In Re Zantac (Ranitidine) Litigation

IN THE SUPERIOR COURT OF THE STATE OF DELAWARE
)
IN RE ZANTAC (RANITIDINE) )
LITIGATION )
)
) C.A. NO. N22C-09-101 ZAN
)
)
Submitted: March 7, 2024
Decided: May 31, 2024
Corrected: June 3, 2024
OMNIBUS ORDER
ON MOTIONS TO EXCLUDE EXPERT OPINIONS
I. INTRODUCTION
Nearly 75,000 Plaintiffs seek to be heard in Delaware for claims alleging that
their cancer was caused due to the ingestion of a heartburn medication commonly
known as Zantac. In this early stage of these proceedings, before the Court for
disposition are the parties’ competing motions to exclude expert testimony pursuant
to Rule 702 of the Delaware Rules of Evidence and Daubert v. Merrell Dow Pharm.
Inc.,1 (the “Motions”).
The Motions were the subject of discovery, a three-day “Daubert” hearing,
multiple layers of briefing, and post-hearing submissions all supported by more than
1
509 U.S. 579 (1993).
1
forty volumes of exhibits. Having considered the pleadings, oral arguments,
supplemental submissions, and the full record herein, for the reasons now stated, the
parties’ Motions are DENIED.
II. FACTUAL AND PROCEDURAL HISTORY2
This case involves a molecule known as ranitidine. Ranitidine is marketed
under the label name of Zantac. N-Nitrosodimethylamine (“NDMA”) is found in
ranitidine.3 NDMA causes cancer.4
Zantac is a part of a class of medications known as Histamine-2 Receptor
Antagonists (“H2Ras”).5 Ranitidine is a histamine-2 receptor blocker used to “treat
heartburn and many other gastro-intestinal disorders, including duodenal ulcers,
gastroesophageal reflux disease (“GERD”) and esophagitis.”6
In 1983, based on extensive testing, including humans, the FDA approved
ranitidine for prescription use to treat ulcers and later approved it to treat other
2
The recitation of the history and facts in this section are for context only.
3
See Plaintiffs’ Opposition to Defendants’ Motion to Exclude General Causation Experts’
Opinions at 14, Trans. ID 71670509 (Dec. 20, 2023) (herein “Pls.’ Opp’n to Defs.’ Mot. to Exclude
Gen. Causation Experts’ Op.”).
4
Id.5
Defendants’ Brief in Support of Brand Defendants’ and Patheon’s Motion to Exclude
Plaintiffs’ General Causation Experts’ Opinions at 3, Trans. ID 71408977 (Nov. 15, 2023) (herein
“Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op.”).
6
In re Zantac, 644 F. Supp.3d 1075, 1095 (S.D. Fla. 2022).
2
stomach and esophageal conditions.7 In 1995, the FDA authorized ranitidine for over-
the-counter (“OTC”) use.8 By 2004, the FDA had further approved higher dosages of
ranitidine for OTC use.9
Zantac was on the market for more than 35 years.10 During approximately four
decades of marketing, there were four brand pharmaceutical companies and generic
manufacturers that sold versions of the product.11 GlaxoSmithKline (“GSK”)
developed the medication and initially marketed it in prescription form. 12 In 1995,
GSK marketed it as an OTC in a joint venture with a predecessor of Pfizer.13 In 1998,
GSK transferred its rights to sell OTC Zantac in the U.S. to that Pfizer predecessor.14
In 2006, Defendant Boehringer Ingelheim (“BI”) acquired the rights to sell OTC
Zantac.15 In 2017, Defendant Sanofi began selling OTC Zantac after acquiring the
brand from BI.16
7
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 4.
8
Id.9
Id.10
Id.11
Id.12
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 4, n1.
13
Id.14
Id.15
Id.16
Id.3
In September of 2019, Valisure, an online pharmacy submitted a citizen petition
to the FDA claiming detection of “extremely high levels of N-Nitrosodimethylamine
(NDMA)” in ranitidine.17 Valisure reported NDMA at levels in excess of three million
nanograms per tablet. This far exceeded the limit of 96 nanograms per day that the
FDA had set for NDMA ingestion in the context of an unrelated class of medications.18
After reviewing Valisure’s petition, the FDA raised concerns about the testing
methodology.19 FDA and ranitidine manufacturers studied NDMA in ranitidine and
examined whether ranitidine use increases cancer risks in patients.20 Over the next
month, some tests revealed amounts lower than what Valisure reported, and some lots
tested revealed amounts below the acceptable daily intake (ADI).21
In September and October of 2019, then-existing ranitidine manufacturers
recalled their products. And by April 2020—after further testing confirmed NDMA
levels in some samples continued to exceed ADI—the FDA requested manufacturers
initiate a market withdrawal of all remaining batches then remaining on the market.22
After the recall of ranitidine-containing Zantac, litigation ensued around the country.
17
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 5.
18
Id.19
Id.20
Id.21
Id. (citing FDA, FDA Statement: Statement on new Testing Results, Including Low Levels of
Impurities in Ranitidine Drugs (2019) (Brown Decl. Ex. 89) at 1).
22
Id. at 8.
4
A. NATIONAL PROCEDURAL HISTORY - THE “MDL”23
To address these claims, on February 6, 2020, the United States Judicial Panel
on Multidistrict Litigation established a multidistrict litigation process (the “MDL”)
in the U.S. District Court for the Southern District of Florida in West Palm Beach for
all pretrial purposes. The Panel ordered federal lawsuits for personal injury and
economic damages from the purchase or use of Zantac to be transferred to the MDL.
As part of MDL management, a Census Registry (“The Registry”) was created
to allow the parties and the Court to “understand the nature of the unfiled claims that
are a part” of the MDL.24 The MDL Court held a Daubert hearing in early 2022.
On December 6, 2022, the MDL Court issued its opinion on Daubert and
summary judgment motions (“MDL Order”).25 In its 200-page opinion, the MDL
Court, in pertinent part, excluded those plaintiffs’ experts’ general causation opinions
and granted summary judgment for Defendants.26
B. LITIGATION IN OTHER STATES
Similar suits were also proceeding in state courts throughout the United States.
The largest one, other than here, was a coordinated proceeding in California, the
23
See generally, In re Zantac, 644 F.Supp.3d at 1095.
24
Id. at 1096.
25
As of the date of this ruling, it appears that the MDL decision is on appeal in the Eleventh
Circuit Court of Appeals.
26
See generally, id.
5
Judicial Council Coordinated Proceeding (“JCCP”). In the California state court,
several thousand cases were being coordinated in the JCCP, with sixteen bellwether
trials scheduled for 2024. The JCCP Plaintiffs were pursuing their claims for the same
cancers claimed here. Those cases advanced beyond the general causation phase.27
C. THE PARTIES AND PROCEDURAL HISTORY HERE
Plaintiffs in this litigation were not before the federal MDL Court. Nor are the
experts the same. Plaintiffs here are pursuing ten cancers—bladder, esophageal,
gastric, liver, pancreatic, breast, colorectal, kidney, lung and prostate. Notably, in the
MDL, Plaintiffs’ Leadership (also not present here) notified that Court that it had
decided not to pursue general causation expert reports for breast and kidney cancers
and initially narrowed their list from ten to eight cancers.28 In January of 2022, they
again notified the MDL Court that they were not moving forward with certain cancers,
and again, narrowed the list to five cancers. Thus, five of the cancer claims here were
not before the MDL Court.29
In September of 2022, nearly 75,000 complaints were filed in this Court.
27
See Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex 75.
28
In re Zantac, 644 F.Supp.3d at 1098.
29
Id. (The MDL noted in its final disclosure that the plaintiffs in the MDL intended to “prove
that ranitidine causes bladder, esophageal, gastric, liver, and pancreatic cancers (the ‘Designated
Cancers’), as opposed to other cancers (‘Non-Designated Cancers.’). The Defendants do not
address Non-Designated Cancers in the Daubert motions, so individual cases in which Plaintiffs
allege their ranitidine use caused their Non-Designated Cancers remain pending at this time and
are not the subject of this Order.”).
6
Plaintiffs allege Defendants collectively bear responsibility for their cancer
diagnoses, and the related injuries or deaths caused from their ingestion of the
medication known as Zantac.
The Defendants are GlaxoSmithKline LLC (“GSK”), Boehringer Ingelheim
Pharmaceuticals, Inc., Boehringer Ingelheim Corporation, and Ingelheim U.S.A.
Corporation (collectively, B.I.), Sanofi US Services Inc., Sanofi-Aventis U.S. LLC,
and Chattem, Inc. (collectively, “Sanofi), Pfizer Inc. (“Pfizer”) (together with all
those just mentioned are referred to as the “Brand Defendants”) and Patheon, (all
collectively “Defendants”).30
In these initial proceedings, the first phase addresses “general causation,”
which involves the question of whether the ingestion of this product is capable of
causing cancer as alleged. To carry their burden at this stage, Plaintiffs have retained
ten experts to offer opinions on general causation for the ten mentioned cancers.
Defendants move to exclude them all.31 Plaintiffs also move to exclude certain
opinions proffered by Defendants’ sole General Causation Expert, William C.
30
Brand Defendants’ and Patheon’s Motion to Exclude Plaintiffs’ Expert Dr. Charles Jameson,
Trans. ID 71409144 (Nov. 15, 2023) (herein “Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’
Expert Dr. Jameson”).
31
Defendants move to exclude all of Plaintiffs’ General Causation Experts: Drs. Charles William
Jameson, PhD; William Sawyer, PhD; Alfred I. Neugut, M.D., PhD; Vinod K. Rustgi M.D., MBA;
Ioannis Hatzaras, M.D. MPH, PhD, F.A.C.S.; Dan J. Raz, M.D.; Bruce J. Trock, MPH, PhD;
George Miller, M.D.; Pablo Leone, M.D.; and Vitaly Margulis, M.D. (collectively “Plaintiffs’
General Causation Experts”).
7
Zamboni, Pharm.D., PhD.
III. APPLICABLE LEGAL STANDARDS
As in any products liability case, each party bears the burden of proof on the
admissibility of their expert opinion testimony.32 Delaware Rule of Evidence 702
addresses the admissibility of expert testimony. It provides:
A witness who is qualified as an expert by knowledge,
skill, experience, training, or education may testify in the
form of an opinion or otherwise if:
(a) the expert’s scientific, technical, or other specialized
knowledge will help the trier of fact to understand the
evidence or to determine a fact in issue;
(b) the testimony is based on sufficient facts or data;
(c) the testimony is the product of reliable principles and
methods; and
(d) the expert has reliably applied the principles and
methods to the facts of the case.33
This rule is nearly identical to Federal Rule of Evidence 702.34 Our Supreme
Court has interpreted Federal Rule of Evidence 702, addressed the admissibility of
expert testimony,35 and adopted the holdings of Daubert v. Merrell Dow Pharm.,
32
Minner v. Amer. Mort. & Guar. Co., 791 A.2d 826, 843 (Del. Super. 2000).
33
D.R.E. 702.
34
Barrera v. Monsanto Co., 2019 WL 2331090, at *3 (Del. Super. May 31, 2019).; see also
Minner, 791 A.2d at 833 n.2.
35
See Tumlinson v. Advanced Micro Devices, Inc., 81 A.3d 1264, 1269 (Del. 2013) (herein
“Tumlinson”).
8
Inc. (“Daubert”) and its progeny as the correct interpretation of Delaware Rule of
Evidence 702.36
A. THE DAUBERT STANDARD
Decided in 1993 by the United States Supreme Court, Daubert is a name
well-known to most lawyers. Even so, the Court has urged litigants to appreciate
“the perspective from which this Court will view so-called Daubert motions, and the
process by which such motions will be addressed.”37 This encouragement merits
respect, as Daubert at first blush may seem contradictory, expanding the power of
the trial court by rejecting the “general acceptance” requirement for admissibility
while at the same time emphasizing the limitations on the court’s role in deference
to the role of the jury.38 And although Daubert rejected the exclusivity of the
“general acceptance” requirement, an expert’s “access to the courtroom is not
unfettered.”39
A few factors can be implicated in Daubert reviews. Some are enumerated in
Rule 702; others, some identified in Daubert, are deemed nonexclusive.40 But even
the expanded list is not exclusive. None of the Daubert factors, specific or
36
See M.G. Bancorporation, Inc. v. LeBeau, 737 A.2d 513, 522 (Del. 1999).
37
In re Asbestos Litig., 911 A.2d 1176, 1197 (Del. Super. 2006).
38
Minner, 791 A.2d at 841.
39
In re Asbestos Litig., 911 A.2d at 1197.
40
Daubert, 509 U.S. at 590.
9
otherwise, is binding on the trial court.41 The trial court also has broad discretion to
consider factors not articulated by Daubert.42
B. THE GATEKEEPER AND THE JURY
Predominant among Daubert’s holdings is the recognition of the trial court’s
role as gatekeeper. In that role, the “Trial Judge…insure[s] that the scientific
testimony is not only relevant but reliable.”43 While Daubert may require trial courts
to dive deeper into certain preliminary facts than had historically been the case, it
was not intended to abrogate the jury’s constitutionally protected role as the ultimate
fact-finder; a role the courts of this State defend vigorously.44 Daubert and its
progeny have repeatedly emphasized the importance of the trial system and the role
of juries as the ultimate arbiters in expert evidentiary issues.
Therefore, “[a]s a threshold matter, Daubert neither requires nor empowers
Trial Courts to determine which of . . . competing scientific theories has the best
performance.”45 Daubert “requires only that the trial court determine whether the
41
Tumlinson, 81 A.3d at 1269.
42
Id. at 1272–73; Long v. Weider Nutrition Group, 2004 WL 1543226, at *5 (Del. Super. June
25, 2004) (citing Kumho Tire Co., Ltd. v. Carmichael, 526 U.S. 137, 150 (1999)).
43
Minner, 791 A.2d at 843 (citations omitted).
44
In re Asbestos Litig., 911 A.2d at 1199; see. e.g., Kaur v. Bos. Sci. Corp., 2022 WL 1486178,
at *3 (Del. Super. May 11, 2022) (an expert’s investigations and assumptions “are readily subject
to cross examination and to evaluation by the fact finder . . .”).
45
Minner, 791 A.2d at 848 (citation omitted).
10
proponent of the evidence has demonstrated that scientific conclusions have been
generated using sound and reliable approaches.”46 But “the judge is not a scientist
and the courtroom is not a science laboratory.”47 Indeed,
“[i]t would be unreasonable to conclude that the subject of
scientific testimony must be ‘known’ to a certainty . . . .
[N]ot knowing the mechanism whereby a particular agent
causes a particular effect is not always fatal to a plaintiff’s
claim. Causation can be proved even where we do not
know precisely how the damage occurred if there is
sufficiently compelling proof that the agent must have
caused the damage somehow.”48
As such, to determine the admissibility of scientific evidence consistent with
Daubert, the trial judge must determine whether:
(1) the witness is qualified as an expert by knowledge,
skill, experience, training or education;
(2) the evidence is relevant;
(3) the expert’s opinion is based upon information
reasonably relied upon by the experts in the
particular field;
(4) the expert testimony will assist the trier of fact to
understand the evidence or to determine a fact in
46
In re Asbestos, 911 A.2d at 1201; see also Minner, 791 A.2d at 842 (citations omitted).
47
Daubert, 509 U.S. at 596–97 (quoting “Introduction to Reference Manual on Scientific
Evidence”, Fed. Jud. Ctr. at 2 (2000)).
48
Daubert v. Merrell Dow Pharms., Inc., 43 F.3d 1311, 1314 (9th Cir. 1995) (emphasis in
original); accord, Bowen v. E.I. Du Pont de Nemours and Co., 2005 WL 1952859, at *9 (Del.
Super. June 23, 2005) (herein “Bowen”), aff’d 906 A.2d 787 (Del. 2006) (explaining that the trial
court need not “decide the admissibility of scientific evidence with the degree of certainty required
in scientific circles”).
11
issue; and
(5) the expert will not create unfair prejudice or confuse
or mislead the jury.49
The gatekeeper must apply these particular “factors in a flexible manner that
takes into account the particular specialty of the expert under review and the
particular facts of the underlying case.”50 “Where the question of admissibility is a
close one, exclusion of the evidence is not appropriate where cross examination, the
presentation of contrary evidence and careful instruction regarding the burden of
proof will insure that the jury is not misled or confused.”51 Restated, “[t]he reliability
requirement is not a tool for the Court to use to exclude questionably reliable
evidence.”52 This Court’s refusal to establish a bright line rule for proving causality
has previously been considered.53 And no doubt, “the requisite proof necessary to
establish causation will vary greatly case by case.”54
The Supreme Court in Daubert was more direct: “Vigorous cross-
examination, presentation of contrary evidence, and careful instruction on the burden
of proof are the traditional and appropriate means of attacking shaky but admissible
49
Bowen v. E.I. DuPont de Nemours & Co., Inc., 906 A2d 787, 795 (Del. 2006) (herein “Bowen
I”).
50
Id.; Scaife v. Astrazeneca LP, 2009 WL 1610575, at *14 (Del. Super. June 9, 2009).
51
Bowen, 2005 WL 1952859, at *8, aff’d sub nom. Bowen II, 906 A.2d at 787.
