Warner v. Amgen Inc.

United States Court of Appeals For the First Circuit No. 25-1268 ELISSA E. WARNER, as Personal Representative of the Estate of Decedent Lucas Joseph Warner, Plaintiff, Appellant, v. AMGEN INC.; AMGEN USA INC., Defendants, Appellees, NOVARTIS INSTITUTE FOR BIOMEDICAL RESEARCH, INC., Defendant. APPEAL FROM THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF MASSACHUSETTS [Hon. Julia E. Kobick, U.S. District Judge] Before Montecalvo, Lipez, and Kayatta, Circuit Judges. Abbye R. K. Ognibene, with whom Thomas M. Sobol, Mark T. Vazquez, and Hagens Berman Sobol Shapiro LLP were on brief, for appellant. Jessica L. Ellsworth, with whom Lauren S. Colton, Maria R. Durant, Johannah Cassel-Walker, and Hogan Lovells US LLP were on brief, for appellees. October 9, 2026  KAYATTA, Circuit Judge. This appeal arises out of a wrongful death suit concerning the prescription medication Aimovig, a biologic manufactured by Amgen Inc. and Amgen U.S.A. Inc. (collectively, "Amgen") for the prevention of migraines. Lucas Warner, who had a history of seizures and cerebrovascular disease, died at the age of twenty-five from cerebrovascular complications after taking a single dose of Aimovig. His mother, Elissa Warner,1 challenged under state law the adequacy of the drug's label as originally approved by the U.S. Food and Drug Administration (FDA, or the "agency"). The district court dismissed Warner's complaint, finding her claims preempted by the Federal Food, Drug, and Cosmetic Act (FDCA), 21 U.S.C. §§ 301 et seq. The court also denied Warner leave to amend her complaint to include allegations that Amgen should have supplemented its label after it was initially approved but before Lucas received the drug, finding that such an amendment would be futile. We affirm the district court's dismissal of Warner's original complaint but reverse the court's decision to deny Warner leave to amend her complaint. Our reasoning follows. 1 For consistency with the proceedings below, we refer to Lucas Warner as "Lucas" and his mother as "Warner." - 3 -  I. A. We begin with the regulatory framework underpinning this appeal. In 1962, Congress amended the FDCA, "shift[ing] the burden of proof" for drug safety and labeling "from the FDA to the manufacturer." Wyeth v. Levine, 555 U.S. 555, 567 (2009). Under the amended FDCA, a manufacturer seeking FDA approval of a license to market a drug must "demonstrate that its drug [is] safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling before it [can] distribute the drug." Id. (citation modified); 21 U.S.C § 355(b)(1). Prior to marketing a pharmaceutical drug, a manufacturer must submit a new drug application (NDA) that meets the requirements for FDA approval promulgated under 21 C.F.R. § 314.50(c). See Wyeth, 555 U.S. at 566; 21 C.F.R. § 314.50. Aimovig is a biologic product. Biologic products -- which include viruses, vaccines, blood components, allergenic products, and proteins -- are a "type of drug," though they are "derived from natural, biological sources" rather than "synthesized from chemicals" like typical drugs. Sandoz Inc. v. Amgen Inc., 582 U.S. 1, 6 (2017); see also 42 U.S.C. § 262(i)(1) (defining "biological product"). 2 Like other drugs, biologic 2 The parties use the term "biologic product," whereas the statute and regulations refer to "biological product[s]." See 42 - 4 - products are regulated under the FDCA. 42 U.S.C. § 262(j). The licensing of biologic products is nevertheless governed primarily by section 351 of the Public Health Service Act (PHSA), 42 U.S.C. § 262.3 Thus, rather than submit an NDA to obtain permission to market a new drug, a biologic manufacturer must instead submit to the FDA a Biologics License Application (BLA) under the PHSA. 21 C.F.R. § 601.2(a). Notwithstanding the differing regulatory authorities for licensing biologics versus other drugs, for our purposes the approval process and the implications of that process are materially the same. Compare id., with 21 C.F.R. § 314.50. Manufacturers submitting a BLA are required, among other things, to "submit data derived from nonclinical laboratory and clinical studies which demonstrate that the manufactured product meets prescribed requirements of safety, purity, and potency." 21 C.F.R. § 601.2(a). And they cannot market the drug until the FDA approves both the drug and its label. 