Gustavsen v. Alcon Laboratories, Inc.

United States Court of Appeals
For the First Circuit

No. 17-2066

ROBERT GUSTAVSEN; JOSEPH CUGINI; DEMETRA COHEN; JACKIE CORBIN;
LEE WILBURN; MARY LAW; CECILIA BRATHWAITE,

Plaintiffs, Appellants,

v.

ALCON LABORATORIES, INC.; ALCON RESEARCH, LTD.; FALCON
PHARMACEUTICALS, LTD.; SANDOZ, INC.; ALLERGAN, INC.; ALLERGAN
USA, INC.; ALLERGAN SALES, LLC; PFIZER, INC.; VALEANT
PHARMACEUTICALS INTERNATIONAL, INC.; BAUSCH AND LOMB, INC.; ATON
PHARMA, INC.; MERCK & CO., INC.; MERCK, SHARP & DOHME (I.A.)
CORP.; PRASCO, LLC; AKORN, INC.,

Defendants, Appellees.

APPEAL FROM THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF MASSACHUSETTS

[Hon. Mark L. Wolf, Senior U.S. District Judge]

Before

Thompson, Kayatta, and Barron,
Circuit Judges.

Leah M. Nicholls, with whom Public Justice, P.C., Richard S.
Cornfeld, Law Office of Richard S. Cornfeld, John C. Simon, Kevin
M. Carnie, Jr., The Simon Law Firm, P.C., Kenneth J. DeMoura,
DeMoura Smith LLP, Emily Lisa Perini, Perini-Hegarty & Associates,
P.C., and Brian Wolfman were on brief, for appellants.
Gregory E. Ostfeld, with whom David G. Thomas, Michael
Pastore, Christiana Jacxsens, Greenberg Taurig, LLP, Peter
Simshauser, Skadden, Arps, Slate, Meagher & Flom LLP, Robyn E.
Bladow, Austin Norris, Kirkland & Ellis LLP, Joseph P. Crimmins,
Posternak Blankstein & Lund LLP, John M. Kilroy, Jr., J. Santon
Hill, Polsinelli PC, W. Scott O'Connell, Nixon Peadoby LLP, James
P. Muehlberger, Lori A. McGroder, Shook, Hardy & Bacon LLP, Stephen
G. Strauss, Bryan Cave LLP, David J. Volkin, Law Offices of David
J. Volkin, David B. Chaffin, and White and Williams LLP were on
brief, for appellees.
Jeffrey S. Bucholz, Paul Alessio Mezzina, King & Spalding
LLP, Peter Tolsdorf, and Manufacturers' Center for Legal Action,
on brief for American Tort Reform Association, The Chamber of
Commerce of the United States of America, The National Association
of Manufacturers, and Pharmaceutical Research & Manufacturers of
America, amici curiae.
David R. Geiger, Kristyn M. DeFillip, and Foley Hoag LLP, on
brief for Product Liability Advisory Council, Inc., amicus curiae.

August 27, 2018
 KAYATTA, Circuit Judge. Our disposition of the merits

of this appeal turns on a single question: Can manufacturers of

prescription eye drops change the medication's bottle so as to

alter the amount of medication dispensed into the eye without first

getting the FDA's approval? Finding that federal law requires

prior approval for such a change, we hold that state law claims

challenging the manufacturers' refusal to make this change are

preempted. Our reasoning follows.

I.

Because this appeal comes to us following the district

court's grant of a motion to dismiss, we draw the facts from the

operative complaint. SEC v. Tambone, 597 F.3d 436, 438 (1st Cir.

2010) (en banc).

Defendants in this case are companies engaged in the

manufacturing, marketing, and distribution of both brand name and

generic prescription eye drops. These drops treat a multitude of

ailments, including glaucoma, allergies, infections, inflammation,

and pre- and post-operative conditions. The eye drop solutions

are sold in plastic bottles shaped at one end to form a plastic

dispenser. To use the eye solution, consumers must squeeze or tap

the bottle, emitting a drop of solution directly into the eye.

Consumers cannot dispense less than one drop at a time. And the

dimensions of the bottle's dispenser, rather than any factor under

human control, determine the size of each drop. Specifically, the

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complaint explains, the volume of the drop dispensed varies based

on the "inner diameter or hole and the outer diameter of the tip"

of the dispenser. The bottles do not disclose the size of the eye

drops, nor do they reveal an estimate of the number of drops or

doses contained in each bottle.