52
Barrera, 2019 WL 2331090, at *10.
53
Id. at *5 (citing In re Zoloft, 858 F.3d 787, 783 (3d Cir. 2017)).
54
In re Zoloft, 858 F.3d at 787.
12
evidence.”55 Thus guided, courts confronted by “shaky but admissible evidence”
conduct their Daubert analyses “with a ‘liberal thrust’ favoring admission.”56
C. DAUBERT AND GENERAL CAUSATION CONSIDERATIONS
As the preliminary question concerns general causation, this Court finds the
federal district court’s approach in In re Roundup Products Liability Litigation57
instructive:
The question at this early phase in the proceedings - the
‘general causation phase - is whether a reasonable jury
could conclude that glyphosate . . . can cause Non
Hodgkins Lymphoma (“NHL”) . . . . There are two
significant problems with the plaintiffs’ presentation,
which combine to make this a very close question.
* * *
The evidence, viewed in its totality, seems too equivocal
to support any firm conclusion that glyphosate causes
NHL. This calls into question the credibility of some of
the plaintiffs’ experts, who have confidently identified a
causal link.
However, the question at this phase is not whether the
plaintiffs’ experts are right. The question is whether they
have offered opinions that would be admissible at a jury
trial. And the case law - particularly Ninth Circuit case
law - emphasizes that a trial judge should not exclude an
expert opinion merely because he thinks it’s shaky, or
55
Daubert, 509 U.S. at 596.
56
Messick v. Novartis Pharmaceuticals Corp., 747 F.3d 1193, 1196 (9th Cir. 2014) (quoting
Daubert, 509. U.S. at 588); M.G. Bancorporation, Inc., 737 A.2d at 522.
57
390 F.Supp.3d 1102 (N.D. CA 2018) (herein “In re Roundup”).
13
because he thinks the jury will have cause to question the
expert’s credibility. So long as an opinion is premised on
reliable science principles, it should not be excluded by the
trial judge; instead, the weaknesses in an unpersuasive
expert opinion can be exposed at trial, through cross-
examination or testimony by opposing experts.58
In Kennedy v. Collagen Corp., the Ninth Circuit emphasized that, while
competing experts, science, experiments, and publications “may increase or lessen
the value of the expert’s testimony . . . their presence should not preclude the
admission of the expert’s testimony—they go to the weight, not the admissibility.”59
Also important in Daubert proceedings is the gravity of the decision to be
made. This Court in In re Asbestos Litig. placed particular emphasis on the risks
attending expert opinion decisions:
In the products liability context, an incorrect decision can
either deprive a plaintiff of warranted compensation while
discouraging other similarly situated individuals from
trying to obtain compensation, or it can improperly impose
liability in a manner that will cause the abandonment of an
important product or technology. Either result is
unacceptable. The Court must tread carefully.60
Notably, in Long v. Weider Nutrition Group, Inc.,61 this Court likewise
counseled judicial restraint from a different, but equally compelling, perspective:
58
Id. at 1108–09; see also Kennedy v. Collagen Corp., 161 F.3d 1226, 1229–31 (9th Cir. 1998).
59
161 F.3d at 1230–31 (italics in original) (quoting McCullock v. H.B. Fuller Co., 61 F.3d 1038,
1044 (2d Cir. 1995). Accord, In re Asbestos Litig., 911 A.2d at 1180.
60
In re Asbestos Litig., 911 A.2d at 1200.
61
2004 WL 1543226, at *1.
14
The first of several victims of a new toxic tort should not
be barred from having their day in court simply because
the medical literature, which will eventually show the
connection between the victims’ condition and the toxic
substance, has not yet been completed.62
The cautions urged in In re Asbestos and Long seem self-evident even where
the plaintiffs are few. Here, where there are nearly 75,000 plaintiffs, the implications
are much more profound. Therefore, this Court proceeds cautiously.
IV. DISCUSSION
A. THE DISCRETIONARY MDL ORDER
Defendants extol the MDL Court’s decision with great fervor.63 Several issues
confound that reliance. First, the Delaware Supreme Court has made plain that
issues of admissibility, as procedural questions, are governed by Delaware law. 64
Therefore, Delaware evidentiary decisions control here.65
For example:
• that an expert may change her opinion goes to the
weight, not the admissibility, of the expert
opinion;66
• the use of animal studies in the course of an expert
62
Id. at 6 (quoting Turner v. Iowa Fire Equip. Co., 229 F.3d 1202, 1208–09 (8th Cir. 2000)).
63
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 13–37.
64
Tumlinson, 81 A.3d at 1270.
65
Id. at 1273 (stating that it is improper to consider the law of a foreign forum when the
admissibility of evidence is a Delaware issue).
66
Barrera, 2019 WL 2331090, at *11.
15
analysis does not bar admissibility of the expert
opinion on human disease;67
• Delaware law holds that statistical significance is
“not necessary to prove causality”;68
• Delaware does not recognize a “threshold dose”
requirement as part of the general causation
analysis; an issue discussed below;69
• epidemiological studies are not required as a
threshold for the admission of an expert opinion on
general causation.70
Second, the MDL Order concerned the exclusion of different experts; none of
whom are designated nor challenged here.71
Third, similar to other state courts that considered and opted not to be bound
by the MDL Order (e.g., the California JCCP Court) so, too, here, this Court views
the MDL Order as a “discretionary decision on the exclusion of evidence.”72 “Two
different trial judges can review the same evidence, weigh the evidence differently,
67
Id. at *14.
68
Id. at *4; see In re Zoloft, 858 F.3d at 793.
69
Barrera, 2019 WL 2331090, at *5.
70
Long, 2004 WL 1543226, at *6; see also Tumlinson v. Advanced Micro Devices, Inc., 2013
WL 7084888, at *9 (Del. Super. Oct. 15, 2013) (herein “Tumlinson II”), aff’d, 81 A.3d 1264 (Del.
2013) (stating that the Bradford Hill factors are not all-inclusive and only establish a framework
to establish causation).
71
See Index of Exhibits in Support of Plaintiffs’ Opposition to Defendants’ Motion to Exclude
Plaintiffs’ General Causation Experts’ Opinions, Trans. ID 71666233 (Dec. 20, 2023) (herein the
exhibits will be cited in reference to the corresponding motion, such as “Pls.’ Opp’n to Defs.’ Mot.
to Exclude Gen. Causation Experts’ Op., Ex. _”) Ex. 75 at 8.
72
Id. at 6.
16
and make different decisions . . . .”73 This is especially true where the evidentiary
law governing some of the salient issues differs. Defendants’ praise of the MDL
Court’s rationale breathes not a whisper to the differences in Delaware law
implicated here.
Fourth, as the preceding discussion reflects, Delaware courts approach
Daubert decisions cautiously and with deep deference for the role of juries as the
ultimate fact finders. To that end, our trial courts need not definitely “resolve” every
expert query posed, even those that might present “close calls” or “shaky opinions.”
When experts disagree, or credibility or other questions confound the reliability
issue, resolution of those issues rests with the jurors.74 Delaware courts are loath to
step into the heart of technical debate between opposing scientists. In that regard,
the jurisprudence reflected in the Floridian Zantac differs from Delaware’s. This
Court—with great respect for the hard judicial work done there—distinguishes that
ruling from what was presented here.75
73
See Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 34; Ex. 75, at 6.
74
In re Asbestos Litig., 911 A.2d at 1207.
75
The post-Daubert briefing here followed adjournment of the three-day Daubert
hearing. Defendants’ submissions are noteworthy only for their zealous endorsement yet again of
In Re Zantac and ask this Court to agree that “[the] MDL Decision is a Roadmap for this Court.”
Of the 18 pages of argument in their Opening Post-Daubert brief, 14 pages are devoted to the
MDL Order, which this Court has already addressed. Defendants also again cite to Long v. Weider
Nutrition, 2004 WL 1543226 (Del. Super. June 25, 2004). See id., at 5. This Court affords great
deference to the Long decision: in a case of this legal and medical gravity, the Court should
proceed cautiously. See Long, 2004 WL 1543226, at *6; see also In re Asbestos, 911 A.2d at
1200.
17
B. GENERAL CAUSATION FOCUSES ON NDMA
The discrete issue before the Court at this stage is whether NDMA can cause
cancer. Both sides disagree as to how to frame the general causation question.
Plaintiffs cast the issue directly:
It is undisputed that N-Nitrosodimethylamine (“NDMA”)
is found in ranitidine and that NDMA causes cancer. That
is why the U.S. Food and Drug Administration ordered an
immediate recall after independent testing showed
unacceptable levels of NDMA in the drug. In turn, it
would seem obvious then, that if a person ingested
ranitidine with NDMA, they could develop cancer.76
Plaintiffs maintain that the issue is not whether ranitidine, untethered to
NDMA, can cause cancer because the cancer-causing agent is NDMA, and its route
of exposure to NDMA is through the ingestion of ranitidine.77
Conversely, Defendants frame the general causation question as turning on
“the consensus of the scientific community that ranitidine use does not increase the
risk of cancer, and the unreliable methodologies employed by Plaintiffs’ experts []
to avoid that reality.”78 In support, Defendants cite the “largest and highest quality
healthcare databases,” “leading medical journals,” “40 medical institutions, research
76
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 14 (emphasis in original).
77
Id. at 40 (emphasis in original).
78
Brand Defendants’ Opposition to Plaintiffs’ Motion to Exclude Certain Opinions of
Defendants’ Expert William C. Zamboni at 1–2, Trans. ID 71683862 (Dec. 22, 2023) (herein
“Brand Defs.’ Opp’n to Pls.’ Mot. to Exclude Certain Op. of Defs.’ Expert Zamboni”) (emphasis
added).
18
topics” and “15 peer-reviewed studies” addressing “whether ranitidine causes
cancer.”79 Defendants add that these “studies of ranitidine necessarily account for
any exposure to NDMA contained in ranitidine products.”80
Yet, Defendants do not dilate on how the studies “necessarily account” for
any exposure to NDMA contained in ranitidine products. Whether describing source
documents, like those above, or setting the predicate for a point of advocacy,
Defendants speak in terms of ranitidine: “patients who took ranitidine,”81 “whether
ranitidine causes cancer,”82 “studies of ranitidine,”83 “exposure to NDMA contained
in ranitidine,”84 “‘no demonstrable association’ between ranitidine use and any
cancer types[,] ranitidine patients,”85 and “real-world ranitidine data in humans.”86
At the same time, Defendants concede that in September and October of 2019,
“as a precautionary public health measure, then-existing ranitidine manufacturers
voluntarily recalled their ranitidine products pending further investigation into the
79
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 9–13 (emphasis added).
80
Id. at 10 (emphasis added).
81
Id. at 9.
82
Id. at 10.
83
Id.
84
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op.
85
Id.
86
Id. at 11 (quotation marks in original); see also id. at 12 (“[N]o evidence of a causal association
between ranitidine therapy and . . . cancer . . . none of these organizations has concluded that
ranitidine use increases the risk of any type of cancer.”).
19
potential root-causes of NDMA found in some lots” of ranitidine.87 Defendants
likewise acknowledge that, in April 2020, after “further investigation” confirmed
that NDMA levels in some samples continued to exceed the ADI, the “FDA
requested that manufacturers initiate a market withdrawal of any batches remaining
in the market.”88 The recall was based on the FDA’s conclusion that NDMA is a
“substance that can cause cancer.”89
Since the FDA recall, ranitidine is no longer sold in the United States and
many other parts of the world.90 Plaintiffs emphasize that no evidence has been
offered that the FDA ever stated that ranitidine is safe to be returned to the market
or that any Defendant has sought to do so.91 And although Defendants place little
significance on the recall, they also do not challenge that assertion.
Instead, they rely on an FDA July 2021 study (Florian) to suggest that its
findings “do not support that ranitidine is converted to NDMA in a general, healthy
population.”92 This does little to advance their arguments. If that were the only
87
Id. at 8 (emphasis added).
88
Id. (emphasis added); In re Zantac, 644 F.Supp.3d at 1095–96.
89
Plaintiffs’ Brief in Support of Plaintiffs’ Motion to Exclude Certain Opinions of Defendants’
Expert Dr. William C. Zamboni, Trans. ID 71466806 (Nov. 21, 2023) (herein “Pls.’ Br. in Supp.
of Pls.’ Mot. to Exclude Certain Op. of Defs.’ Expert Dr. Zamboni”) at 2.
90
In re Zantac, 644 F.Supp.3d at 1091–92; see also Pls.’ Br. in Supp. of Pls.’ Mot. to Exclude
Certain Op. of Defs.’ Expert Dr. Zamboni at 4.
91
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 19.
92
Id. at 11 (emphasis added) (referring to the Florian study).
20
issue here, that study might have some utility.
Zantac was not marketed to serve a generally healthy population. It was
intended to treat persons with heartburn, and many other gastro-intestinal disorders,
including duodenal ulcers, gastroesophageal reflux disease (“GERD”) and
esophagitis. Notably, the record suggests that at least one defendant understood the
importance of marketing it to this population. The record suggests that Defendant
GSK’s marketing efforts, from day one, focused on the off-label promotion of
Zantac for long-term use, despite the drug’s approved indication only for short-term
use. One GSK executive expressed that very sentiment in 1983.93
Nevertheless, Defendants insist that the inquiry should focus on ranitidine, not
NDMA.94 That focus is understandable, but the Court cannot turn a blind eye to the
focus on NDMA, especially where the record suggests that Defendants
acknowledged the dangers of it:
On September 25, 2019, GSK’s scientists prepared a
Hazard Assessment Report on NDMA (“Hazard
Assessment”) to “protect the scientists and anybody
handling” NDMA in the laboratory.95 Some of its
93
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex. 33, at 2 (“The sheer
size of this opportunity and the potential rewards from it dwarf anything we’ve done so far. It’s
not just that Zantac is bigger than all our other products put together . . . It’s bigger than the whole
company. You’ve all heard the numbers. My mind finds it difficult to absorb all those zeroes . .
.”).
94
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 9–10.
95
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex. 12, at 16:1–17
(emphasis added).
21
conclusions:
[NDMA] is reasonably anticipated to be a human
carcinogen based on sufficient evidence of carcinogenicity
from studies in experimental animals.
* * *
There is overwhelming evidence that NDMA is mutagenic
and clastogenic . . . Positive results have been observed in
human as well as rodent cells.
* * *
Qualitatively, the metabolism of NDMA appears to be
similar in humans and animals; as a result, it is considered
highly likely that NDMA is carcinogenic to humans,
potentially at relatively low levels of exposure.
* * *
NDMA is a genotoxic carcinogen, and exposure should be
reduced to the extent possible.
N-nitrosamines such as NDMA [] are considered
carcinogens and have been implicated in human cancers
such as bladder, esophagus, stomach and naso-pharynx.96
This fundamental dispute of whether the science should focus on ranitidine
versus NDMA lies at the heart of every challenge mounted in the Motions. This
Court was confronted with a similar issue in In re Asbestos Litig. The Court’s ruling
there speaks to Defendants’ ranitidine premise:
Plaintiffs must establish that their experts can reliably
conclude that exposure to friction products increases the
risk of contracting an asbestos-related disease. This does
96
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 19–20; Ex. 13, at 2.
22
not, however, preclude the plaintiffs from attempting to
carry this burden by presenting competent evidence that
friction products, in certain circumstances, release
respirable products [that can cause cancer].97
Similarly, in Kennedy, the Ninth Circuit rejected the trial court’s refusal to
consider collagen in a general causation analysis, emphasizing that “the body breaks
down the collagen into amino acids, which are then absorbed into the body.”98 The
Kennedy court reversed the trial court’s ruling, finding that such evidence will assist
the trier of fact and is therefore admissible under Daubert and Rule 702.99 At this
stage, the particular facts here compel the same conclusion.
For these reasons, this Court cannot constrain its gatekeeping function solely
to the studies related to ranitidine. NDMA’s dangers, the science, the studies, and
the opinions therein must be given due consideration.
The Court now considers the specific challenges as to each expert.
C. PLAINTIFFS’ DAUBERT CHALLENGE
Defendants have disclosed William C. Zamboni as their sole causation expert.
Dr. Zamboni will opine, in part, that Defendant GSK’s Tanner study, discussed
below, is the type of study “often not submitted to FDA nor requested by the
97
In re Asbestos Litig., 911 A.2d at 1202 (emphasis added); see also Kennedy, 161 F.3d at 1229.
98
Kennedy, 161 F.3d at 1229 (emphasis added).
99
Id. at 1231; see also Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex.
75 at 33–34 (holding that cases in California “do not suggest that experts cannot consider studies
on NDMA and must rely on epidemiology studies regarding ranitidine.”).
23
FDA.”100 Dr. Zamboni bases that conclusion on his “experience with drug
development.”101 Plaintiffs move to exclude that one sentence opinion as wholly
speculative, citing, inter alia, Dr. Zamboni’s lack of relevant experience in FDA
drug applications and his failure to review or consider documents relevant to the
FDA’s request of GSK for data on ranitidine studies.102 Plaintiffs do not move to
exclude the “majority” of Dr. Zamboni’s opinions.103
Instead, they urge that “an expert is not permitted to opine on the FDA’s state
of mind,” which, they claim, is exactly what Dr. Zamboni is doing. 104 Defendants
do not quarrel with that proposition.
