Paul A. Engelmayer, United States District Judge.
This multi-district litigation involves products liability claims regarding a contraceptive product: the Mirena intrauterine device developed, manufactured, and distributed by defendants Bayer Health-Care Pharmaceuticals, Inc., Bayer Pharma AG, and Bayer Oy (together, "Bayer"). The Mirena IUD functions by releasing a synthetic steroid hormone known as levonorgestrel ("LNG"). Plaintiffs claim that the hormonal component of Mirena caused them to suffer from a disease known as idiopathic intracranial hypertension ("IIH"), also known as pseudotumor cerebri ("PTC"). IIH is an uncommon disease marked by increased cerebrospinal fluid ("CSF") pressure in the skull. If untreated, IIH can cause headaches and vision problems, including, in extreme cases, blindness.
Currently before the Court are motions by each side, pursuant to Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579, 113 S.Ct. 2786, 125 L.Ed.2d 469 (1993), to exclude the other's expert testimony with respect to the issue of general causation — that is, whether Mirena's release of its hormonal component, LNG, is capable of causing IIH. In overseeing this MDL, this Court, heeding the guidance of the United States Judicial Panel on Multi-District Litigation ("JPML"), prioritized discovery and Daubert motions and briefing with respect to this issue.
Plaintiffs have put forward seven expert witnesses on general causation. Each opines that use of Mirena can cause IIH. These are: two obstetrician-gynecologists ("OB/GYNs"), an ophthalmologist, a neuroscientist, a pediatric neurologist, an epidemiologist, and a pharmacologist-toxicologist. In response, Bayer has put forward 12 expert witnesses. Each opines that the available scientific evidence does not reliably permit the conclusion that using Mirena can cause IIH. These are: three epidemiologists, a pharmaco-kineticist, five neuro-ophthalmologists, and three OB/GYNs.
Each of these 19 expert witnesses submitted an expert report, was deposed, and was the subject of separate Daubert briefing. On April 10-11, 2018, the Court held a
For the reasons that follow, the Court grants Bayer's motions under Daubert to preclude the testimony of plaintiffs' general causation experts. In light of the possible implications of this ruling for this litigation, the Court denies as potentially moot plaintiffs' motions to preclude the testimony of Bayer's general causation experts. This ruling is without prejudice to plaintiffs' right to renew their motions to preclude Bayer's general causation experts should the litigation proceed past summary judgment.
On April 6, 2017, the JPML centralized in this District pretrial proceedings in the 113 cases then pending across 17 districts nationwide in which plaintiffs had alleged IIH injuries caused by the hormonal component of the Mirena IUD. Most of the Mirena/IIH cases were at a relatively early stage of discovery or at the pleading stage, although fact and expert discovery had closed in the 10 longest pending actions. See generally Dkt. 1, at 2-3 (JPML transfer order).
The JPML had previously, in July 2014, denied a motion to centralize the Mirena/IIH actions, at a time when nine such actions, spanning six districts, were pending. Explaining its 2017 decision to centralize the pending cases, the JPML emphasized several factors that made centralized proceedings more efficient. Two are relevant here.
First, the JPML noted the heightened difficulty coordinating discovery and other pretrial proceedings given the increased number and dispersal of pending actions and of participating law firms. Id. at 2. "The record," the JPML stated, "demonstrates that centralization is necessary to facilitate the efficient conduct of common discovery." Id. at 3.
Second, the JPML noted, general causation had emerged as an important issue common to all proceedings. "[T]he records in the many actions filed since [2014] demonstrate that discovery and pretrial motions concerning the issue of general causation have been, or will be, at the center of all actions — that is, whether the hormonal component in Mirena is capable of causing intracranial hypertension." Dkt. 1, at 3; see also id. at 4 ("Issues concerning general causation [and] the background science ... will be common to all actions.").
In overseeing this action, this Court has given priority to the matters that led the JPML to centralize the Mirena/IIH actions.
In prioritizing general causation, the Court was informed by, in addition to the guidance of the JPML, the representations of counsel in this case that the issue of general causation would be common and
For that reason, the Court deferred almost all plaintiff-side discovery until after the anticipated Daubert motions were resolved. The MDL currently encompasses more than 850 plaintiffs, a result of the fact that, since creation of this MDL, nearly 750 plaintiffs have filed new lawsuits that have been received into it. The Court required only that each existing or new plaintiff file a detailed fact sheet (e.g., as to her Mirena usage, medical history, and symptoms). See Dkt. 62; see also Dkt. 78 (August 30, 2017) (order approving plaintiff fact sheet). The requirement of filing such fact sheets was intended to enable the litigation to move forward expeditiously in the event that admissible evidence sufficient to establish general causation were to be found, including by expediting selection of plaintiffs for individualized discovery in anticipation of bellwether trials.
The seven expert witnesses whom plaintiffs propose to call as to general causation are: (1) Dr. Lemuel A. Moyé, an epidemiologist; (2) Dr. Laura M. Plunkett, a pharmacologist and toxicologist; (3) Dr. James M. Wheeler, an OB/GYN; (4) Dr. Frederick W. Fraunfelder, an ophthalmologist; (5) Dr. Philip Darney, an OB/GYN; (6) Dr. Conrad E. Johanson, a neuroscientist; and (7) Dr. Vincent Salpietro, a pediatric neurologist.
The 12 expert witnesses whom Bayer would call are: (1) Dr. Robert Langer, an epidemiologist; (2) Dr. Kurt T. Barnhardt, an epidemiologist; (3) Dr. Todd A. Lee, an epidemiologist; (4) Dr. William Jusko, a pharmaco-kineticist; (5)-(9) Drs. Nancy J. Newman, Gregory Van Stavern, Joseph F. Rizzo, Dean M. Cestari, and Marc J. Dinkin, each a neuro-opthalmologist; and (10)-(12) Drs. Vanessa Dalton, Geri D. Hewitt, and Dana R. Gossett, each an OB/GYN.
Each expert has authored a report, was deposed, and was the subject of individualized Daubert briefing and oral argument.
This section sets out background relevant to all Daubert motions. It addresses: (1) the Mirena product; (2) Mirena's hormonal component, the progestin LNG; (3) the disease IIH and its history and characteristics; and (4) the state of scientific research, prior to the instant Daubert proceedings, regarding both the causes of IIH in general and, more specifically, as to whether contraceptives (including Mirena) that use LNG as a hormonal component can cause IIH.
Mirena is a commonly used type of long-acting reversible contraceptive ("LARC"). There are several different types. Some LARCs are copper intrauterine devices ("IUDs").
Mirena is made of a T-shaped polyethylene frame with a silicon-based steroid reservoir around the vertical stem. It is inserted into the uterus vaginally. See Mirena Prescribing Information and Label § 11.1 (Dkt. 135-6) ("Mirena Label"). In the uterus, Mirena releases the synthetic steroid hormone LNG, a progestin, at an initial rate of 20 μg LNG/day, decreasing over its five-year life-span. See Mirena Label §§ 2, 11, 12.3.
The FDA approved Mirena on December 6, 2000, following studies for safety and efficacy in two large clinical trials in Finland and Sweden. It is currently approved in the United States for up to five years of use. See id. §§ 14.1-14.2. As of May 2017, an estimated 45.5 million Mirenas had been inserted worldwide amounting to close to 142 million woman-years of use since its introduction. See Bayer Response to Questions from German Federal Institute for Drugs and Medical Devices ("BfArM") (Oct. 2017) (Dkt. 167-71) ("Bayer BfArM Response"), at 44-45.
In contrast to combined oral contraceptives, which contain both progestin and estrogen and whose effectiveness among obese women has been questioned, Mirena is believed to be effective regardless of the user's weight. Also commending its use among obese women, studies indicate that Mirena does not increase the risk of weight loss and blood clots and does not expose the user to potential risks associated with estrogen-containing contraceptives. See, e.g., Alison Edelman & Bliss Kaneshiro, Contraception counseling for obese women, UptoDate.com (Jan. 25, 2017) at 2 (Dkt. 167-26) ("Edelman & Kaneshiro") (terming efficacy of oral contraceptives "suboptimal" for obese women; reasons hypothesized include "that the inherent effectiveness of oral contraceptives may be diminished in obese women because obesity increases metabolic rate, increases
As a result, Mirena is widely believed to be preferentially, i.e., disproportionately, prescribed to overweight and obese women. One recent study found that 63% of Mirena users were overweight or obese, compared to 48% of the general population of reproductive-age women. See Bayer Omnibus Br. at 3 (collecting studies); see also Edelman & Kaneshiro, supra, at 3 (terming such IUDs "the best contraceptive option for obese women who have no contraindications to use of this method" and stating that [LNG] implants "appear to be highly effective in overweight and obese women"); id. at 6 (recommending such IUDs for this population); Cestari Rpt. at 14 ("According to evidence-based guidelines, Mirena is a preferred contraceptive for obese women."); Wheeler Rpt. at 12 ("[O]ral contraceptives are less effective in obese women."); Wheeler Dep. at 90 ("[H]ormonal IUDs are preferentially prescribed to obese women.").
LNG, the hormone Mirena releases, is a synthetic progestin compound derived from testosterone. It has "been used as an active ingredient in contraceptives since the 1980's." Plunkett Rpt. at 9.
LNG mimics the effects of the naturally occurring sex hormone progesterone, which is involved in pregnancy and menstruation. LNG is widely used in gynecology, including in hormonal replacement therapy. Its primary use is in numerous contraceptives. These include (1) LNG-releasing intrauterine devices such as Mirena; (2) LNG-releasing subdermal implants such as Norplant, which from 1991 to 2002 was marketed in the United States, and Jadelle, which is currently marketed in Europe; (3) in the single-dose hormone contraceptive known as Plan B; and (4) as the progestin component of numerous combined oral contraceptives (which usually include both LNG and an estrogen compound). Id. at 8-9.
The exact mechanism by which LNG prevents pregnancy is unknown. See Mirena Label § 12.1 ("The local mechanism by which continuously released LNG enhances contraceptive effectiveness of Mirena has not been conclusively demonstrated."). However, it is generally understood that LNG, and Mirena by extension, inhibits contraception by bringing about various systemic effects, including blocking ovulation, thickening cervical mucous (decreasing sperm penetration), and altering the endometrium, the lining of the uterus (impairing the implantation of fertilized eggs). See id. ("Studies of Mirena and similar LNG IU[D] prototypes have suggested several mechanisms that prevent pregnancy: thickening of cervical mucus preventing passage of sperm into the uterus, inhibition of sperm capacitation or survival, and alteration of the endometrium."); see also Plunkett Rpt. at 9-10.
The Court notes here two chemical characteristics of LNG relevant to the pending motions. These characteristics are germane
First, as noted, LNG is a progestin. It is not an androgen, a male sex hormone like testosterone. However, progestins can have androgenic effects. LNG, for example, is known to have a low but substantial affinity to bond with androgen receptors and to cause systemic androgenic side effects, such as acne. See Philip D. Darney, The Androgenicity of Progestins, 98 Am. J. Med. (1995) at 1A-105S (Dkt. 199-8); Christina Björklun, Expert report on the toxico-pharmacological documentation to the application for drug marketing approval of Mirena (2003), at 8 (Dkt. 199-9) ("Björklun") ("LNG is not a pure progesterone agonist. It has a low, but substantial affinity to the androgen receptor and the mineralocorticoid receptor, and to some transport proteins."); Hofmann 30(b)(6) Dep. at 167-68. Androgen receptors are found in the choroid plexus ("CP"), the area of the brain that produces cerebrospinal fluid ("CSF"). As discussed below, IIH arises from the excessive buildup of CSF.
Second, LNG is known to bond with mineralocorticoid receptors ("MRs"). See Björklun, supra, at 8. It is a point of dispute in this litigation whether LNG is an MR agonist (meaning it binds to a receptor and activates it) or antagonist (meaning it binds to a receptor and blocks it). MRs are also found in the choroid plexus. See Brian E. McGeeney & Deborah I. Friedman, Pseudotumor Cerebri Pathophysiology, 54 Headache 445, 452 (2014) (Dkt. 196-14) ("McGeeney & Friedman").
Idiopathic intracranial hypertension, or IIH, "is the clinical syndrome of raised intracranial pressure, in the absence of space-occupying lesions or vascular lesions, without enlargement of the cerebral ventricles, for which no causative factor can be identified." Alex K. Ball & Carl E. Clarke, Idiopathic intracranial hypertension, 5 Lancet Neurology 433, 433 (2006) (Dkt. 167-17) ("Ball & Clark"); see also McGeeney & Friedman, supra, at 445. IIH is alternatively referred to in the scientific literature as "pseudotumor cerebri syndrome" ("PTC" or "PTCS"). See, e.g., Deborah Friedman, et al., Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children, 81 Neurology 1159 (2013); Fraunfelder Rpt. at 7.
By whichever name, these terms connote a syndrome marked by heightened intracranial pressure that derives not from a tumor or other lesion but from the excessive buildup of cerebral spinal fluid, or CSF. Because the parties have most often used the term IIH in this litigation, and because the term "idiopathic" usefully captures the heretofore scientifically indeterminate causes of the applications of the syndrome at issue here, the Court will use the term IIH in this decision, save when directly quoting sources that use other terms.
Although the immediate cause of IIH is the excessive buildup of CSF, IIH's pathogenesis — the biological mechanism that brings it about — is poorly understood. See McGeeney & Friedman, supra, at 445
Some scientists have theorized that IIH is caused by an increase in the production of CSF. See Johanson Rpt. at 8-9. Others have theorized that IIH is caused by impaired CSF absorption; this latter theory appears to have a greater number of proponents. See Vincenzo Salpietro, et al., Recent insights on pediatric pseudotumor cerebri syndrome pathophysiology: From the "Unifying neuroendocrine perspective" to the "Integrated bioenergetic-hormonal mechanism," 13 J. Pediatric Neurology 11, 12 (2015) (Dkt. 167-57) (noting that "the paraphysiology of [PTCS] is still poorly understood," but describing "hampered outflow of CSF into the venous system" as "a more generally accepted hypothesis" of the cause of IIH); McGeeney & Friedman, supra, at 447 (reviewing competing theories, and noting that "[m]ost of the focus in PTCS has been on resistance to CSF absorption"); Ball & Clark, supra, at 435 (observing that the "more popular hypothesis is that [IIH] is a syndrome of reduced CSF absorption").
Symptoms of IIH vary dramatically. The most common is a headache, which occurs in almost all (92-94% of) cases. Many patients (64-87%) also experience a whooshing sound in their ears called pulsatile tinnitus. Other symptoms include papilledema, photophobia, phonophobia, nausea, transient visual obscurations, binocular diplopia, and blurred vision. Papilledema, the swelling of the optic nerves due to intracranial pressure, is sometimes called the hallmark symptom of IIH. However, a patient can still be diagnosed with IIH without this symptom, and these symptoms can result from other causes. A papilledema is detected with an ophthalmoscopic or funduscopic examination. Most patients show a degree of visual loss. And, in extreme cases, if untreated, papilledema can cause serious vision loss and even blindness. See Ball & Clark, supra, at 433, 436-438; Vincent Giuseffi, et al., Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): A case-control study, 41 Neurology 239, 239-41 (1991) (Dkt. 167-33) ("Giuseffi"); Cestari Rpt. at 4-7; Darney Rpt. at 21; Fraunfelder Rpt. at 4; Moyé Rpt. at 26; Plunkett Rpt. at 24; Salpietro Rpt. at 12-13.
Ultimately, IIH is a diagnosis of exclusion. While doctors use two largely overlapping sets of diagnostic criteria — the "modified Dandy criteria" and the "Friedman criteria" — in their diagnoses, IIH is ultimately diagnosed by excluding alternative causes of these symptoms. Fraunfelder Rpt. at 4. Papilledema, for example, can also be caused by brain tumors, meningitis, or intracranial thrombosis, id., and headaches can arise from numerous causes. To exclude alternative causes of IIH, doctors use a combination of neural imaging, neurologic examination, and a spinal tap or lumbar puncture, which directly measures CSF pressure. See Bayer BfArM Resp. at 9-11; Cestari Rpt. at 2-3; Fraunfelder Rpt. at 4; Moyé Rpt. at 25-27.
IIH is an extremely rare disease. It occurs with a frequency of about one case
IIH is treated in a variety of ways. It is typically recommended that overweight patients with IIH lose weight; medications are often prescribed to assist weight loss. Doctors also often prescribe acetazolamide, a diuretic, to prevent CSF production. Lumbar punctures, which are used to diagnose IIH, can also be used to drain excess CSF. Optic nerve sheath fenestration — the "cutting into the sheath, or covering, of the optic nerve" — "may [also] be used to decrease pressure on the optic disc, thereby preserving vision." Fraunfelder Rpt. at 7. Finally, shunts can be placed in the brain or lumbar spine to drain excess CSF into the abdominal cavity. See Ball & Clark, supra, at 439-40; Cestari Rpt. at 7-8; Moyé Rpt at 28.
Symptoms consistent with intracranial hypertension were first observed centuries ago by Eskimos, who came to associate these symptoms with excess ingestion of polar bear liver. John Chen & Michael Wall, Epidemiology and risk factors for idiopathic intracranial hypertension, 54 Int'l Ophthalmology Clinics 1, 6 (2014) (Dkt. 196-10) ("Chen & Wall").
Scientists have, however, identified a number of risk factors associated with IIH. These include: (1) being a woman of child-bearing age; (2) being overweight, obese, or having experienced recent weight gain; (3) using certain drugs, such as vitamin A and retinoids; and (4) experiencing endocrine disturbances caused by diseases such as Addison's Disease and steroid withdrawal. See generally Ball & Clark, supra, at 434-35; Chen & Wall, supra, at 5-6; Giuseffi, supra, at 239-40; McGeeney & Friedman, supra, at 450-53; see also Fraunfelder Rpt. at 5; Moyé Rpt. at 27-28; Salpietro Rpt. at 12-13.
The first two risk factors are particularly common, as IIH "predominantly affects obese women of childbearing age." Cestari Rpt. at 2; see also Fraunfelder Rpt. at 5.
More than 90% of patients afflicted with IIH are women, see Chen & Wall, supra, at 5. And the incidence of IIH among women of child-bearing age is approximately 3.3 to 3.5 cases per 100,000, more than three times that of the population as a whole. Id. at 1; Cestari Rpt. at 3.
IIH's incidence among obese women, meanwhile, has been calculated as close to 20 times that of women of normal weight; and its incidence among overweight women
As addressed later, the heightened incidence of IIH among overweight and obese women of reproductive age complicates the study of the relationship between Mirena and IIH. That is because Mirena, by definition, is prescribed only to women of reproductive age, and because Mirena is widely understood to be disproportionately prescribed to overweight or obese women.
The Court next reviews the state of research, outside of the instant litigation, as to the question whether use of Mirena is a cause of IIH.
In brief, although plaintiffs' experts in this litigation have now so opined, outside of this litigation, no medical organization, regulatory agency, article in peer-reviewed scientific literature, or other research has found that use of Mirena is a cause of IIH.
However, writings in several categories exist that bear on this question. First, two published epidemiological studies have addressed the possibility of a causal connection between use of Mirena and IIH. One was principally authored by Dr. Mahyar Etminan; the other, by Reuben M. Valenzuela.
In addition, epidemiological studies have been conducted as to certain other contraceptive products containing LNG. None have found that the use of these products causes IIH.
Finally, published case reports involving patients with IIH symptoms, where the patient had used Mirena or another LNG-based contraceptive, have raised the question of a connection between the use of these products and IIH.
The above-summarized pre-litigation writings figure prominently in the reports of the experts in this case and in the parties' Daubert briefing. In particular, to varying degrees, plaintiffs' seven experts draw on these materials to support their claim that using Mirena can cause IIH.
Because these materials are foundational sources for the experts who are the subjects of the instant Daubert motions, the Court — before considering any individual expert — reviews the preexisting scholarship and data. The Court first discusses conceptually the categories of studies and other evidence upon which experts may draw in exploring whether a drug can cause a given disease. The Court then reviews the publications that exist, outside of this litigation, regarding Mirena and IIH. Lastly, the Court reviews the publications regarding other (i.e., non-Mirena) LNG-based contraceptive products and IIH.
In general, three broad categories of human studies can be used to explore a possible causal connection between a drug and a disease or the efficacy of particular modes of treatment of a disease: randomized control trials, epidemiological studies, and studies analyzing anecdotal evidence (i.e., case reports).
Cohort studies involve sorting subjects into separate groups based on their exposure (or lack of exposure) to the drug in question. Such studies may be prospective or retrospective. In prospective cohort studies, patients are followed over time to see which persons develop the disease; in retrospective studies, patients are interviewed to determine whether they have been diagnosed with the disease and, if so, under what circumstances. See Speroff & Darney, supra, at 429-30. A case-control study, in contrast, involves sorting patients into separate groups based on their having been diagnosed with having (or not having) the disease in question, and comparing these groups. Id. at 430.
Relative to randomized control tests, however, both types of epidemiological studies, when used to test a thesis of general causation, present inherent challenges
Individual manufacturers of drugs, such as Bayer, maintain their own adverse events databases. Another database — relevant here because one of the two epidemiological studies of Mirena and IIH, that by Dr. Etminan, drew upon it — is maintained by the Food and Drug Administration (FDA): the FDA Adverse Event Reporting System ("FAERS"). It contains approximately 5 million adverse event reports, medication error reports, and product quality complaints resulting in adverse events that were submitted to the FDA. The database is designed, inter alia, to support the FDA's post-marketing safety surveillance program for FDA-approved biologic products. Reports are submitted to FAERS by healthcare professionals, consumers, and manufacturers. Reports from healthcare professionals (e.g., physicians, pharmacists, and nurses) and consumers (e.g., patients, family members, and lawyers) are voluntary. If a manufacturer receives a report from a healthcare professional or consumer, however, regulations require it to send the report to the FDA.
Consistent with the case law reviewed infra, scholars, including plaintiffs' experts in this litigation, agree that while case reports often have utility in generating hypotheses about the possible relationship between a drug and a medical condition, such anecdotal accounts — except in extremely rare circumstances — cannot, without more, demonstrate the causation by a drug of such a condition.
