F OR P UBLICATION



### UNIT E D ST AT E S CO URT O F APPE AL S FO R T H E NINT H CIRCUIT

S T E P H E N W E N D E L L ; L I S A W E N D E L L , for themselves and as successors-in-interest to Max x W endell, deceased,

Plaintiffs-Appellants

,

v.

G L A X O S M I T H K L I

N E L L C; T E V

A P H A R M A C E U T I C A L S USA, I

N C ., Defendants-Appellees. No. 14-16321

D.C. No. 4 :09-cv-04124-CW

OPI NI ON

A ppeal from the United States District Court for the Northern District of California Claudia W ilken, District J udg e, Presiding

Arg u ed and Submitted September 16, 2016 San F rancisco, California

F iled J une 2, 2017

B efore: Ronald M. Gould and Marsha S. B erz o n, Circuit J udg es, and W illiam K. Sessions I I I
, * District J udg e.

O pinion by

J udg e Gould

* T h e Ho n o rab le W illiam K. Sessio n s III, U n ited States District J u dg e f o r th e District o f

Verm o n t, sittin g b y

d esig n atio n

.W E N D E L L V

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SUMMARY * *

Expert Testim ony / Duty to Warn

The panel reversed the district court’s summary judg ment in f a v o r o f Teva Pharmaceuticals USA, I nc., and the dismissal, as moot, o f plaintiffs’ motion to r econsider, in an action alleg ing neg lig ence and strict liability concerning the manufacture and distribution of drug s that were used to treat plaintiffs’ deceased s o n , Max x W endell, for inflammatory bowel disease.

Plaintiffs alleg ed that the drug s caused Max x W endell to develop Hepatosplenic T-cell ly mphoma, and that the manufacturers and distributors did no t gi ve adequate warning s about the risks associated with t h e drug s. The district court g r anted summary judg ment for Teva because the testimony of plaintiffs’ causation ex perts was not reliable a nd
not admissible under F ed. R. Evid. 702, and because plaintiffs did not present evidence that Max x ’s prescribing phy sician relied on Teva’s warning

labels.

The panel held that the district court erred by ex c l u d ing the ex perts’ testimony

. The panel held that the district court looked too narrowly at each individual consideration under Da ubert v

. Merrell Dow P h arm., I nc. , 509 U.S. 579, 589 (1993), without taking into account the broader picture of the

ex p erts’ overall me t h o d olog y

. Specifically

, the panel h eld that the district court improperly ig nored the ex perts’

ex p erience, reliance on a variety of literature and studies, a nd

** T h is su m m ary co n stitu

t es n o p art o f th e o p in io n o f th e co u rt. It h as b een p rep ared b y

co u rt staf

f f o r th e co n v en i en ce o f

th e read er.W E N D E L L V

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A X O S M I T H K L I

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review of Max x ’s medical records and h istory

, as w ell as the fundam e ntal importance of differential diag nosis b y

ex p erienced d octors treating troubled patients. T he panel further held that the distri c t court o veremphasiz ed c ertain facts; and taken tog ether, these mistakes warranted reversal. The p anel c oncluded that the proposed testimony was sufficiently reliable, and plaintiffs’ e x perts should have been allowe d to testify under Daubert

, and admitted as ex pert testimony under F ed. R. Evid. 702.

The panel reversed the district court’s summary judg ment to Teva on the duty to w arn claim. The p anel held that under Calif o r nia law, viewing the evidence in the lig ht most favorable to p laintiffs, there was a g enuine dispute of material fact as to whether the p r escribing phy sician’s conduct would have chang ed with warning s from Tev a , and its predecessor Glax o SmithKline L L C.

The panel declined to affirm the d istrict court’s judg ment

on alternative g rounds, and held that Teva may raise the issues with the district court on remand.

F inally

, the panel reversed the dis t r ict c ourt’s denial o f plaintiffs’ motion for reconsideration, and remanded.W E N D E L L V

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COUNSEL

Michael J

. Quirk (arg

ued), W illiams Cuker B erez ofsky L L C, Philadelphia, Pennsy lvania; Kevin Haverty
, W illiams Cuker Berez ofsky L L C, Cherry H ill, New J ersey ; for Plaintif fs

Appellants.

Alan J

. L az arus (arg

ued) and William A. Hanssen, Drinker B iddle & Reath L L P, San F rancisco, Ca l i f o rnia, for Defendant-Appellee Glax oSmithKline, L L C.

J effrey F

. Peck (arg

ued) and Pr e n t i ss W

. Hallenback, J r ., Ulmer & B erne L L P, Cincinnati, Ohio, for Defend a n tAppellee Teva Pharmaceuticals USA, I n c.

OP INION

GOUL D, Circuit J udg e :

Max x Wendell 1 trag ically died at the a g e of 21 o f Hepatosplenic T-cell ly

mphoma (HSTC L ), an ex ceeding ly

rare and ag g ressive f

o rm of cancer. F or m a n y y e ars before h i s development of HSTCL
, Max x was treated with a combination of drug s for inflammatory bowel disease. After his death, his parents, Stephen and L isa W endell (Plaintiffs), sued the manufacturers and distrib u t o r s o f these drug s, asserting claims u n d er California law for neg lig ence a nd strict liability

. Plaintiffs alleg ed that the drug s caused Max x to develop HSTCL and that the manufacturers a nd

1 W e ref er to Max x W en d ell b y

h is f irst n am e to av o id co n f

u s io n

.W E N D E L L V

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distributors d id not g ive a dequate w a rning s about the risks associated with the drug s.

