J   -A31039-16

NON-PRECEDENTIAL DECISION - SEE SUPERIOR COURT I.O.P. 65.37

ROBERT AND KATHERINE PORTER,                      IN THE SUPERIOR COURT OF
INDIVIDUALLY, AND AS PARENTS AND                        PENNSYLVANIA
NATURAL GUARDIANS OF ROBERT T.
"BO" PORTER, A MINOR

                             Appellants

                      v.

SMITHKLINE BEECHAM CORPORATION,
PFIZER, INC. AND WOLTERS KLUWER
HEALTH, INC.

                                                         No. 3516 EDA 2015


                Appeal from the Order Entered October 8, 2015
       in the Court of Common Pleas of Philadelphia County Civil Division
                  at No(s): September Term, 2007 No. 03275

BEFORE: BENDER, P.J.E., DUBOW, J., and FITZGERALD, J.*

MEMORANDUM BY FITZGERALD, J.:                              FILED MAY 08, 2017

        Appellants, Robert and Katherine Porter, individually, and as parents

and natural guardians of Robert T. "Bo" Porter,      a   minor, appeal from the

order entered in the Philadelphia County Court of Common Pleas granting

the motion of Appellee, Pfizer, Inc., for summary judgment.' Appellants


*   Former Justice specially assigned to the Superior Court.

'   On September 29, 2014, the     trial court granted GlaxoSmithKlein, LLC's
renewed motion to dismiss and ordered the claims against them be
dismissed with prejudice. See R.R. at 21a. Appellants had settled with
Wolters Kluwer Health, Inc. prior to trial. See id. at 96a. Therefore, this
appeal is properly before this Court. See Pa.R.A.P. 341(b)(1). For the
parties' convenience, we refer to the reproduced record where applicable.
J   -A31039-16

contend the trial court erred in precluding the testimony of their expert

witness based upon Frye v. United States, 293            F.   1013 (D.C. Cir. 1923).

We affirm.

        The trial court summarized the facts and procedural posture of this

case as follows:

                    On   June     2012 [Appellants] filed an Amended
                                  15,
              Complaint against [Appellee] Pfizer alleging that the
              ingestion of Zoloft[2] by [Appellant] Mrs. Porter during her
              pregnancy caused Minor [Appellant] to be born with the
              serious birth defect onnphalocele.[3] On August 14, 2015
              [Appellee] filed Frye Motions seeking to preclude the
              Expert Testimony of Dr. [Michael] Freedman [M.D., Ph.D.]
              and [Robert M.] Cabrera[, Ph.D].[4] On August 26, 2015
              [Appellants] filed a Response. A two day hearing was held
              on September 16 and September 17, 2015.             At that
              hearing the court heard from Dr. Freeman and [Appellee's
              expert, Dr. Stephen Edward Kimmel M.D.] and received
              into evidence numerous documents including the written
              report of Dr. Cabrera. On September 30, 2015 Appellee's
              Motion was Granted as to Dr. Freeman and he was not
              permitted to testify at trial.       On October 5, 2015
              [Appellee's] Motion was Granted as to Dr. Cabrera and he

2   Zoloft   is a   sertraline.

                Sertraline is a medication used to treat depression,
             obsessive -compulsive disorder, panic disorder, and post -
             traumatic stress disorder. A brand name for sertraline is
             Zoloft.   Zoloft belongs to the class of antidepressants
             known as selective serotonin reuptake inhibitors (SSRIs).

R.R. at 906a.

3 "An omphalocele is a midline abdominal wall birth defect. This defect
occurs when the intestines and potentially other visceral organs protrude
outside the body through the umbilical opening." R.R. at 959a.

4   See R.R. at 247a.


                                         -2
J   -A31039-16

            was not permitted to testify at trial.  On September
                                                         .   .   .


            15, 2015[, Appellee] filed a Motion for Summary
            Judgment.   On October 8, 2015[, Appellant] filed a
            Response to [Appellee's] Motion for Summary Judgment.
            On October 8, 2015[, Appellee's] Motion for Summary
            Judgment was Granted.

Trial Ct. Op., 2/10/16, at 1-2 (footnotes omitted).                     This timely appeal

followed.        Appellants filed     a   Pa.R.A.P.   1925(b)        statement of errors

complained of on appeal and the trial court filed            a   responsive opinion.

        Appellants raise the following issue for our review: "Did the trial court

improperly       preclude     Dr.   Cabrera    from   testifying      on     Frye grounds?"
Appellants' Brief at 3. Dr. Cabrera was offered as an expert "on general and

specific causation."        Id. Appellants    contend the trial court "overlooked the

general acceptance of Dr. Cabrera's methodological tools, and inserted

[itself]    as   an   independent assessor of Dr.                Cabrera's    credibility and

persuasiveness."      Id.   at 22. Appellants argue:

            Dr. Cabrera described the foundational principles of the
            modern study of teratology as expressed by James Wilson,
            the co-founder of the Teratology Society and founder of
            the field.    The principles include the so-called "dose
            response" principle restated in the context of teratology:
            "Manifestations of deviant development increase in
            frequency and degree as dosage increased from the No
            Observable Adverse Effect Level to a dose producing 100%
            Lethality." The central point made by Dr. Cabrera is that
            low doses "may exert no or very little toxicity or
            teratogenicity, while higher doses are expected to increase
            the incidence and severity of the observed malformations."




