Rutledge v. Walgreen Co.; Phippen v. Walgreen Co.

24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. UNITED STATES COURT OF APPEALS FOR THE SECOND CIRCUIT August Term 2025 Argued: November 17, 2025 Decided: July 13, 2026 Docket Nos. 24-916-cv(L), 24-1121(Con), 24-2360(Con); 24-2594-cv TIFFANY RUTLEDGE, INDIVIDUALLY AND AS MOTHER, GENERAL GUARDIAN OF, ET AL., KRISTOPHER WHITE, BRIDGET MCCONNELL, ALEXANDER HOLLAND, CHRISTINE HOLLAND, Plaintiffs-Appellants, v. WALGREEN CO., COSTCO WHOLESALE CORPORATION, CVS HEALTH CORPORATION, CVS PHARMACY, INC., SAFEWAY INC., WALMART INC., A DELAWARE CORPORATION, RITE AID CORPORATION, FAMILY DOLLAR, INC., TARGET CORPORATION, SAM’S WEST, INC., DOLLAR TREE, INC., 7-ELEVEN, INC., FAMILY DOLLAR STORES, INC., THE KROGER CO., DOLLAR TREE STORES, INC., JOHNSON & JOHNSON CONSUMER INC., BIG LOTS, GIANT FOOD LLC, ALBERTSON’S, HARRIS TEETER LLC, DOLGENCORP, LLC, Defendants-Appellees. MICHELLE PHIPPEN, INDIVIDUALLY AND AS GENERAL GUARDIAN OF P.P. AND L.A., MINORS, ALISHA DAY, INDIVIDUALLY AND AS MOTHER, GENERAL GUARDIAN OF A.D., A MINOR, SARAH STOKES, INDIVIDUALLY AND AS GENERAL GUARDIAN OF K.G., A MINOR, JUAN EMANUEL BORDOY, INDIVIDUALLY, MARY ELIN ARCE, INDIVIDUALLY AND AS MOTHER OF JUAN EMANUEL BORDOY, AMANDA TRIGLOFF, INDIVIDUALLY AND AS GENERAL GUARDIAN OF R.S., A MINOR, DEANDRE BARBEE, INDIVIDUALLY, JANTAIL BARBEE, INDIVIDUALLY AND AS MOTHER OF DEANDRE BARBEE, LAURIE  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. COURINGTON, HUNTER COURINGTON, JENNIFER MORROW, ALENA MORROW, CALLISTA BASSETT, ANDREW BASSETT, SONNITA ROBY, INDIVIDUALLY AND AS GENERAL GUARDIAN OF D.P., A MINOR, SHANNON MIKUSKI, BRAYDON MCKENZIE, HEATHER GILLIAM, COLBY GILLIAM, TAYLOR BROWN, TARYNE BURKE, INDIVIDUALLY AND AS MOTHER WITH COURT-APPOINTED GUARDIAN OF ASHTON BURKE, SAMARI SIMS, INDIVIDUALLY, DENISA CULLOM, INDIVIDUALLY AND AS MOTHER OF SAMARI SIMS, COLLIN STOVER, INDIVIDUALLY, DANA STEWART, INDIVIDUALLY AND AS MOTHER OF COLLIN STOVER, RIAN CZAR JOHNSON, INDIVIDUALLY, SHILO RICH, INDIVIDUALLY AND AS MOTHER OF RIAN CZAR JOHNSON, SHEENA SCHNEPP, INDIVIDUALLY AND AS MOTHER AND NATURAL GUARDIAN OF H.S., A MINOR, ZAYNE COSTELLO, INDIVIDUALLY, CRYSTAL ALEXANDER, COURTNEY TILLOTSON, MICHELLE BROWN, Plaintiffs-Appellants, v. WALGREEN CO., JOHNSON & JOHNSON CONSUMER INC., WALMART INC., Defendants-Appellees. * APPEAL FROM THE UNITED STATES DISTRICT COURT FOR THE SOUTHERN DISTRICT OF NEW YORK Before: CALABRESI, LYNCH, and LEE, Circuit Judges. Plaintiffs-Appellants appeal from judgments of the U.S. District Court for the Southern District of New York (Denise L. Cote, District Judge), dismissing Plaintiffs-Appellants’ complaints alleging that Defendants-Appellees failed to * The Clerk of Court is respectfully directed to amend the official caption in this case to conform with the caption above. 2  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. warn them that prenatal ingestion of their acetaminophen products could cause attention-deficit/hyperactivity disorder and autism spectrum disorder. In Rutledge, the District Court excluded the general causation evidence offered by Plaintiffs-Appellants’ five experts, Drs. Baccarelli, Hollander, Pearson, Cabrera, and Louie. In Phippen, it excluded the evidence offered by an additional expert, Dr. Ness. The District Court granted summary judgment for Defendants-Appellees in both cases. With respect to expert testimony, the district court serves a “gatekeeping” function—it is charged with “the task of ensuring that an expert’s testimony both rests on a reliable foundation and is relevant to the task at hand.” Daubert v. Merrell Dow Pharms., Inc., 509 U.S. 579, 597 (1993). Where a particular technique or theory has gained general acceptance in the scientific community, and an expert reliably applies that methodology to the subject of inquiry, testimony is admissible. We conclude that the District Court exceeded its discretion by excluding the expert testimony of Drs. Baccarelli, Hollander, and Pearson, but was within its discretion in excluding the testimony of Drs. Cabrera and Louie. In Phippen, we conclude that reconsideration of the exclusion of Dr. Ness’s testimony is warranted in light of our opinion in Rutledge. We further conclude that the District Court correctly declined to dismiss the case on the ground that Plaintiffs- Appellants’ failure-to-warn claims were preempted by federal drug labeling laws. We therefore VACATE and REMAND for further proceedings consistent with this opinion. ASHLEY