Case 9:20-md-02924-RLR Document 3750 Entered on FLSD Docket 07/08/2021 Page 1 of 49
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`UNITED STATES DISTRICT COURT
`SOUTHERN DISTRICT OF FLORIDA
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`IN RE: ZANTAC (RANITIDINE) MDL NO. 2924
`PRODUCTS LIABILITY 20-MD-2924
`LITIGATION
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`JUDGE ROBIN L. ROSENBERG
`MAGISTRATE JUDGE BRUCE E. REINHART
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` ________________________________/
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`ORDER GRANTING THE GENERIC DEFENDANTS’
`RULE 12 MOTION TO DISMISS ON THE GROUND OF PREEMPTION,
`GRANTING THE STORE-BRAND RETAILER DEFENDANTS’ MOTION
`TO DISMISS OR STRIKE CONSOLIDATED MEDICAL MONITORING
`CLASS ACTION COMPLAINT AND CONSOLIDATED AMENDED CONSUMER
`ECONOMIC LOSS CLASS ACTION COMPLAINT, AND DENYING AS MOOT THE
`SPECIALLY-APPEARING NON-U.S. GENERIC MANUFACTURER DEFENDANTS’
`RENEWED MOTION TO DISMISS FOR LACK OF PERSONAL JURISDICTION
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`This matter is before the Court on the Generic Defendants’ (“Generic Manufacturer
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`Defendants”) Rule 12 Motion to Dismiss on the Ground of Preemption [DE 3105], the Store-Brand
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`Retailer Defendants’ (“Store-Brand Defendants”) Motion to Dismiss or Strike Consolidated
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`Medical Monitoring Class Action Complaint and Consolidated Amended Consumer Economic
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`Loss Class Action Complaint [DE 3113], and the Specially-Appearing Non-U.S. Generic
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`Manufacturer Defendants’ (“Specially-Appearing Defendants”) Renewed Motion to Dismiss for
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`Lack of Personal Jurisdiction [DE 3108]. The Court held Hearings on the Generic Manufacturer
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`and Store-Brand Defendants’ Motions on June 4 and 7, 2021.1 The Court has carefully considered
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`the Motions, the Responses [DE 3326, 3329, 3409], the Replies [DE 3407, 3422, 3505], the
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`Plaintiffs’ Supplemental Filing [DE 3525], the arguments that the parties made during the
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`Hearings, and the record and is otherwise fully advised in the premises. For the reasons set forth
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`below, the Generic Manufacturer Defendants’ Rule 12 Motion to Dismiss is GRANTED, the
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`1 The Court also held a Hearing on other motions to dismiss pending in this litigation on June 3, 2021. The Court cites
`to arguments from all three Hearings in this Order.
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`Case 9:20-md-02924-RLR Document 3750 Entered on FLSD Docket 07/08/2021 Page 2 of 49
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`Store-Brand Defendants’ Motion to Dismiss or Strike is GRANTED, and the Specially-Appearing
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`Defendants’ Renewed Motion to Dismiss is DENIED AS MOOT. The Plaintiffs’ claims against
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`the Generic Manufacturer and Store-Brand Defendants are DISMISSED WITHOUT LEAVE
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`TO AMEND.
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`I.
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`Factual Background2
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`This case concerns the pharmaceutical product Zantac and its generic forms, which are
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`widely sold as heartburn and gastric treatments. The molecule in question—ranitidine—is the
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`active ingredient in both Zantac and its generic forms.
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`Zantac has been sold since the early 1980s, first by prescription and later as an over-the-
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`counter (“OTC”) medication. In 1983, the U.S. Food and Drug Administration (“FDA”) approved
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`the sale of prescription Zantac. AMPIC ¶ 240. GlaxoSmithKline (“GSK”) first developed and
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`patented Zantac. Id. ¶ 239. Zantac was a blockbuster—the first prescription drug in history to
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`reach $1 billion in sales. Id. ¶ 240.
