United States Court of Appeals

For the First Circuit

No. 141290
IN RE: CELEXA AND LEXAPRO MARKETING AND
SALES PRACTICES LITIGATION

RANDY and BONNIE MARCUS, on behalf of themselves and all other

persons similarly situated,
Plaintiffs, Appellants,
v.
FOREST LABORATORIES, INC. and FOREST PHARMACEUTICALS, INC.,
Defendants, Appellees.

APPEAL FROM THE UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF MASSACHUSETTS
[Hon. Nathaniel M. Gorton, U.S. District Judge]

Before
Lynch, Chief Judge,
Selya and Kayatta, Circuit Judges.

R. Brent Wisner, with whom Baum, Hedlund, Aristei & Goldman,

P.C. and Pendley, Baudin & Coffin, LLP were on brief, for
appellant.
Edwin G. Schallert, with whom Debevoise & Plimpton LLP and
Sugarman, Rogers, Barshak & Cohen, P.C. were on brief, for
appellee.

February 20, 2015

KAYATTA, Circuit Judge.

putative

class

action

against

This appeal arises out of a

Forest

Pharmaceuticals,

manufacturer of Lexapro, an antidepressant medication.

the

Plaintiffs

claim that Lexapro's FDA-approved drug label misleads California

consumers by omitting material efficacy information, in violation
of California's Consumer Legal Remedies Act ("CLRA"), Cal. Civ.
Code 1750 et seq., False Advertising Law ("FAL"), Cal. Bus. &
Prof. Code 17500 et seq., and Unfair Competition Law ("UCL"),
Cal. Bus. & Prof. Code 17200 et seq.

The district court

dismissed these claims, finding them barred by California's safe

harbor doctrine.

See In re Celexa & Lexapro Mktg. Sales Practices

Litig. (Marcus v. Forest Labs., Inc.), No. 1311343NMG, 2014 WL

866571 (D. Mass. March 5, 2014).

See generally Cel-Tech Commc'ns,

Inc. v. L.A. Cellular Tel. Co., 20 Cal. 4th 163, 182 (1999)
(outlining California's safe harbor doctrine).
Expressing

no

view

on

the

California

safe

harbor

doctrine's applicability here, we instead find that federal law

impliedly preempts these claims because the Federal Food, Drug, and
Cosmetic Act ("FDCA"), 21 U.S.C. 301 et seq., prohibits Forest
from independently changing its FDA-approved label as plaintiffs
claim California law requires.
S.Ct. 2567, 258081 (2011).

See PLIVA, Inc. v. Mensing, 131

Therefore, we affirm the judgment

dismissing the complaint.

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I.

Background

Lexapro belongs to a class of antidepressants known as

selective serotonin reuptake inhibitors.

Forest also manufactures

Celexa, a drug with a chemical composition closely related to

Lexapro.

In 2002, the FDA first approved Lexapro to treat adults

for depression. In 2008, Forest sought FDA approval for the use of
Lexapro to treat major depressive disorder in adolescents.
A.

FDA's Drug Approval Process

The FDA drug approval process is "onerous and lengthy."

Mut. Pharm. Co., Inc. v. Bartlett, 133 S.Ct. 2466, 2471 (2013).
The FDCA requires that drug manufacturers gain FDA approval prior
to marketing or selling a drug in interstate commerce.
U.S.C. 355(a).

See 21

To gain FDA approval, a drug manufacturer must

submit either a new-drug application ("NDA"), for a new drug, or a

supplemental new-drug application ("sNDA"), for a new treatment.
See 21 C.F.R. 314.1 et seq.
same approval requirements.

NDAs and sNDAs are subject to the

See id.

The NDA or sNDA must include

"full reports of [all clinical] investigations which have been made

to show whether . . . such drug is effective in use."
355(b)(1)(A).

21 U.S.C.

The FDA may only approve the drug if the NDA or

sNDA provides "substantial evidence that the drug will have the
effect it . . . is represented to have."

Id. 355(d)(5).

