United States District Court, D. Massachusetts
IN RE ZOFRAN (ONDANSETRON) PRODUCTS LIABILITY LITIGATION This Document Relates To: All Actions
MEMORANDUM AND ORDER ON DEFENDANT'S MOTION FOR
SUMMARY JUDGMENT BASED ON FEDERAL PREEMPTION
Dennis Saylor IV, United States District Judge.
a multi-district litigation (“MDL”) proceeding
arising out of product-liability claims that the use of the
drug Zofran (ondansetron) by pregnant women caused birth
defects in their children. Defendant GlaxoSmithKline LLC
(“GSK”) has moved for summary judgment based on
federal preemption-in substance, that state-law claims of
failure to provide an adequate warning label are preempted by
federal law. For the following reasons, the motion will be
is an anti-emetic-that is, a drug that prevents or treats
nausea or vomiting. It was initially approved by the Food and
Drug Administration in 1991 for the prevention of nausea and
vomiting induced by chemotherapy or radiation therapy and
post-operative nausea and vomiting.
was not approved, and never has been approved, for the
prevention of nausea and vomiting in pregnancy. Nonetheless,
Zofran has been prescribed off-label to pregnant women for
many years. According to plaintiffs, that widespread practice
was due in large part to unlawful marketing practices by GSK
that sought to promote off-label usage.
point, the FDA became aware that Zofran was being prescribed
to pregnant women in significant numbers. In 2010, the FDA
requested that the GSK provide supplemental information
concerning the safety of Zofran when used during pregnancy.
In response, GSK provided an analysis of the then-available
safety data. The FDA did not require any labeling changes. In
2013, a citizen petition requested that the FDA revise the
Zofran label to indicate an increased risk to fetal safety if
ingested during pregnancy. The FDA rejected that request. In
2015, the current manufacturer of Zofran, Novartis, submitted
a proposed label change to provide, among other things, a
warning that use in pregnancy could cause harm to the fetus
and is not recommended. That, too, was rejected.
short, whether Zofran poses a risk to fetal safety has been
considered, and rejected, by the FDA on multiple occasions
since the drug's initial approval. Even today, it is not
contraindicated for use during pregnancy, and its label
contains no enhanced form of warning for such use. Indeed,
the current label states that “[a]vailable data do not
reliably inform the association of Zofran and adverse fetal
outcomes.” Plaintiffs nonetheless contend that
ingestion of Zofran during pregnancy in fact causes birth
defects, that the label should contain such a warning, and
that GSK's failure to provide such a warning should
result in tort liability under state law. Plaintiffs contend
that the FDA's initial approval of Zofran in 1991, and
its subsequent rejection of label changes, were based on
incomplete information-essentially, because GSK withheld
certain data from the FDA and made material
misrepresentations. GSK denies that it withheld information
and contends that any state-law failure-to-warn claims are
preempted by federal law.
potential preemption issue arises out of a clash between
federal regulation of prescription drugs and state-law
product-liability principles. By federal law, the FDA closely
regulates the labeling of drugs, including warning labels; as
a general matter, a drug label may only be created or changed
with FDA approval. That creates an obvious tension with state
laws, which generally permit recovery for failure to provide
an adequate warning, but which assume that a manufacturer is
free to provide such warnings as it sees fit.
is, however, a process under federal law-called the
“changes being effected, ” or “CBE, ”
process-that permits a drug company to change a label
unilaterally, based on certain “newly acquired
information” concerning its safety, subject to later
FDA approval. Because of the existence of the CBE process,
the Supreme Court has held that a drug company can in fact
add safety information to its label without FDA approval.
See Wyeth v. Levine, 555 U.S. 555, 570-71 (2009). As
a result, a drug company may prove that federal law preempts
state law only if it can show by “clear evidence”
that the FDA would have rejected the warning that plaintiffs
contend state law required. Id. at 571.
there is little doubt that the FDA would have
rejected plaintiffs' proposed warning: it in fact
did reject it, at least in substance. But plaintiffs
contend that GSK's failure to make complete disclosures
to the FDA means that the agency's decisions were not
fully informed, and therefore a finding of federal preemption
legal framework for considering preemption claims is muddy at
best. Among other things, there is considerable debate as to
such basic matters as the required standard of proof and the
appropriate roles of the judge and jury. The United States
Supreme Court recently granted a writ of certiorari in an FDA
preemption case, presumably to clarify some of those issues.
See In re Fosamax, 852 F.3d 268 (3d Cir. 2017),
cert. granted sub nom. Merck Sharp & Dohme Corp. v.
