United States District Court, D. Arizona
G. CAMPBELL, SENIOR UNITED STATES DISTRICT JUDGE
Hillary Davis, Srihari Munnuru, and Susan Fischer have sued
Defendants Bayer Healthcare Pharmaceuticals, Inc., McKesson
Corporation, Guerbet, LLC, and other gadolinium-based
contrast agent (“GBCA”) manufacturers and
distributors. Plaintiffs were administered GBCAs for the
medical procedure known as magnetic resonance imaging
(“MRI”), and claim they developed various health
problems as a result. After conferring with the parties, the
Court decided that the issue of general medical causation -
whether Plaintiffs can present admissible evidence that GBCAs
cause the health problems they claim - should be decided
first. Doc. 110, 111, 115. Accordingly, after focused
discovery and Plaintiffs' production of expert reports on
general causation, Defendants filed motions to exclude the
experts' testimony under Daubert v. Merrell Dow
Pharmaceuticals, Inc., 509 U.S. 579, 597 (1993), and
Rule 702 of the Federal Rules of Evidence. Docs. 153, 157.
The motions are fully briefed, and the Court heard oral
arguments on July 3, 2019. For the reasons that follow, the
Court will grant Defendants' motions with respect to the
medical causation experts and deny them with respect to the
is a lanthanide element (rare earth metal), which exhibits
high paramagnetism, a form of magnetism occurring only in the
presence of an externally applied magnetic field.”
In re Gadolinium-Based Contrast Agents Prods. Liab.
Litig., No. 1:08 GD 50000, 2010 WL 1796334, at * 3 (N.D.
Ohio May 4, 2010) [hereinafter In re GBCAs]. When
GBCAs are injected intravenously, they enhance MRI scans,
resulting in high quality images that aid in identifying
serious health conditions such as cancer, infections, and
bleeding. Docs. 154-27 at 2, 154-47 at 2. Since their initial
approval in 1988, GBCAs have been used more than 450 million
times worldwide. Doc. 154-24 at 2.
in its free state is toxic to humans. In re GBCAs,
2010 WL 1796334, at *3. Because of this toxicity, gadolinium
must be chemically bound to a chelate (a compound that can be
bound to a metal atom) before it is intravenously injected.
This binding prevents the gadolinium from interacting with
human tissue. Id. GBCAs can be chelated in a linear
model or a macrocyclic model. Doc. 154-24 at 4. While all
GBCAs are mostly eliminated from the body through the
kidneys, scientific evidence clearly suggests that linear
GBCAs are less stable and tend to dechelate in the body (the
gadolinium separates from the chelate) more readily than
macrocyclic GBCAs. Doc. 154-47 at 2; see also Doc.
154-24 at 5 (92-96% excreted in 1 hour). All of
Defendants' products in this case are linear GBCAs.
2006, several doctors and researchers noted a strong
association between GBCA use in patients with advanced kidney
disease and the development of a medical condition known as
nephrogenic systemic fibrosis (“NSF”). Doc.
154-14 at 84. Subsequent studies revealed that the
elimination of GBCAs from patients with kidney disease takes
significantly longer than from patients with healthy kidneys,
and that the GBCAs were never entirely eliminated. In re
GBCAs, 2010 WL 1796334, at *6.
a disease that primarily involves the skin and subcutaneous
tissues, but also may involve other organs such as the lungs,
esophagus, heart, and skeletal muscles. Id. Symptoms
may develop and progress rapidly or appear months or even
years after GBCA exposure. Id. Once the medical
community stopped using GBCAs in renally-impaired patients,
NSF was “essentially eradicated.” Doc. 154-24 at
the persons who developed NSF brought suit against the
manufacturers of GBCAs, and the cases were consolidated in a
multi-district litigation in 2010 (the “NSF
MDL”). See In re GBCAs, 2010 WL 1796334, at
*1. Experts in the NSF MDL opined that NSF was caused by
dechelation of GBCAs after they were injected into the body,
which exposed the body to toxic gadolinium. Id. at
*6. Although the experts could not identify the precise
mechanism by which gadolinium caused NSF, the district court
admitted their causation opinions. Id. The court
found sufficient evidence - including the rapid elimination
of NSF when GBCAs were no longer used in renally-impaired
patients - that GBCAs caused NSF. Id. at *6. One
jury trial was held in the NSF MDL, resulting in a verdict
for the plaintiff, and the remainder of the MDL cases
case differs from the NSF MDL in two important respects.
Although Plaintiffs in this matter allege that they were
exposed to GBCAs when they received MRIs, they do not have
impaired kidneys and they have not been diagnosed with NSF.
Rather, Plaintiffs and other patients with normal kidney
function claim they began to suffer a wide range of symptoms
after they received GBCAs. Doc. 191-2 at 2. This range of
symptoms has not been recognized as a disease by regulatory
authorities or medical associations, but the collection of
symptoms has been referred to in some literature as
“gadolinium deposition disease”
(“GDD”). Id. For the sake of simplicity,
the Court will refer to Plaintiffs' alleged illnesses as
either GDD or gadolinium toxicity. In doing so, the Court
makes no judgment about whether GDD is or should be
recognized as a distinct illness, or whether GBCAs are in
fact toxic in patients who have healthy kidneys.
Hilary Davis alleges that she contracted GDD after receiving
an intravenous GBCA injection. Doc. 1 ¶ 2. In her first
and amended complaints, she alleged extreme cognitive
impairment; difficult mentation; headaches; swollen, red,
thickening, and peeling skin; and pain throughout her body.
Id. ¶ 39, Doc. 4 ¶ 43. In her second
amended complaint, she alleges that the gadolinium from the
GBCA deposited indefinitely in her organs and soft tissues
and caused fibrosis in her organs, bone, and skin, and
crossed the blood-brain barrier to deposit in the neuronal
nuclei of her brain. Doc. 142 ¶ 12.
