LEE v. ASTRAZENECA PHARMACEUTICALS LP et al

Filing 76

REPORT & RECOMMENDATION of Special Master Ellen Reisman Regarding Defendants' Summary Judgment Motions as to Preemption of Failure to Warn Claims. Signed by Special Master Ellen Reisman on 8/1/2022. (Attachments: # 1 Exhibit 1 (Oral Argument, Apr. 5, 2022), # 2 Proposed Order)(jl, )

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UNITED STATES DISTRICT COURT
DISTRICT OF NEW JERSEY

IN RE: PROTON-PUMP INHIBITOR
PRODUCTS LIABILITY LITIGATION
This Document Relates to:

Bales v. AstraZeneca Pharmaceuticals LP,
et. al., No. 2:17-cv-06124

2:17-MD-2789 (CCC) (LDW)
(MDL 2789)
and all member and related cases
Judge Claire C. Cecchi

Foster v. AstraZeneca Pharmaceuticals LP,
et al., No. 2:17-cv-02475
Kersch v. AstraZeneca Pharmaceuticals LP,
et al., No. 2:18-cv-03159
Lee v. AstraZeneca Pharmaceuticals LP, et
al., No. 2:17-cv-00212
Nelson v. AstraZeneca Pharmaceuticals LP,
et al., No. 2:17-cv-13727
Rieder v. AstraZeneca Pharmaceuticals LP,
et al., No. 2:19-cv-00850

REPORT & RECOMMENDATION
OF SPECIAL MASTER ELLEN K. REISMAN
REGARDING DEFENDANTS’ PREEMPTION MOTIONS

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TABLE OF CONTENTS

I.

INTRODUCTION .............................................................................................1

II.

PLAINTIFFS’ FAILURE TO WARN CLAIMS ..............................................4
1.
2.
3.
4.
5.
6.

James Rieder ..............................................................................................7
Freddy Bales ...............................................................................................7
David Foster ...............................................................................................8
Steven Kersch .............................................................................................9
Kimberly Lee..............................................................................................9
Diane Nelson ..............................................................................................9

III. OVERVIEW OF FEDERAL REGULATION OF PHARMACEUTICAL
SAFETY AND LABELING ............................................................................10
IV. OVERVIEW OF RELEVANT LABELING HISTORY ................................14
A.
B.

Initial Nexium Labeling ..............................................................................14
Initial Prevacid Labeling .............................................................................15

C.

Post-Marketing Reports and 2006/2007 Amendments Of The Adverse
Reactions Sections Of The Nexium and Prevacid Labels To Add Interstitial
Nephritis ......................................................................................................16

D.

Publication Of Additional Data, The 2011 Citizen’s Petition, And The
2014 Amendment Of The Warnings and Precautions Section Of PPI Labels
To Include “Acute Interstitial Nephritis” ....................................................20
FDA Review Of Additional, Subsequent Literature And Other Information
Regarding Potential Renal Injury From PPI Use And The 2020 PPI Class
Label Amendment .......................................................................................23

E.

V.

GOVERNING LEGAL STANDARDS...........................................................27
A.

Preemption...................................................................................................27

B.

Summary Judgment Standard On Preemption Motions ..............................32

VI. ANALYSIS ......................................................................................................35
A.

The Relevance Of Timing To Preemption Analysis ...................................35

B.

Defendants’ Argument That There Is No Preemption Because No “Newly
Acquired Evidence” Regarding “Chronic Kidney Disease” Existed At The

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Time When Plaintiffs Consumed PPIs And Developed Chronic Kidney
Disease.........................................................................................................35
C.

Whether FDA’s PPI Labeling Decisions Are “Clear Evidence” That It
Would Have Rejected A Kidney Injury Risk Warning If Defendants Had
Sought To Provide One ...............................................................................41

D.

Fosamax ......................................................................................................50

VII. CONCLUSION ................................................................................................51

ii

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I.

INTRODUCTION
The Judicial Panel on Multidistrict Litigation (“JPML”) established this MDL

proceeding in August 2017 to consolidate claims alleging personal injury and
wrongful death resulting from the use of proton pump inhibitor (“PPI”) drugs. In
Case Management Order (“CMO”) No. 33, the Court created a process for
bellwether selection, and in accordance with CMO No. 36, twenty plaintiffs were
identified as those whose cases would be worked up as potential bellwethers.1 In
CMO No. 48, the Court selected six cases as the Bellwether Trial Cases, and the
parties have been preparing these cases for trial.2 Trial in the first bellwether case,
Rieder, is scheduled to begin on November 14, 2022, with trial in Foster scheduled
on March 1, 2023, and trial in Bales scheduled on April 10, 2023.3
AstraZeneca Pharmaceuticals LP and AstraZeneca LP (collectively
“AstraZeneca”) are defendants in all six of the Bellwether Trial Cases, and Merck
Sharp & Dohme Corporation is named as a defendant in the Rieder and Kersch
cases.4
1

Takeda Pharmaceuticals Company Limited, Takeda Pharmaceuticals

CMO No. 33, No. 2:17-md-2789, ECF No. 513; CMO No. 36, No. 2:17-md-2789,
ECF No. 548.
2
CMO No. 48, No. 2:17-md-2789, ECF No. 665. The six cases selected as the
Bellwether Trial Cases are: Freddy Bales, No. 2:17-cv-06124; David Foster, No.
2:17-cv-02475; Steve Kersch, No. 2:18-cv-03159; Kimberly Lee, No. 2:17-cv00212; Diane Nelson, No. 2:17-cv-13727; and James Rieder, No. 2:19-cv-00850.
3
CMO No. 76, No. 2:17-md-2789, ECF No. 801.
4
For purposes of this Report and Recommendation (“R&R”), “AstraZeneca” also
includes Merck Sharp & Dohme Corporation for those two cases.

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America, Inc., Takeda Development Center Americas, Inc. f/k/a Takeda Global
Research & Development Center, Inc., and Takeda Pharmaceuticals U.S.A., Inc.
(collectively “Takeda”) are defendants in Bales only.
In CMO No. 50, amended by subsequent CMOs, including CMO Nos. 75 and
No. 76, the Court directed me to prepare Reports and Recommendations (“R&R”)
as to, inter alia, motions for summary judgment filed by the parties in the six
Bellwether Trial Cases.5 Among those summary judgment motions are motions by
AstraZeneca in the six Bellwether Trial Cases and Takeda in Bales seeking partial
summary judgment on Plaintiffs’ state law failure to warn claims on the ground that
they are preempted by federal law.6 Defendants argue that under the provisions of

5

See CMO No. 50, No. 2:17-md-2789, ECF No. 685; CMO NO. 67, No. 2:17-md2789, ECF No. 747; CMO No. 75, No. 2:17-md-2789, ECF No. 784, CMO No. 76.
6
See (1) AstraZeneca Defendants’ Notice of Motion For Summary Judgment On
The Grounds That Plaintiffs’ State Law Failure-To-Warn Claims Are Preempted By
Federal Law, No. 2:19-cv-00850, ECF No. 31; AstraZeneca Defendants’ Statement
of Undisputed Material Facts In Support of Motion, No. 2:19-cv-00850, ECF No.
31-1 (“AstraZeneca Def. Rieder Undisp. Facts”); AstraZeneca Memorandum Of
Law In Support Of Motion, No. 2:19-cv-00850, ECF No. 31-2 (“AstraZeneca Rieder
Preemption Mem.”); (2) AstraZeneca Defendants’ Notice of Motion For Summary
Judgment On The Grounds That Plaintiffs’ State Law Failure-To-Warn Claims Are
Preempted By Federal Law, No. 2:17-cv-06124, ECF No. 73; AstraZeneca
Defendants’ Statement of Undisputed Material Facts In Support of Motion, No.
2:17-cv-06124, ECF No. 73-1 (“AstraZeneca Def. Bales Undisp. Facts”),
AstraZeneca Memorandum Of Law In Support Of Motion, No. 2:17-cv-06124, ECF
No. 73-2 (“AstraZeneca Bales Preemption Mem.”); (3) Takeda Defendants’ Notice
of Motion For Partial Summary Judgment On Preemption Grounds, No. 2:17-cv06124, ECF No. 71, Takeda Defendants’ Statement of Undisputed Material Facts In
Support of Motion, No. 2:17-cv-06124, ECF No. 71-1 (“Takeda Bales Undisp.
Facts”), Takeda Memorandum Of Law In Support Of Motion, No. 2:17-cv-06124,
2

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the federal Food, Drug and Cosmetic Act (“FDCA”) providing for regulation of
pharmaceutical labeling by the U.S. Food and Drug Administration (“FDA”), FDA’s
implementing regulations, and FDA’s labeling decisions regarding PPI drugs, the
manufacturers were prohibited from changing their FDA-approved labels to reflect
additional warnings of potential kidney injury.7 Thus, Defendants argue, citing the
Supreme Court’s decisions in Merck Sharpe & Dohme Corp. v. Albrecht, 139 S. Ct.
1668 (2019), and Wyeth v. Levine, 555 U.S. 555 (2009), the state law failure to warn
claims are preempted under the Supremacy Clause of the U.S. Constitution because
it would have been impossible for Defendants to comply with both federal law and
any alleged additional state law duty to warn.8 The Plaintiffs’ Steering Committee
(“PSC”), on behalf of Plaintiffs in these cases, opposes the motions.9
To facilitate the preparation of my R&R on the preemption motions, I
requested and on April 5, 2022, heard oral argument via Zoom by counsel for
AstraZeneca, Takeda, and the PSC. A copy of the oral argument transcript and
certain PowerPoint slides presented by AstraZeneca’s counsel are attached as

ECF No. 71-2 (“Takeda Bales Preemption Mem.”). The AstraZeneca motions and
supporting documents related to Rieder and Bales address the plaintiffs in all six
Bellwether Trial Cases.
7
See AstraZeneca Rieder Preemption Mem. 29-40; AstraZeneca Bales Preemption
Mem. 29-40; Takeda Bales Preemption Mem. 20-27.
8
See AstraZeneca Rieder Preemption Mem. 29-40; AstraZeneca Bales Preemption
Mem. 29-40; Takeda Bales Preemption Mem. 20-27.
9
PSC’s Brief Opposing Defendants’ Motions for Summary Judgment On Failureto-Warn Preemption, ECF No. 728 (“PSC Opp. Mem.”).
3

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Exhibit 1 to this R&R. Thereafter, the parties were ordered in CMO No. 75 to
provide supplemental briefing addressing certain issues, including but not limited to
the recent decision of the United States District Court for the District of New Jersey
on remand from the Supreme Court and the U.S. Court of Appeals for the Third
Circuit in the Merck v. Albrecht case.10 Those supplemental submissions were
received on May 31 and June 8, 2022.11
After a careful review of the voluminous record, I recommend that
Defendants’ motions be denied for the reasons set forth below.
II.