There have not been randomized control trials addressing whether Mirena can cause IIH. The parties appear to agree that such a trial would not realistically be attainable, as a result of medical ethics and/or prohibitive cost. The latter is because IIH's rarity would likely make it prohibitive to design a statistically significant study. See, e.g., Moyé Rpt. at 16.
Outside of this litigation, two epidemiological studies have been published addressing the relationship between Mirena and IIH: the Etminan and Valenzuela studies. Because these two studies figure centrally in the Daubert litigation, the Court reviews each in detail. As to the Etminan study, the Court further reviews the unusual series of events that culminated in lead author Etminan's repudiation of a significant portion of his study.
The Etminan study contained two analyses designed to supplement one another. The outcomes of the analyses pointed in opposite directions. The first was a "disproportionality analysis" (DPA) of adverse event reports in the FDA's FAERS database. Id. The DPA analysis found that the "reporting odds ratio" as to IIH, and as to search terms associated with IIH, was higher for Mirena than for a comparison group consisting of users of all other drugs in the FAERS database, which captured some 5 million reported adverse events. Id. at 112.
Etminan's study, which described itself as "the first large epidemiologic study that has examined the risk of [IIH] with Mirena," id. at 112, did not definitively conclude that Mirena causes IIH. And, the study noted, the authors "did not have information on all risk factors for [IIH]." Id. at 113. However, the authors urged that "the risk of [IIH] with Mirena must be clearly conveyed to young women who are planning to use them." They further opined that "the small risk of [IIH] may outweigh the risk of unintended pregnancies." Id. at 113.
As to Etminan's DPA analysis, Friedman wrote, the search terms that Etminan had used to isolate IIH-related symptoms within the FAERS database had been overbroad and had included terms not demonstrably related to that condition. Id. As to Etminan's second analysis — the cohort study comparing Mirena to two oral contraceptives in the IMS LifeLink database — Friedman wrote, Etminan's data set and methodology were problematic in multiple respects.
As to his DPA analysis, Dr. Etminan's 2016 letter stated that, even limiting the search terms used within the FAERS database to exclude conditions such as "cerebral edema" not associated with IIH, there were still a disproportionate number of adverse events associated IH for "women with Mirena." Id. at 1. As to his cohort study, Dr. Etminan clarified and/or defended his methodology.
Addressing his study's disproportionality analysis, Dr. Etminan clarified that the study had calculated "reporting odds ratios" (RORs) for Mirena "versus all other products in the FAERS database"; "the comparator group," he now acknowledged, "had not been limited to oral contraceptive pills or any other specific product." Id. ¶¶ 3-4. Further compromising the results, Dr. Etminan admitted, the analyst whom he had used to extract data from that database
Id. ¶ 6. And, Dr. Etminan stated, the study's DPA analysis might separately be flawed in that:
Id. ¶ 7. In sum, Dr. Etminan stated, as to his study's DPA analysis:
Id. ¶ 8 (emphasis added).
As for his retrospective cohort study, Dr. Etminan's affidavit noted that it had not found any statistically significant difference in risk between Mirena and either of the combination oral contraceptive comparators. Id. ¶ 9. Dr. Etminan further explained, "For neither the FAERS DPA nor the retrospective cohort analysis did I have weight data (BMI or recent weight gain) that would have allowed me to control for weight as a potential confounding variable as the FAERS data do not generally provide BMI information for each case." Id. ¶ 10.
Dr. Etminan summed up the implications of his revelations as follows.
Id. ¶ 11 (emphasis added).
The Valenzuela study was published in 2017. See Reuben M. Valenzuela, et al., An estimation of the risk of pseudotumor cerebri among users of the levonorgestrel intrauterine device, 41 Neuro-Ophthalmology 192 (2017) (Dkt. 167-64) ("Valenzuela" or the "Valenzuela study"). A retrospective case-control study, it addressed the risk of IIH among certain patients in Utah and Denmark.
In particular, the study examined whether IIH patients in these populations were using LNG-releasing IUDs (principally Mirena),
The Valenzuela study found a statistically significant correlation between a patient's use of an LNG-releasing IUD and the patient's having IIH. However, the authors emphasized that they had not found causation of IIH by use of an IUD, but merely a correlation between the two:
Id. at 4 (emphasis in original).
The Valenzuela study noted two possible explanations for the correlation between IIH and use of LNG-based IUDs. Id. at 5. One is that LNG causes increased intracranial pressure, through an as-yet undetermined biological mechanism. Id. at 5.
Id. (footnotes omitted).
The Valenzuela study further noted that future research "may or may not be able to distinguish between these two possibilities." Id. As to possible future areas of research, the study noted that there are currently "no reliable animal models of PTC," and that a prospective trial of LNG-IUDs in a population of women at risk for PTC "would likely be too costly and would not settle the question of whether an LNG actually causes [IIH]." Id. The authors added that "[l]imitations of our study include the retrospective nature of the investigation and the relatively small number of PTC subjects with an LNG-IU[D] at the time of diagnosis." Id. The authors emphasized that "[o]ur findings are preliminary, and caution should be exercised in applying this information to clinical practice." Id.
The Valenzuela study concluded: "We do not recommend the removal of LNG-IU[D]s from women with PTC, as the benefit of effective contraception for these women likely outweighs the risk. Likewise, if a woman with PTC or at risk for PTC needs contraception, an LNG-IU[D]
Outside of this litigation, two published case reports have addressed IIH in the context of usage of LNG-based IUDs.
One 2010 report from a doctor discussed the case of a 45-year-old woman and noted a possible connection between an LNG-based IUD and IIH. See H. Martinez, et al., Atypical pseudotumour cerebri, 34 Neuro-Ophthalmology 255 (2010) (abstract); but see Cestari Rpt. at 14 (questioning whether this woman, who did not have headaches or papilledema, met the Dandy criteria for IIH and noting that the case report did not state whether the woman was overweight or had had recent weight gain or whether her IUD use predated the IIH symptoms).
A second case report, published in 2017, described an overweight woman who had developed IIH approximately two years after starting use of Mirena. It noted that the woman, soon before developing symptoms, had been prescribed a medicine, minocycline, that is associated with IIH, and that the IIH symptoms had abated shortly after the minocycline use (although not the woman's Mirena use) had ceased. See F.J. Ros Forteza, et al., Minocycline-induced intracranial hypertension in a patient with a levonorgestrel intrauterine device, Neurologia (2017) (letter to the editor) (in Spanish).
As to adverse event reports, Bayer has periodically conducted "signal analyses" regarding Mirena and IIH, utilizing the adverse events reports in its pharmacovigilance database.
The most recent, and therefore the most comprehensive, was in October 2017 during discovery in this case. Bayer summarized the findings of this analysis in a submission to a German regulator, BfArM. Bayer identified a total of 315 reported cases involving symptoms indicative of possible IIH symptoms among users of Mirena, and an additional four cases indicative of possible IIH symptoms involving Bayer's more recent Skyla IUD product, which is also LNG-based. See Bayer BfArM Response at 44-45. Of those patients for whom weight data is available, Bayer reported, most were obese or overweight. See Cestari Rpt. at 20. More than 60% of the 315 reported cases were in the form of lawsuits filed after December 2013. See Bayer BfArM Response at 17, 45-46. As developed later, various of plaintiffs' experts draw upon case reports within this
The Court next summarizes the existing studies and data bearing on the relationship between other LNG-based contraceptives and IIH.
Between 1984 and 1993, five epidemiological studies into IIH were conducted that considered, among other issues, whether there was a link between combined oral contraceptives (those containing both estrogen and progestin) and IIH.
All five studies failed to find a causal link.
Norplant, a contraceptive product manufactured by American Home Products and its subsidiary, Wyeth-Ayerst Laboratories, was approved by the FDA in 1990 and introduced in 1991. Norplant released LNG from an implant placed in the woman's arm. Norplant marketing was discontinued in the United States in 2002 and globally in 2008, although a different implant that releases LNG, Jadelle, is currently marketed by Bayer outside the United States. Norplant contained substantially more LNG than Mirena and produced substantially higher total blood concentrations of LNG. Compare 1997 Norplant Label, Dkt. 167-69, at 00055905 (216 mg) with Mirena Label at § 11.1 (52 mg); compare 1997 Norplant Label, at 00055898 (327 ± 119 pg/mL after one year) with Mirena Label at § 12.3 (180 ± 66 pg/mL after one year).
As various plaintiffs' experts observe, see, e.g., Darney Rpt. at 22; Fraunfelder Rpt. at 16; Plunkett Rpt. at 34, Salpietro Rpt. at 28-29, during the period Norplant was in use, several case studies noted an association or possible association between Norplant and IIH. See John B. Alder, et al., Levonorgestrel implants and intracranial hypertension, 332 New England J. Med. 1720, 1720-21 (1995) (Dkt. 167-16) ("Alder") (letter to editor, reporting the development of IIH in two women following the insertion of Norplant and identifying 56 additional possible cases of IIH; author, however, notes existence of confounding factors and adds, "[LNG] may have contributed to the onset of [IIH], or it may have had nothing to do with it"); A.J. Sunku, et al., Benign intracranial hypertension associated with levonorgestrel implants, 34 Annals Neurology 299, 299 (1993) (Dkt. 167-63) ("Sunku") (poster presentation, reporting two women who developed IIH while using Norplant; author concludes that further study is needed to determine whether relationship between Norplant and IIH is "etiological or coincidental"); see generally Diane E. Wysowski & Lanh Green, Serious adverse events in Norplant users reported to the Food and Drug Administration's Med-Watch Spontaneous Reporting System, 85 Obstet Gynecology 538, 540 (1995) (Dkt. 167-67) ("Wysowski & Green").
Another study drawn from the FDA's adverse events database described 39 reports of women with symptoms associated with IIH that developed during Norplant use between February 2001 and December 2003. See Wysowski & Green, supra, at 540. Of the 39 women, the study noted, all for whom weight data was available were obese (16 women) or overweight (2 women). The study noted that the duration of time between the insert of the Norplant and the onset of IIH symptoms had ranged from one to 17 months; that four patients had continued using Norplant yet the symptoms resolved; that 16 patients had the Norplant removed and the symptoms resolved; and that six had the Norplant removed but their IIH symptoms continued. Id. The authors found the assembled data inconclusive. They stated, "[I]t is not possible to determine whether Norplant, obesity or weight gain, or both factors are related to the occurrence of [IIH] .... Epidemiologic research (case-control or cohort studies) would be required to determine if a causal association between Norplant and ... [PTC] exists." Id. at 541. No such studies of Norplant, however, were ever conducted. See Valenzuela, supra, at 4 ("[T]hese previous [Norplant] reports did not imply a causative role in the pathogenesis of PTC.").
Notwithstanding the absence of epidemiological studies, as a result of early adverse event reports of IIH, Norplant's
1997 Norplant Label (Dkt. 167-69) at 00055901. A similar warning as to IIH has been — and remains — included on the label of Bayer's Jadelle product, an LNG-based implant that is not currently marketed in the United States. See Fraunfelder Rpt. at 15; Plunkett Rpt. at 9 n.7.
Finally, apart from the contraceptives reviewed above — Mirena, combined oral contraceptives, and Norplant and Jadelle — other contraceptive devices have had LNG as their hormonal component. Those referenced in the expert reports include: (1) Kyleena and Skyla, both of which are IUDs manufactured by Bayer (Skyla, approved in 2013, has an average release rate of 6 μg LNG/day for up to three years, while Kyleena, approved in 2016, has an average in vivo release rate of 9 μg LNG/day for up to 5 years); and (2) Allergan's Liletta, an IUD releasing 19.5 μg LNG/day for up to three years. Darney Rpt. at 7; Plunkett Rpt. at 9 n.8, 23-24; Wheeler Rpt. at 2. The parties have not drawn to the Court's attention studies or case reports bearing on a possible connection between these products and IIH.
The state of research outside of this litigation as to the general causation proposition here — that using the Mirena IUD can cause a woman to develop IIH — presents a challenge for an expert witness here who would so testify.
As the above review reflects, to date, no prospective experiments have been undertaken that sought to address that question. Two epidemiological studies have examined that question but neither has found such causation. One such study, Etminan, has been retracted to the extent that it — based on its DPA analysis of reports in the FAERS database — had initially found an increased IIH risk among Mirena users. And the surviving half of the Etminan study (which compared Mirena with oral contraceptives) did not find any such increased risk. The other epidemiological study (Valenzuela) found a correlation between Mirena use and IIH. But it found only that. In language that warned against conflating correlation with causation, the Valenzuela study emphasized that its finding of such a correlation "does not indicate" that an LNG-based IUD such as Mirena is an "independent risk factor" for IIH. Rather, as Valenzuela recognized, alternative explanations for the correlation between Mirena and IIH are apparent — notably, the confounding factors of overweightness and obesity among reproductive-age women. As to the other contraceptive products using LNG, five studies of combined oral contraceptives have affirmatively found that these products, which contain notably higher amounts of LNG than Mirena, do not cause IIH. And no study has established a causal link between IIH and Norplant, which also contained substantially more LNG than Mirena.
In the face of this assembled historical record, with no medical organization or regulator or peer-reviewed scientific literature
Each of plaintiffs' seven expert witnesses reach this conclusion in their reports. None has done so through an experiment, laboratory work, or a new epidemiological study of his or her own. Four of plaintiffs' expert witnesses (Drs. Moyé, Plunkett, Wheeler, and Fraunfelder) arrive at this result largely by drawing upon existing sources. These include the Valenzuela study plus, depending on the witness, some or all of the following: the repudiated portion of the Etminan study; case reports regarding Mirena; case reports regarding Norplant and other subdural implants; and Norplant's warning label. These experts also draw upon a newly available source of data: the case reports regarding Mirena first added in Bayer's 2017 signal investigation, which was made available to plaintiffs in discovery. To varying degrees, each of these four experts also articulates a theory as to a biological mechanism by which Mirena might cause IIH.
Plaintiffs' remaining three expert witnesses (Drs. Darney, Johanson, and Salpietro) are predominantly "mechanism" experts. Their reports each develop a thesis as to how, biologically, use of Mirena may cause IIH.
Bayer, for its part, argues that plaintiffs' experts' proposed testimony is unreliable, measured against the requirements for admission of expert testimony. As to the four experts who rely largely on existing studies and data, Bayer contends, inter alia, that the alchemy is elusive by which a witness can reliably find such causation where the studies that comprise the expert's central source material have not so found. As to the three "mechanism" experts, Bayer contends that their untested theories are based on conjecture, and often on mishandling the scholarship on which they postulate causal mechanisms. Overall, Bayer contends that, rather than reflecting rigorous application to scientific methodologies, the conclusions of each of the seven witnesses amounts to a non-scientific ipse dixit.
The Court's analysis proceeds as follows.
The Court first reviews the legal standards governing receipt of expert testimony as set out in Daubert and ensuing decisions.
The Court then summarizes each witness' proposed testimony and assesses it against these standards. The Court first considers the four witnesses who reach the conclusion that Mirena is a cause of IIH based largely on existing studies and data. These witnesses describe the multi-factor methodologies they use in assessing this evidence as, alternatively, a "Bradford Hill" and/or a "totality of the circumstances" methodology.
The Court then considers the remaining three witnesses, whose reports, as noted, largely articulate theories about biological mechanisms by which Mirena might cause IIH.
Trial courts serve as "gatekeep[ers]," responsible for "ensuring that an expert's testimony both rests on a reliable foundation and is relevant to the task at hand." Daubert, 509 U.S. at 597, 113 S.Ct. 2786; see also Wills v. Amerada Hess Corp., 379 F.3d 32, 48 (2d Cir. 2004). Pursuant to Federal Rule of Evidence 702, the party seeking to admit expert testimony must show by a preponderance of the evidence that: (i) the expert is qualified, (ii) the testimony is based on sufficient data,
In Daubert, the Supreme Court set out a list of non-exclusive factors that courts should consider in determining whether an expert's methodology is reliable. These are: (1) whether the expert's technique or theory can be or has been tested; (2) whether it has been subjected to peer review and publication; (3) whether there is a high error rate for the expert's technique, and whether there are "standards controlling the technique's operation"; and (4) whether the expert's technique or theory is generally accepted by the relevant scientific community. Daubert, 509 U.S. at 592-94, 113 S.Ct. 2786; accord Nimely v. City of New York, 414 F.3d 381, 396 (2d Cir. 2005). Courts also consider whether the proffered expert opinions were developed for the purposes of litigation. In re Rezulin Prods. Liab. Litig., 369 F.Supp.2d 398, 420 (S.D.N.Y. 2005) ("In re Rezulin II").
A proffered opinion may fail all four Daubert reliability factors and still be admitted. Before admitting proposed testimony in those circumstances, however, a court must "carefully scrutinize," pause, and take a "hard look" at the expert's methodology. Mirena Perforation/Daubert, 169 F.Supp.3d at 430, 449; In re Methyl Tertiary Butyl Ether (MTBE) Prods. Liab. Litig., 593 F.Supp.2d 549, 564 (S.D.N.Y. 2008). "The flexible Daubert inquiry gives the district court the discretion needed to ensure that the courtroom door remains closed to junk science while admitting reliable expert testimony that will assist the trier of fact." Amorgianos v. Nat'l R.R. Passenger Corp., 303 F.3d 256, 267 (2d Cir. 2002).
Experts can fail to meet Rule 702 and Daubert's standards for various reasons, relating to the expert's qualifications and/or methodology:
Qualifications: The witness simply may not be qualified to address the area in question. See Fed. R. Evid. 702 (providing that in order to testify as an expert under Rule 702, a witness must be "qualified as an expert by knowledge, skill, experience, training, or education."). "To determine whether a witness qualifies as an expert, courts compare the area in which the witness has superior knowledge, education, experience, or skill with the subject matter of the proffered testimony." United States v. Tin Yat Chin, 371 F.3d 31, 40 (2d Cir. 2004).
In determining whether the witness has the relevant experience, courts consider factors including the degree to which that experience was developed for the litigation. See, e.g., Mancuso v. Consol. Edison Co. of N.Y., 967 F.Supp. 1437, 1443 (S.D.N.Y. 1997) ("We cannot help but conclude that [the plaintiffs' expert] was not in fact an expert ... when he was hired by plaintiffs, but that he subsequently attempted, with dubious success, to qualify himself as such by a selective review of the relevant literature."); Prohaska v. Sofamor, S.N.C., 138 F.Supp.2d 422, 437 (W.D.N.Y. 2001) (criticizing "litigation-driven expertise" where expert "relied upon the plaintiff's attorney to provide him with the relevant scientific literature"). Although extensive experience can make up for an absence in specialized training,
Methodology: A witness may also be excluded if his or her proposed methodology is not sufficiently rigorous. See Nimely, 414 F.3d at 396 ("[R]eliability within the meaning of Rule 702 requires a sufficiently rigorous analytical connection between that methodology and the expert's conclusions."). The following are among the principles that guide a court's assessment of reliability.
"To warrant admissibility, ... it is critical that an expert's analysis be reliable at every step." Amorgianos, 303 F.3d at 267. "[N]othing 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." Gen. Elec. Co. v. Joiner, 522 U.S. 136, 146, 118 S.Ct. 512, 139 L.Ed.2d 508 (1997). "A court may conclude that there is simply too great an analytical gap between the data and the opinion proffered" to permit admission. Id.
Courts have found analytical gaps to be too great, for example, when a critical step in a prospective expert's reasoning is based on a highly dubious analogy. See, e.g., Mirena Perforation/Daubert, 169 F.Supp.3d at 439 ("Such a subjective comparison of muscle of a pig heart to a female uterus creates simply too great an analytical gap between the data and the opinion proffered to pass muster under Rule 702 and Daubert." (quotation marks omitted)); Shatkin v. McDonnell Douglas Corp., 727 F.2d 202, 208 (2d Cir. 1984) (rejecting expert methodology based on an "apples and oranges" comparison).
An expert is, further, expected to "employ[] in the courtroom the same level of intellectual rigor that characterizes the practice of an expert in the relevant field." Kumho Tire Co. v. Carmichael, 526 U.S. 137, 152, 119 S.Ct. 1167, 143 L.Ed.2d 238 (1999). "Expert testimony should be excluded if it is speculative or conjectural," Boucher v. U.S. Suzuki Motor Corp., 73 F.3d 18, 21 (2d Cir. 1996), or where the proffered opinion is "based on data, a methodology, or studies that are simply inadequate to support the conclusions reached," Amorgianos, 303 F.3d at 266.
"[W]hen an expert relies on the studies of others, he must not exceed the limitations the authors themselves place on the study." In re Accutane Prods. Liab., No. 8:04-MD-2523-T-30TBM, 2009 WL 2496444, at *2 (M.D. Fla. Aug. 11, 2009), aff'd, 378 F. App'x 929 (11th Cir. 2010); Mirena Perforation/Daubert, 169 F.Supp.3d at 452 (same).
Opinions that assume a conclusion and "reverse-engineer[] a theory" to fit that conclusion are, similarly, inadmissible. Mirena Perforation/Daubert, 169 F.Supp.3d at 430; In re Gen. Motors LLC Ignition Switch Litig., No. 14-CV-5810, 2017 WL 6729295, at *8 (S.D.N.Y. Dec. 28, 2017); see also Faulkner v. Arista Records LLC, 46 F.Supp.3d 365, 381 (S.D.N.Y. 2014) ("[M]ethodology ... aimed at achieving one result ... is unreliable, and ... must be excluded."); In re Zoloft (Sertraline Hydrochloride) Prods. Liab. Litig., 858 F.3d 787, 796-800 (3d Cir. 2017) ("In re Zoloft") (affirming exclusion of "conclusion-driven" analysis).
Dr. Moyé is a trained medical doctor with a Ph.D. in Community Sciences Biostatistics. He bases his opinion that Mirena is a cause of IIH on what he describes as an application of the Bradford Hill criteria.