Plaintiffs complain that defendants deliberately

designed their dispensers to emit unnecessarily large drops, on

the order of 24 to 52 microliters. This ploy, plaintiffs say,

forces patients to waste medication, to their detriment and to

defendants' gain. Plaintiffs marshal a body of scientific

literature to support their argument. The scientific consensus,

they say, is that the optimal size of drops rests between 5 and

15 microliters. The reason is a matter of human anatomy. The

fornix, which is the area between the eye and the lower eyelid, is

only capable of absorbing a small portion of the unnecessarily

large drops dispensed by defendants' bottles.

All manufacturers of prescription eye drops, plaintiffs

say, engage in this practice; there is no prescription eye solution

on the market that dispenses drops that are not substantially

larger than 15 microliters. Plaintiffs do not allege, however,

that this industry standard is the result of conspiracy, or that

defendants otherwise acted in concert. Rather, they allege that

defendants "separately engaged in" the challenged conduct. And

that conduct, plaintiffs allege, harms patients in two ways.

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 First, it costs patients money. If the bottles dispensed

smaller drops, then each bottle would deliver more doses, and

patients would be able to purchase fewer bottles over any set

amount of time. By comparing the number of bottles a patient would

use if the bottles dispensed 15 microliter doses against the number

of bottles each patient is now required to purchase, plaintiffs

calculate that a patient, on a yearly basis, could save upwards of

$500, depending on the brand and type of solution used.

These calculations naturally rely on an assumption that

a manufacturer would not substantially increase the price of a

bottle that dispensed smaller drops. Support for this assumption

in the complaint comes in two forms. Plaintiffs point out that

defendants currently price the various sized bottles proportionate

to their volume. A bottle twice the size costs approximately twice

as much. The inference they would have us draw is that, if only

the drop size were to change but the volume of solution in the

bottle were to stay consistent, the price of the bottle would stay

constant too. Plaintiffs also point to various statements in

academic studies that draw a connection between the drop size and

cost to plaintiffs. For example, in a study published by Allergen

(one of the defendants here), the authors say that "a smaller drop

size would mean that more doses could be dispensed from each bottle

of medication, providing cost savings to patients and managed care

providers." They also allege that, following a study by scientists

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employed by Alcon (another defendant here) that concluded that

16 microliter drops were as effective as 30 microliter drops,

Alcon's top marketing executive said that Alcon would not make the

change to its bottles because "patients would use the bottles

longer and Alcon would therefore sell less product and make less

money."

The second alleged impact on patients is physical.

Excess eye drops that stream down the cheek can cause allergies

and pigmentation. The excess drops that enter the bloodstream do

so without first going through metabolic inactivation in the liver.

And without the liver's processes, say plaintiffs, the eye solution

can lead to decreased cardiovascular response to exercise, lowered

blood pressure, and emotional and psychiatric side effects.

Although plaintiffs allege an increased risk of these

consequences, they do not allege that any named plaintiff did, in

fact, experience any such side effect.

Armed with these grievances, the named plaintiffs filed

suit in federal court on their own behalf and on behalf of a

putative class of prescription eye solution purchasers. The named

plaintiffs are residents of either Massachusetts or New York who

purchased eye solution from at least one of the defendant

manufacturers during the four years preceding the filing of their

lawsuit. They allege two categories of violations.

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 First, they allege that defendants' practice is "unfair"

under Massachusetts state law and the laws of twenty-five other

states and the District of Columbia, all of which adopt the meaning

of "unfair" as applied in section 5 of the Federal Trade Commission

Act. 15 U.S.C. § 45(a)(1). Plaintiffs do not allege that

defendants' actions are deceptive.

Second, under the laws of New York and sixteen other

states, plaintiffs allege claims for unjust enrichment and for

"money had and received." The basis for these latter two causes

of action is plaintiffs' contention that defendants received

excess profits from their actions to which they are not entitled.

All defendants moved to dismiss. They asserted first

that the court lacked subject-matter jurisdiction because

plaintiffs had failed to satisfy the "injury in fact" requirement

of Article III standing. Second, defendants argued that

plaintiffs' claims were preempted by Food and Drug Administration

regulations. Specifically, they contended that changing the

dispensers to reduce the size of the eye drops -- the change

plaintiffs claim state law mandates -- requires pre-approval from

the FDA, thus implicating the doctrine of impossibility

preemption. Third, defendants argued that plaintiffs failed to

state a claim under the state laws pleaded.1

1For the sake of simplicity, we mention only the grounds
for defendants' motion that they repeat on appeal.