As part

of its showing that it has provided such substantial evidence, a

manufacturer submits the results of "adequate and well-controlled

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investigations,

including

clinical

investigations,

by

experts

qualified by scientific training and experience to evaluate the

effectiveness of the drug involved."
In

its

evaluation

of

an

Id. 355(d)(7).
NDA

or

sNDA,

the

FDA

has

discretion to determine that data from "one adequate and wellcontrolled clinical investigation," along with other "confirmatory
evidence," are "sufficient to establish effectiveness."

Id.; see

21 C.F.R. 314.105(c) ("[The] FDA is required to exercise its

scientific judgment to determine the kind and quantity of data and
information an applicant is required to provide for a particular
drug to meet the statutory standards.")

The FDA will not approve

a drug if the NDA or sNDA lacks "substantial evidence that the drug
will have the effect it purports or is represented to have."

21

U.S.C. 355(d)(5).
The drug manufacturer must also submit "the labeling
proposed to be used for such drug."
314.50(c)(2)(i).

Id. 355(b)(1)(F); 21 C.F.R.

The application must include the proposed

label's text "with annotations to the information in the [drug

application] that support the inclusion of each statement [on the
label]."

21 C.F.R. 314.50(c)(2)(i).

In order to approve an NDA

or sNDA, the FDA must determine, "based on a fair evaluation of all

material

facts,"

that

the

proposed

misleading in any particular."

314.125(b)(6).

label

is

not

"false

or

21 U.S.C. 355(d)(7); 21 C.F.R.

After approval, the manufacturer may distribute

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the drug without violating federal law as long as it uses the FDAapproved label.

See 21 U.S.C. 331(c), 333(a), & 352(a), (c).

In an effort to secure FDA approval to sell Lexapro for

the treatment of major depressive disorder in adolescents, Forest
submitted to the FDA the results of four studies:

Celexa Study

94404, Celexa Study 18, Lexapro Study 15, and Lexapro Study 32.
Celexa Study 94404 and Lexapro Study 15 showed no efficacy. Celexa
Study 18 and Lexapro Study 32 found positive efficacy that was
statistically significant, but only barely so.

In March 2009, the

FDA nevertheless approved the sale of Lexapro to treat major

depressive

disorder

in

adolescents

based

on

finding

that

substantial evidence supported the efficacy of that use. In making

this finding, the FDA "extrapolate[d] on the basis of a previously
reviewed positive study with [Celexa]," along with the positive
statistical efficacy results from Lexapro Study 32. As required by
the FDCA, in approving the sNDA, the FDA made a specific finding
that

Lexapro's

particular."

label

was

not

"false

or

misleading

in

any

21 U.S.C. 355(d)(7); 21 C.F.R. 314.125(b)(6).

That approved label included the following:

Clinical Studies, Major Depressive Disorder -Adolescents
The efficacy of Lexapro as an acute treatment
for major depressive disorder in adolescent
patients was established in an 8-week,
flexible-dose, placebo-controlled study that
compared Lexapro 10-20 mg/day to placebo in
outpatients 12 to 17 years of age inclusive
who met DSM-IV criteria for major depressive
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disorder. The primary outcome was change from

baseline to endpoint in the Children's
Depression Rating Scale -- Revised (CDRS-R).
In this study, Lexapro showed statistically
significant greater mean improvement compared
to placebo on the CDRS-R.
The efficacy of Lexapro in the acute treatment
of major depressive disorder in adolescents
was established, in part, on the basis of
extrapolation from the 8-week, flexible-dose,
placebo-controlled
study
with
racemic
citalopram [i.e., Celexa] 20-40 mg/day. In
this
outpatient
study
in
children
and
adolescents 7 to 17 years of age who met DSMIV criteria for major depressive disorder,
citalopram treatment showed statistically
significant greater mean improvement from
baseline, compared to placebo, on the CDRS-R;
the positive results for this trial largely
came from the adolescent subgroup.
Two
additional
flexible-dose,
placebocontrolled MDD studies (one Lexapro study in
patients ages 7 to 17 and one citalopram
[Celexa] study in adolescents) did not
demonstrate efficacy.
Although maintenance efficacy in adolescent
patients
has
not
been
systematically
evaluated,
maintenance
efficacy
can
be
extrapolated from adult data along with
comparisons of escitalopram pharmacokinetic
parameters in adults and adolescent patients.
B.

