Third Circuit disposition — 22-3412

PRECEDENTIAL
UNITED STATES COURT OF APPEALS
FOR THE THIRD CIRCUIT
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No. 22-3412
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In re: FOSAMAX (ALENDRONATE SODIUM)
PRODUCTS LIABILITY LITIGATION
Phyllis Molnar and all other plaintiffs listed in Exhibit A to
notice of appeal,
Appellants
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On Appeal from the United States District Court
For the District of New Jersey
(D.C. No. 3-08-cv-00008)
District Judge: Honorable Freda L. Wolfson (Ret.)
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Argued
March 5, 2024
Before: JORDAN, PHIPPS, and FREEMAN, Circuit Judges
(Filed: September 20, 2024)
_______________

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David C. Frederick [ARGUED]
Ariela Migdal
James Ruck
Kellogg Hansen Todd Figel & Frederick
1615 M Street NW
Sumner Square, Suite 400
Washington, DC 20036
Mark Sparks
Ferguson Law Firm
3155 Executive Boulevard
Beaumont, TX 77705
Counsel for Appellants
John R. Boule III
Jeffrey R. Johnson
Jacob M. Roth [ARGUED]
Jones Day
51 Louisiana Avenue NW
Washington, DC 20001
Karen A. Confoy
Fox Rothschild
997 Lenox Drive
Princeton Pike Corporate Center, Building 3
Lawrenceville, NJ 08648
Stephen E. Marshall
Venable
750 E Pratt Street – Suite 900
Baltimore, MD 21202

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Eileen O. Muskett
Fox Rothschild
1301 Atlantic Avenue
Suite 400, Midtown Building
Atlantic City, NJ 08401
Counsel for Appellee Merck Sharp & Dohme Corp
William B. Schultz
Zuckerman Spaeder
1800 M Street NW – Suite 1000
Washington, DC 20036
Counsel for Amicus Appellants Medshadow
Foundation, Joshua M. Sharfstein, MD,
Mary K. Pendergast, JD, and Jeremy Sharp
Robert S. Peck
Center for Constitutional Litigation
1901 Connecticut Avenue NW – Suite 1101
Washington, DC 20009
Counsel for Amicus Appellant Gregory Curfman, MD
Andrew N. Ferguson
Kevin M. Gallagher
Office of Attorney General of Virginia
202 N 9th Street
Richmond, VA 23219
Counsel for Amicus Appellants Commonwealth of
Virginia, State of Alaska, State of Colorado, State of
Connecticut, State of Delaware, State of Georgia, State
of Illinois, State of Indiana, Commonwealth of
Kentucky, State of Maryland, Commonwealth of
Massachusetts, State of Minnesota, State of Mississippi,
State of Montana, State of Nebraska, State of New

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Jersey, State of New Mexico, Commonwealth of
Pennsylvania, State of South Carolina, State of Texas,
State of Utah, and State of Vermont
Karen B. Menzies
KBM Law
6701 Center Drive W – Suite 1400
Los Angeles, CA 90045
Counsel for Amicus Appellants Joseph Lane, M.D.,
Vincent Vigorita, M.D., and David Burr, Ph.D.
Elizabeth J. Cabraser
Lieff Cabraser Heimann & Bernstein
275 Battery Street – 29 th Floor
San Francisco, CA 94619
Avery S. Halfon
Lieff Cabraser Heimann & Bernstein
250 Hudson Street – 8 th Floor
New York, NY 10013
Andrew R. Kaufman
Lieff Cabraser Heimann & Bernstein
222 Second Avenue South
Nashville, TN 37219
Ernest A. Young
3208 Fox Terrace Drive
Apex, NC 27502
Counsel for Amicus Appellant Public Law Scholars
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OPINION OF THE COURT

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JORDAN, Circuit Judge.
Drug manufacturers have the primary responsibility to
ensure that the labels on their products comply with federal and
state law. In this case, hundreds of Plaintiffs accuse drug
manufacturer Merck Sharp & Dohme (“Merck” or the
“Company”) of failing to comply with drug labeling
requirements under state law. According to the Plaintiffs, they
were injured by the drug Fosamax and would not have taken it
had they been properly warned. The District Court concluded
at the summary judgment stage that the Plaintiffs’ state law
claims are preempted because Merck in fact proposed a label
change that would have addressed the risk with Fosamax that
the Plaintiffs complain of, but the Food and Drug
Administration (the “FDA” or the “Agency”) rejected the
proposed change as lacking sufficient scientific support.
With real respect for the thorough and thoughtful work
the District Court did in this complex case, we nonetheless
conclude that it erred in its pre-emption analysis by giving too
little weight to the required presumption against pre-emption.
Applying that presumption, and considering the record here,
we conclude that Plaintiffs’ state law claims are not preempted.
Accordingly, we will vacate the District Court’s judgment for
Merck and remand for further proceedings.

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I. BACKGROUND
A. Statutory and Regulatory Background
1. Federal and State Power in Prescription
Drug Labeling
“Throughout our [nation’s] history the several States
have exercised their police powers to protect the health and
safety of their citizens” and “traditionally have had great
latitude … to legislate as to” those matters. Medtronic, Inc. v.
Lohr, 518 U.S. 470, 475 (1996). “In the 1930’s, Congress
became increasingly concerned about unsafe drugs and
fraudulent marketing, and it enacted the Federal Food, Drug,
and Cosmetic Act (FDCA).” Wyeth v. Levine, 555 U.S. 555,
566 (2009) (citation omitted). Through the FDCA, Congress
“charged the Food and Drug Administration with ensuring that
prescription drugs are ‘safe for use under the conditions
prescribed, recommended, or suggested’ in the drug’s
‘labeling.’” Merck Sharp & Dohme Corp. v. Albrecht, 587
U.S. 299, 302 (2019) (quoting 21 U.S.C. § 355(d)).1
Accordingly, the FDA “regulates the safety information that
1 Unless otherwise noted, all section references in this
opinion are to the FDCA, ch. 675, 52 Stat. 1040 (1938)
(codified as amended at 21 U.S.C. §§ 301, et seq.), and its
corresponding regulations (codified at 21 C.F.R. §§ 1.1, et
seq.).

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appears on the labels of prescription drugs that are marketed in
the United States.”2 Id. at 303.
“The FDCA’s most substantial innovation was its
provision for premarket approval of new drugs[, which]
required every manufacturer to submit a new drug application
… to the FDA for review.” Wyeth, 555 U.S. at 566. The statute
originally prohibited a manufacturer from distributing a drug
only if the FDA “determined that the drug was not safe for use
as labeled[.]”3 Id. But, “[i]n 1962, Congress amended the
FDCA and shifted the burden of proof from the FDA to the
manufacturer” by requiring “the manufacturer to demonstrate
that its drug was safe for use under the conditions prescribed,
2 The Supreme Court noted:
Although we commonly understand a drug’s
“label” to refer to the sticker affixed to a
prescription bottle, in this context the term refers
more broadly to the written material that is sent
to the physician who prescribes the drug and the
written material that comes with the prescription
bottle when the drug is handed to the patient at
the pharmacy. These (often lengthy) package
inserts contain detailed information about the
drug’s medical uses and health risks.
Merck Sharp & Dohme Corp. v. Albrecht, 587 U.S. 299, 303-
04 (2019) (citation omitted).
3 The manufacturer was permitted to distribute the drug
if the FDA failed to respond within 60 days from the
application’s filing. Wyeth v. Levine, 555 U.S. 555, 566
(2009).

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recommended, or suggested in the proposed labeling before it
could distribute the drug.” Id. at 567 (internal quotation marks
omitted).
Over time, as Congress “enlarged the FDA’s powers to
protect the public health and assure the safety, effectiveness,
and reliability of drugs,” it also “took care to preserve state
law.” Id. (internal quotation marks and citation omitted). “The
1962 amendments [to the FDCA] added a saving clause,
indicating that a provision of state law would only be
invalidated upon a direct and positive conflict with the FDCA.”
Id. (internal quotation marks omitted). “Consistent with that
provision, state common-law suits continued unabated despite
FDA regulation.” Id. (cleaned up) (internal quotation marks
omitted). Furthermore, “when Congress enacted an express
pre-emption provision for medical devices in 1976, it declined
to enact such a provision for prescription drugs.” Id. (citation
omitted) (citing § 360k(a)).
2. Federal Drug Labeling Regulations
“FDA regulations set out requirements for the content,
the format, and the order of the safety information on … drug
label[s].” Albrecht, 587 U.S. at 304 (citing § 201.57(c)).
Labels must include various types of information, organized in
a specific manner, by sections. § 201.57(a). Two sections of
a label are relevant to this litigation: the “Warnings and
Precautions” section, discussed in § 201.57(c)(6), and the
“Adverse Reactions” section, covered by § 201.57(c)(7). The
section “in which a particular risk appears on a drug label is an
indicator of the likelihood and severity of the risk.” Albrecht,
587 U.S. at 304. In the Warnings and Precautions section, a
drug manufacturer “must describe clinically significant

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adverse reactions[,] including any that are potentially fatal, are
serious even if infrequent, or can be prevented or mitigated
through appropriate use of the drug[.]” § 201.57(c)(6)(i). That
section “must be revised to include a warning about a clinically
significant hazard as soon as there is reasonable evidence of a
causal association with a drug[.]” Id. (emphasis added). “[A]
causal relationship need not have been definitely established”
before making such a revision. Id.
In the Adverse Reactions section of a label, the drug
manufacturer must “describe the overall adverse reaction
profile of the drug[,]” with “adverse reaction” being defined as
“an undesirable effect, reasonably associated with use of a
drug, that may occur as part of the pharmacological action of
the drug or may be unpredictable in its occurrence.”
§ 201.57(c)(7). “[That] definition does not include all adverse
events observed during use of a drug, only those adverse events
for which there is some basis to believe there is a causal
relationship between the drug and the occurrence of the
adverse event.” Id. (emphasis added).
To summarize, risks described in the Warnings and
Precautions section of a label (i.e., risks of clinically significant
adverse reactions) are presumably more serious than those that
appear only in the Adverse Reactions section. And, while the
Warnings and Precautions section requires “reasonable
evidence of a causal association with a drug” before a risk will
be listed, § 201.57(c)(6)(i), drug manufacturers need only have
“some basis to believe there is a causal relationship between
[a] drug and the occurrence of [an] adverse event” to list the
event in the Adverse Reactions section, § 201.57(c)(7). That
“hierarchy of label information is designed to ‘prevent
overwarning’ so that less important information does not

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‘overshadow’ more important information[,]” Albrecht, 587
U.S. at 304 (quoting 73 Fed. Reg. 49603, 49605-06 (Aug. 22,
2008)), and the order represents an effort to avoid
‘“exaggeration of risk, or inclusion of speculative or
hypothetical risks,’ that ‘could discourage appropriate use of a
beneficial drug,’” id. (cleaned up) (quoting 73 Fed. Reg. 2848,
2851 (Jan. 16, 2008)).
3. Responsibilities of the Drug
Manufacturer and the FDA in the
Labeling Approval Process
“Prospective drug manufacturers work with the FDA to
develop an appropriate label when they apply for FDA
approval of a new drug.” Id. “[T]hrough many amendments
to the FDCA and to FDA regulations” (see supra Section
I.A.1.), “it has remained a central premise of federal drug
regulation that the manufacturer bears responsibility for the
content of its label at all times.” Albrecht, 587 U.S. at 312.
Thus, “[a] drug manufacturer ‘is charged both with crafting an
adequate label and with ensuring that its warnings remain
adequate as long as the drug is on the market.’” Id. (quoting
Wyeth, 555 U.S. at 571). “FDA regulations … acknowledge
that information about drug safety may change over time, and
that new information may require changes to the drug label.”
Id. at 304 (citing §§ 314.80(c), 314.81(b)(2)(i)).
In 2007, Congress granted to the FDA, “[f]or the first
time,” the “authority to require a manufacturer to change its
drug label based on safety information that becomes available
after a drug’s initial approval.” Wyeth, 555 U.S. at 567 (citing
§ 901(a)). “In doing so, however, Congress did not enact a
provision … that would have required the FDA to preapprove

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all changes to drug labels.” Id. at 567-68 (citing S. 1082, 110th
Cong. § 208 (2007) as passed). “Instead, it adopted a rule of
construction to make it clear that manufacturers remain
responsible for updating their labels.” Id. at 568; see
§ 355(o)(4)(I) (“This paragraph shall not be construed to affect
the responsibility of the [drug manufacturer] … to maintain its
label in accordance with existing requirements[.]”).
That does not mean, however, that manufacturers are
free to make labeling changes without notifying the FDA. To
change a drug’s label, the manufacturer has to file a
supplement to its new drug application. For “major changes,”
a manufacturer must submit a “Prior Approval Supplement,”
which requires FDA approval before the manufacturer can
implement the proposed change. § 314.70(b). In contrast, for
“moderate changes,” the manufacturer files a “Changes Being
Effected” (“CBE”) supplement, which allows the manufacturer
to make a labeling change without prior FDA approval.
§ 314.70(c). But the “FDA reviews all such submissions and
may later deny approval of [a CBE] supplement[.]” 71 Fed.
Reg. 3922, 3934 (Jan. 24, 2006). “Thus, in practice,
manufacturers typically consult with [the] FDA prior to adding
risk information to labeling.” Id. A change to a drug’s label
may be considered a major change, § 314.70(b)(2)(v)(A), but
a change in labeling “to reflect newly acquired information” in
order to, among other things, “add or strengthen a
contraindication, warning, precaution, or adverse reaction for
which the evidence of a causal association satisfies the
standard for inclusion in the labeling” is, by regulation,
classified as a moderate change, § 314.70(c)(6)(iii).

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“During the course of reviewing an application [4] …,
[the] FDA … communicate[s] with applicants about scientific,
medical, and procedural issues that arise during the review
process.” § 314.102(a). That “communication may take the
form of telephone conversations, letters, or meetings,
whichever is most appropriate to discuss the particular issue at
hand.” Id. The Agency is required to “make every reasonable
effort to communicate promptly to applicants easily
correctable deficiencies found in … application[s]” to “permit
applicants to correct such readily identified deficiencies
relatively early in the review process and to submit an
amendment before the review period has elapsed.”
§ 314.102(b).
If there are no reasons to deny the application, the FDA
will send the applicant an approval letter. § 314.105(a). “[I]f
the only deficiencies in the [application] concern editorial or
similar minor deficiencies in the draft labeling,” the “FDA will
approve” the application, “conditioned upon the applicant
incorporating the [FDA’s] specified labeling changes.”
§ 314.105(b).
4 The FDCA regulations often refer to a “new drug
application,” but that term is defined to “includ[e] all
amendments and supplements to the [initial] application.”
§ 314.3(b); see also § 314.71(c) (“All procedures and actions
that apply to applications under this part, including actions by
applicants and the [FDA], also apply to supplements except as
specified otherwise in this part.”). Thus, regulations using the
term “application” also apply to a drug manufacturer’s labeling
supplements.

