In re Abilify (Aripiprazole) Prods. Liab. Litig.
This text of 299 F. Supp. 3d 1291 (In re Abilify (Aripiprazole) Prods. Liab. Litig.) is published on Counsel Stack Legal Research, covering District Court, N.D. Florida primary law. Counsel Stack provides free access to over 12 million legal documents including statutes, case law, regulations, and constitutions.
Opinion
M. CASEY RODGERS, CHIEF UNITED STATES DISTRICT JUDGE
This is a multidistrict product liability action against the manufacturers and marketers of the prescription drug Aripiprazole, more commonly known as Abilify.2 Plaintiffs allege that, after taking Abilify as prescribed, they developed impulsive and irrepressible urges to engage in certain harmful behaviors, including impulsive gambling, eating, shopping, and sex.3 Defendants *1301deny the allegations and maintain that Abilify could not, and did not, cause Plaintiffs' impulse control problems.
Defendants have moved for summary judgment on the issue of general causation-that is, whether Abilify is capable of causing uncontrollable impulses to engage in certain harmful behaviors. See ECF No. 428. Both the motion, see id. , and the response, see ECF No. 463, are supported by expert testimony. Each side challenges the other's experts as unreliable and those motions are also pending.4 A four-day evidentiary hearing was conducted jointly with Magistrate Judge Gary R. Jones of this Court, and Judge James J. Deluca of the New Jersey Superior Court, who presides over multiple similar cases in New Jersey state court. Now, having carefully considered the law, the voluminous record, and the parties' arguments, the Court concludes that Plaintiffs have satisfied their burden to demonstrate that a genuine dispute of material fact exists as to whether Abilify can cause uncontrollable impulsive behaviors in individuals taking the drug.
I. Background
Abilify is an atypical antipsychotic drug developed and manufactured by Defendants Otsuka Pharmaceutical Co., Ltd. and Otsuka America Pharmaceutical, Inc., who jointly market and distribute it in the United States with Defendant Bristol-Myers Squibb Company (collectively, "Defendants"). See Master Complaint, ECF No. 108-1 at 5.5 In 2002, Abilify was approved by the Food and Drug Administration ("FDA") for the treatment of schizophrenia. Since then, Abilify also has been approved for use in patients with bipolar disorder, irritability associated with autistic disorder, Tourette's Syndrome, and as an add-on treatment for major depressive disorder. See Product Label, ECF No. 428-1 at 2. "[T]ens of millions of patients worldwide have used Abilify to help manage the symptoms of these very debilitating mental health conditions." See DSJ, ECF No. 428-26 at 9.6
In 2010, the first published reports suggesting a possible link between Abilify and pathological gambling began appearing in the medical literature. More published reports followed, as well as hundreds of informal reports from patients and healthcare professionals to Defendants and the FDA, describing the onset of impulsive gambling and other impulse control disorders in patients treated with Abilify. The scientific community, the FDA, Defendants, and public health agencies worldwide took notice and began examining whether Abilify is linked to impulse control disorders. The research findings and conclusions of these bodies are at the heart of the motions currently pending before this Court.
*1302In 2012, following a safety review of Abilify based on reports of pathological gambling with patients' use of the drug, the European Medicines Agency ("EMA") required Defendants to modify the drug's product label in Europe to include pathological gambling as a possible "post-marketing undesirable effect" of Abilify and to warn of an "increased risk" of pathological gambling in Abilify patients with a prior history of gambling.7 See FDA Pharm. Vigil., ECF No. 428-11 at 5, 12.8 In November 2015, Health Canada also found an "increased risk" of pathological gambling, as well as hypersexuality, with Abilify use and ordered that the drug's product monograph in Canada be updated to advise of these possible adverse effects.9 See id. at 5, 12. Health Canada's safety review and subsequent product monograph update prompted the FDA to initiate a pharmacovigilance review in the United States to evaluate whether the potential link between Abilify and impulse control disorders presented a "safety issue warrant[ing] any regulatory action." See id. at 5. The FDA's review identified an association between Abilify and impulse control disorders, based on an analysis of cases in its adverse event reporting database (FAERS), the published scientific literature, and Defendant's clinical trial and post-marketing patient data.10 See id. at 4, 29. On May 3, 2016, the FDA issued a safety warning that "uncontrollable and excessive urges" to "gamble, binge eat, shop and have sex" had been reported with the use of Abilify, even in patients with no prior history of impulsive behaviors.11 In August 2016, the FDA required Defendants to modify Abilify's product label in the United States to warn of "post-marketing case reports suggest[ing] that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking" the drug. See Product Label, ECF No. 428-1 at 2, 24. The United States product label was also modified to warn of "[o]ther compulsive urges, reported less frequently, [which] include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors." See id. At that point, Abilify had been on the market in the United States for almost 14 years.
A short biochemistry discussion may be helpful at this point.12 The human brain is a tremendously complex biochemical system. It contains billions of interconnected nerve cells, called neurons, that use chemical *1303and electrical signals to send information throughout the body. The function of a neuron is to process and transmit information-it receives signals from other neurons, integrates and interprets those signals, and transmits signals to other, adjacent neurons. The signals within neurons are carried throughout the brain in the form of electrical impulses. When a signal is sent from one neuron to another, it must cross a microscopic gap between the two communicating neurons. This gap is called a synapse or synaptic cleft. At the synapse, the electrical signal within the neuron is converted to a chemical signal and sent across the synapse towards the receiving neuron.13 This chemical signal is transported by molecules, called neurotransmitters, that attach to special structures on the outer surface of the receiving neuron, called receptors.14 There are many different types of receptors, categorized by the type of neurotransmitters with which they interact. The attachment of neurotransmitters to receptors can either stimulate or inhibit electrical activity in the receiving neuron, depending on which neurotransmitter is released and which receptors it activates. In any one synapse, there may be hundreds of neurotransmitters continually moving between, and acting on, neurons, triggering varying physiological effects throughout the brain and the body.
Free access — add to your briefcase to read the full text and ask questions with AI
M. CASEY RODGERS, CHIEF UNITED STATES DISTRICT JUDGE
This is a multidistrict product liability action against the manufacturers and marketers of the prescription drug Aripiprazole, more commonly known as Abilify.2 Plaintiffs allege that, after taking Abilify as prescribed, they developed impulsive and irrepressible urges to engage in certain harmful behaviors, including impulsive gambling, eating, shopping, and sex.3 Defendants *1301deny the allegations and maintain that Abilify could not, and did not, cause Plaintiffs' impulse control problems.
Defendants have moved for summary judgment on the issue of general causation-that is, whether Abilify is capable of causing uncontrollable impulses to engage in certain harmful behaviors. See ECF No. 428. Both the motion, see id. , and the response, see ECF No. 463, are supported by expert testimony. Each side challenges the other's experts as unreliable and those motions are also pending.4 A four-day evidentiary hearing was conducted jointly with Magistrate Judge Gary R. Jones of this Court, and Judge James J. Deluca of the New Jersey Superior Court, who presides over multiple similar cases in New Jersey state court. Now, having carefully considered the law, the voluminous record, and the parties' arguments, the Court concludes that Plaintiffs have satisfied their burden to demonstrate that a genuine dispute of material fact exists as to whether Abilify can cause uncontrollable impulsive behaviors in individuals taking the drug.
I. Background
Abilify is an atypical antipsychotic drug developed and manufactured by Defendants Otsuka Pharmaceutical Co., Ltd. and Otsuka America Pharmaceutical, Inc., who jointly market and distribute it in the United States with Defendant Bristol-Myers Squibb Company (collectively, "Defendants"). See Master Complaint, ECF No. 108-1 at 5.5 In 2002, Abilify was approved by the Food and Drug Administration ("FDA") for the treatment of schizophrenia. Since then, Abilify also has been approved for use in patients with bipolar disorder, irritability associated with autistic disorder, Tourette's Syndrome, and as an add-on treatment for major depressive disorder. See Product Label, ECF No. 428-1 at 2. "[T]ens of millions of patients worldwide have used Abilify to help manage the symptoms of these very debilitating mental health conditions." See DSJ, ECF No. 428-26 at 9.6
In 2010, the first published reports suggesting a possible link between Abilify and pathological gambling began appearing in the medical literature. More published reports followed, as well as hundreds of informal reports from patients and healthcare professionals to Defendants and the FDA, describing the onset of impulsive gambling and other impulse control disorders in patients treated with Abilify. The scientific community, the FDA, Defendants, and public health agencies worldwide took notice and began examining whether Abilify is linked to impulse control disorders. The research findings and conclusions of these bodies are at the heart of the motions currently pending before this Court.
*1302In 2012, following a safety review of Abilify based on reports of pathological gambling with patients' use of the drug, the European Medicines Agency ("EMA") required Defendants to modify the drug's product label in Europe to include pathological gambling as a possible "post-marketing undesirable effect" of Abilify and to warn of an "increased risk" of pathological gambling in Abilify patients with a prior history of gambling.7 See FDA Pharm. Vigil., ECF No. 428-11 at 5, 12.8 In November 2015, Health Canada also found an "increased risk" of pathological gambling, as well as hypersexuality, with Abilify use and ordered that the drug's product monograph in Canada be updated to advise of these possible adverse effects.9 See id. at 5, 12. Health Canada's safety review and subsequent product monograph update prompted the FDA to initiate a pharmacovigilance review in the United States to evaluate whether the potential link between Abilify and impulse control disorders presented a "safety issue warrant[ing] any regulatory action." See id. at 5. The FDA's review identified an association between Abilify and impulse control disorders, based on an analysis of cases in its adverse event reporting database (FAERS), the published scientific literature, and Defendant's clinical trial and post-marketing patient data.10 See id. at 4, 29. On May 3, 2016, the FDA issued a safety warning that "uncontrollable and excessive urges" to "gamble, binge eat, shop and have sex" had been reported with the use of Abilify, even in patients with no prior history of impulsive behaviors.11 In August 2016, the FDA required Defendants to modify Abilify's product label in the United States to warn of "post-marketing case reports suggest[ing] that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking" the drug. See Product Label, ECF No. 428-1 at 2, 24. The United States product label was also modified to warn of "[o]ther compulsive urges, reported less frequently, [which] include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors." See id. At that point, Abilify had been on the market in the United States for almost 14 years.
A short biochemistry discussion may be helpful at this point.12 The human brain is a tremendously complex biochemical system. It contains billions of interconnected nerve cells, called neurons, that use chemical *1303and electrical signals to send information throughout the body. The function of a neuron is to process and transmit information-it receives signals from other neurons, integrates and interprets those signals, and transmits signals to other, adjacent neurons. The signals within neurons are carried throughout the brain in the form of electrical impulses. When a signal is sent from one neuron to another, it must cross a microscopic gap between the two communicating neurons. This gap is called a synapse or synaptic cleft. At the synapse, the electrical signal within the neuron is converted to a chemical signal and sent across the synapse towards the receiving neuron.13 This chemical signal is transported by molecules, called neurotransmitters, that attach to special structures on the outer surface of the receiving neuron, called receptors.14 There are many different types of receptors, categorized by the type of neurotransmitters with which they interact. The attachment of neurotransmitters to receptors can either stimulate or inhibit electrical activity in the receiving neuron, depending on which neurotransmitter is released and which receptors it activates. In any one synapse, there may be hundreds of neurotransmitters continually moving between, and acting on, neurons, triggering varying physiological effects throughout the brain and the body. Any disruption to the neuronal communication process-whether to the production, release, or attachment of the various neurotransmitters-can alter brain function and, as it relates to this case, human behavior.
Dopamine is a neurotransmitter in the central nervous system that is believed to play an integral role in a number of physiological processes, including movement, cognition, emotional stability, and, relevant to this case, reward-motivated behaviors. It acts on five different receptors-D1, D2, D3, D4, and D5-along four major pathways in the brain-the nigrostriatal pathway, the mesocortical pathway, the mesolimbic pathway, the tuberoinfundibular pathway.15 This case is primarily concerned with the activity of dopamine in the mesolimbic pathway, which regulates pleasure, reward processing, and motivation. Under normal circumstances, the brain responds to rewarding activities or stimuli by releasing dopamine into the mesolimbic pathway, where it binds with dopamine receptors to produce feelings of pleasure. As dopamine levels subside, so do the feelings of pleasure. If the rewarding activity is repeated, then dopamine is again released, and more feelings of pleasure are produced. The release of dopamine and the resulting pleasurable feelings serve as positive reinforcements that motivate repetition of the pleasure-inducing activity.
Pharmaceutical companies create drugs that can mimic, duplicate, or block the activity of natural, or "endogenous," dopamine in the brain. The effect of a given drug depends on two pharmacological properties that relate to the manner in which the drug interacts with dopamine receptors: affinity and intrinsic activity. Affinity refers to whether and how tightly the drug binds to dopamine receptors. Intrinsic *1304activity refers to the degree to which the drug, once bound, activates dopamine receptors to produce a measurable physiological effect. Based on these properties, drugs that bind to dopamine receptors can act as agonists or antagonists. A full agonist has both high affinity and 100% intrinsic activity, meaning that it binds tightly to dopamine receptors and mimics the activity of dopamine, producing the same level of physiological response that dopamine naturally produces. Antagonists bind to dopamine receptors, but produce no physiological effects; instead, they simply occupy a receptor site, thereby preventing endogenous dopamine from binding to and activating it. A partial agonist binds to dopamine receptors, but produces less of a response than a full agonist. The functional activity of some partial agonists depends on the presence or absence of endogenous dopamine in the surrounding area. Where dopamine concentrations are high, the partial agonist functions as an antagonist (i.e. , functional antagonist), but where dopamine concentration is low, the partial agonist functions as a full agonist (i.e. , functional agonist). In this case, Plaintiffs' position as to how Abilify causes impulse control problems centers on how the drug binds and interacts with two dopamine receptors-D2and D3-to produce physiological effects in the form of impulsive behaviors.
II. Expert Challenges
To establish general causation, Plaintiffs have proffered the testimony of five experts: Dr. Antoine Bechara, Dr. Joseph Glenmullen, Dr. Eric Hollander, Dr. Russell V. Luepker, and Dr. David Madigan. Simply stated, each of Plaintiffs' experts opines that Abilify can cause impulsive behaviors and each presents scientific evidence in support of his conclusion. Defendants challenge the admissibility of Plaintiffs' expert testimony on general causation as unreliable under Federal Rule of Evidence 702 and Daubert v. Merrell Dow Pharmaceuticals, Inc. ,
A. Legal Standard for Expert Testimony
Rule 702, as explained by Daubert and its progeny, governs the admissibility of expert testimony. Rink v. Cheminova, Inc. ,
To meet the qualification requirement, a party must show that its expert has sufficient "knowledge, skill, experience, training, or education to form a reliable opinion about an issue that is before the court." Hendrix ex.Rel. G.P. v. Evenflo Co., Inc. ,
To meet the reliability requirement, an expert's opinion must be based on scientifically valid principles, reasoning, and methodology that are properly applied to the facts at issue. Frazier ,
Finally, to satisfy the helpfulness requirement, expert testimony must be relevant to an issue in the case and offer insights "beyond the understanding and experience of the average citizen." United States v. Rouco ,
When scrutinizing the reliability and relevance of expert testimony, a court must remain mindful of the delicate balance between its role as a gatekeeper and the jury's role as the ultimate factfinder. Frazier ,
*1306B. Reliability of Expert Testimony on General Causation
To prevail in a pharmaceutical products liability case, a plaintiff must establish both general and specific causation through reliable expert testimony.16 Chapman v. Procter & Gamble Distributing, LLC ,
The Eleventh Circuit has developed an extensive body of Daubert jurisprudence around the reliability of different categories of scientific evidence that may support an expert opinion on general causation. The Eleventh Circuit considers three "primary" methodologies "indispensable" for proving that a drug can cause a specific adverse effect: epidemiological studies, dose-response relationship, and background risk of disease. Chapman ,
In this case, the parties' experts offer various combinations of primary and secondary methodologies in support of their general causation opinions. To frame the Court's analysis of the expert opinions, a brief review of the scientific and legal principles governing the reliability of each methodology follows.