Albrecht, 138 S.Ct. 2705 (2018).
meantime, this Court is required to consider the matter under
the existing framework, without the benefit of that guidance,
and notwithstanding the fact that the applicable principles
as determined by this Court may eventually prove to be
erroneous. Under the existing legal framework, as this Court
understands and interprets it, the basic factual question
underlying preemption-that is, whether the FDA would have
rejected the label had it been presented with the evidence
plaintiffs contend was withheld-must be resolved by a jury.
and for the following reasons, the motion of GSK for summary
judgment based on preemption will be denied.
otherwise noted, the following facts are undisputed.
The Regulatory Framework
federal law, a drug company may not market or sell a new
pharmaceutical drug without the approval of the Food and Drug
Administration. 21 U.S.C. § 355(a). To obtain that
approval, the company (which is referred to as the
“sponsor”) must submit a New Drug Application
(“NDA”) to the FDA. (Id.). An NDA must
provide comprehensive information about the drug, including
its formulation, the proposed labeling, and scientific data
about its safety and efficacy. Id. §
355(b)(1)(F); 21 C.F.R. §§ 314.50(d)(5)(viii),
surprisingly, FDA regulations require that an NDA fully
disclose all “pertinent” safety information.
See, e.g., 21 C.F.R. §§ 314.50 (requiring
“reports of all investigations of the drug product
sponsored by the applicant, and all other information about
the drug pertinent to an evaluation of the NDA that is
received or otherwise obtained by the applicant from any
source”); 314.50(d)(5)(vi)(A) (requiring “an
integrated summary of all available information about the
safety of the drug product, including pertinent animal data[
and] demonstrated or potential adverse effects of the
drug”); 312.50 (stating that “[s]ponsors are
responsible for . . . providing [investigators] with the
information they need to conduct an investigation properly .
. . and ensuring that FDA and all participating investigators
are promptly informed of significant new adverse effects or
risks with respect to the drug”).
sponsor's duty to make full disclosure continues beyond
the initial submission of its NDA. See, e.g., Id.
§§ 314.50(d)(5)(vi)(B) (“The applicant must .
. . update periodically its pending NDA with new safety
information learned about the drug that may reasonably affect
the statement of contraindications, warnings, precautions,
and adverse reactions in the draft labeling . . . [including
information from] animal studies.”); 312.33 (requiring
annual reports for investigational NDAs that include
“[a] list of the preclinical studies (including animal
studies} completed or in progress during the past year and a
summary of the major preclinical findings, ” and,
“[i]f the study has been completed, or if interim
results are known, a brief description of any available study
approval process is “onerous and lengthy.”
Mutual Pharm. Co. v. Bartlett, 570 U.S. 472, 476
(2013). The FDA will approve a drug only if the NDA
demonstrates that the drug (1) is “safe for use,
” (2) “will have the effect it purports or is
represented to have, ” and (3) is accompanied by
labeling that is neither “false [n]or misleading in any
particular.” 21 U.S.C. §§ 355(c)(1)(A), (d).
does not only approve the drug and its intended use; it also
approves the exact text of the label. Id. §
355; see Wyeth, 555 U.S. at 568. With one exception,
noted below, the sponsor may not alter the label in any
respect without the approval of the FDA. Wyeth, 555
U.S. at 565.
Process for Changing Labels
approval of a drug, the FDA retains the authority to require
changes to the label to reflect new information concerning
its safety and efficacy. 21 U.S.C. § 355(o)(4); 21
C.F.R. § 314.93. Nonetheless, a “central premise
of federal drug regulation [is] that the manufacturer bears
responsibility for the content of its label at all
times.” Wyeth, 555 U.S. at 570-71. The
manufacturer is “charged both with crafting an adequate
label and with ensuring that its warnings remain adequate as
long as the drug is on the market.” Id. at
are two ways in which a manufacturer can seek to change the
warnings on a drug label. See In re Celexa & Lexapro
Mktg. & Sales Practices Litig., 779 F.3d 34, 37 (1st
Cir. 2015) (citing 21 C.F.R. § 314.70(b)(2), (c)(6)).
a manufacturer can file a “Prior Approval
Supplement” (“PAS”) requesting revisions to
the label. 21 C.F.R. § 314.70(b). That process requires
FDA approval before implementation, and in substance is
similar to the process for initial approval of a label.