The district court g ranted summa ry judg ment to Teva Pharmaceuticals U SA, I n c. (Teva), concluding that the Plaintiffs did not present admissible ex pert testimony o f causation and did not show that Max x ’s prescribing phy sician relied o n t he warning labels. F or the same reasons, the di s t r i c t court dismissed as moot Plaintiffs’ motion for leave
to file a motion for reconsideration of the district court’s prior order g ranting summary judg ment to G lax oSmithKline L L C (GSK). W e reverse and remand.

I

I n 1 998, at the ag e of twe l v e , M ax x was diag nosed with

a form of inflammatory bowel disease (I B D) called ulcerative colitis. I B D is an a

u toimmune disease characteriz ed b y chronic inf

l ammation. Max x beg an treatment with Dr. Edward Ric h

, a pediatric g a stroenterolog ist at Kaiser Permanente in San F rancisco. Relevan t h e r e , in J une 1999, D r

. R i c h p r e s c r i b e d m e r c a p t o p u r i n e ( 6

- M P )

, a n immunos uppressant, and one of a class of d rug s known a s thiopurines. At the time, 6-MP was manufactured by GSK

a n d marketed as Purinethol. Althoug h it has b e en widely used off-label since 1980 to treat I B D, 2 Purinethol has never received approval for this use.

I n J uly 2002, Dr. Rich prescribed an additional drug

, the
tumor necrosis factor alfa antag onist (anti-TNF) d rug

2 Of f

- l ab el u s e o f a d ru g is leg al, an d is “ g en erally b ased o n p u b lish ed scien t if ic rep o rts p u rp o rtin g to s h o w a ben ef icial ef f ect o f th e d ru g in su ch in d icatio n s o r p atien t p op u latio n s.”W E N D E L L V

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inflix imab, marketed as Remicade. Anti-TNF drug s a r e approved to treat v arious autoimmune disorders, such a s Crohn’s disease and rheumatoid arthritis.

Max x r eceived his last dose of Remicade in March 2006, after which his I B D w ent into remission. Two months later, the F ood and Drug Administration approved a new label for the drug

. Th e label included a warning reporting postmarke t i n g cases of HSTCL in y o ung male patients with Crohn’s disease treated with both Remicade and a thiopurine such as 6-MP or az athioprine. Centocor, the maker o f Remicade, also issued a “Dear Health Care Prov i d e r” letter

a l e r t i ng prescribers to the labeling chang e and g iving more details o n t he cases of HSTCL

. W hen Max x ’s sy mptoms returne d

, Dr. Rich prescribed another anti-TNF drug

, Humira, which Max x took until J une 2007. At the time Dr. Rich prescribed Humira, its label did n o t warn of the risk o f HSTCL

.

Max x remained continuously on 6-MP from J une 1999 until a bout March o r April 2007. GSK stopped market i n g Purinethol on J uly

1, 2003, and transferred ownership rig hts for the drug to Teva. Max x continu e d on Teva’s Purinethol until J uly 2 004, w hen D r. Rich switched him to a g eneric 6- MP

. A ccording to Max x ’s mother, Max x decided to stop taking 6-MP in 2007 after reading in Men’s Health that
y oung men on a c ombination of R e m icade and other immunosupressive medication had developed HSTCL

.

I n J uly 2 007, Max x checked into the emerg ency room with fevers, fatig ue, a

nd malai s e

. Several day s later he was diag nosed with HSTCL

—a non-Hodg kin’s ly

mphoma that is

ex c e eding ly rare and ag g re s sive. I t has “low responses to chemotherapy

, f

r eq u e n t r el a p s e s a f

t e r contemporaryW E N D E L L V

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treatments and the inability of the majority o f the patients to underg o bone marrow transplantation.” Most p a tients die within the first y ear o f diag nosis; only a very small fraction

ac h i e ve long -term survival. Max x died from H STCL on December 6, 2007, at the ag e of 21.

I n J uly 2009, Plaintiffs, Max x ’s pare n t s , sued multiple drug c ompanies in Superior Court in California. The case

was removed t o f

e d eral court in September 2 009. Plaintiffs filed the operative fourth amended complaint in April 2011. Several defendants, including G SK a nd T eva, then moved for
summary judg ment. The district c o u r t g ranted the motion, but subseque n tly withdrew its summary judg ment order in ligh t o f P laintiffs’ need for further discovery

. I n J uly 2012, after r eviewing new evidence, the district court denie d the motion for summary judg ment as to Teva and two other d rug

c o m p a n i e s , P ar Pharmaceutical, I n c. and A bbott L aboratori e s

. T h e court g ranted summary judg ment to G SK because it determined that Plaintiffs had not present ed sufficient evidence that a reasonable jury could find GSK had a duty to

w a rn o f the risk of HSTCL before J uly 1, 2003, when G S K stopped distributing Purinethol. A y ear later, the district court g ranted summary

judg ment to Par Pharmaceuticals.

I n J anuary 2014, the r emaining defendants—includin g Tev a

— filed another motion for summary judg ment. Plaintiffs settled t h e i r claims ag ainst the remaining defendants, ex cept for Teva, before the d istrict court ruled on the motion for summary

judg ment.

