Case 1:21-cv-10906-FDS Document 5 Filed 06/01/21 Page 1 of 68
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`UNITED STATES DISTRICT COURT
`DISTRICT OF MASSACHUSETTS
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`_______________________________________
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`IN RE: ZOFRAN (ONDANSETRON)
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`PRODUCTS LIABILITY LITIGATION
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`This Document Relates To:
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`All Actions
`_______________________________________)
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`MDL No. 1:15-md-2657-FDS
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`MEMORANDUM AND ORDER ON DEFENDANT’S RENEWED MOTION FOR
`SUMMARY JUDGMENT BASED ON FEDERAL PREEMPTION
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`SAYLOR, C.J.
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`This is a multi-district litigation (“MDL”) proceeding arising out of product-liability
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`claims that the use of the drug Zofran (ondansetron) by pregnant women caused birth defects in
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`their children. Defendant GlaxoSmithKline LLC (“GSK”) has filed a renewed motion for
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`summary judgment based on federal preemption—in substance, that state-law claims of failure to
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`provide an adequate warning label are preempted by federal law.1 For the following reasons, the
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`motion will be granted.
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`I.
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`Introduction
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`Zofran is an anti-emetic—that is, a drug that prevents or treats nausea or vomiting. It was
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`initially approved by the Food and Drug Administration in 1991 for the prevention of nausea and
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`vomiting induced by chemotherapy or radiation therapy and post-operative nausea and vomiting.
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`Zofran was not approved, and never has been approved, for the prevention of nausea and
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`1 This Court originally denied a similar motion on February 5, 2019, on the ground that the issue of
`preemption presented disputed issues of material fact that precluded summary judgment. See generally In re Zofran
`(Ondansetron) Prods. Liab. Litig., 368 F. Supp. 3d 94 (D. Mass. 2019). After that decision, the Supreme Court held
`in Merck Sharp & Dohme Corp. v. Albrecht, 139 S. Ct. 1668 (2019), that preemption presented issues of law to be
`resolved by the judge, not a jury. GSK then renewed its motion on a supplemented factual record.
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`Case 1:21-cv-10906-FDS Document 5 Filed 06/01/21 Page 2 of 68
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`vomiting in pregnancy. Nonetheless, Zofran has been prescribed off-label to pregnant women
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`for many years. According to plaintiffs, that widespread practice was due in large part to
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`unlawful marketing practices by GSK that sought to promote off-label usage.
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`Plaintiffs in this case are principally women who took Zofran during pregnancy and their
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`children, who are alleged to have a variety of birth defects, largely consisting of orofacial defects
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`and cardiac ventricular and/or septal defects. The basic premise of each lawsuit is that Zofran
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`caused those injuries, and that GSK failed to provide an adequate warning label concerning the
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`risks of ingesting Zofran during pregnancy.
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`At some point, the FDA became aware that Zofran was being prescribed to pregnant
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`women in significant numbers. In 2010, the FDA requested that GSK provide supplemental
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`information concerning the safety of Zofran when used during pregnancy. In response, GSK
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`provided an analysis of the then-available safety data. The FDA did not require any labeling
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`changes. In 2013, a citizen petition requested that the FDA revise the Zofran label to indicate an
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`increased risk to fetal safety if ingested during pregnancy. The FDA rejected that request. In
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`2015, the current manufacturer of Zofran, Novartis, submitted a proposed label change to the
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`FDA to provide, among other things, a warning that use in pregnancy could cause harm to the
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`fetus and is not recommended. That, too, was rejected. In 2019, GSK itself filed a citizen
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`petition, asking that the FDA review various pieces of information concerning the safety of
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`Zofran that plaintiffs allege had not been provided to the agency. In the course of that
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`proceeding, counsel for both GSK and plaintiffs met with the FDA and provided information
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`concerning the safety of Zofran. Although the FDA rejected the GSK petition, it did not require
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`a label change.