Dr. Moyé works as a tenured professor of biostatistics within the Department of Biostatistics and Data Sciences at the University of Texas School of Public Health in Houston, Texas. He became a licensed physician in Texas in 1984 and worked as a general practitioner for eight years. See Moyé Rpt. at 2. Dr. Moyé does not, however, hold himself out as an expert in pharmacokinetics or pharmacodynamics, specialties associated with expertise in developing biological mechanisms for diseases. Moyé Dep. at 85-86.
Dr. Moyé has extensive experience in conducting large clinical trials and analyzing their results statistically. He has been a Principal Investigator in a large cardiovascular study, a Coordinating Center Principal Investigator in a study regarding the treatment of strokes, and is currently the Coordinating Center Principal Investigator for the Cardiovascular Cell Therapy Research Network. He has published numerous peer-reviewed articles about the studies he has conducted, as well as several books on the use of statistics in medicine. See Moyé Rpt. at 2-3.
Dr. Moyé has also been hired as an expert witness on numerous occasions. In the last four years, he has been deposed as an expert witness 14 times. Before this litigation, he did not have any experience related to Mirena, and he had limited exposure to IIH. Moyé Dep. at 85. Outside of this litigation, he has never conducted research on LNG. Id. at 85-88.
The Bradford Hill criteria derive from a 1965 lecture by a British epidemiologist and statistician, Sir Austin Bradford Hill. See David E. Bernstein, The Admissibility of Scientific Evidence After Daubert v. Merrell Dow Pharmaceuticals, Inc., 15 Cardozo L. Rev. 2139, 2167 (1994) ("In a celebrated lecture in 1965, Sir Austin Bradford Hill proposed nine criteria to aid scientists in deciding whether a reported association in an epidemiological study is causal."). "The Bradford Hill criteria are metrics that epidemiologists use to distinguish a causal connection from a mere association." In re Zoloft, 858 F.3d at 795. These criteria "start with an association demonstrated by epidemiology and then apply" eight or nine criteria to determine whether that association is causal. In re Breast Implant Litig., 11 F.Supp.2d 1217, 1234 (D. Colo. 1998).
The nine Bradford Hill criteria are as follows.
Thompson, supra, at 268; see also In re Zoloft, 858 F.3d at 795; Moyé Rpt. at 16-20.
Dr. Moyé principally relies on the following materials in applying the Bradford Hill criteria: (1) the Valenzuela study, (2) 36 case reports, drawn from among the 315 adverse event reports as to Mirena and IIH noted in Bayer's 2017 signal investigation, and Bayer's summary of that investigation in its BfArM submission; (3) a single published article involving Norplant, and (4) a review of literature based upon which Dr. Moyé develops a theory as to a "biologic[ally] plausib[le]" mechanism. Moyé Rpt. at 39; see id. at 29-43. He applies the nine Bradford Hill criteria, or factors, to that evidence as follows:
Strength of association: Dr. Moyé bases his finding of a "positive" strength of association, Moyé Rpt. at 34, on the Valenzuela cohort study. See id. at 29-34. As noted, that study reviewed populations in Utah and Denmark. Dr. Moyé concludes that that, as to both populations, the Valenzuela data revealed an association between Mirena and IIH. The relative risk ratio (a measure of the likelihood of IIH occurring in patients using Mirena compared to those not using Mirena) for both populations was, he states, statistically significant. See id. at 31 (relative risk ratio for LNG-IUD group in Utah population was 7.69); id. at 32 (relative risk ratio for LNG-IUD group in Denmark population was 3.90). Dr. Moyé concedes that those ratios, being derived from Valenzuela, did not control for the confounding factors of age or weight. He terms that shortcoming "regrettable." Id. at 31. Nevertheless, Dr. Moyé concludes, because the relative risk ratios (particularly as to Utah) were substantial, "it would be unreasonable to assume that the large odds ratios observed in the Utah cohort would be completely adumbrated by adjustment for obesity and age." Id. at 31-32. The association between Mirena and IIH, he states, was "not likely to be overshadowed by any adjustment for confounders." Id. at 32.
In discussing this factor, Dr. Moyé also responds to Bayer's argument that the
Temporality: Dr. Moyé finds the temporality factor met, based on case reports in Bayer's 2017 adverse events database. See Moyé Rpt. at 34-37. "Temporality requires that exposure occur before the disease," Dr. Moyé notes, and "[c]ases in the Bayer database demonstrate the occurrence of [IIH] after the insertion of the Mirena device." Id. at 34. Dr. Moyé identifies 13 cases in that database that he states showed that Mirena had likely caused the patient's IIH symptoms. Id. at 34-36. Each, he contends, reflected "a reasonable time relationship between Mirena exposure" and the patient's IIH; "it is unlikely," he states, "that the [IIH] would be attributed to other factors." Id. at 37. Dr. Moyé draws these 13 examples from the approximately 36 case reports that he reviewed from the Bayer database. Moyé Dep. at 231. It is unclear how the 36 cases were selected. Dr. Moyé appears to have reviewed them either in the order they were provided to him by counsel and/or by reviewing a chart of all case reports and deciding (based on criteria that are unclear) which to examine. Dr. Moyé did not review all of Bayer's adverse event reports regarding IIH. Id. at 229, 231.
Biological gradient: Dr. Moyé finds that "there is a biological gradient" — i.e., that IIH occurs more frequently in Mirena users whose LNG levels are highest. See Moyé Rpt. at 39; id. at 37-39. He bases this finding on three sources: (1) the Valenzuela study, (2) Bayer's 2015 signal investigation, and (3) Bayer's 2017 BfArM response.
Biological plausibility: Dr. Moyé proposes a biological mechanism as to how LNG might plausibly cause IIH. He embraces an "androgen" theory: He posits that LNG mimics "the action of the mineralocorticoid aldosterone, thereby increasing sodium ion and water flow into the central spinal fluid, and subsequently increasing CSF pressure." Moyé Rpt. at 40. Dr. Moyé does not develop this theory. Instead, he recites nine propositions for which he stated there are biomedical sources. These, he states, when viewed in combination, support such a causal mechanism for Mirena. Id. Dr. Moyé includes a blanket citation to 40 academic articles. Id. at 40-41.
Coherence: Dr. Moyé finds this factor met, because the biological mechanism he endorses "relies on known science ... and is therefore in concordance with modern molecular biology." Id. at 41.
Consistency: Dr. Moyé finds this factor met, because the Valenzuela study had involved two different populations and had used different protocols to select patients (health data in Utah; census data in Denmark). Id.
Specificity: Dr. Moyé concedes that IIH has multiple causes. But, he states, alternative causes to Mirena "can either be excluded, statistically adjusted out of consideration, or accounted for in a multi-factorial causation model." Id. He does not state that this exercise has ever been performed anywhere.
Experimental evidence: In finding this factor met, id. at 41-42, Dr. Moyé relies on five case reports drawn from the 2017 Bayer database. He terms these "representative" examples of a "challenge-dechallenge" — that is, a situation in which a patient developed IIH while using Mirena, and then, after the Mirena had been removed, "either recovered or improved." Id. at 41. Dr. Moyé's examples, however, are not representative of the cases in Bayer's adverse events database, as described in Bayer's BfArM report. That report states that, of the 68 patients whose Mirena had been removed and for whom further information was available, 31 (or 46%) "did not recover," 23 (or 34%) had "improved," and 14 (or 20%) had "recovered." Bayer BfArM Response at 49. For an additional 128 patients, "no information on the further course of the disease was provided. Id. In contrast, of Dr. Moyé's five case reports, four patients (80%) had recovered, one (20%) had "improved," and none "did not recover." See Moyé Rpt. at 41-42. Pressed in his deposition on his claim that his five-case sample was "representative," Dr. Moyé stated that he had viewed his sample as representative not of the Bayer database, but of the subset of patients where the "phenomenon of dechallenge was observed" — that is, where the IIH symptoms had disappeared after a Mirena was removed. Moyé Dep. at 241.
Analogy: In finding this factor met, Moyé Rpt. at 42-43, Dr. Moyé analogizes to one published study of Norplant, by Wysowski and Green. He opines that it supported that Mirena causes IIH. However, as noted earlier, that study is not an epidemiological study. It discusses a collection of adverse event reports involving Norplant. Wysowski and Green concluded that, based on the evidence before them, it was "not possible" to determine whether "a causal association exists" between Norplant and IIH. Wysowski and Green, supra, at 541.
Either explicitly or implicitly, Dr. Moyé finds that each of the nine Bradford Hill factors is met here. On that basis, he
Of the four plaintiffs' experts who reached this conclusion by applying the Bradford Hill or on a similar totality-of-the-circumstances approach, Dr. Moyé's assessment of the constituent factors is, in the Court's assessment, the most thorough and substantial. However, on inspection, his analysis is flawed by serious methodological deficiencies. These include an unweighted and unmoored application of the nine Bradford Hill factors, a failure to consider known contrary evidence, a contravention of principles which Dr. Moyé has acknowledged should guide an epidemiologist's inquiry, a selective use of case report data, a lack of qualification to opine on biological mechanisms by which Mirena might cause IIH, and the citation of the Valenzuela study for propositions that it did not find. Under Daubert principles, these flaws, reviewed below, make Dr. Moyé's proposed testimony unreliable and inadmissible.
To begin, as appears undisputed, Dr. Moyé's opinion does not satisfy any of the four reliability factors identified in Daubert. He has not tested his theory. He has not subjected it to peer review or had it published. He has not identified an error rate for his application of the nine Bradford Hill factors. And vetting of a multi-factor inquiry to yield a numeric error rate appears realistically impossible, as there are no "standards controlling the technique's operation." Daubert, 509 U.S. at 594, 113 S.Ct. 2786. Finally, the theory he advances in this litigation has not been "generally accepted by the relevant scientific community." Id. at 584, 113 S.Ct. 2786. Quite the contrary: Outside of this litigation, there is a complete absence of scholarship opining that Mirena, or for that matter any LNG-based contraceptive, is a cause of IIH.
The Court therefore must take a "hard look" at Dr. Moyé's methodology. See Mirena Perforation/Daubert, 169 F.Supp.3d at 430, 449.
Such scrutiny is particularly warranted given Dr. Moyé's choice of methodology. As courts have recognized, it is imperative that experts who apply multi-criteria methodologies such as Bradford Hill or the "weight of the evidence" rigorously explain how they have weighted the criteria. Otherwise, such methodologies are virtually standardless and their applications to a particular problem can prove unacceptably manipulable. Rather than advancing the search for truth, these flexible methodologies may serve as vehicles to support a desired conclusion.
As the Third Circuit has put the point: "To ensure that the Bradford Hill/weight of the evidence criteria is truly a methodology, rather than a mere conclusion-oriented selection process ... there must be a scientific method of weighting that is used and explained." In re Zoloft, 858 F.3d at 796 (quotation marks omitted); Magistrini v. One Hour Martinizing Dry Cleaning, 180 F.Supp.2d 584, 607 (D.N.J. 2002) (same), aff'd, 68 F. App'x 356 (3d Cir. 2003). And as the First Circuit has required, while the expert's bottom-line conclusion need not be independently supported by each of the nine Bradford Hill factors,
Accordingly, where experts have claimed to apply Bradford Hill, courts have insisted on a clear explication of the weighting assigned to the different criteria. They have also demanded that the expert's application of the individual criteria be performed with proper rigor. "[T]he specific techniques by which the weight of the evidence/Bradford Hill methodology is conducted must themselves be reliable according to the principles articulated in Daubert." In re Zoloft, 858 F.3d at 796; see id. ("An expert can theoretically assign the most weight to only a few factors, or draw conclusions about one factor based on a particular combination of evidence. The specific way an expert conducts such an analysis must be reliable; `all of the relevant evidence must be gathered, and the assessment or weighing of that evidence must not be arbitrary, but must itself be based on methods of science.'" (quoting Magistrini, 180 F.Supp.2d at 602)). Insistence upon such rigor guards against the pitfall of which Judge Seibel warned in excluding expert testimony in the earlier Mirena litigation: "reverse-engineering a theory to fit the desired outcome." Mirena Perforation/Daubert, 169 F.Supp.3d at 430; see also Faulkner, 46 F.Supp.3d at 381.
Measured against these standards, Dr. Moyé's report falls short.
At the most general level, his report does not explain the weight that he attaches to any of the Bradford Hill criteria or address the relationship among them. Instead, he finds that all nine criteria support a finding that Mirena causes IIH. Indeed, he nowhere concedes that any criterion even is only weakly supportive of a finding of causation. By leaving obscure the weight that he attaches to each of the nine Bradford Hill factors and the relationship among them, Dr. Moyé's approach effectively disables a finder of fact from critically evaluating his work.
To illustrate the point: A finder of fact might, for example, take issue with Dr. Moyé's assessment of the first factor — the gating factor of strength of association. Dr. Moyé finds a "strong association" based principally on the Utah component of the Valenzuela study. Moyé Rpt. at 31. Dr. Moyé's fellow expert, Dr. Wheeler, however, reaches a different conclusion — he concludes that, based on the Valenzuela and Etminan studies, "there is no association demonstrated." Wheeler Dep. 200. And the Valenzuela study on which Dr. Moyé bases his strength-of-association finding stopped well short of finding a strong association. The authors pointedly cautioned that "[a]lthough use of an LNG-IU[D] seems [to] be associated with an increased risk of PTC, it is possible that this observation occurred because use of an LNG-IU[D] is also associated with other risk factors that are known to be associated with PTC (e.g., obesity and recent weight gain)." Valenzuela, at 4; see also id. at 5 ("[I]t is also important to consider that the risk analysis does not account for potential confounders."). A finder of fact might therefore come to a conclusion other than that of Dr. Moyé as to strength of association, perhaps finding, for example, in between Drs. Moyé and Wheeler, that there is a statistical association, but only a weak one, between Mirena and IIH. Such a finder would then have to consider whether the other Bradford Hill factors, if now viewed in the context of only a weak statistical association, support a finding of causation. Dr. Moyé's failure to weigh or explain the relationship among the factors in his analysis, however, would disable such an inquiry.
As to his assessment of individual Bradford Hill factors, Dr. Moyé's mode of analysis, too, departs repeatedly from reliable methodology. Four examples, among others, illustrate the point.
As to the Bradford Hill factor of analogy, this factor requires "substantiation of relationships similar to the putative causal relationship ...." Thompson, supra, at 268. Dr. Moyé elsewhere has acknowledged this requirement.
As to the Bradford Hill factor of specificity, this factor inquires into the number of causes of a disease. As Dr. Moyé explained: "The greater the number of causes of a disease (i.e., the more multifactorial
As to the Bradford Hill factor of consistency, it tends to require "similar findings... generated by several epidemiological studies involving various investigators." See Thompson, supra, at 268; see also Reference Manual on Scientific Evidence at 604 ("It is important that a study be replicated in different populations and by different investigators before a causal relationship is accepted by epidemiologists and other scientists."). Dr. Moyé opines that the Valenzuela study "satisfies the consistency metric," because Valenzuela considered two separate populations. Moyé Rpt. at 41. These studies, however, were conducted by the same investigators.
Finally, as to the Bradford Hill factor of biologic plausibility, Dr. Moyé bases his finding that this factor was satisfied on his conclusion that a mineralocorticoid (MR) theory by which Mirena causes IIH is plausible. He posits that LNG mimics "the action of the mineralocorticoid aldosterone, thereby increasing sodium ion and water flow into the cerebral spinal fluid, and subsequently increasing CSF pressure." Moyé Rpt. at 40; see Moyé Dep. 249 ("Q: As I understand what you have written in your report you rely on the MR theory; is that correct?" A: Correct. Q: Not the androgen receptor theory? A: [T]hat is correct.").
Simply stated, by any measure, Dr. Moyé is unqualified to give an expert opinion as to a biological mechanism of causation of IIH. His lack of qualifications to so opine makes unreliable not only Dr. Moyé's assessment as to biological plausibility — that the MR mechanism is a biologically plausible one. It also compromises his assessment of the companion Bradford Hill factor of coherence, because Dr. Moyé finds that factor met explicitly based on his assessment that the mechanism he had endorsed is a coherent one. See Moyé Rpt. at 41 ("The mechanism of 1) increased egress of Na+ ion and water flow into the CSF from the choroid plexus producing CSF, and 2) decreased flow [ ]either by decreased activity of carbonic anhydrase, or reversal of the effect of steroid hormones that mimic aldosterone in the MR can reduce the symptoms of [IIH] does not contradict known science.")
Common to Dr. Moyé's misapplications of the above Bradford Hill factors is this: Each of Dr. Moyé's departures from settled and rigorous methodology favors the same outcome. Each enables him to find that the Bradford Hill factor at issue supports concluding that Mirena is a cause of IIH. At bottom, as the Supreme Court instructed in Daubert, expert testimony "must be supported by appropriate validation — i.e., good grounds, based on what is known." Daubert, 509 U.S. at 590, 113 S.Ct. 2786 (internal quotation marks omitted). Dr. Moyé's unidirectional misapplication of a series of Bradford Hill criteria is concerning — it is a red flag. Rather than suggesting a scholar's considered neutral engagement with the general causation question at hand, it suggests motivated, result-driven, reasoning. See Faulkner, 46 F.Supp.3d at 381 ("[M]ethodology... aimed at achieving one result ... is unreliable.").
Yet other methodological lapses also preclude, as unreliable under Daubert, Dr. Moyé's proposed testimony.
For one, Dr. Moyé ignores scientific standards that he has conceded govern inquiries into general causation. In his deposition, Dr. Moyé agreed, for example, with certain widely accepted principles of medical research. One is that case reports do no more than raise the question of a causal connection between a drug and a disease; they cannot establish causation. Moyé Dep. at 272. A related principle that he acknowledged is that, to prove general causation, observational studies, such as a case control study or a cohort study, generally are required. See id. at 125 (agreeing that a single observational study "[r]arely, if ever ... persuasively demonstrate[s] a cause-effect relationship"); id. (agreeing that "it is important that an observational study be replicated in different populations and by different investigators
Dr. Moyé's report is unfaithful to these precepts. Dr. Moyé finds causation of IIH by Mirena in the absence of any of the sorts of studies that he concedes generally are required. As to studies, he relies solely on the Valenzuela study, a retrospective epidemiological study which stopped well short of finding causation, recognizing that it had not controlled for major confounding variables such as obesity and weight gain that are prevalent both among IIH patients and the population of Mirena users. In his deposition, Dr. Moyé admitted Valenzuela's limitations. See, e.g., Moyé Dep. at 215 ("Q: Would you conclude causation with just the results of Valenzuela standing alone? A: No, sir, I would not."); id. at 216 ("I think an appropriate statement would be to say that it's possible that LNG-IU[D] causes PTC, but this study doesn't show it."). And Dr. Moyé also appears to rely on case reports for more than merely raising a question about whether a causal relationship between Mirena and IIH existed. In his report, Dr. Moyé uses case reports (and a study aggregating such reports) almost exclusively to establish three of the nine Bradford Hill factors: experimental evidence, temporality, and analogy. See Amorgianos, 303 F.3d at 269 (affirming exclusion of proffered expert who "fail[ed] to apply his stated methodology reliably to the facts of the case") (internal quotation marks omitted); Soldo v. Sandoz Pharm. Corp., 244 F.Supp.2d 434, 561 (W.D. Pa. 2003) (excluding experts "[b]ecause consistency is a hallmark of the scientific method [and] plaintiff's experts must be required to satisfy their own standards of reliability"); cf. Kumho Tire Co., 526 U.S. at 152, 119 S.Ct. 1167 (expert is expected to "employ[ ] in the courtroom the same level of intellectual rigor that characterizes the practice of an expert in the relevant field").
Dr. Moyé also chooses not to consider evidence that undercuts his opinion — potentially very materially. This is a separate methodological failing. It is most strikingly apparent in Dr. Moyé's consideration of the analogy factor. Dr. Moyé elects to analogize to Norplant. As to Norplant, he draws on isolated case reports canvassed in a study (Wysowski and Green) that disclaimed a finding of causation. He also analogizes to case reports in which, he states, a relationship was indicated between IIH and "elevated testosterone levels." Moyé at 42-43. As to this factor, he thus is willing to range outside the area of LNG-containing intra-uterine devices, considering case reports as to other products and other hormones.
In so doing, however, Dr. Moyé, tellingly, does not consider an analogy between Mirena and other LNG-containing contraceptive drugs: combined oral contraceptives containing LNG. Consideration of those products stood to seriously undermine Dr. Moyé's conclusion. As noted, five epidemiological studies have uniformly failed to demonstrate a link between such oral contraceptives and IIH, even though LNG-containing oral contraceptives generally contain far higher doses of LNG than Mirena, and IIH. Whatever the scientific distinctions that might have been made between oral and intra-uterine delivery systems for LNG, these studies demanded Dr. Moyé's consideration. Yet Dr. Moyé does not review them. Moyé Dep. at 51-52.
Dr. Moyé's decision to brush aside these epidemiological studies, while analogizing to a different medical device and a different hormone based exclusively on case reports, departs from reliable, rigorous methodology. "[A]n expert may not pick and choose from the scientific landscape." In re Rezulin Prod. Liab. Litig., 309 F.Supp.2d at 563 (internal quotation marks omitted); see also MTX Commc'ns
Finally, Dr. Moyé's sampling of case reports — which played a central role in his report at various points — is performed in a manner not bespeaking scientific rigor or neutrality. Rather than selecting case reports through random sampling or by a representative cross section, Dr. Moyé appears to draw the case reports that he considers from those presented to him by counsel or from a spreadsheet whose design is elusive. This skewed methodology has obvious potential to yield a skewed sample and result. Relatedly, Dr. Moyé's five chosen "dechallenge" cases are unrepresentative of the much larger sample covered by the BfArM report; and the examples he chooses tended to favor his bottom-line causation conclusion.