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On the other hand, if the FDA “determines that [it] will
not approve” an application “in its present form,” it will send
the applicant something called a “complete response letter.”
§ 314.110(a). Such a letter “describe[s] all of the specific
deficiencies that the agency has identified in an application[,]”
§ 314.110(a)(1), and “reflects [the] FDA’s complete review of
the data submitted[,]” § 314.110(a)(2). Any “major scientific
issues will ordinarily be addressed” in a complete response
letter. § 314.102(b). Using a complete response letter, the
Agency may deny an application for many reasons, including
if “[t]he proposed labeling is false or misleading in any
particular.” § 314.125(b)(6). If the FDA “determines … that
the data submitted are inadequate to support approval, the
agency might issue a complete response letter without …
reviewing proposed product labeling.” § 314.110(a)(3).
“When possible, a complete response letter will
recommend actions that the applicant might take to place the
application … in condition for approval.” § 314.110(a)(4). A
complete response letter conveys “no implication as to the
ultimate approvability of the application.” 73 Fed. Reg. 39588,
39589 (July 10, 2008). After receiving such a letter, an
applicant has several options. It may resubmit the application
after “addressing all deficiencies identified in the complete
response letter[,]” withdraw the application without prejudice,
or request a hearing. § 314.110(b).
B. The Federal Pre-emption Doctrine in the
Drug Labeling Context
Federal law is, of course, “the supreme Law of the
Land.” U.S. Const. art. VI, cl. 2. “[I]t has long been settled
that state laws that conflict with federal law are without effect.”

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Mut. Pharm. Co. v. Bartlett, 570 U.S. 472, 479-80 (2013)
(internal quotation marks omitted). Here, Merck asserts that it
has been put in an impossible dilemma because it cannot
comply with both federal and state law labeling demands. The
main question in the case thus concerns federal pre-emption of
state law. As already mentioned, Merck makes the drug
“Fosamax,” which is prescribed to prevent and treat
osteoporosis in post-menopausal women. Albrecht, 587 U.S.
at 305. When evidence emerged that Fosamax might actually
cause bone fractures, especially of the femur, the need to warn
doctors and patients, and the simultaneous need to comply with
FDA regulations on label changes, created the cross-currents
that have caught Merck in this long-running litigation.
There are “two cornerstones of … pre-emption
jurisprudence.” Wyeth, 555 U.S. at 565. “First, the purpose of
Congress is the ultimate touchstone in every pre-emption
case.” Id. (internal quotation marks omitted). “Second, in all
pre-emption cases, and particularly in those in which Congress
has legislated in a field which the States have traditionally
occupied, we start with the assumption that the historic police
powers of the States were not to be superseded by the Federal
Act unless that was the clear and manifest purpose of
Congress.” Id. (cleaned up). The Plaintiffs here claim that
state law required Merck to add a warning about atypical
femoral fractures to the Precautions section of the Fosamax
label. At issue is whether federal law, specifically FDA
regulations, prevented Merck from adding such a warning.
The Supreme Court’s decision in Wyeth v. Levine sets
forth the general federal pre-emption doctrine regarding brand-
name drug labeling. 555 U.S. 555 (2009). In Wyeth, “the
plaintiff developed gangrene after a physician’s assistant

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injected her with Phenergan, an antinausea drug.” Albrecht,
587 U.S. at 310. “The plaintiff brought a state-law failure-to-
warn claim against Wyeth, the drug’s manufacturer, for failing
to provide an adequate warning about the risks that accompany
various methods of administering the drug.” Id. at 310-11. “A
jury concluded that Wyeth’s warning label was inadequate, and
that the label’s inadequacy caused the plaintiff’s injury.” Id. at
311. “On appeal, Wyeth argued that the plaintiff’s state-law
failure-to-warn claims were pre-empted because it was
impossible for Wyeth to comply with both state law duties and
federal labeling obligations.” Id. In short, as Merck does here,
Wyeth advanced what is called an “impossibility pre-emption”
defense. The question in Wyeth was “whether the FDA’s
approvals” regarding a drug’s labeling provided a drug
manufacturer “with a complete defense” to a plaintiff’s tort
claims under state law. Wyeth, 555 U.S. at 558-59.
After undertaking “a careful review of the history of
federal regulation of drugs and drug labeling[,]” the Supreme
Court “found nothing within that history to indicate that the
FDA’s power to approve or to disapprove labeling changes, by
itself, pre-empts state law.” Albrecht, 587 U.S. at 311. In fact,
Congress, through the FDCA, “took care to preserve state law”
and “did not intend FDA oversight to be the exclusive means
of ensuring drug safety and effectiveness.” Wyeth, 555 U.S. at
567, 575. The Court was “unpersuaded by [the drug
manufacturer]’s pre-emption argument[,]” given
“Congress’[s] reluctance to displace state laws that would
penalize drug manufacturers for failing to warn consumers of
the risks associated with their drugs, and Congress’[s]
insistence on requiring drug manufacturers to bear the
responsibility for the content of their drug labels[.]” Albrecht,
587 U.S. at 312.

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The Court “concluded, ‘when the risk of gangrene from
IV-push injection of Phenergan became apparent, Wyeth had a
duty’ under state law ‘to provide a warning that adequately
described that risk, and the CBE regulation permitted it to
provide such a warning before receiving the FDA’s approval.’”
Id. (quoting Wyeth, 555 U.S. at 571). In sum, “[t]he CBE
regulation permitted [the manufacturer] to unilaterally
strengthen its warning, and the mere fact that the FDA
approved Phenergan’s label [did] not establish that it would
have prohibited such a change.” Wyeth, 555 U.S. at 573.
The Supreme Court declared that “[i]mpossibility pre-
emption is a demanding defense.” Id. In order to prove
impossibility pre-emption in a failure-to-warn case,
manufacturers must adduce “clear evidence that the FDA
would not have approved a change to [the drug] label[.]” Id.
at 571. Absent such evidence, the Court said, “we will not
conclude that it was impossible for [the drug manufacturer] to
comply with both federal and state requirements.” Id.
C. Factual Background
“Fosamax belongs to a class of drugs called
‘bisphosphonates.’”5 Albrecht, 587 U.S. at 305. It and other
bisphosphonates “work by affecting the bone remodeling
process, that is, the process through which bones are
continuously broken down and built back up again.” Id.
(internal quotation marks omitted). “For some
5 Fosamax’s generic scientific name is “alendronate
sodium.” (J.A. at 1006).

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postmenopausal women, the two parts of the bone remodeling
process fall out of sync; the body removes old bone cells faster
than it can replace them.” Id. “That imbalance can lead to
osteoporosis, a disease that is characterized by low bone mass
and an increased risk of bone fractures.” Id.
“Fosamax (like other bisphosphonates) slows the
breakdown of old bone cells and thereby helps postmenopausal
women avoid osteoporotic fractures.” Id. At the same time,
however, “the mechanism through which Fosamax decreases
the risk of osteoporotic fractures may increase the risk of”
stress fractures. Id. While stress fractures “ordinarily heal on
their own through the bone remodeling process[,]” “Fosamax
and other bisphosphonates may cause stress fractures to
progress to complete breaks that cause great pain and require
surgical intervention to repair.” Id. “When that rare type of
complete, low-energy fracture affects the thigh bone, it is
called an ‘atypical femoral fracture.’” Id. at 306.
“[A]s far back as 1990 and 1991, when Fosamax was
undergoing preapproval clinical trials, Merck scientists
expressed concern in internal discussions that Fosamax could
inhibit bone remodeling to such a profound degree that
inadequate repair may take place and micro-fractures would
not heal.” Id. at 306 (internal quotation marks omitted).
“When Merck applied to the FDA for approval of Fosamax,
Merck brought those theoretical considerations to the FDA’s
attention.” Id. “But, perhaps because the concerns were only
theoretical, the FDA approved Fosamax’s label [in 1995]
without requiring any mention of this risk.” Id.
Evidence that linked Fosamax to atypical femoral
fractures continued to develop after 1995. Id. “Merck began

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receiving adverse event reports from the medical community
indicating that long-term Fosamax users were suffering
atypical femoral fractures.”6 Id. “Merck performed a
statistical analysis of [those] adverse event reports, concluding
that [they] revealed a statistically significant incidence of
femur fractures.” Id. But “none of these studies concluded that
Fosamax actually caused atypical femoral fractures, or even
that they were definitively associated with Fosamax use.”
(J.A. at 45.)
In March 2008, Merck submitted a periodic safety
update to the FDA that included thirty pages “dedicated to
recent publications implicating a link between prolonged
bisphosphonate therapy and atypical low-energy non-vertebral
fractures[.]” (J.A. at 45 (cleaned up).) That same month,
Merck also sent the FDA a letter that was published in the New
England Journal of Medicine “describing ‘a potential link
between [bisphosphonate] use and low-energy fractures of the
femur.’” (J.A. at 46 (alteration in original).) Three months
later, the FDA “requested information from all bisphosphonate
drug manufacturers regarding this potential safety signal.”
(J.A. at 1160.) “Merck complied” by submitting the
“additional data” it had received and the “investigations” it had
conducted regarding femoral fractures. (J.A. at 46.)
6 One orthopedic surgeon called such fractures
“Fosamax Fracture[s]” because “100% of patients in his
practice who [had] experienced femoral fractures (without
being hit by a taxicab)” had been taking Fosamax over an
extended period of time. (J.A. at 959-60).

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While the FDA was analyzing that data, Merck
submitted a Prior Approval Supplement asking “the FDA for
preapproval to change Fosamax’s label to add language to both
the ‘Adverse Reactions’ and the ‘Precautions’ [7] sections of the
label” regarding atypical femoral fractures. Albrecht, 587 U.S.
at 307. In its submission, Merck explained that “[i]t is not
possible with the present data to establish whether treatment
with [Fosamax] increases the risk of low-energy
subtrochanteric and/or proximal femoral shaft fractures.” (J.A.
at 1257.) “Nevertheless, considering the clinical importance
of these fractures in patients with osteoporosis and their
temporal association with bisphosphonate use, [Merck]
believe[d] that it [was] important to include an appropriate
statement about them in the product label.” (J.A. at 1257.) In
support of its application, “Merck submitted a lengthy analysis
of femoral fractures in Fosamax users, cited to nine articles on
such cases, and summarized the findings in a clinical
overview.” (J.A. at 47.) Merck proposed that the following
language be added to the Precautions section of Fosamax’s
label:
7 Although the FDCA regulations call for a “Warnings
and [P]recautions” section, § 201.57(c)(6), Merck’s Fosamax
label includes a section for Warnings and a separate section for
Precautions. (See J.A. at 1278-79.) The proposed atypical
femoral fractures risk was listed in the Precautions section, so,
in keeping with the parties’ practice, we sometimes use the
term “Precautions” section instead of “Warnings and
Precautions” section.

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Low-Energy Femoral Shaft Fracture
Low-energy fractures of the subtrochanteric and
proximal femoral shaft have been reported in a
small number of bisphosphonate-treated
patients. Some were stress fractures (also known
as insufficiency fractures) occurring in the
absence of trauma. Some patients experienced
prodromal pain in the affected area, often
associated with imaging features of stress
fracture, weeks to months before a complete
fracture occurred. The number of reports of this
condition is very low, and stress fractures with
similar clinical features also have occurred in
patients not treated with bisphosphonates.
Patients with suspected stress fractures should be
evaluated, including evaluation for known
causes and risk factors (e.g., vitamin D
deficiency, malabsorption, glucocorticoid use,
previous stress fracture, lower extremity arthritis
or fracture, extreme or increased exercise,
diabetes mellitus, chronic alcohol abuse), and
receive appropriate orthopedic care. Interruption
of bisphosphonate therapy in patients with stress
fractures should be considered, pending
evaluation of the patient, based on individual
benefit/risk assessment.
(J.A. at 1280 (cleaned up).) In addition to this warning in the
Precautions section, Merck also “proposed adding a reference
to ‘low-energy femoral shaft fracture’ in the Adverse
Reactions section, and cross-referencing [the] discussion in the
Precautions section.” Albrecht, 587 U.S. at 307.

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In April 2009, Merck employee Charlotte Merritt
discussed the Company’s pending Prior Approval Supplement
with FDA officials Dr. Scott Monroe and Dr. Theresa Kehoe
on a phone call. According to Merck’s internal notes
summarizing the call, Merritt explained to the FDA “that
Merck was anxious to understand [the] FDA’s timelines for
completing their review of [the Fosamax Prior Approval
Supplement and another labeling supplement] and that this
information had not been forthcoming[.]” (J.A. at 1251.) Dr.
Monroe explained that the FDA’s “duration of review was
related to [Merck’s] elevation of [the atypical femoral
fractures] issue to a [P]recaution in the labeling.” (J.A. at
1251.) “He indicated that they could agree quickly to language
in the [Adverse Reactions] section of the labeling[,]” but that
the “FDA would like to approach the issue of a precaution from
the [perspective]8 of all bisphosphonates” and was working to
do so. (J.A. at 1251.) According to the call notes, “[t]he
conflicting nature of the literature [did] not provide a clear path
forward, … [so] more time [was] need[ed] for [the] FDA to
formulate a formal opinion on the issue of a [P]recaution
around these data.” (J.A. at 1251.) Dr. Monroe suggested that,
“as an interim measure,” Merck could amend only the Adverse
Reactions section of the Fosamax label.9 (J.A. at 1250.)
8 The original uses the word “prospective.” (J.A. at
1251.)
9 Specifically, Merck’s internal call notes provide that
Dr. Monroe suggested Merck amend the “post-marketing
section” of the Fosamax label. (J.A. at 1250.) That section is
a subsection of the Adverse Reactions section. See

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Because there was “some confusion regarding the
[phone] discussion[,]” the FDA sent an email to Merck a week
later stating that the Prior Approval Supplement “could be
approved at this time only for inclusion of the atypical fracture
language proposed in the … adverse events section of the
label.” (J.A. at 1150.) The FDA told Merck that if it “agree[d]
to hold off on the [Precautions section] language at [that] time,
then [it could] go ahead and close out these supplements.”
(J.A. at 1150.) The FDA said it “would then work with [the
FDA’s Office of Surveillance and Epidemiology] and Merck
to decide on language” for the Precaution section, “if it is
warranted.” (J.A. at 1150.)
The next month, in May 2009, the FDA sent Merck a
complete response letter (the “Complete Response Letter” or
the “Letter”), authored by Dr. Monroe, that agreed to the
addition of “low energy femoral shaft and subtrochanteric
fractures” in the Adverse Reactions section but rejected
Merck’s proposed addition to the Precautions section. (J.A. at
1152-53.) The Agency’s Letter explained the FDA’s denial as
follows:
While the [FDA] agrees that atypical and
subtrochanteric fractures should be added to the
ADVERSE REACTIONS, Post-Marketing
Experience subsections of the [Fosamax] labels,
§ 201.57(c)(7)(ii)(B) (explaining that the “[p]ostmarketing
experience” section “must list the adverse reactions … that are
identified from domestic and foreign … reports); (see also J.A.
at 1150 (the FDA calling the section the “postmarketing
adverse events section of the label”).)

