In Re: Zofran (Ondansetron) Products Liability Lit v. ( 2023 )


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  •            United States Court of Appeals
    For the First Circuit
    No. 21-1517
    IN RE: ZOFRAN (ONDANSETRON) PRODUCTS LIABILITY LITIGATION
    HEATHER PERHAM, et al.,
    Plaintiffs, Appellants,
    v.
    GLAXOSMITHKLINE LLC,
    Defendant, Appellee,
    SUN PHARMACEUTICAL INDUSTRIES LTD.; SANDOZ, INC.; PROVIDENCE
    HEALTH SYSTEM; NOVARTIS PHARMACEUTICALS CORP.; MCKESSON
    CORPORATION; DOES 1 through 100, inclusive, TEVA PHARMACEUTICAL
    USA; GLAXOSMITHKLINE HOLDINGS (AMERICAS) INC.,
    Defendants.
    APPEAL FROM THE UNITED STATES DISTRICT COURT
    FOR THE DISTRICT OF MASSACHUSETTS
    [Hon. F. Dennis Saylor, IV, U.S. District Judge]
    Before
    Kayatta and Howard, Circuit Judges,
    and Walker, District Judge.*
    Louis M. Bograd, with whom Motley Rice LLC was on brief, for
    appellants.
    Lisa S. Blatt, with whom Amy Mason Saharia, J. Matthew Rice,
    Jami M. King, Williams & Connolly LLP, Scott A. Chesin, and Shook,
    *   Of the District of Maine, sitting by designation.
    Hardy & Bacon, were on brief, for appellee GlaxoSmithKline LLC.
    Matthew W.H. Wessler, Joanne Grace Dela Peña, Gupta Wessler
    PLLC, Ellen Noble, and Public Justice on brief for amici curiae
    American Association for Justice and Public Justice.
    Emily Ullman, Michael X. Imbroscio, Nicole Antoine, Paul W.
    Schmidt, and Covington & Burling LLP on brief for amicus curiae
    Pharmaceutical Research and Manufacturers of America.
    January 9, 2023
    KAYATTA, Circuit Judge.                 This appeal arises out of
    multidistrict      litigation         concerning      the   pharmaceutical          drug
    ondansetron     hydrochloride         (better       known   by   its      brand    name,
    Zofran),   which    is    commonly      taken    off-label       during     pregnancy.
    Plaintiffs      claim     that    GlaxoSmithKline           (GSK),        the    company
    responsible for initially putting Zofran on the market and for
    manufacturing the drug until 2015, should be held liable under
    various state product liability laws for failing to warn consumers
    that   animal    studies      revealed      adverse     effects      on    the    fetus,
    including birth defects -- a warning that does not appear on
    Zofran's federally approved label.                  The district court granted
    summary    judgment      in   favor    of    GSK,    finding     that     federal    law
    preempted plaintiffs' state law claims because there was clear
    evidence that the Food and Drug Administration (FDA) would have
    rejected the warning that plaintiffs allege is required under state
    law.   We affirm the district court's grant of summary judgment.
    Our reasoning follows.
    I.
    A.
    We begin by detailing the complex federal regulatory
    scheme governing pharmaceutical drug labels.                 Congress enacted the
    Food, Drug, and Cosmetic Act (FDCA) in 1938 "to bolster consumer
    protection against harmful products."                 Wyeth v. Levine, 
    555 U.S. 555
    , 574 (2009); see 
    21 U.S.C.A. §§ 301
     et seq.                   Pursuant to that
    - 3 -
    statute, drug companies cannot sell or market a new pharmaceutical
    drug product without prior approval from the FDA.                   See 
    21 U.S.C. § 355
    (a).    To obtain this approval, a manufacturer (also commonly
    referred to as the drug's sponsor) must submit comprehensive
    information about the drug to the FDA in a New Drug Application.
    See 
    id.
     § 355(b)(1). During this process, the FDA reviews a drug's
    safety and efficacy as well as the drug's proposed labeling.                      See
    id.
    The FDA extensively regulates the format and substance
    of the information that appears on a drug's label.                   See, e.g., 
    21 C.F.R. §§ 201.56
    , 201.57.           In so doing, one of its objectives is
    to "prevent overwarning, which may deter appropriate use of medical
    products, or overshadow more important warnings."                       Supplemental
    Applications      Proposing      Labeling       Changes    for    Approved    Drugs,
    Biologics, and Medical Devices, 
    73 Fed. Reg. 49603
    , 49605–06
    (Aug. 22, 2008). It therefore "allow[s] only information for which
    there is a scientific basis to be included in the FDA-approved
    labeling."        
    Id. at 49604
    .         And   it   guards       against   the
    "[e]xaggeration      of     risk,       or     inclusion    of    speculative     or
    hypothetical risks."       Supplemental Applications Proposing Labeling
    Changes for Approved Drugs, Biologics, and Medical Devices, 
    73 Fed. Reg. 2848
    , 2851 (Jan. 16, 2008).
    The   FDA     also    has     an   extensive    set    of    regulations
    governing the use of drugs during pregnancy.                        To obtain FDA
    - 4 -
    approval for any such use, a drug's sponsor must include in its
    application, among other things, an "integrated summary of the
    toxicological effects of the drug in animals," including "tests of
    the drug's effects on reproduction and the developing fetus."                   
    21 C.F.R. § 312.23
    (a)(8)(ii)(a).
    At the time Zofran was initially approved by the FDA,
    the FDA classified drugs into five categories of safety for use by
    pregnant   people:   A,    B,   C,    D,     and    X.        See   
    21 C.F.R. § 201.57
    (c)(9)(i)(A)      (2006).       Each       category    came      with    a
    standardized set of warnings.          
    Id.
         Under the then-applicable
    regulations, if animal studies "failed to demonstrate a risk to
    the fetus and there [were] no adequate and well-controlled studies
    in pregnant women," the drug would be classified into Pregnancy
    Category B and include the following label:
    Pregnancy Category B.    Reproduction studies
    have been performed in (kind(s) of animal(s))
    at doses up to (x) times the human dose and
    have   revealed  no   evidence   of   impaired
    fertility or harm to the fetus due to (name of
    drug).   There are, however, no adequate and
    well-controlled studies in pregnant women.