Dr. Moyé's failure to apply neutral selection methodology as among such anecdotal evidence is unscientific. Viewed in combination with the other deficiencies noted, this failing, too, supports excluding his testimony. See U.S. Info. Sys., Inc. v. Int'l Bhd. of Elec. Workers Local Union No. 3, AFL-CIO, 313 F.Supp.2d 213, 235 (S.D.N.Y. 2004) (excluding expert who relied on biased sample of data); Rowe Entm't, Inc. v. William Morris Agency, Inc., No. 98 Civ. 8272 (RPP), 2003 WL 22124991, at *3 (S.D.N.Y. Sept. 15, 2003) (same); but see Auto. Ins. Co. of Hartford, Conn. v. Electrolux Home Prods., Inc., No. 10-CV-0011 CS, 2012 WL 6629238, at *2 (S.D.N.Y. Dec. 20, 2012) ("Potential sample bias is a subject for cross-examination, and goes to the weight, not the admissibility, of the expert testimony.")
In conclusion, Dr. Moyé's proposed testimony is compromised by a range of serious methodological flaws. It fails to meet the standard for reliability required by Daubert. The Court must exclude it.
Dr. Plunkett is a pharmacologist and toxicologist with more than 20 years' experience
Dr. Plunkett has experience "examining the risks associated with exposure to hormones and the risks associated with altered hormonal status in women." Id. at 2. However, she is not a medical doctor. She has neither published on IIH nor spoken about the disease to doctors who treat it. Plunkett Dep. at 111-12.
Dr. Plunkett's proposed testimony can be divided into two parts: (1) a discussion of the pharmacokinetics of LNG-releasing contraceptives, and (2) an application of the Bradford Hill methodology, which she alternatively describes as a "weight of the evidence" analysis, with the conclusion that Mirena causes IIH.
Dr. Plunkett's discussion of the pharmacokinetics of LNG informs her application of the Bradford Hill methodology. Because Bayer either concedes or does not substantially contest most of this discussion, the Court highlights only Dr. Plunkett's major points.
First, Dr. Plunkett discusses the difference between "free" LNG and total LNG. She asserts that free LNG levels should be used to access a patient's exposure and response to the hormone. The vast majority of LNG in the blood stream is not "free" floating. Instead, she states, upwards of 98% of LNG is bound to plasma proteins (specifically albumin and a carrier protein called steroid hormone binding globulin). However, she states, LNG's effects are not generally created by such bound LNG. Rather, they are created by "free" LNG activating nuclear hormone receptors. Thus: "It is the free or unbound LNG levels that correlate best with the biological responses observed in humans, not the total level of LNG in blood." Plunkett Rpt. at 7.
Dr. Plunkett also states that, although free LNG levels for Mirena are lower than the levels associated with other LNG-releasing contraceptive devices (such as Norplant), the LNG levels in the blood of patients using such devices overlap with the levels observed in Mirena patients. This overlap, Dr. Plunkett asserts, justifies analogizing Mirena to Norplant and other LNG-containing contraceptive devices. Id.
Dr. Plunkett notes that LNG is a progestin, which mimics the effects of progesterone. She observes that, relative to other progestins, LNG is androgenic, meaning that it can bind with androgen receptors. However, Dr. Plunkett notes, discerning a mechanism to explain the pharmacological and toxicological effects of progestins like LNG is extremely complicated. Id. at 10-12.
Dr. Plunkett applies the Bradford Hill factors, as follows.
Id. Dr. Plunkett's report does not mention or contend with the fact that the Valenzuela study had explicitly disclaimed a finding of a causal connection between IIH and Mirena. Nor does Dr. Plunkett's report note that the Rai poster presentation was a preview of the Valenzuela data presented prior to its 2017 publication and thus was substantively the same study as Valenzuela. In her deposition, Dr. Plunkett conceded those facts. Plunkett Dep. at 136-37, 165-66.
Temporality: In finding this factor satisfied, Dr. Plunkett states that she relies on three studies which, she stated, had "addressed" temporality (by Valenzuela, Rai, and Alder) and on three case reports drawn from the Bayer database. Plunkett Rpt. at 28. Beyond identifying these materials, however, Dr. Plunkett does not address their contents. The Valenzuela authors, for instance, specifically noted in their publication that they lacked temporal data. See Valenzuela, supra, at 4 ("The analysis was also limited by the lack of temporal data to confirm that exposure to LNG-IU[D] occurred prior to PTC symptom onset or diagnosis."). And Rai, as noted, was a precursor to Valenzuela and based on the same data. The third publication she cites, by Alder, was a letter to the editor that discussed two cases of IIH which arose in Norplant users after the Norplant's implantation. The Alder authors disclaimed any causal findings: "[Norplant] may have contributed to the onset of [IIH], or it may have had nothing to do with it." Alder, supra, at 1721. Dr. Plunkett's report does not note this disclaimer. As to the three case reports Dr. Plunkett cites, two involved Mirena and one involved Skyla.
Biological gradient: Dr. Plunkett quotes Sir Bradford Hill in framing her discussion of this factor, in recognizing the "difficulty [of] secur[ing] some satisfactory" data to permit assessment of a dose-response effect. Id. In finding a possible such effect with respect to Mirena and IIH, Dr. Plunkett states that she relies on three sources: (1) a 1992 article (V. Brache, et al., Free Levonorgestrel Index and Its Relationship with Luteal Activity During Long-Term Use of Norplant Implants, 8 Soc'y for the Adv. of Contraception 319 (1992) ("Branche"); (2) Bayer's 2015 signal investigation; and (3) the Mirena 2017 signal assessment. The Branche article, according to Dr. Plunkett, had shown that in the first two years of LNG exposure, free LNG levels are higher than they otherwise would be. Plunkett Rpt. at 29. Dr. Plunkett finds that probative of a biological gradient, because approximately 75-80% of the IIH adverse events in Bayer's 2015 signal investigation had been reported during the first two years of Mirena use. Id. at 29. As for Bayer's 2017 signal assessment, Dr. Plunkett notes, it had compared the reporting frequency for IIH in Mirena and Skyla, which releases substantially less LNG than Mirena. The reporting frequency of IIH for each product was the same, which might seem to suggest, Dr. Plunkett acknowledges, the lack of a biological gradient. Id. at 30. However, Dr. Plunkett rejects that conclusion. She notes that there is "variability in LNG pharmacokinetics with both products, which would affect the levels of LNG in the blood achieved from patient to patient, and confound any attempt to identify a dose-response for LNG exposure and [IIH] in humans." Id. She also ventures that adverse events as to these drugs may have been significantly under-reported, a phenomenon particularly likely as to "drugs that may have been on the market for many years." Id. She ultimately concludes that "the available dose-response data provide support for the cause and effect assessment in terms of showing that increased levels of LNG in blood are more likely to be associated with adverse effects generally." Id. at 31. However, she acknowledges, "[u]nfortunately, no dose or blood level threshold that is associated with an increased risk of [IIH] has been identified to date." Id.
Biological plausibility: Dr. Plunkett embraces the "androgen theory" of how LNG might cause IIH.
Coherence: Dr. Plunkett does not cite any sources as to this factor, which she addresses in a short paragraph. Instead, she refers to her discussion of the biological plausibility that Mirena causes IIH, in that IIH "has been linked with androgenic activity." Id. at 33. She also cites "human epidemiological data" as to Mirena and IIH, apparently although not explicitly referring to the Valenzuela and Etminan studies. "[T]he data reported" in those studies, she states, "are consistent with what is known about the etiology of [IIH]." Id.
Specificity: Dr. Plunkett states that this factor considers "whether the association is limited to specific types of activities or injuries." Id. at 27. Dr. Plunkett does not explicitly find this factor met, stating more obliquely that "considering specificity of the relationship has been part of my overall assessment." Id. at 28. She acknowledges that the scientific literature addressing the relationship between Mirena and IIH described "confounding factors ... such as obesity [and] female gender." Id. at 27-28.
Experimental evidence: Dr. Plunkett casts this factor as "relat[ing] to the ability to collect data in order to analyze the cause and effect relationship." Id. at 33. In finding it met, Dr. Plunkett relies on publications above regarding Norplant, and on Bayer's 2015 signal assessment data, the latter of which, she stated, contained examples of "dechallenge." She concedes, however, that animal or cell experiments are the evidence typically used in experiments used to find causation, and that none have been conducted regarding LNG and IIH. Plunkett Rpt. at 35.
Analogy: Dr. Plunkett analogizes Mirena to Norplant. She relies on the publications cited above regarding Norplant. As noted, however, these were not epidemiological studies — they instead discussed case reports — and none found causation by Norplant of IIH. Dr. Plunkett also cites several studies which discuss IIH's etiology and list LNG as associated with IIH. None, however, had found that LNG is causally linked to IIH. See id. at 34-35.
Bayer argues that Dr. Plunkett's methodology in applying Bradford Hill is unreliable. Bayer is correct. The application of Bradford Hill in Dr. Plunkett's report has a number of methodological flaws. Some are common with those noted in connection with Dr. Moyé. Dr. Plunkett's report is also validly called out for independent lapses, as reflected in the Court's assessment, below, of her applications of certain Bradford Hill factors.
To begin, in common with Dr. Moyé, Dr. Plunkett's report does not meet any of the four Daubert reliability factors. She has not tested her theory. She has not subjected it to peer review or had it published. She has not identified an error rate for her technique, and, as with Dr. Moyé's application of the Bradford Hill methodology, there are no standards controlling its operation. Finally, Dr. Plunkett's theory that Mirena is a cause of IIH, far from achieving general acceptance, has not been accepted by any part of the scientific community outside of this litigation. A "hard look" is therefore warranted as to her analysis, too. Compounding these problems, Dr. Plunkett, in common with Dr. Moyé, does not explain the weights she places on the various Bradford Hill factors. Instead, she reviews each in isolation, and opines or
The Court begins with Dr. Plunkett's reliance on the discredited portion of the Etminan study. That study is a centerpiece of her application of the first Bradford Hill factor. That factor requires a statistical, or strong, association between the cause under review and its asserted effect.
As reviewed earlier, Dr. Etminan retracted as unsound the disproportionality analysis in his study. He did so expressly in his 2016 affidavit and again functionally in his 2017 letter to the editor. As he explained in those writings, once the control group in the FAERS database was limited to reproductive age females, no elevated reporting odds ratio was observed for Mirena (statistically significant or otherwise). This, Dr. Etminan stated, "suggest[ed] that intracranial hypertension and Mirena use are `likely not related.'" Etminan Affidavit ¶ 8 (emphasis added).
Notwithstanding these serial retractions, Dr. Plunkett relies on the Etminan study as a whole, including its DPA analysis, as a basis for her finding of a significant statistical association between Mirena usage and IIH.
Dr. Plunkett did not do so. Defending this component of her analysis in her deposition, Dr. Plunkett embraced anew the results of Etminan's study. She testified that the 1.85 reporting odds ratio used in Dr. Etminan's 2015 disproportionality analysis survived and remained "a reliable piece of evidence to be used within the weight of the evidence for causation." See Plunkett Dep. at 138-39. That premise is wrong. In his 2016 affidavit, Dr. Etminan explicitly repudiated the 1.85 reporting odds ratio. He implicitly did so again in his 2017 letter to the editor. There, he made clear that once the subject's reproductive age was taken into account, the reporting odds ratio would change.
A similar methodological lack of rigor is reflected in Dr. Plunkett's application of Bradford Hill's analogy factor. In finding that the analogy factor supported finding that Mirena causes IIH, Dr. Plunkett, like Dr. Moyé, centrally analogizes Mirena to Norplant. Plunkett Rpt. at 34-35. But, as Dr. Plunkett conceded in her deposition, she has not concluded that Norplant causes IIH. See Plunkett Dep. at 33-34. Nor, as noted earlier, has any existing scholarship reached that conclusion, as various of plaintiffs' other experts conceded. See, e.g., Darney Dep. at 138. Dr. Plunkett's treatment of the analogy factor, like Dr. Moyé's, is therefore unsound, insofar as the premise of its analogy is an assumed, not an established, fact. For both of these experts, there is too great an analytic gap between the available data and the conclusion they draw.
Dr. Plunkett's approach as to the Bradford Hill factor that assesses experimental evidence is also problematic. Like Dr. Moyé, Dr. Plunkett does not, and given the non-existence of any experiment testing whether Mirena tended to cause IIH, could not point to any such experiment.
To find the experimental evidence factor satisfied, Dr. Plunkett instead, like Dr. Moyé, turns to examples of purported "dechallenges." Dr. Plunkett does not, however, cite, let alone analyze, any concrete such example. Instead, she cites without comment Bayer's 2015 signal assessment and publications addressing Norplant. Even on Dr. Plunkett's own terms, however, these sources were flawed as a basis for that conclusion, because the "dechallenge" examples addressed therein either explicitly were, or potentially were, subject to confounding factors. Bayer's 2015 signal assessment, for example, states that "[n]o unambiguous case of positive dechallenge could be identified." Bayer BfArM Resp. at 49. The writings that Dr. Plunkett cites regarding Norplant are much the same. Sunku's poster presentation recounted two anecdotal examples of dechallenge; in each, the patient was treated with diuretics, supplying an obvious alternative to the removal of the Norplant as an explanation for the resolution of the patient's IIH symptoms. See Sunku, et al., supra. And Wysowski's study is silent about whether the Norplant removal of the patients that he described coincided with other treatment. See Wysowski & Green, supra, at 540. In any event, all the patients addressed by Wysowski for whom weight data was available were overweight, and most were obese. Id.
Like Dr. Moyé's, Dr. Plunkett's report also departs at points from standards that she acknowledges govern her work. This is exemplified by her discussion of the Bradford Hill factor of temporality. As background, Dr. Plunkett is not a medical doctor. She is not qualified to diagnose IIH or to apply a differential diagnosis to determine what caused a patient's IIH. And in her deposition, she therefore acknowledged that she cannot offer an opinion on why a patient's IIH resolved. Plunkett Dep. at 111, 124, 127-29, 131-35. Rather, she acknowledged that, when considering case reports, she was limited to considering "what is described by the doctor." Id. at 126. Dr. Plunkett, however, does not thus confine the analysis in her report. Drawing on Bayer's adverse events database in the course of discussing the Bradford Hill factor of temporality, her report cites three case reports. See Dkt, 167-73 ("Case Report A"); id. Ex. 74 ("Case Report B"); id. Ex. 75 ("Case Report C"). Yet in each, the patient's physician specifically reported that
Dr. Plunkett also fails to consider evidence that did not support her opinion. In her discussion of Bradford Hill's biological gradient (dose-response effect) factor, for example, Dr. Plunkett does not consider any data regarding combined oral contraceptives that contain LNG. These contraceptives have total LNG serum levels that are some 20-30 times higher than Mirena. To be sure, Dr. Plunkett asserts in her report and stated in her deposition that the more relevant measure of LNG exposure is the patient's free LNG level, not total LNG serum levels. But Dr. Plunkett does not take the next logical step: to explore the free LNG levels of combined oral contraceptives, which would have permitted her to make a useful comparison between Mirena and these contraceptives, which, as noted, have been found in five epidemiological studies not to cause IIH. See Plunkett Dep. 22, 28, 30, 95-96. She instead writes off these products as irrelevant. Dr. Plunkett's decision to liken Mirena to Norplant (as to which no epidemiological studies regarding IIH exist) while ignoring the entire category of LNG-based combined oral contraceptives (which have been studied extensively) is suggestive, too, of an outcome-driven approach, not a search for truth. See In re Rezulin, 309 F.Supp.2d at 563 ("[A]n expert may not pick and choose from the scientific landscape....").
Dr. Plunkett's handling of the Valenzuela study is similarly problematic. Her report cites that study (and its preview in Rai) as support for finding no fewer than three of the nine Bradford Hill criteria: strength of association, Plunkett Rpt. at
This lapse bespeaks a larger methodological deficiency characterizing Dr. Plunkett's proposed testimony. For an expert's testimony to be reliable, she "must demonstrate that [she] has adequately accounted for obvious alternative explanations." U.S. Info. Sys., Inc., 313 F.Supp.2d at 238; see also Reference Manual on Scientific Evidence ("[R]esearchers first look for alternative explanations for the association, such as bias or confounding factors.... Once this process is completed, researchers consider how guidelines for inferring causation from an association apply to the available evidence."); In re Lipitor (Atorvastatin Calcium) Marketing, Sales Practices and Products Liability Litigation, 174 F.Supp.3d 911, 916 (D.S.C. 2016) (same). Although his report proved methodologically deficient on other grounds, Dr. Moyé at least attempts to engage with Valenzuela's caveat about confounding factors, opining that because of the large reporting ratio observed in Valenzuela's Utah population, the correlation between Mirena and IIH was not likely to be confounded. Dr. Plunkett's report makes no such effort. Nor does it advance any scientific argument for why the IIH of the patients in Valenzuela could not equally plausibly be attributed to the non-Mirena factors of obesity and recent weight gain.
Finally, Dr. Plunkett's embrace of the "androgen theory" of the biological mechanism by which Mirena might cause IIH suffers from severe analytical gaps. As addressed infra in connection with Dr. Darney's and Dr. Johanson's proposed testimony, it is not tenable for an expert simply to assume that LNG, a progestin, causes IIH by the same mechanism as androgens (e.g., testosterone). See Brumbaugh v. Sandoz Pharm. Corp., 77 F.Supp.2d 1153, 1157 (D. Mont. 1999) ("Testimony extending general conclusions about similar drugs does not meet Daubert's requirement of reliability."); Dunn v. Sandoz Pharm. Corp., 275 F.Supp.2d 672, 681 (M.D.N.C. 2003) ("Dr. Kulig's assertion that because bromocriptine is an ergot alkaloid and may behave like other ergot alkaloids and cause vasoconstriction simply does not support the proposition that Parlodel causes stroke in postpartum women."); Mirena Perforation/Daubert, 169 F.Supp.3d at 433 ("To conclude that Mirena would cause the same effect as Depo-Provera because they both contain progestin ... is to impermissibly draw grossly `overreaching conclusions,' which are connected solely to the data by [the witness's] say-so." (internal citation omitted)). Yet Dr. Plunkett did so here.
For all the above reasons, Dr. Plunkett's proposed testimony is beset by methodological
Dr. Wheeler is an OB/GYN who works in private practice. He is a graduate of Harvard College and Baylor College of Medicine, where he received his medical degree and concentrated in reproductive medicine. Wheeler Rpt. at 3-4. He completed a residency in obstetrics and gynecology at Baylor, and a post-residency subspecialty in reproductive endocrinology and infertility at Yale University School of Medicine. Id. at 4. While at Yale he was a member of Yale's Robert Wood Johnson Clinical Scholars Program, which teaches clinical epidemiology;
Since 1994, Dr. Wheeler has been in private practice. Id. at 4-5. He has provided contraceptive counseling and advice, including as it relates to IUDs, to thousands of patients. Id. He has personally placed or supervised the placement of many IUDs, including Mirenas. Id. at 5. However, Dr. Wheeler has not conducted research on Mirena or LNG outside of this litigation. Nor has Dr. Wheeler ever diagnosed a case of IIH. Wheeler Dep. at 39-40, 63, 329-30. Dr. Wheeler frequently serves as an expert in litigation. During the last five years, he estimates, he has spent between 15 and 20 percent of his professional time on legal matters. Id. at 46.
Dr. Wheeler's testimony that Mirena causes IIH, like that of Drs. Moyé and Plunkett, is primarily based on an application of the Bradford Hill factors. See Wheeler Rpt. at 31, 34-39.
He applies the Bradford Hill factors as follows.
Strength of association: In finding this factor "sufficiently demonstrated," Dr. Wheeler notes that within Bayer's 2015 dataset, there were "115 cases of [IIH] in women with a Mirena in situ." Wheeler Rpt. at 35. Although he acknowledges "the potential for selection bias and accrual bias operating due to the manner in which these cases were collected," he states that "this is nonetheless a significant number of cases collected." Id. Dr. Wheeler also cites the Rai/Valenzuela study as "medical literature reporting on possible association of [IHH] with intrauterine use of LNG." Id.
During his deposition, however, Dr. Wheeler reversed course. He conceded that the Rai/Valenzuela study does not demonstrate an association between Mirena and IIH:
Wheeler Dep. 200 (objection omitted).
Consistency of association: Dr. Wheeler opines that this factor is met because of a "sufficient degree of heterogeneity" in his dataset of 115 cases that he drew from Bayer's 2015 signal investigation, because "the association of [IIH] and LNG was sufficiently consistent with other LNG-containing devices to be included in the Product Information brochure of LNG implants Norplant and Jadelle," and because "the Rai/Valenzuela group found a statistically significant increased risk of [IIH] in a large case-control observational study of two different groups." Wheeler Rpt. at 35.
Specificity: Dr. Wheeler opines that this factor is met based on the 115 cases he draws from Bayer's data set, the Rai/Valenzuela study, and the Norplant and Jadelle labels. Although Dr. Wheeler's report elsewhere notes that IIH has associated risk factors, id. at 44, his analysis of specificity does not address these factors, id. at 36.
Temporality: Because almost every case in the data set that Dr. Wheeler extracts from Bayer's 2015 signal investigation arose after a Mirena had been inserted, Dr. Wheeler finds that the "[a]nalysis of Temporality favors a causal relationship." Id.
Biological gradient: Dr. Wheeler notes that within Bayer's 2015 signal investigation, one case had been included involving Bayer's lower-dose LNG, Skyla. While Dr. Wheeler states that he does not know why only one Skyla case was included in that data set, he postulates that, "if it is the only known case, or one of only a few," in which IIH was associated with Skyla, given the larger number of IIH cases associated with Mirena, "a dose-response between LNG and [IIH] may be proposed." Id. at 36-37. Dr. Wheeler also notes that women with an embedded Mirena have higher systemic levels of LNG and that at least two patients in Bayer's 2015 dataset had an embedded Mirena. "This," he states, "also lends support to a biologic gradient." Id.
Biological plausibility: Addressing this factor, Dr. Wheeler embraces the androgen theory of IIH causation. It is "more likely than not," he states, that IIH is "caused by sex hormones including androgens." Id. at 37. He does not articulate a mechanism by which this occurs.
