                            NOT FOR PUBLICATION WITHOUT THE
                           APPROVAL OF THE APPELLATE DIVISION
    This opinion shall not "constitute precedent or be binding upon any court." Although it is posted on the
 internet, this opinion is binding only on the parties in the case and its use in other cases is limited. R. 1:36-3.




                                                     SUPERIOR COURT OF NEW JERSEY
                                                     APPELLATE DIVISION
                                                     DOCKET NO. A-4952-16T1

IN RE: ACCUTANE LITIGATION
_______________________________

                Argued January 7, 2020 – Decided January 17, 2020

                Before Judges Fisher, Accurso and Rose.

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

                Bruce Daniel Greenberg argued the cause for appellants
                (Seeger Weiss LLP, attorneys; David Robert Buchanan,
                on the brief); (Mary Jane Bass (Beggs & Lane) of the
                Florida bar, admitted pro hac vice, on the brief); (Lite
                DePalma Greenberg, LLC, attorneys; Bruce Daniel
                Greenberg, on the brief); (Weitz & Luxenberg, PC,
                attorneys; Peter Samberg, on the brief); (Eisbrouch
                Marsh, LLC, attorneys; David Lloyd Eisbrouch, on the
                brief); (Cohen Placitella & Roth, PC, attorneys; Jillian
                Audrey Smith Roman, on the brief); (Cohn Lifland
                Pearlman Herrmann & Knopf, LLP, attorneys; Leonard
                Zee Kaufman, on the brief); (D'Arcy Johnson Day,
                attorneys; Andrew James D'Arcy, on the brief);
                (Folkman Law Offices, PC, attorneys; Paul C. Jensen,
                on the brief); (Hutton & Hutton Law Firm, LLC,
                attorneys; Blake A. Shuart, on the brief); (Lopez
                McHugh, LLP, attorneys; Michael Scott Katz, on the
                brief); (Meyerson & O'Neill, attorneys; Jack A.
                Meyerson, on the brief); (Mintz & Geftic, attorneys;
Bryan H. Mintz, on the brief); (Nagel Rice, LLP,
attorneys; Andrew L. O'Connor, on the brief); (Marc J.
Bern & Partners LLP, attorneys; Diane M. Coffey, on
the brief); (Oshman & Mirisola, LLP, attorneys; Ted
Oshman, on the brief); (Parker Waichman LLP,
attorneys; Jerrold S. Parker, on the brief); (Perskie &
Fendt, PC, attorneys; Robert Fendt, on the brief);
(Rheingold, Valet, Rheingold, McCartney & Giuffra,
LLP, attorneys; Morris Dweck, on the brief);
(Sugarman Law LLC, attorneys; Barry Sugarman, on
the brief); (The D'Onofrio Firm LLC, attorneys; Lou
D'Onofrio, on the brief); (The Ferrara Law Firm LLC,
attorneys; Michael A. Ferrara, Jr., on the brief); (The
Lanier Law Firm, PLLC, attorneys; Richard D.
Meadow, on the brief); (The Miller Firm, LLC,
attorneys; Tayjes Matthew Shah, on the brief); (The
Orlando Firm, PC, attorneys; Roger W. Orlando, on the
brief); (Wilentz Goldman & Spitzer, PC, attorneys;
Gregory Shaffer, on the brief); (Williams Cuker
Berezofsky, LLC, attorneys; Esther Berezofsky, on the
brief); (Jacob Fuchsberg Law Firm, attorneys;
Christopher Michael Nyberg, on the brief); (Locks Law
Firm, attorneys; Michael Andrew Galpern, on the
brief); and (Lieff Cabraser Heimann & Bernstein, LLP,
attorneys; Adam Herbert Weintraub, on the brief).

Paul W. Schmidt (Covington & Burling LLP) of the
District of Columbia bar, admitted pro hac vice, argued
the cause for respondents Hoffmann-La Roche Inc. and
Roche Laboratories Inc. (Gibbons, PC, Dughi Hewit &
Domalewski, PC, and Paul W. Schmidt, attorneys;
Natalie H. Mantell, Kim Marie Catullo, Russell L.
Hewit, Paul W. Schmidt, Michael X. Imbroscio
(Covington & Burling LLP) of the District of Columbia
bar, admitted pro hac vice, and Colleen M. Hennessey
(Peabody & Arnold) of the Massachusetts bar, admitted
pro hac vice, on the brief).


                                                          A-4952-16T1
                          2
PER CURIAM

       This multicounty litigation consists of thousands of cases filed by

plaintiffs who alleged they developed inflammatory bowel disease, either in the

form of ulcerative colitis or Crohn's disease as a result of their use of Accutane

(isotretinoin). In 2015, the trial judge granted a defense motion to exclude two

plaintiffs' experts – Dr. Arthur Kornbluth, a gastroenterologist, and Dr. David

Madigan, a statistician – from testifying that Accutane, a prescription acne drug

manufactured by defendants Hoffman-La Roche Inc., and Roche Laboratories,

Inc., can cause Crohn's disease. We reversed that determination, In re Accutane

Litigation, 451 N.J. Super. 153 (App. Div. 2017), but the Supreme Court

reversed our judgment and upheld the trial judge's exclusion of the expert

testimony of Drs. Kornbluth and Madigan, In re Accutane Litigation, 234 N.J.

340, 348 (2018).