Srihari Munnuru received one or multiple MRIs where he was
injected with a GBCA. Munnuru Doc. 1 ¶ 4. He alleges
that he developed GDD “soon thereafter, ” which
has caused him severe injury and pain and suffering due to
GDD. Id. at 8 ¶ 17. In his deposition, he
testified to leg stiffness, weakness, bone pain and joint
popping, foot pain, brain fog, and eye and teeth pain. Doc.
154-3 at 14.
Susan Fischer alleges that she contracted GDD from
intravenous GBCA injections. Fischer Doc. 1 ¶ 2. She
alleges the following symptoms: burning sensation; violent
shaking; tremors; clouded mentation; confusion; weakness;
fatigue; hypoglycemia; difficult, painful movement; low body
temperature; inflammation, especially throughout her
lymphatic system; muscle cramps; numbness; tingling
sensation; aching joints; weight loss; hair loss; lumps and
rashes on her body; kidney damage; and osteoporosis.
Id. ¶ 16. In her amended complaint, Fischer
alleges gadolinium retention in multiple organs years after
the GBCAs were administered. Fischer Doc. 10 ¶ 2. She
alleges that the gadolinium has caused fibrosis in her
organs, bone, and skin, and that it has crossed the
blood-brain barrier and deposited in the neuronal nuclei of
her brain. Id. ¶ 26; see also Fischer
Doc. 60 ¶ 30.
cases are among several actions pending in district courts
across the United States. Fischer Doc. 39 at 1. All claim
adverse health effects related to GBCA administration. On
October 10, 2018, the Judicial Panel on Multidistrict
Litigation considered and denied the motion of 17 plaintiffs
to centralize pretrial proceedings in an MDL. Id.
The panel determined that even though there are common issues
about gadolinium toxicity and retention, the injuries alleged
in each case appear highly specific to each individual
plaintiff and the actions involve GBCAs manufactured by four
different defendant groups, involving different GBCA
Relevant Legal Standards.
motions are governed by Rule 702 of the Federal Rules of
Evidence. That rule 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
(d) the expert has reliably applied the principles and
methods to the facts of the case.
Fed. R. Evid. 702.
the parties make few references in their briefs to Rule 702,
relying instead almost exclusively on Daubert and
related cases. The Court notes, however, that
Daubert applied the then-existing version of Rule
702 and held that it superseded the common law rule in
Frye v. United States, 293 F. 1013, 1014 (D.C. Cir.
1923). See Daubert, 509 U.S. at 587-89. Rule 702 was
amended in 2000, seven years after Daubert was
decided. Amendment of the rule required approval by the
Supreme Court and acceptance by Congress under the Rules
Enabling Act, and the amended rule superseded any other law.
See 28 U.S.C. § 2072(b) (“All laws in
conflict with such rules shall be of no further force or
effect after such rules have taken effect.”). Thus,
Rule 702 provides the governing law for this case. Because
the 2000 amendment sought to codify and clarify the
admissibility of expert testimony in light of
Daubert and related cases, those cases clearly
remain relevant, but the Court will structure its analysis
primarily around the requirements of Rule 702. See
Fed. R. Evid. 702 advisory committee's note to 2000
legal principles are particularly relevant to the Court's
gatekeeping role in this case.
the proponent of expert testimony bears the burden of showing
that the proposed testimony is admissible under Rule 702.
Cooper v. Brown, 510 F.3d 870, 942 (9th Cir. 2007);
Lust ex rel. Lust v. Merrell Dow Pharm., Inc., 89
F.3d 594, 598 (9th Cir. 1996). If Plaintiffs fail to carry
this burden, the opinions of their experts are not
admissible. Cooper, 510 F.3d at 942.
the admissibility of expert testimony under Rule 702 is a
preliminary question the Court must decide under Federal Rule
of Evidence 104(a), and the Rule 104(a) decision must be made
by a preponderance of the evidence. See Daubert, 509
U.S. at 592 & n.10; Bourjaily v. United States,
483 U.S. 171, 175-76 (1987). Some cases mistakenly suggest
that some of the elements in Rule 702 are jury questions -
that whether an expert's opinion is based on reliable
principles and methods, and whether those principles and
methods have been applied to the facts of the case reliably,
go to the weight of the evidence and should be decided by the
jury after cross examination and argument at trial. But the
requirements of Rule 702 are conditions for admissibility,
and the Supreme Court has made clear that “the trial
judge must determine at the outset, pursuant to Rule 104(a),
” whether the expert's testimony is admissible
under Rule 702. Daubert, 509 U.S. at 592. Thus, the
Court's task in this order is to determine whether
Plaintiffs have shown by a preponderance of the evidence that
the requirements of Rule 702(a)-(d) have been satisfied with
respect to each expert's opinions. Id. at 592
n.10; Bourjaily, 483 U.S. at 175-76. Both sides
agreed with this principle during the hearing on the
experts must explain the basis for their conclusions in a
manner that allows the Court to determine whether they are
using reliable principles and methods and are applying them
to the facts of the case in a reliable manner. Fed.R.Evid.
702(c), (d). Although “[t]rained experts commonly
extrapolate from existing data . . . nothing in either
Daubert or the Federal Rules of Evidence requires a
district court to admit opinion evidence that is connected to
existing data only by the ipse dixit of the expert.
A court may conclude that there is simply too great an
analytical gap between the data and the opinion
proffered.” Gen. Elec. Co. v. Joiner, 522 U.S.
136, 146 (1997).
these legal standards in mind, the Court will discuss the
current state of the science with respect to NSF and GDD and
the basic approach to causation used by Plaintiffs'
medical causation experts. The Court then will address the
individual causation experts, two cases cited heavily by
Plaintiffs, and Plaintiffs' chemistry expert.
Background Information on NSF and GDD.
liberally from a decision of the district court in the NSF
MDL, the Court provides the following description of NSF.
See In re GBCAs, 2010 WL 1796334, at *3. NSF was
first described in the medical literature in 2000, with the
first reported cases going back to 1997. NSF causes fibrosis
of the skin, connective tissue, and organs throughout the
body, and is a painful, progressive, and debilitating
disease. While the precise pathogenesis of NSF is unknown, it
has been reported only in patients who have severe kidney
disease and, with the exception of a few reported cases with
inconclusive medical histories, has been found exclusively in
kidney patients who have had one or more exposures to GBCAs.