Changing The Label

There are two ways pertinent to this lawsuit in which a

manufacturer of a brand name prescription drug can change the

drug's label.

First, the default rule is that a manufacturer must

secure FDA approval for a proposed change prior to distributing the

product with the changed label.

21 C.F.R. 314.70(b)(2)(v)(A).

-6-

Second, under what is known as the Changes Being Effected ("CBE")

regulation,

id.

314.70(c)(6)(iii),

manufacturer

can

make

certain types of changes to its label, without prior FDA approval,

by sending the FDA a "supplement submission."
To

make

change

under

the

CBE

regulation,

manufacturer must satisfy at least two requirements.

change must "reflect newly acquired information."

the

First, the

Id.; see also

id. 314.3(b) (defining "newly acquired information").

Second,

the change must be for the purpose of accomplishing at least one of

the five following objectives:
(A) To
add
or
strengthen
a
contraindication, warning, precaution, or
adverse reaction for which the evidence of a
causal association satisfies the standard for
inclusion in the labeling . . .;
(B) To add or strengthen a statement
about drug abuse, dependence, psychological
effect, or overdosage;
(C) To
add
or
strengthen
an
instruction about dosage and administration
that is intended to increase the safe use of
the drug product;
(D) To delete false, misleading, or
unsupported indications for use or claims for
effectiveness; or
(E) Any
labeling
change normally
requiring a supplement submission and approval
prior to distribution of the drug product that
FDA specifically requests be submitted under
this provision.
Id. 314.70(c)(6)(iii).

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C.

The Complaint
According to the complaint, in April 2009, Randy and

Bonnie Marcus, the plaintiffs, purchased Lexapro to treat their

adolescent son's depression.

Based on their reading of Lexapro's

FDA-approved label, they and their son's physician overestimated

Lexapro's effectiveness.

As a result, they spent money purchasing

a drug that they describe as no more clinically effective than a

placebo. On behalf of all other Californians who purchased Lexapro
for an adolescent from March 2009 until present, they claim that
Forest Pharmaceuticals omitted material efficacy information, in
violation of California state consumer protection laws: the CLRA,
FAL, and UCL.
The CLRA prohibits unfair methods of competition and
unfair or deceptive acts that result in the sale of goods to any
consumer.

Cal. Civ. Code. 1770(a).

The complaint alleges that

Forest violated four different provisions of the CLRA, specifically

1770(a)(2) ("Misrepresenting the source, sponsorship, approval,
or

certification

of

goods

or

services.");

1770(a)(5)

("Representing that goods or services have sponsorship, approval,

. . ., [or] benefits, . . . which they do not have . . . .");
1770(a)(7) ("Representing that goods . . . are of a particular
standard, quality, or grade, . . . if they are of another."); and
1770(a)(9) ("Advertising goods . . . with intent not to sell them
as advertised."). The FAL prohibits companies from disseminating

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"untrue or misleading" statements.

17500.

Cal. Bus. & Prof. Code.

And the UCL prohibits "unfair or fraudulent business

act[s] or practice[s] and unfair, deceptive, untrue or misleading

advertising."

Id. 17200.

In support of these state law claims, the complaint takes

issue with "the FDA['s] accept[ance of] the questionable data from
Lexapro Study 32 and the flawed data from Celexa Study 18 to
conclude that Forest met its regulatory requirement of providing
two well-controlled studies showing that Lexapro was effective for
the treatment of adolescent [depression]."

Expressing displeasure

with federal law as well as the FDA, the complaint further notes
that the FDA's "standards for approving antidepressants are minimal
according to the law."
The complaint gives a different read to Celexa Study 18
than did the FDA's experts, who found that the study showed a
statistically significant difference between Celexa and a placebo
for an acute treatment of major depressive disorder in adolescents.
The complaint disagrees, and asserts instead that "[a] close
evaluation of the unpublished version of Celexa Study 18 reveals
that data was manipulated to create the appearance of statistical
significance."

