Though the regulations are largely analogous, the district","paragraph_id":"para_202"},{"text":"court based its analysis on the CBE regulations pertaining to","paragraph_id":"para_203"},{"text":"general pharmaceutical drugs under 21 C.F.R. § 314.70(c)(6) rather","paragraph_id":"para_204"},{"text":"than those pertaining to biologic products under 21 C.F.R.","paragraph_id":"para_205"},{"text":"§ 601.12(f)(2).","paragraph_id":"para_206"},{"text":"- 10 -","paragraph_id":"para_207"},{"text":"FDA considers whether to approve the change. 21 C.F.R.","paragraph_id":"para_208"},{"text":"§ 601.12(f)(2)(ii).","paragraph_id":"para_209"},{"text":"B.","paragraph_id":"para_210"},{"text":"With this regulatory framework in mind, we turn to the","paragraph_id":"para_211"},{"text":"facts of this case. Because this case was resolved on a motion","paragraph_id":"para_212"},{"text":"to dismiss, we take as given the well-pleaded facts in the","paragraph_id":"para_213"},{"text":"complaint. O'Brien v. United States, 155 F.4th 50, 53–54 (1st","paragraph_id":"para_214"},{"text":"Cir. 2025).","paragraph_id":"para_215"},{"text":"Aimovig is the proprietary name for the biologic drug","paragraph_id":"para_216"},{"text":"erenumab. \"Erenumab is a human monoclonal antibody that","paragraph_id":"para_217"},{"text":"antagonizes the calcitonin gene-related peptide (CGRP) receptor.\"","paragraph_id":"para_218"},{"text":"Because CGRP plays \"a role\" in the development of migraines,","paragraph_id":"para_219"},{"text":"Aimovig aims to prevent migraines by inhibiting CGRP's ability to","paragraph_id":"para_220"},{"text":"bind to CGRP receptors. At the time of its BLA submission, Aimovig","paragraph_id":"para_221"},{"text":"was \"the first product of this class to be reviewed in an FDA","paragraph_id":"para_222"},{"text":"marketing application.\"","paragraph_id":"para_223"},{"text":"Amgen submitted a biologics license application for","paragraph_id":"para_224"},{"text":"Aimovig on May 17, 2017. Aimovig received FDA approval exactly","paragraph_id":"para_225"},{"text":"one year later. The label as approved by the agency contained 12","paragraph_id":"para_226"},{"text":"sections, numbered (with some omissions) from 1 to 17.5 Section 14","paragraph_id":"para_227"},{"text":"of Aimovig's label, titled \"Clinical Studies,\" states that","paragraph_id":"para_228"},{"text":"5 A biologic's label can contain up to 17 possible sections.","paragraph_id":"para_229"},{"text":"See 21 C.F.R. § 201.57(c)(2)–(18) (listing all 17 possible","paragraph_id":"para_230"},{"text":"sections). Sections number 5, 7, 9, 10, and 15 were omitted from","paragraph_id":"para_231"},{"text":"Aimovig's label.","paragraph_id":"para_232"},{"text":"- 11 -","paragraph_id":"para_233"},{"text":"patients \"with myocardial infarction, stroke, transient ischemic","paragraph_id":"para_234"},{"text":"attacks, unstable angina, coronary artery bypass surgery, or other","paragraph_id":"para_235"},{"text":"revascularization procedures within 12 months prior to screening\"","paragraph_id":"para_236"},{"text":"were excluded from the drug's clinical trials. (Emphasis added).","paragraph_id":"para_237"},{"text":"Warner criticizes that description because it failed to disclose","paragraph_id":"para_238"},{"text":"that the Aimovig studies also excluded anyone who had ever suffered","paragraph_id":"para_239"},{"text":"from seizures or neurological disorders. The label similarly","paragraph_id":"para_240"},{"text":"noted no particular risk of Aimovig use for those in either of","paragraph_id":"para_241"},{"text":"these clinical trial exclusion groups.","paragraph_id":"para_242"},{"text":"Knowing of these undisclosed exclusions would have been","paragraph_id":"para_243"},{"text":"relevant to Lucas and his doctor, Warner alleges, because Lucas","paragraph_id":"para_244"},{"text":"had suffered from \"both seizures and cerebrovascular","paragraph_id":"para_245"},{"text":"disease/surgery\" more than a year prior to taking Aimovig. Lucas","paragraph_id":"para_246"},{"text":"was diagnosed with an arteriovenous malformation6 (AVM) at the age","paragraph_id":"para_247"},{"text":"of six that led him to have \"frequent and severe migraines\" as","paragraph_id":"para_248"},{"text":"well as \"periodic brain bleeds.\" In 2011 and then again in 2012,","paragraph_id":"para_249"},{"text":"Lucas underwent an embolization7 to help treat his AVM and migraine","paragraph_id":"para_250"},{"text":"6 An arteriovenous malformation is an \"improper or abnormal","paragraph_id":"para_251"},{"text":"development related to arteries or veins.\" Arteriovenous","paragraph_id":"para_252"},{"text":"Malformations (AVM), Stedman's Medical Dictionary 1147 (28th ed.","paragraph_id":"para_253"},{"text":"2006). With an AVM, \"blood is shunted from arterioles to venules","paragraph_id":"para_254"},{"text":"without passing through the capillaries.\" Id.","paragraph_id":"para_255"},{"text":"7 An embolization is the \"[t]herapeutic introduction of","paragraph_id":"para_256"},{"text":"various substances into the circulation to occlude vessels, either","paragraph_id":"para_257"},{"text":"to arrest or prevent hemorrhaging, to devitalize a structure,","paragraph_id":"para_258"},{"text":"tumor, or organ by occluding its blood supply, or to reduce blood","paragraph_id":"para_259"},{"text":"flow to an arteriovenous malformation.\" Embolization, Stedman's","paragraph_id":"para_260"},{"text":"Medical Dictionary, supra, at 627.","paragraph_id":"para_261"},{"text":"- 12 -","paragraph_id":"para_262"},{"text":"symptoms, though these procedures provided limited relief. In","paragraph_id":"para_263"},{"text":"2014, he suffered a subacute hemorrhage from his AVM.","paragraph_id":"para_264"},{"text":"In June 2018, unaware that persons with any history of","paragraph_id":"para_265"},{"text":"seizures and neurological disease had been excluded from the","paragraph_id":"para_266"},{"text":"Aimovig clinical trials, Lucas's doctor prescribed him Aimovig to","paragraph_id":"para_267"},{"text":"treat his migraines. Lucas took one dose of Aimovig on June 17,","paragraph_id":"para_268"},{"text":"2018, at age twenty-three. Less than 48 hours later, Lucas","paragraph_id":"para_269"},{"text":"suffered seizures and was placed in a coma. He experienced \"multi-","paragraph_id":"para_270"},{"text":"organ failure.\" His doctors believed that Aimovig had \"cross[ed]","paragraph_id":"para_271"},{"text":"[his] blood brain barrier,\"8 thereby causing the seizures, and they","paragraph_id":"para_272"},{"text":"\"attempt[ed] to remove [Aimovig] from his brain and blood.\" Due","paragraph_id":"para_273"},{"text":"to those seizures, Lucas \"suffered significant irreversible brain","paragraph_id":"para_274"},{"text":"damage, including the near-total loss of his short-term memory\"","paragraph_id":"para_275"},{"text":"and the inability to eat or drink. He struggled to walk and stand.","paragraph_id":"para_276"},{"text":"He was left \"cognitively severely impaired,\" forcing him to","paragraph_id":"para_277"},{"text":"discontinue his university studies, as the doctors could not do","paragraph_id":"para_278"},{"text":"anything \"to reverse the damage caused by [Aimovig].\" In 2020,","paragraph_id":"para_279"},{"text":"Lucas's condition worsened, and he suffered repetitive seizures","paragraph_id":"para_280"},{"text":"8 The blood-brain barrier is \"a selective mechanism\" that","paragraph_id":"para_281"},{"text":"\"oppos[es] the passage of most ions and high molecular weight","paragraph_id":"para_282"},{"text":"compounds from the blood to brain tissue.\" Blood-Brain Barrier,","paragraph_id":"para_283"},{"text":"Stedman's Medical Dictionary, supra, at 205; see also In re Vertex","paragraph_id":"para_284"},{"text":"Pharms. Inc., Sec. Litig., 357 F. Supp. 2d 343, 345 (D. Mass. 2005)","paragraph_id":"para_285"},{"text":"(\"The blood-brain barrier is a selective filter that regulates the","paragraph_id":"para_286"},{"text":"transport of certain molecules from the blood to the brain, and","paragraph_id":"para_287"},{"text":"protects the brain from substances in the blood that would cause","paragraph_id":"para_288"},{"text":"undesirable effects in the brain.\").","paragraph_id":"para_289"},{"text":"- 13 -","paragraph_id":"para_290"},{"text":"\"due to temporal mesial sclerosis, a result of the brain damage\"","paragraph_id":"para_291"},{"text":"from Aimovig.","paragraph_id":"para_292"},{"text":"Lucas died on November 17, 2020. His death certificate","paragraph_id":"para_293"},{"text":"lists his primary cause of death as \"hypoxia respiratory failure\"","paragraph_id":"para_294"},{"text":"caused by \"stroke,\" \"refractory seizures,\" and \"cerebral","paragraph_id":"para_295"},{"text":"angiopathy.\" 9 His death certificate also states that","paragraph_id":"para_296"},{"text":"\"complications from Aimovig\" \"contribut[ed]\" to his death.","paragraph_id":"para_297"},{"text":"Warner filed a wrongful death complaint against Amgen in","paragraph_id":"para_298"},{"text":"Massachusetts state court, alleging that her son died from medical","paragraph_id":"para_299"},{"text":"complications due to taking Aimovig and asserting liability on a","paragraph_id":"para_300"},{"text":"failure-to-warn theory. Warner alleged that Aimovig's label as","paragraph_id":"para_301"},{"text":"approved by the FDA should have contained a warning that the","paragraph_id":"para_302"},{"text":"biologic drug had not been tested on persons like Lucas with any","paragraph_id":"para_303"},{"text":"history at all of \"seizures or cerebrovascular disease/surgery,\"","paragraph_id":"para_304"},{"text":"as well as a warning regarding the \"complications suffered by","paragraph_id":"para_305"},{"text":"Lucas.\"","paragraph_id":"para_306"},{"text":"Amgen removed the suit to the U.S. District Court for","paragraph_id":"para_307"},{"text":"the District of Massachusetts. Amgen then filed a motion to","paragraph_id":"para_308"},{"text":"dismiss for failure to state a claim pursuant to Federal Rule of","paragraph_id":"para_309"},{"text":"9 Hypoxia involves the \"[d]ecrease below normal levels of","paragraph_id":"para_310"},{"text":"oxygen in inspired gases, arterial blood, or tissue.\" Hypoxia,","paragraph_id":"para_311"},{"text":"Stedman's Medical Dictionary, supra, at 939. \"Refractory\"","paragraph_id":"para_312"},{"text":"seizures are seizures that are \"resistant to treatment.\"","paragraph_id":"para_313"},{"text":"Refractory, Stedman's Medical Dictionary, supra, at 1664. And","paragraph_id":"para_314"},{"text":"angiopathy is \"[a]ny disease of the blood vessels or lymphatics.\"","paragraph_id":"para_315"},{"text":"Angiopathy, Stedman's Medical Dictionary, supra, at 88.","paragraph_id":"para_316"},{"text":"- 14 -","paragraph_id":"para_317"},{"text":"Civil Procedure 12(b)(6), contending (among other things) that","paragraph_id":"para_318"},{"text":"because it was required to use the label approved by the FDA, and","paragraph_id":"para_319"},{"text":"because Warner had not shown Amgen could have changed that label,","paragraph_id":"para_320"},{"text":"federal law preempted Warner's state law claim that Aimovig's label","paragraph_id":"para_321"},{"text":"should have disclosed more about the drug's clinical trial","paragraph_id":"para_322"},{"text":"exclusions or the possible complications related to those","paragraph_id":"para_323"},{"text":"exclusions.","paragraph_id":"para_324"},{"text":"At the motion hearing for Amgen's motion to dismiss,","paragraph_id":"para_325"},{"text":"Warner introduced a new contention. In addition to critiquing","paragraph_id":"para_326"},{"text":"Amgen's efforts to secure FDA approval of the label in the first","paragraph_id":"para_327"},{"text":"instance, she contended that a series of studies and literature","paragraph_id":"para_328"},{"text":"reviews not known to the FDA during the approval process would","paragraph_id":"para_329"},{"text":"have allowed Amgen to employ the CBE procedure to change the label","paragraph_id":"para_330"},{"text":"after it was approved and before Lucas took the drug. Such a","paragraph_id":"para_331"},{"text":"change, argued Warner, would have mentioned not just the lifetime","paragraph_id":"para_332"},{"text":"exclusion group, but also additional risks for patients like Lucas.","paragraph_id":"para_333"},{"text":"Following argument, the court requested that Warner file a","paragraph_id":"para_334"},{"text":"supplemental brief \"including more information on studies","paragraph_id":"para_335"},{"text":"identified\" during the hearing.","paragraph_id":"para_336"},{"text":"With her supplemental brief, Warner submitted nine","paragraph_id":"para_337"},{"text":"articles -- including studies and literature reviews, most of which","paragraph_id":"para_338"},{"text":"were published before the FDA approved the label -- that she","paragraph_id":"para_339"},{"text":"asserted qualified as newly acquired information that would have","paragraph_id":"para_340"},{"text":"allowed Amgen to amend its approved label under the CBE procedure.","paragraph_id":"para_341"},{"text":"- 15 -","paragraph_id":"para_342"},{"text":"Warner argued that these articles \"establishe[d] a reasonable","paragraph_id":"para_343"},{"text":"basis for believing that a CGRP blockade pose[s] a type, severity,","paragraph_id":"para_344"},{"text":"or frequency of risk that was not submitted to or analyzed by the","paragraph_id":"para_345"},{"text":"FDA prior to Aimovig's approval.\" Warner also requested leave to","paragraph_id":"para_346"},{"text":"amend her complaint to counter Amgen's affirmative preemption","paragraph_id":"para_347"},{"text":"defense and to assert that, based on the studies and reviews","paragraph_id":"para_348"},{"text":"presented, Amgen could have updated its label using the CBE process","paragraph_id":"para_349"},{"text":"to reflect \"cerebral risks presented by CGRP-blocking drugs, like","paragraph_id":"para_350"},{"text":"Aimovig, that were not previously submitted to the FDA.