       In early 2017, the trial judge conducted a ten-day Kemp1 hearing and, for

the reasons expressed in a thorough written opinion, granted a defense motion

to bar the expert testimony of Dr. David Sachar, a gastroenterologist, and Dr.

April Zambelli-Weiner, an epidemiologist, about whether Accutane caused




1
    Kemp ex rel. Wright v. State, 174 N.J. 412 (2002).
                                                                          A-4952-16T1
                                        3
plaintiffs' ulcerative colitis. A later order identified the 3231 claims that were

dismissed as a result of that determination.

       Plaintiffs filed a timely appeal, which we stayed while awaiting the

Supreme Court's decision concerning Drs. Kornbluth and Madigan's opinions.

Once the Court rendered its decision, we requested supplemental briefs as to

whether the Daubert2 factors of expert admissibility adopted by the Court ought

to be applied here, and if so, whether the existing record was sufficient or a

remand was required. In their supplemental briefs, the parties agreed that the

Daubert factors applied and a remand was not required.

       After close examination of the record in light of the guidelines and factors

adopted in the Supreme Court's recent Accutane decision, we conclude that

although Drs. Sachar and Zambelli-Weiner appear to be qualified, the judge did

not abuse his discretion in excluding their testimony because the opinions of

these experts incorporated the same methodological defects identified by the

Court, including the disregarding of eight of the nine epidemiological studies in

favor of animal studies and case reports. And, even though the data in the

epidemiological studies is slightly more supportive of an association between

Accutane and ulcerative colitis, there is not enough evidence of a difference


2
    Daubert v. Merrell Dow Pharm., Inc., 509 U.S. 579 (1993).
                                                                           A-4952-16T1
                                         4
between these subtypes of irritable bowel disease (IBD) to warrant excluding

the causation experts' testimony on Crohn's disease while allowing similar

expert causation testimony as to ulcerative colitis.

      No one disputes that the cause or causes of ulcerative colitis and Crohn's

disease remain for now unknown, but the diseases share the same core

symptoms, and the biological mechanism for both diseases is essentially the

same. So, despite the differences between the matter at hand and the rulings

regarding Drs. Kornbluth and Madigan, we conclude that the trial judge did not

exceed his discretion in excluding Dr. Sachar's and Dr. Zambelli-Weiner's

causation testimony.

                                        I

      We start by agreeing with the parties that the Supreme Court's recent

Accutane decision is applicable even though it was decided after the trial judge's

ruling here.    In civil cases, judicial decisions are "presumed to apply

retroactively." In re Contest of Nov. 8, 2011 Gen. Election of Office of N.J.

Gen. Assembly, 210 N.J. 29, 68 (2012) (quoting Fischer v. Canario, 143 N.J.

235, 243 (1996)). To avoid that presumption, a party must show the decision

established a new principle "either by overruling clear past precedent on which

litigants may have relied . . . or by deciding an issue of first impression whose


                                                                          A-4952-16T1
                                        5
resolution was not clearly foreshadowed." Coons v. Am. Honda Motor Co., Inc.,

96 N.J. 419, 427 (1984) (quoting Chevron Oil Co. v. Hudson, 404 U.S. 97, 106

(1971)).

      The Supreme Court's Accutane decision, which came down while this

appeal was pending, did not alter N.J.R.E. 702 or 703, nor would its holding

"produce substantial inequitable results if applied retroactively." Coons, 96 N.J.

at 427 (quoting Chevron Oil Co., 404 U.S. at 107).         Instead, in reaching its

decision, the Supreme Court "perceive[d] little distinction between Daubert's

principles regarding expert testimony and our own, and believe[d] that its factors

for assessing the reliability of expert testimony will aid our trial courts in their

role as the gatekeeper of scientific expert testimony in civil cases." Accutane

Litigation, 234 N.J. at 347-48. The Court merely "reconcile[d] our standard

under N.J.R.E. 702, and relatedly N.J.R.E. 703, with the federal Daubert

standard to incorporate its factors for civil cases." Id. at 348. And so, we will

apply the Court's recent holding to the issues presented in this appeal.

      An expert's opinion on causation in prescription drug cases may be

admitted when "based on a sound, adequately-founded scientific methodology

involving data and information of the type reasonably relied on by experts in the

scientific field." Id. at 349-50 (quoting Rubanick v. Witco Chem. Corp., 125


                                                                            A-4952-16T1
                                         6
N.J. 421, 449 (1991)). In cases "involving novel theories of causation," a court

must review the "data and studies relied on by experts proffering an opinion in

order to 'determine whether the expert's opinion is derived from a sound and

well-founded methodology that is supported by some expert consensus in the

appropriate field.'" Id. at 350 (quoting Landrigan v. Celotex Corp., 127 N.J.

404, 417 (1992)).    A court must also assess "the soundness of the proffered

methodology and the qualifications of the expert." Rubanick, 125 N.J. at 454.

The focus must be "solely on principles and methodology, not on the conclusions

that they generate." Kemp, 174 N.J. at 426 (quoting Daubert, 509 U.S. at 594-

95).

       Given the adversarial setting and full record before it, the Court took the

opportunity to "clarify and reinforce the proper role for the trial court as the

gatekeeper of expert witness testimony," Accutane Litigation, 234 N.J. at 388,

and explained that when it adopted the more relaxed approach for causation

expert testimony in toxic tort and medical cause-effect expert testimony, it

envisioned

             the trial court's function as that of a gatekeeper –
             deciding what is reliable enough to be admitted and
             what is to be excluded. Those are not credibility
             determinations that are the province of the jury, but
             rather legal determinations about the reliability of the
             expert's methodology.

