We’re old enough that we remember the pre-Daubert Bendectin litigation. Bendectin was the only FDA-approved drug indicated for nausea and vomiting from pregnancy. Yellow journalism (the National Enquirer) and scientific fraud (deliberately falsified scientific data) fanned a birth defect scare, which led to an avalanche of factually baseless litigation – Daubert was a Bendectin case. Throughout it all, the FDA repeatedly found no teratogenic association, but to no avail, as litigation costs forced Bendectin off the market. It remains the only FDA-approved morning sickness drug.
The Bendectin litigation occurred before the Supreme Court recognized tort preemption in Cipollone v. Liggett Group, Inc., 505 US 504 (1992), and extended such preemption to FDA-regulated prescription medical products. E.g., Riegel v. Medtronic, Inc., 552 U.S. 312 (2008); Wyeth v. Levine, 555 U.S. 555 (2009); PLIVA, Inc. v. Mensing, 564 U.S. 604 (2011).
So when plaintiffs attempted to make the drug Zofran – indicated for combating nausea in chemotherapy patients, but widely used off-label as a morning sickness treatment – into the Bendectin of the twenty-first century, the result was dramatically different. Plaintiffs tried the same Bendectin playbook, including their own round of scientific shenanigans (which we described here and here), and ignoring repeated FDA findings of no demonstrable teratogenicity.
Thanks to preemption, this time the other side lost, big time. We predicted this would be the result back in 2015. In In re Zofran (Ondansetron) Products Liability Litigation, ___ F. Supp.3d ___, 2021 WL 2209871 (D. Mass. June 1, 2021), implied preemption resulted in dismissal of the entire MDL. Unlike in Bendectin litigation, preemption now precludes state-law tort plaintiffs from buying their own supposed “science” and ignoring the conclusions drawn by the FDA. In Zofran, as we will now discuss, preemption functioned like the proverbial hot knife through bull***t.
First, here’s a thumbnail FDA regulatory history of this product:
- 1/4/1991 – Initial FDA approval of anti-nausea indication (several more for different formulations follow).
- 12/2010 – FDA awareness of “common” off-label use causes the agency to demand the defendant “review and analyze” the literature for any “adverse” pregnancy outcomes.
- 4/2011 – The defendant submitted the requested information, concluding that no label change was needed.
- After 4/2011 – FDA did not require any label changes to discuss this off-label use, as only the Agency could mandate pursuant to 21 C.F.R. §201.80(e).
- 1/2013 – “Reichmann” citizen’s petition filed requesting “heightened pregnancy warnings.”
- 2015 – defendant sold the New Drug Application to its current successor.
- 2015 – Plaintiffs start filing birth defect litigation, leading to creation of Zofran MDL on October 13, 2015. See (for this bullet only) In re Zofran (Ondansetron) Products Liability Litigation, 138 F. Supp.3d 1381 (Jud. Pan. MDL 2015).
- 9/22/2015 – Successor sought a prior approval supplement (“PAS”) label change from the FDA to add “possible” teratogenic risk.
- 10/27/2015 – FDA denies Reichmann petition, noting its awareness of the off-label use and the Agency’s conclusion that “[t]he available evidence is not sufficient to conclude that there is an increased risk of birth defects.” That denial is why we predicted that birth defect litigation (which had barely begun) would wind up preempted.
- 11/2015 – The FDA rejected successor’s PAS label change for essentially the same reason it rejected the Reichmann petition – lack of sufficient scientific data supporting any increased risk.
- 12/2015 – Successor submitted a second PAS “not recommending” the off-label use.
- 4/2016 – FDA denies second PAS, deleting the comment about the off-label use.
- 2016 – More FDA statements that data do not support any birth defect risk warning in communications with the successor.
- 2016 – Label change allowed stating that “[a]vailable data do not reliably inform [any] association” with, and provide “no clear evidence” of, “adverse fetal outcomes.”
- 11/1/2019 – Defendant submits Japanese animal data, plaintiffs’ alleged “biological mechanism,” adverse event data, and 2004 Einerson study to FDA in citizen’s petition seeking to resolve MDL preemption questions.
