Stephen Wendell v. Glaxosmithkline LLC

FOR PUBLICATION

UNITED STATES COURT OF APPEALS

FOR THE NINTH CIRCUIT

STEPHEN WENDELL; LISA No. 14-16321

WENDELL, for themselves and as

successors-in-interest to Maxx D.C. No.

Wendell, deceased, 4:09-cv-04124-CW

Plaintiffs-Appellants,

v. OPINION

GLAXOSMITHKLINE LLC; TEVA

PHARMACEUTICALS USA, INC.,

Defendants-Appellees.

Appeal from the United States District Court

for the Northern District of California

Claudia Wilken, District Judge, Presiding

Argued and Submitted September 16, 2016

San Francisco, California

Filed June 2, 2017

Before: Ronald M. Gould and Marsha S. Berzon, Circuit

Judges, and William K. Sessions III,* District Judge.

Opinion by Judge Gould

*

The Honorable William K. Sessions III, United States District Judge

for the District of Vermont, sitting by designation.

2 WENDELL V. GLAXOSMITHKLINE

SUMMARY**

Expert Testimony / Duty to Warn

The panel reversed the district court’s summary judgment

in favor of Teva Pharmaceuticals USA, Inc., and the

dismissal, as moot, of plaintiffs’ motion to reconsider, in an

action alleging negligence and strict liability concerning the

manufacture and distribution of drugs that were used to treat

plaintiffs’ deceased son, Maxx Wendell, for inflammatory

bowel disease.

Plaintiffs alleged that the drugs caused Maxx Wendell to

develop Hepatosplenic T-cell lymphoma, and that the

manufacturers and distributors did not give adequate

warnings about the risks associated with the drugs. The

district court granted summary judgment for Teva because the

testimony of plaintiffs’ causation experts was not reliable and

not admissible under Fed. R. Evid. 702, and because plaintiffs

did not present evidence that Maxx’s prescribing physician

relied on Teva’s warning labels.

The panel held that the district court erred by excluding

the experts’ testimony. The panel held that the district court

looked too narrowly at each individual consideration under

Daubert v. Merrell Dow Pharm., Inc., 509 U.S. 579, 589

(1993), without taking into account the broader picture of the

experts’ overall methodology. Specifically, the panel held

that the district court improperly ignored the experts’

experience, reliance on a variety of literature and studies, and

**

This summary constitutes no part of the opinion of the court. It has

been prepared by court staff for the convenience of the reader.

WENDELL V. GLAXOSMITHKLINE 3

review of Maxx’s medical records and history, as well as the

fundamental importance of differential diagnosis by

experienced doctors treating troubled patients. The panel

further held that the district court overemphasized certain

facts; and taken together, these mistakes warranted reversal.

The panel concluded that the proposed testimony was

sufficiently reliable, and plaintiffs’ experts should have been

allowed to testify under Daubert, and admitted as expert

testimony under Fed. R. Evid. 702.

The panel reversed the district court’s summary judgment

to Teva on the duty to warn claim. The panel held that under

California law, viewing the evidence in the light most

favorable to plaintiffs, there was a genuine dispute of material

fact as to whether the prescribing physician’s conduct would

have changed with warnings from Teva, and its predecessor

GlaxoSmithKline LLC.

The panel declined to affirm the district court’s judgment

on alternative grounds, and held that Teva may raise the

issues with the district court on remand.

Finally, the panel reversed the district court’s denial of

plaintiffs’ motion for reconsideration, and remanded.

4 WENDELL V. GLAXOSMITHKLINE

COUNSEL

Michael J. Quirk (argued), Williams Cuker Berezofsky LLC,

Philadelphia, Pennsylvania; Kevin Haverty, Williams Cuker

Berezofsky LLC, Cherry Hill, New Jersey; for Plaintiffs-

Appellants.

Alan J. Lazarus (argued) and William A. Hanssen, Drinker

Biddle & Reath LLP, San Francisco, California, for

Defendant-Appellee GlaxoSmithKline, LLC.

Jeffrey F. Peck (argued) and Prentiss W. Hallenback, Jr.,

Ulmer & Berne LLP, Cincinnati, Ohio, for Defendant-

Appellee Teva Pharmaceuticals USA, Inc.