a manufacturer can unilaterally amend a label to “add
or strengthen a contraindication, warning, precaution, or
adverse reaction” when “newly acquired
information” reflects a “clinically significant
hazard.” 21 C.F.R. §§ 201.57(c)(6),
314.70(b)(2). That action, known as the “changes being
effected” (“CBE”) process, allows a sponsor
to make an immediate labeling change upon filing a
supplemental application with the FDA. The amended label will
then be reviewed by the FDA and will be approved if it is
based on new “reasonable evidence of a causal
association with [the] drug” and a “clinically
significant hazard.” 21 C.F.R. § 201.57(c)(6).
term “newly acquired information” is not limited
to entirely new data. Wyeth, 555 U.S. at 569. It
also includes the following:
[D]ata, analyses, or other information not previously
submitted to [the FDA], 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 [the]
21 C.F.R. § 314.3. See Celexa, 779 F.3d at 42
(giving examples of “newly acquired
The FDA's Approach to Warning Labels
most types of consumer products, manufacturers have an
incentive to warn against every conceivable type of hazard or
risk in order to try to forestall tort liability under state
law. Many products thus come covered with labels, and
packaged with booklets, containing multiple warnings against
dangers both real and remote.
pharmaceuticals, however, the FDA has adopted a more balanced
[T]he FDA does not simply approve warnings out of an
abundance of caution whenever the manufacturer posits a
theoretical association between drug use and an adverse
event. As the FDA has recognized, “[e]xaggeration of
risk, or inclusion of speculative or hypothetical risks,
could discourage appropriate use of a beneficial drug.”
Moreover, “labeling that includes theoretical hazards
not well-grounded in scientific evidence can cause meaningful
risk information to lose its significance.”
Accordingly, the FDA will reject a PAS application or CBE
amendment if there is insufficient evidence of a causal link
between drug use and the adverse event.
In re Fosamax, 852 F.3d 268, 274 (3d Cir. 2017)
standard for requiring a warning label is thus different from
that imposed by state tort law. See, e.g.,
PLIVA, Inc. v. Mensing, 564 U.S. 604, 611 (2011)
(“It is undisputed that Minnesota and Louisiana tort
law require a drug manufacturer that is or should be aware of
its product's danger to label that product in a way that
renders it reasonably safe.”); Wooderson v. Ortho
Pharm. Corp., 681 P.2d 1038, 1049 (Kan. 1984) (“It
is well settled, however, that the manufacturer of ethical
drugs bears the additional duty of making timely and adequate
warnings to the medical profession of any dangerous side
effects produced by its drugs of which it knows, or has
reason to know.”) (collecting cases from various
Warning Labels for Pregnancy
provisions govern the labeling of drugs that may be taken by
pregnant women. Until June 30, 2015, the FDA classified drugs
into five categories of safety for use during pregnancy: A,
B, C, D, or X. According to the then-applicable statutory
language, “[i]f animal reproduction studies have failed
to demonstrate a risk to the fetus and there are no adequate
and well-controlled studies in pregnant women, ” the
label must contain the following language:
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).
classification system was eliminated by the FDA when it
issued a final rule amending the regulations concerning
pregnancy and lactation labeling. 79 Fed. Reg. 72064 (Dec. 4,
The Approval of the Zofran Label
or ondansetron hydrochloride, is a prescription drug that
prevents nausea and vomiting. It is part of a class of
anti-emetics referred to as selective serotonin 5-HT3
receptor antagonists. (Hill Decl. Ex. 10).
January 4, 1991, the FDA approved the marketing and sale of
Zofran for the prevention of nausea and vomiting induced by
chemotherapy or radiation therapy and postoperative nausea
and vomiting. (Id. Ex. 3). The 1991 approval was for an
injection formulation; in 1992, 1995, 1997, and 1999, the FDA
approved four additional formulations, covering oral tablets,
premixed injections, oral solutions, and orally disintegrated
tablets, respectively. (Id. Exs. 3, 6-9).
The Use of Zofran by Pregnant Women
and vomiting during pregnancy (“NVP”) is a common
condition affecting 50% to 90% of women during their
pregnancies. (Id. Ex. 17 at 3). The most severe form
of NVP is known as hyperemesis gravidarum (“HG”).
(Id.). “HG has been reported in 0.5% to 2% of
pregnancies and is characterized by persistent and severe
nausea and vomiting, ” and may pose a serious health
risk to both the mother and the fetus. (Id.).
was not approved by the FDA for treatment of nausea
and vomiting during pregnancy. Indeed, GSK never sought
approval for that use. However, it is generally lawful for
physicians to prescribe medications for purposes for which
they have not been FDA-approved (although it is generally
unlawful for pharmaceutical companies to promote such
“off-label” use). See United States ex rel.