2006, the FDA issued a Public Health Advisory notifying
healthcare professionals and the public about the risk of NSF
following the administration of GBCAs. In December 2006, the
FDA issued an updated Public Health Advisory stating that
there was a potential for NSF to occur in at-risk patients
following administration of GBCAs. In May 2007, the FDA asked
GBCA license holders to issue a warning about the risk of NSF
in patients with renal failure. This warning, along with
policies and procedures adopted by healthcare facilities and
notice to healthcare providers, led to the virtual
elimination of new NSF cases. Id.
response to the growing number of NSF cases, medical
professionals identified specific diagnostic criteria for
identifying the disease. Doc. 154-17. The court in the NSF
MDL described NSF as “a singular disease.” In
re GBCAs, 2010 WL 1796334 at *6. Although the
plaintiffs' experts in the MDL could not identify with
certainty the mechanism by which gadolinium in GBCAs caused
NSF, the court found their general causation opinions
admissible, providing this explanation:
The dominant theory is that dechelation occurs through
transmetalation (simply, a chemical reaction involving the
exchange of ligands between two metal centers), although
there are other theories including that dechelated (or, free)
gadolinium has a proliferative effect on human dermal
fibrosis and gadolinium's propensities as a calcium
blocker triggers the fibrotic process. In any event, given
the wealth of evidence on causation - that is, the rapid
emergence and decline of NSF associated with the rise and
fall of its use in renally impaired persons, the presence of
gadolinium in the tissue of NSF patients, the known toxicity
of gadolinium, and the majority view in the published and
peer reviewed studies and articles that dechelated gadolinium
causes NSF - the Court concludes that it is not necessary for
Plaintiffs' experts to identify the precise mechanism by
which dechelated gadolinium causes NSF in order to present
the theory to a jury.
short, the general medical causation opinions were admissible
in the NSF MDL because (1) the increase and decrease of NSF
cases tracked the increase and decrease of GBCA use in
renally-impaired patients, (2) a majority of published and
peer reviewed studies found a causal link between GBCAs and
NSF in such patients, (3) gadolinium was found in the tissue
of NSF patients, and (4) free gadolinium was known to be
toxic. The evidence in this case is less clear.
do not argue that GDD has been recognized as a distinct
disease by any regulatory body or medical association, but
note that it has been proposed as an illness in some
published literature. See Semelka et al. (2016),
Doc. 156-16 (proposing GDD as an illness). Other literature
has asserted that labelling symptoms as GDD is too strong a
suggestion that it is an actual illness, and has proposed
instead that the name be changed to
“gadolinium-associated symptoms.” See
Parillo et al. (2018), Doc. 154-26 at 7.
2017, the FDA convened its Medical Imaging Drugs Advisory
Committee (“MIDAC”) to consider “the
potential risk of gadolinium retention . . . in patients
receiving [GBCAs].” Doc. 154-42 at 2. The committee
consisted of 15 voting members, all of whom (with the
exception of one patient and one consumer representative)
were medical doctors or Ph.D.s. They included seven
professors at major universities, laboratory directors, and
directors from the National Institutes of Health and the
National Cancer Institute. See Transcript of
September 8, 2017 MIDAC Conference, Doc. 156-7 at 3-9
[hereinafter MIDAC Trans.]. The FDA convened MIDAC because
“[t]he evidence indicating retention following the use
of GBCAs has led to concerns that gadolinium retention may
cause adverse reactions, if not immediately then at some
later date.” Doc. 154-43 at 4. The focus of MIDAC's
inquiry was the connection, if any, between the retention of
GBCAs or gadolinium in the body and various symptoms reported
in patients with healthy kidneys.
prepared a lengthy briefing document for the MIDAC inquiry
that reviewed all medical literature since 1988, case
reports, regulatory decisions, and reports from the FDA's
adverse event reporting system (“FAERS”). Doc.
154-43. MIDAC then held a conference on September 8, 2017,
where it heard presentations from FDA medical officers,
invited scholars, industry representatives, and the public. A
401-page transcript records all of the presentations and
discussions, as well as MIDAC's vote on key questions.
See MIDAC Trans., Doc. 156-7. After considering all
of the evidence and hearing presentations from scholars,
experts, and patient advocacy groups, MIDAC unanimously
concluded that the medical and scientific evidence does not
establish that GBCAs cause GDD. See Id. at 338-56.
This does not appear to have been a difficult decision for
the committee members - there was no equivocation in their
views. See Id. The chair, Dr. Peter Herscovitch,
summarized the committee's views in these words: “I
think there is fair uniformity that there is no evidence of a
causal relationship between the symptoms and signs in
patients with normal renal function and the retention of
gadolinium.” Id. at 356. MIDAC recommended
that the FDA revise GBCA warnings to note that retention of
gadolinium in some organs, including the brain, is possible
following GBCA use, but otherwise did not recommend that GBCA
use be restricted. Id. at 377; Doc. 154-45 at 8-9.
The FDA and Other Regulatory and Medical
MIDAC's conference, the FDA approved this revised GBCA
product label in April 2018:
Gadolinium is retained for months and years in several
organs. . . . Consequences of gadolinium retention in the
brain have not been established. . . . There are rare reports
of pathologic skin changes in patients with normal renal
function. Adverse events involving multiple organ systems
have been reported in patients with normal renal function
without an established causal link to gadolinium retention. .
. . [C]linical consequences of gadolinium retention have not
been established in plaintiffs with normal renal function[.]
Doc. 154-29 at 5.
the retention of gadolinium in the body, other national
organizations such as the Australian Department of Health,
Health Canada, the European Medicines Agency
(“EMA”), the Japanese Pharmaceuticals and Medical
Devices Agency, and the New Zealand Ministry of Health have
suspended the use of some linear GBCAs. Doc. 153 at 12. But
these organizations have also concluded that there is
insufficient evidence to show that gadolinium deposition in
brain tissues causes harm to patients. See Docs.
