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We’ll get to the recent Second Circuit decision, Ignacuinos v. Boehringer Ingelheim Pharms., Inc., — F.4th —-, 2021 WL 3438355 (2d Cir. 2021), in due course, but first some background.

One of our top ten decisions in 2018 was Gustavsen v. Alcon Labs., Inc., 903 F.3d 1 (1st Cir. 2018), an important implied-preemption decision. In a one-two punch, Gustavsen held (1) that federal law preempts any state-law tort claim that would require what 21 C.F.R. § 314.70(b) defines as a “major change” in a pharmaceutical product; and (2) that any change identified in § 314.70(b)(2) is necessarily a “major change” within the meaning of § 314.70(b).

In holding that federal law preempts any state-law tort claim that would require a “major change” within the meaning of § 314.70(b), Gustavsen—which involved prescription eye drops—confirmed that the logic of PLIVA, Inc. v. Mensing, 564 U.S. 604 (2011), and Mutual Pharmaceutical Co. v. Bartlett, 570 U.S. 472 (2013), applied not only to generic drugs but to all FDA-approved pharmaceutical products.

As readers of this blog know, Mensing held that failure-to-warn claims targeting generic drugs are impliedly preempted because federal law requires that generic drug labels be identical to their branded counterparts. That federal requirement—the so-called “duty of sameness” embodied in 21 C.F.R. §§ 314.94(a)(8)(iii), 314.150(b)(10)—makes it impossible for a generic manufacturer to unilaterally change its label to comply with a purported state-law duty to provide different or additional warnings. Given that simultaneous compliance with state and federal law is impossible, any state-law duty to provide such warnings is preempted under the Supremacy Clause.

Bartlett built on Mensing. In addition to requiring that generic labels have the same labeling as their branded counterparts, federal law also requires that generic drugs have the same active ingredients, route of administration, dosage form, and strength as their branded counterparts. See 21 U.S.C. §§ 355(j)(2)(A)(ii)–(v) and (8)(B); 21 C.F.R. § 320.1(c). Moreover, federal law prohibits a drug manufacturer from making any “major changes” to the “qualitative or quantitative formulation of the drug product.” 21 C.F.R. § 314.70(b)(2)(i). Taken together, this means that, as a matter of federal law, a generic drug manufacturer may neither reformulate its drug nor warn of its supposed risks (unless the branded label also warns of those supposed risks). Consequently, a state-law claim predicated on a generic manufacturer’s failure to reformulate its drug or warn of the risks supposedly associated with the drug is preempted by federal law because simultaneous compliance with federal law and the purported state-law duty is impossible.

Mensing and Bartlett involved generic drugs. But as Bartlett noted, the regulation prohibiting “major changes” in approved drugs without prior FDA approval, 21 C.F.R. § 314.70(b), applies to all FDA-approved drugs “whether generic or brand-name.” 570 U.S. at 477.

The First Circuit took that observation seriously. Gustavsen addressed claims that targeted “both brand name and generic prescription eye drops.” 903 F.3d at 4. Asserting claims under state law, the plaintiffs claimed that they had been harmed both economically and physically by eye-drop dispensers that dispensed supposedly larger-than-necessary drops. According to the plaintiffs, state-law required the manufacturers to redesign their dispensers so that they dispensed smaller drops. The First Circuit concluded that federal law preempted the plaintiffs’ claims against all of the manufacturers—both generic and branded—because redesigning the dispensers would constitute a “major change” under 21 C.F.R. § 314.70(b) and “major changes” are not permitted without prior FDA approval. In other words, neither the generic manufacturers nor the branded manufacturers “could ‘unilaterally’ do what state law [purportedly] required.” Mensing, 564 U.S. at 620 (quoting Wyeth v. Levine, 555 U.S. 555, 573 (2009)). As a result, state law conflicted with federal law and the plaintiffs’ state-law claims were preempted.

In the course of reaching that conclusion, Gustavsen had to determine what constitutes a “major change” within the meaning of 21 C.F.R. § 314.70(b), which provides that “major changes” require prior FDA approval.