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your justification for the proposed
PRECAUTIONS section language is
inadequate. Identification of “stress fractures”
may not be clearly related to the atypical
subtrochanteric fractures that have been reported
in the literature. Discussion of the risk factors
for stress fractures is not warranted and is not
adequately supported by the available literature
and post-marketing adverse event reporting.
(J.A. at 1152-53.)
In the Complete Response Letter, the FDA told Merck
that it had one year to “resubmit” its application, after “fully
address[ing] all the deficiencies listed.” (J.A. at 1153.)
“Merck instead withdrew its application and decided to make
the changes [only] to the Adverse Reactions section through
the CBE process.” Albrecht, 587 U.S. at 307. It “made no
changes to the Precautions section[.]” Id.
“[I]n March 2010, after reviewing the data submitted by
Merck (and other manufacturers), the FDA issued a Drug
Safety Announcement reiterating that there was not yet ‘a clear
connection between bisphosphonate use and a risk of atypical
subtrochanteric femur fractures.’” (J.A. at 49-50 (quoting J.A.
at 1160).)10 The FDA announced that it was “working closely
with outside experts, including members of the recently
convened American Society of Bone and Mineral Research
10 For convenience, throughout this opinion, we cite to
the applicable pages in the joint appendix, which vary from the
docket-item citations used by the District Court.

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Subtrochanteric Femoral Fracture Task Force” (the “Task
Force”), “to gather additional information that may provide
more insight into [the] issue.” (J.A. at 1160.)
Later that year, in September 2010, the Task Force
published a report finding that “there is evidence of a
relationship between long-term [bisphosphonate] use and a
specific type of subtrochanteric and femoral shaft fracture.”
(J.A. at 1078.) But that association “ha[d] not been proven to
be causal.” (J.A. at 1060.) The task force recommended that
“[p]hysicians and patients should be made aware of the
possibility of atypical femoral fractures … through a change in
labeling of [bisphosphonates].” (J.A. at 1078.)
The next month, the FDA announced that it had
determined that “atypical fractures may be related to long-term
… bisphosphonate use” and that it would require all
bisphosphonate drug labels to include the risk of atypical
femoral fractures in the Warnings and Precautions section of
the label. (J.A. at 1030.) The FDA held a conference call to
discuss the announcement, in which the FDA’s Deputy
Director of the Office of New Drugs stated that the Task Force
report “really helped [the FDA] understand these fractures a
little bit better and ma[d]e [it] confident that this is something
that is potentially more closely related to these drugs,
particularly long-term use than we previously had evidence
for.” (J.A. at 1139.)
On the same day as the FDA’s announcement that it
would require changes to bisphosphonate drug labeling, the
Agency wrote to Merck requesting that the following language
be added to the Precautions section of the Fosamax label:

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Atypical Subtrochanteric and Diaphyseal Femoral
Fractures:
Atypical, low-energy, or low trauma fractures of
the femoral shaft have been reported in
bisphosphonate-treated patients. These fractures
can occur anywhere in the femoral shaft from
just below the lesser trochanter to above the
supracondylar flare and are transverse or short
oblique in orientation without evidence of
comminution. Causality has not been
established as these fractures also occur in
osteoporotic patients who have not been treated
with bisphosphonates.
Atypical femur fractures most commonly occur
with minimal or no impact to the affected area.
They may be bilateral and many patients report
prodromal pain in the affected area, usually
presenting as dull, aching thigh pain, weeks to
months before a complete fracture occurs. A
number of reports note that patients were also
receiving treatment with glucocorticoids (e.g.
prednisone) at the time of fracture.
Any patient with a history of bisphosphonate
exposure who presents with thigh or groin pain
should be suspected of having an atypical
fracture and should be evaluated to rule out a
femur fracture. Subjects presenting with an
atypical fracture should also be assessed for
symptoms and signs of fracture in the
contralateral limb. Interruption of
bisphosphonate therapy should be considered,

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pending a risk/benefit assessment, on an
individual basis.
(J.A. at 1168-69 (cleaned up).)
In response, Merck “propos[ed] revised language that,
once again, referred to the risk of ‘stress fractures.’” Albrecht,
587 U.S. at 307. “But the FDA, once again, rejected that
language” and sent Merck a redline rewriting Merck’s
proposal, deleting all references to stress fractures. Id. “[T]his
time, the FDA explained that ‘the term “stress fracture” was
considered and was not accepted’ because, ‘for most
practitioners, the term “stress fracture” represents a minor
fracture and this would contradict the seriousness of the
atypical femoral fractures associated with bisphosphonate
use.’” Id. (quoting J.A. at 1192). “In January 2011, Merck
added the FDA’s language, nearly verbatim, to the Precautions
section of the Fosamax label[,]” and “[t]hat warning remains
in place today.” (J.A. at 51-52.)
D. Procedural History
1. Initial District Court Proceedings
“The [Plaintiffs] here are more than 500 individuals
who took Fosamax and who suffered atypical femoral fractures
between 1999 and 2010.” Albrecht, 587 U.S. at 308.
“[I]nvoking federal diversity jurisdiction, [they] filed separate
actions seeking tort damages on the ground that, during the
relevant period, state law imposed upon Merck a legal duty to
warn them and their doctors about the risk of atypical femoral
fractures associated with using Fosamax.” Id. “Merck argued,
in response, that federal law preempted [the] Plaintiffs’ claims

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– specifically, the May 2009 [Complete Response Letter]
rejecting Merck’s proposed label change.” (J.A. at 53.)
“In 2011, the Judicial Panel on Multidistrict Litigation
consolidated these cases … for pre-trial administration in a
multi-district litigation (‘MDL’) in the District of New Jersey”
and assigned the case to the late Judge Joel A. Pisano. (J.A. at
53 n.6.) A bellwether trial was held in the so-called Glynn
case. In re Fosamax (Alendronate Sodium) Prods. Liab. Litig.,
951 F. Supp. 2d 695 (D.N.J. 2013), vacated, 852 F.3d 268 (3d
Cir. 2017), vacated and remanded sub nom. Merck Sharp &
Dohme Corp. v. Albrecht, 587 U.S. 299 (2019) [hereinafter
Glynn]. Prior to trial, Merck “moved for summary judgment
based on federal preemption[.]” Id. at 700. The District Court
“reserved decision on the federal preemption motion until there
was a complete trial record in the case[.]” Id. At the
conclusion of the trial, the jury returned a verdict for Merck,
but the Court still decided to resolve the pre-emption question.
Id. at 701.
The Court concluded that “preemption is warranted
because … [t]he FDA’s rejection constitutes clear evidence …
that the FDA would not have approved a change to the
Precautions section of the Fosamax label prior to Mrs. Glynn’s
injury[,]” which occurred in April 2009. Id. at 697, 703. The
Court found that “the FDA never required [Merck] to submit
new language or change the label, which demonstrates that the
FDA did not think that the label should have been changed at
that time.”11 Id. at 703-04.
11 The Court further stated that the “Plaintiffs did not
present any evidence at trial to refute preemption.” Glynn, 951

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“Merck then moved for an [order to show cause] why
the claims of all other Plaintiffs with injury dates prior to
September 14, 2010, [12] should not be dismissed pursuant to the
Court’s preemption ruling in Glynn[,]” which the Court
granted. In re Fosamax (Alendronate Sodium): Prods. Liab.
Litig., MDL No. 2243, 2014 WL 1266994, at *2 (D.N.J. Mar.
26, 2014). The Court concluded that Merck was “entitled to
judgment as a matter of law on all claims made by the Plaintiffs
… with injuries that occurred prior to September 14, 2010,
because [the] Plaintiffs have failed to show cause why their
claims are not preempted under [the] … ruling in Glynn.” Id.
at *17.
F. Supp. 2d at 704. For example, they “did not offer any
evidence that [Merck]’s [Prior Approval Supplement] was
rejected due to language, specifically the use of ‘stress
fracture’ instead of ‘[atypical femoral fracture],’ or that the
FDA would have approved a properly worded label change.”
Id. Nor did they “offer any evidence that [Merck] could have
submitted a CBE supplement to change the Precautions section
of the Fosamax label.” Id. “[B]ased on [that] record[,]” the
Court found that the “Plaintiffs’ failure to warn claim [was]
preempted.” Id. at 705.
12 September 14, 2010, is the date the Task Force
published its report recommending a labeling change for
Fosamax. Glynn, 951 F. Supp. 2d at 699.

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29
2. Vacatur of the District Court’s Glynn
Decision
In In re Fosamax (Alendronate Sodium) Prods. Liab.
Litig., 852 F.3d 268, 302 (3d Cir. 2017), vacated and remanded
sub nom. Merck Sharp & Dohme Corp. v. Albrecht, 587 U.S.
299 (2019) [hereinafter Fosamax I], we vacated the District
Court’s decision and remanded for further proceedings. We
explained that, in Wyeth, the Supreme Court “did not define the
‘clear evidence’ standard or explain how courts should apply
it[,]” and noted that courts had applied the standard in different
ways. Id. at 284. Interpreting the clear-evidence standard, we
concluded:
The term “clear evidence” … does not refer
directly to the type of facts that a manufacturer
must show, or to the circumstances in which
preemption will be appropriate. Rather, it
specifies how difficult it will be for the
manufacturer to convince the factfinder that the
FDA would have rejected a proposed label
change. The manufacturer must prove that the
FDA would have rejected a warning not simply
by a preponderance of the evidence, as in most
civil cases, but by “clear evidence.”
Id. at 285. Based on that conclusion, we reasoned that the
Supreme Court “intended to announce a standard of proof
when it used the term ‘clear evidence’ in Wyeth.” Id. at 284.
We held that, “to establish a preemption defense under Wyeth,
the factfinder must conclude that it is highly probable that the
FDA would not have approved a change to the drug’s label.”
Id. at 286.

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30
We then “conclude[d] that the question of whether the
FDA would have rejected a proposed label change is a question
of fact that must be answered by a jury.” Id. We said that “[a]t
root, Wyeth requires the decisionmaker to use an existing fact
record to predict the outcome of a hypothetical scenario.” Id.
at 289. “The question posed to the decisionmaker in this case
is: based on the contemporaneous medical literature and the
interactions between Merck and the FDA that actually did
happen, what would have happened if Merck had proposed the
warning plaintiffs say was required?” Id. (emphasis omitted).
We determined that “a reasonable jury could conclude
that Merck could have amended the Fosamax label via the CBE
process” and that “a reasonable jury could also conclude that
the FDA rejected Merck’s proposed warning about femoral
fractures in 2009 not because it denied the existence of a causal
link between Fosamax and fractures, but because Merck
repeatedly characterized the fractures at issue as ‘stress
fractures’” in the Prior Approval Supplement. Id. at 297-98.
We thus vacated the District Court’s grant of summary
judgment to Merck and remanded for further proceedings. Id.
at 302.
3. The Supreme Court Vacates our Fosamax
I Decision
Merck filed a petition for a writ of certiorari, and, “[i]n
light of differences and uncertainties among the courts of
appeals and state supreme courts in respect to the application
of Wyeth,” the Supreme Court granted the writ. Albrecht, 587
U.S. at 310.
In Merck Sharp & Dohme Corp. v. Albrecht, the Court
“elaborate[d] Wyeth’s requirements” and created a two-

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31
pronged test that courts must use to determine whether the drug
manufacturer showed by clear evidence that “federal law
prohibited the drug manufacturer from adding a warning that
would satisfy state law[.]” 587 U.S. at 310, 314. Clear
evidence, it said, “is evidence that shows the court[, first,] that
the drug manufacturer fully informed the FDA of the
justifications for the warning required by state law and[,
second,] that the FDA, in turn, informed the drug manufacturer
that the FDA would not approve a change to the drug’s label to
include that warning.” Id. at 303.
The Supreme Court declared that meeting that standard
would be “difficult” because “impossibility pre-emption is a
demanding defense.” Id. at 313 (cleaned up). Indeed, it stated
that “[t]he underlying question for this type of impossibility
pre-emption defense is whether federal law (including
appropriate FDA actions) prohibited the drug manufacturer
from adding any and all warnings to the drug label that would
satisfy state law.” Id. at 313-14 (emphasis added). And, as it
had “cautioned many times before,” the Court reminded
litigants and lower courts that the “‘possibility of impossibility
[is] not enough.’” Id. at 314 (alteration in original) (quoting
PLIVA, Inc. v. Mensing, 564 U.S. 604, 625 n.8 (2011)). Of
high significance here, the Court observed that because
“federal law – the FDA’s CBE regulation – permits drug
manufacturers to change a label … without prior approval from
the FDA[,] … a drug manufacturer will not ordinarily be able
to show that there is an actual conflict between state and federal
law such that it was impossible to comply with both.” Id. at
314-15.
Against that background, the Court assigned
responsibility for assessing an impossibility defense to judges

