One of the decisions we were looking forward to at the end of 2022 has occurred. In In re Zofran (Ondansetron) Products Liability Litigation, ___ F.4th ___, 2023 WL 128570 (1st Cir. Jan. 9, 2023), the court unanimously affirmed the MDL-wide preemption order dismissing all claims. Since the history of the Zofran litigation is well covered in our prior posts, we’ll stick to the First Circuit’s preemption rationale here.
The claims in Zofran concerned plaintiffs’ demands for warnings about the off-label use of this product for relief of morning sickness during pregnancy. Id. at *1. As we’ve also discussed previously, the FDA imposes tight restrictions about anything that a regulated entity proposes to say about off-label uses in the label. Thus, we always expected that preemption would bar the claims in Zofran.
The First Circuit first discussed the FDA’s “extensive regulat[ion]” of drug labeling generally – emphasizing the agency’s scientific basis requirements for warnings and its “objective” of “prevent overwarning, which may deter appropriate use of medical products, or overshadow more important warnings.” Id. (quoting 73 Fed. Reg. 49603, 49605-06 (FDA Aug. 22, 2008)). Next, Zofran discussed the FDA’s regulations governing pregnancy-related information in labeling – particularly how those regulations treated animal studies. Id. Oddly, that the plaintiffs were suing over off-label use, while mentioned in passing, did not figure in the court’s legal analysis. 2023 WL 128570, at *1, 3.
The focus on animal studies was because preemption involved plaintiffs’ allegations that defendants did not timely inform the FDA of three Japanese animal studies. Id. at *4 (“plaintiffs focus their appeal on the three Japanese studies not originally submitted to the FDA”). The First Circuit affirmed that those allegations were meritless, for the following reasons:
- The FDA reviewed the scientific basis for birth defect claims five times between 2010 and 2021 – including three times after the MDL was created in 2015 – and concluded every time that there was no support for any warning about birth defects. Id. at *4-5.
- None of the three studies revealed any statistically significant risk increase in birth defects, or any “dose dependency,” so the authors did not associate any birth defects with the drug. Id. at *8-9.
- The three studies involved the same animal species, the same doses, and evaluated the same risks, as other studies previously submitted to the FDA, so they could not constitute evidence of any “different type” or “greater severity” of risk as required by the regulatory definition of “newly acquired information.” Id. at *9.
- Plaintiffs’ expert’s contrary opinion that the three studies were “newly acquired information” was “likely inadmissible” as an improper legal opinion. Id. at *10.
- Another plaintiffs’ expert’s opinion was contrary to what the FDA concluded and thus improperly “applied a standard not utilized by the FDA.” Id. “[I]t is not up to us [courts] to second-guess the FDA on such matters.” Id. at n.8 (citation omitted).
Interestingly, Zofran avoided deciding certain other preemption related issues, two because both sides “presume[d]” the same outcome. Those issues were “whether a judicial finding of newly acquired information serves as a threshold prerequisite for determining that the CBE procedure was available,” and “whether certain information is ‘newly acquired’ is a legal question.” Id. at *7. Since both sides answered these questions, “yes,” the court followed their lead. Id. Due to plaintiffs’ waiver, Zofran also avoided deciding “whether a plaintiff’s expert report, presented in litigation, can qualify as ‘newly acquired information.’” Id. at *10 n.9 (citations omitted).
Zofran also held that, even assuming the three Japanese animal studies could be newly acquired information, “clear evidence” existed that the FDA would have rejected the sort of birth defect warning that plaintiffs demanded. First, the First Circuit determined that Zofran was not a case “like” Levine, since unlike both Wyeth v. Levine, 555 U.S. 555 (2009), and Merck Sharp & Dohme Corp. v. Albrecht, 139 S. Ct. 1668 (U.S. 2019), the defendant in Zofran “disputes the existence of newly acquired information that would have supported a [CBE label] change.” Zofran, 2023 WL 128570, at *11 n.10.
As mentioned, the FDA evaluated teratogenic risk five times since 2010, and three times after litigation began, and in each instance rejected adding any warnings concerning birth defects, due to insufficient and conflicting scientific data. For that reason, “the FDA, after being fully informed of the case for making plaintiffs’ proposed label change, made clear through agency action having the force of law that it would not have allowed the change had the defendant initiated it through the CBE procedure.” Id. at *11. These five instances of FDA review of the relevant risks left “no doubt that . . . the FDA was fully informed of the Japanese studies” by the end of the process, and did not require any teratogenicity warning. Id. at *12. Who provided the FDA with the information – the regulated manufacturer or someone else – was of little if any import:
Indeed, the FDA was also fully informed of plaintiffs’ contentions and the opinions of plaintiffs’ experts. Some of this information was arguably supplied to the FDA by plaintiffs, not the manufacturer. But we find the relevant issue to be whether the FDA was informed in a relevant context, not who exactly first informed it.
Id. (quotation marks omitted). Thus, the FDA both knew all the relevant information, and gave the issue much more than the “passing attention” in Levine, so that the necessary “clear evidence” was present. Id. Since even plaintiffs “concede[d]” that the 2021 label approval was “formal agency action with the force of law,” the FDA’s decision was preemptive “law” under the Supremacy Clause. Id. (citation omitted).
Finally, verbatim identity of the plaintiffs’ warning claim to the FDA’s action was not necessary to preemption in Zofran. An absolute, substantive contradiction between FDA action and the plaintiffs’ position was preemptive:
We think it clear that when the FDA formally approves a statement that data reveals no effects, it necessarily rejects the contention that the data does reveal effects. . . . The fully informed FDA in approving the label stating “not-X” necessarily rejected plaintiffs’ prominently presented case for stating “X”. . . . [W]hen the FDA formally approves a label stating one thing with full and obvious notice of the directly contrary position, one can read the approval as rejecting the contrary position.
Id. (footnote omitted).
This complete defense win in Zofran was well worth the wait. We fully expect it will make this year’s top-ten list.