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 Citing In re Pharmaceutical Industry Average Wholesale

Price Litigation, 582 F.3d 156, 190-91 (1st Cir. 2009), the

district court ruled that plaintiffs' "plausible claim that

they've overpaid for the defendants' eyedrops," alleged a

"cognizable form of injury for standing purposes." The district

court nevertheless dismissed the complaint without ruling on the

merits of the claims under state laws, finding that the FDA

regulations preempted plaintiffs' suit. See Gustavsen v. Alcon

Labs., Inc., 272 F. Supp. 3d 241, 250 (D. Mass. 2017). In so

doing, the court relied on a section of an FDA regulation that

categorized changes "that may affect . . . drug product sterility

assurance" as major changes requiring FDA approval prior to

implementation. Id. at 251; 21 C.F.R. § 314.70(b)(2)(iii).

Plaintiffs now appeal.

II.

Because Article III standing implicates our ability to

hear a case, see Baena v. KPMG LLP, 453 F.3d 1, 4 (1st Cir. 2006),

we begin with defendants' contention that plaintiffs fail to

satisfy the injury in fact requirement of Article III standing.

Our review is de novo. Hochendoner v. Genzyme Corp., 823 F.3d

724, 730 (1st Cir. 2016).

Article III of the Constitution limits the judicial

power of the federal courts to "Cases" and "Controversies." U.S.

Const. art. III, § 2. Such a case or controversy exists only when

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the plaintiff demonstrates "such a personal stake in the outcome

of the controversy as to assure that concrete adverseness which

sharpens the presentation of issues upon which the court so largely

depends." Katz v. Pershing, LLC, 672 F.3d 64, 71 (1st Cir. 2012)

(quoting Baker v. Carr, 369 U.S. 186, 204 (1962)). To demonstrate

a "personal stake" necessary to invoke the jurisdiction of the

federal courts, a plaintiff must satisfy the familiar triad of

injury in fact, causation, and redressability. Lujan v. Defs. of

Wildlife, 504 U.S. 555, 560-61 (1992).

Plaintiffs bear the burden of establishing standing.

See Lujan, 504 U.S. at 561; Hochendoner, 823 F.3d at 730. The

manner in which plaintiffs must make these showings varies with

"the manner and degree of evidence required at the successive

stages of the litigation." Lujan, 504 U.S. at 561. Thus, at the

motion to dismiss stage, we apply the same plausibility standard

used to evaluate a motion under Rule 12(b)(6). See Hochendoner,

823 F.3d at 731. We first "accept as true all well-pleaded factual

averments in the plaintiff's . . . complaint and indulge all

reasonable inferences therefrom in his favor." Katz, 672 F.3d at

70-71 (quoting Deniz v. Mun'y of Guaynabo, 285 F.3d 142, 144 (1st

Cir. 2002)). We then ask whether the plaintiff has pleaded

"sufficient factual matter to plausibly demonstrate his standing

to bring the action." Hochendoner, 823 F.3d at 731. Because this

appeal comes to us before any class is certified, we evaluate only

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whether the named plaintiffs have standing to pursue their own

claims. Katz, 672 F.3d at 71.

With this general framework in mind, we begin with the

question of whether the complaint adequately alleges injury in

fact. The injury in fact requirement is, itself, composed of

several prongs. A constitutionally sufficient injury arises from

an "invasion of a legally protected interest" that is both

"concrete and particularized" as well as "actual or imminent,"

rather than "conjectural or hypothetical." Lujan, 504 U.S. at 560

(internal quotation marks omitted); see also Spokeo, Inc. v.

Robins, 136 S. Ct. 1540, 1545 (2016) (clarifying that "concrete"

and "particularized" constitute independent, necessary

requirements for standing).

The injury alleged here takes the form of an out-of-

pocket loss of $500 to $1000 per year.2 This alleged loss passes

muster under each of these prongs. Certainly plaintiffs have a

legally protected interest in their own money. See Cent. Az. Water

Conservation Dist. v. EPA, 990 F.2d 1531, 1537 (9th Cir. 1993)

(noting that "pecuniary or economic injury is generally a legally

protected interest"). Nor do defendants argue otherwise.

