### In the



# United States Court of Appeals

For the Seventh Circuit

____________________

No. 17

‐ 3030

W ENDY B. D OLIN

, Individually and as Independent

Executor of the Estate of S TEWART D OLIN

, Deceased,

Plaintiff

‐ Appellee

,

v.

G LAXO S MITH K LINE LLC,

Formerly Known as S MITH K LINE B EECHAM C ORP

., Defendant

‐ Appellant

.

____________________

Appeal from the United States District Court for the

For the Northern District of Illinois, Eastern Division.

No. 12

‐ CV

‐ 6403

— William T. Hart

, Judge

.

____________________

A RGUED M AY 30, 2018

— D ECIDED A UGUST 22, 2018

____________________

Before W OOD

, Chief Judge

, and S YKES and H AMILTON

,

Circuit Judges

.

H AMILTON

, Circuit Judge

. Defendant GlaxoSmithKline LLC

(GSK) appeals from a jury verdict awarding $3 million to

plainti ff Wendy Dolin for the death of her husband, Stewart

Dolin. Mrs. Dolin alleges that GSK’s negligent omissions in

the drug label for Paxil caused her husband’s death. Stewart2 No. 17

‐ 3030

did not actually take Paxil. In 2010, a doctor prescribed Paxil,

the brand

‐ name version of paroxetine, to treat Stewart’s de

‐ pression and anxiety. But his prescription was fi lled with ge

‐

neric paroxetine manufactured by another company (one that

is no longer a defendant). Six days later, Stewart commi tt ed

suicide. Blood tests showed that paroxetine was in his system.

He was 57 years old.

At the time of Stewart’s death, GSK manufactured brand

‐

name Paxil and was responsible under federal law for the con

‐

tent of the drug’s label. When Stewart died, the labels for par

‐

oxetine and similar antidepressant drugs warned that they

were associated with suicide in patients under the age of 24.

The labels did not warn about any association between the

drugs and an increased risk of suicide in older adults.

The current state of federal law makes it virtually impos

‐

sible to sue generic drug manufacturers on a state

‐ law theory

for failure to warn. In response to this legal landscape, plain

‐

ti ff s have advanced a new theory of liability and have sued

brand

‐ name manufacturers, who have more control over

drug labels, for injuries caused by taking the generic drugs.

Mrs. Dolin followed this recent trend here, suing GSK on the

theory that it negligently failed to include warnings that par

‐

oxetine was associated with suicide in patients older than 24.

Throughout the lawsuit, GSK has maintained that it is not

liable under Illinois law simply because Stewart Dolin did not

consume a drug that GSK manufactured. Mrs. Dolin responds

that the relevant harm was caused by the incomplete label, not

the drug, and that under federal law, only GSK could change

the label. GSK also argued that federal law preempted Illinois

law from requiring the warning that Mrs. Dolin claims wasNo. 17

‐ 3030 3

negligently omi tt ed because the FDA had rejected GSK’s at

‐

tempts to add just such a warning. The district court disa

‐ greed with GSK’s various arguments, and the case proceeded

to trial and a verdict for Mrs. Dolin.

In this appeal, GSK challenges the district court’s conclu

‐

sions about liability under Illinois law and preemption. GSK

also argues that the evidence at trial did not support the jury’s

verdict. We agree with GSK that federal law prevented GSK

from adding a warning about the alleged association between

paroxetine and suicides in adults. On that basis of federal

preemption, we reverse the judgment. The case must be dis

‐

missed.

I. Legal and Factual Background

A. Regulation of Drug Labels

We start with the regulatory background that explains

why the parties make the arguments they do. The Food, Drug,

and Cosmetic Act bars pharmaceutical companies from man

‐ ufacturing new drugs unless the Food and Drug Administra

‐

tion approves a “new drug application.” 21 U.S.C. § 355(a).

The new drug application must show that the drug is safe and

e ff ective, which requires an extensive series of clinical trials.

Guilbeau v. P fi zer, Inc.

, 880 F.3d 304, 307 (7th Cir. 2018); see also

21 U.S.C. §§ 355(b) & (d). The application must also include

“the labeling proposed to be used for such drug.”

§ 355(b)(1)(F); 21 C.F.R. § 314.50(c)(2)(i).

The label contains a lot more than the drug’s name. It must

disclose, among other things, warnings and precautions re

‐

lated to the drug’s e ff ects. The FDA reviews the proposed la

‐

bel to determine whether it is “false or misleading.” 21 U.S.C.4 No. 17

‐ 3030

§ 355(d)(7); 21 C.F.R. § 314.125(b)(6). Once the new drug ap

‐ plication is approved, the manufacturer must distribute the

drug using the FDA

‐ approved label. Otherwise, the drug is

misbranded and may not be distributed in the United States.

See 21 U.S.C. §§ 331(a), 333(a), & 352(a), (c). In 1992, the FDA

approved GSK’s new drug application for paroxetine, includ

‐ ing a label.

Plainti ff ’s theory of liability is based on GSK’s ability to

change the paroxetine label after the FDA approved it in 1992.