\"","paragraph_id":"para_351"},{"text":"After reviewing Warner's submissions, the court","paragraph_id":"para_352"},{"text":"concluded that \"the articles [did] not plausibly constitute newly","paragraph_id":"para_353"},{"text":"acquired information\" and failed to \"link Aimovig or any other","paragraph_id":"para_354"},{"text":"CGRP-blocking drug to an adverse event or risk\" that would have","paragraph_id":"para_355"},{"text":"allowed Amgen to amend Aimovig's label. Warner v. Amgen Inc.,","paragraph_id":"para_356"},{"text":"No. 24-CV-10632, 2025 WL 490720, at *9 (D. Mass. Feb. 13, 2025).","paragraph_id":"para_357"},{"text":"The court further surmised that because the FDA had \"reviewed 'the","paragraph_id":"para_358"},{"text":"world's literature'\" on \"the theoretical risks associated with","paragraph_id":"para_359"},{"text":"CGRP antagonism,\" it was \"not plausible that articles bearing on","paragraph_id":"para_360"},{"text":"that subject\" that were published before the FDA began its review","paragraph_id":"para_361"},{"text":"would constitute newly acquired information not previously","paragraph_id":"para_362"},{"text":"considered by the FDA. Id. at *10. As to Warner's argument that,","paragraph_id":"para_363"},{"text":"pre-approval, Amgen should have submitted a proposed label to the","paragraph_id":"para_364"},{"text":"FDA disclosing that patients like Lucas had been excluded from","paragraph_id":"para_365"},{"text":"Aimovig's trials, the court found that \"the FDA was aware that","paragraph_id":"para_366"},{"text":"- 16 -","paragraph_id":"para_367"},{"text":"individuals who had ever been diagnosed with a seizure disorder or","paragraph_id":"para_368"},{"text":"cerebrovascular disease were excluded from Aimovig's clinical","paragraph_id":"para_369"},{"text":"trials\" and that the FDA \"considered the risks and safety concerns","paragraph_id":"para_370"},{"text":"associated with these exclusions\" before approving a label lacking","paragraph_id":"para_371"},{"text":"any disclosure of them. Id. at *8. Accordingly, the court","paragraph_id":"para_372"},{"text":"granted Amgen's motion to dismiss with prejudice and denied","paragraph_id":"para_373"},{"text":"Warner's request for leave to amend her complaint as futile. Id.","paragraph_id":"para_374"},{"text":"at *12. This appeal followed.","paragraph_id":"para_375"},{"text":"II.","paragraph_id":"para_376"},{"text":"This court \"review[s] the grant of a motion to dismiss","paragraph_id":"para_377"},{"text":"de novo, accepting well-pled facts as true and drawing all","paragraph_id":"para_378"},{"text":"inferences in favor of the non-moving party.\" O'Brien, 155 F.4th","paragraph_id":"para_379"},{"text":"at 53–54 (quoting 3137, LLC v. Town of Harwich, 126 F.4th 1, 8","paragraph_id":"para_380"},{"text":"(1st Cir. 2025)). To survive dismissal for failure to state a","paragraph_id":"para_381"},{"text":"claim under Rule 12(b)(6), a complaint must \"'state a claim to","paragraph_id":"para_382"},{"text":"relief that is plausible on its face,'\" such that we can \"draw the","paragraph_id":"para_383"},{"text":"reasonable inference that the defendant is liable for the","paragraph_id":"para_384"},{"text":"misconduct alleged.\" Ashcroft v. Iqbal, 556 U.S. 662, 678 (2009)","paragraph_id":"para_385"},{"text":"(quoting Bell Atl. Corp. v. Twombly, 550 U.S. 544, 570 (2007)).","paragraph_id":"para_386"},{"text":"We are mindful that this plausibility requirement does not \"impose","paragraph_id":"para_387"},{"text":"a . . . requirement\" of probability. Twombly, 550 U.S. at 556.","paragraph_id":"para_388"},{"text":"On the other hand, a \"sheer possibility\" is not enough. Iqbal,","paragraph_id":"para_389"},{"text":"556 U.S. at 678. As such, \"[t]he relevant inquiry focuses on the","paragraph_id":"para_390"},{"text":"reasonableness of the inference of liability that the plaintiff is","paragraph_id":"para_391"},{"text":"- 17 -","paragraph_id":"para_392"},{"text":"asking the court to draw from the facts alleged in the complaint.\"","paragraph_id":"para_393"},{"text":"Ocasio-Hernández v. Fortuño-Burset, 640 F.3d 1, 13 (1st Cir. 2011).","paragraph_id":"para_394"},{"text":"On appeal, Amgen does not contend that Warner's","paragraph_id":"para_395"},{"text":"complaint fails to state a plausible claim for relief under","paragraph_id":"para_396"},{"text":"applicable state law. Rather, Amgen argues that the district","paragraph_id":"para_397"},{"text":"court correctly found that Amgen's affirmative defense -- federal","paragraph_id":"para_398"},{"text":"preemption -- defeats Warner's state-law claim before it gets out","paragraph_id":"para_399"},{"text":"of the starting blocks. See PLIVA, Inc. v. Mensing, 564 U.S. 604,","paragraph_id":"para_400"},{"text":"619 (2011) (referring to preemption as an affirmative defense);","paragraph_id":"para_401"},{"text":"Durnford v. MusclePharm Corp., 907 F.3d 595, 603 n.8 (9th Cir.","paragraph_id":"para_402"},{"text":"2018) (\"FDCA preemption, like all federal preemption, is an","paragraph_id":"para_403"},{"text":"affirmative defense.\").","paragraph_id":"para_404"},{"text":"When an order of dismissal under Rule 12(b)(6) is","paragraph_id":"para_405"},{"text":"\"premised on the inevitable success of an affirmative defense,\" we","paragraph_id":"para_406"},{"text":"will uphold the order so long as (1) \"the facts establishing the","paragraph_id":"para_407"},{"text":"defense are definitively ascertainable from the complaint and the","paragraph_id":"para_408"},{"text":"other allowable sources of information\" and (2) \"those facts","paragraph_id":"para_409"},{"text":"suffice to establish the affirmative defense with certitude.\"","paragraph_id":"para_410"},{"text":"Burt v. Bd. of Trs. of Univ. of R.I., 84 F.4th 42, 50 (1st Cir.","paragraph_id":"para_411"},{"text":"2023) (quoting Nisselson v. Lernout, 469 F.3d 143, 150 (1st Cir.","paragraph_id":"para_412"},{"text":"2006)); see also Scheibe v. ProSupps USA, LLC, 141 F.4th 1094,","paragraph_id":"para_413"},{"text":"1098 (9th Cir. 2025) (\"Under Rule 12(b)(6), only when the plaintiff","paragraph_id":"para_414"},{"text":"pleads itself out of court, by admitting all the elements of an","paragraph_id":"para_415"},{"text":"- 18 -","paragraph_id":"para_416"},{"text":"affirmative defense, may a complaint that otherwise states a claim","paragraph_id":"para_417"},{"text":"be dismissed.\" (citation modified)).","paragraph_id":"para_418"},{"text":"III.","paragraph_id":"para_419"},{"text":"This appeal does not call on us to apply a statutory","paragraph_id":"para_420"},{"text":"preemption clause. Cf. Monsanto Co. v. Durnell, 146 S. Ct. 2001,","paragraph_id":"para_421"},{"text":"2006 (2026) (reviewing an express preemption clause contained in","paragraph_id":"para_422"},{"text":"7 U.S.C. § 136v(b)). Rather, Amgen's FDCA preemption defense","paragraph_id":"para_423"},{"text":"rests on the proposition that it was not legally possible to use","paragraph_id":"para_424"},{"text":"a label other than the label originally approved by the FDA. This","paragraph_id":"para_425"},{"text":"type of preemption is often called impossibility preemption, which","paragraph_id":"para_426"},{"text":"exists \"where it is impossible for a private party to comply with","paragraph_id":"para_427"},{"text":"both state and federal requirements.\" Zofran, 57 F.4th at 335–36","paragraph_id":"para_428"},{"text":"(citation modified).","paragraph_id":"para_429"},{"text":"Impossibility preemption \"is a demanding defense.\"","paragraph_id":"para_430"},{"text":"Wyeth, 555 U.S. at 573. As a general matter, there is a","paragraph_id":"para_431"},{"text":"presumption against preemption. See id. at 565 (\"[W]e start with","paragraph_id":"para_432"},{"text":"the assumption that the historic police powers of the States were","paragraph_id":"para_433"},{"text":"not to be superseded by the Federal Act unless that was the clear","paragraph_id":"para_434"},{"text":"and manifest purpose of Congress.\" (citation modified)). In the","paragraph_id":"para_435"},{"text":"prescription drug context, the drug manufacturer bears the","paragraph_id":"para_436"},{"text":"ultimate burden of establishing a preemption defense. See","paragraph_id":"para_437"},{"text":"Albrecht, 587 U.S. at 313–14.","paragraph_id":"para_438"},{"text":"Warner claims in support of her complaint that it would","paragraph_id":"para_439"},{"text":"have been possible for Amgen to comply with Massachusetts state","paragraph_id":"para_440"},{"text":"- 19 -","paragraph_id":"para_441"},{"text":"law by proposing a better label when originally seeking FDA","paragraph_id":"para_442"},{"text":"approval. Alternatively, she claims in support of her motion to","paragraph_id":"para_443"},{"text":"amend her complaint that Amgen could have later changed the","paragraph_id":"para_444"},{"text":"approved label. We assess each claim in turn.","paragraph_id":"para_445"},{"text":"A.","paragraph_id":"para_446"},{"text":"We begin with what the parties call Warner's","paragraph_id":"para_447"},{"text":"\"pre-approval\" theory, which is the theory tendered in support of","paragraph_id":"para_448"},{"text":"her complaint. In substance, Warner asserts that, in its BLA","paragraph_id":"para_449"},{"text":"submission to the FDA, Amgen could have proposed a label disclosing","paragraph_id":"para_450"},{"text":"that Aimovig's clinical trials excluded \"people with a history of","paragraph_id":"para_451"},{"text":"seizures\" or \"cerebrovascular disease/surgery\" at any time in","paragraph_id":"para_452"},{"text":"their lives. Such a disclosure would have revealed that","paragraph_id":"para_453"},{"text":"\"potential complications related to those exclusions\" could have","paragraph_id":"para_454"},{"text":"escaped notice in the clinical trials.","paragraph_id":"para_455"},{"text":"We see two flaws in this argument, one legal and one","paragraph_id":"para_456"},{"text":"factual, each sufficient to sustain the dismissal of Warner's","paragraph_id":"para_457"},{"text":"complaint. First, as a matter of law, a manufacturer's ability","paragraph_id":"para_458"},{"text":"to ask the FDA to include something in a label falls short of the","paragraph_id":"para_459"},{"text":"unilateral power required to preclude an impossibility preemption","paragraph_id":"para_460"},{"text":"defense. Second, as a matter of fact, the record in this case is","paragraph_id":"para_461"},{"text":"clear that the FDA would have rejected a request to further","paragraph_id":"para_462"},{"text":"describe in the label the exclusions from Aimovig's clinical","paragraph_id":"para_463"},{"text":"trials. We explain these independent grounds for affirming","paragraph_id":"para_464"},{"text":"dismissal in turn below.","paragraph_id":"para_465"},{"text":"- 20 -","paragraph_id":"para_466"},{"text":"1.","paragraph_id":"para_467"},{"text":"\"[W]hether a private party can act sufficiently","paragraph_id":"para_468"},{"text":"independently under federal law to do what state law requires may","paragraph_id":"para_469"},{"text":"sometimes be difficult to determine.\" PLIVA, 564 U.S. at 623.","paragraph_id":"para_470"},{"text":"Indeed, the Supreme Court itself has recognized that prescription","paragraph_id":"para_471"},{"text":"drug preemption matters \"h[ave] repeatedly vexed the Court -- and","paragraph_id":"para_472"},{"text":"produced widely divergent views -- in recent years.\" Bartlett,","paragraph_id":"para_473"},{"text":"570 U.S. at 492–93 (citing Wyeth, 555 U.S. 555, and PLIVA, 564","paragraph_id":"para_474"},{"text":"U.S. 604). That puzzlement arises in part due to the lack of","paragraph_id":"para_475"},{"text":"congressional clarity regarding preemption in federal law: \"[T]he","paragraph_id":"para_476"},{"text":"FDCA's treatment of prescription drugs includes neither an express","paragraph_id":"para_477"},{"text":"pre-emption clause (as in the vaccine context, 42 U.S.C.","paragraph_id":"para_478"},{"text":"§ 300aa-22(b)(1)), nor an express non-preemption clause (as in the","paragraph_id":"para_479"},{"text":"over-the-counter drug context, 21 U.S.C. §§ 379r(e), 379s(d)).\"","paragraph_id":"para_480"},{"text":"Id. at 493. This lack of clarity leaves courts to \"divine","paragraph_id":"para_481"},{"text":"Congress' will from the duties the statute imposes.\" Id. So we","paragraph_id":"para_482"},{"text":"do our best, following the guidance provided by the Supreme Court","paragraph_id":"para_483"},{"text":"and our own circuit precedent.","paragraph_id":"para_484"},{"text":"We start with Wyeth. If Warner were correct that a","paragraph_id":"para_485"},{"text":"manufacturer's ability to ask the FDA to include certain language","paragraph_id":"para_486"},{"text":"on a label precluded an impossibility preemption defense to a claim","paragraph_id":"para_487"},{"text":"that the label was insufficient, then the Supreme Court in Wyeth","paragraph_id":"para_488"},{"text":"would have had little reason to hinge its discussion on the","paragraph_id":"para_489"},{"text":"availability of the CBE procedure. The Court could have simply","paragraph_id":"para_490"},{"text":"- 21 -","paragraph_id":"para_491"},{"text":"rested its decision on whether it was possible for the manufacturer","paragraph_id":"para_492"},{"text":"to request that the FDA take certain action -- in this case, to","paragraph_id":"para_493"},{"text":"approve a change to the label. Indeed, the Court's segue from","paragraph_id":"para_494"},{"text":"noting the manufacturer's ability to request approval to focusing","paragraph_id":"para_495"},{"text":"instead on the CBE procedure strongly suggests that the Court","paragraph_id":"para_496"},{"text":"presumed that the mere ability to request approval of a change did","paragraph_id":"para_497"},{"text":"not defeat the preemption defense. See Wyeth, 555 U.S. at 568","paragraph_id":"para_498"},{"text":"(\"There is, however . . . the 'changes being effected' (CBE)","paragraph_id":"para_499"},{"text":"regulation.