- 1/8/2020 – Plaintiffs submit information in opposition to defendant’s citizen’s petition.
- 3/2020 – Both sides meet with FDA in separate meetings; both sides’ materials publicly posted on FDA website.
- 6/4/2020 – Successor submits third PAS seeking label changes to add statements about “possible” birth defect risk and “conflicting” study results.
- 1/15/2021 – FDA denies defendant’s citizen’s petition as “hypothetical”; makes no label changes.
- 4/29/2021 – Successor and FDA agree to negotiated label change that again deletes all references to birth defect risks except that current data “preclude an assessment” of teratogenic risk.
Zofran, 2021 WL 2209871, at *6-15.
The Zofran MDL plaintiffs had managed, prior to Merck Sharp & Dohme Corp. v. Albrecht, 139 S. Ct. 1668 (U.S. 2019), to muddy the waters enough with fraud-on-the-FDA claims to convince the court that preemption presented a “question of fact” for a jury to answer. In re Zofran (Ondansetron) Products Liability Litigation, 368 F. Supp.3d 94, 116-17 (D. Mass. 2019). Albrecht’s holding that preemption is “a matter of law for the judge to decide” changed all that. 139 S. Ct. at 1672. Now free to “simply ask . . . whether the relevant federal and state laws ‘irreconcilably conflict,’” id. at 1679, the MDL court recognized that the defendant in Zofran had by far the more persuasive preemption argument. If anyone out there is still wondering why we chose Albrecht as our number one best case of 2019, Zofran is “Exhibit A.” We said then, “[i]n 95% of preemption cases (at least), we think defendants have the better side of the regulatory record, thus we should win most straight-up preemption arguments.” We say it again, now.
Here’s how the defense won in Zofran. First, the court noted two paths to preemption:
(1) the CBE process was not available, and therefore [a manufacturer] could not make unilateral changes to the label, or (2) [the manufacturer] establishes by “clear evidence” that the FDA would not have approved the changes to the label that the plaintiffs contend should have been made.
2021 WL 2209871, at *25. Given the FDA administrative record, the Zofran court chose the “clear evidence” path. Id. at *28. Between the defendant’s 2020 citizen’s petition and the successor’s 2021 label change, the FDA had in fact reviewed everything the Zofran plaintiffs had prepared in litigation and still rejected any teratogenicity-based label change. Thus, there probably wasn’t any “newly acquired information” either (the first path), but with “clear evidence” of the FDA’s position as recently as two months prior, Zofran did not need to go there.
“Clear evidence” required that the defendant manufacturer “show both (1) that ‘it fully informed the FDA of the justifications for the warning required by state law’; and (2) that ‘the FDA, in turn, informed the drug manufacturer that the FDA would not approve changing the drug/s label to include that warning.’” 2021 WL 2209871, at *25 (quoting Albrecht). Further, the FDA evaluates warnings differently than the common law:
[T]he FDA’s approach to warning labels is very different from the manner in which state-law tort principles drive the labeling of consumer products as a general matter. The FDA is concerned not only with avoiding insufficient warnings (that is, failing to warn against risks), but also avoiding over-warning (that is, warning against risks that are unduly speculative, hypothetical, or not adequately supported by science). Thus, while a consumer product . . . might bear dozens and dozens of warnings, with little regard for the remoteness or obviousness of the risk, the FDA takes a more measured approach that is intended to provide accurate information to medical professionals and patients without unduly discouraging the use of the product.
Id. at *2. See Albrecht, 139 S. Ct. at 1673 (FDA labeling process is “designed to exclude exaggeration of risk, or inclusion of speculative or hypothetical risks, that could discourage appropriate use of a beneficial drug”) (citations and quotation marks omitted).
