Full opinion text
OPINION AND ORDER DENISE COTE, District Judge: Plaintiffs Charlie and Ciara Utts bring this product liability lawsuit against defendants Bristol-Myers Squibb Company (“BMS”) and Pfizer Inc. (“Pfizer”), alleging that Mr. Utts suffered severe gastrointestinal bleeding from taking Eliquis, a prescription drug manufactured, marketed, and distributed by the defendants. They assert that thé label did not adequately warn of the risk of excessive bleeding. The defendants have moved to dismiss the Second Amended Complaint (“SAC”) pursuant to Federal Rules of Civil Procedure 12(b)(6) and 9(b). The primary issues in this motion to dismiss are whether the plaintiffs’ state law failure to warn claims are preempted by federal law and whether the label is adequate as a matter of law. For the following reasons, the defendants’ motion is granted in its entirety. Before describing each of the SAC’s claims and addressing the legal challenges to them brought through this motion to dismiss, it is useful to provide an overview of the analysis that follows. Although the focus of the SAC is on an alleged failure by the defendants to warn that use of Eliquis, which belongs to a new class of blood thinners, runs the risk of causing excessive bleeding and has no known antidote, those allegations are largely abandoned in opposition to the motion to dismiss. The reason for this choice is not hard to discern.. The risk of excessive bleeding from this blood thinner and the lack of an antidoté were clearly disclosed to the Food & Drug Administration (“FDA”) when it approved-the drug, -and are prominently disclosed to medical practitioners and patients on the FDA-approved labeling for the drug. In opposition to this motion, therefore, the plaintiffs emphasize two other, albeit related, issues with the drug. The plaintiffs emphasize in their brief that, despite the fact that there is a risk of excessive bleeding and no known antidote for the drug, the dosage recommendations for the drug are not individually tailored and the defendants do not recommend constant monitoring of patients using the drug. These claims fare no better, ■ When the SAC’s allegations about dosage and monitoring are examined, those allegations fail as well. For instance, the SAC does not identify any specific warnings or guidance that should have been included on the label regarding either dosage or monitoring but were not. The plaintiffs have not identified any research or other clinical work that recommends another dosage strategy than that currently described on the label, or explains what specialized monitoring of a patient would accomplish. These two complaints concern features of the design of the drug that were well known to the FDA when it approved the drug. Faced with the fact that, as of today, there is no research or clinical experience to suggest that any changes to the Eliquis label’s disclosures related.to a risk of excessive bleeding are warranted,¡the plaintiffs argue vehemently that the motion to dismiss should be denied and that they should be permitted to conduct discovery to try'to locate evidence in the defendants’ files that might support their failure to warn claims. They emphasize that there is substantial ongoing litigation over the earlier drugs in the class of drugs to which Eliquis belongs. But, the ability of other plaintiffs in other litigation over other drugs to survive a motion to dismiss does not relieve the plaintiffs of the requirements imposed by Rule 12(b). Accordingly, the claims in the SAC, which reduced to their essence are attacks on the design of this drug, will be dismissed. BACKGROUND The facts are construed in favor of the plaintiffs. See Keiler v. Harlequin Enters. Ltd., 751 F.3d 64, 68 (2d Cir. 2014). Plaintiffs Charlie and Ciara Utts are both residents of California. Mr. Utts was diagnosed with atrial fibrillation and prescribed Eliquis by his doctor. After taking Eliquis, Mr. Utts suffered severe gastrointestinal bleeding and was hospitalized in July 2014 for approximately three weeks to undergo blood transfusions and several rounds of dialysis. Eliquis—the brand name of the prescription medicine apixaban—is a blood-thinning medication used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Eliquis belongs to a class of drugs known as novel oral anticoagulants (“NOACs”). It does not have a known antidote or reversal agent. Unlike anticoagulant medications such as warfarin, NOACs, including Eli-quis, do not require periodic blood testing or impose dietary restrictions on users. I. FDA Approval of Eliquis The FDA approved Eliquis for sale and marketing in the United States in 2012. Pursuant to federal law, all applications for FDA approval of new drugs must include a description of the clinical investigations of the drug, including an analysis of each clinical pharmacology study of the drug and each controlled clinical study pertinent to a proposed use of the drug. See 21 C.F.R. § 314.50(d)(5). In accordance with this requirement, the defendants submitted the results of the international clinical trials known as ARISTOTLE. The plaintiffs allege that the defendants’ agents “committed fraud in their conduct of the ARISTOTLE study,” by, amongst other things, “concealing side effects which occurred in test users of Eliquis.” While the defendants’ application was pending before the FDA, Dr. Thomas Marcinak, an FDA employee appointed to review the Eliquis application, recommended that the proposed Eliquis label discuss the quality control problems associated with the ARISTOTLE study. In response to concerns about the rigor of the ARISTOTLE study, the defendants stated that they were submitting additional data to the FDA for its consideration. II. The Eliquis Label At the time Mr. Utts was prescribed Eliquis, the label contained several warnings about the risk of bleeding and the lack of an effective antidote. The label also offered specific dosing recommendations and discussed the results of the controversial ARISTOTLE study. The warnings that are pertinent to the present motion to dismiss are described here. A. Warnings about Bleeding Risks The Eliquis label warns about the risk of serious bleeding no less than five times. First, in the “Highlights of Prescribing Information” section, under the “Warnings and Precautions” heading, the label states that “ELIQUIS can cause serious, potentially fatal bleeding.” In the “Full Prescribing Information” section of the label, there is a heading entitled ‘Warnings and Precautions” with a subheading entitled “Bleeding.” This subheading provides: “ELIQUIS increases the risk of- bleeding and can cause serious, potentially fatal, bleeding.” Under the “Adverse Reactions” heading,- the label states: “The most serious adverse reactions reported with ELI-QUIS were related to bleeding.” Also under the “Adverse Reactions” heading, the “Clinical Trials Experience” subheading explains that the “most common reason for treatment discontinuation in both [clinical] studies was for bleeding-related adverse reactions.’” Under the “Overdosage” heading, the label states that “[ojverdose of ELIQUIS increases the risk of bleeding.” Finally, under the “Patient Counseling Information” heading, the label advises physicians to inform their patients that “it might take longer than