In sum, the complaint characterizes Celexa Study

18's results as "fraudulent and misleading."

The complaint also reads Lexapro Study 32 differently
than did the FDA's experts, who found that this study also showed

-9-

a statistically significant difference between Lexapro and placebo

for an acute treatment of major depressive disorder in adolescents.
As with Celexa Study 18, the complaint questions the study's
finding of statistical significance, and underscores the fact-known to the FDA at the time of approval--that the difference
indicated "is not clinically significant."
Based on the foregoing, the complaint argues that the
"drug label for Lexapro is misleading and inadequate."

In its

prayer for relief, plaintiffs request that the court "[p]ermanently

enjoin[] Forest from continuing to sell or market Lexapro with its
current drug label and direct[] Forest to seek FDA approval of a
new

[drug]

label."

Although

the

complaint

contains

general

allegations of deceptive marketing, and quotes a press release from

Forest,1 plaintiffs (who seek to represent a class) hinge their
claims and the relief they seek on their challenge to the adequacy
of the efficacy discussion in the FDA-approved label. For example,
plaintiffs allege that "Forest's misconduct was uniformly directed
at all consumers and their prescribing healthcare professionals in
California through the use of a misleading drug label.

Thus, all

Paragraph 53 of the complaint alleges that Forest issued a

press release in which Forest's CEO stated, "[w]e have long
believed that Lexapro would be of benefit for the treatment of
depression in adolescents and that is why we undertook the several
studies described in the package insert.
We are enormously
gratified that Lexapro will be available for depressed adolescents
who so much require the benefits which Lexapro has made available
for depressed adults for the past seven years."
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members of the [class] have a common cause of action . . . ."

Plaintiffs then allege that "the question of Forest's conduct,
i.e., whether the drug label was misleading, predominates over any
individual issues."
D.

Procedural History
Randy and Bonnie Marcus filed the complaint in May 2013,

seeking class certification, in the Central District of California.

The

Judicial

Panel

on

Multidistrict

Litigation

subsequently

transferred the case to the District of Massachusetts as part of

ongoing

multidistrict

litigation,

In

re

Celexa

and

Lexapro

Marketing and Sales Practices Litigation, No. 09MDL2067NMG.

Forest

moved

to

dismiss,

relying

California's safe harbor doctrine.

on

FDCA

preemption

and

While both parties fully

briefed Forest's federal preemption defense, the district court did

not reach it, relying instead on its conclusion that the complaint
failed under California's safe harbor doctrine.
II.

Standard of Review

We give de novo review to the district court's grant of

Forest's motion to dismiss for failure to state a claim.

See,

e.g., Cooper v. Charter Commc'ns Entm'ts I, LLC, 760 F.3d 103, 106
(1st Cir. 2014).

We accept as true all facts in the complaint and

draw all reasonable inferences in the plaintiffs' favor.

-11-

Id.

III.

Analysis
A.

In deciding whether the complaint states a claim upon

which relief may be granted, we are urged by plaintiffs to restrict
our inquiry to determining whether the safe harbor doctrine under
California law defeats plaintiffs' claims.

Hornbook principles of

appellate procedure, however, grant us discretion to rely on any

basis made apparent in the record for affirming a district court's
decision.

E.g., Debnam v. FedEx Home Delivery, 766 F.3d 93, 96

(1st Cir. 2014).

In moving to dismiss, Forest relied upon not just the
California safe harbor doctrine, but also on principles of federal
preemption.

The parties briefed the federal preemption issue in

the district court.

On appeal, Forest repeats that argument,

urging that we may affirm on that ground.

Plaintiffs in response

concede that "unpacking how federal law interacts with state law is
key" to applying California's safe harbor doctrine.

We agree.

It

therefore makes more sense to look first at this question of

federal law rather than skipping forward to figuring out--or
certifying to California's Supreme Court--the question of whether
California's safe harbor doctrine would shield Forest even if

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federal law did not preempt the California consumer protection

claims.2
B.
The

United

States

Constitution's

Supremacy

Clause

provides that federal law "shall be the supreme Law of the Land;
. . . any Thing in the Constitution or Laws of any state to the
Contrary notwithstanding."