Experimental evidence: Dr. Wheeler acknowledges that, in epidemiology, "`experiment' usually means a randomized clinical trial." Id. at 38. But, he states, a "randomized placebo-controlled trial involving contraceptive choices" is likely "not practical, and potentially not ethical due to the differential likely effects on pregnancy rates and complications within a placebo-controlled group, of a comparison otherwise-treated group." Id. at 38. Dr. Wheeler states that, in lieu of experiments, he would look to "`challenge-dechallenge-rechallenge'" evidence. Id. He states that the 11 "dechallenge" cases he had noted in Bayer's dataset, of which nine patients "recovered" from their symptoms and signs of IIH, "may also inform this criterion." Id. at 25, 38. Dr. Wheeler admits, however, that "the sample to which this applies is relatively small," id. at 38, and that he had been "unable to discover any dechallenged, then rechallenged, patients" within the dataset. Id. at 25.
Analogy: Dr. Wheeler states that "[IIH] is associated with other hyperandrogenic symptoms including Polycystic Ovary Syndrome" and that "[t]his clinical observation satisfies Analogy to a reasonable degree." Id. at 38.
For the reasons reviewed below, methodologically, Dr. Wheeler's application of Bradford Hill is flawed in multiple respects. Some flaws echo those noted about the Bradford Hill analyses conducted by Drs. Moyé and Plunkett. Other flaws are specific to Dr. Wheeler's analysis.
Specific to Dr. Wheeler, his use of Bradford Hill is fatally compromised, at the threshold, by a concession he made at his deposition. He testified that there is no statistical association between Mirena and IIH. As explained earlier, the Bradford Hill criteria are, at bottom, a methodology for evaluating whether a demonstrated epidemiological association is, or is not, causal. It follows that, absent such an association, there is no basis to apply the Bradford Hill criteria. See Federal Judicial Center, Reference Manual on Scientific Evidence 599, n.141 (3d. ed. 2011) ("In a number of cases, experts attempted to use these guidelines to support the existence of causation in the absence of any epidemiologic studies finding an association.... There may be some logic to that effort, but it does not reflect accepted epidemiologic methodology."); see also Soldo, 244 F.Supp.2d at 569 ("The Bradford-Hill criteria start with an association demonstrated by epidemiology and then apply such criteria as the temporal sequence of events, the strength of the association, the consistency of the observed association, the dose-response relationship, and the biologic plausibility of the observed association."); Dunn, 275 F.Supp.2d at 679 ("The first step in the causation analysis pursuant to Bradford Hill is an epidemiological study that has identified an association between two variables."); cf. In re Fosamax Prods. Liab. Litig., 645 F.Supp.2d 164, 187 (S.D.N.Y. 2009) ("[W]here there is a positive association between the exposure and the disease," "epidemiologists often apply a set of considerations described by Sir Austin Bradford Hill in a famous 1965 lecture").
The only other evidence which Dr. Wheeler's report cites in finding Bradford Hill's first factor ("strength of association") satisfied are the 115 adverse event reports that he drew from Bayer's 2015 signal assessment. See Wheeler Rpt. at 39 ("Additional evidence that Mirena causes or substantially contributes to [IIH] is derived from the collection of 115 cases of women with [IIH] who have a Mirena in place."); id. at 35 ("This is a sizable series of [IIH] patients, especially with any knowledge as to their contraceptive practices."). But these case reports — on which Dr. Wheeler relies in his report to satisfy fully five of the nine Bradford Hill factors, see id. at 34-39 — are inadequate as a basis upon which to find Bradford Hill's vital first factor, an association demonstrated by epidemiology. As virtually all experts in this case (including Dr. Wheeler) acknowledge, adverse event data primarily serves instead a more limited function — as a tool to generate hypotheses.
And the set of case reports on which Dr. Wheeler relies, without more, certainly do not reveal the required association. An association exists when the rate of a reported condition is greater among the group taking a drug than among the portion of the population not taking that drug. The adverse event reports which Dr. Wheeler cites, however, by definition cannot reveal any such association, because they are silent as to the comparison group: They do not reveal the reporting rate of IIH among the portion of the population not taking Mirena. They do not provide a basis on which Dr. Wheeler can opine as to whether there is an elevated rate at which Mirena patients experience IIH relative to persons without a Mirena inserted — i.e., whether there is an association between Mirena and IIH. Dr. Wheeler has not undertaken this inquiry. See Wheeler Dep. at 221 ("Q: So you can't tell us whether there is an elevated reporting rate of intracranial hypertension with Mirena users compared to any other group of patients, true? A: True."); see also id. at 220-23.
The 115 adverse event reports, which Dr. Wheeler draws from a spreadsheet given to him, in fact supply an unusually good illustration of why the case law, including
Further, even assuming that all 115 case reports on which Dr. Wheeler relied could be credited as true to the extent they reported that the subject both had used Mirena and had experienced IIH symptoms, the observation that the number 115 is "sizable," Wheeler Rpt. at 35, falls short of supporting an epidemiological association between these two facts. More than this absolute number would be needed for this correlation to have such meaning. Such information would include how the 115 reports (as among the broader universe of Mirena users) compared with the incidence of such symptoms in the population generally. It would also include whether the subject cases were subject to confounding factors (e.g., obesity, recent weight gain) that could supply obvious alternative explanations for the IIH symptoms. In his deposition, Dr. Wheeler acknowledged that Mirena is preferentially prescribed to the precise population with the highest reporting of IIH — obese women of reproductive age.
Unsurprisingly, then, at his deposition, Dr. Wheeler retracted his report's claim of a statistical association between Mirena and IIH. That claim had been based on
Independent of his inability to find this gating criterion, Dr. Wheeler's proposed expert testimony report, like that of Dr. Moyé and Dr. Plunkett, does not satisfy any of Daubert's four core reliability factors: It is untested; it has not been subject to peer review; there is neither an error rate nor are there standards controlling its operation; and his conclusion lacks any acceptance, let alone general acceptance, in the scientific community outside of this litigation.
These include:
Lack of weighting or discussion of relationship of factors: Like Drs. Moyé and Plunkett, Dr. Wheeler applies the Bradford Hill factors without revealing the weight he attaches to individual factors or addressing the relationship among them. See Wheeler Rpt. at 35-39. As discussed in connection with Dr. Moyé, this malleable and vague approach is in tension with first principles under Daubert, because it makes it all too easy for an expert to manipulate the Bradford Hill factors to support a desired conclusion of causation, and far too hard for an ensuing expert to replicate and rigorously test the expert's analytic approach. See In re Zoloft, 858 F.3d at 796 ("To ensure that the Bradford Hill/weight of the evidence criteria is truly a methodology, rather than a mere conclusion-oriented selection process ... there must be a scientific method of weighting that is used and explained." (internal quotation marks omitted)).
Generalized assessments of individual factors: In serially reviewing the factors, Dr. Wheeler's report generally pronounces each satisfied. With two exceptions, he does not indicate that the factor was anything more than minimally satisfied. See, e.g., Wheeler Rpt. at 35 (strength of association factor "is sufficiently demonstrated"); id. at 36 (specificity factor "is sufficiently demonstrated"); id. (temporality factor "is satisfied"); id. at 37 ("[T]here is sufficient information that Biologic Gradient is demonstrated...."); id. at 38 ("Coherence is satisfied...."); id. at 38 ("[T]here is sufficient evidence of an Experimental type" as to experimental evidence factor); id. ("I conclude Analogy is sufficient to support a causal relationship between LNG-IU[D] and [IIH]."); but see id. at 35-36 (consistency of association is "particularly well established"); id. at 37 ("Analysis of Biologic Plausibility definitely favors a causal relationship.").
Factors conceded to lack evidentiary support: Like Dr. Moyé, Dr. Wheeler finds that all Bradford Hill factors support a finding of causation, even though, as his deposition testimony revealed, some demonstrably cannot, or cannot non-speculatively, be so viewed. Three examples are illustrative.
As to the first factor, strength of association, as noted, Dr. Wheeler, in his deposition, took back his conclusion that this fact had been "sufficiently demonstrated." Wheeler Dep. at 264-65; Wheeler Rpt. at 35.
As to the third factor, specificity, Dr. Wheeler's report finds it, too, met, on the basis of the adverse event reports found in 2015 Bayer signal investigation, whose limitations as a basis for positing causation or even epidemiological association are addressed above. Dr. Wheeler's discussion of that factor does not address the alternative demonstrated and/or theorized causes and risk factors for IIH. This is so even though elsewhere in his report Dr. Wheeler acknowledges the confounding factors (e.g., obesity) that outside this litigation have prevented all scholars (including the Valenzuela study authors) from isolating Mirena as a cause of IIH. See, e.g., id. at 21-24. In his deposition, Dr. Wheeler agreed that the Valenzuela study merely "raises the question of an increased risk of IIH with Mirena, but does not establish an association." Wheeler Dep. at 190; see Dunn, 275 F.Supp.2d at 681 ("Opinions merely expressing `possibilities' do not suffice to support the admissibility of expert testimony.").
And, as to the eighth factor, experimental evidence, Dr. Wheeler's statements are internally contradictory. His report acknowledges the lack of any such actual experimental evidence, explaining that practical considerations made this factor "impossible to satisfy." Id. at 46. Yet in his tally of the nine factors, Dr. Wheeler, rather than treating this factor as null, ultimately opines that it, too, was supported by "sufficient evidence," in the form of a "relatively small" sample of "dechallenge" cases reported by clinicians. Id. at 38.
Unsubstantiated assumptions about Norplant and the Norplant/Jadelle labeling: As to two of its foundational factual propositions, both involving Norplant, Dr. Wheeler's report departs from sound methodology by assuming facts that have nowhere been established.
First, on the apparent premise that LNG-based implant Norplant has been found to cause IIH, Dr. Wheeler, in finding various Bradford Hill factors met, repeatedly analogizes Mirena to Norplant. See, e.g., Wheeler Rpt. at 35 (consistency of association); id. at 36 (specificity); id. at 37 (coherence). However, as reviewed above, no epidemiological study has so found as to Norplant, Jadelle, or any other LNG-based contraceptive. The data that exists as to these different (and higher-LNG) products is limited to case reports that have not been controlled for potential confounders. To the extent that Dr. Wheeler's anticipated testimony is built on an analogy to products that he only assumes to be associated with or causal of IIH, it, like the reports of Drs. Moyé and Plunkett, starts from an unsound premise.
Second, and relatedly, on the premise that the Jadelle and Norplant labels bespeak a predicate finding of causation of IIH, Dr. Wheeler repeatedly cites these
Speculative androgen theory: In finding the factor of biological plausibility met, Dr. Wheeler opines that it is "more likely than not" that IIH is caused by sex hormones including androgens and that it is biologically plausible "that LNG from Mirena could cause [IIH] as an androgenic side effect." Wheeler Rpt. at 37-38 ("Analysis of Biologic Plausibility definitely favors a causal relationship."). Bayer counters that Dr. Wheeler's conclusion to this effect is unduly speculative. Although aspects of Bayer's critique conflate issues of factual persuasiveness reserved for the trier of fact with issues of admissibility under Daubert, the Court is persuaded that Dr. Wheeler's theory is sufficiently grounded in conjecture and guesswork to make his testimony on this point unreliable as a matter of law. In his deposition, Dr. Wheeler was not able to identify any peer-reviewed publication establishing his androgen theory, nor any presentation to this effect at a scientific conference supportive of this theory. Wheeler Dep. at 132. He testified that it was "too early" for any support to be published. Id. at 143 ("[T]oo early. Hasn't been done."). And while there is scientific evidence that LNG has androgenic effects, LNG itself is a progestin, not an androgen. All of the articles on which Dr. Wheeler relies, however, involve androgens. None involve progestins, let alone LNG. See Wheeler Dep. at 140, 147 (sources cited do not involve progestins, LNG, or Mirena); id. at 142 (LNG a progestin, not an androgen).
Under these circumstances, Dr. Wheeler's theory as to the Bradford Hill factor of biologic plausibility relies on too many unsupported leaps. To permit Dr. Wheeler to testify to his theory of causation would invite the jury to guess as to the validity of a novel and untested theory based essentially on his say-so. "[T]he
For all the above reasons, Dr. Wheeler's proposed testimony fails to meet the standard for reliability set out in Daubert. As to various components of his reasoning, there is "too great an analytical gap between the data and the opinion proffered" to permit the testimony to be found reliable. See Gen. Elec. Co., 522 U.S. at 146, 118 S.Ct. 512 (1997) ("[N]othing in either Daubert or the Federal Rules of Evidence requires a district court to admit opinion evidence which is connected to existing data only by the ipse dixit of the expert. A court may conclude that there is simply too great an analytic gap between the data and the opinion proffered."). His testimony, therefore, must be excluded.
Dr. Fraunfelder is a 1990 graduate of Baylor University, where he received a Bachelor of Arts in Economics, and a 1994 graduate of Oregon Health Sciences University in Portland, where he received a degree as a medical doctor. Dr. Fraunfelder then completed a residency in ophthalmology and several fellowships. He was certified by the American Board of Opthalmology in June 2002 and was recertified in January 2013.
Dr. Fraunfelder has worked in clinical practice and as a professor. He served in Portland, Oregon, as an Assistant Professor at the Casey Eye Institute, then an Associate Professor, and then a Director. Dr. Fraunfelder then moved to Missouri, where he chaired the Mason Eye Institute. He has done work on drug safety monitoring, written books on ocular therapy, and been a reviewer for several medical journals. See Fraunfelder Rpt. at 2-3.
He does not, however, have independent expertise in IIH. See Fraunfelder Dep. at 129-30 ("I'm not an expert in IIH or the mechanism of IIH."); id. at 104 (when asked about textbook criteria for diagnosing IIH, responding, "I need you to refresh me on those").
Dr. Fraunfelder is the only one of plaintiffs' experts who, before this litigation, had written publicly about the relationship between LNG and IIH. He is also the only plaintiffs' expert who had authored an expert report on that subject prior to the formation of this MDL.
In a 2015 book he co-authored, Drug-Induced Ocular Side Effects, Dr. Fraunfelder stated that he believed there was a possible, rather than a probable, causal association between LNG and IIH. Fraunfelder Rpt. at 23 (citations omitted). His expert report in this case explained what he had meant in that book by the terms "possible" and "probable": "Causation of an event is assessed as possible where there is a temporal relationship, but the
On January 21, 2016, Dr. Fraunfelder filed an expert report on behalf of plaintiffs in a case that later became part of this MDL. See Dkt. 167-79 ("Fraunfelder 2016 Rpt."). Dr. Fraunfelder spent about 10 hours on that 12-page report. Fraunfelder Dep. 79. Opining there that Mirena is a cause of IIH, Dr. Fraunfelder's 2016 report relied on the Etminan study. It termed Etminan's two analyses — a disproportionality analysis of adverse event reports in the FDA's database, and a cohort study — "two important pieces of literature." See Fraunfelder 2016 Rpt. at 11. Dr. Fraunfelder's 2016 report contained four paragraphs of analysis. Two covered published medical literature:
Fraunfelder 2016 Rpt. at 13-14.
Dr. Fraunfelder's 28-page report in the current litigation expands upon his earlier report. In connection with the current report, he testified, he did an additional "probably ... less than ten hours" work. Fraunfelder Dep. at 80.
His report opines that based on his "systematic analysis" of various items of evidence and his "education, experience, and training in drug safety monitoring and drug-induced ocular side effects," "it is more likely than not that Mirena causes or
As to the report's methodology, Dr. Fraunfelder disclaimed having performed a Bradford Hill analysis. Fraunfelder Dep. at 23. Asked in his deposition what methodology he had used, he responded that he had considered multiple pieces of evidence. Id. at 598-99 ("I looked at individual case reports. I looked at spontaneous reports. I looked at the available literature. I looked at the epidemiological papers. I looked at the plausible biological mechanism for sex hormones causing pseudotumor cerebri."). Although Dr. Fraunfelder did not label it as such, his approach appears best styled as a weight-of-the-evidence approach.
The evidence which Dr. Fraunfelder cites in his report in support of his conclusion that Mirena likely causes IIH consists of the following: (1) his assessment of IIH's "biological mechanism," (2) the Valenzuela study, (3) the Etminan study, (4) a discussion of Norplant, and (5) a discussion of case reports.
Mechanism: Dr. Fraunfelder's report does not set out in any detail the mechanism by which Mirena ostensibly causes IIH. Instead, in a page and a half, he articulates two broader propositions from which, he suggests, this conclusion follows. First, he states, it is likely that IIH's "underlying mechanism relate[s] to sex hormones." Fraunfelder Rpt. at 6. In support, Dr. Fraunfelder notes that IIH is common among obese women of childbearing age, has been observed in men with testosterone deficiency, and has been reported in transgender individuals undergoing testosterone therapy. Id. at 6. Second, he states, steroid hormones are associated with IIH. Id. at 6-7. In support, Dr. Fraunfelder notes that the medicines and medical conditions with which high rates of PTC are associated mostly consist of "steroid hormones, steroid hormone derivatives, or states of endocrine dysfunction," although the mechanism by which this occurs "is also unknown." Id. at 6. He states that "[s]teroid hormone activity in the region of the brain where CSF is produced (the Choroid Plexus) may be one important modulator of CSF production." Id. at 7.
At his deposition, however, Dr. Fraunfelder repudiated his opinion as to a mechanism by which Mirena ostensibly causes IIH. He attested: "I think ... the mechanism is unknown. I'm not being put forward as an expert on the mechanism of [IIH and Mirena]." Fraunfelder Dep. at 384. He stated that although he believes there is "a plausible biological mechanism," "[t]hat's not something that I'm going to be an expert on." Id. at 571. Consistent with his distancing himself from the mechanism opinion that his report articulated, Dr. Fraunfelder, during his deposition, disclaimed knowledge of biological facts potentially germane to this inquiry. These included whether there is data suggesting that LNG can cross the blood-brain barrier, whether there are mineral corticoid receptors in the brain, and whether, if there were such receptors, Mirena could act on them. See, e.g., id. at 578-83; see also id. at 571, 573 (admitting lack of knowledge about hormone levels, stating, "I don't know women's hormones levels," "I do not want to opine on the hormone
The Valenzuela study: Dr. Fraunfelder recounts the Valenzuela study's methodology and the populations that that study considered (in Utah and Denmark). Fraunfelder Rpt. at 11-12. He concludes: "Valenzuela et al. suggest that women with an LNG-IU[D] have an increased risk of developing PTC, despite identifying possible limitations to their methods and analyses." Id. at 12. Dr. Fraunfelder notes that, as the Valenzuela study itself recognized, "patients with an LNG-IU[D] device may not be aware that their device contains a drug, and are less likely to report the LNG-IU[D] device during their intakes with medical practitioners when presenting for symptoms such as headache and vision disturbances, even when specifically questioned about `current medications.'" Id. at 12. He notes that the Valenzuela study authors gave two alternative explanations for their results: "1) that LNG causes increased intracranial pressure, through an already-postulated or yet unknown mechanism; or 2) that PTC is more likely to occur in the same population of women who are more likely to have an LNG-IU[D]." Id. Dr. Fraunfelder discounts the second explanation — that the correlation between Mirena and IIH resulted from confounding factors: "[E]ven considering the possibility of confounding by other risk factors, a causative or contributory role for LNG cannot be excluded from a differential diagnosis, even accounting for the possibility of confounders." Id.
The Etminan study: Dr. Fraunfelder's report extensively discusses the Etminan study. Fraunfelder Rpt. at 12-15. He recounts the study and Dr. Etminan's ensuing exchange with Dr. Friedman. In so doing, Dr. Fraunfelder notes a methodological flaw in the Etminan study. See id. at 13 ("[T]his methodology assumed a binominal distribution, and the relationship between BMI and Mirena may be more complex."). In the main, however, Dr. Fraunfelder's report focuses on undermining the methodology that Dr. Etminan used in 2017 when retracting his disproportionality (DPA) analysis. Id. at 14-15. In particular, Dr. Fraunfelder challenges the manner in which Dr. Etminan conducted his age-adjusted analysis, stating that Dr. Etminan had failed to explain why his corrected analysis had excluded wholesale "cases without reported age data." Id. at 14. He writes: "Although it is possible that some of those cases involve women over 40, it is inappropriate to assume that all of those cases involve women over 40." Id. Dr. Fraunfelder adds that while it was "unfortunate that many of the adverse event reports" in the FAERS database "did not include age information," it had been "unreasonable" to assume that such cases involved women over 40. Id.
Norplant: Dr. Fraunfelder also cites information relating to Norplant as supporting that Mirena likely causes IIH. Id. at 15-17. He notes that Norplant, marketed in the United States between 1991 and 2000, had been "plagued by allegations of harmful side effects." Id. at 15. He notes that, in 1993, Norplant's label had been changed "to include warnings about reports" of IIH; that the 1993 Sunku and 1995 Alder studies had described cases of IIH observed among Norplant users; and that the 2015 book that Dr. Fraunfelder co-authored had listed IIH "as a possible side effect of Norplant/LNG...." Id. Dr. Fraunfelder acknowledges, however, that while "epidemiological research was needed in order to investigate the potential increased risk of PTC with use of the Norplant," none had been undertaken. Id. at 16 ("[N]o large epidemiological study
Case reports: Dr. Fraunfelder's report draws upon case reports from several sources. First, he reviews reports relating to three patients from among the subjects included in Mirena's clinical trials for safety: (1) a 2001 case involving a 23-year-old woman of normal body weight who was diagnosed with diplopia and chronic papilledema but never, it appears, IIH; (2) a case dating to 2008 of a 37-year-old obese woman who was diagnosed with IIH; and (3) a case dating to 2009 of a 17-year-old woman of normal body weight (or possibly slightly overweight) who had first been diagnosed with IIH in 2009, had a Mirena inserted in 2012, and thereafter experienced IIH symptoms. Id. at 17-19. Dr. Fraunfelder's report also lists a number of cases drawn from Bayer's signal assessments that he describes as examples of dechallenges — where IIH symptoms abated after the removal of a Mirena. He identifies four cases of "unambiguous dechallenge"; eight of "positive dechallenge" (where some recovery by the patient was noted); three where the "patient was recovering while receiving treatment"; and five where, among conflicting data, some was suggestive of dechallenge. Id. at 21-23. At his deposition, Dr. Fraunfelder admitted, however, that the cases he cited, including those he called "unambiguous dechallenge," were subject to possible confounding variables. See Fraunfelder Dep. at 428-52.
