RUFE, District Judge.
Zoloft (sertraline hydrocloride) is a prescription antidepressant, commonly used to treat depression, anxiety, and other mental health conditions.
Federal Rule of Evidence 702 reads:
The Third Circuit has distilled this rule to two essential inquiries: 1) is the proffered expert qualified to express an expert opinion; and 2) is the expert opinion reliable?
Under the Third Circuit's framework, the focus of the Court's inquiry must be on the experts' methods, not their conclusions. Therefore, the fact that Plaintiffs' experts and Defendants' experts reach different conclusions does not factor into the Court's assessment of the reliability of their methods. The experts must use good grounds to reach their conclusions, but not necessarily the best grounds or unflawed methods.
Expert evidence must be relevant and reliable to be admissible. The Court must consider: 1) whether the expert's theory can be tested; 2) whether studies have been subject to peer review and publication; 3) the potential for error in a technique used; and 4) the degree to which a technique or theory (but not necessarily a conclusion) is generally accepted in the scientific community.
Drs. Sadler, Cabrera, and Levin have been retained by the PSC to opine as to whether: (1) there is a plausible biological mechanism by which Zoloft could cause the injuries at issue in this litigation; and (2) Zoloft causes the birth defects at issue when taken by pregnant women, in clinically appropriate doses, during the first trimester of pregnancy.
Biological plausibility is one of the criteria scientists need to address in opining as to whether an association between a substance and an adverse outcome reflects a causal relationship (i.e. whether the substance is a teratogen), and the PSC has asked three experts to address this criteria.
Dr. Cabrera is a teratologist, with a Ph.D. in Medical Sciences, whose research focuses on identifying agents that may cause or prevent birth defects. He has conducted in vitro and in vivo animal studies, most often using mouse models. His research focuses on the impact of immunizations and anti-epileptic medications on developing embryos. He has never performed studies of Zoloft or other SSRIs, but has reviewed relevant publications in connection with this litigation.
Dr. Cabrera opines that serotonin is an important signaling molecule for organ development in a developing embryo, regulating "cell proliferation, migration, differentiation, and gene expression ... processes [] fundamental to creating a normally formed embryo."
In forming his opinion for this litigation, Dr. Cabrera reviewed some of the relevant scientific literature on Zoloft, with a particular focus upon Pfizer's pre-clinical animal reproductive toxicity studies data on rodents and rabbits, the only whole animal studies of which he is aware.
Dr. Cabrera also reviewed in vitro studies testing the importance of serotonin pathways in embryonic development and the impact of disruptions to those pathways on various organs and systems. He concluded that there is a plausible mechanism of action by which Zoloft may impact embryonic development and produce the birth defects at issue in this litigation.
Pfizer argues that Dr. Cabrera has never tested his hypothesis about Zoloft, noting that although "in his non-litigation work he conducts and publishes peer-reviewed animal studies regarding medications and birth defects ... Dr. Cabrera has performed no studies of Zoloft, or any other SSRI, to test any aspect of his hypothesis." While hypothesis testing is indisputably a requirement for scientifically reliable opinions, the Court does not agree that Dr. Cabrera must perform his own studies in order to form a reliable opinion. It is acceptable to rely on the hypothesis testing of others, so long as one addresses both supportive and contrary evidence in reaching one's opinion. In his analysis of the Pfizer animal studies, Dr. Cabrera demonstrates that he has done just that: he did not ignore the findings of those studies from which conclusions at odds with his opinion were drawn; rather he analyzed those studies and explained why those studies did not alter or undermine his own opinion regarding a plausible biological mechanism of injury.
Dr. Sadler is an embryologist and teratologist with a Ph.D. in anatomy and embryology, who studies the mechanisms of normal and abnormal development in embryos, generally using an in vitro whole embryo culture system he co-developed. In an in vitro whole embryo study, an embryo is removed from an animal's uterus by caesarian section, with the yolk sac and membranes intact, and the embryo is placed in a prepared laboratory vessel where it can be maintained for 24-48 hours. The embryo is then directly exposed to the medication of interest and observed for one to two days. One advantage of conducting such studies is the ability to introduce a medication at levels which would be lethal if given to a pregnant animal. Disadvantages include the short time frame in which the embryo can be observed and the lack of maternal metabolism in the system.
