# Amicus Curiae Brief — Merck Sharp & Dohme Corp. v. Albrecht (No. 17-290)

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URL: https://www.frixlaw.com/law-library/documents/brief%3Amicro_IA40385016_0777%3A15

## Record

- **Collection:** Supreme Court brief
- **Document type:** Amicus Curiae Brief
- **Published:** January 1, 2019

## Text

No. 17-290

In the Supreme Court of the United States

MERCK SHARP & DOHME CORP., PETITIONER

vz.

DortIs ALBRECHT, ET AL.

ON WRIT OF CERTIORARI
TO THE UNITED STATES COURT OF APPEALS
FOR THE THIRD CIRCUIT

BRIEF FOR THE UNITED STATES
AS AMICUS CURIAE SUPPORTING PETITIONER

Acting Solicitor General
Counsel of Record
JosePH H. HUNT
BRIAN R. STIMSON Assistant Attorney General
+ —~ ~ ieee EDWIN S. KNEEDLER
ELIZABETH H. DICKINSON ———
Associate ANG
Assistant to the Solicitor
General
ANNAMARIE KEMPIC
Chief Counsel Scort R. McINTOSH
"Vaidation JOSHUA M. SALZMAN
KAREN E. SCHIFTER Attorneys
Senior Counsel Justice
——— of Health and Ww C. 20530-0001
uman Services S gov

Washington, D.C. 20201 (202) 514-2217

QUESTION PRESENTED

Whether a state-law failure-to-warn claim alleging
the insufficiency of brand-name drug labeling is pre-
empted by the Federal Food, Drug, and Cosmetic Act,
21 U.S.C. 301 et seqg., when the Food and Drug Admin-
istration, after the drug manufacturer provided it with
the relevant scientific data, rejected the manufacturer's
application to modify its labeling to warn about the risk
underlying the tort claim.

(I)

TABLE OF CONTENTS

Page
Interest of the United States ................c.ccccceseensecneenneeesnnnnnnnnenes 1
IIIS ccnssenneccmnssnnsesresssrersesesnazemnsencsemssessnemanesnnqnssacesnennenens 1
TN GE GRIEG ccccsncscccsczsssscssesecssscscssanasscsrsmenssnesneneenssness 14
Argument:
The court of appeals erred in rejecting petitioner’s
UA GU RID cxcsccssscscssmscscemssenmesessmnseeemmesnenvesseneesnese 16
A. Petitioner’s preemption defense turns on the
meaning and effect of FDA’s 2909 Complete
Response Letter, which are legal questions that
a court must resolve 17
1. Courts, not juries, determine the meaning
of federal agency decisions ..................<.c000--0-0--- 18
2. Factual findings necessary to interpret a
federal agency decision are also matters for
courts to resolve =

B. age ty meets ee on

to a clear-and-convincing-evidence standard ............ 21
1. Wyeth did not address whether courts or
juries should construe an actual FDA
Qe cecrerensesmmenmsmmsemnenene 22
2. Any factual findings necessary to resolve
a preemption defense need only rest on a
preponderance of the evi ence.................0-0.00-0-0+- 24
3. Resolving this case does not require factual
findings =
C. FDA's May 2009 decision rejected a change to
Fosamax’s warnings and precautions because the
data at that time was insufficient to justify a
change 30
ee 35

(IIT)

IV

TABLE OF AUTHORITIES
Cases: Page
Addington v. Texas, 441 U.S. 418 (1979) ......ccccccccccecevee 2A, 25
Arizona v. Inter Tribal Council of Ariz., Inc.,

DIO UB. 3 GIBB) enccccccccscsccscsuscsccscscscsvsscsnsesveesesecscccccececeseeee 25
Armour & Co. v. Wantock, 323 U.S. 126 (1944) ................. 24
Block v. Community Nutrition Inst., 467 U.S. 340

(1984) 26

Boyle v. United Techs. Corp., 487 U.S. 500 (1988)....... 28, 29
Buckman Co. v. Plaintiffs’ Legal Comm.,

GD TE, a Go ecennensssnsnssnsssnvmensernsnssssnsssssccscssssescscsseseces 28
Cohens v. Virginia, 19 U.S. (6 Wheat.) 264 (1821)............. 24
Dolin v. GlaxoSmithKline LLC, No. 17-3030,

2018 WL 4001208 (7th Cir. Aug. 22, 2018) ..............000000 33
Emich Motors Corp. v. General Motors Corp.,

GD GE, Ga Ca rascccsnsnsscensnsscsnssssszasssscemsssnenemcssescccsssecss 19
English v. General Elec. Co., 496 U.S. 72 (1990) ..........00000 26

Geier v. American Honda Motor Co., 529 U.S. 361

(2000) -» 26
Grogan v. Garner, 498 U.S. 279 (1991) 24
Landgraf v. USI Film Prods. , 511 U.S. 244 (1994) ........... 24
Markman v. Westview Instruments, Inc.,

is 15, 19
Microsoft Corp. v. isi Ltd. P’ship, 564 U.S. 91

(2011) 2A, 25
Mutual Pharm. Co. v. Bartlett, 510 U.S. 472 (2013) coco. 4
PLIVA, Ine. v. Mensing, 564 U.S. 604

(2011) 4, 17, 18, 21,
Perez v. Mortgage Bankers Ass'n, 135 8. Ct. 1199

(2015) 20
Riegel v. Medtronic, Inc., 552 U.S. B12 (2008) ..cccccccoccoo 29

Rivera v. Minnich, 483 U.S. 574 (1987) ......0c00ccccecererenenenens 25

Cases—Continued: Page
Santosky v. Kramer, 455 U.S. 745 (1982) ......cccccceceeeeeeeenees 24
Sprietama v. Mercury Marine, 537 U.S. 51 (2002)............ 20
Teva Pharm. USA, Inc. v. Sandoz, Inc.,

135 S. Ct. 881 (201B) ......-.cccneseresnenenesesnsnennsnsnsnenensnnnseenennns 21
Wyeth v. Levine, 555 U.S. 555 (2009) .000....cccccccceeenves passim

Statutes, regulations, and rules:

Administrative Procedure Act, 5 U.S.C. 551 et seq.,
701 et seq. —
5 U.S.C. 551(6) - 18
5 U.S.C. 561(7) 18
5 U.S.C. 706 —_ 15, 18
Federal Food, Drug, and Cosmetic Act,
21 U.S.C. 301 et seq.:
a eR rncnscnccsnssecnsnsccemsesemsnsccmnsmnesememncsennies 2
21 U.S.C. 352(f) =
21 U.S.C. 3565(b)(1) 4
21 U.S.C. 355d) 2,4
21 U.S.C. 355(02) Ai) 10
21 U.S.C. 365(0)(4) 10, 11, 33, 34
21 U.S.C. 355(0)(4)(A) 10, 33
21 U.S.C. 355(0)(4)(B) 10
21 U.S.C. 355(04)(B)(D) we OO
21 U.S.C. 365(04)(C) il
21 U.S.C. 355(0)(4)(D) il
21 U.S.C. BECO AE) .....000ecceeceesensnnseneennsnnennnsnnennnennennees il
BD ae ID diccsnesecnsesnsscsscssecscssstnstsccssessssonssssetees 4
21 C.F.R.:
Pt. 201:
a cerecerercsccrscsesmennsemesscteesensensniens 2
Boction BO1 BRE) 222c.ccceccocecscecsccccscsescsesssessnseossscsoosees 4

Vi

Regulations and rules—Continued: Page
Section BO1 BBW) 1) ..0.-ccccccsecessereccsvseosersersrenseceessnsensonse 2
Section 201 .56(e) 2
Section B01 IT ...0c.0ccecsersevsevsessersnssersessersnssersersnssosssososoess 2
Section BILGE) .ccccccscosscecsececesrsecsessescssesscsssscresensensones 3
Section 201.57(¢)(6) ie 2,3
Section 201.57(¢)(6)(i) sasenenhsinmmenaesvnnt 4, 31, 33
Section 201.57(e)(7) ... 2, 3, 4, 30
Section 201.57(e)T)GIMB) «0... cecersercereennenenneennnnnnnne 4
Sloction BO1 BD....cccccecserseceecsecsevsevscssesenssessssenssssensseeees 2,3
Section B01. 10D(]) ....00ccscesessrscsessessossosnvscssesecscsesenssneeses 2

