             NOT FOR PUBLICATION WITHOUT THE APPROVAL
                     OF THE APPELLATE DIVISION

                               SUPERIOR COURT OF NEW JERSEY
                               APPELLATE DIVISION
                               DOCKET NO. A-4698-14T1
                                           A-0910-16T1
                                  APPROVED FOR PUBLICATION

IN RE:   ACCUTANE LITIGATION             July 28, 2017

                                     APPELLATE DIVISION


          Argued March 7, 2017 – Decided July 28, 2017

          Before Judges Reisner, Koblitz and Sumners.

          On appeal from the Superior Court of New
          Jersey, Law Division, Atlantic County, Case
          No. 271 (MCL).

          Bruce D. Greenberg and David R. Buchanan
          argued the cause for appellants (Seeger Weiss,
          LLP, Lite, DePalma, Greenberg, LLC, and Weitz
          & Luxenberg, PC, attorneys; Mr. Buchanan and
          Peter Samberg, of counsel; Mr. Buchanan, on
          the briefs).

          Paul W. Schmidt (Covington & Burling, LLP) of
          the District of Columbia bar, admitted pro hac
          vice, argued the cause for respondents Hoffman
          LaRoche, Inc. and Roche Laboratories, Inc.
          (Gibbons PC, Dughi Hewit & Domalewski, PC and
          Mr. Schmidt, attorneys; Michelle M. Bufano,
          Natalie H. Mantell, Russell L. Hewit, Mr.
          Schmidt and Michael X. Imbroscio (Covington &
          Burling, LLP) of the District of Columbia bar,
          admitted pro hac vice, of counsel; Ms. Bufano,
          on the brief).

          Hollingsworth LLP, attorneys for amicus curiae
          Pharmaceutical Research and Manufacturers of
          America (Gregory S. Chernack, of counsel and
          on the brief).
              The parties have not filed briefs in A-0910-
              16.

       The opinion of the court was delivered by

REISNER, P.J.A.D.

       Plaintiffs,         in   these   2076     multicounty    litigation     (MCL)

products liability cases, alleged that they developed Crohn's
          1
disease       as    a    result   of    taking    Accutane     (isotretinoin),       a

prescription acne drug manufactured by defendants Hoffman-La Roche

Inc.    and        Roche    Laboratories       Inc.   (collectively    Roche        or

defendants).            After a Kemp2 hearing, the trial court issued a

February 20, 2015 order granting defendants' omnibus motion to bar

plaintiffs' experts - Dr. David Madigan, a statistician, and                      Dr.

Arthur Kornbluth, a gastroenterologist - from testifying, among

other things, that the epidemiology studies on which the defense

relied were flawed and unreliable, and that Accutane can cause

Crohn's disease.           The trial court also directed the parties to

prepare an order listing the lawsuits affected by the ruling, and

subsequently issued a May 8, 2015 order dismissing 2076 MCL claims




1
    Crohn's disease is a form of inflammatory bowel disease (IBD).
2
    Kemp ex rel. Wright v. State, 174 N.J. 412, 417 (2002).


                                           2                                 A-4698-14T1
with prejudice.    Plaintiffs appeal from those orders.3

       On this appeal, plaintiffs primarily contend that the trial

court misapplied its discretion in finding that the methodologies

Madigan and Kornbluth used were scientifically unreliable and

inadmissible.     After reviewing the record, we reverse the orders

on appeal and remand this case to the trial court.

       We agree with plaintiffs that the trial court went beyond its

gatekeeping function, as set forth in Rubanick v. Witco Chemical

Corp., 125 N.J. 421, 449 (1991), Landrigan v. Celotex Corp., 127

N.J. 404 (1992), and Kemp, supra, 174 N.J. at 412.4           The trial

court took too narrow a view in determining whether the experts

were   using   accepted   scientific   methodologies   to   analyze     the

evidence, and improperly determined the weight and credibility of

the    experts'   testimony.     Among    other   things,    the     judge


3
  In a second appeal (A-0910-16), ninety-eight plaintiffs appeal
from a September 19, 2016 order dismissing their complaints on the
same basis. By order dated December 7, 2016, we granted an
unopposed motion to consolidate A-0910-16 with the current appeal,
A-4698-14 (the first appeal); however, we excused the parties in
the second appeal from filing briefs or appendices, based on their
agreement to be bound by the outcome of the first appeal.
4
  Plaintiffs also argue that the trial court erred as a matter of
law in applying the strict, scientific certainty admissibility
standard, instead of the relaxed standard set forth in Rubanick.
That argument is without sufficient merit to warrant discussion.
R. 2:11-3(e)(1)(E).

                                   3                               A-4698-14T1
inappropriately condemned the experts for relying on relevant

scientific evidence other than epidemiological studies, despite

their plausible explanations for doing do. 5                 Consequently, we

conclude that the trial court mistakenly exercised discretion in

barring the experts' testimony.

     In reaching our conclusion, we emphasize that we are not

placing this court's imprimatur on plaintiffs' experts or on their

opinions.    The    experts   on   both       sides    are   highly     reputable

scientists, who view the evidence differently.               We find no basis

to describe plaintiffs' experts pejoratively as "hired guns," any

more than the defense experts are "hired guns."                 Their testimony

should not have been barred because their analyses emphasized

different evidence and produced different conclusions than those

reached by the defense experts.         The fact that plaintiffs' experts

found   certain    evidence   to   be       critically   important       did   not

constitute   improper   "cherry    picking,"          because    they    provided

plausible scientific explanations for their choices.                    See State

v. Dreher, 302 N.J. Super. 408, 464 (App. Div. 1997) ("Expert

testimony should not be excluded merely because it fails to account



5
  Those same types of evidence were held admissible by a prior
judge, who had handled the Accutane MCL litigation for a decade.

                                        4                                 A-4698-14T1
for some condition or fact that the opposing party considers

relevant.").

      We are not predicting whether a jury will find plaintiffs'

experts - or defendants' experts - credible or persuasive.           That

is not our role, as it was not the trial court's role in the Kemp

hearing.   See Hisenaj v. Kuehner, 194 N.J. 6, 24 (2008) (N.J.R.E.

104   hearings   "are   intended   to   determine   admissibility,    not

credibility.").    We only hold that, on the record created in the

Kemp hearing in this case, the plaintiffs' experts provided well-

explained scientific reasons for analyzing the available evidence

differently from the defense experts, and for relying more heavily

on different evidence than the defense experts relied on.

      Accordingly, plaintiffs are entitled to present the experts'

testimony at trial.

                                    I

      This case cannot be viewed in a vacuum.       It is one in a long

series of mass tort litigations concerning Accutane.6       We need not


6
  McCarrell v. Hoffman-La Roche, Inc. (McCarrell I), No. A-3280-
07 (App. Div. Mar. 12, 2009), certif. denied, 199 N.J. 518 (2009);
Kendall v. Hoffman-La Roche, Inc. (Kendall I), No. A-2633-08 (App.
Div. Aug. 5, 2010), aff'd, 209 N.J. 173 (2012); Sager v. Hoffman-
La Roche, Inc., No. A-3427-09 (App. Div. Aug. 7, 2012), certif.
denied, 213 N.J. 568 (2013); Gaghan v. Hoffman-La Roche, Nos. A-
2717-11, A-3211-11, A-3217-11 (App. Div. Aug. 4, 2014); McCarrell

                                    5                           A-4698-14T1
review the history in detail, as it is set forth in a series of

previous unpublished opinions issued by different panels of this

court.   We summarize only what is important to this case.

     For more than a decade, the same trial judge had handled the

Accutane cases.   To some extent, that judge's familiarity with the

prior litigation, and with the multiplicity of scientific issues

involved, may have shaped the way the parties and their experts

prepared for the current litigation.7    The first judge's rulings

no doubt also shaped the parties' litigation strategies.

     In particular, during the course of the litigation, the first

judge determined that the opinions of plaintiffs' experts, based

on the same types of evidence relied on by plaintiff's experts in

this case, would be admissible as scientifically reliable.          We




v. Hoffman-La Roche, Inc. (McCarrell II), No. A-4481-12 (Aug. 11,
2015), rev’d and remanded, 227 N.J. 569 (2017); Kendall v. Hoffman-
La Roche, Inc. (Kendall II), No. A-0301-14 (June 16, 2016);
and Rossitto v. Hoffman-La Roche, Nos. A-1236-13, A-1237-13 (July
22, 2016), certif. denied, 228 N.J. 419 (2016).
7
  Both of the parties' epidemiology experts (Dr. Madigan and Dr.
Steven N. Goodman) who had testified previously, expressed their
belief that, to some extent, their current reports and testimony
would be viewed in light of their testimony in previous Accutane
trials.


                                 6                           A-4698-14T1
affirmed that determination in McCarrell I, supra, A-3280-07,8

finding that animal studies, case reports, analogous medications,

and other evidence relied on by plaintiffs' experts, were types

of evidence accepted in the scientific community.9

     In the present case, defendants contend that the existence

of epidemiological studies now precludes reliance on the other

types of evidence on which plaintiff's experts had previously

relied.   However, the studies on which defendants rely are not the

controlled clinical trials that the Federal Judicial Center's

Research Manual on Scientific Evidence calls "the gold standard"

of scientific evidence. Rather they are observational studies that


8
  Unpublished opinions are not to be cited as legal precedent, and
we do not do so here. R. 1:36-3. However, it is appropriate to
consider an unpublished opinion of this court where, as here, it
forms a part of the history of the case on appeal. See Mountain
Hill, L.L.C. v. Twp. Comm. of Twp. of Middletown, 403 N.J. Super.
146, 155 n.3 (App. Div. 2008), certif. denied, 199 N.J. 129 (2009).
Moreover, an unpublished opinion of this court is binding on the
trial court in the same case. Ibid.    The parties have not briefed
and, hence, we do not decide, whether an unpublished opinion of
this court is binding on the trial court in the same MCL docket,
albeit in a different case within that docket.
9
  In a 2014 oral opinion, the first trial judge made a detailed
analysis of similar testimony by Dr. David Sachar and Dr. Madigan
concerning the connection between Accutane and ulcerative colitis.
The first judge concluded that the expert testimony, which relied
on very similar types of evidence as that used in this case, was
admissible. That decision was appealed, but was settled before
we decided the appeal. See Kendall II, supra, A-0301-14.

                                 7                          A-4698-14T1
depend on the collection of information from databases or from

patient questionnaires.             Plaintiffs' experts testified that the

studies   are    biased      and   otherwise      flawed.       We   conclude    that

plaintiffs should be entitled to present that testimony at trial,

along with their affirmative evidence in support of their case.

                                          II

     We    begin      with    some      background       as   to     Accutane,    the

epidemiological       studies      of   the    drug,   and    relevant   scientific

principles of epidemiology.

     A.   Accutane

     In 1982, the Food and Drug Administration (FDA) approved

defendants' application to market Accutane, the brand name for

isotretinoin, "to treat recalcitrant nodular acne that has not

responded to other regimens."            Kendall I, supra, 209 N.J. at 180.

The drug is a retinoid, derived from vitamin A, and is very

effective in treating severe acne.               Ibid.    It is well established

that Accutane "has a number of known side effects, including dry

lips,   skin    and   eyes;     conjunctivitis;        decreased     night   vision;

muscle and joint aches; elevated triglycerides; and a high risk

of birth defects if a woman ingests the drug while pregnant."

Ibid.     There is also some evidence that Accutane, which was


                                          8                                  A-4698-14T1
originally studied for use in treating cancer, has an effect on

the gastrointestinal tract.

      The MCL cases concern the alleged propensity of Accutane to

cause IBD, a chronic disease which primarily manifests as one of

two diseases:     Crohn's disease or ulcerative colitis.     Id. at 180-

81.   Although both ulcerative colitis and Crohn's disease share

the same core symptoms, including abdominal pain, frequent and

often bloody bowel movements, and rectal bleeding, there are

differences in the clinical presentation of the disease and the

triggers statistically associated for developing it, which include

family history, infections, frequent use of some antibiotics,

smoking,    and   possibly   the   use   of   oral   contraceptives   and

nonsteroidal anti-inflammatory drugs.         Id. at 181.

      The peak onset of the disease occurs during adolescence—the

same period that individuals are likely to have been prescribed

Accutane.    Ibid.     For both diseases there may be a significant

latency effect (the time from the exposure to the trigger for IBD

to the first symptom of the disease) and a prodromal period (the

time from the first symptom of the disease to diagnosis).

      B.   Epidemiological studies

      For the first six years of this MCL litigation, from 2003 to


                                    9                            A-4698-14T1
2009, there were no epidemiological studies regarding Accutane and

IBD.    In previous trials, the plaintiffs were permitted to present

expert testimony that relied on animal studies, human clinical

studies,     case    reports,      class     effects,    published   scientific

literature, causality assessments, and biological plausibility.

McCarrell I, supra, slip op. at 86; Kendall I, supra, slip op. at

85-86; Sager, supra, slip op. at 20.

       The   first        two   epidemiological     studies    (Crockett       and

Bernstein), 10 were published in 2009 and in 2010, finding no

statistically significant increased risk of developing Crohn's

disease from the use of Accutane, although the Crockett study

found ulcerative colitis is associated with exposure to the drug.