1. Primary Methodologies
a. Epidemiological Studies
The "best evidence of causation in toxic tort actions" is grounded in epidemiology, Rider v. Sandoz Pharmaceuticals Corp. ,
This causation inquiry is guided by nine well-established factors, known in the scientific community as the Bradford Hill factors.19 These include: (1) temporal relationship; (2) strength of the association; (3) dose-response relationship; (4) replication of the findings; (5) biological plausibility; (6) consideration of alternative explanations; (7) cessation of exposure; (8) specificity of the association; and (9) consistency with other knowledge. See Ref. Man. at 599-600. No one factor is dispositive. Id. at 600. Determining whether an association is causal is a matter of scientific judgment, and scientists reliably applying the Bradford Hill factors may reasonably come to different conclusions about whether a causal inference may be drawn. Milward v. Acuity Specialty Products Group, Inc. ,
An epidemiological study identifying a statistically significant association between the use of a drug and a particular adverse effect, accompanied by a reliable expert opinion that the association is causal, is "powerful" evidence of general causation. See Rider ,
b. Dose-Response Relationship
Another primary methodology for establishing causation is through evidence of a dose-response relationship, which is a "relationship in which a change in amount, intensity, or duration of exposure to [a drug] is associated with a change-either an increase or decrease-in risk of" adverse effects from that exposure. McClain v. Metabolife Int'l, Inc. ,
c. Background Risk
A reliable methodology also should take into account the background risk for the disease at issue in the case. McClain ,
2. Secondary Methodologies
a. Biological Plausibility
Biological plausibility refers to a credible scientific explanation of the physiological processes or mechanisms by which a drug can cause a particular disease or adverse effect, based on current biological and pharmacological knowledge. See Ref. Man. at 604; see also McClain ,
*1309b. Case Studies and Adverse Event Reports
Case studies document medical observations occurring coincident with the use of a prescription drug either by a single patient (a case report) or a small number of patients (a case series). Rider v. Sandoz Pharmaceuticals Corp. ,
One type of case report is more worthy of consideration in the general causation assessment, however. This report documents a patient's dechallenge and rechallenge events while taking a particular drug. A dechallenge event occurs where a patient's adverse side effects partially or completely disappear once the drug is stopped. Rider ,
Adverse event reports describe medical events that occurred during or after an individual's use of a prescription drug, which are submitted directly to the FDA by patients, healthcare professionals, and drug manufacturers.21 See
*1310McClain ,
c. In vivo and In vitro Studies
Toxicological knowledge often derives from in vivo studies, in which laboratory animals are exposed to a particular drug, with the outcomes monitored and compared to those for an unexposed control group.23 Ref. Man. at 639. In vivo studies offer a number of advantages, including that they can be conducted as true experiments, with exposure controlled and measured, they are replicable, they usually follow a generally accepted methodology, and they present fewer ethical limitations than human experimentation. See id. at 563; see also In re Paoli R.R. Yard PCB Litigation ,
These limitations apply with equal force to in vitro studies, which analyze the effects of drugs on human and animal cells, organs, or tissue cultures in a controlled laboratory setting. See Ref. Man. at 639. Observations about a drug's mechanism of action may be more readily gleaned from in vitro studies than from other sources, but the chemical reactions that occur in the artificial environment of a test tube or petri dish may differ from how the drug will react in, and impact, the complex biological system that is the human body. Ref. Man. at 564; Accutane ,
*1311d. Analogous Drugs
In analyzing causation, scientists sometimes draw from existing studies conducted on other drugs in the same class as, or which have a similar chemical structure to, the particular drug at issue in a case. See McClain ,
3. Weight of the Evidence
The preceding sections addressed the extent to which individual categories of scientific evidence may support an expert opinion on general causation in the Eleventh Circuit. In practice, however, many experts form a general causation opinion by weighing an entire body of scientific evidence. This "weight of the evidence" approach to analyzing causation can be considered reliable, provided the expert considers all available evidence carefully and explains how the relative weight of the various pieces of evidence led to his conclusion. See Milward ,
(1) identify an association between an exposure and a disease, (2) consider a range of plausible explanations for the association, (3) rank the rival explanations according to their plausibility, (4) seek additional evidence to separate the more plausible from the less plausible explanations, (5) consider all of the relevant available evidence, and (6) integrate the evidence using professional judgment to come to a conclusion about the best explanation.
Milward ,
C. Reliability of Common Evidence of General Causation
Plaintiffs' experts, each to a greater or lesser extent, rely on much of the same evidence to conclude that Abilify can cause impulsive gambling and other impulse control disorders. The Court addresses the reliability of the common evidence together in this section. In Section II(D), the Court addresses Defendants' expert-specific objections to Drs. Bechara, Glenmullen, Hollander, Luepker, and Madigan.
1. Epidemiological Evidence-The Etminan Study24
Three of Plaintiffs' experts-Drs. Glenmullen, Hollander, and Madigan-base their opinions, in part, on an epidemiological study published by Dr. Mahyar Etminan and Dr. Ric M. Procyshyn in February 2017, in which a statistically significant association was found to exist between Abilify and impulse control disorder, and also between Abilify and gambling disorder ("Etminan Study"). See Mahyar Etminan, Risk of Gambling Disorder and Impulse Control Disorder with Aripiprazole, Pramipexole, and Ropinirole , 37 J. CLINICAL PSYCHOPHARMACOLOGY 1 (2017), ECF No. 428-13.25 The Etminan Study is the only epidemiological study conducted to date that analyzes whether Abilify is associated with an increased risk of gambling and impulse control disorder.26 Defendants *1313challenge the reliability of the Etminan Study on multiple grounds, arguing that it is "so riddled with flaws as to be inherently unreliable." See ECF No. DSJ, 428-26 at 45. The Court disagrees and, for the reasons that follow, finds the Etminan Study sufficiently reliable to support an expert opinion on general causation in this case.
The Etminan Study is an epidemiological case-control study in which the authors analyzed medical and pharmaceutical billing information for over six million individuals, drawn from a large insurance claims database known as LifeLink.27 See Etminan Study, ECF No. 428-13 at 1. The database included, inter alia , patients' diagnoses, as identified by ICD-9-CM Codes,28 and all prescriptions they filled between 2006 and 2014. See
The Etminan Study described the existence and strength of the association found between Abilify, pathological gambling, and impulse control disorder in the random sample from the LifeLink database in terms of "rate ratios," also known as relative risk. Relative risk is simply a comparison of the incidence of a disease in exposed individuals with its incidence in unexposed individuals. See Ref. Man. at 566. A relative risk of 1.0 means there is no difference in risk between the exposed and unexposed groups; in other words, there is no association between exposure to the drug and the disease. See Ref. Man. at 567; see also Allison ,
In this case, the Etminan Study reported a relative risk of 5.23 for pathological gambling in individuals exposed to Abilify as compared to unexposed individuals, with a 95% confidence interval of 1.78-15.38. See Etminan Study, ECF No. 428-13 at 3. This means that the Study predicted that the increased risk of pathological gambling for Abilify patients within any given sample of the entire LifeLink database would likely fall anywhere between 1.78-15.38. Because the lower bound of the confidence interval (1.78) exceeds 1.0, this is statistically significant. The Study also reported a relative risk of 7.71 for impulse control disorder, with a 95% confidence interval of 5.81 and 10.34. This too is statistically significant. Finally, an analysis restricted to patients with bipolar disorder alone yielded a relative risk of 3.38 for pathological gambling in Abilify patients, with a 95% confidence interval of 1.68-8.48, which is also statistically significant. Defendants do not dispute the accuracy of the Etminan Study's relative risk and confidence interval calculations.
Plaintiffs' biostatistician, Dr. David Madigan, analyzed the Etminan Study and found it to be "methodologically sound" with a "highly statistically significant result."32 ,33 See Madigan Rep., ECF No. 427-1 at 30. This conclusion was based, in part, on the "strong" and "very substantial" relative risk figures reported in the Study; again, numbers that Defendants do not dispute. See Madigan Tr., ECF No. 596-4 at 49. Dr. Madigan also calculated a p -value for the Study's relative risk finding for pathological gambling. A p -value is a separate, widely established indicator of statistical significance, which measures the probability of obtaining the observed results-in this case, the increased risk of developing pathological gambling with exposure to Abilify-if, in reality, there is no true association between the drug and the adverse effect. See Ref. Man. at 249-50, 576-77; see also *1315Matrixx Initiatives, Inc. v. Siracusano ,
Dr. Madigan discussed, at length, the strengths and limitations of case-control studies generally, as well as those of the Etminan Study specifically. See Madigan Rep., ECF No. 427-1 at 21-25, Madigan Supp., ECF No. 427-1 at 85-90; Madigan Tr., ECF No. 596-4 at 42-47, 54-58. In particular, with respect to the potential effect of bias on the Study's results, Dr. Madigan explained that the relative risk calculations are simply too "substantial" and "robust" to be explained by investigator bias. See Madigan Tr., ECF No. 596-4 at 70. In short, Dr. Madigan opines that a case-control study is "highly unlikely" to yield increased risk estimates like those found in the Etminan Study "in the absence of a true" association. See Madigan Supp., ECF No. 427-1 at 91. In his view, the FDA called for a case-control study "clarify[ing]" the association between Abilify and impulse control disorders, and the Etminan Study reliably did exactly that. See Madigan Tr., ECF No. 596-4 at 71.
Defendants argue that numerous methodological flaws render the Etminan Study unreliable under Rule 702 and Daubert , including a deficient study design, failure to account for the risk of confounders, and the presence of bias. They also challenge Dr. Madigan's defense of the Etminan Study, which they claim is untenable in light of his prior published research criticizing both healthcare database research and the use of p -values as a measure of statistical significance. The Court addresses each category of objections in turn.
a. Study Design
Defendants criticize the Etminan Study's use of the LifeLink database because the database was not designed for research purposes. This criticism has little, if any, merit. The use of health insurance claims databases for epidemiologic research is well-supported by the medical literature, which is an important consideration under Daubert.34 See Daubert ,
With that said, large database research is not without limitations, one of which is the unavailability of medical records to confirm the accuracy of the data and to provide potentially significant clinical information not reported in the database. Defendants argue that this limitation is fatal to the Etminan Study's reliability under Daubert.35 The Court disagrees. While it is true that the medical literature encourages record review, the medical community also recognizes that health information privacy laws have "constrained the availability of" individual medical records "for uses other than the direct care of patients." See id. at 327-28, DX-122 at 5-6. Large database research for pharmacovigilance purposes is generally accepted in the scientific community, see supra n.34, and has been found to be a reliable methodology by other courts, even where no medical record review occurred. See Rheinfrank v. Abbott Labs., Inc. , No. 1:13-cv-133,
The LifeLink database, despite Defendants' criticisms, contains a sufficiently comprehensive dataset of patients, medical diagnoses and prescription claims to reliably serve the epidemiological objectives of the Etminan Study. Indeed, "claims data of this type provide some of the best data on drug exposure in pharmacoepidemiology." Brian L. Strom, Overview of Automated Databased in Pharmacoepidemiology , in PHARMACOEPIDEMIOLOGY 158, 159 (Brian L. Strom et al. eds., 5th ed. 2012), DX-129 at 2. The Etminan Study's statistical analysis of the LifeLink data is capable of being tested, and the Study itself has been subjected to peer review and publication in a reputable medical journal. This is all that Rule 702 and *1317Daubert require. See Chapman ,
Defendants' next argument, which relates to the database challenges addressed above, is that the Etminan Study is unreliable for its inability to confirm that individual patients in the LifeLink database were ever actually exposed to Abilify ; that is, that they actually took the Abilify they were prescribed. The Study did not attempt to validate medication usage, even though its lead author, Dr. Etminan, has done so in other epidemiological studies. This criticism also fails.
All epidemiological studies that make use of large healthcare databases are vulnerable to the risk of drug exposure misclassification, which is the risk of inaccurately measuring actual exposure to a drug. See Schneeweiss, 48 J. CLIN. EPIDEMIOLOGY at 328, DX-122 at 6. This is because claims databases only reflect the dispensing of medications and not actual medication use. See
The fact that the Etminan Study did not attempt to correct for the risk of drug exposure misclassification does not render it unreliable under Daubert. There is no evidence in the record of an established epidemiological protocol for addressing drug exposure misclassification concerns. See Kumho Tire, at 152,
Defendants' next argument with respect to the Etminan Study's design is that the Study cannot reliably measure the incidence of iatrogenic gambling (i.e. , medication-induced) in Abilify patients because it identified cases of gambling disorder in the LifeLink database using medical billing codes that are based on the DSM-5 diagnostic criteria for idiopathic gambling (i.e. , gambling disorder that occurs spontaneously and with no known cause).40 The Court disagrees. The LifeLink database classifies diagnoses according to ICD-9-CM codes, not the DSM-5 diagnostic criteria. See Etminan Study, ECF No. 428-13 at 1. Although the drafters of these two classification systems have, in recent years, attempted to "harmonize [them] as much as possible," the ICD-9-CM and DSM-5 are not identical. See DSM-5 at 11. Indeed, the two publications serve different purposes and, in some circumstances, diverge or are discordant with one another.41 See
Defendants' last argument is that the Etminan Study is unreliable because the time between exposure to Abilify and the diagnoses of pathological gambling in the random sample taken from the LifeLink database was too short to be compatible with a cause-effect relationship. This argument is based on the Study's finding that five patients were exposed to Abilify in the year preceding their diagnoses of pathological gambling, with an average, or mean, time to diagnosis of 20 days and a standard deviation of 17.4 days.43 See Etminan Study, ECF No. 428-13 at 3. The standard deviation is a measure of statistical dispersion; that is, the average distance between the five individual time-to-diagnosis data points and the mean.44 See Ref. Man. at 239. None of the five actual time-to-diagnosis periods was individually reported *1320in the Study. See
This criticism is not fatal to the Study's reliability under Daubert for several reasons. First, the standard deviation of 17.4 days does not dictate a conclusion that there must have been a three-day period between exposure and diagnosis for at least one of the five patients in the random sample analyzed in the Study. At his deposition, Dr. Etminan, the Study's lead author, testified that while the time-to-diagnosis for one of the patients could have been "a matter of days," he could "not [be] sure exactly what" the actual times-to-diagnosis were for any of the five patients "without having the data" from the LifeLink database to review.45 See Etminan Dep., ECF No. 457-7 at 42.46 Dr. Madigan, who is the only statistics expert in this case, calculated at least two possible distributions of the five individual time-to-diagnosis periods, given the mean time of 20 days and the standard deviation of 17.4 days: (1) a distribution of 3, 41, 13, 37, and 8 days, respectively; or (2) a distribution of 50, 16, 8, 8, and 17 days.47 See Madigan PPT, PX-051 at 22;48 Madigan Rep., ECF No. 427-1 at 24. According to Dr. Madigan, there is no way to determine, from the information reported in the Study, which of these two possible distributions represents the actual distribution of time-to-diagnosis periods for the five patients found to have been exposed to Abilify within the year preceding their diagnosis of pathological gambling in the LifeLink database. See Madigan Tr., ECF No. 596-4 at 62-63. None of Defendants' experts disputed Dr. Madigan's calculations.49 Thus, the evidence shows that the minimum *1321time-to-diagnosis in the Etminan Study could have been as few as three, or as many as eight, days.