154-34 at 2, 154-33 at 2, 154-35 at 2, 154-36 at 2, 154-38 at
many scientific and medical societies have agreed that no
adverse health effects from gadolinium retention in
renally-healthy patients have been proven. See Doc.
153 at 13. These include 2018 findings by the National
Institutes of Health, the American College of Radiology, the
Radiological Society of North America, and the Canadian
Association of Radiologists (Docs. 154-24 at 2, 154-16 at 2),
and 2017 findings by the American Society of Neuroradiology
and the International Society for Magnetic Resonance in
Medicine (Docs. 154-13 at 2, 154-18 at 2, 154-12 at 2).
Evidence Supporting GDD and its GBCA Cause.
regulators and scientific organizations have not found enough
evidence to conclude that GBCAs cause an illness like GDD,
there is evidence that some level of GBCAs and gadolinium are
retrained in the brain, bone, and other organs of patients
who have received GBCAs in connection with an MRI, even when
they do not have impaired renal function. See Kanda
et al. (2014), Doc. 154-24 at 2; 191-5 (hypothesizing the
existence of intracranial gadolinium retention based on the
observation of unenhanced T1 signal intensity increases in
the dentate and globus pallidus); see also Semelka
et al. (2016), Doc. 187-34 at 2 (describing studies that
determined gadolinium was being retained in the brain and
bone). No party appears to contest this, but the parties
disagree on the form of the retained gadolinium and whether
it is toxic in that form and at all doses. And as already
noted, research indicates that linear GBCAs deposit in larger
amounts or in dechelated forms more often than macrocyclic
forms. Doc. 154-24 at 4 (study showed after two weeks in
human serum that macrocyclic GBCA disassociations were
undetectable but linear GBCAs showed variable degrees of
also point to publications that have drawn a connection
between retained GBCAs and various symptoms in
renally-healthy patients. These include Burke (2016), where
researchers conducted an anonymous online survey of patients
who believed that they suffered from gadolinium toxicity.
Doc. 187-33 at 2. The researchers received 50 responses, 33
of which described the onset of symptoms immediately
following GBCA administration and 16 of which described the
onset within six weeks. Id. The most commonly
reported symptoms were bone and joint pain and head and neck
symptoms, including headaches, vision change, and hearing
change. Id. Skin changes were also indicated by
about 60% of the respondents. Id. The authors of the
Burke study acknowledged that the “risk of severe
adverse reaction to GBCA exposure is extremely small, hence
it may be difficult to determine characteristics of
individuals that predispose to this type of reaction.”
Id. at 3.
Semelka (2016), researchers reviewed the medical history and
physical examinations of four individuals with normal renal
function who reported development of new disease features
within hours to four weeks of receiving GBCA injections. Doc.
187-34 at 2. The authors concluded that gadolinium toxicity
may occur in subjects with normal renal function.
Id. Central torso and peripheral arm and leg pain
were common features. Id. Distal arm and leg pain
and rubbery subcutaneous tissue were seen in later stages.
Id. Clouded mentation was also common. Id.
The authors noted features that resembled NSF. Id.
another Semelka article (2016), the authors recruited
participants with normal renal function and evidence of
gadolinium in their system beyond 30 days from two online
gadolinium toxicity support groups. Doc. 156-16 at 2.
Participants were asked to answer survey questions about
their symptoms. Id. The most common symptoms were
central pain, peripheral pain, headache, and bone pain.
Id. Subjects with distal leg and arm distribution
described skin thickening. Id. Clouded mentation and
headaches were described as persistent beyond three months in
29 of the 42 subjects. Id. From the results, the
authors proposed to call this condition GDD. Id. at
4. Many of the reported symptoms appeared to resemble less
severe symptoms of NSF. Id. The authors theorized
that the symptoms may come from an immune system response to
these agents. Id. They were careful to note the
limitations of their study - self reported survey answers,
subjectivity, predefined questions, and lack of a control
group, noting that “further prospective investigation
is needed to verify this condition.” Id.
history of NSF and GDD frame the issue in this case. On one
hand, we have the recognized disease of NSF in
renally-impaired patients and its accepted link to GBCAs. On
the other hand, we have the broad-ranging proposed illness of
GDD in renally-healthy patients and its alleged link to
GBCAs. The distinction between the two was captured in this
comment by Dr. Jeffrey Brent, a member of the FDA's MIDAC
committee, during MIDAC's 2017 conference:
We know NSF is a disease. It's a very clear-cut
unambiguous disease caused by gadolinium retention in
patients who have renal failure. It's interesting to
contrast that with the gadolinium retention disease we're
hearing about today in patients with normal renal function.
NSF is an unmistakable, easy to diagnose, clear cut, limited
but devastatingly serious clinical condition, limited in the
sense of clinical manifestations. What we heard about today
is multisystem, multisymptom disease without any unifying
presentations that would suggest a physiology that would seem
to make sense. So there are a lot of questions here about
what this actually is, if it actually is a disease.
Trans., Doc. 156-7 at 329-30.
question to be answered in this case is whether Plaintiffs
can present admissible expert opinions that GBCAs cause an
illness described as GDD, or whether such causation remains
in the realm of reasonable suspicion, unsupported by
sufficient scientific and medical evidence to satisfy Rule
702. In resolving this question, the Court must remember that
reliable scientific principles and methods, applied reliably,
are required by Rule 702. Reasonable suspicions and plausible
theories are not enough. As other courts have noted,
“an opinion that is an insightful, or even inspired,
hunch is not admissible if it lacks scientific rigor.”
Anderson v. Bristol Myers Squibb, No. Civ.A.
H-95-0093, 1998 WL 35178199, at *12 (S.D. Tex. Apr. 20,
1998). “The courtroom is not the place for scientific
guess work, even of the inspired sort. Law lags science; it
does not lead it.” Rosen v. Ciba-Geigy Corp.,
78 F.3d 316, 319 (7th Cir. 1996).
counsel argued at the hearing on these Daubert
motions that the relevant question is whether GBCAs should be
included in the list of potential causes to be considered in
any differential diagnosis of Plaintiffs' illnesses.