The    Crockett     and    Bernstein   studies    were   addressed   in    expert

testimony in Gaghan, McCarrell II, and Rossitto.                In Kendall II,

the expert witnesses addressed four new epidemiological studies




10
  Seth D. Crockett et al., Isotretinoin Use and the Risk of
Inflammatory Bowel Disease:    A Case-Control Study, 105 Am. J.
Gastroenterol. 1986 (Sept. 2010) (ulcerative colitis but not
Crohn's disease is associated with isotretinoin use); Charles N.
Bernstein et al., Isotretinoin is not Associated with Inflammatory
Bowel Disease: A Population-Based Case-Control Study, 104 Am. J.
Gastroenterol. 2774 (Nov. 2009) (unlikely that isotretinoin use
is associated with development of IBD).


                                        10                                A-4698-14T1
(Etminan, Alhusayen, Fenerty, and Racine).11       After the trial in

Kendall II, two additional studies were published (Rashtak and

Sivaraman).12   The epidemiological studies vary in whether they

show that Accutane increases or decreases the risk of developing

Crohn's disease.      However, with one exception, none of them

demonstrates    a   statistically    significant   increased   risk    of

developing Crohn's disease from exposure to Accutane. One small

study (Sivaraman) did find a statistically significant increased

risk. However, when the study authors adjusted the study results

for antibiotic use, the results were no longer statistically

significant.    Plaintiffs' experts questioned the appropriateness

of that adjustment.

     C.   Epidemiology


11
  Mahyar Etminan et al., Isotretinoin and Risk for Inflammatory
Bowel Disease, 149 JAMA Dermatol. 216 (Feb. 2013) (no increased
risk for IBD); Raed O. Alhusayen et al., Isotretinoin Use and the
Risk of Inflammatory Bowel Disease:    A Population-Based Cohort
Study, 133 J. Invest. Dermatol. 907 (2013); Sarah Fenerty et al.,
Impact of Acne Treatment on Inflammatory Bowel Disease, 68 J. Am.
Acad. Dermatol. 6751 (Apr. 2013); Antoine Racine et al.,
Isotretinoin and Risk of Inflammatory Bowel Disease: A French
Nationwide Study, 109 Am. J. Gastroenterol. 563 (Apr. 2014).
12
   Shadi Rashtak et al., Isotretinoin Exposure and Risk of
Inflammatory Bowel Disease, 150 JAMA Dermatol. 1322 (Dec. 2014);
Susil Silverman et al., Risk of Inflammatory Bowel Disease from
Isotretinoin: A Case Control Study (Oct. 2014).


                                    11                          A-4698-14T1
     In understanding the epidemiological studies, it is first

helpful to define the methodology used in conducting such studies

and the relevant terms, as testified by the experts at the hearing

and as set forth in the Federal Judicial Center, Reference Manual

on Scientific Evidence 549, 555 (3d. ed. 2011) (Reference Manual

or Manual).13     "Epidemiology is the field of public health and

medicine that studies the incidence, distribution, and etiology

of disease in human populations."                Id. at 551.    "Epidemiology

assumes that disease is not distributed randomly in a group of

individuals     and   the    identifiable       subgroups,   including     those

exposed to certain agents [such as prescription drugs], are at

increased   risk      of   contracting        particular   diseases."      Ibid.

Epidemiological studies identify agents that are associated with

an increased risk of a disease in groups of individuals, but "is

not equivalent to causation."            Id. at 552.

     There are two types of epidemiological studies:             experimental

and observational.         Id. at 555.    Experimental studies, or double-

blind randomized control trials, in which one group is exposed to



13
   Available    at  https://www.fjc.gov/sites/default/files/2015/
SciMan3D01.pdf.    The epidemiological section was written by
Michael D. Green, among others, and is entitled Reference Guide
on Epidemiology.

                                         12                              A-4698-14T1
an agent and the other is not, are "considered the gold standard

for determining the relationship of an agent to a health outcome

or adverse side effect."        Ibid.       There are, however, no Accutane

experimental      studies    because    although   such   studies   have   the

potential    to    provide    higher     quality   evidence,   they    cannot

ethically be conducted if researchers suspect that a drug's side-

effects are harmful.        Id. at 555-56.

     Instead, all of the Accutane epidemiological studies to date

are less rigorous observational studies, which are considered to

be the next best available evidence.            Id. at 556.    There are two

types of observational studies:             1) a case-control study, which

measures and compares the frequency of exposure in the group with

the disease (cases) and a similar group without the disease

(controls); and 2) a cohort study, which compares a group of

exposed and unexposed individuals over a period of time.              Id. at

557-59.     In these studies, researchers "observe" individuals who

have already been exposed to the drug and compare them to a group

of individuals who have not.           Id. at 555-56.

     Unlike experimental studies in which risk factors can be

controlled, observational studies generally focus on individuals

living in a community, "for whom characteristics other than the


                                       13                             A-4698-14T1
one     of   interest,   such    as    diet,    exercise,   exposure    to     other

environmental      agents,      and   genetic    background,    may    distort       a

study's      results."     Id.    at     556.     "[T]he    Achilles'    heel       of

observational studies is the possibility of differences in the two

populations being studied with regard to risk factors other than

exposure to the agent."          Ibid.

        Epidemiological studies commonly express the strength of

association between exposure to a drug and a disease in numerical

terms as:       1) "relative risk" (RR), the ratio of the incidence

rate of a disease in exposed individuals to the risk among the

unexposed; or 2) "odds ratio" (OR), the ratio of the odds that an

individual with the disease was exposed to the drug to the odds

that an individual without the disease was exposed.                   Id. at 566-

69.14    An RR of 1.0 means that the relative risk is equal to the

"null hypothesis," that is, that the risk in individuals exposed

to Accutane is the same as the risk in unexposed individuals, or

that Accutane use is not associated with an increased risk of



14
  The Manual explains that an OR is "a convenient way to estimate
the relative risk in a case-control study when the disease under
investigation is rare." Id. at 568. Most of the studies at issue
in this case are case-control studies.      An OR is calculated
somewhat differently in a cohort study but the difference is not
pertinent here.

                                         14                                  A-4698-14T1
developing Crohn's disease.      Id. at 567.    If the RR is greater

than 1.0, the risk in exposed individuals is greater than the risk

in unexposed individuals.     Ibid.   For example, an RR of 1.5 means

that an exposed individual has a 50% greater chance of contracting

Crohn's disease.   If the RR is less than 1.0, the exposed group

has a decreased risk of contracting the disease.       Ibid.        Thus,

an RR of .32 represents a 68% reduction in risk, which might mean

that the drug had a protective effect on developing the disease.

     The OR or RR is, however, only an estimate of the true value.

Determining   whether    an     association     identified     in     an

epidemiological study is causal "requires an understanding of the

strengths and weaknesses of the study's design and implementation,

as well as a judgment about how the study findings fit with other

scientific knowledge."   Id. at 553.      An assessment must be made

of the power of the study to detect associations, the role of

chance, and what sources of error might have produced a false

result, including sampling variability, bias, and confounding

variables (extraneous variables that may affect result).        Id. at

566-97.

     Therefore, a showing of an increased relative risk for Crohn's

disease does not automatically prove that Accutane use creates a


                                 15                            A-4698-14T1
higher risk of developing the disease because the discrepancy

between the exposed and unexposed groups could be the product of

chance as a result of random sampling error.       Id. at 553.      In

determining whether a relative risk greater than 1.0 is a true

association or the result of random error, researchers consider

whether the association is statistically significant.    Id. at 628.

In making that assessment, researchers calculate a p-value, which

"represents the probability that an observed positive association

could result from random error even if no association were in fact

present."    Id. at 576.    The p-value quantifies the statistical

significance of a relationship; the smaller the p-value the greater

the likelihood that associations determined in a study do not

result from chance.    Id. at 626.    The most commonly used p-value

is .05, that is for example, that there is a 5% chance that the

relative risk could have occurred by random error.      Id. at 576-

77.

      A more sophisticated approach, which was used in the studies

at issue in this case, involves calculating a confidence interval

(CI):

            A confidence interval is a range of possible
            values calculated from the results of a study.
            If a 95% confidence interval is specified, the
            range encompasses the results we would expect

                                 16                          A-4698-14T1
           95% of the time if samples for new studies
           were   repeatedly   drawn   from   the   same
           population. . . .       The advantage of a
           confidence interval is that it displays more
           information   than    significance   testing.
           "Statistically significant" does not convey
           the magnitude of the association found in the
           study or indicate how statistically stable
           that association is. A confidence interval
           shows the boundaries of the relative risk
           based on selected levels of . . . statistical
           significance. . . . [T]he confidence interval
           reveals the likely range of risk estimates
           consistent with random error.

           [Id. at 580.]

     If, for example, a study reveals a RR of 1.5, which represents

an elevated risk of developing Crohn's disease, that result might

or might not be considered statistically significant, depending

on the boundaries of the confidence interval.            If the CI includes

1.0 (the null hypothesis, meaning that taking Accutane neither

increases nor decreases the risk of developing Crohn's disease),

then the 1.5 result is said not to be statistically significant.

However, if the CI is entirely above 1.0, for example if it ranges

from 1.2 to 3.2, then the 1.5 RR would be considered statistically

significant.   Id. at 580-81.

     In   assessing   whether   the   failure   of   a   study   to   find    a

statistically significant association was exonerative of the drug

or simply inconclusive, scientists consider the "power" of a study,

                                  17                                  A-4698-14T1
or   "the   probability   of   finding    a   statistically    significant

association of a given magnitude (if it exists) in light of the

sample sizes used in the study."          Id. at 582.      "The power of a

study depends on several factors:         the sample size; the level of

statistical significance specified; the background incidence of

disease; and the specified relative risk that the researcher would

like to detect."    Ibid.      The higher the power of the study the

less likely it will show a false negative.         Ibid.    For example, a

study with a likelihood of .25 of failing to detect a true RR of

2.0, has a power of .75, meaning the study has a 75% chance of

detecting a true RR of 2.0.       Ibid.       On the other hand, a study

with low power has a greater likelihood of failing to detect a

significant relative risk, even though such a risk exists.           "With

large numbers [of individuals included in the study group], the

outcome of the test is less likely to be influenced by random

error, and the researcher would have greater confidence in the

inferences drawn from the data."         Id. at 576.

      Under the proper circumstances, researchers can increase the

power of a series of studies by conducting a meta-analysis, which

involves pooling the results of different studies, some of which

are small and lack statistical power, to arrive at a single figure


                                   18                              A-4698-14T1
to represent the totality of the studies.   Id. at 608.    The Manual

indicates, however, that a meta-analysis may produce an unreliable

result.

          The appeal of a meta-analysis is that it
          generates a single estimate of risk (along
          with an associated confidence interval), but
          this strength can also be a weakness, and may
          lead to a false sense of security regarding
          the certainty of the estimate. A key issue
          is the matter of heterogeneity of results
          among the studies being summarized. If there
          is more variance among study results than one
          would expect by chance, this creates further
          uncertainty about the summary measure from the
          meta-analysis.    Such differences can arise
          from variations in study quality, or in study
          populations or in study designs.          Such
          differences in results make it harder to trust
          a single estimate of effect; the reasons for
          such differences need at least to be
          acknowledged and, if possible, explained.
          People often tend to have an inordinate belief
          in the validity of the findings when a single
          number is attached to them, and many of the
          difficulties that may arise in conducting a
          meta-analysis, especially of observational
          studies such as epidemiologic ones, may
          consequently be overlooked.

          [Ibid.]