Second, the possibility of pathological gambling or other impulse control symptoms developing within either three or eight days of exposure to Abilify is consistent with the scientific literature. Multiple published case reports describe a "rapid onset" of such symptoms following exposure to Abilify, with patients' times-to-onset ranging from a few days to a week after starting treatment with the drug.50 See Glenmullen Tr., ECF No. 596-2 at 64. While this anecdotal evidence obviously cannot establish the times-to-onset or diagnosis for the patients in the Etminan Study, it does reliably indicate that a three-or eight-day time-to-onset and diagnosis is not wholly "implausible." See Weed Tr., ECF No. 596-8 at 65. Instead, the Court agrees with Dr. Glenmullen that a patient with "a very sudden onset" of "distressing" impulse control problems after starting "a new [and] powerful antipsychotic drug" like Abilify could reasonably be expected to call his doctor's office and get a diagnosis of pathological gambling or impulse control disorder"within days or a week" of beginning treatment. See Glenmullen Tr., ECF No. 596-2 at 65.
Finally, as the Court has already found, the DSM-5 diagnostic criteria for gambling disorder do not govern the diagnosis of iatrogenic (medication-induced) gambling. See DSM-5, ECF No. 428-3 at 68. Indeed, the DSM-5 clearly contemplates that "patients taking dopaminergic medications" may "experience urges to gamble" that "dissipate when [the] medications are reduced in dosage or ceased." See
b. Confounders
Defendants also argue that the Etminan Study is unreliable for its failure to control for potential confounders, i.e. , known risk factors for pathological gambling, specifically, depressive disorders, anxiety disorder, and personality disorders. See DSJ, ECF No. 428-26 at 29. According to Defendants, this flaw is "independently fatal" to the Etminan Study because it means that the pathological gambling diagnoses in the LifeLink database could be attributable to one or more of these underlying conditions rather than Abilify, particularly since they are in many cases the precise medical conditions for which Abilify is prescribed. See DSJ Reply, ECF No. 484 at 10-11.52 Defendants insist that because the Etminan Study failed to take into account the relationship between pathological gambling and these medical conditions, it cannot reliably establish the existence of an association between pathological gambling and Abilify.
When assessing the reliability of an epidemiological study, a court must consider whether the study adequately accounted for confounding factors, or confounders. See Ref. Man. at 591; see also Deutsch v. Novartis Pharm. Corp. ,
Applying these principles to this case, the Court finds that the failure to control for depressive disorders, anxiety disorders, and personality disorders does not invalidate the results of the Etminan Study. First, Abilify is not indicated for treatment of anxiety or personality disorders. See Product Label, ECF No. 428-1 at 2, 4. Nothing in the record as it currently stands suggests that Abilify is even prescribed off-label for these two categories of psychiatric conditions. This is significant because, for epidemiological purposes, no matter how strongly a variable is related to the disease in question, if it is not also related in some way to drug exposure, it cannot be a true confounder. See Ref. Man. at 591; Weiss & Koepsell at 216. Here, there is no evidence that anxiety and personality disorders are related in any way to Abilify exposure.55 Therefore, no matter how strongly those disorders may be related to pathological gambling, neither is a true confounder.
Second, the medical literature is inconclusive on the question of whether depressive, anxiety and personality disorders are causal risk factors for pathological gambling. It is true that the DSM-5 provides that "[i]ndividuals with gambling disorder have high rates of comorbidity with" these categories of psychiatric conditions. Am. Psychiatric Ass'n, DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS 589 (5th ed. 2013) ("DSM-5"), ECF No. 428-3 at 68. It also is true that at least two cross-sectional studies have confirmed the prevalence of problem gambling behavior in the major depression and mood disorder populations.56 See Lena C. Quilty et al., The Prevalence and Course of Pathological Gambling in the Mood Disorders , 27 J. Gambling Studies 191, 191-92 (2011) (discussing "elevated prevalence" of pathological gambling with mood disorders, depression, and bipolar disorder ), ECF No. 427-13; Sidney H. Kennedy et al., Frequency and Correlates of Gambling Problems in Outpatients with Major Depressive Disorder and Bipolar Disorder , 55 Canadian J. Psychiatry 568, 574 (2010) (discussing "higher prevalence" of "problem gamblers"
*1324with major depressive disorder ), ECF No. 427-12. But "comorbidity" and "prevalence" are not synonymous with "causative." Notably, both cross-sectional studies explicitly caution against inferring a causal relationship from the presence of these observed comorbidities. See Quilty at 198, ECF No. 427-13 at 9; Kennedy at 574, ECF No. 427-12 at 8. The Quilty study, in particular, concluded that there is "no direct association" between pathological gambling and mood disorders, including depression. See Quilty at 198, ECF No. 427-13 at 9. In any event, "it is not possible to establish the temporal relation between exposure and disease-that is, that the exposure preceded the disease, which would be necessary for drawing any causal inference"-by reference to a cross-sectional study. Ref. Man. at 560-61. In sum, science has not yet determined with any reliability the precise nature of the relationship, if any, between pathological gambling and depressive, anxiety, and personality disorders. The Court may not simply ignore this gap in scientific understanding by excluding the Etminan Study for failing to consider these psychiatric conditions as causal risk factors for pathological gambling. See Hendrix II ,
Finally, other evidence in the record reliably supports the conclusion that depressive, anxiety, and personality disorders did not confound the results of the Etminan Study. For example, as part of a 2016 Pharmacovigilance Review, the FDA performed a disproportionality analysis of its adverse event reporting system database, comparing the relative frequency of pathological gambling reports among 11 different atypical antipsychotics, one of which was Abilify.57 See FDA, Abilify Pharmacovigilance Review 27 (March 10, 2016) ("FDA Pharm. Vigil."), ECF No. 428-11 at 27. The FDA found that only Abilify had a statistically significant percentage of patients reporting pathological gambling. See
[* * * REDACTED * * *] .59 [* * * REDACTED * * *] . The results of these disproportionality analyses-one by the FDA, [* * * REDACTED * * *] -certainly are not conclusive evidence that Abilify causes pathological gambling. However, they do reliably support a conclusion that controlling for depressive, anxiety, and personality disorders does not decrease the statistical incidence of pathological gambling reports associated with Abilify. Thus, an expert could reasonably conclude that these psychiatric conditions are not confounding factors that must be controlled *1325for in a reliable epidemiological study of the possible relationship between Abilify and gambling disorder.
In sum, confounding is a "reality" inherent in all epidemiological research. Ref. Man. at 590. As such, confounders "do not reflect an error made by" a particular researcher; rather "they reflect the inherently uncontrolled nature" of observational studies. See id. at 593 (internal marks omitted). Identifying and mitigating the effects of confounding is key to ensuring the reliability of an epidemiological study. See id. at 591-97; see also Deutsch v. Novartis Pharm. Corp. ,
c. Bias
Defendants further argue that the Etminan Study is unreliable because its results were compromised by bias. More specifically, they first argue that through his actions, Dr. Etminan created a conflict of interest that affects the integrity of the Study's findings. This argument is based on the fact that Dr. Etminan contacted Plaintiffs' counsel shortly after learning about this litigation on AboutLawsuits.com, before he developed the research protocol for the Study. The implication, of course, is that Dr. Etminan was predisposed towards results that would support Plaintiffs' theory of general causation in this case. The problem with Defendants' position is that the uncontroverted record evidence with respect to this communication does not demonstrate impropriety by either Dr. Etminan or Plaintiffs' counsel. According to Dr. Etminan, the conversation lasted only two minutes, during which he advised Plaintiffs' counsel that he intended to conduct a study on Abilify, gambling, and impulse control disorders, but he did not discuss any specifics about how the study would be designed or what its results might be. See Etminan Dep., ECF No. 457-7 at 27-30. Plaintiffs' counsel immediately ended the conversation and refrained from any further discussions about the study with Dr. Etminan until after it was published in a peer-reviewed journal.60 See
Importantly, there is no evidence in the record to suggest that any methodological aspect of the Etminan Study or its results was tainted by Dr. Etminan's alleged bias. Although the Etminan Study has its limitations, see In re Orthopedic Bone Screw Prod. Liab. Litig. , No. 1014,
Defendants next argue that the Etminan Study is unreliable due to its failure to control for detection bias, also called reporting bias. In this context, detection bias refers to the possibility that pathological gambling and impulse control disorders were more likely to be detected and diagnosed in the exposed group (individuals taking Abilify ) than in the unexposed group, due to increased medical awareness of the particular problems allegedly associated with Abilify. See Zoloft I ,
The only evidence offered by Defendants to demonstrate the potential for detection bias in this case is a single "suspect adverse reaction report" by a patient who only reported having experienced an "urge to gamble" when he took Abilify after seeing an advertisement in 2014, which said that Abilify"causes compulsive gambling and was a bad drug." See ECF No. 460-13 at 1. A single adverse reaction report is insufficient to discredit the Etminan Study as a whole. As the Court has already noted, adverse event reports are "one of the least reliable sources" of scientific information. See *1327McClain ,
d. Dr. Madigan's Etminan Analysis67
Defendants raise two objections to Dr. Madigan's statistical analysis of the Etminan Study.68 First, Defendants argue that his defense of the Study, an observational healthcare database study, is untenable in light of his published research criticizing observational healthcare database studies.69 According to Defendants, Dr. Madigan's *1328opinion in this case "violates his own standard of proper methodology" and suggests that he "does not apply the same rigor in the courtroom that he would apply to his scientific endeavors." See Def. Madigan Motion, ECF No. 427-20 at 15 (quoting In re Rezulin Products Liability Litigation (MDL No. 1348) ,
From 2009 to 2013, Dr. Madigan served as principal investigator for the Observational Medical Outcome Partnership ("OMOP"), a public-private partnership between the FDA, academia, and the pharmaceutical industry that was established, in part, to empirically evaluate the strengths and weaknesses of observational healthcare database studies of the effects of medical products.70 Dr. Madigan testified that the focus of his research with the OMOP was large-scale automated observational health database research, which involves the use of high volume, generic data mining techniques to uncover hidden relationships of potential clinical significance to drug safety. Madigan Dep., ECF No. 427-1 at 106, 133-35; Madigan Tr., ECF No. 596-4 at 43-44. His work with the OMOP culminated in the publication of a series of peer-reviewed, scientific articles criticizing generic automated database analysis for its potential for bias, confounding, and inaccurate results.
Dr. Madigan's published criticisms of generic automated database research do not contradict his endorsement of the Etminan Study because, in short, the Etminan Study is not the product of generic automated database research. Rather, it was custom-designed to analyze a very specific clinical question-whether Abilify is associated with pathological gambling and other impulse control disorders-and narrowly tailored to account for a number of factors unique to the LifeLink database and to the Abilify patient population. See Madigan Tr., ECF No. 596-4 at 44-45, 88-89; Madigan Dep., ECF No. 427-21 at 40. This customized design and implementation distinguishes the Etminan Study from the generic automated studies criticized by Dr. Madigan and the OMOP. Indeed, several of Dr. Madigan's publications actually recommend such "customizing [of] analyses to databases" and "thoughtful and careful study design" as means of improving the accuracy and performance of generic automated database research. See Madigan 2014, DX-117 at 27, 35; see also Madigan 2013b, ECF No. 427-8 ("It is conceivable that customizing the analytical approach to [drug-outcome] pairs could lead to greater consistency across databases."). The Etminan Study also implements many of the specific design-level and analytical strategies that Dr. Madigan and the OMOP suggest for reducing potential errors in generic automated database research, including careful matching of cases and controls, adjusting and controlling for potential confounders, and the use of sensitivity analyses to assess the potential consequences of unknown confounders. See Madigan 2014, DX-117 at 15-17. None of Defendants' experts disputed Dr. Madigan's explanation of the distinctions between customized database research, like the Etminan Study, and generic database research, like the studies criticized by Dr. Madigan. To the contrary, on this record, Dr. Madigan's opinion with respect to the Etminan Study is consistent with his prior *1329published literature and does not "violate[ ] his own standard of proper methodology." See Rezulin ,
Defendants also argue that Dr. Madigan's reliance on p -values to demonstrate the validity of the statistical evidence in this case is untenable in light of his published research criticizing traditional p -values for their vulnerability to systematic error, such as bias. See Martijn J. Schuemie et al., Interpreting Observational Studies: Why Empirical Calibration is Needed to Correct P-Values , 33 STATISTICS MED. 209 (2014) ("Schuemie 2014"), ECF No. 427-5 at 2, 3. The Court disagrees. The p -value is a generally accepted statistical technique for evaluating the significance of the results of a statistical analysis. See Ref. Man. at 249-56, 258; see also Jones v. City of Boston ,
While it is true that Dr. Madigan and his colleagues have proposed "a new empirical framework" for evaluating statistical significance, called a calibrated p -value, which they assert will "minimiz[e] the potential effects of bias when interpreting observational study results," see Schuemie 2014, ECF No. 427-5 at 3, this calibrated p -value framework is "controversial" and has not yet gained general acceptance or approval in the scientific community, Madigan Tr., ECF No. 596-4 at 50. Indeed, Dr. Madigan testified at his deposition that, at least as of that time, "the only people to have ever calculated calibrated p -values [were him]self and [his] coworkers." See Madigan Dep., ECF No. 427-1 at 148.73 Perhaps one day Dr. Madigan's calibrated p -value framework will become the gold standard for evaluating statistical significance, but it simply is not there yet and, for now at least, it is not altogether clear whether the framework is sufficiently well-established and reliable to satisfy Rule 702 and Daubert. See Rider ,
Based on the foregoing, the Court finds the Etminan Study is a scientifically sound epidemiological study and, therefore, reliable evidence of general causation in this case.
2. Dose-Response Relationship
In addition to epidemiology, Plaintiffs' experts offer a series of case studies and adverse event reports as evidence of a dose-response relationship between Abilify, impulsive gambling, and other impulse control disorders.75 These materials describe the onset of new impulse control problems in individual patients after their doses of Abilify were increased, problems which disappeared when the Abilify doses were reduced or discontinued.76 While the Court finds this evidence suggestive of a dose-response relationship, it ultimately lacks the intrinsic reliability that is the hallmark of a primary methodology under Eleventh Circuit Daubert jurisprudence.
In the Eleventh Circuit, the use of dose-response evidence as a "primary" means of establishing causation generally requires a scientifically reliable showing of a correlation between dosage and disease, the minimum dose at which adverse effects are seen and the dose at which a substance is lethal. See McClain ,
In this case, Plaintiffs' experts have not presented any controlled, experimentally derived evidence of a dose-response relationship between Abilify and impulse control disorders. While the absence of such evidence is not fatal to the experts' general causation opinions, it does weaken the force and reliability of their conclusions as to dose-response. Nonetheless, the Court agrees with the FDA that a number of the published case studies-those describing positive dechallenge and rechallenge events, in particular-indicate a "temporal relationship between the initiation of [Abilify ] treatment and the onset of" impulse control problems. See FDA Pharm. Vigil., ECF No. 428-11 at 21-25. Some of these case studies and adverse event reports also strongly suggest that an increase in a patient's dose of Abilify may increase that patient's risk of impulse control problems, while a decrease in dose may correspondingly decrease the risk.78 This evidence is "substantially more valuable than run-of-the-mill case reports." See Glastetter ,
3. Background Risk
Two of Plaintiffs' experts, Drs. Glenmullen and Hollander, provide the background risk or prevalence of various *1332impulse control disorders, including compulsive gambling, in the general population, as reflected in the scientific literature. More specifically, Dr. Glenmullen, relying on the DSM-5, stated that the past-year prevalence rate of gambling disorder is approximately 0.2%-0.3% in the general population. See Glenmullen Rep., ECF No. 424-1 at 59.80 According to the DSM-5, the lifetime prevalence rate of gambling disorder in the general population is about 0.4%-1.0%. See DSM-5, ECF No. 428-3 at 66. Dr. Hollander referenced several scientific studies identifying the background risks for compulsive shopping (6%-7%) and hypersexuality (3%-6%) in the general population, and for compulsive eating (1.6%) in the general adolescent population. See Hollander Rep., ECF No. 459-1 at 8-9. The Court finds that these figures constitute reliable evidence of background risk.
