Perham v. GlaxoSmithKline LLC (In re Zofran (Ondansetron) Prods. Liab. Litig.)

• Decision Date: 09 January 2023
• Docket Number: 21-1517
• Citation: 57 F.4th 327
• Parties: IN RE: ZOFRAN (ONDANSETRON) PRODUCTS LIABILITY LITIGATION Heather Perham, et al., Plaintiffs, Appellants, v. GlaxoSmithKline LLC, Defendant, Appellee, Sun Pharmaceutical Industries Ltd.; Sandoz, Inc.; Providence Health System ; Novartis Pharmaceuticals Corp.; McKesson Corporation; Does 1 through 100, inclusive, Teva Pharmaceutical USA; GlaxoSmithKline Holdings (Americas) Inc., Defendants.
• Court: U.S. Court of Appeals — First Circuit

57 F.4th 327

IN RE: ZOFRAN (ONDANSETRON) PRODUCTS LIABILITY LITIGATIONHeather Perham, et al., Plaintiffs, Appellants,

v. GlaxoSmithKline LLC, Defendant, Appellee,Sun Pharmaceutical Industries Ltd.; Sandoz, Inc.; Providence Health System ; Novartis Pharmaceuticals Corp.; McKesson Corporation; Does 1 through 100, inclusive, Teva Pharmaceutical USA; GlaxoSmithKline Holdings (Americas) Inc., Defendants.

No. 21-1517

United States Court of Appeals, First Circuit.

January 9, 2023

Louis M. Bograd, with whom Motley Rice LLC was on brief, for appellants.

Lisa S. Blatt, with whom Amy Mason Saharia, J. Matthew Rice, Jami M. King, Williams & Connolly LLP, Scott A. Chesin, and Shook, Hardy & Bacon, were on brief, for appellee GlaxoSmithKline LLC.

Matthew W.H. Wessler, Joanne Grace Dela Peña, Gupta Wessler PLLC, Ellen Noble, and Public Justice on brief for amici curiae American Association for Justice and Public Justice.

Emily Ullman, Michael X. Imbroscio, Nicole Antoine, Paul W. Schmidt, and Covington & Burling LLP on brief for amicus curiae Pharmaceutical Research and Manufacturers of America.

Before Kayatta and Howard, Circuit Judges, and Walker, District Judge.^*

KAYATTA, Circuit Judge.

This appeal arises out of multidistrict litigation concerning the pharmaceutical drug ondansetron

hydrochloride (better known by its brand name, Zofran ), which is commonly taken off-label during pregnancy. Plaintiffs claim that GlaxoSmithKline (GSK), the company responsible for initially putting Zofran on the market and for manufacturing the drug until 2015, should be held liable under various state product liability laws for failing to warn consumers that animal studies revealed adverse effects on the fetus, including birth defects -- a warning that does not appear on Zofran's federally approved label. The district court granted summary judgment in favor of GSK, finding that federal law preempted plaintiffs' state law claims because there was clear evidence that the Food and Drug Administration (FDA) would have rejected the warning that plaintiffs allege is required under state law. We affirm the district court's grant of summary judgment. Our reasoning follows.

I.

A.

We begin by detailing the complex federal regulatory scheme governing pharmaceutical drug labels. Congress enacted the Food, Drug, and Cosmetic Act (FDCA) in 1938 "to bolster consumer protection against harmful products." Wyeth v. Levine, 555 U.S. 555, 574, 129 S.Ct. 1187, 173 L.Ed.2d 51 (2009) ; see 21 U.S.C. §§ 301 et seq. Pursuant to that statute, drug companies cannot sell or market a new pharmaceutical drug product without prior approval from the FDA. See 21 U.S.C. § 355(a). To obtain this approval, a manufacturer (also commonly referred to as the drug's sponsor) must submit comprehensive information about the drug to the FDA in a New Drug Application. See id. § 355(b)(1). During this process, the FDA reviews a drug's safety and efficacy as well as the drug's proposed labeling. See id.

The FDA extensively regulates the format and substance of the information that appears on a drug's label. See, e.g., 21 C.F.R. §§ 201.56, 201.57. In so doing, one of its objectives is to "prevent overwarning, which may deter appropriate use of medical products, or overshadow more important warnings." Supplemental Applications Proposing Labeling Changes for Approved Drugs, Biologics, and Medical Devices, 73 Fed. Reg. 49603, 49605–06 (Aug. 22, 2008). It therefore "allow[s] only information for which there is a scientific basis to be included in the FDA-approved labeling." Id. at 49604. And it guards against the "[e]xaggeration of risk, or inclusion of speculative or hypothetical risks." Supplemental Applications Proposing Labeling Changes for Approved Drugs, Biologics, and Medical Devices, 73 Fed. Reg. 2848, 2851 (Jan. 16, 2008).

The FDA also has an extensive set of regulations governing the use of drugs during pregnancy. To obtain FDA approval for any such use, a drug's sponsor must include in its application, among other things, an "integrated summary of the toxicological effects of the drug in animals," including "tests of the drug's effects on reproduction and the developing fetus." 21 C.F.R. § 312.23(a)(8)(ii)(a).