C. KELLER, Keller Postman LLC, Chicago, IL; with Ashley L.F. Barriere, Keller Postman LLC, Chicago, IL; John J. Snidow & Roseann R. Romano, Keller Postman LLC, Washington, DC, for Plaintiffs-Appellants Tiffany Rutledge Kristopher White, Bridget McConnell, Alexander Holland, Christine Holland in Rutledge v. Walgreen Co., and for Plaintiffs-Appellants Sonnita Roby, Taylor Brown, Michelle Phippen, Amanda Trigloff, Laurie Courington, Hunter Courington, Jennifer Morrow, Alena Morrow, Callista Bassett, Andrew Bassett, Shannon Mikuski, Braydon McKenzie, Heather Gilliam, Colby Gilliam, and Michelle Brown in Phippen v. Walgreen Co. 3 24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. Daniel C. Burke, Bernstein Liebhard LLP, New York, NY, for Plaintiffs-Appellants Juan Emanuel Bordoy, Mary Elin Arce, Deandre Barbee, Jantail Barbee, Taryne Burke, Samari Sims, Denisa Cullom, Collin Stover, Dana Stewart, Rian Czar Johnson, Shilo Rich, Sheena Schnepp, Zayne Costello, Crystal Alexander, and Courtney Tillotson. Lindsey Scarcello, Wagstaff & Cartmell, LLP, Kansas City, MO, for Plaintiff-Appellant Alisha Day. JAY P. LEFKOWITZ, Kirkland & Ellis LLP, New York, NY; with Cole T. Carter, Kirkland & Ellis, LLP, Chicago, IL, for Defendant- Appellee Johnson & Johnson Consumer Inc. Jeffrey S. Bucholtz & Amy R. Upshaw, King & Spalding LLP, Washington, DC; Matthew Noller, King & Spalding LLP, San Francisco, CA for Defendants-Appellees Walmart Inc. and Sam’s West, Inc. Kristen L. Richer, Barnes & Thornburg LLP, Los Angeles, CA, for Defendants-Appellees CVS Pharmacy, Inc., Walgreen Co., and Costco Wholesale Corporation. Amanda Groves, Winston & Strawn LLP, Los Angeles, CA, for Defendants-Appellees Safeway, Inc., and Albertsons Companies, Inc. Joseph A. Lara, Stone | Dean LLP, Woodland Hills, CA, for Defendant-Appellee The Kroger Company. Lori B. Leskin & Mitchell Russell Stern, Arnold & Porter Kaye Scholer LLP, New York, NY; William C. Perdue & Anthony J. Franze, Arnold & Porter Kaye Scholer LLP, Washington, DC, for Defendants-Appellees 7-Eleven, Inc., Dollar Tree Stores, Inc., and Family Dollar Stores, LLC. Anne A. Gruner, Duane Morris LLP, Philadelphia, PA, for Defendant-Appellee Dolgencorp, LLC. Deanne E. Maynard, Morrison & Foerster LLP, Washington, DC; Julie Y. Park & Alexandra Preece Barlow, Morrison & Foerster LLP, San Diego, CA; Alexandra M. Avvocato, 4  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. Morrison & Foerster LLP, New York, NY, for Defendant-Appellee Target Corporation. Jeffrey R. White, American Association for Justice, Washington DC, for Amicus Curiae American Association for Justice, in support of Plaintiffs-Appellants. Lawrence P. Eagel, J. Brandon Walker, and Marion C. Passmore, Bragar Eagel & Squire, P.C., New York, NY, for Amici Curiae Law Professors Anne Bloom, Erwin Chemerinsky, Valerie P. Hans, and Richard L. Jolly, in support of Plaintiffs-Appellants. John R. Byrne, Maderal Byrne & Furst PLLC, Coral Gables, FL, for Amici Curiae Epidemiologists Yinong Young-Xu, Marc Weisskopf, and Graham Colditz, in support of Plaintiffs-Appellants. Jennifer B. Dickey & Mariel A. Brookins, Chamber of Commerce of the United States of America, Washington, DC; Joshua J. Fougere & Madeleine Joseph, Sidley Austin LLP, Washington, DC, for Amicus Curiae Chamber of Commerce of the United States, in support of Defendants-Appellees. Raffi Melkonian, Wright, Close & Barger LLP, Houston, TX, for Amicus Curiae Lawyers for Civil Justice, in support of Defendants- Appellees. CALABRESI, Circuit Judge: Plaintiffs-Appellants in these tandem cases bring failure-to-warn claims under state law relating to acetaminophen, the active ingredient in Tylenol and its generic equivalents. They are children, parents, and guardians who allege that prenatal ingestion of acetaminophen caused them or their children to develop attention-deficit/hyperactivity disorder (“ADHD”) and/or autism spectrum disorder (“ASD”). Defendants-Appellees are the pharmaceutical companies, 5  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. pharmacies, and retailers involved in the manufacturing, marketing, and/or sale of acetaminophen products. In the cases underlying the first appeal, Rutledge v. Walgreen Co., Plaintiffs- Appellants relied on the general causation testimony of five experts—Dr. Andrea Baccarelli, M.D., Ph.D., Dr. Eric Hollander, M.D., Dr. Brandon Pearson, Ph.D., Dr. Robert Cabrera, Ph.D., and Dr. Stan Louie, Pharm.D.