Finally, Dr. Fraunfelder's report notes that over the past several decades, medical literature has increasingly noted an association between LNG and IIH and raised the question whether LNG causes IIH. "In practice," he notes, "physicians often look to the medical literature when identifying potential causes of disease in patients." Id. at 27.
Dr. Fraunfelder's proposed testimony amounts to a blend of disparate items that he contends together show that Mirena causes IIH. Unlike Drs. Moyé, Plunkett, and Wheeler, Dr. Fraunfelder does not purport to use the flexible Bradford Hill methodology to guide his analysis. Instead, his approach consists of listing factors that he argues support this conclusion. Beyond its non-replicable mode of analysis, Dr. Fraunfelder's handling of individual items has hallmarks of unreliability — some shared with other proposed expert witnesses, others unique to Dr. Fraunfelder. His proposed testimony falls short of Daubert's standards.
At the outset, like the testimony of the three preceding witnesses, Dr. Fraunfelder's proposed testimony fails to meet any of the Daubert reliability factors. His opinion that Mirena causes IIH has not been tested; it has not been subjected to peer review; it has no known error rate and there are no standards controlling its operation; and it has not been generally accepted by the scientific community. His analysis, developed in the course of litigation, therefore merits a "hard look."
Dr. Fraunfelder's handling of virtually every one of the individual items on which he relies is, however, methodologically suspect.
The Court considers, first, Dr. Fraunfelder's handling of the repudiated Etminan study. In his report, Dr. Fraunfelder
Beyond this shortcoming, Dr. Fraunfelder, in seeking to rehabilitate the Etminan study's DPA analysis, overlooks the flaw in that study that ultimately led Dr. Etminan himself to correct his methodology and repudiate its initial finding. As noted above, Dr. Fraunfelder objects to Dr. Etminan's decision in the course of correcting that study in 2017 to exclude patients within the LNG-IUD group as to whom age data was lacking. Dr. Fraunfelder notes that, inasmuch as most women using a Mirena IUD are presumably of reproductive age, excluding Mirena patients for whom age data was lacking may have not been strictly necessary.
That critique is coherent. But in training his critique on this narrow point, Dr. Fraunfelder misses the bigger picture: The reason why a corrective was necessary lest the Etminan DPA analysis be methodologically unsound. As diagnosed by Dr. Friedman and belatedly admitted by Dr. Etminan, there was a gaping design flaw in the Etminan study's DPA analysis: It did not exclude women of non-reproductive age from the control group. The FAERS database includes data related to all kinds of drugs, most of which (unlike Mirena) are not earmarked for reproductive-age women, the group all but uniquely at risk for IIH. By failing to limit his control group to reproductive age women (and by using an experimental group that was de facto limited to reproductive age women), Etminan's DPA study was subject to a severe sample bias. This compromised its results. Dr. Etminan's 2017 correctives attempted to redress that defect. See Etminan Affidavit ¶ 6 ("[A] proper analysis would be limited to women of reproductive age."). The result of these correctives was to eliminate the statistical basis for inferring Mirena's causation of IIH. The corrected data showed "no elevated [risk] for Mirena, suggesting that intracranial hypertension and Mirena use are `likely not related.'" Id. ¶ 8; see also id. ¶ 11 ("[N]either of the analyses in the article provide evidence that Mirena use increases the risk for intracranial hypertension.").
Dr. Fraunfelder's expert report does not grapple with this methodological deficiency at the heart of the DPA analysis on which he relies — despite the fact that by the date of his report (December 23, 2017), he had access not only to Dr. Friedman's critique of Etminan's DPA study but also to Dr. Etminan's letter and affidavit repudiating the study's methodology and outcome. And, when confronted at his deposition with the Etminan study's design flaw, Dr. Fraunfelder reaffirmed his reliance on the DPA study as supporting his finding that Mirena use likely causes IIH. To be sure, Dr. Fraunfelder eventually admitted that the Etminan study had less value than he had initially assigned it. But Dr. Fraunfelder continued to make the repudiated study a basis for his opinion. See Fraunfelder Dep. at 268 (stating that he relies on Etminan to "a very small amount"); id. at 318 ("I think that his first paper has some validity."); id. at 331 ("I put his paper low on the evidence scale as far as the data I used to form my opinion."). As another plaintiffs' expert has recognized, reliance on analysis that has been repudiated by its
Dr. Fraunfelder's continued embrace of Etminan's repudiated DPA analysis is, further, methodologically suspect in that Dr. Fraunfelder attaches little to no weight to the other half of Etminan's study: the retrospective cohort portion of its analysis, which has never been retracted. And the retrospective cohort study did not find a statistically significant difference between the risk for IIH among individuals using Mirena and those using two types of oral contraceptives, EE-norethindrone and EE-norgestimate. Dr. Fraunfelder's selectivity — in which he embraces the spoiled half of Etminan's 2015 study while disregarding the unspoiled half — strongly suggests outcome bias, if not a predetermined outcome. Without a good explanation for this counter-intuitive approach, the Court finds it unreliable and inconsistent with rigorous scientific inquiry. See In re Rezulin, 369 F.Supp.2d at 425 (excluding experts who "selectively chose [their] support from the scientific landscape").
This lapse was not anomalous. Dr. Fraunfelder's report elsewhere chooses not to engage with consequential evidence contrary to his outcome. Like plaintiffs' first three experts — who referenced Norplant in applying the Bradford Hill analogy factor — Dr. Fraunfelder's report likens Mirena to Norplant. Dr. Fraunfelder uses these analogies to support both his claim that Mirena, ostensibly like Norplant, causes IIH, and his conclusion — subsidiary to his mechanism opinion — that IIH is related to sex hormones. See Fraunfelder Rpt. at 5-6. Yet, like Drs. Moyé, Plunkett, and Wheeler, Dr. Fraunfelder does not consider another analogy that was in plain sight: to combined oral contraceptives. Dr. Fraunfelder's report acknowledges that an association between oral contraceptives and IIH has been "largely disproven." Id. at 27. Such contraceptives, too, involve synthetic sex hormones. But Dr. Fraunfelder does not consider what the studies exonerating IIH-heavy oral contraceptives might signify as to whether Mirena causes IIH. Dr. Fraunfelder's decision not to grapple with these studies is all the more dubious given his reliance on lesser evidence (case reports) related to Norplant and mortally compromised evidence (the initial Etminan DPA study) as to Mirena.
In the same vein, in his consideration of the Valenzuela study, Dr. Fraunfelder fails to consider the alternative, and benign, explanations that that study identified for the correlation it found between Mirena and IIH. See In re Rezulin, 369 F.Supp.2d at 425 ("A factor that courts have considered in Daubert analyses is whether an expert has accounted adequately for obvious alternative explanations."); U.S. Info. Sys., Inc., 313 F.Supp.2d at 238 ("An expert must demonstrate that he has adequately accounted for obvious alternative explanations in order for his testimony to be reliable."); In re: Gen. Motors LLC Ignition Switch Litig., No. 14-MD-2543 (JMF), 2015 WL 9480448, at *2 n.1 (S.D.N.Y. Dec. 29, 2015) (explaining that an expert must address "obvious alternative causes") (emphasis omitted)). The Valenzuela study, by its own account, did not control for the widely accepted IIH risk factors of obesity and recent weight gain; for that reason, the study disclaimed any finding that Mirena caused IIH.
Dr. Fraunfelder's report, however, pays only lip service to Valenzuela's caveat about confounders. It nowhere reveals that the Valenzuela study had not controlled for
Dr. Fraunfelder, finally, makes his mechanism opinion an important component of his expert report. But at his deposition, he repeatedly distanced himself from it — indeed, he repudiated any mechanism opinion as beyond his expertise. The removal of that pillar alone is fatal to Dr. Fraunfelder's weight of the evidence analysis. In any event, had Dr. Fraunfelder not repudiated his mechanism opinion, the Court would have found — as was inescapable — that he is not qualified to offer it. Dr. Fraunfelder admits that he is "not a pharmacokinetics expert." Fraunfelder Dep. at 515; see also id. at 571 ("You know I'm an ophthalmologist, right?"). Plaintiffs have not mustered any evidence of practical experience on his part — or prior publications of pharmacokinetics studies — that could make up for a lack of training in pharmacokinetics. He is unqualified to offer a mechanism opinion. See Fed. R. Evid. 702 (providing that expert witness must be "qualified as an expert by knowledge, skill, experience, training, or education").
For all these reasons, Dr. Fraunfelder's proposed testimony does not meet the standards for reliability articulated in Daubert. It, too, must be excluded.
Dr. Darney is an obstretrician/gynecologist. He attended the University of California
Dr. Darney's opinion, unlike those of the four earlier discussed experts, predominantly concerns a mechanism by which IIH is caused. He embraces the "androgen theory" by which Mirena purportedly causes IIH — specifically, that androgens may cause IIH and, that, because LNG, while a progestin, has androgenic effects, LNG in turn may cause IIH.
Before this litigation, Dr. Darney had not published on or addressed any relationship between Mirena and IIH. He has recommended — and continues to recommend — Mirena to his patients, though he states he no longer recommends it to "those who are androgen sensitive." Darney Dep. at 100.
Dr. Darney has published on Mirena generally, and has addressed its side effects (some of which are considered androgenic in nature, like a reduction in acne).
In a 2002 article, for example, Dr. Darney endorsed Mirena: Mirena, he wrote, "is the most effective form of reversible contraception currently available, even more effective than female sterilization." Eleanor A. Drey & Philip D. Darney, Recent Developments in Hormonal Contraception, 3 Reviews in Endocrine & Metabolic Disorders 257, 261 (2002) (Dkt. 167-24). In that same publication, Dr. Darney stated that "[Mirena] causes few hormonal adverse effects," id., although he did identify a 2002 clinical monograph in which a colleague suggested, in a different publication, that women using the LNG-based implant Jadelle should have it removed if they experience papilledema. See Darney Rpt. at 22; Irving Sivin, et al., Jadelle Levonorgestrel Rod Implants: A Summary of Scientific Data and Lessons Learned from Programmatic Experience, Population Council (2002), http://www.respondproject.org/pages/files/4_result_areas/Result_1_Global_Learning/LA_PM_CoP/june2009-launch/Jadelle-Levonorgestrel-Rod-Implants.pdf.
In a 2011 book, Dr. Darney addressed the issue of androgenic effects of LNG-based IUDs: "Sufficient progestin reaches the systemic circulation from the levonorgestrel-containing IU[D] so that androgenic
In this litigation, Dr. Darney articulates new conclusions. He opines, for the first time, that an LNG-based product may have the capacity to cause IIH. The central thesis of his expert report is that "[i]n susceptible individuals, relatively high unbound LNG concentrations can cause, or be a substantial contributing factor in causing intracranial hypertension/pseudotumor cerebri (IH/PTC)." For this purpose, Dr. Darney defines "susceptible individuals" narrowly.
This opinion, Dr. Darney states, derives from linking four distinct propositions:
Darney Rpt. at 5.
The Court recaps Dr. Darney's proposed testimony as to each of these propositions. The instant Daubert litigation focuses on the fourth of these propositions.
LNG is a potent androgenic progestin: In support of this first proposition, Dr. Darney describes certain properties of LNG. It is a synthetic progestin that is derived from testosterone. And, like other synthetic progestins derived from testosterone, it has had removed from its chemical structure the element carbon 19, present in testosterone, "in order to change the major hormonal effect from androgenic to progestogenic [while] retain[ing] varying degrees of androgenic activity." Id. at 11.
Dr. Darney further states that three factors affect the androgenicity of a sex steroid: its ability to bind to the relevant receptors, its effects on SHBG, and the degree to which it binds to SHBG. Id. at 13.
As to the first factor, LNG, he states, "is the most potent and androgenic of the progestins used in contraceptives." Id. at 11. Dr. Darney notes that — as is undisputed — LNG can and does bond to androgen receptors. Id. at 13. Dr. Darney acknowledges that LNG's affinity for such receptors is still only 22% of that of the androgen standard, dihydrotestosterone ("DHT"). See id. at 11. LNG's androgen-to-progestin
As to the second factor, Dr. Darney states, "LNG is known to decrease SHBG over time." Id. at 13. Oral administration of LNG alone results in an approximately 50% decrease in SHBG; "a mean decline of about 30% [in SHBG] was seen up to 6 months after insertion of Mirena in 10 healthy young women." Id. This result is important, he states, because "a decrease in SHBG means that a higher proportion of circulating androgens are `free' and available for binding to androgen receptors resulting in androgenic side effects." Id.
As to the third factor, involving the degree to which LNG binds with SHBG, Dr. Darney states that LNG does so "with high specificity" and "affinity." Id. But, he acknowledges, LNG's affinity to SHBG is only 50% of that of endogenous DHT, and 13% that of (presumably non-endogenous) DHT. Id. Dr. Darney asserts that, when LNG binds to SHBG, it prevents endogenous androgens from doing the same, leaving them "free" to activate androgen receptors and cause IIH. Id. Studies involving Norplant, Dr. Darney states, have "found resultant increase in circulating androgens." Id.
As a result of these factors, Dr. Darney opines, "androgenic side effects of LNG can be expected even at low doses." Id. Dr. Darney states that concerns about the androgenic effects of LNG have led Bayer to work to develop new synthetic progestins and to release new products, such as Skyla and Kyleena with lower rates of expected LNG release. See id. at 14-15.
Intra-uterine delivery results in wide variations in serum concentration of LNG: In support of his second proposition, that intrauterine delivery "results in wide intra- and inter-individual serum concentrations of LNG," id. at 15, Dr. Darney focuses on the "profound effects" of LNG on the structure of the endometrium, the layer of epithelial cells in the uterus. "These changes include: the appearance of prominent, dilated surface vessels, and cytoplasmic contraction, increased electron density, and plasmolemmal vesicles of the capillaries. Endometrial veins are also increased and dilated ...." Id. Because LNG can affect the endometrium, Dr. Darney states, it "provides a much less stable network for drug absorption than subdermal (for implant contraception) or intestinal (for oral contraception) vasculature networks that are not primarily modulated by sex hormones." Id. at 16. "Hence, systemic LNG concentrations from intrauterine delivery systems like Mirena are much less predictable and stable than those from subdermal or oral administration." Id. Comparative studies, Dr. Darney states, show that LNG concentrations vary more when IUDs are used than with other forms of LNG-based contraception. Id. at 16-17. And, the same individual may experience substantial variability with an LNG-based IUD. A Japanese study demonstrated, anecdotally, that some women had higher LNG levels after six months than after one month despite the anticipated decline in the release of LNG. Id. at 17.
Wide range of physiological reactions to LNG: In support of his third proposition, that women vary in their physiological reactions to LNG, Dr. Darney makes several points.
First, he asserts, it is important to consider concentrations of circulating SHBG and the resultant levels of free LNG when assessing LNG's effects (including its androgenic
In susceptible individuals, high unbound LNG may contribute to IIH: Dr. Darney's fourth and most consequential proposition, that LNG can cause or substantially contribute to IIH in susceptible persons under certain circumstances, is based on twin premises: that androgens cause IIH; and that LNG, as a progestin with androgenic side effects or qualities, similarly does so.
In support of this proposition, Dr. Darney relies on an article by Charles J. Glueck, et al., Idiopathic intracranial hypertension, polycystic-ovary syndrome, and thrombophilia, 145 J. Lab. Clin. Med. 72 (2005) (Dkt. 167-34) ("Glueck"). Darney Rpt. at 21. Glueck had reviewed case studies of 65 women diagnosed with IIH. Thirty-seven, all obese, had polycystic-ovary syndrome ("PCOS"), a condition diagnosed when a patient experiences two of three symptoms: (1) irregular periods, (2) excess androgen, and (3) polycystic ovaries, which become "enlarged and contain follicles that surround the eggs" causing abnormal ovary function.
At his deposition, however, while noting that PCOS patients develop IIH at a higher rate than patients without PCOS, Dr. Darney acknowledged that the Glueck study had not concluded that the high levels of androgens in PCOS patients cause IIH. See Darney Dep. at 247. To the contrary, that study hypothesized that a different hormone, estrogen, might cause IIH, or that PCOS-driven morbid obesity might be responsible. See Glueck, supra, at 76 ("The increased prevalence of PCOS in women with IIH may reflect PCOS-driven morbid obesity, which in turn facilitates the development of IIH." (internal citations omitted)); id. ("[P]aradoxically high levels of endogenous estrogens, common in PCOS and in severe obesity ... may play a role in the development of IIH...."); id. at 72 ("We speculated that PCOS, associated with obesity and extreme obesity in adolescence and young adulthood, is a treatable promoter of IIH."). When confronted with these aspects of the Glueck study, Dr. Darney retreated from his earlier characterization of that study. He asserted that a link between androgens and IIH "may[]be the understanding of the author," Darney Dep. at 249, and stated that the study had an "implication for something [the link between androgens and IIH] that's not yet well understood." Id. at 251.
In the final two pages of his report, Dr. Darney cites a series of other writings. He cites a "2013 study," Ainat Klein, et al., Hyperandrogenism is associated with earlier age of onset of idiopathic intracranial hypertension in women, 38 Current Eye Research 972 (2013) (Dkt. 167-40). Dr. Darney cites this study for the proposition that circulating androgens "were clearly linked to an early age of onset of IIH." Darney Rpt. at 22. He cites Connar Westgate, et al., Evaluating the role of testosterone in cerebrospinal fluid secretion, 50 Endocrine Abstracts P325 (2017) (Dkt. 167-66), for the proposition that "women with increased secretion of CSF also have high androgen levels." Darney Rpt. at 22; see also Darney Dep. at 256-58 (discussing Westgate). In fact, as Dr. Darney acknowledged in his deposition, the Westgate abstract did not so establish, or even test the relationship between androgen levels and CSF. It instead recounted an in vitro study of the effect of testosterone on rats' choroid plexus cells — the choroid plexus being the area of the brain that produces CSF. From that, Westgate "speculate[d] that testosterone may have a pathogenic role in IIH though modulation of CSF formation and increasing [intercranial pressure]." Darney Dep. at 258
Dr. Darney, finally, cites sources which some or all of the earlier experts addressed: the Valenzuela study, the notation on the Norplant and Jadelle labels to the effect that there had been reports of IIH among users of these products, Bayer's BfArM response, and certain case studies (as to Mirena, the Martinez and Ros Forteza case studies; and as to Norplant, the Wysowski and Green case study). Id. at 23-24. In describing Valenzuela as "f[inding] a significantly greater risk among women who used or were using Mirena," Dr. Darney, like Dr. Fraunfelder, does not acknowledge that the Valenzuela study had not controlled for obesity or recent weight gain, or that it had disclaimed any finding of causation of IIH by Mirena. Id. at 2. In his deposition, however, Dr. Darney acknowledged these points, Darney Dep. 184, and that a study "would have to control for [body mass index], female gender, and age, in order to conclude that Mirena is associated with IIH," id. at 165.
Dr. Darney is the first of plaintiffs' experts who does not base his opinion largely on an assessment of study and case report data bearing on the relationship (if any) between Mirena and IIH. Instead, Dr. Darney articulates a mechanism theory: In an opinion articulated for the first time in his report in this litigation, he opines that "relatively high unbound LNG concentrations can cause" IIH in "susceptible women" through "androgenic side effects." Darney Rpt. at 5, 21-24; Darney Dep. at 295-96 (defining "susceptible women" as women with a history of androgenic side effects, such as acne). This theory, however, does not withstand Daubert review.
As a threshold consideration, Dr. Darney's theory that Mirena causes IIH through androgenic side effects does not satisfy any of the four Daubert reliability factors. First, he has not tested it in a direct experiment, an epidemiological study, or a clinical trial. And Dr. Darney does not claim that such testing would be impossible.
Under these circumstances, the Court — like Judge Seibel in considering the theory that Mirena causes uterine perforation, also largely based on mechanism opinions articulated for the first time in the litigation — must "pause and take a hard look
Here, that opinion turns on two premises, each captured within the fourth and final step of his syllogism: (1) that androgens can cause IIH; and (2) that by extension, LNG, a progestin, can cause IIH. A "hard look" at Dr. Darney's analysis as to each premise is necessary, because, to warrant admissibility, "it is critical that an expert's analysis be reliable at every step," and "any step that renders the analysis unreliable under the Daubert factors renders the expert's testimony inadmissible." Amorgianos, 303 F.3d at 267.
Bayer argues that Dr. Darney's analysis is deficient as to each premise. While Bayer's critiques are valid, before addressing them, the Court discerns a broader overarching lapse of methodology affecting Dr. Darney's mechanism opinion: Dr. Darney's expert report scarcely addresses IIH. His limited discussion of the disease, Darney Rpt. at 21-23, at no point engages with the threshold issue of what IIH is and how this condition comes about. In venturing a mechanism theory as to Mirena's purported causation of IIH, Dr. Darney does not explain the most fundamental proposition about IIH: that it is caused by the build-up of CSF in the brain resulting in an increase in intracranial pressure. And he does not acknowledge, let alone address, the unresolved debate about whether IIH is caused by CSF's over-production or under-absorption or both, despite the fact that that the debate over this unsettled question is identified by the sources he cites. Compare Westgate, supra, at P325 ("The etiology [of IIH] is poorly understood but involves imbalance of cerebrospinal fluid (CSF) secretion and absorption.... We hypothesise that obesity and androgen excess may be pathogenic in IIH through dysregulation of CSF secretion."); with Glueck, supra, at 72 ("Our hypothesis: IIH results in part from inadequate drainage of cerebrospinal fluid (CSF) resulting from thrombotic obstruction to CSF resorption-outflow ....").
In theorizing based on a syllogistic construct why a "potent androgenic progestin" might cause IIH in "susceptible individuals" who have "relatively high unbound LNG concentrations," Darney Rpt. at 5, Dr. Darney gives scant attention to the actual pharmacokinetic process that must underlie the causal sequence that he postulates. He does not identify the androgen receptors in the human body with which LNG supposedly bonds to trigger the biological pathway that, on his theory, causes the over-production and/or the under-absorption of CSF.
