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-applicationsbla/frequently-asked-questions-about-therapeutic-biologicalproducts [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 "multiorgan 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: "There were two deaths in the
[Aimovig] database" of the clinical trials, and "both were
cardiovascular-related sudden deaths."
- 25 -disregard the FDA's final approval of an Aimovig label detailing
only the description of the twelve-month exclusion (but not the
lifetime exclusion) and conveying that exclusion as and where it
did. It is true that no one proposed the FDA should word the
label precisely as Warner says it should have been worded. But
as we have described, the only reason to make such a change would
be to flag the theoretical risks the agency had already decided
did not warrant mentioning. We must therefore read the FDA's
inclusion of the twelve–month exclusion in the Clinical Studies
section of the label -- but not the lifetime exclusion -- as
"constitut[ing] [the agency's] determination," 21 C.F.R
§ 601.2(d), that the description of the clinical studies on the
approved label would "facilitate an understanding of how to use
the drug safely and effectively," id. § 201.57(c)(15). In the
same manner, we must read the agency's omission of any indication,
contraindication, warning or precaution, or adverse reaction
related to the clinical trial exclusion criteria as the FDA's
determination that the label as approved would be adequate to
ensure the "safety, purity, and potency" of Aimovig such that it
could enter the market. Id. § 601.2(d). As such, the agency's
formal approval of the Aimovig label made clear that the agency
would have rejected a suggestion by Amgen to include in the
approved label the language that Warner says state law required.
"[W]hen the FDA formally approves a label stating one thing with
- 26 -full and obvious notice of the directly contrary position, one can
read the approval as rejecting the contrary position." Zofran,
57 F.4th at 343.
* * *
In sum, we conclude that the district court correctly
found that Warner's complaint did not survive Amgen's preemption
defense. Amgen's ability to have proposed a different original
label does not defeat its preemption defense because it did not
have the ability to act unilaterally in the context of this
"pre-approval" claim. And, in any event, it is clear that the FDA
would have rejected the type of label Warner proposes in her
complaint even if Amgen had requested it.
B.
We turn next to the district court's denial of Warner's
request for leave to amend her complaint. In her request, Warner
sought to add a claim based on a new theory of recovery that, postapproval, Amgen should have amended its label of its own accord
using the CBE procedure to reflect newly acquired information.
The district court determined that Amgen could not have revised
its FDA-approved label as Warner alleged it should have; hence,
the request to file an amended complaint was futile. Warner, 2025
WL 490720, at *12.
"A district court's ruling under Rule 15(a) that
amendment would be futile 'means that the complaint, as amended,
- 27 -would fail to state a claim upon which relief could be granted.'"
D'Agostino v. ev3, Inc., 845 F.3d 1, 6 (1st Cir. 2016) (quoting
Glassman v. Computervision Corp., 90 F.3d 617, 623 (1st Cir.
1996)); see also Fed. R. Civ. P. 15(a). We therefore review the
district court's ruling de novo. D'Agostino, 845 F.3d at 6. In
so doing, we ask whether the proposed amended complaint would have
stated a plausible claim for relief that would not have been
certainly precluded by Amgen's preemption defense. See Burt, 84
F.4th at 50.
Warner's proposed amendment to the complaint would have
added reference to nine studies or articles advancing her new
argument that, in light of any or all of the articles' findings,
Amgen could have unilaterally changed Aimovig's approved label to
add a warning that blocking CGRP disrupts neuroprotective
mechanisms in the setting of cerebral injury. This argument puts
in play consideration of the CBE procedure set forth at 21 C.F.R.
§ 601.12(f)(2). That procedure allows a manufacturer to change
an approved label -- and then distribute the drug with the changed
label before receiving FDA approval of the changes -- when, as
relevant here, the added information "reflect[s] newly acquired
information" that "add[s] or strengthen[s] a contraindication,
warning, precaution, or adverse reaction." 21 C.F.R.
§ 601.12(f)(2)(i)(A).
- 28 -The Supreme Court has considered several times how the
availability of the CBE procedure bears on the adjudication of a
preemption defense when a person challenges the adequacy of the
warnings on a label previously approved by the FDA. See Wyeth,
555 U.S. 555; Albrecht, 587 U.S. 299. So, too, has this court.
See, e.g., Celexa, 779 F.3d 34; Zofran, 57 F.4th 327.
Keeping in mind that we are reviewing the viability of
an affirmative defense to reject a proposed pleading without the
benefit of discovery, expert testimony, or fact finding, we must
be left with "certitude" that Warner does not have a plausible
basis for undercutting Amgen's affirmative defense in order to
affirm the district court's denial of Warner's motion for leave to
amend. Burt, 84 F.4th at 50 (citation modified); see also In re
Colonial Mortg. Bankers Corp., 324 F.3d 12, 16 (1st Cir. 2003)
(holding that, to dismiss a case based on an affirmative defense,
"the facts that establish the defense must be definitively
ascertainable from the allegations of the complaint" and other
allowable sources, and "the facts so gleaned must conclusively
establish the affirmative defense"). So, what need Warner
plausibly show in order to rely on the CBE procedure at this stage
of the lawsuit?