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`GSK entered into a joint venture with Warner-Lambert in 1993 to develop an OTC form
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`of Zantac. Id. ¶ 233. Beginning in 1995, the FDA approved the sale of various forms of OTC
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`Zantac. Id. ¶¶ 233, 237. The joint venture between GSK and Warner-Lambert ended in 1998, with
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`Warner-Lambert retaining control over the sale of OTC Zantac in the United States and GSK
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`retaining control over the sale of prescription Zantac in the United States. Id. ¶ 243. Pfizer acquired
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`Warner-Lambert in 2000 and took control of the sale of OTC Zantac in the United States. Id. ¶ 245.
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`2 A court must accept a plaintiff’s factual allegations as true at the motion–to–dismiss stage. West v. Warden, 869 F.3d
`1289, 1296 (11th Cir. 2017) (“When considering a motion to dismiss, we accept as true the facts as set forth in the
`complaint and draw all reasonable inferences in the plaintiff’s favor.”) (quotation marks omitted). Plaintiffs have set
`forth their factual allegations in three “master” complaints: the Amended Master Personal Injury Complaint
`(“AMPIC”); the Consolidated Amended Consumer Economic Loss Class Action Complaint (“ELC”); and the
`Consolidated Medical Monitoring Class Action Complaint (“MMC”) (collectively, the “Master Complaints”).
`DE 2759, 2835, 2832-1. Unless otherwise noted, all citations will be made to the redacted versions of the Master
`Complaints.
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`2
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`The right to sell OTC Zantac in the United States later passed to Boehringer Ingelheim
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`Pharmaceuticals and then to Sanofi. Id. ¶¶ 249-50, 253-55. When the patents on prescription and
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`OTC Zantac expired, numerous generic drug manufacturers began to produce generic ranitidine
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`products in prescription and OTC forms. Id. ¶¶ 260-62.
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`Scientific studies have demonstrated that ranitidine can transform into a cancer-causing
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`molecule called N-nitrosodimethylamine (“NDMA”), which is part of a carcinogenic group of
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`compounds called N-nitrosamines. Id. ¶¶ 348, 359, 365, 367. Studies have shown that these
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`compounds increase the risk of cancer in humans and animals. Id. ¶¶ 398-404. The FDA, the
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`Environmental Protection Agency, and the International Agency for Research on Cancer consider
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`NDMA to be a probable human carcinogen. Id. ¶¶ 275, 279. The FDA has set the acceptable daily
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`intake level for NDMA at 96 nanograms. Id. ¶ 302.
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`Valisure LLC and ValisureRX LLC, a pharmacy and testing laboratory, filed a Citizen
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`Petition on September 9, 2019, calling for the recall of all ranitidine products due to high levels of
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`NDMA in the products. Id. ¶ 322. The FDA issued a statement on September 13 warning that
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`some ranitidine products may contain NDMA. Id. ¶ 323. On November 1, the FDA announced
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`that testing had revealed the presence of NDMA in ranitidine products. Id. ¶ 333. The FDA
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`recommended that drug manufacturers recall ranitidine products with NDMA levels above the
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`acceptable daily intake level. Id. Five months later, on April 1, 2020, the FDA requested the
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`voluntary withdrawal of all ranitidine products from the market. Id. ¶ 338.
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`II.
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`Procedural Background
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`After the discovery that ranitidine products may contain NDMA, plaintiffs across the
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`country began initiating lawsuits related to their purchase and/or use of the products. On February
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`6, 2020, the United States Judicial Panel on Multidistrict Litigation created this multi-district
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`3
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`litigation (“MDL”) pursuant to 28 U.S.C. § 1407 for all pretrial purposes and ordered federal
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`lawsuits for personal injury and economic damages from the purchase and/or use of ranitidine
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`products to be transferred to the undersigned. DE 1. Since that time, approximately 1,400 plaintiffs
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`have filed lawsuits in, or had their lawsuits transferred to, the United States District Court for the
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`Southern District of Florida. In addition, this Court has created a Census Registry where tens of
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`thousands of claimants who have not filed lawsuits have registered their claims. See DE 547.