usual for bleeding to stop, and they may bruise or bleed more easily when treated with ELIQUIS.” It also instructs physicians to “[a]dvise patients about how to recognize bleeding or symptoms of hypovolemia and of - the urgent need to report any unusual bleeding to their physician.” B. Warnings about Concomitant Therapy In addition to warning generally about the risk of bleeding, the' Eliquis label also specifically warns about the risk of bleeding when Eliquis is used in conjunction with antiplatelet agents, such as aspirin. The “Bleeding” subheading provides that: Concomitant use of drugs affecting he-mostasis increases the risk of bleeding. These include aspirin and other anti-platelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitor, and nonsteroidal anti-inflammatory drugs (NSAIDs). Furthermore, the “Anticoagulants and An-tiplatelet Agents” subheading asserts that “[cjoadministration of antiplatelet agents, ‘fibrinolytics, heparin, aspirin, and chronic NSAID use increases-the risk of bleeding,” and that in the ARISTOTLE study, for ' example, “concomitant use of aspirin increased the bleeding risk on ELIQUIS from 1.8% per year to 3.4% per year.” C. Warnings about the Lack of an Effective Antidote The Eliquis- label twice warns about the fact that there is no specific antidote to Eliquis. First, under the “Bleeding” subheading, the label unambiguously states: “A specific antidote' for ELIQUIS is not available,” and “[t]here is no established way to reverse the anticoagulant effect of apixaban, which can be expected to persist for about 24 hours after the last dose ,... ” Second, under the ‘ “Overdosage” heading, the label states: “There is no antidote to ELIQUIS.” In addition to warning about the lack of a specific antidote, the label also discusses potential reversal strategies and to what extent these strategies are supported by clinical research:- Because of high plasma protein binding, apixaban is not expected to be dialyzable ..:. Protamine sulfate and vitamin K would not be expected to affect the- anticoagulant activity of apixaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban. There is neither scientific rationale for reversal nor experience with systemic hemostatics (desmopressin and aproti-nin) in individuals receiving apixaban. Use of procoagulant reversal agents such as prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor Vila may be considered but has not been evaluated in clinical studies. Activated oral charcoal reduces absorption of apix-aban, thereby lowering apixaban plasma concentration ...... D. Dosing Recommendations Under the heading “Dosage and Administration,” the Eliquis label recommends dosing adjustments for older and higher risk patients. While the recommended dose for most patients is 5 ’mg taken orally twice daily,, a twice daily dose-of 2.5 mg is recommended for patients with any two of the following characteristics: (1) 80-years or older; (2) 60 kg or less; (3) serum creatinine levels of 1.5 mg/dL or more. The label further advises that when Eliquis is coadministered with drugs that are strong dual inhibitors of “CYP3A4” and “P-gp,” the recommended dose is 2.6 mg twice daily, E. No Way to Measure or. Monitor the Anticoagulation Effect of Eli-quis The “Pharmacodynamics” heading of the label advises that “apixaban prolongs clotting tests such as prothrombin time (PT, INR, and activated partial thromboplastin time (aPTT),” and that “[cjhanges > observed in these clotting tests at the expected therapeutic dose, however, are. small, subject to a high degree of variability, and not useful in monitoring the anticoagulation effect of apixaban.” The label further advises that the Rotachrom Heparin chro-mogenic assay “is not recommended for assessing the anticoagulant effect of apixa-ban.” F. The ARISTOTLE Study The Eliquis label discusses the ARISTOTLE study at length. Some of the reported findings from the ARISTOTLE, trial include that: ELIQUIS was superior to warfarin for the primary endpoint of reducing the risk of stroke and systemic embolism .... Superiority to warfarin was primarily attributable to- a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin. Purely ischemic strokes occurred with similar rates' on both drugs. The label also reports that in the ARISTOTLE trial, Eliquis showed “significantly fewer major bleeds than warfarin.” III. Procedural History The plaintiffs filed their complaint on July 15, 2016. On October 5, the defendants filed a motion to dismiss the initial complaint pursuant to Rules 12(b)(6) and 9(b). On October 13, the defendants moved the Judicial Panel on Multidistrict Litigation (“JPML”) to transfer and coordinate what were then 34 actions pending in 13 different districts—including the instant action—pursuant to 28 U.S.C. § 1407. On October 21, the parties in the instant action filed a letter requesting that the Honorable Lewis A. Kaplan stay all proceedings pending -resolution of the JPML petition. The request to enter a stay was denied on October 28. On November 21, the case was reassigned to this Court as related to sixteen other product liability cases filed in this district concerning the medication Eliquis. That same day, this Court issued an Order instructing the parties in this case and all related actions to confer and identify one or two actions to proceed with early motion practice. The November 21 Order also explained that the initiation' of discovery in all actions would turn on whether or not the Court denies the selected motions to dismiss. On December 2, the parties agreed to proceed with a motion to dismiss in the Utts action. On December 23, the Court issued its Opinion in Utts, granting in part the October 5 motion to dismiss and giving the plaintiffs leave to amend all claims except for the design defect claim, which was entirely preempted. Utts v. Bristol-Myers Squibb Co. & Pfizer Inc., 16cv5668 (DLC), 226 F.Supp.3d 166, 184-86, 2016 WL 7429449, at *11-12 (S.D.N.Y. Dec. 23, 2016) (“Utts”). An amended complaint was filed on January 20, 2017. On February 3, the defendants filed a renewed motion to dismiss the amended complaint pursuant to Rules 12(b)(6) and 9(b). On February 6, the Court issued an Order granting the plaintiffs leave to file a second amended complaint by February 24, noting that it would be unlikely that the plaintiffs would have a further opportunity to amend. On February 7, the multi-district litigation panel issued an order transferring In re: Eliquis Products Liability Litigation, 17md2754, to this Court. The SAC was filed on February 24. The SAC asserts ten causes of action against the defendants: (1) manufacturing defect; (2) failure to warn; (3) strict liability; (4) negligence and gross negligence; (5) breach of express warranty; (6) breach of implied warranty; (7) fraud/fraudulent concealment; (8) negligent misrepresentation; (9) violation of consumer protection laws; and (10) loss of consortium. In pleading these claims, the plaintiffs rely on nine articles or documents to assert what they contend is a plausible claim that the Eliquis labeling fails to adequately warn of the risk of excessive bleeding. The plaintiffs have since withdrawn their manufacturing defect cause of action. In addition to compensatory damages, the plaintiffs seek punitive damages. On March 10, the