On J une 30, 2014, the dist ri c t court g ranted T eva’s

m o t i o n for summary judg ment because the testimony o f Plaintiffs’ causation ex perts, Dr. Andrei Shustov an d D r. Dennis W e i s enburg er, was not reliable and therefore notW E N D E L L V

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admissible under F ederal Rule of Evidence 702, and because Plaintiffs did not present e videnc e t h at Max x ’s p rescribing phy sician relied on Teva’s warning labels. I t also den ied P laintiffs’ motion for leave to file a moti o n f o r reconsideration of the Cour t ’ s J uly 2012 order g ranting

s u mmary judg ment to GSK. Plaintiffs filed a timely n o t i c e of appeal, challeng ing the district court’s g ra n t of summary judg ment to Teva and its denial of their m otion for leave to file a motion for reconsideration.

II

W e review the district court’s ruling on the admissibility

o f e x p ert testimony for an a buse of discretion. Messick v. Novartis Pharm. Corp.
, 747 F .3d 1193, 1196 (9th Cir. 2014). However, we “r e v i e w de novo the ‘construction o r interpretation of

. . . the F ederal Rules of Evidence, including whether p a

rticular evidence falls w ithin the scope of a g iven rule.’” Id

. ( al t eration in o r ig inal) (quoting United States v

. Durham

, 464 F .3d 976, 981 (9th Cir. 2006)). W e also r eview de novo the d istrict court’s g rant of s u m m a ry judg ment. Id. at 1199.

III

The issues presented in this appeal arise under the F ederal Rules of Evidence and California substantive law. See Motus

v. Pfizer Inc. (

Roerig D iv.)

, 358 F .3d 659, 660 (9th Cir. 2 004) (ex plaining that in diversity actions the cou r t a p plies state substantive law and the federal rules o f procedure). W e beg in with the rules of evidence.W E N D E L L V

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A

F ederal Rule of Evidence 702 g overns ex pert testimony

. I t provides:

A witness who is qualified a s a n ex pert b y knowledg e, skill, ex per ience, training

, o r education may testify i n the form of an opinion or otherwise if:

(a) the ex pert’ s scientific, technical, o r other specializ ed knowledg e will help the trier of fact to understand the evidence or to determine a fact in issue;

(b) the testimony is b a s ed on sufficient facts or data;

(c) the testimony is the product of reliable principles and methods; and

(d) t h e e x pert has reliably applied the principles and methods to the facts of the

case.

F ed. R. Evid. 702.

Pursuant to the F ederal Rules of E v i d e nce, the district
court judg e must ensure that all admitted ex pert testimony is both r elevant and reliable. See Daubert v

. Merrell Dow Pharm., Inc.
, 509 U.S. 579, 5 8 9 (1993). Defendants do not contest that t h e opinions of D r. W eisenburg er and Dr. Shustov are relevant; the only question, therefore, is whether they are reliable.W E N D E L L V

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Scientific evidence is reliab l e “if the principles a nd methodolog y used by an ex pert are g rounded in the methods of science.” Clausen v. M/V New Carissa
, 339 F. 3 d 1 049, 1 056 (9th Cir. 2003). The focus of the district c o u r t ’s analy sis “must be solely

on principles and methodolog y , not

on the conclusions that they g enerate.” Daubert

, 509 U.S. at 595. As we ex plained in Da u b e r t v. Merrell Dow Pharmaceuticals, Inc.
, the court’s “task . . . is to analy z e not what the ex perts say , but what basis they have for say ing it.” 43 F .3d 1311, 1316 (9th Cir. 1995) ( hereinafter Daubert II ).

T o a s sist courts with this task, the Supreme Court h a s listed several n on-ex clusive factor s that judg es can consider when d etermining whether t o admit ex pert testimony under Rule 702. See Daubert

, 509 U.S. at 593–95. T hese include: “whether the theory o r technique employ ed b y the e x pert is
g enerally accepted in the scientific community ; whether it’s been subjected to peer review and publication; whether it can be and has been tested; and whether the k n o w n or potential
rate o f error is acceptable.” Daubert II
, 43 F .3d at 1316. W e also consider whether ex perts are te s t i f y ing “about matters g rowing naturally ” out of their own independent research, o r if “they h ave developed their opinions ex pressly for purposes of testify ing .” Id. at 1317. These factors are illustrative, a nd they are n o t a l l a pplicable in e a ch case. Id

. The inquiry is “flex ible,” Daubert

, 5 09 U.S. at 5 94, and “Rule 702 should be applied w ith a ‘liberal thrust’ favoring admission,” M

essick

, 747 F .3d at 1196 (quoting D aubert , 509 U.S. at 588).

The district court concluded that the ex pert testimony o f Dr. Shustov and Dr. Weisenburg er did not meet the Daubert standard of reliability

. The district court first focused on the fact that the ex perts developed their opinions specifically for litig ation, and had never conducted independent research onW E N D E L L V

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the relationship between 6-MP and anti-TN F d rug s and the develop m e n t of HSTCL

. T he court also noted that both doctors conceded that a lthoug h their opinions were based on

a reasonable deg ree of medical certainty

, they “would not satisfy the standards r equired for publ i c a t i o n in p eer-reviewed medical journals.” I t concluded that the lack o f independent research combined with the doctors’ reluctance to p u b lish, “casts doubt [ on] the reliability of their methodolog ies under Rule 702.”

Second, the district court determined that th e l ack o f animal or epidemiolog ical studies showing a causal link between HSTCL and the combination of 6MP and anti-TNF drug s also undermined the ex perts’ methodolog y

. T h e court concluded that althoug h it mig ht be difficult to conduct such studies, g iven the rarity o f H S T C L
, that ty pe o f causal

e v i dence was “especially important here in lig ht of the f a ct that more than seventy percent of observed HSTCL cases a re idiopathic.” 3 “[ W ] ithout some reliable evidence o f a positive link between the drug s at issue and the disease,” the d i s trict
court concluded that the e x perts “ cannot r easonably eliminate other potential causes of Max x ’s HSTCL .”