Here, it didn’t matter whether or not preemption was an “affirmative defense.” 2021 WL 2209871, at *27. Key to the analysis is the power, and the duty, that Congress recently conferred on the FDA in 21 U.S.C. §355(o)(4)(A) – “to initiate a label change ‘[i]f the Secretary becomes aware of new information, including any new safety information . . . that the Secretary determines should be included in the labeling of the drug.’” Id. at *25 (also quoting Albrecht). The defendant’s post-litigation citizen’s petition placed all of the plaintiffs’ litigation-generated material squarely before the FDA, and the Agency chose not to require any label change as a result of its consideration of that evidence.
The FDA was fully informed of the plaintiffs’ four purported justifications for a teratogenicity warning. (1) The defendant had informed the Agency of certain Japanese animal studies as far back as 1993, and its post-litigation citizen’s petition “provided the FDA with full English translations of all three study reports and translated versions of the peer-reviewed Japanese publications that discussed” them. Id. at *29. (2) Plaintiffs’ junk science – the supposed “biological mechanism of action” devised by their own expert – was also before the FDA. “Plaintiffs submitted [their expert’s] report, rebuttal expert report, and deposition in this case as part of its presentation to the FDA in connection with the citizen petition.” Id. (3) Plaintiffs did not even accuse the defendant of failure to report adverse events; rather they alleged a “miscategoriz[ation]” in 2005 and a “misleading” presentation in 2015. Id. at 30. Regardless, “[i]n its 2019 citizen petition, GSK presented plaintiffs’ contentions concerning adverse event reports to the FDA.” Id. (4) As for plaintiffs’ nitpicking of the 2004 Einarson study, regardless of what happened before, once again “[i]n its 2019 citizen petition, GSK presented plaintiffs’ contentions to the FDA.” Id. The key was, whatever plaintiffs and their experts decided to throw against the wall, the defendant brought it all before the FDA, and given what the Agency did, and did not, do, none of it stuck.
Onto the second half of Albrecht’s “clear evidence” analysis – the FDA’s response to what it received. In early 2021, the FDA accepted only portions of the successor’s latest proposed PAS label change, and in so doing “rejected” warnings “based on the possibility of fetal injury.” Id. at *31. That was fatal:
The FDA thus approved a label that contains language that is directly contrary to the language proposed by plaintiffs. And it rejected language proposed by [the successor] that would have cautioned against the ingestion of Zofran during pregnancy.
Furthermore, it is undisputed that the FDA’s approval of the [successor’s] label on April 29, 2021, constituted a final agency action taken pursuant to the FDA’s congressionally delegated authority.
Id. (citation and quotation marks omitted).
Nor could plaintiffs wiggle out of this decisive, and recent, FDA rejection of their position by distinguishing between “animal studies” and “human epidemiological studies.” Id. at *31. Plaintiffs’ ill-advised resort to legal pettifoggery drew a strongly negative response. It made no difference that the successor had not proposed new labeling language as to the latter. The statute and the FDA’s regulations precluded such a preemption dodge. Plaintiffs’ position would have required the court to “assume that the FDA was not following the statutory requirement that it consider ‘all’ relevant information.” Id. at *32 (citation omitted). No way.
[T]he Court will not assume that the FDA failed to perform, in fact blatantly ignored, its statutory duties to review and monitor the drug for human safety. Accepting plaintiffs’ argument would suggest that the FDA conducted a narrow and myopic review of the safety of the drug, considering only what [the successor] expressly asked it to consider, and that it turned a blind eye to evidence that Zofran causes birth defects.
Id. (citation and footnote omitted). Nor did any precedent support plaintiffs’ nonsensical attempt at splitting regulatory hairs. “Multiple courts have found preemption where the manufacturer had not requested the precise warning sought by the plaintiffs when the FDA had nonetheless made it clear that it would not accept that label change.” Id. (citations omitted).
In sum, “[t]he FDA rejected enhanced pregnancy warnings” when it rejected the first citizen’s petition (that had caught the Blog’s eye), when it rejected a label change in 2015, and again in 2021 “after having considered the very evidence that plaintiffs contend requires an enhanced warning − indeed, after reviewing plaintiffs’ evidence and plaintiffs’ expert witness reports.” Id. at *33. “Preemption does not require a fourth attempt.” Id.