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rather than juries. It chose not to “define Wyeth’s use of the
words ‘clear evidence’ in terms of evidentiary standards, such
as ‘preponderance of the evidence’ or ‘clear and convincing
evidence’ and so forth, because … courts should treat the
critical question not as a matter of fact for a jury but as a matter
of law for the judge to decide.” Id. at 315. “And where that is
so, the judge must simply ask himself or herself whether the
relevant federal and state laws ‘irreconcilably conflic[t].’” Id.
(alteration in original) (quoting Rice v. Norman Williams Co.,
458 U.S. 654, 659 (1982)).
The Court noted that “the only agency actions that can
determine the answer to the pre-emption question, of course,
are agency actions taken pursuant to the FDA’s
congressionally delegated authority[,]” and it listed some of the
means by which that can be done, including the issuance of a
complete response letter under § 314.110(a):
Federal law permits the FDA to communicate its
disapproval of a warning by means of notice-
and-comment rulemaking setting forth labeling
standards, see, e.g., 21 U.S.C. § 355(d); 21
C.F.R. §§ 201.57, 314.105; by formally rejecting
a warning label that would have been adequate
under state law, see, e.g., 21 C.F.R.
§§ 314.110(a), 314.125(b)(6); or with other
agency action carrying the force of law, cf., e.g.,
21 U.S.C. § 355(o)(4)(A).
Id. at 315-16. The Court disclaimed making any ruling about
what agency action would carry the force of law because “[t]he
question of [a] disapproval ‘method’ [was] not [then] before
[it].” Id. at 316. But it wanted to make “the obvious point that,

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33
whatever the means the FDA uses to exercise its authority,
those means must lie within the scope of the authority
Congress has lawfully delegated.”13 Id.
13 Justice Thomas wrote separately in Albrecht to
“explain [his] understanding of the relevant pre-emption
principles and how they apply to this case.” 587 U.S. at 318
(Thomas, J., concurring). Pertinent here, Justice Thomas
explained that “Merck’s impossibility pre-emption defense
fails because it does not identify any federal law that prohibited
it from adding any and all warnings that would satisfy state
law[,]” – reasoning that, “[b]y its reference to ‘the Laws of the
United States,’ the Supremacy Clause requires that pre-
emptive effect be given only to those federal standards and
policies that are set forth in, or necessarily follow from, the
statutory text that was produced through the constitutionally
required bicameral and presentment procedures.” Id. at 321
(cleaned up). He asserted that the Complete Response Letter
that denied Merck’s proposed labeling changes “neither
marked ‘the consummation of the agency’s decisionmaking
process’ nor determined Merck’s ‘rights or obligations[;]’
[i]nstead, it was ‘of a merely tentative or interlocutory nature’”
because such letters “merely ‘infor[m] sponsors of changes
that must be made before an application can be approved, with
no implication as to the ultimate approvability of the
application.’” Id. at 322 (citation omitted) (first quoting
Bennett v. Spear, 520 U.S. 154, 178 (1997) and then quoting
73 Fed. Reg. 39588, 39589 (July 10, 2008)). Therefore, he
concluded that “the [L]etter was not a final agency action with
the force of law, so it cannot be ‘Law’ with pre-emptive
effect.” Id.

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34
The Supreme Court then elaborated on the judge-or-jury
issue, saying “the question of agency disapproval … is a legal
one for the judge, not a jury” because “[t]he question often
involves the use of legal skills to determine whether agency
disapproval fits facts that are not in dispute.” Id. “Moreover,”
the Court said, “judges, rather than lay juries, are better
equipped to evaluate the nature and scope of an agency’s
determination” because they “are experienced in the
construction of written instruments, such as those normally
produced by a federal agency to memorialize its considered
judgments.” Id. (cleaned up). “And judges are better suited
than are juries to understand and to interpret agency decisions
in light of the governing statutory and regulatory context.” Id.
The Court also reasoned that, “[t]o understand the question as
a legal question for judges makes sense given the fact that
judges are normally familiar with principles of administrative
law.” Id. at 317. It predicted that viewing the question as a
Justice Thomas further reasoned that “Merck’s
argument that the 2009 [L]etter and other agency
communications suggest that the FDA would have denied a
future labeling change fares no better” because “hypothetical
agency action is not ‘Law.’” Id. He explained that “Merck’s
primary argument, based on various agency communications,
is that the FDA would have rejected a hypothetical labeling
change submitted via the CBE process.” Id. at 321. But, in his
view, “neither agency musings nor hypothetical future
rejections constitute pre-emptive ‘Laws’ under the Supremacy
Clause.” Id.

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35
legal one “should produce greater uniformity among courts[,]”
and it remarked that “greater uniformity is normally a virtue
when a question requires a determination concerning the scope
and effect of federal agency action.” Id.
Accordingly, the Supreme Court vacated our judgment
in Fosamax I and remanded the case to us for further
proceedings “[b]ecause [we] treated the pre-emption question
as one of fact, not law, and because [we] did not have an
opportunity to consider fully the standards” it had set forth. Id.
at 318.14
14 Justice Alito, with whom Chief Justice Roberts and
Justice Kavanaugh joined, wrote a separate concurring opinion
explaining that he only concurred in the judgment “because
[he] agree[d] with the Court’s decision on the only question
that it actually decides, namely, that whether federal law
allowed Merck to include in the Fosamax label the warning
alleged to be required by state law is a question of law to be
decided by the courts[.]” Albrecht, 587 U.S. at 323 (Alito, J.,
concurring). But he did not join the opinion “because [he was]
concerned that its discussion of the law and the facts may be
misleading on remand.” Id.
Justice Alito noted “a statutory provision … that may
have an important bearing on the ultimate pre-emption analysis
in this case.” Id. at 324. Under § 355(o)(4)(A), “which was
enacted in 2007, Congress has imposed on the FDA a duty to
initiate a label change ‘[i]f the Secretary becomes aware of new
information, including any new safety information … that the
Secretary determines should be included in the labeling of the
drug.’” Id. He explained:

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This provision does not relieve drug
manufacturers of their own responsibility to
maintain their drug labels, but the FDA’s actions
taken pursuant to this duty arguably affect the
pre-emption analysis. This is so because, if the
FDA declines to require a label change despite
having received and considered information
regarding a new risk, the logical conclusion is
that the FDA determined that a label change was
unjustified. The FDA’s duty does not depend on
whether the relevant drug manufacturer, as
opposed to some other entity or individual,
brought the new information to the FDA’s
attention. Nor does § 355(o)(4)(A) require the
FDA to communicate to the relevant drug
manufacturer that a label change is unwarranted;
instead, the FDA could simply consider the new
information and decide not to act.
Section 355(o)(4)(A) is … highly relevant to the
pre-emption analysis, which turns on whether
federal law (including appropriate FDA actions)
prohibited the drug manufacturer from adding
any and all warnings to the drug label that would
satisfy state law.
Id. at 324-25 (cleaned up). And Justice Alito “assume[d]” that
on remand, “the Court of Appeals will consider the effect of
§ 355(o)(4)(A) on the pre-emption issue in this case.” Id. at
325. He also critiqued the Supreme Court’s recitation of the
facts in this case, saying that the Court provided “a one-sided
account” in favor of the Plaintiffs. Id. at 326.

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4. District Court Decision on Remand
“Upon remand, [we] returned the case to [the District]
Court to decide ‘in the first instance whether the [P]laintiffs’
state law claims are preempted by federal law under the
standards described by the Supreme Court.’”15 (J.A. at 38
(quoting Order at 1, In Re: Fosamax (Alendronate Sodium)
Prods. Liab. Litig., No. 14-1900 (3d Cir. Nov. 25, 2019)).) We
instructed the District Court “to determine the effect of the
[FDA]’s Complete Response Letter … and other
communications with Merck on the issue of whether such
agency actions are sufficient to give rise to preemption.” Id.
The District Court granted Merck’s motion for
summary judgment and issued a carefully reasoned 87-page
opinion concluding that Merck “fully informed the FDA of the
justifications for its proposed warning, … and the FDA, in turn,
informed [Merck] that it would not approve changing the
Fosamax label to include that warning in the [Complete
Response Letter].” (J.A. at 38-39.) After combing “through
the extensive record,” the Court found that, “[b]etween its
formal safety updates, periodic emails, and [Prior Approval
Supplement], [Merck] clearly and fully informed the FDA of
the panoply of risks associated with long-term Fosamax use
and the justifications for its proposed label change.” (J.A. at
70.) That satisfied the first prong of the Albrecht pre-emption
test.
15 The MDL was reassigned to then-Chief Judge Freda
L. Wolfson.

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38
As to the second prong of that test – whether the FDA
informed Merck that it would reject any warning about atypical
femoral fractures in the Precautions section of Fosamax’s label
– the Court “appreciate[d] that, as worded, the language of the
[Complete Response Letter] gives rise to competing inferences
with respect to why the FDA rejected [Merck]’s warning.”
(J.A. at 96.) Given that ambiguity, the Court said, “[i]f the
[Letter] were the sum total of the evidence of FDA action in
this case, [the] Plaintiffs might be on firmer footing with
regards to their preemption arguments.” (J.A. at 97.) But it
went on to say that “the [Complete Response Letter] does not
tell the whole story without the proper context gleaned from
other FDA communications.” (J.A. at 99.) Although
“informal communications do not constitute ‘Laws’ with the
power to preempt[,]” the Court reasoned, it was still
“appropriate to consider [those] communications for [the]
limited purpose” of “shed[ding] light on the meaning and scope
of the [Letter].” (J.A. at 98 (internal quotation marks omitted).)
Upon considering the Complete Response Letter “in light [of]
the FDA’s communications,” the Court concluded that the
Letter “rejected [Merck]’s Precautions warning because the
FDA doubted the evidence linking bisphosphonate use to
atypical femoral fractures in a causal sense[,]” not because of
Merck’s use of the term “stress fractures.” (J.A. at 103.)
The District Court also analyzed how the FDCA’s
regulatory regime fits into the pre-emption analysis. It
considered § 355(o)(4)(A), which, as previously noted (supra
note 14), requires the FDA to tell the drug manufacturer if the
Agency “becomes aware of new information” that “should be
included in the labeling of the drug[.]” 21 U.S.C.
§ 355(o)(4)(A). Because of that provision, the Court said, “it
is improbable that the FDA declined to approve [Merck]’s

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39
Precautions warning, or failed to propose a solution to the
problem it perceived with the language, i.e., stress fracture, all
while the FDA had sufficient causal evidence linking
bisphosphonates to atypical femoral fractures and thus
exposing patients to the risk of severe injury in the interim.”
(J.A. at 105-06.) The Court thought that “[t]he more likely
scenario is that the FDA’s actions taken in this case convey
doubts that the Agency had about the underlying science, a
deficiency no revision or edits could solve; hence, the Agency
did not propose any.” (J.A. at 106 (emphases omitted).)
The Court also disagreed with the Plaintiffs’ argument
that Merck could have amended the Precautions section of the
Fosamax label through a CBE amendment after the FDA
denied Merck’s Prior Approval Supplement. It explained that
“[t]he CBE process permits a drug manufacturer to unilaterally
add a Precautions warning to its label, but only if ‘newly
acquired information’ provides ‘reasonable evidence of a
causal association[’] of a [‘]clinically significant adverse
reaction[’] linked to a drug.” (J.A. at 112 (quoting
§§ 314.70(c)(6)(iii), 201.57(c)(6)(i)).) After analyzing
Agency announcements and the Task Force’s report, the Court
determined that “there was no ‘newly acquired information’ as
defined in the CBE regulation on the basis of which [Merck]
could have successfully submitted a CBE amendment” after
the FDA denied Merck’s Prior Approval Supplement.16 (J.A.
at 117.)
16 In determining whether newly acquired information
had arisen during the period of time between the FDA’s denial
of Merck’s Prior Approval Supplement and issuance of the
Task Force report, the District Court may have been

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For those reasons, the Court granted Merck’s motion for
summary judgment, concluding that the Plaintiffs’ state law
claims were preempted. The Plaintiffs have appealed.17
responding to the Supreme Court’s statement from Albrecht
that, because of the FDA’s CBE regulation, “a drug
manufacturer will not ordinarily be able to show that there is
an actual conflict between state and federal law such that it was
impossible to comply with both.” 587 U.S. at 315. Merck
argues that the District Court’s finding that no new information
had arisen was correct because the “Plaintiffs did not provide
or even summarize” any new information that arose during that
period and “thereby waived any such argument[.]”
(Answering Br. at 32 n.2.) That said, “Merck conceded that
the FDA’s CBE regulation would have permitted Merck to try
to change the label to add a warning” prior to the FDA’s denial
of that supplement. Albrecht, 587 U.S. at 308-09.
17 Virginia and twenty-two other states (Alaska,
Colorado, Connecticut, Delaware, Georgia, Idaho, Illinois,
Indiana, Kentucky, Maryland, Massachusetts, Minnesota,
Mississippi, Montana, Nebraska, New Jersey, New Mexico,
Pennsylvania, South Carolina, Texas, Utah, and Vermont) filed
an amicus brief in favor of the Plaintiffs, as did “Public Law
Scholars,” a group of law professors whose scholarship has
addressed federal pre-emption of state law. The following also
filed amicus briefs: Dr. Gregory Curfman; Drs. Joseph Lane,
Vincent Vigorita, and David Burr; and MedShadow
Foundation and three former FDA officials.