                                              -3
J   -A31039-16

           Dr. Cabrera explained the importance of animal studies in
           rabbits and rats as a vehicle for testing whether a
           compound      is a   human teratogen.



           Dr. Cabrera then discussed numerous animal studies             that
           affirmatively suggest that Zoloft       is   a       teratogen that
           causes birth defects.



           At the same time, Dr. Cabrera identified shortcomings with
           the studies that he found reduced their statistical power.
           He ultimately concluded that "while the reported data
           provided indications of the presence of cranial, kidney, and
           heart defects due to [Zoloft] exposure, the studies lacked
           any detailed pathology that might have allowed the
           investigators to draw more reasoned conclusions."



           For present purposes, the key point is that animal studies
           represent a generally accepted tool for building an
           assessment about the teratogenicity of           a       pharmaceutical
           compound.



           [H]e focuses on the 2007 Louik study[5]          The Louik
                                                            .   .    .   .


           study was a peer reviewed, case -controlled study reflecting
           a   strong, statistically significant positive correlation
           between first trimester Zoloft exposure and omphalocele.
           The study found that maternal use of Zoloft during the first
           trimester was associated with a nearly six times greater
           risk of the infant developing an omphalocele.




5    Louik C., A.   Lin, et al. (2007).
                    E.                      "First -trimester use of selective
serotonin-reuptake inhibitors and the risk of birth defects." N. Engl. J. Med.
2007, Vol. 356(26): 2675-2683. R.R. at 624a.


                                           -4
J   -A31039-16

             Of course, Dr. Cabrera did not limit his inquiry to the
          Louik study.  .   .Concededly, some of these studies did
                                .


          not involve enough subjects to show a "statistically
          significant" association between Zoloft taken during
          pregnancy and omphalocele.



             Dr. Cabrera also discussed studies by Reefhuis[61 and
          Furum that, although they did not show a statistically
          significant association between omphalocele and Zoloft in
          particular, did show statistically significant associations
          between omphalocele and other SSRIs exhibiting the same
          mechanism of action as Zoloft.



          Dr. Cabrera made careful and appropriate use of the
          Bradford -Hill criteria[8] in further developing his causation
          analysis.




6
  Reefhuis J., S. M. Gilboa, et al. (2015). "The national birth defects
prevention study: A review of the methods." Birth Defects Res A Clin Mol
Teratol. R.R. at 630a.

  Furu, K., H. Kieler, et al. (2015). "Selective serotonin reuptake inhibitors
and venlafaxine in early pregnancy and risk of birth defects: population
based cohort study and sibling design." BMJ 350: h 1798. R.R. at 628a.

8 "The Bradford -Hill criteria were developed as a mean[s] of interpreting an
established association based on a body of epidemiologic research for the
purpose of trying to judge whether the observed association reflects a causal
relation between an exposure and disease." Soldo v. Sandoz Pharms.
Corp., 244 F.Supp.2d 434, 514 (W.D.Pa. 2003). "While we recognize
federal district court cases are not binding on this court, Pennsylvania
appellate courts may utilize the analysis in those cases to the extent we find
them persuasive." Stephens v. Paris Cleaners, Inc., 885 A.2d 59, 68 (Pa.
Super. 2005) (citations omitted).




                                      -5
J   -A31039-16

             It   conceded that Dr. Cabrera's analysis has limitations
                  is
          based    on the limitations of the available scientific
          evidence, which in turn is based on the impossibility of
          directly conducting studies on pregnant women.



          In other words, Dr. Cabrera explained, after finding a
          general causal relationship between drug and disorder, the
          researcher identifies and rules out other potential causes
          to determine whether the drug caused the disorder in that
          specific instance. That is the differential causation
          analysis that Dr. Cabrera performed here.
Appellants' Brief at 26-27, 29-30, 33, 35, 38-39 (citations and footnote

omitted) (emphasis added).

        Dr. Cabrera opined:

             It   my opinion, within a reasonable degree of scientific
                  is
          certainty, that Zoloft (sertraline) is teratogen,[91 both in
          animals and in humans, when ingested during pregnancy.
          The teratogenicity of sertraline, has been amply
          demonstrated in animal studies, as well as in a number of
          human epidemiological and registry studies. There exists
          a biologically plausible mechanism of teratogenic action
          (MOA) based on the MOA of SSRIs. In general, it is my
          opinion, within a reasonable degree of scientific certainty,
          that alteration of serotonin signaling by sertraline, can
          impact embryonic development resulting in several
          different congenital malformations, involving various organ
          and body systems, including, but not limited to abdominal
          wall defects such as omphalocele. It is my opinion that
          Kathy Porter's ingestion of Zoloft while pregnant caused Bo
          Porter's omphalocele.

R.R. at 578a.


9  "Teratology is the study of abnormal embryonic development.         The
founding principles of the modern study of teratogens were initially
articulated by Janes G. Wilson (Wilson 1973), co-founder of The Teratology
Society, in his monograph, 'Environment and birth Defects.' R.R. at 578a.


                                      -6
J   -A31039-16

        Although the order currently before this court awarded summary

judgment, "an appeal of       a   final order subsumes challenges to previous

interlocutory decisions," such as preclusion of expert testimony.                  Betz v.
Pneumo Abex, 44 A.3d 27, 54 (Pa. 2012).                  "Generally, the appropriate

appellate standard of review      is   the one pertaining to the underlying ruling."