The fact that Plaintiffs' experts do not offer a more expansive analysis of background risk in this case does not present a "serious methodological deficiency" or "substantial weakness" in their general causation opinions. See Chapman ,
4. Biological Plausibility
Plaintiffs' experts share the opinion that the biological mechanism by which Abilify can cause pathological gambling and impulse control disorders is its effect on dopamine neurotransmission in the brain.81 Dr. Antoine Bechara provides the most thorough analysis of the medical literature offered in support of this position. See Bechara Rep., ECF No. 423-1.82 The Court first briefly summarizes Dr. Bechara's biological plausibility opinion and then considers Defendants' reliability challenges.83
According to Dr. Bechara, Abilify binds to over 90% of postsynaptic D2receptors in the nucleus accumbens and acts as a functional antagonist, occupying the D2receptors and preventing dopamine molecules from attaching and activating them, thereby blocking dopamine neurotransmission at those sites. The brain compensates for the resultant decrease in dopaminergic activity by increasing, or upregulating, the number of dopamine receptors in the nucleus accumbens; and also by increasing the sensitivity of those receptors, so that when activated by dopamine they produce greater, more "potentiated" physiological responses than would occur naturally. See Bechara Tr., ECF No. 596-3 at 100-101.84
*1333At the same time, the "displaced" dopamine molecules, unable to bind to D2receptors, diffuse towards the other available receptors in the nucleus accumbens, most of which are D3receptors. Abilify occupies and "strongly stimulates" about 30% of these D3receptors, producing in them between 50% and 100% of the physiological response that dopamine naturally produces. See Bechara Rep., ECF No. 423-1 at 7. The remaining D3receptors, which are upregulating and hypersensitive, bind with the endogenous dopamine to produce "supercharge[d]" reward-seeking behavior. See Bechara Tr., ECF No. 596-3 at 98. Finally, Dr. Bechara also opines that Abilify's functional antagonism at D2receptors may disrupt the brain's ability to process the consequences of negative behavior.
Defendants challenge the reliability of Plaintiffs' experts' proposed mechanism of action on the ground that it lacks evidentiary support and instead is premised on "pure speculation." Def. Bechara Motion, ECF No. 423-10 at 17.85
a. Displacement
Defendants argue that there is no scientific support for the proposition that endogenous dopamine is "displaced" when Abilify occupies a majority of D2receptors in the nucleus accumbens. See id. at 18. The Court disagrees. Even Defendants' own psychopharmacology expert, Dr. Pierre Blier, agrees that Abilify displaces dopamine at D2receptors. See Blier Dep., ECF No. 455-2 at 241, 248, 258-59.86 Moreover, [* * * REDACTED * * *] .87 [* * * REDACTED * * *] . The fact of displacement also appears to be supported by the scientific literature, which indicates that, at therapeutic doses, Abilify occupies and blocks over 90% of postsynaptic D2receptors in the nucleus accumbens, leaving only "10% or fewer D2receptors [ ] available for endogenous dopamine to bind" with. See Takashi Hamamura & Toshiki Harada, Unique Pharmacological Profile of Aripiprazole as the Phasic Component Buster , 191 PSYCHOPHARMACOLOGY 741, 742 (2007) ("Hamamura 2007"), PX-020 at 2.88 Given this evidence, the "displacement" premise of Plaintiffs' experts' opinions cannot be considered "pure speculation." See Def. Bechara Motion, ECF No. 423-10 at 21-22.
Defendants also argue that there is no evidentiary support for a "key assumption" of the "displacement theory," namely, that Abilify"occup[ies] relatively more D2receptors than D3receptors." See id. , ECF No. 423-10 at 22 (citing Bechara Rep., ECF No. 423-1 at 13). Again, the Court disagrees. As explained in Maeda 2014, which is a peer-reviewed, published article relied on by Dr. Blier, see Blier Rep., ECF
*1334No. 455-1 at 15-16, the only available method for directly measuring human receptor occupancy is PET imaging, see Maeda 2014 at 600, DX-062 at 12. Where PET imaging is unavailable, in vitro studies of receptor affinity are used to predict receptor occupancy.89 See id. In this case, there are peer-reviewed, published in vitro studies in the scientific literature describing Abilify's higher affinity for D2receptors than for D3receptors, at least one of which found the drug's affinity to be over three-fold higher for D2receptors than for D3receptors.90 Moreover, [* * * REDACTED * * *].91 Finally, Defendants' psychopharmacology expert, Dr. Blier, agrees that Abilify has "a presence three to ten times lower at D3[receptors] than at D2receptors." See Blier Rep., ECF No. 455-1 at 16. This evidence supports a plausible conclusion that Abilify binds to D2receptors (affinity), and thereby occupies them, with greater frequency and strength than it does to D3receptors. For this reason, the Court finds Dr. Bechara's opinion that "Abilify would occupy relatively more D2receptors" than D3receptors supported by reliable scientific evidence in this case. See Bechara Rep., ECF No. 423-1 at 13.
Dr. Bechara's opinion that "displaced" endogenous dopamine diffuses towards, and binds with, other available receptors in the nucleus accumbens, most of which are D3receptors, is also biologically plausible based on the scientific evidence in this case. It appears to be well-established in the scientific literature that, in humans, D3receptors predominate in the mesolimbic regions of the brain, including the nucleus accumbens.92 In fact, only one expert, Dr. *1335Blier, has offered a different opinion. In his expert report, Dr. Blier stated that D1, D2, D3, and D4receptors "are all expressed in the nucleus accumbens, the first three in high density." See Blier Rep., ECF No. 455-1 at 16. Dr. Blier offers a single citation in support of this opinion, a 2003 book by Jack R. Cooper. See id. (citing Cooper et al. , THE BIOCHEMICAL BASIS OF NEUROPHARMACOLOGY (Oxford Univ. Press 2003)). However, there is no corresponding exhibit in the record (i.e. , a copy of the relevant chapter or pages) for the Court to compare with Dr. Blier's statement. Given that virtually all of the other scientific literature in this case indicates that the mesolimbic reward pathway is a predominantly D3-rich environment, Dr. Blier's representation to the contrary must be supported by more than just his ipse dixit. See Joiner ,
Relatedly, the record evidence also reflects, and Defendants' experts have not disputed, that endogenous dopamine has "higher affinity for" D3receptors than D2receptors. See Tadori 2011a at 51, PX-021 at 9; see also Gurevich 1999 at 78 (stating that dopamine has "significantly higher affinity" for D3receptors than for D2receptors). Dr. Blier testified that displaced endogenous dopamine can diffuse "everywhere," see Blier Tr., ECF No. 596-8 at 27, including postsynaptic dopamine receptors "not located in precise apposition to" the presynaptic, sending neuron, see Blier Rep., ECF No. 455-1 at 15; see also Blier Dep., ECF No. 455-2 at 56-58. According to Dr. Blier, endogenous dopamine"diffuses all around the neuron" and may act on any of the "different types of receptors ... in that region." See Blier Tr., ECF No. 596-8 at 27. The scientific literature confirms Dr. Blier's opinion on this issue.93
Taken together, this evidence reasonably and reliably supports the plausibility of Dr. Bechara's displacement opinion. In short, the scientific evidence reflects that (1) endogenous dopamine has a high affinity for D3receptors; (2) D3receptors are the predominant dopamine receptors in the mesolimbic pathway, including the nucleus accumbens; and (3) displaced endogenous dopamine may diffuse throughout that region of the brain. Under these conditions, it is certainly plausible that displaced endogenous dopamine would diffuse to, and activate, at least some of the D3receptors so abundant in the mesolimbic pathway.
At this point, the Court finds it important to emphasize that determining whether an expert's opinion is "biologically plausible" is a far different inquiry than determining whether an opinion is "biologically certain." See Daubert ,
b. Upregulation and Sensitization
Defendants also argue there is no medical support for Plaintiffs' experts' opinions that Abilify's functional antagonism of D2receptors triggers upregulation and sensitization of dopamine receptors in the brain. This is incorrect. Both phenomena have been described in published case reports94 and, more significantly, demonstrated via peer-reviewed, published in vivo studies.95 [* * * REDACTED * * *] . Dr. Blier testified that he too was "aware of other studies that have shown the sensitization" and upregulation effects of Abilify, though "not necessarily to any greater extent than" a pure D2receptor antagonist. See Blier Tr., ECF No. 596-8 at 30.
*1337Finally, the FDA also has acknowledged, based on the medical literature, that D3partial agonism, upregulation, and sensitization are plausible biological mechanisms that "could" explain the onset of impulse control disorders after Abilify exposure, although it cautioned that more research was necessary before any final conclusion can be reached. See FDA Pharm. Vigil., ECF No. 428-11 at 29. Given this evidence, Dr. Bechara's opinion as to upregulation and sensitization cannot be considered "improper ipse dixit. " See Def. Bechara Motion, ECF No. 423-10 at 26.
The fact that none of the other atypical antipsychotics is associated with a higher incidence of impulse control disorders, even though those drugs may "cause more upregulation than Abilify," see id. at 25, does not detract from the reliability of Dr. Bechara's opinion that Abilify can cause upregulation and sensitization. None of the scientific evidence in this case indicates that earlier atypical antipsychotics are agonists at D3receptors.96 In any event, the record makes clear that Abilify has a "unique" pharmacological profile; therefore, analogies between Abilify and other atypical antipsychotics are not permissible unless reliable scientific evidence establishes the validity of the analogy. See McClain ,
c. Direct Agonism
Defendants argue that Plaintiffs' experts do not have "any methodologically reliable basis" for concluding that Abilify acts differently at D3receptors than it does at D2receptors. See Def. Bechara Motion, ECF No. 423-10 at 12. More specifically, Defendants argue that (1) the in vitro studies offered in support of this conclusion may not reliably support an expert opinion on general causation; and (2) the only way Dr. Bechara can show any difference between Abilify's effects at D2and D3receptors is by "cherry-picking" data from the scientific landscape to give the illusion of clarity in favor of his biological plausibility opinion. Again, the Court disagrees.
Before addressing the merits of Defendants' objection, it is necessary to clarify what is not in dispute. Defendants do not dispute the apparent scientific consensus that Abilify is considered a partial agonist that acts as a functional antagonist at postsynaptic D2receptors.97 See
First, there is support in the scientific literature for the fact that "the actions of [Abilify ] differ markedly across [dopamine ] receptor systems." David A. Shapiro et al., Aripiprazole, A Novel Atypical Antipsychotic Drug with a Unique and Robust Pharmacology , 28 NEUROPSYCHOPHARMACOLOGY 1400, 1407-08 (2003) ("Shapiro 2003"), DX-45 at 8-9. For example, one in vitro study using animal cells transfected with human dopamine receptors found that, at least in a controlled laboratory environment, Abilify was "sometimes an antagonist (e.g. , D2), sometimes a partial agonist (e.g. , D2), and sometimes a full agonist (D3, D4)." See id. at 1408, DX-45 at 9. This finding is consistent with subsequent scientific literature, which has characterized Abilify as "functionally selective" for its "markedly different" effects at individual D2and D2-like receptors in the various dopamine pathways. See Richard B. Mailman and Vishakantha Murthy, Third Generation Antipsychotic Drugs: Partial Agonist or Receptor Functional Selectivity , 16 CURRENT PHARM. DESIGN 488, 492-93 (2011), DX-069 at 5-6. This evidence reliably supports a fundamental premise of Plaintiffs' experts' proposed mechanism of action, that Abilifycan act differently at postsynaptic D3receptors than it acts at postsynaptic D2receptors.
Second, there is scientific literature reflecting that Abilify is not an antagonist at D3receptors. Yoshiro Tadori et al., Characterization of Aripiprazole Partial Agonist Activity at Human Dopamine D3 Receptors , 597 EUROPEAN J. PHARMACOLOGY 27, 31 (2008) (in vitro study) ("Tadori 2008"), DX-58 at 5. This fact alone supports a distinction between Abilify's effects at postsynaptic D2receptors (functional antagonism) and its effects at D3receptors (no antagonism).102 [* * * REDACTED * * *] .103 This evidence reliably supports Plaintiffs' experts' opinions that Abilifydoes act differently at D3receptors than it acts at postsynaptic D2receptors.
Finally, multiple in vitro studies show that Abilify exhibits strong partial to full agonist activity at D3receptors,104 while *1339exhibiting very low partial agonist to antagonistic activities at postsynaptic D2receptors.105 As the Court has already observed, [* * * REDACTED * * *] .106 Thus, the medical science and record in this case reliably support Plaintiffs' experts' opinions that Abilify acts with greater intrinsic activity at postsynaptic D3receptors than at postsynaptic D2receptors.
The fact that Plaintiffs' experts rely primarily on in vitro data does not invalidate their conclusions as to this proposed mechanism of action. In vitro studies are often "the only or best available evidence" of a drug's effects at the cellular level. See Ref. Man. at 564. However, because of its limitations (e.g. , ethical concerns, problems extrapolating from laboratory experimental findings to humans), in vitro evidence cannot be the sole basis for a general causation opinion. See Kilpatrick ,
In this case, Dr. Bechara acknowledged the limitations of in vitro research and explained which of the in vitro findings about Abilify reliably "reflect what happens in a normal human brain." See Bechara Tr., ECF No. 596-3 at 91. This is all that Rule 702 and Daubert require. Moreover, Defendants have not contradicted Dr. Bechara's explanation, nor have they argued that any specific in vitro study he presented is methodologically flawed. Finally, Defendants [* * * REDACTED * * *] .107 In any event, here, the in vitro evidence supporting biological plausibility is not the sole basis for Plaintiffs' experts' general causation opinions. To the contrary, the in vitro data is offered in support of more "powerful" evidence of general causation, namely, the Etminan Study. See Rider ,
Defendants argue that Dr. Bechara "cherry picked" two data points that support his biological plausibility opinion and "ignore[d] the numerous studies that are inconsistent with" it. Def. Bechara Motion, ECF No. 423-10 at 18-19. The first data point was reported in Shapiro 2003, which stated that Abilify exhibited both partial and full agonist actions at D3receptors. See Shapiro 2003, DX-045 at 2, 9. The second data point was drawn from Hamamura 2008, which calculated Abilify's intrinsic activity at D2receptors to be approximately 6%. See Hamamura 2008 at 864, DX-057 at 3. Defendants claim Dr. Bechara deliberately presented only these two data points to the Court, and no others, *1340in order to accentuate the alleged disparity between Abilify's effects at D2and D3receptors. The Court is not persuaded. The uncontroverted evidence-including Dr. Bechara's expert reports and his testimony at the Daubert hearing-shows that Dr. Bechara performed an extensive and systematic review of the scientific literature on Abilify's intrinsic activity at D2and D3receptors. See, e.g. , Bechara Rep., ECF No. 423-1 at 21-25; Bechara Supp., ECF No. 423-1 at 448-454; Bechara Tr., ECF No. 596-3 at 82-83.108 Dr. Bechara testified that he reported the Shapiro 2003 and Hamamura 2008 data points, as well as the other data points he found, for purposes of completeness, because they are part of the body of scientific evidence on this issue. See Bechara Tr., ECF No. 596-3 at 86, 120. The fact that Dr. Bechara ultimately concluded that Abilify is a partial agonist at D3receptors is evidence that he did not put undue weight on Shapiro 2003's description of Abilify as a full agonist at D3receptors. Instead, his partial agonism conclusion is based on "the majority of the articles" in the scientific literature, which report Abilify's partial agonism at D3receptors to be in the 50% range. See id. at 86. This was a reliable approach to analyzing and reporting the scientific evidence on Abilify's activity at D3receptors. Defendants' arguments with respect to Dr. Bechara's inclusion of the Shapiro 2003 and Hamamura 2008 data points go to the weight of Dr. Bechara's biological plausibility opinion, not its admissibility.
Finally, Defendants' argument that Dr. Bechara "ignore[d] the numerous studies that are inconsistent with his opinion," see Def. Bechara Motion, ECF No. 423-10 at 18-19, fails because it misrepresents the findings of the "numerous" in vitro studies that Defendants claim Dr. Bechara ignored. While it is true that there are studies in the medical literature evidencing Abilify's partial agonism at D2receptors, at least six of those studies report findings related to Abilify's effects at presynaptic D2receptors.109 See id. at 19. In that respect, those six studies do not "logically advance" the resolution of questions about Abilify's effects at postsynaptic D2and D3receptors. It was not unreliable for Dr. Bechara to discount those six studies in reaching his opinion.