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II. D ISCUSSION18
On appeal, the Plaintiffs argue that the District Court
erred in concluding Merck satisfied the Albrecht pre-emption
test. They contend that Merck failed on both prongs, that in
reality “Merck failed to fully inform [the] FDA of the
justifications for the warning, required by state law, that
Fosamax can cause atypical femoral fractures” and that
“Merck likewise cannot show that [the] FDA informed it that
[the] FDA would disapprove a change to Fosamax’s label to
warn of atypical femoral fractures.” (Opening Br. at 25.) The
Plaintiffs also argue that the Complete Response Letter in this
case did not carry the force of law and that FDA regulations
allowed Merck to make appropriate labeling changes through
the CBE process. Merck, in response, asserts that it met its
burden on both prongs of the Albrecht pre-emption test, that
the Complete Response Letter had the force of law, and that
the CBE process adds nothing to the pre-emption analysis here.
Before discussing the parties’ specific arguments about
pre-emption, we first have to consider our standard of review.
A. Standard of Review.
The overall pre-emption question in this case is one of
law. That much is clear after Albrecht.19 587 U.S. at 318
18 The District Court had jurisdiction under 28 U.S.C.
§ 1332(a). We have jurisdiction pursuant to 28 U.S.C. § 1291.
19 Few Courts of Appeals have had occasion to apply
the Albrecht pre-emption test in the drug labeling context. See,

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42
(vacating Fosamax I because we “treated the pre-emption
question as one of fact, not law”). But the parties disagree on
the level of deference we must give to the District Court’s
determinations that Merck satisfied both prongs of Albrecht’s
pre-emption test. The Plaintiffs argue that we should review
the entirety of “the District Court’s preemption determination,
including its construction of [the] FDA’s Letter, de novo.”
(Reply Br. at 3 (cleaned up).) Merck argues that “the two
prongs of the preemption test in this case hinge on factual
determinations,” and that the District Court’s determinations
for each prong should accordingly be reviewed for clear error.
(Answering Br. at 21.)
The Supreme Court explained in Albrecht that the pre-
emption question in reality “falls somewhere between a
pristine legal standard and a simple historical fact[,]”
notwithstanding its ultimate characterization as one of law.
587 U.S. at 317 (quoting Markman v. Westview Instruments,
Inc., 517 U.S. 370, 388 (1996)). The Court acknowledged that
“sometimes contested brute facts will prove relevant to a
court’s legal determination about the meaning and effect of an
agency decision.” Id. “For example,” it said, “if the FDA
rejected a drug manufacturer’s supplemental application to
e.g., In re Zofran (Ondansetron) Prods. Liab. Litig., 57 F.4th
327 (1st Cir. 2023); Knight v. Boehringer Ingelheim Pharms.,
Inc., 984 F.3d 329 (4th Cir. 2021); Hickey v. Hospira, Inc., 102
F.4th 748 (5th Cir. 2024); Dolin v. GlaxoSmithKline LLC, 951
F.3d 882 (7th Cir. 2020). We could find no case that engages
in a substantive discussion about the proper standard of review
in the Albrecht pre-emption context, nor have the parties
pointed us to any.

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change a drug label on the ground that the information
supporting the application was insufficient to warrant a
labeling change, the meaning and scope of that decision might
depend on what information the FDA had before it.” Id.
Moreover, “the litigants may dispute whether the drug
manufacturer submitted all material information to the FDA.”
Id. The Court considered those “factual questions to be
subsumed within an already tightly circumscribed legal
analysis[,]” and it “[did] not believe that they warrant
submission alone or together with the larger pre-emption
question to a jury.” Id.
“Generally, questions of law are reviewed de novo and
questions of fact, for clear error[.]” Monasky v. Taglieri, 589
U.S. 68, 83 (2020). Thus, although we are bound to review the
District Court’s overall pre-emption conclusion de novo, In re
Avandia Mktg., Sales & Prods. Liab. Litig., 945 F.3d 749, 757
(3d Cir. 2019) (exercising plenary review when applying the
Albrecht pre-emption standard), when a district court resolves
“subsidiary factual matters … in the course of” deciding that
ultimate legal question, we will review those findings under a
“clearly erroneous” standard. Teva Pharms. USA, Inc. v.
Sandoz, Inc., 574 U.S. 318, 324 (2015). This seems the best
approach not only on general principles but also because the
justification given by the Supreme Court for its analytical
approach in Albrecht is akin to the justification it gave when
tasking judges with construing claim terms in a patent.
In its landmark decision in Markman v. Westview
Instruments, Inc., the Court described claim construction as a
“mongrel practice,” 517 U.S. at 378, just as it described the
pre-emption analysis in Albrecht as posing neither a “pristine
legal standard” nor a question of “simple historical fact,” 587

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44
U.S. at 317 (quoting Markman, 517 U.S. at 388). Despite the
factual questions that often arise in construing patent claims,
the Court in Markman deemed it best to entrust the whole
interpretative process to judges rather than juries. It said, “as
a matter of the sound administration of justice, one judicial
actor is better positioned than another to decide the issue in
question” and that “judges, not juries, are … better suited to
find the acquired meaning of patent terms.” Markman, 517
U.S. at 388. That has a distinctly similar ring to the language
used in Albrecht, which in fact quotes Markman. Albrecht, 587
U.S. at 316, 318 (explaining that “judges, rather than lay juries,
are better equipped to evaluate the nature and scope of an
agency’s determination” and, quoting Markman, holding that
the “better positioned” decisionmaker in pre-emption cases is
a judge).
When the Supreme Court later, in Teva
Pharmaceuticals USA, Inc. v. Sandoz, Inc., looked closely at
the question of how much deference an appellate court should
give to a district court’s fact-finding during claim construction,
it ruled that the clearly erroneous standard should apply. 574
U.S. at 324. We do not think it a mere coincidence that in
Albrecht the Supreme Court quoted Teva in declaring, ‘“courts
may have to resolve subsidiary factual disputes’ that are part
and parcel of the broader legal question.” Albrecht, 587 U.S.
at 317 (quoting Teva, 574 U.S. at 327). Accordingly, the clear-
error standard of review applies to any subsidiary factual
determinations the District Court made in this case. Teva, 574
U.S. at 324. The importance of a district court’s subsidiary fact
finding may vary because, “[i]n some instances, a factual
finding will play only a small role in a judge’s ultimate legal
conclusion[,] … [b]ut in some instances, a factual finding may

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45
be close to dispositive of the ultimate legal question[.]” Id. at
333.
With the foregoing principles in mind, we undertake a
de novo review of the District Court’s conclusion that the
Plaintiff’s state law claims were preempted by federal law,
while giving clear-error deference to subsidiary factual
findings.20
20 Normally, “[s]ummary judgment should be granted
only if a court concludes that ‘there is no genuine issue as to
any material fact and that the moving party is entitled to
judgment as a matter of law.’” Ideal Dairy Farms, Inc. v. John
Labatt, Ltd., 90 F.3d 737, 743 (3d Cir. 1996) (emphasis
omitted) (quoting Fed. R. Civ. P. 56). And “[a]n appellate
court reviews the district court’s grant of summary judgment
de novo, applying the same standard as the district court[,]”
which requires the court to “view the underlying facts and all
reasonable inferences therefrom in the light most favorable to
the party opposing the motion.” Id. But that traditional
standard is effectively modified in cases like this because the
Supreme Court has instructed judges to resolve subsidiary fact
questions rather than leave them for juries to decide. See
Albrecht, 587 U.S. at 315, 317 (explaining that “courts should
treat the [agency disapproval] question not as a matter of fact
for a jury but as a matter of law for the judge to decide” and
that any relevant “contested brute” fact questions are
“subsumed within an already tightly circumscribed legal
analysis” and do not “warrant submission alone or together
with the larger pre-emption question to a jury”).

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B. The Plaintiffs’ State Law Claims are Not
Preempted.
1. Prong #1: The District Court Did Not Err
in Concluding that Merck Fully Informed
the FDA about the Risks of Atypical
Femoral Fractures.
The parties dispute whether Merck “fully informed the
FDA of the justifications for the warning required by state
law[.]” Albrecht, 587 U.S. at 314. Resolving that dispute
requires a fact-intensive analysis, as is evident by the parties’
disagreement about how the information provided to the FDA
was portrayed. Indeed, the Supreme Court’s examples of
“contested brute facts” in Albrecht – “what information the
FDA had before it” and “whether the drug manufacturer
submitted all material information to the FDA” – are among
the central issues in this case. Id. at 317.
The Plaintiffs contend that the District Court improperly
“credited Merck’s 2008 safety update,” which “downplayed
the risk of atypical femoral fractures.” (Opening Br. at 40
(emphasis omitted).) They also claim that, by including
misleading risk factors, Merck “blurred the relationship
between Fosamax and atypical femoral fractures” in its Prior
Approval Supplement. (Opening Br. at 49.) They contend that
our holding in In re: Avandia Marketing, Sales and Products
Liability Litigation, 945 F.3d 749 (3d Cir. 2019), compels us
to rule for them on this prong. Merck, on the other hand,
asserts that the District Court did not err because the record is
clear that the FDA was fully informed and because In re
Avandia does not support the Plaintiffs’ argument.

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a) The District Court did not clearly
err in rejecting the Plaintiffs’
argument that Merck provided
misleading information to the
FDA.
The Plaintiffs contend that the District Court improperly
credited Merck’s 2008 safety update (see supra Section I.C.),
an important component of the Court’s finding that there was
“profuse evidence of information” that Merck warned the FDA
about atypical femoral fractures. (J.A. at 72.) But the Plaintiffs
point to only a handful of instances that, in their view, show
Merck mischaracterized the studies provided in the safety
update. For example, they say that Merck improperly
characterized one article by using terms and phrases like
“hypothetically” and “in only few patients.” (Opening Br. at
41.) They note that when Merck summarized eight other
publications, it again used the word “hypothetical,” which they
allege was meant “to plant doubt regarding these reports’ links
between Fosamax and unusual fractures[.]” (Opening Br. at
42.) The Plaintiffs also quote Merck’s description of one
study, in which it said that “there was no evidence of increased
risk of fractures associated with 10 years of treatment with
alendronate and that data confirms that alendronate is safe.”
(Opening Br. at 43 (cleaned up).) Regarding the Prior
Approval Supplement, the Plaintiffs allege that “Merck
misleadingly listed risk factors (e.g., abnormally decreased
bone mineral density and muscle weakness) that it claimed
were likely to be very important in the development of
insufficiency fractures” but that were actually not. (Opening
Br. at 49 (internal quotation marks omitted).)

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48
The Plaintiffs’ list of examples is thin, and their
characterizations of them do not persuade us that the District
Court clearly erred in finding that Merck did not mislead the
FDA in its safety update and Prior Approval Supplement.
Most notably, it stretches credulity to believe that Merck was
attempting to mislead the FDA when, in the Prior Approval
Supplement itself, the Company advocated for a new
Precautions warning on the Fosamax label, explaining that,
although “[i]t is not possible with present data to establish
whether treatment with alendronate increases the risk of low-
energy subtrochanteric and/or proximal femoral shaft
fractures[,] … it is important to include an appropriate
statement … in the product information and precautions”
sections about the “need[] to identify and manage such
fractures.” (J.A. at 1316.)
In other words, the Plaintiffs’ grievances with the safety
update and Prior Approval Supplement do not establish that the
District Court erred in finding that, through “formal safety
updates, periodic emails, and [the Prior Approval
Supplement],” Merck “clearly and fully informed the FDA of
the panoply of risks associated with long-term Fosamax use
and the justifications for its proposed label change.” (J.A. at
70.) The District Court “culled through the extensive record”
to summarize what Merck had sent the FDA prior to requesting
a label change. (J.A. at 70.) It found that Merck “repeatedly
and voluntarily sent relevant articles to the FDA between 1992
and 2010[,]” including the “safety update, which surveyed
medical studies, journal publications, and internal data[,]” and
“included numerous pages on atypical femoral fractures.”
(J.A. at 70.) In June 2008, Merck “promptly complied with the
FDA’s request for further investigations that Merck had
conducted and reports Merck had received.” (J.A. at 72

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49
(internal quotation marks omitted).) Moreover, Merck’s Prior
Approval Supplement “not only cited nine articles reporting
cases of low-energy femoral fractures in Fosamax users, but
included a clinical overview in which [Merck] itself asserted a
statistically significant association.” (J.A. at 72.) The Court
found “no basis in the record” for concluding that Merck
needed to provide more information to the FDA or that what
was submitted was misleading. (J.A. at 73.) That conclusion
is sound. Accordingly, the District Court did not clearly err in
finding that Merck did not mislead the FDA with its
submissions.21
21 The Plaintiffs also assert that Merck “hid the ball” on
certain “key features” of atypical femoral fractures. (Opening
Br. at 45.) For example, before the District Court, the Plaintiffs
argued that Merck “did not provide the FDA with any possible
pathogenesis, the manner of development of a disease, for
atypical femoral fractures.” (J.A. at 74.) But the Court found
that “[t]he record belies this assertion” because Merck
“repeatedly indicated how Fosamax might cause the very
injury Plaintiffs suffered.” (J.A. at 74.) And the Plaintiffs have
no adequate response for the undisputed fact that, in clinical
trials three decades ago, Merck informed the FDA that
“antiresorptive agents may inhibit microdamage repair by
preventing … bone resorption at the sites of microdamage[.]”
(J.A. at 74.)
The Plaintiffs further assert that Merck and the District
Court “improperly conflated stress fractures with atypical
femoral fractures” by “substitut[ing] ‘atypical femoral’ into the
sentence, when context made clear Merck was discussing all
low-energy fractures, including stress fractures[,]” implying
that atypical femoral fractures were more common (without

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b) The District Court did not clearly
err in finding that Merck did not
withhold any material information
from the FDA.
The Plaintiffs also asserted in the District Court that
Merck “deprived the FDA of relevant information between
2008 and 2009, such as information that the Task Force
eventually reported, leaving the agency uncertain about the
nature of atypical femoral fractures and delayed by [Merck’s]
inaction.” (J.A. at 78 (cleaned up).) As evidence of this, they
say that in April 2009, the month before the FDA issued the
Complete Response Letter, the FDA emailed Merck to say that
if Merck held off on its proposed amendment to the
Precautions section of the label, the FDA would “work with …
taking bisphosphonates) than they actually were. (Opening Br.
at 47.) But we see no clear error in the District Court’s finding
that the safety update was not untrue or misleading in this
respect. The Court explained that the warning label that the
FDA created in 2010, and which is now used by Merck,
“includes the observation that osteoporotic patients, generally,
have suffered such fractures” without being treated by
bisphosphonates like Fosamax. (J.A. at 76.) And, as Merck
points out, it “said nothing [to the FDA] about [the] relative
frequency” of atypical femoral fractures among those who
used biphosphates and those who did not, and the “Plaintiffs
do not point to anything inaccurate in Merck’s submissions
about the data.” (Answering Br. at 30.)