    Because animal reproduction studies are not
    always predictive of human response, this drug
    should be used during pregnancy only if
    clearly needed.
    
    21 C.F.R. § 201.57
    (c)(9)(i)(A)(2).           If, however, animal studies
    "show[ed] an adverse effect on the fetus, if there [were] no
    adequate and well-controlled studies in humans, and if the benefits
    from the use of the drug in pregnant women may be acceptable
    - 5 -
    despite its potential risks," the drug would be categorized into
    Pregnancy Category C.     
    21 C.F.R. § 201.57
    (c)(9)(i)(A)(3).         The
    label would then need to include the following statement:
    Pregnancy Category C. (Name of drug) has been
    shown to be teratogenic1 (or to have an
    embryocidal effect or other adverse effect) in
    (name(s) of species) when given in doses (x)
    times the human dose. There are no adequate
    and well-controlled studies in pregnant women.
    (Name of drug) should be used during pregnancy
    only if the potential benefit justifies the
    potential risk to the fetus.
    
    Id.
       In Category C, the label "must contain a description of the
    animal studies."    
    Id.
    The current regulations, promulgated in 2014 as the
    Pregnancy and Lactation Labeling Rule (PLLR), no longer use risk
    categories   for   pregnancy-drug   labels.    See    Requirements   for
    Pregnancy and Lactation Labeling, 
    79 Fed. Reg. 72064
    , 72076-77
    (Dec. 4, 2014).    Instead, the PLLR requires that labels contain a
    risk statement summarizing animal and human studies, with distinct
    subsections describing animal and human data.        See 
    id.
    After the FDA approves a label for a drug, that label is
    not immutable.     That is because knowledge about a drug's safety
    and efficacy can change over time.      Accordingly, the FDA provides
    several pathways for a drug manufacturer, citizen, or the agency
    itself to make changes to a drug's label.
    1 Teratogenicity refers to a drug's ability to cause defects
    in a developing fetus.
    - 6 -
    First, a drug manufacturer can file a Prior Approval
    Supplement (PAS) with the FDA to request revisions to a label.
    See 
    21 C.F.R. § 314.70
    (b). The PAS procedure resembles the process
    for obtaining initial approval for the drug's label and requires
    the FDA to approve the change in the label before it can be made.
    Second, a drug manufacturer can use the Changes Being
    Effected (CBE) regulations to unilaterally amend a label and seek
    after-the-fact     approval      from   the   FDA.      See   
    21 C.F.R. § 314.70
    (c)(6)(iii).      The CBE procedure permits manufacturers to
    change a label "to reflect newly acquired information" if the
    changes "add or strengthen a . . . warning" for which there is
    "evidence of a causal association."            Id.; see also 
    21 C.F.R. § 201.57
    (c)(6).    Although a manufacturer initiates this process,
    "the FDA reviews CBE submissions and can reject label changes even
    after the manufacturer has made them," and "manufacturers cannot
    propose a change that is not based on reasonable evidence."           Merck
    Sharp & Dohme Corp. v. Albrecht, 
    139 S. Ct. 1668
    , 1679 (2019).
    Third,    the    FDA     permits    private   individuals    and
    organizations to request changes to a drug's             label   based on
    "reasonable evidence of an association of a serious hazard with a
    drug." 
    21 C.F.R. § 201.80
    (e); see 
    21 C.F.R. § 10.30
    (b)(3); Cerveny
    v. Aventis, Inc., 
    855 F.3d 1091
    , 1102 (10th Cir. 2017).
    Fourth, the FDA, on its own initiative, must notify a
    drug manufacturer of the need to submit a supplement proposing
    - 7 -
    changes    to    a    drug's     label   if   the    FDA    becomes   aware    of   new
    information, including safety information, that it determines
    should be included in the drug label.                 
    21 U.S.C. § 355
    (o)(4)(A),
    (B).
    B.
    With this regulatory background in mind, we walk through
    the events that gave rise to the present appeal.                      Zofran is an
    FDA-approved prescription drug for the prevention of chemotherapy-
    induced,    radiation-induced,            and       post-operative     nausea       and
    vomiting.       Although Zofran has never been approved for preventing
    pregnancy-related nausea and vomiting, it is often prescribed off-
    label for that purpose.           GSK owned Zofran from 1991, when the drug
    first received FDA approval, until 2015, when GSK sold the rights
    to manufacture and market the drug to the pharmaceutical company
    Novartis.       Zofran remains on the market, and its label does not
    currently warn of an association between its use and pregnancy-
    related risks, including birth defects.
    As       part   of   Zofran's     New    Drug    Application      approval
    process in 1990 and 1991, GSK submitted data related to Zofran's
    safety and efficacy to the FDA.                The data included a set of four
    animal reproductive studies conducted on rats and rabbits in the
    United Kingdom (study nos. R10590 (UK Oral Rat Study), and R10937
    (UK IV Rat Study), L10649 (UK Oral Rabbit Study), L10873 (UK IV
    Rabbit Study)).             Although the investigators in those studies
    - 8 -
    observed    some    incidences     of    birth    defects   among    the   animal
    subjects, the studies did not conclude that there was a causal
    association between Zofran and birth defects.                  In brief, defects
    can and do occur in the absence of Zofran, and the studies did not
    reveal a statistically significant gap between the number of
    defects seen in subjects treated with Zofran and the control
    groups.    The FDA, in an internal pharmacological review associated
    with the approval of Zofran, assessed the four UK animal studies
    and concluded that the drug did not induce a teratogenic effect.