There were two ways relevant to this lawsuit for GSK to

change the label without running afoul of federal law. First,

GSK could have asked the FDA for permission to change the

label. 21 C.F.R. § 314.70(b)(2)(v)(A). This is the default rule for

most substantive changes to drug labels. Second, in narrow

circumstances GSK could unilaterally change the label under

what is called the “changes being e ff ected” or CBE regulation.

The CBE regulation is an exception to the general rule that

changes require advance FDA permission. It allows manufac

‐

turers to change a label to “re fl ect newly acquired infor

‐

mation” if, as relevant here, the changes “add or strengthen a

... warning” for which there is “evidence of a causal associa

‐

tion

... .” 21 C.F.R. § 314.70(c)(6)(iii)(A). In other words, GSK

needed FDA permission to change the paroxetine label unless

three things were true: (1) GSK had newly acquired infor

‐

mation about paroxetine (2) that showed a causal association

(3) between the drug and an e ff ect that warranted a new or

stronger warning. The FDA reviews CBE submissions and

can reject label changes even after the manufacturer has made

them. See 21 C.F.R. § 314.70(c)(6), (7).

The new drug approval process is “onerous and lengthy.”

Mutual Pharmaceutical Co., Inc. v. Bartle tt

, 570 U.S. 472, 476No. 17

‐ 3030 5

(2013). Generic manufacturers can avoid much of this costly

process, but they have li tt le in fl uence on the contents of drug

labels. Under the Drug Price Competition and Patent Term

Restoration Act of 1984, commonly known as the Hatch

‐ Wax

‐

man Act, a manufacturer can fi le an “abbreviated new drug

application” for approval to distribute a generic drug. See 21

U.S.C. § 355(j). The Supreme Court summarized the require

‐

ments for generics:

First, the proposed generic drug must be

chemically equivalent to the approved brand

‐

name drug: It must have the same “active ingre

‐

dient” or “active ingredients,” “route of admin

‐

istration,” “dosage form,” and “strength” as its

brand

‐ name counterpart. 21 U.S.C.

§§ 355(j)(2)(A)(ii) and (iii). Second, a proposed

generic must be “bioequivalent” to an approved

brand

‐ name drug. § 355(j)(2)(A)(iv). That is, it

must have the same “rate and extent of absorp

‐

tion” as the brand

‐ name drug. § 355(j)(8)(B).

Third, the generic drug manufacturer must

show that “the labeling proposed for the new

drug is the same as the labeling approved for

the [approved brand

‐ name] drug.”

§ 355(j)(2)(A)(v).

Bartle tt

, 570 U.S. at 477. “This allows manufacturers to de

‐ velop generic drugs inexpensively, without duplicating the

clinical trials already performed on the equivalent brand

‐

name drug.” PLIVA, Inc. v. Mensing

, 564 U.S. 604, 612 (2011).

In sum, “brand

‐ name and generic drug manufacturers

have di ff erent federal drug labeling duties.” Mensing

, 564 U.S.6 No. 17

‐ 3030

at 613. “A brand

‐ name manufacturer seeking new drug ap

‐ proval is responsible for the accuracy and adequacy of its la

‐

bel.” Id. ; see also 21 U.S.C. § 355(b)(1), (d); Wyeth v. Levine

, 555

U.S. 555, 570–71 (2009). “A manufacturer seeking generic

drug approval, on the other hand, is responsible for ensuring

that its warning label is the same as the brand name’s.” Mens

‐ ing

, 564 U.S. at 613; see also 21 U.S.C. §§ 355(j)(2)(A)(v) &

(j)(4)(G); 21 C.F.R. §§ 314.94(a)(8) & 314.127(a)(7). Thus, from

1992 to 2014, when GSK sold the right to distribute brand

‐

name Paxil, GSK was responsible for the “accuracy and ade

‐ quacy” of the drug’s label. To change the label, GSK needed

either FDA permission or newly acquired information that

supported a strengthened warning under the CBE regulation.

B. The History of Paroxetine’s Label

Paroxetine is a selective serotonin reuptake inhibitor, one

of a class of antidepressants commonly called SSRIs. For dec

‐

ades, the FDA has scrutinized data on the relationship be

‐

tween SSRIs and suicidal behavior. The FDA’s analysis of that

relationship is central to the preemption question in this ap

‐ peal.

1. The New Drug Application Approval

GSK’s predecessor, SmithKline Beecham Corporation,

submi tt ed a new drug application for paroxetine in 1989.

Around that time, the FDA began investigating a potential re

‐ lationship between suicidal behavior and SSRIs. The FDA re

‐ quested GSK to submit a supplemental analysis of data re

‐

lated to suicide. GSK submi tt ed the additional analysis in

May 1991. In June 1991, the FDA safety reviewer for GSK’s

paroxetine application reported: “there is no signal in this

large data base that paroxetine exposes a subset of depressedNo. 17

‐ 3030 7

patients to additional risk for suicide, suicide a tt empts or su

‐

icidal ideation.”

The FDA continued its investigation of the risk of suicide.

In September 1991, the agency convened an independent

commi tt ee of experts to review whether SSRIs were associ

‐

ated with suicide. The FDA also asked the commi tt ee to eval

‐

uate data speci fi c to paroxetine. The commi tt ee “unanimously

agreed that there is no credible evidence of a causal link be

‐

tween the use of antidepressant drugs

... and suicidality or

violent behavior.” The commi tt ee also found that paroxetine

was safe and e ff ective for treating adult depression.