Pt. 314:
Bastion BIG BW) ...ccceccecoevsecseesecsessescessessnssesseseses 5, 27, 28
Section B14. 70D) .....0.0ec-ccerssssssesseevserseneessensensessosenseess 5
Blection BIA TODA) ..cccccccccsecescecsessescoscoscssccssscsssessonsenes 5
Section 314. 7OQD)MZ) ....0.-0--c-scsscersessereesersesensensssnsensenssees 5
Section 314. 7OMD)M2Z)V) ........---c-eceeeesnerereereennenneennnennnnes 5
Section 314. 7OCD)Z)(v MA) .........-eeveeneeneenreennennnennennns 5
Section 314.70(b)(3) 5
Section 314. 7O(CMG)..........c-ceeceesersnenvserenneeenennneanennennns 4
Section 314.70(e)(6)(iii) - 4, 5
Section 314. 7O(e (GIA) ......------ecceeeeererennennnnee 5, 27
Section 314. 7O(C)(7) ........-ec-eceecevsnveenenecnerneneennnnnnnnes 5, 17
Section B14.71() .....csccececsscsscssvsvsessosersrsesenseresssssnsseseses 5
Section 314.71(c) covcasestsenenessmasnnenesdsacennsees 5
Section B14. 10B(a) ........0.0-c-scesssssssesseesersnssesensssesenssessees 6
Section 314.102(b) 6
Section 314. 105(D) .........-ceee 6
Section 314.1 10(a) ..........-« 6
Section 314.110(a)(1) .......-..-..00 - 6
Section 314.1 10(a)(2) ........ccccecereeenseneneenenennne 6, 31, 32

Vil

Regulations and rules—Continued: Page
ee Be secencnsecvecsccccczsscesasecseressseeees 32
RE 6
ID sereesecessnosscemsccscnescnnssccsnemeseneensnes 6

ed, TR, BI Sie ecenessneversnevenseescassscssvsnssscerecscssssensssssssseemesnetn 25
ar, GR, BR, BID ccccunscscsnsnszssvsrsnsccensesessreseesvemmnesssesssonnemmnecsmnate 27
Miscellaneous:

Center for Drug Evaluation & Research, FDA,
CDER 21st Century Review Process: Desk
Reference Guide (2014), https://www fda.gov/
downloads/AboutF DA/CentersOffices/C DE R/
ManualofPoliciesProcedures/UCM218757.pdf.................. 6
Dorland’s Iliustrated Medical Dictionary
Ee Fie terrectnstnentecntemevesenenssnmtnsnmennmne
FDA:
Approved Drug Products with Therapeutic
Equivalence Evaluations (38th ed. 2018),
https://www.fda.gov/downloads/drugs/

ee anand
uem071436.pdf ... A

Guidance for intuey ‘Safety perrrnas
Changes—I mplementation of Section
505(0)(4) of the FD&C Act (July 2013),
https://www.fda.gov/downloads/
Drugs/GuidanceCompliance Regulatory
Information/Guidancea/UCM250783. pdf .................. 5
(Guidance for Industry: Warnings and
Precautions, Contraindications, and Boxed
Warning Sections of Labeling for Human
Prescription Drug and Biological Products—
Content and Format (Oct. 2011),
https://www .fda.gov/downloads/Drugs/
GuidanceCompliance Regulatory
Information/Guidances/UC M075096. pdf .................. 3

Vill

Miscellaneous—Continued:
Guidance for Review Staff and Industry:
Good Review Management Principles and
Practices for PDUFA Products (Apr. 2005),

https://www.accessdata.fda.gov/

71 Fed. Reg. 3922 (Jan. 24, 2006)

73 Fed. Reg. 49,608 (Aug. 22, 2008) 2...
H.R. Rep. No. 1980, 79th Cong., 2d Sess. (1946)..........

U.S. Dep’t of Justice, Attorney General’s Manual on

the Administrative Procedure Act (1947)...

Page

In the Supreme Court of the United States

No. 17-290
MERCK SHARP & DOHME CorP., PETITIONER
vz.
Doris ALBRECHT, ET AL.

ON WRIT OF CERTIORARI
TO THE UNITED STATES COURT OF APPEALS
FOR THE THIRD CIRCUIT

BRIEF FOR THE UNITED STATES
AS AMICUS CURIAE SUPPORTING PETITIONER

INTEREST OF THE UNITED STATES

This case concerns the circumstances under which a
decision of the Food and Drug Administration (FDA)
rejecting proposed changes to the labeling of a brand-
name drug preempts state-law tort claims that allege
that the drug manufacturer failed to provide adequate
warnings on its labe!ing. At the Court’s invitation, the
United States filed a brief as amicus curiae at the peti-
tion stage of this case.

STATEMENT

1. This case involves a series of tort claims alleging
that petitioner’s labeling for its Fosamax drug products
insufficiently warned of the drugs’ risks. Petitioner has
argued, among other things, that many of the failure-to-
warn claims are preempted because, in 2009, FDA re-
jected its attempt to strengthen relevant warnings on

(1)

2

that labeling. The regulatory scheme for drug labeling
establishes the framework for that defense.

a. Congress has charged FDA with ensuring that
each “drug is safe for use under the conditions pre-
scribed, recommended, or suggested” in its “labeling.”
21 U.S.C. 355(d); ef. 21 U.S.C. 321(m) (defining “label-
ing”); 21 U.S.C. 352(f) (misbranding). FDA regulations
govern the content and format of prescription-drug
labeling. See, eg., 21 C.F.R. 201.56, 201.57; see 21
C.F.R. 201.100(c). Those regulations are intended to
organize labeling information to more effectively com-
municate to healthcare professionals the “information
necessary for the safe and effective use of prescription
drugs.” 71 Fed. Reg. 3922, 3928 (Jan. 24, 2006). Two
separate labeling sections now generally required on
prescription-drug labeling are relevant here: the Warn-
ings and Precautions section and the Adverse Reactions
section. See 21 C.F.R. 201.57(c)(6) and (7).'

' The specific requirements for labeling content and format dis-

cussed in the text generally apply to prescription drugs subject to a
new drug application (NDA) or efficacy supplement approved on or
after June 30, 2001. 21 C.F.R. 201.56(b)(1). The specific labeling
requirements for older drug products differ in certain respects. See
21 C.F.R. 201.56(e), 201.80.

This case involves the labeling of three FDA-approved Fosamax
products: Fosamax tablets (NDA 20560, approved 1995); Fosamax
oral solution (NDA 21575, approved 2003); and Fosamax Plus D tab-
lets (NDA 21762; approved 2005). See J.A. 510-511; see also FDA,

Drug Products with Therapeutic Equivalence Evalua-
tions 3-12, 6-14 (38th ed. 2018) (listing Fosamax products). Al-
though the newer labeling requirements discussed in this brief did
not apply to all of those products at the time relevant here, no party
has suggested that the differences between the two sets of labeling
requirements are relevant to this case. The government agrees
This brief therefore follows the path taken by the court of appeals,

3

The Warnings and Precautions section must identify
“clinically significant adverse reactions” and certain
other safety hazards where “reasonable evidence of a
causal association” between the drug and such hazards
exists. 21 C.F.R. 201.57(c)(6); see 73 Fed. Reg. 49,603,
49,604 (Aug. 22, 2008) (stating that a “‘preponderance’
of evidence” is not required). FDA adopted that causal
standard in part to “prevent overwarning” of potential
risks, which, if included in the Warnings and Precau-
tions section, could dilute other “more important warn-
ings” or “deter appropriate use” of the drug. 73 Fed.
Reg. at 49,605-49,606. FDA thus reserves this section
for only a “discrete set” of hazards serious enough
to affect prescribing decisions. FDA, Guidance for
Industry: Warnings and Precautions, Contraindica-
tions, and Boxed Warning Sections of Labeling for Hu-
man Prescription Drug and Biological Products—
Content and Format 3 (Oct. 2011), https://www.fda.gov/
downloads/Drugs/GuidanceCompliance Regulatory
Information/Guidances/UCM075096.pdf.”

The Adverse Reactions section, by contrast, de-
scribes “the overall adverse reaction profile of the
drug.” 21 C.F.R. 201.57(c)(7). The causal threshold for
including an adverse reaction in this section is lower
than that for the Warnings and Precautions section: An
adverse reaction must be listed if “some basis” exists

which based its decision on the newer labeling requirements in Sec-
tion 201.57(c) without discussing Section 201.80. See Pet. App. 7a-9a
& nn.6, 9-10, 16, 51a n.130, 68a-64a nn.154, 156.

* The 2011 guidance describes FDA’s interpretation of its 2006 la-
beling regulations. FDA has informed this Office that the 2011 guid-
ance accurately reflects how FDA treated the Warnings and Pre-
cautions section during the period relevant here.

