In re Mirena Ius Levonorgestrel-Related Prods. Liab. Litig. (341 F. Supp. 3d 213, 2018)

Paul A. Engelmayer, United States District Judge

This multi-district litigation involves products liability claims regarding a contraceptive product: the Mirenaintrauterine device developed, manufactured, and distributed by defendants Bayer HealthCare 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 Daubert hearing and heard argument as to the admissibility of each expert's testimony as to general causation.

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.

I. Procedural Background

A. Brief History of This Litigation

1. The JPML's Centralization of Mirena IIH Cases Before This Court

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.").

2. Organization of This MDL

In overseeing this action, this Court has given priority to the matters that led the JPML to centralize the Mirena/IIH actions.

Specifically, on June 21, 2017, after appointing plaintiffs' leadership team and reviewing written submissions and eliciting input at an initial conference as to the proper sequencing of proceedings, see generally Dkt. 51 (transcript of June 13, 2017 hearing), the Court issued an order stating that priority would be given to: (1) "the process of providing common fact discovery to plaintiff from Bayer," and (2) "resolving whether plaintiffs have admissible evidence sufficient to establish general causation" by Mirena of IIH. Dkt. 40, at 1 (June 21, 2017). The Court has done so as follows.

Outgoing discovery from Bayer : On July 27, 2017, after receiving submissions delineating the 14 discovery disputes identified by the parties and inquiring about them at a hearing, the Court resolved these disputes in a series of bench rulings. See generally Dkt. 51, at 10-59 (transcript of July 27, 2017 hearing). The Court ordered that Bayer broadly produce written discovery on all common issues, including electronic records from more than 50 Bayer custodians, and including broad production from Bayer's adverse-events database. Both as to custodians and as to search parameters, the common discovery ordered from Bayer extended well beyond the parameters theretofore utilized in the individual cases comprising the MDL. It also substantially exceeded the discovery that Bayer had produced in an immediately prior MDL also relating to the Mirena IUD. See MDL No. 2434 (the "Perforation MDL"). In that case, overseen by the Hon. Cathy Seibel of this District, the plaintiffs had alleged different injuries: that the hormone-release feature of Mirena had caused the IUD to migrate within the uterus after its insertion, leading to uterine perforation and related migration injuries.

General causation : The Court directed that the issue of general causation be litigated in the MDL as a threshold issue. To facilitate that issue's prompt resolution, the Court ordered that all fact discovery relating to general causation-including all document and deposition discovery-be completed by December 8, 2017. Dkt. 62. Alerted by counsel that each side expected to make Daubert challenges to the admissibility of each other's experts on general causation, the Court set deadlines spanning late December 2017 through late March 2018 for the submission of all expert reports on general causation, depositions of general causation experts, and reciprocal Daubert briefing. The Court set for the week of April 9, 2018 a "Science Day" tutorial for the Court on the background scientific issues in the case, followed by a Daubert hearing as to expert testimony on general causation. Id.

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 identical to all potential Mirena/IIH plaintiffs so as make it an appropriate issue for this transferee court to resolve at the threshold. See, e.g. , Dkt. 51, at 29. The Court was also informed by the experience of the Perforation MDL. There, Judge Seibel held that plaintiffs' proposed expert testimony as to the general causation proposition at issue-that the Mirena IUD's release of the hormone LNG was capable of causing the Mirena IUD to migrate after insertion and cause uterine perforation-was not reliable under Daubert . See In re Mirena IUD Prods. Liab. Litig. , 169 F.Supp.3d 396, 427-461 (S.D.N.Y. 2016) (" Mirena Perforation/Daubert "). Based on that ruling, Judge Seibel thereafter granted summary judgment for Bayer on all claims, holding that, without any admissible expert testimony, the remaining evidence was insufficient to establish general causation. See In re Mirena IUD Products Liability Litigation , 202 F.Supp.3d 304, 310-28 (S.D.N.Y. 2016) (" Mirena Perforation/SJ ", aff'd , 713 Fed. Appx. 11 (2d Cir. 2017). The possibility of a similar outcome here, this Court determined, counseled deferring other time- and cost-intensive phases of this litigation pending resolution of the anticipated Daubert motions.

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.

B. The Expert Witnesses at Issue

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.

II. Factual Background

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.

A. Mirena

Mirena is a commonly used type of long-acting reversible contraceptive ("LARC"). There are several different types. Some LARCs are copper intrauterine devices ("IUDs"). Others are subdermal, hormone-releasing implants. Others, of which Mirena is by far the most predominant, are hormone-releasing IUDs. Of these types of LARCs, hormone-releasing implants are generally considered the most effective at preventing conception, followed by hormone-releasing IUDs, followed by copper IUDs. Statistically, all LARCs are far more effective in preventing conception than traditional contraceptive methods such as the Pill or the male condom.

