Merck Sharp & Dohme Corp. v. Albrecht

*1672When Congress enacted the Federal Food, Drug, and Cosmetic Act, ch. 675, 52 Stat. 1040, as amended, 21 U.S.C. § 301 et seq. , it 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." § 355(d). When the FDA exercises this authority, it makes careful judgments about what warnings should appear on a drug's label for the safety of consumers.

For that reason, we have previously held that "clear evidence" that the FDA would not have approved a change to the drug's label pre-empts a claim, grounded in state law, that a drug manufacturer failed to warn consumers of the change-related risks associated with using the drug. See Wyeth v. Levine , 555 U. S. 555, 571, 129 S.Ct. 1187, 173 L.Ed.2d 51 (2009). We here determine that this question of pre-emption is one for a judge to decide, not a jury. We also hold that "clear evidence" is 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.

I

The central issue in this case concerns federal pre-emption, which as relevant here, takes place when it is " 'impossible for a private party to comply with both state and federal requirements.' " Mutual Pharmaceutical Co. v. Bartlett , 570 U. S. 472, 480, 133 S.Ct. 2466, 186 L.Ed.2d 607 (2013). See also U. S. Const., Art. VI, cl. 2. The state law that we consider is state common law or state statutes that require drug manufacturers to warn drug consumers of the risks associated with drugs. The federal law that we consider is the statutory and regulatory scheme through which the FDA regulates the information that appears on brand-name prescription drug labels. The alleged conflict between state and federal law in this case has to do with a drug that was manufactured by petitioner Merck Sharp & Dohme and was administered to respondents without a warning of certain associated risks.

A

The FDA regulates the safety information that appears on the labels of prescription drugs that are marketed in the United States. 21 U.S.C. § 355(b)(1)(F) ; 21 C.F.R. § 201.57(a) (2018). 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. 21 U.S.C. § 321(m). These (often lengthy) package inserts contain detailed information about *1673the drug's medical uses and health risks. § 355(b)(1)(F) ; 21 C.F.R. § 201.57(a).

FDA regulations set out requirements for the content, the format, and the order of the safety information on the drug label. § 201.57(c). Those regulations require drug labels to include, among other things: (1) prominent "boxed" warnings about risks that may lead to death or serious injury; (2) contraindications describing any situation in which the drug should not be used because the risk of use outweighs any therapeutic benefit; (3) warnings and precautions about other potential safety hazards; and (4) any adverse reactions for which there is some basis to believe a causal relationship exists between the drug and the occurrence of the adverse event. Ibid.

As those requirements make clear, the category in which a particular risk appears on a drug label is an indicator of the likelihood and severity of the risk. The hierarchy of label information is designed to "prevent overwarning" so that less important information does not "overshadow" more important information. 73 Fed. Reg. 49605-49606 (2008). It is also designed to exclude "[e]xaggeration of risk, or inclusion of speculative or hypothetical risks," that "could discourage appropriate use of a beneficial drug." Id ., at 2851.

Prospective drug manufacturers work with the FDA to develop an appropriate label when they apply for FDA approval of a new drug. 21 U.S.C. §§ 355(a), 355(b), 355(d)(7) ; 21 C.F.R. § 314.125(b)(6). But FDA regulations also acknowledge that information about drug safety may change over time, and that new information may require changes to the drug label. §§ 314.80(c), 314.81(b)(2)(i). Drug manufacturers generally seek advance permission from the FDA to make substantive changes to their drug labels. However, an FDA regulation called the "changes being effected" or "CBE" regulation permits drug manufacturers to change a label without prior FDA approval if the change is designed to "add or strengthen a ... warning" where there is "newly acquired information" about the "evidence of a causal association" between the drug and a risk of harm. 21 C.F.R. § 314.70(c)(6)(iii)(A).

B

Petitioner Merck Sharp & Dohme manufactures Fosamax, a drug that treats and prevents osteoporosis in postmenopausal women. App. 192; In re Fosamax (Alendronate Sodium) Products Liability Litigation , 852 F. 3d 268, 271, 274-275 (CA3 2017). Fosamax belongs to a class of drugs called "bisphosphonates." Fosamax 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. App. 102, 111. For some 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. That imbalance can lead to osteoporosis, a disease that is characterized by low bone mass and an increased risk of bone fractures. Fosamax (like other bisphosphonates) slows the breakdown of old bone cells and thereby helps postmenopausal women avoid osteoporotic fractures. Id., at 102.