                                                                          A-4952-16T1
                                        7
            [Ibid.]

In performing that function, "the trial court is responsible for advancing the

truth-seeking function of our system of justice, while still allowing for new or

developing opinions on medical causation that may not yet have gained general

acceptance." Id. at 389. In essence, the trial court "is the spigot that allows

novel expert testimony in areas of evolving medical causation science, provided

the proponent of the expert can demonstrate that the expert adheres to scientific

norms in distinct ways that we have identified." Ibid.

      This gatekeeping role "requires care." Ibid. The Court emphasized that

the trial court "must ensure compliance with the requirement of 'some expert

consensus that the methodology and the underlying data are generally followed

by experts in the field,'" ibid. (quoting Rubanick, 125 N.J. at 450), "distinguish

scientifically sound reasoning from that of the self-validating expert,"

Landrigan, 127 N.J. at 414, and disallow "unsubstantiated personal beliefs,"

Kemp, 174 N.J. at 427. "Properly exercised, the gatekeeping function prevents

the jury's exposure to unsound science through the compelling voice of an

expert." Accutane Litigation, 234 N.J. at 389.

      The Court emphasized that it expects trial courts "to assess both the

methodology used by the expert to arrive at an opinion and the underlying data


                                                                          A-4952-16T1
                                        8
used in the formation of the opinion" to "ensure that the expert is adhering to

norms accepted by fellow members of the pertinent scientific community." Id.

at 396-97. In short, "[m]ethodology, in all its parts, is the focus of the reliability

assessment, not outcome." Ibid. "It is not for a trial court to bless new 'inspired'

science theory; the goal is to permit the jury to hear reliable science to support

the expert opinion." Id. at 397; cf. Rosen v. Ciba-Geigy Corp., 78 F.3d 316, 319

(7th Cir. 1996) (observing that "the courtroom is not the place for scientific

guesswork, even of the inspired sort").

      The Court therefore concluded that New Jersey law and Daubert were

"aligned in their general approach to a methodology-based test for reliability.

Both ask whether an expert's reasoning or methodology underlying the

testimony is scientifically valid." Accutane Litigation, 234 N.J. at 397 (citing

Daubert, 509 U.S. at 594-95 and Rubanick, 125 N.J. at 449). "[B]oth standards

look to whether that reasoning or methodology properly can be applied to facts

in issue." Ibid. The Court, thus, "[d]istilled" the Daubert factors into the

following "general factors":

             1) Whether the scientific theory can be, or at any time
             has been, tested;

             2) Whether the scientific theory has been subjected to
             peer review and publication, noting that publication is
             one form of peer review but is not a "sine qua non";

                                                                              A-4952-16T1
                                          9
             3) Whether there is any known or potential rate of error
             and whether there exist any standards for maintaining
             or controlling the technique's operation; and

             4) Whether there does exist a general acceptance in the
             scientific community about the scientific theory.

             [Id. at 398.]

      These factors, according to the Court, "dovetail with the overall goals of

our evidential standard and . . . provide a helpful – but not necessary or definitive

– guide for our courts to consider when performing their gatekeeper role

concerning the admission of expert testimony." Id. at 398-99. The factors, the

Court held, should be incorporated for use by our courts, with no obligation to

apply the federal case law or the case law of any other state that adopted the

factors. Id. at 399; see Dreier, Karg, Keefe & Katz, Current N.J. Products

Liability & Toxic Torts Law § 9:4-2(b) (2019) (recognizing that application of

the Daubert factors may serve to strengthen the court's role as a gatekeeper).

      The Court concluded that its "view of proper gatekeeping in a

methodology-based approach to reliability for expert scientific testimony

requires the proponent to demonstrate that the expert applies . . . scientifically

recognized methodology in the way that others in the field practice the

methodology." Accutane Litigation, 234 N.J. at 399-400. When a proponent

fails to demonstrate "the soundness of a methodology, both in terms of its

                                                                             A-4952-16T1
                                        10
approach to reasoning and to its use of data, from the perspective of others

within the relevant scientific community, the gatekeeper should exclude the

proposed expert testimony on the basis that it is unreliable." Id. at 400.

                                        II

      The trial judge conducted a Kemp hearing over the course of ten days,

during which he heard the testimony of plaintiffs' experts: Drs. Sachar and

Zambelli-Weiner. Defendants also provided the testimony of experts: Dr.

Steven Goodman, an epidemiologist and biostatistician, and Dr. Maria Oliva-

Hemker, a gastroenterologist.     At the hearing's conclusion, the trial judge

entered an order that precluded the expert testimony of plaintiffs' experts. In his

written decision, the judge examined the expert testimony and scientific studies,

set forth the relevant legal standard for the admission of expert testimony, and

found that plaintiffs' experts' testimony failed to meet that standard.

      In ascertaining whether the expert testimony was based on a "sound,

adequately-founded scientific methodology involving data and information of

the type reasonably relied on by experts in the scientific field," Rubanick, 125

N.J. at 449, the judge correctly considered "whether other scientists in the field

use similar methodologies in forming their opinions and also should consider

other factors that are normally relied upon by medical professionals."             He


                                                                             A-4952-16T1
                                       11
explained that the "appropriate inquiry is not whether the [c]ourt thinks that the

expert's reliance on the underlying data was reasonable, but rather whether

comparable experts in the field would actually rely on that information." He

identified "[t]he trial court's role" as essentially requiring a determination

"whether the expert's opinion is derived from a sound and well-founded

methodology" and is supported by "some expert consensus."