Id. Instantly, the trial court granted summary judgment after precluding
Appellant's expert testimony.            "[The a]ppellant's issue[       ]    on   appeal,

therefore, challenge[s] the court's preclusion of [her] expert testimony."

Haney v. Pagnanelli, 830 A.2d 978, 980           (Pa. Super. 2003)

        Our review is governed by the following principles:

          [A]s to the standard of appellate review that applies to the
          Frye issue, we have stated that the admission of expert
          scientific testimony is an evidentiary matter for the trial
          court's discretion and should not be disturbed on appeal
          unless the trial court abuses its discretion. An abuse of
          discretion may not be found merely because an appellate
          court might have reached a different conclusion, but
          requires a result of manifest unreasonableness, or
          partiality, prejudice, bias, or ill -will, or such lack of support
          so as to be clearly erroneous.

Grady v. Frito-Lay, Inc., 839 A.2d 1038, 1046 (Pa. 2003) (citations

omitted).

        Rule   702   of the   Pennsylvania       Rules   of   Evidence       governs   the

admissibility of expert opinion. Rule 702 provides as follows:

          A witness who is qualified as an   expert by knowledge, skill,
            experience, training, or education may testify in the form
            of an opinion or otherwise if:




                                           -7
J   -A31039-16

           (a) the expert's scientific, technical, or other specialized
           knowledge is beyond that possessed by the average
           layperson;

           (b) the expert's scientific, technical, or other specialized
           knowledge will help the trier of fact to understand the
           evidence or to determine a fact in issue; and

           (c) the expert's methodology is generally accepted in
           the relevant field.
Pa.R.E. 702 (emphasis added).

        "The Frye test   .   .   .   adopted in Pennsylvania in Commonwealth v.

Topa,    []   369 A.2d 1277 (Pa. 1977), is part of Rule 702." Grady, 839 A.2d

at 1043. "Frye only applies when           a   party seeks to introduce novel scientific

evidence."      Trach v. Fellin, 817 A.2d 1102, 1109 (Pa. Super. 2003) (en

banc).        In Betz, our Supreme Court opined that "a reasonably broad

meaning should be ascribed to the term novel."            Id.   44 A.3d at 53.

         However, "Frye only applies to determine if the relevant scientific

community has generally accepted the principles and methodology the

scientist employs, not the conclusions the scientist reaches, before the court

may allow the expert to testify." Trach, 817 A.2d at 1112. In Trach, this

Court noted that

           the scientific method is a method of research in which a
           problem is identified, relevant data are gathered, a
           hypothesis is formulated from these data, and the
           hypothesis is empirically tested. Within the meaning of
           the definition of the scientific method, empirical means
           provable or verifiable by experience or experiment. Key
           aspects of the scientific method include the ability to test
           or verify a scientific experiment by a parallel experiment or



                                               -8
J   -A31039-16

            other standard of comparison (control) and to replicate the
            experiment to expose or reduce error.

Id. at   1113 (citations and quotation marks omitted).

         Our Pennsylvania Supreme Court in Grady "emphasize[d] that the

proponent of expert scientific evidence bears the burden of establishing all of

the elements for its admission under Pa.R.E. 702, which includes showing

that the Frye rule    is   satisfied." Grady, 839 A.2d at 1045. Pennsylvania law

does not permit "experts to evade          a   reasoned Frye inquiry merely by

making references to accepted methods in the abstract." Betz, 44 A.3d at

58.

         In the case sub judice, the trial court opined:

           [Appellants] seek[ ] to have [Dr. Cabrera] testify as to
           general and specific causation of the birth defects of this
           case. Within Dr. Cabera's forty-seven page report,[10n are
           five pages devoted to his training, education, and
           experience and twelve pages devoted to animal studies
           concerning SSRIs, Zoloft, and birth defects. The most
           recent animal study referenced is a seventeen year old
           study from 1998. Animal studies can be instructive in
           determining the teratogenicity of a pharmaceutical and
           indeed in the absence of human studies may become the
           basis for a valid extrapolated scientific opinion. However,
           animal studies are of limited utility in determining
           teratogenicity where a significant body of human exposure
           studies exists in the published medical literature.     Dr.
           Cabrera does not acknowledge these limitations.

               Dr. Cabrera's opinions rely on a limited number of the
            peer review articles. Dr. Freeman relied on these same
            studies and formed a comparable analysis. Dr. Cabrera's

10   See R.R. at 572a.



                                         -9
J   -A31039-16

                 analysis suffers from many of the same methodological
                 defects in Dr. Freeman's opinions. The methodological
                 defects identified as to Dr. Freeman's opinions are
                 incorporated herein.
                     Dr. Cabrera's report contains other methodology
                 failings. Dr. Cabrera finds that the studies show that
                 SSRIs significantly increase the risk of birth defects in
                 human studies and opines that SSRIs are teratogenic.
                 However, he does not specifically analyze SSRIs results
                 which exclude the pharmaceutical Paxil.E11] This is a fatal
                 methodological flaw because Paxil has been identified as
                 having significantly different effects from Zoloft and other
                 SSRIs.   Paxil is a causal factor in birth defects.      Dr.
                 Cabrera's opinion, as reflected in his report, does not
                 contain any adequate discussion of the differences
                 between Paxil and Zoloft with respect to causation of birth
                 defects.