However, the mechanism through which Fosamax decreases the risk of osteoporotic fractures may increase the risk of a different type of fracture. Id ., at 400-444, 661-663. That is because all bones-healthy and osteoporotic alike-sometimes develop microscopic cracks that are not due to any trauma, but are instead caused by the mechanical stress of everyday activity. Id., at 102. Those so-called "stress fractures" ordinarily heal on their own through the bone remodeling process. But, by slowing *1674the breakdown of old bone cells, Fosamax and other bisphosphonates may cause stress fractures to progress to complete breaks that cause great pain and require surgical intervention to repair.Id., at 106-109, 139, 144-145. When that rare type of complete, low-energy fracture affects the thigh bone, it is called an "atypical femoral fracture." Id., at 101.

The Fosamax label that the FDA approved in 1995 did not warn of the risk of atypical femoral fractures. 852 F. 3d at 274-275. At that time, Merck's scientists were aware of at least a theoretical risk of those fractures. Indeed, as 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.' " App. 111-113. When Merck applied to the FDA for approval of Fosamax, Merck brought those theoretical considerations to the FDA's attention. 852 F. 3d at 274-275. But, perhaps because the concerns were only theoretical, the FDA approved Fosamax's label without requiring any mention of this risk. Ibid.

Evidence connecting Fosamax to atypical femoral fractures developed after 1995. Merck began receiving adverse event reports from the medical community indicating that long-term Fosamax users were suffering atypical femoral fractures. App. 122-125. For example, Merck received a report from a doctor who said that hospital staff had begun calling atypical femoral fractures the " 'Fosamax Fracture' " because " '100% of patients in his practice who have experienced femoral fractures (without being hit by a taxicab), were taking Fosamax... for over 5 years. ' " Id., at 126. Merck performed a statistical analysis of Fosamax adverse event reports, concluding that these reports revealed a statistically significant incidence of femur fractures. 3 App. in No. 14-1900 (CA3), pp. A1272-A1273, A1443. And about the same time, Merck began to see numerous scholarly articles and case studies documenting possible connections between long-term Fosamax use and atypical femoral fractures. App. 106-110, 116-122.

In 2008, Merck applied to the FDA for preapproval to change Fosamax's label to add language to both the "Adverse Reaction[s]" and the "Precaution[s]" sections of the label. Id., at 670. In particular, Merck proposed adding a reference to " 'low-energy femoral shaft fracture ' " in the Adverse Reactions section, and cross-referencing a longer discussion in the Precautions section that focused on the risk of stress fractures associated with Fosamax. Id., at 728. The FDA approved the addition to the Adverse Reactions section, but rejected Merck's proposal to warn of a risk of "stress fractures." Id., at 511-512. The FDA explained that Merck's "justification" for the proposed change to the Precautions section was "inadequate," because "[i]dentification of 'stress fractures ' may not be clearly related to the atypical subtrochanteric fractures that have been reported in the literature." Id., at 511. The FDA invited Merck to "resubmit" its application and to "fully address all the deficiencies listed." Id ., at 512; see 21 C.F.R. § 314.110(b). But Merck instead withdrew its application and decided to make the changes to the Adverse Reactions section through the CBE process. App. 654-660. Merck made no changes to the Precautions section at issue here. Id., at 274.

A warning about "atypical femoral fractures" did not appear on the Fosamax label until 2011, when the FDA ordered that change based on its own analyses. Id., at 246-252, 526-534. Merck was initially resistant to the change, proposing revised *1675language that, once again, referred to the risk of "stress fractures." Id., at 629-634. But the FDA, once again, rejected that language. And this 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., at 566. In January 2011, Merck and the FDA ultimately agreed upon adding a three-paragraph discussion of atypical femoral fractures to the Warnings and Precautions section of the Fosamax label. Id., at 223-224. The label now refers to the fractures five times as "atypical" without using the term "stress fracture." Ibid.

C

The respondents here are more than 500 individuals who took Fosamax and who suffered atypical femoral fractures between 1999 and 2010. Brief for Respondents 7. Respondents, invoking federal diversity jurisdiction, 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. , at 1. One respondent, for example, filed a complaint alleging that she took Fosamax for roughly 10 years and suffered an atypical femoral fracture. One day in 2009, when the respondent was 70 years old, she turned to unlock the front door of her house, heard a popping sound, and suddenly felt her left leg give out beneath her. She needed surgery, in which doctors repaired her leg with a rod and screws. She explained she would not have used Fosamax for so many years if she had known that she might suffer an atypical femoral fracture as a result. See id., at 18-19.

