Miller v. Boehringer Ingelheim Pharmaceuticals, Inc.

MOTION TO DISMISS FOR FAILURE TO STATE A CLAIM

M.D. Ala.June 27, 2017

1 UNITED STATES DISTRICT COURT FOR THE MIDDLE DISTRICT OF ALABAMA NORTHERN DIVISION TIMMIE MILLER, § § Plaintiff, § § v. § 2:17-cv-00293-JZ-GMB § BOEHRINGER INGELHEIM PHARMACEUTICALS, INC. § § § Defendant. § DEFENDANT BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.’S MOTION TO DISMISS PLAINTIFF’S COMPLAINT AND MEMORANDUM IN SUPPORT Pursuant to Federal Rules of Civil Procedure 8(a) and 12(b)(6), Defendant Boehringer Ingelheim Pharmaceuticals, Inc. (“BIPI”) submits this Motion to Dismiss Plaintiff’s Complaint for failure to state a claim upon which relief can be granted. INTRODUCTION This case arises out of Timmie Miller’s alleged development of diabetic ketoacidosis (“DKA”), which he attributes to his use of Jardiance. Jardiance is a prescription drug that belongs to the class of drugs known as sodium-glucose cotransporter-2 (“SGLT-2”) inhibitors. Jardiance was approved by the U.S. Food and Drug Administration (“FDA”) as safe and effective for the treatment of type 2 diabetes on August 1, 2014. Plaintiff’s Complaint [D.E. 1] does not plead a cognizable claim against BIPI based on his injuries allegedly caused by Jardiance, and therefore the Complaint should be dismissed for failure to state a claim. Plaintiff’s failure-to-warn allegations are premised on a theory that the initial FDA-approved warnings in Jardiance’s labeling should have contained different information. Specifically, the Complaint cites information collected from March 2013 to June 6, 2014 that Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 1 of 26 2 served as the basis for a May 15, 2015 FDA safety alert (“FDA Alert”) regarding the SGLT-2 inhibitor class and DKA. Importantly, the information collected from March 2013 to June 6, 2014 did not concern Jardiance at all, but concerned two other medications in the SGLT-2 inhibitor class. Moreover, pursuant to existing federal regulations and Supreme Court precedent, the FDA assessed Jardiance’s warning at the time of approval in August 2014, deemed Jardiance to be safe and effective when accompanied by that warning, and required Jardiance to be accompanied by the precise warning approved by the FDA at the commencement of marketing Jardiance. Thus, any state law duty to provide a different warning at the time of Jardiance’s FDA approval is preempted. Additionally, Plaintiff’s Complaint does not plausibly allege that BIPI became aware of any “newly acquired information” that was unknown to the FDA and thus would have allowed BIPI to voluntarily change Jardiance’s label after the FDA approved Jardiance through the FDA’s Changes Being Effected (“CBE”) process. Accordingly, all of Plaintiff’s claims that are predicated on a failure-to-warn theory are preempted by federal law. Without his failure-to-warn theory, which is preempted, Plaintiff is left with a Complaint that is devoid of facts sufficient to state a claim under federal pleading requirements. Even if Plaintiff’s new failure-to-warn theory is not preempted (which it is), Plaintiff’s Complaint still does not plausibly allege how the warnings contained in Jardiance’s label were defective or how the alleged defect in those warnings caused Plaintiff’s injuries. Such insufficient allegations cannot overcome federal pleading standards that require Plaintiff to allege facts in support of his claims. Because Plaintiff has failed to plead facts sufficient to withstand a motion to dismiss, his Complaint should be dismissed. Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 2 of 26 3 FACTUAL BACKGROUND Diabetes is a serious healthcare epidemic in the United States and worldwide, characterized by uncontrolled blood glucose (sugar) levels. Jardiance (empagliflozin) was approved by the FDA on August 1, 2014 for the treatment of type 2 diabetes. Compl. ¶ 15. It is a member of the newest class of medications used to treat type 2 diabetes known as SGLT-2 inhibitors. Id. SGLT-2 inhibitors provide a novel mechanism for lowering glucose levels. Id. ¶ 17. Plaintiff alleges he began taking Jardiance to treat diabetes “in or about March 2015,” id. ¶ 26, and experienced DKA “on or about May 8, 2015,” id. ¶ 31. “[O]n May 15, 2015, the FDA issued a safety announcement covering the SGLT-2 inhibitor class, warning about the risk of DKA and advising that the FDA would continue to evaluate the safety issue.” Id. ¶ 35. “FDA analyzed data collected in the FDA Adverse Event Reporting System (“FAERS”) between March 2013 and June 6, 2014 to put together its May 15, 2015 safety alert.” Based on the “same information FDA relied on to issue its May 15, 2015” FDA Alert, Plaintiff contends that BIPI violated state law because BIPI “did not warn about the risks of DKA” at the time “JARDIANCE was approved,” id. ¶ 52, and did not “amend the label or utilize the CBE process” to warn about the risk of DKA before Plaintiff used Jardiance, id. ¶ 68(c). Plaintiff’s Complaint still does not provide any factual statements about Plaintiff’s diabetes, other (non-SGLT-2 inhibitor) diabetes medication use, or his development of DKA. In addition to developing DKA, Plaintiff alleges that he experienced “other related health complications,” id. ¶¶ 91, 115, but nowhere does Plaintiff identify them, much less allege a failure to warn about alleged “other” complications. Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 3 of 26 4 REGULATORY BACKGROUND Congress has entrusted to the FDA sole authority to approve prescription drugs for sale in the United States. See, e.g., 21 U.S.C. § 393(b). The Federal Food, Drug, and Cosmetic Act (“FDCA”) requires drug manufacturers to gain FDA approval before marketing or selling a new drug in interstate commerce. Id. § 355(a). To receive approval, the drug must “meet[] the statutory standards for safety and effectiveness, manufacturing and controls, and labeling,” as determined by the FDA. 21 C.F.R. § 314.105(c). To seek FDA approval of a drug, a drug manufacturer must submit either a New Drug Application (“NDA”) for a new drug or a supplemental NDA (“sNDA”) for a new drug treatment, which are subject to the same approval requirements.1 See 21 C.F.R. § 314.1, et seq. The FDA drug approval process is “onerous and lengthy,” Mut. Pharm. Co. v. Bartlett, 133 S. Ct. 2466, 2471 (2013), and the FDA will refuse to approve a drug if it lacks either “adequate tests . . . to show whether or not [the] drug is safe for use” or “substantial evidence that the drug will have the effect it purports or is represented to have.” 21 U.S.C. § 355(d)(1), (5).2 “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). The NDA or sNDA must include “the labeling proposed to be used” for the drug, 21 U.S.C. § 355(b)(1)(F); 21 C.F.R. § 314.50(c)(2)(i), and “a discussion of why the [drug’s] benefits exceed the risks under the 1 An NDA or sNDA consists of a compilation of materials that includes “full reports of [all clinical] investigations,” 21 U.S.C. § 355(b)(1)(A); 21 C.F.R. § 314.50(d)(5), relevant nonclinical studies, and “any other data or information relevant to an evaluation of the safety and effectiveness of the drug product.” 21 C.F.R. § 314.50(d)(2), (d)(5)(iv). 2 Substantial evidence that a drug will have the effect it purports or is represented to have generally consists of “adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved.” Id. § 355(d); see also 21 C.F.R. § 314.126 (defining adequate and well-controlled studies). “[D]ata from one adequate and well-controlled clinical investigation and [other] confirmatory evidence” may constitute “substantial evidence” if the FDA “determines, based on relevant science, that [such] data . . . are sufficient to establish effectiveness.” 21 U.S.C. § 355(d). Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 4 of 26 5 conditions stated in the labeling.” 21 C.F.R. § 314.50(d)(5)(viii). 