    GSK also sponsored animal studies in Japan in the late
    1980s to satisfy Japanese regulatory requirements.                 These studies
    included    three    rat   and     rabbit       reproductive     studies   (study
    nos. 100422 (Japan Submitted Oral Rat Study), 100424 (Japan IV Rat
    Study), and 100441 (Japan Oral Rabbit Study)) and a preliminary
    animal    study    designed   to    select       appropriate     dosages   (study
    no. 100423 (Japan Preliminary Dosage Study)), all of which GSK
    characterizes in this appeal as "parallel" to the UK studies.                 The
    Japanese studies used the same types of animals (rats and rabbits)
    and the same formulations of the drug (oral and intravenous) as
    the UK studies.      None of these studies, however, were included in
    GSK's New Drug Application filed with the FDA.2                  As will become
    2  The studies were disclosed by name and number in a list
    with dozens of other studies in a 1993 GSK annual report published
    after Zofran was approved. That report described the studies as
    "[s]tudies performed specifically to satisfy Japanese regulatory
    - 9 -
    clear, plaintiffs focus their appeal on the three Japanese studies
    not originally submitted to the FDA: the Japan Preliminary Dosage
    Study, the Japan IV Rat Study, and the Japan Oral Rabbit Study.
    When Zofran was       first approved    by the FDA, it was
    categorized into Pregnancy Category B, because animal studies had
    not shown evidence of teratogenicity (under the then-applicable
    risk categorization regulations).         The next designation, Pregnancy
    Category C, would have been appropriate if, among other things,
    animal studies had shown that the drug was teratogenic -- i.e.,
    that the drug was causally related to birth defects when taken
    during a pregnancy.        The FDA ultimately approved four additional
    New Drug Applications for varying Zofran formulations in 1992,
    1995, 1997, and 1999, classifying each in Pregnancy Category B.
    In 1997, in connection with the New Drug Application for
    one of Zofran's formulations (the oral solution), GSK submitted a
    translated version of the Japan Submitted Oral Rat Study to the
    FDA.    The FDA, in an internal pharmacological review that included
    an     assessment    of   that   study,   noted   that   Zofran   "was   not
    teratogenic."       In that same review, the FDA also explained that
    the results in that study were "comparable to those [in the]
    teratogenic study in female rats that was included in the original
    submission."        The oral solution formulation of Zofran, like the
    requirements" and as "either repetitive or provid[ing] no new
    significant safety information."
    - 10 -
    other formulations, was classified into Pregnancy Category B.            GSK
    did not submit the Japan Preliminary Dosage Study, the Japan IV
    Rat Study, or the Japan Oral Rabbit Study with any of the New Drug
    Applications for the various formulations of Zofran.
    Over the next several years, the FDA reviewed a number
    of requests for label changes to Zofran related to the potential
    link between Zofran and birth defects, as outlined below.
    2010 FDA Review.     In 2010, because of its awareness of
    the frequency with which Zofran was used during pregnancy, the FDA
    asked GSK to review and analyze the literature on the use of Zofran
    during pregnancy and provide an assessment of the data.            The FDA
    also requested that GSK propose labeling changes to Zofran if
    needed   through   the   PAS   procedure.     GSK     responded   in   2011,
    concluding that it "d[id] not believe there [wa]s sufficient
    evidence to warrant a change" to the label.              The FDA did not
    conduct further action related to this request.
    2013    Reichmann   Citizen    Petition.      In   2013,    James
    Reichmann, a private individual, submitted a citizen petition
    asking the FDA to revise Zofran's pregnancy-related labeling and
    to reclassify Zofran's pregnancy category.          The FDA rejected the
    petition, concluding that the totality of the data it had at the
    time "d[id] not support a conclusion that there is an increased
    risk of fetal adverse outcomes."     The Japanese animal studies were
    - 11 -
    not provided to the FDA or referenced in connection with the 2013
    citizen petition.
    2015 Novartis PAS.      In 2015, after Novartis acquired
    Zofran from GSK, Novartis assumed responsibility for amending
    Zofran's label to conform with the PLLR, the pregnancy labeling
    regime that replaced the prior risk categorization system.                 Using
    the PAS process, Novartis proposed a set of warnings advising
    against use of Zofran during pregnancy, based on published human
    data suggesting the possibility of an increased risk of major birth
    defects or congenital malformations associated with such use.
    Novartis did not refer to the Japanese animal studies.
    The FDA rejected the labeling proposals.          In particular,
    the FDA rejected Novartis's proposal to add the following language:
    "Animal studies are not always predictive of human response,
    therefore, the use of ondansetron in pregnancy is not recommended."
    The agency explained: "We do not agree with keeping this statement
    in labeling based on the available human information."                Novartis
    and the FDA engaged in additional rounds of revisions before the
    FDA approved the new Zofran label in 2016.               The approved label
    indicated   that   "[a]vailable   data     do    not    reliably    inform    the
    association   of   ZOFRAN   and   adverse       fetal   outcomes"    and     that
    "[r]eproductive studies in rats and rabbits did not show evidence
    of harm to the fetus."
    - 12 -
    2019 GSK Citizen Petition.       In 2019, GSK filed its own
    citizen petition with the FDA to obtain clarification from the
    agency on whether the information identified by plaintiffs in their
    suit "contain[ed] any new and material information about Zofran"
    that would necessitate a change to the drug's label.           The petition
    sought review of, among other things, translated versions of the
    Japan Preliminary Dosage Study, the Japan IV Rat Study, and the
    Japan Oral Rabbit Study -- the studies plaintiffs rely on -- by
    the FDA for the first time.        GSK requested that the FDA "either
    refrain from taking action to alter Zofran’s pregnancy-related
    labeling or take action to alter the labeling" in light of the
    information submitted with the petition.
    In 2021, the FDA denied GSK's citizen petition, refusing
    to   undertake   any   updated   analysis   regarding    the   label.    It
    explained that GSK's "request that FDA review and opine on certain
    pieces of information to answer a hypothetical question separate
    and apart from FDA’s ongoing product review . . . would detract
    from fulfilling the Agency’s statutory obligations" and "is not
    the appropriate subject of a citizen petition."            Thus, the FDA
    expressly "decline[d] to conduct the evaluation [GSK] request[ed]
    related to the . . . information at issue in the litigation."