The Court is constrained to pause on the context in which Plaintiffs’ Motion
arises. Plaintiffs dedicate considerable argument to what it characterizes as GSK’s
concealment of material science pertaining to NDMA beginning in 1982. Plaintiffs’
100
Brand Defs.’ Opp’n to Pls.’ Mot. to Exclude Certain Op. of Defs.’ Expert Dr. Zamboni at 3
(citing Pls.’ Br. in Supp. of Pls.’ Mot. to Exclude Certain Op. of Defs.’ Expert Dr. Zamboni Ex. 2,
at 28).
101
Pls.’ Br. in Supp. of Pls.’ Mot. to Exclude Certain Op. of Defs.’ Expert Dr. Zamboni at 28; Ex.
2 at 1–2.
102
Pls.’ Br. in Supp. of Pls.’ Mot. to Exclude Certain Op. of Defs.’ Expert Dr. Zamboni at 29
(“Dr. Zamboni’s opinion regarding what the FDA would not want to know was rendered without
reference to the very document summarizing what [information] the FDA requested.”).
103
Id. at 2 n.1.
104
Plaintiffs’ Reply in Support of Plaintiffs’ Motion to Exclude Certain Opinions of Defendants’
Expert Dr. William C. Zamboni, Trans. ID 71806319 (Jan. 12, 2024) (herein “Pls.’ Reply in Supp.
of Pls.’ Mot. to Exclude Certain Op. of Defs.’ Expert Dr. Zamboni”) at 1.
24
effort is detailed and grounded in quotations from GSK and FDA documents.105
By way of background, Plaintiffs allege that as early as 1982, before Zantac
was approved by the FDA, GSK conducted tests that directly linked ranitidine to
NDMA formation. A 1982 series of tests, called the Tanner study, named for the
scientist who performed and reported on the tests, has become a focus of the parties
here.106 Plaintiffs assert that the Tanner study found that “molecules . . . like
ranitidine, can react with nitrite under certain conditions to yield [NDMA].”107
Therefore, NDMA “was already a well-established genotoxic and mutagenic
nitrosamine.”108
The Tanner Study was only “circulated internally at GSK.”109 Beginning in
1980, prior to FDA Approval of Zantac, the FDA had voiced concerns about the
nitrosation potential of ranitidine.110 It is alleged that GSK met with the FDA in
May 1982, to discuss ranitidine’s mutagenicity and nitrosation. Neither the Tanner
Study nor NDMA was raised by GSK.111 The meeting never reached those topics
105
See Pls.’ Br. in Supp. of Pls.’ Mot. to Exclude Certain Op. of Defs.’ Expert Dr. Zamboni at 4–
24.
106
Id. at 11.
107
Id. (internal quotes omitted).
108
Id. (emphasis omitted).
109
Id.
110
Id. at 5 (quotation omitted).
111
Pls.’ Br. in Supp. of Pls.’ Mot. to Exclude Certain Op. of Defs.’ Expert Dr. Zamboni at 12–13.
25
and the Tanner Study was not made public until 2019.112
In the intervening years, Zantac went through the FDA pre-approval process.
The FDA requested of GSK specific information relative to nitrosation and
ranitidine. Despite various interactions with the FDA, and additional internal testing
and reports, GSK did not disclose the Tanner Study until 2019.
Plaintiffs allege that for almost four decades GSK “concealed the fact that
ranitidine degrades into NDMA.”113 Defendants dispute Plaintiffs’ allegations,
emphasizing both that 1) substantively, that the Tanner Study addresses whether
ranitidine “reacts with nitrite within the human stomach to form NDMA”, that is,
endogenously;114 and 2) procedurally, that the Tanner study was a type of study
“often not submitted to FDA nor requested by the FDA.”115 Dr. Zamboni bases that
conclusion on his “experience with drug development.”116
The potential implications of the Tanner Study were compounded by a 1984
report—the Preliminary Results of an Investigation into the Thermal Degradation of
Ranitidine Hydrochloride (“Preliminary Results”)—where GSK reported that
112
Id. at 2, 23.
113
Brand Defs.’ Opp’n to Pls.’ Mot. to Exclude Certain Op. of Defs.’ Expert Zamboni at 2; 2 n.5.
114
Id.
115
Id. at 1 (quoting Pls.’ Br. in Supp. of Pls.’ Mot. to Exclude Certain Op. of Defs.’ Expert Dr.
Zamboni Ex. 2, at 28).
116
Pls.’ Br. in Supp. of Pls.’ Mot. to Exclude Certain Op. of Defs.’ Expert Dr. Zamboni Ex. 2, at
28.
26
ranitidine would rapidly degrade in the presence of moisture and heat, yielding
“unidentified, breakdown products . . . within the liquid mass formed as a result.”117
Plaintiffs allege that, despite the Tanner Study, the Preliminary Results report and
numerous other inquiries and opportunities to do so, GSK did not test the
unidentified breakdown products for NDMA.118 The Tanner Study remained
internal.
Furthermore, when ranitidine breaks down to NDMA, discoloration can
indicate that this degradation process has begun.119 It is alleged that after concluding
that discoloration could not be avoided, GSK scientists recommended changing the
color of the tablets to “mask any potential discoloration.”120 That recommendation
was accepted.121 Plaintiffs point to these issues to support the notion that GSK had
knowledge of the dangers associated with NDMA as early as 1982.122
Defendants devote the majority of their opposition contesting Plaintiffs’
history.123 The one sentence in Dr. Zamboni’s opinion which Plaintiffs move to
117
Id. at 19; Ex. 27, at 2.
118
Id.
119
Id. at 20–21 (responding to the discoloration problem, one GSK scientist asked, “surely [the
discoloration] begs the question, ‘if it changes with time, is it safe to use?’ . . . which we do not
have sufficient information on.”) (quoting Ex. 33 at 5); Ex. 28–31.
120
Pls.’ Br. in Supp. of Pls.’ Mot. to Exclude Certain Op. of Defs.’ Expert Dr. Zamboni at 20; Ex.
28, at 1; Ex. 29, at 1; Ex. 30, at 6.
121
Id.
122
Pls.’ Br. in Supp. of Pls.’ Mot. to Exclude Certain Op. of Defs.’ Expert Dr. Zamboni at 2–3.
123
Brand Defs.’ Opp’n to Pls.’ Mot. to Exclude Certain Op. of Defs.’ Expert Zamboni at 6–15.
27
exclude seems intended to support Defendants’ challenge of GSK’s failure to
disclose the Tanner Report, and any other data, until 2019. The potential
implications of Plaintiffs’ history are disturbing. But it is not for the Court to plumb
their depths at this time.
It may be more than generous to call Dr. Zamboni’s opinion “shaky.”124 But,
as Daubert and progeny teach us, “[t]he reliability requirement is not a tool for the
Court to use to exclude questionably reliable evidence.”125 The one sentence opinion
of Dr. Tanner targeted by Plaintiffs’ Motion will not be excluded. Dr. Zamboni can
testify to that assertion, though his testimony on that issue should be limited to the
discrete issue which Plaintiffs move to exclude. Plaintiffs are not without recourse.
His opinion can be properly measured by cross examination.126 Plaintiffs’ Motion
to Exclude Certain Opinions of Defendants’ Expert William C. Zamboni is
DENIED.
D. DEFENDANTS’ BROAD DAUBERT CHALLENGES
Defendants muster several broad challenges to general causation. Most of
these are asserted in the context of Defendants’ Motion to exclude certain experts
124
In re Roundup, 390 F.Supp.3d at 1109.
125
Barrera, 2019 WL 2331090, at *10.
126
In re Roundup, 390 F.Supp.3d at 1109 (“[T]he weaknesses [in an] unpersuasive expert opinion
can be exposed at trial, through cross-examination or testimony by opposing experts”); see also
Kaur, 2022 WL 1486178, at *3 (“[C]hallenges to the ‘factual basis of an expert opinion go to the
credibility of the testimony, not the admissibility, and it is for the opposing party to challenge . . .
the expert opinion on cross-examination.’”).
28
and are addressed below.
One challenge merits discussion at the outset: Plaintiffs’ alleged failure to
offer satisfactory proof of threshold dose.127 Plaintiffs rely on In re TMI Litig.,128
where the Third Circuit Court recognized that “it is currently believed that there is
no threshold dose below which the probability of cancer induction is zero.”129
Defendants point to Tumlinson II130 in support.131
In Tumlinson II, this Court was confronted with a causation question
involving ten possible airborne, causative agents. Plaintiffs’ expert did not rely on
a dosage in her causative analysis “but instead on atmospheric concentration ranges
as a surrogate.”132 Tumlinson recognized that no black letter requirement for
threshold dose exists. To the contrary, the Court discussed those cases excusing
threshold dose, emphasizing that “[i]n each case, however, the substance in question
127
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 32; see Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 79–84; see
also Reply Brief in Support of Brand Defendants’ and Patheon’s Motions to Exclude: (1)
Plaintiffs’ General Causation Experts’ Opinions; and (2) Dr. Charles Jameson, Trans. ID 71797654
(Jan. 12, 2024) (herein “Reply Br. in Supp. of Defs.’ Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. & Dr. Jameson”) at 32–35.
128
193 F.3d 613 (3d Cir. 1999), amended, 199 F.3d 158 (3rd Cir. 2000).
129
Id. at 642. In re TMI is not mentioned in Defendants’ Opening or Reply brief, and Defendants
do not discuss threshold dose in their Reply.
130
Tumlinson II, 2013 WL 7084888, at *7.
131
See Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation
Experts’ Op. at 32–36; Reply Br. in Supp. of Defs.’ Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. & Dr. Jameson at 32–35.
132
Tumlinson II, 2013 WL 7084888, at *7.
29
is known to be harmful at some level and the plaintiff suffered the precise harm
connected to that exposure.”133
The first prong of Tumlinson II’s comment goes to general causation; the
second to specific causation.134 Ostensibly, Defendants’ focus on “precise harm” is
intended to require something more than cancer.135 The Court rejects such a precious
reading, at least at the general causation phase, especially given the conclusions of
GSK’s 2019 Hazard Assessment, quoted at length above. Daubert counsels against
black letter standards. Like general acceptance and statistical significance, threshold
dose is another factor to be considered in the Daubert analysis, but its presence or
absence is not outcome determinative.
Moreover, the record suggests that Defendants, particularly GSK, have been
on notice of the harm that can result from NDMA in their product since the Tanner
Study in 1982. The Hazard Assessment reflects GSK’s own conclusions about
carcinogenicity and NDMA.136 Defendants’ expert testified that threshold dose is a
133
Id.134
See id. at *5, 8 (“General causation does not consider the likelihood that a certain exposure
caused a certain harm. Rather, it only considers the possibility.”); see also Pls.’ Opp’n to Defs.’
Mot. to Exclude Gen. Causation Experts’ Op. at 84 nn.271–273; Reply Br. in Supp. of Defs.’ Mot.
to Exclude Pls.’ Gen. Causation Experts’ Op. & Dr. Jameson at 33.
135
See Reply Br. in Supp. of Defs.’ Mot. to Exclude Pls.’ Gen. Causation Experts’ Op. & Dr.
Jameson at 33.
136
See Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex. 12, at 16:1–17.
30
“somewhat meaningless statement [] scientifically.”137 Defendants debate the
meaning of that concession.138 Resolution of that debate awaits the jury’s attention.
But Daubert supports broad, flexible consideration at this stage.
Also, the parties do not dispute that the FDA has established an ADI limit for
NDMA based on cancer risk.139 Plaintiffs maintain the testing evidence shows “that
ranitidine products expose consumers to levels in excess of that ADI.”140 The
Hazard Assessment provides strong evidence that GSK admits the carcinogenic
threat in NDMA.141
Notwithstanding Defendants’ vigorous quarrel with the implications drawn
from the Tanner history, it can fairly be inferred that GSK delayed revealing the
cancer-causing potential of NDMA into the science marketplace. Plaintiffs should
also be able to argue inferences that the collective delays by all Defendants
forestalled development of the science of NDMA exposure.142 At this stage, it does
137
Id. at 81; id. at 81 n.264.
138
Reply Br. in Supp. of Defs.’ Mot. to Exclude Pls.’ Gen. Causation Experts’ Op. & Dr. Jameson
at 32.
139
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 83, 83 n.265; Ex. 84, at
8 (stating that the ADI “is a level that approximates an increased cancer risk”).
140
See id. at 83, 92.
141
Id. Ex. 11 (e.g., “There is overwhelming evidence that NDMA is mutagenic and clastogenic .
. . Qualitatively, the metabolism of NDMA appears to be similar in humans and animals; as a
result, it is considered highly likely that NDMA is carcinogenic to humans, potentially at relatively
low levels of exposure.”).
142
See Long, 2004 WL 1543226, at *6 (“[V]ictims of a new toxic tort should not be barred from
having their day in court simply because the medical literature, which will eventually show the
connection between the victims’ condition and the toxic substance, has not yet been completed.”).
31
not lie in the mouths of Defendants to assert a defense based on lack of threshold
dose. That issue awaits a specific causation finding by the jury.
This is not a case where the imposition of a bright line rule is appropriate.
That is not to suggest that [threshold dose] is irrelevant.”143 It remains, like general
acceptance and statistical significance, one of the factors enumerated by Daubert
and its progeny to be considered in the general causation analysis. But it is not, and
should not, be deemed, alone, outcome determinative. That consideration belongs
to the jury.
The Court now considers the specific challenges against Plaintiffs’ experts.
E. DEFENDANTS’ SPECIFIC DAUBERT CHALLENGES
1. Dr. Charles Jameson
Dr. Jameson has been asked to provide expert testimony on ranitidine’s ability
to form NDMA endogenously and exogenously and to provide “background
information about the mechanism through which NDMA causes cancer.”144
Dr. Jameson is a chemist and toxicologist specializing in carcinogenesis. He
began his career as a senior chemist at the National Institute of Health (“NIH”)’s
National Cancer Institute. Later, Dr. Jameson was responsible for the National
Institute of Health’s Environmental Health Services division of Toxicology
143
In re Zoloft, 858 F.3d at 793.
144
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 90.
32
Research and Testing. For 18 years, he served as a director on the National
Toxicology Program’s Report on Carcinogens.145 He has authored or co-authored
over 80 peer-reviewed scientific publications.146 Dr. Jameson’s methodology, when
called upon to provide expert testimony, has been upheld by this Court,147 as well as
the California court overseeing the JCCP, where he provided expert testimony on
NDMA and ranitidine.148 In both cases, Dr. Jameson’s testimony was admitted.
Defendants do not challenge Dr. Jameson’s qualifications to consider and opine on
the questions before him. Dr. Jameson offers four opinions here:149
• ranitidine produces NDMA exogenously (outside the
body);
• ranitidine produces NDMA endogenously (inside the
body);
• NDMA “meets 5 characteristics of the generally
accepted characteristics of a carcinogen; and,
145
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex. 19.
146
Id., see also id. at 88–90 (providing a complete summary of Dr. Jameson’s qualifications).
147
See Barrera, 2019 WL 2331090, at *14.
148
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 88; Ex. 75.
149
The scope of Dr. Jameson’s opinion is specifically defined. Yet defendants challenge his
failure to opine “that NDMA in ranitidine can cause cancer in any of the ten cancers at issue,” a
topic on which he is not offering an opinion. Reply Br. in Supp. of Defs.’ Mot. to Exclude Pls.’
Gen. Causation Experts’ Op. & Dr. Jameson at 5. Calling that the “central issue at this stage” of
the case, defendants argue that Dr. Jameson’s expert testimony is “irrelevant.” Id. at 6. The Court
rejects that conclusion. Endogenous and exogenous formation of NDMA are a part of plaintiffs’
case, as are the carcinogenic characteristics of NDMA and the generally accepted opinion among
science researchers that NDMA is capable of causing cancer in animals, and humans; topics on
which Dr. Jameson has been proffered, based on his review of scientific, chemical and medical
data.
33
• “It is generally accepted among cancer science
researchers that NDMA is capable of causing cancer in
animals, including cancer in humans.”150
In support of his expert opinion, Dr. Jameson opines that “the level of NDMA
found in ranitidine upon its storage reaches levels that exceed the daily intake
limit.”151 In its root cause analysis, GSK likewise concludes that degradation of
ranitidine, which begins from the point of manufacture, increases NDMA levels, a
point confirmed by the FDA.152 This conclusion was also confirmed by independent,
peer-reviewed testing.153
In preparing his opinions, Dr. Jameson reviewed data about “exogenous
NDMA formation from ranitidine,” including testing by FDA, Australia’s TGA,
GSK, Sanofi, and Emery Pharma, among others.154 He considered GSK’s root cause
analysis which “concludes, definitively, that ranitidine decomposes into NDMA on
150
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex. 19, at 3; see id. at 90–
91.
151
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex. 19, at 11–12 (emphasis
added).
152
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex. 15, at 9 (“NDMA levels
in drug substances start to increase at a slow rate from the point of manufacture; both elevated
temperatures and RH contribute to an increase in the rate of degradation”) (emphasis added); id.
Ex. 19, at 7; id. Ex. 8, at 2 (“NDMA levels increase in ranitidine even under normal storage
conditions…and may raise the level of NDMA in the ranitidine product above the acceptable daily
intake limit”) (emphasis added); see also id. Ex. 19 at 7.