                               III

     We next address the parties' conflicting testimony on the

subjects of gastroenterology and epidemiology.   As background, the




                               19                             A-4698-14T1
following chart15 summarizes the epidemiological studies at issue

in this case:



 STUDY        DATABASE      NO. OF       RR for CD     ACCUTANE    STUDY
              AND           SUBJECTS     at CI 95%     EXPOSURE    RESULTS
              SUBJECTS                                 PRIOR TO
                                                       DIAGNOSIS
 Bernstein    Canadian      21,500         1.15        2.6 years   Positive
 2009         Health        (total)      (0.61-2.02)               association
 manuscript   Ins.          1118                                   (increased risk),
 (case-                     (CD)                                   but not SS
 control)
 Crockett     US Health     29,000         0.68        1 year      Negative
 2010         Ins. (55      (total)      (0.28-1.68)               association
 manuscript   million)      3664                                   (decreased risk)
 (case-                     (CD)
 control)                                  0.89        2 year      Negative
                                         (0.32-2.52)               association
                                                                   (decreased risk)
 Etminan      US Health     45,000         1.05        1 year      Positive
 2013         Ins. (women   (total)      (0.5501.98)               unadjusted
 manuscript   who had       1103                                   association
 (case-       taken oral    (CD)
 control)     contracep-                   0.91                    Negative adjusted
              tives)                     (0.37-2.25)               association
 (meta-                                                            (decreased risk)
 analysis)
                                           0.75                    Negative
                                         (0.46-1.24)               association (meta-
                                                                   analysis)
 Racine       French        44,000         0.45        1 to 2      SS protective
 2014         Health        (total)      (0.24-0.85)   years       association
 manuscript   Ins. (47      2829                                   (reduced risk)
 (case-       million)      (CD)
 control)
 Alhusayen    Canadian      46,922         1.17        1 year      Positive
 2013         Database      (treated     (0.90-1.52)               association
 manuscript   (4.5          with                                   (increased risk),
 (cohort)     million)      Accutane)                              but not SS




15
  For purposes of the chart, we abbreviate Crohn's disease as "CD"
and statistical significance as "SS."

                                        20                              A-4698-14T1
STUDY             DATABASE       NO. OF      RR for CD      ACCUTANE    STUDY
                  AND            SUBJECTS    at CI 95%      EXPOSURE    RESULTS
                  SUBJECTS                                  PRIOR TO
                                                            DIAGNOSIS
Sivaraman         US Patient     509           5.6          unknown     Positive
2014              Question-      (total)     (1.1-28.0)                 unadjusted
abstract/         naire                                                 association and
poster            from three                                            SS for CD
(case-            clinics
control)                                       4.8                      Positive adjusted
                                             (0.3-70)                   association, but
                                                                        not SS for CD
Fenerty           Marketscan     176,889     For IBD                    Negative
2013              Medicaid       (total)       0.57                     association for
abstract/         Database       324         (0.28-1.16)                IBD (decreased
power-point                      (CD)                                   risk)
(case-                                       Not reported
control)                                     for CD
Rashtak           Mayo Clinic    1078        For IBD                    Negative
2014              patients       (total)       0.28                     association for
manuscript                                   (0.10-0.79)                IBD
(cohort)                                                                (decreased risk)
                                             Not reported
                                             for CD

     A.     Gastroenterology experts

              1.    Dr. Asher Kornbluth

     Plaintiffs' expert, Dr. Kornbluth, was a highly qualified

expert      who     was      board-certified      in     internal   medicine      and

gastroenterology and was a professor of medicine at Mount Sinai,

the preeminent hospital for IBD.                 He had specialized in Crohn's

disease     for     twenty-seven      years,     conducted    research     on     IBD,

conducted clinical trials on several drugs intended for use in the

management of IBD, treated between 5,000 and 10,000 patients with

Crohn's disease, been retained as a consultant to pharmaceutical



                                            21                               A-4698-14T1
companies, and published more than 100 articles on IBD in peer-

reviewed scientific journals, textbooks, and other publications.

      Kornbluth opined that Accutane can cause Crohn's disease in

humans.      In reaching that conclusion, Kornbluth relied on his

personal experience in treating thousands of patients with the

disease.     Additionally, he relied on some of the same evidence

that Dr. David Sachar, a previous plaintiffs' expert, had relied

on   in    seven   previous    Accutane        trials   in   this   MCL   docket, 16

including animal studies, case reports, class effects of Vesanoid,

biological plausibility, scientific articles, internal studies,

causality assessments, and epidemiological studies.                   However, as

more fully discussed infra, both Dr. Kornbluth and Dr. Madigan

testified that most of the epidemiological studies done to date

were fundamentally flawed, thus warranting greater reliance on

other forms of scientific evidence.

      Evidence of an Association

      In    accord   with     what   he    testified     was    the   established

scientific methodology, Kornbluth first considered whether there

was an association between Accutane and Crohn's disease. In making



16
  McCarrell I and II, Kendall I and II, Sager, Gaghan, and
Rossitto.

                                          22                                A-4698-14T1
that determination, he reviewed scientific articles, MedWatch

reports, epidemiological studies, and causality assessments, which

he found reflected a strong association between Accutane and

Crohn's disease.

          a.   Scientific articles

     Kornbluth     reviewed   articles   published   in   peer-reviewed

scientific journals, many of which analyzed a single anecdotal

case report, which he found supported a finding that there was an

association between Accutane and Crohn's disease.17        For example,

an article by Reddy and several colleagues reported that of the



17
  P. Martin et al., Isotretinoin-Associated Proctosigmoiditis, 93
Gastroenterology 606 (1987) (case report); Philippe Deplaix et al.,
Acute Hemorrhagic Colitis Probably Due to Isotretinoin with
Recurrence    Following    Reintroduction    of    Treatment,    20
Gastroenterol. Clin. Biol. 113 (1996) (case report); Marianne Melki
et al., Granulomatous Colitis Probably Due to Isotretinoin, 25
Gastroenterol. Clin. Biol. 433 (2001) (case report); J.L.M. Passier
et al., Isotretinoin-Induced Inflammatory Bowel Disease, 64 Neth.
J. Med. 52 (Feb. 2006) (case reports); Deepa Reddy, M.D. et al.,
Possible Association Between Isotretinoin and Inflammatory Bowel
Disease, 101 Am. J. Gastroenterol. 1569 (July 2006) (adverse event
reports); Cristiano Spada, M.D. et al., Isotretinoin-associated
Pan-enteritis, 42 J. Clin. Gastroenerol. 923 (Sept. 2008) (case
report); Matthew Shale et al., Isotretinoin and Intestinal
Inflammation: What Gastroenterologists Need To Know, 58 Gut 737,
739 (June 2009) (study of adverse event reports concluding
isotretinoin may act as trigger for IBD in susceptible patients);
and Michael B. Brodin, M.D., Inflammatory Bowel Disease and
Isotretinoin, 14 J. Am. Acad. Dermatol. 843 (1986) (letter to
editor).

                                  23                            A-4698-14T1
approximately four or five million people that took Accutane

between 1997 and 2002, the FDA received eighty-five reports of

IBD. Using the Naranjo ADR probability scale, the authors found

that "4 cases (5%) scored in the 'highly probable' range for

isotretinoin as the cause of IBD, 58 cases (68%) were 'probable,'

23 cases (27%) were 'possible,' and no cases were doubtful."

Reddy,   supra   note   17,   at   1571.   The   authors   concluded   that

"isotretinoin appears to be a potential precipitant of IBD."             Id.

at 1572.

           b.    MedWatch reports

     Kornbluth next reviewed a series of MedWatch reports, reports

which are made by physicians, patients and others to the FDA

listing among other information, a description of the adverse

event and whether it abated after the patient stopped using

Accutane   and   returned     after   reintroduction   (referred    to    as

challenge/dechallenge/rechallenge).        He found that if corrected

for underreporting, the number of MedWatch reports suggested a

strong association between Accutane and Crohn's disease.

           c.    Epidemiological studies

     Kornbluth also reviewed six observational epidemiological

studies (Bernstein, Crockett, Alhusayen, Etminan, Racine, and


                                      24                           A-4698-14T1
Sivaraman), only one of which (Sivaraman) found a statistically

significant positive association (before adjustment for antibiotic

use)    between   Accutane   and     Crohn's     disease,      one    found    a

statistically significant negative association (Racine) and no

study concluded that Accutane use presents an increased risk for

developing   Crohn's   disease. 18        Kornbluth   opined   that    despite

"significant flaws" in five of those studies that distorted the

results, the studies nonetheless provided some evidence of an

association between Accutane and Crohn's disease.

       Kornbluth relied on the unadjusted results of the Sivaraman

study, which was summarized in a published abstract (not manuscript

form), and selected by the American College of Gastroenterology

to be presented as a poster at their annual conference to enable

peers and colleagues to discuss the findings with the researchers.

In that small study (509 patients), the authors initially found a

statistically significant association between Accutane and Crohn's

disease: that the risk of developing the disease was more than

five times higher in the group exposed to Accutane.              The authors


18
  The studies yielded different results for ulcerative colitis:
Crockett found a statistically significant association; Bernstein,
Etminan, Racine, and Alhusayen found a positive association, but
not a statistically significant association; and Fenerty and
Rashtak found a negative association.

                                     25                                A-4698-14T1
collected data using a questionnaire, which included information

about use of antibiotics, family history of IBD, and smoking,

thereby accounting for confounding variables.             The authors then

"adjusted"    the   analysis    to   remove    subjects      who   had     taken

antibiotics, which Kornbluth said still yielded a "very striking

increased risk" of developing Crohn's disease from Accutane use,

although the adjusted sample size was too small to demonstrate

statistical    significance.          The     authors     concluded          that

"isotretinoin exposure does not appear to confer risk for Crohn's

disease   independent   of     antibiotic    exposure."       Kornbluth       and

Madigan both questioned the basis for the adjustment the authors

made.19

     Kornbluth opined that the results of the other five studies

(Bernstein,   Crockett,      Alhusayen,     Etminan,   and    Racine),       were

inconclusive because they:        failed to account for the prodrome

(see section 1 below); were insufficiently "powered"; or contained

design flaws that biased or distorted the results to show a reduced

risk of developing Crohn's disease.         Nonetheless, Kornbluth found



19
  The authors noted that taking antibiotics alone did not appear
to affect the risk of developing Crohn's disease. Nonetheless,
they removed the subjects who had taken antibiotics when they
recalculated the study results.

                                     26                                  A-4698-14T1
that the studies were informative in determining causation, noting

that   four   of   the    studies    (Bernstein,    Etminan   (unadjusted),

Alhusayen, and Sivaraman) found a positive association between the

drug and the disease.

                   1.    Prodrome

       Kornbluth    opined    that   four   of    the   studies   (Crockett,

Alhusayen, Etminan, and Racine) had not followed patients for long

enough to detect an effect from Accutane exposure and thus had

failed to account for the prodrome of Crohn's disease, that is,

the delay between the time of the first or early symptoms and the

diagnosis.    He opined, based on his decades of experience as a

treating gastroenterologist, that the average prodrome for Crohn's

disease was from two to four years.              He found support for that

opinion in several studies, including:           1) the Pimentel study,20 a

referral-based study (45 of the 66 subjects had Crohn's disease),

in which the authors found the mean prodrome for Crohn's disease

was 6.9 years; and 2) the Barratt study,21 in which the authors



20
  Mark Pimentel, M.D. et al., Identification of a Prodromal Period
in Crohn's Disease but Not Ulcerative Colitis, 95 Am. J.
Gastroenterol. 3458 (Dec. 2000).
21
  S.M. Barratt et al., Prodromal Irritable Bowel Syndrome May Be
Responsible For Delays In Diagnosis In Patients Presenting With

                                      27                             A-4698-14T1
found the mean prodrome was four years.      He distinguished the

findings of a larger study by Chouraki22 in which the authors found

a three-month prodrome, based upon the selection of the patients

for the study and the use of patient charts as opposed to patient

questionnaires, as used in the Barratt and Pimentel studies.

     Kornbluth explained that because the prodrome for Crohn's

disease is two to four years, a study that looks back only one-

year from diagnosis would not capture patients who developed

Crohn's disease from Accutane exposure 366 days to four years

after taking the drug. He noted, for example, that in the Crockett

study the odds ratio increased from 0.68 (one-year analysis) to

0.89 (two-year analysis), which he said was likely a result of

capturing more patients who had developed the disease.   Similarly,

the Bernstein study, which looked back approximately 2.6 years,

found a positive association between Accutane and Crohn's disease,

which Kornbluth opined may also have resulted from capturing more


Unrecognized Crohn's Disease And Celiac Disease, But             Not
Ulcerative Colitis, 56 Dig. Dis. Sci. 3270 (Nov. 2011).
22
  V. Chouraki et al., The changing pattern of Crohn's disease
incidence in northern France: a continuing increase in the 10- to
19-year-old age bracket (1988-2007), 33 Aliment. Pharmacol. Ther.
1133 (2011). Chouraki was not a study of the prodrome for Crohn's
disease. It was a study of the increased incidence of the disease
in northern France.

                               28                           A-4698-14T1
Crohn's disease patients than the other shorter studies.             He found

that these four studies were not designed to accurately account

for all of the Accutane patients who had developed Crohn's disease,

thereby distorting the results.        He opined that if the studies had

been designed to account for the long prodrome, the results would

have   shown   a   greater      increased   risk   of   developing   Crohn's

disease.23

                   2.   Power

       Next, Kornbluth opined that three of the studies (Bernstein,

Crockett, and Etminan), were insufficiently powered to detect a

statistically significant association; in other words, that the

sample size was not large enough to make a definitive conclusion

as to whether there was a statistically significant risk.                  For

example, in the Bernstein study, a large case-control study using

a Canadian database, the study population only comprised 1118

Crohn's disease cases out of a control population of 19,419.                 He

calculated that the "power" of the Bernstein study was low (about

25% to 30%), that is, there was only a 25% to 30% chance of


23
  Kornbluth's view about the length of the prodrome was hardly
unique to him or scientifically unorthodox. It was supported by
the Pimentel and Barratt studies, references in Passier, supra
note 17, at 52, and admissions made by defendant's expert, Dr.
Oliva-Hemker.

                                      29                              A-4698-14T1
detecting a statistically significant association (greater than

2%) between Accutane and Crohn's disease.      He explained that 80%

power was appropriate for a study. He opined that if these studies

had   not   been   underpowered,    the   results   would   have   been

statistically significant for an increased risk of developing the

disease.