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. SeeMirena 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. SeeMirena 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 clearance of hepatically metabolized drugs, increases circulating blood volume, and increases absorption of contraceptive steroids by adipose tissue"); id. ("[T]he pharmacokinetics of steroid hormones appear to be altered in obese oral contraceptives users compared with normal weight users."); Mary L. Marnach, et al., Current issues in contraception , 88 Mayo Clin Proc. 295, 297 (2013) (Dkt. 167-43) ("Progestogen-only and non-hormonal contraceptives are preferred methods of contraception for women who are obese."); see generally Centers for Disease Control and Prevention, US medical eligibility criteria for contraceptive use, 2016 , Morbidity and Mortality Weekly Report (July 29, 2016) (Dkt. 167-77); Darney Dep. at 99-100.

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.").

B. Levonorgestrel

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 to the analyses of the plaintiff experts, who theorize scientific mechanism(s) by which Mirena can cause IIH.

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").

C. Idiopathic Intracranial Hypertension

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 ("[C]erebrospinal fluid dynamics and homeostatis in PTCS are complex and incompletely understood."); Ball & Clark, supra , at 435 ("The pathophysiology underlying the raised intracranial pressure is unclear."); Cestari Rpt. at 9 (canvassing alternative theories and noting that "[t]he mechanism by which excess weight and weight gain increase the risk for IIH is [also] poorly understood"); see also Bayer Omnibus Br. at 2 n.1 (quoting scholarly literature sources cited by plaintiffs' experts to the effect, inter alia , that IIH's pathogenesis "is currently unknown," that its "pathogenesis remains a mystery," that its "underlying pathogenesis is uncertain," and that "IIH is a disorder of unclear pathophysiology") (citations omitted).

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 per year out of a population of 100,000. See, e.g. , Giuseffi, supra , at 239; Ball & Clark, supra , at 433 (canvassing studies reporting incidences of IIH of between 0.03 per 100,000 and 2.2 per 100,000); Cestari Rpt. at 3 (0.9 cases per 100,000 population); Fraunfelder Rpt. at 5. As reviewed infra , IIH differentially affects certain demographic groups. Relevant here, IIH occurs by far most commonly-and its incidence is far greater-among women of child-bearing age, and in particular among overweight and obese such women.

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.

D. Incidence of, and Risk Factors for IIH

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"). More recently, however, the cause or causes of the elevated CSF pressure in the skull that marks IIH have proven elusive to scientists. Their inquiries have been complicated by factors including the rarity of the condition and, as discussed infra , the practical inability to study causation using randomized, prospective trials involving control groups.

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 has been calculated as some 6.5 times that of women of normal weight. Calculations on this point vary among the scientific literature, but in general, researchers describe IIH's incidence among obese women as between approximately 15 and 22 cases per 100,000 population, and as particularly affecting women who have recently gained weight. This literature also describes IIH's incidence as rising over time in the United States as the nation's population has become more obese. See, e.g. , Anthony B. Daniels, et al., Profiles of obesity, weight gain and quality of life in idiopathic intracranial hypertension (pseudotumor cerebri ) , 143 Am. J. Ophthalmology 635, 637 & n.1 (2007) (Dkt. 167-22) (noting that IIH "tends to occur in young women of childbearing age"; "the strongest evidence for association exists for obesity and weight gain"); see also Giuseffi, supra , at 239; Ball & Clark, supra , at 433, 440 (reporting 15 to 19 IIH cases per 100,000 women who are 20% or more above their normal body weight; IIH's "association with female sex and obesity is striking"); McGeeney & Friedman, supra , at 445 (reporting 11.9 IIH cases per 100,000 obese women; "studies have confirmed that the vast majority of patients with IIH are obese women of child-bearing age"); Chen & Wall, supra , at 2 (reporting 19 IIH cases per 100,000 obese women); see also Bayer BfArM response, supra (reporting more than 20 IIH cases per 100,000 obese women); Cestari Rpt. at 3 (reporting 19.3 IIH cases per 100,000 obese women); Fraunfelder Rpt. at 5 (reporting 11.9 to 21.4 IIH cases per 100,000 population); Moyé Rpt. at 27 (reporting 22 IIH cases per 100,000 obese 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.

E. Studies and Data, Outside of this Litigation, Bearing on Whether Use of Mirena Causes IIH

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.