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Merck to decide” on “atypical fracture language … if it is
warranted.” (J.A. at 1150.) According to the Plaintiffs, it is
thus clear that the FDA “needed and sought more information
about appropriate warning language.” (Opening Br. at 50.)
The District Court found that argument “lack[ed] merit”
because the “Plaintiffs do not point to any specific instance in
which [Merck] failed to provide any timely and relevant
information, data, case studies, or evidence to the FDA, or
rebuffed a request for further engagement.” (J.A. at 78.)
Furthermore, the Court found that “[t]he Task Force relied on
24 new case studies and 63 new articles after the FDA issued
its [Complete Response Letter], according to [the] Plaintiffs’
own experts[,]” so it was not possible for Merck, at the time of
submitting its Prior Approval Supplement, to have provided
the FDA with those studies and reports. (J.A. at 79.)
On appeal, the Plaintiffs argue that the District Court
“improperly shifted the burden from Merck to [the] FDA”
because “[t]he standard is whether Merck fully informed [the]
FDA of the justifications for an adequate warning, not whether
FDA was able to ask Merck the right questions, piece together
relevant data, see through Merck’s obfuscations, and discern
how best to draft a warning label.” (Opening Br. at 51.) That
argument is flawed. The District Court did not shift the burden;
rather, it appropriately scrutinized the Plaintiffs’ claim that
Merck failed to submit additional information. Even now on
appeal, the Plaintiffs do not point to what information Merck
neglected to provide to the FDA. Accordingly, the District
Court did not clearly err in rejecting the Plaintiffs’ argument
that Merck failed to provide necessary and available additional
information to the FDA.

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c) In re Avandia is Distinguishable.
The Plaintiffs also argue that our holding in In re
Avandia, 945 F.3d 749, “compels reversal.” (Reply Br. at 12.)
In that case, we reversed a district court’s order granting
summary judgment in favor of a drug manufacturer that
asserted an impossibility pre-emption defense. In re Avandia,
945 F.3d at 752.
The relevant facts were as follows. The drug
manufacturer, GSK, advertised its drug, Avandia, “as being
capable of both controlling a patient’s blood sugar levels and
reducing cardiovascular risk.” Id. at 753 (emphasis omitted).
After FDA approval, “however, concerns arose that Avandia
may in fact increase certain cardiac risks.” Id. (emphasis
omitted). For that reason, GSK submitted a Prior Approval
Supplement to the FDA, requesting to add a warning to its label
for those risks. Id. After the supplement was submitted, a new
study was published about the risks of Avandia. Id. An FDA
official told GSK that “it was difficult for FDA officials to
agree on labeling language for Avandia.” Id. at 754. “GSK’s
representative then proposed implementing the labelling
changes” through the CBE process. Id. In response, “[t]he
FDA official strongly advised against proceeding through the
CBE process, stating that doing so may give legitimacy to [the
new study] and will make people think that GSK must have
other information.” Id. (internal quotation marks omitted).
The FDA sent GSK a complete response letter, stating that “the
information presented [by GSK was] inadequate” and that the
“data require[d] further analysis[.]” Id. (second alteration in
original). The letter requested GSK to submit various types of
specific data and information “in order to address the
deficiency of [the] application.” Id. at 758 (emphasis omitted).

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Because the complete response letter “indicated that
GSK needed to submit various data and information[,]” and
“because the FDA itself stated that it was inadequately
informed of the justifications for the warning,” we concluded
that “GSK could not demonstrate that the FDA was fully
informed of the justifications for the warning.” Id. (cleaned
up). GSK argued that it “did not have access to the information
that the FDA requested until after the [Agency] issued the
[complete response] [l]etter[.]” Id. We called that argument
“unavailing” because “we read Albrecht as holding that, in
order to prove impossibility preemption, the drug manufacturer
must show that the FDA was fully informed of the
justifications for the proposed warning at the time that the FDA
rejected the proposed warning[,]” id. at 758-59 (cleaned up):
In other words, [we explained,] the upshot of
[Albrecht] is that a drug manufacturer must show
that the FDA made a fully informed decision to
reject a change to a drug’s label in order to
establish the demanding defense of impossibility
preemption. If the question of whether the FDA
was fully informed was not tethered in time to
the question of whether the FDA indeed rejected
the proposed warning, the fully informed prong
of the test espoused in [Albrecht] would be
rendered superfluous.
Thus, if GSK wishes to rely on the [complete
response] [l]etter as proof that the FDA rejected
its proposed label change, it must also
demonstrate that the FDA possessed all the
information it deemed necessary to decide

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whether to approve or reject the proposed
warning at the time it issued the [l]etter. By
arguing that it did not have the FDA’s requested
data and information until after the FDA issued
its letter, however, GSK is, in effect, conceding
that the FDA was not fully informed at the time
of the [l]etter’s issuance. For that reason, among
[] others …, GSK cannot satisfy the first prong
of the test espoused in [Albrecht].
Id. at 759 (internal quotation marks omitted).
The Plaintiffs argue that “Avandia requires the
conclusion that Merck fail[ed] to show clear evidence that
FDA prohibited it from adding the warning state law
required[,]” reasoning that, “[a]s in Avandia, [the] FDA sent a
[complete response] [l]etter calling Merck’s proposed
‘justification’ for its stress fracture language ‘inadequate’”
and, “[l]ike in Avandia, [the] FDA invited Merck to resubmit
its application and to fully address all the deficiencies.” (Reply
Br. at 13 (internal quotation marks omitted).)
Avandia cannot be read as broadly as the Plaintiffs
insist. In the Complete Response Letter that Merck received,
the FDA did not request specific information, nor did it
characterize as deficient the information it had received from
Merck. Rather, the FDA denied Merck’s Prior Approval
Supplement because Merck’s “justification for the proposed
precautions section language [was] inadequate.” (J.A. at
1152.) To say that the FDA disagrees with a proposed label
change is not the same as saying there is inadequate
information to make a judgment. The FDA may disagree with
a proposed change for any number of reasons, including the

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55
specific wording proposed for the label. The question is not
whether the FDA agrees with the drug manufacturer; the
question is whether the manufacturer provided the FDA with
all the relevant data and information for the FDA to make a
fully informed decision. Here, the FDA did not tell Merck that
it failed to provide necessary data, as it told the drug
manufacturer in Avandia. 945 F.3d at 758. Thus, Avandia
does not control the outcome of this case.
For all of the forgoing reasons, the District Court did not
err in finding that Merck fully informed the FDA of the
justifications for adding to the Fosamax label a warning about
atypical femoral fractures.22
2. Prong #2: Merck Has Not Shown that the
FDA Would Have Rejected Any and All
Warnings that Satisfied State Law.
The Plaintiffs argue that the District Court erred in
various ways when concluding that the FDA denied Merck’s
label because the science did not show a sufficient causal
connection between Fosamax and atypical femoral fractures.
They contend that Merck proposed a warning for ordinary
stress fractures rather than atypical femoral fractures. They
also assert that the Complete Response Letter lacked
preemptive effect so the Court should not have relied on it to
22 Because we conclude that the District Court did not
err in finding that Merck fully informed the FDA of the risks
of atypical femoral fractures, we do not address Merck’s
assertion that the Plaintiffs forfeited their argument on this
point.

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find the state law claims were preempted. Even if the Letter
did have preemptive effect, the Plaintiffs say, the District Court
misinterpreted it because the denial was based on inadequate
wording, not lack of causal evidence. They further argue that
the District Court “erred in relying on informal
communications” with the FDA to interpret the meaning of the
Letter. (Opening Br. at 59.) Finally, they claim that Merck
could have used the CBE route to change the Fosamax label
and warn doctors and patients of atypical femoral fractures,
contrary to the District Court’s conclusion that it could not.
Merck, naturally, contests all those assertions.
a) Merck offered a warning for
atypical femoral fractures, not
“garden-variety” stress fractures.
The Plaintiffs first argue that the District Court “missed
the most fundamental point of the preemption inquiry: [the]
FDA could not have informed Merck that it would disapprove
a warning of atypical femoral fractures because Merck never
proposed such a change.” (Opening Br. at 53.) They say “the
[C]ourt correctly recognized Merck’s burden to establish that
it” advanced a warning of atypical femoral fractures, “but
erroneously concluded Merck had met its burden, despite
acknowledging that Merck’s warning did not employ the word
‘atypical.’” (Opening Br. at 53 (internal quotation marks
omitted).) In their view, the warning was one for “garden-
variety” stress fractures, rather than atypical femoral fractures.
(Opening Br. at 13.)
The Plaintiffs have no response to the District Court’s
finding that the use of ‘“atypical’ was hardly settled scientific
jargon at the time” (J.A. at 94) and thus not determinative as to

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the appropriate characterization of the warning. Moreover, the
District Court conducted an extensive ten-page analysis
explaining how Merck’s proposed warning “had all the
hallmarks of atypical femoral fracture such that not having
employed the word ‘atypical’ would not somehow change the
nature of the proposed warning as plainly expressed by its
language.” (J.A. at 94.) For example, the title of the warning
itself was “Low-Energy Femoral Shaft Fracture,” which refers
to a fracture that results from minimal trauma to the thigh bone.
(J.A. at 87-88.) The District Court found that Merck had
explained in its Prior Approval Supplement that it used the
term “stress fracture” in its warning “to mean an ‘insufficiency
fracture’ that occurs with no ‘identifiable external traumatic
event.’” (J.A. at 89.)
Further, the District Court found that, “regardless of any
inadequacies in the text of [Merck’s] warning, the FDA clearly
understood the type of fracture at issue.” (J.A. at 93.) As the
Court noted, the FDA sent Merck a June 2008 email titled
“Fosamax Information Request – Atypical Fractures,” in
which it asked Merck “for more data concerning the
occurrence of atypical fractures.” (J.A. at 93 (internal
quotation marks omitted).) “What is more, the FDA even
called the fractures at issue ‘atypical’” in its Complete
Response Letter. (J.A. at 93); (J.A. at 96 (“Identification of
‘stress fractures’ may not be clearly related to the atypical
subtrochanteric fractures that have been reported in the
literature.” (emphasis omitted) (quoting J.A. at 1152)).)
Again, the District Court’s reasoning is sound. There is
no legitimate basis to believe that the FDA did not understand
that Merck was proposing a warning about atypical femoral
fractures. The language of Merck’s Prior Approval

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Supplement supports its position, and the plain text of the
Complete Response Letter confirms that the FDA understood
Merck’s proposal to be one about atypical femoral fractures.
b) Complete response letters can
have preemptive effect.
Before the District Court, the Plaintiffs argued that a
complete response letter “does not carry preemptive effect
because it is not a final agency action.” (J.A. at 81.) At oral
argument, the Plaintiffs conceded that complete responses
letters may have preemptive effect, but they contend that the
Letter in this case did not have such effect because it “invited
further action” and because other FDA communications
confirm its “provisional nature.” (Opening Br. at 36-37.)
Merck, at oral argument, conceded that not every complete
response letter has preemptive effect, but it argues that the
Letter in this case did. Thus, on appeal, the parties are in
accord that the particular language of a complete response
letter governs its preemptive effect.
We too agree. The Supreme Court “has recognized that
an agency regulation with the force of law can pre-empt
conflicting state requirements.” Wyeth, 555 U.S. at 576. In
Albrecht, the Court stated that “[f]ederal law permits the FDA
to communicate its disapproval of a warning” “by formally
rejecting a warning label that would have been adequate under
state law[.]” Albrecht, 587 U.S. at 315-16. The Court cited
§ 314.110(a), the regulation setting forth the rules regarding
complete response letters, for that statement. Id. at 316.
Although the Supreme Court’s statement was dicta because, as
it recognized, “[t]he question of [a] disapproval ‘method’ [was]
not … before [it,]” we do not take lightly the Court’s citation

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to the regulation governing complete response letters as an
example of an “agency action[] that can determine the answer
to the pre-emption question[.]”23 Id. at 315-16. The bottom
line is that a complete response letter may have preemptive
effect, but whether it does depends upon the specific language
it uses.
c) The District Court erred in
concluding that the FDA would
have rejected any and all labels
that would have satisfied state law.
The outcome of this case thus largely depends on the
interpretation of the Complete Response Letter the FDA issued
to deny Merck’s Prior Approval Supplement. The paragraph
in the Letter explaining the FDA’s reasons for denying
Merck’s proposed label change is, again (see supra Section
I.C.), as follows:
While the Division agrees that atypical and
subtrochanteric fractures should be added to the
ADVERSE REACTIONS, Post-Marketing
23 The Plaintiffs relied on Justice Thomas’s concurrence
in Albrecht (see supra note 13) where he held that complete
response letters “cannot be ‘Law’ with pre-emptive effect”
because they “merely ‘infor[m] sponsors of changes that must
be made before an application can be approved, with no
implication as to the ultimate approvability of the
application[.]’” 587 U.S. at 322 (Thomas, J., concurring)
(emphasis omitted) (quoting 73 Fed. Reg. at 39589). The
majority, however, did not adopt his view.