153
See id. Ex. 30, at 1.
154
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 91, 91 nn.292–93.
34
standing, exacerbated by heat and humidity.”155 Dr. Jameson holds a PhD in organic
chemistry, and opines as to the molecular reaction beneath the instability of the
ranitidine molecules.156 His opinion, which is confirmed by independent, peer-
reviewed testing, “strongly suggest[s] that environmental factors such as heat and
oxygen are involved in the formation of NDMA.”157
Dr. Jameson concludes that the “evidence is very strong that ranitidine
decomposes to NDMA which is formed because of an intermolecular degradation
reaction of the ranitidine molecules that occurs primarily in ranitidine formations”
and that the “level of NDMA formed in ranitidine upon its storage reaches levels
that exceed the daily intake limit.”158 This is the same conclusion reached in GSK’s
root cause analysis and by the FDA, as evidenced by Defendants’ recalling their
products from the market.159
Dr. Jameson reviewed in vitro and in vivo data, including numerous in vitro
studies prepared by Defendants and independent laboratories, and peer-reviewed
literature that, inter alia, support the formation of NDMA from ranitidine within the
155
Id. at 91–92, 92 n.294.
156
Id. at 92, 92 n.295.
157
Id., 92 n.296.
158
Id., 92 n.297.
159
Id. at 92–93, 92 nn.298–99.
35
human stomach when exposed to sodium nitrite.160 The in vitro data “demonstrates
that NDMA forms in conditions found in the human stomach.”161 Dr. Jameson also
relied on an Emery Pharma simulated food study designed to explore how ranitidine
interacted with nitrite to form NDMA.162 Using the food tests, Emery was able to
show that in simulated gastric fluid ranitidine reacts to form NDMA.163 In his
opinion and in his deposition, he explained his acceptance of or disagreement with
literature he reviewed or pressed upon him by Defendants’ counsel.164
Dr. Jameson also considered conclusions and recommendations from a litany
of federal and international agencies, as well as GSK’s internal studies, that NDMA
“should be regarded for practical purposes as if it were carcinogenic to humans.”165
Conclusions with which he agrees. Some of the agencies reaching that conclusion
include the FDA, the EPA, The Department of Health and Human Services’ Report
on Carcinogens, the U.S. Department Health and Human Services’ Agency for Toxic
160
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex. 19, at 7–9, 10–18; see
id. at 93–94, 93–94 nn.300–311.
161
Id.
162
See Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 95, 95 nn.315–18.
163
See id. at 95–100.
164
See id. at 115–21. Beyond the ranitidine issue, Defendants challenge the science of the Hidajat
study: the duration of the study, measurements of “actual NDMA” available, and estimates and
imputations of NDMA detected and to which workers were exposed. These critiques go to weight
and, as a consequence, fail to support the Motion.
165
See id. at 16–22 (quoting Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op.
Ex. 1, at 36).
36
Substances and Disease Registry (“ATSDR”), and the World Health Organization
(“WHO”).166 It cannot be suggested that Dr. Jameson “neglected the core facts of
the case.”167 Upon completion of his review, he performed a Bradford Hill
analysis.168 Plaintiffs offer a brief comment on Bradford Hill analysis, none of which
is remarkable or cause for debate, but three points merit repetition:
(1) methods used by experts in forming opinions as to
causation substantially rely on the expert’s judgment in
selecting and weighing their sources;
(2) Daubert does not prescribe a specific weight that
evidence should be given; and,
(3) it is not the Court’s role to weigh that evidence, second
guess researchers or pass judgment on substantive
issues.169
Dr. Jameson’s review supports his conclusion that ranitidine produces NDMA
endogenously and exogenously, meets five characteristics of the generally accepted
characteristics of a carcinogen, and is generally accepted among cancer science
researchers that NDMA is capable of causing cancer in animals, including cancer in
166
Id. at 16–19.
167
Kaur, 2022 WL 1486178, at *3.
168
Defendants do not voice challenges to Dr. Jameson’s Bradford Hill analysis, either in their
Opening Brief (filed separately) in support of their Motion to Exclude certain of his opinions, or
in their Reply Brief. Defendants include three pages on alleged failings they ascribe to Defendants’
Bradford Hill analyses, collectively, referring in that argument to “Plaintiffs’ experts” and “some”
of them. This does not give fair notice of specific challenges to Plaintiffs, their experts, or the
Court. Defendants in their arguments directed at specific experts do raise Bradford Hill, which
arguments are addressed later in this ruling.
169
See Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 67–68.
37
humans.170
Defendants’ challenges to the reliability of Dr. Jameson’s methodology are as
follows: he cherry picked his evidence;171 did not rank or weigh his studies;172 the
tests do not imitate conditions in humans;173 his reliance on non-peer reviewed
studies;174 reliance on bad science and improperly rejecting or favoring unreliable
studies;175 and, generally, relying on unreliable exogenous studies.176 These
challenges are for the jury.
The Court finds he utilized sound scientific methodology in formulating his
opinions. His opinion is generally admissible.177 The science with which Dr.
Jameson approached his task here, detailed in Plaintiffs’ Opposition, commends that
170
Id. at 90–91.
171
Brief in Support of Brand Defendants’ and Patheon’s Motion to Exclude Plaintiffs’ Expert Dr.
Charles Jameson, Trans. ID 71409144 (Nov. 15, 2023) (herein “Defs.’ Br. in Supp. of Brand Defs.’
& Patheon’s Mot. to Exclude Pls.’ Expert Dr. Jameson”) at 15.
172
Id. at 16; see Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 100, 100
n.321 (stating that regulatory and scientific bodies do not rank studies but simply assess their
strengths and weaknesses); see also id. at 116–117 (responding to questions from counsel, Dr.
Jameson explains his methodology and explains the strengths and weaknesses of pertinent studies).
173
Id. at 16; but see id. at 101, 101 nn.323–326 (rebutting the assertion that the tests do not imitate
conditions in humans and relying in part on the Braunstein study).
174
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Expert Dr. Jameson at
16.
175
Id. at 17; but see Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 103–
20.
176
Id. at 18.
177
In re Asbestos Litig., 911 A.2d at 1204–06; In re Roundup, 390 F.Supp.3d at 1150–51
(admitting expert opinion where the expert “conducted a literature review and evaluated the quality
of each of the studies”); See Barrera, 2019 WL 2331090, at *14, 17.
38
methodology.178 Defendants may reject that science and the conclusions Dr.
Jameson derives from it. But that makes for a battle of the experts; it does not make
Dr. Jameson’s opinion inadmissible.179 This dispute presents a classic battle of the
experts.180 Defendants’ Motion to exclude the expert opinions of Dr. Charles
Jameson is DENIED.
2. William Sawyer, PhD
Plaintiffs offer Dr. William Sawyer for one purpose: to “convert the inhalation
doses of NDMA observed in the Hidajat study into an equivalent oral dose.”181 Dr.
Sawyer was not proffered, and will not offer, an opinion on causation; similarly he
does not intend to discuss the “merits or demerits of any epidemiological study.”182
The express limits of Dr. Sawyer’s opinion notwithstanding, Defendants criticize
Sawyer for not opining on issues not within his specific task.183
178
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 103–120.
179
McCullock, 61 F.3d at 1044 (“Disputes as to the strength of [an expert’s] credentials, faults in
his use of [a particular] methodology, or lack of textual authority for his opinion, go to the weight,
not the admissibility of his testimony”) (parentheticals added); see also Karlo v. Pittsburgh Glass
Works, LLC, 849 F.3d 61, 83 (3d Cir. 2017) (“The question of whether a study’s results were
properly calculated or interpreted ordinarily goes to the weight of the evidence, not to its
admissibility”) (citation omitted).
180
Long, 2004 WL 1543226, at *6.
181
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 121.
182
Id. at 122; Reply Br. in Supp. of Defs.’ Mot. to Exclude Pls.’ Gen. Causation Experts’ Op. &
Dr. Charles Jameson at 87, 89 (“Plaintiffs acknowledge Dr. Sawyer is not offering a general
causation opinion”).
183
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 126–127; Reply Br. in Supp. of Defs.’ Mot. to Exclude Pls.’ Gen. Causation Experts’ Op.
39
Defendants’ challenges are several, but they focus on one primary issue: Dr.
Sawyer’s reliance on the 2019 Hidajat study. Defendants attack the Hidajat study
because, they say, it “did not involve ranitidine at all,”184 and stand on the limiting,
mechanistic distinction they draw on ranitidine’s role. But Dr. Hidajat did testify
that “[her] study provided important evidence of. . . the association between NDMA
exposure and cancer.”185 Thus, at this juncture, her study “fits” the facts of the case.
The science behind the Hidajat study, and Dr. Sawyer’s use of it, merits pause.
Beyond the ranitidine issue, Defendants challenge the science of the Hidajat
study:186 the duration of the study,187 measurements of “actual NDMA” available,188
and estimates and imputations of NDMA detected and to which workers were
exposed.189 These critiques go to weight and, as a consequence, fail to support the
Motion.190
The Hidajat study “followed 36,441 rubber workers for 49 years—the longest
& Dr. Charles Jameson at 89 (stating that Dr. Sawyer’s analysis “could not bridge the analytical
gap” on cancer causation).
184
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 124, 126.
185
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 78–79.
186
Id. at 124–126.
187
Id. at 125.
188
Id.
189
Id. at 125–26.
190
Kaur, 2022 WL 1486178, at *4; Bowen, 2005 WL 1952859, at *8; McCullock, 61 F.3d at 1038.
40
follow-up (by 25 years) of any other study in this case.”191 The length of the follow-
up period allowed “near-complete dataset, with 94% of the cohort diseased.”192 To
estimate exposure to NDMA, the authors “developed a peer-reviewed matrix based
on the fumes at various locations in the rubber factories…[where workers were]
‘divided into quartiles of exposure,’ each quartile being compared to the first to see
whether greater NDMA exposure was associated with specific cancers.”193 The
Hidajat study documented a “clear dose-response relationship between NDMA
exposure and the development of bladder, esophageal, liver, lung, pancreatic,
prostate, and stomach cancer.”194 Because exposure in that study “was through
inhalation,” Dr. Sawyer “calculated what the equivalent lifetime oral dose would be
in each quartile.”195
Defendants protest that Dr. Sawyer’s method is “flawed because the amount
of bioavailable NDMA can depend on dose.”196 When challenged at his deposition,
he explained that “this was the appropriate method used by forensic
191
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 74, 74 nn.242–247.
192
Id.193
Id.194
Id. at 74–77 (noting Dr. Sawyer offers no opinions on these findings. His opinion is limited to
“convert[ing] the inhalation doses of NDMA observed in the Hidajat study into an equivalent oral
dose.”
195
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 74, 74 n.247.
196
Id. at 121–122; see Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen.
Causation Experts’ Op. at 124–26.
41
toxicologists.”197 He further stated that “by using bioavailable data based on higher
doses, he actually made a more conservative estimate of how much NDMA exposure
is occurring in the Hidajat study.”198 That is, that he was erring “on the side of
caution,” as, Plaintiffs note, is “customarily done in toxicological dose
assessments.”199 This challenge, like the various challenges Defendants assert
against the Hidajat study, fails under Daubert and its progeny.
Dr. Sawyer’s opinion is limited, plainly so. He is not testifying on causation,
but instead on his conversion of inhalation dose to oral dose.200 Defendants reject
his science. Perhaps, as presented during oral arguments, his science may be a bridge
too far. But at this juncture, the criticisms go to weight and do not preclude
admission.201 Defendants’ Motion to exclude Dr. Sawyer is DENIED.
3. Alfred I. Neugut, M.D., PhD.
As his CV makes plain,202 Dr. Neugut is an accomplished epidemiologist at
Columbia University. Dr. Neugut received his MD and PhD from Columbia
197
Id. at 122, 122 n.409.
198
Id.
199
Id., 122 nn.409–411 (citing to deposition testimony); Pls.’ Opp’n to Defs.’ Mot. to Exclude
Gen. Causation Experts’ Op. Ex. 136.
200
Reply Br. in Supp. of Defs.’ Mot. to Exclude Pls.’ Gen. Causation Experts’ Op. & Dr. Jameson
at 89.
201
See Kaur, 2022 WL 1486178, at *4; see also Bowen, 2005 WL 1952859, at *8; see also
McCullock, 61 F.3d at 1038.
202
See Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex. 54.
42
University and a fellowship in Medical Oncology at Sloan-Kettering Cancer Center
as well as Columbia. Dr. Neugut has published over 800 peer reviewed chapters and
papers and received over $60 million in funding from the National Cancer Institute,
American Cancer Society, Department of Defense, and various foundations. Dr.
Neugut has taught cancer epidemiology at Columbia for over 40 years.203
Here, he was tasked to “assess whether the ingestion of ranitidine,
contaminated with NDMA, is causally associated with the development of urinary
bladder cancer.”204 Dr. Neugut was disclosed by plaintiffs in the JCCP litigation to
offer general causation opinions on carcinogenicity and ranitidine.205 The JCCP
Court reviewed his methodology, found it to be reliable and denied defendants’
motion to exclude his opinions.206 The California Court of Appeals has also
acknowledged Dr. Neugut as “an expert in the areas of medical oncology and cancer
epidemiology.”207
His opinions were excluded in In re Roundup Products Liability Litig.,208 and
the Barrera Court—then relying on In re Roundup—also excluded his opinions.209
203
Id.204
Id. at 5.
205
See id. Ex. 75, at 34–38.
206
See id.
207
Johnson, 266 Cal.Rptr.3d at 118, modified on denial of reh’g (Aug. 18, 2020).
208
390 F.3d at 1144–46.
209
Barrera, 2019 WL 2331090, at *15, 15 nn.199–200.
43
The Roundup court noted that Dr. Neugut was “eminently qualified and refreshingly
candid,” and lauded his reports as “high quality.”210 But that court was disturbed by
Dr. Neugut’s presentation, commenting on issues with his testimony, not reflected
in the written transcript.211 The Roundup Court quite correctly noted that “[e]ach
problem with Dr. Neugut’s testimony is not sufficient, on its own, to justify
exclusion.”212 The cases discussed cited herein confirm that point. As to statistical
significance, neither Delaware nor the Third Circuit requires “statistical significance
to prove causality.”213
In preparing his opinion on the question before him here, Dr. Neugut looked
at peer-reviewed literature on NDMA, ranitidine, and bladder cancer, and considered
the strengths and weaknesses of each study.214 He then prepared a forest plot
synthesizing the studies,215 which revealed a consistent increased risk of cancer.216
Dr. Neugut’s approach “reflects a sound methodology consistent with Daubert’s
210
In re Roundup, 390 F.Supp.3d at 1144.
211
Id. (The Roundup Court listed its reasons for its findings that Dr. Neugut’s opinion was not
sufficiently reliable to be admissible. Two related to his conclusions: one to his characterization
of glyphosate as something other than a hazard assessment, the other about an IARC conclusion
as to the meaning of “a probable carcinogen,” and Dr. Neugut’s agreement in his deposition
regarding associations between glyphosate and NHL). None of those issues present here.
212
Id. at 1146.
213
Barrera, 2019 WL 2331090, at *5, 5 n.56 (citing In re Zoloft, 858 F.3d at 793).
214
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex. 54, at 15–26; compare
In re Roundup, 390 F.Supp.3d at 1144.
215
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex. 54, at 33.
216
Id.; see also id. at 126.
44
‘reliability’ component.”217 Dr. Neugut’s review and synthesis of the data and his
creation of the forest plot make his opinion generally admissible.
Dr. Neugut then synthesized the literature using the Bradford Hill factors:
After reviewing the data and studies described above with
regard to the association between ranitidine and bladder
cancer and weighing the evidence in the light of the
Bradford Hill criteria, it is my expert opinion, within a
reasonable degree of medical certainty, that there is a
causal association between ranitidine and urinary bladder
cancer.
Again, there is good biological plausibility that supports
this conclusion. Human epidemiologic studies address this
finding, and many are large, well done, and present
reasonable strong associations for the finding. Also,
several studies of NDMA exposure support an association
with bladder cancer.218
In response to Dr. Neugut’s review and opinion, Defendants pursue an
“unreliable methodology” analysis, which they begin with the suggestion that Dr.
Neugut applies a lower standard of proof in litigation than in his professional
work.219 Defendants do not make clear if they mean to say that Dr. Neugut’s opinion
217
In re Asbestos Litig., 911 A.2d at 1206. Accord, In re Roundup, 390 F.Supp.3d at 1150–51
(admitting expert opinion where the expert “conducted a literature review and evaluated the quality
of each of the studies”). Compare id. at 1148 (excluding expert where the expert report “did not
demonstrate that he engaged in his own objective analysis” of the medical literature on which he
relied).
218
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 126.
219
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 105; Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 126–27.
45
is not made to a “reasonable degree of medical certainty.”220 If so, Dr. Neugut
declares directly that his opinion is provided to that degree of certainty.221
If Defendants’ challenge goes to Dr. Neugut’s call of the question, it is still
not a proper basis for excluding his opinions. “Disputes as to the strength of [an
expert’s] credentials, faults in his use of [a particular] methodology, or lack of textual
authority for his opinion, go to the weight, not the admissibility of his testimony.”222
That notwithstanding, Dr. Neugut applied the same “generally accepted scientific
and medical principles and methodologies” used by cancer epidemiologists.223 Any
challenge to his application of those methodologies goes to the jury.