defendants filed a renewed motion to dismiss the SAC. They urge that the plaintiffs’ claims are preempted. Analyzing each of the documents on which the plaintiffs have relied to state a claim, the defendants contend that the information in those documents does not constitute newly acquired information and therefore, the federal law of preemption bars the plaintiffs’ state law claims. In addition, even if the plaintiffs’ claims were not preempted, the defendants argue that they must be dismissed because the warnings given on the Eliquis label were, as a matter of law, sufficient to warn of the risks associated with excessive bleeding on which the plaintiffs’ claims are premised. Finally, the defendants argue that the SAC fails to meet the relevant pleading standards. The March 10 motion to dismiss became fully submitted on April 18. DISCUSSION The discussion of this motion begins by describing the federal pleading standards and identifying which state’s law governs the Utts’ claims in the SAC. The Opinion then turns to the issue of preemption. As background to the preemption discussion, the Opinion outlines the FDA’s regulatory regime for brand name pharmaceutical drugs. It then applies the law of preemption to the SAC’s state law claims, and also analyzes whether it pleads plausible claims for relief under federal pleading standards. When deciding a motion to dismiss, a court must “accept all allegations in the complaint as true and draw all inferences in the non-moving party’s favor.” LaFaro v. N.Y. Cardiothoracic Grp., PLLC, 570 F.3d 471, 475 (2d Cir. 2009) (citation omitted). “To survive a motion to dismiss under Rule 12(b)(6), a complaint must allege sufficient facts which, taken as true, state a plausible claim for relief.” Keiler, 751 F.3d at 68. See also Ashcroft v. Iqbal, 556 U.S. 662, 678, 129 S.Ct. 1937, 173 L.Ed.2d 868 (2009) (“[A] complaint must contain sufficient factual matter, accepted as true,- to state a claim to relief that is plausible, on its face.” (citation omitted)). A claim has-facial plausibility when “the factual content” of the complaint “allows the court to draw the reasonable inference that the defendant is liable for the misconduct alleged.” Tongue v. Sanofi, 816 F.3d 199, 209 (2d Cir. 2016) (citation omitted). The plausibility standard is not a “probability requirement”; “[i]t simply calls for enough fact to raise a reasonable expectation that discovery will reveal evidence supporting a plaintiffs claim for relief.” Pension Benefit Guar. Corp. ex rel. St. Vincent Catholic Med. Ctrs. Retirement Plan v. Morgan Stanley Inv. Mgmt. Inc., 712 F.3d 705, 729 (2d Cir. 2013) (citation omitted). Nevertheless, “[w]here a complaint pleads facts that are merely consistent with a defendant’s liability, it stops short of the line between possibility and plausibility of entitlement to relief.” Iqbal, 556 U.S. at 678, 129 S.Ct. 1937 (citation omitted). In sum, “a plaintiffs obligation to provide the grounds of his entitlement to relief requires more than labels and conclusions, and a formulaic recitation of the elements of a cause of action will not do.” Bell Atl. Corp. v. Twombly, 550 U.S. 544, 555, 127 S.Ct. 1955, 167 L.Ed.2d 929 (2007) (citation omitted). To satisfy the requirements of Rule 9(b), which applies to any pleading of fraud, the complaint must: (1) detail the events giving rise to the fraud, such as the statement/omission that is alleged to be fraudulent, the identity of the speaker, the location of the fraud, and the reason the statement is fraudulent; and (2) allege facts “that give rise to a strong inference of fraudulent intent.” Loreley Fin. (Jersey) No. 3 Ltd. v. Wells Fargo Sec., LLC, 797 F.3d 160, 171 (2d Cir. 2015) (citation omitted). In deciding a motion to dismiss, the court considers “any written instrument attached to the complaint as an exhibit or any statements or documents incorporated in it by reference.” Stratte-McClure v. Morgan Stanley, 776 F.3d 94, 100 (2d Cir. 2015) (citation omitted). The court may also consider “documents upon which the complaint relies and which are integral to the complaint.” Subaru Distribs. Corp. v. Subaru of Am., Inc., 425 F.3d 119, 122 (2d Cir. 2005). The Eliquis labeling is integral to the SAC. I. Choice of Law Mr. Utts is a resident of California and asserts violations of California consumer protection laws. Moreover, both parties rely on California law in their briefing. Accordingly, there is no dispute that the SAC’s claims arise from California statutory and common law. II. FDA Approval Process The Food, Drug, and Cosmetic Act of 1938 (“FDCA”) is a federal law that regulates the manufacture, use, or sale of drugs. Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193, 196, 125 S.Ct. 2372, 162 L.Ed.2d 160 (2005). To obtain authorization to market a new drug, a drugmaker must submit a new drug application (“NDA”).'Such applications must include “full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use.” 21 U.S.C. § 355(b)(1)(A). The manufacturer’s NDA must demonstrate that the drug is “safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling.” Id. § 355(d). The manufacturer’s NDA must also prove the drug’s effectiveness by “substantial evidence that the drug will have the effect it purports or' is represented to have under the conditions of.use prescribed, recommended, .or suggested. in the proposed labeling.” Id. Drug' manufacturers must also submit proposed labeling, with annotations, to be used with the drug. Id. § 355(b)(1)(F); 21 C.F.R. § 314,50(c)(2)(i). The FDA’s pre-market approval of an NDA includes the approval of the exact text in the proposed label. ..See 21 U.S.C. § 355; 21 C.F.R. § 314.105(b). In making a detailed review of proposed labeling, the FDA seeks, to allow “only information for which there is a scientific basis to be included.” Supplemental Applications Proposing Labeling Changes for Approved Drugs, Biologies, and Medical. Devices, 73 Fed. Reg, 49603, 49604 (Aug. 22, 2008) (hereinafter, “Labeling Changes”), The labeling must include certain categories of information organized into predetermined headings and subheadings. See 21 C.F.R. §§ 201.56, 201.57, and 201.80. For example, the “Warnings and Precautions” section of a label must describe clinically significant 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), other potential safety hazards (including those that are expected for the pharmacological class or those resulting from drug/drug interactions), limitations in use imposed by them (e.g., avoiding certain concomitant, therapy), and steps that should be taken, if they occur (e.g., dosage modification). Id. § 201.57(c)(6)©. The “Adverse Reactions” section requires a description of “the overall adverse • reaction profile of the drug based on the entire safety database.” Id. § 201.57(c)(7). An “adverse reaction” is defined as an “undesirable effect, reasonably associated with use of a drug.” Id. “This definition does not include all adverse events observed during use of a drug,” but rather “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. In addition, “any claiiri comparing the drug to which the labeling applies with other drugs in terms of frequency, severity, or character of adverse reactions must be based on adequate and well-controlled studies ....” Id. § 201.57(c)(7)(iii). After approval, manufacturers are required to maintain records and disclose to the FDA any adverse health consequences reported during the prescription drug’s use. 21 U.S.C. § 365(k)(1); 21 C.F.R. §§ 314.80(c), 314.81. If, on the basis of these disclosures, the FDA learns of new safety information which it believes should be included in the labeling of the drug, it retains the authority to require amendments to the drug’s label. 