    2020 Novartis PAS.       While GSK's citizen petition was
    pending, Novartis submitted a PAS to the FDA based on "recently
    published [human] epidemiological studies."             Novartis proposed
    - 13 -
    changes to the Risk Summary and Human Data sections of the Zofran
    label to account for the new epidemiological studies.                  It did not,
    however, propose any changes to the Animal Data or Risk Summary
    sections reflecting findings from animal data.3
    In     response   to   Novartis's    PAS,   the   FDA    noted   that
    "[g]iven       the    inconsistency     in    published    findings      and    the
    limitations in the design of [human epidemiological] studies, an
    increased risk of fetal orofacial clefts4 from maternal ondansetron
    use cannot be concluded."            After another round of communications
    in which Novartis proposed to warn that an association between
    Zofran and birth defects "cannot be ruled out," the FDA repeated
    that       "[g]iven    inconsistencies       in   the   results   of    published
    epidemiological studies on the association between ondansetron use
    and major birth defects, we are not able to make any conclusions
    regarding the safety of ondansetron use in pregnancy."                    The FDA
    did permit Novartis to include a proposed paragraph in the Human
    Data section discussing the fact that "[s]everal studies have
    3In documentation submitted concurrently with the PAS,
    Novartis did inform the FDA that Zofran "did not affect embryo-
    fetal development in the rat or rabbit [studies] and had no adverse
    effects on fertility or on the general reproductive performance
    and the post-natal development of rats." In so doing, it discussed
    a recent study by plaintiffs' expert Dr. Bengt Danielsson as well
    as two peer-reviewed articles discussing the Japanese animal
    studies at issue here.
    4Orofacial clefts are openings or slits in the upper lip
    (cleft lip), roof of the mouth (cleft palate), or both.
    - 14 -
    assessed ondansetron and the risk of oral clefts with inconsistent
    findings."
    The final approved label from the Novartis PAS also
    included (unchanged from the previous version of the label) a
    sentence in the Risk Summary portion of the label that reads:
    "Reproductive studies in rats and rabbits did not show evidence of
    harm to the fetus when ondansetron was administered intravenously
    during organogenesis at approximately 3.6 and 2.9 times the maximum
    recommended human intravenous dose of 0.15 mg/kg given three times
    a day, based on body surface area, respectively."        Novartis did
    not propose changes to either the Risk Summary or the Animal Data
    section of Zofran's label based on animal studies.            Nor did
    Novartis or the FDA comment specifically on animal studies during
    the PAS process.
    C.
    In 2015, various plaintiffs filed separate suits in
    federal court alleging that the use of Zofran during pregnancy
    caused birth defects.   These suits were based in part on the theory
    that GSK engaged in an intentionally misleading plan to market
    Zofran for pregnancy in violation of state law by failing to warn
    that animal studies showed the drug's potential to harm pregnant
    people and fetuses when ingested during pregnancy.       The Judicial
    Panel   on    Multidistrict   Litigation   created   a   multidistrict
    - 15 -
    litigation proceeding for the individual suits, assigning the case
    to the District of Massachusetts.
    Eyeing a potential conflict between plaintiffs' state
    law claims and the federal labeling scheme described above, GSK
    moved for summary judgment before the district court on preemption
    grounds, arguing that federal law preempts all of plaintiffs' state
    law failure-to-warn claims.         In February 2019, the district court
    denied     GSK's   motion   for    summary        judgment,   concluding    that
    preemption raised issues of fact for the jury as to whether the
    Japanese    animal   studies      were    newly    acquired   information    and
    whether there was clear evidence that the FDA would not have
    approved the warnings sought by plaintiffs.               However, after the
    district court's decision, the Supreme Court decided Albrecht,
    which held that at least one portion of the preemption question is
    a matter of law for the judge to decide and not a matter of fact
    to be reserved for the jury.        See 
    139 S. Ct. at 1679
    .       Accordingly,
    the district court vacated its prior decision in part and allowed
    GSK to renew its motion for summary judgment, which GSK did.
    In June 2021, the district court granted GSK's renewed
    motion for summary judgment, holding that federal law preempts
    plaintiffs' state law claims.            Plaintiffs timely appealed.
    II.
    We review an order granting summary judgment de novo.
    Alston v. Town of Brookline, 
    997 F.3d 23
    , 35 (1st Cir. 2021).                 In
    - 16 -
    so doing, "we evaluate the facts of record in the light most
    flattering    to   the    nonmovant . . .    and   draw   all    reasonable
    inferences in that party's favor."         
    Id.
    III.
    This appeal broadly asks one critical question:          Whether
    federal law preempts plaintiffs' state law claims that GSK should
    have warned both prescribing doctors and pregnant people that
    "animal studies showed harm to the fetus when Zofran was ingested
    during pregnancy."       The Supremacy Clause provides that federal law
    "shall be the supreme Law of the Land; . . . any Thing in the
    Constitution or Laws of any State to the Contrary notwithstanding."
    U.S. Const. art. VI, cl. 2.      Accordingly, "[f]ederal law impliedly
    preempts state law 'where it is "impossible for a private party to
    comply with both state and federal requirements."'"             In re Celexa
    & Lexapro Mktg. & Sales Pracs. Litig., 
    779 F.3d 34
    , 40 (1st Cir.
    2015) (quoting Mut. Pharm. Co. v. Bartlett, 
    570 U.S. 472
    , 480
    (2013)).     The Supreme Court has instructed that preemption based
    on impossibility is a "demanding defense."           Wyeth, 
    555 U.S. at 573
    .   The district court assigned the burden of establishing
    impossibility to the defendant.           Neither party challenges that
    assignment.    See, e.g., Albrecht, 
    139 S. Ct. at 1678
     (referring to
    preemption as a "defense" requiring the manufacturer to show that
    federal law prohibited making plaintiffs' proposed label changes).
    - 17 -
    On appeal, plaintiffs contend that GSK failed to carry
    its burden of establishing impossibility.                    In support of this
    contention, plaintiffs advance a two-step argument.                     First, they
    argue that GSK has failed to show that it could not have employed
    the CBE procedure to change its label by treating the previously
    undisclosed      Japanese      animal    studies        as     "newly      acquired
    information."     Second, plaintiffs argue that "none of the FDA's
    actions [once fully informed] constitute clear evidence that the
    FDA would have rejected a stronger pregnancy warning concerning
    the animal study data."        We consider each step in turn.