      However, Kornbluth admitted that where individual studies are

underpowered to detect outcomes, studies can be pooled using a

meta-analysis, to increase the power to detect a risk.        One such

study was done by Etminan, which combined the Bernstein, Crockett,

Etminan (case-control study) and Racine studies, and found a pooled

RR of .75 with a CI of 0.46 to 1.24, indicating no increased risk

of developing Crohn's disease.     Another study was done by Goodman,

defendants' expert, as discussed more fully infra, who found a

pooled RR of 0.87 with a CI of 0.59 to 1.28, or, again, no

statistically significant increased risk of developing Crohn's

disease.    However, Kornbluth, like Madigan, rejected the results

of these meta-analyses, explaining that a meta-analysis using

underpowered and flawed studies (as he said existed in this case),

which did not account for the prodrome, are not informative and

should not be relied upon by scientists in determining causation.


                                   30                          A-4698-14T1
                    3.    Design flaws

     Kornbluth also found the results of the five studies were

inconclusive because they had design flaws, including differences

in the populations and the failure to account for confounding

variables.     For example, he opined that the Bernstein study, a

Canadian     study,      was    flawed     because        of   the    differences      in

recommended doses between the United States (higher dose) and

Canada (lower dose).           He expected that given that difference there

would be far fewer cases of Crohn's disease in Canada thereby

decreasing    the     relative      risk    ratio.         Similarly,     there     were

differences      in   recommended        doses      between     the    United     States

(higher)   and    France       (lower),     which    Kornbluth        testified   could

account for the Racine study's finding of a protective effect.

     Next, Kornbluth found that most of the studies had failed to

account for smoking and family history confounders, that is,

alternative      causes    of     Crohn's       disease    unrelated     to   Accutane

exposure that can bias the study by making the association appear

higher or lower than it actually is.24                For example, the Alhusayen



24
  Many of the studies had accounted for other confounders,
including gender, oral contraceptive use, use of NSAIDs, and
antibiotics. And the Etminan study adjusted, in part, for patients
who had made a claim for tobacco cessation counseling.

                                           31                                   A-4698-14T1
study, which comprised 46,922 patients treated with Accutane,

reported an unadjusted RR for Crohn's disease of 1.40, and an

adjusted (for antibiotic use) RR of 1.17.              He testified that the

study     should    have   adjusted    for    more     relevant   confounders,

including family history and smoking, which presumably would have

yielded a higher risk ratio of developing Crohn's disease from

Accutane. In other words, removing all of the individuals who had

a family history of Crohn's disease from the sample would yield a

better measure of whether Accutane use is associated with Crohn's

disease.

     Lastly,       Kornbluth   did    not   consider    the   results   of   two

additional studies (Rashtak and Fenerty), because those studies

were designed to only report general IBD results, and did not

calculate the relative risk of developing Crohn's disease, which

has different triggers than ulcerative colitis and therefore did

not provide reliable information on the risk of developing Crohn's

disease.

     d.    Causality assessments

     Next, Kornbluth considered defendants' internal causality

assessments of adverse drug experience (ADE) reports of Crohn's

disease in patients taking Accutane, in which defendants had


                                       32                               A-4698-14T1
concluded that there was an association between Accutane and the

disease.     For example, in an internal causality assessment dated

December 17, 2002, defendants reported that there were 159 reports

of adverse events from exposure to Accutane received from worldwide

sources; of those patients, sixty-four had Crohn's disease, of

which Roche assessed causality as "related" in twenty-seven cases,

with the remainder designated either as unrelated or unknown.

Additionally, defendants concluded in an internal report dated

November 16, 2000, that "[i]sotretinoin has been found to be

causally associated with inflammatory bowel disease, including

colitis."

       Similarly,    in    its   "general     data   memo,"   a   document    that

reflected    the    company's    scientific     and   medical     opinion    about

Accutane, defendants provided that IBD "is a possible side effect

of ROACCUTANE in very rare cases, possibly in patients predisposed

to inflammatory gastro-intestinal diseases," and that although the

side-effect "does not seem to represent a serious problem in

practice,"    it    is    "reasonable    to   conclude"   that     the   drug    is

"basically contraindicated" for patients "in the active phase" of

IBD.    Kornbluth testified that those "strong statement[s]" by

defendants, who had a great deal of pharmacovigilance experience


                                        33                                A-4698-14T1
in assessing ADE reports, were significant in assessing whether

Accutane use was associated with Crohn's disease.                    In its core

data sheet, which is a compilation of information set forth in

labels or in reports sent to regulatory boards, defendants also

stated that IBD had been reported in Accutane users and that

adverse events are dose-related.

      Existence of a Causal Relationship

      After determining that there was an association between

Accutane and Crohn's disease based on the literature, MedWatch

reports,    epidemiological     studies,       and    causality      assessments,

Kornbluth then considered whether that association reflected a

causal relationship.

     a.    Bradford Hill

     As set forth above, epidemiology cannot prove causation.

Reference    Manual,   supra,   at      598.     In    making     the   causation

determination, Kornbluth considered, among other factors, the

widely recognized criteria identified by Sir Austin Bradford Hill

(Bradford Hill criteria): (1) strength of the association; (2)

temporal    relationship;   (3)      consistency      of   relationship;       (4)

biological    plausibility;       (5)      consideration        of   alternative

explanations; (6) specificity; (7) dose-response relationship; (8)


                                      34                                  A-4698-14T1
replication; and (9) cessation of exposure.                 Sir Arthur Bradford

Hill, The Environment and Disease:              Association or Causation, 58

Proc. Royal Soc'y of Med. 295, 299 (1965).                   In assessing these

criteria

            [t]here is no formula or algorithm that can
            be used to assess whether a causal inference
            is appropriate based on these guidelines. One
            or more factors may be absent even when a true
            causal relationship exists.    Similarly, the
            existence of some factors does not ensure that
            a causal relationship exists. Drawing causal
            inferences after finding an association and
            considering these factors requires judgment
            and searching analysis, based on biology, of
            why a factor or factors may be absent despite
            a causal relationship, and vice versa.
            Although the drawing of causal inferences is
            informed by scientific expertise, it is not a
            determination that is made by using an
            objective or algorithmic methodology.

            [Reference Manual, supra, at 600.]

                  1.     Strength of association

      Kornbluth opined that the association evidence (scientific

literature,      MedWatch     reports,         epidemiological        studies    and

causality assessments) reflected a strong association between

Crohn's disease and Accutane, even though no medical organization

or   epidemiological      study     had    concluded      that   Accutane    causes

Crohn's    disease.    He   found    that      although    the   epidemiological

studies    had   "some    major   shortcomings,"          most   of   the   studies

                                          35                                A-4698-14T1
nonetheless   showed   a   "fairly      substantial   increased      risk    of

Accutane causing Crohn's disease."

                 2.   Temporal relationship

     Kornbluth    found    that   the     medical   literature,      MedWatch

reports, and animal studies supported a finding that there was a

temporal   relationship    between      Accutane    exposure   and    Crohn's

disease, that is, the timing of the exposure to the drug and the

onset of the disease was consistent with the lengthy latency and

prodromal period for the disease.

                 3.   Biological plausibility

     Although the precise mechanism by which Accutane could cause

Crohn's disease is unknown, Kornbluth opined that there was a

biologically plausible mechanism by which Accutane could cause

Crohn's disease, namely, that Accutane may cause the migration of

inflammatory T cells to the intestinal tract.          Kornbluth explained

that retinoic acid, which is a metabolite of Accutane, causes and

perpetuates Crohn's disease by directing inflammatory T-cells,

using "antenna" known as "alpha 4 beta 7," to the intestines and

allowing the T-cells to bind to "receptors" (or "mucosal addressing

cell adhesion molecules" ("MAdCAMs")), which then spurs invasion

of inflammatory cells into the lining of the intestines.              Without


                                     36                               A-4698-14T1
retinoic acid, the antenna (alpha 4 beta 7), does not imprint on

the T-cells and are not guided back to the intestines.                          He said

that studies have shown that blocking retinoic acid prevents

intestinal    inflammation,       which       is    characteristic         of   Crohn's

disease.    In other words, without alpha 4 beta 7, one cannot "get

Crohn's disease, because the T cells that are the driver of the

inflammation have no way of getting into the small intestine."25

     In    fact,   he    noted    that    two      new    drugs   (Vedolizumab        and

Natalizumab), which Kornbluth said had been very effective in

treating Crohn's disease, operated to block the retinoic acid

antenna (alpha 4 beta 7), thereby preventing the T-cells from

binding to the MAdCAMs and entering the intestine where they cause

damage.    The success of these drugs indicated to Kornbluth "that

retinoic acid is a damaging toxic pathway for patients with Crohn's

disease," because inhibition of the harmful molecule caused the

patient to get better.

     Moreover,      he      noted        that       a     Canadian        case-control

epidemiological     study    on     children        supported       his    opinion      on

biological    plausibility        because       it       reported    that       children


25
  Kornbluth's explanation as to biological plausibility had some
support in scientific literature. See, e.g., Spada, supra note
17, at 24; Shale, supra note 17, at 737-39.

                                         37                                      A-4698-14T1
ingesting dietary supplements of retinol (vitamin A), a compound

related to Accutane, which also breaks down into retinoic acid,

had   a   statistically   significant      (two-fold)     increased      risk   of

developing Crohn's disease.26        There was a dose effect, in that

only the children taking higher than normal doses of retinol showed

an increased risk of developing Crohn's disease.

                 4.    Dose relationship

      Next,   Kornbluth   testified       that   there   was   a   dose-related

relationship between Accutane and gastrointestinal injury—higher

doses cause greater injury—as set forth in the Core Data sheet,

dog studies, MedWatch reports, and epidemiological studies.                     He

explained that "a dose-response curve" is "scientific evidence"

of causation.

                 5.    Consistency, coherence, and specificity

      Lastly, Kornbluth testified that he had observed consistency

across     different    lines   of      evidence    supporting       a    causal

relationship, including the MedWatch reports, dog studies, and the

epidemiological    studies,     which     except   for   the   Racine     study,



26
  Devendra K. Amre et al., Imbalances in Dietary Consumption of
Fatty Acids, Vegetables, and Fruits Are Associated with Risk for
Crohn's Disease in Children, 102 Am. J. Gastroenterol. 2016 (Sept.
2007).

                                     38                                  A-4698-14T1
reported an increased risk of developing the disease.

     He     also   found    that   the   evidence    was    coherent   with     the

scientific understanding of the cause and presentation of the

disease. For example, evidence from the dog studies was consistent

with the knowledge of the pathogenesis of the disease in that a

breakdown of the epithelium (as observed in some of the dogs) can

serve as a trigger for Crohn's disease.                    The Vedolizumab and

Natalizumab       studies   demonstrated      that   blocking   the    effect    of

retinoic acid (an Accutane metabolite) vastly improved a patient's

Crohn's disease.

     Kornbluth did not, however, find any specificity for Crohn's

disease because the disease is not caused solely by Accutane use,

and it is not the only side-effect of taking the drug.

             b.    Other evidence of a causal relationship

                    1.   Animal studies

     In reaching his conclusion on causation, Kornbluth relied on

studies in which dogs were given high doses of Accutane (the dogs

achieved similar levels of the active metabolite as humans because

a   dogs'    metabolism      is    different).        The    studies    reported

gastrointestinal upset, diarrhea, bloody mucoid stools, intestinal

adhesions, thickening of the mucosa, and epithelial damage, with


                                         39                               A-4698-14T1
crypt abscess formation as seen in Crohn's patients, in the treated

dogs.   He explained that even though dogs cannot develop IBD, the

studies   showed    that      Accutane     can    cause   "significant     obvious

symptomatic damage to the gastrointestinal tract" because a dog's

intestine "is quite analogous to the human intestinal tract."

                   2.    Challenge/dechallenge/rechallenge reports

      Kornbluth opined that the challenge/dechallenge/rechallenge

reports contained in the medical literature (Martin, Deplaix, and

Melki) and in the MedWatch reports were "very compelling" evidence

of   causation.         He    explained    that    the    reports    of   positive

rechallenges were significant because they were essentially a non-

deliberate human experiment, in that a potentially toxic substance

was reintroduced to a patient resulting in further injury.

                   3.    Class effects

      Kornbluth also reviewed side effects reported from use of

Vesanoid, a chemically similar retinoid manufactured by Roche used

to treat acute promyelocytic leukemia (APL).               Chemically, Vesanoid

is   tretinoin,     an       all-trans    retinoic       acid.      Accutane,     or

isotretinoin, another retinoid, metabolizes into tretinoin and 4-

oxo-isotretinoin.            The Vesanoid package insert indicates that

gastrointestinal             disorders,        including         gastrointestinal


                                          40                               A-4698-14T1
hemorrhage, were reported in thirty-four percent of clinical trial

patients.     These results were significant because such a high

percentage of gastrointestinal disorders would not be expected,

even in APL patients, who have a "tremendous tendency to bleed."

Thus, he testified that this evidence supported his opinion that

Accutane can cause gastrointestinal injuries.

     2.   Dr. Maria Oliva-Hemker

     Like Dr. Kornbluth, defendant's gastroenterology expert, Dr.

Oliva-Hemker, was highly qualified.    She was board certified in

gastroenterology and was a professor of medicine at Johns Hopkins

University.    She had treated hundreds of children who suffered

from IBD, published more than seventy peer-reviewed scientific

articles on IBD, and chaired various gastroenterology committees.