PLAINTIFFS’ FAILURE TO WARN CLAIMS

A Master Long Form Complaint (“Master Complaint”) was filed in MDL 2789
that allows individual plaintiffs to incorporate relevant allegations and causes of
action by reference in their individual short form complaints.12

The Master

Complaint alleges that PPIs cause a variety of serious kidney injuries, including
Acute Interstitial Nephritis (“AIN”), Acute Kidney Injury (“AKI”), End-Stage Renal
Disease (“ESRD”) and Chronic Kidney Disease (“CKD”).13 Count III, Failure to

10

CMO No. 75 (Setting deadlines for submissions and a revised schedule for
issuance of an R&R and any appeal process).
11
Brief extensions of the time limits in CMO No. 75 were granted.
12
Pls.’ Master Long Form Compl. and Jury Demand, ECF No. 118 (“Master
Complaint”).
13
Master Complaint ¶¶ 179-211. “Consumers, including Plaintiffs, who have used
Defendants’ PPI Products have suffered from severe kidney injuries including, but
not limited to, AIN, AKI, CKD and ESRD.” Master Complaint ¶ 226.
4

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Warn, alleges that “Defendants had a duty to warn Plaintiffs and their healthcare
providers regarding the risks associated with ingesting PPI Products and failed to
warn of the risk of kidney injuries that may be irreversible, permanently disabling
and life-threatening.”14 It further alleges that “Plaintiffs and/or Plaintiffs [sic]
healthcare providers were unaware, and could not have reasonably known or have
learned through reasonable diligence, that Plaintiffs had been exposed to the risks
identified in this Master Long Form Complaint.”15 It alleges that, had such warnings
been provided, Plaintiffs and their physicians would have been on notice of the risks,
so that “they would not have used [PPI Products] or they would have altered the
frequency or duration of use.”16 And it alleges that, as a result of the absence of

14

Master Complaint ¶ 325; see also Master Complaint ¶¶ 327 (“Defendants failed
to provide adequate warnings or instructions that a manufacturer exercising
reasonable care would have provided concerning the risk of kidney injury that may
be irreversible, permanently disabling and life-threatening in light of the likelihood
that the PPI Products would cause these injuries.”), 343 (“The warnings that were
given by the Defendants failed to properly warn physicians and/or other healthcare
providers, including those of the Plaintiffs, of the risks associated with Defendants’
PPI Products, thereby subjecting patients, including the Plaintiffs, to unreasonable
and foreseeable risks that exceeded the purported and marketed benefits of
Defendants’ PPI Products.”); PSC. Stmt. Of Undisp. Facts ¶¶ 7, 50 (Complaint
alleges that labels should have contained warnings of a risk of “permanent or chronic
renal injury” or potential “permanent and irreversible renal injuries.”); Oral Args.
40:6-12, Apr. 5, 2022, attached hereto in pertinent part as Ex. 1. (Mr. Autry: “There
were no warnings in Takeda’s label at the time about any possible harm to Bales’
kidneys, zero, at the time that Bales took Prevacid. . . . Dr. Fowler said that if he
had known about the risk of kidney injuries, he would not have recommended PPIs
to Mr. Bales.”); Oral Args. 42:8-25, 43:1-13, Apr. 5, 2022.
15
Master Complaint ¶ 231; see also Master Complaint ¶¶ 333, 343.
16
Master Complaint ¶ 338; see also Master Complaint ¶¶ 344-48.
5

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adequate warnings, “Plaintiffs were caused to suffer serious and dangerous side
effects, including serious kidney injuries and other severe and personal injuries (in
some cases death), which are permanent and lasting in nature, physical pain and
mental anguish, diminished enjoyment of life and financial expenses for
hospitalization and medical care.”17
Four of the six Bellwether Trial Case Plaintiffs (Rieder, Bales, Foster, and
Kersch) incorporate by reference in a Short Form Complaint the allegations of the
Master Complaint and each alleges, among other claims, a failure to warn claim.18
The Complaints in the Lee and Nelson cases, like the Master Complaint, allege that

17

Master Complaint ¶ 348.
See, e.g., Second Am. Short Form Compl. 1, 5-6, No. 19-cv-00850, ECF No. 1
(“Rieder Second Am. Compl.”).
I note that, in addition to their failure to warn claims, Plaintiffs in the six
Bellwether Trial Cases also assert other state law claims related to alleged
misrepresentations, breaches of warranty, and fraudulent concealment by
Defendants AstraZeneca and Takeda. See Master Complaint Counts VI, VII, VIII,
IX, X; infra n.18 (incorporations by reference in short form complaints).
AstraZeneca’s and Takeda’s motions for partial summary judgment on preemption
grounds address only the failure to warn claims, not those other claims. See motions
cited in n.6, supra; Oral Args. 67:22-68:10, Apr. 5, 2022. At oral argument, in
response to my question noting that the preemption motions did not address these
other causes of action, counsel for AstraZeneca argued that “to the degree any of
those claims are based on the labeling and the content of the label, they would be
preempted as well,” but to the extent they asserted independent claims, they would
not be. See Oral Args. 68:11-69:2, Apr. 5, 2022. Given my recommendation that
the motion for summary judgment on preemption grounds with respect to the failure
to warn claims should be denied, and AstraZeneca’s counsel’s position that those
claims should be treated similarly to the extent they rely on the warnings in the
labels, I need not address those claims specifically or whether any preemption
argument as them has been waived.
6
18

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PPIs can cause a variety of serious kidney injuries, including among others AIN,
CKD, and AKI, and that the Nexium label failed to warn adequately of the risks of
kidney injury.19
1. James Rieder
Plaintiff James Rieder used Nexium, which was marketed by AstraZeneca, to
treat gastroesophageal reflux disease (“GERD”) between 2002 and 2015.20 In his
complaint against AstraZeneca, Plaintiff Rieder alleges that Nexium use was a cause
of his chronic kidney disease (“CKD”).21 The complaint in Rieder asserts a failure
to warn claim under Ohio law (among other claims).22
2. Freddy Bales
Plaintiff Freddy Bales used Nexium to treat GERD between November 2007
and April 2016.23 Plaintiff Bales alleges that Nexium use was a cause of his CKD,

19

See Complaint ¶¶ 24-47, Count II, Lee v. AstraZeneca Pharms. LP, et al., No.
2:17-cv-00212, ECF No. 1 (“Lee Compl.”); Complaint ¶¶ 40-58, Count II, Nelson v.
AstraZeneca Pharms. LP, et al., No. 2:17-cv-13727, ECF No. 1 (“Nelson Compl.”).
20
Rieder Second Am. Compl. ¶¶ 10–11; see also Plaintiff Steering Committee’s
Proposed Statement of Facts and Conclusions of Law (“PSC Supp. SOF-COL”)
¶ 10, ECF No. 791.
21
Rieder Second Am. Compl. ¶ 11; see also Derek M. Fine Report 8, Hindy Cert. I,
Ex. O (“It is my opinion with reasonable medical and scientific certainty that Mr.
Rieder’s long-term use of PPIs (in this case Nexium) was a substantial factor to his
developing chronic kidney disease . . . .”), ECF No. 73-18; PSC Supp. SOF-COL
¶ 1. (Unless otherwise indicated herein, “Hindy Cert.” refers to the certification of
exhibits in support of AstraZeneca’s preemption motion filed in No. 2:17-cv-06124.)
22
See Rieder Second Am. Compl. ¶ 14; PSC Supp. SOF-COL ¶ 1.
23
See Pl. Bales’ Second Am. Fact Sheet 10, Hindy Cert. I, Ex. C, ECF No. 73-6.
7

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which his physician diagnosed in June 2015.24 He asserts a state law failure to warn
claim against AstraZeneca (among other claims).25
Plaintiff Bales also asserts a state law failure to warn claim against Takeda,
which manufactured and sold the Prevacid that Plaintiff Bales used from April 2005
to September 2007 prior to switching to Nexium.26 He alleges that his Prevacid use
was also a cause of his CKD.27
3. David Foster
Plaintiff’s Decedent David Foster used Nexium, which was marketed by
AstraZeneca, to treat GERD between February 2010 and October 2014, and Angel
Maria Lee, the Administrator of David Foster’s Estate, alleges that it was a cause of
David Foster’s CKD and caused his death.28 The complaint in Foster asserts a state
law failure to warn claim (among other claims).29

24

See Pl. Bales’ Second Am. Fact Sheet 12–13; Second Am. Short Form Compl.
¶ 11, Bales v. AstraZeneca Pharms. LP, No. 17-cv-06124, ECF No. 42 (“Bales
Compl.”); see also David R. Powers Report (Bales) 10, Hindy Cert. I, Ex. E (“[I]t is
my opinion with reasonable medical certainty that PPIs were the cause of Mr. Bales’
chronic kidney disease.”), ECF No. 73-8.
25
See Bales Compl. ¶¶ 13-14.
26
See Takeda Bales Undisp. Facts ¶ 3; Bales Compl. ¶¶ 5, 10, 11, 14; PSC Supp.
FOF-COL ¶ 5.
27
Bales Compl. ¶¶ 5, 10, 11.
28
See AstraZeneca Defendants Proposed Findings of Fact and Conclusions of Law
¶ 24, No. 2:19-cv-00850, ECF. No. 59-1 (“AstraZeneca Supp. Proposed FOFCOL”); Pl. Supp. FOF-COL ¶ 6; Third Am. Short Form Compl. and Jury Demand
¶¶ 4, 11, Foster v. AstraZeneca Pharms. LP, et al., No. 2:17-cv-02475, ECF No. 83
(“Foster Am. Compl.”).
29
See Foster Am. Compl. ¶ 14, Count III.
8

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4. Steven Kersch
Plaintiff Steven Kersch used Nexium, which was marketed by AstraZeneca,
to treat GERD between February 2010 and October 2018.30 In his complaint,
Plaintiff Kersch alleges that Nexium use was a cause of his CKD and AKI.31 The
Kersch complaint asserts a state law failure to warn claim (among other claims).32
5. Kimberly Lee
Plaintiff Kimberly Lee used Nexium, which was marketed by AstraZeneca, to
treat GERD between July 2010 and at least October 2014.33 In her complaint,
Plaintiff Lee alleges that Nexium use was a cause of her CKD.34 The Lee complaint
asserts a state law failure to warn claim (among other claims).35
6. Diane Nelson
Plaintiff Diane Nelson used Nexium, which was marketed by AstraZeneca, to
treat GERD between March 2007 and February 2016.36 In her complaint, Plaintiff

30

See PSC Supp. SOF-COL ¶ 7; AstraZeneca Supp. FOF-COL ¶ 100.
Short Form Compl. And Jury Demand 1, 3, 6-7, Kersch v. AstraZeneca Pharms.
LP, et al., No. 2:18-cv-03159, ECF No. 1 (“Kersch Compl.”).
32
Kersch Compl. ¶ 14.
33
See PSC Supp. SOF-COL ¶ 8; AstraZeneca Supp. FOF-COL ¶ 101.
34
See PSC Supp. SOF-COL ¶ 8; AstraZeneca Supp. FOF-COL ¶ 101; Lee Compl.
¶ 1.
35
Lee Compl. Count II.
36
See PSC Supp. SOF-COL ¶ 9; AstraZeneca Supp. FOF-COL ¶ 102.
9
31

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Nelson alleges that Nexium use was a cause of her CKD.37 The Nelson complaint
asserts a failure to warn claim (among other claims).38
III.