Moreover, according to Dr. Bechara, five studies, including all but one of the studies discussed above involving presynaptic D2receptors, also report in vitro findings based on tissue cultures that were "artificially manipulated" by researchers to increase the number of D2receptors, called a *1341receptor reserve, far beyond the amount present in the human brain.110 See Bechara Tr., ECF No. 596-3 at 90-92; Bechara Dep., ECF No. 423-1 at 290-96.111 Dr. Bechara testified that such artificially manipulated tissues "do not reflect what actually happens in a normal brain," therefore the findings about a drug's effects on those tissues cannot be reliably extrapolated to predict the drug's effect in humans. See Bechara Tr., 596-3 at 90-92; Bechara Dep., ECF No. 423-1 at 290-96. Defendants essentially concede this point, responding only that "most" of the in vitro studies of postsynaptic D3receptors also involve artificially high receptor density. This response is unpersuasive. None of Defendants' experts criticized the in vitro data involving D3receptors on this basis. See Marmo v. Tyson Fresh Meats, Inc. ,
There are two other scientific articles containing data points that Defendants claim Dr. Bechara ignored. The first, Lawler 1999, DX-051, Dr. Bechara clearly cites in his expert report, see Bechara Rep., ECF No. 423-1 at 12. Moreover, at the Daubert hearing, Dr. Bechara referenced the Lawler article as part of the basis for his opinion that Abilify exerts very low partial agonist to antagonistic action at postsynaptic D2receptors. See Bechara Tr., ECF No. 596-3 at 92. The second article, Maeda 2014, DX-062, described an in vitro finding that Abilify exhibited 61% intrinsic activity at postsynaptic D2receptors. At the Daubert hearing, Dr. Bechara acknowledged that he did not rely on or cite the Maeda article as part of his opinion in this case. See Bechara Tr., ECF No. 596-3 at 126. However, there is no evidence that Dr. Bechara knew of and willfully excluded the Maeda article from his analysis. There also is no evidence that his search of the scientific literature was in any other way infirm. Under these circumstances, the Court finds that Dr. Bechara's failure to cite a single article out of the vast body of scientific literature connected with this case cannot render his entire analysis and opinion unreliable. This issue may be fodder for vigorous cross-examination, but it is not grounds for exclusion of Dr. Bechara's testimony.
In sum, the Court finds there is a methodologically sound basis for Dr. Bechara's conclusion that Abilify acts with greater intrinsic activity at D3receptors than it does at postsynaptic D2receptors. Dr. Bechara did not simply ignore the medical science that did not support his opinion. Instead, he analyzed all of the available medical literature and explained how and why certain studies did not alter *1342or undermine his opinion regarding Abilify's functional antagonism at postsynaptic D2receptors and partial agonism at D3receptors. Defendants' criticisms go to the credibility, and thus the weight, of Dr. Bechara's opinion, not its admissibility.
d. Negative Reward Prediction Error
Defendants also argue there is insufficient evidentiary support for Dr. Bechara's opinion that Abilify impairs negative reward prediction error, also called reversal learning. On this issue, the Court agrees. Reward prediction error learning refers to the process by which the brain learns from associations between actions and consequences. The mesolimbic dopamine system plays a central role in such reward-motivated behavior. See Roy A. Wise, Brain Reward Circuitry: Insights from Unsensed Incentives , 36 NEURON 229, 234 (2002) ("Wise 2002").112 In brief, mesolimbic dopamine neurons have been shown to fire in two modes, tonic and phasic, which are thought to modulate two distinct aspects of human behavior. The tonic firing mode involves a slow and steady release of dopamine that maintains the baseline levels necessary for proper brain function. Tonically fired dopamine binds with and activates autoreceptors on presynaptic neurons, which regulate dopamine synthesis and release; it cannot activate or produce a physiological response in postsynaptic receptors. In phasic mode, dopamine neurons sharply increase or decrease their firing rate based on events or stimuli with motivational significance. For example, where an action yields more reward than predicted (positive prediction error), the neurons fire in short, high frequency bursts, rapidly increasing the concentration of synaptic dopamine. The release of dopamine and accompanying positive feelings motivate repetition of the rewarding activity. In contrast, where a reward is worse than predicted (negative prediction error), phasic firing activity drops, sharply decreasing synaptic dopamine concentrations. This "dip" in dopamine levels and the accompanying negative feelings motivate avoidance of the aversive activity. In either scenario, learning occurs and behavior changes.
Dr. Bechara opines that Abilify may cause pathological gambling and impulse control disorders by preventing the dopamine "dip" that is critical for "teach[ing]" an individual to avoid activities with negative consequences. See Bechara Rep., ECF No. 423-1 at 11. According to Dr. Bechara, Abilify's functional antagonism at 90% of D2receptors signals a drop in baseline dopamine concentration, which triggers increased tonic transmission of dopamine. The excess tonically fired dopamine accumulates in the synapses and offsets, or blocks the effects of, the phasic dopamine dips associated with negative prediction errors. Without the phasic dips, no negative dopaminergic signal is sent when an activity should be stopped and avoided. The behavioral effect is an increase in risky, reward-directed activities, such as pathological gambling and other impulse control disorders, despite the potential for and occurrence of negative consequences.
As support for his negative reward prediction error opinion, Dr. Bechara relies heavily on the findings of a 2006 study investigating reward and punishment processing in Parkinson's disease patients taking one or more dopamine replacement medications, none of which was Abilify.113
*1343See Roshan Cools et al., Reversal Learning in Parkinson's Disease Depends on Medication Status and Outcome Valence , 44 NEUROPSYCHOLOGIA 1663 (2006) ("Cools Study"), DX-143. The Cools Study found that patients on dopamine replacement medications exhibited "significantly impaired" capacity to process and learn from unexpected negative outcomes (i.e. , punishment) relative to healthy controls. See id. at 1670, DX-143 at 8. Consistent with theoretical models proposed in earlier medical literature, the Cools Study attributed the patients' negative reward prediction errors to artificially high tonic dopamine levels induced by the dopamine replacement medications, which the authors hypothesized as having functionally eliminated the effectiveness of phasic dopamine dips. See id. at 1669, DX-143 at 7.
The Court finds that the Cools Study cannot reliably establish biological plausibility in this case because it involved dopamine replacement medications that either directly increase dopamine levels in the brain (e.g. , Levodopa ) or directly stimulate dopamine receptors, including D2receptors, by mimicking the activity of endogenous dopamine (e.g. , full agonists like Mirapex). None of the drugs in the Cools Study were functional antagonists at D2receptors like Abilify, blocking dopamine neurotransmission at those sites. Importantly, none of Plaintiffs' experts explained why the Cools Study's findings as to the behavioral effects of stimulating D2receptors through dopamine replacement therapy can be extrapolated to reliably predict the behavioral effects of a D2receptor antagonist. See McClain ,
Additionally, a 2015 study of reversal learning in individuals taking the D2receptor antagonist Sulpiride, which was cited by Dr. Hollander, also presents an extrapolation problem, although it is a closer call. See L. Janssen et al., Abnormal Modulation of Reward Versus Punishment Learning by a Dopamine D2-Receptor Antagonist in Pathological Gamblers , 232 PSYCHOPHARMACOLOGY 3345 (2015) ("Janssen Study"), DX-189. The Janssen Study found that administration of the drug Sulpiride impaired reversal learning in healthy controls, but did not appear to alter reversal learning in pathological gamblers. The Study's authors also described the "seemingly paradoxical" state of the scientific literature with respect to a relationship between D2receptor antagonism and reward prediction error learning: some studies report that D2receptor antagonists impaired reward prediction error learning, while other studies report that they improved it. See id. at 3350-51, DX-189 at 6-7. None of the studies investigating D2receptor antagonism and reward prediction errors involved Abilify. Moreover, none of Plaintiffs' experts even attempted to explain how or why Abilify is sufficiently similar to Sulpiride in its mechanism of *1344action to warrant an extrapolation. This is significant because within a given class of drugs-such as D2receptor antagonists-there may be "great chemical diversity" and those "minor deviations in chemical structure can radically change a particular substance's properties and propensities." See Rider ,
e. Conclusion
In sum, the Court finds Plaintiffs' experts' biological plausibility opinions that Abilify can cause impulse control problems through its effects on dopamine neurotransmission in the brain to be scientifically reliable, based on current biochemistry and pharmacological knowledge. Each element of this proposed mechanism of action is adequately supported by peer-reviewed, published scientific literature and sound scientific reasoning. Moreover, Plaintiffs' experts' opinions are consistent with the FDA's assessment, based on the scientific literature, that Abilify's partial agonism, upregulation, and sensitization "could theoretically stimulate dopamine transmission in the mesolimbic pathway, a core component of the brain reward circuitry, providing biological plausibility for treatment-emergent [impulse control disorders ]." See FDA Pharm. Vigil., ECF No. 428-11 at 4, 29. The opinions are also consistent with [* * * REDACTED * * *] . Finally, Plaintiffs' experts' proposed mechanism of action is consistent with [* * * REDACTED * * *] .114 [* * * REDACTED * * *] . Although this biological plausibility evidence, standing alone, cannot establish general causation, it may "lend[ ] credence to an inference of causality" drawn from other, more substantial evidence. See Ref. Man. at 604; see also Chapman ,
5. Case Studies and Adverse Event Reports
Since 2010, there have been hundreds of reports of gambling and/or impulse control disorders in patients treated with Abilify. A number of the reports are published case studies that contain details about dosage, duration of use, concomitant medications, comorbid conditions, and other pertinent clinical information.115 Many *1345more involve adverse event reports submitted to Defendants or the FDA, with varying levels of narrative detail about the patient and the relevant medical circumstances.116 Defendants argue, broadly, that case studies and adverse event reports cannot reliably support a general causation opinion in the Eleventh Circuit. This is misplaced.
Although it is true that case studies and other anecdotal evidence may not, standing alone, support a general causation opinion, Rider ,
6. Disproportionality Analyses
Several statistical analyses, called disproportionality analyses, have been conducted by the FDA and Defendant Otsuka on the FAERS and VigiBase adverse event reporting databases, comparing the relative frequency of pathological gambling reports among various patient populations.117 Disproportionality analysis is an industry standard pharmacovigilance technique used to detect and evaluate safety signals-that is, the existence of an excess of reported adverse medical events-associated with the use of FDA-regulated medical products. See FDA Pharm. Guide, DX-299 at 7, 11; see also Fosamax ,
As the Court already discussed, the FDA's disproportionality analysis of the FAERS database found a statistically significant, disproportionately higher proportion of patients reporting pathological gambling with Abilify relative to all other atypical antipsychotics. See FDA Pharm. Vigil., ECF No. 428-11 at 28. The FDA calculated an EB05 score of 6.304 for this finding, which represents a statistically significant result. Defendant Otsuka [* * * REDACTED * * *] .
Defendants argue, again broadly, that disproportionality analyses cannot establish causation. The Court agrees. The safety signals identified through disproportionality analyses in this case "do not, by themselves, demonstrate [a] causal association." See FDA Pharm. Vigil., ECF No. 428-11 at 28. However, they do reliably support a conclusion that pathological gambling is disproportionately reported with Abilify relative to all other antipsychotics. See
D. Expert-Specific Challenges
1. Plaintiffs' Experts
a. Antoine Bechara, Ph.D.
Dr. Antoine Bechara is a professor of neuroscience and psychology at the University of Southern California with extensive professional experience in neurobiology and, in particular, the anatomical and neurotransmitter systems involved in human decision-making, behavioral addictions, and gambling. ECF No. 423-1 at 2. He is offered primarily for the purpose of explaining how Abilify can cause Plaintiffs' impulse control disorders. More specifically, Dr. Bechara has offered his opinion that there is a biologically plausible mechanism by which Abilify causes impulsive gambling and other impulse control behaviors, *1347namely, its effect on dopamine neurotransmission in the brain. Defendants challenge Dr. Bechara's testimony on qualification and reliability grounds. The Court has already found that the science on which Dr. Bechara based his biological plausibility opinion is reliable. See supra Section II(C). Therefore, the only question that remains to be resolved with respect to Dr. Bechara is whether he is qualified to render an expert opinion in this case.
Defendants argue that Dr. Bechara is not qualified to offer opinions on biological plausibility or general causation because he does not have a medical degree or a degree in pharmacology, has never diagnosed or treated patients with impulse control disorders, and has conducted no independent studies into how Abilify affects brain chemistry. As to biological plausibility, the Court disagrees. First, the record evidence reflects that Dr. Bechara does, in fact, have "a university degree in pharmacology from the University of Toronto," as well as a Ph.D. in neuroscience. ECF No. 423-1 at 80-82. More importantly, Dr. Bechara has over 25 years of clinical experience studying, publishing, and teaching courses on brain function and the effects of drugs-both prescription and street drugs-on human behavior. Of particular relevance to this case is the extensive research Dr. Bechara has conducted on dopamine systems and the neurobiological mechanisms of human decision-making, substance use and abuse, and behavioral and psychiatric disorders, including impulsive gambling and other impulse control disorders. He has written and collaborated on hundreds of peer-reviewed articles, papers, and book chapters on these subjects. Finally, Dr. Bechara developed the Iowa Gambling Task, which is currently used worldwide to detect and measure brain dysfunction and decision-making deficits in numerous clinical populations. As Dr. Bechara has not been offered as a medical doctor, it is irrelevant that he lacks a medical degree. Given the breadth of Dr. Bechara's knowledge and clinical experience in the field of neurobiology, the fact that he had not studied Abilify until he became involved in this case does not disqualify him from reviewing the scientific literature and offering an expert opinion on Abilify's mechanism of action.118
As to a more comprehensive general causation opinion-that is, an opinion beyond the neurobiological mechanisms by which Abilify can cause pathological gambling or impulse control disorders-the Court agrees with Defendants. Although Dr. Bechara's expert reports frequently frame his conclusions in very broad and definitive language (i.e. , explaining that Abilify"causes" impulsive behaviors, rather than how it "can cause" the behaviors), most of the scientific support for his positions relates only to biological plausibility. His opinion does not meaningfully depend on any of the three categories of primary evidence considered indispensable in the Eleventh Circuit. He did not perform a Bradford Hill or weight-of-the-evidence analysis of general causation.119 These facts do not disqualify him from testifying as an expert regarding Abilify's biological mechanism of action, but they do preclude him from offering a comprehensive general causation opinion. Accordingly, Defendants' Motion to Exclude the General Causation Opinion of Antoine Bechara, ECF
*1348No. 423, is granted with respect to medical causation and denied with respect to biological plausibility.
b. Joseph Glenmullen, M.D.