                     Dr. Cabrera opines that the mechanism of action
                 resulting in birth defects is that an "alteration of serotonin
                 signaling by sertraline, can impact embryonic development
                 resulting in several different congenital malformations.ff[12]
                 This opinion is speculative and without scientific basis. Dr.
                 Cabrera presents no information as to the baseline
                 serotonin level in the developing fetus or the change
                 caused by Zoloft. Without this data there can be no valid
                 opinion as to whether the level of serotonin changes in
                 positive or negative manner or has any outcome
                 determinative effect at all. Likewise, Dr. Cabrera did not
                 perform the dose response analysis necessary to draw a
                 valid scientific conclusion that a medication causes a
                 specific biological mechanism.

                    For the reasons precluding the testimony of Dr.
                 Freeman and those herein Dr. Cabrera likewise was

11"In 2005, Mrs. Porter's Paxil was prescribed by her primary care physician
.    .   She was switched to Zoloft
         .   .                                 by her obstetrician
                                                  .   .   .                in     .   .   .


approximately the 7th week of her pregnancy." R.R. at 948a.

12   See R.R. at 578a.



                                             - 10 -
J   -A31039-16

           properly precluded from offering causation opinions   in   this
           matter.

Trial Ct. Op. at 18-19 (footnotes omitted and emphasis added).

        The trial court precluded Dr. Freeman from testifying on Frye grounds

and opined:

              Dr. Freeman correctly concedes that the studies reveal
           precious little specific data on Zoloft and omphalocele. Dr.
           Freeman effectively solely relies on the Louik study as
           evidence of causation between Zoloft and the birth defect.
          The Louik study is the only study to report a statistically
          significant association between Zoloft and omphalocele.
          Reliance on this one study is questionable because of its
          limitations.     Louik's confidence interval which ranges
          between 1.6 and 20.7 is exceptionally broad.         Equally
          significant is the lack of power concerning the omphalocele
          results. The Louik study had only 3 exposed subjects who
          developed omphalocele thus limiting its statistical power.
          Studies that rely on a very small number of cases can
          present a random statistically unstable clustering pattern
          that may not replicate the reality of a larger population.
          The Louik authors were unable to rule out confounding or
          chance. The results have never been replicated concerning
          omphalocele. Dr. Freeman's testimony does not explain,
          or seemingly even consider these serious limitations.



          [T]he Louik authors themselves expressed concern that
          they cannot distinguish true associations from random
          elevations of risk. The Louik authors were unable to rule
          out the possibility of chance:

                     "The previously unreported associations we
              identified      warrant       particularly    cautious
              interpretation.     In the absence of preexisting
              hypotheses      and   the    presence      of  multiple
              comparisons, distinguishing random variation from
              true elevation in risk is difficult. Despite the large
              size of our study overall, we had limited numbers to
              evaluate associations between rare outcomes and
J   -A31039-16

              rare exposures. We included results based on small
              numbers of exposed subjects in order to allow other
              researchers to compare their observations with ours,
              but we caution that these estimates should not be
              interpreted as strong evidence of increased risks."[13]

           Dr. Freeman ignores the issues specifically pointed out by
           the authors.

               In addition to proper analysis of the appropriate
           literature, generally accepted methodology required that
           the epidemiologist consider the problem of confounding by
           indication. Women who are depressed and take SSRIs

13   The Louik study concluded:

           Our findings do not show that there are significantly
           increased risks of craniosynostosis, omphalocele, or heart
           defects associated with SSRI use overall. They suggest
           that individual SSRIs may confer increased risks for some
           specific defects, but it should be recognized that the
           specific defects implicated are rare and the absolute risks
           are small.

R.R. at 915a. Dr. Cabrera relied upon the Louik study in his expert report.
He opined as follows:

               Louik and co-workers published on SRRI exposure and
           risk of birth defects in the New England Journal of Medicine
           (NEJM) in 2007.   .   .   .In regard to study limitations, the
           authors report concerns for recall bias were minimized
           through multilevel structured questionnaire design. Recall
           bias will also not explain specific risk associated with
           individual SSRIs.       Selection bias was also reported as
           unlikely, since mothers were invited to participate without
           knowledge of exposure.          In regard to confounding by
           indication, the authors report, "the absence of significantly
           increased risk of various birth defects associated with the
           use of non-SSRI antidepressants suggests that depression
           itself is unlikely to be the cause of the defects studied."

R.R. at 605a -606a.




                                         - 12 -
J   -A31039-16

           have been more likely to smoke, be older, have less
           education, have poor nutrition, use other drugs, and have
           chronic diseases such a diabetes and hypertension, than
           women who do not use SSRIs. These factors have been
           linked to an increased risk of birth defects. Dr. Freeman
           does not properly analyze confounding.