OVERVIEW OF FEDERAL REGULATION OF
PHARMACEUTICAL SAFETY AND LABELING
The federal FDCA establishes a regulatory regime designed to ensure that

every prescription drug on the market is “safe for use under the conditions
prescribed, recommended, or suggested” in its “labeling.”39 Under the FDCA, drug
manufacturers bear “ultimate responsibility” for appropriately labeling drugs,
including to warn of safety risks.40 However, the FDCA also requires manufacturers
to work with FDA to develop an appropriate label when they submit a new drug for
approval.41 FDA closely regulates the safety information on drug labels.42 It is a
violation of federal law for a manufacturer to distribute a drug that is not labeled in
compliance with FDA regulations.43
Drug labels include two sections relevant to this case: a “Warnings and
Precautions” section and an “Adverse Reactions” section.44

37

See PSC Supp. SOF-COL ¶ 9; AstraZeneca Supp. FOF-COL ¶ 102; Nelson
Compl. ¶ 69.
38
Nelson Compl. Count II.
39
21 U.S.C. § 355(d).
40
Wyeth v. Levine, 555 U.S. 555, 571 (2009).
41
21 U.S.C. §§ 355(a), (b), (d)(7); 21 C.F.R. § 314.125(b)(6).
42
21 U.S.C. § 355(b)(1)(F); 21 C.F.R. § 201.57(a).
43
See generally Wyeth v. Levine, 555 U.S. at 571; 21 C.F.R. § 201.57.
44
See 21 C.F.R. §§ 201.57(a)(10) (“Warnings and precautions”), 201.57(a)(11)
10

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The Warnings and Precautions section is required to “include[e] information
that would affect decisions about whether to prescribe a drug, recommendations for
patient monitoring that are critical to safe use of the drug, and measures that can be
taken to prevent or mitigate harm.”45 It must
describe clinically significant adverse reactions, (including any that
are potentially fatal, are serious even if infrequent, or can be
prevented or mitigated through appropriate use of the drug), other
potential safety hazards (including those that are expected for the
pharmacological class . . .), limitations on use imposed by them (e.g.,
avoiding certain concomitant therapy), and steps that should be taken
if they occur (e.g., dosage modification). The frequency of all
clinically significant adverse reactions and the approximate mortality
and morbidity rates for patients experiencing the reaction, if known
and necessary for the safe and effective use of the drug, must be
expressed as provided under paragraph (c)(7) of this section.46
Thus, the Warnings and Precautions section of the label identifies a “discrete set” of
serious risks that would affect a doctor’s prescribing decisions or be “potentially
fatal.”47 FDA regulations provide that “the labeling must be revised to include a
warning about a clinically significant hazard as soon as there is reasonable evidence
of a causal association with a drug; a causal relationship need not have been
definitely established.”48

(“Adverse reactions”).
45
21 C.F.R. § 201.57(a)(10).
46
21 C.F.R. § 201.57(c)(6)(i).
47
71 Fed. Reg. 3922-01, 3946; FDA, Guidance for Industry: Warnings and
Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human
Prescription Drug and Biological Products – Content and Format, at 3 (Oct. 2011).
48
21 C.F.R. § 201.57(c)(6)(i).
11

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FDA regulations regarding the Adverse Reactions section of a drug label
require a description of “the overall . . . profile of the drug based on the entire safety
database,” including a list of all “undesirable effect[s], reasonably associated with
use.”49 Given its broader scope, the threshold for warning of an adverse event in the
Adverse Reactions section is comparatively lower: there must be “some basis to
believe there is a causal relationship between the drug and the occurrence of the
adverse event.”50
FDA regulations also impose a duty on manufacturers authorized to market a
drug to perform continuous surveillance of post-marketing adverse events and
medical literature, among other sources, to monitor the safety of their products.51
Moreover, the manufacturer is required to report this information to FDA pursuant
to FDA regulations and guidance.52

49

21 C.F.R. § 201.57(c)(7).
21 C.F.R. § 201.57(c)(7).
51
21 C.F.R. § 314.80(b).
52
See 21 C.F.R. §§ 314.80, 314.81, 201.57. An adverse drug experience that “is
both serious and unexpected, whether foreign or domestic,” must be reported “as
soon as possible but no later than 15 calendar days from initial receipt of the
information by the applicant” or other entity (manufacturer, packer or distributor)
whose name appears on the label. 21 C.F.R. §§ 314.80(c)(1)(i), (iii). Prompt
investigation and follow up reporting regarding such 15-day Alert reports also is
required. 21 C.F.R. §§ 314.80(c)(1)(ii), (iii). Other adverse drug experiences must
be reported quarterly for three years from the date of approval of the application, and
annually thereafter, unless FDA reimposes the quarterly reporting requirement or
other reporting schedule. 21 C.F.R. § 314.80(c)(2)(a).
12
50

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New information about a drug may require changing its label.53 A drug
manufacturer may change its FDA-approved label in one of two ways. The typical
way is for the manufacturer to seek advance permission from FDA to make a label
change through a Prior Approval Supplement Application (“PAS”).54

If the

manufacturer seeks such advance permission, it may not change the label until and
unless it receives FDA approval.55
“Alternatively, a manufacturer may change a label immediately and
unilaterally through an exception to the normal advance FDA approval process – a
Changes Being Effected Application (‘CBE’) to reflect ‘newly acquired
information’ about ‘evidence of a causal association between the drug and a risk of
harm.’”56 “Newly acquired information” means risks not previously known or
previously underestimated.57 In particular, “newly acquired information” includes
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,

53

See 21 C.F.R. §§ 314.70(b)(ii)(v)(C), 314.70(c)(6)(iii), 314.81(b)(2)(i); Merck v.
Albrecht, 139 S. Ct. at 830; In re Fosamax Alendronate Sodium Prods. Liab. Litig.,
2022 U.S. Dist. LEXIS 52627, at *38 (D. N.J. Mar. 23, 2022) (“Fosamax”).
54
See 21 C.F.R. §§ 314.70(b)(ii)(v)(C), 314.70(c)(6)(iii); Fosamax, 2022 U.S. Dist.
LEXIS 52627, at *39.
55
21 C.F.R. §§ 314.70(b)(2)(v)(A), (b)(4).
56
Fosamax, 2022 U.S. Dist. LEXIS 52627, at *39 (citing 21 U.S.C.
§§ 314.70(c)(6)(iii)(A) (CBE regulation), 314.3(b) (defining “newly acquired
information”)).
57
21 C.F.R. § 314.3(b).
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or analyses reveal risks of a different type or greater severity or
frequency than previously included in submissions to FDA.58
When a manufacturer changes a label through the CBE process, it can use the
modified label after notifying FDA but before FDA completes its review of the
change.

If FDA subsequently rejects a labeling change implemented by the

manufacturer, the manufacturer must cease using it.59
Whichever method a manufacturer chooses to modify a label, any
modification to the Warnings and Precautions section or the Adverse Reactions
section must meet the relevant causal thresholds described above for inclusion in
that section.60
IV.

OVERVIEW OF RELEVANT LABELING HISTORY
A. Initial Nexium Labeling
Nexium is the brand name for esomeprazole magnesium, a PPI manufactured

by AstraZeneca that was approved by FDA for marketing in the United States on
February 20, 2001.61 The original Nexium label did not contain any information in
either the Warnings and Precautions section or the Adverse Reactions section about

58

21 C.F.R. § 314.3(b); see also Wyeth v. Levine, 555 U.S. at 569.
See Wyeth v. Levine, 555 U.S. at 571.
60
21 C.F.R. §§ 201.57(e), 201.80(e).
61
PSC Supp. FOF-COL ¶ 2; see also AstraZeneca Defendants’ Proposed Findings
Of Fact And Conclusions Of Law ¶ 12, No. 2:17-cv-06124, ECF No. 111-1
(“AstraZeneca Supp. FOF-COL”).
14
59

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kidney conditions observed in patients taking the drug; however, in the Adverse
Reactions section, the Nexium label did cross-reference the label of omeprazole
(Prilosec) – another PPI drug that is a “racemate” (close chemical relative) of
esomeprazole (Nexium) – stating that “[o]ther adverse events not observed with
NEXIUM but occurring with omeprazole can be found in the omeprazole package
insert, ADVERSE REACTIONS section.”62

The omeprazole ADVERSE

REACTIONS section listed interstitial nephritis as an adverse reaction that had been
observed.63
B. Initial Prevacid Labeling
Prevacid is the brand name for lansoprazole, a PPI manufactured by Takeda
that was approved by the FDA for marketing in the United States on May 10, 1995.64
As with Nexium, as of 2001, Prevacid’s labeling did not include any reference in the
Warnings and Precautions section or Adverse Reactions section of the label to
kidney conditions observed in patients taking the drug.65

62

AstraZeneca Supp. FOF-COL ¶ 14 (quoting Feb. 2001 Nexium label at 22, copy
submitted as Hindy Cert., Ex. Q, ECF No. 73-20).
63
See AstraZeneca Supp. FOF-COL ¶¶ 5-8.
64
See PSC Supp. SOF-COL ¶ 3; Takeda Def. L. R. 56.1 Statement of Undisputed
Material Facts in Support of Motion for Partial Summary Judgment ¶ 12.
65
See Letter dated May 3, 2001 from L. Talarico, M.D., Director, Div. of
Gastrointestinal and Coagulation Drug Products, Office of Drug Evaluation III,
Center for Drug Evaluation and Research, FDA and related correspondence to TAP
Pharmaceutical Products, Inc. enclosing approved text for Prevacid label, at 23, 28
(copy attached as Ex. J to Anderson Cert., No. 2:17-cv-06124, ECF No. 71-13).
15

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C. Post-Marketing Reports and 2006/2007 Amendments Of The
Adverse Reactions Sections Of The Nexium and Prevacid Labels
To Add Interstitial Nephritis
During the period after Nexium and Prevacid were initially approved by FDA,
various adverse event reports, case studies, and other publications reported kidneyrelated conditions among users of PPIs, including but not limited to reports of
interstitial nephritis.66 These included, among other case reports and case series:
 Delve (2003), a case study of two women who suffered progressive
renal failure due to acute tubulointerstitial nephritis (“AIN” or
“ATIN”), which also discussed 11 cases of AIN in PPI patients reported
in New Zealand and reviewed published literature;67
 Ra and Tobe (2004), a case report regarding AIN in a patient using the
PPI pantoprazole;68

66

See PSC Supp. FOF-COL ¶¶ 39-45; AstraZeneca Supp. FOF-COL ¶ 15; Takeda
Defendants’ Proposed Findings Of Fact And Conclusions Of Law In Support Of Its
Motion For Partial Summary Judgment On Preemption Grounds ¶¶ 34-36, No. 2:17cv-06124, ECF No. 109 (“Takeda Supp. FOF-COL”).
67
See PSC Supp. FOF-COL ¶ 39, PSC Opp. Ex. 29 (Peter Delve, et al.,
“Omeprazole-Induced Acute Interstitial Nephritis,” The New Zealand Medical
Journal (Online) 116, no. 1169 (2003)); see also Takeda Supp. FOF-COL ¶ 33
(noting 2006 submission to FDA of Delve).
68
See PSC Supp. FOF-COL ¶ 41, PSC Opp. Ex. 19 (Amy Ra and Sheldon W. Tobe,
“Acute Interstitial Nephritis Due to Pantoprazole,” Annals of Pharmacotherapy 38,
no. 1 (2004)); AstraZeneca’s Response To PSC Supp. FOF-COL App. A at 3 (noting
no dispute regarding submission to FDA).
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 Yamamoto (2004), a case report of a patient who developed renal
insufficiency after taking the PPI lansoprazole, experienced improved
renal function on discontinuation, experienced renal function
deterioration when started on another PPI, and ultimately was
diagnosed with acute renal failure and AIN;69
 Torpey (2004), a published case series analyzing renal biopsy results
from 296 patients that found an association between AIN and the PPIs
omeprazole and lansoprazole in one-third of the cases, noted that many
patients stabilized after withdrawal of PPI, and that many patients did
not present with traditional symptoms of AIN;70 and
 Geevasinga (2005), reporting AIN in two patients using Nexium, one
of whom ultimately developed renal failure and the other of whom