4

“to believe there is a causal relationship between the
drug and the occurrence of the adverse event.” /bid.

b. A brand-name drug “manufacturer bears respon-
sibility for the content of its labelfing] at all times.”
Wyeth v. Levine, 555 U.S. 555, 570-571 (2009); see
21 U.S.C. 355(0)(4)(1). When new information becomes
available about a new risk or a new aspect of a known
risk that causes existing labeling to become inadequate,
the manufacturer is responsible for pursuing a revision
to its labeling. See 21 C.F.R. 201.57(c)(6)(i) (stating that
updated warning must be added “as soon as” sufficient
causal evidence of a clinically significant hazard exists);
21 C.F.R. 201.57(c)(7)(ii)(B) (requiring list of adverse
reactions identified in postmarketing experience); cf.
21 C.F.R. 201.56(a)(2) (requiring updated labeling “when
new information becomes available that causes the la-
beling to become inaccurate, false, or misleading”).’

i. After FDA has approved a new drug application
(N DA) for a drug, 21 U.S.C. 355(b)(1) and (d), two mech-
anisms exist for changing a brand-name prescription
drug’s labeling, both of which require that the manufac-
turer file a supplemental NDA for FDA approval. First,
the sponsor may submit a Changes Being Effected
(CBE) supplement for certain labeling changes, which
allows the manufacturer immediately to implement its
proposed labeling changes upon FDA’s receipt of the
supplement. 21 C.F.R. 314.70(c)(6) and (iii); see Wyeth,
555 U.S. at 571, 573. A CBE supplement may be sub-
mitted, for instance, to add or strengthen a warning,

* Becaus. a generic drug’s labeling generally must track that of
its reference listed drug, generic-drug manufacturers cannot inde-
pendently change such labeling. See, eg., Mutual Pharm. Co. v.
Bartlett, 570 U.S. 472, 486, 488 (2013); PLIVA, Inc. v. Mensing,
564 U.S. 604, 613-615, 618 (2011).

5

precaution, or adverse reaction to reflect “newly ac-
quired information” if “the evidence of a causal associa-
tion satisfies the [relevant] standard for inclusion in the
labeling.” 21 C.F.R. 314.70(ce)(6)(iii A); see 21 C.F.R.
314.3(b) (defining “[njewly acquired information”). If
FDA later disapproves the supplement, however, it may
order the manufacturer to cease distributing the drug
with the labeling changes. 21 C.F.R. 314.70(c)(7).

Second, the sponsor may submit a Prior Approval
Supplement (PAS) to propose labeling changes. 21 C.F.R.
314.70(b) and (2)(v). Under that procedure, FDA ap-
proval is required before the changes are made. 21 C.F .R.
314.70(b)(3). A PAS “must be submitted” for certain
types of changes that “include, but are not limited to,”
certain labeling changes other than those described in
Section 314.70(c)(6)(iii) for CBE supplements. 21 C.F .R.
314.70(b)(1), (2), and (v)(A). Historically, FDA has also
accepted PAS applications instead of CBE supple-
ments, as occurred in this case, particularly where sig-
nificant questions exist on whether to revise or how to
modify existing drug labeling.‘

ii. “All procedures and actions that apply to an ap-
plication” submitted to FDA generally apply “to supple-
ments.” 21 C.F.R. 314.71(b) and (c). FDA has accord-
ingly confirmed to this Office that it follows many of the

general principles applicable to its review of an NDA
when undertaking the more limited task of reviewing sup-
plements that propose safety-related labeling changes.
More specifically, FDA communicates with the appli-
cant about “scientific, medical, and procedural issues that

* Cf. FDA, Guidance for Industry: Safety Labeling Changes—
Implementation of Section 505(0)(4) of the FD&C Act 7 (July 2013),
https://www.fda.gov/downloads/Drugs/GuidanceCompliance
Regulatory Information/Guidances/UCM250783. pdf.

6

arise” in the course of its review. 21 C.F.R. 314.102(a).
The “{djevelopment of final labeling” generally is then

“an iterative process between the applicant and FDA”
involving a series of communications.’ If FDA reviewers
identify “easily correctable deficiencies” in a supplement,
they will “make every reasonable effort to communicate
[them] promptly to applicants.” 21 C.F.R. 314.102(b).
And if only “editorial or similar minor deficiencies in the
| proposed] labeling” exist, FDA may approve the sup-
plement on the condition that the applicant makes ap-
propriate corrections and submits a copy of the final la-
beling before marketing the drug with that labeling.
21 C.F.R. 314.105(b).

FDA will reject a supplement, however, if the pro-
posed labeling change is false or misleading or if it does
“not comply with the requirements for labels and label-
ing in {21 C.F.R. PJart 201.” 21 C.F.R. 314.125(b)(6) and
(8). In such circumstances, FDA will send the applicant
a “complete response letter.” 21 C.F.R. 314.110(a). A
complete response letter reflects FDA’s “complete re.
view of the data submitted” and “will describe all of the
specific deficiencies that the agency has identified.”
21 C.F.R. 314.110(a)(1) and (2).

2. a. Petitioner is the manufacturer of Fosamax, a
brand-name drug that FDA approved in tablet form in

* See Center for Drug Evaluation & Research, FDA, CDER 21st
Century Review Process: Desk Reference Guide 37 (2014), https-//
www.fda gov/downloads/AboutF D A/Centers Offices/CD E R/Manua!
of Policies Procedures/UCM218757.pdf, see also FDA, Guidance for
Review Staff and Industry: Good Review Management Principles
and Practices for PDUF A Products 21 (Apr. 2005), https-//www.fda.
gov/downloads/drugs/guidancecomplianceregulatory information/
guidances/ucm0797 48. pdf (addressing “communication between the
FDA and applicants” during “labeling discussions”).

7

1995 for the treatment of osteoporosis in postmenopau-
sal women. Pet. App. 5a, 12a; see p. 2 n.1, supra. Evi-
dence later began to emerge suggesting a connection
between Fosamax and an increased risk of an unusual
type of thigh-bone fracture known as an “atypical fem-
oral fracture[],” which occurs with no or minimal exter-
nal trauma and results in a complete fracture of the fe-
mur. Pet. App. 6a, 13a-14a. Petitioner kept FDA in-
formed of those studies. /d. at 13a.

In June 2008, FDA informed petitioner that it was

aware of reports regarding the occurrence of atypical!
femoral fractures in patients using bisphosphonates
like Fosamax. C.A. App. A1935-A1936. FDA stated
that it was “concerned about this developing safety sig-
nal” and asked petitioner to submit any information it
had on the issue. /bid. Petitioner promptly complied.
Pet. App. 14a.

b. In September 2008, petitioner submitted three
Prior Approval Supplements for its three Fosamax
products that proposed changing the relevant labeling
to address atypical femoral fractures in two respects.
Pet. App. 14a-15a; see p. 2 n.1, supra.®

First, in the Adverse Reactions section (J.A. 715-
729), petitioner proposed adding a reference to “low-
energy femoral shaft fracture.” J.A. 728; see Pet. App.
16a. Petitioner also proposed including a parenthetical
cross-reference to direct readers to a discussion of
“Low-Energy Femoral Shaft Fracture” proposed for
the Warnings and Precautions section. J.A. 728 (“(see

* Relevant portions of one of the PAS applications are available at
J.A. 669-761; see C.A. App. A2697-A2928 (reproducing additional
portions). FDA has confirmed to this Office that petitioner pro-
posed the same relevant labeling language for each of its three

Fosamax products.

8

PRECAUTIONS, Low-Energy Femoral! Shaft Frac-
ture)”) (emphasis omitted).

Second, in the Warnings and Precautions section
(J.A. 703-715), petitioner proposed adding a new
subsection with an identical title: “Low-Energy Femo-
ral Shaft Fracture.” J.A. 707 (emphasis omitted); see
Pet. App. 15a. That subsection stated that “[ljow-
energy fractures of the subtrochanteric and proximal
femoral shaft have been reported in a small number of
bisphosphonate-treated patients.” J.A. 707. The pro-
posed warning added that “[sjome” of those fractures
were “stress fractures (also known as insufficiency frac-
tures),” and the remainder of petitioner’s proposed text
repeatedly referenced stress fractures. /bid.'

Petitioner supported its applications with evidence
regarding femoral fractures in Fosamax users. Pet.
App. 16a; see, eg., J.A. 745-761; C.A. App. A2748-
A2928. The applications stated, as relevant, that peti-
tioner’s use of the term “stress fracture” in connection
with reports of “low-energy subtrochanteric/mid femo-
ral shaft fractures” referred to an “insufficiency frac-
ture” that occurs with no “identifiable external trau-
matic event.” J.A. 746, 748; see J.A. 748-749, 751. The
treatment data in the applications indicated that 91% of
the fractures resulted in surgical intervention and the
other 9% involved patients who sustained only “incom-
plete stress fractures.” J.A. 753.