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`The Plaintiffs filed their first Master Complaints on June 22, 2020. DE 887, 888, 889. In
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`those Master Complaints, the Plaintiffs contended that the ranitidine molecule is unstable, breaks
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`down into NDMA, and has caused thousands of consumers of ranitidine products to develop
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`various forms of cancer. DE 887 ¶¶ 1, 6, 19. They alleged that “a single pill of ranitidine can
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`contain quantities of NDMA that are hundreds of times higher” than the FDA’s allowable limit.
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`Id. ¶ 4. The Plaintiffs pursued federal claims and state claims under the laws of all 50 U.S. states,
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`Puerto Rico, and the District of Columbia. See generally DE 889.
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`The Court has entered numerous Pretrial Orders to assist in the management of this MDL.
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`In Pretrial Order # 36, the Court set a schedule for the filing and briefing of the first round of
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`motions to dismiss under Rule 12 directed to the Master Complaints. DE 1346. The various
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`Defendants filed motions to dismiss. The Court issued rulings on those motions on December 31,
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`2020, January 8, 2021, and February 23, 2021. See DE 2512, 2513, 2515, 2516, 2532, 2840.
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`Following an amendment to Pretrial Order # 36, the Plaintiffs filed the AMPIC on February
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`8, 2021. DE 2759. After the Court granted a two-week extension of time [DE 2720], the Plaintiffs
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`filed the MMC [DE 2832-1] and the ELC [DE 2835] on February 22, 2021. In Pretrial Order # 61,
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`the Court set a schedule for the filing and briefing of the second round of motions to dismiss under
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`4
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`Rule 12 directed to the Master Complaints. DE 2968. The Motions addressed herein were filed
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`pursuant to that schedule.
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`III. The Master Complaints
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`A. The Amended Master Personal Injury Complaint
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`All individuals who filed a Short Form Complaint adopt the AMPIC. AMPIC at 2.3 The
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`Plaintiffs allege that they developed cancers from taking Defendants’ ranitidine products. Id. at 1.
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`The AMPIC “sets forth allegations of fact and law common to the personal-injury claims” within
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`the MDL. Id. at 1-2. Each Plaintiff seeks compensatory damages, punitive damages, restitution,
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`and all other available remedies. Id. at 1-2.
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`The Defendants “are entities that designed, manufactured, marketed, distributed, labeled,
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`packaged, handled, stored, and/or sold ranitidine.” Id. ¶ 21. They are categorized into four groups:
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`(1) Brand Manufacturer Defendants; (2) Generic Manufacturer Defendants; (3) Distributor
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`Defendants; and (4) Retailer Defendants. Within each category, the AMPIC combines distinct
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`corporate entities, including parents, subsidiaries, and affiliates, into single named Defendants.4
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`The AMPIC contains 17 counts and numerous state-specific sub-counts: Strict Products
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`Liability—Failure to Warn Through Warnings and Precautions (Count I, 46 sub-counts);
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`Negligence—Failure to Warn Through Warnings and Precautions (Count II, 48 sub-counts); Strict
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`Products Liability—Failure to Warn Through Proper Expiration Dates (Count III, 46 sub-counts);
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`Negligence—Failure to Warn Through Proper Expiration Dates (Count IV, 48 sub-counts); Failure
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`to Warn Through the FDA (Count V, 15 sub-counts); Strict Products Liability—Design Defect
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`Due to Warnings and Precautions (Count VI, 46 sub-counts); Strict Products Liability—Design
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`3 Unless noted otherwise, all page number references herein are to the page numbers generated by CM/ECF in the
`header of each document.
`4 For example, Defendant “Sanofi” refers to five entities: Sanofi-Aventis U.S. LLC, Sanofi US Services Inc., Sanofi
`SA, Patheon Manufacturing Services LLC, and Chattem, Inc. AMPIC ¶¶ 33-39.