69

See PSC Supp. FOF-COL ¶ 41, PSC Opp. Ex. 18; AstraZeneca’s Response To
PSC Supp. FOF-COL App. A at 3 (noting report to FDA in AstraZeneca 2005 PostMarketing Safety Update Report); Takeda Supp. FOF-COL ¶¶ 31-32 (noting 2004
Takeda submissions to FDA).
70
See PSC Supp. FOF-COL ¶ 43, PSC Opp. Ex. 31 (N. Torpey, T. Barker, and C.
Ross, “Drug-Induced Tubulo-Interstitial Nephritis Secondary to Proton Pump
Inhibitors: Experience from a Single UK Renal Unit,” Nephrology Dialysis
Transplantation 19, no. 6 (June 1, 2004): 1441-46); AstraZeneca’s Response To PSC
FOF-COL App. A at 3 (noting FDA awareness of Torpey, which is cited in 2005
Postmarketing Safety Review, Hindy Cert. I Ex. CC at 2, ECF No. 73-34); Takeda
Supp. FOF-COL ¶ 33 (noting reference to Torpey in 2005 Takeda Prevacid Annual
Report submission to FDA).
17

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developed end-stage renal disease, which the authors noted could be
downstream consequences of AIN.71
In April 2005, after reviewing post-marketing adverse event reports and
medical literature regarding interstitial nephritis associated with PPI use, FDA’s
Office of Safety and Epidemiology prepared a post-marketing safety review.72 The
review specifically referenced Torpey and Geevasinga (2005) and “79 reports, 10
reports, and 22 reports of interstitial nephritis for PPIs esomeprazole, rabeprazole,
and pantoprazole, respectively . . ..”73 It noted that only three of five PPIs on the
market listed interstitial nephritis in the label as a post-marketing reported event and
recommended class labeling for all PPIs regarding interstitial nephritis.74
On March 16, 2006, after reviewing post-marketing adverse event reports
associated with Nexium, AstraZeneca notified FDA that it intended to modify the
Adverse Reactions section of the Nexium label to include “interstitial nephritis.”75

71

See PSC Supp. FOF-COL ¶ 45, PSC Opp. Ex. 32 (Nimeshan Geevasinga et al.,
“Acute Interstitial Nephritis Secondary to Esomeprazole,” The Medical Journal of
Australia 182, no. 5 (2005): 235-36 (“Geevasinga (2005)”); AstraZeneca’s Response
To PSC FOF-COL App. A at 4 (AstraZeneca disclosed to FDA).
72
See PSC Supp. FOF-COL ¶ 47, Ex. 226; AstraZeneca Supp. FOF-COL ¶ 17.
73
See Takeda Supp. FOF-COL ¶ 35 (quoting FDA review); see also PSC Supp.
FOF-COL ¶ 48.
74
See PSC Supp. FOF-COL ¶ 47, PSC Opp. Ex. 226; Takeda Supp. FOF-COL ¶ 36.
75
See AstraZeneca Supp. Proposed FOF-COL ¶ 18 (citing Nexium Special
Supplement CBE, copy attached as Hindy Cert. I, Ex. AA, ECF No. 73-72).
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Although AstraZeneca styled its request as a CBE, it also stated that it did not intend
to implement the proposed label change until after receiving FDA approval.76
In September 2006, FDA approved modification of the Adverse Reactions
section of the Nexium labeling to read as follows:
Postmarketing Reports – There have been spontaneous reports of
adverse events with postmarketing use of esomeprazole. These
reports occurred rarely and are listed below by body system: . . .
Renal and Urinary Disorders: interstitial nephritis.77
No change was proposed by AstraZeneca or made to the Warnings and Precautions
section of the Nexium label.
On July 31, 2006, FDA requested that “interstitial nephritis” be added to the
“postmarketing . . . urogenital system” section of the Prevacid labeling under the
Adverse Reactions section.78 Takeda filed a CBE to that affect, which FDA
approved on June 20, 2007.79 Takeda, like AstraZeneca, did not propose or make

76

See Nexium Special Supplement CBE, copy attached as Hindy Cert. I, Ex. AA;
see also AstraZeneca Preemption Mem. 17-19 and exhibits cited therein.
77
See Letter from Joyce Korvick, M.D., M.P.H., Deputy Dir., Div. of
Gastroenterology Prods., Center for Drug Evaluation and Research, to George A.
Kummeth, Dir., Regulatory Affairs (Sept. 15, 2006), Hindy Cert. I, Ex. DD;
AstraZeneca, Nexium Label (Sept. 15, 2006), Hindy Cert. I, Ex. EE, at 21.
78
See Letter from J. Korvick, FDA to TAP Pharmaceutical Products Inc. (July 31,
2006), copy attached as Anderson Cert. Ex. L, No. 2:17-cv-06124, ECF No. 71-18;
Takeda Bales Undisp. Facts ¶ 19.
79
See Takeda Bales Undisp. Facts ¶ 20; Anderson Cert. Ex. M, No. 2:17-cv-06124,
ECF No. 71-19.
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any change in its 2006 CBE to the Warnings and Precautions section of the Prevacid
labeling.
D. Publication Of Additional Data, The 2011 Citizen’s Petition, And
The 2014 Amendment Of The Warnings and Precautions Section
Of PPI Labels To Include “Acute Interstitial Nephritis”
Additional data continued to be generated concerning post-marketing kidney
related adverse events in patients taking PPIs. A May 2006 Geevasinga article was
submitted to FDA in May 2007 in AstraZeneca’s annual Periodic Safety Update
Report (“PSUR”) for Nexium’s racemate omeprazole (Prilosec) for the period April
2006-April 2007.80 The 2006 Geevasinga article was a retrospective case review
that found 18 cases of biopsy-proven, PPI-induced acute renal failure. The authors
observed that while “[m]ost patients diagnosed with AIN recover renal function . . .
some patients retain a degree of renal impairment, and some even progress to endstage chronic kidney disease (CKD).”81

Additionally, an article by Simpson

published on September 29, 2006 was a case series of 15 cases in New Zealand,
many of which involved asymptomatic patients subsequently diagnosed with AIN,

80

See PSC Supp. FOF-COL ¶¶ 53-54 (citing PSC Opp. Ex. 37, 357-60), Ex. 37
(AstraZeneca Periodic Safety Update, 23 May 2007, AZ-KID-01735387); Takeda
Supp. FOF-COL ¶ 4 (stating that “FDA was informed of and addressed Geevasinga
(2006) in conjunction with Simpson in 2014 and 2018.”). The article, which was
published in May 2006, is N. Geevasinga, et al., “Proton Pump Inhibitors and Acute
Interstitial Nephritis,” Clinical Gastroenterology and Hepatology 2006; 4: 597-604,
copy available at https://pubmed.ncbi.nlm.nih.gov/16630752/ (last visited July 31,
2022) (“Geevasinga (2006)”).
81
PSC Supp. FOF-COL ¶ 51 (quoting Geevasinga (2006)), PSC Opp. Ex. 35).
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some of whom did not recover complete renal function.82 The 2006 Simpson article
was also included in AstraZeneca’s PSUR for omeprazole in May 2007.83
AstraZeneca’s PSUR for Nexium (esomeprazole) itself for the March 2006-March
2007 period did not report either the 2006 Geevasinga or Simpson articles.84 Nor
were the articles discussed in the relevant Prevacid (lansoprazole) PSUR submitted
in June 2006 and December 2006 by Takeda.85
In 2011, Public Citizen filed a Citizen’s Petition with FDA requesting, among
other things, that PPI labels be amended to reflect the literature associating PPIs with
AIN, as well as a review by FDA of the issue.86 The Citizen’s Petition referred to
literature published over the past several years and requested that PPI labels be
amended on a class basis to reflect the risk of AIN:
Acute interstitial nephritis: Information regarding the potential for
drug-induced acute interstitial nephritis, seen in at least 60 case
reports, should be included in the appropriate section.87

82

PSC Supp. FOF-COL ¶ 52 (citing Simpson et al., Proton Pump Inhibitors and
Acute Interstitial Nephritis, Nephrology 2006; 11, 381-85, PSC Opp. Ex. 36).
83
See PSC Supp. FOF-COL ¶¶ 53-54 (citing PSC Opp. Ex. 37, 357-60), Ex. 37
(AstraZeneca Periodic Safety Update, 23 May 2007, AZ-KID-01735387); Takeda
Supp. FOF-COL ¶ 4 (stating that “FDA was informed of and addressed Geevasinga
(2006) in conjunction with Simpson in 2014 and 2018.”)
84
See PSC Supp. FOF-COL ¶ 54, Ex. 357-58.
85
See PSC Supp. FOF-COL ¶ 54, Ex. 359-60.
86
AstraZeneca Rieder Preemption Mem. 20; Citizen’s Pet. from Eric Nellis,
Researcher, Public Citizen’s Health Research Group et al., to Margaret A. Hamburg,
M.D., Comm’r, FDA (Aug. 23, 2011) (“Citizen’s Petition”) 15-16, Hindy Cert. I,
Ex. FF, ECF No. 73-37.
87
Citizen’s Petition 3; see also Citizen’s Petition 15-16.
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In support of this request, the Citizen’s Petition focused on the potential for severe
and possibly permanent injury resulting from PPI-induced AIN. It stated that
one-third of the subjects required corticosteroid therapy, and three
patients required dialysis, with one remaining on dialysis
permanently. Thus, the potential for severe sequelae following AIN
[ATIN] possibly induced by PPI use necessitates proper alerting of
patients and provider to this serious adverse effect.88
After evaluating the relevant literature and data, FDA’s Center for Drug
Evaluation and Research (“CDER”) similarly concluded that
Untreated drug associated AIN may cause acute renal insufficiency
or failure. Treatment of drug induced AIN requires identifying and
discontinuing the offending agent. Severe cases may require
treatment with steroids or dialysis.89
Thus, CDER concluded “increased patient and healthcare provider awareness of
AIN with PPIs use may facilitate more rapid diagnosis and management of this
serious but potentially reversible condition.”90
Thereafter, in October 2014, FDA issued a Safety Labeling Change
Notification requiring amendment of the Warnings and Precautions sections of all
PPI labels to warn of AIN risk.91 The new language required by FDA in the

88

Citizen’s Petition 15.
Mem. from Joyce Korvick, M.D., M.P.H. to Emily C. Helms Williams version
dated Sept. 26, 2014 (“2014 CDER Review”) 22-23 (PSC Supp. Opp. Ex. 376).
90
2014 CDER Review 22.
91
Letter from Joyce Korvick, M.D., M.P.H. to Takeda Pharmaceuticals dated Oct.
30, 2014, copy attached at No. 2:17-cv-06124, ECF No. 71-23; Letter from Joyce
Korvick, M.D., M.P.H. to AstraZeneca LP dated Oct. 30, 2014, copy attached as
PSC Opp. Ex. Hindy Cert. Ex. 242. See also PSC Supp. FOF-COL ¶ 12 (citing
22
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Warnings and Precautions section of the labeling implemented by AstraZeneca and
Takeda (and other PPI manufacturers) read:
Acute interstitial nephritis has been observed in patients taking PPIs
including [PPI] Acute interstitial nephritis may occur at any time
during PPI therapy and is generally attributed to an idiopathic
hypersensitivity reaction. Discontinue [PPI]if acute interstitial
nephritis develops.92
E. FDA Review Of Additional, Subsequent Literature And Other
Information Regarding Potential Renal Injury From PPI Use And
The 2020 PPI Class Label Amendment
Additional studies and reports continued to be published after the 2014 label
change regarding kidney-related adverse events occurring in patients taking PPIs.93
These included a 2015 Antoniou population-based cohort study of 290,592
individuals that showed a more than two-fold risk of hospitalization for acute kidney
injury in patients taking PPIs compared to non-users, and a three-fold risk for AIN
in PPI users compared to non-users.94 They also included 2016 studies by Lazarus