Much of Dr. Sadler's research has focused upon the association between maternal use of folic acid and a reduction in neural tube defects. He has also extensively studied the impact of diabetes on fetal development. In addition, he has conducted in vitro studies of the potential role of serotonin in prenatal craniofacial and cardiac development. He has been retired from active research for approximately 12 years.
Pfizer points out certain difficulties in drawing conclusions about biological mechanisms from in vitro studies. For example, when a medication is administered to a pregnant mammal (including a human), the maternal system absorbs, distributes, metabolizes, and eliminates the medication, which effects the embryonic exposure; in an in vitro system, the embryo is directly exposed to the drug of interest. Pfizer also notes that when researchers study embryos in vitro, rather than live animals, medication can be administered at concentrations which would be lethal to a pregnant animal. While the Court recognizes these limitations to the in vitro methodology Dr. Sadler relies upon, the Court does not find that these limitations are methodological flaws which render Dr. Sadler's opinion on plausible biological mechanism of injury inadmissible, and the Court is confident that these limitations can be effectively addressed on cross-examination.
Dr. Levin is a molecular developmental biologist with a doctorate in genetics. His relevant research focuses upon mechanisms that govern the patterning of the embryo (e.g., genetic and molecular mechanisms that dictate the asymmetrical positioning of the heart and other organs). He has studied the role of cell signaling mechanisms in embryonic patterning, "with a specific focus on the role of serotonin and voltage gradients [ion channel activity] in this process."
Dr. Levin's opinion is based primarily upon studies conducted using non-mammals, such as xenopodes (frogs), chickens, and zebrafish. He explained that that for certain developmental processes, such as the development of left-right asymmetry in organ placement, frogs are better models than rats or mice because of their embryonic body architecture.
Dr. Levin opines that serotonin is a "profoundly important medium for cell to cell communication during embryogenesis," and "there are at least three obvious and distinct routes by which SSRI, including Zoloft, exposure can affect embryonic development, causing malformations of the brain and central nervous system, mispatterning of the limbs, heart, and face, and mispositioning of the visceral organs."
Dr. Levin's report summarizes the basis for his opinions. He explains how the serotonin transporter works, how Zoloft and other SSRIs affect the transporter, by design, and why this may lead to a variety of birth defects. He points to a study conducted on frog embryos, in which the serotonin pathway was perturbed by treatment with SSRIs, resulting in laterality defects of the heart, gut, or gallbladder, although not the specific types of defects at issue in this litigation.
Pfizer argues that Dr. Levin's opinions regarding plausible biological mechanisms are not reliable because he has not demonstrated that blocking serotonin receptors causes laterality defects. However, the Court finds that Dr. Levin sufficiently supported his opinion that serotonin plays an essential role in embryonic patterning in some species.
Pfizer also argues that Dr. Levin has pointed to no studies demonstrating that Zoloft (or any other SSRI) alters ion or calcium signaling in developing embryos at relevant doses, and that his opinion on these proposed channels are no more than untested hypotheses. Pfizer notes that the two studies on which Dr. Levin relies for his hypothesis regarding calcium signaling were conducted on human cancer cells and canine kidney cells (not embryos),
For the reasons set forth above, the Court will not exclude the opinions of these experts to the extent that they opine as to plausible biological mechanisms of injury, except that Dr. Levin will not be allowed to testify regarding ion and calcium channels.
In addition to opining as to plausible biological mechanisms, the experts retained by the PSC have all opined regarding human causation, i.e. that Zoloft can cause birth defects in the children born to pregnant women who take Zoloft in the first trimester of pregnancy. Specifically, Dr. Cabrera opines:
Dr. Sadler's opinion is summarized in his report as follows:
And Dr. Levin also opines that Zoloft may cause birth defects in human babies born to exposed mothers:
To meet the Daubert standard, the experts must demonstrate that these opinions are based on methods and procedures of science, not speculation or subjective belief, and they must possess a reasonable degree of scientific certainty regarding their causation opinions.
Wilson's principles of teratology require scientists to consider the following when evaluating a potential teratogen: 1) the genotype of the embryo or the mother, which may interact with the adverse environmental factors; 2) susceptibility to injury will vary with the developmental stage at the time of exposure, with injury most likely during certain critical periods; 3) teratogenic agents act in specific ways on the developing embryos; 4) the route and degree of embryonic exposure, including the characteristics of the agent, the degree of maternal exposure, the rate of systemic absorption and placental transfer, etc, are relevant; 5) the four manifestations of deviant development are death, malformation, growth retardation and functional defect;
Scientists use the Bradford-Hill criteria to analyze whether an observed association between a medication and an outcome reflects a causal relationship.