OPINION

GOULD, Circuit Judge:

Maxx Wendell1 tragically died at the age of 21 of

Hepatosplenic T-cell lymphoma (HSTCL), an exceedingly

rare and aggressive form of cancer. For many years before

his development of HSTCL, Maxx was treated with a

combination of drugs for inflammatory bowel disease. After

his death, his parents, Stephen and Lisa Wendell (Plaintiffs),

sued the manufacturers and distributors of these drugs,

asserting claims under California law for negligence and

strict liability. Plaintiffs alleged that the drugs caused Maxx

to develop HSTCL and that the manufacturers and

1

We refer to Maxx Wendell by his first name to avoid confusion.

WENDELL V. GLAXOSMITHKLINE 5

distributors did not give adequate warnings about the risks

associated with the drugs.

The district court granted summary judgment to Teva

Pharmaceuticals USA, Inc. (Teva), concluding that the

Plaintiffs did not present admissible expert testimony of

causation and did not show that Maxx’s prescribing physician

relied on the warning labels. For the same reasons, the

district court dismissed as moot Plaintiffs’ motion for leave

to file a motion for reconsideration of the district court’s prior

order granting summary judgment to GlaxoSmithKline LLC

(GSK). We reverse and remand.

I

In 1998, at the age of twelve, Maxx was diagnosed with

a form of inflammatory bowel disease (IBD) called ulcerative

colitis. IBD is an autoimmune disease characterized by

chronic inflammation. Maxx began treatment with Dr.

Edward Rich, a pediatric gastroenterologist at Kaiser

Permanente in San Francisco. Relevant here, in June 1999,

Dr. Rich prescribed mercaptopurine (6-MP), an

immunosuppressant, and one of a class of drugs known as

thiopurines. At the time, 6-MP was manufactured by GSK

and marketed as Purinethol. Although it has been widely

used off-label since 1980 to treat IBD,2 Purinethol has never

received approval for this use.

In July 2002, Dr. Rich prescribed an additional drug, the

tumor necrosis factor alfa antagonist (anti-TNF) drug

2

Off-label use of a drug is legal, and is “generally based on published

scientific reports purporting to show a beneficial effect of the drug in such

indications or patient populations.”

6 WENDELL V. GLAXOSMITHKLINE

infliximab, marketed as Remicade. Anti-TNF drugs are

approved to treat various autoimmune disorders, such as

Crohn’s disease and rheumatoid arthritis.

Maxx received his last dose of Remicade in March 2006,

after which his IBD went into remission. Two months later,

the Food and Drug Administration approved a new label for

the drug. The label included a warning reporting

postmarketing cases of HSTCL in young male patients with

Crohn’s disease treated with both Remicade and a thiopurine

such as 6-MP or azathioprine. Centocor, the maker of

Remicade, also issued a “Dear Health Care Provider” letter

alerting prescribers to the labeling change and giving more

details on the cases of HSTCL. When Maxx’s symptoms

returned, Dr. Rich prescribed another anti-TNF drug, Humira,

which Maxx took until June 2007. At the time Dr. Rich

prescribed Humira, its label did not warn of the risk of

HSTCL.

Maxx remained continuously on 6-MP from June 1999

until about March or April 2007. GSK stopped marketing

Purinethol on July 1, 2003, and transferred ownership rights

for the drug to Teva. Maxx continued on Teva’s Purinethol

until July 2004, when Dr. Rich switched him to a generic 6-

MP. According to Maxx’s mother, Maxx decided to stop

taking 6-MP in 2007 after reading in Men’s Health that

young men on a combination of Remicade and other

immunosupressive medication had developed HSTCL.

In July 2007, Maxx checked into the emergency room

with fevers, fatigue, and malaise. Several days later he was

diagnosed with HSTCL—a non-Hodgkin’s lymphoma that is

exceedingly rare and aggressive. It has “low responses to

chemotherapy, frequent relapses after contemporary

WENDELL V. GLAXOSMITHKLINE 7

treatments and the inability of the majority of the patients to

undergo bone marrow transplantation.” Most patients die

within the first year of diagnosis; only a very small fraction

achieve long-term survival. Maxx died from HSTCL on

December 6, 2007, at the age of 21.

In July 2009, Plaintiffs, Maxx’s parents, sued multiple

drug companies in Superior Court in California. The case

was removed to federal court in September 2009. Plaintiffs

filed the operative fourth amended complaint in April 2011.

Several defendants, including GSK and Teva, then moved for

summary judgment. The district court granted the motion,

but subsequently withdrew its summary judgment order in

light of Plaintiffs’ need for further discovery. In July 2012,

after reviewing new evidence, the district court denied the

motion for summary judgment as to Teva and two other drug

companies, Par Pharmaceutical, Inc. and Abbott Laboratories.