Takeda Defendants’ Statements of Fact and Plaintiffs’ Responses to Takeda’s
Statements of Fact ¶¶ 17-19, AstraZeneca Defendants’ Statements of Fact and
Plaintiffs’ Responses to AstraZeneca’s Statements of Fact ¶¶ 35-36); AstraZeneca
Rieder Preemption Mem. 21 (regarding class label requirement for Warnings and
Precautions section of label).
92
See AstraZeneca Rieder Preemption Mem. 21 (citing AstraZeneca, Nexium Label
(Dec. 19, 2014); Hindy Cert. I, Ex. II, § 5.3, ECF No. 73-40).
93
See PSC Supp. FOF-COL ¶¶ 72-77 (citing studies attached as exhibits to PSC
Opp.).
94
See PSC Supp. FOF-COL ¶ 72 & PSC Opp. Ex 48 (T. Antoniou et al., “Proton
Pump Inhibitors and the Risk of Acute Kidney Injury in Older Patients: A
Population-Based Cohort Study,” CMAJ Open 3, no. 2 (Apr. 16, 2005)).
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and Xie that found an increased risk of CKD associated with PPI use.95 Multiple
additional reports were published after 2016 through 2020.96
In response to these newly published data, starting in 2016 FDA identified a
potential safety signal for CKD, and requested its Division of Epidemiology I
(“DEPI”) to prepare memoranda addressing the studies.97 Thereafter, FDA opened
a Tracked Safety Issue (“TSI”) in April 2017 to consider CKD and AKI in
connection with PPI use.98 FDA’s DEPI continued to study the issue and ultimately
identified three potential options for FDA action: (1) requiring additional evidence
before changing FDA labels for PPI class drugs; (2) adding CKD as a discrete
adverse reaction to the Warnings and Precautions section of labels for PPI class
drugs; and (3) clarifying information about AIN in the Warnings and Precautions
section of PPI class drug labels.99

95

See PSC Supp. FOF-COL ¶¶ 74-75; see also PSC Opp. Exs. 49 (Benjamin Lazarus
et al., “Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease,” JAMA
Internal Medicine 176, no. 2 (Feb. 1, 2016): 238), 50 (Yan Xie et al., “Proton Pump
Inhibitors and Risk of Incident CKD and Progression to ESRD,” Journal of the
American Society of Nephrology 27, no. 10 (Oct. 2016): 3153-63).
96
See PSC Supp. FOF-COL ¶¶ 76-77; AstraZeneca Supp. FOF-COL ¶ 41 (noting
FDA Division of Epidemiology I review of 12 articles, published in 2016 or later,
and other studies regarding PPIs and kidney disease).
97
See AstraZeneca Supp. FOF-COL ¶¶ 29-37; PSC Supp. FOF-COL ¶¶ 79-82.
98
See AstraZeneca Supp. FOF-COL ¶¶ 38, 40.
99
See AstraZeneca Supp. FOF-COL ¶¶ 44-48.
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On June 18, 2020, FDA proposed a class labeling change for all PPIs,
including Nexium and Prevacid, regarding tubulointerstitial nephritis (“TIN”).100
FDA proposed the following PPI class labeling language (“2020 Proposed PPI Class
Labeling Revision”):
Tubulointerstitial nephritis (TIN) has been observed in patients
taking PPIs and may occur at any point during PPI therapy.
Presentation ranges from symptomatic acute hypersensitivity
reactions to an asymptomatic gradual reduction in glomerular
filtration rate. In reported case series, TIN was diagnosed on biopsy
and in the absence of extra-renal manifestations of systemic
inflammatory symptoms up to two years after the start of PPI
therapy.
Discontinue [PPI] and evaluate patients with an unexplained
decrease in glomerular filtration rate for TIN. Discontinue PPIs in
patients with prior history of PPI-induced TIN.101
Takeda was willing to accept the revision as drafted by FDA.102 AstraZeneca,
however, expressed its disagreement with certain aspects of the language proposed
by the FDA and proposed alternative language.103

100

See AstraZeneca Rieder Preemption Mem. 27; FDA Safety Labeling Change
Notification from Joyce A. Korvick, M.D., M.P.H., Deputy Dir. For Safety, to
Emery Gigger, Regulatory Affairs Dir. (June 18, 2020), copy attached as Hindy Cert.
I, Ex. TT, ECF No. 73-52.
101
See AstraZeneca Rieder Preemption Mem. 27; FDA Safety Labeling Change
Notification from Joyce A. Korvick, M.D., M.P.H., Deputy Dir. For Safety, to
Emery Gigger, Regulatory Affairs Dir. (June 18, 2020), copy attached as Hindy Cert.
I, Ex. TT, ECF No. 73-52; see also PSC Supp. FOF-COL ¶ 83.
102
See Takeda Supp. FOF-COL ¶ 67.
103
AstraZeneca Supp. FOF-COL ¶ 61 (citing AstraZeneca response to FDA safety
labeling change notification (Oct. 14, 2020), copy attached as PSC Opp. Ex. 90).
25

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By letter dated November 27, 2020, FDA approved the following Warnings
and Precautions language addition to Nexium labeling (“November 2020
Warning”):
Acute tubulointerstitial nephritis (TIN) has been observed in patients
taking PPIs and may occur at any point during PPI therapy. Patients
may present with varying signs and symptoms from symptomatic
hypersensitivity reactions to non-specific symptoms of decreased
renal function (e.g., malaise, nausea, anorexia). In reported case
series, some patients were diagnosed on biopsy and in the absence of
extra-renal manifestations (e.g., fever, rash or arthralgia).
Discontinue NEXIUM with suspected acute TIN.104
Notably, the warning ultimately approved by FDA accepted AstraZeneca’s proposal
to insert “acute” before “tubulointerstitial nephritis” and eliminated reference to “an
asymptomatic gradual reduction in glomerular filtration rate” and “reported case
series indicating that TIN was diagnosed on biopsy and in the absence of extra-renal
manifestations of systemic inflammatory symptoms up to two years after the start of
PPI therapy.”
Although Takeda had indicated its willingness to accept FDA’s original
proposed language, because FDA accepted AstraZeneca’s proposed changes to the
proposed PPI class label amendment, FDA directed Takeda to modify its Prevacid
label to include the PPI drug class warning reflecting AstraZeneca’s changes:

104

AstraZeneca Supp. FOF-COL ¶ 62; FDA Supp. Approval from Joyce A. Korvick,
M.D., M.P.H, Deputy Dir. Of Safety, to Emery Gigger, Regulatory Affairs (Nov.
27, 2020) at 10, Hindy Cert. I, Ex. VV, ECF No. 73-54.
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Acute tubulointerstitial nephritis (TIN) has been observed in patients
taking PPIs and may occur at any point during PPI therapy. Patients
may present with varying signs and symptoms from symptomatic
hypersensitivity reactions to non-specific symptoms of decreased
renal function (e.g., malaise, nausea, anorexia). In reported case
series, some patients were diagnosed on biopsy and in the absence of
extra-renal manifestations (e.g., fever, rash or arthralgia).
Discontinue PREVACID with suspected acute TIN.105
V.

GOVERNING LEGAL STANDARDS
A. Preemption
The Supremacy Clause of the United States Constitution provides:
This Constitution, and the Laws of the United States which shall be
made in Pursuance thereof; and all Treaties made, or which shall be
made, under the Authority of the United States, shall be 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.106

Under the Supremacy Clause, “[w]here state and federal law ‘directly conflict,’ state
law must give way.”107 The “directly conflict” standard is a demanding one, rooted
in the Tenth Amendment’s preservation of the States’ historic police powers unless
superseded by a lawful act of Congress.108

105

See Takeda Bales Undisp. Facts ¶¶ 59-60; see also Email dated Nov. 9, 2020 from
J. Lee, FDA to K. Shah, Takeda with final Warning language, copy attached as
Anderson Cert. Ex. EE, No. 2:17-cv-06124, ECF No. 71-38.
106
U.S. Const., Art. VI, cl. 2.
107
PLIVA, Inc. v. Mensing, 564 U.S. 604, 617 (2011).
108
Merck v. Albrecht, 139 S. Ct. at 1677 (citing Wyeth v. Levine, 555 U.S. at 565).
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Merck v. Albrecht and Wyeth v. Levine are the leading Supreme Court cases
addressing the issue of whether and, if so, when FDA’s actions under the FDCA
preempt state laws requiring a warning beyond that contained in the FDA-approved
prescription drug label. In those cases, the Supreme Court recognized that, in
enacting the FDCA, Congress did not seek to occupy the field and expressly preempt
all state laws addressing pharmaceutical safety, including through product liability
lawsuits. To the contrary: as the Supreme Court recognized, Congress expressed
“reluctance to displace state laws that would penalize drug manufacturers for failing
to warn consumers of the risks associated with their drugs.”109 Indeed, Congress
specifically rejected an express preemption provision with respect to federal drug
regulation.
Congress took care to preserve state law. The 1962 amendments
added a saving clause, indicating that a provision of state law would
only be invalidated upon a “direct and positive conflict” with the
FDCA. . . . Consistent with that provision, state common-law suits
“continued unabated despite . . . FDA regulation.” Riegel v.
Medtronic, Inc. (2008) (Ginsburg, J., dissenting); see ibid., n 11
(collecting state cases). And when Congress enacted an express preemption provision for medical devices in 1976, see § 2, 90 Stat. 574
(codified at 21 U.S.C. § 360k(a)), it declined to enact such a
provision for prescription drugs.110
Thus, the Supreme Court has held that Congress contemplated a role for both
federal and state governments in regulating drug safety:

109
110

Merck v. Albrecht, 139 S. Ct. at 1677.
Wyeth v. Levine, 555 U.S. at 567; see also Merck v. Albrecht, 139 S. Ct. at 1677.
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[W]e concluded that Congress enacted the FDCA “to bolster
consumer protection against harmful products;” that Congress
provided no “federal remedy for consumers harmed by unsafe or
ineffective drugs”; that Congress was “awar[e] of the prevalence of
state tort litigation;” and that, whether Congress’ general purpose
was to protect consumers, to provide safety-related incentives to
manufacturers, or both, language, history, and purpose all indicate
that “Congress did not intend FDA oversight to be the exclusive
means of ensuring drug safety and effectiveness.111
The Supreme Court went on to observe that “[i]f Congress thought state-law suits
posed an obstacle to its objectives, it surely would have enacted an express preemption provision at some point during the FDCA’s 70-year history.”112 Congress
never has done so.
In light of the clear “language, history, and purpose” of the FDCA, and the
absence of an express preemption provision, the Supreme Court has been willing to
find implied preemption of state laws regarding drug safety only in very narrow
circumstances.113 In Wyeth v. Levine, the Supreme Court held, and reiterated
subsequently in Merck v. Albrecht, that federal preemption of a state law failure to
warn claim could only be established if “‘it was impossible for [the manufacturer]
to comply with both federal and state requirements.’”114 The question is “whether

111

Merck v. Albrecht, 139 S. Ct. at 1677 (citing Wyeth v. Levine, 555 U.S. at 574-75
(emphasis added)).
112
Merck v. Albrecht, 139 S. Ct. at 1677 (quoting Wyeth v. Levine, 555 U.S. at 574).
113
Merck v. Albrecht, 139 S. Ct. at 1677 (citing Wyeth v. Levine, 555 U.S. at 57475).
114
Merck v. Albrecht, 139 S. Ct. at 1678 (quoting Wyeth v. Levine, 555 U.S. at 571).
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the relevant federal and state laws ‘irreconcilably conflic[t].’”115 The manufacturer
defendant asserting the preemption defense bears the burden of establishing its
validity.116
As it reiterated in Merck v. Albrecht, in Wyeth v. Levine the Supreme Court
“acknowledged that meeting the standard we set forth would be difficult, but, we
said, ‘[i]mpossibility pre-emption is a demanding defense.’”117 Indeed, even though
the Supreme Court recognized in Wyeth v. Levine the legal principle that a state
failure to warn claim in a pharmaceutical product liability case could be preempted,
the Supreme Court held that the state law claim in that particular case was not
preempted because the manufacturer in that case could have changed the labeling of
its drug to add a stronger warning.118
The “demanding” nature of the “impossibility preemption” defense for a
manufacturer is due to two factors. First, “through many amendments to the FDCA
and to FDA regulations, it has remained a central premise of federal drug regulation
that the manufacturer bears responsibility for the content of its label at all times.”119

