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

57 F.4th 327

• Court: Court of Appeals for the First Circuit
• Decided: January 9, 2023
• Docket: 21-1517
• Status: Published

Opinion

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.

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.

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 -