2A careful reader will also remember that plaintiffs alleged an
increased risk of certain physical side effects. But plaintiffs
do not press that allegation as a basis for standing. See Kerin
v. Titeflex Corp., 770 F.3d 978, 979 (1st Cir. 2014) (identifying
the situations in which increased risk of harm can be a cognizable
injury for standing).

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 We also have no trouble concluding that the injury is

particularized. Here, we are concerned with whether a plaintiff

has been affected "in a personal and individual way." Spokeo, 136

S. Ct. at 1548 (quoting Lujan, 504 U.S. at 560 n.1). An out-of-

pocket loss of money satisfies the requirement of

particularization because it constitutes undisputed harm to the

plaintiff specifically. See Katz, 672 F.3d at 71 ("Particularity

demands that a plaintiff must have personally suffered some

harm.").

The injury as alleged is also concrete. Like the

requirement of a "legally protected interest," concreteness

concerns the nature of the injury alleged. It asks whether the

alleged injury is something courts recognize to be cognizable for

the purpose of Article III standing. See Spokeo, 136 S. Ct. at

1548. Thus, "[f]or example, when an alleged injury is nothing

more than 'a bare procedural violation,' there may be no cognizable

harm to the plaintiff and thus no concreteness." Hochendoner, 823

F.3d at 731 (quoting Spokeo, 136 S. Ct. at 1549). Here, by

contrast, we have actual economic loss, which is the prototypical

concrete harm. See Danvers Motor Co. v. Ford Motor Co., 432 F.3d

286, 291 (3d Cir. 2005).

Last, we consider whether the injury is "actual or

imminent," as opposed to "conjectural or hypothetical." This

requirement "ensures that the harm has either happened or is

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sufficiently threatening; it is not enough that the harm might

occur at some future time." Katz, 672 F.3d at 71; see also Clapper

v. Amnesty Int'l USA, 568 U.S. 398, 409 (2013) (requiring an injury

to be "certainly impending"); McInnis-Misenor v. Me. Med. Ctr.,

319 F.3d 63, 68 (1st Cir. 2003) (requiring some "immediacy or

imminence to the threatened injury"). In this instance, the

complaint alleges a harm that has already occurred.

Defendants respond to the foregoing by challenging the

assumption on which the claim of actual existing harm is

predicated: that a bottle that dispensed smaller drops would not

be priced in such a way as to obliterate any cost savings that

would result from a consumer's ability to squeeze more drops out

of the bottle. The fact that defendants have "discretion to base

prices on the number of drops or doses provided," they say, renders

plaintiffs' theory of injury speculative.

Assessing the ultimate merits of plaintiffs' "but-for"

pricing scenario could indeed keep an economist busy for a while,

given the unusual market posited by the complaint in which a large

number of companies independently forgo what seems like a profit

maximizing opportunity of lowering marginal costs. Be that as it

may, plaintiffs expressly allege that scientific studies and the

admission of a marketing executive for one of the major defendants

all state that consumer cost would fall to some degree were the

drops smaller. At this stage of the case, these allegations are

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enough to satisfy the minimal plausibility standard applicable to

our assessment of the complaint.

Defendants also contend that plaintiffs suffered no

injury because they received the "benefit of the bargain."

Plaintiffs bought an "effective product, consume[d] it fully," and

now, defendants say, "seek a partial refund solely on the basis of

their belief that the product should have been more efficiently

designed."

This argument sweeps too broadly. Suppose, for example,

that defendants successfully conspired directly to fix prices on

any competing products, or entered into a similar collusive

agreement to, perhaps, sell products with unnecessarily large

drops while holding price constant. It would still be true that

consumers bought an "effective product, consume[d] it fully" and

now "seek a partial refund" solely based on their belief that the

price should have been lower. Yet certainly in such a case the

aggrieved consumer who directly purchased the product would have

standing to sue for the anticompetitive surcharge. Similarly, if

the consumers alleged similar conduct but instead brought their

cause of action under an applicable price-gouging statute, we would

have no trouble concluding that plaintiffs would have standing (as

defendants conceded at oral argument). What differs here is the

nature of the alleged duty violated by the defendant. But

defendants do not explain how that difference bears on the

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concreteness of plaintiffs' alleged injury, nor do we see how it

would.