The court granted summary judgment to GSK because it

determined that Plaintiffs had not presented sufficient

evidence that a reasonable jury could find GSK had a duty to

warn of the risk of HSTCL before July 1, 2003, when GSK

stopped distributing Purinethol. A year later, the district

court granted summary judgment to Par Pharmaceuticals.

In January 2014, the remaining defendants—including

Teva—filed another motion for summary judgment.

Plaintiffs settled their claims against the remaining

defendants, except for Teva, before the district court ruled on

the motion for summary judgment.

On June 30, 2014, the district court granted Teva’s

motion for summary judgment because the testimony of

Plaintiffs’ causation experts, Dr. Andrei Shustov and Dr.

Dennis Weisenburger, was not reliable and therefore not

8 WENDELL V. GLAXOSMITHKLINE

admissible under Federal Rule of Evidence 702, and because

Plaintiffs did not present evidence that Maxx’s prescribing

physician relied on Teva’s warning labels. It also denied

Plaintiffs’ motion for leave to file a motion for

reconsideration of the Court’s July 2012 order granting

summary judgment to GSK. Plaintiffs filed a timely notice

of appeal, challenging the district court’s grant of summary

judgment to Teva and its denial of their motion for leave to

file a motion for reconsideration.

II

We review the district court’s ruling on the admissibility

of expert testimony for an abuse of discretion. Messick v.

Novartis Pharm. Corp., 747 F.3d 1193, 1196 (9th Cir. 2014).

However, we “review de novo the ‘construction or

interpretation of . . . the Federal Rules of Evidence, including

whether particular evidence falls within the scope of a given

rule.’” Id. (alteration in original) (quoting United States v.

Durham, 464 F.3d 976, 981 (9th Cir. 2006)). We also review

de novo the district court’s grant of summary judgment. Id.

at 1199.

III

The issues presented in this appeal arise under the Federal

Rules of Evidence and California substantive law. See Motus

v. Pfizer Inc. (Roerig Div.), 358 F.3d 659, 660 (9th Cir. 2004)

(explaining that in diversity actions the court applies state

substantive law and the federal rules of procedure). We begin

with the rules of evidence.

WENDELL V. GLAXOSMITHKLINE 9

A

Federal Rule of Evidence 702 governs expert testimony.

It provides:

A witness who is qualified as an expert by

knowledge, skill, experience, training, or

education may testify in the form of an

opinion or otherwise if:

(a) the expert’s scientific, technical, or

other specialized knowledge will help the

trier of fact to understand the evidence or

to determine a fact in issue;

(b) the testimony is based on sufficient

facts or data;

(c) the testimony is the product of reliable

principles and methods; and

(d) the expert has reliably applied the

principles and methods to the facts of the

case.

Fed. R. Evid. 702.

Pursuant to the Federal Rules of Evidence, the district

court judge must ensure that all admitted expert testimony is

both relevant and reliable. See Daubert v. Merrell Dow

Pharm., Inc., 509 U.S. 579, 589 (1993). Defendants do not

contest that the opinions of Dr. Weisenburger and Dr.

Shustov are relevant; the only question, therefore, is whether

they are reliable.

10 WENDELL V. GLAXOSMITHKLINE

Scientific evidence is reliable “if the principles and

methodology used by an expert are grounded in the methods

of science.” Clausen v. M/V New Carissa, 339 F.3d 1049,

1056 (9th Cir. 2003). The focus of the district court’s

analysis “must be solely on principles and methodology, not

on the conclusions that they generate.” Daubert, 509 U.S. at

595. As we explained in Daubert v. Merrell Dow

Pharmaceuticals, Inc., the court’s “task . . . is to analyze not

what the experts say, but what basis they have for saying it.”