`5
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`Defect Due to Improper Expiration Dates (Count VII, 46 sub-counts); Negligent Failure to Test
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`(Count VIII, 2 sub-counts); Negligent Product Containers (Count IX, 52 sub-counts); Negligent
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`Storage and Transportation Outside the Labeled Range (Count X, 52 sub-counts); Negligent
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`Storage and Transportation (Count XI, 52 sub-counts); Negligent Misrepresentation (Count XII);
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`Reckless Misrepresentation (Count XIII); Unjust Enrichment (Count XIV, 52 sub-counts); Loss
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`of Consortium (Count XV, 52 sub-counts); Survival Actions (Count XVI, 52 sub-counts); and
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`Wrongful Death (Count XVII, 52 sub-counts). Counts I, II, VI, XII, and XIII are brought against
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`every Brand Manufacturer Defendant. Counts III, IV, V, VII, VIII, and XI are brought against
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`every Brand and Generic Manufacturer Defendant. Count IX is brought against every Brand and
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`Generic Manufacturer Defendant that manufactured and sold ranitidine-containing pills. Count X
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`is brought against every Retailer and Distributer Defendant. Counts XIV, XV, XVI, and XVII are
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`brought against every Defendant.
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`B. The Consolidated Amended Consumer Economic Loss Class Action Complaint
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`One hundred and eighty named individuals bring the ELC on behalf of themselves and all
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`others similarly situated. Each Plaintiff asserts that he or she purchased and/or used a ranitidine
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`product during an approximate timeframe.
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`The Plaintiffs bring the action in their individual capacities and on behalf of numerous
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`classes pursuant to Rule 23. The Plaintiffs bring state class actions under various state laws
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`stemming from the Defendants’ sale of prescription-strength ranitidine for approximately forty
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`states.5 Additionally, the Plaintiffs bring state class actions under approximately forty-three states’
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`laws for the Defendants’ sale of OTC ranitidine.
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`5 The Plaintiffs have brought a varying number of state-law counts against each Defendant.
`6
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`The Defendants named in the ELC are entities that “designed, manufactured, marketed,
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`distributed, labeled, packaged, handled, stored and/or sold Zantac or generic Ranitidine-
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`Containing Products.” ELC ¶ 1. The Defendants are categorized into three groups: (1) Brand
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`Manufacturer Defendants (Prescription and OTC); (2) Generic Prescription Manufacturer and/or
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`Store-Brand Manufacturer Defendants (collectively, the “Generic Manufacturer Defendants”); and
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`(3) Store-Brand Defendants. The ELC alleges 1,675 counts against the Defendants. The Plaintiffs
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`bring claims for violation of various state consumer protection statutes, common-law unjust
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`enrichment, common-law breach of quasi-contract, and breach of implied warranty.
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`C. The Consolidated Medical Monitoring Class Action Complaint
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`Fifty-two named individuals bring the MMC on behalf of themselves and the various
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`classes established in the MMC. MMC ¶¶ 93-144. The Plaintiffs purchased and used ranitidine
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`products in fourteen jurisdictions.6 Each Plaintiff alleges that he or she purchased and used
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`ranitidine products during an approximate timeframe.
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`There are five categories of classes: (1) Brand Manufacturer Prescription Medical
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`Monitoring Classes; (2) Brand Manufacturer OTC Medical Monitoring Classes; (3) Generic
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`Prescription Medical Monitoring Classes; (4) Store-Brand Medical Monitoring Classes; and
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`(5) Store-Brand Manufacturer Medical Monitoring Classes. Within each category, there are state-
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`and Defendant-specific classes. For example, within the third category (Generic Prescription
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`Medical Monitoring Classes), several named Plaintiffs bring claims against Defendant Amneal on
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`behalf of themselves and eleven state-specific “Amneal Prescription Medical Monitoring Classes.”
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`Id. ¶ 998. Within the fourth category (Store-Brand Medical Monitoring Classes), five named
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`Plaintiffs bring claims against Defendant CVS on behalf of themselves and four state-specific
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`6 Arizona, California, Colorado, District of Columbia, Florida, Indiana, Maryland, Missouri, Montana, Nevada, Ohio,
`Pennsylvania, Utah, and West Virginia.