Finally, defendants contend that plaintiffs' theory

rests on speculation because, in order for a "but for" world to

exist in which plaintiffs could benefit from a bottle that

dispensed smaller drops, the FDA would have to approve that bottle

design and doctors would have to prescribe medications using that

design. Pointing to Clapper, 568 U.S. at 414, they argue that

plaintiffs' theory rests on "speculation about the decisions of

independent actors." Clapper, though, spoke of the speculation

inherent in a claim of injury that might arise in the future as

the result of decisions by independent actors. Here, the alleged

injury (the claimed overpayment) has already occurred, and does

not "require guesswork as to how independent decisionmakers will

exercise their judgment." Clapper, 568 U.S. at 413. The only

relevant uncertainty is whether defendants can show that they

lacked the ability to change their behavior that was causing the

alleged harm.

We therefore conclude that plaintiffs satisfy the injury

in fact requirement of Article III. The two additional factors in

our analysis -- causation and redressability -- follow easily.

There can be no real dispute that plaintiffs' claim of injury

traces itself directly to the challenged conduct. Nor can there

be any doubt that plaintiffs' financial injury can be redressed by

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damages. Plaintiffs, therefore, have standing to assert their

cause of action.

In reaching this conclusion, we do not write on a blank

slate. Two other circuits have decided this issue. Our decision

is in accord with that of the Third Circuit. See Cottrell v. Alcon

Labs., 874 F.3d 154, 159 (3d Cir. 2017). And although the Seventh

Circuit has dismissed a similar suit on what appear to be standing

grounds, see Eike v. Allergen, 850 F.3d 315, 318 (7th Cir. 2017),

we agree with the Third Circuit that the rationale in Eike is more

appropriately aimed at the merits. See Cottrell, 874 F.3d at 165-

66 (stating that the Seventh Circuit in Eike "blended standing and

merits together in a manner that the Supreme Court has exhaustively

cautioned against"). Satisfied that we have jurisdiction, we turn

to the merits.

III.

Plaintiffs seek a judgment based on an allegation that

defendants have breached duties owed to plaintiffs under various

state laws. For present purposes, we assume without deciding that

plaintiffs correctly describe the duties owed and breached under

state law. The question is whether application of those state

laws is preempted by federal law. In analyzing this question, "we

are not wedded to the lower court's rationale, but may affirm the

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order of dismissal on any ground made manifest by the record."

Katz, 672 F.3d at 71 (brackets omitted).

The principles of federal preemption that control our

disposal of this appeal are not in dispute. If a private party

(such as the manufacturers here) cannot comply with state law

without first obtaining the approval of a federal regulatory

agency, then the application of that law to that private party is

preempted. See PLIVA, Inc. v. Mensing, 564 U.S. 604, 620 (2011);

In re Celexa & Lexapro Mktg. & Sales Practices Litig., 779 F.3d

34, 41 (1st Cir. 2015). Conversely, a private party's ability to

do without prior agency approval that which state law requires

defeats a preemption defense even if the federal regulatory agency

"retains authority to reject [the] changes," unless the defendant

establishes by clear evidence that the agency would, in fact,

reject the changes. Wyeth v. Levine, 555 U.S. 555, 571-72 (2009).

In applying these principles, we proceed de novo, accepting as

true all of plaintiffs' well-pleaded facts and drawing all

reasonable inferences in plaintiffs' favor. In re Celexa, 779

F.3d at 39.

Defendants point us to an FDA regulation as the source

of federal law that purportedly preempts plaintiffs' state law

claims. See 21 C.F.R. § 314.70. This regulation governs the

manner in which a manufacturer can make a change to an already-

approved drug product. It operates by dividing changes into three

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categories: major, moderate, and minor changes. The

classification of the manufacturer's anticipated alteration into

one of these three categories dictates the manufacturer's ability

to unilaterally implement its change. Major changes require

approval from the FDA prior to implementation, while moderate and

minor changes do not. Id. § 314.70(b). Controlling case law is

clear -- and plaintiffs here concede -- that if the change they

contend state law requires qualifies as "major," then federal law

preempts plaintiffs' cause of action because defendants cannot

lawfully make such a change without prior FDA approval. See Mut.

Pharm. Co. v. Bartlett, 570 U.S. 472, 486-87 (2013); PLVIA, Inc.,

564 U.S. at 620; In re Celexa, 779 F.3d at 41. Our inquiry thus

appears, at first glance, straightforward: Does the change urged

by plaintiffs qualify as "major"? If so, our work is done.