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, Biologics, and Medical Devices, 73 Fed. Reg. 49603-01, 49604 (Aug. 22, 2008) (hereinafter Labeling Changes). To approve an NDA or sNDA, the FDA must determine, “based on a fair evaluation of all material facts,” that the proposed label is not “false or misleading in any particular,” 21 U.S.C. § 355(d)(7), or otherwise “does not comply with the requirements for labels and labeling.” 21 C.F.R. § 314.125(b)(6), (8). Once the FDA has approved an NDA or sNDA, a manufacturer may distribute the drug so long as it uses the FDA-approved label; if it does not do so, it violates federal law. See 21 U.S.C. §§ 331(c), 333(a), 352(a), (c). After the FDA approves a drug, there are two ways a manufacturer can change the drug’s label. “First, the default rule is that a manufacturer must secure FDA approval for a proposed change prior to distributing the product with the changed label.” In re Celexa & Lexapro Mktg. & Sales Practices Litig., 779 F.3d 34, 37 (1st Cir. 2015) (citing 21 C.F.R. § 314.70(b)(2)(v)(A)). Second, under the CBE regulation, a drug manufacturer can, without prior FDA approval, make certain types of changes to the drug’s label by sending a “supplement submission” to the FDA. See 21 C.F.R. § 314.70(c)(6)(iii). To make changes to the drug’s label pursuant to the CBE process, the drug manufacturer must satisfy two requirements. First, the label change must reflect “newly acquired information.” Id. “Newly acquired information” is defined by regulation as data, analyses, or other information not previously submitted to the Agency, which may include (but is not limited to) data derived from new clinical studies, reports of adverse events, or new analyses 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. Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 5 of 26 6 Id. § 314.3(b) (emphasis added). Second, the label change must be for the purpose of accomplishing at least one of five objectives, including, inter alia, “[t]o add or strengthen a contraindication, warning, precaution, or adverse reaction for which the evidence of a causal association satisfies the standard for inclusion in the labeling.” Id. § 314.70(c)(6)(iii)(A). The FDA has recognized that “[e]xaggeration 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.” Labeling Changes, 73 Fed. Reg. 2848-01, 2850-51 (Jan. 16, 2008). 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. Id.; see also 21 C.F.R. § 201.57(c)(6)(i). By expressly requiring that a CBE change 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 (Aug. 22, 2008). LEGAL STANDARD “To survive a motion to dismiss, a complaint must contain sufficient factual matter, accepted as true, to ‘state a claim to relief that is plausible on its face.’” Ashcroft v. Iqbal, 556 U.S. 662, 678 (2009) (quoting Bell Atl. Corp. v. Twombly, 550 U.S. 544, 570 (2007)). That is, the complaint must include factual allegations sufficient “to raise a right to relief above the speculative level.” Mallory v. Biomet, Inc., No. 2:14cv984-SRW, 2014 WL 6890740, at *1 (M.D. Ala. Dec. 4, 2014). Plausibility requires more than a “sheer possibility that a defendant has acted unlawfully,” Iqbal, 556 U.S. at 678, and “necessarily requires that a plaintiff include factual allegations for each essential element of his or her claim.” GeorgiaCarry.Org, Inc. v. Georgia, 687 F.3d 1244, 1254 (11th Cir. 2012). “Threadbare recitals of the elements of a cause of action, Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 6 of 26 7 supported by mere conclusory statements, and unadorned, the-defendant-unlawfully-harmed-me accusation[s], cannot withstand a motion to dismiss.” Odion v. Google Inc., 628 F. App’x 635, 637 (11th Cir. 2015) (per curiam) (quotation marks omitted). In ruling upon a Rule 12(b)(6) motion to dismiss, the court may consider the complaint as well as documents that are “(1) central to the plaintiff's claim and (2) undisputed,” meaning “the authenticity of the document is not challenged.” Day v. Taylor, 400 F.3d 1272, 1276 (11th Cir. 2005). Additionally, “[a] district court may take judicial notice of matters of public record.” Halmos v. Bomardier Aerospace Corp., 404 F. App’x 376, 377 (11th Cir. 2010) (per curiam). FDA documents may properly be considered on a motion to dismiss. See, e.g., Miller v. Pfizer Inc., No. 4:13-cv-01687-KOB, 2014 WL 2155020, at *2 (N.D. Ala. May 22, 2014) (considering FDA-approved labels). I. PLAINTIFF’S FAILURE-TO-WARN CLAIMS, SOLELY BASED ON DATA SUBMITTED TO THE FDA BEFORE THE FDA APPROVED JARDIANCE, FAIL. To support his claim that “Defendant knew or should have known the risks associated with using JARDIANCE, including the risk of developing [DKA],” Compl. ¶ 34, Plaintiff solely relies on allegations regarding “at least 20 cases of DKA” contained in the FAERS database that occurred with other SGLT-2 inhibitors before Jardiance received FDA approval. Id. ¶ 68(b). Plaintiff alleges that BIPI, “armed with this data,” should have changed Jardiance’s label to include a DKA warning; in other words, Plaintiff alleges that BIPI should have sought approval of a different initial label from the FDA or utilized the CBE process to change the label after the FDA approved Jardiance. Id. ¶ 68(c). However, because Plaintiff bases his failure-to-warn claims on data related to other SGLT-2 inhibitors that was available and submitted to the FDA through the FAERS database before the FDA approved Jardiance, Plaintiff’s claims are preempted by federal law, a purely legal issue that the Court may decide at the pleading stage. See, e.g., PLIVA, Inc. v. Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 7 of 26 8 Mensing, 564 U.S. 604, 611-12, 626 (2011); see also In re Celexa, 779 F.3d at 43 (affirming dismissal of complaint on preemption grounds, because defendants could not have independently changed prescription drug label at time of FDA approval or after FDA approval pursuant to CBE process); Utts v. Bristol-Myers Squibb Co., -- F. Supp. 3d --, 2016 WL 7429449, at *10-11 (S.D.N.Y. Dec. 23, 2016) (hereinafter Utts I) (holding on motion to dismiss that failure-to-warn claims were preempted, where claims were premised on adequacy of label as approved by FDA when drug was first marketed and where plaintiffs did not plead any “newly acquired information” that would have allowed manufacturer to independently change drug label to add or improve warnings pursuant to CBE process); Utts v. Bristol-Myers Squibb Co., -- F. Supp. 3d --, 2017 WL 1906875, at *1 (S.D.N.Y. May 8, 2017) (hereinafter Utts II) (after plaintiffs amended complaint dismissed in Utts I, dismissing preempted failure-to-warn claims with prejudice, because plaintiffs did not plausibly plead any “newly acquired information” that would have allowed manufacturer to use CBE process to add or improve warnings to drug label). And because no amount of re- pleading can save Plaintiff’s failure-to-warn claims, the Court should dismiss these claims with prejudice. a. State Laws That Conflict With Federal Laws Are Preempted. The doctrine of preemption arises from the Supremacy Clause of the United States Constitution, which provides that the Constitution, federal law, and all treaties are “the supreme Law of the Land; and the Judges in every State shall be bound thereby, any Thing in the Constitution or Laws of any State to the Contrary notwithstanding.” U.S. CONST. art. VI, cl. 2. Thus, since the Supreme Court’s decision in McCulloch v. Maryland, it has been settled that state law that conflicts with federal law is “without effect.” Bartlett, 133 S. Ct. at 2470. Conflict preemption precludes the application of state law when it is “impossible for a private party to Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 8 of 26 9 comply with both state and federal requirements.” Geier v. Am. Honda Motor Co., 529 U.S. 861, 899 (2000). Three recent Supreme Court decisions have outlined the test for conflict preemption in pharmaceutical drug cases. In Wyeth, the Court explained that the impossibility variety of conflict preemption does not exist where a federal regulatory provision expressly allows a manufacturer to unilaterally do what state law allegedly would require. See 555 U.S. at 572-73. There, a jury found a brand name drug manufacturer liable under Vermont law for inadequately warning of the dangers of administering a drug through a certain intravenous method. Id. at 558. The Supreme Court rejected the manufacturer’s preemption defense, reasoning that, after receiving FDA approval for the drug, the manufacturer could have used the CBE process to update the drug’s label when the risks alleged by the plaintiff became apparent. Id. at 572-73. “By hinging preemption on the availability [to use the CBE process] in a particular case, Wyeth effectively reserves the launch of new drugs to the expertise of the FDA, but then preserves a wide scope for the states in requiring manufacturers to respond to information not considered by the FDA.” In re Celexa, 779 F.3d at 41. Two years later, in Mensing, the Court clarified that “[t]he question for ‘impossibility’ is whether the private party could independently do under federal law what state law requires of it,” defining independently to mean unilaterally, “without the Federal Government’s special permission and assistance.” 