42 U.S.C. § 262(a); see U.S.C. § 262(i)(1); 21 C.F.R. § 601.2(a). For purposes of this appeal, we use the terminology of the parties and refer to Aimovig as a "biologic" or "biologic product." 3 See Frequently Asked Questions About Therapeutic Biological Products, FDA (May 16, 2024), https://www.fda.gov/drugs/therapeutic-biologics-applications- bla/frequently-asked-questions-about-therapeutic-biological- products [https://perma.cc/64F7-6BSQ] (noting that "[b]iological products are a subset of drugs" that are "regulated under provisions of the [FDCA]," but "only biological products are licensed under section 351 of the [PHSA]"). - 5 - also In re Celexa & Lexapro Mktg. & Sales Pracs. Litig., 779 F.3d 34, 35–36 (1st Cir. 2015) (explaining that "[t]he FDA will not approve a drug," and thus the drug cannot be marketed, "if the NDA or [supplemental NDA] lacks substantial evidence that the drug will have the effect it purports or is represented to have," but "[a]fter approval, the manufacturer may distribute the drug without violating federal law as long as it uses the FDA-approved label" (citation omitted)). The FDA's process for reviewing a BLA submission and determining the appropriate content of a biologic's label involves (1) an FDA review committee that "[p]articipates in the labeling review to ensure the content and formatting of the label comply with requirements per applicable regulations"; (2) a regulatory project manager who oversees and coordinates the labeling review; (3) a clinical reviewer who "[e]nsures [the] accuracy of clinically relevant product information in the labeling"; (4) a clinical pharmacology reviewer who "[e]nsures [the] accuracy of mechanism of action statements, pharmacodynamics, pharmacokinetics, and information on the impact of age, sex, and race in the labeling"; (5) a chemistry manufacturing and control reviewer who "[e]nsures [the] accuracy of chemistry and manufacturing product information provided in the labeling"; (6) an advertising and promotional labeling branch reviewer who "[e]nsures the information in the labeling is not false or - 6 - misleading to the target audience(s)"; (7) a statistician; and (8) a non-clinical toxicologist reviewer. FDA Ctr. for Biologics Evaluation & Rsch., SOPP 8412: Review of Product Labeling 5–6 (2026), https://www.fda.gov/media/81790/download [https://perma. cc/TY7V-H59X]. The review committee is further tasked with "[c]omplet[ing] a thorough review of the labeling," meeting with the BLA applicant (in this case, the manufacturer), "identify[ing] labeling revisions," and "[s]end[ing] . . . revision requests" to the manufacturer. Id. at 8–9. When the manufacturer revises the draft labeling, the review committee and the regulatory project manager work together to confirm that the changes are consistent with the agency's requested revisions. Id. at 9. Pursuant to FDA regulations, the contents of a drug label must include, in order (and among other things): (1) prominent "boxed" warnings about risks that may lead to death or serious injury; (2) contraindications describing any situation in which the drug should not be used because the risk of use outweighs any therapeutic benefit; (3) warnings and precautions about other potential safety hazards; and (4) any adverse reactions for which there is some basis to believe a causal relationship exists between the drug and the occurrence of the adverse event. Merck Sharp & Dohme Corp. v. Albrecht, 587 U.S. 299, 304 (2019) (quoting 21 C.F.R § 201.57(c)). The order in which these categories must appear is far from random; rather, "the category - 7 - in which a particular risk appears on a drug label is an indicator of the likelihood and severity of the risk." Id. With this "hierarchy of label information," the FDA assures that "more important information" is not "overshadowed" by "less important information." Id. (citation modified). In approving the final label for a new drug or biologic, the FDA aims to warn of risks while at the same time "prevent[ing] overwarning, which may deter appropriate use of medical products." In re Zofran (Ondansetron) Prods. Liab. Litig., 57 F.4th 327, 330 (1st Cir. 2023) (quoting Supplemental Applications Proposing Labeling Changes for Approved Drugs, Biologics, and Medical Devices, 73 