Various of these experts also draw upon case reports made to Bayer of "adverse events." The subset of Bayer's "adverse events" database relating to Mirena and IIH was made available in discovery during this MDL.

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.

1. Categories of Studies Generally

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).

Randomized control trials : A randomized control study is widely considered the gold standard of human studies. Such a study consists of a "true clinical experiment in which an intervention is compared with a standard treatment, no treatment, or a placebo, with allocation to treatment by chance." Leon Speroff & Philip D. Darney, A Clinical Guide for Contraception 429 (5th ed. 2011) (Dkt. 167-62) ("Speroff & Darney"). Such experiments are often used to test possible treatments for a disease. The hallmarks of a classic clinical trial include a contemporary control group, the allocation of participants so as to assure that participant characteristics are distributed evenly across the treatment and placebo groups, and blinded as to both participants and investigators. These features enable researchers, inter alia , to control for known and unknown confounding factors. However, in the context of testing the capacity of a drug to cause a disease, randomized control studies are often unattainable in practice. Constraints presented by norms of medical ethics may preclude certain tests. And, in the context of rare ailments, such a study might have to be impracticably large to yield statistically significant results, particularly where confounding factors are present. See, e.g. , Moyé Rpt. at 12, 15-16.

Epidemiological studies : Epidemiology is the study and analysis of the distribution and determinants of health and disease conditions in defined populations. The two most common types of epidemiological studies are cohort observational studies and case-controlled observational studies.

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 controlling for potential confounding factors. Addressing such factors calls for intelligent study design and/or rigorous statistical analysis of results. See id. at 431.

Anecdotal evidence/case reports : Anecdotal evidence in cases involving claims that a drug caused a disease usually takes the form of "case reports." A case report is a report of an individual incident or episode, generally keyed to a specific user of a drug, "that serves to bring attention to a possible problem or condition." Id. at 430.

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. See, e.g. , Darney Dep. at 206 ("[C]ase reports cannot establish causation."); id. at 144 (noting that the "principal use" of case reports is "to generate a hypothesis for epidemiologic ... investigation"); Moyé Rpt. at 21 ("[I]t is the rare case report that demonstrates causality in and of itself"; case reports are "essential to the causation process" because they "demonstrate what is possible"); Moyé Dep. at 131 ("[C]ase reports are not even sufficient to show association because there is no comparison group."); Plunkett Dep. at 184 (noting case reports "show[ ] associations, not general cause"); Wheeler Dep. at 206 ("[A]dverse event data cannot be used to establish causation" and "the proper use of adverse event report data is ... hypothesis generating ...."); cf. Fraunfelder Rpt. at 8 (observing that case reports may serve as "signals," defined as "reported information on a possible causal relationship between an adverse event and a drug").

Animal studies : Animal studies can sometimes be used to test a causal connection between a drug and a disease. Advantages of animal studies include the fact that, because fewer ethical constraints apply to such studies, these can be "conducted as true experiments." Michael D. Green, et al., Reference Guide on Epidemiology, in Reference Manual on Scientific Evidence 549, 563 (Fed. Jud. Ctr., 3d ed. 2000). But animal studies have several disadvantages. One is that it may be difficult to extrapolate from such studies to the context of humans. Another "difficulty with inferring human causation from animal studies is that the high doses customarily used in animal studies require consideration of the dose-response relationship and whether a threshold no-effect dose exists." Id. at 345-46. Animal studies are of limited relevance in this case, in that no such study has assessed whether LNG (however administered) causes IIH. The animal studies cited by the parties (involving other hormones) instead relate to discrete steps in longer biological chains of causation posited by individual experts who opine as to possible mechanisms by which Mirena might cause IIH.

2. Studies and Case Reports Regarding Mirena

a. Randomized Control Trials

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.

b. Epidemiological Studies

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.

(i) The Etminan study

2015-Etminan's initial study : Etminan's study was published in 2015 in the Journal of Therapeutic Advances in Drug Safety. See Mahyar Etminan, et al., Risk of intracranial hypertension with intrauterine levonorgestrel , 6 Therapeutic Advances in Drug Safety 110 (2015) (Dkt. 167-27) ("Etminan" or the "Etminan study"). At the time that he published the study, Dr. Etminan was serving as a retained expert for plaintiffs in the pre-MDL Mirena/IIH litigation. The Etminan study did not disclose this relationship. The study declared in its "conflict of interest statement" that the authors did not have any conflict of interest to declare. Id. at 113.

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 opined that this finding was statistically significant. Id. at 112.

