Lack of “Newly Acquired Information” Defeats Plaintiffs’ Claims in Zofran MDL

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Zofran (ondansetron) has often been used to combat nausea during pregnancy.  It has never been approved by the FDA for that indication, but clinical experience has not supported an association with pregnancy-related risks – for example, a recent systematic review and meta-analysis concluded that use of ondansetron during pregnancy was associated with a reduced incidence of miscarriage but “was not associated with abnormal pregnancy outcomes,” including a variety of birth defects.  Nevertheless, plaintiffs have alleged that Zofran causes birth defects and that the warnings accompanying the drug should have said so.  Those claims were dismissed in 2021 when the district court held them preempted, and the First Circuit recently affirmed that decision in In re Zofran (Ondansetron) Products Liability Litigation, — F.4th —, 2023 WL 128570 (1st Cir. Jan. 9, 2023).

Plaintiffs in the Zofran MDL alleged, among other things, that the defendants failed to warn of birth defects observed in certain animal studies.  Because such claims implicate the warnings accompanying an FDA-approved drug, they are preempted unless the manufacturer could have unilaterally amended the label through the Changes Being Effected (CBE) regulation.  The CBE regulation permits a manufacturer to amend a product’s labeling without prior FDA approval “to reflect newly acquired information” and thereby “add or strengthen” the warnings where there is “evidence of a causal association” between the drug and the subject on which the warnings are being amended.

In the case of Zofran, four animal studies conducted in the United Kingdom and one conducted in Japan had been submitted to the FDA at various times and had been deemed not to show any teratogenic (i.e., developmental defect-causing) effect.  Plaintiffs, however, pointed to three Japanese animal studies that had not been provided to the FDA and alleged that they constituted “newly acquired information” that enabled the manufacturer to amend the label via the CBE procedure.

The First Circuit opened by questioning whether the absence of “newly acquired information” on which to base a CBE amendment was dispositive or whether it had to decide “whether there is clear evidence that the FDA would have rejected a CBE change because the information is not newly acquired.”  Given that the CBE regulation only enables changes in the labeling “to reflect newly acquired information,” it seems clear that the CBE procedure is not available – and, therefore, warnings-based claims are preempted – unless there exists “newly acquired information” that could be reflected.  See, e.g., Knight v. Boehringer Ingelheim Pharms., Inc., 984 F.3d 329 (4th Cir. 2021).  If a lack of “newly acquired information” on which a CBE amendment could have been based is not itself enough to establish a preemption defense, what more must a manufacturer do?  Would the courts call on manufacturers to attempt a CBE amendment – despite the lack of “newly acquired information” – solely to prove that the FDA would reject such an amendment?

Ultimately, the First Circuit observed that the parties had all treated a lack of “newly acquired information” as dispositive and decided to follow suit.  It therefore assessed whether the Japanese studies constituted “newly acquired information” that would have enabled a CBE amendment.  They were not.  “Newly acquired information” is defined by regulation and, among other things, must “reveal risks of a different type or greater severity or frequency than previously included in submissions to FDA.”  And it must constitute “evidence of a causal association” between the drug and the additional warning urged.  But the three Japanese studies in question had each concluded there was no statistically significant relationship between Zofran and observed birth defects in animals.  And even if the studies had supported a causal association, the defects seen in the three Japanese studies were not different in type, severity, or frequency than those that had been observed in the four UK studies and the one Japanese study that had been submitted to the FDA.

Plaintiffs cited two litigation experts in an effort to save their claims.  First, they offered a regulatory expert to opine that the Japanese studies constituted “newly acquired information” under the CBE regulations.  But the court held that this was a question of law on which the expert’s opinion was “likely inadmissible.”  Moreover, the expert opined on the wrong question – he could not say he had ever read any of the animal studies at issue and merely opined that all animal studies should have been submitted regardless of their content.

Next, Plaintiffs pointed to an expert who had “reinterpreted” the data and opined that both the unsubmitted Japanese studies and the UK/Japanese studies that had been submitted – and which the FDA had determined did not evidence teratogenicity – constituted evidence that Zofran was teratogenic.  Plaintiffs claimed that it was his analysis, and not the Japanese studies themselves, that constituted “newly acquired information.”  But even assuming that the expert’s analysis could constitute “newly acquired information,” the expert did not opine that the unsubmitted studies showed anything new.  In effect, he merely sought to second-guess FDA’s conclusions regarding the submitted studies.

Having determined that the Japanese studies were not “newly acquired information,” the First Circuit concluded that “plaintiffs’ argument on appeal fails at its first step.”  Nevertheless, the court went on to observe that Plaintiffs’ claims also failed “step two” of the analysis.  The FDA, having become fully informed of the Japanese studies after the Zofran litigation had commenced, nevertheless approved an updated label stating that animal data did not reveal significant effects on the development of offspring.  Because this language was “fundamentally incompatible” with Plaintiffs’ position, there was clear evidence that the FDA would have rejected the warnings that the Plaintiffs urged.  Thus, their claims would have been preempted even if the Japanese studies had been “newly acquired information.”

In re Zofran went the way that such cases ought to go.  Despite some initial hesitancy, the First Circuit dutifully spent the majority of its analysis on whether the studies in question were in fact “newly acquired information.”  By the end of its analysis, the court referred to this inquiry as the “first step” of a two-step inquiry, to be decided before asking whether FDA would have rejected the CBE amendment in question.  This is the right approach to the question – where there is no “newly acquired information,” there can be no CBE amendment and, thus, no viable failure to warn claim.

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About the Author: Eric M. Friedman

Eric Friedman guides clients through all stages of product liability litigation, particularly working with expert witnesses to present the science behind clients' products. By leaning on his pre-law history as a biochemist, he is able to identify key arguments for and against clients and craft winning strategies for both motion practice and trial.