Fed. Reg. at 49605-06). The agency's final determinations are thus meant to "guard[] against the exaggeration of risk, or inclusion of speculative or hypothetical risks," id. (citation modified), such as "theoretical hazards not well-grounded in scientific evidence [that] can cause meaningful risk information to lose its significance," Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products, 71 Fed. Reg. 3922, 3935 (Jan. 24, 2006) (citation modified). Only after this "onerous and lengthy" process is complete, Mut. Pharm. Co. v. Bartlett, 570 U.S. 472, 476 (2013), does the agency confirm its acceptance of a BLA or NDA with the manufacturer. Accordingly, the approval of a BLA "constitute[s] - 8 - a determination that the . . . product meet[s] applicable requirements to ensure the continued safety, purity, and potency" of biologics such that the product may enter the market. 21 C.F.R § 601.2(d); see also 42 U.S.C. § 262(a)(2)(C). After the FDA has approved a label, the manufacturer must usually obtain permission from the FDA before making any changes to it. See In re MDL 2700 Genentech Herceptin (Trastuzumab) Mktg. & Sales Prac. Litig., 960 F.3d 1210, 1236 (10th Cir. 2020); 21 C.F.R. § 601.12(f)(1)–(3) (describing the pathways available to manufacturers seeking to amend a biologic label). The so-called Changes Being Effected (CBE) regulations provide an exception, applicable to both general pharmaceutical drugs under 21 C.F.R. § 314.70(c)(6) and biologics under 21 C.F.R. § 601.12(f)(2). 4 Under the CBE procedure, a manufacturer may without prior permission alter a drug or biologic's approved label based on "newly acquired information" in order to "accomplish" one of five possible labeling objectives provided by the regulations. 21 C.F.R. § 601.12(f)(2)(i)(A)–(E). Upon making such a labeling change, the manufacturer must submit a supplemental label to the FDA and may immediately begin using the revised label even as the 4 Though the regulations are largely analogous, the district court based its analysis on the CBE regulations pertaining to general pharmaceutical drugs under 21 C.F.R. § 314.70(c)(6) rather than those pertaining to biologic products under 21 C.F.R. § 601.12(f)(2). - 9 - FDA considers whether to approve the change. 21 C.F.R. § 601.12(f)(2)(ii). B. With this regulatory framework in mind, we turn to the facts of this case. Because this case was resolved on a motion to dismiss, we take as given the well-pleaded facts in the complaint. O'Brien v. United States, 155 F.4th 50, 53–54 (1st Cir. 2025). Aimovig is the proprietary name for the biologic drug erenumab. "Erenumab is a human monoclonal antibody that antagonizes the calcitonin gene-related peptide (CGRP) receptor." Because CGRP plays "a role" in the development of migraines, Aimovig aims to prevent migraines by inhibiting CGRP's ability to bind to CGRP receptors. At the time of its BLA submission, Aimovig was "the first product of this class to be reviewed in an FDA marketing application." Amgen submitted a biologics license application for Aimovig on May 17, 2017. Aimovig received FDA approval exactly one year later. The label as approved by the agency contained 12 sections, numbered (with some omissions) from 1 to 17.5 Section 14 of Aimovig's label, titled "Clinical Studies," states that 5A biologic's label can contain up to 17 possible sections. See 21 C.F.R. § 201.57(c)(2)–(18) (listing all 17 possible sections). Sections number 5, 7, 9, 10, and 15 were omitted from Aimovig's label. - 10 - patients "with myocardial infarction, stroke, transient ischemic attacks, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months prior to screening" were excluded from the drug's clinical trials. (Emphasis added). Warner criticizes that description because it failed to disclose that the Aimovig studies also excluded anyone who had ever suffered from seizures or neurological disorders. The label similarly noted no particular risk of Aimovig use for those in either of these clinical trial exclusion groups. Knowing of these undisclosed exclusions would have been relevant to Lucas and his doctor, Warner alleges, because Lucas had suffered from "both seizures and cerebrovascular disease/surgery" more than a year prior to taking Aimovig. Lucas was diagnosed with an arteriovenous malformation6 (AVM) at the