Merck, in defense, argued that respondents' state-law failure-to-warn claims should be dismissed as pre-empted by federal law. Both Merck and the FDA have long been aware that Fosamax could theoretically increase the risk of atypical femoral fractures. But for some period of time between 1995 (when the FDA first approved a drug label for Fosamax ) and 2010 (when the FDA decided to require Merck to add a warning about atypical femoral fractures to Fosamax's label), both Merck and the FDA were unsure whether the developing evidence of a causal link between Fosamax and atypical femoral fractures was strong enough to require adding a warning to the Fosamax drug label. Merck conceded that the FDA's CBE regulation would have permitted Merck to try to change the label to add a warning before 2010, but Merck asserted that the FDA would have rejected that attempt. In particular, Merck pointed to the FDA's rejection of Merck's 2008 attempt to amend the Fosamax label to warn of the risk of "stress fractures" associated with Fosamax. On that basis, Merck claimed that federal law prevented Merck from complying with any state-law duty to warn the respondents of the risk of atypical femoral fractures associated with Fosamax.

The District Court agreed with Merck's pre-emption argument and granted summary judgment to Merck, In re Fosamax (Alendronate Sodium): Products Liability Litigation , 2014 WL 1266994, *17 (D NJ, Mar. 22, 2017), but the Court of Appeals vacated and remanded, 852 F. 3d at 302. The Court of Appeals concluded that its pre-emption analysis was controlled by this Court's decision in Wyeth . Ibid . The Court of Appeals understood that case as making clear that a failure-to-warn claim grounded in state law is pre-empted where there is " 'clear evidence that the FDA

*1676would not have approved a change to the ... label.' " Id., at 280 (quoting Wyeth , 555 U. S. at 571, 129 S.Ct. 1187 ). The Court of Appeals, however, suggested that this statement had led to varying lower court applications and that it would be helpful for this Court to "clarif[y] or buil[d] out the doctrine." 852 F. 3d at 284.

In attempting to do so itself, the Court of Appeals held that "the Supreme Court intended to announce a standard of proof when it used the term 'clear evidence' in Wyeth ." Ibid. That is, the Court of Appeals believed that "[t]he 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." Id ., at 285. "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." Ibid. And in the Court of Appeals' view, "for a defendant 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. Moreover and importantly, the Court of Appeals also held that "whether the FDA would have rejected a proposed label change is a question of fact that must be answered by a jury." Ibid .

Merck filed a petition for a writ of certiorari. Merck's petition asked the Court to decide whether Merck's case and others like it "must ... go to a jury" to determine whether the FDA, in effect, has disapproved a state-law-required labeling change. In light of differences and uncertainties among the courts of appeals and state supreme courts in respect to the application of Wyeth , we granted certiorari. See, e.g., Mason v. SmithKline Beecham Corp. , 596 F. 3d 387, 391 (CA7 2010) ("The Supreme Court ... did not clarify what constitutes 'clear evidence' "); Reckis v. Johnson & Johnson , 471 Mass. 272, 286, 28 N. E. 3d 445, 457 (2015) (" Wyeth did not define 'clear evidence' ... " (some internal quotation marks omitted)).

II

We stated in Wyeth v.Levine that state law failure-to-warn claims are pre-empted by the Federal Food, Drug, and Cosmetic Act and related labeling regulations when there is "clear evidence" that the FDA would not have approved the warning that state law requires. 555 U. S. at 571, 129 S.Ct. 1187. We here decide that a judge, not the jury, must decide the pre-emption question. And we elaborate Wyeth 's requirements along the way.

A

We begin by describing Wyeth. In that case, the plaintiff developed gangrene after a physician's assistant injected her with Phenergan, an antinausea drug. 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. In particular, the plaintiff claimed that directly injecting Phenergan into a patient's vein (the "IV-push" method of administration) creates a significant risk of catastrophic consequences. And those consequences could be avoided by introducing the drug into a saline solution that slowly descends into a patient's vein (the "IV-drip" method of administration). A jury concluded that Wyeth's warning label was inadequate, and that the label's inadequacy caused the plaintiff's injury. 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. The Vermont *1677Supreme Court rejected Wyeth's pre-emption claim. Id., at 563, 129 S.Ct. 1187.

We too considered Wyeth's pre-emption argument, and we too rejected it. In rejecting Wyeth's argument, we undertook a careful review of the history of federal regulation of drugs and drug labeling. Id., at 566-568, 129 S.Ct. 1187. In doing so, we "assum[ed] 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., at 565, 129 S.Ct. 1187 (internal quotation marks omitted). And we 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.