" An “insufficiency f[racture!’—-which can be associated with
“osteoporosis”—is “a stress fracture that occurs during norma!
stress on a bone of abnormally decreased density”; it is thus differ-
ent from the type of “stress f[racture!” experienced by athletes (a
fatigue fracture) “caused by unusual or repeated stress on a bone.”
Dorland’s Illustrated Medical Dictionary 710-711 (29th ed. 2000).

9

In May 2009, FDA issued a Complete Response Let-
ter (J.A. 510-513) informing petitioner that FDA could
not “approve the[] applications in their present form.”
J.A. 511; see Pet. App. 18a. FDA stated that it “agree/d]
that atypical and subtrochanteric fractures should be
added” to the Adverse Reactions labeling section. J.A.
511. FDA therefore recommended that petitioner mod-
ify its proposed text (J.A. 728) for that section to read
“low energy femoral shaft and subtrochanteric frac-
tures.” J.A. 512. With respect to petitioner’s Warnings
and Precautions proposal, however, FDA determined
that the “justification for the proposed [Warnings and
Precautions] section language is inadequate.” J.A. 511.
The letter also stated that “[iJdentification of ‘stress
fractures’ may not be clearly related to the atypical sub-
trochanteric fractures that have been reported in the
literature” and that “[d]iscussion of the risk factors
for stress fractures is not warranted and is not ade-
quately supported by the available literature and post-
marketing adverse event reporting.” J.A. 511-512.

In June 2009, petitioner updated the Adverse Reac-
tions section of its Fosamax labeling (J.A. 253, 267-274)
using FDA’s recommended text. J.A. 274; see J.A. 279.
Petitioner then withdrew its three pending PASs, J.A.
654-655, and submitted new CBE supplements for that
labeling change as the “quickest route to upd. e” its la-
beling, J.A. 657-658. FDA later approved these CBE
supplements.*

* See FDA, Supplement Approval 1-2 (Mar. 1, 2010), https://www.
accessdata fda gov/drugsatfda docs/appletter/2010/020560805 1805
58057 ,021575801280168018ltr.pdf (NDA 20560/S-057 and 21575/
S-018); FDA, Supplement Approval 1-2 (Mar. 1, 2010), https://www.
accessdata. fda. gov/drugsatfda docs/appletter/2010/02 17628005800
98S010itr.pdf (NDA 21762/S-010).

10

c. Nearly a year after its Complete Response Let-
ter, and after reviewing additional data submitted by
petitioner and other manufacturers, FDA issued a
Safety Announcement in March 2010 (J.A. 519-522)
stating that “FDA’s review of these data did not show
an increase in [a] risk [of atypical subtrochanteric fe-
mur fractures] in women using [bisphosphonates],” but
that FDA was working with an outside expert task force
to “gather additional information.” J.A. 519-520 (stat-
ing that the data “hajd] not shown a clear connection
between bisphosphonate use and [that] risk”); see Pet.
App. 19a.

On September 14, 2010, the task force completed its
report, which identified an apparent association be-
tween long-term bisphosphonate use and certain atypi-
cal femoral fractures. Pet. App. 20a; see J.A. 523.

d. On October 13, 2010, after studying the report,
FDA exercised its authority under 21 U.S.C. 355(0)(4)
to initiate safety-based changes to Fosamax’s labeling.
See J.A. 526-527, 546 (FDA letter dated Oct. 13, 2010).
Under Section 355(0)(4), the Secretary of Health and
Human Services, acting through FDA, “shall promptly
notify” a brand-name drug manufacturer as the “re-
sponsible person” for a drug “(i]f the Secretary becomes
aware of new safety information that the Secretary be-
lieves should be included in the labeling of the drug.”
21 U.S.C. 355(0)(4)(A); see 21 U.S.C. 355(0)(2)(A)(ii)
(defining “responsible person”). Within 30 days, the
manufacturer then must either submit a supplemental
application to change the labeling or notify the Secre-
tary that (and explain why) it believes that no change is
warranted. 21 U.S.C. 355(0)(4)(B). The Secretary must
“promptly review and act upon such supplement” and,

11

if the Secretary disagrees with the manufacturer’s la-
beling proposal or disagrees with the manufacturer's
view that no changes are warranted, the Secretary “shal!
initiate discussions” to reach agreement within 30 days
regarding a labeling change. 21 U.S.C. 355(0)(4)(C) and
(D). The Secretary may thereafter “issue an order di-
recting” the manufacturer “to make such a labeling
change as the Secretary deems appropriate to address
the new safety information.” 21 U.S.C. 355(0)(4)(E).

FDA announced its decision to the public by explain-
ing that it was requiring bisphosphonate manufacturers
to modify their labeling to include information regard-
ing the risk of such fractures in, among other places, the
Warnings and Precautions section. J.A. 246, 249. Ina
briefing to reporters, FDA’s Deputy Director for the
Office of New Drugs explained that the data that FDA
had previously reviewed was insufficient to allow the
agency to “tease out the association between [bisphos-
phonates] and these rare atypical fractures,” but that
the task force’s September 2010 report had helped FDA
“understand the[] fractures” better, “provide[d] more
information that more closely associate[d] the[] atypical
fractures with long-term bisphosphonate use,” and per-
suaded FDA that such fractures were “more closely re-
lated to these drugs * * * than[F'DA] previously had ev-
idence for.” J.A. 488-489, 493-494; see J.A. 486.

FDA’s October 2010 letter invoking Section 355(0)(4)
likewise notified petitioner that FDA “ha[d] become
aware of a possible increased risk of atypical subtro-
chanteric and diaphyseal femoral fractures in patients
taking bisphosphonates, including Fosamax,” and that
FDA now believed that new safety information about
that risk should be included in Fosamax’s labeling, in-

12

cluding changes to the Warnings and Precautions sec-
tion. J.A. 527, 528-529. In response, petitioner pro-
posed a labeling change that utilized the term “stress
fractures.” Pet. App. 22a. FDA thereafter struck those
references from petitioner’s proposal in the course
of approving the labeling change because, an FDA
employee explained, the term would suggest to most
practitioners “a minor fracture” that “would contradict
the seriousness of the atypical femoral fractures” at is-
sue. J.A. 566, 606-607; see Pet. App. 22a-23a; cf. J.A.
547, 549-628 (redline showing FDA edits to petitioner’s
proposed labeling).

3. Over 1000 plaintiffs subsequently filed separate
state-law tort actions against petitioner, alleging that
they had sustained atypical femoral fractures caused by
taking Fosamax. Pet. App. 4a, 23a. Although plaintiffs
asserted an array of tort theories, they generally al-
leged that petitioner had failed to provide adequate
warnings on its Fosamax labeling. /d. at 4a, 24a. The
cases were consolidated for pretrial proceedings as a
multidistrict litigation (MDL). Jd. at 23a.

One bellwether case within the MDL was selected
for trial on its failure-to-warn claim. Pet. App. 24a-25a
& n.64. Petitioner moved for summary judgment on
preemption grounds, but the district court did not im-
mediately rule on the motion. /d. at 163a. After a jury
rendered a verdict for petitioner on case-specific grounds,
the court rendered a post-trial decision holding that the
bellwether plaintiffs’ failure-to-warn claim was pre-
empted. /d. at 25a-26a, 153a-174a.

The district court subsequently extended that pre-
emption holding to the other MDL cases in which the
plaintiff was injured before September 14, 2010—the

13

date of the expert task force report—and granted judg-
ment to petitioner in those cases. Pet. App. 152a; see
id. at 113a-152a.

4. The court of appeals vacated and remanded. Pet.
App. la-74a.

The court of appeals concluded that its impossibility -
preemption analysis was controlled by this Court’s de-
cision in Wyeth v. Levine, supra, which the court viewed
as teaching that a drug-focused failure-to-warn claim is
preempted “where there is ‘clear evidence that the FDA
would not have approved a change’ to the label,” Pet.
App. 32a-33a (quoting Wyeth, 555 U.S. at 571). See id.
at 28a-55a. The court concluded that Wyeth’s “clear ev-
idence” discussion “announce|d] a standard of proof”
that is “synonymous with ‘clear and convincing evi-
dence’” and required proof showing it “is highly proba-
ble that the FDA would not have approved a change to
the drug’s label.” /d. at 35a, 37a; see id. at 33a-37a. The
court further concluded that the relevant preemption
determination—which involves “predicti{ing] how the
FDA would have reacted in a hypothetical scenario” in-
volving a new proposal to strengthen labeling warnings,
id. at 5la-52a—is a factual determination for a jury, not
a legal one for a court. /d. at 38a-55a.