age of six that led him to have "frequent and severe migraines" as well as "periodic brain bleeds." In 2011 and then again in 2012, Lucas underwent an embolization7 to help treat his AVM and migraine 6 An arteriovenous malformation is an "improper or abnormal development related to arteries or veins." Arteriovenous Malformations (AVM), Stedman's Medical Dictionary 1147 (28th ed. 2006). With an AVM, "blood is shunted from arterioles to venules without passing through the capillaries." Id. 7 An embolization is the "[t]herapeutic introduction of various substances into the circulation to occlude vessels, either to arrest or prevent hemorrhaging, to devitalize a structure, tumor, or organ by occluding its blood supply, or to reduce blood flow to an arteriovenous malformation." Embolization, Stedman's Medical Dictionary, supra, at 627. - 11 - symptoms, though these procedures provided limited relief. In 2014, he suffered a subacute hemorrhage from his AVM. In June 2018, unaware that persons with any history of seizures and neurological disease had been excluded from the Aimovig clinical trials, Lucas's doctor prescribed him Aimovig to treat his migraines. Lucas took one dose of Aimovig on June 17, 2018, at age twenty-three. Less than 48 hours later, Lucas suffered seizures and was placed in a coma. He experienced "multi- organ failure." His doctors believed that Aimovig had "cross[ed] [his] blood brain barrier,"8 thereby causing the seizures, and they "attempt[ed] to remove [Aimovig] from his brain and blood." Due to those seizures, Lucas "suffered significant irreversible brain damage, including the near-total loss of his short-term memory" and the inability to eat or drink. He struggled to walk and stand. He was left "cognitively severely impaired," forcing him to discontinue his university studies, as the doctors could not do anything "to reverse the damage caused by [Aimovig]." In 2020, Lucas's condition worsened, and he suffered repetitive seizures 8 The blood-brain barrier is "a selective mechanism" that "oppos[es] the passage of most ions and high molecular weight compounds from the blood to brain tissue." Blood-Brain Barrier, Stedman's Medical Dictionary, supra, at 205; see also In re Vertex Pharms. Inc., Sec. Litig., 357 F. Supp. 2d 343, 345 (D. Mass. 2005) ("The blood-brain barrier is a selective filter that regulates the transport of certain molecules from the blood to the brain, and protects the brain from substances in the blood that would cause undesirable effects in the brain."). - 12 - "due to temporal mesial sclerosis, a result of the brain damage" from Aimovig. Lucas died on November 17, 2020. His death certificate lists his primary cause of death as "hypoxia respiratory failure" caused by "stroke," "refractory seizures," and "cerebral angiopathy." 9 His death certificate also states that "complications from Aimovig" "contribut[ed]" to his death. Warner filed a wrongful death complaint against Amgen in Massachusetts state court, alleging that her son died from medical complications due to taking Aimovig and asserting liability on a failure-to-warn theory. Warner alleged that Aimovig's label as approved by the FDA should have contained a warning that the biologic drug had not been tested on persons like Lucas with any history at all of "seizures or cerebrovascular disease/surgery," as well as a warning regarding the "complications suffered by Lucas." Amgen removed the suit to the U.S. District Court for the District of Massachusetts. Amgen then filed a motion to dismiss for failure to state a claim pursuant to Federal Rule of 9 Hypoxia involves the "[d]ecrease below normal levels of oxygen in inspired gases, arterial blood, or tissue." Hypoxia, Stedman's Medical Dictionary, supra, at 939. "Refractory" seizures are seizures that are "resistant to treatment." Refractory, Stedman's Medical Dictionary, supra, at 1664. And angiopathy is "[a]ny disease of the blood vessels or lymphatics." Angiopathy, Stedman's Medical Dictionary, supra, at 88. - 13 - Civil Procedure 12(b)(6), contending (among other things) that because it was required to use the label approved by the FDA, and because Warner had not shown Amgen could have changed that label, federal law preempted Warner's state law claim that Aimovig's label should have disclosed more about the drug's