U.S. Const., art. VI, cl. 2.

Where

state law requires a private party to violate federal law, that

state law is "without effect."

Bartlett, 133 S. Ct. at 247677

(internal quotation marks omitted). Federal law impliedly preempts

state law "where it is 'impossible for a private party to comply
with both state and federal requirements.'"

Id. (quoting English

v. Gen. Elec. Co., 496 U.S. 72, 79 (1990)); see also Freightliner
Corp. v. Myrick, 514 U.S. 280, 287 (1995) (noting that conflict
pre-emption also applies "where state law stands as an obstacle to

Inexplicably, plaintiffs announced in their reply that they

did not have enough pages to address the issue even though Forest
properly raised it as an alternative ground for affirmance. And
instead of asking for a page extension, they presumed that we would
either ignore the issue, or postpone the case to solicit more
briefing. We follow instead the normal course of not allowing a
party to unilaterally dictate a change in customary practice. We
also note that plaintiffs hedged their bet, devoting two pages of
their reply brief to an express discussion of the preemption
defense, and another four pages to discussing the pivotal
preemption case, Wyeth v. Levine, 555 U.S. 555 (2009). Finally, we
have reviewed the full brief on the preemption issue filed by
plaintiffs with the district court, and we addressed the issue with
counsel at oral argument.
-13-

the

accomplishment

and

execution

of

the

full

purposes

and

objectives of Congress" (internal quotation marks omitted)).

Plaintiffs' complaint seeks to impose liability on Forest
because of what Lexapro's FDA-approved label states or fails to
state.

In other words, as the complaint reads, Forest would need

to change Lexapro's label in order to avoid liability under state

law.
In two recent cases, the Supreme Court has addressed how
principles of federal preemption apply to such claims.

See PLIVA,

131 S. Ct. 2567 (2011); Wyeth v. Levine, 555 U.S. 555 (2009).

We

turn to these opinions to find the preemption rules that guide our
decision here.
In Wyeth, a jury found a brand name drug manufacturer
liable under Vermont law for what the jurors deemed to be an
inadequate warning of risks in an FDA-approved label.

555 U.S. at

558.

defense

In

liability

rejecting
under

regulation,

the

Vermont

"which

both

manufacturer's
law,

the

reflects

preemption

Court
the

pointed

to

manufacturer's

the

to
CBE

ultimate

responsibility for its label and provides a mechanism for adding

safety information to the label prior to FDA approval."
571.

Id. at

"Thus, when the risk . . . became apparent, Wyeth had a duty

[under federal law] to provide a warning that adequately described

that risk, and the CBE regulation permitted it to provide such a
warning before receiving the FDA's approval."

-14-

Id.

Based on these

observations,

the

Court

found

that

state

law

effectively

penalizing the manufacturer for not having exercised its federally

sanctioned ability to improve the label under the CBE regulation
was not preempted.

Id. at 581.

Two years later, the Supreme Court distinguished Wyeth in

sustaining a preemption bar to the imposition of tort liability on
a generic drug manufacturer for failure to add a warning of a risk
to its label.

PLIVA, 131 S. Ct. at 2581.

The court observed two

differences in the federal "drug labeling duties" that applied to

generic manufacturers as compared to brand name manufacturers. Id.
at 2574.

First, a generic manufacturer "is responsible for

ensuring that its warning label is the same as the brand name's."
Id.

Second,

manufacturers]."

"the
Id.

CBE

process

at 2575.

was

not

open

to

[generic

Therefore, the generic drug

manufacturer in PLIVA could not have changed its label without

prior FDA approval, which it could only have obtained by proposing
that the FDA require a change in the corresponding brand name
label.

Id. at 2576.

Assuming that the manufacturer had a duty

under federal law to make such a proposal, the Court nevertheless

found that the possibility that the FDA would have agreed to
require such a change did not preclude the court from concluding
that compliance with both state and federal branding requirements
was impossible.