—who opined as to a possible causal relationship between prenatal acetaminophen use and ADHD and ASD. The district court excluded the testimony of those five experts and granted summary judgment to Defendants-Appellees. The second appeal, Phippen v. Walgreen Co., involves a separate group of Plaintiffs-Appellants alleging injury solely from ADHD. After the district court’s initial ruling, those Plaintiffs-Appellants introduced an additional expert, Dr. Roberta Ness, M.D., M.P.H., to testify as to a possible causal relationship between prenatal acetaminophen use and ADHD only. The district court excluded her testimony and granted summary judgment to Defendants-Appellees. We consider these appeals together because of the substantial overlap of the issues they present. These appeals concern what qualifies as admissible epidemiological testimony in support of a general causal relationship. They arise against the backdrop of significant debate in the relevant scientific communities. That debate has also become political. But the issue before us is not political. It is not about positions taken by elected officials or political appointees. Nor do these appeals require us to decide whether acetaminophen use during pregnancy has adverse effects on fetal development. The issues before us concern the rules of evidence, 6  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. specifically the requirements for the admissibility of expert testimony. And so it is important that before we begin, we make clear what we are deciding and what we are not. We are not deciding whether there is a general causal relationship between acetaminophen and ADHD and/or ASD. We are also not deciding whether the manufacturers of acetaminophen must warn consumers about any alleged risk posed by such a potential causal relationship. And we are certainly not deciding the approach that policymakers concerned with protecting public health should take to regulating the use of acetaminophen. Rather, we are called upon to decide how closely a trial court may scrutinize a qualified expert’s conclusions when that expert follows methodologies that are generally accepted in their field, and the standard of reliability required for the admission of expert testimony on issues that are the subject of ongoing scientific debate. We conclude that, in Rutledge v. Walgreen Co., the district court exceeded its discretion in excluding the expert testimony of Drs. Baccarelli, Hollander, and Pearson. Those concededly qualified experts offered opinions that comport with methodologies applied by other scientists in their fields, and constitute acceptable interpretations of scientific evidence where scientists may, and in fact do, disagree on the ultimate answer to the causal question that they are assessing. The district court did not, however, abuse its discretion in excluding the testimony of Drs. Cabrera and Louie. The district court was entitled to conclude that Cabrera’s opinion was unreliable because it did not weigh or properly synthesize the factors under the so-called Bradford Hill methodology that he 7  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. employed. And the district court was similarly entitled to conclude that Louie’s opinion did not reliably address the dose and duration exposure threshold for risk of ADHD and ASD because he failed to explain how he extrapolated from the studies he analyzed to reach his final conclusion. We therefore vacate and remand the district court’s judgment in Rutledge. In Phippen, Plaintiffs-Appellants offered Ness as an expert only after the district court’s exclusion of Baccarelli, Hollander, Pearson, Cabrera, and Louie. With the admission of expert testimony from Baccarelli, Hollander, and Pearson, or for other reasons discussed below, it may be that Plaintiffs-Appellants would no longer seek to offer Ness’s testimony. We therefore vacate the district court’s judgment in Phippen, and remand for such further proceedings as the district court finds appropriate, consistent with this opinion. Finally, Defendants-Appellees argue that in both Rutledge and Phippen we should affirm the district court’s judgment on the alternative ground that federal drug labeling law preempts Plaintiffs-Appellants’ failure-to-warn claims. The district court rejected that argument at the pleading stage. Here, the district court did not err. Federal regulations require acetaminophen manufacturers to display verbatim a general pregnancy warning, but they do not prohibit supplemental, specific warnings against plausible risks. 