Dr. Darney's silences on these points — about the mechanics of IIH, and about the basic operation of the "mechanism" and "pathway" that he posits link Mirena to this rare disease — are non-trivial lacunas. For a litigation expert who advances a novel conceptual theory as to the cause and the mechanism of a disease, they are failures of methodology. Presented with Dr. Darney's general causation syllogism and no more, a jury would be left, unhelpfully, with Dr. Darney's bare assumption that some such biological pathway must exist.
It is true that, where more than a correlation between a product and a disease
Independent of Dr. Darney's failure to engage with the biology of IIH, Bayer, as noted, faults his report for the speculative "leaps" it makes in support of his two central premises: that androgens can cause IIH, and that LNG, a progestin with androgen receptor affinity, can cause IIH. The Court holds with Bayer on both points: For the reasons that follow, as to each premise, Dr. Darney's conclusion lacks a reliable foundation.
First, as to the premise that androgens cause IIH, Dr. Darney does not cite any article that so concludes. Instead he cites, or refers to without explicitly citing, several articles that speculate or hypothesize about the role of androgens in IIH. These include the Glueck, Klein, and Westgate studies discussed earlier.
The Glueck and Klein studies identified some possible characteristics of patients already diagnosed with IIH. These studies did not attempt to, nor did they find, any definitive causal link between those characteristics and IIH. And the design of both studies — case series of patients who were diagnosed with IIH, with no control group — would not permit this conclusion.
Notably, neither the Glueck nor the Klein study concluded (or even speculated) that androgens specifically cause IIH. The authors of the Glueck study hypothesized that the number of patients with PCOS, a condition often characterized by excess androgen, might indicate a relationship between IIH and obesity or estrogen. At no point did they state that androgens were in fact related to IIH. At his deposition, Dr. Darney conceded that the Glueck study only "suggests an implication" of a causal relationship between androgens and IIH. Darney Dep. at 251.
The Klein study also did not conclude that androgens cause IIH. It found that "circulating androgens ... originating in either the ovaries or the adrenal cortex, were clearly linked to an early age of onset of IIH." Klein, supra, at 975. Based on this finding, the Klein study notes that one might "speculate ... that in women susceptible to the evolution of IIH, increased circulating androgens might function as a precipitating factor allowing earlier expression of the disease." Id. (emphasis added). However, the Klein study does not purport to establish such a causal role. See In re Accutane Prods. Liab., 2009 WL 2496444, at *2 ("[W]hen an expert relies on the studies of others, he must not exceed the limitations the authors themselves place on the study."); In re Mirena Perforation/Daubert, 169 F.Supp.3d at 452 (same).
Dr. Darney also overstates the findings of the Westgate study. Dr. Darney states that Westgate "observ[ed] that women with increased secretion of CSF also have high androgen levels." Darney Rpt. at 22. But the Westgate study did not so observe. It did not study women specifically, let alone receive or evaluate data on women's
Apart from assigning undue weight to propositions that the studies upon which he relies present as mere hypotheses, Dr. Darney fails to explain how the inferences from these studies, or others, separately or concatenated, support that IIH is caused by androgens. The most apposite of the three above studies is Westgate. It at least speculated about a relationship between androgens and IIH. It performed an in vitro experiment to test that proposition: an immortalized choroid plexus cell line (i.e., a cell line, not in a live rat) was incubated with testosterone, a potent androgen,
As to Dr. Darney's second premise, that progestin LNG is akin to androgens in ways that make it a cause of IIH, it, too, rests on speculation. Dr. Darney theorizes that LNG, because it has stronger androgenic potential than other progestins, can also cause IIH. But Dr. Darney has not identified any article that has tested
"Even minor deviations in molecular structure can radically change a particular substance's properties and propensities." Glastetter v. Novartis Pharm. Corp., 252 F.3d 986, 990 (8th Cir. 2001); Rider v. Sandoz Pharm. Corp., 295 F.3d 1194, 1201 (11th Cir. 2002). And courts regularly exclude expert opinions built on analogies to different chemical compounds than the one at issue. See, e.g., Glastetter, 252 F.3d at 990 (excluding opinion that "hypothesized that bromocriptine may behave like its chemical cousins" because the "generic assumption that bromocriptine behaves like other ergot alkaloids carries little scientific value"); McClain, 401 F.3d at 1246 (excluding opinion where expert "failed to show that the PPA analogy is valid or that the differences in chemical structure between PPA and ephedrine make no difference"); Konrick v. Exxon Mobil Corp., No. 14-CV-524, 2016 WL 439361, at *7 (E.D. La. Feb. 4, 2016) (excluding opinion that "relies heavily on studies that focus on `solvents' or `organic solvents' as a class, instead of the specific substances that allegedly caused plaintiff's stillbirth"); In re Prempro Prods. Liab. Litig., 738 F.Supp.2d 887, 893 (E.D. Ark. 2010) (excluding expert testimony that analogized to two different kinds of estrogen based on a class effect, noting that "where an expert summarily attributes effects of one substance to another similarly classified substance, federal courts have consistently concluded that such methodology is not reliable."). Here, Dr. Darney has formulated a theory — a proposed analogy — that may or may not merit further close scientific review. But, for purposes of admissibility under Rule 702 and Daubert, his leap extends too far given the existing scholarship. Even assuming the validity of his first premise that androgens cause IIH, he has not adduced a sound basis on which to claim to have demonstrated that LNG behaves sufficiently like such androgens to also cause this condition.
As noted, in support of his ultimate opinion, Dr. Darney cites, briefly, the Valenzuela study and various Norplant case studies. These materials do not close the gaps in his mechanism theory. They do not speak, at all, to whether androgens cause IIH or whether LNG behaves like other androgens in ways relevant to the causation of IIH. And, for the reasons reviewed above, viewed as epidemiological source
Relatedly, Dr. Darney briefly suggests that there is a dose-response relationship between LNG and IIH, see Darney Rpt. at 14, but he ignores contrary data about contraceptives that use LNG in much higher doses (i.e., combined oral contraceptives) which Dr. Darney acknowledges do not cause IIH. See Darney Dep. at 43, 233; see also In re Rezulin, 369 F.Supp.2d at 425 ("A factor that courts have considered in Daubert analyses is whether an expert has accounted adequately for obvious alternative explanations."); U.S. Info. Sys., Inc., 313 F.Supp.2d at 238 ("An expert must demonstrate that he has adequately accounted for obvious alternative explanations in order for his testimony to be reliable."); In re: Gen. Motors LLC Ignition Switch Litig., 2015 WL 9480448, at *2 n.1 (noting that an expert must address "obvious alternative causes") (emphasis omitted)).
In the end, while Dr. Darney's credentials are sterling, the methodology underlying his opinion in this case is not. He relies on supposition and attempts to link disconnected studies by others. And he uses some of his source material for more than it can fairly support. The result is a hypothesis that may or may not bear up when and if it is ultimately tested, not a reliable expert opinion admissible under the governing standards. The Court therefore must exclude his testimony.
Dr. Johanson is a physiologist and neuroscientist. He completed his undergraduate studies at Eastern Nazarene College, and received his Ph.D in physiology from Kansas University Medical School in 1970. Johanson Rpt. at 4. He has been a professor at the University of Utah in Salt Lake City and is currently a professor of clinical neuroscience/neurosurgery at Brown University Medical School, where he has worked for the last 30 years. Id. His academic research has been focused on brain fluid dynamics, choroid plexus-CSF physiology and pharmacology, and intracranial hypertension and hydrocephalus. Id. He has "conducted investigations in cerebral ischemia, hyperthermia, Alzheimer's disease, and arterial hypertensive effects on CNS barrier systems and CSF." Id. He has presented lectures on IIH "at the meetings of the Intracranial Hypertension Research Foundation." Id. at 5. He was a founding member of the journal Cerebrospinal Fluid Research (now known as Fluids and Barriers of the CNS). Id. He has served as a consultant for the National Aeronautics and Space Agency and has been awarded the Pudenz Prize for research in the fields of CSF physiology and hydrocephalus. Id. at 4.
Dr. Johanson's report is substantially more technical than any of the reports
Dr. Johanson's report begins by discussing the formation, travel, and reabsorption of CSF, and normal versus elevated levels of CSF pressure. Id. at 6-9. His discussion of IIH in this respect is brief. Relevant here, Dr. Johanson suggests that IIH is caused by the "hypersecretion of CSF"; for this proposition, he cites, in the commentary he appends to a graphic illustrating the CDF circulatory system, the following article: P. Gideon, et al., Assessment of CSF dynamics and venous flow in the superior sagittal sinus by MRI in idiopathic intracranial hypertension: a preliminary study, 36 Neuroradiology 350, 353 (1994) (Dkt. 167-32) ("Gideon"). Johanson Rpt. at 9. The Gideon article, however, expressly does not endorse this proposition. See Gideon, supra, at 353 ("Our results do not support the suggestion that hypersecretion is an important factor in the majority of patients with IIH."). And, as noted, while the issue is unresolved, the bulk of scholarship appears to adopt the alternative hypothesis: that the root cause of excess CSF in IIH patients is impaired absorption of CSF. See Vincenzo Salpietro, et al., Recent insights on pediatric pseudotumor cerebri syndrome pathophysiology: From the "Unifying Neuroendocrine Perspective" to the "Integrated Bioenergetic-Hormonal Mechanism," 13 J. Pediatric Neurology 11, 12 (2015) (Salpietro) (observing that the more generally accepted hypothesis for the cause of CSF production is "hampered outflow of CSF into the venous system"). Dr. Johanson acknowledged this in his deposition. See Johanson Dep. at 84 (agreeing that hampered CSF outflow is the more generally accepted hypothesis).
Dr. Johanson's report then discusses the choroid plexus's role in generating CSF. He cites clinical studies that, he states, have demonstrated that the choroid plexus is the source of CSF production. Among these studies are ones that demonstrate that surgically cauterizing and removing choroid plexus cells reduce CSF pressure; and that patients with abnormal choroid plexuses over-secrete CSF. Johanson Rpt. at 10. Dr. Johanson states that, in addition to this clinical evidence, "[p]harmacologic experimentation reinforces the concept of a high-capacity fluid production at the blood-CSF interface." Id. Therefore, he states, "it is now widely accepted by neuroscientific and neurosurgical communities that [the choroid plexus] is the focal point of fluid production within the [central nervous system]."
Dr. Johanson then discusses how, in his view, sodium channel and pump activity drive CSF formation in the choroid plexus. At its most basic level, the process is as follows: sodium is diffused into the epithelial cells of the choroid plexus through sodium channels (Step 1), where it is then expelled from the cells into the CSF through a sodium pump (Step 2). This creates a sodium imbalance between the choroid plexus epithelial cells and the CSF. To correct this imbalance, water flows through aquaporin channels, causing the formation of CSF (Step 3). Johanson Rpt. at 14-15. This process is summarized in the chart below, copied from Dr. Johanson's report.
Id. at 15.
Dr. Johanson then sets out his view of the role of sex hormones and their receptors in this process. He posits that, when the androgens testosterone and dihydrotestosterone bind to androgen receptors in the choroid plexus, they trigger the sodium mediated mechanism by which CSF is generated. As he sets out, the building blocks of this hypothesis are (1) the fact that "androgen receptors (AR) have been characterized in CP of female and male mice," (2) an analogy to studies of the effect of testosterone on the kidneys of rats, (3) two case reports of the development of IIH in transgender men who were taking high doses of testosterone, and (4) studies involving the effect of testosterone on sodium channels, pumps and aquaporins — the only one involving the choroid plexus being the Westgate study.
Dr. Johanson also opines that two other hormones, estrogen and progesterone, affect CSF production. He suggests that estrogen imbalance with progesterone increases CSF production. See id. at 18-19, 21-22. Progesterone, on the other hand, he states, likely inhibits CSF production. In particular, Dr. Johanson suggests that progesterone reduces the transport of sodium into the choroid plexus epithelial cells (Step 1) by "reducing channel opening time" and "lowering channel expression." Id. at 21. It also inhibits sodium pumps generally (Step 2), and down regulates the aquaporins in multiple tissues and, by analogy, in the choroid plexus too (Step 3).
Finally, Dr. Johanson pivots to consider LNG. He proposes the following mechanisms as to how LNG causes CSF production and thus IIH. First, he posits, LNG directly travels to the central nervous system and choroid plexus and bonds to the androgen and MR. This causes CSF production for the reasons described above as to the androgen mechanism and for the
In addition to these hormone-related factors, Dr. Johanson also suggests that LNG induces the secretion of insulin which "can drive androgen production in the ovaries." Id. at 27. However, as Dr. Johanson later acknowledges, the evidence is mixed in suggesting that LNG increases insulin levels. He also suggests that hormone and insulin-related weight gain (a so-called "secondary mechanism") might support his finding that LNG causes IIH because obese patients and those with recent weight gain are more likely to develop IIH.
Finally, Dr. Johanson points to "epidemiological evidence" of LNG's ostensible ability to cause IIH, citing what appears to be a single case of a "dechallenge." He did not, however, review either the Valenzuela or Etminan studies or consider any clinical data showing that Mirena users, given the preferential prescribing practices of that contraceptives, are at an increased risk for IIH. See Johanson Rpt. at 38-50 (list of authorities does not include Valenzuela or Etminan); Johanson Dep. at 135. At his deposition, Dr. Johanson admitted that no study, in animals or humans, had tested LNG and found that it dysregulated sodium transport in the choroid plexus or increased CSF production. See id. at 119, 173.
As with the previous experts, Dr. Johanson's opinion — that the LNG in Mirena causes the hypersecretion of CSF and thus IIH, based on a mechanism consisting of a series of theorized steps — fails to satisfy any of the Daubert reliability factors.
Dr. Johanson first developed this theory in the course of this litigation. In his deposition, he admitted that he had never communicated this theory outside of this litigation and that, before being hired by plaintiffs, he had never even considered whether LNG could cause IIH. Johanson Dep. at 109. Nor has this theory been tested: As to the mechanism he proposes by which LNG would have this effect, Dr. Johanson acknowledges that he has not tested the effects of LNG on choroid plexus ion transporters, even though he stated that it would take only one week to do so. Id. at 14-15. Dr. Johanson is unaware of anyone else who has tested this theory. Id. at 119. He also has not published the theories he articulates in his expert report anywhere, including in a peer-reviewed journal. He is unaware of anyone else who has done so. Id. at 63; see also id. at 109-10, 173-74. And he admits that his theory
Id. at 215.
Under these circumstances, the "cleverly buil[t] together ... plausible working model" that is Dr. Johanson's mechanism opinion is arguably, by his own account, "speculative" and "conjectural," so as, without more, to require exclusion. Boucher, 73 F.3d at 21. At a minimum, because it fails the Daubert reliability factors, this opinion, like those of the experts addressed earlier, requires the following "hard look."
The mechanism that Dr. Johanson theorizes, while complex, can be reduced to the following series of premises and steps: (1) IIH is caused by an overproduction of CSF; (2) the choroid plexus produces CSF through a sodium mechanism; (3) the sodium mechanism that produces CSF is triggered by androgens binding to androgen receptors in the choroid plexus; and (4) LNG binds to those same androgen receptors, triggering the same mechanism. In connection with these propositions, Dr. Johanson adds his views about how certain other hormones (estrogen and progesterone) activate or inhibit that same sodium mechanism, and how LNG affects those hormones. Dr. Johanson also articulates a secondary, indirect mechanism of causation, under which Mirena causes a patient to gain weight, which in turn causes IIH.
As the Second Circuit has held, "it is critical" that the analysis of an expert "be reliable at every step." Amorgianos, 303 F.3d at 267. Otherwise, the expert's opinion must be excluded. See In re Paoli R.R. Yard PCB Litig., 35 F.3d 717, 745 (3d Cir. 1994) ("[A]ny step that renders the analysis unreliable under the Daubert factors renders the expert's testimony inadmissible.") That proposition guides the Court's analysis of Dr. Johanson's opinion, comprised as it is of a sequence of postulates. Bayer disputes as unreliable and conjectural steps one, three, and four of Dr. Johanson's proposed biological mechanism, as well as some of his secondary premises. The Court considers these in turn.
In support of his theory's first step — that IIH is caused by an overproduction of CSF — Dr. Johanson cites the Gideon study. However, as noted, the authors of that study do not so state. Their study explains that "CSF production may contribute to the development of [IIH]" in some individuals, but the study's results "do not support the suggestion that hypersecretion is an important factor in the majority of patients with IIH." Gideon, supra, at 353 (emphasis added).
When confronted with this aspect of the Gideon study at his deposition, Dr. Johanson backtracked. No longer relying on the conclusion of the study, he argued that three outlier data points in that study "kind of stood out" so as to favor his conclusion. Id. at 168. He blamed the Gideon study's authors for "misjudgment." Id. But, as noted earlier in connection with similar handling of others' studies by others of plaintiffs' experts, "exceed[ing] the limitations the authors themselves" placed on their studies is not good science. See Mirena Perforation/Daubert, 169 F.Supp.3d at 431 (quoting In re Accutane Prods. Liab., 2009 WL 2496444, at *2); see also Anderson v. Bristol Myers Squibb Co., No. CIV.A. H-95-0003, 1998 WL 35178199, at *11-12 (S.D. Tex. Apr. 20, 1998) (excluding expert testimony where expert drew a "causation conclusion that the authors of the study never even reached in their published work"). Ignoring
Significant too, the premise that IIH results from the overproduction — rather than the under-absorption — of CSF, which Dr. Johanson endorses in this litigation, is one that he has not previously embraced, despite addressing this subject in a prior writing. Specifically, an article Dr. Johanson co-authored recognized that CSF overproduction is the less favored hypothesis in the academy. The article did not indicate that any of the authors embraced that hypothesis. See Salpietro, supra, at 12. The article instead stated, as Dr. Johanson synopsized in his deposition, that the molecular physiology basis for elevated CSF pressure in IIH is unknown and that "the patho-physiology of PTCS [IIH] is still poorly understood." Johanson Dep. at 76-78, 82-83. To be sure, Dr. Johanson's earlier article falls short of making his present report a reversal of position for purposes of litigation. But it does bear on the reliability of the view he has adopted in this litigation, particularly insofar as Dr. Johanson's new view does not derive from new or original research. And, as noted, this hypothesis is disputed in the literature, the majority of which has hypothesized an under-absorption theory. Dr. Johanson's report does not seriously engage with this contrary theory, including the writings that he cites in his earlier co-authored article, which question that CSF overproduction is the more probable explanation for IIH. See In re Rezulin, 309 F.Supp.2d at 563.
As to the first step in Dr. Johanson's analysis, the Court — and a jury — would be left only with the non-supportive Gideon study and Dr. Johanson's ipse dixit assertion that an increase in CSF production is the likely cause of IIH. That is too great an analytic leap. His opinion on this critical first step lacks a sufficient evidentiary basis to permit it, under Daubert, to reach a jury. See R.F.M.A.S., Inc. v. So, 748 F.Supp.2d 244, 248 (S.D.N.Y. 2010) ("Expert testimony that is merely subjective belief or unsupported speculation should be excluded." (quotations omitted)).
The next disputed step in Dr. Johanson's mechanism theory is his statement that the sodium mechanism that produces CSF is triggered by androgens binding to androgen receptors in the choroid plexus. By far the most apposite writing cited by Dr. Johanson for this point is the Westgate study. But, as discussed in connection with Dr. Darney's report, that was an in vitro study involving the choroid plexus cells in rats and involving testosterone. Bayer validly argues that extrapolating from a study involving testosterone and rats to the context of non-androgen LNG (a progestin) and humans is too great a leap. The Court agrees. In any event, even if such extrapolation were otherwise a viable basis for permitting such a theory to reach a jury, the Westgate study speculated, but stopped short of concluding, that testosterone may play a role in the production of CSF so as to cause IIH. See Westgate, supra, at P325 ("[H]ypothesis[ing] that obesity and androgen excess may be pathogenic in IIH through dysregulation of CSF secretion and hence [IIH]." (emphasis added)); see also Johanson Dep. 188-89.
Dr. Johanson also cited in support of his litigation theory's second step (1) two case reports involving transgender patients who had taken massive doses of testosterone, and (2) in vitro studies involving sodium transport in other organs, such as the kidneys. The authors of the transgender case reports, however, emphasize that the relationship between testosterone and IIH
Step four in Dr. Johanson's mechanism theory posits that LNG binds to androgen receptors in the choroid plexus, causing sodium ion transport. But this theory, too, does not rest on a base of data that is nearly solid enough to reach a factfinder. As Dr. Johanson admitted at his deposition, he is unaware of any study suggesting that LNG dysregulates sodium transport in the choroid plexus or that LNG results in an increase in CSF production or pressure. Johanson Dep. 173 ("Q: [C]an you identify any study that [] found that LNG dysregulates sodium transport in the choroid plexus? A: No. I cannot."); see also id. at 119. He also testified that he is unaware of any articles that discuss LNG and its androgenic activity in relation to IIH. Id. at 214-15. Relative to Dr. Darney, Dr. Johanson devotes little attention to discussing the androgenic potential of LNG. But, as noted in the discussion of Dr. Darney's similar postulate, LNG's androgenic potential is substantially less than that of testosterone. Even assuming arguendo that testosterone could cause the sodium transport posited by Dr. Johanson, it does not non-speculatively follow that LNG has a similar androgenic effect — especially to the degree necessary to cause IIH.