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`Finally, in 2020, Novartis again submitted to the FDA a proposed label change with a
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`2
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`Case 1:21-cv-10906-FDS Document 5 Filed 06/01/21 Page 3 of 68
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`pregnancy warning, based largely on recently published epidemiological studies with new data.
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`By that point, the FDA had been provided with every study and piece of scientific literature on
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`which plaintiffs rely in this case to establish that Zofran causes birth defects. In early 2021, the
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`FDA again rejected the proposed pregnancy warning.
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`Thus, the question of whether Zofran poses a sufficiently significant risk to fetal safety to
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`justify an enhanced warning has been considered, and rejected, by the FDA on multiple
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`occasions since the drug’s initial approval. As of today, it is not contraindicated for use during
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`pregnancy, and its label contains no enhanced form of warning for such use. Indeed, the current
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`label states that “[p]ublished epidemiological studies on the association between ondansetron use
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`and major birth defects have reported inconsistent findings and have important methodological
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`limitations that preclude conclusions about the safety of ondansetron use in pregnancy.”
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`Plaintiffs nonetheless contend that ingestion of Zofran during pregnancy in fact causes
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`birth defects, that the label should contain a warning to that effect, and that GSK’s failure to
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`provide such a warning should result in tort liability under state law. Plaintiffs further contend
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`that the FDA’s initial approval of Zofran in 1991, and its subsequent rejections of label changes,
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`were based on incomplete information—essentially, because GSK withheld certain data from the
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`FDA and made material misrepresentations—and that the FDA did not specifically address
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`certain animal studies that plaintiffs say show a risk of fetal injury. Plaintiffs thus argue that
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`their state-law claims are not preempted by federal law.
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`The preemption issue arises out of a clash between federal regulation of prescription
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`drugs and state-law product-liability principles. By federal law, the FDA closely regulates the
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`labeling of drugs, including warning labels; as a general matter, a drug label may only be created
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`or changed with FDA approval. That creates an obvious tension with state laws, which generally
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`permit recovery for failure to provide an adequate warning, but which assume that a
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`manufacturer is free to provide such warnings as it sees fit.
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`The process of considering labels, and label changes, at the FDA is relatively complex.
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`Among other things, the FDA does not simply “approve” or “reject” labels. It requires the
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`submission of medical and scientific data and analysis with a proposed label. And it mandates
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`the form and layout of the label and scrutinizes its content, down to the most minute details, in
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`what is typically an interactive process with the pharmaceutical company. It may reject or
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`approve a particular form of wording, or mandate certain changes.
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`Furthermore, the FDA’s approach to warning labels is very different from the manner in
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`which state-law tort principles drive the labeling of consumer products as a general matter. The
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`FDA is concerned not only with avoiding insufficient warnings (that is, failing to warn against
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`risks), but also avoiding over-warning (that is, warning against risks that are unduly speculative,
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`hypothetical, or not adequately supported by science). Thus, while a consumer product such as a
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`chainsaw might bear dozens and dozens of warnings, with little regard for the remoteness or
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`obviousness of the risk, the FDA takes a more measured approach that is intended to provide
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`accurate information to medical professionals and patients without unduly discouraging the use
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`of the product.
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`Normally, therefore, an FDA-approved warning is mandatory, and does not represent a
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`minimum, or a “floor,” that the pharmaceutical company may exceed in its discretion. There is,
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`however, a process under federal law—called the “changes being effected,” or “CBE,” process—
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`that permits a drug company to change a label unilaterally, based on certain “newly acquired
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`information” concerning a drug’s safety, subject to later FDA approval. Because of the existence
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`of the CBE process, the Supreme Court has held that a pharmaceutical company can in fact add
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`safety information to its label without FDA approval, at least in the short term. See Wyeth v.
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`Levine, 555 U.S. 555, 570-71 (2009). In addition, a pharmaceutical company can seek a label
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`change by filing a “Prior Approval Supplement” (“PAS”) requesting revisions to the label, which
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`the FDA must approve before implementation. That, in fact, is what Novartis did in 2020. And
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`anyone, even a private individual, can request a label change through a citizen petition submitted
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`to the FDA. Finally, the FDA has an independent duty imposed by statute to require label
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`changes if it becomes aware of new information that it determines should be included in the
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`drug’s label.