43 F.3d 1311, 1316 (9th Cir. 1995) (hereinafter Daubert II).

To assist courts with this task, the Supreme Court has

listed several non-exclusive factors that judges can consider

when determining whether to admit expert testimony under

Rule 702. See Daubert, 509 U.S. at 593–95. These include:

“whether the theory or technique employed by the expert is

generally 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 known or potential

rate of error is acceptable.” Daubert II, 43 F.3d at 1316. We

also consider whether experts are testifying “about matters

growing naturally” out of their own independent research, or

if “they have developed their opinions expressly for purposes

of testifying.” Id. at 1317. These factors are illustrative, and

they are not all applicable in each case. Id. The inquiry is

“flexible,” Daubert, 509 U.S. at 594, and “Rule 702 should be

applied with a ‘liberal thrust’ favoring admission,” Messick,

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

The district court concluded that the expert testimony of

Dr. Shustov and Dr. Weisenburger did not meet the Daubert

standard of reliability. The district court first focused on the

fact that the experts developed their opinions specifically for

litigation, and had never conducted independent research on

WENDELL V. GLAXOSMITHKLINE 11

the relationship between 6-MP and anti-TNF drugs and the

development of HSTCL. The court also noted that both

doctors conceded that although their opinions were based on

a reasonable degree of medical certainty, they “would not

satisfy the standards required for publication in peer-reviewed

medical journals.” It concluded that the lack of independent

research combined with the doctors’ reluctance to publish,

“casts doubt [on] the reliability of their methodologies under

Rule 702.”

Second, the district court determined that the lack of

animal or epidemiological studies showing a causal link

between HSTCL and the combination of 6MP and anti-TNF

drugs also undermined the experts’ methodology. The court

concluded that although it might be difficult to conduct such

studies, given the rarity of HSTCL, that type of causal

evidence was “especially important here in light of the fact

that more than seventy percent of observed HSTCL cases are

idiopathic.”3 “[W]ithout some reliable evidence of a positive

link between the drugs at issue and the disease,” the district

court concluded that the experts “cannot reasonably eliminate

other potential causes of Maxx’s HSTCL.”

Finally, the district court found that the studies Drs.

Weisenburger and Shustov cited did not “purport[] to show

that the specific combination of drugs prescribed to Maxx

actually causes HSTCL.” Although these studies contained

statistics about the incidence of HSTCL in different patient

populations, the court found that the experts did not show

“that all of the observed differences in these incidence rates

are statistically significant or that they account for plausible

3

A disease that is idiopathic, or de novo, is one that does not have a

known cause.

12 WENDELL V. GLAXOSMITHKLINE

alternative causes of HSTCL, such as IBD itself.” Further,

the doctors did not present scientific evidence to support their

opinion that IBD is not a risk factor for HSTCL.

Although we think it a close question, we conclude that

the district court erred by excluding the experts’ testimony.

The district court looked too narrowly at each individual

consideration, without taking into account the broader picture

of the experts’ overall methodology. It improperly ignored

the experts’ experience, reliance on a variety of literature and

studies, and review of Maxx’s medical records and history, as

well as the fundamental importance of differential diagnosis

by experienced doctors treating troubled patients. The district

court also overemphasized the facts that (1) the experts did

not develop their opinions based on independent research and

(2) the experts did not cite epidemiological studies. We hold

that all together, these mistakes warrant reversal. Cf.

Kennedy v. Collagen Corp., 161 F.3d 1226, 1228–30 (9th Cir.

1998) (concluding that the expert’s reliance on studies that

showed a connection between collagen and autoimmune

disorders combined with the expert’s observations of the

patient and review of her medical history was a sufficiently

reliable methodology even though the cause-effect

relationship between the collagen and the disease was not

conclusively established).

To begin, the experts were highly qualified doctors. Dr.

Shustov is a licensed, board-certified physician and an

Associate Professor of Medicine at the University of

Washington Medical Center. He specializes in the diagnosis

and treatment of lymphomas, with a clinical research focus on

T-cell leukemia and lymphomas. He has treated “hundreds

of patients with T-cell lymphomas,” and “thousands of

patients with lymphomas,” including seven patients with

WENDELL V. GLAXOSMITHKLINE 13

HSTCL. Two of those patients were treated with the

combination of drugs at issue here. Given the rarity of

HSTCL, Dr. Shustov estimated that he has seen more cases

of the disease than 99% of oncologists in the country. Dr.

Weisenburger is an expert hematopathologist—a physician

trained in the study and diagnosis of diseases of the bone

marrow and the immune system—with more than 30 years of

experience diagnosing non-Hodgkin lymphoma. He is the

professor and Chair of the Department of Pathology at City

of Hope Medical Center. Although he has not written

specifically on HSTCL, he has written hundreds of papers on

the subject of non-Hodgkin’s lymphoma, including some on

the potential causes of non-Hodgkin’s lymphoma.