The second analysis consisted of a retrospective cohort study. It compared the risk of intracranial hypertension between, on the one hand, LNG-releasing IUDs, and, on the other hand, two combination oral contraceptives that did not contain LNG: ethinyl estradiol (EE) and norethindrone and EE-norgestimate. Id. at 111. The study drew upon a large health claims database, IMS LifeLink, which contained more than 102 healthcare plans. This comparison was undertaken, Etminan stated, because "[o]ral and intramuscular contraceptives including progestins have been linked to [intracranial hypertension ]." Id. at 112. This second analysis did not find any difference in the risk of IIH between users of EE-norgestimate and Mirena. Id. It found, in fact, a lower risk of IIH for users of EE-norethindrone relative to users of Mirena, although it concluded that that result was not statistically significant. Id.

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.

2016-Dr. Friedman's critique : In 2016, the Etminan study came under attack. Dr. Deborah Friedman, the author of various studies relating to IIH, published, in the same journal as the Etminan study, a letter critiquing on multiple grounds the Etminan study's methodology. Centrally, she noted that Etminan's disproportionality analysis-the part of his study that had pointed to an increased IIH risk for Mirena uses-had failed to adjust for age and gender, thus comparing Mirena patients (reproductive-age females) to populations like older men who almost never get IIH. Friedman termed the Etminan study's conclusions "erroneous and misleading." See Deborah Friedman, Risk of intracranial hypertension with intrauterine levonorgestrel , 7 Therapeutic Advances in Drug Safety 23, 23 (2016) (Dkt. 213-7) ("Friedman Letter").

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. Etminan's cohort study was also faulty, Friedman wrote, because it did not include a control group of women who were not using the hormonal contraceptives at issue, or any such contraceptives at all. Id. at 24. The study, she stated, had not found a statistically significant difference in the development of IIH between users of the two oral contraceptives and Mirena. Further, it had failed to assess whether the rate among users of Mirena"is higher than would be expected in their population sample in general." Id. She noted that no published evidence had shown a causal relationship between IIH and hormonal contraception. Id.

2016-Dr. Etminan's letter response : In 2016, Dr. Etminan published a brief (1.5 page) letter response to Friedman's letter. That letter, Dr. Etminan acknowledged, had raised "some questions." See Mahyar Etminan, Risk of intracranial hypertension with intrauterine levonorgestrel : reply , 7 Therapeutic Advances in Drug Safety (2016) (Dkt. 167-28) ("Etminan Letter").

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. Finally, Dr. Etminan disputed "that there are no epidemiological studies linking hormonal contraceptives to intracranial hypertension." He noted two studies (from 1990 and 1993) that he acknowledged "lacked statistical power," and a 2015 case-control study (a study by Rai, et al. , that previewed the Valenzuela study addressed infra ) that, Etminan stated, had found a statistically significant increase in IIH among women with intrauterine LNG use compared to nonusers, but which, Dr. Etminan acknowledged, did "not seem to have adjusted for body mass index (BMI), a major confounder for this question." Id.

2016-Dr. Etminan's affidavit repudiating his findings : Later in 2016, Dr. Etminan changed course. He repudiated much of his study's analysis. On December 17, 2016, after being served with a notice of a deposition in a lawsuit against Bayer that is now part of this MDL, Dr. Etminan furnished to counsel for Bayer a sworn affidavit retracting many of his study's findings. See Dkt. 167-29 ("Etminan Affidavit").

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

did not limit the groups compared in the FAERS DPA to reproductive age females. Because the background incidence of intracranial hypertension is higher in reproductive age females than in other demographic groups, failing to limit the comparator group to reproductive age females can artificially inflate the ROR for Mirena, as almost all Mirena users are reproductive age females. Therefore, a proper analysis would be limited to women of reproductive age.

Id. ¶ 6. And, Dr. Etminan stated, the study's DPA analysis might separately be flawed in that:

I do not know if my analyst used unique cases, or instead used unique reports, for the FAERS DPA. Because the same individual case can have multiple unique reports filed in the FAERS database, using unique reports can result in individual cases being counted more than once in the analysis. The proper analysis should use unique cases, not unique reports.

Id. ¶ 7. In sum, Dr. Etminan stated, as to his study's DPA analysis:

I have no basis to say that the results of the FAERS DPA would have been statistically significant, or that the point estimate would have been greater than 2.0, had the control group been properly limited to reproductive age females and had the analysis properly used unique cases rather than unique reports. Indeed, rerunning DPA analysis of the FAERS data using OpenVigil 2.1 software and properly limiting it to unique cases and women of reproductive age results in no elevated ROR for Mirena, suggesting that intracranial hypertension and Mirena use are "likely not related."