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`The interaction between the FDA process and state tort law has created a variety of
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`difficult legal questions over the years. Indeed, the Supreme Court has considered the
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`preemption issue three times over the past dozen or so years without resolving all of the
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`significant questions. See Wyeth, 555 U.S. 555 (2009); PLIVA, Inc. v. Mensing, 564 U.S. 604
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`(2011); Merck Sharp & Dohme Corp. v. Albrecht, 139 S. Ct. 1668 (2019). In PLIVA, the court
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`found that state-law claims are preempted when a manufacturer could not use the CBE process
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`and unilaterally change the label. 564 U.S. at 623-24. In Albrecht, the court framed the
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`preemption inquiry—assuming a manufacturer could avail itself of the CBE process—as having
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`two parts: the manufacturer must show first “that it fully informed the FDA of the justifications
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`for the warning required by state law,” and second, “that the FDA, in turn, informed the drug
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`manufacturer that the FDA would not approve changing the drug’s label to include that
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`warning.” 139 S. Ct. at 1678.
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`Here, the Court will assume, without deciding, that GSK had the ability to change the
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`Zofran label unilaterally through the CBE process prior to the time it sold the rights to the drug
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`to Novartis in 2015. For the reasons set forth below, the Court concludes that the FDA has been
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`Case 1:21-cv-10906-FDS Document 5 Filed 06/01/21 Page 6 of 68
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`fully informed of the justifications for the warning proposed by plaintiffs—in particular, the
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`scientific studies and literature, including the disputed animal studies, concerning the likelihood
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`that Zofran poses a risk to the fetus when ingested by pregnant women. There is no basis at this
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`point for concluding that any relevant information had been withheld from the FDA by the time
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`of its 2021 decision. The Court further concludes that there is no doubt that the FDA would not
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`approve the changes to the warning label proposed by plaintiffs. It has effectively rejected those
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`changes, and indeed approved contrary language.
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`One potential wrinkle in the analysis arises from the fact that GSK submitted the original
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`new drug applications for Zofran to the FDA, beginning in 1991, but then sold the rights to the
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`drug to Novartis in 2015. Subsequently, Novartis proposed changes to the label through the PAS
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`process on two different occasions, both of which the FDA rejected. The FDA therefore
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`informed Novartis—not GSK—that it would not approve the proposed changes. And there was
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`never a point between 1991 and 2015 when the FDA prevented GSK from changing the label.
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`Nonetheless, for the reasons set forth below, there is no reasonable basis to treat GSK and
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`Novartis differently for purposes of the preemption analysis.
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`In short, even assuming that GSK did, in fact, fail to make complete disclosures to the
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`FDA in 1991, and at various later points, there is no question that the FDA is now fully informed
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`of all relevant information concerning the safety of the drug. And the FDA has made the
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`determination that a label change is not warranted. Thus, the FDA, acting pursuant to the duty
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`imposed on it by federal law, has rejected the pregnancy warning label that plaintiffs insist was
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`required by state law at the time of the alleged injuries.
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`Accordingly, and for the following reasons, plaintiffs’ state-law claims of failure to warn
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`are preempted by federal law, and GSK’s renewed motion for summary judgment based on
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`Case 1:21-cv-10906-FDS Document 5 Filed 06/01/21 Page 7 of 68
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`federal preemption will be granted.
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`II.
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`Background
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`Unless otherwise noted, the following facts are undisputed.
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`A.
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`The Regulatory Framework
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`1.