F inally

, the d i strict court found that the studies Drs. W e isenburg e r and Shustov cited d id not “purp o r t [ ] to show that the specific combination of drug s prescr i b e d to Max x actually causes HSTCL .” A lthoug h these studie s c o n tained
st a t i s t ics about the incidence of HSTCL in d ifferent patient populations, the court found t h a t the ex perts did not show “that all of the observed d i fferences in these incidence rates

are statistically sig nificant or that they a ccount for plausible

3 A d isease th at is id io p ath ic, o r d e n o v o , is o n e th at d o es n ot h av e a k n o w n cau se.W E N D E L L V

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alternative causes of HSTCL
, such as I BD itself.” F urther, the d o ctors did not present scientific evidence to support their opinion that I B D is not a risk factor for HSTCL

. Althoug h we think it a clos e q uestion, w e conclude that the district court erre d b y e x cluding the ex perts’ testimony

. The district court looked too narrowly at each individual consideration, without taking into account the broader picture of the ex pert s ’ overall methodolog y

. I t improperly ig nored the e x perts’ ex perience, reliance on a variety of literature a nd studies, a nd review of Max x ’s medical records and history

, a s well as the fundamental importance of differential diag nosis by ex perienced doctors treating troubled patients. T h e district
court also overemphasiz ed the f a c ts that (1) the ex perts did
not develop their opinions based on independent research a nd (2) the ex p erts did not cite epidemiolog ical studies. W e hold that all tog ether, these mistakes warrant reversal. Cf. Kennedy v. Collagen Corp.
, 161 F .3d 1226, 1228–30 (9th Cir. 1998) ( c oncluding that the ex pert’s reliance on s t u d ies that showed a connection between collag en and autoimmune disorders combined with the ex pert’s observations of the patient and review of her medical history was a sufficiently reliable methodolog y ev e n t h o u gh the cause-effect relationship between the collag en and the d i s e ase was not conclusively

established).

To beg in, the ex perts were h ig hly qualified doctors. Dr. Shustov is a licensed, board-cer t i f i ed phy sician a

nd an Associate Profess o r of Medicine at the University o f W a shing ton Medical Center. He specializ es in the diag nosis and treatment of ly

mphomas, with a clinical research f ocus on T-cell leukemia and ly

mphomas. He has treated “hundreds of patients with T-ce ll ly mphomas,” and “thousands o f patient s with ly

mphomas,” including seven patients withW E N D E L L V

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HSTCL

. Two of those patients were treated w i t h the combination of drug s at issue here. Given t h e r a rity o f HSTCL
, Dr. Shustov e stimated that he has seen m o r e cases of the disease than 99% of o n c o l og ists in the country

. Dr. W e isenburg e r is an e x pert h e m atopatholog ist—a phy sician
t r a ined in the study and diag n osis of d iseases of th e b o n e

marrow and the immune sy stem—with more than 30 y ears o f

ex p erience diag nosing no n

- H o d g kin ly mphoma. H e is the professor and Chair o f the Department of Pathology a t C i ty of Hope Medical Center. A lthoug h he has not written specifically on HSTCL
, h e has written hundreds of papers on the subject of non-Hodg kin’s ly mphoma, including some on the potential causes of non-Hodg kin’s ly mphoma.

The d octors employ ed sound methodolog ies to reach their conclusions. Dr. Shustov base d h i s opinions “on medical

r ecords a s w ell as [ his] education, training and ex perien c e, knowledg e of the pertinent medical li t e r a t ure and [ his] knowledg e of the epidemiolog y , diag nosis and natural history of HSTCL .” He e x plained: “ I reviewed the literature, I pulled the f

acts out of the literatu r e

. ” He found that the li t e r a ture shows there is an increased risk of HSTCL in
p atients taking 6-MP over the g eneral population. A f t e r

r eviewing the literature, h e “compiled the numbers abo u t frequency of diseases, about freque n c y of inflammatory bowel d iseas e and [ he] looked at the b iolog ical causation o f ly mphoma pertaining to this case.”

Dr. Shustov stated that he performs differential diag nosis in attempting to d i ag nose every patient, and that he has applied the same techni q u e to determine the cause of a disease. W hen performing a differential diag nosis, he first

assumes the pertinence of all potential causes, then rules out the ones as to which there is no plausible e v i d e n c e o fW E N D E L L V

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c ausation, and then determines the most likely cause amon g those that cannot be e x cluded. W e have recog niz ed that this method of conducting a differential d iag n osis is scientifically sound. See Clausen

, 3 3 9 F. 3 d a t 1057–58. F or c ases o f HST C L i n p atients that have taken 6-MP, like Max x , Dr. Shustov recog niz ed:

that 6-MP is a well-know n m u tag e n a nd carcinog en and puts every person who takes it
at risk. And g iven the frequency o f hepatosplenic l y

mphoma in [the] g eneral population as

. . . [ compared t o ] those who take 6-MP, it makes it plausible o r biolog ically plausible that that’s [ an] etiolog ic factor. You c onstruct y our differential diag nosis

. . . [ o f] w h at mig ht have c aused l y mphoma. Y ou come up with the stro n ge s t probability that patient was taking carcinog en and developed ly

mphoma a n d y ou start thinking ag ain what can cause his ly mphoma,
y ou can’t identify any thing else i n the patient’s history

or his medical records.