Applying those principles, the court of appeals held
that summary judgment should not have been granted
to petitioner. Pet. App. 55a-74a. As relevant here, the
court determined that a “reasonable jury” could con-
clude that petitioner could have revised the Warnings
and Precautions section of its labeling before Septem-
ber 2010. /d. at 56a-57a, 67a. A jury, the court rea-
soned, could find that FDA’s 2009 decision to reject pe-
titioner’s proposed revision to that section was not
based on FDA’s determination that the evidence at the

14

time was insufficient to indicate that Fosamax caused
atypical femoral fractures, but rather was based on
FDA's dissatisfaction with the proposal’s use of the
term “stress fractures,” which medical practitioners
might misunderstand to refer to fractures less serious
than the femoral fractures in question, id. at 64a-66a.
See id. at 59a-68a.°

SUMMARY OF ARGUMENT

Petitioner provided FDA with the relevant scientific
data about Fosamax’s risks and, in May 2009, FDA re-
jected petitioner’s proposal to add a warning about
atypical femoral fractures in the Warnings and Precau-
tions section of Fosamax’s labeling. The court of ap-
peals erroneously rejected petitioner’s impossibility-
preemption defense to respondents’ state-law failure-
to-warn claims, based on its determination that preemp-
tion required petitioner to establish by “clear and con-
vincing” evidence that FDA would have denied a CBE
supplement, which the court deemed to be a factual
question for a jury to decide. The proper focus here is
on whether F DA’s May 2009 decision embodied a deter-
mination by FDA that insufficient causal evidence existed
to warrant strengthening the Warnings and Precau-
tions section of the Fosamax labeling to address atypi-
cal femoral fractures. That is a question of law for a
court to resolve, not a question of fact for a jury. More-
over, FDA’s 2009 decision, construed in light of the
governing regulatory regime, and FDA’s subsequent

* The court of appeals also concluded that the district court erred
in granting summary judgment on claims based on the Adverse
Reactions section of Fosamax’s labeling before its 2009 revision,
Pet. App. 69a-73a, and on non-failure-to-warn claims, id. at 74a.

15

actions show that petitioner could not have altered
F'osamax’s labeling until late 2010.

A. FDA’s May 2009 Complete Response Letter is a
legal document reflecting the agency’s exercise of legal
authority to adjudicate petitioner’s regulatory labeling
application. The meaning and effect of such agency
action is a legal question within the exclusive province
of a court. Indeed, courts have long been vested with
authority to interpret agency action as a question of law.
See, e.g., 5 U.S.C. 706. Judges, rather than lay juries,
are best suited to evaluate the scope of an agency’s de-
termination because judges are trained and experi-
enced in construing legal documents and are far better
equipped to understand agency decisions in light of the
governing statutory and regulatory context. Vesting
that legal construction in judges familiar with adminis-
trative law also fosters the type of interpretive uni-
formity appropriate when determining the scope and ef-
fect of federal agency action. That holds true even when
subsidiary factual questions are relevant to the court’s
legal determination of the meaning and effect of agency
action. Cf. Markman v. Westview Instruments, Inc.,
517 U.S. 370, 388-389 (1996).

B. The court of appeals concluded that Wyeth v.
Levine, 555 U.S. 555 (2009), required a clear-and-
convincing-evidence standard, Pet. App. 35a-37a, that a
jury must apply in this case, id. at 38a-55a. But Wyeth
addressed distinct circumstances and did not address
how to determine the meaning and effect of an actual
FDA labeling decision. The longstanding rule is that
judges, not courts, interpret such agency action as a
question of law. Nor does Wyeth’s passing reference to
“clear evidence” alter the preponderance-of-the-evidence

16

standard that applies in civil actions involving monetary
disputes between private litigants.

C. FDA’s May 2009 Complete Response Letter, the
relevant regulatory context, and the agency’r subse-
quent actions concerning Fosamax demonstrate that
FDA determined that existing information about atypical
femoral fractures was insufficient to warrant a change
to Fosamax’s Warnings and Precautions section. The
record amply demonstrates that petitioner could not
have updated its labeling until late 2010. Accordingly,
respondents’ corresponding state-law failure-to-warn
claims are preempted.

ARGUMENT

THE COURT OF APPEALS ERRED IN REJECTING
PETITIONER’S PREEMPTION DEFENSE

The court of appeals erred in holding that a jury
must determine whether FDA’s May 2009 decision—
which declined to approve petitioner’s proposal to re-
vise Fosamax’s Warnings and Precautions section to
warn against “[l]ow-energy fractures of the subtrochan-
teric and proximal femoral shaft,” J.A. 707—-preempted
respondents’ state-law failure-to-warn claims arising
from that same type of injury. Where, as here, FDA
renders a decision declining to approve a drug-labeling
change, the interpretation of that administrative deci-
sion and its significance for a failure-to-warn claim are le-
gal questions for a court to resolve, not factual ques-
tions for a jury. Moreover, because FDA’s action pre-
vented petitioner from modifying the relevant labeling
before late 2010, the court of appeals erred in rejecting
petitioner’s impossibility-preemption defense.

17

A. Petitioner’s Preemption Defense Turns On The Meaning
And Effect Of FDA’s 2009 Complete Response Letter,
Which Are Legal Questions That A Court Must Resolve

“The question for ‘impossibility’ [preemption] is
whether the private party could independently do under
federal law what state law requires of it.” PLIVA, Inc.
v. Mensing, 564 U.S. 604, (2011). A state-law failure-
to-warn claim that rests on the contention that a drug
manufacturer failed to provide adequate warnings on
drug labeling is therefore preempted if, under federal!
law, the manufacturer could not have “independently”
altered the labeling at the relevant time without FDA’s
“special permission and assistance.” /d. at 618-619, 623-
624 & n.8. As a general matter, a name-brand drug
“manufacturer may only change a drug label after the
FDA approves a supplemental application.” Wyeth v.
Levine, 555 U.S. 555, 568 (2009). When that is so, po-
tential failure-to-warn claims are preempted.

Some failure-to-warn claims, however, are not pre-
empted under the Court’s formulation in Mensing. A
manufacturer may in certain circumstances submit a
CBE supplement, which, upon its receipt by FDA, “per-
mits [the] manufacturer to make certain [safety-based |
changes to its labelling] before receiving the agency’s
approval.” Wyeth, 555 U.S. at 568 (emphasis added);
see pp. 4-5, supra (discussing CBE process). FDA may
thereafter disapprove the supplemental application and
order the manufacturer to cease distributing the drug
with such labeling changes. 21 C.F.R. 314.70(c)(7).
This Court has accordingly concluded that a brand-
name drug manufacturer will establish an impossibility-
preemption defense by sufficiently establishing that
FDA “would not have approved [the relevant] change to

18

{the drug’s] label{ing]” under its CBE regulation. Wyeth,
555 U.S. at 571; see Mensing, 564 U.S. at 624 n.8.

In this case, the court of appeals held that the rele-
vant judicial task in resolving petitioner’s preemption
defense “is to predict how the FDA would have reacted”
under the requirements of its “CBE regulation” “in a
hypothetical scenario” involving “a different label
amendment than the one it actually rejected in [its] May
2009 [Complete Response] letter.” Pet. App. 5la-52a.
That is incorrect. The threshold inquiry here is whether
F DA’s May 2009 decision embodied a determination by
FDA that insufficient causal evidence existed to warrant
strengthening Fosamax’s Warnings and Precautions
section to address atypical femoral fractures. If FDA’s
May 2009 decision did reflect such a determination, then
petitioner has established an impossibility-preemption
defense. And the meaning of FDA’s Complete Response
Letter is a question of law for a court to resolve, not a
question of fact for a jury.

I. Courts, not juries, determine the meaning of federal
agency decisions

A federal agency’s written decision on a regulatory
application is a legal document: an agency action that
embodies the agency’s exercise of legal authority to ad-
judicate the application. Cf. 5 U.S.C. 551(6) and (7) (de-
fining agency adjudication). The meaning and effect of
such agency action present legal questions within the
exclusive province of a court.

When Congress enacted the Administrative Proce-
dure Act (APA), 5 U.S.C. 551 et seq., 701 et seq., it spec-
ified that a “reviewing court shall * * * determine the
meaning or applicability of the terms of an agency ac-
tion.” 5 U.S.C. 706. That provision reflects the long-
standing view that “questions respecting the * * *

19

terms of any agency action” and the “application”
thereof are “questions of law” and therefore matters for
“courts * * * to decide.” H.R. Rep. No. 1980, 79th Cong..,
2d Sess. 44 (1946); see U.S. Dep’t of Justice, Attorney
General’s Manual on the Administrative Procedure
Act 108 (1947) (APA’s review provision “restates the
present law”).