8  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. I. BACKGROUND A. Acetaminophen, ADHD, and ASD Plaintiffs-Appellants are parents, guardians, and children who claim that they or their children developed ADHD and/or ASD due to prenatal acetaminophen exposure. Acetaminophen, also called paracetamol or APAP, is the active ingredient in Tylenol and other over-the-counter pain relievers. It is one of the few drugs indicated for use by pregnant women for pain and fever which, if left untreated, can harm both the woman and fetus. It is also a drug intended for systemic absorption (i.e., absorption through the blood stream). As such, when taken by pregnant women, acetaminophen can cross the placental barrier and enter fetal circulation. The FDA requires all such drugs to bear a general warning to pregnant and nursing women advising that they consult “a health professional before use.” 21 C.F.R. § 201.63. But, as relevant to Plaintiffs-Appellants’ claims, the FDA does not require that acetaminophen carry any warning related to ADHD and/or ASD, nor do Defendants-Appellees offer such a warning. ADHD and ASD are neurological developmental disorders (“NDDs”). ADHD is characterized by “a persistent pattern of” inattention, hyperactivity, and impulsivity “that interferes with functioning or development.” American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders (5th ed., Text Revision, 2022) (“DSM”) at 70. ASD is characterized by a “persistent impairment” in “social communication” and “restricted, repetitive patterns of behavior, interests, or activities.” Id. at 60. Although both disorders are highly 9  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. heritable, a fact that indicates some genetic influence, their precise causes are unknown. Id. at 64 (ASD), 71 (ADHD). For example, while some ASD cases are associated with a known genetic mutation, “[a] variety of risk factors for neurodevelopmental disorders, such as advanced parental age, extreme prematurity, or in utero exposures to certain drugs or teratogens like valproic acid, may broadly contribute to risk of [ASD].” Id. at 64. Scientists have been investigating a potential causal relationship between prenatal acetaminophen use and neurodevelopmental disorders for decades but no study has established such a relationship. The FDA opened a Tracked Safety Issue for prenatal acetaminophen exposure in 2014 and has since conducted periodic reviews of the evidence scientists have collected. In each such review, the FDA has noted that while prenatal acetaminophen exposure is associated in some studies with adverse neurological outcomes, study limitations and inconsistent results between studies have prevented the agency from determining causality. See, e.g., Abraham et al., Functional Neurobehavioral Outcomes and Urogenital Outcomes Associated with Prenatal Acetaminophen Exposure, U.S. Food and Drug Administration (July 15, 2022), at 33; Abraham et al., Updated Literature Review of Studies that Examine the Association between Acetaminophen Exposure During Pregnancy and Neurobehavioral or Urogenital Outcomes, U.S. Food and Drug Administration (March 10, 2023), at 17-18. In 2021, a group of thirteen authors and seventy-eight signees—consisting of scientists, clinicians, and public health professionals—published a “Consensus Statement” reviewing the literature on prenatal acetaminophen use and ADHD 10  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. and ASD. 2 The Consensus Statement concluded that “the combined weight of animal and human scientific evidence is strong enough for pregnant women to be cautioned by health professionals against its indiscriminate use.” Bauer et al., Consensus Statement: Paracetamol Use During Pregnancy—A Call for Precautionary Action, 17 Nature Revs. Endocrinology 757, 764 (2021) (“Consensus Statement”). And it recommended that acetaminophen “be used by pregnant women cautiously at the lowest effective dose for the shortest possible time.” Id. But it notably did not conclude that the available data allowed for an inference that a causal relationship exists. 