Joseph Glenmullen, M.D. is a board-certified psychiatrist and lecturer in psychiatry at Harvard Medical School, with more than 30 years of clinical experience treating psychiatric patients in private practice. Dr. Glenmullen offers a general causation opinion that Abilify is capable of causing pathological gambling and impulse control disorders. Dr. Glenmullen supports his opinion with epidemiological evidence (i.e. , the Etminan Study), medical literature evidencing a plausible mechanism of action, case and adverse event reports, disproportionality analyses and clinical trial data, all of which he analyzed under the Bradford Hill factors.120 Defendants challenge Dr. Glenmullen's testimony on qualification and reliability grounds.
i. Qualification
Defendants argue that Dr. Glenmullen lacks the requisite expertise to offer opinions related to general causation, such as biological plausibility, epidemiology, toxicology, biostatistics, FDA regulations, and pathological gambling. In essence, Defendants contend that Dr. Glenmullen's medical education, post-graduate training, and professional experience in the field of psychiatry do not translate into qualifications that enable him to testify competently based on the scientific evidence in this case. Defendants read the "qualification" prong of Rule 702 too stringently. "An expert is not necessarily unqualified simply because [his] experience does not precisely match the matter at hand." Furmanite Am., Inc. v. T.D. Williamson, Inc. ,
In this case, the Court finds Dr. Glenmullen at least minimally qualified to offer expert opinions that will assist the trier of fact in understanding and resolving general causation issues related to biological plausibility, epidemiology, toxicology, and pathological gambling. Again, Dr. Glenmullen is a medical doctor and board-certified psychiatrist who has spent most of his career training psychiatric residents at Harvard Medical School and treating psychiatric patients in private practice, including "plenty of" patients with pathological gambling or impulse control disorders, albeit none with a diagnosis of drug-induced pathological gambling.122 See Glenmullen *1349Tr., ECF No. 596-2 at 135-36. Notably, he has authored two books on the side effects of psychiatric medications and co-authored five peer-reviewed published studies related to the neuropsychopharmacology of psychiatric or dopamine agonist medications. See Glenmullen Curriculum Vitae, ECF No. 457-1 at 140-41; see also Glenmullen Tr., ECF No. 596-2 at 13. In recent years, much of his time has been devoted to forensic or expert consulting work on legal cases involving adverse side effects of psychiatric medications. Indeed, Dr. Glenmullen has been qualified as an expert on general causation by numerous federal courts in pharmaceutical products liability cases.123
The fact that Dr. Glenmullen is not an epidemiologist does not disqualify him from testifying about epidemiological studies. See United States v. Thorn ,
ii. Reliability and Helpfulness
Defendants challenge the reliability of Dr. Glenmullen's methodology on two primary grounds. First, they argue that the evidence on which Dr. Glenmullen bases his opinion is unreliable and, thus, insufficient to support his opinion. Second, Defendants maintain that Dr. Glenmullen did not reliably apply the Bradford Hill factors in reaching his conclusion on general causation. With one exception, the Court disagrees.
With respect to the evidence, the Court has already found that most of the scientific literature on which Dr. Glenmullen relied, including the Etminan Study, is sufficiently reliable to support or bolster his general causation opinion. See supra Section II(C). However, one of the studies cited by Dr. Glenmullen, referred to by the parties as the Moore Study, must be excluded as unhelpful in this case. See Thomas J. Moore et al., Reports of Pathological Gambling, Hypersexuality, and Compulsive Shopping Associated with Dopamine Receptor Agonist Drugs , 174 JAMA INTERNAL MED. 1930, 1930-33 (2014) ("Moore Study"), ECF No. 428-10 at 2-5. The Moore Study is based on a disproportionality analysis of the FAERS database examining the association between six dopamine receptor agonist drugs and "unusual but severe" impulsive behaviors.125 See id. at 1931, ECF No. 428-10 at 3. The Moore Study found that those six drugs had a statistically significant higher proportion of patients reporting impulse control disorders from 2003 to 2012, when compared to "all other drugs" in the FAERS database. See id. at 1931, ECF No. 428-10 at 3.
The Court has no reason to doubt the reliability of the Moore Study's methodology or findings as to those six drugs. But as to Abilify, "there is simply too great an analytical gap" between the Moore Study and any conclusion about a possible association between Abilify and reports of severe impulsive behaviors. See Joiner ,
Defendants final argument for excluding Dr. Glenmullen is that he did not reliably apply the Bradford Hill factors in reaching his general causation opinion. More specifically, Defendants contend that Dr. Glenmullen erred by applying the Bradford Hill factors at all because there is no reliable epidemiological study in existence finding a statistically significant association between Abilify and impulsive behaviors. Since the Court has already found that the Etminan Study reliably establishes the requisite association, this challenge is moot.
Defendants also argue that even if Dr. Glenmullen had statistically significant epidemiological evidence of an association between Abilify and compulsive behaviors, he misapplied the Bradford Hill factors by "giv[ing] all of the criteria equal weight" and "discussing each criteria in check-the-box fashion." See Def. Glenmullen Motion, ECF No. 424-15 at 37.128 The Court disagrees. As discussed in Section II(B) above, the following nine Bradford Hill factors guide scientists in making judgments about causation: (1) temporal relationship; (2) strength of the association; (3) dose-response relationship; (4) consistency *1352or replication of the findings; (5) biological plausibility; (6) consideration of alternative explanations; (7) cessation of exposure; (8) specificity of the association; and (9) consistency with other knowledge. See Ref. Man. at 599-600. Importantly, "[t]here is no formula or algorithm that can be used to assess whether a causal inference is appropriate based on the" Bradford Hill factors. See Ref. Man. at 600. The drawing of causal inferences "requires judgment and searching analysis ... informed by scientific expertise" and reasonable scientists reliably applying the Bradford Hill factors may come to different conclusions about whether a causal inference is appropriate. See id.; see also Milward ,
Dr. Glenmullen began his Bradford Hill analysis by assessing the "experiment" and "strength of association" factors, which address whether a body of experimental findings exists showing a statistically significant association between a drug and disease of interest. See Ref. Man. at 602. Dr. Glenmullen identified several experimental studies showing a statistically significant association between either (1) Abilify and diagnoses of gambling and other impulse control disorders129 or (2) Abilify and FDA adverse event reports of pathological gambling, hypersexuality, impulsive behavior, and other impulse control disorders.130 See Glenmullen Rep., ECF No. 424-1 at 132-33.131 It is worth noting that Defendants have not challenged the accuracy of these statistical calculations. Dr. Glenmullen also addressed the consistency factor, see
Regarding temporality and cessation of exposure, Defendants concede that the numerous case studies cited by Dr. Glenmullen "show ... a temporal relationship" between the use of Abilify and "a change in the presence or severity of symptoms" of gambling and other impulse control disorders. See Def. Glenmullen Motion, ECF No. 424-15 at 24. These case studies, as well as the many adverse event reports Dr. Glenmullen describes, are strongly suggestive of a dose-response relationship between Abilify, gambling and other impulse control disorders. Dr. Glenmullen also references [* * * REDACTED * * *] .
*1353See Glenmullen Rep., ECF No. 424-1 at 134. Defendants do not question Dr. Glenmullen's characterization of the clinical trial data.
Dr. Glenmullen also considered alternative explanations for the association between Abilify, impulsive gambling, and other impulse control disorders by reference to the Etminan Study, FDA's disproportionality analysis, Bristol-Myers Squibb disproportionality analyses and clinical trial data, and other medical literature. See
As to biological plausibility, Dr. Glenmullen concluded from the medical literature, as did Plaintiffs' other experts, that the biological mechanism by which Abilify can cause impulsive behaviors is its effect on dopamine neurotransmission in the brain. See
On balance, the Court finds that Dr. Glenmullen's application of the Bradford Hill factors is sufficiently reliable to support a conclusion that the observed association between Abilify and impulsive behaviors, such as pathological gambling, reflects a "true cause-effect relationship." See Ref. Man. at 597. Accordingly, Defendants' Motion to Exclude the General Causation Opinion of Joseph Glenmullen, ECF No. 424-15, is due to be denied.132
c. Eric Hollander, M.D.
Dr. Eric Hollander is a board-certified psychiatrist and clinical professor at Albert Einstein College of Medicine, with specialized training and experience in the fields of psychopharmacology and neuropsychopharmacology,133 as well as over thirty years of clinical practice experience treating individuals with impulsive and compulsive behaviors, including pathological gambling, depression, schizophrenia, autism spectrum disorder, and bipolar disorder. See Hollander Rep., ECF No. 459-1 at 3-4. Dr. Hollander offers a general causation opinion that Abilify can cause impulsive behaviors, including drug-induced gambling. See id. at 8-9, 12.134 Dr. Hollander *1354supports his opinion with epidemiological evidence (i.e. , the Etminan Study), scientific literature supporting a plausible biological mechanism of action, animal and in vitro data, case and adverse event reports, including dechallenge and rechallenge events, disproportionality analyses, and Defendants' clinical trial data, all of which he analyzed using the Bradford Hill factors and a weight-of-the-evidence methodology. See Hollander Tr., ECF No. 596-4 at 117-18. Defendants challenge Dr. Hollander's testimony on qualification and reliability grounds.
Defendants argue that Dr. Hollander is not qualified to offer a general causation opinion because he lacks sufficient training and experience in the fields of epidemiology and toxicology. The Court disagrees. As already explained, a witness may be qualified "by knowledge, skill, experience, training, or education" to offer an expert opinion that will help the trier of fact understand the evidence or resolve a factual issue. See Fed. R. Evid. 702. The qualification standard is "not stringent" and "so long as the witness is minimally qualified, objections to the level of [his] expertise go to credibility and weight, not admissibility." Hendrix I ,
In this case, the Court finds that Dr. Hollander is amply qualified to offer an expert opinion on whether Abilify can cause impulse control disorders. Dr. Hollander is a medical doctor and board-certified psychiatrist with over thirty years of experience researching, publishing, and teaching in the fields of psychopharmacology and neuropsychopharmacology. See Hollander Curriculum Vitae, ECF No. 459-1 at 38-96. This background, with its emphasis on the study of how psychiatric drugs affect brain chemistry and behavior, well equips Dr. Hollander to assist the trier of fact in understanding the biological mechanisms by which Abilify can cause impulsive behaviors. Dr. Hollander also has formal training in epidemiology, has "worked closely with epidemiologists to publish epidemiologic papers in peer review[ed] journals," and as an academic, has taught "epidemiologic principles as it relates to psychiatry and psychopharmacology" to "medical students, residents, and fellows." See Hollander Tr., 596-4 at 114-15. This specialized education and experience with epidemiology qualifies Dr. Hollander to give an expert opinion about the epidemiological study in this case (i.e. , the Etminan Study). See Thorn ,
Notably, Defendants do not dispute that Dr. Hollander is a leading expert on the etiology and treatment of impulse control disorders, including impulsive gambling. Indeed, Dr. Hollander was a member of the research agenda workgroup that, quite literally, wrote the DSM-IV diagnostic criteria for pathological gambling and, several years later, he oversaw the reorganization of the DSM-5 diagnostic criteria for gambling disorder and impulse control disorders.135 See Hollander Tr., 596-4 at 113-14. Dr. Hollander also has written and collaborated on hundreds of peer-reviewed articles related to uncontrollable impulsive behaviors, such as pathological gambling, and the brain circuitry underlying these psychiatric problems. See Hollander Curriculum *1355Vitae, ECF No. 459-1 at 57-96. Finally, Dr. Hollander has treated thousands of patients with impulse control disorders, including hundreds with gambling disorders. See Hollander Tr., ECF No. 596-4 at 111. Given the breadth of Dr. Hollander's academic and clinical experience in the fields of psychiatry, psychopharmacology, and neuropsychopharmacology, the Court finds him qualified to offer an expert opinion on general causation in this case. Objections to the level of Dr. Hollander's expertise go to the credibility and weight of his opinion, not its admissibility. See Hendrix I ,
ii. Reliability
Defendants challenge the reliability of Dr. Hollander's general causation opinion on two primary grounds. First, they argue that the evidence on which Dr. Hollander bases his opinion is unreliable and, thus, insufficient to support his opinion. Second, Defendants maintain that Dr. Hollander did not reliably analyze the evidence in reaching his conclusion on general causation.
Regarding the evidence, the Court has already found that most of the scientific literature on which Dr. Hollander relied, including the Etminan Study, is sufficiently reliable to support or bolster his general causation opinion. See supra Section II(C). Only one of Defendants' specific evidentiary challenges warrants additional comment. As part of the support for his general causation opinion, Dr. Hollander cites a 2016 article from the scientific literature comparing the characteristics of "possibly iatrogenic" problem gambling in patients taking Abilify with the characteristics of such gambling in patients taking a full dopamine replacement therapy.136 ,137 See Marie Grall-Bronnec et al., Pathological Gambling Associated with Aripiprazole or Dopamine Replacement Therapy: Do Patients Share the Same Features? A Review , 36 J. CLINICAL PSYCHOPHARMACOLOGY 63, 64 (2016) ("Grall-Bronnec Article"), ECF No. 425-4 at 2, 3. Defendants argue that the Grall-Bronnec Article is not a valid epidemiological study and, therefore, cannot support a general causation opinion. See Def. Hollander Motion, ECF No. 425-14 at 13.138
The problem with Defendants' challenge to the Grall-Bronnec Article is that neither Dr. Hollander nor the Article's authors offered the Article as epidemiological evidence of causation. See Hollander Rep., ECF No. 459-1 at 22; Grall-Bronnec Article, ECF No. 425-4 at 7. Defendants' argument appears to be based on a misinterpretation of the authors' use of the term "cohort" to describe the "problem gamblers" who were interviewed as part of their research. A "cohort," as defined by Merriam-Webster, is "a group of individuals having a statistical factor (such as age or class membership) in common in a demographic study." See Merriam-Webster *1356Online Dictionary, https://www.merriam-webster.com/dictionary/cohort (retrieved Dec. 3, 2017). In this case, the Grall-Bronnec Article's authors evaluated a group of individuals with the statistical factors of problem gambling and Abilify use in common. Thus, the term "cohort" aptly describes the subjects of their work. A "cohort," as used in this context, differs from a "cohort study," which is a type of epidemiological study used to "measure and compare the incidence of disease" in certain populations. See Ref. Man. at 557. Neither Dr. Hollander nor the Article's authors characterize the Grall-Bronnec Article as a cohort study, and neither treats the Article's findings as carrying the same weight as epidemiology. Indeed, the Grall-Bronnec Article's authors actually recommend a cohort study as "a promising way to obtain further evidence" on causation. See Grall-Bronnec Article, ECF No. 425-4 at 7.
While the Court agrees that the Grall-Bronnec Article is not based on epidemiology, that fact does not preclude Dr. Hollander from relying on the Article as support for his general causation opinion. The Grall-Bronnec Article's authors' objective was to further scientific understanding of the nature of iatrogenic gambling by analyzing the sociodemographic profiles, gambling characteristics, comorbidities, and personality traits of patients whose "problem gambling" behaviors "could possibly result from an adverse drug reaction after the administration of a dopamine medication." See id. , ECF No. 425-4 at 3-4. The authors identified nine published case reports and conducted in-person clinical evaluations of eight individual patients in treatment for problem gambling, resulting in 17 discrete cases involving the use of Abilify.139 See id. From this anecdotal data, the Article's authors concluded it was "possible" that the gambling behavior in 16 of the 17 cases was "actually due to" Abilify, but cautioned that more research would be necessary before the relationship could be characterized as causal.140 See id. at 4, 7. Notably, Defendants do not challenge the reliability of the authors' methodology, findings, or substantive conclusions.
The Court finds that the Grall-Bronnec Article presents a reliable and probative analysis of 17 patients' personal experiences while taking Abilify. In particular, the authors' in-depth clinical assessments and comparisons of the eight individual patients facilitate understanding and evaluation of the characteristics associated with "possibly" iatrogenic (medication-induced) gambling.141 Nevertheless, the Grall-Bronnec Article is not quantitative research and, as acknowledged by the authors, its results cannot be generalized to definitively establish that Abilify causes compulsive gambling. See id. at 7. The Article essentially is a compilation of thoroughly examined case studies and, therefore, it cannot, standing alone, prove general causation. See Rider ,
Defendants' last argument for excluding Dr. Hollander is that he did not reliably analyze the scientific evidence in this case. More specifically, Defendants contend that Dr. Hollander improperly relied on the Naranjo Scale and WHO-UMC criteria, which are specific causation methodologies, to reach his general causation opinion.143 Defendants also argue, in the alternative, that Dr. Hollander did not reliably apply the Bradford Hill factors. The Court disagrees.