clinical trial exclusions or the possible complications related to those exclusions. At the motion hearing for Amgen's motion to dismiss, Warner introduced a new contention. In addition to critiquing Amgen's efforts to secure FDA approval of the label in the first instance, she contended that a series of studies and literature reviews not known to the FDA during the approval process would have allowed Amgen to employ the CBE procedure to change the label after it was approved and before Lucas took the drug. Such a change, argued Warner, would have mentioned not just the lifetime exclusion group, but also additional risks for patients like Lucas. Following argument, the court requested that Warner file a supplemental brief "including more information on studies identified" during the hearing. With her supplemental brief, Warner submitted nine articles -- including studies and literature reviews, most of which were published before the FDA approved the label -- that she asserted qualified as newly acquired information that would have allowed Amgen to amend its approved label under the CBE procedure. - 14 - Warner argued that these articles "establishe[d] a reasonable basis for believing that a CGRP blockade pose[s] a type, severity, or frequency of risk that was not submitted to or analyzed by the FDA prior to Aimovig's approval." Warner also requested leave to amend her complaint to counter Amgen's affirmative preemption defense and to assert that, based on the studies and reviews presented, Amgen could have updated its label using the CBE process to reflect "cerebral risks presented by CGRP-blocking drugs, like Aimovig, that were not previously submitted to the FDA." After reviewing Warner's submissions, the court concluded that "the articles [did] not plausibly constitute newly acquired information" and failed to "link Aimovig or any other CGRP-blocking drug to an adverse event or risk" that would have allowed Amgen to amend Aimovig's label. Warner v. Amgen Inc., No. 24-CV-10632, 2025 WL 490720, at *9 (D. Mass. Feb. 13, 2025). The court further surmised that because the FDA had "reviewed 'the world's literature'" on "the theoretical risks associated with CGRP antagonism," it was "not plausible that articles bearing on that subject" that were published before the FDA began its review would constitute newly acquired information not previously considered by the FDA. Id. at *10. As to Warner's argument that, pre-approval, Amgen should have submitted a proposed label to the FDA disclosing that patients like Lucas had been excluded from Aimovig's trials, the court found that "the FDA was aware that - 15 - individuals who had ever been diagnosed with a seizure disorder or cerebrovascular disease were excluded from Aimovig's clinical trials" and that the FDA "considered the risks and safety concerns associated with these exclusions" before approving a label lacking any disclosure of them. Id. at *8. Accordingly, the court granted Amgen's motion to dismiss with prejudice and denied Warner's request for leave to amend her complaint as futile. Id. at *12. This appeal followed. II. This court "review[s] the grant of a motion to dismiss de novo, accepting well-pled facts as true and drawing all inferences in favor of the non-moving party." O'Brien, 155 F.4th at 53–54 (quoting 3137, LLC v. Town of Harwich, 126 F.4th 1, 8 (1st Cir. 2025)). To survive dismissal for failure to state a claim under Rule 12(b)(6), a complaint must "'state a claim to relief that is plausible on its face,'" such that we can "draw the reasonable inference that the defendant is liable for the misconduct alleged." Ashcroft v. Iqbal, 556 U.S. 662, 678 (2009) (quoting Bell Atl. Corp. v. Twombly, 550 U.S. 544, 570 (2007)). We are mindful that this plausibility requirement does not "impose a . . . requirement" of probability. Twombly, 550 U.S. at 556. On the other hand, a "sheer possibility" is not enough. Iqbal, 556 U.S. at 678. As such, "[t]he relevant inquiry focuses on the reasonableness of the inference of liability that the plaintiff is - 16 - asking the court to draw from the facts alleged in the complaint." Ocasio-Hernández v. Fortuño-Burset, 640 F.3d 1, 13 (1st Cir. 2011). On appeal, Amgen does not contend that Warner's complaint fails to state a plausible claim for relief under applicable