Recent Second Circuit Implied-Preemption Decision Confirms That A ‘Major Change’ Is A Big Deal In Pharmaceutical Litigation – Food, Drugs, Healthcare, Life Sciences

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.

This post was originally published on Drug & Device Law. 

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