Carpenter v. Abbott Labs., Inc., 723 F.Supp.2d 395, 397
n.2, 398-99 (D. Mass. 2010); see also Buckman Co. v
Plaintiffs' Legal Committee, 531 U.S. 341, 350
(2001) (noting that “‘off-label' usage of
medical devices . . . is an accepted and necessary corollary
of the FDA's mission to regulate in this area without
directly interfering with the practice of medicine”).
Over time, many physicians have prescribed Zofran to pregnant
women, particularly those suffering from HG.
the FDA approved Zofran in 1991, it classified it as a
pregnancy category B drug. (Hill Decl. Ex. 3). Between 1992
and 2016, the “Use in Specific Populations”
section of the approved label for intravenous Zofran
containing the pregnancy category B designation contained the
following or similar language:
Reproduction studies have been performed in pregnant rats and
rabbits . . . and have revealed no evidence of impaired
fertility or harm to the fetus due to ondansetron. 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.
(Id. Ex 4; see also Exs. 3, 7, 28).
Zofran label does not, and never has, contained a warning
contraindicating use of the drug to treat pregnant women.
The 2010 FDA PAS Request
December 2010, then-FDA Director Donna Greibel sent GSK a
“Prior Approval Supplement Request” concerning
Zofran. The PAS Request indicated that the FDA was aware of
the common use of Zofran during pregnancy and requested that
GSK “review and analyze available published and
unpublished literature on the use of ondansetron during
pregnancy and lactation, with a focus on the presence or
absence of adverse pregnancy and/or neonatal outcomes.”
(Id. Ex. 12). The requested review and analysis was
to include an “assessment of the strengths and
limitations of the data” and proposed labeling
revisions if GSK concluded changes were necessary to
“furnish adequate information for the safe use of this
April 2011, GSK replied to the FDA. Its response stated that
it had “completed a review of the available data and
has included a summary of that analysis in this
submission.” (Id. Ex. 14). It stated that
“[its] position is that the use of [Zofran] in human
pregnancy has not been established and is not
recommended.” (Id.). And it concluded that it
“[did] not believe there [was] sufficient evidence to
warrant a change in the [Zofran label].”
did not respond and no changes were made to the Zofran label
concerning pregnancy. (Id. Ex. 15).
The 2013 Citizen Petition
January 2013, an individual named James P. Reichmann
submitted a citizen petition asking the FDA to revise the
Zofran label to provide heightened pregnancy warnings.
(Id. Ex. 16). Specifically, he requested that the FDA
reclassify the drug's pregnancy risk category from B to
C, D, or X; notify obstetricians and gynecologists
“that there is insufficient scientifically acceptable
evidence that ondansetron is associated with improved
treatment outcomes and may lead to adverse maternal and fetal
events or outcomes”; and notify OB/GYNs that
“promotion of continuous subcutaneous ondansetron pump
for the treatment of nausea and vomiting of pregnancy (NVP)
is a violation of FDA regulations.” (Id. Ex.
17 at 1). His petition contended that Zofran “may lead
to adverse maternal and fetal events or outcomes” if
ingested during pregnancy. (Id.).
October 27, 2015, the FDA denied the petition. (Id.
Ex. 17). The FDA noted that ondansetron had not been approved
for the treatment of NVP, but that it was “aware of the
unapproved use of oral and injectable ondansetron for the
treatment of NVP.” (Id. at 3). It stated that
“[t]he available evidence is not sufficient to conclude
that there is an increased risk of birth defects, including
cleft palate, among fetuses exposed to ondansetron.”
(Id. at 13). It further indicated that it considered
“information submitted by [GSK] to support approval of
the ondansetron NDA, ” “post-marketing drug and
device adverse event data, ” and scientific literature
obtained through public submissions and through its own
“targeted searches.” (Id. at 18 n.56).
Taking into consideration both the data available at the time
ondansetron was approved and subsequent human data gathered
in the post approval setting, at this time the totality of
the data do not support a conclusion that there is an
increased risk of fetal adverse outcomes, including birth
defects such as cleft palate and cardiac ventricular and/or
septal defects, among fetuses exposed to ondansetron.
(Id. at 18).
the warning label, the FDA stated: “[W]e believe
pregnancy category B was the appropriate risk category for
ondansetron when it was assigned and . . . we believe
pregnancy category B remains appropriate today.”