state law. Rather, Amgen argues that the district court correctly found that Amgen's affirmative defense -- federal preemption -- defeats Warner's state-law claim before it gets out of the starting blocks. See PLIVA, Inc. v. Mensing, 564 U.S. 604, 619 (2011) (referring to preemption as an affirmative defense); Durnford v. MusclePharm Corp., 907 F.3d 595, 603 n.8 (9th Cir. 2018) ("FDCA preemption, like all federal preemption, is an affirmative defense."). When an order of dismissal under Rule 12(b)(6) is "premised on the inevitable success of an affirmative defense," we will uphold the order so long as (1) "the facts establishing the defense are definitively ascertainable from the complaint and the other allowable sources of information" and (2) "those facts suffice to establish the affirmative defense with certitude." Burt v. Bd. of Trs. of Univ. of R.I., 84 F.4th 42, 50 (1st Cir. 2023) (quoting Nisselson v. Lernout, 469 F.3d 143, 150 (1st Cir. 2006)); see also Scheibe v. ProSupps USA, LLC, 141 F.4th 1094, 1098 (9th Cir. 2025) ("Under Rule 12(b)(6), only when the plaintiff pleads itself out of court, by admitting all the elements of an - 17 - affirmative defense, may a complaint that otherwise states a claim be dismissed." (citation modified)). III. This appeal does not call on us to apply a statutory preemption clause. Cf. Monsanto Co. v. Durnell, 146 S. Ct. 2001, 2006 (2026) (reviewing an express preemption clause contained in 7 U.S.C. § 136v(b)). Rather, Amgen's FDCA preemption defense rests on the proposition that it was not legally possible to use a label other than the label originally approved by the FDA. This type of preemption is often called impossibility preemption, which exists "where it is impossible for a private party to comply with both state and federal requirements." Zofran, 57 F.4th at 335–36 (citation modified). Impossibility preemption "is a demanding defense." Wyeth, 555 U.S. at 573. As a general matter, there is a presumption against preemption. See id. at 565 ("[W]e start with the assumption that the historic police powers of the States were not to be superseded by the Federal Act unless that was the clear and manifest purpose of Congress." (citation modified)). In the prescription drug context, the drug manufacturer bears the ultimate burden of establishing a preemption defense. See Albrecht, 587 U.S. at 313–14. Warner claims in support of her complaint that it would have been possible for Amgen to comply with Massachusetts state - 18 - law by proposing a better label when originally seeking FDA approval. Alternatively, she claims in support of her motion to amend her complaint that Amgen could have later changed the approved label. We assess each claim in turn. A. We begin with what the parties call Warner's "pre-approval" theory, which is the theory tendered in support of her complaint. In substance, Warner asserts that, in its BLA submission to the FDA, Amgen could have proposed a label disclosing that Aimovig's clinical trials excluded "people with a history of seizures" or "cerebrovascular disease/surgery" at any time in their lives. Such a disclosure would have revealed that "potential complications related to those exclusions" could have escaped notice in the clinical trials. We see two flaws in this argument, one legal and one factual, each sufficient to sustain the dismissal of Warner's complaint. First, as a matter of law, a manufacturer's ability to ask the FDA to include something in a label falls short of the unilateral power required to preclude an impossibility preemption defense. Second, as a matter of fact, the record in this case is clear that the FDA would have rejected a request to further describe in the label the exclusions from Aimovig's clinical trials. We explain these independent grounds for affirming dismissal in turn below. - 19 -  1. "[W]hether a private party can act sufficiently independently under federal law to do what state law requires may sometimes be difficult to determine." PLIVA, 564 U.S. at 623. Indeed, the Supreme Court itself has recognized that prescription drug preemption matters "h[ave] repeatedly vexed the Court -- and produced widely divergent views -- in recent years." Bartlett, 570 U.S. at 492–93 (citing Wyeth, 555 U.S. 555, and PLIVA, 564 U.S. 604). That puzzlement arises in part due