First, the parties appear to agree that Warner must
plausibly allege facts establishing a "reasonable basis" for
treating the articles she identifies as constituting "newly
- 29 -acquired information." See Zofran, 57 F.4th at 336 (emphasis
omitted) (reasoning that "Albrecht can arguably be read as . . .
deeming the CBE procedure unavailable if there is no reasonable
basis for treating the information identified by plaintiffs as
newly acquired information" (citing Albrecht, 587 U.S. at 315)).
The requirement that the information be "newly acquired" preserves
the FDA's role as "the exclusive judge of safety and efficacy based
on information available at the commencement of marketing, while
allowing the states to reach contrary conclusions when new
information not considered by the FDA develops."12 Celexa, 779
F.3d at 41.
Second, Warner must plausibly allege facts showing that
the proposed change is "for the purpose of accomplishing" -- as
relevant here -- the objective of "add[ing] or strengthen[ing] a
contraindication, warning, precaution, or adverse reaction." Id.
at 37; see also 21 C.F.R. § 601.12(f)(2)(i)(A) (parallel
regulation for biologics).
Third, because Warner argues that Amgen should have
invoked the CBE procedure to add a warning, precaution, or adverse
effect to Aimovig's label, she must also plausibly allege facts
showing Amgen could have satisfied the causal association standard
12 By "available" information we refer to information that
would not be "newly acquired" if submitted after approval. See
21 C.F.R. §§ 314.70(c)(6)(iii), 601.12(f)(6).
- 30 -set forth in 21 C.F.R. § 201.57(c) for those additions to the
label. 21 C.F.R. § 601.12(f)(2)(i)(A). That standard requires
either "reasonable evidence of a causal association" between "a
clinically significant hazard" and a drug, id. § 201.57(c)(6)(i)
(emphasis added), or "some basis to believe there is a causal
relationship between the drug and the occurrence of the adverse
event," id. § 201.57(c)(7) (emphasis added).
If Warner successfully makes the three foregoing
showings, then Amgen's preemption defense fails unless Amgen can
"show that the FDA, after being fully informed of the case for
making [Warner's] proposed label change, made clear through agency
action having the force of law that it would not have allowed the
change had the defendant initiated it through the CBE procedure."
Zofran, 57 F.4th at 342. With that framework in mind, we next
consider the parties' submissions.
1.
We begin with the threshold issue of determining whether
the articles submitted by Warner present a "reasonable basis for
treating the information . . . as newly acquired information."
Id. at 336 (emphasis omitted).
Newly acquired information is defined as "data,
analyses, or other information not previously submitted to the
[FDA]," which may include "data derived from new clinical studies,
reports of adverse events, or new analyses of previously submitted
- 31 -data (e.g., meta-analyses) if the studies, events or analyses
reveal risks of a different type or greater severity or frequency
than previously included in submissions to [the] FDA." 21 C.F.R.
§§ 601.12(f)(6), 314.3(b). In Zofran, the parties all assumed
that "determining whether certain information is 'newly acquired'
[constituted] a legal question." 57 F.4th at 337. So we
similarly assumed. Id. Here, too, the parties also treat the
question as one of law, so we shall, too. That assumption still
leaves room for fact finding. For example, the adjudicator may
need to decide how significant the information is, whether it may
qualify as new, and so on. Albrecht, 587 U.S. at 317. But
resolution of these "brute facts . . . relevant to a court's legal
determination" is "subsumed" under the court's legal analysis.
Id.
In support of her motion for leave to amend her
complaint, Warner posits that the nine articles she submitted "show
increasing knowledge about cerebrovascular risk that would have
enabled Amgen to supplement its label." Warner argues that the
district court's conclusion that these studies did not qualify as
newly acquired information was in error because "[t]he FDA -- at
most -- knew about the vasodilatory 13 effects of CGRP" but
Vasodilatory refers to dilation of the blood vessels.
13 See Vasodilator, Stedman's Medical Dictionary, supra, at 2092.
- 32 -"conduct[ed] no analysis of the specific risks of CGRP-inhibition
in the brain and the non-vasodilatory roles of CGRP."
Turning to the nine articles submitted by Warner, we
first set aside the 2018 Zhao14 and the 2018 Szeto15 literature
reviews. The Zhao literature review suggests that remote ischemic
postconditioning may offer cerebral protection for stroke
patients; however, it mentions neither CGRP nor CGRP antagonism.
Meanwhile, the Szeto literature review references CGRP only in
passing to state that as one of several vasodilators, CGRP
increases KATP channel activity. But the literature review does
not otherwise opine on the role of CGRP. And Warner does not
explain how such a singular, tangential reference would constitute
any type of "data," "new analyses," or "event[]" that we can
consider as newly acquired information. 21 C.F.R.
§§ 601.12(f)(6). Nor does Warner provide us with an explanation
that would allow us to reasonably infer that these literature
reviews present risks not previously considered by the FDA.