More generally, despite the central role that the androgen sodium mechanism plays in his mechanism theory, Dr. Johanson cites little evidence in support of this vital step. He relies mostly on citations to Dr. Salpietro's report in this litigation and on the same case reports and case
There are thus infirmities precluding a finding of reliability as to three of the four steps on which Dr. Johanson's theory of Mirena's causation of IIH is based. Beyond that, to the extent that he sought to buttress his conclusion as to this point with clinical data, Dr. Johanson's use of evidence was impermissibly selective. To the extent he dipped into existing scholarship with respect to the relationship between Mirena and IIH, Dr. Johanson did so by citing case reports. In so doing, he elected not to consider the most important scholarship bearing on that point. He did not consider the Valenzuela study (or any part of the Etminan study, including its uncompromised part) at all. See Johanson Dep. at 38 ("Q: Did you review any of the clinical studies on Mirena and IIH? A: I did not. I have not, no."); id. at 85-86 ("Q: Did you review the literature showing whether patients who used Mirena have an increased rate of IIH as compared to controls? ... A: No."); see also id. at 135-36. To be sure, Dr. Johanson's opinion is ultimately about a theorized mechanism of causation. He was not obliged to have considered these epidemiological studies in formulating his opinion. But, having deployed clinical evidence in the form of case reports in support of his ultimate conclusion, it is fair to examine whether he looked holistically, or only selectively, at this body of evidence. His cherry-picking approach is at odds with principles of sound science.
Finally, as noted, Dr. Johanson articulates a secondary, indirect theory of causation. He asserts that LNG has potential to cause obesity, hypertension, and hormonal imbalance. From these effects, he asserts, it may indirectly cause IIH. But this conclusion is flawed by the same sorts of data holes and analytical gaps as his discussion of the several steps addressed above. As to obesity, for example, Dr. Johanson opines that "weight gain ... can occur with Mirena usage." Johanson Rpt. at 27-28. But the articles he cites for that proposition articles do not support it. He cites Natália Dal'Ava, et al., Body weight and composition in users of levonorgestrel-releasing intrauterine system, 86 Contraception 350 (2012) (Dkt. 167-21), for the proposition that users of LNG-containing IUDs gained an average of seven pounds per year, and that those taking another progestin, depot-medroxyprogesterone, gained 15 pounds. Johanson Rpt. at 28. But Dal'Ava compared LNG-containing IUDs to copper (non-LNG) IUDs. Dal'Ava found "no significant difference in body weight change between the two groups of users at 12 months." Dal'Ava, supra, at 350. Dr. Johanson also cites Waleska Modesto, et al., Weight variation in users of depot-medroxyprogesterone acetate, the levonorgestrel-releasing intrauterine system and a copper intrauterine device for up to ten years of use, 20 Eur. J. of Contraception & Reproductive Health Care 57, 60 (2015), for the proposition that LNG-containing
Dr. Johanson's opinion must be sound at every critical step to be admissible. Instead, it is unsound methodologically at nearly each step. The Court must exclude it.
Dr. Salpietro, plaintiffs' final expert, offers an alternative mechanism explanation with respect to IIH to those of Drs. Darney and Johanson, plaintiffs' other mechanism experts.
Dr. Salpietro is a pediatrician and pediatric neurosurgeon. Salpietro Rpt. at 2. He received his medical training at the University of Messina and the University of Pavia in Italy, and at Imperial College London in the United Kingdom. Dr. Salpietro works in the field of molecular neuroscience. Dr. Salpietro has published extensively in peer-reviewed journals in recent years. In addition to his research, Dr. Salpietro teaches students at Imperial College London Medical School and the University College London Institute of Neurology. Id. at 3.
His research focuses on investigating "the molecular and metabolic alterations causing rare neurological disorders of yet poorly understood pathophysiology." Id. Dr. Salpietro is currently working to characterize the metabolic and genetic basis for a number of rare neurological disorders, including IIH. Id. However, as reviewed infra, before this litigation, his research into a mechanism for causation of IIH had never identified LNG as such a cause.
Dr. Salpietro's opinion is fundamentally about a mechanism by which Mirena might cause IIH. His report embraces a mineralocorticoid theory of a causal link between LNG and IIH. He posits that, because mineral corticoids may cause IIH and because LNG can bind to mineralocorticoid receptors ("MR" or "MRs"), LNG in turn may cause IIH.
Dr. Salpietro's report begins by discussing the basics of LNG, and in particular explains that, as acknowledged by Bayer, LNG binds to MRs. Id. at 6-8. Dr. Salpietro also concludes that LNG exerts agonist (rather than antagonist) effects)* because mineralocorticoid activation symptoms (increase in body weight or blood pressure) have been reported in case reports regarding LNG-IUD users. Id. at 9-10. Animal studies conducted by Bayer have, according to Dr. Salpietro, demonstrated that Mirena use results in weight gain. In Bayer's clinical studies of Mirena, patients also reported some symptoms that are associated with mineralocortoid agonism, including edema, bloating, and weight gain. Id. at 10-12.
Dr. Salpietro then turns to discuss IIH. After reviewing its characteristics and symptoms, id. at 12-14, he notes that "[t]he pathophysiology of PTCS is incompletely
Dr. Salpietro then articulates his theory — namely, that many cases of IIH were related "to the primary event of raised CSF pressure," and that this increase in pressure is caused by "derangements in transport of electrolytes like sodium (Na+) or potassium (K+)." Id. at 17. He states: "Activation of the choroid plexus MRs and their downstream pathways more likely than not stimulates the generation of Na+ (sodium) /K+ (potassium)-ATPase pumps, leading to greater movement of sodium ions at the choroid plexus epithelial cells (CPEC) apical membrane into the cerebral ventricles, thereby actively creating an osmotic gradient to drive secretion of CSF." Id. This mechanism has similarities to the model that Dr. Johanson proposes, although the driver of this mechanism posited by Dr. Salpietro is MR activation, not androgen receptor activation as posited by Dr. Johanson. Dr. Salpietro likens the mechanism he posits to mechanisms seen in the kidney. Id. at 18.
In support of the mechanism he endorses, Dr. Salpietro cites case reports and case series in which PTCS was observed in patients with excess aldosterone — a mineralocorticoid, which binds to MRs in the epithelial cells of the choroid plexus. Id. at 18. However, when questioned on this point at his deposition, Dr. Salpietro disclaimed reliance on case reports to prove his mechanism theory. See Salpietro Dep. at 137 ("Q: You cite a number of case reports in your report, correct? A: Yes. Q: Are you relying on those case reports to prove your mechanism theory? A: No."). Dr. Salpietro further acknowledged that, while he regards his mechanism model as "biologically plausible," it "is not proven." Id. at 350, 393.
In support of this mechanism theory, Dr. Salpietro cites studies that observe MR expression in animal choroid plexus, and other studies that observe the expression of an Na+-K+-ATPase subunit in rat choroid plexus. Salpietro Rpt. at 19-21. He further notes that studies have shown "that children and adults with excess of aldosteronism can develop PTCS as a complication." Id. at 21. One study, he noted, has shown that IIH patients who did not respond to conventional treatment experienced an improvement of their symptoms
As to an association between LNG and IIH, Dr. Salpietro cites studies that observe that some women taking oral contraceptives containing LNG have experienced symptoms associated with IIH. Id. at 28 (noting study in which four of 59 women using oral contraceptives were reported with IIH symptoms; also noting a 1968 study which described a "high proportion of neuro-opthalmic consequences" among 129 women taking oral contraceptives). None of those studies, however, have concluded that the oral contraceptives caused IIH. See id. Dr. Salpietro also cites the Norplant case studies discussed earlier (Sunku; Alder; and Wysowski and Green). Id. at 28-29. Dr. Salpietro also cites a case report in which a patient, after exposure to the powerful progestin Depo Provera, experienced IIH, id. at 29, and the Martinez case report, cited earlier, of a woman whose visual disturbances resolved after an LNG-released IUD had been removed and treatment with the diuretic acetazolamide had begun, id. Finally, Dr. Salpietro also cites the Valenzuela study, id., and to Bayer's summary of individual case reports as submitted to German regulator BfArM. Id. at 29-30.
With respect to the mechanism he posits, Dr. Salpietro terms it "biologically plausible," and consistent with various known facts about IIH. Id. at 30.
At the end of his report, Dr. Salpietro articulates an indirect mechanism by which
In his deposition — addressed further infra — Dr. Salpietro admitted that he was not an expert in epidemiology and that he cannot testify about either it or pharmacology. See Salpietro Dep. 424-25 ("I have included all this pharmacology and epidemiology... because I wanted to do a proper job .... But it's something that I did challenging myself and going in a different territory, so I cannot testify about that."); id. at 427 ("I cannot absolutely testify about pharmacology or epidemiology or gynecology. I mean, I would never — I would never do that."); id. at 137 ("It is not my expertise. I have been not trained like an epidemiologist. I have no experience of epidemiology."); id. at 163 ("[B]ecause I am not an epidemiolog[ist], I exchanged thoughts with [Plaintiff counsel], and she — she helped me to analyze, to interpret this data.").
Unlike the preceding six experts, Dr. Salpietro has written prior to this litigation to propose a component of the theory that he now propounds. In 2012 and 2014, he proposed an MR-mediated mechanism for IIH, although Dr. Salpietro did not then connect it to LNG, let alone to Mirena. Dr. Salpietro did suggest a causal connection to IIH of aldosterone, a classic MR agonist, and progesterone. To be sure, as articulated in his 2012 and 2014 publications, Dr. Salpietro's theory as to such a mechanism for IIH was put in far more qualified and tepid terms than in his present report. See generally Vincenzo Salpietro, et al., Idiopathic intracranial hypertension: a unifying neuroendocrine hypothesis through the adrenal-brain axis, 33 Neuroendocrinology Lett. 569, 569, 572 (2012) (Dkt. 196-23) ("Salpietro 2012") (stating that he was "working toward" a "hypothesis" of IIH that involves MRs in the choroid plexus, that it is "conceivable" that progesterone "can lead to IIH through stimulation of the MR pathway that leads to active sodium secretion ... at the apical membrane of the choroid plexus," but that "[t]hus far, however, there is not a credible and comprehensive hypothesis ... of IIH despite the different mechanisms proposed"); see also Vincenzo Salpietro, et al., Pediatric idiopathic intracranial hypertension and the underlying endocrine-metabolic dysfunction: a pilot study, 27 J. Pediatric Endocrinology& Metabolism 107 (2014) (Dkt. 196-26) ("Salpietro 2014"). And Dr. Salpietro's 2014 writing, which was focused on other IIH co-morbidities, made only a passing reference to progesterone, to which it referred only in a chart. See Salpietro 2014, at 112.
Bayer articulates several objections to Dr. Salpietro's expert conclusion that Mirena is a cause of IIH. At the outset, Bayer does not concede Dr. Salpietro's starting premise, to wit, that MR agonists can bind to MR receptors in the choroid plexus, triggering a biological chain reaction that can leads to an increase in CSF production. This theory, Bayer asserts, is purely a scholar's working hypothesis and has been admitted by Dr. Salpietro himself as unproven. Overwhelmingly, though, Bayer focuses its methodological challenge under Daubert on two "leaps" or "gaps" in Dr. Salpietro's proposed application of that
For the reasons that follow, Bayer is correct. The two "gaps" (unsupported assumptions) that it identifies are central to Dr. Salpietro's theory. Each unsubstantiated leap of logic is too great and too consequential to make Dr. Salpietro's ultimate conclusion as to Mirena the product of reliable methodology. And Dr. Salpietro, in his deposition testimony, repeatedly — and at times, memorably — acknowledged that his is no more than a conjectural, unproven working hypothesis. See, e.g., Salpietro Dep. at 409 ("[W]e are still in the prehistoric age in regard to the research of pseudotumor cerebri."); id. "[W]e don't know the genes involved, the pathways involved, and as a consequence we are not able to offer ... etiologically targeted treatments but just symptomatic reliefs."); id. at 89 ("There is no one in the world who knows the exact cause of pseudotumor cerebri.").
Before addressing the gaps in Dr. Salpietro's mechanism theory, the Court notes that, as related above, Dr. Salpietro has jettisoned the remaining opinions articulated in his report, i.e., all but his mechanism opinion. These include his opinions as to pharmacology, epidemiology, case reports, and Dr. Conrad Johanson's androgen theory. In his deposition, Dr. Salpietro disclaimed reliance on these opinions. See Salpietro Dep. at 424 ("I would never testify about the pharmacology underlying Mirena or the — or the epidemiology or the gynecology side of this litigation."); id. at 274 ("There may be several mechanisms involved in the androgenicity of Mirena, but I am not in the position [to] offer you a proper opinion [about Dr. Johanson's androgen theory] because I should read much more about this."); id. at 423 ("I mean, the only thing I can really offer is my model. I mean, I cannot talk about anything else than my model because I'm not a pharmacologist; I am not an epidemiologist."); see also id. at 137, 163, 274, 423-25. And, following Dr. Salpietro's lead, plaintiffs in their opposition brief did not defend the aspects of his report that embrace these other opinions.
As to Dr. Salpietro's opinion as to a mechanism by which Mirena ostensibly causes IIH, the Court assumes, arguendo, that existing scholarship provides a reliable basis for the starting premise of that opinion: that MR agonists can bind to MR receptors in the choroid plexus, triggering a biological chain reaction that can lead to an increase in CSF production. Like Bayer, the Court focuses its analysis on the two ensuing steps in the reasoning Dr. Salpietro uses to connect that starting premise to his opinion here. The Court gives this analysis a "hard look," because — like the opinions of the preceding six experts — Dr. Salpietro's opinion does not meet any of the Daubert criteria for reliability.
Along the same lines, Dr. Salpietro also cites Anny Souque, et al., The mineralocorticoid activity of progesterone derivatives depends on the nature of the C18 substituent, 136 Endocrinology 5651 (1995) (Dkt. 167-61), for the proposition that "progesterone has a low agonist mineralocorticoid (MC) activity." Salpietro Rpt. at 9. This is not a small point. Dr. Salpietro's model depends on this proposition. It does not logically cohere if progesterone and LNG are not MR agonists.
However, fatally from a Daubert perspective, the studies that his report cites and that he referenced at his deposition for this proposition do not support that progesterone and LNG are MR agonists. The first study, M. Quinkler & S. Diedrich, Difference of in vivo and in vitro antimineralocorticoid potency of progesterone, 28 Endocrine Res. 465 (2002) (Dkt. 167-50), appears to directly contradict itself. It reports both that the preexisting literature found that progesterone was "only a weak
The Souque study paints a more internally consistent, while complex, picture. But in the end, this study does not help Dr. Salpietro's theory either. The study finds that progesterone and several of its derivatives "behave as antagonists." Souque, supra, at 5656. This, of course, is contrary to a core premise of Dr. Salpietro's report. (Plaintiffs' expert Dr. Johanson similarly disagrees with Dr. Salpietro, opining that progesterone is an MR antagonist. See Johanson Rpt. at 18; Johanson Dep. at 175.) That said, the Souque study does find that one progesterone derivative has "agonist properties." Id. But the proposition that one derivative of progesterone has agonist properties is an insufficient ground on which to find a reliable basis for Dr. Salpietro's thesis. The Souque study's findings emphasize the difficulty, even the futility, of inferring from the behavior of one hormone that of a similar hormone — it underscores that one cannot assume that because one hormone has a certain effect, a similar hormone will necessarily have the same effect. As another study puts the point: "[T]he relationship between affinity and biological activity or potency is not straightforward or predictable, and appears be cell and promoter-specific, as well as ligand-dependent." Africander, supra, at 641. Under Daubert, Dr. Salpietro's analysis must be "reliable at every step." Amorgianos, 303 F.3d at 267. But the studies he cites for the necessary proposition that progesterone is an MR agonist are "simply inadequate to support" that conclusion. Id. at 266. They do no more than make that proposition possibly true.
Conceivably, Dr. Salpietro's opinion on this aspect of his mechanism opinion could have been salvaged had he contended with this nuance. Conceivably, for example, he might have explained, if true, that the chemical structure of LNG is closely akin to that of the MR-agonist progesterone derivative addressed by the Souque study, while it is unlike that of derivatives that are not MR agonists. Dr. Salpietro did not, however, do so.
The only evidence, in fact, that Dr. Salpietro musters in support of his thesis that LNG is a MR agonist is his statement that LNG causes "MR agonism-related side effects." Salpietro Rpt. at 10. The side effects that Dr. Salpietro mentions in this regard include bloating or edema, weight gain, and increased blood pressure. Id. at 11. But this statement is problematic because these symptoms may have many causes, and because, with the possible exception of high blood pressure, the evidence that Dr. Salpietro cites does not bear out that LNG causes these symptoms.
Dr. Salpietro supports his opinion that LNG causes edema by citing to patient self-reports of edema and bloating as recounted in a clinical study by Bayer. Dr. Salpietro assumed that the doctors had
Dr. Salpietro supports his opinion that LNG causes weight gain by citing to human and animal studies. At his deposition, however, Dr. Salpietro recognized that he had not read some of the studies he cites, and that others do not support his conclusions. A few examples illustrate the casual nature of Dr. Salpietro's inquiry, and the consequent unreliability of his methodology. Dr. Salpietro cites three animal studies that purportedly show LNG causes weight gain. He read only one of them. See Salpietro Dep. at 286-87. One of the two he did not read was written in Japanese. See id. at 312. Dr. Salpietro also relies on human studies by Dal'Ava and Napolitano. Those studies, however were focused on body composition, not weight. See Salpietro Rpt. 35-36; see also Salpietro Dep. 315, 327-28 (recognizing that Dal'Ava and Napolitano studies did not show a statistically significant increase in weight gain). Dr. Salpietro also cites a study by Silva-Filho involving self-reported weight gain by users of LNG-containing IUDs. However, Dr. Salpietro himself admitted that he did not "believe much in this because [it] is a self report." Salpietro Depo. at 332.
Finally, Dr. Salpietro supports his opinion that LNG increases blood pressure by citing to two studies. The first describes a single case report of increased blood pressure. See A.G. Vos, et al., Hypertension and use of an intrauterine levonorgestrel-releasing device, 70 Neth J. of Med. 431 (2012) (Dkt. 167-65). As the Court has noted repeatedly in this decision, case reports alone do not establish causation. See also Salpietro Dep. at 124 (single case report "very weak" evidence of connection between LNG and increased blood pressure). The second includes a single sentence stating that increases in blood pressure have been reported with Norplant, and citing to three additional studies. T. Rosenthal, et al., Chapter 70: Oral contraceptives, hormone replacement therapy, and hypertension, in Comprehensive Hypertension Clinical Approaches: Secondary Hypertension 865, 877 (2007). In any event, even assuming arguendo that such studies did prove that Norplant causes increased blood pressure, it is too great a leap to assume, on this basis, that LNG is therefore an MR agonist that can trigger Dr. Salpietro's biological mechanism. See Amorgianos, 303 F.3d at 266.
Whether IIH is caused by CSF overproduction: In accusing Dr. Salpietro of a second "leap," Bayer faults his report and testimony for refusing to address whether IIH is caused by CSF overproduction, as opposed to by under-absorption of CSF. As Dr. Johanson recognized, this is indeed a "pivotal question" for an expert proposing to opine on whether Mirena causes IIH. Johanson Dep. at 15-16. The Court reads Dr. Salpietro's report differently from Bayer. In the Court's view, Dr. Salpietro's report, while not a model of clarity, is best read to take the position that IIH is caused by CSF overproduction. As Bayer notes, Dr. Salpietro's mechanism theory would otherwise make little sense.
Plaintiffs do not contest that Dr. Salpietro's theories lack such support. They argue instead that Mirena's purported MR-related side effects, specifically edema and weight gain, themselves reliably establish that LNG increases production of fluids. For multiple reasons, this is far too threadbare and speculative a basis to support Dr. Salpietro's thesis. First, it is too far a leap to posit that an increase in production of a type of fluid in one region of the body (e.g., the limbs) necessarily means that production of a different type of fluid (CSF) is similarly increased in another region (e.g., the brain). Second, as noted, the scientific evidence Dr. Salpietro cites in support of his conclusions that Mirena causes edema and weight gain does not solidly support these conclusions. Third, as noted, even if Dr. Salpietro had non-speculatively tied an increase in CSF production to use of Mirena, he does not establish that over-production of CSF, as opposed to its under-absorption, causes IIH.
In sum, Dr. Salpietro's untested mechanism hypothesis, which he admits is "not proven," Salpietro Dep. at 241, 350, is not reliable. It is beset by analytic and evidentiary gaps at multiple steps, which Dr. Salpietro proposes to fill with theories and assumptions, not data. Accepting Dr. Salpietro's never-vetted model would, unacceptably, require the jury to accept "the ipse dixit of the expert." Gen. Elec. Co., 522 U.S. at 146, 118 S.Ct. 512. This Daubert does not permit.
As noted, plaintiffs have moved to exclude defendants' 12 expert witnesses. The reports of these witnesses are directed principally to the topic of general causation. In large measure, these reports take issue with the methodology of plaintiffs' experts.
In light of this ruling excluding the general-causation testimony of all plaintiffs' experts, the Court does not perceive at this time any reason to resolve plaintiffs' motions to exclude the testimony of Bayer's responsive general-causation experts. The Court expects that this litigation, tracking the Perforation MDL, will likely move next to a defense motion for summary judgment on the issue of general causation. The Court accordingly denies as potentially moot plaintiffs' Daubert motions aimed at Bayer's general-causation experts. This ruling is without prejudice: In the event that this case survives such a motion, the Court will then seek counsel's views as to whether to take up Daubert motions with respect to Bayer's experts.
For the foregoing reasons, the Court grants Bayer's motion to exclude the testimony of plaintiffs' seven general-causation witnesses, and denies, as potentially moot, plaintiffs' motions to exclude Bayer's 12 general-causation witnesses. The Clerk of Court is respectfully directed to terminate
An order as to next steps in this case will follow shortly.
SO ORDERED.
Bayer Omnibus Br. at 17 n.9. And, Bayer has noted as to the Denmark group that:
Id.
The Court agrees with Bayer that a complete analysis by Dr. Moyé ought to have at least considered this scholarship, particularly insofar as Etminan is just one of two epidemiological studies (the other being Valenzuela) of Mirena and IIH, and insofar as the Etminan's study's conclusion in the retrospective cohort study was contrary to the interests of the litigation party that had retained Dr. Etminan. However, given Dr. Etminan's unusual and dramatic repudiation of the other half of his study, the Court regards Dr. Moye's decision not to consider any part of the Etminan study as more understandable and defensible than his other methodological failings. The Court's rulings excluding Dr. Moyé and plaintiffs' other proposed general causation experts do not depend on these experts' failure to consider the Etminan retrospective cohort study.