to the lack of congressional clarity regarding preemption in federal law: "[T]he FDCA's treatment of prescription drugs includes neither an express pre-emption clause (as in the vaccine context, 42 U.S.C. § 300aa-22(b)(1)), nor an express non-preemption clause (as in the over-the-counter drug context, 21 U.S.C. §§ 379r(e), 379s(d))." Id. at 493. This lack of clarity leaves courts to "divine Congress' will from the duties the statute imposes." Id. So we do our best, following the guidance provided by the Supreme Court and our own circuit precedent. We start with Wyeth. If Warner were correct that a manufacturer's ability to ask the FDA to include certain language on a label precluded an impossibility preemption defense to a claim that the label was insufficient, then the Supreme Court in Wyeth would have had little reason to hinge its discussion on the availability of the CBE procedure. The Court could have simply - 20 - rested its decision on whether it was possible for the manufacturer to request that the FDA take certain action -- in this case, to approve a change to the label. Indeed, the Court's segue from noting the manufacturer's ability to request approval to focusing instead on the CBE procedure strongly suggests that the Court presumed that the mere ability to request approval of a change did not defeat the preemption defense. See Wyeth, 555 U.S. at 568 ("There is, however . . . the 'changes being effected' (CBE) regulation." (emphasis added)). This suggestion grew stronger yet with the Court's discussion of Wyeth in PLIVA. There, the Court held that a generic drug manufacturer's ability to ask the FDA to change a drug's label did not defeat an impossibility defense. PLIVA, 564 U.S. at 619–21. In so holding, the Court explained that "[t]he question for 'impossibility' is whether the [defendant] could independently do under federal law what state law requires of it." Id. at 620. In that context, where state law required a stronger label, "[t]he only action the [m]anufacturers could independently take -- asking for the FDA's help -- [was] not a matter of state-law concern." Id. at 624. Because requesting that the FDA take action was simply the first step in a chain of contingencies that, with the FDA's help, "might have eventually" -- but could not have independently -- yielded the requisite stronger warning label, the Court found such a claim to be preempted. Id. at 620-21; see also - 21 - id. at 623–24 ("To decide these cases, it is enough to hold that when a party cannot satisfy its state duties without the Federal Government's special permission and assistance, which is dependent on the exercise of judgment by a federal agency, that party cannot independently satisfy those state duties for pre-emption purposes."). As we subsequently stated in Celexa, the PLIVA Court "thus limited Wyeth to situations in which the drug manufacturer can, of its own volition, strengthen its label in compliance with its state tort duty." 779 F.3d at 41 (citation modified); see also PLIVA, 564 U.S. at 624 (reasoning that Wyeth was not contrary to its holding because a brand-name manufacturer like the one in Wyeth can use the CBE process "to unilaterally strengthen its [drug's] warning" or label without prior FDA approval, whereas a generic manufacturer cannot (quoting Wyeth, 555 U.S. at 573)). And then more recently in Albrecht, the Supreme Court again turned its attention not to a manufacturer's ability to plead with the FDA for a labeling change, but rather to the CBE regulation allowing a change by the manufacturer "without prior approval from the FDA." 587 U.S. at 315. We have gathered from these cases a general principle: Where "a private party . . . cannot comply with state law without first obtaining the approval of a federal regulatory agency, then the application of that law to that private - 22 - party is preempted." Gustavsen v. Alcon Lab'ys, Inc., 903 F.3d 1, 9 (1st Cir. 2018). And while the foregoing cases all apply this principle in the context of considering claims that approved labels should have been revised post-approval, we see no reason not to apply it to claims that the manufacturer should have submitted a different label in its BLA submission to the FDA. It follows, then, that a pre-approval claim like Warner's cannot survive a manufacturer's