The doctors employed sound methodologies to reach their

conclusions. Dr. Shustov based his opinions “on medical

records as well as [his] education, training and experience,

knowledge of the pertinent medical literature and [his]

knowledge of the epidemiology, diagnosis and natural history

of HSTCL.” He explained: “I reviewed the literature, I

pulled the facts out of the literature.” He found that the

literature shows there is an increased risk of HSTCL in

patients taking 6-MP over the general population. After

reviewing the literature, he “compiled the numbers about

frequency of diseases, about frequency of inflammatory

bowel disease and [he] looked at the biological causation of

lymphoma pertaining to this case.”

Dr. Shustov stated that he performs differential diagnosis

in attempting to diagnose every patient, and that he has

applied the same technique to determine the cause of a

disease. When performing a differential diagnosis, he first

assumes the pertinence of all potential causes, then rules out

the ones as to which there is no plausible evidence of

14 WENDELL V. GLAXOSMITHKLINE

causation, and then determines the most likely cause among

those that cannot be excluded. We have recognized that this

method of conducting a differential diagnosis is scientifically

sound. See Clausen, 339 F.3d at 1057–58. For cases of

HSTCL in patients that have taken 6-MP, like Maxx, Dr.

Shustov recognized:

that 6-MP is a well-known mutagen and

carcinogen and puts every person who takes it

at risk. And given the frequency of

hepatosplenic lymphoma in [the] general

population as . . . [compared to] those who

take 6-MP, it makes it plausible or

biologically plausible that that’s [an] etiologic

factor. You construct your differential

diagnosis . . . [of] what might have caused

lymphoma. You come up with the strongest

probability that patient was taking carcinogen

and developed lymphoma and you start

thinking again what can cause his lymphoma,

you can’t identify anything else in the

patient’s history or his medical records.

Regarding Maxx specifically, Dr. Shustov stated that

there was a one in six million chance that Maxx would have

developed HSTCL without being exposed to 6-MP. In light

of those odds, Dr. Shustov stated that “based on [his]

experience in T-cell lymphomas, knowledge of the literature

and being involved in T-cell lymphoma research in the past

ten years” he determined “that it’s much more likely that

exposure to mutagen and immunosuppressants caused the

lymphoma.” Dr. Shustov did not need to eliminate all

potential causes; “[i]t is enough that a [proposed cause] be a

substantial causative factor.” Messick, 747 F.3d at 1199.

WENDELL V. GLAXOSMITHKLINE 15

Dr. Weisenburger described his methodology for reaching

his opinions as follows:

I reviewed the medical records. I reviewed

the pathology slides and confirmed the

diagnosis. I reviewed all of the pathology

records. I reviewed the literature on the

disease, hepatosplenic lymphoma. And I

reviewed all the literature I could find on

causes of hepatopathic T-cell lymphoma,

including literature on inflammatory bowel

disease and treatments for inflammatory

bowel disease. And then I used the Bradford

Hill methodology to come to the conclusion

that I did.[4, 5]

Regarding Maxx specifically, Dr. Weisenburger based his

opinion on “a summary of the medical records of [Maxx] as

well as copies of the pathology reports, and the original slides

of the diagnostic bone marrow,” which he evaluated with

over 30 years of experience diagnosing non-Hodgkin

lymphoma. He stated that he considered that Maxx’s HSTCL

might have been idiopathic, and that although he was not

entirely able to rule that possibility out, “[w]hen you have a

patient with obvious and known risk factors, you tend to

assume that those risk factors were the cause.” He did not

base that assumption on pure conjecture. As he discussed

throughout his deposition testimony and in his expert report,

4

The Bradford Hill methodology refers to a set of criteria that are

well accepted in the medical field for making causal judgments.

5

Dr. Weisenburger also identified at least one paper that showed

there was no risk of lymphoma in IBD patients.

16 WENDELL V. GLAXOSMITHKLINE

the literature shows that patients exposed to 6-MP and anti-

TNF drugs are at an increased risk for HSTCL. Dr.

Weisenburger also weighed other risk factors, including

Maxx’s sex and age, and determined that those were “weak

risk factors; whereas, the disease he had, particularly in the

setting of the drugs he received would be considered very

strong risk factors.”

The proposed testimony was sufficiently reliable that the

Plaintiffs’ experts should have been allowed to testify under

Daubert. The district court improperly required more. The

Supreme Court in Daubert aimed at screening out unreliable

or bogus expert testimony. Nothing in Daubert, or its

progeny, properly understood, suggests that the most

experienced and credentialed doctors in a given field should

be barred from testifying based on a differential diagnosis.