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`Labeling Requirements Generally
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`Under federal law, a drug company may not market or sell a new pharmaceutical drug
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`without the approval of the Food and Drug Administration. 21 U.S.C. § 355(a). To obtain that
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`approval, the company (which is referred to as the “sponsor”) must submit a New Drug
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`Application (“NDA”) to the FDA. Id. An NDA must provide comprehensive information about
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`the drug, including its formulation, the proposed labeling, and scientific data about its safety and
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`efficacy. Id. §§ 355(b)(1)(A)(i), (iii), (vi); 21 C.F.R. §§ 314.50(d)(5)(viii), 201.57(a).
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`Not surprisingly, FDA regulations require that an NDA fully disclose all “pertinent”
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`safety information. See, e.g., 21 C.F.R. §§ 314.50 (requiring “reports of all investigations of the
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`drug product sponsored by the applicant, and all other information about the drug pertinent to an
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`evaluation of the NDA that is received or otherwise obtained by the applicant from any source”);
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`314.50(d)(5)(vi)(a) (requiring “an integrated summary of all available information about the
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`safety of the drug product, including pertinent animal data[ and] demonstrated or potential
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`adverse effects of the drug”); 312.50 (stating that “[s]ponsors are responsible for . . . providing
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`[investigators] with the information they need to conduct an investigation properly . . . and
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`ensuring that [the] FDA and all participating investigators are promptly informed of significant
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`new adverse effects or risks with respect to the drug”).
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`The sponsor’s duty to make full disclosure continues beyond the initial submission of its
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`NDA. See, e.g., id. §§ 314.50(d)(5)(vi)(b) (“The applicant must . . . update periodically its
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`pending NDA with new safety information learned about the drug that may reasonably affect the
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`Case 1:21-cv-10906-FDS Document 5 Filed 06/01/21 Page 8 of 68
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`statement of contraindications, warnings, precautions, and adverse reactions in the draft
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`labeling . . . [including information from] animal studies . . . .”); 312.33 (requiring annual reports
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`for investigational NDAs that include “[a] list of the preclinical studies {including animal
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`studies} completed or in progress during the past year and a summary of the major preclinical
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`findings,” and, “[i]f the study has been completed, or if interim results are known, a brief
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`description of any available study results”).
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`The FDA approval process is “onerous and lengthy.” Mut. Pharm. Co. v. Bartlett, 570
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`U.S. 472, 476 (2013). The FDA will approve a drug only if the NDA demonstrates that the drug
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`(1) is “safe for use,” (2) “will have the effect it purports or is represented to have,” and (3) is
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`accompanied by labeling that is neither “false [n]or misleading in any particular.” 21 U.S.C. §§
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`355(c)(1)(A), (d).
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`The FDA does not only approve the drug and its intended use; it also approves the exact
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`text of the label. Id. § 355; see Wyeth, 555 U.S. at 568. With one exception, noted below, the
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`sponsor may not alter the label in any respect without the approval of the FDA. Wyeth, 555 U.S.
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`at 568.
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`2.
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`The Process for Changing Labels
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`After approval of a drug, the FDA retains the authority to require changes to the label to
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`reflect new information concerning its safety and efficacy. 21 U.S.C. § 355(o)(4) (“If the
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`Secretary becomes aware of new information, including any new safety information . . ., that the
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`Secretary determines should be included in the labeling of the drug, the Secretary shall promptly
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`notify the responsible person . . . .”). Nonetheless, a “central premise of federal drug regulation
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`[is] that the manufacturer bears responsibility for the content of its label at all times.” Wyeth,
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`555 U.S. at 570-71. The manufacturer is “charged both with crafting an adequate label and with
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`ensuring that its warnings remain adequate as long as the drug is on the market.” Id. at 571.
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`There are two ways in which a manufacturer can seek to change the warnings on a drug
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`label. See In re Celexa & Lexapro Mktg. & Sales Pracs. Litig., 779 F.3d 34, 37 (1st Cir. 2015)
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`(citing 21 C.F.R. §§ 314.70(b)(2), (c)(6)).
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`First, a manufacturer can file a “Prior Approval Supplement” (“PAS”) requesting
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`revisions to the label. 21 C.F.R. § 314.70(b). That process requires FDA approval before
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`implementation, and in substance is similar to the process for initial approval of a label.