\" (emphasis added)).","paragraph_id":"para_500"},{"text":"This suggestion grew stronger yet with the Court's","paragraph_id":"para_501"},{"text":"discussion of Wyeth in PLIVA. There, the Court held that a generic","paragraph_id":"para_502"},{"text":"drug manufacturer's ability to ask the FDA to change a drug's label","paragraph_id":"para_503"},{"text":"did not defeat an impossibility defense. PLIVA, 564 U.S. at","paragraph_id":"para_504"},{"text":"619–21. In so holding, the Court explained that \"[t]he question","paragraph_id":"para_505"},{"text":"for 'impossibility' is whether the [defendant] could independently","paragraph_id":"para_506"},{"text":"do under federal law what state law requires of it.\" Id. at 620.","paragraph_id":"para_507"},{"text":"In that context, where state law required a stronger label, \"[t]he","paragraph_id":"para_508"},{"text":"only action the [m]anufacturers could independently take -- asking","paragraph_id":"para_509"},{"text":"for the FDA's help -- [was] not a matter of state-law concern.\"","paragraph_id":"para_510"},{"text":"Id. at 624. Because requesting that the FDA take action was simply","paragraph_id":"para_511"},{"text":"the first step in a chain of contingencies that, with the FDA's","paragraph_id":"para_512"},{"text":"help, \"might have eventually\" -- but could not have","paragraph_id":"para_513"},{"text":"independently -- yielded the requisite stronger warning label, the","paragraph_id":"para_514"},{"text":"Court found such a claim to be preempted. Id. at 620-21; see also","paragraph_id":"para_515"},{"text":"- 22 -","paragraph_id":"para_516"},{"text":"id. at 623–24 (\"To decide these cases, it is enough to hold that","paragraph_id":"para_517"},{"text":"when a party cannot satisfy its state duties without the Federal","paragraph_id":"para_518"},{"text":"Government's special permission and assistance, which is dependent","paragraph_id":"para_519"},{"text":"on the exercise of judgment by a federal agency, that party cannot","paragraph_id":"para_520"},{"text":"independently satisfy those state duties for pre-emption","paragraph_id":"para_521"},{"text":"purposes.\").","paragraph_id":"para_522"},{"text":"As we subsequently stated in Celexa, the PLIVA Court","paragraph_id":"para_523"},{"text":"\"thus limited Wyeth to situations in which the drug manufacturer","paragraph_id":"para_524"},{"text":"can, of its own volition, strengthen its label in compliance with","paragraph_id":"para_525"},{"text":"its state tort duty.\" 779 F.3d at 41 (citation modified); see","paragraph_id":"para_526"},{"text":"also PLIVA, 564 U.S. at 624 (reasoning that Wyeth was not contrary","paragraph_id":"para_527"},{"text":"to its holding because a brand-name manufacturer like the one in","paragraph_id":"para_528"},{"text":"Wyeth can use the CBE process \"to unilaterally strengthen its","paragraph_id":"para_529"},{"text":"[drug's] warning\" or label without prior FDA approval, whereas a","paragraph_id":"para_530"},{"text":"generic manufacturer cannot (quoting Wyeth, 555 U.S. at 573)).","paragraph_id":"para_531"},{"text":"And then more recently in Albrecht, the Supreme Court again turned","paragraph_id":"para_532"},{"text":"its attention not to a manufacturer's ability to plead with the","paragraph_id":"para_533"},{"text":"FDA for a labeling change, but rather to the CBE regulation","paragraph_id":"para_534"},{"text":"allowing a change by the manufacturer \"without prior approval from","paragraph_id":"para_535"},{"text":"the FDA.\" 587 U.S. at 315. We have gathered from these cases a","paragraph_id":"para_536"},{"text":"general principle: Where \"a private party . . . cannot comply","paragraph_id":"para_537"},{"text":"with state law without first obtaining the approval of a federal","paragraph_id":"para_538"},{"text":"regulatory agency, then the application of that law to that private","paragraph_id":"para_539"},{"text":"- 23 -","paragraph_id":"para_540"},{"text":"party is preempted.\" Gustavsen v. Alcon Lab'ys, Inc., 903 F.3d","paragraph_id":"para_541"},{"text":"1, 9 (1st Cir. 2018).","paragraph_id":"para_542"},{"text":"And while the foregoing cases all apply this principle","paragraph_id":"para_543"},{"text":"in the context of considering claims that approved labels should","paragraph_id":"para_544"},{"text":"have been revised post-approval, we see no reason not to apply it","paragraph_id":"para_545"},{"text":"to claims that the manufacturer should have submitted a different","paragraph_id":"para_546"},{"text":"label in its BLA submission to the FDA. It follows, then, that a","paragraph_id":"para_547"},{"text":"pre-approval claim like Warner's cannot survive a manufacturer's","paragraph_id":"para_548"},{"text":"impossibility defense because a BLA submission is, by its nature,","paragraph_id":"para_549"},{"text":"a request for agency approval.10","paragraph_id":"para_550"},{"text":"10 This is not to say that a manufacturer remains free to","paragraph_id":"para_551"},{"text":"mislead the FDA in the approval process. While impossibility","paragraph_id":"para_552"},{"text":"preemption bars a pre-approval claim based on a manufacturer's","paragraph_id":"para_553"},{"text":"failure to propose a different label to the FDA, the enforcement","paragraph_id":"para_554"},{"text":"mechanisms crafted by Congress to protect consumers against","paragraph_id":"para_555"},{"text":"misleading or fraudulent actions by manufacturers remain in place.","paragraph_id":"para_556"},{"text":"The FDCA prohibits manufacturers from obscuring information from","paragraph_id":"para_557"},{"text":"or presenting false information to the FDA in their drug","paragraph_id":"para_558"},{"text":"applications. See 21 U.S.C. § 331(a) (prohibiting introduction","paragraph_id":"para_559"},{"text":"into interstate commerce of any drug \"that is . . . misbranded\");","paragraph_id":"para_560"},{"text":"id. § 352(a)(1) (deeming a drug misbranded where \"its labeling is","paragraph_id":"para_561"},{"text":"false or misleading in any particular\"); see also Yousefzadeh v.","paragraph_id":"para_562"},{"text":"Johnson & Johnson Consumer Inc., 184 F.4th 130, 141 (2d Cir. 2026)","paragraph_id":"para_563"},{"text":"(\"The misbranding provision . . . prohibits not only affirmative","paragraph_id":"para_564"},{"text":"misrepresentations but also failures to disclose material","paragraph_id":"para_565"},{"text":"facts.\"); United States v. Watkins, 278 F.3d 961, 964 (9th Cir.","paragraph_id":"para_566"},{"text":"2002) (describing misdemeanor and felony misbranding provisions","paragraph_id":"para_567"},{"text":"under the FDCA).","paragraph_id":"para_568"},{"text":"And, as we will explain, information not submitted to the FDA","paragraph_id":"para_569"},{"text":"in the approval process may serve as newly acquired information,","paragraph_id":"para_570"},{"text":"requiring a post approval change in the label by the manufacturer","paragraph_id":"para_571"},{"text":"to avoid liability under state law.","paragraph_id":"para_572"},{"text":"- 24 -","paragraph_id":"para_573"},{"text":"2.","paragraph_id":"para_574"},{"text":"Adding belt to suspenders, the record in this case makes","paragraph_id":"para_575"},{"text":"clear that any pre-approval request by Amgen for the label Warner","paragraph_id":"para_576"},{"text":"says it should have proposed would have been denied -- and indeed,","paragraph_id":"para_577"},{"text":"was effectively denied. Certainly, the FDA was aware that the","paragraph_id":"para_578"},{"text":"clinical trials submitted in support of Aimovig's application","paragraph_id":"para_579"},{"text":"excluded persons with any history of \"seizure disorders\" or","paragraph_id":"para_580"},{"text":"\"significant neurological conditions.\" We know that because the","paragraph_id":"para_581"},{"text":"summary of the studies prepared by the FDA's Division of Neurology","paragraph_id":"para_582"},{"text":"Products (DNP) expressly mentioned those exclusions. The DNP","paragraph_id":"para_583"},{"text":"further remarked in its clinical review and integrated safety","paragraph_id":"para_584"},{"text":"assessment that \"the selection criteria for the migraine studies","paragraph_id":"para_585"},{"text":"resulted in a relatively young, healthy population\" that excluded","paragraph_id":"para_586"},{"text":"individuals suffering from \"seizure disorders\" or \"major","paragraph_id":"para_587"},{"text":"neurological disorders.\"","paragraph_id":"para_588"},{"text":"Indeed, Aimovig's DNP reviewer initially proposed adding","paragraph_id":"para_589"},{"text":"a warning of \"theoretical concern\" for all \"patients with","paragraph_id":"para_590"},{"text":"major . . . cerebrovascular disease\" (e.g., persons like Lucas).","paragraph_id":"para_591"},{"text":"That recommendation was rejected after further internal review, as","paragraph_id":"para_592"},{"text":"the FDA's Division of Risk Management determined that, despite the","paragraph_id":"para_593"},{"text":"\"theoretical\" cerebrovascular risks posed by CGRP antagonism,","paragraph_id":"para_594"},{"text":"there was \"insufficient evidence to include th[e] theoretical risk","paragraph_id":"para_595"},{"text":"in labeling.\" The FDA also rejected the DNP's suggestion to add","paragraph_id":"para_596"},{"text":"a caution against Aimovig use in \"[p]atients who ha[d] experienced","paragraph_id":"para_597"},{"text":"- 25 -","paragraph_id":"para_598"},{"text":"a stroke, myocardial infarction, transient ischemic attack,","paragraph_id":"para_599"},{"text":"unstable angina or had coronary artery bypass surgery within the","paragraph_id":"para_600"},{"text":"last year.\"","paragraph_id":"para_601"},{"text":"Ultimately, the final label as approved by the FDA","paragraph_id":"para_602"},{"text":"contained no contraindications, warnings, or precautions, and it","paragraph_id":"para_603"},{"text":"listed only \"injection site reactions and constipation\" as the","paragraph_id":"para_604"},{"text":"\"most common adverse reactions\" to taking Aimovig. And while the","paragraph_id":"para_605"},{"text":"\"Clinical Studies\" section disclosed that patients who had","paragraph_id":"para_606"},{"text":"suffered from certain medical conditions, such as \"myocardial","paragraph_id":"para_607"},{"text":"infarction, stroke, [and] transient ischemic attacks . . . within","paragraph_id":"para_608"},{"text":"12 months prior to screening\" had been excluded from Aimovig's","paragraph_id":"para_609"},{"text":"clinical trials, the label did not disclose the lifetime exclusion","paragraph_id":"para_610"},{"text":"criterion and included no warning, direct or otherwise, of the","paragraph_id":"para_611"},{"text":"theoretical risk left unresolved by the design of the clinical","paragraph_id":"para_612"},{"text":"studies.11","paragraph_id":"para_613"},{"text":"Bearing in mind the FDA's knowledge of the clinical trial","paragraph_id":"para_614"},{"text":"exclusion criteria and its clear consideration and rejection of","paragraph_id":"para_615"},{"text":"added language to account for those exclusions, we are not free to","paragraph_id":"para_616"},{"text":"11 Warner would have us discount the FDA's consideration of","paragraph_id":"para_617"},{"text":"these excluded populations and the risk thereto because, in","paragraph_id":"para_618"},{"text":"Warner's view, the FDA trained its attention more (but not","paragraph_id":"para_619"},{"text":"exclusively) on cardiovascular risks than on cerebrovascular","paragraph_id":"para_620"},{"text":"risks, as \"evidenced\" by Warner's counting of the number of","paragraph_id":"para_621"},{"text":"references to cardiovascular versus cerebrovascular risks in the","paragraph_id":"para_622"},{"text":"FDA's review. But there was good reason for the FDA to home in","paragraph_id":"para_623"},{"text":"on cardiovascular considerations: \"There were two deaths in the","paragraph_id":"para_624"},{"text":"[Aimovig] database\" of the clinical trials, and \"both were","paragraph_id":"para_625"},{"text":"cardiovascular-related sudden deaths.\"","paragraph_id":"para_626"},{"text":"- 26 -","paragraph_id":"para_627"},{"text":"disregard the FDA's final approval of an Aimovig label detailing","paragraph_id":"para_628"},{"text":"only the description of the twelve-month exclusion (but not the","paragraph_id":"para_629"},{"text":"lifetime exclusion) and conveying that exclusion as and where it","paragraph_id":"para_630"},{"text":"did. It is true that no one proposed the FDA should word the","paragraph_id":"para_631"},{"text":"label precisely as Warner says it should have been worded. But","paragraph_id":"para_632"},{"text":"as we have described, the only reason to make such a change would","paragraph_id":"para_633"},{"text":"be to flag the theoretical risks the agency had already decided","paragraph_id":"para_634"},{"text":"did not warrant mentioning. We must therefore read the FDA's","paragraph_id":"para_635"},{"text":"inclusion of the twelve–month exclusion in the Clinical Studies","paragraph_id":"para_636"},{"text":"section of the label -- but not the lifetime exclusion -- as","paragraph_id":"para_637"},{"text":"\"constitut[ing] [the agency's] determination,\" 21 C.F.R","paragraph_id":"para_638"},{"text":"§ 601.2(d), that the description of the clinical studies on the","paragraph_id":"para_639"},{"text":"approved label would \"facilitate an understanding of how to use","paragraph_id":"para_640"},{"text":"the drug safely and effectively,\" id. § 201.57(c)(15). In the","paragraph_id":"para_641"},{"text":"same manner, we must read the agency's omission of any indication,","paragraph_id":"para_642"},{"text":"contraindication, warning or precaution, or adverse reaction","paragraph_id":"para_643"},{"text":"related to the clinical trial exclusion criteria as the FDA's","paragraph_id":"para_644"},{"text":"determination that the label as approved would be adequate to","paragraph_id":"para_645"},{"text":"ensure the \"safety, purity, and potency\" of Aimovig such that it","paragraph_id":"para_646"},{"text":"could enter the market. Id. § 601.2(d). As such, the agency's","paragraph_id":"para_647"},{"text":"formal approval of the Aimovig label made clear that the agency","paragraph_id":"para_648"},{"text":"would have rejected a suggestion by Amgen to include in the","paragraph_id":"para_649"},{"text":"approved label the language that Warner says state law required.","paragraph_id":"para_650"},{"text":"\"[W]hen the FDA formally approves a label stating one thing with","paragraph_id":"para_651"},{"text":"- 27 -","paragraph_id":"para_652"},{"text":"full and obvious notice of the directly contrary position, one can","paragraph_id":"para_653"},{"text":"read the approval as rejecting the contrary position.