By Michael Hoenig -
This article was first published on Law.com Network - August 11, 2014
In my May and June columns,1 I discussed some of the
problems presented in litigations that essentially boil down to
"trial by literature," where experts rely on hearsay articles to
create or fortify their opinions. I reported that many articles
are not truly peer reviewed. Further, I elaborated massive
shortcomings in the peer review process even when it is
The instant column demonstrates how painstaking the "gatekeeping"
task of a judge is when an expert, even one well qualified in
the scientific field, expresses opinions and uses methods that
depart from accepted principles and methodology recognized by
the relevant scientific community. The gatekeeping challenge is
particularly onerous when the field in question reflects
publication of numerous technical articles or studies that may
allow the expert to "cherry-pick" here and there in order to
slap together a litigation opinion. Everyone should be on "red
alert" in "trial by literature" scenarios.
The case on which I report here is complex. It involves
questions as to whether reliable causation opinions have been
advanced that a particular drug causes birth defects. To make
the case understandable, I include some explanatory details
about the science involved (as the court has described it). But
the methodological issues and the tactic of experts
"cherry-picking" among articles are common enough in numerous
other litigation scenarios, so that the lessons to be gleaned
are generally relevant.
On June 27, in multidistrict litigation (MDL) alleging that the
antidepressant Zoloft caused birth defects in children born to
mothers who took the drug during pregnancy, a federal judge in
the Eastern District of Pennsylvania excluded the testimony of
plaintiffs' expert, Anick Berard, a Canadian perinatal
pharmaco-epidemiologist.2 The order
granting defendants' motion was
issued by Judge Cynthia M. Rufe months after a Daubert hearing
at which testimony and evidence were presented in support of
Berard has conducted research on the effect of drugs, including
antidepressants, on human fetal developments. She opined that
Zoloft, when used at therapeutic dose levels during pregnancy,
is capable of causing a range of birth defects and, thus, is a
teratogen. Defendants did not challenge Berard's academic
qualifications but argued that she used unreliable methods and
principles to reach her conclusions that Zoloft may cause birth
The challenge was to the reliability of the expert opinion. The
expert was opining on "general" causation, i.e., whether the
drug may cause birth defects, and not on "specific" causation,
which would ask whether Zoloft caused the particular
malformations detected in any particular child. Under the
framework of the U.S. Court of Appeals for the Third Circuit (in
which Judge Rufe presided), the focus of the court's inquiry on
reliability must be on the expert's methods, not her
conclusions. Experts "must use good grounds to reach their
conclusions, but not necessarily the best grounds or unflawed
methods." Nevertheless, where the scientific community considers
the evidence to be inconclusive, a difference of opinion "may
undermine the reliability of an expert's conclusion that there
is a causal link, and may justify excluding that expert."3
Berard was asked whether she believes that Zoloft may cause
birth defects to exposed mothers, to a reasonable degree of
scientific certainty. But to meet the Daubert standard she must
demonstrate "good grounds" for her causation opinion, not
subjective belief. There must be a reasonable degree of
scientific certainty regarding her causation opinion. The
Daubert reliability factors are (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 is generally accepted in the scientific community.4 The
burden was on plaintiffs to demonstrate the requisite
Zoloft is a prescription antidepressant. It is used to treat
depression, anxiety and other mental health conditions. Its
active ingredient is sertraline. Zoloft belongs to the class of
drugs called selective serotonin reuptake inhibitors (SSRIs).
Serotonin is a neuro-transmitter produced by the human body.
SSRIs do not contain serotonin. Rather, they alter the
availability in the nervous system of the serotonin produced by
the body. The Food and Drug Administration (FDA) categorizes
Zoloft as a "Pregnancy Category C" drug (one of five
categories). Category C means that animal reproduction studies
have shown an adverse effect on the (animal) fetus, but there
are no adequate and well-controlled studies in humans.
Teratology is the scientific field which deals with the cause
and prevention of birth defects. The "gold standard" for
epidemiological studies is the "double-blind, randomized control
trial." But there is a huge problem. Such studies may not
ethically be conducted on pregnant women. Therefore,
epidemiologists must rely upon observational evidence.
Epidemiological studies examining the effects of medication
taken during pregnancy on birth defects calculate a so-called
"relative risk" (RR) or "odds ratio" (OR). These ratios are
calculated by dividing the risk or odds of a particular birth
defect in children born to medication users by the risk or odds
of finding that birth defect in children born without prenatal
exposure. Where the incidence of birth defects is about the same
in medication-exposed and unexposed women, the RR or OR value
will be close to one. In other words, one looks at what is the
increase in risk of the outcome "above and beyond the baseline
There are certain suspected and measurable "confounding factors"
such as maternal age, weight, smoking, alcohol use, folic acid
use and others. These may themselves contribute to an increased
risk of the particular birth defect. Thus, researchers often
statistically control for such factors. When this is done,
researchers will report an "adjusted" ratio. Relative risks and
odds risks ratios are only estimates. They may be affected by
the confounding factors or by biases, sample sizes and study
methods. Researchers also use statistical formulas to calculate
a "confidence interval." A 95 percent confidence interval, for
example, would mean that there is a 95 percent chance that the
"true" ratio falls within the confidence interval range.