There is some vagueness in this argument. On one hand, it
could mean that Plaintiffs can clear the Daubert
hurdle on general causation with expert opinions that GBCAs
could potentially cause GDD, even if GBCAs have not been
identified as a known cause. On the other hand, it could mean
that Plaintiffs must present expert opinions that GBCAs are
in fact a cause of GDD, and that GBCAs are therefore a
potential cause of Plaintiffs' illnesses when considered
with all of the other potential causes in a particular
Plaintiff such as, for example, fibromyalgia, other
autoimmune illnesses, muscle and bone maladies, or other
factors from Plaintiffs' personal medical histories.
latter formulation is correct. The Court's Case
Management Order identified the subject of this order as
“Daubert motions on general causation.”
Doc. 115 at 4. Plaintiffs must show that their experts can
present admissible opinions that GBCAs cause GDD. Stated
differently, the issue to be decided is whether
Plaintiffs' experts can present admissible opinions under
Rule 702 that GBCAs are in fact a cause of GDD. Whether GBCAs
actually caused any particular Plaintiff's illness is an
issue of specific causation to be decided later in this
Rules 702(a) and (b) - Qualifications and Sufficiency of
Facts and Data.
offer four experts to support their theory of general medical
causation: Brent Wagner, M.D., Jody Tversky, M.D., Margert
Whittaker, Ph.D., and Kenneth Raymond, Ph.D. The three
causation experts - Drs. Wagner, Tversky, and Whittaker -
opine that GBCAs cause GDD in patients with healthy kidneys.
The fourth expert, Dr. Raymond, is a chemist who explains the
nature of GBCAs and how they react in the human body.
Plaintiffs assert that Dr. Raymond's chemistry testimony
will be essential to the jury's understanding of GBCAs
and their fate in the body, but that they will not use him to
state a causation opinion.
Rule 702(a) - Qualifications.
Wagner is a board-certified physician in internal medicine
and nephrology. Doc. 154-10 at 2. He currently serves as the
Director of the Kidney Institute of New Mexico, as the Renal
Section Chief of the Medicine Section of the New Mexico
Veterans Health Care System, and as an Associate Professor of
Medicine at the University of New Mexico Health Science
Center. Id. He has done research on patients with
impaired kidney function exposed to GBCAs and the subsequent
development of NSF. Id. For nearly two decades, Dr.
Wagner's research has focused on renal development and
mechanisms implicated in kidney injury. Id. at 4. He
was the keynote speaker at MIDAC's 2017 conference.
See MIDAC Trans., Doc. 156-7 at 44-62.
Tversky is a full-time faculty member and former clinical
director of the Division of Allergy and Clinical Immunology
at The John Hopkins University School of Medicine. Doc. 154-9
at 2. He is board certified in internal medicine and allergy.
Id. He is a practicing allergist “with
extensive experience managing drug reactions, anaphylaxis,
and immunological pathology.” Id. at 3.
Whittaker is the managing director and chief toxicologist of
ToxServices LLC, a scientific consulting firm headquartered
in Washington, D.C. Doc. 154-11 at 5. She is a Diplomate of
the American Board of Toxicology and a board-certified
toxicologist. Id. She has more than 25 years of
experience assessing human health and environmental hazards
from substances including inorganic and organic chemicals,
microorganisms, and radiological substances. Id.
Raymond is an organic chemist and professor emeritus in
chemistry at the University of California, Berkeley. Doc. 154
8 at 2. He has lectured extensively on metal chelate design
and has an interest in lanthanide coordination chemistry.
Id. For many years, he had National Institutes of
Health support for the development of GBCAs, which resulted
in patents that have been licensed to GBCA providers.
Id. He has served as a consultant on MRI contrast
agents and studies the role of metals in biology and
Court finds by a preponderance of the evidence that these
experts are qualified by training and experience to opine on
the subjects each will address, and that their testimony, if
admitted, would be helpful to the jury. Rule 702(a) is
Rule 702(b) - Sufficiency of Facts and Data.
experts do not opine on specific causation - whether any
Plaintiff's symptoms have in fact been caused by his or
her exposure to GBCAs. As a result, they have not focused on
Plaintiffs or their medical conditions and histories. The
facts and data considered by the experts consist of studies,
surveys, and case reports related to the question of
gadolinium toxicity in patients with healthy kidneys. The
Court finds that their opinions are based on sufficient facts
and data. Rule 702(b) is satisfied by a preponderance of the
Rule 702(c) and (d) - General Discussion of the Medical
section of the order, the Court will engage in a general
discussion of the causation experts' opinions,
identifying serious flaws in some of the principles and
methods they use, as well as a lack of reliability in how
they apply some otherwise reliable principles and methods. In
the three sections that follow, the Court will address each
of the causation experts individually, applying this general
Unproven Hypotheses Are Not Admissible.
Supreme Court explained in Daubert:
“Scientific methodology today is based on generating
hypotheses and testing them to see if they can be falsified;
indeed, this methodology is what distinguishes science from
other fields of human inquiry.” 509 U.S. at 593
(quotation marks and citations omitted). Merely generating
hypotheses - even reasonable ones - is not enough.
“[I]n order to qualify as ‘scientific
knowledge' an inference or assertion must be derived by
the scientific method. Proposed testimony must be supported
by appropriate validation - i.e., ‘good grounds,'
based on what is known.” Id. at 590; Claar
v. Burlington N. R.R. Co., 29 F.3d 499, 502-03 (9th Cir.