           In  his report Dr. Freeman cites Jinnene[z]-Solenn,[14]
           Furu,[15] and Huybrechts as three studies that also found


14   Dr. Cabrera opined:

              Two additional studies that specifically report on SSRIs
           or sertraline exposure and risk of omphalocele merit
           mentioning. The first is a Danish cohort study on the
           teratogenicity of covering pregnancies from 1997-2009
           [Jiminez-Solem, E., J. T. Andersen et al. (2012) "Exposure
           to selective serotonin reuptake inhibitors and the risk of
           congenital malformations: a nationwide cohort study."
           BMJ Open 2(3); e001148]. This study reported association
           with major congenital malformations and exposure to
           sertraline, adjusted [ ] and association between congenital
           malformations of the heart and exposure to sertraline,
           adjusted [ ].     However, they indicate, "We found an
           association for exposure to an SSRI in the first
           trimester and craniosynostosis [ ] but not for
           omphalocele or anencephaly."
R.R. at 608a (emphasis added), 629a.

15
     Dr. Cabrera opined:

              The latest study to report on omphalocele is a Nordic
           population based cohort study (Denmark, Finland, Iceland,
           Norway, and Sweden) conducted between the periods of
           1996-2010 (Furu, Kieler et al. 2015). The study utilized
           national health registry data from each of the participating
           countries.     It reported an odds ratio (OR) for SSRI
           exposure and omphalocele risk [ ], indicative of a
           significant increased risk for omphalocele amongst infants


                                      - 13 -
J   -A31039-16

          statistically significant increased risk of congenital
          malformation associated with SSRI exposure. All three of
          these studies acknowledged the problem of confounding,
          and discussed the problem in their analysis. Dr. Freeman
          does not address the authors' conclusions about
          confounding.

              Generally accepted methodology considers statistically
          significant replication of study results in different
          populations because apparent associations may reflect
          flaws in methodology. Dr. Freeman claims the Alwan[161

          of mothers receiving SSRI treatment during pregnancy,
          but no Zoloft-specific risk was reported.
             There are three additional studies that examined SSRI
          exposure and present general population rates of
          omphalocele, but in each report the incidence is too
          low generally and in exposed population to perform
          statistical testing for risk of omphalocele. These
          studies include reports from Danish [Pedersen, L. H., T. B.
          Henriksen et al. 2009). "Selective serotonin reuptake
          inhibitors in pregnancy and congenital malformations:
          population based cohort study."        BMJ.1 339:b3569.],
          Canadian [Berard, A., J. P. Zhao, et al. (2015) "Sertraline
          use     during   pregnancy and      the   risk of major
          malformations." Am J Obstet Gynecol 212(6): 795 e791-
          795 e712.] and European registries [Wemakor, A., K.
          Casson et al. (2015). "Selective serotonin reuptake
          inhibitor antidepressant use in first trimester pregnancy
          and risk of specific congenital anomalies: a European
          register -based study." Eur J Epidemiol.]

R.R. at 609a -610a (emphases added), 625a, 627a, 631a.

16 Alwan, S., J. Reefhuis, et al. (2007). "Use of selective serotonin-reuptake
inhibitors in pregnancy and the risk of birth defects." New England Journal
of Medicine 356(26): 2684-2692. R.R. at 621a. The Alwan study concluded
that

          [m]aternal use of SSRIs during early pregnancy was not
          associated with significantly increased risks of congenital
          heart defects or of most other categories of birth defects.


                                    - 14 -
J   -A31039-16

           and ReefhuisEln studies demonstrate replication. However,
           the population Alwan studied is only a subset of the
           Reefhuis population and therefore they are effectively the
           same.     More significantly neither Reefhuis nor Alwan
           reported statistically significant associations between
           Zoloft and onnphalocele.  . .[18]
                                         .




           Associations were observed between SSRI use and three
           types of birth defects, but the absolute risks were small,
           and these observations require confirmation by other
           studies.

R.R. at 2014a.  The authors identified the three types of birth defects as
anencephaly, craniosynostosis, and omphalocele. Id. at 2016a.

17  Reefhhuis et al. "Specific SSRI's and birth defects: bayesian analysis to
interpret new data   in the context of previous reports."   BMJ 2015; 350;
h3190. R.R. at 839a. The study acknowledged its limitations, inter alia, as
follows:

           This analysis does not address whether the birth defect
           associations we observed were caused by maternal SSRI
           treatment, underlying maternal disease, or some other
           factor. Since there was no specific question on depression
           and we cannot identify all participants with untreated
           depression, there is the possibility of confounding by
           indication.

R.R. at 935a.

18
     Dr. Cabrera opined:

               In 2007, Alwan also published on SSRI exposure and
           risk of birth defects in the NEJM. The study employed a
           case -control design using data from the US National Birth
           Defects Prevention Study (Alwan, Reefhuis et al. 2007).
           The study utilized maternal reporting of SSRI usage
           (fluoxetine, sertraline, and paroxetine).          The study
           reported an odds ratio for SSRI exposure and anencephaly
           risk [ ], indicative of a significant increased risk for neural
           tube defects amongst infants of mothers receiving SSRI
           treatment during pregnancy, and a Zoloft-specific
           increased risk [ ].      For those birth defects previously



                                             - 15 -
J   -A31039-16

               Dr. Freeman agrees that he must, and claims he has,
           applied the Bradford -Hill Criteria to support his opinion.
           However, the starting procedure of any Bradford -Hill
           analysis is "an association between two variables" that is
           "perfectly clear-cut and beyond what we would care to
           attribute to the play of chance." Dr. Freeman testified that
           generally accepted methodology requires a determination,
           first, that there's evidence of an association and, second,
           whether chance, bias and confounding have been
           accounted for, before application of the Bradford -Hill
           criteria. Because no such association has been properly
           demonstrated, the Bradford -Hill criteria could not have
           been properly applied.E19]

           associated with SSRI use (anencephaly, craniosynostosis,
           and omphalocele) there was also an increased risk [ ]
           associated with reported maternal sertraline usage. There
           was a significant increased risk [ ] with any SSRI usage
           and omphalocele [ ] and a non -significant increased risk [ ]
           with sertraline exposure and omphalocele [ ]. Limitations
           reported by the authors in the study included the inability
           to separate the effect of maternal SSRI use from that of
           the underlying depression, under -reporting of other SSRI
           usage, potential for recall bias, and selection bias towards
           the null hypothesis.