In December 1992, the FDA approved the new drug appli

‐

cation for paroxetine, which allowed GSK to market the drug

as Paxil. The original label did not contain any paroxetine

‐ speci fi c warning about suicidality. Instead, the FDA required

that the label contain the same warning as all other antide

‐

pressants at the time: “The possibility of a suicide a tt empt is

inherent in depression and may persist until signi fi cant remis

‐

sion occurs. Close supervision of high

‐ risk patients should ac

‐

company initial drug therapy.”

Throughout the late 1990s and early 2000s, GSK submi tt ed

additional data on paroxetine to the FDA. The FDA continued

to reject any link between paroxetine and suicidality. In Janu

‐

ary 2004, the FDA summarized its fi ndings as follows:

FDA has done several analyses on com

‐ pleted suicides for adult data sets provided to

us in response to a request for patient level data

sets for all relevant studies involving 20 antide

‐

pressant drugs studied in 234 randomized con

‐

trolled trials with [major depressive disorder].8 No. 17

‐ 3030

Based on our initial analyses of these data, we

have reached a similar conclusion, i.e., that

there does not appear to be an increased risk of

completed suicide associated with assignment

to either active drug or placebo in adults with

[major depressive disorder].

2. The FDA’s 2004 Pediatric Suicide Warning

Later in 2004, however, the FDA found an association be

‐

tween SSRIs and suicide in pediatric patients. The FDA con

‐

vened an advisory commi tt ee to review data on nine antide

‐

pressant drugs, including paroxetine and other SSRIs, in pe

‐

diatric patients. The commi tt ee unanimously agreed that the

“data in aggregate indicate an increased risk of suicidality” in

“pediatric patients.” As a result, the FDA required that the la

‐

bels for paroxetine and other SSRIs be changed to include a

warning that antidepressants “increase the risk of suicidal

thinking and behavior (suicidality) in children and adoles

‐

cents with major depressive disorder (MDD) and other psy

‐

chiatric disorders.”

The FDA required that this appear as a “black

‐ box” warn

‐ ing, meaning that it “should be added to the beginning” of the

label “with bolded font and enclosed in a black box.” The

FDA also required new language in the “WARNINGS—

Clinical Worsening and Suicide Risk” section of the previous

label applicable to all SSRIs. The new language warned that

patients “with major depressive disorder (MDD), both adult

and pediatric, may experience worsening of their depression

and/or the emergence of suicidal ideation and behavior

... whether or not they are taking antidepressant medication,”

and that a “causal role for antidepressants in inducing suicid

‐ ality has been established in pediatric patients.” The FDA didNo. 17

‐ 3030 9

not require a warning about any association between antide

‐

pressants and suicidality in adults.

3. GSK’s 2006 Adult Suicide Warning

After fi nding that SSRIs were associated with suicide in

pediatric patients, the FDA began a similar analysis of suicide

in adults. The FDA requested more data from manufacturers

of antidepressants, including data from GSK on paroxetine.

The FDA limited its data request to “completed, double

‐ blind,

randomized, placebo

‐ controlled trials.” GSK submi tt ed data

to the FDA.

At the same time, GSK conducted its own re

‐ analysis of

data on adult suicidality and paroxetine. In the re

‐ analysis,

GSK looked for an association between paroxetine use with

suicidal ideation and increased suicide a tt empts. GSK found

no statistically signi fi cant di ff erence when looking at suicidal

ideation, but it found “evidence of an increase in suicide at

‐

tempts in adults with [major depressive disorder] treated

with paroxetine compared with placebo.” GSK submi tt ed its

fi ndings to the FDA, explaining that its data showed a 6.7

‐ fold

increase in suicide a tt empts in adults treated with paroxetine

compared to a placebo. GSK cautioned the FDA that “these

data should be interpreted with caution” because “the abso

‐

lute number and incidence of events” were “very small.”

After completing the re

‐ analysis, GSK acted unilaterally to

change paroxetine labeling on April 27, 2006. It did so under

the CBE regulation, i.e., without advance FDA approval. GSK

removed language that described the risk of suicide in adults

as “unknown” and added the following:10 No. 17

‐ 3030

In adults with [major depressive disorder]

(all ages), there was a statistically signi fi cant in

‐

crease in the frequency of suicidal behavior in

patients treated with paroxetine compared with

placebo (11/3,455 [0.32%] versus 1/1,978

[0.05%]); all of the events were suicide a tt empts.

However, the majority of these a tt empts for par

‐

oxetine (8 of 11) were in younger adults aged 18

‐

30 years. These [major depressive disorder] data

suggest that the higher frequency observed in

the younger adult population across psychiatric

disorders may extend beyond the age of 24.

GSK also sent a le tt er to doctors nationwide, a tt aching the

new paroxetine label and explaining the “important changes

to the Clinical Worsening and Suicide Risk subsection of the

Warnings section.”