Rather, we 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 "awar[e] 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., at 574-575, 129 S.Ct. 1187 (emphasis added). See also id., at 574, 129 S.Ct. 1187 ("If Congress thought state-law suits posed an obstacle to its objectives, it surely would have enacted an express pre-emption provision at some point during the FDCA's 70-year history").

We 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 570-571, 129 S.Ct. 1187. 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., at 571, 129 S.Ct. 1187. Thus, when the risks of a particular drug become apparent, the manufacturer has "a duty to provide a warning that adequately describe[s] that risk." Ibid. "Indeed," we noted, "prior to 2007, the FDA lacked the authority to order manufacturers to revise their labels." Ibid. And even when "Congress granted the FDA this authority," in the 2007 Amendments to the FDCA, Congress simultaneously "reaffirmed the manufacturer's obligations and referred specifically to the CBE regulation, which both reflects the manufacturer's ultimate responsibility for its label and provides a mechanism for adding safety information to the label prior to FDA approval." Ibid.

In 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, we were unpersuaded by Wyeth's pre-emption argument. In Wyeth's case, we 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." Ibid.

At the same time, and more directly relevant here, we pointed out that "the FDA retains authority to reject labeling changes made pursuant to the CBE regulation in its review of the manufacturer's supplemental application, just as it retains such authority in reviewing all supplemental applications." Ibid. We then said that, *1678nonetheless, "absent clear evidence that the FDA would not have approved a change to Phenergan's label, we will not conclude that it was impossible for Wyeth to comply with both federal and state requirements." Ibid. (emphasis added).

We reviewed the record and concluded that "Wyeth has offered no such evidence." Id ., at 572, 129 S.Ct. 1187. We said that Wyeth's evidence of pre-emption fell short for two reasons. First, the record did not show that Wyeth "supplied the FDA with an evaluation or analysis concerning the specific dangers" that would have merited the warning. Id ., at 572-573, 129 S.Ct. 1187. We could find "no evidence in this record that either the FDA or the manufacturer gave more than passing attention to the issue of IV-push versus IV-drip administration"-the matter at issue in the case. Id ., at 572, 129 S.Ct. 1187 (internal quotation marks omitted). Second, the record did not show that Wyeth "attempted to give the kind of warning required by [state law] but was prohibited from doing so by the FDA." Ibid ., and n. 5. The "FDA had not made an affirmative decision to preserve" the warning as it was or "to prohibit Wyeth from strengthening its warning." Id ., at 572, 129 S.Ct. 1187. For those reasons, we could not "credit Wyeth's contention that the FDA would have prevented it from adding a stronger warning about the IV-push method of intravenous administration." And we could not conclude that "it was impossible for Wyeth to comply with both federal and state requirements." Id ., at 573, 129 S.Ct. 1187. We acknowledged that meeting the standard we set forth would be difficult, but, we said, "[i]mpossibility pre-emption is a demanding defense." Ibid .

B

The 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. And, of course, in order to succeed with that defense the manufacturer must show that the answer to this question is yes. But in Wyeth , we confronted that question in the context of a particular set of circumstances. Accordingly, for purposes of this case, we assume-but do not decide-that, as was true of the warning at issue in Wyeth , 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. In a case like Wyeth , showing that federal law prohibited the drug manufacturer from adding a warning that would satisfy state law requires the drug manufacturer to show that it 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 changing the drug's label to include that warning.

These conclusions flow from our precedents on impossibility pre-emption and the statutory and regulatory scheme that we reviewed in Wyeth . See 555 U. S. at 578, 129 S.Ct. 1187. In particular, "it has long been settled that state laws that conflict with federal law are without effect." Mutual Pharmaceutical Co. , 570 U. S. at 480, 133 S.Ct. 2466. But as we have cautioned many times before, the "possibility of impossibility [is] not enough." PLIVA, Inc. v. Mensing , 564 U. S. 604, 625, n. 8, 131 S.Ct. 2567, 180 L.Ed.2d 580 (2011) (internal quotation marks omitted). Consequently, we have refused to find clear evidence of such impossibility where the laws of one sovereign permit an activity that the laws of the other sovereign restrict or even prohibit. See, e.g., *1679Barnett Bank of Marion Cty., N. A. v. Nelson , 517 U. S. 25, 31, 116 S.Ct. 1103, 134 L.Ed.2d 237 (1996) ; Michigan Canners & Freezers Assn., Inc. v. Agricultural Marketing and Bargaining Bd. , 467 U. S. 461, 478, and n. 21,