              Reefhuis et al. utilized the data from 10 centers in the
           United States, as part of the National Birth Defects
           Prevention Study, to test SSRI exposure and risk of birth
           defects (Reefhuis, Gilboa et al. 2015).         The study
           specifically reported an odds ratio [ ] for sertraline
           exposure and omphalocele risk [ ] indicative of a non-
           significant increased risk for omphalocele amongst
           infants of mothers receiving SSRI treatment during
           pregnancy.      Limitations reported by the authors in the
           study included the inability to separate the effect of
           maternal SSRI use from that of the underlying depression,
           self -reporting, multiple testing, and small numbers for
           individual defects.

R.R. at 606a -607a (emphasis added).

19
     Dr. Cabrera stated:



                                      - 16 -
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             Dr.  Freeman opines specifically that [Appellant] Bo
          Porter's giant omphalocele birth defect was caused by
          exposure to Zoloft in utero.



              The temporal relationship between the exposure and
          disease is also a factor which must be considered in
          assessing specific causation. For an exposure to be the
          cause of a disease the exposure must have occurred prior
          to the disease. Dr. Freeman fails to address the temporal
          failure of exposure between Mrs. Porter's use of Zoloft and
          minor plaintiff's giant omphalocele. A Giant Omphalocele
          is the result of an incomplete folding of the abdominal wall
          during the third to fifth weeks of pregnancy. During the
          third to fifth weeks of her pregnancy Mrs. Porter was
          taking Peroxetine (a generic version of the known
          teratogene Paxil). Mrs. Porter did not being taking Zoloft
          until her seventh week of pregnancy. While Dr. Freeman
          concedes this timing failure is an issue, he does not form
          any opinion of his own but instead claims to defer to other
          experts offering opinions which have not been revealed
          and     therefore necessarily not subject to cross-
          examination.




             A review of the literature indicates that Zoloft is
          associated with teratogenicity. Association, however, does
          not alone prove causation and further analysis is
          necessary. Sir Bradford -Hill proposed a set of criteria to
          determine association between exposure and outcome.
          These criteria are accepted in the scientific community as a
          viable method of determining the potential existence of
          causality.

R.R. at 614a (emphasis added).




                                     - 17 -
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           Clinical differential diagnosis is a generally accepted
           methodology. Dr. Freeman is not a clinician and does not
           profess to perform a clinical differential diagnosis of cause.
           Dr. Freeman fails to properly rule out genetic causes.



                  Freeman does not discuss and fails to rule out
                 Dr.
           maternal risk factors such as age, obesity, cigarette
           smoking, alcohol, maternal stress, and family history. Dr.
           Freeman fails to exclude Paxil (Peroxetine) as a risk factor.



           Dr. Freeman's failure to analyze, discuss, and exclude
           other possible causes departs from generally accepted
           methodology.

Trial Ct. Op. at 8-10, 12, 13-15, 17 (footnotes in original omitted).

        Stephen Edward Kimmel, M.D., Appellee's expert in epidemiology and

a   pharmacoepidemiology, testified at the Frye hearing, inter alia, as follows:

           [Appellee's counsel]: Did Dr. Freeman employ generally
           accepted methodology?

           A: No.

           Q: Did you identify a number of specific ways in which you
           believe that Dr. Freeman deviated from a generally
           accepted methodology?

           A: Yes, I did.

           Q:      And   is   this-does
                                     this slide summarize the
           methodological flaws you identified with respect to Dr.
           Freeman's methodology?

           A: Yes, it does.

           Q: Would you please     briefly describe what those flaws are?




                                          - 18 -
J   -A31039-16

          A: Sure.   So there are four groupings listed there. The
          first  ignoring chance, confounding and bias as a possible
                  is
          cause of false associations, essentially not applying any
          epidemiological principles to reviewing the results and
          ignoring the lack of replications        .   .   .




          Q: I'd       just ask you to slow down               a   little bit, if you don't
          mind?

          A: And ignoring the lack of replication. The second is
          improperly grouping all SSRIs as a class to draw
          conclusions about Zoloft. The third is improperly drawing
          conclusions about Zoloft and omphalocele based on
          findings from other unrelated congenital defects. And the
          forth is incorrectly reporting several findings from the
          literature.



          Q: You're       familiar with the Louik study?

          A: Yes.

          Q:       Louik study
                  The                    has   a       finding         with   respect to
          omphalocele, correct?

          A: Correct.




          Q: So when it says       three exposed subjects, what does that
          mean?

          A: That's only three Zoloft-three women used Zoloft had
          omphaloceles.     So there's only three Zoloft-exposed
          women.