\" Zofran,","paragraph_id":"para_654"},{"text":"57 F.4th at 343.","paragraph_id":"para_655"},{"text":"* * *","paragraph_id":"para_656"},{"text":"In sum, we conclude that the district court correctly","paragraph_id":"para_657"},{"text":"found that Warner's complaint did not survive Amgen's preemption","paragraph_id":"para_658"},{"text":"defense. Amgen's ability to have proposed a different original","paragraph_id":"para_659"},{"text":"label does not defeat its preemption defense because it did not","paragraph_id":"para_660"},{"text":"have the ability to act unilaterally in the context of this","paragraph_id":"para_661"},{"text":"\"pre-approval\" claim. And, in any event, it is clear that the FDA","paragraph_id":"para_662"},{"text":"would have rejected the type of label Warner proposes in her","paragraph_id":"para_663"},{"text":"complaint even if Amgen had requested it.","paragraph_id":"para_664"},{"text":"B.","paragraph_id":"para_665"},{"text":"We turn next to the district court's denial of Warner's","paragraph_id":"para_666"},{"text":"request for leave to amend her complaint. In her request, Warner","paragraph_id":"para_667"},{"text":"sought to add a claim based on a new theory of recovery that, post-","paragraph_id":"para_668"},{"text":"approval, Amgen should have amended its label of its own accord","paragraph_id":"para_669"},{"text":"using the CBE procedure to reflect newly acquired information.","paragraph_id":"para_670"},{"text":"The district court determined that Amgen could not have revised","paragraph_id":"para_671"},{"text":"its FDA-approved label as Warner alleged it should have; hence,","paragraph_id":"para_672"},{"text":"the request to file an amended complaint was futile. Warner, 2025","paragraph_id":"para_673"},{"text":"WL 490720, at *12.","paragraph_id":"para_674"},{"text":"\"A district court's ruling under Rule 15(a) that","paragraph_id":"para_675"},{"text":"amendment would be futile 'means that the complaint, as amended,","paragraph_id":"para_676"},{"text":"- 28 -","paragraph_id":"para_677"},{"text":"would fail to state a claim upon which relief could be granted.'\"","paragraph_id":"para_678"},{"text":"D'Agostino v. ev3, Inc., 845 F.3d 1, 6 (1st Cir. 2016) (quoting","paragraph_id":"para_679"},{"text":"Glassman v. Computervision Corp., 90 F.3d 617, 623 (1st Cir.","paragraph_id":"para_680"},{"text":"1996)); see also Fed. R. Civ. P. 15(a). We therefore review the","paragraph_id":"para_681"},{"text":"district court's ruling de novo. D'Agostino, 845 F.3d at 6. In","paragraph_id":"para_682"},{"text":"so doing, we ask whether the proposed amended complaint would have","paragraph_id":"para_683"},{"text":"stated a plausible claim for relief that would not have been","paragraph_id":"para_684"},{"text":"certainly precluded by Amgen's preemption defense. See Burt, 84","paragraph_id":"para_685"},{"text":"F.4th at 50.","paragraph_id":"para_686"},{"text":"Warner's proposed amendment to the complaint would have","paragraph_id":"para_687"},{"text":"added reference to nine studies or articles advancing her new","paragraph_id":"para_688"},{"text":"argument that, in light of any or all of the articles' findings,","paragraph_id":"para_689"},{"text":"Amgen could have unilaterally changed Aimovig's approved label to","paragraph_id":"para_690"},{"text":"add a warning that blocking CGRP disrupts neuroprotective","paragraph_id":"para_691"},{"text":"mechanisms in the setting of cerebral injury. This argument puts","paragraph_id":"para_692"},{"text":"in play consideration of the CBE procedure set forth at 21 C.F.R.","paragraph_id":"para_693"},{"text":"§ 601.12(f)(2). That procedure allows a manufacturer to change","paragraph_id":"para_694"},{"text":"an approved label -- and then distribute the drug with the changed","paragraph_id":"para_695"},{"text":"label before receiving FDA approval of the changes -- when, as","paragraph_id":"para_696"},{"text":"relevant here, the added information \"reflect[s] newly acquired","paragraph_id":"para_697"},{"text":"information\" that \"add[s] or strengthen[s] a contraindication,","paragraph_id":"para_698"},{"text":"warning, precaution, or adverse reaction.\" 21 C.F.R.","paragraph_id":"para_699"},{"text":"§ 601.12(f)(2)(i)(A).","paragraph_id":"para_700"},{"text":"- 29 -","paragraph_id":"para_701"},{"text":"The Supreme Court has considered several times how the","paragraph_id":"para_702"},{"text":"availability of the CBE procedure bears on the adjudication of a","paragraph_id":"para_703"},{"text":"preemption defense when a person challenges the adequacy of the","paragraph_id":"para_704"},{"text":"warnings on a label previously approved by the FDA. See Wyeth,","paragraph_id":"para_705"},{"text":"555 U.S. 555; Albrecht, 587 U.S. 299. So, too, has this court.","paragraph_id":"para_706"},{"text":"See, e.g., Celexa, 779 F.3d 34; Zofran, 57 F.4th 327.","paragraph_id":"para_707"},{"text":"Keeping in mind that we are reviewing the viability of","paragraph_id":"para_708"},{"text":"an affirmative defense to reject a proposed pleading without the","paragraph_id":"para_709"},{"text":"benefit of discovery, expert testimony, or fact finding, we must","paragraph_id":"para_710"},{"text":"be left with \"certitude\" that Warner does not have a plausible","paragraph_id":"para_711"},{"text":"basis for undercutting Amgen's affirmative defense in order to","paragraph_id":"para_712"},{"text":"affirm the district court's denial of Warner's motion for leave to","paragraph_id":"para_713"},{"text":"amend. Burt, 84 F.4th at 50 (citation modified); see also In re","paragraph_id":"para_714"},{"text":"Colonial Mortg. Bankers Corp., 324 F.3d 12, 16 (1st Cir. 2003)","paragraph_id":"para_715"},{"text":"(holding that, to dismiss a case based on an affirmative defense,","paragraph_id":"para_716"},{"text":"\"the facts that establish the defense must be definitively","paragraph_id":"para_717"},{"text":"ascertainable from the allegations of the complaint\" and other","paragraph_id":"para_718"},{"text":"allowable sources, and \"the facts so gleaned must conclusively","paragraph_id":"para_719"},{"text":"establish the affirmative defense\"). So, what need Warner","paragraph_id":"para_720"},{"text":"plausibly show in order to rely on the CBE procedure at this stage","paragraph_id":"para_721"},{"text":"of the lawsuit?","paragraph_id":"para_722"},{"text":"First, the parties appear to agree that Warner must","paragraph_id":"para_723"},{"text":"plausibly allege facts establishing a \"reasonable basis\" for","paragraph_id":"para_724"},{"text":"treating the articles she identifies as constituting \"newly","paragraph_id":"para_725"},{"text":"- 30 -","paragraph_id":"para_726"},{"text":"acquired information.\" See Zofran, 57 F.4th at 336 (emphasis","paragraph_id":"para_727"},{"text":"omitted) (reasoning that \"Albrecht can arguably be read as . . .","paragraph_id":"para_728"},{"text":"deeming the CBE procedure unavailable if there is no reasonable","paragraph_id":"para_729"},{"text":"basis for treating the information identified by plaintiffs as","paragraph_id":"para_730"},{"text":"newly acquired information\" (citing Albrecht, 587 U.S. at 315)).","paragraph_id":"para_731"},{"text":"The requirement that the information be \"newly acquired\" preserves","paragraph_id":"para_732"},{"text":"the FDA's role as \"the exclusive judge of safety and efficacy based","paragraph_id":"para_733"},{"text":"on information available at the commencement of marketing, while","paragraph_id":"para_734"},{"text":"allowing the states to reach contrary conclusions when new","paragraph_id":"para_735"},{"text":"information not considered by the FDA develops.\"12 Celexa, 779","paragraph_id":"para_736"},{"text":"F.3d at 41.","paragraph_id":"para_737"},{"text":"Second, Warner must plausibly allege facts showing that","paragraph_id":"para_738"},{"text":"the proposed change is \"for the purpose of accomplishing\" -- as","paragraph_id":"para_739"},{"text":"relevant here -- the objective of \"add[ing] or strengthen[ing] a","paragraph_id":"para_740"},{"text":"contraindication, warning, precaution, or adverse reaction.\" Id.","paragraph_id":"para_741"},{"text":"at 37; see also 21 C.F.R. § 601.12(f)(2)(i)(A) (parallel","paragraph_id":"para_742"},{"text":"regulation for biologics).","paragraph_id":"para_743"},{"text":"Third, because Warner argues that Amgen should have","paragraph_id":"para_744"},{"text":"invoked the CBE procedure to add a warning, precaution, or adverse","paragraph_id":"para_745"},{"text":"effect to Aimovig's label, she must also plausibly allege facts","paragraph_id":"para_746"},{"text":"showing Amgen could have satisfied the causal association standard","paragraph_id":"para_747"},{"text":"12 By \"available\" information we refer to information that","paragraph_id":"para_748"},{"text":"would not be \"newly acquired\" if submitted after approval. See","paragraph_id":"para_749"},{"text":"21 C.F.R. §§ 314.70(c)(6)(iii), 601.12(f)(6).","paragraph_id":"para_750"},{"text":"- 31 -","paragraph_id":"para_751"},{"text":"set forth in 21 C.F.R. § 201.57(c) for those additions to the","paragraph_id":"para_752"},{"text":"label. 21 C.F.R. § 601.12(f)(2)(i)(A). That standard requires","paragraph_id":"para_753"},{"text":"either \"reasonable evidence of a causal association\" between \"a","paragraph_id":"para_754"},{"text":"clinically significant hazard\" and a drug, id. § 201.57(c)(6)(i)","paragraph_id":"para_755"},{"text":"(emphasis added), or \"some basis to believe there is a causal","paragraph_id":"para_756"},{"text":"relationship between the drug and the occurrence of the adverse","paragraph_id":"para_757"},{"text":"event,\" id. § 201.57(c)(7) (emphasis added).","paragraph_id":"para_758"},{"text":"If Warner successfully makes the three foregoing","paragraph_id":"para_759"},{"text":"showings, then Amgen's preemption defense fails unless Amgen can","paragraph_id":"para_760"},{"text":"\"show that the FDA, after being fully informed of the case for","paragraph_id":"para_761"},{"text":"making [Warner's] proposed label change, made clear through agency","paragraph_id":"para_762"},{"text":"action having the force of law that it would not have allowed the","paragraph_id":"para_763"},{"text":"change had the defendant initiated it through the CBE procedure.\"","paragraph_id":"para_764"},{"text":"Zofran, 57 F.4th at 342. With that framework in mind, we next","paragraph_id":"para_765"},{"text":"consider the parties' submissions.","paragraph_id":"para_766"},{"text":"1.","paragraph_id":"para_767"},{"text":"We begin with the threshold issue of determining whether","paragraph_id":"para_768"},{"text":"the articles submitted by Warner present a \"reasonable basis for","paragraph_id":"para_769"},{"text":"treating the information . . . as newly acquired information.\"","paragraph_id":"para_770"},{"text":"Id. at 336 (emphasis omitted).","paragraph_id":"para_771"},{"text":"Newly acquired information is defined as \"data,","paragraph_id":"para_772"},{"text":"analyses, or other information not previously submitted to the","paragraph_id":"para_773"},{"text":"[FDA],\" which may include \"data derived from new clinical studies,","paragraph_id":"para_774"},{"text":"reports of adverse events, or new analyses of previously submitted","paragraph_id":"para_775"},{"text":"- 32 -","paragraph_id":"para_776"},{"text":"data (e.g., meta-analyses) if the studies, events or analyses","paragraph_id":"para_777"},{"text":"reveal risks of a different type or greater severity or frequency","paragraph_id":"para_778"},{"text":"than previously included in submissions to [the] FDA.\" 21 C.F.R.","paragraph_id":"para_779"},{"text":"§§ 601.12(f)(6), 314.3(b). In Zofran, the parties all assumed","paragraph_id":"para_780"},{"text":"that \"determining whether certain information is 'newly acquired'","paragraph_id":"para_781"},{"text":"[constituted] a legal question.\" 57 F.4th at 337. So we","paragraph_id":"para_782"},{"text":"similarly assumed. Id. Here, too, the parties also treat the","paragraph_id":"para_783"},{"text":"question as one of law, so we shall, too. That assumption still","paragraph_id":"para_784"},{"text":"leaves room for fact finding. For example, the adjudicator may","paragraph_id":"para_785"},{"text":"need to decide how significant the information is, whether it may","paragraph_id":"para_786"},{"text":"qualify as new, and so on. Albrecht, 587 U.S. at 317. But","paragraph_id":"para_787"},{"text":"resolution of these \"brute facts . . . relevant to a court's legal","paragraph_id":"para_788"},{"text":"determination\" is \"subsumed\" under the court's legal analysis.","paragraph_id":"para_789"},{"text":"Id.","paragraph_id":"para_790"},{"text":"In support of her motion for leave to amend her","paragraph_id":"para_791"},{"text":"complaint, Warner posits that the nine articles she submitted \"show","paragraph_id":"para_792"},{"text":"increasing knowledge about cerebrovascular risk that would have","paragraph_id":"para_793"},{"text":"enabled Amgen to supplement its label.\" Warner argues that the","paragraph_id":"para_794"},{"text":"district court's conclusion that these studies did not qualify as","paragraph_id":"para_795"},{"text":"newly acquired information was in error because \"[t]he FDA -- at","paragraph_id":"para_796"},{"text":"most -- knew about the vasodilatory 13 effects of CGRP\" but","paragraph_id":"para_797"},{"text":"13 Vasodilatory refers to dilation of the blood vessels. See","paragraph_id":"para_798"},{"text":"Vasodilator, Stedman's Medical Dictionary, supra, at 2092.","paragraph_id":"para_799"},{"text":"- 33 -","paragraph_id":"para_800"},{"text":"\"conduct[ed] no analysis of the specific risks of CGRP-inhibition","paragraph_id":"para_801"},{"text":"in the brain and the non-vasodilatory roles of CGRP.