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.

Based on the above, as the lead author of this article, I acknowledge that neither of the analyses in the article provide evidence that Mirena use increases the risk for intracranial hypertension . Therefore, there is no basis to say, based on these analyses, that the risk of intracranial hypertension with Mirena use outweighs the risk of unplanned pregnancies.

Id. ¶ 11 (emphasis added).

2017-Dr. Etminan's letter repudiating his findings : In April 2017, Dr. Etminan submitted another letter to the editor. See Mahyar Etminan, Revised disproportionality analysis of Mirena and benign intracranial hypertension , 8 Therapeutic Advances in Drug Safety 299, 299-300 (2017) (Dkt. 167-30) ("Etminan Second Letter"). The letter largely reprised the points Dr. Etminan had made in his affidavit. It acknowledged that both of his 2015 analyses had failed to "control[ ] for reproductive age[,] which has a strong correlation with [IIH]." Id. at 1. In this 2017 letter, Dr. Etminan added: "[A]n unstratified analysis by reproductive age can artificially overestimate the risk of [IIH] with Mirena." Id. at 1 (illustrating the point with data). And he further conceded, "Based on the age-restricted analysis a signal is not detected with Mirena with respect to [IIH] when child bearing age is accounted for." Id. (emphasis added).

(ii) The Valenzuela study

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 levonorgestrelintrauterine 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 ), whether the use of such IUDs was associated with an increased risk of IIH, and whether IIH patients who used such IUDs had signs or symptoms different from those observed in IIH patients who did not use such IUDs. Id. at 1-2. Towards this end, the study compared the incidence of IIH among reproductive age women who used LNG-releasing IUDs with the incidence of IIH among reproductive age women who were not using LNG-releasing IUDs. Id. at 2.

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:

Our investigation does not indicate that an LNG-IU[D] [such as Mirena ] can cause PTC, and the number of women with an LNG-IU[D] was too small to determine if an LNG-IU[D] is an independent risk factor for PTC. Although use of an LNGIU[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 established risk factors that are known to be associated with PTC (e.g., obesity and recent weight gain). This 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.

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. The other

is that LNG does not cause increased intracranial hypertension, but that the PTC is more likely to occur in the same population of women who are more likely to have an LNG-IU[D] recommended to them by their physician. LNG-IU[D] is often, although not exclusively, recommended for women who may have difficulty with other forms of contraception. For instance, women with obesity, headache, and/or polycystic ovarian syndrome are more likely to be intolerant to oral contraceptives. For this group of women, LNG-IU[D] may be better tolerated as a form of contraception. This same group of women, with obesity, headache, and polycystic ovarian syndrome, are also more likely to develop PTC. When interpreting the findings presented here, it is also important to consider that the risk analysis does not account for potential confounders.

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]

should still be considered as an effective form of contraception." Id. at 6.

c. Case and Adverse Event Reports

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 levonorgestrelintrauterine 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 set in support of their conclusions. See, e.g. , Darney Rpt. at 24; Fraunfelder Rpt. at 17-24; Moyé Rpt. at 34-37; Plunkett Rpt. at 28, 34; Salpietro Rpt. at 30; Wheeler Rpt. at 39.

3. Studies of Other LNG-Based Contraceptive Devices

The Court next summarizes the existing studies and data bearing on the relationship between other LNG-based contraceptives and IIH.

a. Combined Oral Contraceptives

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. LNG-containing oral contraceptives result in a substantially higher rate of LNG circulating in the user's blood stream than does Mirena. See Plunkett Rpt. at 22 and Plunkett Dep. at 94 (noting that LNG-containing oral contraceptives have LNG levels between 3,000-6,000 pg/ml, some 20-30 times more than in Mirena).

All five studies failed to find a causal link. Two of plaintiffs' experts, Drs. Fraunfelder and Darney, in fact, have acknowledged that science has largely disproven a link between IIH and combined oral contraceptives containing LNG. See Fraunfelder Dep. at 16 (agreeing that "an association between oral contraceptives and IIH has been largely disproven"); Darney Dep. at 43 ("My opinion is that [oral contraceptives] do not [cause IIH]."). Bayer's experts similarly assess the state of such research. See, e.g. , Cestari Rpt. at 11 ("This lack of an association has been consistently confirmed ....")

b. Norplant

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 MedWatch Spontaneous Reporting System , 85 Obstet Gynecology 538, 540 (1995) (Dkt. 167-67) ("Wysowski & G