Davis v. McKesson Corporation

          ORDER

          DAVID G. CAMPBELL, SENIOR UNITED STATES DISTRICT JUDGE

         Plaintiffs 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 chemistry tutorial.^[1]

         I. Background.

         “Gadolinium 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.

         Gadolinium 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.

         In 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.

         NSF is 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 2.

         Many of 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 settled.

         This 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.

         Plaintiff 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.

         Plaintiff 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.

         Plaintiff 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.

         Plaintiffs' 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 formulations. Id.

         II. Relevant Legal Standards.

         Defendants' 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 methods; and

(d) the expert has reliably applied the principles and methods to the facts of the case.

Fed. R. Evid. 702.

         Curiously, 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 amendment.

         Three legal principles are particularly relevant to the Court's gatekeeping role in this case.

         First, 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.

         Second, 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 motions.^[2]

         Third, 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).

         With 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.

         III. Background Information on NSF and GDD.

         A. NSF.

         Borrowing 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.

         In June 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.

         In 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.

Id.

         In 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.

         B. GDD.

         Plaintiffs 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.

         1. MIDAC Review.

         In 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.

         The FDA 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.

         2. The FDA and Other Regulatory and Medical Organizations.

         Following 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.

         Due to 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 2.^[3]

         Additionally, 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).

         3. Evidence Supporting GDD and its GBCA Cause.

         Although 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 dissociation).

         Plaintiffs 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.

         In 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. at 4.

         In 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.

         C. The Issue.

         The 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.

         MIDAC Trans., Doc. 156-7 at 329-30.

         The 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).

         Plaintiffs' 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.

         The 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 litigation.^[4]

         IV. Rules 702(a) and (b) - Qualifications and Sufficiency of Facts and Data.

         Plaintiffs 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.

         A. Rule 702(a) - Qualifications.

         Dr. 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.

         Dr. 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.

         Dr. 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.

         Dr. 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 medicine. Id.

         The 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 satisfied.

         B. Rule 702(b) - Sufficiency of Facts and Data.

         Plaintiffs' 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 evidence.

         V. Rule 702(c) and (d) - General Discussion of the Medical Causation Opinions.

         In this 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 discussion.

         A. Unproven Hypotheses Are Not Admissible.

         As the 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).

         Daubert 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 discussed below.

         These 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.

         B. The Common Approach of Plaintiffs' Experts.

         Plaintiffs' 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.^[5] 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.

         The key 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.

         Plaintiffs' 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 methods.^[6]

         C. The Continuum.

         Plaintiffs' 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?

         1. Dr. Wagner.

         After 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 31-32.

         Because 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.

         Dr. 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).

         Dr. 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.

         Dr. 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.

         In 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 concerning.

         2. Dr. Tversky.

         Dr. 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.

         Later 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.

         3. If GBCAs Cause NSF, Then Why Not GDD?

         Dr. 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.

         And as 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 active.

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.

         MIDAC 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.

         In 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.

         If the 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 simple proposition.

         4. Continuum Conclusion.

         Plaintiffs 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.

         D. Individual Case Reports and Surveys.

         The 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.

         “Such 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 has explained:

[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).

         The 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 Manual].^[7]

         And the FDA itself has identified these limitations for its FAERS database:

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.

         https://www.fda.gov/drugs/surveillance/fda-adverse-event-reporting-system-faers (last visited July 8, 2019); see also MIDAC Trans., Doc. 156-7 at 148 (FDA official describing limitations of FAERS database).^[8]

         “Simply 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.

         Surveys 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 ...