\"","paragraph_id":"para_802"},{"text":"Turning to the nine articles submitted by Warner, we","paragraph_id":"para_803"},{"text":"first set aside the 2018 Zhao14 and the 2018 Szeto15 literature","paragraph_id":"para_804"},{"text":"reviews. The Zhao literature review suggests that remote ischemic","paragraph_id":"para_805"},{"text":"postconditioning may offer cerebral protection for stroke","paragraph_id":"para_806"},{"text":"patients; however, it mentions neither CGRP nor CGRP antagonism.","paragraph_id":"para_807"},{"text":"Meanwhile, the Szeto literature review references CGRP only in","paragraph_id":"para_808"},{"text":"passing to state that as one of several vasodilators, CGRP","paragraph_id":"para_809"},{"text":"increases KATP channel activity. But the literature review does","paragraph_id":"para_810"},{"text":"not otherwise opine on the role of CGRP. And Warner does not","paragraph_id":"para_811"},{"text":"explain how such a singular, tangential reference would constitute","paragraph_id":"para_812"},{"text":"any type of \"data,\" \"new analyses,\" or \"event[]\" that we can","paragraph_id":"para_813"},{"text":"consider as newly acquired information. 21 C.F.R.","paragraph_id":"para_814"},{"text":"§§ 601.12(f)(6). Nor does Warner provide us with an explanation","paragraph_id":"para_815"},{"text":"that would allow us to reasonably infer that these literature","paragraph_id":"para_816"},{"text":"reviews present risks not previously considered by the FDA.","paragraph_id":"para_817"},{"text":"Without more, we do not consider these articles newly acquired","paragraph_id":"para_818"},{"text":"information for purposes of this appeal.","paragraph_id":"para_819"},{"text":"14 See Jing-Jing Zhao et al., Remote Ischemic","paragraph_id":"para_820"},{"text":"Postconditioning for Ischemic Stroke: A Systematic Review and","paragraph_id":"para_821"},{"text":"Meta-Analysis of Randomized Controlled Trials, 131 Chinese Med. J.","paragraph_id":"para_822"},{"text":"956 (2018).","paragraph_id":"para_823"},{"text":"15 See Vivian Szeto et al., The Role of KATP Channels in","paragraph_id":"para_824"},{"text":"Cerebral Ischemic Stroke and Diabetes, 39 Acta Pharmacologica","paragraph_id":"para_825"},{"text":"Sinica 683 (2018).","paragraph_id":"para_826"},{"text":"- 34 -","paragraph_id":"para_827"},{"text":"That leaves us with seven articles. We can also dispose","paragraph_id":"para_828"},{"text":"of the 2012 Kokkoris literature review16 as not constituting newly","paragraph_id":"para_829"},{"text":"acquired information for purposes of this appeal. That review","paragraph_id":"para_830"},{"text":"discusses some possible neuroprotective mechanisms of CGRP during","paragraph_id":"para_831"},{"text":"subarachnoid hemorrhage.17 However, the FDA specifically reviewed","paragraph_id":"para_832"},{"text":"a study finding that \"elevated CGRP levels may prevent focal","paragraph_id":"para_833"},{"text":"cerebral ischemia following subarachnoid hemorrhage.\" Like the","paragraph_id":"para_834"},{"text":"district court, we therefore lack any basis for determining that","paragraph_id":"para_835"},{"text":"this article \"reveal[s] risks of a different type or greater","paragraph_id":"para_836"},{"text":"severity or frequency than previously included in submissions to","paragraph_id":"para_837"},{"text":"[the] FDA.\" Warner, 2025 WL 490720, at *10 (citation modified).","paragraph_id":"para_838"},{"text":"This leaves us with six articles, including the 2018 Guo","paragraph_id":"para_839"},{"text":"study,18 which administered a CGRP antagonist to rats undergoing","paragraph_id":"para_840"},{"text":"myocardial ischemia. That study found that CGRP influences","paragraph_id":"para_841"},{"text":"myocardial infarct size and \"may protect [such] cardiomyocytes via","paragraph_id":"para_842"},{"text":"homeostasis of mitochondrial function.\" But, as we discuss in","paragraph_id":"para_843"},{"text":"16 See Stelios Kokkoris et al., Role of Calcitonin Gene-","paragraph_id":"para_844"},{"text":"Related Peptide in Cerebral Vasospasm, and As a Therapeutic","paragraph_id":"para_845"},{"text":"Approach to Subarachnoid Hemorrhage, 3 Frontiers Endocrinology 135","paragraph_id":"para_846"},{"text":"(2012).","paragraph_id":"para_847"},{"text":"17 A subarachnoid hemorrhage is a bleed within the","paragraph_id":"para_848"},{"text":"subarachnoid space, which lies between two of the three membranes","paragraph_id":"para_849"},{"text":"that cover the central nervous system. See Subarachnoid","paragraph_id":"para_850"},{"text":"Hemorrhage, Stedman's Medical Dictionary, supra, at 873; Arachnoid","paragraph_id":"para_851"},{"text":"Mater, Stedman's Medical Dictionary, supra, at 127.","paragraph_id":"para_852"},{"text":"18 See Zheng Guo et al., Independent Roles of CGRP in","paragraph_id":"para_853"},{"text":"Cardioprotection and Hemodynamic Regulation in Ischemic","paragraph_id":"para_854"},{"text":"Postconditioning, 828 Eur. J. Pharmacology 18 (2018).","paragraph_id":"para_855"},{"text":"- 35 -","paragraph_id":"para_856"},{"text":"section III.B.3 of this opinion, a manufacturer cannot employ the","paragraph_id":"para_857"},{"text":"CBE procedure to change the warnings or precautions on a label","paragraph_id":"para_858"},{"text":"without also meeting the causal association standard set forth in","paragraph_id":"para_859"},{"text":"21 C.F.R. § 201.57(c). Warner does not address how the study's","paragraph_id":"para_860"},{"text":"findings -- pertaining only to the effects of CGRP on the","paragraph_id":"para_861"},{"text":"mitochondrial membrane as it relates to cells in the heart, rather","paragraph_id":"para_862"},{"text":"than the brain -- would have any causal relationship with the","paragraph_id":"para_863"},{"text":"cerebral outcomes suffered by Lucas. So we need not address it","paragraph_id":"para_864"},{"text":"any further.","paragraph_id":"para_865"},{"text":"The 2018 Basalay literature review 19 discusses the","paragraph_id":"para_866"},{"text":"neuroprotective qualities of remote ischemic conditioning20 and","paragraph_id":"para_867"},{"text":"suggests that the mechanisms of ischemic conditioning may differ","paragraph_id":"para_868"},{"text":"between the heart and brain. The review makes only passing","paragraph_id":"para_869"},{"text":"reference to CGRP's function in the brain. But the FDA at multiple","paragraph_id":"para_870"},{"text":"points considered the theoretical concern of CGRP antagonism and","paragraph_id":"para_871"},{"text":"19 See Marina V. Basalay et al., Neural Mechanisms in Remote","paragraph_id":"para_872"},{"text":"Ischaemic Conditioning in the Heart and Brain: Mechanistic and","paragraph_id":"para_873"},{"text":"Translational Aspects, 113 Basic Rsch. Cardiology 25 (2018).","paragraph_id":"para_874"},{"text":"20 Ischemia is the \"[l]ocal loss of blood supply due to a","paragraph_id":"para_875"},{"text":"mechanical obstruction . . . of the blood vessel.\" Ischemia,","paragraph_id":"para_876"},{"text":"Stedman's Medical Dictionary, supra, at 1001. As the district","paragraph_id":"para_877"},{"text":"court explained, \"[i]schemic conditioning involves intentionally","paragraph_id":"para_878"},{"text":"exposing tissue or organs to brief periods of ischemia (i.e.,","paragraph_id":"para_879"},{"text":"reduced blood flow and oxygenation), followed by reperfusion","paragraph_id":"para_880"},{"text":"(i.e., restoration of blood flow to the tissue or organ), to","paragraph_id":"para_881"},{"text":"protect against organ damage following a major ischemic event,","paragraph_id":"para_882"},{"text":"such as a heart attack or stroke.\" Warner, 2025 WL 490720, at *9.","paragraph_id":"para_883"},{"text":"- 36 -","paragraph_id":"para_884"},{"text":"its \"potential . . . to adversely impact the beneficial effects of","paragraph_id":"para_885"},{"text":"ischemic preconditioning,\" including in reviews by the Division of","paragraph_id":"para_886"},{"text":"Neurology Products and the Division of Cardiovascular and Renal","paragraph_id":"para_887"},{"text":"Products. Indeed, the DNP noted that \"[t]here are numerous","paragraph_id":"para_888"},{"text":"publications on preconditioning and its potential beneficial","paragraph_id":"para_889"},{"text":"effects, not only on the cardiovascular system,\" but also on the","paragraph_id":"para_890"},{"text":"\"neurological\" system. Citing in part to a publication concerning","paragraph_id":"para_891"},{"text":"the neuroprotective effects of ischemic preconditioning, the DNP","paragraph_id":"para_892"},{"text":"noted that \"[s]several publications . . . point out that multiple","paragraph_id":"para_893"},{"text":"endogenous factors may be involved in the complex process(es)","paragraph_id":"para_894"},{"text":"underlying the phenomenon and the current limited understanding of","paragraph_id":"para_895"},{"text":"the role of any one of these factors, including CGRP.\" In light","paragraph_id":"para_896"},{"text":"of these considerations by the FDA, we are certain that the Basalay","paragraph_id":"para_897"},{"text":"literature review does not plausibly \"reveal risks of a different","paragraph_id":"para_898"},{"text":"type or greater severity or frequency than previously included in","paragraph_id":"para_899"},{"text":"submissions to [the] FDA.\" 21 C.F.R. §§ 601.12(f)(6), 314.3(b).","paragraph_id":"para_900"},{"text":"The 2007 Rehni study21 presents a close call. This study","paragraph_id":"para_901"},{"text":"found that the administration of a CGRP antagonist to mice","paragraph_id":"para_902"},{"text":"\"attenuated\" \"the neuroprotective effect of remote mesenteric","paragraph_id":"para_903"},{"text":"ischaemic preconditioning.\"22 As we explained regarding the 2018","paragraph_id":"para_904"},{"text":"21 See Ashish K. Rehni et al., Possible Involvement of","paragraph_id":"para_905"},{"text":"Insulin, Endogenous Opioids and Calcitonin Gene-Related Peptide in","paragraph_id":"para_906"},{"text":"Remote Ischaemic Preconditioning of Brain, 127 Pharm. Soc'y of","paragraph_id":"para_907"},{"text":"Japan 1013 (2007).","paragraph_id":"para_908"},{"text":"22 Rehni noted that cerebral ischemia in particular \" has been","paragraph_id":"para_909"},{"text":"reported to impair short-term memory\" and \" sensorimotor ability.\"","paragraph_id":"para_910"},{"text":"- 37 -","paragraph_id":"para_911"},{"text":"Basalay review, the FDA was well-aware of the \"theoretical concern\"","paragraph_id":"para_912"},{"text":"of CGRP antagonism and its \"potential . . . to adversely impact","paragraph_id":"para_913"},{"text":"the beneficial effects of ischemic preconditioning.\" But the","paragraph_id":"para_914"},{"text":"Rehni study -- at least on this record -- arguably took a step","paragraph_id":"para_915"},{"text":"further by reporting that the introduction of a CGRP receptor","paragraph_id":"para_916"},{"text":"antagonist \"abolished the neuroprotection afforded by remote","paragraph_id":"para_917"},{"text":"mesenteric ischaemic preconditioning.\" According to the study,","paragraph_id":"para_918"},{"text":"\"it may be concluded that remote mesenteric ischaemic","paragraph_id":"para_919"},{"text":"preconditioning exerts neuroprotective effect possibly[] mediated","paragraph_id":"para_920"},{"text":"through the release of . . . [CGRP] with consequent activation of","paragraph_id":"para_921"},{"text":"[its] receptors.\" On this record and given the generous pleading","paragraph_id":"para_922"},{"text":"standard, we cannot be certain that the Rehni study's findings do","paragraph_id":"para_923"},{"text":"not plausibly \"reveal risks of . . . a greater severity . . . than","paragraph_id":"para_924"},{"text":"previously included in submissions to [the] FDA.\" 21 C.F.R.","paragraph_id":"para_925"},{"text":"§ 601.12(f)(6).","paragraph_id":"para_926"},{"text":"That leaves three articles concerning the interactions","paragraph_id":"para_927"},{"text":"between CGRP and the blood-brain barrier.23 In the first, the 2011","paragraph_id":"para_928"},{"text":"However, \"remote mesenteric ischaemic preconditioning has been","paragraph_id":"para_929"},{"text":"observed to prevent ischaemia\" and has also prevented an \"increase","paragraph_id":"para_930"},{"text":"in cerebral infarct size, impairment of short-term memory, [and]","paragraph_id":"para_931"},{"text":"motor incoordination.\"","paragraph_id":"para_932"},{"text":"23 As further defined by the Sorby-Adams literature review","paragraph_id":"para_933"},{"text":"presented by Warner, the blood-brain barrier is a \"semi-permeable","paragraph_id":"para_934"},{"text":"barrier existing between the brain and blood\" that is composed of","paragraph_id":"para_935"},{"text":"\"endothelial cells with tight junctions (TJ), adherens junctions,","paragraph_id":"para_936"},{"text":"astrocytes, pericytes, and the basement membrane,\" which,","paragraph_id":"para_937"},{"text":"together, assist in the barrier's functions of \"supplying the brain","paragraph_id":"para_938"},{"text":"with essential nutrients such as oxygen and glucose, mediating the","paragraph_id":"para_939"},{"text":"efflux of waste products, and facilitating the movement of","paragraph_id":"para_940"},{"text":"- 38 -","paragraph_id":"para_941"},{"text":"Liu study,24 researchers placed rats under stroke conditions and","paragraph_id":"para_942"},{"text":"administered CGRP to one group and saline solution to the other.","paragraph_id":"para_943"},{"text":"The findings suggest that the effects of blood-brain barrier","paragraph_id":"para_944"},{"text":"disruption in the study's rats were not short-lived: \"[Blood-","paragraph_id":"para_945"},{"text":"brain barrier] leakage after ischemia–reperfusion injury in the","paragraph_id":"para_946"},{"text":"rat was continuous and long-lasting, without any closure up to","paragraph_id":"para_947"},{"text":"several weeks.