Reg arding Max x specifically

, Dr. Shustov stated that there was a one in six million c hance that Max x would have developed HSTCL

without being ex posed to 6-MP. I n lig ht of those odds, Dr. Shustov stated that “based o n [ h i s ]

ex p erience in T-cell ly

mphomas, knowledg e of the literature and being involved in T-cell ly mphoma research in the past ten y ears” he determined “that it’s much more likely that

ex p o sure to mutag en and immunosuppressants caused the ly mphoma.” Dr. Shustov did not need to eliminate all potential causes; “[ i] t is enoug h that a [ proposed cause] be a substantial causative factor.” Messick , 747 F .3d at 1199.W E N D E L L V

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Dr. W ei s e n

b u r g e r described his methodolog y for reaching his opinions as follows:

I r eviewed the medical r ecords. I reviewed
t h e patholog y slides and confirmed the diag nosis. I reviewed all of the patholog y records. I reviewed th e l iterature on the disease, hepatosplenic ly mphoma. And I reviewed all the literature I c ould find on

causes of hepatop a t hic T-cell ly mphoma, including literature o n inflammatory bowel disease and t r e atments for inflammatory bowel d isease. And then I used the B radford Hill methodolog y to come to th e conclusion that I did. [ 4
, 5 ]

Reg arding Max x specifically

, Dr. We i senburg er b ased his opinion on “a summary of the medical records of [ Max x ] as well as c opies o f the p atholog y reports, and the orig inal slides of the diag n ostic bone marrow,” which he evalua t ed with

over 30 y ears of ex perience diag nosing n o n-Hodg kin ly mphoma. He stated that h e considered that Max x ’s HSTCL mig ht have been idiopathic, and that althoug h h e wa s n ot entirely able to r u l e that p ossibility out, “[ w] hen y ou have a p a t i ent with obvious and known risk factors, y ou tend to

assume that those ris k f

a c tors were the cause.” H e did not base that a ssumption on pure conjecture. As h e d i s cussed throug hout his deposition testimony and in his ex pert report,

4 T h e B rad f

o rd Hill m eth o d olo g y ref ers to a set o f criteria th at are

w ell accep ted in

th e m ed ical f

ield f or m ak in g cau sal j u d g m en ts.

5 Dr. W eisen

b u rg er also id en tif

ied at least o n e p a p er th at sh o w ed th ere w as n o risk

o f ly m p h o m a in IB D p atien ts.W E N D E L L V

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the literature sh o w s that patients ex p osed to 6-MP and antiTNF drug s are at an increased r i s k for HSTCL

. Dr. W e isenburg e r also weig hed other risk factors, including Max x ’s sex and ag e, and determined that those were “weak risk factors; whereas, the disease he h ad, particularly in the setting of the drug s he r e c e ived would be considered very strong risk factors.”

The proposed testimony was sufficiently reliable that the Plaintiffs’ ex perts should have been allowed to testify under Daubert

. The district court improperly required more. The Supreme Court in D aubert aimed a t screening out unreliable

or bo gu s ex p ert testimony

. Nothing in Daubert

, or its
prog e ny , properly understood, sug g ests that the most

ex p erienced and credentialed doctors in a g iven field should be barred from testify

ing based on a differential diag nosis.

F irst, the district court was wrong to put so much w eig ht

on the fact that the ex perts’ opinions w e r e n ot developed independently of litig ation and had not been pu b l i shed. W h ile independent research into the topi c at issue is helpful
to e stablish reliability

, its absence does n ot mean the e x perts’ methods w ere unreliable. W here “the proffered ex pert testimony is not based o n independent research,” the ex perts

can instead present “other o bjective, verifiable evidence that the t e s t i mony is based on ‘scientifically valid p rinciples.’” Daubert II

, 43 F .3d at 1317–18. To be sure, “[ o] ne means o f sh owing [ that the testimony is b ased on scientifically valid principle s ] i s by proof that the research and analy sis supporting the proffered conclusions h ave been subjected to normal scientific scrutiny throug h peer review a nd publication.” Id. at 1 318

. H owever, ex pert testimony may still be reliable and a dmissible without peer review a nd publication. See Clausen

, 339 F. 3 d at 1056. That isW E N D E L L V

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especially true when dealing with rar e d i s eases that d o not impel published studi es

. See Milward v. Acuity Specialty Prods. Grp., Inc.
, 639 F .3d 11, 24 ( 1st Cir. 2 011) (recogniz ing that the “rarity ” of a particular form of leukemia

was one reason that it w ould be “very d ifficult to perform an epidemiolog ical study of t h e c a uses of [ the disease] that would y ield statistically

sig nificant results.”).

The district court also wrong ly conflated the standards for publication in a peer-reviewed journal with the standards for admitting ex pert testimony in a courtroom. Dr. W eisenburg er stated on cross-ex amination that to publish h i s o p i n ion he would use a “more r ig orous” standard than the one he used to come up with his ex pert opinion. Dr. Shustov stated that he would not be comfortable publishing h is opinion because he did not have any new data, and any meta-an a l y s i s or r eview of the literature could only be published upon invitation. The district c ourt viewed these statements reg arding the ex perts’ willing ness to publish a s e vidence that their methods were not up to snuff. B ut this analy sis misses t h a t while an ex pert must “employ [ ] in the courtroom the same level o f intellectual rig or that characteriz es the p r a ctice of an ex pert in the relevant field,” Kumho Tire Co., Ltd. v. Carmichael

, 526 U.S. 137, 152 ( 1999), the standards for co u rtroom testimony do not necessarily p arallel those of the professional publications