     She opined that the available scientific evidence did not

support a finding that Accutane can cause Crohn's disease.       She

testified that the scientific evidence supported a finding that

retinoic acid had an anti-inflammatory or protective effect on the

gastrointestinal tract.   Moreover, she testified that all of the

epidemiological data--the best available evidence--reported no

increased risk of Crohn's disease associated with Accutane, which

was consistent with the biological evidence of a protective effect.


                                41                          A-4698-14T1
She testified that Kornbluth had failed to follow well-recognized

principles of medical evidence hierarchy by relying on lower-level

data (such as case reports and animal studies), instead of higher-

level epidemiological evidence.

     However, on cross-examination, Oliva-Hemker admitted that

Crohn's disease often has a lengthy prodrome.                In fact, she

admitted that information was reflected in her own professional

writings.

     B.    Biostatistical and epidemiological experts

     1.    Dr. David Madigan

     Plaintiff's expert, Dr. Madigan, had a Ph.D. in statistics,

taught statistics at Columbia University, had published more than

150 papers on biostatistics and pharmacovigilance, and served as

an investigator on an FDA pilot program to monitor the safety of

FDA-regulated    medical     products.    He    did   not   testify    as    to

causation,    but   rather    explained   the    process    of   conducting

epidemiological studies, and examined the six epidemiological

studies on Accutane and Crohn's disease (Crockett, Bernstein,

Alhusayen, Etminan, Racine, and Sivaraman).

     Madigan was critical of the design of the epidemiological

studies.     He found that the studies were biased toward a finding


                                    42                                A-4698-14T1
of decreased risk as a result of:         1) power (Crockett, Alhusayen,

and   Etminan);    2)   prodrome     (Crockett,    Etminan,   Racine,     and

Alhusayen); and 3) unmeasured confounders (Bernstein (dose and

duration), Crockett (exposure and outcome), Alhusayen (allowing

reentry of patients after 12-month period), Etminan (confined to

contraceptive     users),   Racine   (dose),    and   Sivaraman   (dose   and

duration)).

      For example, he found that the power of the studies, or "the

power to detect a true effect of a particular size," was low.               In

reaching that determination, he employed standard statistical

techniques and determined that the Accutane studies were not

sufficiently powered to detect even a 50% increased risk -- a

"meaningful" measure of risk.        He calculated the nominal power of

the four studies (that did not find a statistically significant

risk to detect a 50% increased risk of Crohn's disease) as follows:

Bernstein   (37.8%);    Crockett     (18.2%);     Alhusayen   (89.4%);    and

Etminan (22.6%).     In other words, the Bernstein study had only a

37.8% chance of finding a statistically significant increase when

there is a 50% increased risk, or a 62.2% chance of finding a

false negative.

      He also opined that because Crohn's disease has a long


                                     43                              A-4698-14T1
variable prodrome (ranging from a few months to several years),

these studies, which focused on a short observation window to

measure exposure, failed to account for all of the patients who

developed Crohn's disease as a result of ingesting Accutane.

Madigan explained that failing to account for just a few patients

will "introduce bias into the study" toward a showing of no or

decreased    risk    and   will   decrease     the   power    of   the    study.

Accounting for a 6.9-year prodrome (which he derived from the

Pimentel study), Madigan calculated that the power of some of the

studies   further     decreased   to:     Crockett     (5.12%);      Alhusayen

(36.2%); and Etminan (4.5%).         He found that only Bernstein (with

its 2.6-year study) and Sivaraman (with its questionnaire format)

had addressed prodrome through their study designs.

     Moreover, Madigan testified, that it was not scientifically

"appropriate to conduct a meta-analysis in this context, because

of concerns with the individual studies."            He explained that the

purpose     of   a   meta-analysis   is   to    combine      the   results      of

epidemiological studies "to make a combined estimate," however,

he noted that you cannot "make the bias" in a study "disappear"

by combining several biased studies.             Madigan, like Kornbluth,

found that all of the studies in this case were "biased towards


                                     44                                  A-4698-14T1
the null," that is, "systematically biased to lower the estimated

effect" and thus combining the studies would not yield an accurate

result.

     Instead, Madigan conducted a statistical disproportionality

analysis of the spontaneous ADE reports for Accutane and Crohn's

disease contained in the FDA's ADE reporting system database.          He

explained that spontaneous ADE reports "serve as a primary data

source with which we, as a society, study drug safety concerns,"

and is an important component of drug safety investigation even

though the data has limitations due to its reliance on voluntary

reporting.    He   said   that   a    disproportionality   analysis    is

"standard" in analyzing ADE reports and is routinely used by the

FDA and the pharmaceutical industry in assessing emerging safety

concerns.

     In his disproportionality analysis, which he conducted using

the same methods as he used in conducting an analysis for the

pharmaceutical industry, Madigan compared the observed rate of

reporting for Accutane and Crohn's disease with the rate at which

Crohn's disease was reported for other drugs in that database. He

found that from 1997 to the present, there was a "striking signal

of disproportionality" or a "strong association" between Accutane


                                     45                         A-4698-14T1
use and Crohn's disease.         Further, when Madigan removed the ADE

reports    generated   through    litigation      by   lawyer    reporting,     or

approximately 88% of the reports, the results still showed a

moderate increased risk of developing the disease.

     He testified that a similar disproportionality analysis had

been conducted, by researchers affiliated with the World Health

Organization (WHO), of the WHO's drug safety database (Uppsala

Monitoring Centre) in which the researchers compared the observed

rate of ADE reports of Crohn's disease for Accutane to the observed

rate of reports of Crohn's disease for other drugs in the WHO

database.27    They found a statistically significant increased risk

(nineteen     times   greater)   for    developing     Crohn's    disease    from

Accutane use.

     2.    Dr. Steven N. Goodman

     The defense expert, Dr. Goodman, had an M.D. degree, as well

as a Ph.D. in epidemiology, was a professor and associate dean for

clinical    research    at   Stanford       University,   and    had   published

numerous peer-reviewed scientific articles.               He opined that the

epidemiological evidence supported a finding that there was a



27
  The findings are cited in an article on case reports, Passier,
supra note 17, at 52.

                                       46                                A-4698-14T1
"strongly   negative"      association    between   Accutane      and   Crohn's

disease, and that there was no biologic evidence or scientifically

accepted causal mechanism that outweighed the results of the

epidemiological studies.      He opined that Kornbluth's and Madigan's

methodology was not scientifically valid because they placed "very

little weight" on the epidemiological studies, which were the

highest tier of evidence in this case, and placed much more weight

on "lesser forms of evidence," including case reports, animal

studies, and causality assessments.

       In forming his opinion, Goodman reviewed nine epidemiological

studies (Bernstein, Crockett, Etminan (case-control and meta-

analysis), Alhusayen, Racine, Rashtak, Sivaraman, and Fenerty).

He considered the overall results of these studies for IBD as well

as the results for Crohn's disease, because ulcerative colitis and

Crohn's disease share a variety of risk factors and because it is

difficult to distinguish between the diseases in the early stages.

He opined that although the Sivaraman study showed an unadjusted

statistically significant association between the drug and the

disease, the study was too small to have any significance.                     He

also opined that, viewed collectively, the epidemiological studies

were   consistent   with    Accutane     having   "either   [a]   potentially


                                    47                                  A-4698-14T1
protective effect" or "no effect."

     To increase the power of the epidemiological studies, Goodman

conducted a meta-analysis of Accutane and IBD (both ulcerative

colitis and Crohn's disease), in which the larger more precise

studies were given more weight.     He found an RR of developing IBD

of 0.87 (0.65-1.17), a negative association.       He also conducted a

meta-analysis of Accutane and Crohn's disease, and found a similar

RR of 0.87 (0.59-1.28), another negative association.

     Further,   Goodman   found   that   the   epidemiological   studies

properly accounted for the prodrome of Crohn's disease.                 In

determining the prodrome, Goodman reviewed several epidemiological

studies, including the Chouraki study, and concluded that the

average prodrome for Crohn's disease was nine months or less. He

criticized Madigan's reliance on what Goodman characterized as the

outlier non-population-based Pimentel study (6.9-years prodrome),

which Goodman said was too small to provide any valid information.

He concluded that the nine epidemiological studies, which applied

a prodrome from one to two years, were properly designed and

powered, and strongly supported a finding of no association between

Accutane and Crohn's disease.




                                  48                             A-4698-14T1
                                            IV

      Before we address plaintiffs' appellate arguments, it is

helpful    to   review   the        legal        principles   applicable      to     the

admissibility of expert testimony in toxic tort and similar cases.

     To establish liability, plaintiffs must prove through expert

testimony that ingestion of Accutane can cause Crohn's disease in

humans     (general   causation).                In   addition,    each    individual

plaintiff must prove specific causation, i.e., that Accutane was

the cause of his or her disease.             See DeLuca v. Merrell Dow Pharm.,

Inc., 911 F.2d 941, 958 (3d Cir. 1990). See also Perry v. Novartis

Pharm. Corp., 564 F. Supp. 2d 452, 463 (E.D. Pa. 2008) ("Courts

in toxic tort cases often separate the causation inquiry into

general causation -- whether the substance is capable of causing

the observed harm in general -- and specific causation -- whether

the substance actually caused the harm a particular individual

suffered.").     The Kemp hearing at issue here concerned general,

not specific, causation.

     The    admissibility      of    scientific         evidence   is     governed    by

N.J.R.E. 702, which provides that "[i]f scientific, technical, or

other specialized knowledge will assist the trier of fact to

understand the evidence or to determine a fact in issue, a witness


                                        49                                    A-4698-14T1
qualified as an expert by knowledge, skill, experience, training,

or education may testify thereto in the form of an opinion or

otherwise."    The Rule imposes three requirements:

           (1) the intended testimony must concern a
           subject matter that is beyond the ken of the
           average juror; (2) the field testified to must
           be at a state of the art such that an expert's
           testimony could be sufficiently reliable; and
           (3) the witness must have sufficient expertise
           to offer the intended testimony.

           [Hisenaj, supra, 194 N.J. at 15.]

The   second   requirement   is   at    issue   here,   that   is,    whether

Kornbluth's causation testimony and Madigan's statistical analysis

testimony was sufficiently reliable in the field of scientific

research to be admitted.     Ibid.

      In most cases, the proponent of scientific evidence must

demonstrate that the opinions are "generally accepted, within the

relevant scientific community" (the Frye standard).                  State v.

Chun, 194 N.J. 54, 91, cert. denied, 555 U.S. 825, 129 S. Ct. 158,

172 L. Ed. 2d 41 (2008); State v. Harvey, 151 N.J. 117, 169-70

(1997) (citing Frye v. United States, 293 F. 1013, 1014 (D.C. Cir.

1923)), cert. denied, 528 U.S. 1085, 120 S. Ct. 811, 145 L. Ed.




                                   50                                 A-4698-14T1
2d 683 (2000).28     See also Hisenaj, supra, 194 N.J. at 17.                 "That

acceptance   entails        the    strict     application   of    the    scientific

method, which requires an extraordinarily high level of proof

based   on   prolonged,           controlled,    consistent,      and     validated

experience."    Rubanick, supra, 125 N.J. at 436.

     However,    our        Supreme    Court     has   relaxed     the     "general

acceptance" standard in tort cases involving injuries caused by

toxic   substances     or    medications,       involving   new    or    developing

theories of causation. Kemp, supra, 174 N.J. at 430-31; Landrigan,

supra, 127 N.J. at 414; Rubanick, supra, 125 N.J. at 449.                     Under

the relaxed standard, "a scientific theory of causation that has

not yet reached general acceptance may be found to be sufficiently

reliable if it is based on a sound, adequately-founded scientific


28
  In 1993, the United States Supreme Court, construing the Federal
Rules of Evidence, held that Federal Rule of Evidence 702
superseded Frye and mandated that the federal courts apply a more
relaxed scientific reliability standard. Daubert v. Merrell Dow
Pharm., Inc., 509 U.S. 579, 113 S. Ct. 2786, 125 L. Ed. 2d 469
(1993).   Daubert was a pharmacological tort case involving the
drug Benedictin. Id. at 582, 113 S. Ct. at 2791, 125 L. Ed. 2d
at 476. In criminal cases, New Jersey courts have not followed
Daubert, but continue to strictly apply the Frye test, i.e.,
whether the scientific community generally accepts the reliability
of the proffered evidence. See Harvey, supra, 151 N.J. at 168.
As noted, in civil cases involving toxic torts, our courts use the
relaxed standard set forth in Rubanick. See Kemp, supra, 174 N.J.
at 430-31.


                                         51                                 A-4698-14T1
methodology involving data and information of the type reasonably

relied on by experts in the scientific field."               Rubanick, supra,

125 N.J. at 449.     Thus, the Court "changed the focus of the inquiry

from the scientific community's acceptance of the substance of the

opinion   to   its   acceptance     of     the   methodology     and   reasoning

underlying it."      Clark v. Safety-Kleen Corp., 179 N.J. 318, 337

(2004).        The    Rubanick      standard      does     not    require       the

"extraordinarily     high   level    of    proof[,]"     ordinarily     required

before a scientific theory will attain general acceptance in the

scientific community.       Rubanick, supra, 125 N.J. at 436.

     The rationale behind relaxation of the standard was "the

extraordinary and unique burdens facing plaintiffs who seek to

prove causation” in such cases.          Id. at 433.29     The task of proving

causation in toxic tort cases "is invariably made more complex

because   of   the   long   latency      period    of    illnesses     caused    by

carcinogens or other toxic chemicals."            Ayers v. Jackson, 106 N.J.