Defendants also charge that Dr. Neugut’s analysis is “blatantly results-
oriented,”224 uses “cherry picked” data,225 “outcome driven reasoning,”226 and is
“flatly contradict[ed] by his prior [deposition] testimony.”227 These criticisms attack
the expert’s credibility, the bases and calculations underlying his opinion, or seek to
220
See Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation
Experts’ Op. at 105.
221
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 127; see id. Ex. 54, at
35; Ex. 193, at 143:17–25, 144:2–19.
222
McCullock, 61 F.3d at 1044 (parentheticals added).
223
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 127.
224
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 110.
225
Id. at 109.
226
Id.
227
Id. at 107–08.
46
elevate Defendants’ science over that of Dr. Neugut.228 These are all arguments that
Daubert and its progeny reserve to the jury.229
As the gatekeeper, the Court has spent considerable effort in considering Dr.
Neugut’s opinion and Delaware’s jurisprudence on point. The Court is not bound
by the rulings made in RoundUp and Barrera excluding him, particularly given the
comments of the Court on the merits of his opinion, and the presentation of the
science presented here.
Every case is different. In this early phase of the litigation, the Court is more
compelled to its conclusion by the legal concepts that animate Daubert proceedings,
especially as they recognize and uphold the distinct roles of the Court as gatekeeper
and that of the jury as the ultimate fact finder, and by the encouragement of In re
Asbestos Litig. and Long to allow the jury to consider debatable scientific
approaches. Defendants can take up their challenges before the jury on cross
examination. Defendants’ Motion to exclude Dr. Neugut’s expert testimony is
DENIED.
228
Id. at 101–13.
229
See McCullock, 61 F.3d at 1038; see also Karlo, 849 F.3d at 83 (“The question of whether a
study’s results were properly calculated or interpreted ordinarily goes to the weight of the
evidence, not to its admissibility.”) (citation omitted); see also In re Roundup, 390 F.Supp.3d at
1150–51 (“different interpretations of [carcinogenicity] studies are not necessarily evidence of
unreliability . . . plaintiffs may raise their concerns via cross-examination . . .”).
47
4. Dr. Vinod K. Rustgi
Plaintiffs ask Dr. Vinod Rustgi to provide “an expert opinion regarding the
role of high levels of NDMA found in ranitidine products in the risk of development
of Hepatocellular carcinoma” (“HCC”).230 Defendants do not challenge his
qualifications or his actual methodology of conducting a review of peer-reviewed
literature and applying the Bradford Hill factors.231
In conducting his analysis, Dr. Rustgi relied on in vitro data, in vivo data,
tissue culture and animal models, as well as epidemiological evidence in humans.232
Following a review of this data, and a Bradford Hill analysis, Dr. Rustgi concluded
that “NDMA-contaminated Ranitidine can cause the development of HCC.”233 This
base of analysis supports admissibility of Dr. Rustgi’s opinion.234
Yet Defendants challenge Dr. Rustgi’s opinion on several fronts. As
predicate, they argue that Dr. Rustgi concedes that “ranitidine or NDMA” is not
generally accepted by the community of liver specialists as a cause of liver cancer.235
230
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 138.
231
Id.232
Id.233
Id. (quoting Ex. 62, at 1).
234
In re Asbestos Litig., 911 A.2d at 1205–06; In re Roundup, 390 F.Supp.3d at 1150–51
(admitting expert opinion where the expert “conducted a literature review and evaluated the quality
of each of the studies.”).
235
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 117.
48
But Daubert disposed of the general acceptance requirement for admissibility.236
Defendants urge that only one of seven epidemiological studies reported a
significant association between ranitidine and cancer. But Defendants note that
those “results have not been replicated in subsequent studies, and so could be due
to change.”237 Defendants cite the MDL Order from In re Zantac238 in support of
these arguments. For the reasons discussed above, this Court is not guided by that
ruling on these issues. Defendants’ qualification undermines the value of this point.
More directly, the record reflects that Defendants’ assertion misses the mark.
Dr. Rustgi testified that it is generally accepted that NDMA causes liver damage and
liver tumors, and that this is the “preponderance of the evidence going back
decades.”239 With respect to ranitidine, Dr. Rustgi opines that “exposure to NDMA
from ranitidine can cause the development of liver cancer.”240 Dr. Rustgi’s Bradford
Hill analysis, which he conducted, supports this opinion.241
This Court will not inject itself into a dispute over which party has the better
236
Minner, 791 A.2d at 841.
237
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 117 (emphasis added).
238
644 F.Supp.3d at 1258–59.
239
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 139 (citing Ex. 141, at
332:1–10, 331:1–2).
240
Id. (citing Ex. 53, at 35).
241
Id. (citing Ex. 141, at 331:9–18); In re Roundup, 390 F.Supp.3d at 1150–51.
49
science.242 Defendants’ quarrel with Dr. Rustgi’s reading of the Wang study is also
unavailing, as the balance of Defendants’ challenges to admissibility sound in areas
reserved in the first instance to the expert witness’s discretion and, ultimately, the
jury’s wisdom (i.e., cherry picking evidence, improper rejection of relevant data,
vagueness in describing methodology, inconsistent testimony, etc.)243 These issues
present a classic battle of the experts. Resolution of those disputes lies with the jury.
Defendants have failed to satisfy the Daubert requirements to exclude Dr.
Rustgi. The Motion is DENIED.
5. Dr. Ioannis Hatzaras
Plaintiffs identified Dr. Ioannis Hatzaras to evaluate whether NDMA
exposure from ranitidine can cause esophageal, stomach and colorectal cancer.244 In
conducting his evaluation, Dr. Hatzaras reviewed studies “demonstrating that
NDMA is a carcinogen” and reviewed “clinical studies looking into the relationship
between ranitidine containing NDMA. . . and development of foregut/colorectal
242
See McCullock, 61 F.3d at 1038; Karlo, 849 F.3d at 83 (“The question of whether a study’s
results were properly calculated or interpreted ordinarily goes to the weight of the evidence, not to
its admissibility”) (citation omitted); In re Roundup, 390 F.Supp.3d at 1150–51 (“different
interpretations of [carcinogenicity] studies are not necessarily evidence of unreliability…plaintiffs
may raise their concerns via cross-examination.”).
243
See Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation
Experts’ Op. at 116–22; compare Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’
Op. at 139–46.
244
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 149; Ex. 194, at 1.
50
cancer.”245 Dr. Hatzaras “examined 36 particular studies in detail in his report. . .
and catalogued [their] strengths and weaknesses over 30 pages.”246 His report
“dissect[s] each study’s merits and drawbacks” to understand whether any
association is, in fact, causal.247
Upon completing his review of the literature, Dr. Hatzaras performed a
Bradford Hill analysis.248 He then conducted a separate Bradford Hill analysis for
esophageal, gastric, and colorectal cancer.249 Based on his review, evaluation and
analyses, Dr. Hatzaras concludes to a “reasonable degree of scientific certainty” that
“NDMA in ranitidine causes foregut/colorectal carcinoma.”250 His Bradford Hill
analysis confirms that opinion. Dr. Hatzaras’ analysis supports admissibility of his
opinion.251 Defendants present several challenges, notwithstanding.
Relying again on the MDL Order, Defendants contend that Dr. Hatzaras
employed “an inconsistent, results-driven approach” that “turn[s] science on its
head,” cherry picked his data, altered his opinion “mid-way through his deposition,”
245
Id.246
Id.247
Id. at 149–50.
248
Id. at 150.
249
Id.250
Id.251
In re Asbestos Litig., 911 A.2d at 1204–06; see In re Roundup, 390 F.Supp.3d at 1150–51
(admitting expert opinion where the expert “conducted a literature review and evaluated the quality
of each of the studies.”).
51
and applied flawed methods, or none through a “standardless” approach.252 For the
reasons previously stated, the Court is not bound by that ruling.
Moreover, Plaintiffs’ comprehensive presentation of Dr. Hatzaras’ testimony
sufficiently addresses Defendants’ challenges,253 including but not limited to an
explanation of the science behind Dr. Hatzaras’ rejection of the “binary approach to
statistical significance extolled” by Defendants.254 Defendants’ arguments may
undermine Dr. Hatzaras’ opinion and be fodder for cross examination, but they
cannot exclude that opinion. These expert battles are to be fought before the
factfinders. This Motion is DENIED.
6. Dr. Dan J. Raz
Dr. Dan J. Raz, a thoracic surgeon and scientist specializing in lung cancer,
was asked by Plaintiffs to give opinions as to the causal relationship between
ranitidine and lung cancer.255 As with all of Plaintiffs experts, Defendants do not
challenge Dr. Raz’ qualifications to offer the opinion sought.256
Dr. Raz used a “comprehensive review of electronic databases to provide
sources for his opinions. He also looked to public health authorities, including the
252
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 76–78.
253
See Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 150–62.
254
Id. at 151–52.
255
Id. at 163.
256
See id. at 163–64 (detailing recitation of Dr. Raz’ CV).
52
FDA, WHO, and IARC. He carefully considered the strengths and weaknesses of
each source.”257 Upon completing his review, Dr. Raz performed a Bradford Hill
analysis to determine whether ranitidine causes lung cancer. He opined that
“NDMA exposure from ranitidine use is capable of causing lung cancer.”258
Dr. Raz’ methodology supports admission of his opinion.259 His
methodology appears to mirror that of Defendants’ lung cancer expert, Anil
Vachani, M.D., M.S.260 Though they reach different conclusions, “different
interpretations of these [sources] are not necessarily evidence of unreliability[.]”261
This is, literally, a battle of the experts.
Nonetheless, Defendants advance several challenges to Dr. Raz’ opinion.
They begin with the charge that his opinions are not generally accepted.262
Defendants conflate acceptance of methodology with acceptance of expert
conclusions.263 As noted above, while Daubert gives great latitude to the gatekeeper
in evaluating what factors may be implicated in these disputes, none of those
factors—including general acceptance of medical conclusions—is determinative in
257
Id. at 165.
258
Id. at 164–65.
259
See In re Asbestos Litig., 911 A.2d at 1205–06; In re Roundup, 390 F.Supp.3d at 1102.
260
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 165 n.614.
261
In re Roundup, 390 F.Supp.3d at 1150.
262
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 166.
263
See Daubert, 509 U.S. at 580; Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’
Op. at 166.
53
the trial court’s analysis. Indeed, Daubert holds that methods, not conclusions, are
to be tested.264 Each factor is but one among many that this Court may consider.
Importantly, Plaintiffs’ experts point to several public, private, and
governmental medical and regulatory entities that have studied NDMA and
concluded that NDMA is capable of causing cancer in humans. The record suggests
that GSK conceded as much in 2019.265 Also, the Wang study specifically showed
a “statistically significant association between exposure to ranitidine and lung
cancer.”266 The Habel study found an “overall increased cancer risk,” but fell just
short of statistical significance for lung cancer. But a positive association may still
be relied upon by experts; Daubert does not preclude it. It permits it.267
Defendants’ remaining challenges echo those cited in other expert challenges
discussed above, such as improper weighing/cherry picking studies on which to rely,
reliance on NDMA dietary studies, failing to consider/elevating Defendants’ science
over the witnesses. For example, Defendants complain that Dr. Raz’ opinion should
264
Daubert, 509 U.S. at 580; see Tumlinson, 81 A.3d at 1272 (noting that “an expert may also
rely on techniques that have gained widespread acceptance in the scientific community.”)
(emphasis added).
265
See Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex. 12, at 16:1–17
(“[P]rotect the scientists and anybody handling” NDMA in the laboratory.) (emphasis added); see
also Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex. 11.
266
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 169; Ex. 146, at 119:7–
8.
267
Barrera, 2019 WL 2331090, at *5 (permitting expert to testify where opinions were based on
some studies showing statistically significant associations or positive associations).
54
be excluded because he improperly weighed seven epidemiological studies on
ranitidine and lung cancer, and that his analysis of the studies was flawed.268 In his
report and deposition, Dr. Raz went into detail explaining that he considered all
seven of the studies and his reasons for giving more weight to two of them: Wang
and Habel.269
Yet, Defendants offer a one-page challenge to Dr. Raz’ Bradford Hill analysis
on three points: consistency, temporality, and strength of association.270
Defendants claim that the analysis is “unreliable’ because he relied upon only two
data points cited in those two studies of Wang and Habel. As discussed previously,
Dr. Raz’ reliance upon these studies is reasonable. Any quarrel with the application
of his methodology is for the fact finder.271
Evaluation of Bradford Hill factors turns on the “expert’s judgment in
selecting and weighing her sources.”272 “[E]xperts operating on reliable scientific
268
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 59–62.
269
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 167–71.
270
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 62–63.
271
Karlo, 849 F.3d at 83 (“The question of whether a study’s results were properly calculated or
interpreted ordinarily goes to the weight of the evidence, not to its admissibility”); see also In re
Roundup, 390 F.Supp.3d at 1150–51 (“different interpretations of [carcinogenicity] studies are not
necessarily evidence of unreliability…plaintiffs may raise their concerns via cross-examination.”).
272
Barrera, 2019 WL 2331090, at *4.
55
principles could weigh the studies differently[.]”273 Any disputes about those
judgments are not for the Court to resolve. These decisions, made within the
framework constructed by Daubert and progeny, are reserved to the jury. Therefore,
Defendants’ Motion as to Dr. Raz is DENIED.
7. Dr. Pablo Leone
Dr. Leone is expected to offer a general causation opinion as to whether
NDMA exposure from ranitidine causes breast cancer based upon the
epidemiological evidence.274 Defendants do not challenge Dr. Leone’s
qualifications.275 To answer the general causation question, Dr. Leone reviewed the
“available scientific evidence regarding, Zantac (ranitidine) and NDMA”276 He used
a method “consistent with what is followed by cancer research scientists when
evaluating whether a chemical agent is a carcinogen and whether individuals are at
risk of developing cancer based on exposure.”277 His methodology involved:
• a review and evaluation of extensive medical
scientific literature, including epidemiological, in
vivo animal, in vitro studies and reviews of all
relevant topics;
• research on publicly available information related to
ranitidine and NDMA, their safety and association
273
Id. at *8.
274
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 200.
275
See id. at 200–04 (providing summary of Dr. Leone’s credentials).
276
Id. at 203.
277
Id.
56
with cancer generally via articles and references
from Dr. Leone’s personal library of journals and
textbooks, as well as PubMed and other relevant
literature searches;
• a review and analysis of publications from scientific
and governmental agencies, including WHO,
IARC, FDA, and the EPA. and,
• a review and analysis of documents produced by
Defendants in this litigation.278
Dr. Leone then assessed the totality of the evidence using a weight of the
evidence methodology in the context of Bradford Hill and different etiology
concepts, where he concluded to a reasonable degree of medical and scientific
certainty that “Zantac/ranitidine can cause breast cancer in humans, [and that] the
causal association is strongest for invasive ductal carcinoma.”279 Dr. Leone’s
methodology tracks that of many of the experts herein, including Defendants’ lung
expert, Anil Vachani.280
As noted, application of this methodology generally supports the admissibility
of the opinions at issue.281 To overcome this presumption, Defendants assert four
challenges to Dr. Leone’s opinion beyond the mechanics of the methodology: (1) his
278
Id. at 203–04.
279
Id. at 204.
280
Id. at 165.
281
See In re Asbestos Litig., 911 A.2d at 1204–06; In re Roundup, 390 F.Supp.3d at 1150–51
(admitting expert opinion where the expert “conducted a literature review and evaluated the quality
of each of the studies.”). See also Barrera, 2019 WL 2331090, at *14, 17.
57
conclusions are not generally accepted;282 (2) he cannot explain the formulation of
his opinion;283 (3) he committed “several methodological errors that are red flags
under Daubert,” such as ignoring the principle of statistical significance and
applying an inappropriate substitute;284 and (4) he perform[ed] an “unreliable
Bradford Hill analysis.”285 The Court addresses these briefly, seriatim.
General acceptance. In considering this issue, one must bear in mind that the
Daubert analysis, rejecting the general acceptance requirement, focuses on “the
principles and methodology used in formulating an expert’s testimony, not the []
resulting conclusions.”286 Defendants assert that Dr. Leone concedes no other
agency or government has concluded that ranitidine can cause breast cancer and that
Dr. Leone has made “an analytical leap from available data that no other scientist
outside this litigation has made.”287 Not so. In the findings of the Mathes study,288
the authors reported a “2.2-fold increased risk of ductal type breast cancer,
representing a 120% increase in the risk of developing breast cancer associated with
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
282
Op. at 41.
283
Id.284
Id. at 43.
285
Id. at 46.
286
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 205 (quoting Bowen,
906 A.2d at 794).
287
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 41 (quoting In re Zantac, 644 F.Supp.3d at 1187).
288
See Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 205 n.757; Ex. 117.
58
current use of ranitidine.”289 Therefore, the general acceptance argument does not
advance Defendants’ cause.