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`“CVS Medical Monitoring Classes.” Id. ¶ 1004. The various classes are comprised of individuals
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`who purchased and used one of the Defendants’ ranitidine products while residing in a particular
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`state, and who have not been diagnosed with a Subject Cancer.7
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`The Defendants named in the MMC are “entities that designed, manufactured, marketed,
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`distributed, labeled, packaged, handled, stored, and/or sold Zantac or generic Ranitidine-
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`Containing Products.” Id. ¶ 6. The Plaintiffs categorized the Defendants into three groups:
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`(1) Brand Manufacturer Defendants (Prescription and OTC); (2) Generic Prescription
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`Manufacturer Defendants and/or Store-Brand Manufacturer Defendants; and (3) Store-Brand
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`Defendants. The MMC alleges 638 counts against the various Defendants.8 Each count falls
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`within one of five general causes of action: (1) Failure to Warn through Warnings and Precautions;
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`(2) Failure to Warn through Proper Expiration Dates; (3) Failure to Warn Consumers through the
`FDA; (4) Negligent Product Containers; and (5) Negligent Storage and Transportation.
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`IV.
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`Summary of the Parties’ Arguments and the Court’s Rulings
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`The Generic Manufacturer Defendants contend that all of the Plaintiffs’ claims against
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`them are pre-empted under two key Supreme Court cases that addressed the pre-emption of claims
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`against generic drug manufacturers: PLIVA, Inc. v. Mensing, 564 U.S. 604 (2011) and Mutual
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`Pharmaceutical Co. v. Bartlett, 570 U.S. 472 (2013). The Generic Manufacturer Defendants argue
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`that the claims against them for failure to warn consumers through the FDA are additionally
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`pre-empted under Buckman Co. v. Plaintiffs’ Legal Committee, 531 U.S. 341 (2001). Thus, the
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`Generic Manufacturer Defendants maintain that all of the claims against them in all three Master
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`Complaints must be dismissed. The Store-Brand Defendants assert that all of the claims against
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`7 The Plaintiffs define “Subject Cancers” as “[t]hose cancers includ[ing] serious and potentially fatal bladder, breast,
`colorectal/intestinal, esophageal, gastric, kidney, liver, lung, pancreatic, and prostate cancers.” MMC at 3.
`8 While the MMC lists 640 total counts, there is no Count 222 or Count 223.
`8
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`them likewise must be dismissed. The Specially-Appearing Defendants bring a challenge to
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`personal jurisdiction. The Plaintiffs respond that none of their claims against the Generic
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`Manufacturer and Store-Brand Defendants are pre-empted or subject to dismissal. The Plaintiffs
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`maintain that the Specially-Appearing Defendants’ personal-jurisdiction challenge is without
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`merit.
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`The Court finds that Mink v. Smith & Nephew, Inc., 860 F.3d 1319 (11th Cir. 2017),
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`compels the conclusion that Buckman pre-empts the claims against the Generic Manufacturer
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`Defendants for failure to warn consumers through the FDA. The Plaintiffs’ remaining claims
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`against the Generic Manufacturer Defendants, as well as the claims against the Store-Brand
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`Defendants, are pre-empted under Mensing and Bartlett. Therefore, the Court grants the Generic
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`Manufacturer and Store-Brand Defendants’ Motions to Dismiss. The Court’s dismissal is without
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`leave to amend. The Court denies as moot the Specially-Appearing Defendants’ Renewed Motion
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`to Dismiss.
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`V.
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`Standard of Review
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`A court may grant a motion to dismiss a pleading if the pleading fails to state a claim upon
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`which relief can be granted. Fed. R. Civ. P. 12(b)(6). A Rule 12(b)(6) motion to dismiss should
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`be granted only when the pleading fails to contain “enough facts to state a claim to relief that is
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`plausible on its face.” Bell Atl. Corp. v. Twombly, 550 U.S. 544, 570 (2007). “A claim has facial
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`plausibility when the plaintiff pleads factual content that allows the court to draw the reasonable
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`inference that the defendant is liable for the misconduct alleged.” Ashcroft v. Iqbal, 556 U.S. 662,
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`678 (2009). The pleading must contain more than labels, conclusions, a formulaic recitation of
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`the elements of a cause of action, and naked assertions devoid of further factual enhancement. Id.