564 U.S. at 620-24. “The Court thus limited Levine to situations in which the drug manufacturer can, ‘of its own volition, . . . strengthen its label in compliance with its state tort duty.’” Yates v. Ortho-McNeil-Janssen Pharm., Inc., 808 F.3d 281, 295 (6th Cir. 2015); see also In re Celexa, 779 F.3d at 41 (same). Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 9 of 26 10 Finally, in Bartlett, the Court held that the Mensing impossibility preemption test applies beyond Mensing’s facts-i.e., a failure-to-warn claim against a generic drug manufacturer-by applying the test to hold that it would be impossible for a drug manufacturer to make major changes to the design of any drug, “whether generic or brand-name,” without the FDA’s special assistance or permission. 133 S. Ct. at 2471. Any such change, the Court held, would render the drug a “new drug” that must receive prior FDA approval before it can be marketed to the public, therefore confirming the core holding of Mensing that, when a party cannot satisfy its alleged duties underlying a plaintiff’s state law claim before obtaining the FDA’s approval, those state law claims are preempted by federal law. Id. at 2475. “Read holistically,” Wyeth, Mensing, and Bartlett, “indicate that federal law preempts all pre-FDA approval failure to warn and design defect claims for branded prescription medication.” Utts II, 2017 WL 1906875, at *9. The Wyeth, Mensing, and Bartlett decisions leave lower courts with an easily applied framework for determining when impossibility preemption applies to a state law claim. First, courts should determine what duties the state law underlying the plaintiff’s claims places on the defendant related to the product in question. Then, courts must determine whether a federal law or regulation exists that would prevent the defendant from taking that action independently, i.e. without a federal agency’s “special permission and assistance.” Mensing, 564 U.S. at 623-24. Where the federal law or regulation prohibits the defendant from independently taking the action required by state law, the state law claim is preempted. Id. b. According To Plaintiff’s Own Allegations, BIPI Could Not Have Changed The Jardiance Label Prior To Or After FDA Approval. Plaintiff attempts to plead warnings-based claims under Alabama state law. The Alabama Supreme Court has stated that a duty to warn arises when a manufacturer has knowledge or could have developed knowledge “by the application of reasonable, developed human skill and foresight Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 10 of 26 11 that the product presented a danger of injury of the kind suffered by [plaintiff].” Griggs v. Combe, Inc., 456 So. 2d 790, 792 (Ala. 1984) (internal quotation marks omitted). Specifically, Plaintiff claims that the initial Jardiance label was inadequate as a matter of state law, despite being approved by the FDA, because BIPI did not warn of the alleged risk of DKA even though the FAERS database “established a signal between SGLT-2 inhibitors and DKA,” Compl. ¶ 68(a), based on 20 DKA-related “reports provided before JARDIANCE entered the market,” id. ¶ 50. Plaintiff’s failure-to-warn claims, solely premised on data publicly available and indeed submitted to the FDA before the FDA approved Jardiance, fail because BIPI was compelled by federal law to use the FDA-approved Jardiance label when it first marketed Jardiance and could not have changed the Jardiance label after FDA approval based on alleged pre-launch data related to other SGLT-2 inhibitors that was already known to the FDA. i. Upon FDA Approval To Market Jardiance, Federal Law Required BIPI To Provide The FDA-Approved Jardiance Label, Which Did Not Include A DKA Warning. Plaintiff’s claims that BIPI knew or should have known of the risk of DKA based on the 20 DKA cases involving other SGLT-2 inhibitor drugs, which were known to the FDA and published in the FDA’s own database, and that therefore BIPI should have provided a DKA warning upon first marketing Jardiance, are preempted. Such failure-to-warn claims, predicated on the notion that a different warning should have been provided at the time of FDA approval, directly challenge aspects of the drug that the FDA expressly approved, and from which BIPI could not deviate. As other courts have recognized, permitting such a claim to proceed would render FDA approval all but meaningless, and therefore the state law claim is preempted. See, e.g., In re Celexa, 779 F.3d at 41 (explaining that the FDA is the “exclusive judge” of “how a drug can be marketed” on approval); Utts I, 2016 WL 7429449, at *10 (finding failure-to-warn claims Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 11 of 26 12 premised on adequacy of label as approved by FDA when drug was first marketed preempted, because labeling is “centerpiece of risk management for prescription drugs” and “reflects thorough FDA review of the pertinent scientific evidence”). The FDA approves a drug only if it determines that the drug in question is safe for use under its proposed labeling and that the drug’s probable therapeutic benefits outweigh its risks of harm. 21 U.S.C. § 355(d). In Wyeth, the Supreme Court made clear that “[t]he FDA’s premarket approval of a new drug application includes the approval of the exact text in the proposed label.” 555 U.S. at 568. Here, in approving Jardiance, the FDA commanded BIPI that “[c]ontent of labeling must be identical to the enclosed labeling (text for the package insert and text for the patient package insert).” Jardiance NDA Approval Letter (Aug. 1, 2014) at 1, http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/204629Orig1s000ltr.pdf (last visited June 16, 2017) and attached hereto as Exhibit 1. BIPI would have violated federal law (i.e., Jardiance would have been misbranded) if, upon approval, BIPI instead had marketed Jardiance with labeling and warnings other than what the FDA approved. See 21 U.S.C. §§ 331(c), 333(a), 352(a), (c). Thus, as the First Circuit has explained, Wyeth and Mensing drew a line that “lets the FDA be the exclusive judge of safety and efficacy based on information available at the commencement of marketing, while allowing the states to reach contrary conclusions when new information not considered by the FDA develops.” In re Celexa, 779 F.3d at 41. Plaintiff’s state law claim that a different warning should have been provided when BIPI commenced marketing Jardiance is therefore preempted. Allowing state law tort juries to find otherwise-i.e., that from the time the drug was first marketed, it was “unreasonably dangerous” as a result of the drug’s FDA-approved labeling-would invariably conflict with the FDA’s considered judgment regarding the same. As other courts have held, “[t]o the extent that the failure Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 12 of 26 13 to warn claims are premised on the adequacy of the label as approved by the FDA when the drug was first marketed in