115

Merck v. Albrecht, 139 S. Ct. at 1679 (citing Rice v. Norman Williams Co., 458
U.S. 654, 659 (1982)).
116
See Wyeth v. Levine, 555 U.S. at 571; Merck v. Albrecht, 139 S. Ct. at 1678.
117
Merck v. Albrecht, 139 S. Ct. at 1678 (quoting Wyeth v. Levine, 555 U.S. at 572).
118
See Wyeth v. Levine, 555 U.S. at 558, 581.
119
Merck v. Albrecht, 139 S. Ct. at 1677 (citing Wyeth v. Levine, 555 U.S. at 57071); see also Wyeth v. Levine, 555 U.S. at 568 (noting that in connection with 2007
FDCA amendments Congress rejected a provision that would have required FDA to
preapprove all changes to drug labels and “adopted a rule of construction to make it
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Second, FDA’s CBE regulation permits branded drug manufacturers unilaterally to
change a label without prior FDA approval to “reflect newly acquired information”
if the changes “add or strengthen a . . . warning” for which there is “evidence of a
causal association.”120 Even though FDA reviews CBE changes and may ultimately
reject them after publication, “in the interim, the CBE regulation permits changes,
so a drug manufacturer will not ordinarily be able to show that there is an actual
conflict between state and federal law such that it was impossible to comply with
both.”121

clear that manufacturers remain responsible for updating their labels.”).
120
21 U.S.C. § 314.70(c)(6)(iii)(A); see also Wyeth v. Levine, 555 U.S. at 573 (“The
CBE regulation permitted Wyeth to unilaterally strengthen its warning, and the mere
fact that the FDA approved Phenergan’s label does not establish that it would have
prohibited such a change.”).
121
Merck v. Albrecht, 139 S. Ct. at 1679. In light of my experience in pharmaceutical
regulation, I recognize that, in practice, manufacturers infrequently seek to exercise
unilateral authority to change a drug label by CBE. Rather, because the standard for
changing a label by CBE or a PAS amendment is the same, and to avoid any risk of
needless expense and confusion in the event FDA were to reject a CBE label change
after implementation, manufacturers typically seek FDA approval before making
any label change. Indeed, as explained above, that is what happened in 2006, when
AstraZeneca informed FDA that it intended to amend the Nexium label to add
interstitial nephritis as an Adverse Event – but also informed FDA that the change
would not be implemented prior to FDA approval. However, notwithstanding
industry practice, the Supreme Court’s preemption opinions make clear that the
significance of FDA’s CBE regulation is that as a matter of law, it permits a branded
drug manufacturer unilaterally to amend a label where the regulation’s prerequisites
for amendment are satisfied. See Merck v. Albrecht, 139 S. Ct. at 1678; PLIVA, Inc.
v. Mensing, 564 U.S. at 625 n.8 (stating that “[t]he question for ‘impossibility’ is
whether the private party could independently do under federal law what state law
requires of it” (citing Wyeth v. Levine, and finding preemption where FDA’s CBE
regulation did not apply to generic drug manufacturers)); Wyeth v. Levine, 555 U.S.
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While FDA’s CBE regulation poses a substantial hurdle to a manufacturer
seeking to invoke “impossibility” conflict preemption, federal courts have not found
that hurdle insurmountable. Indeed, just a few months ago, within this circuit and
this district, the court found on remand from the Supreme Court’s decision in Merck
v. Albrecht that a state law failure to warn claim was preempted.122
To establish such impossibility, a manufacturer must provide “clear evidence
that the FDA would not have approved a change to [the] label.”123 “Clear evidence”
is “evidence that shows the court that the drug manufacturer fully informed the FDA
of the justifications for the warning required by state law and that the FDA, in turn,
informed the drug manufacturer that the FDA would not approve a change to the
drug’s label to include that warning.”124

The determination whether “clear

evidence” has been provided is a legal determination to be made by the court.125
B. Summary Judgment Standard On Preemption Motions
In seeking summary judgment under Fed. R. Civ. P. 56, moving parties
AstraZeneca and Takeda each bear the burden of stating the basis for their motion
and “identifying those portions of the record that demonstrate the absence of a

at 571-73.
122
See Fosamax., 2022 U.S. Dist. LEXIS 52627, at *35, *143-45.
123
Wyeth v. Levine, 555 U.S. at 571; see also Merck v. Albrecht, 139 S. Ct. at 1678.
124
Merck v. Albrecht, 139 S. Ct. at 1672.
125
Id. at 1672, 1679.
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genuine issue of material fact.”126 If the moving party meets its burden, the party
opposing summary judgment “must set forth specific facts showing that there is a
genuine issue for trial” and “may not rest upon the mere allegations or denials” of
the pleading.127 The evidence of the nonmovant is to be trusted and all inferences
shall be drawn in his favor.128 Moreover, the nonmovant “must identify specific
facts and affirmative evidence that contradict those offered by the moving party.”129
These familiar summary judgment standards must be applied taking into
account the Supreme Court’s holding in Merck v. Albrecht that “the question of preemption is one for a judge to decide, not a jury.”130 The Supreme Court explained
that it reached this holding because
The question often involves the use of legal skills to determine
whether agency disapproval fits facts that are not in dispute.
Moreover, judges, rather than lay juries, are better equipped to
evaluate the nature and scope of an agency’s determination.131
Even while characterizing preemption as predominantly a legal question, the
Court also recognized that “sometimes contested brute facts will prove relevant to a

126

Alley v. MTD Prods. Inc., 2017 U.S. Dist. LEXIS 208742 (W.D. Pa. Dec. 20,
2017).
127
Saldana v. Kmart Corp., 260 F.3d 228, 232 (3d Cir. 2001).
128
Anderson v. Liberty Lobby, Inc., 477 U.S. 242, 249 (1986) (quoting Adickes v.
S.H. Kress & Co., 398 U.S. 144 (1970)).
129
Solomon v. Bristol-Myers Squibb Co., 916 F. Supp. 2d 556 (D.N.J. 2013) (quoting
Anderson v. Liberty Lobby, Inc., 477 U.S. at 256-57).
130
Merck v. Albrecht, 139 S. Ct. at 1672; see also Merck v. Albrecht, 139 S. Ct. at
1676.
131
Id. at 1679-80.
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court’s legal determination about the meaning and effect of an agency decision.”132
In particular, it recognized that “in litigation between a drug consumer and a drug
manufacturer (which will ordinarily lack an official administrative record for an
FDA decision), the litigants may dispute whether the drug manufacturer submitted
all material information to the FDA.”133 Nevertheless, the Court “consider[ed] these
factual questions to be subsumed within an already tightly circumscribed legal
analysis” and that the court, rather than a jury, was better positioned to “‘resolve
subsidiary factual disputes’ that are part and parcel of the broader legal question.”134
Thus, the Supreme Court’s decision in Merck v. Albrecht modifies the normal
summary judgment standard with respect to preemption motions. In deciding such
motions the court, rather than the jury, is authorized to resolve “subsidiary factual
disputes” to the extent necessary in connection with resolving the “broader legal
question” of whether it would have been impossible for the manufacture to modify
label warnings because there is clear evidence that FDA, after being fully informed
of “all material information,” would have rejected the change.135 Accordingly, this
R&R applies the Merck v. Albrecht principle in addressing the motions.

132

Id. at 1680.
Id.
134
Id., quoting Teva Pharmaceuticals USA, Inc. v. Sandoz, Inc., 574 U.S. 318, 327,
(2015).
135
See Merck v. Albrecht, 139 S. Ct. at 1680.
34
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VI.

ANALYSIS
A. The Relevance Of Timing To Preemption Analysis
There is no dispute that Defendants could have unilaterally amended their

labels by the CBE process to add a warning if (1) “newly acquired information”
established “reasonable evidence of a causal association” between a reported kidney
injury adverse event and PPI use and (2) FDA, after having been fully informed of
the justification for the warning, would not have prohibited or invalidated such a
label change.136
B. Defendants’ Argument That There Is No Preemption Because No
“Newly Acquired Evidence” Regarding “Chronic Kidney Disease”
Existed At The Time When Plaintiffs Consumed PPIs And
Developed Chronic Kidney Disease
Defendants mount a threshold challenge to the assertion of failure to warn
claims by Plaintiffs. Defendants’ position is that during the period when Plaintiffs
took PPIs and prior to their diagnoses of chronic kidney disease (“CKD”), there was

136

See supra § V.A. I note that the hypothetical “would not have prohibited”
standard articulated in Wyeth v. Levine remains the standard after Merck v. Albrecht.
That is, to assert a preemption defense, a manufacturer is not required actually to
have sought a label change and had the FDA reject it. See In re Avandia Marketing,
Sales and Prod. Liab. Litig., 945 F.3d 749, 759 (3d Cir. 2019); see also Fosamax,
2022 U.S. Dist. LEXIS 52627, at *67-68 (collecting cases and finding that “the
‘universal’ standard that a manufacturer need not submit a PAS and CBE to the FDA
to preserve its preemption defense remains intact after [Merck v. Albrecht].”), *8485 (manufacturer has no obligation to pursue a CBE amendment to preserve a
preemption defense).
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no scientific evidence that would have supported a warning regarding CKD. There
are several elements to Defendants’ argument:
First, Defendants assert that both Plaintiff Rieder and Plaintiff Bales
(and others) were diagnosed with CKD (but not AIN) and allege that their
consumption of PPIs was a cause of the CKD injury.137
Second, Defendants note that Plaintiffs Rieder and Bales started using
PPIs in 2002 and 2005 respectively, and that both Mr. Rieder and Mr. Bales
ceased using PPIs and were diagnosed with CKD prior to 2016; they make
similar arguments with respect to other Plaintiffs.138
Third, Defendants quote a statement by Plaintiffs’ expert Dr. Ross in
his report that “[i]n 2016, Lazarus et al, was the first group of scientists to
report on the association between PPI and CKD.”139
Fourth, Defendants note that in 2020 FDA, after its TSI considering
Lazarus and other studies, decided not to require a CKD warning.140

137

See AstraZeneca Rieder Preemption Mem. 4, 8; Takeda Bales Preemption Mem.
1-4. (The AstraZeneca Rieder Preemption Mem. addresses the points discussed in
this paragraph with respect to both Plaintiffs Rieder and Bales.)
138
AstraZeneca Rieder Preemption Mem. 4, 8; Takeda Bales Preemption Mem. 1-4.
139
See AstraZeneca Rieder Preemption Mem. 22 (citing Expert Report of Dr. David
Ross ¶ 317, No. 2:17-cv-06124, ECF Doc. 75-3 (“Ross Expert Report”)); Takeda
Bales Preemption Mem. 1-2 (citing Takeda Bales Undisp. Facts ¶ 31).
140
See AstraZeneca Rieder Preemption Mem. 21-29; Takeda Bales Preemption
Mem. 9-16.
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Based on this chronology, Defendants argue that there was no information
that could have constituted “newly acquired evidence” to support a label change to
warn of “CKD” during Plaintiffs’ use of PPIs or prior to their diagnoses of CKD.
This argument fails for two related reasons. First, the argument confuses Plaintiffs’
allegations of their ultimate injury from ingestion of PPIs with their claims of failure
to warn. Plaintiff Rieder, Plaintiff Bales, and the Plaintiffs in the other four
Bellwether Trial Cases allege an injury of CKD, but their failure to warn claims are
broader than simply a failure to warn of CKD. Rather, as explained in Section II
above, Plaintiffs’ failure to warn claims are alleged in more general terms. They
allege that “Defendants had a duty to warn Plaintiffs and their healthcare providers
regarding the risks associated with ingesting PPI Products and failed to warn of the
risk of kidney injuries that may be irreversible, permanently disabling and lifethreatening.”141 And the complaints allege that PPIs can cause a variety of severe
kidney injuries, including AIN, AKI, CKD and ESRD. The complaints further
allege that the manufacturers provided inadequate warnings regarding the risk of
kidney injuries.142