But before getting to the meat of this question, we must

address a threshold question regarding the interpretation of

regulatory text. "Major changes" are defined in section (b) of

the FDA regulation. See 21 C.F.R. § 314.70(b). The top level

heading -- "(b)" -- is a title: "Changes requiring supplement

submission and approval prior to distribution of the product made

using the change (major changes)." Id. The next level down --

"(b)(1)" -- defines a broad category of qualifying changes:

A supplement must be submitted for any change
in the drug substance, drug product,
production process, quality controls,

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 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 as
these factors may relate to the safety or
effectiveness of the drug product.

Id. (b)(1) (emphasis added). Following, at the same level heading,

is section (b)(2), which states: "These changes include, but are

not limited to" a host of ensuing categories of changes to drug

products, listed at sections (b)(2)(i) through (viii). The

threshold question is: To what do the words "[t]hese changes"

refer. The answer is relevant because, if "[t]hese changes" refer

to the "major changes" in the top level heading "(b)," then all

the categories of changes included in section (b)(2) are examples

of major changes. Conversely, if the words "[t]hese changes" refer

only to the "changes" in section (b)(1), then perhaps any category

identified in section (b)(2) must also be shown to have a

"substantial potential to have an adverse effect" in order to

qualify as "major."3

No party or amicus advocates for this latter reading.

Nor do we think it the better reading of the text. For one, the

3 There is also a third possible interpretation: that
"[t]hese changes" refer to changes that meet the entire definition
provided in (b)(1), i.e., they per se qualify as changes that have
a "substantial potential" for an "adverse effect." But since the
consequence of this reading -- changes identified in (b)(2) are
necessarily major changes -- is the same as the first reading
identified above, we do not discuss this possibility in more
detail, nor do we rule out the possibility that it might be
correct, should it matter in a future case.

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inclusion of "[t]hese changes" in a heading of the same level as

the broad definition in section (b)(1) (rather than in

section (b)(1) itself, or as perhaps in a hypothetical

section (b)(1)(i)), makes it unlikely that the "changes" in (b)(2)

are a subcategory of the changes in (b)(1). Second, "moderate

changes" are defined with the identical broad definition,

substituting out only the word "substantial" for "moderate." Thus,

if we read "[t]hese changes" in section (b)(2) as referring only

to "changes" in section (b)(1), then whether a change is major or

moderate would depend in every case on a separate determination of

the qualitative magnitude of the change. Third, the categories

later defined in section (b)(2) do not map easily onto the types

of changes identified in (b)(1). For example, section (b)(2)(v)

lists a variety of labeling changes. But in order for this

category to have any meaning under the latter reading, labeling

changes would have to, in at least some instances, qualify as

changes to a "drug substance, drug product, production process,

quality controls, equipment, or facilities." Id. § 314.70(b)(1).

This, too, makes it more likely that the changes identified in

section (b)(2) are a separate category. Finally, neither the

Supreme Court nor our court has previously read these regulations

to impose a requirement that every major change be shown to have

a "substantial potential to have an adverse effect," nor,

relatedly, that every moderate change to thus have a "moderate

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potential." See Wyeth, 555 U.S. at 568; In re Celexa, 779 F.3d at

37. We therefore conclude 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.

With this holding in mind, we turn to the categories of

major changes listed in (b)(2). One such category strikes us as

particularly applicable:

Changes in a drug product container closure
system that controls the drug product
delivered to a patient or changes in the type
(e.g., glass to high density polyethylene
(HDPE), HDPE to polyvinyl chloride, vial to
syringe) or composition (e.g., one HDPE resin
to another HDPE resin) of a packaging
component that may affect the impurity profile
of the drug product.

21 C.F.R. § 314.70(b)(2)(vi). Under a plain reading, this language

establishes three categories of changes that qualify as major.

They are: (1) changes in a drug product container closure system

that control the drug product delivered to a patient; (2) changes

in the type of packaging component that may affect the impurity

profile of the drug product; or (3) changes in the composition of

a packaging component that may affect the impurity profile of the

drug product.