, s e e Ambrosini v. Labarraque

, 101 F .3d 129, 138 (D.C. Cir. 1996) (“[ T] he fact ‘that science wo u l d re quire

more evidence before conclusively considering the causation question resolved is irrelevant [ to the admissibility of ex pert testimony ] .’”) (quoting Ferebee v. Chevron Chem

. Co.
, 736 F .2d 1529, 1536 ( D

. C

. Cir. 1984)). F or ex ample, Dr. Shustov ex plained that, “[ o] pinions are not publishable. Data is publishable. W hat I ’ m r e p o r ting here is my opinion.” A l t houg h unwilling ne s s t o p u b l i s h w e i gh s a ga i n s tW E N D E L L V

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admissibility

, it a lone is not determin at i v e. See Daubert II
, 43 F .3d at 1318 n .9 (“That p laintiffs’ ex per t s h av e been unable or unwilling to publish their work undermines plaintiffs’ claim that the f inding s t h e s e ex perts proffer a re ‘g round[ ed] in the metho d s and procedures of science’ a nd ‘derived b y the scienti f

i c method.’” (alteration in orig inal) (qu o ting Daubert

, 509 U.S. at 590)). W e have previously held ex pert o pinions to be reliable that were not subject to peer review throug h publication. See Clausen

, 33 9 F .3d at 1056, 1061.

The district court also wrong fully req uired that the

ex p erts’ opinions rely on animal or epidemiolog ical studies. N e i t h er a re n ecessary for an ex pert’s testimony to be fou n d reliable and admissible. S ee Kennedy

, 161 F

. 3d at 1229. W e have long recog niz ed that it may not alway s be possible to conduct c ertain ty

pes of studies. S

e e, e.g. , Daubert II

, 43 F .3d at 1318 n.9 (“There may w ell b e g ood r easons why

a scientific study has not been p ublished. Fo r ex ample, it
may be too recent or of insufficiently b r o ad interest.”). HSTCL is an e x c eeding ly rare cancer, wit h o n l y 100 to 200

cases reported since it w as first recog niz ed. I t i s not surprising that the scientific community h as not invested substantial time or resources into investig ating the causes of such a rare disease.

Althoug h they did not rely on animal or epidemiolog ical studies, the ex perts here did rely o n other publishe d studies and articles. The district court only addressed a few of these, quickly dismissing them because they are case reports and do
not control or account for alternative causes of HSTCL

. Althoug h case studies a lone g enerally d o not p rove causation, they “ may support other proof of causation.” Rider v. Sandoz Pharm. Corp.

, 295 F .3d 1194, 1199 (11th Cir. 2002). Here,W E N D E L L V

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the ex p erts relied not just o n these s t u d i e s—which not only

ex a mined reported cases but also used statistical a n a l y s is to

come up with risk r at es—but also on their o wn wealth o f

ex p erience and additional literature. 6

W e a lso note that “[ n] ot knowing the mechanism whereby

a particular ag ent causes a particular effect is not alway s fatal
to a plaintiff’s claim. Causation can be proved even when we don’t k now precisely how the d a m ag e occurred, if there is sufficiently c ompelling proof that the a g ent must have c aused the damag e some h o w .” D aubert II
, 43 F .3d at 1314 (emphasis in orig inal). That there is no study that definitively
states HSTCL is caused by the in g estion of 6-MP and antiTNF drug s does no t prevent the a dmission of Plaintiffs’

ex p erts’ testimony

. S

ee Kennedy , 161 F .3d at 1230.

F inally

, t h e district court erred when it ex cluded Plaintiffs’ ex perts’ opinion testimony because of the hig h rate of idiopathic HSTCL and the alleg ed inability of the ex perts to rule out an idiopathic orig in or I BD i t s e lf. W e do not require ex perts to eliminate a ll oth e r p o s s ible causes of a condition for the ex pert’s testimony to be reliable. Messick

, 747 F

. 3d at 1199. I t is enoug h that the p roposed cause “be a substantial c ausative factor.” Id. This is true in patients with multiple risk f

actors, and analog ously

, in cases where there is

a hig h r ate of idiopathy

. See id. (holding that the district
court abused its d iscretion when it ex cluded ex pert testimony

as u nreliable b ecause the ex pert could n ot determine w hich o f

6 T ev a ar g u e s th at its o w n ex p erts h ig h lig h t th e d earth of scien tif ic

ev id en ce to su

p p o rt P lain tif

f s ’ claim s an d u n d erm in e an y assertio n th at Drs. Sh u sto v an d W eisen

b u rg er em

p lo y ed so u

n d scien t if

ic m eth o d olo g y

. T h e d istrict co u rt d i d n o t co n sid er th is ev id en ce, an d w e d eclin e to d o so in th e f irst in stan ce.W E N D E L L V

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m u l tiple r isk factors caused plaintiff’s disease). Moreov e r, when an ex pert establishes causation based on a differential diag nosis, the ex pert may r ely on his or her ex tensive c linical

ex p erience as a basis for ruling out a p o t e n t ial cause of the disease. See id. at 1198. T he district court a bused its d i s c r e t i o n b y e x c l u d i n g D r

. S h u s t o v ’ s a n d D r

. W e isenburg e r’s testimony because they could not completely rule out the possibility

that Max x ’s HSTCL was idiopathic.