141

See Master Complaint ¶¶ 325, 327, 343; see also supra § II; PSC. Stmt. Of
Undisp. Facts ¶¶ 7, 50 (Complaint alleges that labels should have contained
warnings of a risk of “permanent or chronic renal injury” or potential “permanent
and irreversible renal injuries.”); Lee Compl. Count II; Nelson Compl. Count II.
142
See Master Complaint Count III; Lee Compl. Count II; Nelson Compl. Count II.
See also Master Complaint ¶¶ 179-211, 226 (“Consumers, including Plaintiffs, who
have used Defendants’ PPI Products have suffered from severe kidney injuries
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Thus, with respect to kidney injuries, Plaintiffs have not asserted that the
labels needed to warn specifically of “CKD”. Rather, they allege that the labels
should have contained warnings of a risk of “permanent or chronic renal injury” or
potential “permanent and irreversible renal injuries.”143 Plaintiffs contend that, had
such warnings been provided, their physicians would have been on notice of the risk
and either chosen not to prescribe the PPI or arranged careful monitoring to detect
any renal injury before it became irreversible and progressed to CKD.144 It is
undisputed that, during the time Plaintiffs used the PPIs at issue, the drug labels did
not contain such warnings.145 Plaintiffs also note, correctly, that a plaintiff asserting
a failure to warn claim is not required to propose specific wording that should have
been included in the label; rather, it is sufficient to describe the deficiencies in the
existing warning in the labeling.146

including, but not limited to, AIN, AKI, CKD and ESRD.”).
143
PSC. Stmt. Of Undisp. Facts ¶¶ 7, 50; see also Oral Args. 40:6-12, Apr. 5, 2022
(Mr. Autry: “There were no warnings in Takeda’s label at the time about any
possible harm to Bales’ kidneys, zero, at the time that Bales took Prevacid. Dr.
Fowler said that if he had known about the risk of kidney injuries, he would not have
recommended PPIs to Mr. Bales.”); Oral Args. 42:8-43:13, Apr. 5, 2022.
144
See supra § II.
145
See supra § IV.
146
See PSC’s Brief Opposing Defendants’ Motions For Summary Judgment on
Failure-to-Warn Preemption 11 (citing Wyeth v. Levine, 555 U.S. at 565 (“We
therefore need not decide whether a state rule proscribing intravenous administration
would be pre-empted. The narrower question presented is whether federal law preempts Levine’s claim that Phenergan's label did not contain an adequate warning
about using the IV-push method of administration.”)).
Takeda’s contrary argument in its supplemental briefing that warnings about
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Second, as explained more fully in my R&R regarding the Daubert motions,
Defendants’ argument takes Dr. Ross’s statement regarding the Lazarus study
completely out of context.147 Dr. Ross’s report contains a lengthy and detailed
review of scientific publications, clinical trial data, and post-marketing adverse event
data linking PPI use with both acute tubulointerstitial nephritis (AIN) and chronic
tubulointerstitial nephritis (CTIN).148 Based upon these data, Dr. Ross concluded
that “[t]he connection between acute and chronic injury in the tubulointerstitium is
grounded in the understanding that interstitial nephritis constitutes ‘a final common
pathway to all forms of end-stage renal disease.’”149 He further concluded that the
risk that PPI use could have an adverse effect on the kidneys was known to

the risk of injuries from PPIs other than the CKD with which Plaintiffs have been
diagnosed are “beyond the scope of this case and irrelevant to the preemption
question” fails because it relies on purported authority that is plainly inapposite. See
Takeda Supp. FOF-COL ¶ 24 (citing Amorgianos v. Nat’l R.R. Passenger Corp.,
137 F. Supp.2d 147, 163 (E.D.N.Y. 2001); Peterson v. Sealed Air Corp., No. 86 C
3498, 1991 WL 66370, at *7 (N.D. Ill. Apr. 23, 1991)). Those out-of-circuit district
court cases both predate Wyeth v. Levine and Merck v. Albrecht and have nothing to
do with preemption. Rather, they are cases applying Federal Rule of Evidence 702
as interpreted by the Supreme Court in Daubert v. Merrell Dow Pharmaceuticals,
Inc., 509 U.S. 579 (1993), and stand only for the unrelated proposition that expert
testimony in a product liability case regarding a potential harm that plaintiff does not
claim to have suffered does not fit the facts of the case and is not admissible in
evidence because it will not assist the jury in deciding the case.
147
See Report and Recommendation of Special Master Ellen K. Reisman Regarding
Daubert Motions 58-59, No. 2:17-md-2789, ECF No. 811; Ross Expert Report 9498.
148
Ross Expert Report 98-248.
149
Ross Expert Report 270 (quoting Neilson, “Pathogenesis and Therapy of
Interstitial Nephritis”, Kidney International, Vol. 35 (1989) 1257).
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AstraZeneca and Takeda by the late 1990s and that “the threshold of reasonable
evidence of a causal association between PPI use and chronic, progressive renal
toxicity was crossed by early 2003.”150 Failure to warn of this risk, in Dr. Ross’s
view, resulted in the lack of monitoring and treatment of PPI users so that renal
injury caused by PPI use would go undetected until it had progressed to CKD.151 In
his expert report, Dr. Ross opines that, well before 2016 and during the periods of
Plaintiffs’ PPI use, Defendants were on notice of an association between AIN and
PPI use and of an association between CTIN and PPI use, and that they should have
warned physicians and the public of these associations because, among other things,
these conditions can lead to CKD.152
Accordingly, it is necessary to consider that earlier information, including
information regarding adverse events of AIN, CTIN, and other renal injuries, that
was published after the initial FDA approvals of Nexium and Prevacid, to determine
whether it constituted “newly acquired evidence” sufficient to support a CBE
amendment providing the more general warnings of kidney injury that Plaintiffs
allege should have been included on the labels.

150

Ross Expert Report 271-72.
Ross Expert Report 272-74.
152
Ross Expert Report 12, 94-250.
151

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C. Whether FDA’s PPI Labeling Decisions Are “Clear Evidence”
That It Would Have Rejected A Kidney Injury Risk Warning If
Defendants Had Sought To Provide One
The undisputed facts clearly reflect that after FDA’s approval of Prevacid in
1995 and Nexium in 2001, there was “newly acquired information” about evidence
of a causal association between PPIs and kidney injury, including AIN and its
sequelae. As noted above, “newly acquired information” includes
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.153
The various 2003-2005 studies discussed in Section IV.C, above, amply satisfy that
definition. AstraZeneca’s submission of a CBE in March 2006 to amend the
Adverse Reactions section of the label in reliance on Geevasinga (2005) and other
information, and the 2005 FDA Office of Safety and Epidemiology review discussed
previously, further confirm that there was “newly acquired information.”
AstraZeneca’s submission of a CBE to amend the Adverse Reactions section
of the Nexium label based on the “newly acquired information” necessarily reflects
its conclusion that there was “some basis to believe there is a causal relationship
between the drug and the occurrence of the adverse event.”154 Thus, the only

153
154

21 C.F.R. § 314.3(b); see also Wyeth v. Levine, 555 U.S. at 569.
21 C.F.R. § 201.57(c)(7).
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question is whether the newly acquired evidence also satisfied the somewhat more
rigorous “reasonable evidence of a causal association” standard for a change to the
Warnings and Precautions section of the labels.155
A fair reading of the 2003-2005 studies suggests that this “newly acquired
evidence” could satisfy the “reasonable evidence of a causal association” standard
for amending the Warnings and Precautions sections of the Nexium and Prevacid
labels. In particular, the 2004 Torpey case series of 296 patients found an association
between AIN and PPIs omeprazole and lansoprazole in one-third of the cases, noted
that many patients stabilized after withdrawal of PPI, and that many patients did not
present with traditional symptoms of AIN.156

155

As discussed in Section III, supra, the Warnings and Precautions section of a
label must describe “clinically significant adverse reactions, (including any that are
potentially fatal, are serious even if infrequent, or can be prevented or mitigated
through appropriate use of the drug), other potential safety hazards (including those
that are expected for the pharmacological class . . .), limitations on use imposed by
them (e.g., avoiding certain concomitant therapy), and steps that should be taken if
they occur (e.g., dosage modification).” 21 C.F.R. § 201.57(c)(6)(i).
156
See PSC Supp. FOF-COL ¶ 43, PSC Opp. Ex. 31 (N. Torpey, T. Barker, and C.
Ross, “Drug-Induced Tubulo-Interstitial Nephritis Secondary to Proton Pump
Inhibitors: Experience from a Single UK Renal Unit,” Nephrology Dialysis
Transplantation 19, no. 6 (June 1, 2004): 1441-46); AstraZeneca’s Response To PSC
FOF-COL App. A at 3 (noting FDA awareness of Torpey, which is cited in 2005
Postmarketing Safety Review, Hindy Cert. I, Ex. CC, at 2, ECF No. 73-34); Takeda
Supp. FOF-COL ¶ 33 (noting reference to Torpey in 2005 Takeda Prevacid Annual
Report submission to FDA).
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Moreover, and significantly, the studies included “dechallenge-rechallenge”
case reports.157 A “dechallenge-rechallenge” report is one in which a patient using
a drug who experiences adverse symptoms discontinues the drug, the symptoms
resolve, and then the patient resumes using the drug and again suffers the adverse
symptoms. As AstraZeneca’s regulatory expert Dr. Marianne Mann has explained,
Rechallenge is simply that the patient presented perhaps with the
AIN improved when the drug was withdraw[n], but that kidney
toxicity recurred when that drug was reintroduced, really making, if
you will, a tighter association between the drug and the event.158
As Dr. Mann also explained, determination of a causal association sufficient to
support adding a warning to the Warnings and Precautions section of a label can be
supported by case reports involving dechallenge and rechallenge.159 In the language
of the applicable regulation, dechallenge-rechallenge reports can support a

157

See PSC Supp. FOF-COL ¶¶ 39-45.
Mann Dep. 157:7-13, PSC Opp. Ex. 21; see also PSC Supp. FOF-COL ¶ 19.
159
Mann Dep. 157:7-13, 35:19-36:11; see also PSC Supp. FOF-COL ¶ 19.
AstraZeneca notes that Dr. Mann’s discussion of the potential significance of a
dechallenge-rechallenge case study came in discussion of the FDA’s 2014 label
amendment, and that she testified that she thought it was “reasonable” for
AstraZeneca to list AIN as an “adverse event” until 2014 because that is what the
“large majority” of manufacturers did. AstraZeneca Resp. to PSC Supp. FOF-COL
7 (citing Mann. Dep. 160:11-161:25, 162:14-16). But that is beside the point for the
preemption analysis. Dr. Mann’s opinion that AstraZeneca’s pre-2014 practice was
“reasonable” does not address the issue whether the available evidence was
sufficient to support a label amendment adding a warning in the Precautions section
if Defendants had sought to do so. And her logic is somewhat circular in that it
assumes the practice of other manufacturers was appropriate – which is precisely
what is at issue in this MDL litigation.
43
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conclusion of “reasonable evidence of causal association” sufficient to support
addition of a warning.160
Indeed,