Second, Defendants argue that Dr. Leone cannot explain how he formulated
his opinion. Yet, he testified that he did not ascribe an individual weight to each
element of his data set, but instead that all of the data “informed [his] opinion.”290
Dr. Leone’s notes on the strengths and weaknesses of each study were taken into
account in his Bradford Hill analysis.291 He lays out in detail the various bases for
his opinion.292 To the extent Defendants dislike the explanations, they can present
their protestations to a jury.
Defendants also give a short shrift to Dr. Leone’s reference to the Braunstein
study, asserting that it has not been “subject to the rigors of peer-review.”293
Although Braunstein was posted on a pre-print online database, the underlying
epidemiological data in the study had already been peer-reviewed.294 The effort to
get the Braunstein study published does not impact the admissibility of Dr. Leone’s
289
Id.
290
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 41 (quoting Dr. Leone’s Tr.).
291
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 206; Ex. 155, at 23.
292
See id. at 206.
293
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 42.
294
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 206; Ex. 113, Ex. 142,
at 8–9.
59
opinion, especially since general acceptance is not a requirement under Daubert.295
Moreover, the reasonableness of Dr. Leone’s reliance on Braunstein is for the jury’s
consideration.
Defendants’ challenges to Dr. Leone’s opinion assert also that he “cherry-
picks” favorable evidence, fails to consider contrary evidence,296 and ignores the
principle of statistical significance.297 These allegations have been held repeatedly
to be reserved for cross examination.298 Moreover, Plaintiffs rebut each of these
allegations.299 At this early stage, there is more than enough evidence to overcome
Defendants’ challenge to Dr. Leone’s formulation of his opinion.
Defendants’ final challenge is that Dr. Leone has performed an unreliable
Bradford Hill analysis.300 They assert Dr. Leone’s consistency conclusion is
unsupported, as the studies are noteworthy for their “consistent finding of no
295
See id. at 206–07.
296
Id. at 208–09.
297
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 43.
298
See Karlo, 849 F.3d at 83 (“The question of whether a study’s results were properly calculated
or interpreted ordinarily goes to the weight of the evidence, not to its admissibility”); see also In
re Roundup, 390 F.Supp.3d at 1150–51 (“different interpretations of [carcinogenicity] studies are
not necessarily evidence of unreliability…plaintiffs may raise their concerns via cross-
examination.”).
299
See Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 208–11.
300
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 46.
60
statistically significant association.”301 They declare his dose-response analysis
“unscientific” in part due to his failure to use the “generally accepted definition of a
“dose-response study.”302 They further reject Dr. Leone’s explanations defending
the applications and conclusions drawn on this issue, including his inability to
identify any threshold dose of exposure.303 Delaware law does not impose a bright
line threshold dose requirement, as discussed above. Moreover, none of these
challenges rises above the credibility-oriented questions that Daubert and progeny
for years have reserved to the jury. Defendants’ Motion as to Dr. Leone is DENIED.
8. Dr. Vitaly Margulis
Dr. Margulis has been asked to opine on whether it is likely that the NDMA
in ranitidine can cause cancer.304 Defendants do not challenge Dr. Margulis’s
qualifications.305 Dr. Margulis reviewed publicly available literature on ranitidine,
NDMA and renal cancer, including both primary studies and “publications from
scientific and governmental authorities, such as WHO, TARC, FDA and others.306
In his report, Dr. Margulis discusses how ranitidine breaks down into NDMA
301
Id.302
Id.303
Id. at 47, 47 n.85.
304
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 212.
305
See id. (providing Dr. Margulis’ professional education and practice).
306
Id. at 213.
61
and the mechanism by which NDMA can cause cancer.307 Relying on in vitro and
animal studies, he explains that, in the human body, NDMA metabolizes into “DNA
adducts,” which induce “carcinogenic point mutations.”308 Based on his review, Dr.
Margulis concludes that NDMA is a “potent carcinogen in every species tested” at
“single doses and after long-term exposure to smaller doses.”309 The animal studies
found animals were particularly likely to develop kidney tumors.310
Dr. Margulis then analyzed ranitidine-specific epidemiology. Six studies
reported a kidney cancer result.311 He analyzed each, finding some strong and others
seriously flawed.312 Overall, Dr. Margulis found that every study had “non-
differential misclassification of exposure” which “likely biased risk estimates
toward the null;” that is, the studies “were particularly likely to report a false
negative result.”313 In Dr. Margulis’s expert opinion, none of the epidemiological
studies could measure “important data points,” which led to “limitations” impossible
to overcome.
After consideration of the literature, Dr. Margulis conducted a Bradford Hill
307
Id.
308
Id.
309
Id. at 213–14.
310
Id. at 214.
311
Id.
312
Id.
313
Id.
62
analysis, which led him to opine that “the NDMA in ranitidine can cause cancer.”314
Thereafter, Dr. Margulis authored a peer-reviewed article describing the background
of NDMA and ranitidine and proffering—as a specific mechanism for
carcinogenesis—his conclusions as to the harmful metabolization of NDMA.315 The
mechanism is based on human in vitro studies and animal studies.316
In both his expert report and his peer-reviewed article, Dr. Margulis “explains
that animal and in vitro studies can be applied to humans. . . based on the similarities
in NDMA metabolism seen in animal studies and in vitro human cellular
experiments.”317 Dr. Margulis included in his article ranitidine epidemiological
studies, including the same criticisms he raised in his expert report, one of which
noted that “any conclusions drawn from these observational studies, whether
supporting or challenging. . . should be interpreted with caution.”318
Defendants challenge Dr. Margulis’s opinion much as they have many of the
others; he is inconsistent in his approach to statistical significance;319 his conclusion
314
Id. at 215.
315
Id. at 215–16.
316
Id. at 216.
317
Id. (internal quotation marks omitted).
318
Id. (emphasis omitted).
319
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 50.
63
is not accepted by the scientific community;320 he “cherry-picks” his evidence;321
and his “principal” reliance on dietary and worker NDMA studies is not
appropriate.322
The extended discussion of Dr. Margulis’s methodology and findings make
plain the detailed nature of his statistical analysis.323 He is not a poseur.324
Defendants admit he is qualified to offer his opinion, and at this stage, his methods
confirm as much.
As to “principally” relying on NDMA dietary and worker studies, in his report
Dr. Margulis spends one paragraph each on dietary and occupational studies,
summarizing them, and emphasizes that the role those studies played in his
conclusion was “not significant.”325 He further considered the contrary statistical
findings in the six ranitidine studies.326 Plaintiffs emphasize that “[t]here is nothing
inconsistent about accurately reporting the actual results from these studies.”327
Defendants pause on these mixed results as “the definition of inconsistent
320
Id. at 49.
321
Id. at 50–53.
322
Id. at 53–55.
323
See Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 214, 217–19.
324
In re Asbestos Litig., 911 A.2d at 1207.
325
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 218.
326
Id. at 214, 217–18.
327
Id. at 217.
64
results,”328 although they point out Dr. Margulis’s conclusion that the six studies
broke evenly, three showing an increased risk and three a decreased risk. At this
level of science, any characterization of these numbers would do the data a
disservice. And asking this Court to do the math is not a good idea. Numerically,
the results, inconsistent or otherwise, do not tip the scale in either direction.329
Defendants further throw several accusations at Dr. Margulis’s report. While
the Court considers many herein, review of the Opposition gives a more fulsome
recitation of Dr. Margulis’ rebuttal in defense of his opinion.330 Some, Plaintiffs
suggest, mischaracterize his opinions.331 Some, they claim, ignore his testimony.332
These challenges, along with claims of cherry-picking and flawed reliance on certain
NDMA studies, fall victim to the wisdom of Daubert: they belong to the jury.333
The Motion to exclude Dr. Margulis’s opinion is DENIED.
9. Dr. George Miller
Plaintiffs have asked Dr. Miller to provide opinions regarding whether
328
See Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation
Experts’ Op. at 51; Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 217.
From a non-scientist’s perspective, that the six studies broke evenly on the point 3 to 3 does not
seem to fit the definition of inconsistent.
329
Barrera, 2019 WL 2331090, at *17 (stating that opposing experts interpreted the same studies
differently “does not render [their] opinions inadmissible.”).
330
See Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 216–21.
331
See, e.g., id. at 217–19.
332
Id. at 219.
333
Karlo, 849 F.3d at 83; In re Roundup, 390 F.Supp.3d at 1150–51.
65
NDMA exposure from ranitidine causes pancreatic cancer.334 Defendants do not
challenge Dr. Miller’s qualifications to opine on that question.335 Defendants would
exploit Dr. Miller’s lack of formal epidemiological training, but they have not voiced
objection to the expert’s qualifications to offer those opinions. Dr. Miller may testify
on epidemiological issues implicated in his report.336
Dr. Miller is expected to opine within a reasonable degree of medical certainty
that there is a causal link between ranitidine and pancreatic cancer.337 In preparing
that opinion, Dr. Miller first analyzed “whether ranitidine contains a cancer-causing
agent” and—relying in part on GSK’s root cause analysis—found that NDMA is a
toxic degeneration byproduct of ranitidine.338 Dr. Miller also relied upon testing
outlined in the expert report by Emery Pharma.339 He analyzed studies that showed
a link between dietary sources and pancreatic cancer. Dr. Miller then compared the
studies with others that did not show an association between ingestion of nitrates and
pancreatic cancer, finding serious flaws with those that did not show an
association.340
334
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 184.
335
See id. at 185–87 (providing summary of Dr. Miller's educational and professional
background).
336
See Barrera, 2019 WL 2331090, at *13.
337
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 187.
338
Id.339
Id. at 187–88.
340
Id. at 188.
66
Dr. Miller also analyzed studies showing a link between occupational
exposure to NDMA and pancreatic cancer, and weighed the strengths and
weaknesses of each study to determine if the peer-reviewed studies supported such
a link. Dr. Miller then analyzed peer-reviewed studies regarding the link between
NDMA exposure from ranitidine use and pancreatic cancer. After weighing the
strengths and weaknesses of each study, Dr. Miller then analyzed the Bradford Hill
criteria, and concluded the existence of a causal link between ranitidine and
pancreatic cancer.341 And added that “[t]here is considerable biologic plausibility to
support this conclusion and lend support to the well-conducted human
epidemiological studies.”342
Defendants argue that Dr. Miller’s methodology is unreliable. Pointing to a
number of alleged deficiencies across the breadth of his opinion, the gist is that the
augmentation of his opinions are evidence of the “results-oriented nature of his
analyses.”343 These allegations do not support exclusion of his opinion.344 Nor does
what Defendants characterize as Dr. Miller’s “inconsistent application of power and
341
Id. at 189.
342
Id.
343
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 63.
344
Barrera, 2019 WL 2331090, at *11 (changing opinion goes to the weight, not admissibility).
67
follow-up to the studies.”345 Their rejection of his analysis and application of follow-
up time,346 does not compel exclusion. Likewise, the arguments that Dr. Miller made
a “faulty assumption” and improperly “flipped the burden” of proof,347 or turned
“limitations in the ‘negative’ studies into strengths in the studies he preferred,”348 go
to weight, not admissibility.349
In a broader attack, Defendants accuse Dr. Miller of providing no
methodology for how he evaluated studies. First, this claim is rebutted by the
extensive background review Dr. Miller performed as part of his preparation. Miller
testified that he “conducted a systematic review of the literature and evaluated the
science to arrive at his conclusions.”350 Second, Dr. Miller dedicates eleven pages
of his report discussing the various studies and their strengths and limitations.351
345
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 93–94; see Reply Brief in Support of Brand Defendants’ and Patheon’s Motions to Exclude:
(1) Plaintiffs’ General Causation Experts’ Opinions; and (2) Dr. Charles Jameson, Trans. ID
71797654 (Jan. 12, 2024) (herein “Reply Br. in Supp. of Defs.’ Mot. to Exclude Pls.’ Gen.
Causation Experts’ Op. & Dr. Jameson”) at 63–64.
346
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 194–95; see Defs.’ Br.
in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’ Op. at 94–
95.
347
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 91.
348
Id. (emphasis in original).
349
McCullock, 61 F.3d at 1038; Karlo, 849 F.3d at 83.
350
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 91.
351
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 192.
68
Defendants accuse Dr. Miller of not ranking the studies by quality.352 But Dr.
Miller wrote extensively in his report regarding the strengths and weaknesses of each
study.353 They complain that Dr. Miller was not able to identify the key criteria he
used to determine a study’s reliability. Yet, he testified that the most critical factors
for him in evaluating studies were “median age to study an appropriate population
and follow-up time.”354 Defendants discredit Dr. Miller’s Bradford Hill analysis,
although he testified at length about same.355
Dr. Miller’s conclusions are reliable.356 At this stage, it cannot be said that
the scope of his review and the science used to formulate his opinions do not support
admissibility.357 Defendants may have succeeded at times in making this a close
call. But close calls go to the jury. The Motion to exclude his opinion is DENIED.
10. Bruce J. Trock, MPH, PhD
Dr. Trock has been disclosed to give general causation opinions regarding
whether NDMA exposure from ranitidine causes prostate cancer.358 Dr. Trock is a
352
Id. at 193.
353
Id.354
Id.355
See id. at 198–99.
356
Barrera, 2019 WL 2331090, at *14.
357
In re Asbestos Litig., 911 A.2d at 1205–06; In re Roundup, 390 F.Supp.3d at 1150–51 (expert
opinion admitted where the expert “conducted a literature review and evaluated the quality of each
of the studies.”); accord, Barrera, 2019 WL 2331090, at *14, 17.
358
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 174.
69
cancer epidemiologist at Johns Hopkins University, with 37 years of experience in
cancer research, 21 of which were focused on prostate cancer.359 He has authored,
or co-authored, over 320 peer-reviewed publications, 201 of which focus on prostate
cancer.360 Defendants do not challenge Dr. Trock’s qualifications to testify here.361
In preparing his opinions, Dr. Trock reviewed and analyzed “the entirety of
the relevant scientific and epidemiological literature concerning the association
between ranitidine and prostate cancer.”362 In doing so, Dr. Trock “assessed the
strength of the relevant evidence derived from animal and occupational studies, and
Dr. Trock used his review and analysis of the medical literature, including the
strengths and weaknesses of the pertinent studies, to perform a Bradford Hill
analysis.363 Based on his reviews and his Bradford Hill analysis, Dr. Trock
concluded, to a reasonable degree of scientific certainty, that exposure to ranitidine
can cause prostate cancer in humans.364 His opinions are based on sound, reliable
scientific methodology, and are generally admissible.365
359
Id.360
Id.361
See id. at 174–75 (providing a more complete summary of Dr. Trock’s qualifications).
362
Id. at 175; Ex. 147, at 24–38.
363
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 175.
364
Id. at 176.
365
Id.; see In re Asbestos Litig., 911 A.2d at 1205–06; see also In re Roundup, 390 F.3d at 1150–
51 (expert opinion admitted where the expert “conducted a literature review and evaluated the
quality of each of the studies.”); accord, Barrera, 2019 WL 2331090, at *14, 17.
70
Defendants interpose several challenges to that admissibility. Their initial
challenge argues that relevant epidemiological studies “reported no statistically
significant positive associations between ranitidine use and prostate cancer.”366
Plaintiffs counter that, in fact, Dr. Trock noted that of the nine relevant
epidemiological studies concerning ranitidine, three actually observed “increases in
the incidence of prostate cancer.”367 Dr. Trock further distinguished five of the
remaining six studies as considerably flawed (i.e., they used inadequate follow up
periods, had short durations of exposure to ranitidine, and failed to adjust for
potential confounders).368 Several studies “lacked data on duration or cumulative
dose of ranitidine, and recorded only at baseline,” and were therefore susceptible to
misclassification.369
Defendants first reject Dr. Trock’s analysis and conclusions. That is, of
course, their prerogative, but does not support exclusion. Similarly, Defendants
raise again the charge that his opinion is inadmissible because his conclusions are
not generally accepted in the medical community.370
366
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 64.
367
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 177.
368
Id.369
Id.370
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 64–65.
71
As noted, Daubert rejected the general acceptance requirement. Defendants
nonetheless urge that general acceptance is still an indicator of unreliable
methodology.371 But, the record establishes that Dr. Trock analyzed the relevant
data, and his opinions align with three of the relevant studies. This evidence is to be
used flexibly when evaluating reliability. Again, Daubert does not charge the trial
court to pick one expert’s science over another’s.372
Defendants next argue that Dr. Trock’s conclusions are unreliable because he
“ignores epidemiological ranitidine studies and takes the novel approach of drawing
conclusions about ranitidine based on studies” of rubber workers and animals.373
Defendants point to the MDL Order and its rejection of the Hidajat study as
flawed.374 Those may have been appropriate conclusions for that court to draw. But
as presented through these experts, in Delaware, it is not the role of this Court to
substitute its scientific conclusions for those of an expert scientist.
Dr. Trock analyzed the Hidajat study and compared it to a second rubber
worker study, which he rejected as marred by speculation.375 Dr. Trock did not rely
371
Id. at 65.
372
In re Asbestos Litig., 911 A.2d at 1207.
373
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 65–67; Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 179.
374
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 66.