          Q: In the Louik            group,    did         they        conduct    multiple
          comparisons?

          A: They did.

          Q: How many comparisons did              they do?



                                           - 19 -
J   -A31039-16

          A: Just from the paper, 42 initial, 66 additional that they
          reported in the paper, so over   a   hundred comparisons.

          Q:     Did the authors recognize the limitations of doing a
          hundred plus comparisons?

          A: Yes, they do.  The quote here is that they state in the
          presence of multiple comparisons distinguishing random
          variation from two elevations in risk is difficult. Meaning,
          we can't tell whether these are true findings or false
          positives.

          Q: So assuming the authors of the Louik      study were aware
          of the concept of chance, right?

          A: Yes.

          Q: Is what they did improper by conducting      a   hundred and
          six comparisons?

          A: No, it's not improper.

          Q: Why would   authors like the Louik authors do so many
          comparisons understanding the potential limitations that
          arise from concepts like chance?

          A: Because they were doing it to generate hypothesis, not
          to answer or address hypothesis. As they state, in the
          absence of preexisting hypothesis. So it was to generate
          hypothesis that could then be tested later.

          The  Court:   Could any scientific conclusion about
          omphalocele be made on the basis of the Louik paper?

          The Witness: No.

          The Court: Next question.

          [Appellee's counsel]: And have subsequent studies looked
          at the issue of Zoloft and omphalocele?

          A: Yes.




                                      - 20 -
J   -A31039-16

          The Court: Can any scientific conclusion be drawn from
          about omphalocele from the Louik study and any other
          studies subsequent that examined it?

          The Witness: Yes, when you put it all together you can.

          [Appellee's counsel]:  .    Dr. Freeman lists four studies
                                      .   .


          with respect to Zoloft and omphalocele, correct?


          A: Correct.



          Q: Does Alwan replicate the Louik finding                           with respect to
          omphalocele?

          A: No, it does not.

          Q: Why not?

          A: Because the odds ratio of 1.5                .   .   .   is   consistent with the
          play of chance.

          Q:     Andwould it be fair and generally accepted and
          accurate to say that Alwan shows that a woman taking
          Zoloft had a 50 percent increased risks of having a child
          with omphalocele?

          A: No.

          The Court: Why is that improper to conclude?

          The Witness: Because this is based on the results of this
          population -based study, they did not demonstrate a
          relationship overall between Zoloft and omphalocele that
          could be attributed to a real association. The relationship
          there is attributable to chance         .   .   .   .




          [Appellee's counsel]: Dr. Freeman also cites this Jiminez-
          Solem finding as at least having a relationship between
          Zoloft and omphalocele, correct?

          A: He does in his report.


                                              - 21 -
J   -A31039-16


                              what he cited here with respect to
          Q: Is the odds ratio in
          Jiminez-Solem and the confidence interval, are those
          correct?

          A: No, they're not.

          Q: You've had a chance to take a look at the Jiminez-
          Solem paper, right?

          A: Yes, I have.




          Q: But there is actually data that's reported or information
          reported in Jiminez-Solem about abdominal wall defects,
          right?

          A: There was.

          Q: And abdominal wall defects would be something                          that
          would,               a       category that would encompass omphalocele?

          A: Yes, that's correct.

          Q: And what were the findings with respect to abdominal
          wall defects?

          A: So in this study there were no omphalocele defects
          among the women who took Zoloft.



          Q:       .       .       .    And then Reefhuis also looked at Zoloft and
          omphalocele, right?

          A: Yes.

          Q: Do you                     remember who sponsored the Reefhuis study?

          A: That was a study sponsored by the Centers For Disease
          Control.

          Q:   .       .   .   Carol Louik is an author on this paper, right?


                                                       - 22 -
J   -A31039-16


          A: Correct.

          Q: That's the same Carol Louik who             actually wrote the
          Louik paper?

          A: Correct.

          Q: Dr. Freeman cites this CDC study as supporting his
          findings in his paper, right?

          A: He does.




          Q: And   what do the authors say about their own data?

          A:  So the authors say this is just a quote from their
          paper-and I just want to clarify, they were doing this very
          specifically because they were trying to answer the
          question of does-can Zoloft be associated with
          omphalocele because of the prior literature. And what
          they found and what they said was it is reassuring that
          none of the five previously reported associations between
          Zoloft and birth defects, which includes omphaloceles were
          confirmed in this analysis.



          Q: Now, did Reefhuis and      .   .   .   her colleagues employ   a
          generally accepted methodology?

          A: Yes, they did.

          Q: Peer reviewed?

          A: Yes, it is.




          Q: Did Dr. Freeman use a     generally accepted methodology
          in evaluating these papers   that he relied on?



                                       - 23 -
J   -A31039-16

          A: No, he did not.

          Q: Why not?

          A:     Soseveral reasons.   First of all, there was no
          application of epidemiologic methods to determine the
          issues that we talked about before, chance, bias and
          confounding. There was no critical appraisal of these
          results.   And there was-he did not account for or
          acknowledge the play of chance in these findings.



          Q: Based on all the data, both the data on Dr. Freeman's
          chart and the other data that you evaluated, is there     a
          consistent association between Zoloft and omphalocele?

          A: No, there's none.




          Q:   Has the CDC also indicated whether SSRIs can be
          treated as a class with respect to birth defects generally
          and omphalocele specifically?