557, 585 (1987).     And, in some drug cases, causation may not have


29
  Rubanick relied heavily on persuasive federal court opinions,
in rejecting the general acceptance test. Rubanick, supra, 125
N.J. at 445 (citing United States v. Downing, 753 F.2d 1224, 1237
(3d Cir. 1985), and DeLuca, supra, 911 F.2d at 941). See also
Ferebee v. Chevron Chem. Co., 736 F.2d 1529 (D.C. Cir.), cert.
denied, 469 U.S. 1062, 105 S. Ct. 545, 83 L. Ed. 2d 432 (1984)
(cited in Rubanick, supra, 125 N.J. at 440).

                                      52                                  A-4698-14T1
been   "confirmed     by     the   scientific      community       but    compelling

evidence nevertheless suggests that such a relationship exists."

Kemp, supra, 174 N.J. at 430.

                                         V

       Against     that    legal   backdrop,        we    consider       plaintiffs'

contention that the trial court erred in barring their experts'

testimony.       Plaintiffs assert that:          1) their       experts relied on

methodologies and data of the type relied on by comparable experts;

2) the judge substituted his judgment on the epidemiological

studies for that of the expert scientists; 3) the experts' reliance

on   the   studies   involved      a   methodology       generally       followed    by

comparable experts; 4) Kornbluth appropriately considered the

epidemiological studies in assessing the relationship between

Accutane    and    Crohn's    disease;       5)   the    judge    mischaracterized

Madigan's testimony; 6) the judge impermissibly weighed evidence

of ADE reports and animal studies; and 7) the judge abused his

discretion in assessing the credibility of plaintiffs' experts.

We agree that the judge erred in excluding the experts' testimony.

       Under the relaxed standard, as applicable here, the trial

court assesses "the soundness of the proffered methodology and the

qualifications of the expert."                Kemp, supra, 174 N.J. at 426


                                        53                                    A-4698-14T1
(quoting Rubanick, supra, 125 N.J. at 454).                    The focus of the

trial     court's     inquiry     must   be   "solely     on     principles     and

methodology, not on the conclusions that they generate."                      Ibid.

(quoting Daubert, supra, 509 U.S. at 594-95, 113 S. Ct. at 2797,

125 L. Ed. 2d at 484).            In evaluating the methodology, "courts

should     consider     whether     others    in    the   field     use   similar

methodologies."       Rubanick, supra, 125 N.J. at 449.

     In making that determination the court should not "directly

and independently determine as a matter of law that a controversial

and complex scientific methodology is sound."                  Id. at 451.     "The

critical determination is whether comparable experts accept the

soundness of the methodology, including the reasonableness of

relying on this type of underlying data and information.                      Great

difficulties can arise when judges, assuming the role of scientist,

attempt     to   assess     the    validity    of    a    complex     scientific

methodology."       Ibid.   Nor is it appropriate for the trial judge

to second-guess an expert's interpretation of the underlying data.

Ibid.     For example, in Rubanick the Court found that:

            the trial court . . . "independently reviewed"
            each of the thirteen studies on which Dr.
            Balis relied, and decided that they "do not
            say what plaintiff's expert concludes."     In
            engaging in such an analysis, the court
            substituted its own assessment of the studies

                                         54                               A-4698-14T1
           for that of an acknowledged expert. . . .
           "[t]he interpretation of the data . . . is the
           function of the qualified expert . . . .
           [C]ourts should be loath to determine whether
           the particular expert has properly relied upon
           data which experts in the field generally rely
           on." Thus, the inquiry is not the reliability
           of the expert's ultimate opinion nor is it
           whether the expert thought his or her own
           reliance   on   the    underlying   data   was
           reasonable, nor whether the court thinks that
           the expert's reliance was reasonable[.] The
           proper inquiry is whether comparable "experts
           in the field [would] actually rely" on that
           information.

           [Id. at 451-52 (quoting Ryan v. KDI Sylvan
           Pools, Inc., 121 N.J. 276, 289 (1990)
           (additional citations omitted).]

The qualifications of the expert must also "be factored into the

determination of the soundness of the methodology used."             Id. at

452.

       "If epidemiological studies are to provide the basis for an

expert's   opinion,   they   must   have   been   'soundly    and   reliably

generated' and be 'of a type reasonably relied on by comparable

experts in the particular field.'"         Landrigan, supra, 127 N.J. at

419-20 (quoting Rubanick, supra, 125 N.J. at 447).           When an expert

relies on epidemiological studies, the "court should review the

studies, as well as other information proffered by the parties,

to determine if they are of a kind on which such experts ordinarily


                                    55                               A-4698-14T1
rely."    Id. at 417.     Significantly, the court must "examine the

manner    in   which   experts   reason   from   the   studies   and     other

information to a conclusion[,]" which "must derive from a sound

methodology that is supported by some consensus of experts in the

field."    Id. at 420.    See In re Zoloft Prods. Liab. Litig., 26 F.

Supp. 3d 449, 460 (E.D. Pa. 2014) (excluded expert whose "opinion

regarding class effects is not evidence based, and is directly

contrary to the findings of her own peer-reviewed, published

research"); In re Rezulin Prods. Liab. Litig., 369 F. Supp. 2d

398, 425 (S.D.N.Y. 2005) (court excluded expert testimony where

expert selectively chose his support from scientific literature

and failed to "acknowledge or account for" evidence that tended

to refute his theory).

     A court's assessment of scientific expert evidence should

include an evaluation of the studies upon which the experts rely,

but the court must not substitute "its own assessment of the

studies for that of an acknowledged expert."           Rubanick, supra, 125

N.J. at 451.       "Although trial courts are expected to act as

gatekeepers to the proper admission of expert testimony," courts

are not expected "to investigate sua sponte the extent to which

the scientific community holds in esteem the particular analytical


                                    56                                 A-4698-14T1
writings or research that a proponent of testimony advances as

foundational to an expert opinion."               Hisenaj, supra, 194 N.J. at

16.   "The court's function is to distinguish scientifically sound

reasoning    from    that   of   the    self-validating       expert,     who   uses

scientific       terminology     to     present    unsubstantiated        personal

beliefs."    Landrigan, supra, 127 N.J. at 414.           The plaintiff bears

the burden of proof in establishing admissibility.                 Kemp, supra,

174 N.J. at 429.

      Ordinarily, the admission or exclusion of expert testimony

is "committed to the sound discretion of the trial court[,]"

Townsend v. Pierre, 221 N.J. 36, 52 (2015), and we review the

decision for abuse of discretion.            Hisenaj, supra, 194 N.J. at 12.

However,    we    owe   somewhat      less   deference   to   a   trial    court's

determination in a case of this type.               See State v. Torres, 183

N.J. 554, 567 (2005).        "Although 'the trial court is in a better

position to shape the record and make credibility determinations,'

an 'appellate court need not be as deferential to the trial court's

ruling on the admissibility of expert scientific evidence as it

should be with the admissibility of other forms of evidence.'"

State v. J.R., 227 N.J. 393, 410 (2017) (quoting Torres, supra,

183 N.J. at 567).              In determining whether the trial court


                                        57                                  A-4698-14T1
misapplied discretion, we consider whether the court's analysis

of the evidence was faithful to the principles set forth in

Rubanick, or whether the court misapplied the standards.                   See

State v. Darby, 174 N.J. 509, 518 (2002) (no deference is to be

accorded   to    the   trial   court's    decision   to   admit   other-crime

evidence, nor is that decision entitled to be reviewed under an

abuse of discretion standard, where the trial judge failed to

apply applicable law); Konop v. Rosen, 425 N.J. Super. 391, 401

(App. Div. 2012) (appellate review is de novo when the trial court

fails to apply the proper test in analyzing the admissibility of

proffered evidence).       See also Pressler & Verniero, Current N.J.

Court Rules, comment 4.7 on R. 2:10-2 (2017) ("When the trial

court fails to apply the proper test in analyzing the admissibility

of proffered evidence, the de novo standard of review . . .

applies").

       Here, the court found that although both of plaintiffs'

experts were "eminently qualified, their reasoning and methodology

is slanted away from objective science and in the direction of

advocacy."      The court found that Kornbluth's methodology was not

supported by the scientific community because he interpreted the

Sivaraman study differently than its authors did.            Similarly, the


                                     58                               A-4698-14T1
court found that Madigan placed undue weight on the Sivaraman

study, and "ignored" the other studies.            The judge also criticized

Madigan for failing to perform a meta-analysis of all of the

studies.

   The court further reasoned that plaintiffs' experts had failed

to follow valid scientific methodology in relying on the Sivaraman

and Pimentel studies to the exclusion of the larger population-

based epidemiological studies, concluding that the "scientific

literature    does   not   support    reliance      upon   such   insignificant

studies to arrive at conclusions."                 The court concluded that

Kornbluth's    "contrived       reasoning     is    not    supported       by   the

scientific    community    as    a   reliable      basis   for    making    causal

determinations,"     and   Madigan's       opinions   were   not    methodology

based, but rather conclusion-driven.

     Additionally, the court found that Kornbluth's testimony was

"replete with what can be described as convenient assumptions.

When he needs to bridge an analytical gap in his methodology he

assumes facts, events and conclusions as he wants them to be in

support of his hypothesis."          For example,

           in response to counsel's questioning regarding
           the results of various studies, Dr. Kornbluth
           assumed: (a) that all the patients in the two
           studies upon which he relied filled out their

                                      59                                   A-4698-14T1
         questionnaires correctly; (b) despite the fact
         that the authors of the Sivaraman study got
         it   wrong  as   to   their   adjustment   for
         antibiotics, he assumed they got everything
         else correct; (c) he assumed that in the
         Rashtak Study, the patients with Accutane
         exposure were followed for less time than the
         control group; and (d) he assumed the size of
         the doses of Accutane given to the subjects
         in various studies.

    With regard to biological plausibility, the court found

         Kornbluth's discussion of his hypothesis for
         the biological mechanism of the development
         of CD [Crohn's disease] as caused by
         Isotretinoin    falls   far   short  of   being
         "compelling."    His basis for the discussion
         are    the    medications    Natalizumab    and
         Vedolizumab.     He attempts to extrapolate
         causation of CD by Isotretinoin by discussing
         treatment of CD by these other medications.
         Dr. Oliva-Hempker [sic] explained the inherent
         weakness of trying to rely upon the data on
         Natalizumab and Vedolizumab as being probative
         of causation.       In essence, treating a
         "pathway" that develops once a disease occurs,
         does not mean that . . . a particular treatment
         mechanism informs as to the original cause of
         the disease. She also pointed out that this
         hypothesis is contrary to a significant body
         of scientific literature showing that Retinoic
         acid is actually anti-inflammatory . . .

    The court described Madigan as "an expert on a mission," and

criticized Kornbluth's approach as being less convincing than

Oliva-Hemker's analysis as to causation.   He was also critical of

plaintiffs' experts' reliance on lines of evidence other than


                              60                           A-4698-14T1
epidemiological studies:

           [C]oursing through Plaintiffs' presentation
           is a refrain that is a ruse.       Repeatedly,
           counsel for the Plaintiffs and their witnesses
           spoke of "lines of evidence," emphasizing that
           their experts examined the same "lines of
           evidence" as did the experts for the Defense.
           Counsels' sophistry is belied by the fact that
           the examination of the "lines of evidence" by
           Plaintiffs' experts was highly selective,
           looking no further than they wanted to --
           cherry picking the evidence -- in order to
           find support for their conclusion-driven
           testimony in support of a hypothesis made of
           disparate pieces, all at the bottom of the
           medical evidence hierarchy.       This crafty
           stratagem cannot bridge the analytical gaps
           inherent in Plaintiffs' hypothesis.

     Plaintiffs contend that, whether or not the trial judge found

their experts opinions persuasive in substance, the experts relied

on methodologies and data of the type reasonably relied upon by

comparable experts.       We agree.

     A.    Data and Information

     Whether or not it persuades a jury, it is clear to us that

in forming their conclusions Kornbluth and Madigan relied on the

types of data and information reasonably relied on by comparable

experts in the scientific field, and by the experts in previous

Accutane    cases    in     this     docket.    That   evidence    includes

epidemiological     studies,       scientific   articles,   case   studies,


                                      61                            A-4698-14T1
clinical studies, animal studies, and causality assessments.

     It     is   well-established     that    epidemiological       studies,

published in peer-reviewed scientific journals, as were considered

in this case, are the type of data reasonably relied on by the

scientific community to determine whether exposure to a drug is

associated with a disease.        Landrigan, supra, 127 N.J. at 419-20.

Properly     conducted   epidemiological     studies   are   a   significant

factor in establishing causation in toxic tort cases. See Reference

Manual, supra, at 551 n.2.        "[E]pidemiology is a well-established

branch of science and medicine, and epidemiological evidence has

been accepted in numerous cases."         DeLuca, supra, 911 F.2d at 954.

See Magistrini v. One Hour Martinizing Dry Cleaning, 180 F. Supp.