Some reports will identify a ratio that is a "statistically
significant" correlation or association between the medication
exposure and the birth defect at issue. A statistically
significant result does not necessarily indicate a large
increase in risk. "It simply indicates that the increased risk
found is unlikely to result from chance alone."6 Teratologists
will not draw firm conclusions from a single study since
apparent associations may reflect methodological flaws. In
general, before concluding that there is a "true" association
between a medication and an adverse outcome, the teratology
community requires "repeated, consistent, statistically
significant human epidemiological findings, and studies which
address suspected confounders and biases."
Epidemiological scientists employ a well-established methodology
but Dr. Berard, though using it in her published, peer-reviewed
work, departed from it in her litigation report here. The
methods she advanced were not shown to have been "exposed to
critical scientific scrutiny" or to have been "adopted by other
scientists in the field."7 Berard claimed that one
can assume teratogenicity based upon multiple weak associations
found across many studies. But, an "equally plausible"
conclusion is that the "true" association is "so weak that one
cannot conclude that the risk is greater than that seen in the
general population." And that, in fact, is the conclusion most
researchers in Berard's field have reached regarding the
association between Zoloft and birth defects.
The court relied on the famous Wade-Greaux decision,8 where
the court excluded the opinion of a well-respected pediatric
pathologist who, like Berard here, urged that repeated,
consistent studies showing increased risk of malformations
associated with use of a medicine were not needed. The
Wade-Greaux court held the expert's conclusions were not derived
from methodology generally accepted by the teratology community.
Similarly, Berard's reliance on non-statistically significant
findings has not been shown to be accepted within her scientific
Berard did not address her reasons for relying upon her novel
method of examining trends in odds ratios nor did she provide
objective, independent validation for her novel method. The
expert simply presumed that SSRIs, although distinct from one
another in chemical structure and pharmacokinetic properties,
will have similar birth-defect-causing effects. But the court
disagreed. Even assuming a common biological mechanism that
could possibly impact fetal development, such evidence would
only give rise to the hypothesis of a class-wide effect. That
hypothesis would have to be tested since even small differences
in chemical structures can result in different effects.
The court analyzed a large number of studies and concluded that
the published literature and studies did not support Berard's
conclusions.10 With respect to the expert's opinion
regarding Zoloft specifically, the court found that Berard
"selectively" discussed studies "most supportive of her
conclusions" but failed "to account adequately for contrary
evidence." That methodology is not reliable or scientifically
sound. A causal conclusion requires examination of the
literature as a whole. Her rationale for not doing so was not
The court said, "cherry-picking" is always a concern, but is of
heightened concern in this case. Also of concern was the lack of
scientific support for her altered opinion in the selected
studies on which she does rely. "An opinion based on subjective
belief, rather than grounded in science, is not admissible."11
The court next discussed the well-established causation factors,
the "Bradford-Hill Criteria." These include the strength of the
association between the exposure and the outcome; the temporal
relationship between the exposure and the outcome; the
dose-response relationship; replication of findings; the
biological plausibility of or mechanism for such an association;
alternative explanations for the association; the specificity of
the association; and the consistency with other scientific
knowledge. An expert need not consider or satisfy all these
criteria in order to support a causal inference.
The court found that the strength of the associations between
exposure to Zoloft and various birth defects "is weak, often not
greater than one would expect by chance alone, and replications
of statistically significant associations is rare." Further,
with respect to the factor of temporal relationship between
exposure and outcome, one study showed the same risk in the
absence of a temporal relationship, as well as confounding
factors and biological mechanisms. Berard did not address any of
them. The other "Bradford-Hill criteria" (dosage effects,
biological plausibility, alternative explanations, etc.)
likewise presented questions and issues that Berard did not
In summary, said the court, the expert "takes a position in this
litigation which is contrary to the opinion she has expressed to
her peers in the past, relies upon research which her peers do
not recognize as supportive of her litigation opinion, and uses
principles and methods which are not recognized by the relevant
scientific community and are not subject to scientific
verification." Accordingly, the opinion did not satisfy Federal
Evidence Rule 702 and had to be excluded.13
The Zoloft decision provides analytical insights that seem
relevant in a host of other litigation scenarios involving other
scientific and technical fields. Cases involving asbestos, toxic
torts, medical causation, psychology and other areas where
hearsay literature and/or published studies abound are all
settings where peer review weaknesses or expert "cherry-picking"
among articles can possibly distort the accepted science and,
possibly, even sneak unreliable opinions past the "gatekeeper."
Vigilance is required.
Articles, 'Trial By Literature' Revisited," New York
Law Journal, May 12, 2014, p. 3; "'Unreliable'
Articles: More on Peer Review's Frailties," NYLJ,
June 9, 2014, p. 3.
2. In Re Zoloft Products Liability Litigation, 2014 U.S.
Dist. LEXIS 87592 (E.D. Pa. June 27, 2014).
3. Id. LEXIS, at *3 and n. 3.
4. Id. LEXIS at *4 (citing Daubert v. Merrell Dow Pharms.,
509 U.S. 579, 593-94 (1993)).
5. Id. LEXIS at *7.
6. Id. LEXIS at *9.
7. Id. LEXIS at *15.
8. Wade-Greaux v. Whitehall Lab., 874 F.Supp. 1441 (D.
V.I. 1994), aff'd, 46 F. 3d 1120 (3d Cir. 1994).
9. In Re Zoloft, supra n. 2, LEXIS at *17 - *18.
10. Id. LEXIS at *18 - *29.
11. Id. LEXIS at *29 - *34.
12. Id. LEXIS at *34 - *42.
13. Id. LEXIS at *43.
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