      Applying that standard, the judge found unsound the experts'

methodology. He found that Dr. Zambelli-Weiner appeared to have had "very

limited exposure" to issues related to pharmaco-epidemiology, and frequently

disregarded "the fundamentals of the scientific method, particularly, the

medical-evidence hierarchy." For example, the judge found that Dr. Zambelli-

Weiner's inclusion of the widely-criticized Sivaraman 3 non-peer-reviewed




3
    This was a case-control questionnaire study comprising 509 subjects
summarized in a published abstract. Susil Sivaraman et al., Risk of
Inflammatory Bowel Disease from Isotretinoin: A Case-Control Study, Am. J.
Gastroenterol. (Oct. 2014). The authors found that antibiotic exposure prior to
IBD diagnosis was associated with a risk for ulcerative colitis but not Crohn's
disease. After adjusting for antibiotic exposure, the risk for IBD following
isotretinoin exposure lost statistical significance; the authors concluded the
"[r]isk of IBD from isotretinoin is modulated by antibiotic exposure."



                                                                          A-4952-16T1
                                       12
abstract in her meta-analysis and the exclusion of the Rashtak 4 study bespoke

"litigation-driven science." The judge also found that the expert's reliance on

case reports (including those contained in the scientific literature) of anecdotal

information and her characterization of that evidence as "quite compelling"

demonstrated a "disregard for the hierarchy of scientific evidence" because case

reports "are at the very bottom of the medical-evidence hierarchy." Her reliance

on challenge/dechallenge/rechallenge reports in case reports as evidence of a

causal relationship also ignored "the evidence-based medical hierarchy" and was

inconsistent with the nature of the disease, which waxes and wanes.



4
   In this retrospective, single-center cohort study, the authors reviewed the
electronic medical records of Mayo Clinic patients who sought treatment for
severe acne. Shadi Rashtak et al., Isotretinoin Exposure and Risk of
Inflammatory Bowel Disease, 150 JAMA Dermatol. 1322 (Dec. 2014). They
selected 1078 patients; 576 were exposed to isotretinoin and 502 never received
isotretinoin or received it after their diagnosis of IBD. The authors found that
IBD developed less frequently in the isotretinoin-exposed group versus the non-
exposed group. The authors reported the event counts for ulcerative colitis and
Crohn's disease, noting that, "[i]nterestingly, a subsequent diagnosis of IBD was
found in only 5 of 576 exposed patients (1 with Crohn disease and 4 with
ulcerative colitis) compared with 13 of 502 nonexposed patients (3 with Crohn
disease and 10 with ulcerative colitis)." The authors observed that even though
"these results may be due to chance given the small number of IBD cases, the
anti-inflammatory and immune-modulating effects of isotretinoin may be worth
exploring." They wrote, "clinicians should not unnecessarily avoid prescribing
this effective acne therapy for largely unfounded or meager associations with
IBD."


                                                                          A-4952-16T1
                                       13
      The judge next found that her testimony regarding the rate ratio (RR) and

odds ratio (OR) results from the epidemiological studies was inconsistent with

the standards set forth in the Federal Judicial Center and National Research

Council's Reference Manual on Scientific Evidence (Nat'l Acad. Press 3d ed.

2011) at 602, 612 (Reference Manual), about the degree of strength necessary

to reflect a true causal relationship. 5 He found that Dr. Zambelli-Weiner failed

to follow the scientific methodology in placing "unswerving reliance" on only

one study, the Crockett study, 6 which had never been replicated. In conducting


5
  The commonly used method for measuring association is relative risk or rate
ratio (RR) in cohort studies, and odds ratio (OR) in case-control studies.
Reference Manual at 568-69. This is also referred to as the "point estimate."
Accutane Litigation, 234 N.J. at 360 n.17 (citing Reference Manual at 292). RR
is the ratio of the incidence rate of disease in exposed individuals to the
incidence rate in unexposed individuals. Reference Manual at 566. OR is the
ratio of the odds that one with the disease was exposed to the odds that one
without the disease was exposed. Id. at 568. For most purposes, the RR from a
cohort study is "quite similar" to the OR from a case-control study. Id. at 625.
6
  The Crockett study – 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) – is the only study that found a statistically significant
association between isotrentinoin and ulcerative colitis. It is a case-control
study using a large insurance claims database from the United States comprised
of 8189 cases of IBD (4428 ulcerative colitis, 3664 Crohn's disease and 97 IBD
unspecified). The study population included men and women of all ages. Sixty
of the subjects were exposed to isotretinoin (24 cases and 36 controls). The
controls were matched by age, gender, geographic region, health plan, and
enrollment. The authors of the Crockett study concluded that ulcerative colitis


                                                                         A-4952-16T1
                                      14
her meta-analysis, Dr. Zambelli-Weiner improperly excluded – according to the

trial judge – the results of the Rashtak study without more information about the

participants and failed to submit her study for peer review.