With respect to the Naranjo Scale and WHO-UMC criteria, Defendants' argument is misplaced because Dr. Hollander did not employ either technique during his analysis of the scientific evidence in this case. Dr. Hollander testified that he used a weight-of-the-evidence methodology and fully considered all of the Bradford Hill factors. See Hollander Tr., ECF No. 596-4 at 117-19. This is evident from Dr. Hollander's initial expert report, which, in addition to explicitly citing his reliance on the Bradford Hill factors, demonstrates that he applied those factors, in substance, in reaching his general causation opinion. See Hollander Rep., ECF No. 459-1. Dr. Hollander only ever mentions the Naranjo Scale or WHO-UMC criteria twice-once to identify them as "additional method[s]" for determining whether a drug caused an isolated adverse medical event, see id. at 12, and once to disclose that the authors of the Grall-Bronnec Article used the Naranjo Scale to assess whether Abilify caused the "problem gambling" behaviors exhibited by individual patients in their cohort, see id. at 22.144 Defendant has not referenced, and the Court has not found, any other instance in which Dr. Hollander further discussed either the Naranjo Scale or the WHO-UMC criteria in his report or in his testimony, much less relied on them in forming his causation opinion. Consequently, this challenge fails.
Defendants' challenge to the reliability of Dr. Hollander's application of the Bradford Hill factors also fails. As an initial matter, Defendants' argument that Dr. Hollander erred by considering the Bradford Hill factors at all is moot because the prerequisite for applying those factors-that is, an epidemiological study reliably establishing a statistically significant association between the use of a drug and an adverse medical effect-is satisfied by the Etminan Study. See Section II(C). Thus, the only remaining question is whether Dr. Hollander reliably weighed the Bradford *1358Hill factors as part of his general causation analysis.145 The Court finds that he did.
Dr. Hollander found a "very strong" association between Abilify and impulse control disorders based on his assessments of the Etminan Study, the FDA's 2016 Pharmacovigilance Review and [* * * REDACTED * * *] . See Hollander Tr., 596-5 at 37. As the Court has already observed, this evidence reliably establishes the existence of a statistically significant association between both (1) Abilify and medical diagnoses of pathological gambling and other impulse control disorders ; and (2) Abilify and adverse event reports of pathological gambling and other impulse control disorders. The Bradford Hill factor of specificity is also met, as the association in this case involves only the very narrow and specific adverse effect of impulse control problems. Dr. Hollander found that the evidence also reliably demonstrates the Bradford Hill factor of consistency, in that the association has been shown to be consistently present in a number of different analyses using different criteria, populations and methods. See Hollander Rep., 459-1 at 27; Hollander Tr., ECF No. 596-5 at 36. As Dr. Hollander noted, there does not appear to be "any evidence at all that suggests" there is no association between Abilify and impulsive behaviors. See Hollander Tr., ECF No. 596-5 at 38.
As to temporality, Dr. Hollander cites numerous case studies and adverse event reports in which impulsive behaviors emerged only after a patient's exposure to Abilify. See Hollander Rep., ECF No. 459-1 at 23. These case studies and adverse event reports, although not dispositive of the issue, also are strongly suggestive of a dose-response relationship between Abilify and impulse control disorders. See Section II(C); Hollander Rep., ECF No. 459-1 at 30-31. Moreover, the reports of dechallenge events, in particular, satisfy the Bradford Hill factor of cessation of exposure, as they reliably demonstrate that, with many individual patients, impulse control problems disappeared once Abilify was decreased or discontinued.146
Much like Dr. Glenmullen, Dr. Hollander ruled out alternative explanations for the association between Abilify and impulsive behaviors by reference to the Etminan Study and the FDA's 2016 Pharmacovigilance Review, as well as to case studies describing dechallenge events. According to Dr. Hollander, the FDA's disproportionality analysis of 11 different atypical antipsychotics is particularly significant because, although those medications all treat the same patient population with the same underlying conditions, only Abilify showed a statistically significant incidence of adverse event reports involving uncontrollable impulsive behaviors. See Hollander Tr., ECF No. 596-1 at 25-27. Dr. Hollander concluded that if the patients' underlying psychiatric conditions caused the uncontrollable impulses, then all of the atypical antipsychotics should have had statistically significant reporting of impulse control problems. See id. Dr. Hollander observed that the Etminan Study specifically controlled for bipolar disorder, schizophrenia, and substance abuse disorder, which ruled out those conditions as possible explanations for the association between Abilify and impulsive behaviors. See Hollander *1359Rep., ECF No. 459-1 at 33; Hollander Tr., 596-5 at 71.
Regarding the Bradford Hill factor of biological plausibility, Dr. Hollander's opinion as to Abilify's mechanism of action "mirror[s]" that of Plaintiffs' neurobiology expert, Dr. Antoine Bechara, see Def. Hollander Motion, ECF No. 425-14 at 24, and is reliable for the same reasons, see Section II(C). This proposed biological mechanism of action-Abilify's effect on dopamine neurotransmission in the brain-is coherent with existing scientific knowledge about psychopharmacology, neuropsychopharmacology, and the biochemistry of the brain. See Section II(C). Importantly, Dr. Hollander demonstrated a comprehensive understanding of the scientific evidence in support of his opinion. In sum, the Court finds that Dr. Hollander reliably considered all of the Bradford Hill factors in reaching his opinion that Abilify can cause impulse control problems. Dr. Hollander also reliably explained his methodology, reasoning and conclusions at length, both in his expert reports and at the Daubert hearing. See Hollander Rep., ECF No. 459-1 at 1-36; Hollander Supp., DX-641;147 Hollander Tr., ECF Nos. 596-4 at 108-45, 596-5. For these reasons, Dr. Hollander's expert opinion is sufficiently reliable under Rule 702 and Daubert. Accordingly, Defendants' Motion to Exclude the General Causation Opinion of Eric Hollander, ECF No. 425-14, is due to be denied.
d. Russell V. Luepker, M.D.
Dr. Russell V. Luepker is a board-certified cardiologist, and a professor of public health and medicine at the University of Minnesota. He holds a master's degree in epidemiology from Harvard University, is certified in epidemiology by the American College of Epidemiology, and served as head of the Division of Epidemiology at the University of Minnesota for over 13 years. Dr. Luepker also has over 40 years of experience researching, publishing, and teaching on the "design, implementation and interpretation of clinical research" methods. See Luepker Rep., ECF No. 462-1 at 3.148 There is no dispute that Dr. Luepker possesses the formal credentials necessary to offer an expert opinion on medical causation. The Court's concern with respect to Dr. Luepker, based on his expert reports and deposition testimony, is that he does not appear to have brought his considerable expertise to bear in his analysis of the evidence in this case. See Luepker Rep., ECF No. 462-1 at 2-15; Luepker Supp., ECF No. 426-5 at 2-10; Luepker Dep., ECF No. 462-1 at 97-181.149 This presents a reliability problem under Daubert that Plaintiffs have not overcome.
The "primary focus" of Dr. Luepker's "teaching, research, and clinical career" has been epidemiology and other types of clinical research in humans. See Luepker Rep., ECF No. 462-1 at 2. The Court is of the view that this background well equips him to offer unique insights into the methodological soundness of the only epidemiological evidence in this case, the Etminan Study. Yet, Dr. Luepker devotes just a single paragraph of his initial expert report to the Etminan Study, in which he provides only a cursory statement of the Study's findings and nothing more. See id. at 10. Almost two pages of his rebuttal report discuss the Etminan Study further, but this too lacks any meaningful analysis *1360beyond general assertions about health insurance claims database research becoming a "major trend[ ] in epidemiology over the past 10 years." See Luepker Supp., ECF No. 426-5 at 3. Dr. Luepker also failed to meaningfully examine the background risk of pathological gambling and other impulse control problems in either the general or psychiatric patient populations. Although Dr. Luepker expressed "some hesitation" and "worry" about Dr. Potenza's background risk estimates, he did not attempt to independently verify the accuracy of those figures. See Luepker Dep., ECF No. 462-1 at 118-19. Since the aim of epidemiology is to "identif[y] agents that are associated with an increased risk of disease," the Court would expect a more robust background risk analysis from an expert epidemiologist. See Ref. Man. at 552. Equally, if not more troubling is Dr. Luepker's opinion that a published case series, and even a single case report, are "definitely" types of epidemiological studies. See Luepker Dep., ECF No. 462-1 at 128. Both from a scientific perspective and for legal causation purposes, the distinction between epidemiological evidence and anecdotal evidence (i.e. , case series and case reports) is substantial and consequential. Dr. Luepker, apparently, disagrees.
There are also Daubert reliability problems with Dr. Luepker's general causation analysis. First, he employed the WHO-UMC causality criteria, which, as the Court has already discussed, see Section (II)(D)(1)(c)(ii), is a scientific tool designed to assess specific causation, see WHO-UMC Reference at 1. It "cannot" be used to prove general causation. See id. Second, Dr. Luepker's explanation of the biological mechanism by which Abilify can cause impulse control problems is inadequate, likely because much of the subject matter is, by his own admission, beyond the scope of his expertise.150 Indeed, he does not appear to have much more than a superficial understanding of how dopamine functions in the brain. He readily conceded as much at his deposition, testifying that he has only "some ancillary knowledge" about dopamine binding, intrinsic activity, in vivo and in vitro toxicological studies of activity at dopamine receptors, and dopaminergic drugs, including Abilify. See Luepker Dep., ECF No. 462-1 at 114-16. As a result, Dr. Luepker's initial expert report speaks in overly broad and general terms about the complex and nuanced proposed mechanism of action in this case. While the report contains a lengthy appendix of scientific literature that he "reviewed" or "relied upon" as part of his general causation analysis, at no point does he directly connect these publications to his own biological plausibility analysis.151 In other words, *1361there is very little evidence, based on Dr. Luepker's written submissions and deposition testimony, that these materials meaningfully informed his biological plausibility opinion. This is unacceptable, given Dr. Luepker's unfamiliarity with the biochemistry of the brain.
Taken together, these are not insignificant failings and they cannot be cured by the fact that Dr. Luepker's conclusions are consistent with those of Plaintiffs' other experts. See In re Polypropylene Carpet Antitrust Litig. ,
e. David Madigan, Ph.D.
Dr. David Madigan is a biostatistician with over thirty years of experience researching, publishing, teaching, and consulting in the fields of statistics, biostatistics, epidemiology, and pharmacovigilance. He is offered for the purposes of providing: (1) a biostatistical analysis of the scientific evidence in this case; (2) background and contextual information about pharmacovigilance practices, as well as the design and analysis of clinical trials; and (3) a medical causation opinion that Abilify is capable of causing the specific adverse effects of pathological gambling and impulse control disorder. Defendants challenge Dr. Madigan on qualification and reliability grounds.
Defendants argue that Dr. Madigan lacks the medical knowledge and experience to offer a general causation opinion. The Court agrees. "Dr. Madigan is a man of statistics, not medicine." See Def. Madigan Motion, ECF No. 427-20 at 9. He is not a medical doctor, toxicologist, pharmacologist, or psychologist. He also has no specialized knowledge of, or clinical experience with, pathological gambling or impulse control disorders. The Court finds that Dr. Madigan's admitted lack of expertise in the aforementioned fields precludes him from offering a medical or scientific opinion that Abilify is capable of causing pathological gambling and impulse control disorder.
Nevertheless, the Court finds Dr. Madigan amply qualified to offer a biostatistical analysis of the evidence in this case, as well as opinions related to pharmacovigilance and clinical trials generally, as his credentials in these fields are well beyond reasonable challenge. Briefly, Dr. Madigan is a Professor of Statistics at Columbia University, where he is also Dean of the Faculty and Executive Vice-President for Arts and Sciences. He holds a bachelor's *1362degree in Mathematical Sciences and a doctorate in Statistics. He is an elected Fellow of both the Institute of Mathematical Sciences and the American Statistical Association. He has published more than 160 peer-reviewed academic articles in the areas of statistics, biostatistics, epidemiology, and pharmacovigilance. Drug safety, with a focus on the development and application of statistical methods for pharmacovigilance, is a "significant research interest" of Dr. Madigan's. See Madigan Rep., ECF No. 427-1 at 2. Over the years, he has served the FDA in a number of different capacities related to the identification and evaluation of safety risks of medical products, and he currently serves the FDA as a consultant.152 He has also consulted for various pharmaceutical companies on issues related to statistics, drug safety, and clinical trials. Finally, Dr. Madigan has "extensive experience" designing and analyzing clinical trials, both as a consultant and in the academic context. See Madigan Tr., ECF No. 596-4 at 7.
Defendants do not dispute that Dr. Madigan is a leading expert on biostatistics, pharmacovigilance, and clinical trials. Indeed, Dr. Madigan has been qualified to offer expert opinions in these areas in numerous federal and state courts.153 Likewise here, the Court finds Dr. Madigan qualified to offer expert opinions on the design and analysis of clinical trials, pharmacovigilance, and to provide expert biostatistical analyses of the scientific evidence in this case, including, but not limited to, the Etminan Study, adverse event reports *1363in the FAERS database, various disproportionality analyses by Defendants and the FDA, and Defendants' clinical trial data.
ii. Dr. Madigan's Opinion
Dr. Madigan used a series of different statistical analyses to assess whether and to what extent the evidence in this case indicates the presence of an association between Abilify, pathological gambling, and impulse control disorders. The Court has already discussed Dr. Madigan's statistical analysis of the Etminan Study and his opinion that the Study evidences a "strong" association between Abilify and these two adverse effects. See supra Section II(C).
Dr. Madigan also conducted several disproportionality analyses of the FDA's adverse event reporting database (FAERS), comparing the relative frequency of pathological gambling reports among Abilify and 10 other atypical antipsychotics.154 To address concerns about potential litigation-driven reporting (i.e. , reporting bias), Dr. Madigan excluded all adverse event reports from lawyers and analyzed the data as of four different dates he considered significant in the life of this case.155 He also controlled for potential confounders by performing separate disproportionality analyses restricted to pathological gambling reports involving patients with bipolar disorder or schizophrenia. On each of the four dates, and in each of the separate analyses, Dr. Madigan found that Abilify had statistically significant percentages of pathological gambling reports.156 In other words, according to Dr. Madigan, the association between Abilify and pathological gambling reports was "very strong" at all times.157 Madigan Tr., ECF No. 596-4 at 23-24; Madigan Rep., ECF No. 427-1 at 19. None of the other atypical antipsychotics exhibited an association with pathological gambling reports. See Madigan Tr., ECF No. 596-4 at 23; Madigan Rep., ECF No. 427-1 at 19. Importantly, Defendants do not dispute Dr. Madigan's statistical calculations or findings. Indeed, Dr. Madigan's findings are consistent with the findings of [* * * REDACTED * * *] , and of the FDA's disproportionality analysis in 2016, see FDA Pharm. Vigil., ECF No. 428-11 at 27.
*1364Next, Dr. Madigan analyzed Defendants' clinical trial materials related to pathological gambling. He found that the clinical trials results reflected no patient reports of pathological gambling, so he analyzed the underlying trial data to determine whether the trial was sufficiently powered-essentially, whether it was large enough-to detect a statistically significant association between Abilify and pathological gambling, if in fact such an association existed.158 He found that it was not. More specifically, Dr. Madigan's analysis showed that Defendants' clinical trials were not large enough to detect a statistically significant increased risk of pathological gambling.159 Madigan Rep., ECF No. 427-1 at 30. Dr. Madigan further determined that, to have been adequately powered to detect a statistically significant association, the clinical trials would have needed to have been approximately five times larger than they were.160 See Madigan PPT, PX-051 at 10; Madigan Tr., ECF No. 596-4 at 33. Again, Defendants do not dispute Dr. Madigan's calculations.