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`Second, a manufacturer can unilaterally amend a label to “add or strengthen a
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`contraindication, warning, precaution, or adverse reaction” when “newly acquired information”
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`reflects a “clinically significant hazard.” 21 C.F.R. §§ 201.57(c)(6)(i), 314.70(c)(6)(iii). That
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`action, known as the “changes being effected” (“CBE”) process, allows a sponsor to make an
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`immediate labeling change upon filing a supplemental application with the FDA. The amended
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`label will then be reviewed by the FDA and will be approved if it is based on new “reasonable
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`evidence of a causal association with [the] drug” and a “clinically significant hazard.” 21 C.F.R.
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`§ 201.57(c)(6)(i).
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`The term “newly acquired information” is not limited to entirely new data. Wyeth, 555
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`U.S. at 569. It also includes the following:
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`[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]
`FDA.
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`21 C.F.R. § 314.3; see also Celexa, 779 F.3d at 42 (giving examples of “newly acquired
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`information”).
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`3.
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`The FDA’s Approach to Warning Labels
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`For most types of consumer products, manufacturers have an incentive to warn against
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`every conceivable type of hazard or risk in order to try to forestall tort liability under state law.
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`Many products thus come covered with labels, and packaged with booklets, containing multiple
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`warnings against dangers both real and remote.
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`With pharmaceuticals, however, the FDA has adopted a more balanced approach.
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`[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.
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`In re Fosamax (Alendronate Sodium) Prods. Liab. Litig., 852 F.3d 268, 274 (3d Cir. 2017)
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`(citations omitted).
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`The FDA standard for requiring a warning label is thus different from that imposed by
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`state tort law. See, e.g., PLIVA, 564 U.S. at 611 (“It is undisputed that Minnesota and Louisiana
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`tort law require a drug manufacturer that is or should be aware of its product’s danger to label
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`that product in a way that renders it reasonably safe.”); Wooderson v. Ortho Pharm. Corp., 681
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`P.2d 1038, 1049 (Kan. 1984) (“It is well settled, however, that the manufacturer of ethical drugs
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`bears the additional duty of making timely and adequate warnings to the medical profession of
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`any dangerous side effects produced by its drugs of which it knows, or has reason to know.”)
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`(collecting cases from various jurisdictions).
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`4. Warning Labels for Pregnancy
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`Special provisions govern the labeling of drugs that may be taken by pregnant women.
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`Until June 30, 2015, the FDA classified drugs into five categories of safety for use during
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`pregnancy: A, B, C, D, or X. According to the then-applicable statutory language, “[i]f animal
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`reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and
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`Case 1:21-cv-10906-FDS Document 5 Filed 06/01/21 Page 11 of 68
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`well-controlled studies in pregnant women,” the label must contain the following language:
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`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.
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`21 C.F.R. § 201.57(c)(9)(i)(A)(2).
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`Alternatively, “[i]f animal reproduction studies have shown an adverse effect on the
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`fetus, if there are no adequate and well-controlled studies in humans, and if the benefits from the
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`use of the drug in pregnant women may be acceptable despite its potential risks,” the label must
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`contain the following language:
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`Pregnancy Category C. (Name of drug) has been shown to be teratogenic (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.
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`21 C.F.R. § 201.57(c)(9)(i)(A)(3).
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`That classification system was eliminated by the FDA when it issued a final rule
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`amending the regulations concerning pregnancy and lactation labeling. Content and Format of
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`Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy
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`and Lactation Labeling, 79 Fed. Reg. 72,064 (Dec. 4, 2014).
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`B.
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`The Approval of the Zofran Label
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`Zofran, or ondansetron hydrochloride, is a prescription drug that prevents nausea and
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`vomiting. It is part of a class of anti-emetics referred to as selective serotonin 5-HT3 receptor
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`antagonists. (Hill Decl., Ex. 75).