The regulation’s first subdivision, § 314.70(b)(1), provides that FDA approval is required for “any change in the drug substance, drug product, production process, quality controls, equipment, or facilities that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product.” The regulation’s second subdivision, § 314.70(b)(2), states that “[t]hese changes include, but are not limited to” various categories of enumerated changes. The question for the First Circuit was whether the phrase “[t]hese changes include” refers to the particular changes identified in § 314.70(b)(1) or whether it instead refers to “major changes” generally. If the phrase “[t]hese changes includes” refers to the particular changes identified in § 314.70(b)(1), then the categories of changes listed in § 314.70(b)(2) are merely subcategories of those listed in § 314.70(b)(1), and any particular change would constitute a “major change” only if it has “a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product.” By contrast, if the phrase “[t]hese changes include” refers to “major changes” generally, then any particular change is a “major change,” whether or not it had “a substantial potential to have an adverse effect” on the enumerated attributes, so long as it falls into a category of change listed in § 314.70(b)(2).

The First Circuit held that the phrase refers to “major changes” generally. The practical consequence of that holding is that a larger range of changes constitute “major changes” that require prior FDA approval, and thus a larger range of purported state-law claims are preempted by federal law.

The First Circuit gave three reasons for its reading of 21 C.F.R. § 314.70(b). First, as a textual matter, the court thought it “unlikely that the ‘changes’” enumerated “in (b)(2) are a subcategory of the changes in (b)(1)” given that they are identified under a distinct “heading of the same level as the broad definition in section (b)(1).” Second, if the changes enumerated in (b)(2) were merely examples of changes identified in (b)(1), “then whether a change is major or moderate,” and thus whether it requires prior FDA approval, “would depend in every case on a separate determination of the qualitative magnitude of the change,” which was something that the Supreme Court had never required and the First Circuit implied would be unworkable. Third, the First Circuit found that several of the changes listed in (b)(2) “do not map easily onto the types of changes identified in (b)(1).” On these bases, the court “conclude[d] that, if a change fits under any of the categories listed in section (b)(2), that change necessarily constitutes a ‘major’ change requiring FDA pre-approval.” Gustavsen, 903 F.3d at 10–11.

So, the upshot of the First Circuit’s decision in Gustavsen is that any change listed in either § 314.70(b)(1) or § 314.70(b)(2) constitutes a “major change” for purposes of § 314.70(b); and that any state-law claim that would require a “major change” in a pharmaceutical product is impliedly preempted by federal law, whether that product is a branded product or a generic product.

That brings us (finally, our patient readers might think) to the Second Circuit’s recent decision in Ignacuinos, which involved state-law claims targeting a brand name metered-dose inhaler used to treat chronic obstructive pulmonary disease. According to the plaintiffs, the inhaler’s label said that the inhaler would deliver 120 doses when in fact it delivered far few doses. Based on this allegation, the plaintiffs asserted design- and manufacturing-defect claims under state law.

The brand name defendant argued that the plaintiffs’ claims were impliedly preempted because 21 C.F.R. § 314.70(b) prevented it from changing the inhaler’s design or manufacturing methods without prior FDA approval. The Second Circuit, agreed and affirmed the dismissal of the plaintiffs’ claims.

Quoting Gustavsen, the Second Circuit “agree[d] … that ‘if a change fits under any of the categories listed in section (b)(2), that change necessarily constitutes a “major” change requiring FDA pre-approval,” regardless of whether the defendant has shown a substantial potential for an adverse effect.” 2021 WL 3438355, at *2. Accordingly, the Second Circuit “conclude[d] that the plaintiffs’ state law design and manufacturing defect claims [we]re preempted to the extent that they would require any change listed in § 314.70(b)(2).”

The court went on to find that the plaintiffs’ claims would in fact require such changes. The defendant manufacturer, said the court, could not have “unilaterally changed the design of the inhaler to release a different amount of medication per puff” because “Section 314.70(b)(2)(vi) provides that any modification to ‘a drug product container closure system that controls the drug product delivered to a patient’ qualifies as a major change.” 2021 WL 3438355, at *3. And the manufacturer could not have “unilaterally increased the amount of liquid … medication in each [inhaler] cartridge” because “Section 314.70(b)(2)(i)’s list of ‘major changes’ includes ‘changes in the qualitative or quantitative formulation of the drug product.’” Id. at *4.

So, like the First Circuit before it, the Second Circuit has held that any change listed in 21 C.F.R. § 314.70(b)(2) constitutes a “major change” that requires prior FDA approval, and that any state-law claim that would require such a change is impliedly preempted, whether the pharmaceutical product at issue is a generic drug or a branded drug.

That’s a big deal.