impossibility defense because a BLA submission is, by its nature, a request for agency approval.10 10 This is not to say that a manufacturer remains free to mislead the FDA in the approval process. While impossibility preemption bars a pre-approval claim based on a manufacturer's failure to propose a different label to the FDA, the enforcement mechanisms crafted by Congress to protect consumers against misleading or fraudulent actions by manufacturers remain in place. The FDCA prohibits manufacturers from obscuring information from or presenting false information to the FDA in their drug applications. See 21 U.S.C. § 331(a) (prohibiting introduction into interstate commerce of any drug "that is . . . misbranded"); id. § 352(a)(1) (deeming a drug misbranded where "its labeling is false or misleading in any particular"); see also Yousefzadeh v. Johnson & Johnson Consumer Inc., 184 F.4th 130, 141 (2d Cir. 2026) ("The misbranding provision . . . prohibits not only affirmative misrepresentations but also failures to disclose material facts."); United States v. Watkins, 278 F.3d 961, 964 (9th Cir. 2002) (describing misdemeanor and felony misbranding provisions under the FDCA). And, as we will explain, information not submitted to the FDA in the approval process may serve as newly acquired information, requiring a post approval change in the label by the manufacturer to avoid liability under state law. - 23 -  2. Adding belt to suspenders, the record in this case makes clear that any pre-approval request by Amgen for the label Warner says it should have proposed would have been denied -- and indeed, was effectively denied. Certainly, the FDA was aware that the clinical trials submitted in support of Aimovig's application excluded persons with any history of "seizure disorders" or "significant neurological conditions." We know that because the summary of the studies prepared by the FDA's Division of Neurology Products (DNP) expressly mentioned those exclusions. The DNP further remarked in its clinical review and integrated safety assessment that "the selection criteria for the migraine studies resulted in a relatively young, healthy population" that excluded individuals suffering from "seizure disorders" or "major neurological disorders." Indeed, Aimovig's DNP reviewer initially proposed adding a warning of "theoretical concern" for all "patients with major . . . cerebrovascular disease" (e.g., persons like Lucas). That recommendation was rejected after further internal review, as the FDA's Division of Risk Management determined that, despite the "theoretical" cerebrovascular risks posed by CGRP antagonism, there was "insufficient evidence to include th[e] theoretical risk in labeling." The FDA also rejected the DNP's suggestion to add a caution against Aimovig use in "[p]atients who ha[d] experienced - 24 - a stroke, myocardial infarction, transient ischemic attack, unstable angina or had coronary artery bypass surgery within the last year." Ultimately, the final label as approved by the FDA contained no contraindications, warnings, or precautions, and it listed only "injection site reactions and constipation" as the "most common adverse reactions" to taking Aimovig. And while the "Clinical Studies" section disclosed that patients who had suffered from certain medical conditions, such as "myocardial infarction, stroke, [and] transient ischemic attacks . . . within 12 months prior to screening" had been excluded from Aimovig's clinical trials, the label did not disclose the lifetime exclusion criterion and included no warning, direct or otherwise, of the theoretical risk left unresolved by the design of the clinical studies.11 Bearing in mind the FDA's knowledge of the clinical trial exclusion criteria and its clear consideration and rejection of added language to account for those exclusions, we are not free to 11Warner would have us discount the FDA's consideration of these excluded populations and the risk thereto because, in Warner's view, the FDA trained its attention more (but not exclusively) on cardiovascular risks than on cerebrovascular risks, as "evidenced" by Warner's counting of the number of references to cardiovascular versus cerebrovascular risks in the FDA's review. But there was good reason for the FDA to home in on cardiovascular considerations: "The