First, the district court was wrong to put so much weight

on the fact that the experts’ opinions were not developed

independently of litigation and had not been published.

While independent research into the topic at issue is helpful

to establish reliability, its absence does not mean the experts’

methods were unreliable. Where “the proffered expert

testimony is not based on independent research,” the experts

can instead present “other objective, verifiable evidence that

the testimony is based on ‘scientifically valid principles.’”

Daubert II, 43 F.3d at 1317–18. To be sure, “[o]ne means of

showing [that the testimony is based on scientifically valid

principles] is by proof that the research and analysis

supporting the proffered conclusions have been subjected to

normal scientific scrutiny through peer review and

publication.” Id. at 1318. However, expert testimony may

still be reliable and admissible without peer review and

publication. See Clausen, 339 F.3d at 1056. That is

WENDELL V. GLAXOSMITHKLINE 17

especially true when dealing with rare diseases that do not

impel published studies. See Milward v. Acuity Specialty

Prods. Grp., Inc., 639 F.3d 11, 24 (1st Cir. 2011)

(recognizing that the “rarity” of a particular form of leukemia

was one reason that it would be “very difficult to perform an

epidemiological study of the causes of [the disease] that

would yield statistically significant results.”).

The district court also wrongly conflated the standards for

publication in a peer-reviewed journal with the standards for

admitting expert testimony in a courtroom. Dr. Weisenburger

stated on cross-examination that to publish his opinion he

would use a “more rigorous” standard than the one he used to

come up with his expert opinion. Dr. Shustov stated that he

would not be comfortable publishing his opinion because he

did not have any new data, and any meta-analysis or review

of the literature could only be published upon invitation. The

district court viewed these statements regarding the experts’

willingness to publish as evidence that their methods were not

up to snuff. But this analysis misses that while an expert

must “employ[] in the courtroom the same level of

intellectual rigor that characterizes the practice of an expert

in the relevant field,” Kumho Tire Co., Ltd. v. Carmichael,

526 U.S. 137, 152 (1999), the standards for courtroom

testimony do not necessarily parallel those of the professional

publications, see Ambrosini v. Labarraque, 101 F.3d 129, 138

(D.C. Cir. 1996) (“[T]he fact ‘that science would require

more evidence before conclusively considering the causation

question resolved is irrelevant [to the admissibility of expert

testimony].’”) (quoting Ferebee v. Chevron Chem. Co.,

736 F.2d 1529, 1536 (D.C. Cir. 1984)). For example, Dr.

Shustov explained that, “[o]pinions are not publishable. Data

is publishable. What I’m reporting here is my opinion.”

Although unwillingness to publish weighs against

18 WENDELL V. GLAXOSMITHKLINE

admissibility, it alone is not determinative. See Daubert II,

43 F.3d at 1318 n.9 (“That plaintiffs’ experts have been

unable or unwilling to publish their work undermines

plaintiffs’ claim that the findings these experts proffer are

‘ground[ed] in the methods and procedures of science’ and

‘derived by the scientific method.’” (alteration in original)

(quoting Daubert, 509 U.S. at 590)). We have previously

held expert opinions to be reliable that were not subject to

peer review through publication. See Clausen, 339 F.3d at

1056, 1061.

The district court also wrongfully required that the

experts’ opinions rely on animal or epidemiological studies.

Neither are necessary for an expert’s testimony to be found

reliable and admissible. See Kennedy, 161 F.3d at 1229. We

have long recognized that it may not always be possible to

conduct certain types of studies. See, e.g., Daubert II,

43 F.3d at 1318 n.9 (“There may well be good reasons why

a scientific study has not been published. For example, it

may be too recent or of insufficiently broad interest.”).

HSTCL is an exceedingly rare cancer, with only 100 to 200

cases reported since it was first recognized. It is not

surprising that the scientific community has not invested

substantial time or resources into investigating the causes of

such a rare disease.

Although they did not rely on animal or epidemiological

studies, the experts here did rely on other published 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.

Although case studies alone generally do not prove causation,

they “may support other proof of causation.” Rider v. Sandoz

Pharm. Corp., 295 F.3d 1194, 1199 (11th Cir. 2002). Here,

WENDELL V. GLAXOSMITHKLINE 19

the experts relied not just on these studies—which not only

examined reported cases but also used statistical analysis to

come up with risk rates—but also on their own wealth of

experience and additional literature.6

We also note that “[n]ot knowing the mechanism whereby

a particular agent causes a particular effect is not always fatal

to a plaintiff’s claim. Causation can be proved even when we

don’t know precisely how the damage occurred, if there is

sufficiently compelling proof that the agent must have caused

the damage somehow.” Daubert II, 43 F.3d at 1314

(emphasis in original). That there is no study that definitively

states HSTCL is caused by the ingestion of 6-MP and anti-

TNF drugs does not prevent the admission of Plaintiffs’

experts’ testimony. See Kennedy, 161 F.3d at 1230.