21 U.S.C. § 355(o)(4); Wyeth v. Levine. 555 U.S. 555, 567, 129 S.Ct. 1187, 173 L.Ed.2d 51 (2009) (observing that the 2007 FDCA amendments for the first time “granted the FDA statutory authority to require a manufacturer to change its drug label based on safety information that becomes available after a drug’s initial approval.”).. Alternatively, if the FDA finds that the drug is not “safe” when used in accordance with its labeling, or if, on the basis of new information, the FDA finds that the labeling of such drug, is “false .or misleading in any particular and was not corrected within a reasonable time after receipt of written notice from the Secretary specifying the matter complained of,” the agency “shall” withdraw its approval of the drug. 21 U.S.C, § 355(e). In addition, the FDA “shall” deem a drug “misbranded” if “it is-dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling.” Id. § 352(j). Notwithstanding the FDA’s post-approval oversight and regulation, “manufacturers, not the FDA, bear primary responsibility for their drug labeling at all times.” Wyeth, 555 U.S. at 579, 129 S.Ct. 1187; see also 21 U.S.C. § 355(o)(4)(I) (providing a rule of construction clarifying that the 2007 amendments to the FDCA “shall not be construed to affect the responsibility of the responsible person or the holder of the approved application ... to maintain its label in accordance with existing requirements”). Thus, the manufacturer is charged “both with crafting an adequate label and with ensuring that ⅜ warnings remain adequate as long as the drug is on the market.” Wyeth, 555 U.S. at 571, 129 S.Ct. 1187. There are two ways for a manufacturer to fulfill its post-FDA approval labeling duties. Generally speaking, a manufacturer may only change a drug label after the FDA approves a supplemental application. See 21 C.F.R. § 314.70(b). A manufacturer may, however, make certain changes to its label without prior agency approval through the “changes being effected” (“CBE”) regulation. The CBE regulation allows a manufacturer to change its label unilaterally to “add or strengthen a contraindication, warning, precaution, or adverse reaction,” id. § 314.70(c)(6)(iii)(A), as soon as there is “reasonable evidence of a causal association with a drug; a causal relationship need not have been definitely established,” id. § 201.57(c)(6)(i). A manufacturer may also, pursuant to the CBE regulation, “add or strengthen an instruction about dosage and administration that is intended to increase the safe use of the drug product,” id. § 314.70(c)(6)(iii)(C), or “delete false, misleading, or unsupported indications for use or claims for effectiveness,” id. § 314.70(c)(6)(iii)(D). Labeling changes pursuant to the CBE regulation may only be made on the basis of “newly acquired information.” ■ Id. § 314.70(c)(6)(iii). “Newly acquired information” is defined as: [D]ata, analyses, or other information not previously submitted to the [FDA], which may include (but is not limited to) data derived from new clinical studies, reports of adverse events, or new analy-ses of previously submitted data (e.g., meta-analyses)' if the studies, events, or analyses reveal risks of a different type or greater severity or frequency than previously included in submissions to FDA. Id. § 3Í4.3(b). Information previously known to the manufacturer, but not submitted to the FDA, may constitute “newly acquired information,” provided that the information meets the other CBE requirements. Labeling Changes, 73 Fed. Reg. at 49606. The FDA has recognized that “[exaggeration of risk, or inclusion of speculative or hypothetical risks, could discourage appropriate use of a beneficial drug ... or decrease the usefulness and accessibility of important information by diluting or obscuring it.” Supplemental Applications Proposing Labeling Changes for Approved Drugs, Biologies; and Medical Devices, 73 Fed. Reg. 2848, 2851 (Jan. 16, 2008). Indeed, “labeling that includes theoretical hazards not well-grounded in scientific evidence can cause meaningful'risk information to lose its significance.” Id. For this reason, the CBE regulation requires that there be sufficient evidence of a causal association between the drug and the information sought to be added. Iff; see also 21 C.F.R. § 201.57(c)(6)©. Moreover, the FDA retains the authority to reject labeling changes made pursuant to the CBE regulation's.’ Wyeth, 555 U.S. at 571, 129 S.Ct. 1187. By expressly requiring that a CBE supplement only reflect newly acquired information and “be based on sufficient evidence of a causal association,” the FDA ensures “that scientifically accurate information appears in the approved labeling.” Labeling Changes, 73 Fed. Reg. at 49604. III. Federal Preemption of Pharmaceutical Claims The. Supremacy Clause establishes that federal law “shall be the supreme Law of the Land ... any Thing in the Constitution or Laws of any State to the Contrary notwithstanding.” U.S. Const., art. VI, cl.2. “A fundamental principle of the Constitution is that Congress has the power to preempt state law.” Crosby v. Nat’l Foreign Trade Council, 530 U.S. 363, 372, 120 S.Ct. 2288, 147 L.Ed.2d 352 (2000). State law is preempted by federal law when Congress intends federal law to “occupy the field,” or where state law conflicts with a federal statute.. Id. (citation omitted). Conflict preemption exists “where it is impossible for a private party to comply with both state and federal law and where, under the circumstances of a particular case, the challenged state law stands as an obstacle to the. accomplishment and execution of the full purposes and objectives of Congress.” Id. (citation omitted). “Impossibility pre-emption is a demanding defense.” Wyeth, 555 U.S. at 573, 129 S.Ct. 1187. Courts must “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. at 565, 129 S.Ct. 1187 (citation omitted). “[T]he historic police powers of the State include the regulation of matters of health and safety.” De Buono v. NYSAILA Med. & Clinical Servs. Fund, 520 U.S. 806, 814, 117 S.Ct. 1747, 138 L.Ed.2d 21 (1997).. As the Supreme Court has explained, [throughout our history the several States have exercised their police powers to protect the health and safety of their citizens. Because these are primarily, and historically, matters of local concern, the States traditionally , have had great latitude under their police powers to legislate as to the protection of the lives, limbs, health, comfort, and quiet of all persons. Medtronic, Inc. v. Lohr, 518 U.S. 470, 475, 116 S.Ct. 2240, 135 L.Ed.2d 700 (1996) (citation omitted). In a recent trilogy of opinions, the Supreme Court addressed the issue of conflict preemption in the context of state product liability claims against'drug manufacturers. As described in more detail in Utts, the Supreme Court’s decisions in Wyeth, 555 U.S. 555, 129 S.Ct. 1187, 173 L.Ed.2d 