Importantly for our purposes, the Court explained

that "[t]he question for 'impossibility' is whether the private

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party could independently do under federal law what state law

requires of it."
Court

thus

Id. at 2579 (citing Wyeth, 555 U.S. at 573).

limited

Wyeth

to

situations

in

which

the

The
drug

manufacturer can, "of its own volition, . . . strengthen its label

in compliance with its state tort duty." PLIVA, 131 S. Ct. at
2581.3
The line Wyeth and PLIVA thus draw between changes that
can be independently made using the CBE regulation and changes that
require prior FDA approval also makes some pragmatic sense.
changes rest on the existence of "newly acquired information."
C.F.R. 314.70(c)(6)(iii).

CBE
21

A state law duty to initiate such a

change is therefore not by its nature a second guess of an FDA

judgment.

Wyeth, 555 U.S. at 57879.

To the extent that the

underlying policy issue is one of who decides whether and how a

drug can be marketed, the line so drawn lets the FDA be the
exclusive

judge

of

safety

and

efficacy

based

on

information

available at the commencement of marketing, while allowing the

states to reach contrary conclusions when new information not

Most recently, in Bartlett, 133 S. Ct. at 2478, the Supreme

Court reversed a decision of this circuit in which we rejected a
preemption defense because the generic drug manufacturer could have
complied with both federal and state law simply by not selling the
drug for use in that state. The Supreme Court reasoned that "an
actor seeking to satisfy both his federal- and state-law
obligations is not required to cease acting altogether in order to
avoid liability." Id. at 2477. "To hold otherwise would render
impossibility preemption 'all but meaningless.'" Id. at 2477 n.3
(quoting PLIVA, 131 S. Ct. at 2579).
-16-

considered by the FDA develops.

The CBE regulation, too, covers

virtually all situations in which new information indicates new or

greater risks, or misleading claims of efficacy.

By hinging

preemption on the availability of that procedure in a particular

case, Wyeth effectively reserves the launch of new drugs to the
expertise of the FDA, but then preserves a wide scope for the
states in requiring manufacturers to respond to information not
considered by the FDA.4
Our review of the Supreme Court opinions discussed above
makes clear that a necessary step in defeating Forest's preemption
defense is to establish that the complaint alleges a labeling
deficiency

that

regulation.

Forest

could

have

corrected

using

the

CBE

The complaint plainly alleges that Forest is a brand

name manufacturer and Lexapro is a brand name drug.

So the

question to which we now turn is whether the CBE regulation allows

a brand name manufacturer to make the particular type of change
that plaintiffs say Forest needed to have made to avoid liability
under California law.
C.
The CBE procedure is only available to make changes that,
among other things, are based on "newly acquired information."

21

C.F.R. 314.70(c)(6)(iii).

Of course, it would be easier for the courts if Congress

would expressly indicate whether this is the line it wants drawn.
-17-

Newly
acquired
information
means
data,
analyses, or other information not previously
submitted to the agency, which may include
(but are not limited to) data derived from new
clinical studies, reports of adverse events,
or new analyses of previously submitted data
(e.g., meta-analyses) if the studies, events
or analyses reveal risks of a different type
or
greater
severity
or
frequency
than
previously included in submissions to FDA.
Id. 314.3(b). For example, "newly acquired information" could be
an increasing body of data of an inherent risk with the drug.

See

Wyeth 555 U.S. at 571 ("[W]hen the risk of gangrene from IV-push
injection of Phenergan became apparent, Wyeth had a duty to provide
a

warning

that

adequately

described

that

risk,

and

the

CBE

regulation permitted it to provide such a warning before receiving

the FDA's approval.").

Or it could be new data from a clinical

study evincing Lexapro's inefficacy in treating major depressive

disorder in adolescents.
We have scrutinized the complaint itself to see if it
might plausibly be read as relying on "newly acquired information"
in contending that Forest could have changed its label through the
CBE procedures.

We find only two fleeting references to academic

articles published after the FDA's approval of the Lexapro label.

Plaintiffs make no claim that these two academic articles are based
on new data. They instead contend that these two studies are metaanalyses that were not included in Forest's submission to the FDA.
The first is a 2010 article evaluating prior efficacy
data on antidepressant medications generally as compared with a
-18-

placebo.