3 See id. The Consensus Statement built on and echoed the findings of other scientists who viewed the research as potentially suggesting a causal relationship. See, e.g., Olson & Liew, Fetal Programming of Mental Health by Acetaminophen? Response to the SMFM Statement: Prenatal Acetaminophen Use and ADHD, 16 Expert Op. on Drug Safety 1395 (2017) (summarizing research to-date as “increas[ing] the probability that the association is causal”); Gou et al., Association of Maternal Prenatal Acetaminophen Use with the Risk of Attention Deficit/Hyperactivity Disorder in Offspring: A Meta-Analysis, 53 Austl. & N.Z. J. of Psychiatry 195 (2019) (similarly concluding that recent research “lend[s] weight to the hypothesis that the association is causal”). And other authorities have noted 2 To be clear, the “consensus” reflects the views held in common by the paper’s signatories. The term does not suggest that the paper reflects a consensus of all experts in the relevant fields of study; as will appear below, it most certainly does not. We use the term because it has become common in the scientific literature as a short-hand reference for the paper in question. 3 As explained in greater detail below, “[e]pidemiologic methods cannot deductively prove causation”; rather, “epidemiologic evidence can justify an inference, and sometimes a very strong inference, that an agent causes a disease.” Federal Judiciary Center, Reference Manual on Scientific Evidence (4th ed. 2025) (RMSE) at 902 n.10. 11  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. the potential risk, including the Briggs reference guide on Drugs in Pregnancy and Lactation (12th ed. 2022) which acknowledged that prior assessments of acetaminophen as “not . . . caus[ing] embryo-fetal harm . . . must change because of recent data.” The Consensus Statement prompted replies and counterstatements from other scientists and medical bodies. Those publications noted the limitations of the various studies upon which the Consensus Statement relied and expressed concern that the Consensus Statement could lead pregnant women experiencing pain and fever to avoid acetaminophen altogether or to turn to less safe alternatives. See, e.g., Alwan et al., Paracetamol Use in Pregnancy—Caution Over Causal Inference from Available Data, 18 Nature Revs. Endocrinology 190 (2022) (“urg[ing] against recommending [] precautionary measures for [acetaminophen] use in pregnancy and against the dissemination of information based on inconclusive and insufficient evidence”); O’Sullivan et al., Paracetamol Use in Pregnancy—Neglecting Context Promotes Misinterpretation, 18 Nat. Rev. Endocrinology 385 (2022) (expressing concern that “[t]he overarching societal message that has been drawn from [the] Consensus Statement is that APAP use in pregnancy is unsafe and should be restricted in both use and access”); American College of Gynecologists, ACOG Response to Consensus Statement on Paracetamol Use During Pregnancy (Sept. 29, 2021) (noting that “ACOG’s clinical guidance remains the same and physicians should not change clinical practice until definitive prospective research is done”). 12  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. B. Epidemiology and Causation Epidemiology is the study of the causes, incidence, and distribution of diseases. RMSE at 972. Since ethical constraints render impossible many experiments that might be most probative of a causal relationship (e.g., random clinical trials), epidemiologists often rely instead upon observational studies. In an observational study, epidemiologists “‘observe’ a group of individuals who have been exposed to an agent of interest, such as . . . an industrial chemical, and compare them with another group of individuals who have not been exposed.” RMSE at 906. An observational study thus allows epidemiologists to determine whether an association exists between an agent and a health outcome. But an association “does not necessarily mean that there is a cause-effect relation” between the agent and that outcome. RMSE at 921. Accordingly, “[t]o make a judgment about causation,” epidemiologists consider observational studies identifying an association through the lens of “several key inquiries.” RMSE at 971, 973. One method generally accepted by the courts for structuring that process is consideration of the Bradford Hill criteria. 4 See, e.g., Sarkees v. E.I. Dupont De Nemours & Co., 15 F.4th 584, 591–92 (2d Cir. 2021); In re Zoloft (Setraline Hydrochloride) Prods. Liab. Litig., 858 F.3d 787, 796 (3d Cir. 2017). The Bradford Hill criteria are a set of factors that epidemiologists examine to assess whether an observed association is causal in nature. RMSE at 973. No single Bradford Hill factor is required to infer causation. Nor are the criteria “an 4 The Bradford Hill method takes its name from a 1965 paper by the epidemiologist Sir Austin Bradford Hill describing the approach. See RMSE at 973. 