At the time Zofran

was initially approved by the FDA, the FDA classified drugs into five categories of safety for use by pregnant people: A, B, C, D, and X. See 21 C.F.R. § 201.57(c)(9)(i)(A) (2006). Each category came with a standardized set of warnings. Id. Under the then-applicable regulations, if animal studies "failed to demonstrate a risk to the fetus and there [were] no adequate and well-controlled studies in pregnant women," the drug would be classified into Pregnancy Category B and include the following label:

Pregnancy Category B. Reproduction studies have been performed in (kind(s) of animal(s)) at doses up to (x) times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to (name of drug). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

21 C.F.R. § 201.57(c)(9)(i)(A)(2). If, however, animal studies "show[ed] an adverse effect on the fetus, if there [were] no adequate and well-controlled studies in humans, and if the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks," the drug would be categorized into Pregnancy Category C. 21 C.F.R. § 201.57(c)(9)(i)(A)(3). The label would then need to include the following statement:

Pregnancy Category C. (Name of drug) has been shown to be teratogenic¹ (or to have an embryocidal effect or other adverse effect) in (name(s) of species) when given in doses (x) times the human dose. There are no adequate and well-controlled studies in pregnant women. (Name of drug) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

.

Id. In Category C, the label "must contain a description of the animal studies." Id.

The current regulations, promulgated in 2014 as the Pregnancy and Lactation Labeling Rule (PLLR), no longer use risk categories for pregnancy-drug labels. See Requirements for Pregnancy and Lactation Labeling, 79 Fed. Reg. 72064, 72076-77 (Dec. 4, 2014). Instead, the PLLR requires that labels contain a risk statement summarizing animal and human studies, with distinct subsections describing animal and human data. See id.

After the FDA approves a label for a drug, that label is not immutable. That is because knowledge about a drug's safety and efficacy can change over time. Accordingly, the FDA provides several pathways for a drug manufacturer, citizen, or the agency itself to make changes to a drug's label.

First, a drug manufacturer can file a Prior Approval Supplement (PAS) with the FDA to request revisions to a label. See 21 C.F.R. § 314.70(b). The PAS procedure resembles the process for obtaining initial approval for the drug's label and requires the FDA to approve the change in the label before it can be made.

Second, a drug manufacturer can use the Changes Being Effected (CBE) regulations to unilaterally amend a label and seek after-the-fact approval from the FDA. See 21 C.F.R. § 314.70(c)(6)(iii). The CBE procedure permits manufacturers to change a label "to reflect newly acquired information" if the changes "add or strengthen a ... warning" for which there is "evidence of a causal association." Id.; see also 21 C.F.R. § 201.57(c)(6). Although a manufacturer initiates this process, "the FDA reviews CBE submissions and can reject label changes even after the manufacturer has made them," and "manufacturers cannot propose a change that is not based on reasonable evidence." Merck Sharp & Dohme Corp. v. Albrecht, ––– U.S. ––––, 139 S. Ct. 1668, 1679, 203 L.Ed.2d 822 (2019).

Third, the FDA permits private individuals and organizations to request changes to a drug's label based on "reasonable evidence of an association of a serious hazard with a drug." 21 C.F.R. § 201.80(e) ; see 21 C.F.R. § 10.30(b)(3) ; Cerveny v. Aventis, Inc., 855 F.3d 1091, 1102 (10th Cir. 2017).

Fourth, the FDA, on its own initiative, must notify a drug manufacturer of the need to submit a supplement proposing changes to a drug's label if the FDA becomes aware of new information, including safety information, that it determines should be included in the drug label. 21 U.S.C. § 355(o)(4)(A), (B).

B.

With this regulatory background in mind, we walk through the events that gave rise to the present appeal. Zofran

is an FDA-approved prescription drug for the prevention of chemotherapy-induced, radiation-induced, and post-operative nausea and vomiting. Although Zofran has never been approved for preventing pregnancy-related nausea and vomiting, it is often prescribed off-label for that purpose. GSK owned Zofran from 1991, when the drug first received FDA approval, until 2015, when GSK sold the rights to manufacture and market the drug to the pharmaceutical company Novartis. Zofran remains on the market, and its label does not currently warn of an association between its use and pregnancy-related risks, including birth defects.

As part of Zofran's

New Drug Application approval process in 1990 and 1991, GSK submitted data related to Zofran's safety and efficacy to the FDA. The data included a set of four animal reproductive studies conducted on rats and rabbits in the United Kingdom (study nos. R10590 (UK Oral Rat Study), and R10937 (UK IV Rat Study), L10649 (UK Oral Rabbit Study), L10873 (UK IV Rabbit Study)). Although the investigators in those studies observed some incidences of birth defects among the animal subjects, the studies did not conclude that there was a causal association between Zofran and birth defects. In brief, defects can and do occur in the absence of Zofran, and the studies did not reveal a statistically significant gap between the number of...