Without more, we do not consider these articles newly acquired
information for purposes of this appeal.
14 See Jing-Jing Zhao et al., Remote Ischemic
Postconditioning for Ischemic Stroke: A Systematic Review and
Meta-Analysis of Randomized Controlled Trials, 131 Chinese Med. J.
956 (2018).
15 See Vivian Szeto et al., The Role of KATP Channels in
Cerebral Ischemic Stroke and Diabetes, 39 Acta Pharmacologica
Sinica 683 (2018).
- 33 -That leaves us with seven articles. We can also dispose
of the 2012 Kokkoris literature review16 as not constituting newly
acquired information for purposes of this appeal. That review
discusses some possible neuroprotective mechanisms of CGRP during
subarachnoid hemorrhage.17 However, the FDA specifically reviewed
a study finding that "elevated CGRP levels may prevent focal
cerebral ischemia following subarachnoid hemorrhage." Like the
district court, we therefore lack any basis for determining that
this article "reveal[s] risks of a different type or greater
severity or frequency than previously included in submissions to
[the] FDA." Warner, 2025 WL 490720, at *10 (citation modified).
This leaves us with six articles, including the 2018 Guo
study,18 which administered a CGRP antagonist to rats undergoing
myocardial ischemia. That study found that CGRP influences
myocardial infarct size and "may protect [such] cardiomyocytes via
homeostasis of mitochondrial function." But, as we discuss in
16 See Stelios Kokkoris et al., Role of Calcitonin GeneRelated Peptide in Cerebral Vasospasm, and As a Therapeutic
Approach to Subarachnoid Hemorrhage, 3 Frontiers Endocrinology 135
(2012).
17 A subarachnoid hemorrhage is a bleed within the
subarachnoid space, which lies between two of the three membranes
that cover the central nervous system. See Subarachnoid
Hemorrhage, Stedman's Medical Dictionary, supra, at 873; Arachnoid
Mater, Stedman's Medical Dictionary, supra, at 127.
18 See Zheng Guo et al., Independent Roles of CGRP in
Cardioprotection and Hemodynamic Regulation in Ischemic
Postconditioning, 828 Eur. J. Pharmacology 18 (2018).
- 34 -section III.B.3 of this opinion, a manufacturer cannot employ the
CBE procedure to change the warnings or precautions on a label
without also meeting the causal association standard set forth in
21 C.F.R. § 201.57(c). Warner does not address how the study's
findings -- pertaining only to the effects of CGRP on the
mitochondrial membrane as it relates to cells in the heart, rather
than the brain -- would have any causal relationship with the
cerebral outcomes suffered by Lucas. So we need not address it
any further.
The 2018 Basalay literature review 19 discusses the
neuroprotective qualities of remote ischemic conditioning 20 and
suggests that the mechanisms of ischemic conditioning may differ
between the heart and brain. The review makes only passing
reference to CGRP's function in the brain. But the FDA at multiple
points considered the theoretical concern of CGRP antagonism and
19 See Marina V. Basalay et al., Neural Mechanisms in Remote
Ischaemic Conditioning in the Heart and Brain: Mechanistic and
Translational Aspects, 113 Basic Rsch. Cardiology 25 (2018).
20 Ischemia is the "[l]ocal loss of blood supply due to a
mechanical obstruction . . . of the blood vessel." Ischemia,
Stedman's Medical Dictionary, supra, at 1001. As the district
court explained, "[i]schemic conditioning involves intentionally
exposing tissue or organs to brief periods of ischemia (i.e.,
reduced blood flow and oxygenation), followed by reperfusion
(i.e., restoration of blood flow to the tissue or organ), to
protect against organ damage following a major ischemic event,
such as a heart attack or stroke." Warner, 2025 WL 490720, at *9.
- 35 -its "potential . . . to adversely impact the beneficial effects of
ischemic preconditioning," including in reviews by the Division of
Neurology Products and the Division of Cardiovascular and Renal
Products. Indeed, the DNP noted that "[t]here are numerous
publications on preconditioning and its potential beneficial
effects, not only on the cardiovascular system," but also on the
"neurological" system. Citing in part to a publication concerning
the neuroprotective effects of ischemic preconditioning, the DNP
noted that "[s]several publications . . . point out that multiple
endogenous factors may be involved in the complex process(es)
underlying the phenomenon and the current limited understanding of
the role of any one of these factors, including CGRP." In light
of these considerations by the FDA, we are certain that the Basalay
literature review does not plausibly "reveal risks of a different
type or greater severity or frequency than previously included in
submissions to [the] FDA." 21 C.F.R. §§ 601.12(f)(6), 314.3(b).
The 2007 Rehni study21 presents a close call. This study
found that the administration of a CGRP antagonist to mice
"attenuated" "the neuroprotective effect of remote mesenteric
ischaemic preconditioning."22 As we explained regarding the 2018
21 See Ashish K. Rehni et al., Possible Involvement of
Insulin, Endogenous Opioids and Calcitonin Gene-Related Peptide in
Remote Ischaemic Preconditioning of Brain, 127 Pharm. Soc'y of
Japan 1013 (2007).