          A: In the Reefhuis paper, yes, they did.

          Q: What did the Reefhuis authors of the CDC paper say
          specifically about the class effect?

          A: So they said, this is a quote, this analysis confirms the
          need to assess the association between specific SSRIs and
          specific birth defects rather than combining an entire drug
          class.



          Q: So in viewing all the data regarding SSRIs and class
          effect,     is   generally accepted methodology to treat
                           it   a
          SSRIs as class with respect to causation when assessing
          birth defects, and in particular, when assessing something
          like omphalocele?

          A: No, it's not.


                                      - 24 -
J   -A31039-16


          Q: Did Dr. Freeman do that?

          A: He did.

                                   *  *    *
          Q: Now, let's move to your third criticism of Dr. Freeman's
          methodology. And this deals again with drawing improper
          conclusions about omphalocele based on findings of
          unrelated birth defects.

          Now, in his report Dr. Freeman grouped together various
          types of malformations into a single outcome, right?

          A: Yes.

          Q:       you explain
                    Can                     whether             such   grouping   raises
          methodological issues?

          A:   It   does.

          Q: Can you explain         why and how?

          A: So, if you find a relationship between a drug and one
          type of defect, those data can't be used to say that that
          drug causes       a   different defect.   .   .   .




          Q: Do the authors of the CDC  study also address generally
          accepted methods for evaluating specific birth defects?

          A: Yes, they do.

          Q: This is from the Reefhuis paper again?

          A: Yes, it is.

          Q: What do        they say?

          A: They say the analysis confirms the need to assess
          associations between specific birth defects rather than
          combining heterogeneous groups of birth defects.



                                             - 25 -
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          Q: Is it consistent with what you believe is generally
          accepted in the field of epidemiology?

          A: Yes.

          Q: Is it consistent with what Dr. Freeman did?

          A: No.

R.R. at 5039a, 5041a -5044a, 5046a -5047a.

        Dr. Cabrera was deposed and testified,   inter alia,   as follows:

          Q:   .   .The same type of birth defects that are at issue in
                       .


          this litigation can and do occur in children whose mothers
          have not taken Zoloft or any other SSRI during pregnancy,
          correct?

          A: That is correct.

          Q: Am I   correct that there's no scientifically validated test,
          procedure or protocol that you could point me to in the
          medical literature, in a textbook that provides a method to
          determine whether or not a specific birth defect in an
          individual has been caused or contributed to by Zoloft; is
          that right?

          A: My understanding is that's something that a medical
          doctor would do for individual cases. As far as individual
          cases goes, I'm not aware, but I don't practice at-you
          know, at a case level for individuals, like a medical doctor.

          Q: And my question is directed to   your knowledge. You're
          not aware, then, of any specific test that would identify
          whether or not a specific birth defect in an individual was
          caused or contributed to by Zoloft?

          A: We're actually developing tests for that, but they're not
          available right now.

R.R. at 3670a -3671a.




                                       - 26 -
J   -A31039-16

        In sum, Dr. Cabrera's opinions rely upon peer review articles.         See

R.R. at 605a -610a.     Dr. Cabrera relied upon the Louik study.      See R.R. at

605a -606a.      However, the Louik authors found that their analysis did not

confirm an association between the use of SSRIs and omphalocele.            Id. at
919a.    Dr. Cabrera refers to the Alwan and Reefhuis studies.       Id. at 606a -
607a.    The Alwan study concluded that confirmation by other studies was

required.   Id. at 2014a.    The Reefhuis study stated that its "analysis does

not address whether the birth defect associations we observed were caused

by maternal SSRI treatment."       Id. at 935a.    Dr. Cabrera concedes that the

Jiminez-Solem, Andersen study did not find an association for exposure to

an SSRI and Omphalocele. See       id. at 608a. Furthermore, he acknowledged

that   in the Furu, Kieler study, there was no   Zoloft specific risk reported with

mothers receiving SSRI treatment during pregnancy. See id. at 609a -610a.

He refers to     three other studies, viz., Pedersen, Henriksen, Berard, Zhao,

and Wemakor, Cassib, which concluded that "the incidence is too low

generally and in exposed population to perform statistical testing for risk of

omphalocele" assocation with SSRI exposure.            See id. at 610.      In his

deposition, Dr. Cabrera conceded he was not aware of any tests that were

available to determine whether Zoloft contributed to any birth defects. See

id. at 3670a -3671a.

          It was Appellant's burden to establish   all of the elements of Rule 702

for the admission of Dr. Cabrera's expert report. See Pa.R.E. 702. Rule 702



                                      - 27 -
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includes the Frye test. See Grady, 839 A.2d at 1043. The trial court found

Dr.    Cabrera's report contained methodological defects, for the reasons

precluding the expert testimony of Dr. Freeman. See Betz, 44 A.3d at 58.

We agree that Appellants failed to prove the methodology Dr. Cabrerra

employed was generally accepted in the relevant scientific community. See

Trach, 817 A.2d at 1112. Accordingly, we discern no abuse of discretion by

the trial court in precluding Dr. Cabrera from testifying on Frye grounds.

See Grady, 839 A.2d at 1046.

        Order affirmed.

Judgment Entered.




J    seph D. Seletyn,
Prothonotary

Date: 5/8/2017




                                   - 28 -