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Experience subsections of the [Fosamax] labels,
your justification for the proposed
PRECAUTIONS section language is
inadequate. Identification of “stress fractures”
may not be clearly related to the atypical
subtrochanteric fractures that have been reported
in the literature. Discussion of the risk factors
for stress fractures is not warranted and is not
adequately supported by the available literature
and post-marketing adverse event reporting.
(J.A. at 1152-53.)
Not surprisingly, the parties diverge in their
interpretation of that paragraph. “In Merck’s view, the FDA
concluded that the science did not yet show a sufficiently clear
connection to justify a warning, and thus the [A]gency would
not approve a change to the drug’s label to include that
warning.” (Answering Br. at 36 (cleaned up).) In contrast, the
Plaintiffs theorize that the “FDA’s critique was not that the
‘literature’ insufficiently linked Fosamax to atypical femoral
fractures; it was that Merck’s discussion of ‘stress fractures’
misidentified the risk.” (Opening Br. at 57.)
The District Court itself thought the Letter to be
ambiguous. It explained that, “as worded, the language of the
[Complete Response Letter] gives rise to competing inferences
with respect to why the FDA rejected [Merck]’s warning.”
(J.A. at 96.) “On the one hand,” the Court said, the Letter
“describes the ‘justification’ for the warning as
‘inadequate[,]’” so, “[l]ogically, the [Letter] was presumably
referencing the data [Merck] submitted with its [Prior
Approval Supplement], linking low-energy femur fractures to

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bisphosphonates.” (J.A. at 96.) The Court continued, “[o]n the
other hand, the [Letter] discusses [Merck]’s use of the term
‘stress fracture,’ stating that such fractures ‘may not be clearly
related to the atypical … fractures that have been reported in
the literature’ and it is ‘not warranted’ to discuss risk factors
for them.” (J.A. at 96-97.)
The District Court acknowledged that “[i]f the
[Complete Response Letter] were the sum total of the evidence
of FDA action in this case, [the] Plaintiffs might be on firmer
footing with regards to their preemption arguments.” (J.A. at
97.) But the Court continued: “Focusing on the sequence of
communications and announcements from the same period, the
[Letter] does not tell the whole story without the proper context
gleaned from other FDA communications.” (J.A. at 99.) “In
light of [the] competing readings, [the District Court] …
look[ed] beyond the [Letter]’s terms alone to ascertain its
meaning and scope.” (J.A. at 97.) The Court recognized that
“informal communications do not constitute ‘Laws’ with the
power to preempt[,]” but believed it was appropriate to use
those communications for the “limited purpose” to ‘“shed light
on’ the meaning and scope of the [Complete Response Letter],
which is ‘Law’ with preemptive effect.” (J.A. at 98 (emphasis
omitted).)
First, the District Court looked at certain phone call
notes (described supra Section I.C.) that were prepared by a
Merck employee, regarding a conversation that took place
between Merck and the FDA one month before the Complete
Response Letter was issued. According to those notes, the
FDA representative indicated that “[t]he conflicting nature of
the literature [did] not provide a clear path forward, and more
time [would] be need[ed] for FDA to formulate a formal

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opinion on the issue of a precaution around these data.” (J.A.
at 1251.) The Court then referred to the FDA’s March 2010
Safety Announcement, which stated that the FDA’s “review of
the data ‘did not show an increase in th[e] risk’ of atypical
femoral fractures from bisphosphonate use.” (J.A. at 97
(quoting J.A. at 1160)). “FDA officials did not change their
assessment[,]” the Court noted, “until October 2010, a month
after the Task Force issued its Report[.]” (J.A. at 97).
The District Court also relied on an amicus brief the
FDA filed in Albrecht, in which the Agency asserted that “it
rejected [Merck]’s warning for ‘the lack of adequate data to
support [it],’ and not ‘because of … the term ‘stress fractures.’”
(J.A. at 101 (alterations in original).) The Court believed that
the FDA’s own interpretation of its Complete Response Letter
“deserve[d] some measure of deference.” (J.A. at 102 (citing
Auer v. Robbins, 519 U.S. 452, 461-62 (1997)).) It reasoned
that it was “appropriate to consider the FDA’s views because
Congress delegated to that agency the authority to implement
federal drug regulations, it has expertise in that highly
‘technical’ subject matter, and it is well-equipped to navigate
‘the relevant history and background’ on such a ‘complex and
extensive’ issue.”24 (J.A. at 102 (quoting Geier v. American
Honda Motor Co., 529 U.S. 861, 883 (2000)).)
24 The District Court noted its awareness “that in Kisor
v. [Wilkie], [588 U.S. 558] (2019), the Supreme Court warned
that ‘a court should decline to defer to a merely convenient
litigation position or post-hoc rationalization advanced to
defend past agency action against attack,’ such as a brand-new
interpretation presented for the first time in legal briefs.” (J.A.
at 102 (quoting Kisor, 588 U.S. at 579 (cleaned up)).)

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The District Court concluded that, when “[c]onstrued in
light of these various FDA communications, the [Complete
Response Letter] clearly rejected [Merck]’s warning, in part,
because the FDA doubted the underlying science causally
connecting bisphosphonate use and atypical femoral
fractures.” (J.A. at 101.) Accordingly, the Court was “satisfied
that the evidence is clear and convincing that the Agency
would not have approved a differently worded warning no
matter how Defendant attempted to submit one.” (J.A. at 123.)
Merck argues that the Court’s conclusion that the FDA
denied Merck’s application for scientific reasons constitutes a
factual finding that we must review for clear error. Not so.
Written instruments, “such as those normally produced by a
federal agency to memorialize its considered judgments[,]”
Albrecht, 587 U.S. at 316, like the Complete Response Letter
in this case, “often present[] a question solely of law, at least
when the words in those instruments are used in their ordinary
meaning[,]” Teva, 574 U.S. at 326 (internal quotation marks
omitted).25 Indeed, the question of agency disapproval “often
25 It is true that “technical words or phrases not
commonly understood … may give rise to a factual dispute”
and that resolution of those factual disputes is reviewed for
clear error. Teva, 574 U.S. at 326 (citation and internal
quotation marks omitted). But the District Court’s conclusion
in this case did not depend on the meaning of any technical
words and phrases in the Complete Response Letter. Rather,
the Court concluded, based on informal communications and
the FDA’s amicus brief, that the reason the FDA denied

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involves the use of legal skills to determine whether [the]
disapproval fits facts that are not in dispute.” Albrecht, 587
U.S. at 316. The “meaning and effect of an agency decision”
is a “legal determination[.]” Id. at 317. Therefore, the
interpretation of the Complete Response Letter is a question of
law that we review de novo.
We agree with the District Court that the Letter’s
language is ambiguous. The FDA told Merck that the
proffered “justification for the proposed precautions section
language is inadequate.” (J.A. at 1152 (cleaned up).) The
word “justification” could be referring to a lack of scientific
support showing a connection between Fosamax and atypical
femoral fractures. But it could also mean that there is no basis
to include language referring to generic stress fractures in a
warning that is supposed to be about atypical femoral fractures.
The FDA then noted that “[i]dentification of ‘stress fractures’
may not be clearly related to the atypical subtrochanteric
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 adequately supported by the available
literature and post-marketing adverse event reporting.” (J.A.
at 1152-53.) Those statements may be a clarification of why
the “justification” for the label was deemed lacking – the term
“stress fractures” does not convey the same meaning as
“atypical femoral fractures.” But the FDA may have also been
communicating a second, independent reason the label was
rejected, in addition to a lack of scientific evidence.
Merck’s Prior Approval Supplement must have been because
of lack of scientific evidence.

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Undertaking our own review of the Complete Response
Letter in the context of the pre-emption question presented
here, we conclude that the District Court erred by placing too
much weight on informal FDA communications and the
Agency’s amicus brief to decide that the Letter preempted the
Plaintiffs’ state law claims. We acknowledge that this is a
close case, but, in a close case, the strong presumption that the
Supreme Court has established will likely be determinative.
The “difficult” and “demanding” clear-evidence standard is
one that “a drug manufacturer will not ordinarily be able to
show[.]” Albrecht, 587 U.S. at 313, 315. Congress’s intent to
preserve state law claims in the drug labeling context would be
undermined, and the presumption against pre-emption that
exists in that context would have diminished effect, if the kinds
of informal communications the District Court relied on here
could readily serve as the determinative evidence in answering
the pre-emption question.
Again, “the purpose of Congress is the ultimate
touchstone in every pre-emption case.” Wyeth, 555 U.S. at
565. In the drug labeling context, Congress has repeatedly
“[taken] care to preserve state law” because it “determined that
widely available state rights of action provide[] appropriate
relief for injured consumers” and because “state-law remedies
further consumer protection by motivating manufacturers to
produce safe and effective drugs and to give adequate
warnings.” Id. at 567, 574. And the Supreme Court, after
undertaking “a careful review of the history of federal
regulation of drugs and drug labeling[,]” “found nothing within
that history to indicate that the FDA’s power to approve or to
disapprove labeling changes, by itself, pre-empts state law.”
Albrecht, 587 U.S. at 311.

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Rather, [the Court] concluded that Congress
enacted the FDCA “to bolster consumer
protection against harmful products;” that
Congress provided no “federal remedy for
consumers harmed by unsafe or ineffective
drugs”; that Congress was “aware of the
prevalence of state tort litigation;” and that,
whether Congress’ general purpose was to
protect consumers, to provide safety-related
incentives to manufacturers, or both, language,
history, and purpose all indicate that “Congress
did not intend FDA oversight to be the exclusive
means of ensuring drug safety and
effectiveness.”
Id. (cleaned up) (quoting Wyeth, 555 U.S. at 574-75).
The Supreme Court has “also observed that, ‘through
many amendments to the FDCA and to FDA regulations, it has
remained a central premise of federal drug regulation that the
manufacturer bears responsibility for the content of its label at
all times.’” Id. at 312 (quoting Wyeth, 555 U.S. at 570-71).
Accordingly, we must view the pre-emption question here “[i]n
light of Congress’ reluctance to displace state laws that would
penalize drug manufacturers for failing to warn consumers of
the risks associated with their drugs, and Congress’ insistence
on requiring drug manufacturers to bear the responsibility for
the content of their drug labels[.]” Id.
We are not unsympathetic to the pressures Merck faced
from the competing demands of a possible state law
requirement and FDA action, but there is no escaping the
consequences of Albrecht. The Supreme Court has established

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a very high bar to show impossibility pre-emption in drug
labeling cases. It is Merck’s burden to show that “federal law
(including appropriate FDA actions) prohibited the drug
manufacturer from adding any and all warnings to the drug
label that would satisfy state law.” Albrecht, 587 U.S. at 313-
14 (emphasis added). And because “federal law – the FDA’s
CBE regulation – permits drug manufacturers to change a label
… without prior approval from the FDA[,]” “a drug
manufacturer will not ordinarily be able to show that there is
an actual conflict between state and federal law such that it was
impossible to comply with both.”26 Id. at 314-15. Merck must
26 While the FDA’s CBE regulation can permit a drug
manufacturer to unilaterally change its drug label without prior
FDA approval, analogous procedures do not necessarily exist
in other product labeling contexts, and that difference can
matter in a pre-emption analysis. In our recent decision in
Schaffner v. Monsanto Corp., the plaintiffs alleged that a
pesticide producer violated Pennsylvania state law by omitting
a required cancer warning from the label of its weed-killer
product. No. 22-3075, ---F.4th ----, 2024 WL 3820973, at *1
(3d Cir. 2024). The applicable federal statute in that case – the
Federal Insecticide, Fungicide, and Rodenticide Act – contains
an express pre-emption clause that overrides any state-law
pesticide labeling requirement differing from the requirements
of federal law. See 7 U.S.C.A. § 136v (States “shall not impose
or continue in effect any requirements for labeling or
packaging in addition to or different from those required under
this subchapter.”). The regulations promulgated under that
statute provide that, barring certain exceptions, pesticide
producers cannot change a product’s labels unless the
Environmental Protection Agency approves the change in

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show that the “federal and state laws irreconcilably conflict.”
Id. at 315 (internal quotation marks omitted) (emphasis added).
In short, we are bound to consider the “presumption against
pre-emption” when analyzing the particular Complete
Response Letter in this case. Bates v. Dow Agrosciences LLC,
544 U.S. 431, 449 (2005). We actually “have a duty to accept
the reading that disfavors pre-emption.” Id.
That is why, despite the superb work of the District
Court, we believe it erred. It did not read the FDA’s Complete
Response Letter in a manner that disfavors pre-emption and
carries out Congress’s intent to permit displacement of state
law only when it is abundantly clear that it is impossible for a
advance. See 40 C.F.R. § 152.44(a) (“If an application for
amended registration is required, the application must be
approved by the Agency before the product, as modified, may
legally be distributed or sold.”).
The statutory and regulatory regime in that case is thus
quite different from the one we are dealing with here. As noted
previously (see supra Section I.A.1.), Congress has not set
forth an express pre-emption provision in the drug labeling
context. And the Supreme Court has said that nothing in the
legislative history of the FDCA shows “that the FDA’s power
to approve or to disapprove labeling changes, by itself, pre-
empts state law.” Albrecht, 587 U.S. at 311. Unlike in the
pesticide labeling context, drug manufactures may have
opportunities to unilaterally change their products’ labels prior
to receiving agency approval. Thus, our decision in Schaffner
does not dictate the pre-emption analysis in this case.

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manufacturer to comply with both federal and state law.27 The
“possibility” that the Letter communicated a conflict between
27 Admittedly, after the Supreme Court vacated our
Fosamax I decision (see supra Section I.D.3.), we instructed
the District Court “to determine the effect of the [FDA]’s
Complete Response Letter … and other communications with
Merck on the issue of whether such agency actions are
sufficient to give rise to preemption.” (J.A. at 38 (quoting
Order at 1, In Re: Fosamax (Alendronate Sodium) Prods. Liab.
Litig., No. 14-1900 (3d Cir. Nov. 25, 2019)).) That instruction
may have misled the District Court to think the extrinsic
evidence in this case could be determinative. While we cannot
exclude the possibility that extrinsic evidence may prove
helpful in some future case, it cannot be determinative in a case
like this, where the ambiguities in the FDA’s Complete
Response Letter are swept away by the heavy Albrecht
presumption. Given how emphatically the Supreme Court has
directed our attention to the weight of that presumption, it
appears that ambiguity alone will seldom, if ever, be enough to
overcome the presumption.
But even if it had been necessary to consult extrinsic
evidence to answer the legal question in this case, it is not clear
that the evidence helps Merck. For example, the District Court
relied on the call notes from April 2009 in which Merck
discussed with FDA officials its pending request to change the
Fosamax label. While the call notes suggest that the FDA
indicated “the conflicting nature of the literature [did] not
provide a clear path forward” at that time, it did not foreclose
the possibility that there was enough scientific evidence of a
connection between bisphosphonates and atypical femoral
fractures to add a warning to the Precautions section of the

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Fosamax label. In fact, the FDA said only that it needed “more
time” to “formulate a formal opinion on the issue of a
precaution around these data.” (J.A. at 1251.) And the FDA’s
suggestion that Merck amend only the Adverse Reactions
section of the Fosamax label was proposed only as “an interim
measure[.]” (J.A. at 1250.)
The only clear extrinsic evidence that the District Court
relied on consisted of the Agency’s statements in an amicus
brief in Albrecht that the proposed label change was rejected
because the science did not show a sufficient connection
between Fosamax and atypical femoral fractures. Although
“we presume that Congress intended for courts to defer to
agencies’ reasonable readings of genuinely ambiguous
regulations” in some circumstances, Kisor v. Wilkie, 588 U.S.
558, 563 (2019) (citing Auer, 519 U.S. at 461-62), “such a
presumption cannot always hold.” Id. (citing City of Arlington
v. FCC, 569 U.S. 290, 309-10 (2013) (Breyer J., concurring in
part and concurring in judgment). And, in this particular
context, the Supreme Court has declared that “agencies have
no special authority to pronounce on pre-emption absent
delegation by Congress” and we do “not defer[] to an agency’s
conclusion that state law is pre-empted.” Wyeth, 555 U.S. at
576-77 (emphasis omitted). Deferring to the FDA’s post-hoc
assertion about the Complete Response Letter would
effectively give the FDA the power to decide the pre-emption
question we are responsible to answer. Id.; Albrecht, 587 U.S.
at 316 (“concluding that the question is a legal one for the
judge”); cf. Loper Bright Enters. v. Raimondo, 144 S. Ct. 2244,
2267 (2024) (“[W]hen an ambiguity happens to implicate a
technical matter, it does not follow that Congress has taken the
power to authoritatively interpret the statute from the courts