22 Rehni noted that cerebral ischemia in particular " has been
reported to impair short-term memory" and " sensorimotor ability."
- 36 -Basalay review, the FDA was well-aware of the "theoretical concern"
of CGRP antagonism and its "potential . . . to adversely impact
the beneficial effects of ischemic preconditioning." But the
Rehni study -- at least on this record -- arguably took a step
further by reporting that the introduction of a CGRP receptor
antagonist "abolished the neuroprotection afforded by remote
mesenteric ischaemic preconditioning." According to the study,
"it may be concluded that remote mesenteric ischaemic
preconditioning exerts neuroprotective effect possibly[] mediated
through the release of . . . [CGRP] with consequent activation of
[its] receptors." On this record and given the generous pleading
standard, we cannot be certain that the Rehni study's findings do
not plausibly "reveal risks of . . . a greater severity . . . than
previously included in submissions to [the] FDA." 21 C.F.R.
§ 601.12(f)(6).
That leaves three articles concerning the interactions
between CGRP and the blood-brain barrier.23 In the first, the 2011
However, "remote mesenteric ischaemic preconditioning has been
observed to prevent ischaemia" and has also prevented an "increase
in cerebral infarct size, impairment of short-term memory, [and]
motor incoordination."
23As further defined by the Sorby-Adams literature review
presented by Warner, the blood-brain barrier is a "semi-permeable
barrier existing between the brain and blood" that is composed of
"endothelial cells with tight junctions (TJ), adherens junctions,
astrocytes, pericytes, and the basement membrane," which,
together, assist in the barrier's functions of "supplying the brain
with essential nutrients such as oxygen and glucose, mediating the
efflux of waste products, and facilitating the movement of
- 37 -Liu study,24 researchers placed rats under stroke conditions and
administered CGRP to one group and saline solution to the other.
The findings suggest that the effects of blood-brain barrier
disruption in the study's rats were not short-lived: "[Bloodbrain barrier] leakage after ischemia–reperfusion injury in the
rat was continuous and long-lasting, without any closure up to
several weeks." The authors found that "CGRP administration could
reduce" the permeability of the blood-brain barrier and that it
"might protect against [blood-brain barrier] disruption after
brain ischemia reperfusion injury by improving the damage of
capillary endothelium cells and enhancing basal membrane."
The second of these articles is the 2017 Sorby-Adams
literature review25 -- published three months after Aimovig's BLA
submission.26 This review concerns blood-brain barrier disruption
nutrients and plasma proteins." See Annabel J. Sorby-Adams et
al., The Role of Neurogenic Inflammation in Blood-Brain Barrier
Disruption and Development of Cerebral Oedema Following Acute
Central Nervous System (CNS) Injury, 18 Int'l J. Molecular Sci.
1788 (2017).
24 See Zhen Liu et al., Calcitonin Gene-Related Peptide
Prevents Blood-Brain Barrier Injury and Brain Edema Induced by
Focal Cerebral Ischemia Reperfusion, 171 Regul. Peptides 19
(2011).
25 See Sorby-Adams et al., supra.
26 The FDA approved Amgen's BLA for Aimovig in May 2018.
Only the Basalay article was published after that approval.
Indeed, five of the articles -- the Zhai, Sorby-Adams, Zhao, Szeto,
and Guo articles -- were published in the year between Amgen's BLA
submission on May 17, 2017 and the FDA's ultimate approval of the
label on May 17, 2018. And the Rehni, Liu, and Kokkoris articles
- 38 -following traumatic brain injury (TBI) or stroke. The review
cites, among other studies, the 2011 Liu study and emphasizes that
"CGRP administered at the onset of reperfusion produced a
significant reduction in infarct volume, [blood-brain barrier]
permeability and cerebral oedema following rodent stroke,"
suggesting that CGRP plays a role in stabilizing the blood-brain
barrier. The review also discusses how CGRP is involved in
angiogenesis, or the development of new blood vessels. See
Angiogenesis, Stedman's Medical Dictionary 86 (28th ed. 2006).
The third of these articles, the 2018 Zhai study,27 was
published nearly a year after Aimovig's BLA submission and only
one month before the FDA's approval of the Aimovig label. In this
study, researchers compared "CGRP knockout mice" -- mice
genetically modified to no longer produce CGRP -- with wild mice
that were administered human CGRP. Researchers then placed the
two groups under conditions of cerebral ischemia by blocking blood
flow in the external carotid artery. The study's findings
indicate that mice that could not produce CGRP exhibited "increased
blood-brain barrier damage-related factors," suggesting that "CGRP
deficiency leads to greater [blood-brain barrier] damage during
were all published prior to the submission of Aimovig's BLA.
See Liuyu Zhai et al., Endogenous Calcitonin Gene-Related
27
Peptide Suppresses Ischemic Brain Injuries and Progression of
Cognitive Decline, 36 J. Hypertension 876 (2018).