4. FDA’s Meta

‐ Analysis & the 2007 Class

‐ Wide Label

Change

About seven months later, in November 2006, the FDA

completed a meta

‐ analysis—that is, a statistical analysis of a

large group of similar studies—to study the risk of suicide in

adults who use antidepressants. The meta

‐ analysis consid

‐

ered 372 placebo

‐ controlled clinical trials and involved nearly

100,000 adult patients, including data on paroxetine submit

‐

ted by GSK. The FDA found “an elevated risk for suicidality

and suicidal behavior among adults younger than 25,” but

concluded that the “net e ff ect appears to be neutral on sui

‐

cidal behavior but possibly protective for suicidality for

adults between the ages of 25 and 64 and to reduce the risk of

both suicidality and suicidal behavior in subjects aged 65

years and older.”No. 17

‐ 3030 11

The FDA’s meta

‐ analysis analyzed the data for each drug.

For paroxetine, the FDA data showed a statistically

‐ signi fi cant 2.76

‐ fold increase in suicidal behavior compared

with adults treated with placebo. The FDA noted this result,

but concluded that “the signi fi cance of those fi ndings must be

discounted for the large number of comparisons being made.”

In response to these fi ndings, in 2007, the FDA took action

that is central to GSK’s preemption defense in this case. The

agency ordered that all SSRI labels be updated based on the

results of the meta

‐ analysis. Critically, the FDA decided to or

‐

der that warnings be uniform for all SSRIs. On May 1, 2007,

the FDA directed GSK to revise the paroxetine labeling “to

ensure standardized labeling pertaining to adult suicidality

with all of the drugs to treat major depressive disorder.” Def.

Ex. 122. The SSRI labels were to warn of a suicidality risk in

patients 24 years old or under, and to state that “studies did

not show an increase in the risk of suicidality with antidepres

‐

sants compared to placebo in adults beyond age 24; there was

a reduction with antidepressants compared to placebo in

adults aged 65 and older.” The FDA required all SSRI labels

to include this language “verbatim.” This action had the e ff ect

of rejecting GSK’s unilateral change to the paroxetine label in

2006 using the CBE regulation to warn of increased risk

among older adults.

5. Later A tt empts to Add a Paroxetine

‐ Speci fi c Warning

After the FDA ordered uniform warnings for all SSRIs,

GSK asked the FDA several times for permission to maintain

a paroxetine

‐ speci fi c suicide warning. Within a week of the

FDA’s announcement, GSK emailed the FDA to “clarify”

whether it could retain the paroxetine

‐ speci fi c warning it had12 No. 17

‐ 3030

added in 2006 under the CBE regulation. The FDA immedi

‐ ately said no. It replied that GSK should “replace the previous

warning section with the new language” that the FDA had

circulated. Def. Ex. 124.

Four days later, on May 11, GSK more formally asked the

FDA to maintain the paroxetine

‐ speci fi c warning. In a le tt er

to the FDA, GSK proposed keeping the paroxetine

‐ speci fi c

language and argued that it “would complement the class la

‐ beling” and “could help physicians.” The FDA advised GSK

to submit the paroxetine

‐ speci fi c warning as a separate CBE

supplement and explained that the FDA would “be discuss

‐ ing all” manufacturers’ “proposals during the last week of

May.” GSK submi tt ed the CBE supplement that the FDA re

‐ quested.

On June 21, 2007, the FDA fi nalized the new class

‐ wide

warnings. The FDA stressed that “it is critical that the labeling

be consistent for all” SSRIs. This fi nal version omi tt ed GSK’s

paroxetine

‐ speci fi c warning. The next day, GSK again fol

‐

lowed up with the FDA to clarify whether the FDA had re

‐ jected its most recent CBE supplement adding a paroxetine

‐ speci fi c warning. It had. The FDA responded that it was re

‐ jecting product

‐ speci fi c warning language:

[T]he Agency has reviewed your proposed

changes, and we do not believe that your prod

‐

uct speci fi c analysis should be included in class

labeling revisions since the labeling is targeted

at the class of drugs. If you would like to discuss

this ma tt er further, please submit a formal meet

‐ ing request.

Def. Ex. 129. GSK did not pursue the ma tt er any further.No. 17

‐ 3030 13

On June 25, 2007, GSK implemented the new class

‐ wide

warning that the FDA ordered. GSK continued to assert to the

FDA that “the paroxetine speci fi c language” would “be useful

for prescribers.” On August 2, 2007, the FDA approved GSK’s

supplement—and thus the new paroxetine label—containing

only the class

‐ wide SSRI suicide warning. GSK continued to

market paroxetine under the Paxil brand name in the United

States using the FDA

‐ approved label through 2014, when

GSK sold the right to sell Paxil to another manufacturer. The

paroxetine label maintains the FDA’s class

‐ wide warning to

‐ day. It does not warn of any association with an increased risk

of suicide in adults older than 24.