1994) (“[S]cientists whose conviction about the
ultimate conclusion of their research is so firm that they
are willing to aver under oath that it is correct prior to
performing the necessary validating tests could properly be
viewed by the district court as lacking the objectivity that
is the hallmark of the scientific method.”); see
also Nease v. Ford Motor Co., 848 F.3d 219, 232 (4th
Cir. 2017); Mitchell v. Gencorp, Inc., 165 F.3d 778,
783 (10th Cir. 1999).
identified several means for determining whether a theory has
been reliably validated. “[A] key question to be
answered in determining whether a theory or technique is
scientific knowledge that will assist the trier of fact will
be whether it can be (and has been) tested.” 509 U.S.
at 593. “Another pertinent consideration is whether the
theory or technique has been subjected to peer review and
publication.” Id. “Additionally, in the
case of a particular scientific technique, the court
ordinarily should consider the known or potential rate of
error[.]” Id. at 594. Finally,
“[w]idespread acceptance can be an important factor in
ruling particular evidence admissible, and a known technique
which has been able to attract only minimal support within
the community may properly be viewed with skepticism.”
Id. (quotation marks and citations omitted).
Additional considerations are identified in the Advisory
Committee Note to the 2000 amendment of Rule 702 and will be
factors underscore the basic Daubert inquiry -
whether an expert's theory or hypothesis has been tested
and shown to be valid. If not, it is inadmissible.
The Common Approach of Plaintiffs' Experts.
causation experts offer theories about the existence of GDD
and how it is caused, and cite sources which suggest that the
theories are worth exploring, but they do not present
reliable scientific principles and methods, or apply accepted
principles and methods reliably, to show that their theories
have been validated. The starting point for the experts'
theories consists of several facts Plaintiffs claim to be
undisputed: (a) GBCAs are an accepted cause of NSF; (b) GBCAs
dechelate in the human body, releasing free gadolinium; (c)
some level of GBCAs and free gadolinium is retained in the
bodies of patients with healthy kidneys; and (d) free
gadolinium is toxic in the human body. See Doc.
154-10 at 7-16 (Wagner Report); Doc. 154-9 at 4-5 (Tversky
Report); Doc. 154-11 at 15-23 (Whittaker Report); see
also Doc. 185 at 22. But these facts alone are not enough to
establish general causation in this case, as Plaintiffs'
experts all seem to concede. These facts suggest that GBCAs
can cause adverse symptoms in renally-healthy patients, and
they may be enough to raise a reasonable hypothesis that must
be tested. But more is needed to conclude reliably that the
variety of symptoms associated with GDD are in fact an
illness, and that the illness is caused by GBCAs. That has
been the conclusion of the FDA and every other regulatory and
medical body that has considered the question. These bodies
are all well aware of Plaintiffs' four foundational
facts, and they have found them to be good reasons for
further study, but they unanimously have found that there is
not enough scientific evidence to conclude that GBCAs cause
GDD. See Doc. 153 at 11-13.
question in this case, therefore, is whether Plaintiffs'
experts present reliable principles and methods, applied
reliably, to bridge the gap between these foundational facts
and the conclusion that GBCAs cause GDD. The gap cannot be
bridged merely by the mere ipse dixit - the say-so -
of the experts. Joiner, 522 U.S. at 146. There must
be a reliable scientific basis.
experts attempt to span the gap by positing that GBCAs cause
a “continuum” of symptoms, the most severe of
which constitute NSF and the less severe of which are
commonly seen in GDD. They rely primarily on four categories
of evidence: case reports, surveys, animal studies, and in
vitro studies. See Doc. 154-10 at 17-31 (Wagner
Report); Doc. 154-9 at 5-10 (Tversky Report); Doc. 154-11 at
23-32 (Whittaker Report). The Court will address the
experts' proposed continuum, each category of evidence,
and other concerns about the experts' principles and
causation experts posit that there is a continuum of symptoms
caused by GBCAs, with the more severe symptoms commonly seen
in patients with renal impairment (NSF) and less severe
symptoms commonly seen in patients without renal impairment
(GDD). Docs. 154-9 at 3 (Tversky Report); 154-10 at 31
(Wagner Report). If this is true, the continuum essentially
establishes the general medical causation Plaintiffs are
trying to prove because all of the symptoms on the continuum,
including those experienced by Plaintiffs, are caused by
GBCAs. The Court will address the continuum evidence cited by
Dr. Wagner and Dr. Tversky (Dr. Whittaker provides little
discussion of the continuum), and then address a basic
question presented by these experts - if GBCAs cause NSF, why
doesn't simple logic lead to the conclusion that they
also cause the range of symptoms labeled GDD?
opining that a continuum of symptoms is caused by GBCAs, Dr.
Wagner asserts that “[m]any individuals with different
backgrounds agree on this point[.]” Doc. 154-10 at 31.
He then cites one source: the briefing document from the 2017
MIDAC conference. Id. at 38 ¶ 78. But the
briefing document, which is part of the record at Doc. 154-43
(and is not available at the website address provided by Dr.
Wagner), makes no mention of the three doctors Dr. Wagner
names as holding the same opinion - Drs. Pierre Desche, Gene
Williams, and Peter Herscovitch. See Doc. 154-10 at
Dr. Wagner's continuum opinion is a very important issue
in this case, and the Court could find no mention of these
doctors in the FDA briefing document, the Court reviewed the
entire transcript of the 2017 MIDAC conference. Sure enough,
all three of the named doctors spoke at the conference, and
each one mentioned the word “continuum.” But
contrary to Dr. Wagner's claim, none of them supported
his opinion of a continuum of symptoms caused by GBCAs.
Desche made this statement: “our conclusion is that
brain hyperintensities and NSF are, in fact, part of the same
continuum from gadolinium retention to gadolinium toxicity,
and renal dysfunction acts as a catalyst.” See
MIDAC Trans., Doc. 156-7 at 107; see also 113
(same). The continuum Dr. Desche mentions is from gadolinium
retention to gadolinium toxicity causing NSF. He does not say
there is a continuum that includes a wide range of milder
symptoms that encompass GDD, as Dr. Wagner posits. Indeed,
during his deposition Dr. Desche made clear that he was
referring to retention that leads to NSF, not some broader
continuum. See Doc. 202 at 10-15 (sealed).