the United States, they are preempted.” Utts I, 2016 WL 7429449, at *10. The Utts I court, for example, explained that brand name drug manufacturers lack the authority to alter a label’s warnings “at the time the NDA process concludes,” because “[t]hey have received approval only for that formulation and that label that survive the NDA process.” Id.; accord Utts II, 2017 WL 1906875, at *9; see also In re Celexa, 779 F.3d at 41 (“Wyeth effectively reserves the launch of new drugs to the expertise of the FDA”); In re Lipitor (Atorvastatin Calcium) Mktg., Sales Practices & Prods. Liab. Litig., 185 F. Supp. 3d 761, 769-70 (D.S.C. 2016) (because “the FDA approved the Lipitor label” and “specifically approved [a particular] statement,” federal law preempted the “claim [that] Lipitor’s label should have included different statements”). Moreover, any argument that preemption does not apply because BIPI could have asked the FDA for help in changing the label before Jardiance’s approval has been rejected by the Supreme Court. See Mensing, 564 U.S. at 620-21. The Mensing plaintiffs argued that, even though federal regulations required that generic labels conform to brand name labels and thus forbade generic manufacturers from changing generic labels using the CBE process, the generic manufacturers could have satisfied their state law duty to warn by asking for the FDA’s help in changing the corresponding brand name label. The Court reasoned that, if the manufacturers had done so, “and if the FDA decided there was sufficient supporting information, and if the FDA undertook negotiations with the brand-name manufacturer, and if adequate label changes were decided on and implemented, then the [m]anufacturers would have started a Mouse Trap game that eventually led to a better label.” Id. at 619. Such an argument, the Court held, “would render conflict pre-emption largely meaningless,” since a private party can always, in principle, try to persuade “the Federal Government . . . [to] do something that makes it lawful for a private party Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 13 of 26 14 to accomplish under federal law what state law requires of it.” Id. at 620. The Supreme Court explained that “[s]tate law demanded a safer label; it did not instruct the [m]anufacturers to communicate with the FDA about the possibility of a safer label.” Id. at 619 (emphasis added).3 The same type of speculation exists as to any inquiry about what the FDA might have done had BIPI submitted a different Jardiance label prior to FDA approval. ii. Plaintiff’s Complaint Does Not Include Any Allegations To Support A Claim That BIPI Should Have Changed The Jardiance Label After FDA Approval. Plaintiff’s Complaint fails to articulate any newly acquired information, received by BIPI, that would have allowed BIPI to “utilize the CBE process,” Compl. ¶ 68(c), to change the Jardiance label after Jardiance was approved. See supra at pp. 5-6 (describing CBE requirements); see generally Utts I, 2016 WL 7429449, at *11 (“[F]ederal law expressly forbids a manufacturer from changing its label after the label has received FDA approval unless such changes are made pursuant to the CBE regulation.”). “[T]he 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.” Utts II, 2017 WL 1906875, at *9. The CBE process is inapplicable here, because the 20 cases of DKA associated with other SGLT-2 inhibitor drugs and reported in FDA’s FAERS database prior to Jardiance’s FDA approval do not constitute “newly acquired information” that was unknown to the FDA and thus would have allowed Defendant to utilize the CBE process to change Jardiance’s label after FDA approval. 21 C.F.R. § 314.70(c)(6)(iii). “The CBE procedure is only available to make changes that, among other 3 Accord Houston v. United States, 638 F. App’x 508, 514 (7th Cir. 2016) (hypothetical “receipt of [FDA approval] would be speculative anyway”); see also Yates, 808 F.3d at 298-300 (rejecting claim against branded drug manufacturer in design defect context as speculative, where plaintiff claimed that drug at issue should have been designed differently in first instance, i.e., prior to FDA approval); Fleming v. Janssen Pharm., Inc., 186 F. Supp. 3d 826, 833 (W.D. Tenn. 2016) (finding allegations resting on defendants’ “duty to design the drug differently before FDA approval” were “too attenuated and speculat[ive]”) (internal quotation marks omitted). Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 14 of 26 15 things, are based on ‘newly acquired information,’” In re Celexa, 779 F.3d at 41-42, which is defined as “data, analyses, or other information not previously submitted to the Agency.” 21 C.F.R. § 314.3 (emphasis added); see also In re Celexa, 779 F.3d at 42-43 (affirming dismissal of failure- to-warn claims on preemption grounds, because plaintiff failed to allege that information in question “was unknown to the FDA prior to label approval” and thus manufacturer could not use CBE process to alter label). Thus, warnings claims are “preempted [where] the information upon which the [complaint] relies to plausibly plead these claims, does not, upon examination, demonstrate that any newly acquired information exists to support a label change pursuant to CBE regulations.” Utts II, 2017 WL 1906875, at *20 (dismissing claims) (emphasis added). Here, Plaintiff pleads himself out of any CBE-related claim, because the Complaint exclusively relies on alleged DKA-related data associated with other SGLT-2 inhibitor drugs that was available and submitted to the FDA “before JARDIANCE entered the market.” Compl. ¶ 50. By only making allegations regarding data available and submitted to the FDA before Jardiance’s approval, Plaintiff “does not allege that [Defendant was] in possession of ‘newly acquired information’ such that [it] could, pursuant to the CBE regulation, act independently of the FDA to update” the Jardiance label with a DKA warning after the FDA approved Jardiance. Utts I, 2016 WL 7429449, at *11 (dismissing strict liability and negligent failure-to-warn claims); see also In re Celexa, 779 F.3d at 42-43 (finding complaint could not “plausibly be read as relying on ‘newly acquired information’ in contending that [defendant] could have changed its label through the CBE procedures”); Utts II, 2017 WL 1906875, *12-13, *20 (finding documents and reports, including report that analyzed adverse drug event data uploaded to FAERS for drug class including drug at issue, did not constitute “newly acquired information” and therefore dismissing failure-to-warn Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 15 of 26 16 claims); In re Lipitor, 185 F. Supp. 3d at 769-71 (finding claims that defendants should have changed label through CBE process based on data already submitted to FDA preempted).4 Moreover, Plaintiff’s allegation that “any of” the “more than 50 additional adverse events FDA collected after June 6, 2014 . . . could have allowed Defendant to utilize the CBE process and change the JARDIANCE label” does not plausibly plead any “newly acquired information” upon which BIPI could have based a label change pursuant to the CBE process. Compl. ¶ 53. Plaintiff does not allege how many (if any) of these reports related to Jardiance and pre- dated his alleged injury, requiring dismissal of his implausibly pled claims. See, e.g., Fleming, 186 F. Supp. 3d at 829, 836 (finding allegations that “FDA has since [approval] received a significant number of [DKA] reports” and that “despite the reported adverse events, [d]efendants have continued to fail to warn patients about [DKA]” amounted to only “conclusory statements as to the failure of [d]efendants to warn about the dangers of Invokana”); House v. Bristol-Myers Squibb Co., No. 15-cv-894, 2017 WL 55876, at *1, *4 (W.D. Ky. Jan. 4, 2017) (dismissing conclusory failure-to-warn allegations, including allegation that “FDA has since [approval] received a significant number of reports of [DKA]”). 