\" The authors found that \"CGRP administration could","paragraph_id":"para_948"},{"text":"reduce\" the permeability of the blood-brain barrier and that it","paragraph_id":"para_949"},{"text":"\"might protect against [blood-brain barrier] disruption after","paragraph_id":"para_950"},{"text":"brain ischemia reperfusion injury by improving the damage of","paragraph_id":"para_951"},{"text":"capillary endothelium cells and enhancing basal membrane.\"","paragraph_id":"para_952"},{"text":"The second of these articles is the 2017 Sorby-Adams","paragraph_id":"para_953"},{"text":"literature review25 -- published three months after Aimovig's BLA","paragraph_id":"para_954"},{"text":"submission.26 This review concerns blood-brain barrier disruption","paragraph_id":"para_955"},{"text":"nutrients and plasma proteins.\" See Annabel J. Sorby-Adams et","paragraph_id":"para_956"},{"text":"al., The Role of Neurogenic Inflammation in Blood-Brain Barrier","paragraph_id":"para_957"},{"text":"Disruption and Development of Cerebral Oedema Following Acute","paragraph_id":"para_958"},{"text":"Central Nervous System (CNS) Injury, 18 Int'l J. Molecular Sci.","paragraph_id":"para_959"},{"text":"1788 (2017).","paragraph_id":"para_960"},{"text":"24 See Zhen Liu et al., Calcitonin Gene-Related Peptide","paragraph_id":"para_961"},{"text":"Prevents Blood-Brain Barrier Injury and Brain Edema Induced by","paragraph_id":"para_962"},{"text":"Focal Cerebral Ischemia Reperfusion, 171 Regul. Peptides 19","paragraph_id":"para_963"},{"text":"(2011).","paragraph_id":"para_964"},{"text":"25 See Sorby-Adams et al., supra.","paragraph_id":"para_965"},{"text":"26 The FDA approved Amgen's BLA for Aimovig in May 2018.","paragraph_id":"para_966"},{"text":"Only the Basalay article was published after that approval.","paragraph_id":"para_967"},{"text":"Indeed, five of the articles -- the Zhai, Sorby-Adams, Zhao, Szeto,","paragraph_id":"para_968"},{"text":"and Guo articles -- were published in the year between Amgen's BLA","paragraph_id":"para_969"},{"text":"submission on May 17, 2017 and the FDA's ultimate approval of the","paragraph_id":"para_970"},{"text":"label on May 17, 2018. And the Rehni, Liu, and Kokkoris articles","paragraph_id":"para_971"},{"text":"- 39 -","paragraph_id":"para_972"},{"text":"following traumatic brain injury (TBI) or stroke. The review","paragraph_id":"para_973"},{"text":"cites, among other studies, the 2011 Liu study and emphasizes that","paragraph_id":"para_974"},{"text":"\"CGRP administered at the onset of reperfusion produced a","paragraph_id":"para_975"},{"text":"significant reduction in infarct volume, [blood-brain barrier]","paragraph_id":"para_976"},{"text":"permeability and cerebral oedema following rodent stroke,\"","paragraph_id":"para_977"},{"text":"suggesting that CGRP plays a role in stabilizing the blood-brain","paragraph_id":"para_978"},{"text":"barrier. The review also discusses how CGRP is involved in","paragraph_id":"para_979"},{"text":"angiogenesis, or the development of new blood vessels. See","paragraph_id":"para_980"},{"text":"Angiogenesis, Stedman's Medical Dictionary 86 (28th ed. 2006).","paragraph_id":"para_981"},{"text":"The third of these articles, the 2018 Zhai study,27 was","paragraph_id":"para_982"},{"text":"published nearly a year after Aimovig's BLA submission and only","paragraph_id":"para_983"},{"text":"one month before the FDA's approval of the Aimovig label. In this","paragraph_id":"para_984"},{"text":"study, researchers compared \"CGRP knockout mice\" -- mice","paragraph_id":"para_985"},{"text":"genetically modified to no longer produce CGRP -- with wild mice","paragraph_id":"para_986"},{"text":"that were administered human CGRP. Researchers then placed the","paragraph_id":"para_987"},{"text":"two groups under conditions of cerebral ischemia by blocking blood","paragraph_id":"para_988"},{"text":"flow in the external carotid artery. The study's findings","paragraph_id":"para_989"},{"text":"indicate that mice that could not produce CGRP exhibited \"increased","paragraph_id":"para_990"},{"text":"blood-brain barrier damage-related factors,\" suggesting that \"CGRP","paragraph_id":"para_991"},{"text":"deficiency leads to greater [blood-brain barrier] damage during","paragraph_id":"para_992"},{"text":"were all published prior to the submission of Aimovig's BLA.","paragraph_id":"para_993"},{"text":"27 See Liuyu Zhai et al., Endogenous Calcitonin Gene-Related","paragraph_id":"para_994"},{"text":"Peptide Suppresses Ischemic Brain Injuries and Progression of","paragraph_id":"para_995"},{"text":"Cognitive Decline, 36 J. Hypertension 876 (2018).","paragraph_id":"para_996"},{"text":"- 40 -","paragraph_id":"para_997"},{"text":"chronic cerebral ischemia.\" And \"[t]he mechanisms underlying","paragraph_id":"para_998"},{"text":"hypoxic–ischemic brain damage include death of neuronal and glial","paragraph_id":"para_999"},{"text":"cells and loss of integrity of the blood–brain barrier.\" The","paragraph_id":"para_1000"},{"text":"authors noted that \"[s]tudies have shown there is a significant","paragraph_id":"para_1001"},{"text":"association between [blood-brain barrier] dysfunction and vascular","paragraph_id":"para_1002"},{"text":"cognitive impairment.\" Thus, cognitive disorder \"may be in part","paragraph_id":"para_1003"},{"text":"attributable to damage to the [blood-brain barrier].\" As a result","paragraph_id":"para_1004"},{"text":"of not being able to produce CGRP, the knockout mice also suffered","paragraph_id":"para_1005"},{"text":"from \"more extensive neuronal cell damage\"; \"more extensive","paragraph_id":"para_1006"},{"text":"irreversible cell damage\";28 \"delayed recovery of cerebral blood","paragraph_id":"para_1007"},{"text":"flow\"; higher levels of \"demyelination\" 29 and \"astrocyte","paragraph_id":"para_1008"},{"text":"activation\";30 a reduction in \"compensative capillary formation\";","paragraph_id":"para_1009"},{"text":"28 The study also found that CGRP-deficient mice had","paragraph_id":"para_1010"},{"text":"\"significantly increased expression of adrenomedullin in the","paragraph_id":"para_1011"},{"text":"cerebral cortex,\" which \"may reflect compensation for the CGRP","paragraph_id":"para_1012"},{"text":"deficiency,\" though we do not find that the study concluded that","paragraph_id":"para_1013"},{"text":"such possible compensation outweighed or prevented the","paragraph_id":"para_1014"},{"text":"irreversible cell damage.","paragraph_id":"para_1015"},{"text":"29 Demyelination is the \"[l]oss of myelin, with preservation","paragraph_id":"para_1016"},{"text":"of the axons or fiber tracts.\" Demyelination, Stedman's Medical","paragraph_id":"para_1017"},{"text":"Dictionary, supra, at 509. The myelin sheath is an \"envelope\"","paragraph_id":"para_1018"},{"text":"that \"surround[s] most axons,\" Myelin Sheath, Stedman's Medical","paragraph_id":"para_1019"},{"text":"Dictionary, supra, at 1758–59, which are the parts of nerve cells","paragraph_id":"para_1020"},{"text":"that \"conduct[] nervous impulses away from the cell body,\" Axon,","paragraph_id":"para_1021"},{"text":"Stedman's Medical Dictionary, supra, at 191.","paragraph_id":"para_1022"},{"text":"30 An astrocyte is \" [o]ne of the large neuroglia cells of","paragraph_id":"para_1023"},{"text":"nervous tissue.\" Astrocyte, Stedman's Medical Dictionary, supra,","paragraph_id":"para_1024"},{"text":"at 171. Neuroglia are \"[n]onneuronal cellular elements of the","paragraph_id":"para_1025"},{"text":"central and peripheral nervous system\" that have \"important","paragraph_id":"para_1026"},{"text":"metabolic functions\" because they are \"invariably interposed","paragraph_id":"para_1027"},{"text":"between neurons and the blood vessels supplying the nervous","paragraph_id":"para_1028"},{"text":"system.\" Neuroglia, Stedman's Medical Dictionary, supra, at 1310.","paragraph_id":"para_1029"},{"text":"- 41 -","paragraph_id":"para_1030"},{"text":"and \"more severe disturbance of memory.\" The authors concluded","paragraph_id":"para_1031"},{"text":"that, in addition to stabilizing the blood-brain barrier, \"CGRP","paragraph_id":"para_1032"},{"text":"may also suppress inflammation and oxidative stress, promote","paragraph_id":"para_1033"},{"text":"angiogenesis and exert a direct antiapoptotic effect.\"31","paragraph_id":"para_1034"},{"text":"The district court found that none of these four articles","paragraph_id":"para_1035"},{"text":"constituted newly acquired information. As to the Rehni and Liu","paragraph_id":"para_1036"},{"text":"studies, the district court concluded that \"[t]he DCRP [had]","paragraph_id":"para_1037"},{"text":"reviewed 'the world's literature' before preparing its report on","paragraph_id":"para_1038"},{"text":"the theoretical risks associated with CGRP antagonism,\" and so","paragraph_id":"para_1039"},{"text":"\"[i]t is not plausible that articles bearing on that subject,","paragraph_id":"para_1040"},{"text":"published at least four years before the DCRP began preparing its","paragraph_id":"para_1041"},{"text":"report, 'reveal risks of a different type or greater severity or","paragraph_id":"para_1042"},{"text":"frequency than previously included in submissions to FDA.'\"","paragraph_id":"para_1043"},{"text":"Warner, 2025 WL 490720, at *10. The district court also concluded","paragraph_id":"para_1044"},{"text":"that the Sorby-Adams literature review could not plausibly","paragraph_id":"para_1045"},{"text":"constitute newly acquired information because that review relied","paragraph_id":"para_1046"},{"text":"upon the Liu study. Id. As to the 2018 Zhai study, the district","paragraph_id":"para_1047"},{"text":"court found this study \"too attenuated from Warner's claim to","paragraph_id":"para_1048"},{"text":"plausibly constitute newly acquired information.\" Id. at *11. As","paragraph_id":"para_1049"},{"text":"part of its reasoning, the district court determined that \"the","paragraph_id":"para_1050"},{"text":"study does not address whether its findings about mice with a CGRP","paragraph_id":"para_1051"},{"text":"deficiency generalize to drugs, like Aimovig, that are CGRP","paragraph_id":"para_1052"},{"text":"31 Apoptosis is the process of \"[p]rogrammed cell death.\"","paragraph_id":"para_1053"},{"text":"Apoptosis, Stedman's Medical Dictionary, supra, at 121.","paragraph_id":"para_1054"},{"text":"- 42 -","paragraph_id":"para_1055"},{"text":"antagonists\" and that Warner had not cited, nor had the court","paragraph_id":"para_1056"},{"text":"uncovered, \"any precedent for treating a single animal study not","paragraph_id":"para_1057"},{"text":"involving the manufacturer's drug as newly acquired information.\"","paragraph_id":"para_1058"},{"text":"Id.","paragraph_id":"para_1059"},{"text":"We are inclined to read the record as the district court","paragraph_id":"para_1060"},{"text":"did. But at the same time -- and without the benefit of any expert","paragraph_id":"para_1061"},{"text":"testimony -- we find that inclination falls short of allowing us","paragraph_id":"para_1062"},{"text":"to conclude with certainty that the CBE procedure would have","paragraph_id":"para_1063"},{"text":"failed. See Burt, 84 F.4th at 50 (requiring an affirmative defense","paragraph_id":"para_1064"},{"text":"be \"establish[ed] . . . with certitude\" in order to uphold a","paragraph_id":"para_1065"},{"text":"court's grant of a motion to dismiss based on that defense","paragraph_id":"para_1066"},{"text":"(citation modified)).","paragraph_id":"para_1067"},{"text":"For example, we are not convinced by the district court's","paragraph_id":"para_1068"},{"text":"assumption that the FDA must have reviewed the Rehni and Liu","paragraph_id":"para_1069"},{"text":"studies as part of its review of the \"world's literature.\" The","paragraph_id":"para_1070"},{"text":"FDA's review of the \"world's literature\" was limited to \"published","paragraph_id":"para_1071"},{"text":"evidence concerning a theoretical risk conferred by [CGRP]","paragraph_id":"para_1072"},{"text":"antagonism via any mechanism of worsened ischemia due to impairment","paragraph_id":"para_1073"},{"text":"of compensatory vasodilation in the setting of ischemic vascular","paragraph_id":"para_1074"},{"text":"events.