- 39 -chronic cerebral ischemia." And "[t]he mechanisms underlying
hypoxic–ischemic brain damage include death of neuronal and glial
cells and loss of integrity of the blood–brain barrier." The
authors noted that "[s]tudies have shown there is a significant
association between [blood-brain barrier] dysfunction and vascular
cognitive impairment." Thus, cognitive disorder "may be in part
attributable to damage to the [blood-brain barrier]." As a result
of not being able to produce CGRP, the knockout mice also suffered
from "more extensive neuronal cell damage"; "more extensive
irreversible cell damage";28 "delayed recovery of cerebral blood
flow"; higher levels of "demyelination" 29 and "astrocyte
activation";30 a reduction in "compensative capillary formation";
28The study also found that CGRP-deficient mice had
"significantly increased expression of adrenomedullin in the
cerebral cortex," which "may reflect compensation for the CGRP
deficiency," though we do not find that the study concluded that
such possible compensation outweighed or prevented the
irreversible cell damage.
Demyelination is the "[l]oss of myelin, with preservation
29
of the axons or fiber tracts." Demyelination, Stedman's Medical
Dictionary, supra, at 509. The myelin sheath is an "envelope"
that "surround[s] most axons," Myelin Sheath, Stedman's Medical
Dictionary, supra, at 1758–59, which are the parts of nerve cells
that "conduct[] nervous impulses away from the cell body," Axon,
Stedman's Medical Dictionary, supra, at 191.
An astrocyte is " [o]ne of the large neuroglia cells of
30
nervous tissue." Astrocyte, Stedman's Medical Dictionary, supra,
at 171. Neuroglia are "[n]onneuronal cellular elements of the
central and peripheral nervous system" that have "important
metabolic functions" because they are "invariably interposed
between neurons and the blood vessels supplying the nervous
system." Neuroglia, Stedman's Medical Dictionary, supra, at 1310.
- 40 -and "more severe disturbance of memory." The authors concluded
that, in addition to stabilizing the blood-brain barrier, "CGRP
may also suppress inflammation and oxidative stress, promote
angiogenesis and exert a direct antiapoptotic effect."31
The district court found that none of these four articles
constituted newly acquired information. As to the Rehni and Liu
studies, the district court concluded that "[t]he DCRP [had]
reviewed 'the world's literature' before preparing its report on
the theoretical risks associated with CGRP antagonism," and so
"[i]t is not plausible that articles bearing on that subject,
published at least four years before the DCRP began preparing its
report, 'reveal risks of a different type or greater severity or
frequency than previously included in submissions to FDA.'"
Warner, 2025 WL 490720, at *10. The district court also concluded
that the Sorby-Adams literature review could not plausibly
constitute newly acquired information because that review relied
upon the Liu study. Id. As to the 2018 Zhai study, the district
court found this study "too attenuated from Warner's claim to
plausibly constitute newly acquired information." Id. at *11. As
part of its reasoning, the district court determined that "the
study does not address whether its findings about mice with a CGRP
deficiency generalize to drugs, like Aimovig, that are CGRP
Apoptosis is the process of "[p]rogrammed cell death."
31
Apoptosis, Stedman's Medical Dictionary, supra, at 121.
- 41 -antagonists" and that Warner had not cited, nor had the court
uncovered, "any precedent for treating a single animal study not
involving the manufacturer's drug as newly acquired information."
Id.
We are inclined to read the record as the district court
did. But at the same time -- and without the benefit of any expert
testimony -- we find that inclination falls short of allowing us
to conclude with certainty that the CBE procedure would have
failed. See Burt, 84 F.4th at 50 (requiring an affirmative defense
be "establish[ed] . . . with certitude" in order to uphold a
court's grant of a motion to dismiss based on that defense
(citation modified)).
For example, we are not convinced by the district court's
assumption that the FDA must have reviewed the Rehni and Liu
studies as part of its review of the "world's literature." The
FDA's review of the "world's literature" was limited to "published
evidence concerning a theoretical risk conferred by [CGRP]
antagonism via any mechanism of worsened ischemia due to impairment
of compensatory vasodilation in the setting of ischemic vascular
events." Nothing in the record suggests that the FDA reviewed the
"world's literature" concerning the possible role of CGRP's effect
on the blood-brain barrier or its possible neuroprotective effects
outside of vasodilation -- or, for that matter, the "attenuat[ing]"
impact of CGRP antagonism as it relates to the neuroprotective
- 42 -effects of ischemic preconditioning.32 We also find no evidence
in the record as it now stands that the Rehni study, Liu study,
Zhai study, or the Sorby-Adams literature review were brought to
the FDA's attention. Nor does Amgen point us toward any analysis
by the FDA of CGRP's effect on the blood-brain barrier in the
setting of cerebral injury.33 At this stage in the proceedings,
we cannot draw a determinative inference against Warner that the
FDA's world-literature review included studies on CGRP's role in
protecting or stabilizing the blood-brain barrier when Amgen
itself points to no language or analysis from the FDA suggesting
as much.