    A.
    The parties dispute whether GSK ever possessed newly
    acquired    information     that   would       have    justified    unilaterally
    changing Zofran's label under the CBE procedure to disclose that
    animal studies indicated that the drug was teratogenic. In theory,
    this dispute poses a bit of a conundrum:              Must we determine whether
    the information qualifies as newly acquired information, or must
    we ask whether there is clear evidence that the FDA would have
    rejected    a   CBE   change   because       the   information     is    not   newly
    acquired?       Under the former inquiry, if a court finds as a
    threshold matter that there is no newly acquired information, then
    the failure to invoke the CBE procedure creates no bar to a
    - 18 -
    preemption defense.5         But, if the latter inquiry were called for,
    it would be quite difficult (although not impossible) to obtain
    clear evidence of the FDA's position in the form of "agency action
    carrying the force of law," Albrecht, 
    139 S. Ct. at 1679
    , in cases
    where the manufacturer never invoked the CBE procedure (perhaps
    because   the   manufacturer        reasonably      did    not    believe     the
    information was newly acquired).
    Albrecht can arguably be read as implying a middle
    ground, deeming the CBE procedure unavailable if there is no
    reasonable   basis     for    treating   the     information     identified    by
    plaintiffs as newly acquired information.                 
    139 S. Ct. at 1679
    (noting that "manufacturers cannot propose a change that is not
    based on reasonable evidence").
    In    this    particular       case,    we     need    not    determine
    definitively    whether       a   judicial     finding    of    newly   acquired
    information serves as a threshold prerequisite for determining
    that the CBE procedure was available to GSK.              All parties presume
    that it so serves.     Plaintiffs in particular repeatedly accept and
    present the framing of their argument as contingent in its first
    "step" on a finding that the Japanese animal studies constituted
    5  The Fourth Circuit recently adopted this inquiry as
    controlling, finding the CBE procedure unavailable based on the
    court's determination that the information at issue was not newly
    acquired. See Knight v. Boehringer Ingelheim Pharms., Inc., 
    984 F.3d 329
    , 339-41 (4th Cir. 2021).
    - 19 -
    "newly acquired information."           See, e.g., Appellant's Br. 28
    ("Plaintiffs'     argument   proceeds   in . . .     steps.      First,   the
    Japanese animal studies . . . are 'newly acquired information.'").
    Thus, we turn to assessing whether the three Japanese
    animal   studies    identified   by     plaintiffs    constituted     "newly
    acquired information" that would have permitted GSK to make use of
    the CBE procedure to unilaterally change Zofran's label (subject
    to after-the-fact FDA approval) in line with what plaintiffs allege
    is required under state law.6          Following the parties' lead, we
    proceed under the assumption that determining whether certain
    information is "newly acquired" is a legal question.             See Knight
    v. Boehringer Ingelheim Pharms., Inc., 
    984 F.3d 329
    , 337–38 (4th
    Cir. 2021) (concluding that preemption is a question of law that
    is reviewed de novo, and proceeding to determine, as part of its
    preemption   analysis,       whether     data   was     "newly      acquired
    information").7
    6  The district court assumed without deciding that the
    information in the Japanese animal studies was "newly acquired,"
    ultimately holding that plaintiffs' claims were preempted on other
    grounds.
    7  The Supreme Court has seemingly left open the question
    whether what constitutes "newly acquired information" is a
    question of law or a question of fact. In relevant part, Albrecht
    holds only that "the question of agency disapproval" in the
    evaluation of "clear evidence" under Wyeth is a question of law
    that a judge must decide.     Albrecht, 
    139 S. Ct. at 1679
    .    In
    reaching this conclusion, the Court pointed to factors that are
    specific to the question of "clear evidence." 
    Id. at 1680
     (noting
    that judges rather than juries are "better equipped to evaluate
    - 20 -
    The CBE procedure is available for "[c]hanges in [a
    drug's] labeling to reflect newly acquired information" in order
    "[t]o 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)."      
    21 C.F.R. § 314.70
    (c)(6)(iii)(A).         The     FDA
    regulations specify that "labeling must be revised to include a
    warning about a clinically significant hazard as soon as there is
    reasonable evidence of a causal association with a drug; a causal
    relationship need not have been definitely established." 
    21 C.F.R. § 201.57
    (c)(6)(i).      The      regulations    define     "newly   acquired
    information" to mean:
    data, analyses, or other information not
    previously submitted to the agency, which may
    include (but is not limited to) data derived
    from new clinical studies, reports of adverse
    events,   or   new  analyses  of   previously
    submitted 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 FDA.
    
    21 C.F.R. § 314.3
    (b).        This includes, among other things, "an
    increasing body of data of an inherent risk with the drug" and
    "new data from a clinical study evincing [a drug's] inefficacy."
    Celexa, 779 F.3d at 42.
    the nature and scope of an agency's determination").
    - 21 -
    Plaintiffs        argue       that    the    Japanese      animal    studies
    constitute "newly acquired information" under the CBE regulations
    for    three     reasons:       (1) the          studies      reveal     evidence        of
    teratogenicity that the animal studies GSK provided to the FDA did
    not;   (2) the    studies      are    meaningfully           different   from    the     UK
    studies; and (3) plaintiffs' regulatory expert Dr. Brian Harvey
    opined that the studies constitute "newly acquired information."
    We consider each reason in turn.
    1.