51, PLIVA, Inc. v. Mensing, 564 U.S. 604, 131 S.Ct. 2567, 180 L.Ed.2d 580 (2011), and Mutual Pharmaceutical Co., Inc. v. Bartlett, — U.S. -, 133 S.Ct. 2466, 186 L.Ed.2d 607 (2013), read holistically, indicate that federal law preempts all pre-FDA approval failure to warn and design defect claims for branded prescription medication. See Utts, 226 F.Supp.3d at 178-79, 2016 WL 7429449, at *6. As Utts explains, brand name drug manufacturers lack the authority to alter a drug’s design or a label’s warnings at the time the NDA approval process concludes. Id. at 182-83, at *9; see Labeling Changes, 73 Fed. Reg. at 49606 (“State law claims that challenge labeling that FDA approved after being informed of the relevant risk are preempted.” (citation omitted)). Thereafter, however, depending on the significance of the change to the drug’s design or the type of change in a label, federal regulations permit—and indeed, require—manufacturers to unilaterally alter the design and label. Thus, there may be no preemption of state product liability law where the plaintiffs’ claims are based on newly acquired information that, pursuant to the CBE regulation, the defendants could unilaterally make without FDA approval. Utts, 226 F.Supp.3d at 182-83, 2016 WL 7429449, at *9. Post-FDA approval preemption analysis proceeds in two stages. First, the plaintiff must show that there existed “newly acquired information” such that the defendants could unilaterally change the label pursuant to the CBE regulation without FDA approval. But, the mere availability of a CBE label amendment does not necessarily defeat a manufacturer’s preemption defense. Because the FDA “retains the authority to reject labeling changes,” a manufacturer may still—even after the plaintiff has identified “newly acquired information”—establish an impossibility preemption defense through “clear evidence that the FDA would not have approved a change” to the label. Wyeth, 555 U.S. at 571, 129 S.Ct. 1187; see also In re: Fosamax (Alendronate Sodium) Prods. Liab. Litig., 852 F.3d 268, 283-84 (3d Cir. 2017). In sum, if the plaintiff can point to the existence of “newly acquired information” to support a labeling change under the CBE regulation, the burden then shifts to the manufacturer to show by “clear evidence” that the FDA would not have approved the labeling change made on the basis of this newly acquired information. IV. California Product Liability: Failure to Warn California recognizes three theories of product liability: failure to warn, design defect, and manufacturing defect. The SAC asserts only a failure to warn theory of product liability. Its failure to warn claim is at the heart of the SAC and the principal focus of the parties’ briefing on the motion to dismiss. Failure to warn arises when a manufacturer has issued no warnings or has failed to adequately warn of dangers posed by its product. See Anderson v. Owens-Corning Fiberglas Corp., 53 Cal.3d 987, 996, 281 Cal.Rptr. 528, 810 P.2d 549 (1991). Under California law, a prescription drug manufacturer is strictly liable if it failed to “adequately warn of a particular risk that was known or knowable in light of the generally recognized and prevailing best scientific and medical knowledge available at the time of manufacture and distribution.” Carlin v. Superior Court, 13 Cal.4th 1104, 1112, 56 Cal.Rptr.2d 162, 920 P.2d 1347 (1996) (emphasis added). Failure to warn based on a negligence theory “requires a plaintiff to prove that a manufacturer or distributor did not warn of a particular risk for reasons which fell below the acceptable standard of care, i.e., what a reasonably prudent manufacturer would have known and warned about.” Anderson, 53 Cal.3d at 1002, 281 Cal.Rptr. 528, 810 P.2d 549. Under California law, application of the failure to warn theory' to pharmaceuticals requires the court to determine: whether available evidence established a causal link between an alleged side effect and a prescription drug, whether any warning should have been given, and, if so, whether the warning was adequate. These are issues of fact involving, -inter alia, questions concerning the state of the art, i.e., what was known or reasonably knowable by the application of scientific and medical knowledge available at the time of manufacture and distribution of the prescription drug. They also necessarily involve questions concerning whether the risk, in light of accepted scientific norths, was more than merely speculative or conjectural, or so remote and insignificant as to be negligible. Carlin, 13 Cal.4th at 1116, 56 Cal.Rptr.2d 162, 920 P.2d 1347. As the California Supreme Court has acknowledged, in the failure-to-warn context, strict liability is, to some extent, “a hybrid of traditional strict liability and negligence doctrine” since “the knowledge or knowability requirement for failure to warn infuses some negligence concepts into strict liability cases.” Id. at 1111-12, 56 Cal.Rptr.2d 162, 920 P.2d 1347. The knowledge or knowability requirement holds a drug manufacturer to the standard of “knowledge and skill of an expert in the field,” and further obligates the manufacturer “to keep abreast of any scientific discoveries” and to “know the results of all such advances.” Id. at 1113, 56 Cal.Rptr.2d 162, 920 P.2d 1347 n.3. The manufacturer’s knowledge “must exist at the time of distribution,” Id. “[Subsequently developed scientific data [is not] controlling.” Id. In sum, the primary difference between a failure to warn action premised on strict liability and a failure to warn action sounding in negligence is -that strict liability “is not concerned with the standard of due care or the reasonableness of a manufacturer’s conduct.” Id. at 1112, 56 Cal.Rptr.2d 162, 920 P.2d 1347. Even where a risk is “known” or “knowable” at the time of distribution,' under California law, a manufacturer “may not be held liable for failing to give a warning it has been expressly precluded by the FDA from giving.” Id. at 1115, 56 Cal.Rptr.2d 162, 920 P.2d 1347 n.4. Thus, if the manufacturer disclosed to the FDA “state-of-the-art scientific data concerning the alleged risk” and the FDA determined, after its review, “that the pharmaceutical manufacturer was not permitted to warn— e.g., because the data was inconclusive or the risk was too speculative to justify, a warning,” then the manufacturer could not be held strictly liable for failure to warn. Id. at 1115, 56 Cal.Rptr.2d 162, 920 P.2d 1347. “[T]he FDA’s conclusion that there was, in effect, no ‘known risk’ is controlling.” Id. California also follows the learned intermediary doctrine, which provides that “in the case of prescription drugs, the duty to warn runs to the physician, not to the patient.” Id. at 1116, 56 Cal.Rptr.2d 162, 920 P.2d 1347. Therefore, a manufacturer discharges its duty to warn if it provides adequate warnings to the physician about any known or reasonably knowable dangerous side effects, regardless of whether the warning reaches the patient. Finally,- “a pharmaceutical manufacturer may not be required to provide warning of a risk known to the medical community.” Id. A. The Plaintiffs’ Failure to Warn Claims Are Preempted. The defendants first assert that the plaintiffs’ California failure to warn claims are preempted -by federal law because the