Products Liability Law Daily Likelihood of FDA’s rejection of Zofran® pregnancy warning a jury question
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Thursday, February 7, 2019

Likelihood of FDA’s rejection of Zofran® pregnancy warning a jury question

By Jeffrey H. Brochin, J.D.

The basic factual question underlying preemption was whether the FDA would have rejected manufacturer’s warning label if adverse research studies were fully disclosed.

In multi-district litigation concerning the drug Zofran®, the federal district court in Massachusetts has ruled that in order to prevail on its motion for summary judgment, GlaxoSmithKline LLC, (GSK), the drug’s manufacturer, needed to show that it could not have changed the warning label regarding the risk of taking the drug during pregnancy, or, if it could have changed the label, to show that there was clear evidence that the Food and Drug Administration (FDA) would have rejected the label. Given the factual dispute as to disclosure of research data to the FDA, as well as the uncertain issue of standard of proof, it was not clear whether the FDA would not have approved the changes to the label, and summary judgment was denied (In re Zofran (Ondansetron) Products Liability Litigation, February 5, 2019, Saylor, F.).

Off-label use by pregnant women. The multi-district litigation arose out of products liability claims that the use of the drug Zofran by pregnant women caused birth defects in their children. Zofran is an anti-emetic, intended to prevent or treat nausea or vomiting. It was initially approved by the FDA in 1991 for the prevention of nausea and vomiting induced by chemotherapy or radiation therapy and post-operative nausea and vomiting, but it was never approved for the prevention of nausea and vomiting during pregnancy. Nevertheless, Zofran has been prescribed off-label to pregnant women for many years, and the patients’ allegations were that the widespread practice was due in large part to unlawful marketing practices by GSK that sought to promote off-label usage.

FDA label-change rejections. In 2010, after the FDA became aware that Zofran was being prescribed to pregnant women in significant numbers, the agency requested that GSK provide supplemental information concerning the safety of Zofran when used during pregnancy. GSK provided an analysis of the then-available safety data, and 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, however, 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 during pregnancy could cause harm to the fetus and was not recommended. That proposal also was rejected by the FDA.

CBE unilateral label changes. The court noted that by federal law, the FDA closely regulates the labeling of drugs, including warning labels, and that generally a drug label only may be changed with FDA approval. However, under a process known as "changes being effected" (CBE), a drug manufacturer may change a label unilaterally based on certain newly acquired information concerning the drug’s safety, subject to later FDA approval. Based on the CBE process, the U.S. Supreme Court has held that a drug company can in fact add safety information to its label without FDA approval. 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 pregnancy warning that the patients contended state law required.

Issue of an informed rejection. The court determined that there was little doubt that the FDA would haverejected the proposed warning because of the prior history of such rejections. However, the patients argued that GSK’s alleged failure to make complete disclosures to the FDA meant that the agency’s decisions were not fully informed, and, therefore, a finding of federal preemption should be precluded. The court addressed the disparate positions by finding that: (1) GSK bears the burden of proof of the affirmative defense of preemption; (2) preemption presents a question of fact, to be considered on summary judgment like any other factual issue; (3) for present purposes, the court would not decide whether the standard of proof is clear and convincing evidence, rather than preponderance of the evidence; (4) the standard is objective—that is, what effect the allegedly omitted information would have had on a reasonable regulator; and (5) that in order to prevail, GSK needed to show that it could not have changed the label—by the CBE process or otherwise—or, if it could have, that there was clear evidence that the FDA would have rejected the label that the patients contended state law would have required.

Preemption. Based on the evidence and drawing all inferences in favor of the plaintiffs, the court found there were disputed issues of material fact concerning the availability of a federal preemption defense. In particular, GSK had not proved, either (1) that the CBE process was unavailable to it to make more substantial warnings concerning the ingestion of Zofran during pregnancy, or (2) that there was "clear evidence" that the FDA would not have approved a label including such warnings. Therefore, the court held that GSK was not entitled to summary judgment based on an affirmative defense of federal preemption.

The case is No. 1:15-md-02657-FDS.

Attorneys: Thomas V. Ayala (Grant & Eisenhofer, P.A.) for Amber Minton. Bradley Thomas (Shook, Hardy & Bacon LLP) for GlazoSmithKline, LLC and GlaxoSmithKline LLC. Sheri C. Browning (Brisbee & Stockton, LLC) for Providence Health System.

Companies: GlazoSmithKline LLC; GlaxoSmithKline LLC; Providence Health System; Novartis Pharmaceuticals Corp.

MainStory: TopStory PreemptionNews WarningsNews DrugsNews MassachusettsNews

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