C. This Lawsuit

Mrs. Dolin sued GSK in state court, alleging that paroxe

‐

tine increases the risk of suicide in adults; that GSK negli

‐ gently failed to update the paroxetine label to re fl ect that risk;

and that GSK’s negligence caused Stewart’s death. GSK re

‐

moved to the Northern District of Illinois, asserting diversity

jurisdiction under 28 U.S.C. § 1332(a)(1). Mrs. Dolin is a citi

‐

zen of Illinois. GSK is a limited liability company organized

under Delaware law, and its sole member is GlaxoSmithKline

Holdings (Americas) Inc., a Delaware corporation with its

principal place of business in Delaware. The amount in con

‐

troversy exceeds $75,000. 1

1 Mrs. Dolin also sued Mylan, Inc., the company that manufactured

the generic paroxetine that Stewart Dolin actually took. Mylan moved to

dismiss on preemption grounds under Mensing

, 564 U.S. 604, and Bartlett

,

570 U.S. 472. The district court granted Mylan’s motion, and Mrs. Dolin

has not appealed that decision.14 No. 17

‐ 3030

Once in federal court, GSK made two arguments that are

relevant to this appeal. First, GSK argued that it did not owe

Stewart—who consumed paroxetine made by another

company—a duty of care under Illinois law. Second, GSK

argued that plainti ff ’s claim was preempted under Wyeth v.

Levine

, 555 U.S. 555 (2009), because the FDA had rejected the

paroxetine

‐ speci fi c warning that, according to plainti ff

, Illinois law required. The district court denied GSK’s motions

for summary judgment, and the case proceeded to trial.

GSK moved for judgment as a ma tt er of law during and

after trial. GSK argued that plainti ff had failed to provide ev

‐

idence that paroxetine causes suicide and that the paroxetine

labeling caused Stewart’s suicide. GSK also renewed its argu

‐

ments that it was not liable both because it did not owe Stew

‐

art a duty under Illinois law and because federal law

preempted the failure

‐ to

‐ warn claim. The district court de

‐

nied GSK’s motions and entered fi nal judgment in favor of

Mrs. Dolin.

II. Preemption

The Supremacy Clause was at the core of the Framers’ ef

‐

fort to provide a national government with the powers

needed to govern the new Republic e ff ectively. It provides:

“This Constitution, and the Laws of the United States which

shall be made in Pursuance thereof; and all Treaties made, or

which shall be made, under the Authority of the United States,

shall be the supreme Law of the Land; and the Judges in every

State shall be bound thereby, any Thing in the Constitution or

Laws of any State to the Contrary notwithstanding.” U.S.

Const. art. VI, cl. 2. The Supremacy Clause “invalidates state

laws that ‘interfere with, or are contrary to,’ federal law.”

Hillsborough County v. Automated Med. Labs., Inc.

, 471 U.S. 707,No. 17

‐ 3030 15

712 (1985), quoting Gibbons v. Ogden

, 22 U.S. 1, 211 (1824).

State law includes duties imposed by court decisions apply

‐ ing state tort law. E.g., Mensing

, 564 U.S. 604 (invalidating

state laws imposing duty on generic manufacturers to change

drug labels).

“Preemption comes in three forms.” Mason v. Smithkline

Beecham Corp.

, 596 F.3d 387, 390 (7th Cir. 2010). First is express

preemption, “which occurs when Congress clearly declares

its intention to preempt state law.” Id. Second is implied

preemption, “which occurs when the ‘structure and purpose’

of federal law shows Congress’s intent to preempt state law.”

Id. This case involves the third form, called con fl ict or impos

‐ sibility preemption. Con fl ict preemption occurs when there is

“an actual con fl ict between state and federal law such that it

is impossible for a person to obey both.” Guilbeau v. P fi zer, Inc.

,

880 F.3d 304, 310 (7th Cir. 2018), quoting Mason

, 596 F.3d at

390. When that is true, “federal law controls and the state

‐ law

tort claims must be dismissed.” Id.

In Wyeth v. Levine

, the Supreme Court addressed how con

‐

fl ict preemption applies to state

‐ law claims against brand

‐

name drug manufacturers. The Court held that state

‐ law

claims based on labeling de fi ciencies are not preempted if the

manufacturer could have added the warning unilaterally un

‐

der the CBE regulation. 555 U.S. at 573 ( fi nding that defendant

had “failed to demonstrate that it was impossible for it to

comply with both federal and state requirements” when the

“CBE regulation permi tt ed” defendant “to unilaterally

strengthen its warning” on its brand

‐ name drug). In a later

case addressing how Levine would apply to claims against

manufacturers of generic drugs, the Court reiterated that the

“question for ‘impossibility’ is whether the private party16 No. 17

‐ 3030

could independently do under federal law what state law re

‐ quires of it.” Mensing

, 564 U.S. at 620, citing Levine

, 555 U.S. at

573. As a general rule, then, state law can hold a brand

‐ name

manufacturer liable for failing to use its powers under the

CBE regulation to add a new warning to a drug label.

There is one fi nal part to this standard, and it is decisive

here. Recall that the FDA can reject CBE submissions and re

‐ quire manufacturers to revert to the prior version of the label.