The legal nature of that inquiry is consistent with
this Court’s precedent addressing the meaning and
effect of a prior judicial adjudication. When issues
adjudicated in prior litigation are relevant to factfinding
in a subsequent civil action, this Court has held that the
question of “[w|hat issues were decided [in that prior]
litigation is * * * a question of law” that the trial court
must itself decide by examining relevant materials from
the prior case. E’mich Motors Corp. v. General Motors
Corp., 340 U.S. 558, 571-572 (1951). That holds true
even where a jury must consider “the scope and effect
of the former judgment on the case at trial.” Jd. at 572;
see id. at 568. In such circumstances, the trial court
must first determine the prior adjudication’s scope and
effect before “instruct[ing] the jury” on its legal deter-
mination. /d. at 571. Just as the scope of a prior judicial!
adjudication is a question of law for a court to decide, so
too is the scope of a federal agency adjudication like the
one at issue here.

No sound reason exists for treating the meaning and
effect of an FDA administrative determination any dif-
ferently. Judges, rather than lay juries, are best suited
to evaluate the scope of an agency’s determination, both
because judges are trained and experienced in “(the
construction of written instruments,” Markman v.
Westview Instruments, Inc., 517 U.S. 370, 388 (1996), and
because judges are far better equipped to understand and

20

interpret agency decisions in light of the governing stat-
utory and regulatory context. Moreover, framing the
decision as a question of law to be decided by judges fa-
miliar with principles of administrative law will foster
the type of uniformity appropriate when determining
the scope and effect of federal agency action. See id. at
390-391; id. at 391 (concluding that uniformity would “be
ill served by submitting issues of document construction
to juries”). Whether the agency action is a notice-and-
comment regulation or something less formal like the
adjudicatory decision at issue here, the meaning of
agency action is a legal question that a court should de-
cide. See, e.g., Sprietsma v. Mercury Marine, 537 U.S.
51, 64-68 (2002); cf. Perez v. Mortgage Bankers Ass'n,
135 S. Ct. 1199, 1208 n.4 (2015) (“{I]t is the court that
ultimately decides wh{at] a given regulation means.”).

2. Factual findings necessary to interpret a federal
agency decision are also matters for courts to resolve

In some contexts, disputed factual questions can be
relevant to a court’s legal determination of the mean-
ing and effect of an agency decision. For example, if
FDA rejected a labeling supplement on the ground that
the information supporting it was insufficient to war-
rant a labeling change, the meaning and scope of that
decision can depend on what information FDA had be-
fore it. Yet in tort litigation between private parties
(which typically will lack compilation of an official ad-
ministrative record for an FDA decision), litigants may
dispute whether a drug manufacturer submitted all ma-
terial data to FDA. In addition, to the extent that an
agency decision read in the proper regulatory context is
insufficiently clear, a private litigant might seek to sub-
mit extrinsic material to provide further context for in-
terpreting the decision. Where consideration of such

21

material requires resolution of factual matters for a
court to determine the meaning and scope of the agency
decision, the court itself should resolve them.

This Court in Markman confronted analogous circum-
stances when it held that “the construction of a patent”
is a “purely legal” issue “exclusively within the province
of the court.” 517 U.S. at 372, 391. The Court reasoned
that “judges, not juries, are the better suited” for dis-
cerning the meaning of patent terms, even though fac-
tual questions involving “credibility determinations”
are sometimes “subsumed” within the relevant analysis.
Id. at 388-389. In other words, the “ultimate issue of
the proper construction of a [patent] claim [is] treated
as a question of law” for a court to decide, even though
“subsidiary factfinding is sometimes necessary.” Teva
Pharm. USA, Inc. v. Sandoz, Inc., 135 8S. Ct. 831, 838
(2015). The same rationale applies here. To the extent
extrinsic evidence may sometimes be relevant in litiga-
tion between private parties to determine the meaning
and effect of FDA’s agency action, the court’s evalua-
tion of such subsidiary facts does not alter the ultimate
legal character of the inquiry or the court’s exclusive
authority to resolve it.

B. The Court Of Appeals Erred In Holding That, Under
Wyeth v. Levine, A Jury Must Resolve Petitioner's
Preemption Defense As A Factual Matter Subject To A
Clear-And-Convincing-Evidence Standard

The court of appeals should have treated the inter-
pretation of FDA’s 2009 labeling decision as a legal
question for the courts to decide. As explained further
below, the basis for FDA’s 2009 Fosamax labeling deci-
sion is properly determined as a matter of law from
FDA’s Complete Response Letter, read in the context
of petitioner’s underlying labeling supplement and the

22

governing regulatory framework and related FDA ac-
tions. See pp. 30-34, infra.

The court of appeals, however, concluded that peti-
tioner’s preemption defense presented a question of
fact for a jury and this Court’s decision in Wyeth v. Lev-
ine, supra, required petitioner to provide “clear evi-
dence” from which a jury could find that FDA “would
{have} reject{ed] [the] plaintiff’s proposed warning” for
Fosamax if petitioner hac proposed that warning to
FDA. Pet. App. 33a, 54a. In addressing that “hypothet-
ical scenario,” the court of appeals determined that a
jury could reasonably conclude that “FDA rejected [peti-
tioner’s] proposed warning about femoral fractures in
2009 not because” FDA deemed the “causal link be-
tween Fosamax and fractures” to be insufficient, but be-
cause FDA was dissatisfied with petitioner’s proposed
text. Jd. at 51a, 64a-65a. There was nothing “hypothet-
ical” about FDA’s actual 2009 decision in this case,
and nothing in Wyeth addresses how courts should de-
termine the meaning and effect of such actual agency
action.

I. Wyeth did not address whether courts or juries
should construe an actual FDA decision

In Wyeth, this Court determined that a state-law
failure-to-warn claim involving a brand-name drug was
not foreclosed by the doctrine of impossibility preemp-
tion, because the drug manufacturer had a duty to en-
sure the adequacy of its own labeling and could have in-
voked FDA’s CBE regulation to update its labeling
promptly to provide additional warnings. 555 U.S. at
570-573. The Court recognized that “FDA retains au-
thority to reject [a manufacturer’s unilateral] labeling
changes made pursuant to the CBE regulation,” id. at
571, but it explained that Wyeth did “not argue” that

23

any actual FDA decision had “prohibited” it from
strengthening its labeling, id. at 572.

The Court instead viewed Wyeth as arguing that
FDA had “intended to prohibit it” from changing the la-
beling when FDA approved prior applications for the
relevant drug, a contention that the state trial and su-
preme courts had rejected. 555 U.S. at 572 & n.5. Thus,
without any relevant agency decision at hand, this
Court stated that it would not conclude that it was
impossible for Wyeth to comply with both federal and
state requirements “absent clear evidence that the
FDA would not have approved a change to [the] la-
bel{ing]” in question. /d. at 571 (emphasis added). In
other words, the Court reasoned that Wyeth needed to
make a clear showing that “FDA would have rescinded
any change in the label” that Wyeth made through the
CBE process in order to establish the impossibility of
such achange. Mensing, 564 U.S. at 624 n.8. The Court
concluded that Wyeth, which did “not argue” that it had
provided FDA with an analysis of the “specific dangers”
in question, had failed to show that “FDA would have
prevented it from adding a stronger warning.” Wyeth,
555 U.S. at 572-573.

Because Wyeth discussed the question whether FDA
would have rejected a CBE labeling change if the man-
ufacturer in that case had unilaterally made such a
change to strengthen its labeling, Wyeth did not resolve
how to determine the meaning and effect of an actual
FDA decision rejecting a proposed labeling change.
For that reason, the court of appeals erred in trans-
planting Wyeth’s discussion about the need for “clear
evidence” of what FDA “would have [done]” to this con-
text, which concerns the meaning and effect of what
FDA actually did. This Court has long cautioned that

24

it is “often misleading” to transplant “[|gjeneral expres-
sions” from one opinion “to other facts” because every
opinion must be “read in the light of the facts of the case
under discussion.” Armour & Co. v. Wantock, 323 U.S.
126, 133 (1944); see Landgraf v. USI Film Prods.,
511 U.S. 244, 266 (1994) (citing Cohens v. Virginia,
19 U.S. (6 Wheat.) 264, 399 (1821) (Marshall, C.J.)). Wy-
eth simply does not speak to the circumstances pre-
sented here.