(Id.). The FDA similarly rejected Reichmann's
request for the FDA to notify doctors that use of Zofran
during pregnancy is not safe for the fetus. Such a
notification, the FDA explained, could actually be misleading
on account of the fact that “the available data do not
support a conclusion that there are increased safety risks .
. . for the fetus.” (Id. at 19).
The 2015 Novartis Proposal
acquired Zofran from GSK in 2015. On September 22, 2015,
Novartis submitted to the FDA a proposed update to the Zofran
pregnancy labelling along with a clinical overview.
(Id. Ex. 21). The proposal included several changes to
the “Risk Summary” section of the label to advise
against using Zofran during pregnancy and warn of potential
risks to a developing fetus.
Novartis proposed the following revisions:
• Beginning the “Risk Summary” subsection
(§ 8.1) with the caution:
“It is possible that ZOFRAN can cause harm to the fetus
when administered to a pregnant woman. Thus, the use of
ZOFRAN in pregnancy is not recommended. If ZOFRAN is used
during pregnancy, or if the patient becomes pregnant while
taking this drug, the patient should be apprised of the
potential risk to a fetus.” (Id. at 2090).
• In the “Risk Summary” section, including
the statement “Animal studies are not always predictive
of human response, therefore, the use of ondansetron in
pregnancy is not recommended.” (Id.).
• Creating a new subsection (§ 8.3) entitled
“Females and males of reproductive potential, ”
which discusses pregnancy testing and contraception and
states, in part, “Advise females of reproductive
potential that it is possible that ZOFRAN can cause harm to
the developing fetus. (Id. at 2092).
(Id. Exs. 21, 22).
also provided a 47-page “clinical overview”
document summarizing the data that it believed was sufficient
to support its revisions and a detailed recitation of the
then-available adverse event data. (Id. Ex. 22).
conclusion section of the document, Novartis stated that
while a review of the science did not offer “consistent
or compelling evidence that exposure to ondansetron in early
pregnancy causes major birth defects, including congenital
cardiac defects, ” the FDA should nevertheless accept
its labeling changes that inform prescribers and patients
“of the potential risk of fetal harm during treatment
in pregnancy.” (Id. at 2309).
November 2015, the FDA rejected that request. It deleted the
paragraph that included the sentence “[i]t is possible
that ZOFRAN can cause harm to the fetus when administered to
a pregnant woman.” (Id. Ex. 23 at 3945). It
also deleted the subsection concerning “[f]emales and
males of reproductive potential” in its entirety,
stating that “the available human data do not support a
clear conclusion on an increased risk of major congenital
malformations, ” and therefore it did “not agree
with recommendations for pregnancy testing and contraception
use.” (Id. at 3947).
December 2015, Novartis submitted a new round of proposed
changes to the pregnancy labeling. It cited reported adverse
advents as sufficient to warrant a statement that
“[c]ases of congenital malformations have been reported
in infants whose mothers took ondansetron during
pregnancy.” (Id. Ex. 24 at 2610). And in an
effort to “provide conservative guidance due to the
potential off label use and the data available, ” it
again suggested including a warning that “[t]he safety
of ondansetron for use in human pregnancy has not been
established.” (Id. at 2611). In light of
reported off-label use, it also requested a new
“Limitations of Use” section stating that
“Zofran has not been studied in pregnant women for the
prevention of nausea and vomiting.” (Id. at
responded in April 2015, again rejecting proposed language
that the “use of ondansetron in pregnancy is not
recommended.” (Id. Exs. 23, 25, 27-28). The
FDA stated that a “limitations on use” statement
is “not intended to prohibit off-label use.”
(Id. Ex. 25 at 4045). Rather, such a statement is
proper only when “there is a known risk that outweighs
the therapeutic benefits in a certain clinical situation,
” and the FDA could not draw that conclusion for the
use of Zofran to treat NVP. (Id.).
in September 2016, Novartis and the FDA agreed upon a revised
label. In the communications leading up to the revision, the
FDA made the following statements:
• “We do not agree with keeping [the phrase
‘Animal studies are not always predictive of human
response, therefore, the use of ondansetron in pregnancy is
not recommended'] in labeling based on the available
human information.” (Id. Ex. 23 at 3945).
• “Based on the Agency's review, the available
human data do not support a clear conclusion on an increased
risk of major congenital malformation.” (Id.
• “Based on review of the submitted
pharmacovigilance database and the literature, we did not
conclude that there is a basis to believe there is a causal
relationship between the congenital malformations and the use
of ondansetron. Therefore, these malformations would ...