    Plaintiffs first assert that the three originally non-
    disclosed       Japanese       animal        studies         reveal      evidence        of
    teratogenicity that the prior studies disclosed to the FDA did
    not.   There is no dispute that GSK had previously submitted to the
    FDA four animal studies conducted in the UK and one animal study
    conducted in Japan.            And all agree that, after reviewing the
    previously      submitted     studies,       the     FDA     concluded    that    Zofran
    belonged in Pregnancy Category B.                  Accordingly, GSK could have
    changed its label pursuant to the CBE regulations only if the
    Japanese    studies        touted    by    plaintiffs        revealed    "risks     of    a
    different      type   or    greater       severity      or   frequency"    than     those
    identified in the previously submitted studies and also provided
    "reasonable evidence of a causal association" between Zofran and
    birth defects.        See 
    21 C.F.R. §§ 201.57
    (c)(6)(i), 314.3(b).
    - 22 -
    Plaintiffs make three assertions as to why the Japanese
    animal studies reveal evidence of teratogenicity not found in the
    prior studies.    According to plaintiffs, the studies reveal: an
    increase in embryofetal death in the 10 mg/kg IV treatment group
    of rats compared to the control group in the Japan Preliminary
    Dosage   Study;   an   increase   in   embryonic   death   and   increased
    incidences of major external malformations, including ventricular
    septal defects (a kind of heart defect), in the 10 mg/kg IV
    treatment group of rats compared to the control group in the Japan
    IV Rat Study; and an increase in skeletal defects in the 2.5 and
    10 mg/kg oral treatment groups of rabbits compared to the control
    group in the Japan Oral Rabbit Study.        These results, plaintiffs
    argue, are reasonable evidence of a causal association between
    Zofran and birth defects and demonstrate risks greater in number,
    magnitude, and kind than the studies previously presented to the
    FDA.
    The first problem for plaintiffs is that the risks they
    identify in the three Japanese studies -- embryofetal death, major
    malformations including ventricular septal defects, and skeletal
    defects -- were not found by the researchers in those studies to
    be attributable to Zofran.    For instance, in the Japan Preliminary
    Dosage Study, the investigators concluded that in the "10 mg/kg
    [treatment] group, there were no embryolethal, growth suppressive
    and teratogenic . . . effects on the fetuses."         So, although the
    - 23 -
    number of embryofetal deaths was greater in a treatment group
    compared to the control group in that study, the researchers
    nonetheless found that there was no statistically significant
    difference between the groups.          Similarly, although the Japan IV
    Rat    Study    revealed    instances       of    malformations,     including
    ventricular septal defects in two fetuses in the 10 mg/kg treatment
    group, the researchers again concluded that "[n]o significant
    differences were found between the [treatment] groups and the
    control group in the total number of fetuses with the above
    anomalies or variations and in . . . each incidence of these
    findings."     And, with respect to skeletal anomalies, in the Japan
    Oral Rabbit Study, the investigators observed that "[t]he effects
    of [treatment] were not observed in the incidences of external,
    visceral or skeletal anomalies and variations in fetuses, and there
    were    no     findings    indicating       the   teratogenicity     of    [the
    treatment]."
    To be sure, the relevant FDA regulations explain that,
    with   respect    to   determining      whether    "evidence    of   a    causal
    association" exists for purposes of the CBE regulations, 
    21 C.F.R. § 314.70
    (c)(6)(iii), "a causal relationship need not have been
    definitely established" and only "reasonable evidence of a causal
    association" between a risk and a drug need be shown.                
    21 C.F.R. § 201.57
    (c)(6)(i).        However, each of the three studies to which
    plaintiffs     point   concluded     that    there   was   no   statistically
    - 24 -
    significant relationship between Zofran and observed birth defects
    in    animal    subjects   --   that    is,    the   studies     concluded    that
    incidences of birth defects were within the background range
    expected to occur naturally in the subjects.                Plaintiffs fail to
    explain why this is any evidence at all of a causal association
    between Zofran and birth defects, much less "reasonable evidence"
    of such an association.
    In any event, the second problem for plaintiffs is that
    the risks flagged by the Japanese animal studies were all known to
    the FDA at the time of its categorization of Zofran into Pregnancy
    Category B. The studies GSK submitted to the FDA for consideration
    in the 1990s -- the four UK studies and one Japanese study -- used
    the    same     combinations    of     animals     (rats   and    rabbits)    and
    administration      methods     (oral    and     intravenous)    as   the    three
    Japanese studies flagged by plaintiffs.              The UK IV Rabbit Study,
    like the Japan Preliminary Dosage Study, observed an increase in
    embryofetal      deaths.      The    Japan    Submitted    Rat   Study   likewise
    reported one instance of a ventricular septal defect (in line with
    the two reported the Japan IV Rat Study, but like the Japan IV Rat
    Study, the researchers concluded that it was within the background
    incidence range.       As for skeletal defects, three of the studies
    submitted to the FDA (the UK Oral Rat Study, the UK Oral Rabbit
    Study, and the UK IV Rabbit Study) reported decreased skeletal
    - 25 -
    ossification, but none of those studies found these skeletal
    defects to be associated with Zofran.
    Thus, the three Japanese studies at issue do not appear
    to "reveal risks of a different type or greater severity or
    frequency than previously included in submissions to FDA" as
    required to meet the definition of "newly acquired information."
    
    21 C.F.R. § 314.3
    (b); cf. Knight, 984 F.3d at 338 (concluding that
    an academic paper discussing the correlation between a drug and a
    risk was not "newly acquired information" because "the FDA was
    already aware of this correlation").    Although we understand that
    "risk information accumulates over time," Wyeth, 
    555 U.S. at 569
    ,
    and "newly acquired information" can include a new analysis of
    preexisting data "showing risks of a different type or of greater
    severity or frequency," 
    id.,
     the Japanese studies neither offer
    nor invite any such new analysis.
    2.
    Plaintiffs next argue that the Japanese animal studies
    at issue are different in kind from the UK studies considered by
    the FDA because the Japanese studies used higher dosing levels,
    which more closely approximate human exposure levels.   Plaintiffs
    explain that the animals in the UK studies were insufficiently
    dosed to approximate human exposure levels.   However, even if the
    Japanese animal studies better approximated human exposure levels
    than the UK studies did, plaintiffs still do not explain why the
    - 26 -
    Japanese studies revealed different or more severe risks than the
    information already provided to the FDA.               Indeed, in each of the
    three Japanese studies plaintiffs point to, the investigators
    concluded that the observed anomalies in the animal subjects were
    not dose related and there was no evidence of teratogenicity.