4 Plaintiff’s allegation that “[u]pon information and belief, FDA did not analyze the data colleted [sic] between March 2013 and June 6, 2014 until after JARDIANCE was approved,” Compl. ¶ 42, is rank speculation. See Twombly, 550 U.S. at 545 (“Factual allegations must be enough to raise a right to relief above the speculative level”). Beyond being speculative, the allegations border on being nonsensical. As a general matter, the FDCA requires the Secretary of Health and Human Services to “conduct regular screenings of the Adverse Event Reporting System database,” and Plaintiff does not allege any facts in support of his allegations. 21 U.S.C. § 355(k)(5)(A). Moreover, as a specific matter, the fact that the FDA ultimately required a label change for the SGLT-2 inhibitor class based on its review of AER data belies the factually unsupported notion that the FDA was somehow ignoring such data. Finally, in all events, it is well settled in the 11th Circuit that “for purposes of a Rule 12(b)(6) motion to dismiss, [courts] do not have to take as true allegations based merely ‘upon information and belief.’” Smith v. City of Sumiton, 578 F. App'x 933, 936 n.4 (11th Cir. 2014) (per curiam); accord Mann v. Palmer, 713 F.3d 1306, 1315 (11th Cir. 2013). Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 16 of 26 17 II. PLAINTIFF’S COMPLAINT ALSO FAILS BECAUSE IT IS INSUFFICIENTLY PLED. Without his failure-to-warn theory, which is preempted, all that remains of Plaintiff’s Complaint are allegations that appear to have been copied nearly verbatim from other complaints related to different SGLT-2 inhibitors, Invokana and Farxiga. As another federal judge recognized in dismissing the Invokana complaint, however, the complaint consisted “largely of legal conclusions” and therefore failed to state a claim. Fleming, 186 F. Supp. 3d at 835-36; see House, 2017 WL 55876, at *4 (dismissing complaint and explaining that, “[j]ust as in Fleming,” plaintiff’s “almost identical” strict liability failure-to-warn and negligence claims were insufficiently pled). Plaintiff’s Complaint should meet a similar fate. a. Plaintiff Has Not Stated A Claim Under The Alabama Extended Manufacturers’ Liability Doctrine (Count I). The Alabama Extended Manufacturer’s Liability Doctrine (“AEMLD”), Alabama’s judicially-created substitute for strict liability, modifies traditional strict liability by permitting affirmative defenses and incorporating “nods to negligence theory.” Foster v. Bridgestone Americas, Inc., No. 11-0175-WS-N, 2013 WL 489162, at *2-4 (S.D. Ala. Feb. 8, 2013); accord Batchelor v. Pfizer, Inc., No. 2:12-CV-908-WKW, 2013 WL 3873242, at *2 (M.D. Ala. July 25, 2013). To establish liability under the AEMLD, a plaintiff must show (1) he suffered injury or damages to himself or his property by one who [sold] a product in a defective condition unreasonably dangerous to the plaintiff, as the ultimate user or consumer, if (a) the seller [was] engaged in the business of selling such a product, and (b) it [was] expected to and [did], reach the user or consumer without substantial change in the condition in which it [was] sold. Bodie v. Purdue Pharma Co., 236 F. App'x 511, 518 (11th Cir. 2007); accord Mallory, 2014 WL 6890740, at *4 (noting that, “[u]nder Alabama law, [t]he fact of an injury . . . does not establish the presence of a defect. . . . [because] a plaintiff must show that the product's failure of Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 17 of 26 18 performance is causally related in fact to the product's defective condition at the time of its sale”) (internal quotation marks omitted). For AEMLD claims involving prescription drugs like Jardiance, “‘the adequacy of [the] accompanying warning determines whether the drug, as marketed is defective, or unreasonably dangerous.’” Bodie, 236 F. App’x at 518 (quoting Stone v. Smith, Kline & French Labs., 447 So. 2d 1301, 1304 (Ala. 1984)). That is, “no AEMLD design defect claim for prescription drugs exists apart from a challenge to the adequacy of the warning.” Barcal v. EMD Serono, Inc., No. 5:14-CV-01709, 2016 WL 1086028, at *3 (N.D. Ala. Mar. 21, 2016). To prevail on a failure-to-warn claim, a plaintiff must prove that (1) the manufacturer failed to provide his prescribing physician with adequate warnings about risks of which it knew or should have known, and (2) the inadequate warning proximately caused his injuries. See, e.g., Bodie, 236 F. App’x at 518-19 (citing Walls v. Alpharma USPD, Inc., 887 So. 2d 881, 883 (Ala. 2004)). The allegations in Plaintiff’s Complaint, like those in the Fleming and House complaints upon which the Complaint is modeled, do not contain facts sufficient to support his failure-to-warn claims. Instead, the Complaint’s allegations, copied and pasted from Fleming, fail to plead how Jardiance’s warnings rendered Jardiance defective and/or how Jardiance’s defective warnings caused Plaintiff’s alleged injuries. Compare Compl. ¶ 76 (“JARDIANCE contained warnings insufficient to alert consumers, including Plaintiff, to the dangerous risks and reactions associated with JARDIANCE, including the development of Plaintiff’s [DKA].”) with Fleming, 186 F. Supp. 3d at 836 (finding plaintiff’s complaint, which included allegation that “INVOKANA contained warnings insufficient to alert consumers, including [p]laintiff, to the dangerous risks and reactions associated with INVOKANA, including the development of [p]laintiff’s injuries,” contained “only conclusory statements as to the failure of [d]efendants to warn about the dangers of Invokana”); Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 18 of 26 19 see also House, 2017 WL 55876, at *4 (likewise dismissing failure-to-warn allegations involving Farxiga, because “[i]n Fleming, the court dismissed the plaintiff’s almost identical failure-to-warn claims as insufficiently pled”); Mallory, 2014 WL 6890740, at *5 (dismissing AEMLD claims where plaintiff “[did] not allege facts sufficient to support her conclusory allegation of causation”).5 Plaintiff also fails to state a claim because Alabama has adopted the learned intermediary doctrine, which “imposes on a pharmaceutical company a duty to provide warnings solely to the prescribing physician, rather than to the patient directly.” Bodie, 236 F. App’x at 516 (emphasis added); see also Batchelor, 2013 WL 3873242, at *2 (“A prescription-drug manufacturer fulfills its duty to warn the ultimate users of the risks of its product by providing adequate warnings to the learned intermediaries who prescribe the drug. Once that duty is fulfilled, the manufacturer has no further duty to warn the patient directly.”). Thus, to prevail on a failure-to-warn claim, “a patient must make a specific showing: that the manufacturer failed to warn the physician of a risk not otherwise known to the physician and that the failure to warn was the actual and proximate cause of the patient’s injury.” Elliott v. Sandoz, Inc., No. 2:16-cv-00861, 2016 WL 4398407, at *6-7 (N.D. Ala. Aug. 18, 2016). Here, the learned intermediary doctrine bars Plaintiff’s claims for two different reasons. First, Plaintiff’s allegations that “Defendant had a continuing duty to warn Plaintiff,” Compl. ¶ 80 (emphasis added), and that “JARDIANCE contained warnings insufficient to alert consumers, including Plaintiff, to the dangerous risks and reactions associated with 5 Even if Plaintiff’s new failure-to-warn theory is not preempted (which it is), Plaintiff does not plausibly allege how Jardiance’s label was defective or how the alleged defect in Jardiance’s label caused Plaintiff’s alleged injuries. If Plaintiff is suggesting that the information contained in the FDA Alert should have been in Jardiance’s label, Plaintiff does not plausibly allege that his unnamed prescribing physician would have read and heeded this alleged adequate warning and made a different prescribing decision. See, e.g., Barnhill v. Teva Pharms., USA, Inc., 819 F. Supp. 2d 1254, 1262 (S.D. Ala. 2011); accord Allain, 2015 WL 178038, at *6. Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 19 of 26 20 JARDIANCE,” id. ¶ 76 (emphasis added), fail to the extent that Plaintiff bases his failure-to-warn claims on a failure to warn him directly of the alleged risk of DKA. See Batchelor, 2013 WL 3873242, at *2 (dismissing claim based on failure to warn plaintiff directly). Similarly, Plaintiff’s allegations that generically reference Defendant’s failure to warn physicians and the medical community at large, see e.g., Compl. ¶¶ 2, 22, 24-25, 85, 103(g), do not contain plausible facts that Defendant failed to warn Plaintiff’s prescribing physician of the alleged risk of DKA and should therefore be dismissed. See, e.g., Elliot, 2016 WL 4398407, at *7 (disregarding “conclusory” allegation that “[d]efendant failed to provide adequate and required warnings to physicians”); accord Allain, 2015 WL 178038, at *6. Second, Plaintiff merely alleges “general, conclusory statements concerning promotions, marketing, and education given to medical providers, but has not set forth any facts suggesting [his unnamed prescribing physician] was the target of or influenced by any of these actions.” Elliot, 2016 WL 4398407, at *7; see also, e.g., Compl. ¶ 25 (“Defendant conducted nationwide sales and marketing campaigns to promote JARDIANCE, and they willfully deceived Plaintiff, Plaintiff’s health care professionals, the medical community, and the general public as to the health risks and consequences of the use of JARDIANCE.”). Finally, Plaintiff’s AEMLD claim is deficient to the extent that it is premised on a failure to warn of unnamed “other related health complications.” Compl. ¶¶ 91, 115. Plaintiff only alleges that he developed DKA, see id. ¶¶ 4, 31, and does not identify what “other” alleged complications and inadequate warnings are at issue here, failing to “plausibly give rise to [his] entitlement to relief” in this regard. Mallory, 2014 WL 6890740, at *1. b. Plaintiff Does Not State Plausible Claims For Negligence Or Gross Negligence (Counts II-III). To prevail on a negligence claim, “Plaintiff must allege that the Defendant (1) breached (2) a duty, which (3) proximately caused (4) plaintiff's injury.” Miller, 2014 WL 2155020, at *4 Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 20 of 26 21 (quoting E.R. Squibb & Sons, Inc. v. Cox, 477 So. 2d 963, 969 (Ala. 1985)). “To establish wantonness, the plaintiff must prove that the defendant, with reckless indifference to the consequences, consciously and intentionally did some wrongful act or omitted some known duty. To be actionable, that act or omission must proximately cause the injury of which the plaintiff complains.” Martin v. Arnold, 643 So. 2d 564, 567 (Ala. 1994). i. Plaintiff’s Negligence Count Is Factually Deficient And Must Be Dismissed (Count II). Plaintiff’s “catch-all” negligence claim-which is premised on Defendant’s alleged failure “to exercise ordinary care in the research, development, marketing, supplying, promotion, marketing [sic], advertisement, packaging, sale, testing, quality assurance, quality control, sale [sic], and distribution of JARDIANCE” (see Compl. ¶ 101)-fails for the same reasons that his AEMLD claims fail. See supra at 16-21. With respect to any alleged manufacturing defect, see Compl. ¶¶ 105, 109, 127, 130, Plaintiff’s Complaint is “bereft of supporting factual allegations” regarding such a claim. Batchelor, 2013 WL 3873242, at *3 (dismissing negligence claim). Rather, Plaintiff appears to argue that, because Plaintiff allegedly suffered DKA after taking Jardiance, there must have been a manufacturing defect in the Jardiance he ingested. These allegations are insufficient, because they simply recite the elements of a manufacturing defect claim with no supporting factual allegations. See, e.g., House, 2017 WL 55876, at *4 (dismissing negligent manufacturing claims involving Farxiga that consisted of “largely legal conclusions . . . insufficient to meet the Twombly- Iqbal standard”). Any negligence theory premised on Defendant’s alleged failure to properly design Jardiance, see, e.g., Compl. ¶¶ 17, 23, 78, 127, 130, fails, because Alabama law does not recognize design defect claims in cases involving prescription drugs, regardless of whether the claims are Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 21 of 26 22 brought under the AEMLD or a negligence theory. Alabama has adopted comment k to § 402A of the Restatement (Second) of Torts, recognizing prescription drugs as within a category of products that are “unavoidably unsafe” or “quite incapable of being made safe for their intended and ordinary use.” Stone, 447 So. 2d at 1303 n1. The Restatement is unambiguous: “in the case of an ‘unavoidably unsafe’ yet properly prepared prescription drug, the adequacy of the accompanying warning determines whether the drug, as marketed, is defective, or unreasonably dangerous.” Id. at 1304. “Because the rationale of the exception turns on the notion that prescription drugs are desirable even though they may never be made fully safe, . . . the exception [is] equally applicable to design defect claims outside of the AEMLD,” including negligent design claims, which also “hinge on the safety of the product.” Barcal, 2016 WL 1086028, at *3 (dismissing all design defect claims, including negligent design claims). Furthermore, Plaintiff has failed to plead any facts alleging how Jardiance’s design was defective or how any defect in Jardiance’s design caused his injuries. Plaintiff alleges that SGLT- 2 inhibitors “are designed to inhibit renal glucose reabsorption with the goal of lowering blood glucose” and, as a result, “excess glucose is not metabolized, but instead is excreted through the kidneys of a population of consumers already at risk for kidney disease.” Compl. ¶ 17. Simply repeating the mechanism of action does not support a design defect claim; at least two federal courts confronted with this exact allegation could not “reasonably infer from the generic description of SGLT-2 inhibitors’ mechanism of action that [the SGLT-2 inhibitor at issue] was defective or unreasonably dangerous” and dismissed the complaints. House, 2017 WL 55876, at *3-5 (quoting Fleming, 186 F. Supp. 3d at 835). Plaintiff does not allege how this or any other aspect of Jardiance’s design supposedly increases the risk of DKA, and therefore fails to allege sufficient facts to support a reasonable inference that a defect in Jardiance’s design caused his Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 22 of 26 23 alleged injury. See, e.g., Hughes v. Stryker Corp., 423 F. App’x 878, 880 (11th Cir. Apr. 14, 2011) (per curiam) (holding that fact of injury does not establish defect; instead, plaintiff must show that defect in product caused alleged injury).6 Finally, any negligent design claim brought by Plaintiff fails for the additional reason that it is preempted by federal law. This preemption analysis applies equally to all design defect claims, whether brought pursuant to the AEMLD or under a negligence theory. See, e.g., Barcal, 2016 WL 1086028, at *4 (dismissing design defect and negligent design claims because such claims “would essentially require [defendant] to redesign [the medication at issue]” without FDA approval and reasoning “[t]his is precisely the kind of impossibility in which the Supreme Court has found preemption”); see also Yates, 808 F.3d at 298-300 (design defect claims against all pharmaceutical manufacturers are “clearly preempted by federal law”); Fleming, 186 F. Supp. 3d at 832-33 (dismissing strict liability design defect and negligent design claims as preempted by federal law). ii. Plaintiff Does Not State A Claim For Willful And Wanton Conduct Or Gross Negligence (Count III). Plaintiff’s gross negligence count merely restates his implausible AEMLD claims, see Compl. ¶ 126 (“Defendant failed to provide adequate warnings”), and should therefore be dismissed for the same reasons. See House, 2017 WL 55876, at *4, (dismissing gross negligence claims premised on “same insufficient allegations” underpinning failure-to-warn claims). Likewise, Plaintiff’s claims premised on Defendant’s “complete indifference to or a conscious 6 Additionally, while Plaintiff alleges that “Consumers . . . have several alternative safer products available to treat the conditions, including metformin, Diabinese, Amaryl, or Glucotrol,” Compl. ¶ 23,” he does not identify this alleged safer alternative design, nor does he explain how it would have prevented his alleged injury, further causing any negligent design claim to fail. See, e.g., Richards v. Michelin Tire Corp., 21 F.3d 1048, 1056 (11th Cir. 1994) (“[A] plaintiff must prove that a safer, practical, alternative design was available to the manufacturer at the time it manufactured its product.”). Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 23 of 26 24 disregard for to [sic] the rights, safety, or welfare of others,” Compl. ¶ 119, “contain no allegations other than legal conclusions,” and should be dismissed. Stanley ex rel. L.B. v. Bullock Cty. BOE, No. 2:07-cv-681, 2007 WL 4105149, at *5 (M.D. Ala. Nov. 15, 2007) (dismissing gross negligence claim, where plaintiff alleged “in conclusory fashion” that defendants’ conduct “was so egregious as to rise to gross negligence inferring malice” but provided no factual allegations regarding such conduct). CONCLUSION For the reasons outlined above, Plaintiff’s Complaint fails to satisfy the requirements of Federal Rules of Civil Procedure 8(a) and 12(b)(6) and should be dismissed. Dated: June 27, 2017 Respectfully submitted, s/F. M. Haston III F. M. Haston III (ASB-885-a64f) thaston@bradley.com Bradley Arant Boult Cummings LLP One Federal Place 1819 Fifth Avenue North Birmingham, AL 35203-2119 Tel. (205) 521-8000 Fax (205) 521-8800 One of the Attorneys for Boehringer Ingelheim Pharmaceuticals, Inc. Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 24 of 26 25 OF COUNSEL Ellen S. Presley (ASB-0135-e49p) epresley@bradley.com BRADLEY ARANT BOULT CUMMINGS LLP One Federal Place 1819 Fifth Avenue North Birmingham, AL 35203-2119 Tel. (205) 521-8000 Fax (205) 521-8800 Heidi Levine, pro hac vice hlevine@sidley.com SIDLEY AUSTIN LLP 787 7th Avenue New York, NY 10019 Telephone: (212) 839-5300 Facsimile: (212) 839-5599 Elizabeth Curtin, pro hac vice ecurtin@sidley.com SIDLEY AUSTIN LLP One South Dearborn Street Chicago, Illinois 60603 Telephone: (312) 853-7000 Facsimile: (312) 853-7036 Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 25 of 26 26 CERTIFICATE OF SERVICE I hereby certify that on June 27, 2017, a copy of the foregoing was filed using the Court’s CM/ECF system, which will send electronic notification to the following: Richard A. Wright B. Kristian W. Rasmussen CORY WATSON, P.C. 2131 Magnolia Avenue, Suite 200 Birmingham, AL 35205 rwright@corywatson.com krasmussen@cwcd.com Counsel for Plaintiff and I hereby certify that I have mailed by United States Postal Service the document to the following non-CM/ECF participant: Timothy J. Becker, Esquire Rolf T. Fiebiger, Esquire JOHNSON BECKER, PLLC 33 South Sixth Street, Suite 4530 Minneapolis, Minnesota 55402 tbecker@johnsonbecker.com rfiebiger@johnsonbecker.com Counsel for Plaintiff s/F. M. Haston III Of Counsel Case 2:17-cv-00293-JZ-GMB Document 18 Filed 06/27/17 Page 26 of 26 EXHIBIT 1 Case 2:17-cv-00293-JZ-GMB Document 18-1 Filed 06/27/17 Page 1 of 8 DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993 NDA 204629 NDA APPROVAL Boehringer Ingelheim Pharmaceuticals, Inc. Attention: Daniel T. Coleman, Ph.D. Sr. Associate Director; Drug Regulatory Affairs 900 Ridgebury Road; P.O. Box 368 Ridgefield, CT 06877 Dear Dr. Coleman: Please refer to your New Drug Application (NDA) dated and received March 5, 2013, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Jardiance (empagliflozin) tablets, 10 mg and 25 mg. We acknowledge receipt of your amendments dated April 12, 24, and 25, May 1, 3, and 7, June 3, 17, 18, and 27, July 3, 19, and 30, August 9, 14, 15, and 16, September 9 and 23, October 1, 2, 11, 14, 15, 29, and 30, November 1, 8, and 19, and December 20, 2013, and February 5 and 28, March 17, June 3, 5, and 18, and July 3 (2), 23, and 31, 2014. The June 3, 2014, submission constituted a complete response to our March 4, 2014, action letter. This new drug application provides for the use of Jardiance (empagliflozin) tablets, 10 mg and 25 mg as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. We have completed our review of this application, as amended. It is approved, effective on the date of this letter, for use as recommended in the enclosed agreed-upon labeling text. CONTENT OF LABELING As soon as possible, but no later than 14 days from the date of this letter, submit the content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA automated drug registration and listing system (eLIST), as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content of labeling must be identical to the enclosed labeling (text for the package insert and text for the patient package insert). Information on submitting SPL files using eLIST may be found in the guidance for industry SPL Standard for Content of Labeling Technical Qs and As, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM072392.pdf. Reference ID: 3603272 Case 2:17-cv-00293-JZ-GMB Document 18-1 Filed 06/27/17 Page 2 of 8 NDA 204629 Page 2 The SPL will be accessible via publicly available labeling repositories. CARTON AND IMMEDIATE CONTAINER LABELS Submit final printed carton and immediate container labels that are identical to the enclosed carton and immediate container labels as soon as they are available, but no more than 30 days after they are printed. Please submit these labels electronically according to the guidance for industry Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (June 2008). Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on heavy-weight paper or similar material. For administrative purposes, designate this submission “Final Printed Carton and Container Labels for approved NDA 204629.” Approval of this submission by FDA is not required before the labeling is used. Marketing the product(s) with FPL that is not identical to the approved labeling text may render the product misbranded and an unapproved new drug. ADVISORY COMMITTEE Your application for empagliflozin tablets was not referred to an FDA advisory committee because this drug is not the first in its class and the safety profile is similar to that of other drugs approved for this indication. REQUIRED PEDIATRIC ASSESSMENTS Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable. We are waiving the pediatric study requirement for ages 0 through 9 years (inclusive) because necessary studies are impossible or highly impracticable. This is because there are too few children in this age range with type 2 diabetes mellitus to study. We are deferring submission of your pediatric studies for ages 10 to 17 years (inclusive) for this application because this product is ready for approval for use in adults and the pediatric studies have not been completed. Your deferred pediatric studies required by section 505B(a) of the FDCA are required postmarketing studies. The status of these postmarketing studies must be reported annually according to 21 CFR 314.81 and section 505B(a)(3)(B) of the FDCA. These required studies are listed below. Reference ID: 3603272 Case 2:17-cv-00293-JZ-GMB Document 18-1 Filed 06/27/17 Page 3 of 8 NDA 204629 Page 3 2755-1 A single-dose pharmacokinetic and pharmacodynamics trial of empagliflozin in pediatric patients 10 to 17 years (inclusive) with type 2 diabetes mellitus. Study Completion: June 2015 Final Report Submission: December 2015 2755-2 A 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of empagliflozin for the treatment of pediatric patients 10 to 17 years (inclusive) with type 2 diabetes mellitus as an add-on to metformin, followed by a 28-week double-blind, placebo- or active-controlled extension period. The efficacy and safety study should have at least 30% of randomized subjects 10 to 14 years (inclusive) of age and at least one-third (but not more than two-thirds) of subjects in both age subsets (10 to 14 years [inclusive] and 15 to 17 [inclusive]) will be female. Secondary safety endpoints should