      The judge found that Dr. Sachar's methodology was unsound because he

"frequently disregard[ed] the fundamentals of the scientific method," that he




was "strongly associated with previous isotretinoin exposure," but there was "no
apparent association" between isotretinoin and Crohn's disease. Increasing the
dose of isotretinoin was associated with an elevated risk of ulcerative colitis; the
risk of ulcerative colitis was highest in those exposed to the drug for more than
two months. The authors concluded that:

            [t]his case-control study demonstrates a possible causal
            association between isotretinoin use and UC [ulcerative
            colitis], but not CD [Crohn's disease]. Temporality,
            effect specificity, and increasing effects for both
            intensity and duration of therapy provide further
            evidence of causation.         As this is the first
            epidemiological study to describe a positive association
            between isotretinoin and UC, these results should be
            confirmed by additional studies in other populations.
            Although the absolute risk of developing IBD after
            taking isotrentinoin is likely quite small, clinicians
            prescribing isotretinoin as well as prospective patients
            should be aware of this possible association.

            [(Emphasis added).]

In a 2010 published interview, one of the authors of the Crockett study explained
that the conflicting results of the Crockett studies with another study indicated
that "causality cannot be firmly established."


                                                                            A-4952-16T1
                                        15
significantly deviated from the accepted scientific methodology in elevating

case reports and animal studies above epidemiological studies. The judge also

found Dr. Sachar's "cavalier use of disparaging language toward the peer-

reviewed treatises of other scientists [was] indicative of the 'hired gun'

mentality."   Notably, in the judge's view, Dr. Sachar characterized the

Alhusayen study7 as "insane" during his testimony but then relied on it in his

written report.   He similarly exhibited, according to the judge, a "lack of




7
  Raed O. Alhusayen et al., Isotretinoin Use and the Risk of Inflammatory Bowel
Disease: A Population-Based Cohort Study, 133 J. Invest. Dermatol. 907 (Oct.
2012). During the twelve-year study period comprised of approximately 1.7
million subjects between age twelve to twenty-nine, the authors identified
46,922 subjects treated with isotretinoin, 184,824 subjects treated with topical
acne medication, and 1,526,946 untreated subjects. As adjusted for potential
confounders including age, gender, socioeconomic status, medical care and
prescription drug use, the authors of the Alhusayen study found no statistically
significant association between isotretinoin use and IBD, or the subtypes,
ulcerative colitis and Crohn's disease. The authors said they had conducted
separate analyses of Crohn's disease and ulcerative colitis because the diseases
had different pathogeneses and concluded that "[o]ur primary analyses found no
association between isotretinoin and IBD." In a prespecified secondary analysis,
the authors of the Alhusayen study found that, as adjusted, isotretinoin use was
associated with IBD among individuals twelve to nineteen years old, but that
topical acne medication was also associated with IBD among individuals in that
same age group. They concluded that this result suggested a "possible
association between IBD and acne itself," and recommended additional research
"to explore this possibility."


                                                                        A-4952-16T1
                                      16
'restraint' in his role as an advocate," by testifying that he "guess[ed]," without

having done a calculation, that the Etminan study 8 was underpowered.

      Further, Dr. Sachar had not published a peer-reviewed article or proposed

"a hypothesis on the purported causal association between isotretinoin and IBD,

nor do any of the peer-reviewed articles cited by him propose such a hypothesis."

Absent a hypothesis pulling together lines of evidence, the judge found Dr.

Sachar's opinions lacked theoretical coherency:



8
   This is a 2012 case-control study using a large United States health claims
database. Mahyar Etminan, Isotretinoin and Risk of Inflammatory Bowel
Disease: A Case-Control Study (2012). The author selected 20,237 cases of
IBD – 11,426 with ulcerative colitis, 8868 with Crohn's disease – and 60,136
controls, and the controls were matched by age and entry to the cohort. The
study found a statistically significant negative association between Accutane
and IBD, no association between previous tetracycline use and IBD, and did not
separately analyze ulcerative colitis and Crohn's disease. The author concluded
that the "results of this study are consistent with a protective effect of
isotretinoin use and IBD," although they acknowledged that it was "possible that
the study is subject to confounding bias." The Etminan 2013 study is a nested
case-control study comprised of 45,500 subjects, using the same insurance
database as the Crockett study. Mahyar Etminan et al., Isotretinoin and Risk for
Inflammatory Bowel Disease, 149 JAMA Dermatol. 216 (Feb. 2013). The
authors formed a cohort of women age eighteen to forty-six, who had received
prescriptions for oral contraceptives over an eight-year period. They identified
2159 IBD cases (1056 ulcerative colitis and 1103 Crohn's disease) and matched
them with 43,180 controls. The authors found no statistically significant
association between isotretinoin and ulcerative colitis or Crohn's disease. The
authors stated that their study differed from the Crockett study in that they
nested their cohort in a population of women, all of whom had been prescribed
oral contraceptives, thereby reducing the risk of confounding bias.
                                                                           A-4952-16T1
                                       17
            It seems likely that one of the reasons Dr. Sachar has
            declined to subject his opinion on isotretinoin to the
            greater scientific community is that he knows that in the
            peer-review process he would have to be "rigorously
            honest" (Reference Manual, page 50). In the courtroom
            he can point to, and highlight, various threads of
            marginal proofs such as animal studies (including
            zebrafish larva) and case reports, and cite them as
            "compelling evidence." Yet Dr. Sachar knows that in
            the peer-review process his editors will scrutinize the
            plausibility of the opinions on which he stands quite
            alone in the scientific community, and force him to
            defend his contentions or risk rejection of his article.