375
Id.72
on animal studies alone. He considered their import along with his evaluation of the
six epidemiological studies available. Defendants acknowledge that Dr. Trock
analyzed the epidemiological ranitidine studies and dismissed them as “severely
flawed.”376 That approach is consistent with the proper methodology applied in such
circumstances.377 Delaware law “does not require that evidence of general causation
take the form of epidemiological evidence . . . Evidence such as animal studies, in
vivo studies, in vitro studies, toxicology, and case studies can be used to show
causation.”378 These factors are to be applied flexibly.379
Defendants’ final charge is that Dr. Trock’s Bradford Hill analysis is
unreliable.380 They argue that an expert must address epidemiological evidence that
is inconsistent with his opinion.381 As discussed above, Dr. Trock did that. Their
argument about dose response, which is another of the Bradford Hill criteria that
may be considered, does not suffice to compel exclusion of Dr. Trock’s opinion.
376
Id. at 65–66.
377
See, e.g., Barrera, 2019 WL 2331090, at *14.
378
Id.379
See Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 182 (discussing Dr.
Trock’s selection of studies on which he relied); see, e.g., id. (“Dr. Trock’s analysis, placing more
weight on NDMA occupational [and animal] studies, is entirely reasonable in light of the
significant limitations in the nine epidemiological studies of ranitidine.”); see also id. at 180
(discussing Dr. Trock’s use of animal studies, emphasizing that “in considering the weight of the
evidence, Dr. Trock considered NDMA animal studies - but not to the exclusion of the relevant
epidemiological literature.”).
380
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Pls.’ Gen. Causation Experts’
Op. at 68–69.
381
Id. at 69.
73
Defendants can take up these challenges before the jury. The Motion to exclude Dr.
Trock is DENIED.
11. Emery Pharma
Plaintiffs retained Emery Pharma (hereinafter “Emery”) to “conduct further
testing on the levels of NDMA in ranitidine provided by Defendants and specifically
the levels in Plaintiffs’ own pills and opine on the nature of ranitidine’s ability to
degrade and transform into NDMA.”382
Emery is a “full-service contract research laboratory, specializing in
analytical, bioanalytical chemistry, microbiology and cell biology services, custom
synthesis, [] general research and development and [] the standards employed in the
manufacture of drugs, not in research.”383 Defendants characterize Emery as a
“litigation support lab.”384 Emery counters that “only approximately twenty percent
of Emery’s revenues are from litigation consulting.”385 Emery describes the
majority of its clients as pharmaceutical companies that reach out to Emery for
“isolation characterization work;” that is, to analyze and identify “an impurity in a
382
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 223.
383
Id. at 224.
384
Brief in Support of Brand Defendants’ and Patheon’s Motion to Exclude Plaintiffs’ Expert,
Emery Pharma, Trans. ID 71408808 (Nov. 15, 2023) (hereinafter “Defs.’ Br. in Supp. of Brand
Defs.’ & Patheon’s Mot. to Exclude Emery Pharma”) at 14 n.23. The Court notes Defendants’
Brief to Exclude Emery Pharma is devoid of pagination, as such the Court references the
corresponding PDF page numbers.
385
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 221 n.829.
74
drug that is being marketed.”386
Defendants do not challenge Emery’s qualifications to render the opinions
requested of it.387 Yet, the parties devote nearly 150 pages of briefing to the
admissibility of the Emery opinion alone. The somewhat more aggressive and
pejorative rhetoric in the briefs suggests the Emery opinion lies at the heart of the
Daubert debate, for both sides.
Defendants offer nine challenges to the admissibility of the Emery Opinion:
(1) Plaintiffs’ use of HILIC methodology is unvalidated
and unreliable;
(2) Plaintiffs’ opinion of manual integration, without
proper protocols, is unreliable;
(3) Plaintiffs failed to keep proper documentation;
(4) Dr. Najafi left all operational decisions in the testing
process to the discretion of his assistants, who did
not follow preset protocols;
(5) the Emery opinion has not been published or
submitted for peer review;
(6) the Emery opinion does not “fit” the parameters of
the issue here;
(7) Emery’s simulated studies fail to meet the Daubert
standards;
386
Id.
387
See id. at 224–28 (providing a more complete recitation of Emery qualifications and its
representatives).
75
(8) Emery’s simulated gastric fluid study is not reliable;
and
(9) Emery’s “miscellaneous tests” do not “fit” the case
and are not reliable.388
The Court addresses briefly each of Defendants’ challenges separately. The
Court prefers not to get into the weeds of the science, but some digging is required.
a. Emery’s Use of HILIC
Emery used Hydrophilic Interaction Chromatography (“HILIC”) to test for
the presence of ranitidine. Defendants argue that HILIC is unvalidated, and
therefore unreliable. Defendants also charge that the increased measure of ranitidine
when HILIC was used supports their charge that HILIC’s use was a litigation-driven
decision, made to skew the numbers in Plaintiffs’ favor.
HILIC is a technique for separation of polar compounds. Plaintiffs explain
that HILIC was used in the first part of Emery’s separation processes “to improve
sample identification and quantification.”389 Plaintiffs further indicate that Emery’s
method known as LC-MS/MS (the combination of liquid chromatography (“LC”)
and mass spectrometry (“MS”)) “uses the same underlying technology the FDA
used, with the difference being the type of initial column used for separation of the
388
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 21–22.
389
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 236.
76
analyte.”390
Plaintiffs further assert that HILIC is a well-established, accepted column for
use in chromatography with polar compounds, which NDMA is.391 They quote from
a monograph by Defendants’ expert, Bernard Olsen, in support:
The popularity of [HILIC] has grown rapidly in recent
years. The HILIC mode can provide retention and
separation of polar compounds that are difficult to analyze
by reversed-phase high-performance liquid
chromatography (RPLC) or other means. HILIC has been
utilized in a variety of applications including drugs and
metabolites in biological fluids, biochemicals,
pharmaceuticals (from drug discovery to quality control),
foods and environmental.392
The Olsen monograph notes that HILIC “can be particularly suited in the
determination of specific impurities, including polar compounds,”393 of which
NDMA is one.
Emery explains its reasons for preferring HILIC columns over reverse-phase
columns.394 Emery also showed that its protocol, including use of an HILIC column,
was “fully validated.”395 Notably, the JCCP court rejected this same Daubert
390
Id.
391
Id. at 237.
392
Id.
393
Id. at 237, 237 n.878.
394
Id. at 236–38.
395
Id. at 239.
77
challenge.396 Emery’s efforts notwithstanding, Defendants reject their science and
stand on the MDL Order.397 Following Delaware jurisprudence, this Court finds that
HILIC has been validated and determined reliable, and its use in measuring
ranitidine constitutes sound methodology to survive a Daubert challenge.
b. Manual Integration
Defendants’ challenge of Emery’s use of manual integration involves data
integrity. They claim Plaintiffs did not follow a Standard Operating Procedure
(SOP) to guide when “analysts perform manual integrations.”398 They further accuse
Emery of performing manual integrations “unreliably, arbitrarily, and following no
set standards.”399
Emery explained that “all decisions regarding when and how to conduct
manual integrations, along with the integrations themselves, were done using the
same scientific principles as written in Emery’s Standard Operating Procedure
(“SOP”) for chromatography analysis [] that was in effect at the time.”400 It appears
396
Id. at 254; see also Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex. 75,
at 2 3.
397
Brand Defendants’ and Patheon’s Reply in Support of their Motion to Exclude Plaintiffs’
Expert, Emery Pharma (herein “Defs.’ Reply Br. in Supp. of Mot. to Exclude Emery Pharma”) at
9–11.
398
See Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 29.
399
Id.; Ex. 15, at 1.
400
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 241.
78
that Defendants’ expert, Dr. Olsen, also relied on the same scientific principles.401
“[W]hether performed automatically or manually. . . integration must be
scientifically justifiable.”402 Defendants concede that an “analyst must exercise
professional judgment in deciding when use of a manual integration is
appropriate.”403 Emery performed manual integrations only when the default
integration was scientifically unsound.404 To the extent that Defendants rely on the
Agilent monograph in support of this argument, this Court accepts the reasons set
for by Plaintiffs that any data manipulation that was focused on FDA compliance is
not at issue here.405
Defendants further argue that Emery “left manual adjustments to the
unfettered discretion of its staff,” and that performing manual engagements “may”
be a sign of a “flawed method.”406 For several reasons, this argument is insufficient
to warrant relief.
Emery makes the point that “Dr. Cheu,” one of the primary representatives of
Emery on the opinion, “did these manual integrations.”407 In their Reply, Defendants
401
Id.
402
Id. at 240.
403
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 29.
404
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 240.
405
Id. at 255–56.
406
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 30 (quoting
In re Zantac, 644 F.Supp.3d at 1123)) (emphasis added).
407
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 240–41.
79
equivocate on this point while doubling down: “Emery allowed its analysts,
including Dr. Cheu, to perform manual integrations in their sole judgment and
discretion.”408 Further, Dr. Najafi testified that he supervised the work being done
at Emery and double-checked the work being done by his staff scientists to make
sure [he was] confident of the numbers.”409 Dr. Najafi reviewed the lab results, the
lab notebooks, and synthesized that data in formulating his opinion.410
Manual versus electronic integration turns on the scientist’s assessments of
the accuracy and utility of each in a particular circumstance. As the discussion
illustrates, these are complicated questions well beyond the wisdom of this trial
judge, who, consistent with Daubert and its progeny, will not pick a winner. The
answer rests with the jury.
c. Lack of Documentation of Lab Results
Defendants allege that Plaintiffs’ protocols and test results fail the reliability
requirement of Daubert due to their failure to “describe the methods they used as
fully and accurately as possible.”411 Defendants emphasize that “[w]ithout
408
Defs.’ Reply Br. in Supp. of Mot. to Exclude Emery Pharma at 12.
409
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 260.
410
Id.
411
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 32 n.51;
see also id. Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma Ex.
35, at 48.
80
documentation the process is meaningless; essentially there has been no study.”412
The initial challenge focuses on Emery’s failure to adequately document its
testing.413 In response, Plaintiffs have sufficiently explained that Emery designed
and created protocols for each experiment, each of which was validated and the
results of that validation produced.414 Plaintiffs add that, beyond those “standalone
validations, each analytical run includes a series of calibrations and quality control
injections to further validate the process in run,” and each test “was documented in
a lab notebook contemporaneously maintained by the analyst conducting the
experiment and counter signed by “another researcher who validated the
experiment.”415
Defendants next attack Emery’s lack of protocols for baseline testing,
emphasizing that “none was ever created.”416 The straight-forward response is that
that “Emery’s task regarding baseline testing [] was simply to determine what levels
of NDMA were detectible, if any, in the pills and API [active pharmaceutical
ingredients] produced to Plaintiffs by Defendants. There was no hypothesis to be
tested. There was no need for a ‘study design’ outside that of testing protocol and
412
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 32 n.51.
413
Id. at 35; Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 257.
414
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 256.
415
Id. at 256–57.
416
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 34 n.54.
81
method. Emery tested the pills and API and reported the results. . . .”417
As to the adequacy of the lab notebooks, Plaintiffs explain that “[m]ost raw
and processed data for LC-MS/MS simply cannot be recorded in lab notebooks, as
it is maintained electronically.418 The lab notebooks, however, “contain a reference
to exactly where on Emery’s system (by folder path) that data was stored.”419 All of
the written validated protocol, underlying raw and processed data from the conduct
of the testing was provided to Defendants in [the relevant] format, with printed
versions in the form of PDFs, and also stored electronically in the [relevant] system,
where it remains to this day, and all of it was produced to the Defendants.”420
Plaintiffs further indicate they provided Defendants with “all of [the test]
results along with the corresponding test names, lot numbers, etc., in Excel format,”
noting that Defendants can “conduct their own data analysis to come up with
whatever statistical calculations they wish,” something, Plaintiffs note, Defendants
have not done.421 If Plaintiffs failed to describe their methods as fully and accurately
as possible, any such failing is reserved as a topic for cross examination.422
417
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 257–58 (emphasis in
original).
418
Id. at 257.
419
Id.
420
Id.; see Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex. 202.
421
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 258.
422
See, e.g., McCullock, 61 F.3d at 1043–44; Karlo, 849 F.3d at 81–84.
82
d. Dr. Najafi’s Reliance on the Work of His Team
Defendants take the position that Dr. Najafi, individually, should be excluded
because he relied “entirely” on the work of his team. They impugn Dr. Najafi with
the statement that he is “merely parroting” work done by others.423 Not so.
Dr. Najafi testified on his role in the preparation of Emery’s testing
conclusions.424 Defendants do not take that testimony on directly. Rather, they rely
on the MDL Order and deposition testimony that contradicts Dr. Najafi’s own
testimony. With that, they argue that Emery analysts conducted testing without
“guiding principles from Dr. Najafi” or without written procedures or instructions.425
They highlight the inclusion of three signatures on the Emery Report as “tacit
acknowledgement of his lack of firsthand knowledge.”426
The fact that several scientists signed the Report may be weighed as a
testament to each scientist’s involvement in its preparation, and their certification of
its accuracy and validity. Dr. Najafi’s testimony supports that conclusion. The
Defendants are free to argue that the actions of the signatories somehow implicate
Dr. Najafi. But not at this juncture. Their allegations on this score present a
423
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 40.
424
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 259–61.
425
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 39 (citing
In re Zantac, 644 F.Supp.3d at 1138).
426
Id.
83
credibility issue for the jury.
e. Lack of Publication or Peer Review
Defendants cite lack of peer review or publication as a “pertinent
consideration” of whether a theory or technique is valid.427 At the outset, Defendants
offer no authority in support, beyond the MDL Order in Zantac.428 Moreover, the
lack of peer review or publication presents an issue for the jury. Nor is Emery’s
science an orphan child.429 And as previously mentioned, even Defendants’ expert,
Dr. Bernard Olsen, extolls the LS-MS/MS technique used by Plaintiffs.430 As
Plaintiffs’ point out, when Defendants’ experts were asked about publication, they
refused to suggest lack of publication as evidence of unreliability.431 If lack of peer
review or publication has any utility here, it is fodder for cross-examination, not
exclusion.
f. Emery’s Baseline Testing “Does Not Fit”
Defendants next challenge the so-called “fit” of Emery’s baseline testing to
427
Id. at 40.
428
Id.
429
See Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 261 (“[T]he use of
LC-MS/MS to detect and quantify impurities in drug substances, and the methodology used to
validate the specific protocol applied by Emery are both not only widely accepted and published
in peer reviewed literature but have been available and in use for decades.”).
430
Id. at 237.
431
Id. at 262.
84
the facts of the case.432 The challenge rests on the premise that the amount of
ranitidine in active pharmaceutical ingredients (API) is different than in a pill that a
user ingests.433 Testing API alone, Defendants argue, “skews testing results high
and does not reflect what individuals actually ingest.”434 Plaintiffs argue that this is
a faulty premise via this explanation:
[N]one of the steps involved in creating the final dosage
form . . . is supposed to change the included [active
pharmaceutical ingredient] API. Thus, any NDMA
contained in the API will be, perforce, also included in the
finished pill. This is why, for example, GSK also tested
and reported the NDMA in API when it conducted its root
cause analysis.435
That is, “the NDMA contained in the API at the time the finished dose is
manufactured will get transferred to the pill itself.”436 Defendants do not counter
this analysis in their Reply. Emery’s testing of API fits the facts of the case and will
not be excluded.
g. Emery’s Simulated Environmental Tests
Emery conducted three “simulated consumer experience” tests to measure
432
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 41; see
Daubert, 509 U.S. at 591.
433
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 41.
434
Id.
435
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 263.
436
Id.
85
how NDMA might form in ranitidine.437 Plaintiffs suggest the simulations show the
breakdown of ranitidine “into NDMA in various real-world scenarios, and produces
high levels of NDMA, [which is] relevant to Defendants’ argument that there is
minimal NDMA exposure from taking ranitidine.”438 Plaintiffs suggest that such
testing shows “that NDMA could reasonably form under specific instances—
instances that would apply to all plaintiffs.”439 Thus, their argument follows, the
simulations are relevant at the general causation stage.440 This Court agrees.
Defendants’ challenge to the simulations follows a common path. They each
begin with a general acceptance attack, which they support in the main with a
quotation from the MDL Order.441 Citing to that ruling, they argue that “no other
laboratory in the world has used these tests to measure drug stability; no agency
requires or recognizes them [;] [and no] paper has ever been published validating
their reliability.”442
As to the car simulation, Defendants note that “Emery did not study Zantac
stored in real-life cars,” instead making “a series of unsupported assumptions about
437
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 42.
438
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 263.
439
Id.
440
Id.
441
See Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 44
(quoting In re Zantac, 644 F.Supp.3d at 1150).
442
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 42.
86
consumer behavior and car conditions” to simulate that experience.443 They criticize
Dr. Najafi’s reliance on the Vanos 1028 study, and urge that “even if modeling an
experiment for a drug stability study. . . were a reliable methodology,” Emery’s car
simulation did not comport with such a model.444
But the Vanos report outlines three bases for its data—Vanos, Grunstein, and
the Assessment of the Common Carrier Shipping Environmental General Technical
Report.445 Defendants concede that Plaintiffs cited a few studies in support of their
data.446 And further concede they missed key data points from the Grunstein study
pertaining to the average air temperature used in the Emery study.447 As the several
cases repeatedly cited above make clear, such criticism goes to weight, not
admissibility.