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`On January 4, 1991, the FDA approved the marketing and sale of Zofran for the
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`prevention of nausea and vomiting induced by chemotherapy or radiation therapy and post-
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`operative nausea and vomiting. (Id., Ex. 19).2 The 1991 approval was for an injection
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`formulation; in 1992, 1995, 1997, and 1999, the FDA approved four additional formulations,
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`covering oral tablets, premixed injections, oral solutions, and orally disintegrating tablets,
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`respectively. (Id., Exs. 19, 22-25).
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`C.
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`The Use of Zofran by Pregnant Women
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`Nausea and vomiting during pregnancy (“NVP”) is a common condition affecting 50% to
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`90% of women during their pregnancies. (Id., Ex. 32 at 3). The most severe form of NVP is
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`known as hyperemesis gravidarum (“HG”). (Id.). “HG has been reported in 0.5% to 2% of
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`pregnancies and is characterized by persistent and severe nausea and vomiting,” and may pose a
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`serious health risk to both the mother and the fetus. (Id.).
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`Zofran was not approved by the FDA for treatment of nausea and vomiting during
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`pregnancy. Indeed, GSK never sought approval for that use. However, it is generally lawful for
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`physicians to prescribe medications for purposes for which they have not been FDA-approved
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`(although it is generally unlawful for pharmaceutical companies to promote such “off-label”
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`use). See United States ex rel. Carpenter v. Abbott Lab’ys, Inc., 723 F. Supp. 2d 395, 397 n.2,
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`398-99 (D. Mass. 2010); see also Buckman Co. v Plaintiffs’ Legal Comm., 531 U.S. 341, 350
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`(2001) (noting that “‘off-label’ usage of medical devices . . . is an accepted and necessary
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`corollary of the FDA’s mission to regulate in this area without directly interfering with the
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`practice of medicine”). Over time, many physicians have prescribed Zofran to pregnant women,
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`particularly those suffering from HG.
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`When the FDA approved Zofran in 1991, it classified it as a pregnancy category B drug.
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`2 A predecessor of GSK, Glaxo, Inc., sponsored the original new drug application for Zofran. (Master
`Compl. ¶ 4).
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`(Hill Decl., Ex. 19 at 8). Between 1992 and 2016, the “Use in Specific Populations” section of
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`the approved label for intravenous Zofran containing the pregnancy category B designation
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`contained the following or similar language:
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`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.
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`(Id., Ex 20; see also Exs. 32, 40).
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`
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`The Zofran label does not, and never has, contained a warning contraindicating use of the
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`drug to treat pregnant women.
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`D.
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`The 2010 FDA PAS Request
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`In December 2010, then-FDA Director Donna Greibel sent GSK a “Prior Approval
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`Supplement Request” concerning Zofran. The PAS Request indicated that the FDA was aware
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`of the common use of Zofran during pregnancy and requested that GSK “review and analyze
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`available published and unpublished literature on the use of ondansetron during pregnancy and
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`lactation, with a focus on the presence or absence of adverse pregnancy and/or neonatal
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`outcomes.” (Id., Ex. 26). The requested review and analysis was to include an “assessment of
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`the strengths and limitations of the data” and proposed labeling revisions if GSK concluded
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`changes were necessary to “furnish adequate information for the safe use of this drug.” (Id.).
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`In April 2011, GSK replied to the FDA. Its response stated that it had “completed a
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`review of the available data and ha[d] included a summary of that analysis in [its] submission.”
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`(Id., Ex. 27). It stated that “[its] position is that the use of [Zofran] in human pregnancy has not
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`been established and is not recommended.” (Id.). And it concluded that it “[did] not believe
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`there [was] sufficient evidence to warrant a change in the [Zofran label].” (Id.).
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`Case 1:21-cv-10906-FDS Document 5 Filed 06/01/21 Page 14 of 68
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`The FDA did not respond and no changes were made to the Zofran label concerning
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`pregnancy. (Id., Ex. 28).
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`E.