The change urged by plaintiffs to the product dispensing

bottle fits comfortably into the first of these categories. The

dispensing bottle in which the eye solution is contained is a "drug

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product container closure system," the eye solution is a "drug

product," and, by dictating the size of the drops, the dispenser

"controls" the "drug product delivered" (specifically, its amount)

to a patient. Merriam-Webster defines "control" to include

"exercise restraining or directing influence over," see Control,

Merriam-Webster Collegiate Dictionary (11th ed. 2012), and Black's

Law Dictionary defines the word as "to regulate or govern," see

Control, Black's Law Dictionary 378 (9th ed. 2009). Dictating the

size of the drops dispensed clearly falls within the ambit of these

definitions. Indeed, plaintiffs' fundamental complaint is

precisely that the FDA-approved current container closure system

controls the drug delivered to a patient in a manner that

systematically delivers too much medication. If the patient could

control the amount of drug product, plaintiffs could simply

dispense only the desired 5 to 15 microliter dose, obviating the

need to bring this case. It therefore seems quite clear that the

change urged by plaintiffs is one to a "drug product container

closure system that controls the drug product delivered to a

patient," 21 C.F.R. § 314.70(b)(2)(vi), and is for that reason

alone a "major" change.

Adding belt to suspenders, regulatory guidance further

bolsters our conclusion that a change in the volume of a dispensed

drop is a "major" change. In the regulation's preamble, the FDA

describes the container closure system category as follows:

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 For some drug products, the container closure
system itself, rather than a person, regulates
the amount of drug product that is
administered to a patient. These container
closure systems are considered to "control
drug delivery." For example, a patient that
uses a metered dose inhalation product as
instructed cannot control the amount of drug
product the container closure system delivers
or verify that the appropriate amount has been
administered. . . . The design and operation
of these container closure systems is critical
to ensure that the patient receives the
correct dose. A drug product may not be safe
or effective if a patient receives too much or
too little of the drug product.

Supplements and Other Changes to an Approved Application, 69 Fed.

Reg. 18,728, 18,739 (Apr. 8, 2004) (codified at 21 C.F.R.

pt. 314). Here, the dispenser determines how much solution --

i.e., "amount of drug product" -- a patient receives. And in a

separate document, the FDA lists as "major changes" ones that "may

affect the controlled (or modified) release, metering or other

characteristics (e.g., particle size) of the dose delivered to the

patient . . . ." U.S. Food & Drug Ass'n, Guidance for Industry:

Changes to an Approved NDA or ANDA 12 (2004),

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory

Information/Guidances/UCM077097.pdf (2004 FDA Industry Guidance).

It is hard to conceive that the size of the drops is anything other

than a "characteristic[] . . . of the dose delivered."

In the face of the foregoing, plaintiffs offer three

retorts.

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 First, they ask us to rely on a "Highlights" portion of

the regulatory preamble to construe section 314.70(b)(2)(vi). As

we have just described it, that section expressly classifies as

major changes three separate types of changes: "[c]hanges in a

drug product container closure system that controls the drug

product delivered . . . or changes in the type . . . or composition

. . . of a packaging component that may affect the impurity

profile." By contrast, the preamble language to which plaintiffs

point mentions only two types of changes in describing the section:

"FDA has limited the requirement to include only those changes to

a drug product container system that involve changes in the type

or composition of a packaging component." 69 Fed. Reg. at 18,729.

From this language, plaintiffs ask us to conclude that a change

that is not to the type or composition of packaging cannot qualify

as "major."

We do not share plaintiffs' reading of the preamble.

The quoted portion describes not the highlights of the rule, but

rather the "Highlights of the Revisions to the Proposed Rule."

See 69 Fed. Reg. at 18,729 (April 8, 2004). The category

describing as major changes any "[c]hanges in a container closure

system that controls drug delivery" was in the proposed rule, see

64 Fed. Reg. 34,606, 34,623 (June 28, 1999), and was not materially

changed by these revisions. Hence, it makes sense that a

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discussion of the highlights of the revisions includes no mention

of the unrevised category.

Later portions of the final rule's preamble confirm this

view. When the FDA described this regulatory category outside of

the context of discussing revisions to the rule as first proposed,

it included within the requirement changes that affect both drug

delivery and the impurity profile of the drug product. See 69

Fed. Reg. at 18,739 (describing the relevant provision as

regulating container closure systems that "control[] drug delivery

or that may affect the impurity profile of the drug" (emphasis

added)). In any event, it is well-established that a regulatory

preamble is incapable of altering regulatory text's plain meaning.

See Christensen v. Harris Cty., 529 U.S. 576, 588 (2000) (holding

that an agency's interpretation of its own regulation cannot

"overcome the regulation's obvious meaning," as it would "permit

the agency, under the guise of interpreting a regulation, to create

de facto a new regulation").