2. Any factual findings necessary to resolve a preemption
defense need only rest on a preponderance of the
evidence

The court of appeals erroneously determined (Pet.
App. 35a-37a) that Wyeth requires “a factual showing”
of impossibility by “clear and convincing evidence” in
order to establish a preemption defense. To the extent
any factual disputes must be resolved to establish
preemption, the proper standard of proof is a prepon-
derance of the evidence.

a. The preponderance-of-the-evidence standard ap-
plies in “civil actions between private litigants unless
‘particularly important individual interests or rights are
at stake’” or a statute prescribes a different standard.
Grogan v. Garner, 498 U.S. 279, 286 (1991); see Mi-
crosoft Corp. v. i4i Ltd. P’ship, 564 U.S. 91, 100-103
(2011) (interpreting patent statute to require clear-and-
convincing evidence in certain contexts)."° Accordingly,

‘© The clear-and-convincing evidence standard applies when, for
instance, the government seeks to terminate an individual’s paren-
tal rights, Santosky v. Kramer, 455 U.S. 745, 769-770 (1982), or
seeks to deprive an individual of liberty in involuntary commitment
proceedings, Addington v. Texas, 441 U.S. 418, 433 (1979).

25

in a “typical civil case involving a monetary dispute be-
tween private parties,” the preponderance standard ap-
plies because private litigants should “share the risk of
error in roughly equal fashion.” Addington v. Texas,
441 U.S. 418, 423 (1979); see, e.g., Rivera v. Minnich,
483 U.S. 574, 576, 579 (1987) (action by mother to obtain
child-support payments by establishing paternity).

This is a typical private civil action for money dam-
ages, and nothing warrants a higher standard of proof
to resolve the preemption question here. The Court’s
preemption decisions do not suggest that a higher
evidentiary showing would generally be required where
resolution of factual issues is necessary to establish that
a state-law duty conflicts with federal law. Although the
Court has applied a presumption against implied con-
flict preemption, that presumption is a “rule of con-
struction [that] rests on an assumption about congres-
sional intent,” Arizona v. Inter Tribal Council of Ariz.,
Inc., 570 U.S. 1, 13 (2013) (emphasis added), not an evi-
dentiary principle governing the standard of proof. Cf.
Microsoft Corp., 564 U.S. at 103 (noting that the exist-
ence of a presumption alone does not “establish{| the
governing standard of proof”); Fed. R. Evid. 301 (evi-
dentiary presumptions shift the burden of production
unless a statute or rule provides otherwise).

b. The court of appeals based its “clear and convinc-
ing evidence” requirement on a single sentence in Wy-
eth, Pet. App. 35a & n.94, 37a, in which the Court stated
that it “w{ould] not conclude that it was impossible” for
Wyeth to strengthen a drug’s labeling under the CBE
process “absent clear evidence that the FDA would not
have approved a change to [the] label,” 555 U.S. at 571
(emphasis added). But Wyeth did not squarely address
or definitively resolve the relevant standard of proof

26

with the phrase “clear evidence.” Cf. Pet. App. 28a, 33a-
35a (characterizing Wyeth’s discussion as “cryptic”).
Wyeth provides no analysis or any citation to suggest
the Court believed it was imposing a higher burden of
proof with respect to factual issues, and Wyeth’s pass-
ing reference to “clear” evidence is not properly read to
require one.

This Court has used the term “clear evidence” in con-
texts in which the Court analyzes preemption issues as
a question of law, reflecting an interpretive presump-
tion against preemption. See, e.g., Geter v. American
Honda Motor Co., 529 U.S. 861, 885 (2000) (noting that
“a court should not find pre-emption too readily in the
absence of clear evidence of a conflict”); English v. Gen-
eral Elec. Co., 496 U.S. 72, 86 (1990) (“[Wle find no evi-
dence of a ‘clear and manifest’ intent on the part of Con-
gress to pre-empt tort claims like petitioner’s.”). The
Court has also held that its use of the even more specific
phrase “clear and convincing evidence” in another con-
text involving a question of law should not be under-
stood in its “strict evidentiary sense,” but merely as a
“useful reminder” that a general presumption concern-
ing a legal interpretation should control if substantial
doubt exists about “congressional intent.” Block v.
Community Nutrition Inst., 467 U.S. 340, 350-351
(1984). The Court in Wyeth appears to have similarly
used the phrase not as a shorthand for a formal clear-
and-convincing evidentiary standard, but merely to in-
dicate that a manufacturer asserting preemption must
show that a labeling change was not warranted under
the relevant statutory and regulatory framework. If
the Court had intended to depart from the preponder-
ance standard that applies to factual issues in almost all

27

civil actions between private litigants, it presumably
would have explained such an unusual departure.

3. Resolving this case does not require factual findings

a. As the case comes to this Court, the preemption
question is limited to a situation in which FDA consid-
ered the “relevant scientific data” in a prior labeling de-
cision, Pet. i. See Gov’t Cert. Amicus Br. 19 n.10; see
also Pet. Br. 35 (discussing Sup. Ct. R. 15.2). This case
is therefore properly resolved solely on the basis of a
legal interpretation of FDA’s 2009 labeling decision in
light of the governing regulatory regime and subse-
quent FDA action. Respondents argue (Br. in Opp. 26)
that, because petitioner relied below on an internal com-
pany document describing a telephone conversation with
an FDA employee about petitioner’s proposed labeling
change, see Pet. App. 17a; J.A. 764-767, a factfinder
should assess the reliability and weight of that evidence.
But assuming that it would be appropriate to rely on
such material in interpreting an agency decision, as ex-
plained above (pp. 20-21, supra), such a subsidiary fac-
tual question would be for courts to resolve in constru-
ing the meaning of FDA’s 2009 decision; and as ex-
plained below (pp. 30-34, infra), there is in any event no
need here for resort to such evidence because the mean-
ing of FDA’s 2009 decision is clear.

To be sure, an actual FDA labeling decision might
not in itself resolve preemption if, for instance, FDA did
not consider certain safety information in approving
name-brand drug labeling or in denying a labeling
change because the information was not provided to
FDA or because it arose after FDA’s decision. In such
a situation, a plaintiff could argue that information that
FDA did not consider constitutes “newly acquired infor-
mation,” 21 C.F.R. 314.3(b), 314.70(c)(6)(iii)( A), showing

28

that the drug caused a sufficiently serious hazard to
have allowed the manufacturer to update its labeling
under the CBE process. Cf. pp. 3-5, supra."' The
proper adjudication of such a contention would need to
account for the meaning and scope of any prior FDA la-
beling decision and the information that FDA previ-
ously evaluated in light of the governing statutory and
regulatory scheme (matters that the court must resolve,
see pp. 18-21, supra) in order to determine whether any
arguably new information is materially different from
the information that FDA previously determined to be
insufficient. This case, however, does not present that
question.

b. Respondents incorrectly analogize (Br. in Opp.
26; Supp. Cert. Br. 11) this case to Boyle v. United Tech-
nologies Corp., 487 U.S. 500 (1988). In Boyle, this Court
discussed the jury’s role in evaluating whether a mili-
tary contractor could raise a federal-common-law de-
fense to a state-law design-defect claim. /d. at 504, 507-
508, 514; see Buckman Co. v. Plaintiffs’ Legal Comm..,
531 U.S. 341, 347 (2001) (describing Boyle). That de-
fense required the contractor to make three factbound
showings: (1) the United States approved reasonably

'! Information—ineluding “new analyses of previously submitted
data”—will qualify as “[njewly acquired information” only if it “re-
veal|s]| risks of a different type or greater severity or frequency than
previously included in submissions to FDA.” 21 C.F.R. 314.3(b).
Accordingly, nominally “new” information concerning risks of a ma-
terially similar type, severity, and frequency as those revealed in
information previously evaluated by FDA is cumulative and not
“newly acquired information” that could justify a CBE supplement.
If for instance, FDA previously determined that that evidence of X
was insufficient to warrant a warning about risk Y, the existence of
additional but similar information about X would be insufficient to
justify a warning.

29

precise specifications; (2) the allegedly defective mili-
tary equipment conformed to those specifications; and
(3) the contractor warned the United States about the
dangers in the use of the equipment that were known to
the contractor but not to the United States. Boyle,
487 U.S. at 512. In that context, the Court concluded
that “whether the facts establish the conditions for the
defense is a question for the jury,” and it “would be er-
ror” for a reviewing court to itself determine that “the
defense had [not] been established” unless “no reason-
able jury” could have found that “that the Government
contractor defense was inapplicable.” /d. at 514.

Boyle, like Wyeth, did not involve the interpretation
of an actual federal agency decision. Boyle thus does
not address the key question here: whether the inter-
pretation of FDA’s 2009 decision is a legal inquiry for a
court. Nor did Boyle address whether a jury should re-
solve the ultimate matter of preemption when preemp-
tion turns on the application of a complex regulatory re-
gime implemented by an expert federal agency like
FDA. Cf. Riegel v. Medtronic, Inc., 552 U.S. 312, 325
(2008) (observing that a jury that “sees only the cost” of
an FDA-approved product in a lawsuit about a plain-
tiff’s injuries is unlikely to “apply cost-benefit analysis
similar to that applied by the experts at the FDA”).
Certainly, Boyle did not hold that the ultimate matter
of preemption must always rest with a jury when the
parties dispute what might be characterized as under-
lying factual issues. That question, which is not pre-
sented here, warrants further development in the lower
courts once this Court has clarified that the preemptive
effect of federal agency decisions involves legal ques-
tions for courts rather than juries.