Contrary to Amgen's assertions, the publication dates of
these articles are also not dispositive of whether a study
32 This is not to say that the FDA was not at all aware of
some possible neuroprotective effects of CGRP in the setting of
cerebral injury. Indeed, and as we noted previously, the FDA had
cited to a study regarding the possible protective effects of
elevated CGRP levels following subarachnoid hemorrhage. But Amgen
does not reference this study in its briefing or provide the study
in the record for our review. Without anything more, we cannot
assess whether this study relates to neuroprotective effects of
CGRP outside of its vasodilatory role. Such technical matters
serve as a reminder that at this stage in the proceedings, our
role is not to determine whether the studies and articles submitted
by Warner constitute newly acquired information; rather, we ask
only whether we can say with certitude that they do not.
33 Indeed, as Aimovig had only been studied in healthy
populations without such histories, the FDA was under the
impression that only a "very small fraction" of Aimovig could cross
the blood-brain barrier. This reference was included in passing
and only as a reason for the Controlled Substance Staff at the FDA
declining to review Aimovig's BLA submission.
- 43 -constitutes newly acquired information. A study published prior
to the approval of a drug or biologic's label may still qualify as
newly acquired information if it had not been "previously
submitted" to the FDA. Celexa, 779 F.3d at 42 (quoting 21 C.F.R.
§ 314.3(b)); see also 21 C.F.R. § 601.12(f)(6) (parallel
regulation for biologics). And, as the Supreme Court has stated,
newly acquired information "also encompasses 'new analyses of
previously submitted data'" to "account[] for the fact that risk
information accumulates over time and that the same data may take
on a different meaning in light of subsequent developments."
Wyeth, 555 U.S. at 569 (quoting Supplemental Applications
Proposing Labeling Changes for Approved Drugs, Biologics, and
Medical Devices, 73 Fed. Reg. at 49604).
Nor are we certain that the Zhai study fails to qualify
as newly acquired information because the article does not discuss
whether its findings of CGRP deficiency in mice can be generalized
to CGRP antagonism in humans. Although labeling requirements for
human prescription drugs and biologic products provide that "[t]he
labeling must be based whenever possible on data derived from human
experience," conclusions based on "animal data" that are
"necessary for safe and effective use of the drug in humans must
[also] be identified as such and included with human data in the
appropriate section of the labeling." 21 C.F.R. § 201.56(a)(3).
Indeed, the parties agree that "FDA guidance permits theoretical
- 44 -warnings 'if the animal data raises substantial concern about the
potential for . . . adverse reaction in humans.'" As Aimovig was
the first drug of its kind to be reviewed by the FDA, the FDA
relied largely on animal studies, including studies on canines and
rats. And the FDA did not restrict its review of studies to those
administering Aimovig or a similar CGRP antagonist. For example,
when the FDA considered the "world's literature," it reviewed two
canine studies where "[n]o [CGRP] antagonist was administered."
The FDA also considered rat studies, including a study on diabetic
rat hearts where researchers did not administer a CGRP antagonist,
as well as studies discussing the use of CGRP knockout mice. We
see no clear reason why we should certainly exclude animal studies
related to CGRP in our assessment of newly acquired information if
the FDA did not do the same.
Viewed together, the Rehni study, the Liu study, the
Sorby-Adams literature review, and the Zhai study plausibly
suggest risks of CGRP antagonism outside of its effect in
regulating blood flow in the body. The Rehni study seems to
indicate that the neuroprotective effects of ischemic
preconditioning may be "attenuated" or "abolished" by a CGRP
antagonist. Meanwhile, the Liu, Sorby-Adams, and Zhai articles
seem to indicate that CGRP deficiency is related to greater bloodbrain barrier damage in the setting of cerebral injury as well as
irreversible cell death in the brain and disturbances in memory.
- 45 -Based on the record before us, we cannot say with certitude that
Warner has failed to plausibly allege a "reasonable basis" to view
the articles by Rehni, Liu, Zhai, and Sorby-Adams collectively as
"reveal[ing] risks of a different type or greater severity or
frequency than previously included in submissions to [the] FDA."
Zofran, 57 F.4th at 337 (quoting 21 C.F.R. § 314.3(b)); see also
21 C.F.R. § 601.12(f)(6) (parallel regulation for biologics).
2.
We turn now to the second prong of our CBE inquiry, which
requires Warner to allege facts plausibly showing a reasonable
basis for establishing that the proposed change is "for the purpose
of accomplishing" one of five permissible objectives under the CBE
procedure.34 Celexa, 779 F.3d at 37. Our discussion here is
34 A manufacturer may use the CBE procedure to supplement a
label "to accomplish any of the following":
(A) To add or strengthen a contraindication,
warning, precaution, or adverse reaction for
which the evidence of a causal association
satisfies the standard for inclusion in the
labeling under § 201.57(c) of this chapter;
(B) To add or strengthen a statement about
abuse, dependence, psychological effect, or
overdosage;
(C) To add or strengthen an instruction about
dosage and administration that is intended to
increase the safety of the use of the product;
and
(D) To delete false, misleading, or
unsupported indications for use or claims for
effectiveness.