    Finally, the Japanese study that was submitted to the FDA, which
    used higher dosages presumably more in line with what plaintiffs
    think is appropriate (and certainly higher than the corresponding
    UK study), found that incidences of the observed fetal anomalies
    had   no   dose-dependency    and    that     Zofran    was   not   teratogenic.
    Accordingly, we are not persuaded that the difference in dosages
    alone makes the Japanese studies highlighted by plaintiffs "newly
    acquired information."
    3.
    Lastly,   plaintiffs      point    out     that   their    regulatory
    expert, Dr. Brian Harvey, a former FDA official, opined that the
    Japanese     animal   studies       would     constitute      "newly      acquired
    information" under the CBE regulations.           As previously noted, like
    the   parties,   we   treat   the    question     of    whether     the   studies
    constitute newly acquired information as a question of law. Expert
    testimony on questions of law "is rarely admissible" because such
    testimony "cannot properly assist the trier of fact."                      Nieves-
    Villanueva v. Soto-Rivera, 
    133 F.3d 92
    , 100 (1st Cir. 1997) (second
    quoting Burkhart v. Wash. Metro Area Transit Auth., 
    112 F.3d 1207
    ,
    - 27 -
    1212 (D.C. Cir. 1997)).         To that end, Dr. Harvey's opinion is
    likely inadmissible.       Although experts can opine on the underlying
    factual    questions,      including    providing       interpretations      of
    pharmaceutical studies, they provide little, if any, relevant
    assistance when they opine on the ultimate legal question of
    whether something is "newly acquired information."              And, even if
    we were to consider Dr. Harvey's opinion on this question, it would
    not   enable   us   to   conclude   that     the   Japanese   animal     studies
    constituted newly acquired information.             Dr. Harvey could not say
    that he had even looked at the reports GSK submitted in 1990 to
    the FDA in connection with the original label approval and was
    uncertain as to whether he even reviewed the Japanese studies.
    His opinion, moreover, was that all animal studies should have
    been reported to the FDA, irrespective of their content.                 Correct
    or not, such an opinion sidesteps the question whether the content
    of the studies constituted the type of evidence that would enable
    the manufacturer to invoke the CBE procedure.
    * * *
    As a final stretch in their first step, plaintiffs appear
    to suggest that it is not the three Japanese animal studies
    themselves that reveal new risks.          Rather, it is their scientific
    expert    Dr. Bengt      Danielsson's   2018       interpretation   of    those
    studies, in conjunction with the prior studies presented to the
    FDA and Dr. Danielsson's research on related drugs, that show the
    - 28 -
    full extent of Zofran's teratogenicity.              There are at least three
    flaws    with    this   approach.    The     first    is   one   of   timing   --
    Dr. Danielsson's expert report was not prepared, and thus not
    available to or possessed by GSK, until 2018.                Thus, it cannot
    serve as newly acquired information that would have triggered an
    obligation by GSK to unilaterally amend Zofran's label prior to
    2018, at a time when GSK still owned the drug.               Second, although
    Dr. Danielsson opines that the three Japanese animal studies at
    issue show evidence of teratogenicity, he also opines that the UK
    and Japanese studies submitted in 1990 by GSK also showed causation
    of birth defects, a conclusion that the FDA rejected in approving
    the original label.       In short, Dr. Danielsson applied a standard
    not utilized by the FDA, and in doing so undercut any claim that
    the three Japanese studies at issue showed anything new.                 Third,
    to the extent that Dr. Danielsson's work can be read as advancing
    a type of meta-study in which two sets of insignificant findings
    become significant when combined, plaintiffs never made such an
    argument in the district court in opposing GSK's motion for summary
    judgment.       Nor is it apparent that any such meta-study exists.8
    8  Dr. Danielsson's point is not so much that the addition of
    the Japanese animal studies would have alerted the FDA to new
    risks, but that the FDA should have been moved to act based on the
    risks raised by the other animal data it already had before it.
    We do not know whether it is Dr. Danielsson or the FDA that is
    correct on the science. Unfortunately for plaintiffs, it is not
    up to us to second-guess the FDA on such matters. See Celexa, 779
    F.3d at 42–43.
    - 29 -
    To the extent plaintiffs now attempt to broaden their argument on
    this point, we treat it as forfeited.          See Young v. Lepone, 
    305 F.3d 1
    , 13 (1st Cir. 2002) ("[L]egal theories not squarely raised
    in the lower court cannot be broached for the first time on
    appeal."   (quoting   Teamsters     Union,   Local   No. 59   v.   Superline
    Transp. Co., 
    953 F.2d 17
    , 21 (1st Cir. 1992))).9
    Accordingly, we find that the three Japanese animal
    studies that form the basis of plaintiffs' contentions on appeal
    are not "newly acquired information" that would have enabled GSK
    to employ the CBE procedure.
    B.
    Our conclusion that plaintiffs' argument on appeal fails
    at its first step because there is no newly acquired information
    that would justify invoking the CBE procedure is sufficient to
    affirm   the   district   court's    ruling    on    alternative   grounds.
    Nevertheless, we will address step two as well. The district court
    focused its analysis on that step, the parties have briefed it,
    9  Given the foregoing, we need not decide whether a
    plaintiff's expert report, presented in litigation, can qualify as
    "newly acquired information." Cf. In re Incretin-Based Therapies
    Prods. Liab. Litig., 
    524 F. Supp. 3d 1007
    , 1024–25 (S.D. Cal.
    2021), aff'd, No. 21-55342, 
    2022 WL 898595
     (9th Cir. Mar. 28, 2022)
    (doubting that a non-peer-reviewed "expert report [that] was
    generated in preparation for litigation" can constitute "newly
    acquired information"); R.S.B. v. Merck & Co., No. 20-civ-1402,
    
    2021 WL 6128161
    , at *4 (E.D. Wis. Dec. 28, 2021) ("Plaintiffs are
    not entitled to create their own 'newly acquired information'
    through the use of experts.").