Perhaps in some cases there w ill be a plethora of peer reviewed evidence that spec i fically shows causation. However, such literature is n ot required in ea c h a nd every

case. “The first several victims o f a n ew tox ic tort should not b e barred from having their day in court simply because t h e medical literature, which will eventually show the connection between the victims’ condition and the tox ic substa n c e, has
not y et been completed.” Clausen

, 339 F .3d at 1 060 (quoting Turner v. I

owa F ire Equip. Co.
, 229 F. 3 d 1202, 1209 (8th Cir. 2000)). I n the case of a rare diseas e l i ke HSTCL
, the Supreme Court’s ma n d a t e that in determining the admissibility of ex pert testimony

, th e f o cus “must be solely

on principles and methodolog y , not o n the conclusions that they g enerate,” is especially important. Daubert

, 509 U .S. at 595.

W h ere, as here, the ex perts’ opinions are not the “junk science” Rule 702 w a s m e a n t to ex clude, see Estate of Barabin v. AstenJohnson, Inc.
, 7 4 0 F.3d 457, 463 (9th Cir. 2014), the interests of justice fav o r l e a ving d ifficult issues in the hands of the jury and rely ing on the safeg uards o f the a dversary sy stem—“[ v] ig orous cross-ex amination, presentation of contrary

evidence, and careful instruction on the burden of proof”—to “attack[ ] sha ky but admissible evidence,” D aubert

, 509 U.S. at 596. B ecause we concludeW E N D E L L V

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that the d istrict court erred in ex c luding the testimony o f Dr. Shustov and Dr. W eisenburg e r , w e reverse the district court’s
g rant of summary judg ment. See Messick

, 747 F .3d at 1199. As ex p lained in Messick

, “[ m] edicine partakes of art as w ell

as science.” Id. at 1198

. W here, as here, two d octors w ho stand at or n ear the top of their field and have ex t en sive clinical ex perience with the rare disease or class of disease at issue, are p repared to give ex pert opinions supporting causation, we conclude that D aubert p oses no bar based on their principles and methodol o gy

. That defendants may be able to offer other equally qualified medical opinion opposing causation a lso does not support the idea that Daubert should bar the admission o f t h e testimony of the doctors o ffered a s

ex p erts by Plaintiffs. I nstead, the testimony of Dr. W e isenburg e r and of Dr. Shustov should have been admitted

as ex pert testimony u nder F ede ra l Rules of Evidence 702. The d efendants’ ex p ert testimony could have been o ffered in opposition. Then, the jury

, as the trier of f a c t , would be empowered to decide, based on the law gi ven in p roper jury instructions and the facts as determined by the jury

.

B

The district court g ranted summary judg ment to Teva on the duty to warn c l a i m fo r two reasons. F irst, the district
court held that the lack of admissible causat i o n e v idence precluded Plaintiffs from preva i l ing on their duty to warn claims. Second, Plaintiffs did not produce “any evidence to sug g est that Dr. Rich actually relied on Teva’s warning labels before prescribi n g Purinethol to Max x .” F or the reasons discussed above, we r everse on the district c ourt’ s f i rst g round. F o r the reasons discussed below, we reverse on the district court’s second g round.W E N D E L L V

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Under California law, drug manufacturers h ave a duty to

warn p hy sicians of ri s k s that are k nown or scientifically knowable at the time of the d r ug ’s distribution. See Carlin v

. Superior Court
, 920 P. 2 d 1 3 4 7
, 1349–54 (Cal. 1996). “A plaintiff a sserting causes of action based on a f ailure to warn must prove not only that n o w arn i n g w as provided or the warning was inadequate, but also that t h e i nadequacy o r absence o f the warning caused the plaintiff’s injury .” Motus

v. Pfizer Inc.
, 196 F

. Supp. 2d 984, 9 91 (C.D. Cal. 2001), aff’d

, 358 F .3d 659. “[ A] product defect claim based on insufficient wa r n ing s cannot survive summary judg ment if strong er warning s would not have altered the conduct of the prescribing phy sician.” Motus , 358 F .3d at 661.

I n this c ase, viewi n g the evidence in the lig ht most favorable to Plaintiffs, there is a g e nuine dispute of material fact as to whether Dr. Rich’s con d u c t would have chang ed with warning s from Teva a nd GSK. Summary judg ment was improper.

Althoug h D r. Rich testified that it is n ot his “reg u l ar practice to look at drug labeling ,” when he d o es read them it is “one of the thing s that is part of [ his] decision-making process.” He a lso testified that “a black box warning means there is a sig nif

i c a n t s i d e e ffect that I need to be a ware o f.” 7 I ndeed, thi s t y

pe of w arning d id influence Dr. Rich’s prescribing decisions for Max x . Centocor beg an circulating warning s—both a b lack b ox warning and a Dear Health Care

7 A black b o x w arn in g is a w arn in g th at is p l aced in a b o x in a d ru g ’ s lab elin g in f

o rm atio n

. A cco rd in g to Plain tif f s’ p h arm aco v i g i l an ce ex p ert, a b lack b o x w arn in g m ay o n ly b e u sed w ith FDA au th o rizatio n , an d it is

“ t h e stro n g est p o ssib le w arn i n g th at can b e g iv en sh o rt o f restrictin g d istrib u tio n

o f a d ru g o r co m

p letely w ith d raw in g it f

ro m th e m ark et.”W E N D E L L V

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P ro v ider letter—about HSTCL for Remicade in May 200 6
, just a f e w m o nths a fter Max x stopped taking Remicade. W h en Max x ’s I B D rel a p s e d in November 2006, Dr. Rich
pr e s c r i bed Humira—which did not h ave a warning about HSTCL —in place of Remicade. D r

. R ich testified that he prescribed H umira because he believed it had a better safety profile, noting tha t a t that point there were no reports o f HSTCL developing in p atients who t o ok Humira. This chang e in prescribing practices which c a n, at least in part, reasonably

be attributed to the lack of a warning for Humira
creates a q

uestion o f material f

act as to whether the presence of a warning on Te v a ’ s P u rinethol would have chang ed Dr. Rich’s prescribing practices as to Max x

.