13  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. exhaustive []or a necessary list.” Zoloft, 858 F.3d at 796. In a Bradford Hill analysis, an epidemiologist typically identifies the body of published scientific literature that is relevant to their question and then analyzes the results of each of those studies for the presence, or lack thereof, of each of the Bradford Hill criteria. The criteria as presented in the Federal Judiciary Center’s Reference Manual on Scientific Evidence 5 are: (1) Replication of the findings (also referred to as “consistency”): When the outcomes of a study are observed “in different populations and by different investigators,” this supports a causal determination. RMSE at 981. (2) Strength: “Larger relative risks (or stronger associations using other statistical measures) are often believed to be more likely to be causal than smaller ones.” RMSE at 977. (3) Specificity: Where an “exposure is associated only with a single disease or type of disease,” this may be strong evidence in support of causality. RMSE at 984. (4) Dose-response relationship: If an exposure to a risk factor causes a disease, then “higher exposures would generally be expected to increase the incidence or severity of that disease.” RMSE at 977. Dose responses may take different shapes, including a straightforward linear relationship, a linear relationship after the dose exceeds a particular 5 Epidemiologists have formulated the Bradford Hill criteria in different ways, for example, referring to the same criterion under a different label or consolidating multiple criteria under a single one. 14  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. threshold, or a non-monotonic effect such as when both under-exposure and over-exposure to a particular agent causes impaired outcomes. RMSE at 978–81. (5) Temporal relationship: Exposure to the risk factor must precede the disease, because “[i]f the exposure occurs after the disease develops, it cannot have caused the disease.” RMSE at 975. (6) Biological plausibility: When a proposed causal relationship is consistent with “current biological knowledge,” the causal inference is strengthened. RMSE at 983. This is “not an easy criterion to use and depends upon existing knowledge about the mechanisms by which the disease develops.” RMSE at 982. “The mechanisms of some diseases are understood quite well based on evidence . . . whereas other mechanism explanations are merely hypothesized—although hypotheses are sometimes also accepted under this factor.” RMSE at 983. (7) Consistency with other relevant knowledge (also referred to as “coherence”): A causal relationship should be consistent with other information known about the disease. RMSE at 985. (8) Cessation of exposure (also referred to as “experiment”): When experimental evidence shows that “eliminating exposure reduces the incidence of disease,” this supports a causal relationship. RMSE at 984. In conducting this inquiry, an epidemiologist must also take care to consider “the possibility that an observed association is caused by something other than the exposure under study,” such as “bias and confounding.” RMSE at 984. 15  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. C. Statutory and Regulatory Framework “Under the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 301 et seq. (‘FFDCA’), a new drug may not enter interstate commerce unless [the] FDA determines that it is generally recognized as safe and effective (‘GRAS/E’) for the particular use described in its product labeling.” NRDC v. FDA, 710 F.3d 71, 75 (2d Cir. 2013). Two such pathways to a GRAS/E determination are relevant here: the New Drug Application (“NDA”) process and the monograph system. Under the NDA process, “a manufacturer seeking federal approval to market a new drug must prove that it is safe and effective and that the proposed label is accurate and adequate.” PLIVA, Inc. v. Mensing, 564 U.S. 604, 612 (2011). “The FDA’s premarket approval of a new drug application includes the approval of the exact text in the proposed label.” Wyeth v. Levine, 555 U.S. 555, 568 (2009). After a manufacturer receives such approval, it remains charged with “ensuring that its warnings remain adequate as long as the drug is on the market.” Id. at 571. Hence a manufacturer may make post-approval label changes that “add or strengthen a contraindication, warning, precaution, or adverse reaction” based on “newly acquired information.” 