\" Nothing in the record suggests that the FDA reviewed the","paragraph_id":"para_1075"},{"text":"\"world's literature\" concerning the possible role of CGRP's effect","paragraph_id":"para_1076"},{"text":"on the blood-brain barrier or its possible neuroprotective effects","paragraph_id":"para_1077"},{"text":"outside of vasodilation -- or, for that matter, the \"attenuat[ing]\"","paragraph_id":"para_1078"},{"text":"impact of CGRP antagonism as it relates to the neuroprotective","paragraph_id":"para_1079"},{"text":"- 43 -","paragraph_id":"para_1080"},{"text":"effects of ischemic preconditioning.32 We also find no evidence","paragraph_id":"para_1081"},{"text":"in the record as it now stands that the Rehni study, Liu study,","paragraph_id":"para_1082"},{"text":"Zhai study, or the Sorby-Adams literature review were brought to","paragraph_id":"para_1083"},{"text":"the FDA's attention. Nor does Amgen point us toward any analysis","paragraph_id":"para_1084"},{"text":"by the FDA of CGRP's effect on the blood-brain barrier in the","paragraph_id":"para_1085"},{"text":"setting of cerebral injury.33 At this stage in the proceedings,","paragraph_id":"para_1086"},{"text":"we cannot draw a determinative inference against Warner that the","paragraph_id":"para_1087"},{"text":"FDA's world-literature review included studies on CGRP's role in","paragraph_id":"para_1088"},{"text":"protecting or stabilizing the blood-brain barrier when Amgen","paragraph_id":"para_1089"},{"text":"itself points to no language or analysis from the FDA suggesting","paragraph_id":"para_1090"},{"text":"as much.","paragraph_id":"para_1091"},{"text":"Contrary to Amgen's assertions, the publication dates of","paragraph_id":"para_1092"},{"text":"these articles are also not dispositive of whether a study","paragraph_id":"para_1093"},{"text":"32 This is not to say that the FDA was not at all aware of","paragraph_id":"para_1094"},{"text":"some possible neuroprotective effects of CGRP in the setting of","paragraph_id":"para_1095"},{"text":"cerebral injury. Indeed, and as we noted previously, the FDA had","paragraph_id":"para_1096"},{"text":"cited to a study regarding the possible protective effects of","paragraph_id":"para_1097"},{"text":"elevated CGRP levels following subarachnoid hemorrhage. But Amgen","paragraph_id":"para_1098"},{"text":"does not reference this study in its briefing or provide the study","paragraph_id":"para_1099"},{"text":"in the record for our review. Without anything more, we cannot","paragraph_id":"para_1100"},{"text":"assess whether this study relates to neuroprotective effects of","paragraph_id":"para_1101"},{"text":"CGRP outside of its vasodilatory role. Such technical matters","paragraph_id":"para_1102"},{"text":"serve as a reminder that at this stage in the proceedings, our","paragraph_id":"para_1103"},{"text":"role is not to determine whether the studies and articles submitted","paragraph_id":"para_1104"},{"text":"by Warner constitute newly acquired information; rather, we ask","paragraph_id":"para_1105"},{"text":"only whether we can say with certitude that they do not.","paragraph_id":"para_1106"},{"text":"33 Indeed, as Aimovig had only been studied in healthy","paragraph_id":"para_1107"},{"text":"populations without such histories, the FDA was under the","paragraph_id":"para_1108"},{"text":"impression that only a \"very small fraction\" of Aimovig could cross","paragraph_id":"para_1109"},{"text":"the blood-brain barrier. This reference was included in passing","paragraph_id":"para_1110"},{"text":"and only as a reason for the Controlled Substance Staff at the FDA","paragraph_id":"para_1111"},{"text":"declining to review Aimovig's BLA submission.","paragraph_id":"para_1112"},{"text":"- 44 -","paragraph_id":"para_1113"},{"text":"constitutes newly acquired information. A study published prior","paragraph_id":"para_1114"},{"text":"to the approval of a drug or biologic's label may still qualify as","paragraph_id":"para_1115"},{"text":"newly acquired information if it had not been \"previously","paragraph_id":"para_1116"},{"text":"submitted\" to the FDA. Celexa, 779 F.3d at 42 (quoting 21 C.F.R.","paragraph_id":"para_1117"},{"text":"§ 314.3(b)); see also 21 C.F.R. § 601.12(f)(6) (parallel","paragraph_id":"para_1118"},{"text":"regulation for biologics). And, as the Supreme Court has stated,","paragraph_id":"para_1119"},{"text":"newly acquired information \"also encompasses 'new analyses of","paragraph_id":"para_1120"},{"text":"previously submitted data'\" to \"account[] for the fact that risk","paragraph_id":"para_1121"},{"text":"information accumulates over time and that the same data may take","paragraph_id":"para_1122"},{"text":"on a different meaning in light of subsequent developments.\"","paragraph_id":"para_1123"},{"text":"Wyeth, 555 U.S. at 569 (quoting Supplemental Applications","paragraph_id":"para_1124"},{"text":"Proposing Labeling Changes for Approved Drugs, Biologics, and","paragraph_id":"para_1125"},{"text":"Medical Devices, 73 Fed. Reg. at 49604).","paragraph_id":"para_1126"},{"text":"Nor are we certain that the Zhai study fails to qualify","paragraph_id":"para_1127"},{"text":"as newly acquired information because the article does not discuss","paragraph_id":"para_1128"},{"text":"whether its findings of CGRP deficiency in mice can be generalized","paragraph_id":"para_1129"},{"text":"to CGRP antagonism in humans. Although labeling requirements for","paragraph_id":"para_1130"},{"text":"human prescription drugs and biologic products provide that \"[t]he","paragraph_id":"para_1131"},{"text":"labeling must be based whenever possible on data derived from human","paragraph_id":"para_1132"},{"text":"experience,\" conclusions based on \"animal data\" that are","paragraph_id":"para_1133"},{"text":"\"necessary for safe and effective use of the drug in humans must","paragraph_id":"para_1134"},{"text":"[also] be identified as such and included with human data in the","paragraph_id":"para_1135"},{"text":"appropriate section of the labeling.\" 21 C.F.R. § 201.56(a)(3).","paragraph_id":"para_1136"},{"text":"Indeed, the parties agree that \"FDA guidance permits theoretical","paragraph_id":"para_1137"},{"text":"- 45 -","paragraph_id":"para_1138"},{"text":"warnings 'if the animal data raises substantial concern about the","paragraph_id":"para_1139"},{"text":"potential for . . . adverse reaction in humans.'\" As Aimovig was","paragraph_id":"para_1140"},{"text":"the first drug of its kind to be reviewed by the FDA, the FDA","paragraph_id":"para_1141"},{"text":"relied largely on animal studies, including studies on canines and","paragraph_id":"para_1142"},{"text":"rats. And the FDA did not restrict its review of studies to those","paragraph_id":"para_1143"},{"text":"administering Aimovig or a similar CGRP antagonist. For example,","paragraph_id":"para_1144"},{"text":"when the FDA considered the \"world's literature,\" it reviewed two","paragraph_id":"para_1145"},{"text":"canine studies where \"[n]o [CGRP] antagonist was administered.\"","paragraph_id":"para_1146"},{"text":"The FDA also considered rat studies, including a study on diabetic","paragraph_id":"para_1147"},{"text":"rat hearts where researchers did not administer a CGRP antagonist,","paragraph_id":"para_1148"},{"text":"as well as studies discussing the use of CGRP knockout mice. We","paragraph_id":"para_1149"},{"text":"see no clear reason why we should certainly exclude animal studies","paragraph_id":"para_1150"},{"text":"related to CGRP in our assessment of newly acquired information if","paragraph_id":"para_1151"},{"text":"the FDA did not do the same.","paragraph_id":"para_1152"},{"text":"Viewed together, the Rehni study, the Liu study, the","paragraph_id":"para_1153"},{"text":"Sorby-Adams literature review, and the Zhai study plausibly","paragraph_id":"para_1154"},{"text":"suggest risks of CGRP antagonism outside of its effect in","paragraph_id":"para_1155"},{"text":"regulating blood flow in the body. The Rehni study seems to","paragraph_id":"para_1156"},{"text":"indicate that the neuroprotective effects of ischemic","paragraph_id":"para_1157"},{"text":"preconditioning may be \"attenuated\" or \"abolished\" by a CGRP","paragraph_id":"para_1158"},{"text":"antagonist. Meanwhile, the Liu, Sorby-Adams, and Zhai articles","paragraph_id":"para_1159"},{"text":"seem to indicate that CGRP deficiency is related to greater blood-","paragraph_id":"para_1160"},{"text":"brain barrier damage in the setting of cerebral injury as well as","paragraph_id":"para_1161"},{"text":"irreversible cell death in the brain and disturbances in memory.","paragraph_id":"para_1162"},{"text":"- 46 -","paragraph_id":"para_1163"},{"text":"Based on the record before us, we cannot say with certitude that","paragraph_id":"para_1164"},{"text":"Warner has failed to plausibly allege a \"reasonable basis\" to view","paragraph_id":"para_1165"},{"text":"the articles by Rehni, Liu, Zhai, and Sorby-Adams collectively as","paragraph_id":"para_1166"},{"text":"\"reveal[ing] risks of a different type or greater severity or","paragraph_id":"para_1167"},{"text":"frequency than previously included in submissions to [the] FDA.\"","paragraph_id":"para_1168"},{"text":"Zofran, 57 F.4th at 337 (quoting 21 C.F.R. § 314.3(b)); see also","paragraph_id":"para_1169"},{"text":"21 C.F.R. § 601.12(f)(6) (parallel regulation for biologics).","paragraph_id":"para_1170"},{"text":"2.","paragraph_id":"para_1171"},{"text":"We turn now to the second prong of our CBE inquiry, which","paragraph_id":"para_1172"},{"text":"requires Warner to allege facts plausibly showing a reasonable","paragraph_id":"para_1173"},{"text":"basis for establishing that the proposed change is \"for the purpose","paragraph_id":"para_1174"},{"text":"of accomplishing\" one of five permissible objectives under the CBE","paragraph_id":"para_1175"},{"text":"procedure.34 Celexa, 779 F.3d at 37. Our discussion here is","paragraph_id":"para_1176"},{"text":"34 A manufacturer may use the CBE procedure to supplement a","paragraph_id":"para_1177"},{"text":"label \"to accomplish any of the following\":","paragraph_id":"para_1178"},{"text":"(A) To add or strengthen a contraindication,","paragraph_id":"para_1179"},{"text":"warning, precaution, or adverse reaction for","paragraph_id":"para_1180"},{"text":"which the evidence of a causal association","paragraph_id":"para_1181"},{"text":"satisfies the standard for inclusion in the","paragraph_id":"para_1182"},{"text":"labeling under § 201.57(c) of this chapter;","paragraph_id":"para_1183"},{"text":"(B) To add or strengthen a statement about","paragraph_id":"para_1184"},{"text":"abuse, dependence, psychological effect, or","paragraph_id":"para_1185"},{"text":"overdosage;","paragraph_id":"para_1186"},{"text":"(C) To add or strengthen an instruction about","paragraph_id":"para_1187"},{"text":"dosage and administration that is intended to","paragraph_id":"para_1188"},{"text":"increase the safety of the use of the product;","paragraph_id":"para_1189"},{"text":"and","paragraph_id":"para_1190"},{"text":"(D) To delete false, misleading, or","paragraph_id":"para_1191"},{"text":"unsupported indications for use or claims for","paragraph_id":"para_1192"},{"text":"effectiveness.","paragraph_id":"para_1193"},{"text":"- 47 -","paragraph_id":"para_1194"},{"text":"brief, as the parties do not dispute that Warner's proposed changes","paragraph_id":"para_1195"},{"text":"if adopted would serve \"[t]o add or strengthen\" a \"warning,","paragraph_id":"para_1196"},{"text":"precaution, or adverse reaction\" on Aimovig's label. 21 C.F.R.","paragraph_id":"para_1197"},{"text":"§ 601.12(f)(2)(i)(A). \"Warnings and precautions\" include","paragraph_id":"para_1198"},{"text":"\"clinically significant adverse reactions,\" as well as \"potential","paragraph_id":"para_1199"},{"text":"safety hazards (including those that are expected for the","paragraph_id":"para_1200"},{"text":"pharmacological class or those resulting from drug/drug","paragraph_id":"para_1201"},{"text":"interactions).\" Id. § 201.57(c)(6)(i). Meanwhile, an \"adverse","paragraph_id":"para_1202"},{"text":"reaction\" is defined as \"an undesirable effect, reasonably","paragraph_id":"para_1203"},{"text":"associated with use of a drug, that may occur as part of the","paragraph_id":"para_1204"},{"text":"pharmacological action of the drug or may be unpredictable in its","paragraph_id":"para_1205"},{"text":"occurrence.\" Id. § 201.57(c)(7) (emphases added). At this stage","paragraph_id":"para_1206"},{"text":"in the proceedings, based on the facts presented by Warner in the","paragraph_id":"para_1207"},{"text":"Liu, Sorby-Adams, and Zhai articles, we cannot say with certainty","paragraph_id":"para_1208"},{"text":"that the labeling changes Warner proposes would not serve the","paragraph_id":"para_1209"},{"text":"purpose of \"add[ing] or strengthen[ing]\" the \"warning[s],","paragraph_id":"para_1210"},{"text":"precaution[s], or adverse reaction[s]\" on Aimovig's label. Id.","paragraph_id":"para_1211"},{"text":"§ 601.12(f)(2)(i)(A).","paragraph_id":"para_1212"},{"text":"(E) Any labeling change normally requiring a","paragraph_id":"para_1213"},{"text":"supplement submission and approval prior to","paragraph_id":"para_1214"},{"text":"distribution of the product that FDA","paragraph_id":"para_1215"},{"text":"specifically requests be submitted under this","paragraph_id":"para_1216"},{"text":"provision.","paragraph_id":"para_1217"},{"text":"21 C.F.R. § 601.12(f)(2)(i)(A)-(E).","paragraph_id":"para_1218"},{"text":"- 48 -","paragraph_id":"para_1219"},{"text":"3.","paragraph_id":"para_1220"},{"text":"Finally, we turn to the issue of causal association. We","paragraph_id":"para_1221"},{"text":"similarly treat this issue as a question of law based on the record","paragraph_id":"para_1222"},{"text":"as it now stands, noting that many of the factual questions in our","paragraph_id":"para_1223"},{"text":"preemption analysis are \"subsumed within an already tightly","paragraph_id":"para_1224"},{"text":"circumscribed legal analysis.\" Albrecht, 587 U.S. at 317.","paragraph_id":"para_1225"},{"text":"Both the \"warnings and precautions\" and \"adverse","paragraph_id":"para_1226"},{"text":"reactions\" sections of a label have their own distinct causal","paragraph_id":"para_1227"},{"text":"association requirements. For \"warnings and precautions,\" a","paragraph_id":"para_1228"},{"text":"manufacturer \"must\" revise the label \"as soon as there is","paragraph_id":"para_1229"},{"text":"reasonable evidence of a causal association with a drug.\" 21","paragraph_id":"para_1230"},{"text":"C.F.R. § 201.57(c)(6)(i) (emphasis added). On the other hand, to","paragraph_id":"para_1231"},{"text":"add an adverse reaction to the label, the manufacturer need only","paragraph_id":"para_1232"},{"text":"have \"some basis to believe there is a causal relationship between","paragraph_id":"para_1233"},{"text":"the drug and the occurrence of the adverse event.\" Id.","paragraph_id":"para_1234"},{"text":"§ 201.57(c)(7) (emphasis added). But in either context, the","paragraph_id":"para_1235"},{"text":"requirement of a causal association is not \"intended to suggest","paragraph_id":"para_1236"},{"text":"that there is a mathematically precise distinction between whether","paragraph_id":"para_1237"},{"text":"there is, or is not, sufficient evidence of a causal relation","paragraph_id":"para_1238"},{"text":"between a drug and an adverse effect.\" Supplemental Applications","paragraph_id":"para_1239"},{"text":"Proposing Labeling Changes for Approved Drugs, Biologics, and","paragraph_id":"para_1240"},{"text":"Medical Devices, 73 Fed. Reg. at 49604. Indeed, because","paragraph_id":"para_1241"},{"text":"\"causation need not have been 'definitely established' for a","paragraph_id":"para_1242"},{"text":"- 49 -","paragraph_id":"para_1243"},{"text":"warning to be required,\" the \"standard [can] be met by a wide range","paragraph_id":"para_1244"},{"text":"of evidence.