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`The 2013 Reichmann Citizen Petition
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`In January 2013, an individual named James P. Reichmann submitted a citizen petition
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`asking the FDA to revise the Zofran label to provide heightened pregnancy warnings. (Id., Ex.
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`29).3 Specifically, he requested that the FDA reclassify the drug’s pregnancy risk category from
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`B to C, D, or X; notify obstetricians and gynecologists “that there is insufficient scientifically
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`acceptable evidence that ondansetron is associated with improved treatment outcomes and may
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`lead to adverse maternal and fetal events or outcomes”; and notify obstetricians and
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`gynecologists that “promotion of continuous subcutaneous ondansetron pump for the treatment
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`of nausea and vomiting of pregnancy (NVP) is a violation of FDA regulations.” (Id., Ex. 32 at
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`1). His petition contended that Zofran “may lead to adverse maternal and fetal events or
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`outcomes” if ingested during pregnancy. (Id.).4
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`On October 27, 2015, the FDA denied the petition. (Id. at 2). The FDA noted that
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`ondansetron had not been approved for the treatment of NVP, but that it was “aware of the
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`unapproved use of oral and injectable ondansetron for the treatment of NVP.” (Id. at 3). It
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`stated that “[t]he available evidence is not sufficient to conclude that there is an increased risk of
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`birth defects, including cleft palate, among fetuses exposed to ondansetron.” (Id. at 13). It
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`further indicated that it considered “information submitted by [GSK] to support approval of the
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`3 A citizen petition is a request that the FDA “issue, amend, or revoke a regulation or order or take or
`refrain from taking any other form of administrative action.” 21 C.F.R. § 10.30(b)(3). A citizen may petition for a
`change in drug labeling. See Cerveny v. Aventis, Inc., 855 F.3d 1091, 1102 (10th Cir. 2017) (noting that “the FDA
`standard for revising a warning label does not discriminate between proposals submitted by manufacturers and
`proposals submitted by citizens”).
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`4 Reichmann supplemented his petition five times. (Hill Decl., Ex. 32 at 1).
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`Case 1:21-cv-10906-FDS Document 5 Filed 06/01/21 Page 15 of 68
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`ondansetron NDA,” “post-marketing drug and device adverse event data,” and scientific
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`literature obtained through public submissions and through its own “targeted searches.” (Id. at
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`18 n.56). It concluded:
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`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.
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`(Id. at 18).
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`As to the warning label, the FDA stated: “[W]e believe pregnancy category B was the
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`appropriate risk category for ondansetron when it was assigned and . . . we believe pregnancy
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`category B remains appropriate today.” (Id.). The FDA similarly rejected Reichmann’s request
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`for the FDA to notify doctors that use of Zofran during pregnancy is not safe for the fetus. (Id. at
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`19). Such a notification, the FDA explained, could actually be misleading on account of the fact
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`that “the available data do not support a conclusion that there are increased safety risks . . . for
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`the fetus.” (Id. at 19).
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`F.
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`The 2015 Novartis Proposal
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`Novartis acquired the rights to Zofran from GSK in 2015. On September 22, 2015,
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`Novartis submitted to the FDA a proposed update to the Zofran pregnancy labeling along with a
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`clinical overview. (Id., Ex. 33).5 The proposal included several changes to the pregnancy “Risk
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`Summary” section of the label to advise against using Zofran during pregnancy and warn of
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`potential risks to a developing fetus.
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`Specifically, Novartis proposed the following revisions:
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`• Beginning the “Risk Summary” subsection (§ 8.1) with the caution:
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`5 Novartis was required to submit a proposed update to the Zofran label in order to conform with the then-
`new Pregnancy and Lactation Labelling Rule, published in December 2014. (Hill Decl., Ex. 33).
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`Case 1:21-cv-10906-FDS Document 5 Filed 06/01/21 Page 16 of 68
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`“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).
`
`•
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`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.).
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`• Creating a new subsection (§ 8.3) entitled “Females and males of
`reproductive potential,” which discusses pregnancy testing and
`contraception and