Finally, the district court erred when it excluded

Plaintiffs’ experts’ opinion testimony because of the high rate

of idiopathic HSTCL and the alleged inability of the experts

to rule out an idiopathic origin or IBD itself. We do not

require experts to eliminate all other possible causes of a

condition for the expert’s testimony to be reliable. Messick,

747 F.3d at 1199. It is enough that the proposed cause “be a

substantial causative factor.” Id. This is true in patients with

multiple risk factors, and analogously, in cases where there is

a high rate of idiopathy. See id. (holding that the district

court abused its discretion when it excluded expert testimony

as unreliable because the expert could not determine which of

6

Teva argues that its own experts highlight the dearth of scientific

evidence to support Plaintiffs’ claims and undermine any assertion that

Drs. Shustov and Weisenburger employed sound scientific methodology.

The district court did not consider this evidence, and we decline to do so

in the first instance.

20 WENDELL V. GLAXOSMITHKLINE

multiple risk factors caused plaintiff’s disease). Moreover,

when an expert establishes causation based on a differential

diagnosis, the expert may rely on his or her extensive clinical

experience as a basis for ruling out a potential cause of the

disease. See id. at 1198. The district court abused its

discretion by excluding Dr. Shustov’s and Dr.

Weisenburger’s testimony because they could not completely

rule out the possibility that Maxx’s HSTCL was idiopathic.

Perhaps in some cases there will be a plethora of peer

reviewed evidence that specifically shows causation.

However, such literature is not required in each and every

case. “The first several victims of a new toxic tort should not

be barred from having their day in court simply because the

medical literature, which will eventually show the connection

between the victims’ condition and the toxic substance, has

not yet been completed.” Clausen, 339 F.3d at 1060 (quoting

Turner v. Iowa Fire Equip. Co., 229 F.3d 1202, 1209 (8th

Cir. 2000)). In the case of a rare disease like HSTCL, the

Supreme Court’s mandate that in determining the

admissibility of expert testimony, the focus “must be solely

on principles and methodology, not on the conclusions that

they generate,” is especially important. Daubert, 509 U.S. at

595.

Where, as here, the experts’ opinions are not the “junk

science” Rule 702 was meant to exclude, see Estate of

Barabin v. AstenJohnson, Inc., 740 F.3d 457, 463 (9th Cir.

2014), the interests of justice favor leaving difficult issues

in the hands of the jury and relying on the safeguards of

the adversary system—“[v]igorous cross-examination,

presentation of contrary evidence, and careful instruction on

the burden of proof”—to “attack[] shaky but admissible

evidence,” Daubert, 509 U.S. at 596. Because we conclude

WENDELL V. GLAXOSMITHKLINE 21

that the district court erred in excluding the testimony of Dr.

Shustov and Dr. Weisenburger, we reverse the district court’s

grant of summary judgment. See Messick, 747 F.3d at 1199.

As explained in Messick, “[m]edicine partakes of art as well

as science.” Id. at 1198. Where, as here, two doctors who

stand at or near the top of their field and have extensive

clinical experience with the rare disease or class of disease at

issue, are prepared to give expert opinions supporting

causation, we conclude that Daubert poses no bar based on

their principles and methodology. That defendants may be

able to offer other equally qualified medical opinion opposing

causation also does not support the idea that Daubert should

bar the admission of the testimony of the doctors offered as

experts by Plaintiffs. Instead, the testimony of Dr.

Weisenburger and of Dr. Shustov should have been admitted

as expert testimony under Federal Rules of Evidence 702.

The defendants’ expert testimony could have been offered in

opposition. Then, the jury, as the trier of fact, would be

empowered to decide, based on the law given in proper jury

instructions and the facts as determined by the jury.

B

The district court granted summary judgment to Teva on

the duty to warn claim for two reasons. First, the district

court held that the lack of admissible causation evidence

precluded Plaintiffs from prevailing on their duty to warn

claims. Second, Plaintiffs did not produce “any evidence to

suggest that Dr. Rich actually relied on Teva’s warning labels

before prescribing Purinethol to Maxx.” For the reasons

discussed above, we reverse on the district court’s first

ground. For the reasons discussed below, we reverse on the

district court’s second ground.