include the effect of empagliflozin on mineral and bone metabolism, and the effect of empagliflozin on growth. This trial should not be initiated until after the data from the juvenile animal study have been submitted to and reviewed by the Agency. Final Protocol Submission: November 2015 Study Completion: February 2019 Final Report Submission: August 2019 2755-3 A study to evaluate empagliflozin toxicity in juvenile rats. Study Completion: November 2014 Final Report Submission: May 2015 Submit the protocol to your IND 102145, with a cross-reference letter to this NDA. Reports of these required pediatric postmarketing studies must be submitted as a new drug application (NDA) or as a supplement to your approved NDA with the proposed labeling changes you believe are warranted based on the data derived from these studies. When submitting the reports, please clearly mark your submission "SUBMISSION OF REQUIRED PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of the submission. POSTMARKETING REQUIREMENTS UNDER 505(o) Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and biological product applications to conduct postmarketing studies and clinical trials for certain purposes, if FDA makes certain findings required by the statute. There have been signals of a serious risk of cardiovascular events with some other medications developed for the treatment of type 2 diabetes mellitus and available data have not definitively excluded the potential for this serious risk with Jardiance (empagliflozin). Reference ID: 3603272 Case 2:17-cv-00293-JZ-GMB Document 18-1 Filed 06/27/17 Page 4 of 8 NDA 204629 Page 4 We have determined that an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal of a serious risk of major adverse cardiovascular events with Jardiance (empagliflozin). Furthermore, the new pharmacovigilance system that FDA is required to establish under section 505(k)(3) of the FDCA will not be sufficient to assess this serious risk. Finally, we have determined that only a clinical trial (rather than a nonclinical or observational study) will be sufficient to assess a signal of a serious risk of major adverse cardiovascular events with Jardiance (empagliflozin), as well as signals of serious risks of liver toxicity, bone fractures, nephrotoxicity/acute kidney injury, breast cancer, bladder cancer, lung cancer, melanoma, complicated genital infections, complicated urinary tract infections/pylenophritis/urosepsis, serious events related to hypovolemia and serious hypersensitivity reactions, which may potentially be long-term effects of Jardiance (empagliflozin). Therefore, based on appropriate scientific data, FDA has determined that you are required to conduct the following: 2755-4 A randomized, double-blind, placebo-controlled trial evaluating the effect of empagliflozin on the incidence of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus. The primary objective of the trial should be to demonstrate that the upper bound of the 2-sided 95% confidence interval for the estimated risk ratio comparing the incidence of MACE (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death) observed with empagliflozin to that observed in the placebo group is less than 1.3. The long-term effects of empagliflozin on the incidence of liver toxicity, bone fractures, nephrotoxicity/acute kidney injury, breast cancer, bladder cancer, lung cancer, melanoma, complicated genital infections, complicated urinary tract infections/pyelonephritis/urosepsis, serious events related to hypovolemia and serious hypersensitivity reactions should also be assessed. Estimated glomerular filtration rate (eGFR) should also be monitored over time to assess for worsening renal function. The timetable you submitted by email on July 9, 2014, states that you will conduct this trial according to the following schedule: Trial Completion: June 2015 Final Report Submission: December 2015 Submit the protocol(s) to your IND 102145, with a cross-reference letter to this NDA. Submit all final report(s) to your NDA. Prominently identify the submission with the following wording in bold capital letters at the top of the first page of the submission, as appropriate: “Required Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under 505(o)”, “Required Postmarketing Correspondence Under 505(o)”. Reference ID: 3603272 Case 2:17-cv-00293-JZ-GMB Document 18-1 Filed 06/27/17 Page 5 of 8 NDA 204629 Page 5 Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any study or clinical trial required under this section. This section also requires you to periodically report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to report annually on the status of any postmarketing commitments or required studies or clinical trials. FDA will consider the submission of your annual report under section 506B and 21 CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR 314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must also include a report on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o) on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action. EXPIRY DATING PERIOD A 36-month expiry dating period is granted for Jardiance (empagliflozin) tablets when stored at 25°C (77°F); excursions permitted from 15° to 30°C (59° to 86 °F). PROMOTIONAL MATERIALS You may request advisory comments on proposed introductory advertising and promotional labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the proposed materials in draft or mock-up form with annotated references, and the package insert to: Food and Drug Administration Center for Drug Evaluation and Research Office of Prescription Drug Promotion 5901-B Ammendale Road Beltsville, MD 20705-1266 As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the package insert, at the time of initial dissemination or publication, accompanied by a Form FDA 2253. Form FDA 2253 is available at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf. Information and Instructions for completing the form can be found at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For more information about submission of promotional materials to the Office of Prescription Drug Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm. Reference ID: 3603272 Case 2:17-cv-00293-JZ-GMB Document 18-1 Filed 06/27/17 Page 6 of 8 NDA 204629 Page 6 REPORTING REQUIREMENTS We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81). MEDWATCH-TO-MANUFACTURER PROGRAM The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse event reports that are received directly by the FDA. New molecular entities and important new biologics qualify for inclusion for three years after approval. Your firm is eligible to receive copies of reports for this product. To participate in the program, please see the enrollment instructions and program description details at http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm. POST APPROVAL FEEDBACK MEETING New molecular entities and new biologics qualify for a post approval feedback meeting. Such meetings are used to discuss the quality of the application and to evaluate the communication process during drug development and marketing application review. The purpose is to learn from successful aspects of the review process and to identify areas that could benefit from improvement. If you would like to have such a meeting with us, call the Regulatory Project Manager for this application. If you have any questions, call Patricia Madara, Regulatory Project Manager, at (301) 796-1249. Sincerely, {See appended electronic signature page} Curtis J. Rosebraugh, M.D., M.P.H. Director Office of Drug Evaluation II Office of New Drugs Center for Drug Evaluation and Research Enclosures: Content of Labeling Carton and Container Labeling Reference ID: 3603272 Case 2:17-cv-00293-JZ-GMB Document 18-1 Filed 06/27/17 Page 7 of 8 --------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------- ---------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. /s/ CURTIS J ROSEBRAUGH 08/01/2014 Reference ID: 3603272 Case 2:17-cv-00293-JZ-GMB Document 18-1 Filed 06/27/17 Page 8 of 8