Levine acknowledged that the FDA retains this authority, and

“held that there could be preemption if the manufacturer met

the stringent standard of proving that there was clear evidence

the FDA would have rejected the proposed change in the

drug’s label.” Mason

, 596 F.3d at 391, citing Levine

, 555 U.S. at

571. The evidence here meets that standard.

In sum, Dolin’s state

‐ law claim against GSK is preempted

if GSK could not have added the adult

‐ suicidality warning us

‐ ing the CBE regulation. See In re Celexa & Lexapro Marketing &

Sales Practices Litigation

, 779 F.3d 34, 41 (1st Cir. 2015) ( fi nding

that plainti ff must allege a label de fi ciency that defendant

“could have corrected using the CBE regulation.”). To add a

warning through the CBE regulation, GSK needed newly ac

‐ quired information about paroxetine that would allow it to

add a warning about suicide risk in adults. And even if GSK

had newly acquired information along these lines, GSK can

still succeed on its preemption defense if there is clear evi

‐

dence that the FDA would have rejected the adult

‐ suicidality

warning that plainti ff argues was tortiously omi tt ed. Based on

the evidence in this case, we conclude that, as a ma tt er of law,

(1) there is clear evidence that the FDA would have rejectedNo. 17

‐ 3030 17

the warning in 2007, and (2) GSK lacked new information af

‐

ter 2007 that would have allowed it to add an adult

‐ suicidality

warning under the CBE regulation. 2

A. Standard of Review

Before we can reach the merits of GSK’s preemption de

‐

fense, we must address a threshold issue. Plainti ff argues that

we must review the district court’s preemption fi nding for

clear error. In the district court, both plainti ff and GSK main

‐

tained that preemption under Levine was a question of law.

The district court initially found that Levine preemption was a

question of fact to be submi tt ed to the jury. GSK objected to

the wording of the court’s proposed jury instructions and con

‐

tinued to argue that the issue was a legal one. The district

court ultimately omi tt ed the instruction and did not submit

the question of preemption to the jury.

Our cases have analyzed preemption under Levine as a le

‐ gal question. In Guilbeau

, we wrote that “preemption is a legal

question for determination by the courts

... .” 880 F.3d at 318,

quoting Wa tt ers v. Wachovia Bank, N.A.

, 550 U.S. 1, 20 (2007);

see Mason

, 596 F.3d at 390, 393–96 (referring to preemption

issue as “a legal one” and analyzing preemption as a ma tt er

of law). Recently, the Third Circuit determined that “the ulti

‐

mate question of whether the FDA would have rejected a label

change is a question of fact for the jury rather than for the

2 Judge Zagel denied GSK’s motion for summary judgment on the

preemption defense, finding that the FDA’s invitation to request a meet

‐ ing after the fourth denial of a paroxetine

‐ specific warning defeated the

Levine preemption defense. App. 28. We respectfully disagree with our

colleague’s finding on this point, though our decision is based on the trial

record rather than the summary judgment record. The case was later re

‐ assigned from Judge Zagel to Judge Hart for trial.18 No. 17

‐ 3030

court.” In re Fosamax Products Liability Litig.

, 852 F.3d 268, 282

(3d Cir. 2017). The district court in this case relied on the Third

Circuit’s decision when it proposed submi tt ing the preemp

‐

tion defense to the jury.

The Third Circuit noted that other circuits treat the Levine

“test” as “a legal question.” Id. at 287 & nn.103–105 (collecting

cases). To reach a contrary conclusion, the Third Circuit relied

in part on Boyle v. United Technologies Corp.

, 487 U.S. 500

(1988), which addressed con fl ict preemption for products lia

‐ bility claims against manufacturers of military equipment

whose products must comply with military speci fi cations.

The Court stated that “whether the facts establish the condi

‐

tions for the [government speci fi cation] defense is a question

for the jury.” Id. at 514. The Supreme Court has granted certi

‐

orari to review the Third Circuit’s decision on this issue.

Merck Sharp & Dohme Corp. v. Albrecht

, 138 S. Ct. 2705 (2018).

We need not determine in this case whether preemption

under Levine involves a factual question for the jury. As the

Third Circuit noted, “when no reasonable jury applying the

clear

‐ evidence standard” could “conclude that the FDA

would have approved a label change,” then “the manufac

‐

turer will be entitled to judgment as a ma tt er of law.” In re

Fosamax

, 852 F.3d at 282. That is the case here. As we explain

next, given the facts in this case, no reasonable jury could fi nd

that the FDA would have approved an adult

‐ suicidality warn

‐ ing for Paxil under the CBE regulation between 2007 and

Stewart Dolin’s suicide in 2010.

B. Clear Evidence of Rejection?

GSK has provided undisputed evidence that the FDA re

‐ jected any adult

‐ suicidality warning in 2007 when the agencyNo. 17

‐ 3030 19

required all SSRIs to adopt the same class

‐ wide warnings. By

2000, a potential association between SSRIs and suicide was a

high

‐ pro fi le controversy at the center of the FDA’s a tt ention.

As part of its response to that controversy, the agency re

‐

viewed data on suicidal behavior in patients taking paroxe

‐

tine. In 2007, after completing that review, the FDA ordered

GSK to remove a paroxetine

‐ speci fi c warning of increased su

‐

icide risk in adults from the paroxetine label. It is hard to im

‐ agine clearer evidence that, considering the data available in

2007, “the FDA would not have approved a change” to the

paroxetine label at that time. Levine

, 555 U.S. at 571. No rea

‐

sonable jury could fi nd otherwise.