2d 584, 591 (D.N.J. 2002) (epidemiological studies), aff'd o.b.,

68   Fed.     App'x   356   (3d    Cir.    2003).      Notably,     although

epidemiological evidence is not required to prove causation, if

it exists, an expert cannot ignore it.        Perry, supra, 564 F. Supp.

2d at 465.    However, the existence of inconclusive epidemiological

studies does not preclude an expert from relying on alternative

data, such as animal studies.        Id. at 466.

     Moreover, although the Sivaraman epidemiological study was

published as an abstract and not a full article, and was presented


                                     62                              A-4698-14T1
at a conference, our courts recognize that "[s]upport for an

expert's methodology may be found in professional journals, texts,

conferences,      symposia,      or   judicial    opinions    accepting     the

methodology."      Kemp, supra, 174 N.J. at 427.             In accord with

accepted scientific methodology, Kornbluth also considered other

forms   of    evidence   in    determining   causation,    including    animal

studies, case reports, challenge/dechallenge/rechallenge reports,

causality assessments, class effects, and published scientific

literature.       Although     case   reports    and   causality   assessments

should be interpreted with caution, there was nothing so inherently

unreliable about the materials Kornbluth cited as to preclude

their consideration as part of a scientific expert's methodology

under N.J.R.E. 702.           Further, the experts did not elevate this

evidence over the epidemiological studies, but rather considered

this evidence in forming their opinions.

     B.      Methodology and Reasoning

     We also conclude that the methodology used by Kornbluth and

Madigan to reach their conclusions was consistent with sound

scientific principles and methodologies accepted in the medical

and scientific community.         Rubanick, supra, 125 N.J. at 449; Kemp,

supra, 174 N.J. at 431.          In making that determination the court


                                       63                              A-4698-14T1
must "examine the manner in which experts reason from the studies

and other information to a conclusion."                Landrigan, supra, 127

N.J. at 420.    The experts' conclusions "must derive from a sound

methodology that is supported by some consensus of experts in the

field."     Ibid.   The experts must identify the factual bases for

their conclusions, explain their methodology, and demonstrate that

both the factual bases and the methodology are reliable.                    Kemp,

supra, 174 N.J. at 427; Rubanick, supra, 125 N.J. at 449-50.

      The primary focus in this appeal is upon Kornbluth's and

Madigan's analysis of the epidemiological studies.                Those studies

indicated    that   the    relationship     between    Accutane    and   Crohn's

disease is more tenuous than the relationship between the drug and

ulcerative colitis.        For example, Crockett (a large study) found

a   statistically    significant       association     between    Accutane     and

ulcerative colitis, and four studies (Bernstein, Etminan, Racine

and Alhusayen) found a positive association between the drug and

the disease.

      In   contrast,      only   one   small   study   (Sivaraman)       found    a

statistically significant positive association (before adjustment

for antibiotic use) between Accutane and Crohn's disease, two

found a positive association (Bernstein and Alhusayen), three


                                       64                                 A-4698-14T1
found a negative association (Crockett, Etminan, and Racine), and

one (Racine) found a statistically significant association for a

protective effect.           The degree to which this contrary opinion

dominates          the   epidemiological      studies   is   relevant      to        the

reliability inquiry.           DeLuca, supra, 911 F.2d at 955.            However,

demonstrable flaws in the studies may undercut their significance.

Ibid.

       In other words, does the relevant scientific community accept

the process by which Kornbluth and Madigan reasoned to a conclusion

that    the        epidemiological    studies     (despite    the   lack        of    a

statistically significant association) and the other relevant

evidence supported a finding of a causal relationship between

Accutane and Crohn's disease?           In some cases, a court may conclude

that there is simply too great an analytical gap between the data

and the expert's opinion.            See Gen. Elec. Co. v. Joiner, 522 U.S.

136, 146, 118 S. Ct. 512, 519, 139 L. Ed. 2d 508, 519 (1997).

However, in this case, we conclude that the data was sufficient

to permit the experts to testify, and any weaknesses in their

opinions can be explored through cross-examination.

       It     is     well-established      that   "[t]he     usefulness     of        an

epidemiological study depends on the quality of the underlying


                                         65                                A-4698-14T1
data, the reliability of the methodology, and the validity of the

interpretations."      Landrigan, supra, 127 N.J. at 420 (quoting

Michael Dore, A Commentary on the Use of Epidemiological Evidence

in Demonstrating Cause-in-Fact, 7 Harv. Envtl. L. Rev. 429, 432

(1983)).   An expert should, under sound scientific methodology,

evaluate the study in assessing its validity.          See ibid.   We infer

from the Manual that an expert should consider a study's possible

flaws and weaknesses before deciding whether to rely on it.

Reference Manual, supra, at 553.           Further, an expert can rely on

the data generated from a study even if he or she disagrees with

the author's conclusion, and need not subject his or her own

analysis to peer review.     DeLuca, supra, 911 F.2d at 954.

     Here, in contrast to the court's finding, Kornbluth and

Madigan, in accordance with established scientific methodology,

evaluated all of the epidemiological and prodrome studies, not

just Sivaraman and Pimentel.         They testified at length as to the

design   flaws   and   limitations    of   the   epidemiological   studies,

including the failure to account for the prodrome, insufficient

power, and design flaws, which are all recognized in the scientific

community as capable of producing an erroneous association in an

epidemiological study.     See Reference Manual, supra, at 583.          For


                                     66                             A-4698-14T1
example, a poorly conceived or conducted study that disproves the

null hypothesis at a high level of significance may be far less

reliable    than   a   well-conceived    and    conducted    study   that    is

significant at a lower level.       DeLuca, supra, 911 F.2d at 955.30

Moreover,    the   fact   that   defendants'       experts   interpret      the

epidemiological studies differently does not, standing alone,

indicate that Kornbluth and Madigan failed to rely upon a sound

methodology.       "Indeed,   'in   most       cases,   objections   to     the

inadequacies of a study are more appropriately considered an

objection going to the weight of the evidence rather than its

admissibility.'"       Rosenfeld v. Oceania Cruises, Inc., 654 F.3d

1190, 1193 (11th Cir. 2011) (quoting Hemmings v. Tidyman's Inc.,

285 F.3d 1174, 1188 (9th Cir. 2002), cert. denied, 537 U.S. 1110,

123 S. Ct. 854, 154 L. Ed. 2d 781 (2003)).

     That said, certainly, as the trial judge correctly observed,


30
  DeLuca was "a diversity action brought under New Jersey law"
against   the  manufacturer   of   Benedictin.   Id.  at   942-43.
Anticipating Daubert, the Third Circuit Court of Appeals rejected
the Frye standard, and reversed a trial court decision barring
testimony from an expert whose approach was remarkably similar to
that of plaintiffs' experts in this case. Id. at 955. Although
DeLuca is not binding on us, we find it persuasive. As previously
noted, DeLuca was also one of the seminal federal cases cited with
approval in Rubanick as being "compatible with our own rules of
evidence." Rubanick, supra, 125 N.J. at 445, 447.


                                    67                                A-4698-14T1
larger   studies   enable   researchers   to   form   a   more   accurate

conclusion and reduce the chance of random error in their results.

Reference Manual, supra, at 576.      However, Kornbluth could, in

applying accepted scientific methodology, properly consider one

small well-designed study over larger seriously flawed studies as

a basis for drawing an inference about the studied subject. 31

Further, Kornbluth did not ignore the results of the larger studies

in favor of the smaller Sivaraman study, but considered the

relative risk and the bounds of the 95% confidence interval in

reviewing the conclusions. He also found that although the results

of the studies were inconclusive, they were informative on his

theory of causation. For example, he noted that four of the studies

(Bernstein, Etminan (unadjusted), Alhusayen, and Sivaraman) found

a positive association between Accutane use and Crohn's disease,

and that one of the studies (Bernstein) showed an increased

association when accounting for a two-year but not a one-year

prodrome.


31
  Scientific acceptance of small studies is not unknown.         A
treatise on pharmacoepidemiology, which is included in the
parties' appendices, notes that "using case control studies, one
can study rare diseases with markedly smaller sample sizes. . . .
For example, the classic study of diethylstilbestrol and clear
cell adenocarcinoma required only 8 cases and 40 controls." (Brian
L. Strom, Pharmacoepidemiology 23 (4th ed. 2006)).

                                 68                               A-4698-14T1
     Similarly, Kornbluth testified at length as to the results

of both the Pimentel (6.9-year prodrome) and Barratt (four-year

prodrome) prodrome studies and opined that the results of those

studies were in agreement with his decades of experience treating

thousands of Crohn's disease patients.                  Kornbluth and Madigan

rejected, but did not ignore, the findings of the Chouraki study

based on the selection of patients and the use of patient charts.

Further, Madigan testified that the Pimentel study, which utilized

questionnaires,    contained    the     most    useful    and   relevant   data,

including   raw   data   from   which      he   could    compute   age-specific

estimated prodromes.32

     Kornbluth's    methodology       in   analyzing      the   epidemiological

studies was also bolstered by Madigan, who presented detailed

testimony as to the insufficient power of the epidemiological

studies.    Further, Madigan testified that the decision whether to

conduct a meta-analysis is a scientific judgment, and explained



32
   Our reading of the Pimentel article supports Kornbluth's
description of the authors' very meticulous approach to gathering
and verifying information about the subjects.    We cannot agree
with the trial judge's view that Kornbluth was "cherry picking"
in relying on Pimentel.     Kornbluth cogently explained why he
believed that the authors' methodology was reliable, and
consistent with his own medical practice in diagnosing Crohn's
disease patients.

                                      69                                A-4698-14T1
that such an analysis would not yield reliable results in this

case. Instead, he conducted and reviewed a disproportionality

analysis, which while not without limitations, is a validated

method in drug safety research and surveillance.

       Both Kornbluth and Madigan explained in considerable detail

why most of the studies were biased toward "the null" or no effect,

and were otherwise inadequate to reliably demonstrate whether or

not   there    was    a   statistically     significant     connection   between

Accutane      and    Crohn's   disease.      They    also   explained    why   the

statistically significant initial results of the Sivaraman study

were more reliable than the adjusted results.

       The reliability of Kornbluth's opinion on causation was also

strengthened by his consideration of other evidence (including

case reports, animal studies, and causality assessments), and most

notably, because he presented a biologically plausible mechanism

for how Accutane causes Crohn's disease.               See Reference Manual,

supra, at 604 ("When biological plausibility exists, it lends

credence to an inference of causality").                Once Kornbluth found

that there was an association between Accutane and Crohn's disease

based on his reading of the epidemiological studies, in addition

to    the   scientific     articles,      MedWatch   reports,   and     causality


                                       70                                 A-4698-14T1
assessments,    he       then    considered    whether     that   association         was

causal, utilizing the Bradford Hill criteria. Under that analysis,

he   considered,         among    other   criteria,       whether    there      was     a

biologically plausible mechanism by which Accutane could cause

Crohn's   disease—an        important     factor    for    determining      a    causal

relationship.

     Kornbluth, like plaintiffs' causation expert in previous

Accutane trials, presented a biologically plausible mechanism

supported by scientifically authoritative sources. He opined,

based on his experience as a board-certified gastroenterologist

and in conducting clinical trials on several drugs intended for

use in the management of IBD, that retinoic acid, a metabolite of

Accutane,   "is      a    damaging    pathway      for    patients   with       Crohn's

disease." He found support for that opinion in the fact that two

new drugs (Vedolizumab and Natalizumab) were effective in treating

Crohn's disease and in a Canadian case-control epidemiological

study that reported an increased risk of Crohn's disease from

retinoic acid.            Olivia-Hemker disagreed with that opinion and

cited to other studies that supported a finding that retinoic acid

had an anti-inflammatory or protective effect on the intestines,

but that dispute goes to the weight, not the admissibility of the


                                          71                                    A-4698-14T1
testimony.   See Harvey, supra, 151 N.J. at 178.

      In conclusion, Kornbluth and Madigan, who are indisputably

extremely well-qualified experts, considered all of the relevant

data and information, applied appropriate methodology in analyzing

the   epidemiological   studies,   and   expressed   valid   reasons   for

rejecting the conclusions of some of the epidemiological studies

and in accepting other studies as supportive of their opinion.

Although the relationship between the epidemiological scientific

evidence and the experts' opinions is more tenuous than the

evidence as to ulcerative colitis, the studies do not render the

experts' testimony inadmissible.        The manner in which plaintiffs'

experts reasoned from the results of the epidemiological studies

and other data is sufficiently sound to be reliable.          Landrigan,

supra, 127 N.J. at 420.     Further, the experts did not ignore the

findings of the larger epidemiological studies but explained the

scientific bases for their criticism of the studies.         Defendants'

criticisms of the experts' choices as to the evidence on which

they relied, can be addressed during cross-examination at trial.

Hisenaj, supra, 194 N.J. at 24.

      We also cannot agree with the trial court's view that because

Kornbluth had not submitted his "current hypothesis" to a peer-


                                   72                             A-4698-14T1
reviewed publication, he must have generated his opinion solely

as a result of litigation and was a mere "hired gun."    An expert

is not required to submit her own analysis to peer review in order

for a court to consider it.   See DeLuca, supra, 911 F.2d at 954.