      That said, the judge recognized that Dr. Sachar's failure to write a peer-

reviewed article supporting his causation opinion "is not in and of itself,

disqualifying to an expert in a Kemp [h]earing." But that failure did "bespeak[]

an expert who expresses a different set of opinions in the courtroom than he is

willing to express to his colleagues." The judge also concluded, in quoting

Reference Manual at 786, that "'[i]f something is not published in a peer-

reviewed journal, it scarcely counts.'" "The scientific community has little

regard for opinions confined to the courtroom." The judge found that Dr. Sachar

had

            more than ample time to organize his thoughts and
            present them for scrutiny by the scientific community.
            He refuses to provide both his colleagues and this
            [c]ourt with a clear articulation of why and how
            isotretinoin can cause [ulcerative colitis]. Absent the
            whys and wherefores of his opinion on the purported

                                                                        A-4952-16T1
                                      18
            causal relationship between isotretinoin and IBD, Dr.
            Sachar's opinion is little more than conjecture, and a net
            opinion.

Thus, the judge found that Dr. Sachar's and Dr. Zambelli-Weiner's testimony

"suffer[ed] from multiple deficiencies, the most salient of which is their

selectivity of the evidence relied upon in disregard of the medical-evidence

hierarchy." Although Dr. Sachar was considerably more qualified than Dr.

Zambelli-Weiner, the judge found both utilized a methodology "slanted away

from objective science and in the direction of advocacy." Notably, while some

of the epidemiological studies showed a positive association between Accutane

and ulcerative colitis, the experts were unable to point to any consistent showing

across the studies. The judge concluded that the opinions expressed by the

experts were "motivated by preconceived conclusions, and that they have failed

to demonstrate 'that the data or information used were soundly and reliably

generated and are of a type reasonably relied upon by comparable experts'"

(quoting Rubanick, 125 N.J. at 477).

      With these views, and aided by expert testimony offered by the defense,

the judge barred plaintiffs' experts from testifying – a determination that led to

the dismissal of these 3231 claims.




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                                        III

      As the Supreme Court emphasized in its recent opinion, appellate courts

must apply an abuse of discretion standard when viewing such determinations.

Accutane Litigation, 234 N.J. at 391; see also Townsend v. Pierre, 221 N.J. 36,

52 (2015); Hisenaj v. Kuehner, 194 N.J. 6, 12 (2008). For the same essential

reasons that led the Court to reinstate the trial judge's exclusion of the expert

testimony of Drs. Kornbluth and Madigan, we affirm the judge's similar

disposition here.

      The Court upheld the trial judge's exclusion of Drs. Kornbluth and

Madigan's expert testimony, finding their "methodology was unsound"

essentially because they did not "interpret the relevant data and apply it to the

facts of this case as would other experts in the field." Accutane Litigation, 234

N.J. at 346. There, 2076 plaintiffs claimed they developed Crohn's disease from

using Accutane.     Id. at 346, 371.     All published epidemiological studies

concluded there was no causal relationship between Accutane and IBD and

between Accutane and Crohn's disease. Id. at 346.9 None of the studies found



9
  Medical societies, including the American Academy of Dermatology, filed an
amicus brief in support of defendants' position stating that "[i]n the past decade,
numerous epidemiological studies have established that isotretinoin use does not
increase the risk of IBD."
                                                                           A-4952-16T1
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a statistically significant adjusted association between the drug and Crohn 's

disease.    Only one small study found a statistically significant unadjusted

positive association, two found a positive association, and four found a

statistically insignificant negative association, one of which found a statistically

significant association for a protective effect.

      Like the record before us, the testimony at the Kemp hearing that

concerned     Drs.   Kornbluth   and    Madigan     "focused   intently"   on    the

epidemiological studies. Id. at 352. Those experts substantially relied on only

the unadjusted results of the Sivaraman study, a very small study presented in

poster form at a medical conference.         Id. at 392-94.    They disputed the

conclusions of the other larger studies, calling them flawed and lacking in value.

Ibid. Having rejected the evidence and conclusions of those epidemiological

studies, Dr. Kornbluth relied on the same facts and other forms of data at issue

here, including animal studies, case reports, causality assessments, internal

Roche documents, and his own biological mechanism hypotheses to support his

conclusion. Id. at 358.

      In addressing the epidemiological studies, the Supreme Court discussed

in detail the general principles and methodology used in conducting such

studies, as set forth in the Reference Manual. Id. at 352-55. The Court stated


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that when using epidemiological studies in legal matters, three basic questions

arise in assessing a study's methodological soundness:

              1. Do the results of an epidemiologic study or studies
              reveal an association between an agent and disease?

              2. Could this association have resulted from limitations
              of the study (bias, confounding, or sampling error), and,
              if so, from which?

              3. Based on the analysis of limitations in Item 2, above,
              and on other evidence, how plausible is a causal
              interpretation of the association?

              [Id. at 354 (quoting Reference Manual at 554).]

        In affirming the trial court's ruling regarding Drs. Kornbluth and Madigan,

the Court identified several methodological defects that are similarly applicable

here.