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`The “[f]actual allegations must be enough to raise a right to relief above the speculative level.”
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`Twombly, 550 U.S. at 555; see also Iqbal, 556 U.S. at 678 (explaining that the plausibility standard
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`“asks for more than a sheer possibility that a defendant has acted unlawfully”).
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`A court ruling on a motion to dismiss accepts the well-pled factual allegations as true and
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`views the facts in the light most favorable to the plaintiff. Jones v. Fransen, 857 F.3d 843, 850
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`(11th Cir. 2017). But the court need not accept as true allegations upon information and belief that
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`lack sufficient facts to make the allegations plausible. Mann v. Palmer, 713 F.3d 1306, 1315
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`(11th Cir. 2013) (citing Twombly, 550 U.S. at 551, 557); see also In re Darvocet, Darvon, &
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`Propoxyphene Prods. Liab. Litig., 756 F.3d 917, 931 (6th Cir. 2014) (“The mere fact that someone
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`believes something to be true does not create a plausible inference that it is true.”). The court also
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`need not accept legal conclusions couched as factual allegations. Diverse Power, Inc. v. City of
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`LaGrange, Ga., 934 F.3d 1270, 1273 (11th Cir. 2019). “Under Rule 12(b)(6), dismissal is proper
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`when, on the basis of a dispositive issue of law, no construction of the factual allegations will
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`support the cause of action.” Allen v. USAA Cas. Ins. Co., 790 F.3d 1274, 1278 (11th Cir. 2015)
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`(quotation marks omitted).
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`VI. Analysis of the Motions to Dismiss
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`A review of the law applicable to drugs approved by the FDA is necessary to evaluate the
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`arguments that the parties make in briefing the Generic Manufacturer and Store-Brand Defendants’
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`Motions to Dismiss. Therefore, the Court first discusses (A) key statutes and regulations that
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`govern the FDA’s regulation of drugs, and (B) impossibility pre-emption and significant cases that
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`have addressed impossibility pre-emption in the drug context. The Court then turns to (C) the
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`Generic Manufacturer Defendants’ Motion to Dismiss, (D) the Store-Brand Defendants’ Motions
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`to Dismiss or Strike, and (E) the Specially-Appearing Defendants’ Renewed Motion to Dismiss.
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`A. Federal Regulation of Drug Products
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`The FDA regulates prescription and OTC drugs under the Federal Food, Drug, and
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`Cosmetic Act, as amended, 21 U.S.C. § 301 et seq. (“FDCA”). The FDCA provides a process for
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`the FDA to approve a new drug through a new drug application (“NDA”) and a process for the
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`FDA to approve a drug that is the same as a previously approved drug through an abbreviated new
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`drug application (“ANDA”). See 21 U.S.C. § 355. A drug must have an FDA-approved NDA or
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`ANDA to be introduced into interstate commerce. Id. § 355(a).
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`1. NDAs
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`An NDA must contain scientific data and other information showing that the new drug is
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`safe and effective and must include proposed labeling. See id. § 355(b)(1). The FDCA defines the
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`term “labeling” as “all labels and other written, printed, or graphic matter (1) upon any article or
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`any of its containers or wrappers, or (2) accompanying such article.” Id. § 321(m). The FDA may
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`approve the NDA only if it finds, among other things, that the new drug is “safe for use under the
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`conditions prescribed, recommended, or suggested in the proposed labeling”; that there is
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`“substantial evidence that the drug will have the effect it purports or is represented to have . . . in
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`the proposed labeling”; that the methods and facilities for manufacturing, processing, and
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`packaging the drug are adequate “to preserve its identity, strength, quality, and purity”; and that
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`the labeling is not “false or misleading in any particular.” Id. § 355(d). A drug approved under the
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`NDA process, commonly referred to as a “brand-name drug,” is “listed” by the FDA as having
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`been “approved for safety and effectiveness.” See id. § 355(j)(7). Following the approval of its
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`NDA, a brand-name drug has a certain period of exclusivity in the marketplace. See id.