Although the Bradford-Hill criteria are used to infer causation from associations in many scientific fields, and their application is not limited to the science of identifying teratogens, there is substantial overlap between the Bradford-Hill criteria and Wilson's principles of teratology, so the Court will generally discuss them together.
Pfizer has moved to exclude the experts opinions on human causation, arguing that they were not based on sufficient facts or data (i.e., they are speculative or subjective) and that they are not the product of reliable scientific principles and methods. Although the Court has found that the experts at issue have offered scientifically
The Bradford-Hill criteria ask first whether there is evidence of a strong, well-replicated association between the variables of interest (here, Zoloft exposure and birth defects). When one is interested in human causation, the most relevant evidence will come from human epidemiological studies. Pfizer challenges the methodology these experts used to reach their litigation opinions on human causation, contending that the experts rely primarily on in vitro and in vivo studies of animals for their opinions regarding human causation, when such studies are only "third tier" and "second tier" evidence that a drug causes birth defects in humans, and "first tier" evidence, from human epidemiological studies, does not support their conclusions.
Several courts have held that positive human epidemiological studies are required to reach reliable conclusions as to whether an agent is teratogenic in humans, and causation opinions based primarily upon in vitro and live animal studies are unreliable and do not meet the Daubert standard.
In Dr. Cabrera's report, he indicates that he applied Wilson's principles of teratology, considering genetic susceptibility, timing of exposure, the biological mechanism of action, the various manifestations of deviant development (including death and growth retardation, as well as malformations), and the dose response, which he described in his testimony as the lowest dose that produces the development effect.
Dr. Sadler offers an opinion that Zoloft exposure in pregnant woman may cause many different birth defects, but Plaintiffs acknowledge that in "extrapolat[ing] from animals to humans, Dr. Sadler relied upon the mechanism of action of the drug."
Dr. Levin does not cite any human epidemiology studies as a basis for his opinion. In fact, Dr. Levin testified that although he has reviewed some human epidemiology studies of SSRI exposure in pregnant humans, he does not have the expertise to analyze those studies and his opinions are not based upon the epidemiological research.
Zoloft has been on the market and used during pregnancy for approximately twenty years, and a great deal of epidemiological research has been conducted and published.
The experts at issue have offered opinions about human causation in this case, based largely on in vitro or in vivo animal studies. As noted above, courts caution against direct extrapolation from cellular and animal studies to humans, because where sound epidemiological data do not exist, or the epidemiological research produces results inconsistent with the animal research, "the rate of error is likely to be quite high."
In this section, the Court will discuss specific issues with the experts' extrapolations in this case.
Nearly any substance can be teratogenic at some concentration. Dose response refers to correlations between dosage and outcome, the minimum dose at which adverse effects are seen, and the dose at which a substance is lethal. According to both Wilson's principles and the Bradford-Hill criteria, scientists drawing conclusions about teratogenicity and causation should consider the evidence regarding the dose response. Because high doses of a medication are often administered in in vitro and live animal studies, it is especially important for scientists relying upon such studies to carefully consider the dose-response relationship.
Because researchers can expose animals and in vitro embryos to extremely high doses of a drug, in vitro and in vivo animal studies can be useful in examining the dose response. When researchers study embryos in vitro, rather than live animals, medication can be administered at concentrations which would be lethal to a pregnant animal. For example, in one in vitro study on mouse embryos, Dr. Sadler exposed the embryos to varying concentrations of Zoloft, and found no adverse effects on the embryos at typical doses, high
Even in live animal studies, in which lethal doses cannot be administered, the doses administered to some study groups may be well in excess of the maximum recommended human concentration. For example, the label for Celexa (another SSRI) indicates that defects occurred when pregnant mice were administered a dose equivalent to 18 times the recommended maximum dose, but no effect was seen at or below nine times the recommended maximum dose, and there was no effect at any dose in rabbits.
In order to reliably opine as to human causation, the experts must address whether the children of pregnant women taking Zoloft in typical (or even maximum) clinical doses are at an increased risk of birth defects. The in vitro and in vivo animal studies have found associations between exposure and adverse outcomes only at concentrations well above the maximum recommended human dose. The experts have not reconciled the dose-response evidence with their opinions on human causation. Under both Wilson's criteria and the Bradford-Hill criteria, reaching conclusions about human causation without careful consideration of the dose response is a significant methodological flaw.