Defendants lodge identical challenges to the bathroom simulation.448 As with
the car simulation, Defendants acknowledge the validation of the “non-peer
443
Id.
444
Id. at 43 (quoting In re Zantac, 644 F.Supp.3d at 1147).
445
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 264.
446
DEFAs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 42; Ex.
10, at 230:16–17.
447
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 264.
448
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 44
(“Emery’s ‘bathroom simulation’ studies did not test Zantac product in a real-world bathroom, but
instead attempted to recreate the conditions of a bathroom based on a series of unsupported
assumptions . . . [it] has nothing to do with drug stability or the effect that a bathroom environment
could have on a drug product.”).
87
reviewed” Aizawa study, but they retrench by alleging that Plaintiffs departed from
the Aizawa model by using more “extreme conditions” than contemplated.449
Defendants also advance lack of general acceptance, and quote a near verbatim
repetition from the MDL Order to that end, just as they did with the car simulation.450
Yet, Defendants, again, missed a study relied upon by Plaintiffs that favors their
position.451
Plaintiffs’ last simulation created “climactic zones” to “simulate. . . common
consumer experiences with Zantac.”452 Defendants again stress that the climatic
zones on which they were based “were not designed to mimic real-world
conditions,” and, citing the MDL order in Zantac, argue that they were “designed to
increase the rate of chemical degradation or physical damage of a drug substance or
drug product by using exaggerated storage conditions[.]”453 Defendants also attack
the climactic zone testing’s reliability because, they say, “it departed from the actual
Zantac container closure system” and for its lack of support for the assumption that
a typical plaintiff or distributor stores ranitidine at 65 % relative humidity in an
outside, non-air conditioned environment.454
449
Id.
450
Id. at 46.
451
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 264–65.
452
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 45.
453
Id. (quoting In re Zantac, 644 F.Supp.3d at 1152) (emphasis in original).
454
Id. at 46.
88
That criticism appears to validate the testing, as Plaintiffs explained, “because
[as noted below] a laboratory cannot actually recreate months’ worth of exposure to
varied temperature and humidity conditions in the time frames involved with
testing.”455
“General causation considers the possibility that a certain exposure caused a
certain harm, not the likelihood that it did.”456 Plaintiffs designed the three
simulations to address a corollary point; that is, “that under the conditions tested,
which simulate real-world conditions, ranitidine breaks down to form NDMA, not
that the exact NDMA levels reported by Emery would be the levels reported by
Emery in any particular pill.”457
Throughout their briefing on the three simulations, Defendants rely
predominantly on the conclusions of the MDL Order. Plaintiffs challenge as
“missing the point” Defendants’ (and the MDL Order’s) overarching criticism of the
design of their simulations: “the entire purpose of stability testing is to see what
happens in exaggerated conditions because a laboratory cannot actually recreate
months’ worth of exposure to varied temperature and humidity conditions in the time
frames involved with testing.”458
455
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 265.
456
Barrera, 2019 WL 2331090, at *4 (quoting Tumlinson II, 2013 WL 7084888, at *4).
457
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 266.
458
Id. at 265.
89
These tests, like opinions—especially those evolving in response to an issue
that, it appears, science has not yet caught up with—depend on the “expert’s
judgment in selecting and weighing her sources.”459 Defendants reject Emery’s
science, including the decisions made in the design and execution of the simulations,
as exemplified by the container system debate: Plaintiffs say the system used in
their testing was proper. Defendants argue it was not. So it goes. But Emery’s
opinion, and testing, are “rooted in science” and therefore “scientifically reliable.”460
That is not to say they are unassailable. But, under these circumstances, the Court
cannot and will not declare one side’s science as reliable and cast off the other’s.461
This dispute is appropriate grist for the jury’s mill.462
h. Emery’s Simulated Gastric Fluid Test
Defendants’ attack on Emery’s Gastric Fluid tests regurgitates the criticism of
Emery’s other tests, discussed above. They are: lack of general acceptance, lack of
publication and peer review, improper and flawed assumptions, conclusions
contradicted by other literature, improper premises, testing did not track
hypothetical, and that the testing was results-oriented.463 For the same reasons
459
Barrera, 2019 WL 2331090, at *4; see Long, 2004 WL 1543226, at *1.
460
Barrera, 2019 WL 2331090, at *14, 17.
461
In re Asbestos Litig., 911 A.2d at 1207.
462
Id.463
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 47.
90
previously stated, there is no need to indulge in an extended discussion of them. The
challenges go to weight, not admissibility.
i. Emery’s Miscellaneous Tests
On this challenge, Defendants concede at the outset that “these studies suffer
the same methodological issues as the testing” above.464 These challenges are
rejected, for the same reasons.
Defendants also assert that “these tests have no purpose or connection to the
facts of the case; i.e., they lack the requisite fit.”465 Not so.
1. WHO NAP Test. The Nitrosation Assay Procedure (“NAP” test),
developed by the World Health Organization (WHO) and the International
Association for Research on Cancer (IARC), “combin[ed] an agent with sodium
nitrite in simulated or real gastric fluid. . . to allow systematic comparisons between
compounds is assessing their ability to nitrosate.”466 The creation of NDMA via
nitrosation of ranitidine is very much a part of the analyses at issue here. The NAP
test fits the case. That the test may not “represent physiological conditions” goes to
weight, not admissibility.467
2. Simulated Gastric Fluid Testing. The Court has already addressed the
464
Id. at 51.
465
Id.
466
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 94.
467
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 52.
91
challenges to Emery’s primary Gastric Fluid Simulation. Defendants here challenge
“additional SGF studies” based on the conclusions Defendants draw from “some of
the experiments.”468 This challenge does not undermine the “fit” of the tests.
3. KSCN Testing. This test was performed to study the hypothesis that
potassium thiocyanate, an endogenous compound present in human gastric juice, can
promote nitrosation of NDMA moieties to form NDMA in the stomach. 469 This is
connected to the facts of this case, as nitrosation of NDMA is one of the processes
at issue in exposure.
4. Refrigeration Testing. This test was performed to confirm GSK’s claim
in its root cause analysis that storage at certain temperatures stops the formation of
NDMA in ranitidine.470 It is relevant to whether Emery’s storage of ranitidine
samples was a factor in the amount of NDMA found in baseline testing. 471 This
issue “fits” as it is connected to the facts of the case.
5. Morphology Study. This challenge is more about challenges to the
construct of and assumptions behind the test than “fit.”472 That said, Plaintiffs
defend the test as intended to determine the accuracy of Defendant GSK’s hypothesis
468
Id.
469
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 267.
470
Id.
471
Id.
472
See id. at 266.
92
regarding rate of degradation of higher bulk density active pharmaceutical
ingredients (API,) compared to other API. This test is relevant to degradation and
to any attempt by GSK to “portray its API” as “superior or more resistant than other
sourced API.”473
6. Content Uniformity Test. Defendants again target Emery’s handling of
the tests, and their conclusions, more than “fit.”474 Plaintiffs defend the test as
“showing that the testing of single pills from a container would be generally
representative of the levels of NDMA to be found in the ranitidine container.”475
This test “fits,” given the issue joined on the proper container to be used preparing
opinions on degradation.
7. Manufactured Table Study. Plaintiffs point out that this study was
necessary because at the time of baseline testing, Defendants had not produced any
tablets from one of the manufacturing sites (Jurong).476 Plaintiffs manufactured its
own tablets from the API from both Jurong and a different manufacturer (BI), to
tests for differences in degradation. It found none, countering any argument that the
pill testing was not representative. Any criticisms of the test relating to Emery’s
473
Id.
474
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 53.
475
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 268.
476
Id.
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failure to use “proprietary protective coating or actual packaging”477 can be
advanced in cross examination.
8. Stress Testing. This challenge, like many of the foregoing, distills to the
design of the test (i.e., Emery exposed ranitidine to: “high levels of heat and
humidity,” employing “implausible conditions.”).478 Emery explained its use of
extreme conditions in defense of its simulations.479 That aside, again these criticisms
go to weight, not admissibility. They also “fit.”
Defendants’ final two challenges go to Reproducibility and the integrity of
Emery’s Delaware report.
j. Reproducibility
On reproducibility, Plaintiffs frame the formative issue this way: “The
question to be answered by this Court is not whether the data reported in Emery’s
MDL Report is reproducible, but whether the data reported in [Emery’s] Delaware
Report, the only proffered opinion here, is reliable, reproducible, and admissible.”480
Plaintiffs counter that this “entire argument hinges on the claim that the results
reported in the Delaware Report do not match the results reported in the MDL
477
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 55.
478
Id. at 53.
479
Id.
480
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 269.
94
Report.”481 Plaintiffs concede that the results from the two studies do not match due
to tabulation and sorting errors.482 But they argue that those errors do not impact the
reproducibility of the testing done by Emery in this case.483
Defendants emphasize that “[n]othing Plaintiffs did [in between the MDL
Report and the Delaware Report] adequately cured the methodological shortcomings
recognized by the MDL Court.”484 But as Plaintiffs emphasize, the only opinion
being proffered here is the Delaware Report. As a practical matter, Defendants are
inviting this Court, again, to defer to the MDL decision on reproducibility. This
Court declines to do so.
The ability to reproduce a test turns on the availability and integrity of the data
from the test to be reproduced. The Court has already plowed this ground. But we
re-visit for ease of reference.
Plaintiffs maintain that “all of the underlying data has been produced to
Defendants,” including “the corresponding test names, lot numbers, etc., in Excel
format.”485 Plaintiffs go further, adding that “all of the written validated protocol,
underlying raw and processed data from the conduct of the testing was provided to
481
Id.
482
Id.
483
Id.
484
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 55.
485
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 270 (emphasis in
original).
95
Defendants in [the proper] format, with printed versions in the form of PDFs, and
also stored electronically in the [proper] system.”486 Plaintiffs add that, for each
experiment that was run, each of which was validated, the results of that validation
were produced,487 and that beyond the “standalone validations,” they produced each
analytical run including calibrations and quality control injections used to further
validate the process run, as well as lab notebooks, in which each test was
documented, maintained contemporaneously by the analyst conducting the
experiment and counter signed by “another researcher who validated the
experiment.”488
All this production, Plaintiffs argue, allows Defendants to “conduct their own
data analysis to come up with whatever statistical calculations they wish;”
something, Plaintiffs note more than once, Defendants did not do.489 Defendants
“have never run any of their own tests on the pill samples tested by Emery, despite
their ability to do so. . . to see if they could or could not reproduce Emery’s results.
They have never done any re-processing or re-integration of the raw data provided
by Emery to determine whether they could or could not reproduce Emery’s
486
Id. at 257, 259; see id. at 272–73.
487
Id. at 256.
488
Id. at 256–57.
489
Id. at 258.
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results.”490 “With this information, Defendants are able to do their own analysis,
their own processing and integration, report their results, and do their own
calculations of means, minimum and maximum values, or any other statistical
measure they wish. They did no such thing.”491 Defendants resort to ipse dixit: the
production, characterized as they deem appropriate, makes reproduction impossible.
They never say they tried to reproduce Emery’s results. Instead, they cite to the
MDL’s Order.492
Defendants devote considerable space to the numerous failings and
inconsistencies they find in Emery’s MDL and Delaware Reports.493 They also
chastise Emery for its inability to reproduce its own results. This criticism might
carry more weight if Emery were somehow prohibited from updating the report, or
even more so if Emery had not explained to Defendants why the data was updated
in the first instance.494 Further, none of the changes cited by Defendants concerns
the baseline testing results.495 Also, some of the results of the changes made by Dr.
Cheu following his review and re-processing are “actually lower than those reported
490
Id. at 269.
491
Id. at 273.
492
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 56–58
(citing In re Zantac, 644 F.Supp.3d at 1130).
493
See id. at 57–63.
494
See Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 271–74.
495
Id. at 276.
97
in the MDL Report,” belying any suggestion of bias to increase NDMA levels.496
None of these challenges is flattering. But many of them involve clerical
errors;497 its resolution fitted for twelve people in the jury box. For that reason, the
Court will not exclude Emery’s opinion. The Court has already considered the
incomplete/inadequate production issue. It stands on that decision.
k. Reverse-engineering of the Emery Report
This challenge is hampered by the fact that some of the re-testing favored
Defendants. Similarly, as noted above, the results from one of the changes made by
Dr. Cheu, following his review and re-processing, are lower than those reported in
the MDL Report.498 That statistic also contradicts an effort to increase NDMA
levels. Some of Plaintiffs’ corrections skewed the testing against Plaintiffs.499 The
extended discussion of what Dr. Cheu did and why also militates against
Defendants’ notion of reverse-engineering.500
l. Transparency and Suggestion of “Lawyer-Driven” Changes
Plaintiffs detail the bases for their defense of transparency:
1. By reporting data and calculating the averages across each individual test,
496
Id. at 274–75.
497
Id. at 271; see Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma
at 63 n.119 (stating chromatogram “mistakenly processed twice”).
498
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 274–76.
499
Id. at 276.
500
Id. at 271–73; see id. at 276.
98
rather than reporting data as averages of multiple tests of the same lot and then
calculating overall average, Emery was able to report results in a format that was
fully transparent and allowed the inclusion of all the information Defendants
complained about not having in the MDL.501
2. Plaintiffs included all baseline testing in the Delaware Report.502
3. Emery re-processed and re-integrated “all of the testing it had done so that
the results contained in the Delaware Report matched 100% with the underlying
MassHunter data, and chromatograms therefrom.”503
These changes were made for three reasons:
First, Defendants complained that they were not able to match up the
individual test data reported with individual chromatograms and underlying raw and
processed data.504 Defendants complain now that this change is evidence of an intent
to bias the results.505
Second, Defendants accused Plaintiffs of cherry-picking data they reported
because there were “many more tests in the native MassHunter data produced to
501
Id. at 277.
502
Id.
503
Id. at 278.
504
See id. at 277.
505
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 63 (citing
Dr. Cheu’s testimony) (arguing that lawyers made the decision to change methods). Contra Pls.’
Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 278–79.
99
Defendants than contained in the MDL Report.”506
Third, Defendants complained in the MDL of problems matching test results
on the printed PDF chromatograms generated by their experts from MassHunter data
produced by Plaintiffs there.507
The re-processing and re-integration resulted in some “changes to reported
values but none made a “material difference to the overall values reported.”508
“None of the above are changes in methodology[;] they are changes in the detail and
manner in which the results were reported.”509 These changes, along with the
production made by Plaintiffs described above, overcome any suggestion that
Plaintiffs’ methodology was not transparent.
Defendants’ final challenge to the Emery study sounds in the unfortunate
allegation that changes in Emery’s method of presentation of chromatograms and
underlying data, raw and processed, were “lawyer driven.”510 In support of that
accusation, Defendants cite one question and its response:
Q: Okay. Well, then why did your methodology of
averaging change?
A: This was a decision that was made I believe with the -
506
See Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 277.
507
Id. at 277–78.
508
Id. at 276–78.
509
Id. at 278.
510
Defs.’ Br. in Supp. of Brand Defs.’ & Patheon’s Mot. to Exclude Emery Pharma at 65.
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what is - the MDL lawyers.511
Defendants celebrate this answer as “definitive proof that Emery lacked a pre-
set protocol.”512 But contrary testimony followed only pages away.513 Dr. Cheu’s
testimony makes clear that “the method of presentation of the averaging and selected
results in the MDL Report was a decision made ‘with. . . the MDL lawyers.’”514 But
the immediately following testimony “makes clear that the method of presentation
of the results in the Delaware Report was made by Emery.”515
The Court finds insufficient evidence that a lawyer-driven methodology
manipulated the Emery study and rejects that assertion. Those allegations comprise
only questions to be resolved by those in the jury box.
The Motion to exclude the Emery Pharma opinions is DENIED.
V. CONCLUSION
Although Daubert may have been intended to streamline expert practice under
Rule 702, this case, like many around the country, suggests that goal has proven
elusive. Differences in jurisprudence, interpretation of the law, and analyses may
confound simpler approaches to such motions.
511
Id. at 68.
512
Id.
513
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 279; Pls.’ Opp’n to
Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. Ex. 173, at 160:7–161:11.
514
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 278–79.
515
Pls.’ Opp’n to Defs.’ Mot. to Exclude Gen. Causation Experts’ Op. at 279 (emphasis added).
101
In Delaware, our jurisprudence counsels that, subject to earnest deliberation,
trial courts entrust questions of science to the scientists. Here, opposing teams of
highly educated, skilled expert medical witnesses offer competing opinions.
Through well-trained counsel, their efforts only clarify the distinct opposition that
defines their respective positions. It would be improper to simply dismiss these
experts as “poseurs or witnesses for hire. They are serious scientists.”516 As
gatekeeper, the Court has found that each side has carried its required burden of
demonstrating the reliability of its proffered Rule 702 evidence. Any remaining
challenges will be made at trial via cross-examination and introduction of counter
evidence. Having considered the full record herein, the parties’ Daubert challenges
fail and their Motions to Exclude are DENIED.
IT IS SO ORDERED.
/s/ Vivian L. Medinilla
Vivian L. Medinilla
Judge
cc: All Counsel of Record
516
In re Asbestos Litig., 911 A.2d at 1207.
102