Williams made this statement at the MIDAC conference:
“if you had information on patients with varying
degrees of renal impairment and you could tease out the
effect of the renal impairment itself, you might expect it to
be a continuum. The idea forwarded by the advisory committee
member from a clinical pharmacology standpoint, I think is a
reasonable idea.” MIDAC Trans., Doc. 156-7 at 222-23.
This statement is classic hypothesis. Dr. Williams suggests
that there “might” be a continuum detected if the
varying degrees of renal impairment could be separated. And
he is talking about the universe of patients with renal
impairment, not individuals like Plaintiffs who have no renal
impairment. Even then, the most he says is that there
“might” be a continuum and it is “a
reasonable idea.” Id. at 223. He does not
endorse Dr. Wagner's continuum conclusion.
Herscovitch's statement at the MIDAC meeting was this:
“renal function is not either normal or abnormal, but
as one of our discussants pointed out, it's a
continuum.” MIDAC Trans., Doc. 156-7 at 358. This
statement has nothing to do with a continuum of symptoms. It
concerns a continuum of renal function. And Dr. Herscovitch,
who chaired the MIDAC conference, actually made statements
that contradict Dr. Wagner's medical causation opinion:
“I think there is fair uniformity that there is no
evidence of a causal relationship between the symptoms and
signs in patients with normal renal function and the
retention of gadolinium.” Id. at 355. He also
presciently addressed the kinds of evidence primarily relied
on by Plaintiffs' experts, saying: “the FAERS data
and other anecdotal reports really perhaps raise questions,
but in themselves do not have a scientific foundation for
reaching any conclusions.” Id. at 356.
short, assuming Dr. Wagner was citing to the MIDAC conference
as support for his claim that “[m]any individuals with
different backgrounds agree” with his posited continuum
of symptoms caused by GBCAs, he is simply incorrect. That Dr.
Wagner would make such a strong but incorrect claim is
Tversky does not cite other authorities to support his claim
of a continuum. He instead provides this rationale: “it
was noted that in patients with NSF there were early signs of
the disease that progressed over time to these more
characteristic later manifestations. This shows that there is
a range or continuum of signs and symptoms caused by
gadolinium toxicity exposure.” Doc. 154-9 at 3. This
assertion - that there is a range of symptoms in NSF patients
- is used by Dr. Tversky to conclude that the same range of
symptoms must exist in everyone else exposed to GBCAs,
including renally-healthy patients. But this leap rests on
nothing more than Dr. Tversky's say-so. He cites no other
authority to support the continuum. And the Court notes that
at least one speaker at MIDAC's conference, Dr. Nicholas
Dainiak, characterized this assertion - “that the brain
deposits may occur prior to eventual evolution to NSF”
- as a mere “hypothesis.” MIDAC Trans., Doc.
156-7 at 316.
in his report Dr. Tversky notes that case reports suggest
milder symptoms for GDD patients than NSF patients, and he
compares those milder symptoms to the early stages of NSF,
again suggesting it's all one continuum. Doc. 154-9 at 8.
This reasoning rests on the reliability of the case reports
he cites. As explained in the discussion below, the Court
finds the case reports insufficiently reliable to support Dr.
Tversky's proposed continuum.
If GBCAs Cause NSF, Then Why Not GDD?
Tversky and Dr. Wagner assert, as do Plaintiffs generally,
that NSF is a misnomer - that the use of
“nephrogenic” in the name of the disease is
incorrect because impaired kidneys don't cause NSF, they
simply allow gadolinium to accumulate in the body to a point
where it causes NSF. It is the gadolinium, not the kidneys,
that causes NSF. Docs. 154-9 at 3-4 (Tversky Report), 154-10
at 16 (Wagner Report). This rationale leads logically to the
conclusion that the accumulation of gadolinium in patients
with healthy kidneys will likewise cause the symptoms seen in
GDD. But if it were that simple, MIDAC, the FDA, and other
organizations would have concluded that GBCAs cause GDD. It
is not that simple. As Dr. Anthony Fotenos, an FDA medical
officer, noted at the MIDAC conference, the vast majority of
patients who receive GBCAs develop no symptoms. “[I]n
the postmarketing setting, millions of patients have
benefited from GBCAs without reported adverse reactions since
the first drug in the class was approved in 1988.”
MIDAC Trans., Doc. 156-7 at 195; see also Endrikat
et al. (2016), Doc. 189-20 at 2 (most patients with severe
renal impairment who receive even multiple doses of GBCAs do
not develop NSF). The mere receipt and even retention of
GBCAs clearly does not cause illness in most patients.
many comments at the MIDAC conference make clear, the
causative mechanism of NSF, although linked to gadolinium, it
still not understood. Dr. Wagner himself provided this
explanation at the conference:
In 2006, when [NSF] was clearly linked to gadolinium, we know
that gadolinium is the cause, so that the kidney is a risk
factor - renal insufficiency is a risk factor - but the
kidney per se is not really causing the disease.
There is now evidence that gadolinium is deposited in the
central nervous system. I believe that the central nervous
deposition warrants more study, and I am going to
show that gadolinium-based contrast agents are biologically
Very little is known about the metabolism of these
agents, their biologic effects, and the implications of
retaining gadolinium in the tissues. The toxic effects and
the mechanisms of how they impart their pathophysiology
is a major gap in our knowledge.
If we understand how the disease processes occur, we are
going to know quite a bit more for stratifying patients who
are at risk, and it will add to our future knowledge. How
these different agents behave once they enter the body is
an active area of investigation.
Trans., Doc. 156-7 at 46-47 (emphasis added). Thus,
Plaintiffs' own causation expert stated less than two
years ago that much is not known about the effects of GBCA
retention and that further investigation is needed. He also
told MIDAC that “dechelation of gadolinium is a
hypothetical pathologic mechanism, ” and that
“[s]tudies concerning the biologic effects of rare
earth minerals in general and their retention in human organs
are in the nascent stage, and the science on this topic is at
ground zero.” Id. at 60.
fact, uncertainty about the precise mechanism by which GBCAs
causes NSF is recognized by many sources. Dr. Wagner stated
at the MIDAC conference that “there are risk factors
out there that have not been defined.” Id. at
135. One of the FDA medical officers stated: “I also
want to note - and this is similar to what Dr. Wagner said -
while consideration of the comparative exposure to gadolinium
from each GBCA is important, patient factors in addition to
renal function are likely to play an important role[.]”