30

C. FDA’s May 2009 Decision Rejected A Change To
Fosamax’s Warnings And Precautions Because The Data
At That Time Was Insufficient To Justify A Change

FDA’s May 2009 decision rejecting petitioner’s pro-
posal to modify Fosamax’s Warnings and Precautions
section to address atypical femoral fractures was based
on the agency’s determination that the information
about that risk was then insufficient to justify such a
warning. That conclusion flows directly from the terms
of the agency’s May 2009 Complete Response Letter,
the relevant regulatory context, and the agency’s sub-
sequent actions. Given FDA’s determination, respond-
ents’ claim that petitioner should have updated its
Warnings and Precautions labeling before late 2010 is
preempted.

FDA’s Complete Response Letter (J.A. 510-513)
shows that FDA determined that the existing data for
atypical femoral fractures was sufficient to update
Fosamax’s Adverse Reactions section, but not its Warn-
ings and Precautions section. FDA determined that
“atypical and subtrochanteric fractures should be
added” as adverse reactions, J.A. 511, reflecting that
FDA found “some basis to believe there |wa]s a causal
relationship between the drug and the occurrence of
th{at] adverse event.” 21 C.F.R. 201.57(c)(7).

Petitioner’s proposed addition to the Warnings and
Precautions section was based on the exact same risk.
Petitioner proposed a title (“Low-Energy Femoral
Shaft Fracture”) for its proposed subsection in Warn-
ings and Precautions, J.A. 707, that was identical (with
only differing capitalization) to its proposed text for the
Adverse Reactions section, J.A. 728. The proposed
warning for “{lJow-energy fractures of the subtrochan-
teric and proximal femoral shaft,” J.A. 707, likewise

31

addressed the same type of adverse reaction that FDA
concluded should be added to Fosamax’s labeling. See
J.A. 512 (FDA’s recommendation to add “low energy
femoral shaft and subtrochanteric fractures” to Ad-
verse Reaction section). And because both proposed la-
beling additions addressed the same risk, petitioner
proposed adding an explicit cross-reference in the label-
ing’s Adverse Reactions section (“[Sjee PRECAUTIONS,
Low-Energy Femoral Shaft Fracture,” J.A. 728) that
would have directed readers to the more fulsome de-
scription of the same hazard proposed for the Warnings
and Precaution section.

Under the governing regulations, however, such an
adverse reaction is to be elevated to the Warnings and
Precautions section only if “reasonable evidence of a
causal association with [the] drug” exists. 21 C.F.R.
201.57(c)(6)(i). Here, FDA rejected petitioner’s addi-
tion because the “justification for the proposed |Warn-
ings and Precautions] section language |wa]s inade-
quate.” J.A. 511 (emphasis added). Petitioner had also
proposed stating that “[slome” of the reported frac-
tures were “insufficiency” “stress fractures,” J.A. 707.
See p. 8 & n.7, supra. But FDA determined that such
fractures “may not be clearly related to the atypical
subtrochanteric fractures * * * reported in the litera-
ture,” and the associated discussion of stress-fracture
risk factors was likewise “not adequately supported by
the available literature and post-marketing adverse
event reporting.” J.A. 511-512 (emphases added).
F'DA’s decision thus was based on the lack of adequate
data to support a warning.

The court of appeals focused instead on the possibil-
ity that “FDA [might have] rejected [petitioner’s| pro-
posed warning” because of the warning’s use of the term

32

“stress fractures.” Pet. App. 64a-65a. But a Complete
Response Letter reflects “FDA’s complete review of
the data submitted”; and FDA’s regulations make clear
that the letter need not address any “proposed product
labeling” if FDA determines that the “data submitted
are inadequate.” 21 C.F.R.314.110(a)(2) and (3) (empha-
sis added). By contrast, if FDA determines that a
safe‘ y-based labeling change is warranted based on the
data, FDA will attempt promptly to identify easily cor-
rectable deficiencies in the proposed text and will develop
final labeling text with the manufacturer in an iterative
process. See pp. 5-6, supra. As a result, the May 2009
letter embodies FDA’s “recommend|ation]” that peti-
tioner modify its proposed Adverse Reactions text with
language (shown here in italics) that FDA itself pro-
posed: “low energy femoral shaft and subtrochanteric
fractures.” J.A. 512 (emphasis added); ef. J.A. 728 (pe-
titioner’s proposal). FDA made no similar suggestions
for revisions to petitioner’s proposed addition in the
Warnings and Precautions section because no warning
was justified based on the information at the time.
That understanding is reinforced by FDA’s subse-
quent actions in late 2010, when it concluded that the
Warnings and Precautions section should be revised.
FDA personnel directly edited petitioner’s proposed
language to remove stress-fracture references deemed
insufficiently clear. Pet. App. 22a-23a; see J.A. 547, 549-
628 (email with redline showing FDA edits to peti-
tioner’s proposed labeling); J.A. 606-607 (FDA edits to
proposed warning about atypical subtrochanteric and
diasphyseal femoral fractions). No sound basis thus ex-
ists for concluding that FDA determined in May 2009
that the data was sufficient to warrant a warning but

33

that it rejected petitioner’s proposal because of peti-
tioner’s proposed text. Cf. Dolin v. GlaroSmithKline
LLC, No. 17-3030, 2018 WL 4001208, at *9 (7th Cir. Aug.
22, 2018) (concluding that it would be “unreasonable” to
conclude that FDA rejected a proposed warning be-
cause the manufacturer had proposed adding it to the
wrong place in the labeling, rather than because FDA
had concluded that the warning was not warranted).

Significantly, FDA’s own regulations require that
the Warnings and Precautions section “must be re-
vised” to add sueh a clinically significant hazard “as
soon as” sufficient causal evidence exists. 21 C.F.R.
201.57(¢)(6)(i) (emphasis added). And if FDA had
“believe[d]” in May 2009 that the “new safety infor-
mation” that petitioner had submitted “should [have]
be[en| included in [Fosamax’s] labeling,” Section
355(0)(4) would have required that FDA “promptly no
tify” petitioner, 21 U.S.C. 355(0)(4)(A), and engage in ex-
pedited discussions to revise the labeling, 21 U.S.C.
355(0)(4)(B)-(D). Given the statutory and regulatory
framework, it would not be reasonable to interpret
FDA’s 2009 decision as reflecting a determination that
a new warning was justified but that FDA rejected pe-
Litioner’s proposed warning because petitioner’s pro-
posed text was inadequate.

Indeed, nearly a year later, in March 2010, FDA
announced—after reviewing further information—that
it had yet to identify an “increase in [a] risk [of atypical!
subtrochanteric femur fractures] in women using [bis -
phosphonates|.” J.A. 520. It was only in October 2010—
after an external task force had completed its report on
the issue—that FDA came to “believe that the infor-
mation” about atypical femoral fractures should be
added to the Warnings and Precautions section and

34

therefore invoked Section 355(0)(4) to revise the label-
ing for Fosamax and other bisphosphonates. See J.A.
527-528; see also pp. 10-12, supra.

In short, FDA’s 2009 Complete Response Letter
rejecting petitioner's PAS proposal to update Fosa-
max’s Warnings and Precautions section, when read in
the proper context of the governing statutory and reg-
ulatory regime—as well as FDA’s subsequent regula-
tory actions regarding Fosamax—demonstrate that, in
F DA’s judgment, an update to Fosamax’s Warnings and
Precautions section to discuss atypical femoral frac-
tures would not have been called for before late 2010.
Accordingly, it would have been impossible under fed-
eral law for petitioner to provide such a warning at an
earlier time. Any state-law failure-to-warn claim pred-
ieated on a state-law duty to provide such a warning is
therefore preempted.

35

CONCLUSION

The judgment of the court of appeals should be
reversed and the case remanded for further proceedings.

Respectfully submitted.

. —— nS JEFFREY B. WALL
Deputy General JosEPH H. HUNT
ELIZABETH H. DICKINSON nee e. omenam
Associate General
5 Deputy Solicitor General
ANTHONY A. YANG
ANNAMARIE KEMPIC
Assistant to the Solicitor
Deputy Chief Counsel, Guana
Scort R. McInTOsH
a JOSHUA M. SALZMAN
of Health and Attorneys
uman Services
SEPTEMBER 2018

* Solicitor General Noel J. Francisco is recused from this matter.
“ General Counsel Robert P. Charrow is recused from this matter.

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Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/brief%3Amicro_IA40385016_0777%3A15. Public record. Not legal advice.