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`§ 355(j)(5)(F).
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`2. ANDAs
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`Subject to that period of exclusivity, a drug manufacturer may seek the approval of a drug
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`that is identical in key respects to a listed drug by filing an ANDA. See id. § 355(j); Bartlett,
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`570 U.S. at 477 (explaining that a generic drug may be approved through the ANDA process
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`“provided the generic drug is identical to the already-approved brand-name drug in several key
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`respects”). A drug approved under the ANDA process is commonly referred to as a “generic
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`drug.” The ANDA must contain information showing that the generic drug has the same active
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`ingredient(s), route of administration, dosage form, strength, therapeutic effect, and labeling as the
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`listed drug and is “bioequivalent” to the listed drug. 21 U.S.C. § 355(j)(2)(A). With limited
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`exceptions, the FDA may approve the ANDA only if it finds that the generic drug and its proposed
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`labeling are the same as the listed drug and the listed drug’s labeling. See id. § 355(j)(4); see also
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`21 C.F.R. § 314.94(a)(8)(iii), (iv) (“Labeling (including the container label, package insert, and, if
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`applicable, Medication Guide) proposed for the drug product must be the same as the labeling
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`approved for the reference listed drug . . . .”). One such exception is that the generic drug’s
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`proposed labeling “may include differences in expiration date” from the listed drug. 21 C.F.R.
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`§ 314.94(a)(8)(iv).
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`3. Changes to Drugs with Approved NDAs and ANDAs
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`The FDA also has requirements for when and how a drug manufacturer may change a drug
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`(or drug labeling) that has an approved NDA or ANDA. See id. §§ 314.70, .97(a). These
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`requirements differ depending on the category of change that the manufacturer seeks to make.
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`A “major change” is
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`any change in the drug substance, drug product, production process, quality
`controls, equipment, or facilities that has a substantial potential to have an adverse
`effect on the identity, strength, quality, purity, or potency of the drug product as
`these factors may relate to the safety or effectiveness of the drug product.
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`Id. § 314.70(b)(1). Such changes include certain labeling changes; changes “in the qualitative or
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`quantitative formulation of the drug product, including inactive ingredients”; changes “in the
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`synthesis or manufacture of the drug substance that may affect the impurity profile and/or the
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`physical, chemical, or biological properties of the drug substance”; and changes “in a drug product
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`container closure system that controls the drug product delivered to a patient or changes in the type
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`. . . or composition . . . of a packaging component that may affect the impurity profile of the drug.”
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`Id. § 314.70(b)(2)(i), (iv), (v), (vi). A major change requires a “supplement submission and [FDA]
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`approval prior to distribution of the product made using the change.” Id. § 314.70(b). This
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`supplement is referred to as a “Prior Approval Supplement.” See In re Darvocet, 756 F.3d at 923.
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`A “moderate change” is
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`any change in the drug substance, drug product, production process, quality
`controls, equipment, or facilities that has a moderate potential to have an adverse
`effect on the identity, strength, quality, purity, or potency of the drug product as
`these factors may relate to the safety or effectiveness of the drug product.
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`21 C.F.R. § 314.70(c)(1). The process for making a moderate change is commonly called the
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`“changes-being-effected” process or “CBE” process. See Mensing, 564 U.S. at 614. A moderate
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`change generally requires a “supplement submission at least 30 days prior to distribution of the
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`drug product made using the change.” 21 C.F.R. § 314.70(c). The drug product with the change
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`may be distributed prior to FDA-approval, but only after the passage of 30 days from the FDA’s
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`receipt of the supplement. Id. § 314.70(c)(4). This supplement is referred to as a “Changes Being
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`Effected in 30 Days” supplement. See id. § 314.70(c)(3).
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`However, the FDA may designate certain moderate changes that may be made upon the
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`FDA’s receipt of the supplement and need not await the passage of 30 days. Id. § 314.70(c)(6).