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federal and state law “is not enough.”28 Albrecht, 587 U.S. at
314 (cleaned up). Although it is possible that, had Merck
and given it to the agency. Congress expects courts to handle
technical statutory questions.”).
28 With the words “possibility” and “not enough,” we
are again confronted with the “is it a question of law or fact”
conundrum. The Supreme Court recognized in Albrecht that
the issue of pre-emption is not a pristine question of law, that
it is instead a question that may involve “contested brute facts.”
587 U.S. at 317. The Court nonetheless endeavored to push
the issue as far toward the “question of law” end of the
spectrum as it could. In light of Wyeth and Albrecht, however,
it is hard to avoid the conclusion that facts will often abound in
these labeling cases, both when asking what the drug
manufacturer did to inform the FDA of justifications for adding
a new warning to a drug’s label and when asking whether “the
FDA would not approve changing the drug’s label to include
that warning.” Id. at 314. The first of those questions requires
an inquiry into historical fact. The second may well invite
consideration of a hypothetical future. When one asks, “would
you or would you not approve this change” there is a foray into
facts, albeit conjectural facts in the future. The potentially
sweeping nature of that inquiry is emphasized by the Supreme
Court’s further statement that the drug manufacturer must
show that “federal law prohibited [it] from adding any and all
warnings ... that would satisfy state law. Id. at 313-14
(emphasis added). That invokes a broad array of possibilities.
True enough, Albrecht can be read as framing the
inquiry in terms of comparing federal law and state law and
looking for an overlap that can accommodate an appropriate

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suggested an atypical femoral fracture label, the FDA would
have prohibited it, “[t]he existence of a hypothetical or
potential conflict is insufficient to warrant the pre-emption of
the state statute.” Rice, 458 U.S. at 659. To support the
conclusion that there was pre-emption, the FDA, acting with
the force of law, must have clearly rejected Merck’s label in a
drug warning. That looks like pretty pristine legal work. But
since the question a drug manufacturer faces first is not what
its lawyers make of legal texts but what the FDA makes of
them, and since an agency’s policies can and sometimes do
vary from administration to administration, the issue starts to
look a good deal less than pristinely legal. As soon as one asks
what the FDA would or would not do, one is confronted with
figuring out just how much proof – regardless of whether a
judge is making the assessment instead of a jury – is enough to
persuade the decisionmaker of what that hypothetical future
looks like. Thus, while the opinion in Albrecht declined to
“further define Wyeth’s use of the words ‘clear evidence’ in
terms of evidentiary standards, such as ‘preponderance of the
evidence’ or ‘clear and convincing evidence’ and so forth,” id.
at 315, it still asks courts to hold drug manufacturers to some
standard of proof. It is not easy to get away from Wyeth’s
statement, not disclaimed in Albrecht, that “clear evidence” is
required. Wyeth, 555 U.S. at 571 (quoted in Albrecht, 587 U.S.
at 313). As discussed, Albrecht defines “clear evidence” as
“evidence that shows the court that the drug manufacturer fully
informed the FDA of the justifications for the warning required
by state law and that the FDA, in turn, informed the drug
manufacturer that the FDA would not approve a change to the
drug’s label to include that warning.” 587 U.S. at 303. That is
the standard we are endeavoring to apply here.

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manner that made it evident that no label about atypical
femoral fractures would have been appropriate at the time of
Merck’s Prior Approval Supplement. That did not happen
here. For that reason, Merck has not shown that the FDA
would have rejected any and all labels that would have satisfied
state law. In addition, the availability of a label change via a
CBE supplement is problematic for Merck, as will very often
be the case for pharmaceutical companies raising an
impossibility defense.29 The bar set by Albrecht is high indeed.
Therefore, Merck has not shown that federal and state law
irreconcilably conflict.30
29 As a reminder (see supra Section I.A.3.), a drug
manufacturer cannot use a CBE supplement to make a major
change to a drug’s label. Instead, it must use a Prior Approval
Supplement to do so. § 314.70(b). For that reason, the CBE
regulation is not relevant to the preemption analysis for any
major changes made to a drug’s label.
30 We are not deciding whether “there is sufficient
evidence to find that Merck violated state law by failing to add
a warning about atypical femoral fractures to the Fosamax
label.” Albrecht, 587 U.S. at 314. That conclusion must be
determined at trial. Nor are we implying anything about the
evidence that will be admissible at trial. Our holding is solely
that the Plaintiffs’ state law claims are not preempted.

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d) The Statutory and Regulatory
Framework Does Not Change Our
Conclusion.
(1) Section 355(o)(4)(A)
Merck relies on § 355(o)(4)(A), which, in his
concurring opinion in Albrecht, Justice Alito noted we would
do well to consider on remand. (See supra note 14.) We do so
now. Under that provision, the FDA has a duty to notify drug
manufacturers if it “becomes aware of new information” that
“should be included in the labeling[.]”31 § 355(o)(4)(A). After
discussions with the manufacturer, the Agency “may issue an
order directing” the manufacturer “to make such a labeling
change as the [FDA] deems appropriate to address the new
safety or new effectiveness information.” § 355(o)(4)(E).
Merck argues that it “strains credulity to claim the FDA did not
agree with Merck’s use of ‘stress fracture’ terminology and
therefore did nothing – even at the expense of patient safety.”
(Answering Br. at 40.) That echoes Justice Alito’s comment
that § 355(o)(4)(A) “arguably affect[s] the pre-emption
analysis” “because, if the FDA declines to require a label
change despite having received and considered information
regarding a new risk, the logical conclusion is that the FDA
determined that a label change was unjustified.” Albrecht, 587
U.S. at 324 (Alito, J., concurring). He suggested that FDA
inaction could communicate disapproval of a warning because
31 We agree with the parties that § 355(o)(4)(A) is
relevant to the second prong of the Albrecht analysis – i.e.,
whether the FDA informed Merck that it would not have
accepted any label about atypical femoral fractures that
satisfies state law.

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§ 355(o)(4)(A) does not “require the FDA to communicate to
the relevant drug manufacturer that a label change is
unwarranted; instead, the FDA could simply consider the new
information and decide not to act.” Id. at 325.
No doubt § 355(o)(4)(A) may prove important when the
FDA has “received and considered information regarding a
new risk[.]” Id. at 324 (emphasis added). But, in this case, it
appears that the FDA had not fully considered the information
that Merck and other bisphosphonate manufacturers had
submitted prior to issuing the Complete Response Letter to
Merck. If one assumes that the FDA’s refusal was based only
on the lack of a satisfactory link between Fosamax and atypical
femoral fractures, then the suggestion that a warning could be
added to the Adverse Reactions section of the label but not the
Precautions section can be seen as a statement by the FDA that
it was not fully convinced of the link yet, not that it could not
be convinced.
And if one looks beyond the Letter, it is more apparent
that the FDA was still assessing evidence. As earlier discussed
(see supra Section I.C.), in April 2009, a Merck representative
had a phone conversation with FDA officials about the pending
request to change the Fosamax label. On that call, Merck
explained to the FDA that it “was anxious to understand [the]
FDA’s timelines for completing their review of [the Fosamax
Prior Approval Supplement] and that this information had not
been forthcoming[.]” (J.A. at 1251.) The FDA officials
explained that the Agency’s “duration of review was related to
[Merck’s] elevation of [the atypical femoral fractures] issue to
a precaution in the labeling.” (J.A. at 1251.) They “indicated
that they could agree quickly to language in the [Adverse
Reactions] section of the labeling[,] but that the Agency

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“would like to approach the issue of a precaution from the
[perspective] of all bisphosphonates” and was working to do
so. (J.A. at 1251 (emphasis added).) According to the call
notes, “the conflicting nature of the literature [did] not provide
a clear path forward, [so] more time [was] need[ed] for [the]
FDA to formulate a formal opinion on the issue of a precaution
around these data.” (J.A. at 1251 (emphasis added).) Again,
the FDA suggested that, “as an interim measure,” Merck could
amend the Adverse Reactions section of the Fosamax label.
(J.A. at 1250 (emphasis added).) In a follow-up email, the
FDA told Merck that it would “work with [the Agency’s Office
of Surveillance and Epidemiology] and Merck to decide on
language” for the Warnings and Precaution section, “if it is
warranted.” (J.A. at 1150 (emphasis added).)
Those undisputed facts indicate that, when the FDA
issued the Complete Response Letter in May 2009, it had not
yet determined whether a change to the Precautions section of
the label was warranted. It was not until the Task Force report
issued in September 2010 that the FDA decided it had enough
information to use its authority under § 355(o)(4)(A) to require
Merck and other bisphosphonate manufacturers to include a
warning about atypical femoral fractures in the Precautions
section of the label. So, while § 355(o)(4)(A) is relevant to the
pre-emption analysis when the FDA has fully considered the
information submitted by a drug manufacturer, it does not
change our analysis in this case because the FDA was in the
process of deciding whether a change to the Precautions

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section of the label was needed at the time it issued the
Complete Response Letter.32
Whether it seems fair or not, the FDA can take its time,
but Merck is responsible “for the content of its label at all
times.” Albrecht, 587 U.S. at 312. Practical considerations are
a factor in laying that continuing responsibility on the drug
manufacturer. “The FDA has limited resources to monitor the
… drugs on the market, and manufacturers have superior
access to information about their drugs, especially … as new
risks emerge.” Wyeth, 555 U.S. at 578-79. “State tort suits
uncover unknown drug hazards and provide incentives for drug
manufacturers to disclose safety risks promptly.” Id. “They
also serve a distinct compensatory function that may motivate
injured persons to come forward with information.” Id. In
short, “[f]ailure-to-warn actions,” like this case, “lend force to
the FDCA’s premise that manufacturers, not the FDA, bear
primary responsibility for their drug labeling at all times.” Id.;
see also § 355(o)(4)(I) (“This paragraph shall not be construed
to affect the responsibility of the [drug manufacturer] … to
32 Analyzing the informal FDA communications to
determine the impact of § 355(o)(4)(A) in this case is not
inconsistent with our previous conclusion that the District
Court erred in relying too heavily on such communications to
answer the preemption question. We must “understand and …
interpret agency decisions in light of the governing statutory
and regulatory context.” Albrecht, 587 U.S. at 316. We do not
analyze the FDA communications here to interpret the
Complete Response Letter; we look at them only to determine
whether § 355(o)(4)(A) has some importance in this particular
case.

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maintain its label in accordance with existing
requirements[.]”). Thus, since the FDA had not formalized a
decision on whether to include atypical femoral fracture
language in the Precautions section of Fosamax’s label, it is not
dispositive that the Agency did not invoke its power under
§ 355(o)(4)(A) to require manufacturers to change its label.
(2) Section 314.105(b)
Merck also argues that § 314.105(b) of the FDA’s
regulations “bolsters the inference that the FDA did not believe
there was reasonable scientific evidence of a causal association
between bisphosphonate use and atypical femoral fractures[.]”
(Answering Br. at 40 (internal quotation marks omitted).) That
provision states the FDA will approve a drug application “if
the only deficiencies in the [application] concern editorial or
similar minor deficiencies in the draft labeling.” § 314.105(b).
Thus, according to Merck, if the FDA had a problem with the
“stress fracture” language, it “could have simply stricken it, as
it did two years later, or approved it on the condition that
[Merck] implement edits.” (Answering Br. at 40 (alteration in
original).)
That argument has some persuasive force if one accepts
that the “stress fracture” language in the proposed warning was
viewed as merely a poor choice of words. We have our doubts
about that premise. All but the first sentence of the proposed
Precautions warning used the term “stress fracture,” and that

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emphasis may well have been significant to the FDA.33 (See
J.A. at 1280.) After all, the regulations provide that the FDA
will use a complete response letter to deny an application if the
33 As a reminder (see supra Section I.C.), the proposed
Precautions warning states:
Low-energy fractures of the subtrochanteric and
proximal femoral shaft have been reported in a
small number of bisphosphonate-treated
patients. Some were stress fractures (also known
as insufficiency fractures) occurring in the
absence of trauma. Some patients experienced
prodromal pain in the affected area, often
associated with imaging features of stress
fracture, weeks to months before a complete
fracture occurred. The number of reports of this
condition is very low, and stress fractures with
similar clinical features also have occurred in
patients not treated with bisphosphonates.
Patients with suspected stress fractures should be
evaluated, including evaluation for known
causes and risk factors (e.g., vitamin D
deficiency, malabsorption, glucocorticoid use,
previous stress fracture, lower extremity arthritis
or fracture, extreme or increased exercise,
diabetes mellitus, chronic alcohol abuse), and
receive appropriate orthopedic care. Interruption
of bisphosphonate therapy in patients with stress
fractures should be considered, pending
evaluation of the patient, based on individual
benefit/risk assessment.
(J.A. at 1280.)

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drug’s “proposed labeling is false or misleading in any
particular.” § 314.125(b)(6) (emphasis added); § 314.110(a)
(The “FDA will send the applicant a complete response letter
if the [A]gency determines that we will not approve the
application or abbreviated application in its present form for
one or more of the reasons given in § 314.125 or § 314.127,
respectively.”). So it may be that the Plaintiffs are correct in
their assertion that the FDA denied the labeling change because
the stress fracture language was viewed as misleading.
Ultimately, the statutory and regulatory provisions that Merck
cites do not change our conclusion that the Plaintiffs’ state law
claims are not preempted.
III. C ONCLUSION
For the foregoing reasons, we will vacate the District
Court’s judgment and remand the case for further
proceedings.34
34 Our opinion today analyzes drug labeling in the
brand-name drug manufacturer context. The statutory and
regulatory regime is different for generic drug manufacturers.
See PLIVA, Inc. v. Mensing, 564 U.S. 604, 626 (2011) (“[T]he
federal statutes and regulations that apply to brand-name drug
manufacturers are meaningfully different than those that apply
to generic drug manufacturers.”). We do not opine on the
principles to be applied in that different context.

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