information on which the SAC relies to plead its claims is not “newly acquired information,” as that term is defined under the CBE regulations. The “newly acquired information,” which is information that was not submitted to the FDA prior to the FDA’s approval of the drug and its label, must reveal risks of a “different type or greater severity or frequency than previously included in submissions to [the] FDA.” 21 C.F.R. § 314.3(b). The SAC identifies 34 warnings that the defendants allegedly failed to provide in the Eliquis label. In opposition to this motion, the plaintiffs largely abandon the failure to warn claims directed toward the risk of excessive bleeding and the lack of an effective reversal agent. They instead focus on three categories of warnings: (1) monitoring; (2) advice regarding bleeding reversal strategies; and (3) dosage recommendations. The SAC relies exclusively on nine re.ports> studies, and articles as the bases for its assertion that thé Eliquis. labeling was inadequate in failing to give these warnings. Most of these documents are appended as exhibits to,the SAC; The information contained in this literature does not constitute “newly acquired information” 'under the FDA’s CBE regulation. Accordingly, the plaintiffs’ claims are preempted because federal law Would not have permitted the defendants to make any change to the Eliquis label. The SAC and the plaintiffs in their brief in opposition to this motion giye the greatest emphasis to a single report, and it is to that report that this Opinion turns first. The remainder of the nine documents or reports are given relatively limited weight in the SAC and in the plaintiffs-’ brief, and will be addressed thereafter.- For five of these reports, the plaintiffs do not actually contend either in the SAC or in opposition to this' motion that they contain -newly acquired information. Those five, are discussed last. 1. Allegation of Newly Acquired Information a. The Institute for Safe Medical Practices QuarterWatch Report (the “ISMP Report”) The plaintiffs rely heavily on four statements in the ISMP Report to support their claim that the defendants have not fully disclosed the incidence of bleeding in users of Eliquis. The ISMP-Report, published in September 2015, analyzed “adverse drug event” data for NOACs from the third and fourth quarters' of 2014. Before assessing whether the four statements constitute newly acquired information, the function of ISMP reports will be described. ISMP reports draw upon “adverse drug event” reports, among other sources of information, to describe drug safety issues. Federal regulations require drug manufacturers to report “[a]ny adverse event associated with the use of a drug in humans, whether or not considered drug related” to the FDA. 21 C.F.R.. § 314.80(a), (c). All reported adverse drug events are uploaded to the FDA,Adverse Event Reporting System (“FAERS”) database. See “Questions and Answers on ■ FDA’s Adverse Event Reporting System (FAERS),” U.S. Food & Drug Admin., -https://www.fda.gov/drugs/ guidancecompliánceregulatdryinformation/ "surveillance/adversedrugeffects (last visited May 7, 2017) (hereinafter, “FDA Website”). Federal regulations advise that a report submitted by. a manufacturer “does not necessarily reflect a conclusion by. the [manufacturer] or -FDA that the report or .information constitutes an admission that the drug caused or contributed to an adverse effect.” 21 C.F.R. § 314.80(Z). As the FDA Website explains: FDA does not require that a causal relationship between a product and'event be proven, and reports do not always contain enough detail to properly evaluate an event. Further; FDA does not receive reports for every adverse event or medication error that occurs with, a product. Many factors can influence whether or not an event will be reported, such as the time a product has been marketed and publicity about an event. The Supreme Court has similarly warned that “[t]he fact that a user of a drug has suffered an adverse event, standing alone, does not mean that the drug caused that event.” Matrixx Initiatives, Inc. v. Siracusano, 563 U.S. 27, 44, 131 S.Ct. 1309, 179 L.Ed.2d 398 (2011). In sum, “the mere existence of reports of adverse events ... says nothing in and of itself about whether the drug is causing the adverse events.” Id. The ISMP Report acknowledges the limitations of its analysis of adverse event report data: “The submission of an individual report does not in itself establish that the suspect drug caused the event described.” The ISMP Report therefore recommends that its findings “be interpreted in light of the known limitations of a reporting system that does not collect data systemically.” The ISMP Report further acknowledges that “[w]hile the sheer numbers of .case reports have scientific weight, because of variation in reporting rates, they reveal little about how frequently the events occur in the broader patient population.” Among the categories of pharmaceuticals it discussed, the ISMP Report compared adverse event reports across three NOACs—Xarelto, Pradaxa, and Eliquis. It found that Eliquis “showed the strongest safety profile from several perspectives” and “had the best adverse event safety profile by several measures.” Not only did Eliquis have the fewest reports in the FAERS database—even after adjusting for prescription volume—but it also had the fewest direct reports to the FDA, the fewest deaths, and the lowest percentage of deaths. i. Comparison of Eliquis and Xarelto The ISMP Report first relies upon a table comparing NOAC pharmaceutical adverse event reports to argue that the defendants failed to adequately warn about the bleeding risks associated with Eliquis. The table lists adverse event reports for Xarelto (rivaroxaban), Pradaxa (dabigatran), and Eliquis (apixaban) across several events, such as death outcomes, embolic-thrombotic events, and hemorrhaging events. The ISMP Report observed that, when the adverse event reports were examined, the difference between Xarelto and Eliquis “in percentage of deaths and total hemorrhage cases were small.” It observed as well, however, that Eliquis had the “best adverse event safety profile by several measures,” even when adjusted for prescription volume. In the SAC, the plaintiffs allege that the fact that Eliquis and Xarelto have a comparable incidence of death outcomes and hemorrhaging in their adverse event reports is “critical because real-world signal data from Xarelto was also found to have a much high[er] incidence of adverse events than reported in the clinical studies.” Xarelto’s real world performance as compared to the clinical studies of Xarelto says nothing about how the real world performance of Eliquis compares to the clinical data disclosed by the defendants to the FDA. The table and the description from the ISMP report do not suggest—nor do the plaintiffs allege—that the real-world signal data for Eliquis shows a greater severity or frequency of bleeding events or deaths than previously disclosed in Eliquis’ submissions to the FDA. 21 C.F.R. § 314.3(b). Accordingly, the information contained in this table does not constitute newly acquired information. ii. Concomitant Use of Eliquis . and Antiplatelet Agents According to the SAC, the ISMP Report “found that Eliquis, when used in