Id. at 180. Dr. Semelka, the author of several
papers cited by Plaintiffs, suggested an entirely different
pathology at the MIDAC conference: “My opinion is [that
GDD] is a genetic disease of the immune system[.]”
Id. at 302. Runge (2018) states that NSF is a
manifestation of toxicity from gadolinium released by MRI
contrast media, but that the illness probably develops in the
presence of “cofactors.” Doc. 189-17 at 5.
Endrikat et al. (2016) notes that multiple cofactors for NSF
have been proposed, including metabolic acidosis, vascular
surgery, or treatment with erythropoietin. Doc. 189-20 at 2;
see also Wagner et al. (2016), Doc. 189-21 at 5-6
(noting that many patients with end-stage renal disease on
chronic dialysis do not acquire the disease despite several
exposures to GBCAs, and some individuals develop NSF without
gadolinium exposure). Finally, Dr. Tversky himself asserts
that there are other potential contributing factors to NSF,
including the activation of free radicals, increased
inflammatory chemicals, and the induction of complex
immunological cascades. Doc. 154-9 at 7.
precise causes of NSF are not yet understood, one cannot
simply conclude that if GBCAs contribute to NSF in
renally-impaired patients they must also cause GDD in
renally-healthy patients. As MIDAC and other organizations
have recognized, causation is more complicated than such a
have not shown by a preponderance of the evidence that the
continuum theory posited by Drs. Wagner and Tversky is the
product of reliable principles and methods applied reliably.
The Court will next look to the actual categories of evidence
relied on by the causation experts.
Individual Case Reports and Surveys.
most common form of evidence cited by the causation experts
consists of individual case reports (descriptions of the
experiences of single patients) and surveys of individuals
who believe they developed adverse health effects after
receiving GBCAs. See Docs. 154-10 at 17, 21-26, 28,
30 (Wagner Report); Doc. 154-9 at 8 (Tversky Report); Doc.
154-11 at 25, 30 (Whittaker Report). Some of these reports
are from the FDA's FAERS database and others are from
published articles, but all of them constitute the experience
of single patients, usually as reported by the patients with
no complete study of the patients and no control group.
case reports are not reliable scientific evidence of
causation, because they simply described reported phenomena
without comparison to the rate at which the phenomena occur
in the general population or in a defined control group; do
not isolate and exclude potentially alternative causes; and
do not investigate or explain the mechanism of
causation.” Casey v. Ohio Med. Prods., 877
F.Supp. 1380, 1385 (N.D. Cal. 1995). As the Eleventh Circuit
[C]ourts must consider that case reports are merely accounts
of medical events. They reflect only reported data, not
scientific methodology. Some case reports are a very basic
form report of symptoms with little or no patient history,
description of course of treatment, or reasoning to exclude
other possible causes. The contents of these case reports
were inadequate, even under the plaintiffs' expert's
standards, to demonstrate a relationship between a drug and a
potential side effect.
Some case reports do contain details of the treatment and
differential diagnosis. Even these more detailed case
reports, however, are not reliable enough, by themselves, to
demonstrate the causal link the plaintiffs assert that they
do because they report symptoms observed in a single patient
in an uncontrolled context. They may rule out other potential
causes of the effect, but they do not rule out the
possibility that the effect manifested in the reported
patient's case is simply idiosyncratic or the result of
unknown confounding factors.
Rider v. Sandoz Pharm. Corp., 295 F.3d 1194, 1199
(11th Cir. 2002) (citation omitted).
Federal Judicial Center Reference Manual on Scientific
Evidence includes this caution about case reports:
Anecdotal reports may be of value, but they are ordinarily
more helpful in generating lines of inquiry than in proving
causation. . . . Anecdotal evidence usually amounts to
reports that events of one kind are followed by events of
another kind. Typically, the reports are not even sufficient
to show association, because there is no comparison group.
2011 WL 7724256 at *4 [hereinafter Reference
FDA itself has identified these limitations for its FAERS
Yes, FAERS data does have limitations. First, there is no
certainty that the reported event (adverse event or
medication error) was due to the product. FDA does not
require that a causal relationship between a product and
event be proven, and reports do not always contain enough
detail to properly evaluate an event. Furthermore, FDA does
not receive reports for every adverse event or medication
error that occurs with a product. Many factors can influence
whether an event will be reported, such as the time a product
has been marketed and publicity about an event. There are
also duplicate reports where the same report was submitted by
a consumer and by the sponsor. Therefore, FAERS data cannot
be used to calculate the incidence of an adverse event or
medication error in the U.S. population.
(last visited July 8, 2019); see also MIDAC Trans.,
Doc. 156-7 at 148 (FDA official describing limitations of
stated, case reports raise questions, they do not answer
them.” McLain v. Metabolife Int'l, Inc.,
401 F.3d 1233, 1245 (11th Cir. 2005); see also Cloud v.
Pfizer, 198 F.Supp.2d 1118, 1133-34 (D. Ariz. 2001);
Jones v. United States, 933 F.Supp. 894, 899-900
(N.D. Cal. 1996), affirmed 127 F.3d 1154 (9th Cir.
1997), cert. denied 524 U.S. 946 (1998). Indeed, Dr.
Wagner admitted in his deposition that case reports do not
provide reliable scientific evidence of causation because
they are anecdotal reports of occurrences, without support
from the scientific method. Doc. 154-6 at 42.
are even less reliable. They consist of unscreened answers
from people who believe they suffer from GBCA-caused
illnesses, often provided anonymously. Unlike case reports,
the survey responses generally are not made by physicians.
They include statements from medically-untrained individuals,
with no verification of exposure to GBCAs or physical
symptoms, and certainly no control group. And yet all three
causation experts rely on surveys without providing any
discussion or acknowledgement of their ...