\" Id. (quoting 21 C.F.R. § 201.57(c)(6)(i)).","paragraph_id":"para_1245"},{"text":"Because the district court hinged its futility finding","paragraph_id":"para_1246"},{"text":"primarily on its conclusion that the articles Warner provided did","paragraph_id":"para_1247"},{"text":"not constitute newly acquired information, it understandably","paragraph_id":"para_1248"},{"text":"dedicated only a few sentences to the causal association prong of","paragraph_id":"para_1249"},{"text":"the analysis, declaring that \"none of the articles link Aimovig or","paragraph_id":"para_1250"},{"text":"any other CGRP-blocking drug to an adverse event or risk.\" Warner,","paragraph_id":"para_1251"},{"text":"2025 WL 490720, at *9. On appeal, the parties disagree as to the","paragraph_id":"para_1252"},{"text":"specific causal association required in this case. Amgen suggests","paragraph_id":"para_1253"},{"text":"that Warner must show a \"plausible connection between Aimovig and","paragraph_id":"para_1254"},{"text":"an increased risk of seizures in people with an AVM or a history","paragraph_id":"para_1255"},{"text":"of seizures\" like Lucas. Warner insists she \"does not need . . .","paragraph_id":"para_1256"},{"text":"to show that Aimovig was associated with an increased risk of","paragraph_id":"para_1257"},{"text":"seizures.\" Rather, she asserts that the newly acquired","paragraph_id":"para_1258"},{"text":"information \"establishes that Aimovig contributed to triggering or","paragraph_id":"para_1259"},{"text":"worsening the effects of Lucas's seizure by, for example, weakening","paragraph_id":"para_1260"},{"text":"his blood-brain barrier,\" and thus \"[s]he need only allege","paragraph_id":"para_1261"},{"text":"Aimovig's association with damage that Lucas experienced, such as","paragraph_id":"para_1262"},{"text":"worsened outcomes following cerebral injury.\"35 (Emphasis added).","paragraph_id":"para_1263"},{"text":"35 At oral argument, Amgen contended that Warner's theory was","paragraph_id":"para_1264"},{"text":"premised only on Aimovig causing seizures, and thus Warner had","paragraph_id":"para_1265"},{"text":"waived any claim \"that CGRP was somehow protective and that","paragraph_id":"para_1266"},{"text":"protective ability was lost from taking Aimovig.\" We disagree.","paragraph_id":"para_1267"},{"text":"At the motion hearing before the district court, Warner argued","paragraph_id":"para_1268"},{"text":"that \"evidence in the record\" explained \"that part of Lucas's","paragraph_id":"para_1269"},{"text":"- 50 -","paragraph_id":"para_1270"},{"text":"We agree with Warner. At this stage in the proceedings,","paragraph_id":"para_1271"},{"text":"expert testimony has not yet established the exact causal chain","paragraph_id":"para_1272"},{"text":"between CGRP inhibition and each symptom suffered by Lucas. And","paragraph_id":"para_1273"},{"text":"because \"precise knowledge of the chain of events . . . may often","paragraph_id":"para_1274"},{"text":"be unavailable to a plaintiff\" at the motion to dismiss stage, \"we","paragraph_id":"para_1275"},{"text":"take to heart the Supreme Court's call to 'draw on our judicial","paragraph_id":"para_1276"},{"text":"experience and common sense as we make a contextual judgment about","paragraph_id":"para_1277"},{"text":"the sufficiency of the pleadings.'\" Fortuño-Burset, 640 F.3d at","paragraph_id":"para_1278"},{"text":"16 (quoting Sanchez v. Pereira-Castillo, 590 F.3d 31, 48 (1st Cir.","paragraph_id":"para_1279"},{"text":"2009)). In making that judgment based on the record as it now","paragraph_id":"para_1280"},{"text":"stands, we are simply not certain that there is no causal","paragraph_id":"para_1281"},{"text":"relationship between Aimovig and the extent of the injuries Lucas","paragraph_id":"para_1282"},{"text":"experienced.","paragraph_id":"para_1283"},{"text":"We are also not convinced by Amgen's argument that the","paragraph_id":"para_1284"},{"text":"studies \"do not discuss Aimovig\" and thus cannot satisfy the causal","paragraph_id":"para_1285"},{"text":"association standard. We do not read the regulations defining","paragraph_id":"para_1286"},{"text":"warnings and precautions under 21 C.F.R. § 201.57(c)(6)(i) and","paragraph_id":"para_1287"},{"text":"adverse reactions under § 201.57(c)(7) to be so restrictive.","paragraph_id":"para_1288"},{"text":"injury was that the drug might have crossed the blood-brain","paragraph_id":"para_1289"},{"text":"barrier.\" This was consistent with scientific studies, claimed","paragraph_id":"para_1290"},{"text":"Warner, regarding how \"the activation of CGRP in the brain . . .","paragraph_id":"para_1291"},{"text":"protects the blood-brain barrier and . . . protects the brain from","paragraph_id":"para_1292"},{"text":"the effects of stroke.\" And in her motion for leave to amend her","paragraph_id":"para_1293"},{"text":"complaint, Warner again provided that the articles she submitted","paragraph_id":"para_1294"},{"text":"constituted newly acquired information that \"illuminated cerebral","paragraph_id":"para_1295"},{"text":"risks not considered by the FDA,\" including that CGRP \"helps","paragraph_id":"para_1296"},{"text":"stabilize the blood-brain barrier\" and that \"[b]locking CGRP risks","paragraph_id":"para_1297"},{"text":"disrupting this protective mechanism.\"","paragraph_id":"para_1298"},{"text":"- 51 -","paragraph_id":"para_1299"},{"text":"Those regulations define an adverse reaction as an \"undesirable","paragraph_id":"para_1300"},{"text":"effect, reasonably associated with use of a drug, that may occur","paragraph_id":"para_1301"},{"text":"as part of the pharmacological action of the drug or may be","paragraph_id":"para_1302"},{"text":"unpredictable in its occurrence.\" Id. § 201.57(c)(7). Nothing","paragraph_id":"para_1303"},{"text":"in this definition requires that the inclusion of an adverse","paragraph_id":"para_1304"},{"text":"reaction in labeling be based solely on clinical studies of the","paragraph_id":"para_1305"},{"text":"drug itself. And FDA guidance documents provide that \"[t]here are","paragraph_id":"para_1306"},{"text":"circumstances in which an adverse reaction that has not been","paragraph_id":"para_1307"},{"text":"observed with a drug can nonetheless be anticipated to occur.\"","paragraph_id":"para_1308"},{"text":"FDA, Warnings and Precautions, Contraindications, and Boxed","paragraph_id":"para_1309"},{"text":"Warning Sections of Labeling for Human Prescription Drug and","paragraph_id":"para_1310"},{"text":"Biological Products -- Content and Format 5 (2011),","paragraph_id":"para_1311"},{"text":"https://www.fda.gov/media/71866/download [https://perma.cc/634T-","paragraph_id":"para_1312"},{"text":"UDZE].36 That guidance further instructs that the Warnings and","paragraph_id":"para_1313"},{"text":"Precautions section of a drug label should include \"anticipated\"","paragraph_id":"para_1314"},{"text":"adverse reactions if \"[i]t appears likely that the adverse reaction","paragraph_id":"para_1315"},{"text":"will occur with the drug based on what is known about the","paragraph_id":"para_1316"},{"text":"pharmacology, chemistry, or class of the drug\" or if \"[a]nimal","paragraph_id":"para_1317"},{"text":"data raises substantial concern about the potential for occurrence","paragraph_id":"para_1318"},{"text":"36 These documents, though not binding, accord with our","paragraph_id":"para_1319"},{"text":"reading of the regulations regarding biologic labeling and the","paragraph_id":"para_1320"},{"text":"pertinent definitions of \"warnings and precautions\" and \"adverse","paragraph_id":"para_1321"},{"text":"reactions\" under those regulations. We also reject Amgen's","paragraph_id":"para_1322"},{"text":"argument that Warner waived reliance on this guidance by not citing","paragraph_id":"para_1323"},{"text":"it in her supplemental brief to the district court, which was","paragraph_id":"para_1324"},{"text":"limited to five pages in length at the court's direction.","paragraph_id":"para_1325"},{"text":"- 52 -","paragraph_id":"para_1326"},{"text":"of the adverse reaction in humans.\" Id. This guidance is","paragraph_id":"para_1327"},{"text":"relevant to our analysis of the facts in this case. As we have","paragraph_id":"para_1328"},{"text":"previously stated, Aimovig was the first drug of its kind to be","paragraph_id":"para_1329"},{"text":"approved or even reviewed by the FDA, and, as such, the FDA","paragraph_id":"para_1330"},{"text":"reviewed multiple animal studies that did not involve the","paragraph_id":"para_1331"},{"text":"administration of Aimovig or even a CGRP antagonist to study the","paragraph_id":"para_1332"},{"text":"pertinent risks of the drug. We decline to read into the","paragraph_id":"para_1333"},{"text":"regulations a more restrictive lens than that required by FDA","paragraph_id":"para_1334"},{"text":"guidance and the FDA's own review of the biologic in this case.","paragraph_id":"para_1335"},{"text":"In the setting of cerebral ischemia, the four articles","paragraph_id":"para_1336"},{"text":"submitted by Warner can be read as finding an association between","paragraph_id":"para_1337"},{"text":"CGRP antagonism and the dilution of neuroprotective effects from","paragraph_id":"para_1338"},{"text":"ischemic conditioning, as well as a relationship between CGRP","paragraph_id":"para_1339"},{"text":"inhibition and an increase in blood-brain barrier permeability,","paragraph_id":"para_1340"},{"text":"irreversible cell death, and damage to memory function. Based on","paragraph_id":"para_1341"},{"text":"these studies, Warner posits that blocking CGRP in patients with","paragraph_id":"para_1342"},{"text":"Lucas's history would be causally associated with a greater risk","paragraph_id":"para_1343"},{"text":"of cerebral harm in situations \"where CGRP response could be","paragraph_id":"para_1344"},{"text":"protective.\" And, because the blood-brain barrier may be damaged","paragraph_id":"para_1345"},{"text":"in the setting of cerebral injury under conditions such as stroke,","paragraph_id":"para_1346"},{"text":"Warner argues that her submitted articles \"suggest[] that blocking","paragraph_id":"para_1347"},{"text":"CGRP could accelerate the death of oxidatively stressed neurons in","paragraph_id":"para_1348"},{"text":"a variety of neurological emergencies, raising concern that","paragraph_id":"para_1349"},{"text":"- 53 -","paragraph_id":"para_1350"},{"text":"patients on a CGRP-blocker could face more disastrous outcomes in","paragraph_id":"para_1351"},{"text":"the settings of brain injury.\"","paragraph_id":"para_1352"},{"text":"Based on the foregoing and as the record now stands, we","paragraph_id":"para_1353"},{"text":"are not certain that the Rehni, Liu, Sorby-Adams, and Zhai articles","paragraph_id":"para_1354"},{"text":"do not present \"reasonable evidence of a causal association\" or,","paragraph_id":"para_1355"},{"text":"alternatively, \"some basis to believe there is a causal","paragraph_id":"para_1356"},{"text":"relationship\" between Aimovig and worsened outcomes in cases of","paragraph_id":"para_1357"},{"text":"cerebral injury in individuals with a history of seizure or","paragraph_id":"para_1358"},{"text":"cerebrovascular disease such as Lucas. See 21 C.F.R","paragraph_id":"para_1359"},{"text":"§ 201.57(c)(6)(i), (c)(7). This satisfies the causal association","paragraph_id":"para_1360"},{"text":"prong of our inquiry into Amgen's affirmative defense at this stage","paragraph_id":"para_1361"},{"text":"of the case.","paragraph_id":"para_1362"},{"text":"4.","paragraph_id":"para_1363"},{"text":"Even given the foregoing, Amgen would still prevail in","paragraph_id":"para_1364"},{"text":"its preemption defense if there was \"clear evidence\" that, had it","paragraph_id":"para_1365"},{"text":"been informed of the three studies discussed above, the FDA would","paragraph_id":"para_1366"},{"text":"still have rejected the label change that Warner says state tort","paragraph_id":"para_1367"},{"text":"law required. See Zofran, 57 F.4th at 342. At this early stage","paragraph_id":"para_1368"},{"text":"of the proceedings, however, Amgen has chosen not to rely on such","paragraph_id":"para_1369"},{"text":"an argument to sustain the court's Rule 15(a) futility","paragraph_id":"para_1370"},{"text":"determination regarding Warner's request to amend her complaint.","paragraph_id":"para_1371"},{"text":"Nor did the district court. We conclude that Warner's proposed","paragraph_id":"para_1372"},{"text":"amendment -- as limited to the four articles that Amgen has failed","paragraph_id":"para_1373"},{"text":"to conclusively establish do not plausibly constitute newly","paragraph_id":"para_1374"},{"text":"- 54 -","paragraph_id":"para_1375"},{"text":"acquired information -- would not have been futile. We therefore","paragraph_id":"para_1376"},{"text":"do not consider the merits of this reserved defense.","paragraph_id":"para_1377"},{"text":"IV.","paragraph_id":"para_1378"},{"text":"For the foregoing reasons, we reverse the district","paragraph_id":"para_1379"},{"text":"court's rejection of Warner's request to amend her complaint -- but","paragraph_id":"para_1380"},{"text":"only to the limited extent that Warner asserts a claim that the","paragraph_id":"para_1381"},{"text":"Rehni, Liu, Sorby-Adams, and Zhai articles enabled Amgen to use","paragraph_id":"para_1382"},{"text":"the CBE procedure to amend its approved label to reflect a concern","paragraph_id":"para_1383"},{"text":"that Aimovig could reduce the protective mechanisms of CGRP in the","paragraph_id":"para_1384"},{"text":"cerebral system in the setting of cerebral injury. The district","paragraph_id":"para_1385"},{"text":"court's rulings are otherwise affirmed, and this case is remanded","paragraph_id":"para_1386"},{"text":"for further proceedings consistent with this opinion. 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