conjunction with commonly used platelet inhibitors [aspirin, NSAIDs, and SSRIs, among others],” shows a “significantly increased risk of bleeding events compared to” the clinical data from the ARISTOTLE study. (Brackets in original.) This assertion is a misreading of the ISMP Report and the Eliquis label. In evaluating the adverse event data, the ISMP Report found that “concomitant therapy with platelet inhibitors increased the odds of a hemorrhage event by three-, fold” in all three NOACs and in warfarin. This “threefold” risk estimate is not specific to Eliquis, but rather is based on combined adverse event data from a number of anticoagulant medications, including warfa-rin. Moreover, the Eliquis label specifically warns about the concomitant use of platelet inhibitors and Eliquis: Concomitant use of drugs affecting he-mostasis increases the risk of bleeding. These include aspirin and other. anti-platelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitor, and nonsteroidal anti-inflammatory drugs (NSAIDs). (Emphasis added.) Section 7.3 of the Eli-quis label—entitled “Anticoagulants and Antiplatelet Agents”—further states that “[c]oadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding.” In connection with its discussion of concomitant therapy, the Eliquis label also cites the results from two clinical studies: ARISTOTLE and APPRAISE-2. While the ARISTOTLE study found less than a twofold increase, the APPRAISE-2 trial found over a fourfold increase in major bleeding, which is greater than the “threefold” ratio cited in the ISMP Report.. Thus, even if one were to assume that the “threefold” estimate cited in the ISMP Report accurately represents the Eliquis-specific bleeding rate, this would still not constitute “newly acquired information,” as the Eliquis label already discloses a higher risk of bleeding than that.contained in the ISMP Report, See 21 C.F.R. § 314.3(b) (providing that newly acquired information must reveal risk of a “greater severity or frequency than previously included in submissions to FDA”). In opposition to this motion, the plaintiffs appear to abandon their assertion that the ISMP Report contains new information regarding the increased risk of bleeding when Eliquis is used in combination with antiplatelet agents. They instead argue that the guidance regarding concomitant use of antiplatelet agents is inadequate because the label “does not advise how or when to use combination therapy with Eliquis” or “how commonly bleeding events will occur.” This omission in guidance was • evident to the FDA when it approved the label and the plaintiffs have not identified any newly acquired information from the ISMP Report that would support a label change. iii. Improved Dosage Guidance The SAC next relief? on the ISMP Report to complain that the Eliquis label does not “mention .., potential problems because of Eliquis’ one size fits all dosing.” As described above, however, Eliquis has two ■ recommended dosing regimens—not just one. In any event, this section- of the Report provides no newly acquired inforr mation that would support a label change regarding dosing. In its discussion of NOAC dosing regimens, the ISMP Report found that apixa-' ban avoided some of the pharmacological issues that the earlier NOACs had confronted. For example, rivaroxaban and da-bigatran were found to have “problems in basic pharmacology that raised questions about their suitability for simple dosing regimens without adjusting for each patient.” By contrast, apixaban “appeared tó avoid the limitations observed for rivaroxa-ban and dabigatran,” in part because- apix-aban was tested in both once- and twice-daily regimens. This section of the Report concludes with the following observation: “[U]nanswered is whether apixaban safety could be further improved with individualizing the dose for each patient, as is- done with warfarin.” This observation does not constitute newly acquired information, as it'simply speculates • whether apixaban safety could be further improved.' ' iv. Comparison with Warfarin Finally,- the SAC relies on. the ISMP Report to contend that the, Eliquis label does not /‘accurately reflect” that treatment with Eliquis increases the risk of a bleeding event for a patient when compared to “the venerable warfarin blood thinner.” The statement cited from the Repoi’t does not, however, concern a bleeding event, and in any event does not reflect any newly acquired information. The ISMP Report compared, adverse event reports fo.r the three NOACs against warfarin. One of the NOACs (not Eliquis) had a significantly worse outcome compared to warfarin when reports regarding embolic-thrombotic events were examined. Eliquis and another NOAC had “increased odds of embolic-thrombotic events compared to warfarin, but less ■ so.” - As the defendants point out in their motion, and the plaintiffs do not dispute, embolic-thrombotic events are ischemic strokes and not bleeding events. Nor do the plaintiffs argue that- any of this data comparing the incidence of embolic-thrombotic events for Eliquis and warfarin constitutes newly acquired information. In sum, data on is-chemic strokes could not form, the basis for a CBE label change related to bleeding risks. b. British Medical Journal Study (the “BMJ Study”) The second study on which the SAC relies is the BMJ Study, which was published in 2016. According to the SAC, the BMJ Study’s finding that NOACs were “not significantly different from warfarin” in terms of the risk of ischemic stroke in patients with atrial fibrillation contradicts Eliquis’ “promotional materials.” The plaintiffs do not assert that there is any deficiency in this regard in the Eliquis labeling. Nor, as explained here, could they. The BMJ Study is an observational study comparing the effectiveness of war-farin and NOACs in patients with nonval-vular atrial fibrillation who were “naive to oral anticoagulants and had no previous indication for valvular atrial fibrillation or venous thromboembolism.” The BMJ Study found that, for ischemic stroke only, “no significant differences were evident .., between NOACs and warfarin.” Otherwise, “[t]he risks for death, any bleeding, or major bleeding were significantly lower for apixaban and dabigatran, compared with warfarin.” The BMJ Study concluded that “[a]ll NOACs are generally safe and effective alternatives to warfarin in a clinical care setting.” ■The finding regarding the risk of is-chemic stroke from the BMJ Study is consistent with the data reported in the -Eli-quis labeling. The Eliquis labeling provides in relevant part: Superiority to warfarin was primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin. Purely ischemic strokes occurred with similar rates on both drugs. (Emphasis added.) Accordingly, the findings directed towards the risk of ischemic stroke for Eliquis users do not constitute newly acquired information. c. Thrombosis Journal Article In support of two related arguments, the SAC cites a 2013 article from the Thrombosis Journal entitled “Practical Management of Patients on Apixaban: A Consensus Guide.” First, the SAC alleges that the Eliquis label has failed to provide guidance on managing “potentially life threatening bleeding” even though physicians are forming a consensus about “potentially effective avenues” to