FDA’s

March

2005

Guidance

for

Industry

on

Good

Pharmacovigilance Practice and Pharmacoepidemiologic Assessment stated that
FDA recommends that sponsors look for features that may suggest a
causal relationship between the use of a product and the adverse
event, including . . . evidence of positive dechallenge or positive
rechallenge.161
And, FDA’s regulation requiring post-marketing pharmacovigilance and adverse
event reporting by manufacturers specifically requires that individual case safety
reports specifically address “(vii) [w]hether adverse drug experience abated after
drug use stopped or dose reduced;” and “(viii) [w]hether adverse drug experience
reappeared after reintroduction of drug.”162
Beyond this “newly acquired evidence,” the 2006 Geevasinga and Simpson
articles provided additional “reasonable evidence of a causal association.”163 Thus,
by no later than 2006 and arguably earlier, there was ample “newly acquired

160

See supra § III.
See
https://www.fda.gov/files/drugs/published/Good-PharmacovigilancePractices-and-Pharmacoepidemiologic-Assessment-March-2005.pdf (last visited
July 31, 2022); see also Ross Expert Report 101.
162
21 C.F.R. §§ 314.80(f)(3)(vii), (viii).
163
See supra § IV.D; PSC Supp. FOF-COL ¶¶ 53-54 (citing PSC Opp. Ex. 37, 357360); Takeda Supp. FOF-COL ¶ 4 (stating that “FDA was informed of and addressed
Geevasinga (2006) in conjunction with Simpson in 2014 and 2018.”)).
44
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evidence” to support a labeling change and certainly no “clear evidence” that FDA
would have rejected one had it been proffered.164
The undisputed facts undermine the Defendants’ position that FDA would
have rejected a proposal to amend the Warnings and Precautions section of PPI
labels to provide additional information about the risk of AIN and its potential
sequelae if they had ever made such a proposal, which they did not. The actual
labeling history shows that FDA approved AstraZeneca’s CBE to amend the
Adverse Events section and required Takeda to make a similar amendment.165 It
also shows that after reviewing the 2011 Citizen’s Petition and materials cited
therein, and having the information in the 2006 Geevasinga and Simpson articles,
along with other information, FDA required – for the first time – a PPI class label
warning of the risk of potential AIN, including a direction to “[d]iscontinue [PPI] if
acute interstitial nephritis develops.”166 As discussed above, the 2014 class label
amendment required the manufacturers of PPIs to include the following language in
the Warnings and Precautions section of the labels:
Acute interstitial nephritis has been observed in patients taking PPIs
including [PPI]. Acute interstitial nephritis may occur at any time
164

See PSC Supp. FOF-COL ¶ 45 & Ex. 32 (Nimeshan Geevasinga et al., “Acute
Interstitial Nephritis Secondary to Esomeprazole,” The Medical Journal of Australia
182, no. 5 (2005): 235-36 (discussing renal failure and ESRD, which can be
downstream consequences of AIN)).
165
See supra § IV.C.
166
See supra § IV.D; AstraZeneca Rieder Preemption Mem. 21 (citing AstraZeneca,
Nexium Label (Dec. 19, 2014), Hindy Cert. I, Ex. II § 5.3, ECF No. 73-40).
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during PPI therapy and is generally attributed to an idiopathic
hypersensitivity reaction. Discontinue [PPI] if acute interstitial
nephritis develops.167
That warning provided some – albeit limited – notice to physicians of kidney
injury risk associated with PPIs. The 2014 label reflects that AIN “may occur at any
time during PPI therapy.” And while it states that AIN “is generally attributed to an
idiopathic hypersensitivity reaction,” it does not say that is the only possible cause,
and it directs discontinuation of the PPI if AIN occurs. Contrary to Defendants’
suggestion, this label change is not “clear evidence” that the FDA would have
rejected a label change with a more robust warning of the risk of kidney injury if the
manufacturers had proposed one during the 2006 to 2014 time frame.
Defendants argue that the language of the 2014 amendment providing an AIN
warning must be read narrowly, to establish the outer limit of what language the
FDA would have permitted had the manufacturer sought to provide it, but that
argument does not withstand scrutiny.168 The 2011 Citizen’s Petition that led to that
amendment referred to literature published over the past several years and requested
only that PPI labels be amended to reflect the risks of AIN:

167

AstraZeneca Rieder Preemption Mem. 21 (citing AstraZeneca, Nexium Label
(Dec. 19, 2014), Hindy Cert. I, Ex. II § 5.3, ECF No. 73-40).
168
See Oral Args. 10:5-11:20, Apr. 5, 2022.
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Acute interstitial nephritis: Information regarding the potential for
drug-induced acute interstitial nephritis, seen in at least 60 case
reports, should be included in the appropriate section.169
Thus, the only request before FDA related to AIN. In the context of the regulatory
history here, FDA’s decision to require a class-wide amendment to PPI labeling to
include language regarding AIN in the Warnings and Precautions section is not
“clear evidence” that FDA would have rejected stronger or additional warnings if
Defendants had sought to provide them in response to the information and literature
developed prior to 2011 and thereafter.170
FDA’s 2020 Proposed PPI Class Labeling Revision would have broadened
the existing Warnings and Precautions language to include “tubulointerstitial
nephritis”, including asymptomatic TIN, and to recommend evaluation of patients
with an unexplained decrease in glomerular filtration rate for TIN. This proposal by
FDA in 2020 to expand significantly the warning language does not support a
conclusion that FDA would have rejected a more robust warning if Defendants had
proposed one at some earlier point in time. To be sure, FDA proposed that label

169

Citizen’s Petition 3; see also Citizen’s Petition 15-16.
Defendants’ observation that both the Citizen’s Petition and the
Pharmacovigilance Analysis performed by FDA’s Center for Drug Evaluation and
Research (“CDER”) noted that AIN had the potential for “severe sequelae”
including permanent kidney injury, does not change this conclusion. See
AstraZeneca Resp. to PSC Supp. FOF-COL 3-4 (citing Citizen Petition and CDER
Report); see also 2014 CDER Review 2, 15. To the contrary, it suggests that FDA
might have been receptive to a CBE seeking a stronger warning.
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change in 2020 after even more data regarding renal adverse events in patients taking
PPIs were available. The point is not that this 2020 proposal proves definitively that
FDA would have permitted the language in the 2020 Proposed PPI Class Labeling
Revision earlier, but rather that it is hardly “clear evidence” that FDA would have
rejected any proposals from the manufacturers to include more detailed information
about the risk of renal injury at an earlier point in time.
Nor is the final FDA-approved 2020 amendment “clear evidence” that FDA
would have rejected a more robust warning had Defendants proposed one earlier.
The final 2020 label included the disclosure that patients could have silent AIN that
“may occur at any point during PPI therapy” and in some cases was only “diagnosed
on biopsy” because of “the absence of extra-renal manifestations (e.g., fever, rash or
arthralgia).”171 The 2020 labeling change disclosed that kidney injury is an ongoing
risk requiring monitoring because it might be asymptomatic. And, since it was well
known that undiagnosed and treated AIN could lead to permanent kidney injury, the
amended 2020 label in effect warned of such injury too.172 Certainly, the language
as revised after AstraZeneca’s objection provided a lesser warning than FDA’s

171

See supra § IV.E.
See PSC Supp. Br. On Preemption 4 nn. 10-11 (Noting literature that TIN
constitutes a final common pathway to all forms of end-stage renal disease and that
TIN can be acute or chronic and that reports indicate that “30-70% of patients with
acute interstitial nephritis did not fully recover renal function”); see also supra
§ IV.D.
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original proposed language. But it is nonetheless a heightened warning of the risk
of kidney injury. And, FDA’s willingness to amend its proposed language in
response to a request from AstraZeneca hardly provides “clear evidence” that the
FDA would have rejected any proposals by the manufacturers over the
approximately two decades from approval of Nexium and Prevacid in 2001 and 1995
respectively until 2020 to bolster the warnings regarding renal injuries, which they
clearly could have done based upon the scientific data as reflected in the medical
literature during that time frame.
In short, there is sufficient evidence to defeat summary judgment on
preemption grounds, including that (i) when a CBE was proposed by a PPI
manufacturer (AstraZeneca) to add “interstitial nephritis” to the Adverse Reactions
section of the label in 2006, FDA approved it, (ii) at multiple points in time, there
was “newly acquired evidence” from the medical literature that could have been used
by the PPI manufacturers to support a request for additional warnings, (iii) the PPI
manufacturers never sought such additional warnings either through a CBE or other
means, and (iv) the actions taken by FDA in 2014 and 2020 do not provide “clear
evidence” that, had such labeling changes been proposed, FDA would have rejected
them.

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D. Fosamax
In CMO No. 75, the parties were ordered to provide supplemental briefing
regarding the recent decision in Fosamax by a different court in this district on
remand from the Supreme Court in Merck v. Albrecht.173 Having reviewed carefully
the district court’s decision in Fosamax, and the parties’ briefing, it is clear that the
Fosamax case is distinguishable from these PPI cases.
In Fosamax, unlike here, the manufacturer repeatedly pressed FDA for
stronger warnings, which were repeatedly rejected by FDA.174 In contrast, the
undisputed facts here reflect that neither AstraZeneca nor Takeda ever sought to add
language in the Warnings and Precautions section of their PPI labels concerning the
risk of kidney injury with PPI use, and when FDA proposed strengthening the
language in 2020, AstraZeneca sought to soften the language proposed by FDA.175
Moreover, in Fosamax – unlike here – FDA itself filed papers in the litigation
asserting that it was “fully informed” in reaching its decision.176 In short, Fosamax

173

CMO No. 75.
See Fosamax, 2022 U.S. Dist. LEXIS 52627, at *46-52, *111-16.
175
See supra §§ IV.C, D, E. In this regard, AstraZeneca’s observation that courts
have held that a manufacturer’s label change request is not a predicate for
preemption is true but, once again, beside the point. See AstraZeneca Response To
PSC Supp. FOF-COL 9 (citing Fosamax and other authorities). The relevance of
AstraZeneca’s conduct is that it is helpful in providing context for understanding
and interpreting what the FDA’s labeling decision means and indicates about what
it would have done. See Fosamax, supra. This is not “speculation” about the FDA’s
intent.
176
See Fosamax, 2022 U.S. Dist. LEXIS 52627, at *78-79, n. 15.
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174

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is a case where (i) the manufacturer repeatedly requested and the FDA repeatedly
denied stronger warnings in the labeling prior to October 2010 and (ii) there was
clear evidence, including from the FDA itself through the Solicitor General, that the
FDA had in fact determined “that a new warning ‘should [not] be included in the
labeling of the drug[.]’”177
VII.

CONCLUSION
As Judge Tjoflat recently observed in another case rejecting a manufacturer’s

argument that “impossibility” preemption barred failure to warn claims: “Federal
preemption is a bitter pill. We should administer it carefully.”178 For the reasons set
forth herein, I recommend that the motions for partial summary judgment as to
Plaintiffs’ failure to warn claims on grounds of preemption by federal law be denied.
A proposed order is attached.
Respectfully submitted,

Date: 8/1/2022

177

Ellen K. Reisman
Special Master

Merck v. Albrecht, 139 S. Ct. at 1686 (Alito, J., concurring) (citing Brief for the
United States as Amicus Curiae 30, 33-34).
178
Carson v. Monsanto Company, C.A. No. 21-10994 (11th Cir., July 12, 2022), slip
op 1.
51