When deciding preemption in this context, “ Levine is our

intellectual anchor.” Mason

, 596 F.3d at 392. We “look at the

long and fairly extensive administrative history” for the drug

in Levine “and compare it to the administrative history of

Paxil.” Id. In Levine

, the Court found four key facts critical

when it found no preemption: (1) there was “no evidence

... that either the FDA or the manufacturer gave more than pass

‐ ing a tt ention” to the risk at issue; (2) the manufacturer had not

“supplied the FDA with an evaluation or analysis” of the risk;

(3) the manufacturer never “a tt empted to give the kind of

warning required” under state law; and (4) the FDA “had not

made an a ffi rmative decision” to reject the warning. Id. at 572–

73.

All four of those evidentiary gaps in Levine were fi lled

here. In 2006, GSK re

‐ analyzed the placebo

‐ controlled data on

paroxetine and found a link between paroxetine and suicide

in adults. It then made a unilateral change to the label, using

the CBE regulation and adding a warning “that the higher fre

‐20 No. 17

‐ 3030

quency” of suicidality “observed in the younger adult popu

‐

lation

... may extend beyond the age of 24.” GSK submi tt ed

that data to the FDA. But within a year, the FDA completed

its own analysis of the same data and ordered GSK to remove

that warning. The FDA noti fi ed manufacturers that all SSRIs

needed to contain the same warning, saying there was a risk

of suicide in patients under 24 but that “studies did not show

an increase in the risk of suicidality

... in adults beyond age

24.”

After the FDA e ff ectively told it to remove the paroxetine

‐ speci fi c warning, GSK followed up with four requests to re

‐

consider and to allow that warning. Each time, the FDA told

GSK not to add the paroxetine

‐ speci fi c warning. These re

‐

quests by GSK and the responses are clearly documented.

They are not subject to reasonable dispute. This is clear evi

‐

dence that, as of 2007, the FDA rejected an adult

‐ suicidality

warning for paroxetine.

To avoid the consequences of this evidence, plainti ff raises

two arguments. Neither argument undermines the preemp

‐

tive e ff ect of the FDA’s actions or decisions. First, plainti ff ar

‐

gues that the FDA rejected the paroxetine

‐ speci fi c warning

only because GSK proposed adding it to the wrong spot on

the label. GSK proposed warning about the risks of paroxetine

in the middle of the class

‐ wide SSRI warning, which FDA

wanted to maintain as a uniform warning for all SSRIs. Be

‐

cause GSK never proposed adding the warning elsewhere in

the label, plainti ff argues, there is no “clear evidence” that the

FDA would have rejected a proposal along those lines.

This is an unreasonable interpretation of the discussions

between the FDA and GSK. When the FDA rejected GSK’sNo. 17

‐ 3030 21

paroxetine

‐ speci fi c warning, the relationship between sui

‐

cide, age, and SSRI use was at the forefront of the agency’s

a tt ention. The FDA had just completed two lengthy meta

‐ analyses on the topic. In its analyses, the FDA observed a sta

‐ tistically signi fi cant association between paroxetine and sui

‐

cidal behavior in adults, but decided to discount that result in

favor of uniform SSRI labeling. That labeling a ffi rmatively

stated that SSRIs’ “net e ff ect appears to be neutral on suicidal

behavior but possibly protective for suicidality for adults be

‐

tween the ages of 25 and 64.” Plainti ff asks us to believe that

the FDA—after deciding against an adult

‐ suicidality warning

based on its own analysis—rejected GSK’s warning only be

‐

cause GSK proposed pu tt ing it in the wrong place. That is un

‐

reasonable.

Second, plainti ff argues that GSK could have followed up

with a formal meeting with the FDA to discuss the

paroxetine

‐ speci fi c warning. According to plainti ff

, GSK lacks

clear evidence that the FDA would have rejected the warning

after such a meeting. This misunderstands the preemption

standard. State laws requiring a label change are preempted

unless the manufacturer could unilaterally add the new

warning under the CBE regulation. Levine

, 555 U.S. at 573; see

also Mensing, 564 U.S. at 620.

The Supreme Court has rejected a very similar preemption

argument in Mensing

, where the Court held that federal law

preempts state laws that require generic drug manufacturers

to change a drug’s label. In reaching that conclusion, the

Court rejected the plainti ff ’s argument that the generic man

‐

ufacturer could have asked the FDA to change the brand

‐

name label. 564 U.S. at 619–20. The Court explained: “when a22 No. 17

‐ 3030

party cannot satisfy its state duties without the Federal Gov

‐

ernment’s special permission and assistance, which is de

‐ pendent on the exercise of judgment by a federal agency, that

party cannot independently satisfy those state duties for pre

‐ emption purposes.” Id. at 623–24. That is what plainti ff ’s sec

‐

ond argument amounts to. The preemption analysis asks only

whether GSK could have added the adult

‐ suicidality warning

through the CBE regulation, not whether GSK might have

been able to persuade the FDA to change its mind in a formal

meeting—and certainly not whether GSK could have per

‐

suaded the FDA after already asking four times to include

that warning and being told no four times. 3

C. Newly Acquired Information?

The FDA’s rejection of the adult

‐ suicidality warning in

2007 does not de fi nitively answer whether GSK could have

added the warning between 2007 and 2010, when Stewart

Dolin took paroxetine and commi tt ed suicide. The CBE regu

‐

lation allows manufacturers to add or strengthen a warning

when they acquire new information about the drug that

makes the warning necessary. Plainti ff has failed to o ff er evi

‐

dence that GSK acquired new information after 2007, when

3 In Mason

, we found that GSK’s predecessor had not shown the clear

evidence needed for Levine preemption for a 23

‐ year

‐ old’s suicide that oc

‐

curred in 2003. 596 F.3d at 395–96. Mason thus addressed a suicide by a

patient who would have fallen within the scope of the 2004 and 2007 class

‐

wide warnings for pediatric suicide risk, so it does not control the preemp

‐

tion question here. Plaintiff also cites Tucker v. Smithline Beecham Corp.