- 46 -brief, as the parties do not dispute that Warner's proposed changes
if adopted would serve "[t]o add or strengthen" a "warning,
precaution, or adverse reaction" on Aimovig's label. 21 C.F.R.
§ 601.12(f)(2)(i)(A). "Warnings and precautions" include
"clinically significant adverse reactions," as well as "potential
safety hazards (including those that are expected for the
pharmacological class or those resulting from drug/drug
interactions)." Id. § 201.57(c)(6)(i). Meanwhile, an "adverse
reaction" is defined as "an undesirable effect, reasonably
associated with use of a drug, that may occur as part of the
pharmacological action of the drug or may be unpredictable in its
occurrence." Id. § 201.57(c)(7) (emphases added). At this stage
in the proceedings, based on the facts presented by Warner in the
Liu, Sorby-Adams, and Zhai articles, we cannot say with certainty
that the labeling changes Warner proposes would not serve the
purpose of "add[ing] or strengthen[ing]" the "warning[s],
precaution[s], or adverse reaction[s]" on Aimovig's label. Id.
§ 601.12(f)(2)(i)(A).
(E) Any labeling change normally requiring a
supplement submission and approval prior to
distribution of the product that FDA
specifically requests be submitted under this
provision.
21 C.F.R. § 601.12(f)(2)(i)(A)-(E).
- 47 -3.
Finally, we turn to the issue of causal association. We
similarly treat this issue as a question of law based on the record
as it now stands, noting that many of the factual questions in our
preemption analysis are "subsumed within an already tightly
circumscribed legal analysis." Albrecht, 587 U.S. at 317.
Both the "warnings and precautions" and "adverse
reactions" sections of a label have their own distinct causal
association requirements. For "warnings and precautions," a
manufacturer "must" revise the label "as soon as there is
reasonable evidence of a causal association with a drug." 21
C.F.R. § 201.57(c)(6)(i) (emphasis added). On the other hand, to
add an adverse reaction to the label, the manufacturer need only
have "some basis to believe there is a causal relationship between
the drug and the occurrence of the adverse event." Id.
§ 201.57(c)(7) (emphasis added). But in either context, the
requirement of a causal association is not "intended to suggest
that there is a mathematically precise distinction between whether
there is, or is not, sufficient evidence of a causal relation
between a drug and an adverse effect." Supplemental Applications
Proposing Labeling Changes for Approved Drugs, Biologics, and
Medical Devices, 73 Fed. Reg. at 49604. Indeed, because
"causation need not have been 'definitely established' for a
- 48 -warning to be required," the "standard [can] be met by a wide range
of evidence." Id. (quoting 21 C.F.R. § 201.57(c)(6)(i)).
Because the district court hinged its futility finding
primarily on its conclusion that the articles Warner provided did
not constitute newly acquired information, it understandably
dedicated only a few sentences to the causal association prong of
the analysis, declaring that "none of the articles link Aimovig or
any other CGRP-blocking drug to an adverse event or risk." Warner,
2025 WL 490720, at *9. On appeal, the parties disagree as to the
specific causal association required in this case. Amgen suggests
that Warner must show a "plausible connection between Aimovig and
an increased risk of seizures in people with an AVM or a history
of seizures" like Lucas. Warner insists she "does not need . . .
to show that Aimovig was associated with an increased risk of
seizures." Rather, she asserts that the newly acquired
information "establishes that Aimovig contributed to triggering or
worsening the effects of Lucas's seizure by, for example, weakening
his blood-brain barrier," and thus "[s]he need only allege
Aimovig's association with damage that Lucas experienced, such as
worsened outcomes following cerebral injury."35 (Emphasis added).
35At oral argument, Amgen contended that Warner's theory was
premised only on Aimovig causing seizures, and thus Warner had
waived any claim "that CGRP was somehow protective and that
protective ability was lost from taking Aimovig." We disagree.
At the motion hearing before the district court, Warner argued
that "evidence in the record" explained "that part of Lucas's
- 49 -We agree with Warner. At this stage in the proceedings,
expert testimony has not yet established the exact causal chain
between CGRP inhibition and each symptom suffered by Lucas. And
because "precise knowledge of the chain of events . . . may often
be unavailable to a plaintiff" at the motion to dismiss stage, "we
take to heart the Supreme Court's call to 'draw on our judicial
experience and common sense as we make a contextual judgment about
the sufficiency of the pleadings.'" Fortuño-Burset, 640 F.3d at
16 (quoting Sanchez v. Pereira-Castillo, 590 F.3d 31, 48 (1st Cir.
2009)). In making that judgment based on the record as it now
stands, we are simply not certain that there is no causal
relationship between Aimovig and the extent of the injuries Lucas
experienced.