Dr. Madigan also analyzed [* * * REDACTED * * *] . Dr. Madigan first calculated the frequency of these three categories of adverse effects in patients exposed to Abilify as compared with the frequency of those effects with comparator drugs and a placebo. This analysis yielded, in statistical terms, an estimate of the relative risk of developing the adverse effect among the three groups.161 See Ref. Man. at 566; see also Allison ,
*1365Based on Dr. Madigan's calculations, [* * * REDACTED * * *] . Dr. Madigan testified that the other five p -values, although not statistically significant, still indicate that the probability that chance alone explains the other relative risk ratios is "very slim." See Madigan Tr., ECF No. 596-4 at 37. [* * * REDACTED * * *] . According to Dr. Madigan, although the corresponding p -value, 0.08, is not statistically significant, it is still relevant because it indicates that the likelihood of the 2.7 relative risk being explained by chance is only 8%.163 See Madigan Tr., ECF No. 596-4 at 38-39. Dr. Madigan characterizes his findings with respect to the hypersexuality, impulsive behavior, and increased libido events reported during the clinical trials as evidence of a "trend or concern." See Madigan Tr., ECF No. 596-4 at 39; see also Madigan Rep., ECF No. 427-1 at 29 ("This shows a concerning trend against [Abilify ]."), [* * * REDACTED * * *] .
iii. Reliability
Defendants challenge the reliability of Dr. Madigan's methodology on multiple grounds.164 Since the Court has already found that Dr. Madigan is not qualified to offer expert opinions on medical causation, several of Defendants' reliability objections are now moot. The Court addresses the remaining objections in turn.
Defendants first challenge Dr. Madigan's expert opinions on the grounds that his initial expert report offers "no discernible methodology" as to how he reached his conclusions and that, at any rate, his opinions are not supported by any of the methodologies-epidemiology, dose-response, and background risk-that the Eleventh Circuit considers "indispensable" for proving that a drug can cause an adverse effect.165 See Chapman ,
Dr. Madigan's opinions are very clearly based on the application of widely accepted statistical methods to data drawn from the "indispensable" field of epidemiology (i.e. , the Etminan Study), the FAERS database, and Defendants' clinical trials. See Madigan Rep., ECF No. 427-1 at 2-30; Madigan Supp., ECF No. 427-1 at 79-92.166 Dr. Madigan's reports and testimony describe, in great detail, the precise steps he took to (1) evaluate the strengths and limitations of the Etminan Study; (2) to determine whether and to what extent a safety signal for pathological gambling existed for Abilify in the FAERS database; and (3) to assess whether Defendants' clinical trials were capable of detecting an association between pathological gambling and Abilify. Notably, Defendants do not challenge the accuracy and reliability of Dr. Madigan's calculations or offer an expert statistician to contradict or refute his mathematical conclusions. Given the scientific support for Dr. Madigan's methodologies and the lack of rebuttal evidence to discredit any step in his analysis, the Court finds no basis for Defendants' argument that his methodology is not discernible or reliable enough to be admissible. To the contrary, in the Eleventh Circuit, mathematical and statistical analyses are well-recognized as reliable and acceptable means of supporting an expert opinion. See *1366City of Tuscaloosa v. Harcros Chemicals, Inc. ,
Defendants also raise arguments regarding Dr. Madigan's analysis of their clinical trial data. First, they challenge as "pure speculation" Dr. Madigan's opinion that the clinical trials were not powered to detect a statistically significant increased risk of pathological gambling, which Defendants appear to claim is based solely on his observation that placebo subjects in the trials had no reports of pathological gambling. The premise of this argument is incorrect. When a study, such as the randomized clinical trials in this case, fails to find a statistically significant association between a drug and an adverse effect, an "important question is whether [that] result tends to exonerate the [drug's] toxicity or is essentially inconclusive with regard to toxicity." See Ref. Man. at 582. A statistical power analysis is a well-established scientific means of evaluating whether the study's outcome is exonerative or inconclusive. See
Finally, Defendants challenge as unreliable Dr. Madigan's use of five statistically insignificant data points as the basis for his opinion that the clinical trials show a *1367"concerning trend" of increased risk of impulsive behaviors with Ability patients.168 See Madigan Rep., ECF No. 427-1 at 29. On this issue, the Court agrees. Statistical significance, by itself, does not mechanically control whether a statistical analysis is sufficiently reliable under Daubert. See In re Viagra Products Liability Litigation ,
In this case, the strength of Dr. Madigan's opinions lies in the statistical context they provide, which is based primarily on his assessments of the statistical significance of various categories of scientific evidence. For example, Dr. Madigan's defense of the Etminan Study is premised, in large part, on its "highly statistically significant results." See Madigan Rep., ECF No. 427-1 at 30. Similarly, according to Dr. Madigan, the statistically significant percentages of pathological gambling reports in the FAERS database evidence their "very strong" association with Abilify. See Madigan Tr., ECF No. 596-4 at 23-24. Dr. Madigan cannot now, with respect to the statistically insignificant "trends" in the clinical trial data, abandon statistical significance as a measure of reliability without a thorough explanation of why doing so is sound and supportable scientific practice. See Lipitor ,
In sum, Defendants' Motion to Exclude the General Causation Opinion of David Madigan, ECF No. 427-20, is due to be granted in part and denied in part. Dr. Madigan may not offer an expert opinion *1368on medical causation and also may not testify about the five statistically insignificant p -values he calculated from the clinical trial data. In all other respects, his expert opinion is admissible.
2. Defendants' Experts
Plaintiffs have moved to exclude the opinions of Defendants' five proposed experts-Drs. Blier, Leiderman, Potenza, Weed, and Winstanley-on multiple grounds. With respect to Drs. Blier, Potenza, and Weed, the Court has carefully considered Plaintiffs' arguments and finds them to be lacking in merit.171 As an initial matter, Plaintiffs have not challenged these three experts' qualifications to testify in this case and the Court finds, from their reports and testimony at the Daubert hearing, that each is amply qualified to offer the expert opinions provided. The Court also finds the three expert opinions reliable, except to the extent otherwise indicated in this Order.172 Briefly, each of the three experts prepared a standard report of the type the Court would expect to see in response to Plaintiffs' experts' reports. See Blier Rep., ECF No. 455-1; Potenza Rep., ECF No. 458-1; Weed Rep., ECF No. 419-3. Their opinions were, essentially, critiques of Plaintiffs' experts' evidence, methodologies, and conclusions. See
The Court next addresses, in turn, the admissibility of the proposed expert testimony of Drs. Leiderman and Winstanley.
a. Deborah B. Leiderman, M.D., M.A., FAAN
Dr. Deborah B. Leiderman is a licensed physician and board-certified neurologist. She has extensive experience in clinical research, as well as drug development, regulation and policy, including just over seven years at the FDA as the Director of the Controlled Substances Staff, during which time she served as the agency's *1369"lead physician and official on issues related to the Controlled Substances Act, abuse liability assessment, and domestic international drug scheduling and prescription drug abuse." Leiderman Rep., ECF No. 420-3 at 2-3.173 In this role, she "consulted on proposed and draft language for many drug labels across multiple therapeutic areas."
The main thrust of Dr. Leiderman's opinions is that the FDA warning label and Pharmacovigilance Review concerning Abilify"do not support the conclusion that Abilify causes compulsive behaviors or impulse control disorders."176 See Leiderman Rep., ECF No. 420-3 at 5, 7. As a threshold matter, Plaintiffs' experts will not be permitted to testify at trial that the FDA warning label and Pharmacovigilance Review, standing alone or together, are definitive proof of causation. See Rider ,
With respect to Dr. Leiderman's opinions, the Court finds that she may testify to the purpose behind the FDA's pharmacovigilance process and how it is conducted; however, she may not testify about language in a warning label or pharmacovigilance review unless her testimony is supported by a specific FDA regulation, rule, policy, or official agency guidance (e.g. , FDA Pharm. Guide, DX-15). In other words, Dr. Leiderman may not simply read FDA materials to the jury and then testify to what the FDA meant or intended by including or excluding certain language.178 The FDA warning label and Pharmacovigilance Review for Abilify speak for themselves. Dr. Leiderman's opinions will be limited to the FDA regulatory process and what can or cannot be concluded about Abilify from that process based on specific, established FDA regulations, rules, policies, or official guidance. She may draw inferences based on her experience, but only if the inferences are reasonably supported by FDA regulations, rules, policies, or guidance. Plaintiffs' Daubert Motion to Exclude the Testimony of Defendants' Expert Deborah B. Leiderman, M.D., M.A., FAAN, ECF No. 420, is granted in part and denied in part, as discussed above.
b. Catharine A. Winstanley, Ph.D.
Dr. Catharine Winstanley is a professor in the psychology department at the University of British Columbia. She holds an undergraduate degree in psychology and physiology, as well as a doctorate in behavioral neuroscience. She has extensive professional experience in the design and use of in vivo studies of "impulsivity and risky decision-making" in rodents to investigate and understand these conditions in humans. See Winstanley Rep., ECF No. 461-1 at 2.179 In brief, Dr. Winstanley offers an opinion that none of the available in vivo data supports Plaintiffs' experts' conclusions that Abilify can cause gambling disorder or impulsivity. Plaintiffs challenge Dr. Winstanley's testimony on a number of grounds, most notably, her lack of qualifications to testify on general causation and her failure to adequately explain how and why in vivo findings about the effects of various drugs on impulsivity in rodents may be reliably extrapolated to prove that Abilify would have comparable effects on gambling and impulsivity in humans.
As to Dr. Winstanley's qualifications, the Court agrees that she is not qualified to *1371offer a comprehensive general causation opinion. She is not a medical doctor, toxicologist, pharmacologist, or epidemiologist, and she has no specialized knowledge of, or clinical experience with, Abilify, pathological gambling, or impulse control disorders in humans. Dr. Winstanley's admitted lack of expertise in the aforementioned areas precludes her from offering a medical or scientific opinion that Abilify cannot cause impulse control problems. However, given Dr. Winstanley's knowledge and experience with animal models of impulsivity, the Court finds her qualified to offer an expert opinion regarding any such evidence that is ultimately deemed admissible in this case.
Dr. Winstanley's opinion is based on her review of in vivo studies investigating impulse control and gambling-related behavior in rodents, studies that she considers contradictory to Plaintiffs' experts' opinions regarding the biological mechanism by which Abilify can cause gambling and impulsivity problems in humans. See Winstanley Tr., ECF No. 596-8 at 107.180 Dr. Winstanley refers to these in vivo studies as "translationally valid," by which she means that the behavioral test each study used to assess impulsivity in rodents is a scientifically accepted, valid model of impulsivity in humans. See Winstanley Tr., ECF No. 596-8 at 110-11. Although Dr. Winstanley defines, in general terms, the three components of a translationally valid animal model, it is not entirely clear from her expert report or her testimony how or why the animal models she cites in this case meet that definition.181 This is problematic because, as gatekeeper for the expert evidence presented to the jury, the Court must ensure that any extrapolations from rodents to humans are based on more than just the ipse dixit of an expert. See McDowell ,
Dr. Winstanley testified that it is "impossible" to translationally validate any model of gambling disorder in rodents and that, to her knowledge, Abilify has never been tested in any rodent models of gambling-related behavior. See Winstanley Tr., ECF No. 596-8 at 99, 108. Therefore, to the extent she has extrapolated from the in vivo studies in this case any conclusions about gambling disorder or gambling-related behavior in humans, the Court finds those conclusions inadmissible at trial. Dr. Winstanley also offers opinions based on the findings of in vivo studies involving drugs that are pharmacologically different from Abilify.182 However, she failed to offer *1372any evidence establishing the reliability of an analogy between those other drugs and Abilify. See Rider ,
When ruling on challenges to expert testimony under Rule 702 and Daubert , the Court is charged with the responsibility of acting as a gatekeeper, excluding "junk science" and other unreliable information, see Joiner ,
In this case, Plaintiffs have shown, by a preponderance of the evidence, that their general causation evidence is sound and reliable. For starters, there is reliable evidence of a broad scientific consensus regarding the existence of an association between Abilify and increased risk of impulse control problems.184 The FDA, EMA, and Health Canada have all concluded as much, based on their reviews of largely the *1373same scientific literature and statistical analyses discussed in this Order, and, as a result, have required that safety warnings be added to the Abilify product labels. In 2015, [* * * REDACTED * * *] . Several months later, [* * * REDACTED * * *] . The FDA's 2016 pharmacovigilance review "confirm[ed]" Defendants' conclusions as to a "possible causal association" between Abilify use and impulse control disorders, and it also called for a case-control study to "help clarify" the nature of the association. See FDA Pharm. Vigil., ECF No. 428-11 at 29-30. The Etminan Study-an epidemiological case-control study that is peer-reviewed, published, and unchallenged in the scientific literature to date-reliably confirms the association as causal. Moreover, the biological mechanism by which Abilify can cause impulse control problems has been reliably established by peer-reviewed, published scientific literature, and notably, Plaintiffs' experts' biological plausibility opinions are consistent with both the FDA and Defendants' assessments of Abilify's mechanism of action. See Section (II)(C)(4)(e). Defendants' experts hotly dispute Plaintiffs' general causation evidence, but a hot dispute is not a basis for excluding Plaintiffs' experts' opinions. "[T]he subject of scientific testimony [need not be] 'known' to a certainty; arguably, there are no certainties in science." Daubert ,
III. Summary Judgment
Defendants have moved for summary judgment on general causation under Daubert based on Plaintiffs' lack of admissible expert testimony. Because the Court has found that most of Plaintiffs' evidence on general causation-including epidemiology (i.e. , Etminan Study), background risk, biological plausibility, disproportionality analyses, in vivo and in vitro studies, voluminous case and adverse event reports (including dose-response, dechallenge, and rechallenge events), FDA materials, Defendants' investigative findings, and Plaintiffs' experts' Bradford Hill and weight-of-the-evidence analyses-satisfies Rule 702 and Daubert , there exists a genuine dispute of material fact on the issue of whether Abilify can cause uncontrollable impulses in individuals taking the drug. Therefore, Defendants' Motion for Summary Judgment on General Causation, ECF No. 428, is due to be denied.
Accordingly, it is ORDERED :
1. Plaintiffs' Daubert Motion to Exclude the Testimony of Defendants' Expert Marc N. Potenza, ECF No. 415, is DENIED .
2. Plaintiffs' Daubert Motion to Exclude the Testimony of Pierre Blier, M.D., Ph.D., ECF No. 418, is GRANTED in part and DENIED in part, as discussed in the body of this Order.
3. Plaintiffs' Daubert Motion to Exclude the Testimony of Defendants' Expert Douglas Weed, M.D., ECF No. 419, is GRANTED in part and DENIED in part, as discussed in the body of this Order.
4. Plaintiffs' Daubert Motion to Exclude the Testimony of Defendants' Expert Deborah B. Leiderman, M.D., M.A., FAAN, ECF No. 420, is GRANTED in part and DENIED in part, as discussed in the body of this Order.
*13745. Plaintiffs' Daubert Motion to Exclude the Testimony of Defendants' Expert Catharine Winstanley, Ph.D., ECF No. 422, is GRANTED in part, DENIED in part, and DEFERRED in part, as discussed in the body of this Order.
6. Defendants' Motion to Exclude the General Causation Opinion of Antoine Bechara, ECF No. 423, is GRANTED in part and DENIED in part, as discussed in the body of this Order.
7. Defendants' Motion to Exclude the General Causation Opinion of Joseph Glenmullen, ECF No. 424, is GRANTED in part and DENIED in part, as discussed in the body of this Order.
8. Defendants' Motion to Exclude the General Causation Opinion of Eric Hollander, ECF No. 425, is DENIED .
9. Defendants' Motion to Exclude the General Causation Opinion of Russell Luepker, ECF No. 426, is GRANTED .
10. Defendants' Motion to Exclude the General Causation Opinion of David Madigan, ECF No. 427, is GRANTED in part and DENIED in part, as discussed in the body of this Order.
11. Defendants' Motion for Summary Judgment on General Causation Based on Plaintiffs' Lack of Admissible Expert Testimony Under Daubert, ECF No. 428, is DENIED .
SO ORDERED , on this 15th day of March, 2018.
Related
Cite This Page — Counsel Stack
299 F. Supp. 3d 1291, Counsel Stack Legal Research, https://law.counselstack.com/opinion/in-re-abilify-aripiprazole-prods-liab-litig-flnd-2018.