T h e re is also evidence that Dr. Rich chang e d h i s prescribing practices g enerally after h e learned of incidents o f HSTCL in patients taking both 6- M P a n d anti-TNF ag e nts. As the information c ame out, his prescribing practices evolved. H e now no long er prescribes combination therapy but uses only monotherapy

. V iewing the facts in the lig ht
most favorable to the Plaintiffs, there are questions o f material fact a s to whether warning s would have chang ed Dr. Rich’s prescribing practice. See Stanley v. Novartis Pharm. Corp.
, 11 F

. Supp. 3d 987, 1003 (C.D. Cal. 2 014) (“[ C] hang es to treatment a n d p rescription procedures

c r e a te[ d] a triable question of f act o n specific causation.”). W e reverse the district court’s g rant of summary judg ment in favor of Teva. 8

8 GSK asserts th at P l ain tif f s’ w arn in g ex p ert’ s testim o n y sh o w s th at P u rin eth o l’ s lab el sh o u l d h av e b een ch an g ed in 2 0 0 6
, ap p ro x im ately th ree y ears af t er GSK sto pp ed d istrib u tin g th e dru g

. It arg u es th at th ere can b e

n o cau s al co n n ect i o n b e t w e en th e alleg ed f ailu re to w arn an d th e h arm

. T h e d istrict co u rt d id n o t ad d ress th is arg u m en t, an d w e d eclin e to d o so

.W E N D E L L V

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C

Teva urg es us to affirm the district court on four alternative g r o unds. 9 Althoug h we may a ffirm on any g r ound

r a i sed below and supported by the record, see Proctor v. Vishay Intertechnology Inc.
, 584 F .3d 1208, 1226 (9t h Cir. 2009), the issues that T e va raises would r equire ex tensive fact finding

, a nd are matters on which the dist r i ct court did not rule. I t would be inappropri at e f o r u s to reach these issues, and we decline to d o so. S e e Greater L.A. Council on Deafness, Inc. v. Zolin

, 8 12 F .2d 1 103, 1107 & n.5 (9th Cir. 1987), superceded b

y statute on o ther grounds

. They may be raised with the district court on remand.

D

F inally

, Plaintiffs challeng e the d i strict court’s order deny ing Plaintiffs’ motion f or leave t o file a motion for reconsideration of the district court’s J u l y 2012 order
g ranting summary judg ment to G SK. GSK asserts t h a t , a s Plaintiffs’ opening b rief does not challeng e the district court’s

un d erlying g rant of summary judg ment to GSK, Plaintiffs

S ee Grea ter L.A. Co u n cil o n Dea fn ess, In c. v. Zo lin

, 81 2 F.2 d 11 0 3, 1 1 0 7 & n .5 (9 th

Cir. 1 9 8 7 ), s u

p erced ed b y sta tu t e o n o th er g ro u nd s

.

9 B rief ly

, T ev a arg u es th at w e s h o u ld af f irm o n each o f th e f

o llo w in g f o u r b a s es: (1 ) it h ad n o d u ty to w arn ab o u t t h e alleg ed risk o f HST CL arisin g f ro m an o f

f

- lab el u se o f P u ri n e t h o l; (2 ) it h ad n o d u ty to w arn ab o u t alleg ed risk s f

ro m u se o f a co m

p etito r’ s p ro d u ct; ( 3 ) P lain tif f s

can n o t m a i n t ain a f

ailu re to w arn claim b ecau se Dr. Rich h ad alread y receiv ed th e in f

o rm atio n ; an d (4 ) b e c a u s e P lain tif f s can n o t pro v e th at Max x d ev elo p ed HST CL af ter May 2 0 0 6
, t

h ey can n o t p ro v e t h a t an alleg ed f ailu re to w arn b y T ev a w as th e p ro x im a te cau se o f Max x ’ s in j u ries.W E N D E L L V

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abandoned their a r gu ment that the district court erroneously
g ranted summary

judg ment to GSK.

GSK’s a rg ument is unpersuasive. As to GSK, Plaintiffs

are c h a l l e n g ing only the district court’s denial of its motion for leave to f

ile a motion for reconsideration. A challeng e to

a denial of a motion f o r leave to file a motion for reconside r a tion b ring s up just the denial of that motion, not the underly

in g m e r its. Cf. Molloy v

. W ilson

, 878 F .2d 313, 315 (9th Cir. 1989) (“An appeal f rom a denial of a Rule 60(b) motion bring s up only the denial of the motion for review, not the merits of the underly ing judg ment.”). Plaintiffs did raise this arg ument in t h eir Opening B r ief, asserting that because
t he district court’s ruling s reg arding the admissibility o f

ex p ert testimony and c a

usation were e r

roneous, “the ruling on Plaintiffs’ motion likewise should be vacated so that it can be decided on its merits on remand.”

W e ag ree with Plaintiffs. T h e district c o u r t denied their motion “as moot” because “Plaintiffs c annot prevail on their claims ag ainst [ GSK ] f or the same r easons they cannot prevail o n their claims ag ainst Teva”: la c k o f admissible causation evidence, and lack of evidence showing Dr. Rich’s reliance on warning s. Be cause we reverse the district court

on those issues, w e also reverse the d istrict court’s denial o f Plaintiffs’ motion for reconsideration.

REVERSED AND REMANDED.