We are also not convinced by Amgen's argument that the
studies "do not discuss Aimovig" and thus cannot satisfy the causal
association standard. We do not read the regulations defining
warnings and precautions under 21 C.F.R. § 201.57(c)(6)(i) and
adverse reactions under § 201.57(c)(7) to be so restrictive.
injury was that the drug might have crossed the blood-brain
barrier." This was consistent with scientific studies, claimed
Warner, regarding how "the activation of CGRP in the brain . . .
protects the blood-brain barrier and . . . protects the brain from
the effects of stroke." And in her motion for leave to amend her
complaint, Warner again provided that the articles she submitted
constituted newly acquired information that "illuminated cerebral
risks not considered by the FDA," including that CGRP "helps
stabilize the blood-brain barrier" and that "[b]locking CGRP risks
disrupting this protective mechanism."
- 50 -Those regulations define an adverse reaction as an "undesirable
effect, reasonably associated with use of a drug, that may occur
as part of the pharmacological action of the drug or may be
unpredictable in its occurrence." Id. § 201.57(c)(7). Nothing
in this definition requires that the inclusion of an adverse
reaction in labeling be based solely on clinical studies of the
drug itself. And FDA guidance documents provide that "[t]here are
circumstances in which an adverse reaction that has not been
observed with a drug can nonetheless be anticipated to occur."
FDA, Warnings and Precautions, Contraindications, and Boxed
Warning Sections of Labeling for Human Prescription Drug and
Biological Products -- Content and Format 5 (2011),
https://www.fda.gov/media/71866/download [https://perma.cc/634TUDZE].36 That guidance further instructs that the Warnings and
Precautions section of a drug label should include "anticipated"
adverse reactions if "[i]t appears likely that the adverse reaction
will occur with the drug based on what is known about the
pharmacology, chemistry, or class of the drug" or if "[a]nimal
data raises substantial concern about the potential for occurrence
36These documents, though not binding, accord with our
reading of the regulations regarding biologic labeling and the
pertinent definitions of "warnings and precautions" and "adverse
reactions" under those regulations. We also reject Amgen's
argument that Warner waived reliance on this guidance by not citing
it in her supplemental brief to the district court, which was
limited to five pages in length at the court's direction.
- 51 -of the adverse reaction in humans." Id. This guidance is
relevant to our analysis of the facts in this case. As we have
previously stated, Aimovig was the first drug of its kind to be
approved or even reviewed by the FDA, and, as such, the FDA
reviewed multiple animal studies that did not involve the
administration of Aimovig or even a CGRP antagonist to study the
pertinent risks of the drug. We decline to read into the
regulations a more restrictive lens than that required by FDA
guidance and the FDA's own review of the biologic in this case.
In the setting of cerebral ischemia, the four articles
submitted by Warner can be read as finding an association between
CGRP antagonism and the dilution of neuroprotective effects from
ischemic conditioning, as well as a relationship between CGRP
inhibition and an increase in blood-brain barrier permeability,
irreversible cell death, and damage to memory function. Based on
these studies, Warner posits that blocking CGRP in patients with
Lucas's history would be causally associated with a greater risk
of cerebral harm in situations "where CGRP response could be
protective." And, because the blood-brain barrier may be damaged
in the setting of cerebral injury under conditions such as stroke,
Warner argues that her submitted articles "suggest[] that blocking
CGRP could accelerate the death of oxidatively stressed neurons in
a variety of neurological emergencies, raising concern that
- 52 -patients on a CGRP-blocker could face more disastrous outcomes in
the settings of brain injury."
Based on the foregoing and as the record now stands, we
are not certain that the Rehni, Liu, Sorby-Adams, and Zhai articles
do not present "reasonable evidence of a causal association" or,
alternatively, "some basis to believe there is a causal
relationship" between Aimovig and worsened outcomes in cases of
cerebral injury in individuals with a history of seizure or
cerebrovascular disease such as Lucas. See 21 C.F.R
§ 201.57(c)(6)(i), (c)(7). This satisfies the causal association
prong of our inquiry into Amgen's affirmative defense at this stage
of the case.
4.
Even given the foregoing, Amgen would still prevail in
its preemption defense if there was "clear evidence" that, had it
been informed of the three studies discussed above, the FDA would
still have rejected the label change that Warner says state tort
law required. See Zofran, 57 F.4th at 342. At this early stage
of the proceedings, however, Amgen has chosen not to rely on such
an argument to sustain the court's Rule 15(a) futility
determination regarding Warner's request to amend her complaint.
Nor did the district court. We conclude that Warner's proposed
amendment -- as limited to the four articles that Amgen has failed
to conclusively establish do not plausibly constitute newly
- 53 -acquired information -- would not have been futile. We therefore
do not consider the merits of this reserved defense.
IV.
For the foregoing reasons, we reverse the district
court's rejection of Warner's request to amend her complaint -- but
only to the limited extent that Warner asserts a claim that the
Rehni, Liu, Sorby-Adams, and Zhai articles enabled Amgen to use
the CBE procedure to amend its approved label to reflect a concern
that Aimovig could reduce the protective mechanisms of CGRP in the
cerebral system in the setting of cerebral injury. The district
court's rulings are otherwise affirmed, and this case is remanded
for further proceedings consistent with this opinion. We award
no costs to either party.
- 54 -