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In re Zofran (Ondansetron) Products Liability Litigation

United States District Court, D. Massachusetts

February 5, 2019



          F. Dennis Saylor IV, United States District Judge.

         This is 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 denied.

         I. Introduction

         Zofran 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.

         Zofran 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.

         At some 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.

         In 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.

         The 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.

         There 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.

         Here, 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 is precluded.

         The 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).

         In the 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.

         Accordingly, and for the following reasons, the motion of GSK for summary judgment based on preemption will be denied.

         II. Background

         Unless otherwise noted, the following facts are undisputed.

         A. The Regulatory Framework

         1.Labeling Requirements Generally

         Under 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), 201.57(a).

         Not 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”).

         The 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 results”).

         The FDA 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).

         The FDA 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.

         2.The Process for Changing Labels

         After 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 571.

         There 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)).

         First, 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.

         Second, 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).

         The 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] FDA.

21 C.F.R. § 314.3. See Celexa, 779 F.3d at 42 (giving examples of “newly acquired information”).

         3. The FDA's Approach to Warning Labels

         For 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.

         With pharmaceuticals, however, the FDA has adopted a more balanced approach.

[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) (citations omitted).

         The FDA 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 jurisdictions).

         4. Warning Labels for Pregnancy

         Special 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).

         That 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, 2014).

         B. The Approval of the Zofran Label

         Zofran, 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).

         On 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).[1] 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).

         C. The Use of Zofran by Pregnant Women

         Nausea 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.).

         Zofran 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.

         When 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).

         The Zofran label does not, and never has, contained a warning contraindicating use of the drug to treat pregnant women.

         D. The 2010 FDA PAS Request

         In 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 drug.” (Id.).

         In 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].” (Id.).

         The FDA did not respond and no changes were made to the Zofran label concerning pregnancy. (Id. Ex. 15).

         E. The 2013 Citizen Petition

         In 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).[2] 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.).[3]

         On 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). It concluded:

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).

         As to 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).

         F. The 2015 Novartis Proposal

         Novartis 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).[4] 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.

         Specifically, 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).

         Novartis 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).

         In the 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).

         In 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).

         In 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 2604).

         The FDA 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.).

         Eventually, 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. at 3947)
• “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 ...

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