21 C.F.R. § 314.70(c)(6)(iii). Over-the-counter (“OTC”) drugs, however, may also be approved through the monograph system. See 21 C.F.R. § 330.10; 21 U.S.C. § 355. “Under this system, FDA issues a detailed regulation—a ‘monograph’—for each therapeutic class of OTC drug products.” NRDC, 710 F.3d at 75. Each final monograph “establish[es] conditions under which a category of OTC drugs . . . are generally recognized as safe and effective and not misbranded.” 21 C.F.R. § 330.10(a)(9). A final 16  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. monograph “may include any conditions relating to active ingredients, labeling indications, warnings and adequate directions for use . . . necessary and appropriate for the safety and effectiveness of drugs covered by the monograph,” id. § 330.10(a)(5)(i), but need not dictate the full label that manufacturers must apply to a product marketed under it. Moreover, manufacturers marketing a specific product under the monograph “are not required to submit labeling to the agency for preapproval.” Over-The-Counter Human Drugs; Labeling Requirements, 64 Fed. Reg. 13254, 13271 (Mar. 17, 1999). Over-the-counter acetaminophen products are marketed pursuant to the monograph for Internal Analgesic, Antipyretic, and Antirheumatic Drug Products (“IAAA”). See U.S. Food and Drug Administration, Over-the Counter (OTC) Monograph M013: Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the Counter Human Use (Oct. 14, 2022). 6 The IAAA monograph sets forth various labeling requirements. For example, acetaminophen labels must specify only the indications for use established in the monograph. The monograph does not, however, expressly prohibit additional warnings not specified therein. Whether approved through the NDA or monograph system, OTC drugs that are intended for systemic absorption must also contain a general pregnancy and breast-feeding warning. 21 C.F.R. § 201.63 (“Pregnancy Warning While the IAAA monograph was not finalized until 2022, it was first proposed as a tentative final 6 monograph in 1988, during which time it had the status of a proposed rule. See Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use; Tentative Final Monograph, 53 Fed. Reg. 46204 (Nov. 16, 1988). 17  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. Regulation”). Acetaminophen is one such drug. The Pregnancy Warning Regulation states: The labeling for all over-the-counter (OTC) drug products that are intended for systemic absorption, unless specifically exempted, shall contain a general warning under the heading “Warning” (or “Warnings” if it appears with additional warning statements) as follows: “If pregnant or breast-feeding, ask a health professional before use.” [first four words of this statement in bold type] In addition to the written warning, a symbol that conveys the intent of the warning may be used in labeling. Id. § 201.63(a) (bracketed text in original). Because the warning language identified in the Pregnancy Warning Regulation is “established and identified by quotation marks,” a separate regulation, the Exact Language Regulation, requires that the warning appear in the “exact language” specified. Id. § 330.1(c)(2). The Pregnancy Warning Regulation further provides, however, that [w]here a specific warning relating to use during pregnancy or while nursing has been established for a particular drug product in [an NDA] or for a product covered by an OTC drug final monograph [then such] specific warning shall be used in place of the warning in paragraph (a) of this section [“If pregnant or breast-feeding, ask a health professional before use”], unless otherwise stated in the NDA or in the final OTC drug monograph. Id. § 201.63(b). D. Procedural Background Several months after publication of the Consensus Statement that suggested possible links between acetaminophen and ADHD and ASD, Plaintiffs-Appellants began to file suits against the manufacturers and retailers of acetaminophen, 18  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. alleging that prenatal exposure to the drug caused them or their children to develop ADHD and/or ASD. Those cases were consolidated and transferred to the Southern District of New York by the Judicial Panel on Multidistrict Litigation pursuant to 28 U.S.C. § 1407. 1. Preemption Defense Two Defendants-Appellees—Walmart, Inc. and Johnson & Johnson Consumer Inc.