We also do not subscribe to the trial court's characterization of

Madigan   as a hired gun whose testimony "was needed to clear the

way for Dr. Kornbluth's hypothesis and that was the role he played,

without regard to whether or not his efforts led the discussion

any closer to scientific truth."    Madigan carefully explained his

methodology and his testimony should not have been discounted

because defendants heavily contested his conclusions.

     Given that our evidence rules embody a strong preference for

admissibility, we conclude that the court mistakenly applied its

discretion in excluding the expert scientific testimony.         See

N.J.R.E. 702; N.J.R.E. 401; State v. Jenewicz, 193 N.J. 440, 454

(2008) (noting "Rule 702's tilt in favor of the admissibility of

expert testimony"); State v. Granskie, 433 N.J. Super. 44, 47-48

(App. Div. 2013); Kuehn v. Pub Zone, 364 N.J. Super. 301, 320

(App. Div. 2003) (expert's testimony was relevant to issues under

consideration), certif. denied, 178 N.J. 454 (2004).




                               73                           A-4698-14T1
                              VI

     In concluding, we emphasize the following observations.      The

trial court's decision, and our decision of this appeal, must be

viewed in the context of this particular MCL litigation. It

presents a close question concerning the survival of plaintiffs'

cause of action in the face of new scientific information about

Accutane and IBD.

     In deciding this appeal, we bear in mind that science is

constantly evolving, and that under our State's legal precedents,

legal decision making in toxic tort and similar cases may vary

from scientific decision making.    The opportunity of thousands of

plaintiffs, claiming injury from Accutane, to have their day in

court may rest on that difference and must be decided now.

          In general . . . clinical, regulatory,
          commercial, and legal decisions need to be
          made based on the best evidence available at
          the time of the decision. To quote Sir Austin
          Bradford Hill:

               All scientific work is incomplete -
               whether it be observational or
               experimental. All scientific work
               is liable to be upset or modified
               by advancing knowledge. That does
               not confer upon us a freedom to
               ignore the knowledge we already
               have, or to postpone the action that
               it appears to demand at a given
               time.

                               74                            A-4698-14T1
                     Who   knows,    asked   Robert
                Browning, but the world may end
                tonight? True, but on available
                evidence, most of us make ready to
                commute on the 8:30 next day.

          [Pharmacoepidemiology,   supra,    at         26-27
          (quoting Hill, supra, at 295-300).]

     The parties in this case differ sharply on the question of

what constitutes "the best evidence available at the time of the

decision."     Id. at 26.     In particular, the case presents the

question whether, in the face of several epidemiological studies

that do not demonstrate a statistically significant relationship

between taking Accutane and developing Crohn's disease, plaintiffs

can continue to rely on other types of evidence - which in this

same MCL docket they were previously permitted to use - to prove

general causation.   We also consider whether they can rely in part

on information from some of the epidemiological studies that show

a   positive   correlation,   albeit   not   reaching   the     level    of

statistical significance.

     We conclude that in this case, the epidemiology studies are

not a conclusive bar to plaintiffs' case, and that their experts

should be allowed to testify.      Although epidemiological studies

are considered as high on the tier of evidence bearing on the


                                  75                              A-4698-14T1
question of causation, like any other form of scientific evidence,

any particular study is only valuable if it is conducted in a

scientifically reliable manner. Any party - plaintiff or defendant

- has the right to challenge the methodology and, hence the

results, of an epidemiological study.

       In fact, the Reference Manual on Scientific Evidence cautions

that

            [A]ll [epidemiological] studies have "flaws"
            in the sense of limitations that add
            uncertainty about the proper interpretation of
            the results. Some flaws are inevitable given
            the limits of technology, resources, the
            ability   and    willingness   of  persons   to
            participate    in    a   study,   and   ethical
            constraints.    In   evaluating   epidemiologic
            evidence, the key questions, then, are the
            extent   to   which    a  study's   limitations
            compromise its findings and permit inferences
            about causation.

            [Reference Manual, supra, at 553.]

After explaining some of the most common biases that may affect

observational epidemiological studies, the Manual states that

["t]here are dozens of other potential biases that can occur in

observational studies, which is an important reason why clinical

studies (when ethical) are often preferable."      Id. at 590.    Thus

it can be expected that, as in this case, the methodology and

limitations     of    epidemiological    studies    -   particularly

                                 76                           A-4698-14T1
observational studies - will be fertile ground for disagreement

among experts.

     Moreover, the Manual supports plaintiffs' continued reliance

on other types of evidence to prove their case, particularly given

their well-explained opinions that most of the epidemiological

studies are fundamentally flawed.      Contrary to the trial judge's

view, the Manual does not discount the value of live animal

studies.   While noting some potential weaknesses of the studies,

the Manual states that toxicological studies, of which animal

studies are one type, are "often . . . the only or best available

evidence of toxicity."   Id. at 564.   The Manual also cautions that

"[w]here both animal toxicologic and epidemiologic studies are

available, no universal rules exist for how to interpret or

reconcile them.   Careful assessment of the methodological validity

and power of the epidemiologic evidence must be undertaken, and

the quality of the toxicologic studies and the questions of

interspecies extrapolation and dose-response relationship must be

considered."   Id. at 564-65.

     The judge, and defendants, relied heavily on a section of the

Manual captioned "Hierarchy of medical evidence" (the medical

hierarchy section).    Id. at 723. However, that section does not


                                77                           A-4698-14T1
appear in the Reference Guide on Epidemiology. Rather, the section

appears in the Reference Guide on Medical Testimony, as part of a

chapter on medical decision-making.     That chapter describes how

doctors make decisions about diagnosing and treating patients and

discusses the difficulties they face in making those decisions.

Id. at 704.   We do not construe the medical hierarchy section of

the Manual as prescribing a rigid hierarchy for the acceptance or

rejection of evidence in a legal setting. See Matrixx Initiatives,

Inc. v. Siracusano, 563 U.S. 27, 40-42, 131 S. Ct. 1309, 1318-20,

179 L. Ed. 2d 398, 410-12 (2011); DeLuca, supra, 911 F.2d at 957.

In fact, the preface to the Manual cautions judges as to "the

proper use of the reference guides. They are not intended to

instruct judges concerning what evidence should be admissible or

to   establish   minimum   standards   for   acceptable   scientific

testimony."   Reference Manual, supra, at xv.     As significantly,

nothing in the Manual suggests that once epidemiological studies

have been done, they are beyond scientific criticism, and no

countervailing evidence should be considered.

     We cannot agree with the trial judge's observation that

plaintiff's experts "ignored" the epidemiological studies in favor

of less reliable evidence. The experts did not ignore the studies.


                                78                           A-4698-14T1
Rather, in extensive and detailed testimony, they opined that most

of the studies were unreliable, and they explained in considerable

detail the reasons for those opinions.

     In   their   testimony,   both       of   plaintiffs'      experts    raised

fundamental objections to the way the studies were conducted -

particularly the length of time for which the studies followed the

subjects.   Based both on a prodrome study he found reliable and

on the decades he has spent treating thousands of Crohn's patients,

Dr. Kornbluth testified that the prodrome for Crohn's disease is

much longer than the one-year time frame covered by most of the

studies. Defendant's biostatistical expert, Dr. Goodman, admitted

that if Dr. Kornbluth was correct about the prodrome, then all of

the epidemiological studies on which the defense relied would be

flawed.

     Kornbluth    also   explained    in       detail   other    weaknesses      of

several of the studies.     For example, the Alhusayan study treated

subjects exposed to Accutane as being non-exposed after a one-year

period following treatment.    Thus, if those subjects developed IBD

after a year and a day, the study reported them as though they had




                                     79                                   A-4698-14T1
never taken Accutane.33   Kornbluth also explained that studies from

other countries would not necessarily reflect the experience of

United States subjects, because the standard dose of Accutane

given to patients in those other countries is half that given to

patients in the United States.

     Kornbluth's view on the prodrome issue was actually bolstered

by some of the defense testimony.     During her cross-examination,

Dr. Oliva-Hemker was confronted with her own book, which answered

the question "How long have I had my IBD" by advising that:     "Some

people have years of symptoms before the diagnosis [of IBD] is

made, while in others, these symptoms appear suddenly. Both groups

may have had intestinal inflammation for days, months, or years,

even though they didn't experience any symptoms at all for most

of that time."   She then clarified that "we traditionally apply

that more to Crohn's patients rather than ulcerative colitis

patients in terms of [it taking] years" to diagnose the disease.

She was also confronted with a book written by a recognized expert

who referred to "the four-year average delay of diagnosis of



33
  Although the study authors downplayed the results, the Alhusayan
study also discovered what the authors characterized as a "weak"
but statistically significant connection between Accutane and the
development of IBD in teenagers, ages twelve to nineteen.

                                 80                           A-4698-14T1
Crohn's disease."

      Oliva-Hemker   also   confirmed    that   IBD   affects   about     one

percent of the population in the United States; Crohn's disease

is a small subset of IBD, so the proportion of persons with Crohn's

is much smaller than one percent.        Those admissions support the

view of plaintiff's experts that a study's failure to detect even

a small number of "exposed cases," i.e., persons with Crohn's

disease who had taken Accutane, could produce skewed results.

      Further, when it suits their litigation strategy, defendants

do not treat epidemiological studies as the last word in scientific

proof.   During the cross-examination of Oliva-Hemker, she admitted

that in earlier Accutane litigation, when four epidemiological

studies - concerning the lack of connection between antibiotics

and ulcerative colitis - did not support her opinion that the

plaintiff's UC was caused by antibiotics rather than Accutane, she

relied on evidence of biological plausibility instead.             It took

almost four pages of repetitive questioning before Oliva-Hemker

finally admitted that the methodology she used was valid.               Yet,

in   this   litigation,   she   criticized   Kornbluth   for    relying    on

evidence of biological plausibility and placing less weight on the

epidemiological studies.


                                    81                              A-4698-14T1
     Additionally, during the cross-examination of defendant's

epidemiology expert, Dr. Goodman, he admitted that some of the

epidemiological studies in this case had biases and weaknesses.

He admitted, for example, that none of the studies controlled for

family history, even though that is recognized as a strong factor

in a person's potentially developing Crohn's disease. He contended

that scientific judgment was required to evaluate how important

those biases or weaknesses were. Goodman was also confronted with

some of his own writings, in which he stated that, "If bias is

present in each or some of the individual studies, meta-analysis

will simply compound the errors and produce a wrong result that

may be interpreted as having more credibility."         That same point

was made by plaintiff's epidemiology expert, Dr. Madigan, and it

finds support in the Manual.

     We appreciate that the trial judge had the opportunity, which

we did not, to see the witnesses testify firsthand.        However, his

extreme   negative   reaction   to     plaintiffs'   witnesses   is   not

supported by the trial record.       See J.R., supra, 227 N.J. at 410;

Torres, supra, 183 N.J. at 567.      In reviewing Madigan's testimony,

we cannot agree with the judge that Madigan was a biased expert

"on a mission." His testimony was coherent and consistent, and the


                                  82                             A-4698-14T1
attorney      who   cross-examined      him    made       little       headway    in

discrediting his direct testimony.

         The judge's disapproval of plaintiffs' experts' reliance on

"lines of evidence"        seems misplaced,         because the defense used

the same terminology and considered the same evidence.                  Dr. Oliva-

Hemker agreed that she and Dr. Kornbluth looked at the same lines

of evidence, although they reached different conclusions from the

evidence.     Further, the defense experts generally agreed with the

proposition that, in looking at the issue of causation, it is

appropriate to consider all of the pertinent evidence and not just

the      epidemiological    studies.        The     judge       also    criticized

plaintiffs' experts for their skepticism about the use of meta-

analysis.      However, the Manual cautions that "when meta-analysis

is applied to observational studies - either case-control or cohort

-   it    becomes   more   controversial"     due    to   the    "methodological

differences among studies."        Reference Manual, supra, at 607.

         In summary, the purpose of a Kemp hearing is to weed out

"junk science," not to shield jurors from hearing expert testimony

that is scientifically-based but unpersuasive to the trial judge.

Landrigan, supra, 127 N.J. at 417; Kemp, supra, 174 N.J. at 427.

"[R]egardless of a trial judge's view of the weight a party's


                                       83                                  A-4698-14T1
evidence deserves, the judge should trust the jury to evaluate

witness credibility and decide what weight to give each side's

evidence."     State v. Stubblefield, __ N.J. Super. __, __ n.6 (App.

Div. 2017) (slip op. at 21 n.16). It is the jury's core function

to weigh the credibility of expert witnesses, and the trial court

should not use a Kemp hearing as a vehicle to dismiss a case the

court    perceives      as   weak."          Vigorous      cross-examination,

presentation of contrary evidence, and careful instruction on the

burden of proof are the traditional and appropriate means of

attacking shaky but admissible evidence."               Daubert, supra, 509

U.S. at 596, 113 S. Ct. at 2798, 125 L. Ed. 2d at 484.

        We conclude that the trial court misapplied its discretion

in   barring    Dr.    Kornbluth   and     Dr.   Madigan    from    testifying.

Accordingly,     the   orders   entered     in   A-4698-14    and    A-0910-16,

barring their testimony and dismissing the complaints on summary

judgment, are reversed and these cases are remanded to the trial

court for further proceedings.           We do not retain jurisdiction.

      Reversed and remanded.




                                      84                                A-4698-14T1