Zofran also rejected out of hand the plaintiffs’ last-ditch argument that the court should ignore anything and everything that the FDA did that was not prompted by something that the defendant itself (which had left market in 2015 by selling the NDA) had submitted. Id. at *33-35. That was another hypertechnical argument of the sort one only finds in MDLs, where no nit goes unpicked, and plaintiffs died in that last ditch:
The essential question in the preemption analysis is whether a manufacturer would be permitted to add a warning proposed by a plaintiff to a drug’s label. . . . Preemption thus does not depend on whether the defendant manufacturer is the one who asked for the changes, or to which the FDA explicitly communicated its decision. . . . Indeed, if [defendant] had never sold Zofran . . ., and itself submitted the 2020 PAS, it would be clear that plaintiffs’ claims would be preempted based on the FDA’s response to that PAS. . . . The fact that the identity of the manufacturer changed is not a material event for preemption purposes.
Id. at *33. Plaintiffs’ contrary argument was “arbitrary,” and “[n]o apparent rational policy goal would be served by making that distinction.” Id. “The significance of the FDA’s response to plaintiffs’ proposed warning is exactly the same when it responded to a PAS submitted by [the sucesssor] as it would have been if [defendant] still owned Zofran.” Id.
Finally, Zofran recognized the importance of timing in the march of scientific progress. That the FDA found an insufficient scientific basis to support a birth defect warning in 2021, when it resolved both the defendant’s post-litigation citizen’s petition and the successor’s most recent PAS supplement, necessarily meant that insufficient scientific evidence existed at all previous dates.
[T]hat the FDA did not approve the warning in 2021 is clear evidence that it would not have approved of the warning at any earlier time. Plaintiffs have not identified any cases where a court has found that state-law claims were preempted only prospectively from the time of the court’s opinion. To the contrary, courts have found when the FDA communicates that it would not approve a label change that the claims of plaintiffs who were injured before that FDA action are preempted.
Id. at *34 (emphasis original).
Thus, the kind of junk – indeed fraudulent – science that allowed plaintiffs back in the 1980s to force a drug off the market purely by litigation exposure and expense did not prevail in the Zofran MDL. The key in Zofran was the defendant’s willingness to bet on its side of the scientific story, and to put everything before the FDA. Since the FDA is now empowered, indeed required, to modify labels in response to valid scientific information, however received; post-litigation submission of a PAS and/or a citizen’s petition (since, on the peculiar facts of Zofran, the defendant and the current NDA holder were different companies) would necessarily prompt a label change, if one were scientifically justified.
As a matter of litigation strategy, Zofran demonstrates that preemption can effectively be merged with Daubert, but with the FDA, rather than a court, making the ultimate scientific decision. A confluence of several legal developments has brought this about: (1) the Levine line of cases tying prescription drug preemption to scientific evidence meeting the criteria of the FDA’s “changes being effected” regulation, rather than some vague court-created standard; (2) Albrecht’s holding that preemption, including any subsidiary factual disputes, is a question of law for courts to decide; and (3) the FDA’s power and obligation, under §355(o)(4)(A), to require label changes on its own initiative based on valid scientific information whenever and however received, thereby making it impossible for the FDA to avoid deciding what amounts to a Daubert question submitted during litigation.
Assuming that the Zofran decision survives the inevitable appeal in the First Circuit (compare In re Celexa & Lexapro Marketing & Sales Practices Litigation, 779 F.3d 34 (1st Cir. 2015), with Bartlett v. Mutual Pharmaceutical Co., 678 F.3d 30 (1st Cir. 2012), rev’d, 570 U.S. 472 (2013)), we expect that the Zofran strategy of post-litigation submissions to the FDA will become much more common – an option to be pursued whenever a defendant is convinced that litigation involving a branded prescription drug is based on “junk science” that the FDA would reject. To win, defendants now only have to convince the FDA – not judges or juries – and preemption will do the rest.