    - 30 -
    and we are cognizant of the fact that this appeal will bear on the
    disposition of many individual complaints in this multi-district
    litigation.
    To   review,    the   second    step       in   plaintiffs'   two-step
    argument goes as follows:           Assuming that the Japanese animal
    studies not disclosed to the FDA in the initial approval process
    constituted newly acquired information with which GSK could have
    invoked the CBE procedure to change its label to state that animal
    studies showed teratogenic effects, GSK has failed to produce clear
    evidence that the FDA would have rejected such a change.                     Hence,
    compliance with both federal and state laws was not impossible.
    To   assess    this   argument,       we    begin   by   reciting   the
    language in Albrecht and Wyeth upon which the parties train their
    dispute. In Wyeth, the Supreme Court stated that: "[A]bsent clear
    evidence that the FDA would not have approved a change to [the
    drug's] label, we will not conclude that it was impossible for
    [the    manufacturer]      to   comply     with    both      federal   and    state
    requirements."     
    555 U.S. at 571
    .        In Albrecht, the Court explained
    what such "clear evidence" would entail "[i]n a case like Wyeth":10
    In Wyeth, there was no dispute whether the drug
    10
    manufacturer possessed newly acquired information that would
    support a label change, and the Wyeth decision assumes that the
    manufacturer possessed such information. See Wyeth, 
    555 U.S. at 571
     ("[W]hen the risk of gangrene from IV-push injection of
    Phenergan became apparent, Wyeth had a duty to provide a warning
    that adequately described that risk, and the CBE regulations
    permitted it to provide such a warning before receiving the FDA's
    - 31 -
    The manufacturer must show "that it fully informed the FDA of the
    justifications for the warning . . . and that the FDA, in turn,
    informed the drug manufacturer that the FDA would not approve
    changing the drug's label to include that warning."   
    139 S. Ct. at 1678
    .   Albrecht also required that the FDA's disapproval must be
    the product of "agency action carrying the force of law."   
    Id. at 1679
    .
    As it applies to this case, we read Wyeth (as elaborated
    on by Albrecht) to require a defendant seeking to invoke preemption
    under the "clear evidence" prong to show that the FDA, after being
    fully informed of the case for making plaintiffs' 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.   Suffice it to say, such
    a demonstration is most easily made if the manufacturer actually
    initiates such a label change through the CBE procedure.    But we
    find nothing in Wyeth or Albrecht to preclude other means of making
    the required showing.
    Here, there is no doubt that by the time Novartis
    submitted the proposed updated label for Zofran in 2020, the FDA
    approval."). This case is not like Wyeth, because GSK disputes
    the existence of newly acquired information that would have
    supported a change to Zofran's label and, as explained earlier in
    this opinion, is entitled to a finding of preemption due to the
    lack of newly acquired information.
    - 32 -
    was fully informed of the Japanese studies.           Indeed, the FDA was
    also fully informed of plaintiffs' contentions and the opinions of
    plaintiffs'   experts.       Some   of   this   information    was   arguably
    supplied to the FDA by plaintiffs, not "the manufacturer."             But we
    find the relevant issue to be whether the FDA was informed in a
    relevant context, not who exactly first informed it.11               Nor was
    this an occasion on which it can be said that the FDA gave only
    "passing attention" to the label's statements concerning animal
    studies; both GSK and plaintiffs met with the FDA specifically on
    this issue.   Cf. Wyeth, 
    555 U.S. at 572
     (determining that the fact
    that neither "the FDA [n]or the manufacturer gave more than passing
    attention" to the risk against which plaintiffs sought a new
    warning undermined the manufacturer's assertion that the FDA would
    have prevented it from adding the requested warning).
    So informed, the FDA approved the updated Zofran label.
    As   plaintiffs   concede,   the    "FDA's   eventual   2021   approval   of
    Novartis's revised label . . . is formal agency action with the
    force of law."      That formal approval, in turn, applied to the
    entire label.     And that approval meant that, absent subsequently
    acquired information, the manufacturer could not unilaterally
    change the label.    
    21 C.F.R. § 314.70
    (a)(1)(i), (c)(6)(iii).
    11In any event, it is clear that GSK and Novartis ultimately
    gave the studies to the FDA.
    - 33 -
    The updated Zofran label that the FDA approved stated
    that animal data revealed "no significant effects of [Zofran] on
    the maternal animals or the development of the offspring."               This
    language is fundamentally incompatible with plaintiffs' position
    that the label should state that the drug had been shown to be
    teratogenic in animal studies.        We think it clear that when the
    FDA formally approves a statement that data reveals no effects, it
    necessarily rejects the contention that the data does reveal
    effects.
    Albrecht reinforces this conclusion by teaching that
    "the meaning and scope of [agency action concerning a label] might
    depend on what information the FDA had before it."             
    139 S. Ct. at 1680
    .   The record shows that the Japanese studies and plaintiffs'
    interpretation of those studies were not only before the agency,
    but   also   were   prominently   presented   as     cause   for   advancing
    plaintiffs'    challenge   to   the   pre-existing    label.       The   fully
    informed FDA in approving the label stating "not-X" necessarily
    rejected plaintiffs' prominently presented case for stating "X."
    In so concluding, we need not opine that an agency's failure to
    sua sponte initiate a label change is equivalent to a determination
    that such a change is prohibited.        We hold only that when the FDA
    formally approves a label stating one thing with full and obvious
    - 34 -
    notice of the directly contrary position, one can read the approval
    as rejecting the contrary position.12
    IV.
    For   the   foregoing    reasons,   we   affirm   the   district
    court's grant of GSK's motion to dismiss.
    12 This is in line with Wyeth's conclusion that there was no
    clear evidence that the FDA would reject a label change where
    (i) newly acquired information existed and (ii) the record did not
    show either that the drug manufacturer informed the FDA of that
    information or that the FDA or manufacturer "gave more than passing
    attention" to the issue potentially supporting a label change.
    
    555 U.S. at 572-73
    .
    - 35 -