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`Such changes include certain changes “in the labeling to reflect newly acquired information” and
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`“changes in the methods or controls to provide increased assurance that the drug substance or drug
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`product will have the characteristics of identity, strength, quality, purity, or potency that it purports
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`or is represented to possess.” Id. § 314.70(c)(6)(i), (iii). Where the passage of 30 days is not
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`required, the supplement is referred to as a “Changes Being Effected” supplement.
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`Id. § 314.70(c)(3).
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`
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`Finally, a “minor change” is a change “in the drug substance, drug product, production
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`process, quality controls, equipment, or facilities that ha[s] a minimal potential to have an adverse
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`effect on the identity, strength, quality, purity, or potency of the drug product as these factors may
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`relate to the safety or effectiveness of the drug product.” Id. § 314.70(d)(1). Such a change
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`includes an “extension of an expiration dating period based upon full shelf life data on production
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`batches obtained from” an approved protocol. Id. § 314.70(d)(2)(vi). A minor change must be
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`“described in an annual report.” Id. § 314.70(d).
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`B. Impossibility Pre-emption
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`The Supremacy Clause of the U.S. Constitution provides that the laws of the United States
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`“shall be the supreme Law of the Land . . . any Thing in the Constitution or Laws of any State to
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`the Contrary notwithstanding.” U.S. Const. art. VI, cl. 2. “It is basic to this constitutional command
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`that all conflicting state provisions be without effect.” Maryland v. Louisiana, 451 U.S. 725, 746
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`(1981) (citing McCulloch v. Maryland, 17 U.S. 316, 427 (1819)). The pre-emption doctrine is
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`derived from the Supremacy Clause. Gade v. Nat’l Solid Wastes Mgmt. Ass’n, 505 U.S. 88, 108
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`(1992).
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`
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`Supreme Court caselaw has recognized that state law is pre-empted under the Supremacy
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`Clause in three circumstances. English v. Gen. Elec. Co., 496 U.S. 72, 78 (1990). First, “Congress
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`can define explicitly the extent to which its enactments pre-empt state law.” Id. Second, “state law
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`is pre-empted where it regulates conduct in a field that Congress intended the Federal Government
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`to occupy exclusively.” Id. at 79. Third, state law is pre-empted “to the extent that it actually
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`conflicts with federal law . . . where it is impossible for a private party to comply with both state
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`and federal requirements, or where state law stands as an obstacle to the accomplishment and
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`execution of the full purposes and objectives of Congress.” Id. (citation and quotation marks
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`omitted). Three key Supreme Court opinions have addressed impossibility pre-emption—a subset
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`of conflict pre-emption—in the drug context.
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`1. Wyeth v. Levine
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`
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`In Wyeth v. Levine, 555 U.S. 555, 559-60 (2009), a consumer of a brand-name drug brought
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`common-law negligence and strict-liability claims under Vermont law against the brand-name
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`drug’s manufacturer for failure to provide an adequate warning on the drug’s labeling. The
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`Supreme Court held that the consumer’s claims were not pre-empted because the brand-name drug
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`manufacturer had not shown that it was impossible to comply with both federal law and the
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`state-law duty to provide an adequate warning. Id. at 573. The CBE process permitted the
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`brand-name drug manufacturer to “unilaterally strengthen” the warning on the drug’s labeling
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`without waiting for FDA approval. Id. at 568, 573 (citing 21 C.F.R. § 314.70(c)). The Court
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`explained that it could not conclude that it was impossible for the brand-name drug manufacturer
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`to comply with both federal and state law “absent clear evidence that the FDA would not have
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`approved” a labeling change. Id. at 571. The brand-name drug manufacturer “offered no such
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`evidence,” and the fact that the FDA had previously approved the labeling did “not establish that
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`it would have prohibited such a change.” Id. at 572-73. Thus, impossibility pre-emption did not
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`bar the consumer’s claims against the brand-name drug manufacturer for an inadequate warning.
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`Id. at 573.
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