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

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 -