—moved to dismiss three failure-to-warn actions on the ground that federal law preempted the addition of ADHD and/or ASD warnings to pregnant women on acetaminophen labels. The district court denied those motions in separate decisions, concluding that while federal law required acetaminophen manufacturers to display a general pregnancy warning, that requirement did not preclude manufacturers from including an additional warning specific to the risk of ADHD and/or ASD. In re Acetaminophen—ASD- ADHD Prods. Liab. Litig., No. 22-md-3043, 2022 WL 17348351 (S.D.N.Y. Nov. 14, 2022); In re Acetaminophen—ASD-ADHD Prods. Liab. Litig., No. 22-md-3043, 2023 WL 3026412 (S.D.N.Y. Apr. 20, 2023). 2. Motions to Exclude Expert Testimony under Rule 702 and for Summary Judgment Following consolidation, the parties agreed first to conduct discovery related to general causation (i.e., whether a causal relationship generally exists between prenatal acetaminophen exposure and ADHD and ASD) and, then, if Plaintiffs-Appellants’ experts survived Rule 702 motions, to proceed with the remainder of discovery, including specific causation (i.e., whether a particular 19  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. plaintiff developed ADHD and/or ASD because of prenatal acetaminophen exposure). While Plaintiffs-Appellants bring their claims under the tort law of various states, there is no dispute that “all fifty states require some evidence of general causation in products liability cases involving complex products liability (or medical) issues.” In re Mirena IUS Levonorgestrel-Related Prods. Liab. Litig. (No. II), 982 F.3d 113, 124 (2d Cir. 2020) (internal quotation marks omitted). Plaintiffs- Appellants produced five experts to opine on general causation. Dr. Baccarelli is an epidemiologist and physician, an elected member of the National Academy of Medicine, and dean of the Harvard T.H. Chan School of Public Health. App’x 5417. He identified and analyzed the peer-reviewed literature on prenatal acetaminophen exposure, then applied two epidemiological methodologies—the Bradford Hill criteria and the Navigation Guide 7—to synthesize that evidence. Under each methodology, Baccarelli concluded that the evidence supports a finding of causality. Dr. Hollander is a psychiatrist and professor at the Albert Einstein College of Medicine. He opined as to the interconnectedness of neurodevelopmental disorders like ADHD and ASD, explaining that it is appropriate for scientists to consider the two outcomes together, as well as to consider studies with symptomatic endpoints, when assessing whether a causal relationship exists 7 The Navigation Guide is a method distinct from the Bradford Hill analysis. According to Baccarelli, the Navigation Guide is used “to more readily evaluate causal relationships for toxic and environmental harms.” App’x 1745. It involves the “systematic rating and review of” individualized studies addressing a potential causal relationship “for bias, strength of evidence, and other indicia of study quality.” Id. 20  24-916(L); 24-2594 Rutledge v. Walgreen Co.; Phippen v. Walgreen Co. between acetaminophen and ADHD and ASD. App’x 2475. Plaintiffs-Appellants offered Hollander’s testimony as support for Baccarelli’s Bradford Hill analysis, which considered ADHD and ASD together, and for Baccarelli’s decision to consider studies that utilized symptomatic endpoints, in addition to those that relied upon ADHD and/or ASD as diagnostic outcomes. In his rebuttal report, Hollander also provided his own Bradford Hill analysis. Dr. Pearson is a toxicologist at Columbia University. He specializes in preclinical research relating to neurodevelopmental disorders. 8 Pearson’s report identified and explained the biological mechanisms by which acetaminophen exposure could cause ADHD and ASD based on the preclinical literature. App’x 2021. Dr. Cabrera is a teratologist and geneticist at Baylor College of Medicine. Teratology is the study of “abnormalities, malformations, and developmental disorders that occur during prenatal development.” App’x 2207. Cabrera reviewed the available literature and used two established methodologies— weight-of-the-evidence 9 and the Bradford Hill criteria—to conclude that acetaminophen can cause ADHD and ASD. He also asserted the biological mechanisms through which acetaminophen exposure can be a cause of ADHD and 8 Preclinical studies involve animal and other non-human testing. 9 As its name suggests, under the weight-of-the-evidence approach, an epidemiologist synthesizes a review of the available scientific literature—including “clinical observations, case reports, epidemiological and animal studies, toxicological experiments, [and] exposure data,” a