        First, the Court found that Drs. Kornbluth and Madigan both "employed a

methodology whereby they disregarded eight of nine epidemiological studies

and relied on case reports and animal studies to support their opinion." Id. at

392. Case reports are clearly "at the bottom of the evidence hierarchy," and

courts from other states have been "skeptical of their value in proving causation

. . . ." Id. at 392-93 (quoting Reference Manual at 724).       Notably, the Court

found that "initial animal studies may have suggested a possible causal

connection between Accutane and Crohn's disease, but since that time a uniform

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body of epidemiological evidence has dispelled any such theory." Id. at 393.

The Court explained that it did "not mean to suggest that animal studies and case

reports can never be relied upon for forming an opinion on causation," but the

Court found "ample support for the trial court's determination that it was not

proper to do so here in light of the uniform body of epidemiological evidence."

Ibid. Similarly, Dr. Sachar relied extensively on non-epidemiological evidence,

including   animal     studies,   individual    case   reports   that   contained

challenge/dechallenge/rechallenge events, causality assessments, internal Roche

documents, biological plausibility hypotheses, and clinical studies, despite the

almost uniform body of epidemiological evidence that has found no association

between Accutane and ulcerative colitis. In doing so, he failed to apply the

methodology followed by other experts in the field. Accutane Litigation, 234

N.J. at 393-96; Rubanick, 125 N.J. at 450-52.

      For example, in this case, Dr. Sachar testified that he uses the scientific

hierarchy of evidence "to the extent" that he does not reject it but does not "rely

on it blindly." He explained that although an epidemiological study is generally

considered a higher level of evidence, a "case report with . . . good

challenge/rechallenge evidence is better than a lousy epidemiological study ."

The Reference Manual at 723-24, however, provides that "[w]hen ordered from


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strongest to weakest, systematic review of randomized trials (meta-analysis) is

at the top, followed by single randomized trials, systematic reviews of

observational studies, single observational studies, physiological st udies, and

unsystematic clinical observations."    Accutane Litigation, 234 N.J. at 355.

"Evidence at the bottom of the hierarchy may sometimes be 'the first signals of

adverse events or associations that are later confirmed with larger or controlled

epidemiological studies.'" Ibid. (quoting Reference Manual at 724). As in the

Court's recent Accutane decision, Dr. Sachar did not follow the accepted

scientific methodology in elevating these lower forms of evidence.

      Second, the Supreme Court observed that Drs. Kornbluth and Madigan

had applied a selective form of reasoning in relying on only one small study,

even as they disagreed with the author's ultimate conclusion. Id. at 393-94. In

this way, according to the Court, "plaintiffs' experts dismissed published studies

examining thousands of subjects as underpowered and biased in favor of relying

on portions of a single unpublished study that examined 509 total subjects." Id.

at 394. Similarly, Dr. Sachar extensively relied on a portion of the Crockett

study, which found a strong statistically significant association between

Accutane and ulcerative colitis, even though he strongly disagreed with the

authors' conclusion on the absence of any link between Accutane and Crohn's


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disease. The Crockett study is a smaller study than others and the study's authors

concluded there was only a "possible causal association" between Accutane and

ulcerative colitis, results that "should be confirmed."       Importantly, those

findings were published nearly ten years ago and have never been replicated. In

fact, the Etminan study, which used the same database as the Crockett study

(using a cohort of women prescribed oral contraceptives), found no statistically

significant association between Accutane and ulcerative colitis.

      In exclusively relying on one study that has never been replicated, Dr.

Sachar failed to follow accepted scientific methodology.         See Cadarian v.

Merrell Dow Pharm., Inc., 745 F. Supp. 409, 412 (E.D. Mich. 1989) (expert

could not rely on a study where the authors "concluded that the results could not

be interpreted without independent confirmatory evidence"). In this regard, the

Reference Manual notes:

            Rarely, if ever, does a single study persuasively
            demonstrate a cause-effect relationship. It is important
            that a study be replicated in different populations and
            by different investigators before a causal relationship is
            accepted by epidemiologists and other scientists.

            The need to replicate research findings permeates most
            fields of science. In epidemiology, research findings
            often are replicated in different populations.
            Consistency in these findings is an important factor in
            making a judgment about causation. Different studies
            that examine the same exposure-disease relationship

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            generally should yield similar results. Although
            inconsistent results do not necessarily rule out a causal
            nexus, any inconsistencies signal a need to explore
            whether different results can be reconciled with
            causality.

            [Reference Manual at 604 (footnotes omitted).]

      And Dr. Sachar dismissed the other published studies examining

thousands of subjects as underpowered or otherwise flawed, another position

that requires skepticism about his methodology. Accutane Litigation, 234 N.J.

at 394.10 Instead, Dr. Sachar was willing to rely on single case reports and small

animal studies. Moreover, the two published meta-analyses, and defendants'

expert's unpublished analysis, which were performed to increase the power of

the studies, found no statistically significant association between Accutane and

ulcerative colitis.   In her meta-analysis, Dr. Zambelli-Weiner found a

statistically significant association, but her analysis did not conform to the

scientific methodology because she did not include all relevant studies .

      Third, the Supreme Court found that the trustworthiness of the

methodology employed by Drs. Kornbluth and Madigan was undermined by


10
   Dr. Sachar, unlike Dr. Kornbluth (regarding Crohn's disease), did not find
that the studies were flawed for failing to account for ulcerative colitis's
"prodrome," i.e., the period between the onset of a disease's symptoms and the
actual diagnosis. Accutane Litigation, 234 N.J. at 358.