As plaintiffs' complaint acknowledges, it contains no

discussion of efficacy for the acute treatment of major depressive

disorders in adolescents, focusing instead on the lack of apparent
efficacy for patients generally when symptoms of depression are not
severe.

In short, even assuming it qualifies as "newly acquired

information," it does not contain the information that plaintiffs

say needs to be added to the label in order to correct the label's
discussion of efficacy for treatment of major depressive disorder
in adolescents.
The second is a 2011 article criticizing the FDA's
approval of Lexapro.

This study is an opinion piece in which the

author looks at the same information that the FDA had in approving
Lexapro.

It simply argues that the FDA should not have approved

Lexapro on the basis of that information.

As described by the

complaint, the only piece of relevant information in the article is

an assertion that a medical communication company acting on behalf
of Forest was a contributor to the published article discussing
Lexapro Study 32.

Plaintiffs do not argue, however, that the FDA

was unaware of this fact, or that Forest is liable for failing to

seek a change adding this fact to the label.

Rather, plaintiffs

argue that this fact means that FDA approval of Lexapro was
premature.5

We note also that neither article discloses "risks of a

different type or greater severity or frequency than previously
included in submissions to [the] FDA." 21 C.F.R. 314.3; see also
-19-

We

have

also

examined

the

complaint's

allegations

claiming that the positive statistical efficacy results of Celexa

Study 18 hinged in part on the inappropriate inclusion of some
subjects in the data pool.6

This is the basis of plaintiffs'

allegation that Celexa Study 18 was "manipulated." Plaintiffs make

no claim, however, that this information was unknown to the FDA
prior to label approval.
Finally,

oral

argument

confirmed

that

the

change

plaintiffs seek in the label is indeed based on information

concerning the marginal extent of Lexapro's effectiveness that was
plainly known to the FDA prior to approving the label:
Court: What specific statement do you say that
Forest should have added to its description of
the drug?

id. 314.70(c)(6)(iii).
6

According to the complaint:

During the study, the first nine (9) participants were

given '1 week of medication with potentially unblinding
information (tablets had an incorrect color coating).'
When the data for Celexa Study 18 was first analyzed, the
researchers correctly excluded the data from the
unblinded participants, realizing it was unreliable. The
results of the initial statistical analysis showed . . .
[that] Celexa Study 18 was negative for efficacy.
However, faced with having a clinical trial show that
Celexa failed to significantly outperform placebo for
treating pediatric depression, the researchers decided to
include the data from the unblinded participants. By
adding the unblinded patients' data, Celexa Study 18 was
able to find statistical significance between the
treatment and placebo-control group--even if only
marginal.
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Plaintiffs' counsel: I believe the drug label

. . . should have disclosed how Lexapro
performed compared to placebo.
. . . .
Plaintiffs' counsel: . . . We are not trying
to contradict the information on the label.
. . . We are simply having them say . . .
[Lexapro] has been shown to be effective in a
clinical trial by one point. The difference
between [Lexapro] and a placebo is clinically
insignificant. Meaning a patient, a doctor,
wouldn't be able to tell the difference.
Court: But that "by one point"--that was known
to the FDA at the time of the approval?
Plaintiffs' counsel: Absolutely.
We can find no precedent--and plaintiffs point to none-that would have allowed Forest to use the CBE procedure to alter
the FDA label in the manner that plaintiffs allege is necessary so
as to render it not "misleading."

Indeed, plaintiffs seem to

concede this in their prayer for relief, as they ask the Court to
"direct[] Forest to seek FDA approval of a new [drug] label."
Plaintiffs

are

thus

stymied:

Forest

could

not

independently change its label to read as plaintiffs say it should

have

read

in

order

to

comply

with

California

law.

That

construction of California law upon which plaintiffs rely--even

assuming it is correct notwithstanding the safe harbor doctrine--is
therefore preempted by federal law.

-21-

PLIVA, 131 S. Ct. at 2581.

IV.

Conclusion

Finding plaintiffs' claims preempted by the FDCA, we

affirm the district court's grant of Forest's motion to dismiss.
So ordered.

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