stop serious injuiy and death from excessive bleeding. The SAC does not identify the particular “avenues” that it contends should be described in the label. Second, the SAC alleges that, even though the Eliquis label discusses the half-life of apixaban, “certain studies” indicate that it “is currently unknown what level of Eliquis would be considered safe for an elective surgery.” An examination of this practical guide for physicians provides.no basis to assert that there is information about Eliquis that should have been included in the label but was not. As the guide explains, in the “absence of robust clinical data for emergency and peri-operative management of patients receiving apixaban,” an expert panel of Australian clinicians from various fields convened to develop tips on managing bleeding and invasive procedures in patients taking apixaban. The consensus guide notes generally that in clinical trials, apixaban demonstrated a “superior reduction in stroke and systemic embolism, compared to warfarin,” and that apixaban resulted in “significantly less major bleeding, compared to warfarin.” The consensus guide contains a flowchart entitled “Considerations for the Management of Bleeding, Based on Expert Consensus.” The article observes as well that “[a] specific antidote for apixaban is not currently available” and that “[i]n the absence of published data regarding the treatment of patients with active bleeding while receiving apixaban, discontinue apix-aban, apply standard supportive treatment and other local measures.” (Emphasis added.) The plaintiffs do not allege, however, that this expert guidance contains, or is founded upon, any newly acquired information regarding reversal agents or the treatment of excessive bleeding that should be included in a drug label. Nor is there any basis to allege, based on this guide, that the Eliquis label’s statements regarding either the drug’s half-life or its safety in connection with elective surgery are misleading. The Eliquis label contains the following warnings about discontinuation of Eliquis for surgery: ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be non-critical in location and easily controlled. The guide agrees that the label correctly describes the half-life for Eliquis, and nothing in it suggests that the label’s statement regarding elective surgery is inaccurate in any respect. The guide notes that apixaban “can be ceased for a shorter period of time than warfarin before invasive procedures,” but that a “ ‘safe’ residual drug level of apixaban for surgery is presently unknown, and no test has been correlated with bleeding risk.” It agrees with the label that “[i]n general, apixaban should be discontinued 2 to 3 days prior to elective surgery.” The plaintiffs do not allege that this statement contains newly acquired information about what constitutes a safe residual drug level of apixaban in advance of surgery. d. FDA News Article In support of its argument that the Eliquis label does not adequately warn about the lack of an effective antidote, the SAC cites to an August 2016 news article about the FDA’s failure to approve “an antidote for Eliquis bleeding.” This article does not refer to any new information that would have permitted the defendants to amend the Eliquis label. And, in their opposition to this motion, the plaintiffs do not argue that it does. As described above, the label discloses in unambiguous terms that no known antidote for apixaban exists. e. Pradaxa Construing the SAC favorably, it may assert that the FDA’s approval of an antidote to Pradaxa—a competing NOAC— constitutes newly acquired information that should have been included in the Eli-quis label. Specifically, the SAC asserts that the Eliquis labeling should mention “this safer alternative NOAC.” Insofar as these allegations are directed toward a claim that Eliquis could or should have been designed more safely—that is, not manufactured or distributed without an effective antidote—such thinly veiled design defect claims are preempted. But even if analyzed as a failure to warn claim, this information does not constitute “newly acquired information.” As described above, the label clearly warns that there is no reversal agent for apixaban. Moreover, federal regulations do not require a manufacturer to include information about a competitor’s product or progress. See 21 C.F.R. §§ 201.56, 201.57, and 201.80. 2. No Allegation of Newly Acquired Information The plaintiffs do not contend that any of the five remaining documents to which the SAC refers contains newly acquired information regarding an undisclosed risk of bleeding. Several of these articles merely express a desire for further investigation into NOAC dosing regimens or reversal agents. As a consequence, none of the reports, studies, or publications upon which the SAC relies help the plaintiffs’ failure to warn claims overcome the defendants’ preemption motion. Each of the additional pieces of literature is described below. a. Journal of American Medical Association Internal Medicine Article (the “JAMA Article”) The SAC cites a February 2015 JAMA Article solely for its critique of the ARISTOTLE study. In opposing this motion, the plaintiffs explain that they are relying on this article to illustrate how some manufacturers may conceal information about clinical studies from the FDA. But, as an examination of the JAMA Article makes clear, its primary critique is with the lack of attention research misconduct receives in the scientific literature. It does not suggest that the FDA was unaware of problems with the ARISTOTLE study when it approved the Eliquis label. The JAMA Article evaluates whether, and to what extent, peer-reviewed literature reflects FDA findings of’ research misconduct in clinical trials. The JAMA Article identified several published clinical trials—including Eliquis’ ARISTOTLE trial—in which an FDA inspection uncovered objectionable conditions or practices at a clinical trial site. With respect to the ARISTOTLE trial, the JAMA Article noted that a clinical site in China “had apparently altered patient records,” and that “[i]f one were to exclude the data from the patients at that site, the claim of a statistically significant mortality benefit disappears.” Notwithstanding this “fraudulent data,” the JAMA Article found that “when [data from] all the suspect Chinese sites are excluded rather than just the one at which the evidence of alleged research misconduct was found, the mortality benefit [of Eliquis] becomes statistically significant.” The JAMA Article criticized the peer-reviewed literature for consistently relying on the full data set from the ARISTOTLE trial without excluding data from the site where the research misconduct was uncovered. b. FDA Signal Report The SAC makes a brief reference to a report of an ongoing FDA investigation into the adverse event signal between Eli-quis and a health condition known as vas-culitis. This does not concern an increased or undisclosed risk of bleeding, and the plaintiffs do not contend that it does. In November 2016, the FDA announced that it had identified a potential signal of a “serious risk/new safety information” for vasculitis in patients taking Eliquis, Pra-daxa, Sávaysa, and Xarelto based on adverse event reports from July to Septemb