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internal inconsistencies, including their refusal to examine the Rashtak and

Fenerty11 studies because those studies did not report on Crohn's disease, while

relying on case reports not specific to Crohn's disease and studies performed on

animals incapable of developing IBD. Id. at 394-95. Dr. Sachar similarly

refused to consider those same studies, even though he relied on animal studies,

causality assessments, internal Roche documents, and published scientific

literature that was not specific to ulcerative colitis. None of the animals in the

studies relied on by Dr. Sachar can develop IBD, or the subtypes ulcerative

colitis and Crohn's disease. Id. at 395.




11
   We briefly described the Rashtak study earlier. See n.4, above. The authors
of the Fenerty case-control study, using a Medicaid dataset, identified 176,889
acne patients who had no prior IBD diagnosis. Sarah Fenerty et al., Impact of
Acne Treatment on Inflammatory Bowel Disease, 68 J. Am. Acad. Dermatol.
6751 (Apr. 2013). They followed these patients for four years, during which
324 patients were diagnosed with Crohn's disease and 194 patients were
diagnosed with ulcerative colitis. They found that there was no association
between the use of isotretinoin and IBD, and that oral antibiotic use was
associated with a decreased risk of the disease. The authors set forth that this
association was comparable for both ulcerative colitis and Crohn's disease, but
they did not separately report the confidence interval findings for the subgroups.
They concluded "[t]here is an inverse association between oral antibiotics and
the development of IBD in acne patients with a dose-response relationship.
Clinicians and prospective patients should be cognizant of the lack of a causal
relationship between isotretinoin for acne and the development of IBD."


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      Fourth, Dr. Sachar, like Dr. Kornbluth, organized his testimony to support

a personal view that a causal association existed between Accutane and

ulcerative colitis through use of the Hill guidelines, 12 including the temporal

relationship, dose-response relationship, biological plausibility, and cessation of

exposure. Id. at 395-96. But, as the Court recognized, "those guidelines are

invoked only after an association between an agent and a particular disease has

been determined to be present; their pointed purpose is to determine whether a

detected association reflects true causality, it is not to create an association that

has not already been detected through appropriate studies." Id. at 396 (citing

Reference Manual at 598-99). The criteria were only meant to be applied after

"an association has been found between exposure to a particular agent and

development of a specific disease." Id. at 354.         In its recent decision, the

Supreme Court observed that "not one of the epidemiological studies found any

statistically significant association between Accutane and Crohn's disease. " Id.

at 396.

      The epidemiological studies also do not support an association between

exposure to Accutane and ulcerative colitis. When considering the admissibility



12
    Austin Bradford Hill, The Environment and Disease: Association or
Causation?, 58 Proc. of the Royal Soc'y of Med. 295 (1965).
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                                        28
of the testimony of Drs. Kornbluth and Madigan, the Supreme Court observed

that not one of the studies found a statistically significant association between

Accutane and Crohn's disease (only one study found an unadjusted statistically

significant association between Accutane and Crohn's disease, three found a

positive association, and four found a negative association). Id. at 396. All of

the studies, except Crockett, found no statistically significant association

between Accutane and ulcerative colitis.        And all of the studies – except

Crockett, which has not been replicated – concluded there is no association

between Accutane and IBD or the subtype ulcerative colitis.                Like the

circumstances in the Supreme Court's recent decision, Dr. Sachar improperly

used the Hill guidelines to create an association that had not been detected by

the studies.

      In short, there is little to distinguish between the Court's disposition of the

trial judge's ruling as to Drs. Kornbluth and Madigan, and the disposition under

review here. The epidemiological data is only slightly more favorable in the

case of ulcerative colitis, but it does not support a finding that there is an

association, much less a causal association, between Accutane and ulcerative

colitis. Significantly, the data has become even less favorable since the prior

judge's March 2014 decision, where she considered six epidemiological studies,


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                                        29
and one meta-analysis.     Since then, two more epidemiological studies and

another meta-analysis pushed the estimate even further away from an

association between Accutane and ulcerative colitis. Despite that data, Dr.

Sachar continued to rely on the same lines of evidence that the Court found

problematic in its recent decision. In adhering to the trial judge's gatekeeping

role as described in Accutane, Dr. Sachar's testimony on ulcerative colitis was

similarly unreliable.

      There is also no evidence that the subtypes of IBD are so different as to

warrant exclusion of the expert testimony of Drs. Kornbluth and Madigan and

the admission of the expert testimony of Drs. Sachar and Zambelli-Weiner here.

It is undisputed that the cause of IBD, including the subtypes ulcerative colitis

and Crohn's disease, is unknown, thereby complicating proof of the causative

link. It is also undisputed that the diseases share the same core symptoms and

some of the same risk factors, and in fact, patients are often misdiagnosed.

Significantly, Dr. Sachar admitted that the biological mechanism for both

ulcerative colitis and Crohn's disease is essentially the same. He also admitted

that he did not have enough information to conclude that Accutane operates in

opposite directions as a risk factor for ulcerative colitis and Crohn's disease.




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                                      ***

      In the final analysis, we find little to distinguish between the record here

concerning the proffered expert testimony of Drs. Sachar and Zambelli-Weiner,

and the record that led the Supreme Court to reinstate the trial judge's exclusion

of the expert testimony of Drs. Kornbluth and Madigan. The trial judge did not

abuse his discretion in barring the expert testimony in question. Instead, he

engaged in the very same type of gatekeeping which the Supreme Court

approved in its prior decision.

      Affirmed.




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