, 596

F. Supp. 2d 1225, 1236 (S.D. Ind. 2008), which similarly found that GSK’s

predecessor had not established a preemption defense for Paxil. Tucker ad

‐

dressed a 55

‐ year

‐ old’s suicide in 2002, and was decided before Levine and

Mensing

, so its analysis does not apply here, to a 2010 suicide with the

direction of Levine and Mensing available to the court.No. 17

‐ 3030 23

the FDA rejected its proposal to add an adult

‐ suicidality

warning to the paroxetine label that would have justi fi ed a

change in the label and thus undermine GSK’s preemption

defense.

Newly acquired information “is data, analyses, or other

information not previously submi tt ed to the Agency.” 21

C.F.R. § 314.3. Newly acquired information is not limited to

new data. It includes new analysis of old data. Id

. The “rule

accounts for the fact that risk information accumulates over

time.” Levine

, 555 U.S. at 569.

Plainti ff proposes two ways that GSK had newly acquired

information that supported the paroxetine

‐ speci fi c warning.

First, plainti ff argues that GSK withheld or manipulated data

in its submissions to the FDA. Plainti ff argues that the com

‐ plete, untainted data showed an association between paroxe

‐

tine and suicide in adults, and that the FDA never considered

this information.

This argument fails because the undisputed evidence

shows that the FDA was aware of the nature of the data it re

‐

ceived from GSK. Plainti ff argues that GSK improperly at

‐

tributed suicides that occurred in the “wash

‐ out” phase of

drug tests as occurring on the placebo. The wash

‐ out phase

refers to the period when patients are given placebos to wash

out other drugs in their system before the study begins. By

a tt ributing negative incidents that occurred during the wash

‐

out phase to the placebo, Paxil looks be tt er by comparison.

We have already rejected this argument about the same

Paxil/paroxetine data in Mason. 596 F.3d at 394. As we noted

then, “each erroneous datum had a star by it which noted that

part of the suicidal behavior occurred during the wash

‐ out24 No. 17

‐ 3030

phase.” Id. The FDA scientist who reviewed the data “under

‐

stood that the wash

‐ out events were included when he ana

‐ lyzed the data,” and his analysis “found no relationship be

‐

tween Paxil and suicidal behavior.” Id. And in 2002 and 2003,

GSK re

‐ analyzed the data while excluding the wash

‐ out

phase and submi tt ed that data to the FDA. Id.

Plainti ff points to one other possible source of newly ac

‐ quired information. She o ff ers an article published in 2011 as

evidence that GSK conducted a re

‐ analysis in 2008 that found

a statistically signi fi cant association between adult suicidality

and paroxetine. Plainti ff ’s expert testi fi ed, however, that this

was not new analysis. He testi fi ed that the article was “sub

‐

mi tt ed for publication in 2008 and published in 2011,” but

“was based on” GSK’s “2006 analysis.” The article contained

the same fi gures as GSK’s 2006 analysis, which GSK submit

‐

ted to the FDA. There is no basis to conclude that this was a

new analysis or that it was “not previously submi tt ed to the

Agency.” 21 C.F.R. § 314.3.

* * *

GSK asked the FDA for permission to modify the paroxe

‐

tine label as plainti ff argues was needed. The FDA said no,

repeatedly. Federal law thus preempted plainti ff ’s Illinois

‐

law claim that GSK should have warned of a risk of adult su

‐ icidality on the paroxetine label in 2010. GSK added a similar

warning in 2006, and the FDA ordered that GSK remove that

label and replace it with a class

‐ wide SSRI warning in 2007.

As a ma tt er of law, this is what Levine called “clear evidence”

that the FDA would have rejected the warning that plainti ff

seeks under Illinois law. After 2007, GSK lacked newly ac

‐ quired information that would have allowed it to add an

adult

‐ suicidality warning under the CBE regulation.No. 17

‐ 3030 25

The parties and amici have briefed extensively whether Il

‐

linois law would impose a duty on a brand

‐ name drug man

‐

ufacturer toward a patient like Stewart Dolin, who took a ge

‐

neric form of the drug manufactured by a di ff erent company.

The Illinois courts have not yet considered the new theory of

liability that plainti ff advances. Because the evidence of fed

‐

eral preemption is decisive, we do not o ff er for that question

of duty a prediction of state law under Erie Railroad Co. v.

Tompkins

, 304 U.S. 64 (1938). We also need not consider GSK’s

other arguments based on the trial evidence. The judgment of

the district court is REVERSED.