One problem with generalizing from in vitro studies is that drugs are not metabolized by the mother in an in vitro system, as they are when a pregnant mammal is exposed. This is also a problem when generalizing from frogs, fish, or chick embryos, which develop in eggs without a maternal metabolism. Therefore, the impact of a medication on a developing embryo may vary significantly in a system which includes a maternal metabolism. The experts have not addressed this issue in their reports.
When one does look at live animal studies, and SSRIs have been studied in living mammals, including rats and rabbits, there is little evidence of an association between Zoloft and birth defects when administered at typically-used concentrations, or even at higher concentrations, as noted above. Although Dr. Cabrera provided a detailed critique of Pfizer's animal reproductive toxicity studies, and explained that the evidence could also support "a hypothesis that vascular damage or malformations were present in these organs,"
In vitro studies can best be used to explore mechanisms of toxicity. However, to then draw conclusions about toxicity in humans, the researcher must establish the link between the animal mechanism and human mechanism (i.e. similar developmental processes, pathways, etc.). This is the concept of biological conservation: certain genetic components and molecular pathways exist (are conserved) throughout the animal kingdom. "Extrapolating data from animals to humans is more accurate if the mechanism of action of the teratogen is well-defined and one that is fundamental to normal development for a wide range of species."
Dr. Levin's opinion is based primarily upon studies conducted using non-mammals (such as frogs, chickens, and zebrafish)
Embryonic serotonin is naturally produced both by the maternal system and the embryo itself.
Because there are individual differences in natural serotonin levels, in making causal conclusions about the impact of Zoloft on the developing embryo, it would be useful to know the optimal range of serotonin in pregnant mothers, the impact of depression on serotonin levels, and the impact of Zoloft on those levels. Yet, none of the experts testified as to the optimal range of serotonin in pregnant women, or the impact of depression or Zoloft on that range. Dr. Cabrera testified that scientists do not know the optimal level of serotonin in human embyros.
Plaintiffs concede the Bradford-Hill criteria "have been recognized for decades as a generally accepted methodological approach for determining causation in tort cases involving toxic exposure."
The Court cannot allow unscientific speculation to be offered, even by genuinely talented scientists. The Court holds that the evidence upon which the experts rely in their reports is not sufficient to support a non-speculative opinion that Zoloft can cause birth defects in humans when used at conventionally prescribed doses. The Court notes that in vitro and in vivo animal research is useful for generating hypotheses about human causation, but each hypothesis must be tested and scientifically verified before it can form the basis for a conclusion about causation. These experts have not demonstrated that such testing and verification has been accomplished to date. In addition, the Court notes that these scientists have never published their litigation opinions about human causation for their peers, and neither their opinions about human causation nor their methods for reaching those opinions, which bypass crucial hypothesis testing and analysis, are generally accepted by scientists in their fields. Finally, many essential questions which would connect the animal data to human embryonic development are unanswered at this time.
Therefore, the Court holds that it is premature to draw conclusions about human causation from the evidence relied upon by these experts. Because of the current state of the science, Drs. Sadler, Cabrera, and Levin's opinions about human causation require speculative leaps which are unacceptable in science and in the courthouse; their opinions about human causation are therefore inadmissible under Daubert.
The Court must act as a gatekeeper, to ensure that expert opinions are based upon reliable scientific methods. The Court holds that the methodology Drs. Sadler, Cabrera and Levin used to reach their opinions that Zoloft, when used by pregnant women at conventional doses, causes an increased risk of congenital malformations in human babies does not meet the Daubert standard, and their opinions on human causation must be excluded.
Pfizer argues that the testimony of Drs. Sadler, Cabrera and Levin should be excluded in its entirety because the experts' opinions on human causation do not meet the Daubert standard. However, this argument conflates the sufficiency of the evidence with the admissibility of the testimony. The experts at issue here have conducted and reviewed in vitro and in vivo research which they believe demonstrates the existence of one or more plausible biological mechanisms by which altered concentrations of serotonin in a developing embryo may cause birth defects. The Court finds that the methodology these experts used to reach their conclusions about biological plausibility is generally reliable, and will not exclude their opinions regarding biological mechanisms, if they are otherwise admissible, except that Dr. Levin may not testify regarding ion and calcium channels.
An appropriate Order follows.
It is so