We turn next to plaintiffs' second retort. In their

reply brief and at oral argument, plaintiffs contend that the

provision governing container closure systems is concerned only

with devices that "verify" that the "correct dose" has been

administered. They claim that "[t]he dose is one drop, no matter

its size," and, unlike a metered dose inhaler mentioned in the FDA

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guidance, see 69 Fed. Reg. at 18,739, a patient can verify whether

"a drop" has been administered.

Neither the text of the regulation nor the substance of

the guidance documents define the dose as only the notional unit

(e.g., a single drop, no matter how big), rather than the amount

of the medication. To the contrary, FDA guidance defines the

qualifying changes as ones that "regulate[] the amount of drug

product." 69 Fed. Reg. at 18,739 (emphasis added). Because this

guidance also defines "drug product" as "[a] finished dosage form,

for example, . . . [a] solution[] that contains an active

ingredient," a change in the amount of solution dispensed would

appear to be a change in the "amount of drug product." 2004 FDA

Industry Guidance at 35. And in the very portion of the guidance

to which plaintiffs point, the FDA notes that a patient "cannot

control the amount of drug product the container delivers or verify

that the appropriate amount has been administered." 69 Fed. Reg.

at 18,739 (emphasis added). For the reasons already stated, it

would appear that a patient using one of defendants' eye solution

dispensers cannot "control the amount of the drug product"

dispensed. Indeed, as we have already noted, that is precisely

the basis of plaintiffs' grievance. Plaintiffs' argument thus

fails in its premise.

Finally, plaintiffs allege that drug manufacturers have

on five previous occasions changed the drop size of their

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prescription eye medication without first obtaining FDA approval.

And, in at least one case, they say, the FDA approved of a

manufacturer's proposed change even though it had been submitted

under the "moderate," rather than "major," changes protocol.4 As

became evident at oral argument, a number of factual questions

swirl around plaintiffs' contentions. The parties dispute, for

example, whether the manufacturers in these instances did, in fact,

make changes sufficiently similar to the one urged here. Nor is

it always clear what role the FDA played, if any, in approving the

relevant changes. But, given that we are reviewing a dismissal of

a complaint for failure to state a claim, we will accept

plaintiffs' allegations as true. Even so, they do too little work

for plaintiffs.

Deference to an agency's interpretation of its own

regulation is "unwarranted when there is reason to suspect that

the agency's interpretation 'does not reflect the agency's fair

and considered judgment on the matter in question.'" Christopher

v. SmithKline Beecham Corp., 567 U.S. 142, 155 (2012) (quoting

4 Plaintiffs also point to additional documents in which an
FDA reviewer appears to have notified a manufacturer that a change
in a dropper tip should be submitted through the "moderate" changes
protocol, rather than the "minor" changes protocol the
manufacturer had originally used. The district court refused to
consider these documents, as they had not been mentioned in the
complaint, a determination plaintiffs ask us to reverse on appeal.
But we need not entertain this contention. For the reasons
articulated below, even if we were to consider these additional
documents, they are incapable of altering our conclusion.

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Auer v. Robbins, 519 U.S. 452, 462 (1997)). Whether sporadic

agency action in individual cases is capable of reflecting the

"fair and considered judgment" of the agency on a matter of

regulatory interpretation is far from clear. This is especially

true when the record reflects, as it does here, that the regulatory

actions to which plaintiffs point are, in at least some cases,

made by mid-level FDA scientists, or even a single "reviewer."

And our suspicion of whether such a decision can reflect the "fair

and considered" judgment of the agency is even stronger when that

decision appears in clear tension with regulatory guidance that

almost certainly reflects the agency's considered judgment, and to

which courts often defer if it represents a reasonable reading of

the text. See, e.g., PLVIA, Inc., 564 U.S. at 613; Rucker v. Lee

Holding Co., 471 F.3d 6, 12 (1st Cir. 2006). Additionally,

regarding the examples cited by plaintiffs that reflect only FDA

inaction, other possible inferences, including the possibility

that the FDA used its discretion not to enforce a rule, or that a

company otherwise slipped through the cracks, further undermine

any probative weight that the examples might hold for plaintiffs'

position.

For the foregoing reasons, we therefore conclude that

changing the product bottle so as to dispense a different amount

of prescription eye solution is a "major change" under 21 C.F.R.

§ 314.70(b). That conclusion, in turn, means that plaintiffs'

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attempt to use state law to require such a change is preempted.

See PLVIA, 564 U.S. at 620.

IV.

The decision of the district court is affirmed.

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