22 WENDELL V. GLAXOSMITHKLINE

Under California law, drug manufacturers have a duty to

warn physicians of risks that are known or scientifically

knowable at the time of the drug’s distribution. See Carlin v.

Superior Court, 920 P.2d 1347, 1349–54 (Cal. 1996). “A

plaintiff asserting causes of action based on a failure to warn

must prove not only that no warning was provided or the

warning was inadequate, but also that the inadequacy or

absence of the warning caused the plaintiff’s injury.” Motus

v. Pfizer Inc., 196 F. Supp. 2d 984, 991 (C.D. Cal. 2001),

aff’d, 358 F.3d 659. “[A] product defect claim based on

insufficient warnings cannot survive summary judgment if

stronger warnings would not have altered the conduct of the

prescribing physician.” Motus, 358 F.3d at 661.

In this case, viewing the evidence in the light most

favorable to Plaintiffs, there is a genuine dispute of material

fact as to whether Dr. Rich’s conduct would have changed

with warnings from Teva and GSK. Summary judgment was

improper.

Although Dr. Rich testified that it is not his “regular

practice to look at drug labeling,” when he does read them it

is “one of the things that is part of [his] decision-making

process.” He also testified that “a black box warning means

there is a significant side effect that I need to be aware of.”7

Indeed, this type of warning did influence Dr. Rich’s

prescribing decisions for Maxx. Centocor began circulating

warnings—both a black box warning and a Dear Health Care

7

A black box warning is a warning that is placed in a box in a drug’s

labeling information. According to Plaintiffs’ pharmacovigilance expert,

a black box warning may only be used with FDA authorization, and it is

“the strongest possible warning that can be given short of restricting

distribution of a drug or completely withdrawing it from the market.”

WENDELL V. GLAXOSMITHKLINE 23

Provider letter—about HSTCL for Remicade in May 2006,

just a few months after Maxx stopped taking Remicade.

When Maxx’s IBD relapsed in November 2006, Dr. Rich

prescribed Humira—which did not have a warning about

HSTCL—in place of Remicade. Dr. Rich testified that he

prescribed Humira because he believed it had a better safety

profile, noting that at that point there were no reports of

HSTCL developing in patients who took Humira. This

change in prescribing practices which can, at least in part,

reasonably be attributed to the lack of a warning for Humira

creates a question of material fact as to whether the presence

of a warning on Teva’s Purinethol would have changed Dr.

Rich’s prescribing practices as to Maxx.

There is also evidence that Dr. Rich changed his

prescribing practices generally after he learned of incidents of

HSTCL in patients taking both 6-MP and anti-TNF agents.

As the information came out, his prescribing practices

evolved. He now no longer prescribes combination therapy

but uses only monotherapy. Viewing the facts in the light

most favorable to the Plaintiffs, there are questions of

material fact as to whether warnings would have changed Dr.

Rich’s prescribing practice. See Stanley v. Novartis Pharm.

Corp., 11 F. Supp. 3d 987, 1003 (C.D. Cal. 2014)

(“[C]hanges to treatment and prescription procedures

create[d] a triable question of fact on specific causation.”).

We reverse the district court’s grant of summary judgment in

favor of Teva.8

8

GSK asserts that Plaintiffs’ warning expert’s testimony shows that

Purinethol’s label should have been changed in 2006, approximately three

years after GSK stopped distributing the drug. It argues that there can be

no causal connection between the alleged failure to warn and the harm.

The district court did not address this argument, and we decline to do so.

24 WENDELL V. GLAXOSMITHKLINE

C

Teva urges us to affirm the district court on four

alternative grounds.9 Although we may affirm on any ground

raised below and supported by the record, see Proctor v.

Vishay Intertechnology Inc., 584 F.3d 1208, 1226 (9th Cir.

2009), the issues that Teva raises would require extensive fact

finding, and are matters on which the district court did not

rule. It would be inappropriate for us to reach these issues,

and we decline to do so. See Greater L.A. Council on

Deafness, Inc. v. Zolin, 812 F.2d 1103, 1107 & n.5 (9th Cir.

1987), superceded by statute on other grounds. They may be

raised with the district court on remand.

D

Finally, Plaintiffs challenge the district court’s order

denying Plaintiffs’ motion for leave to file a motion for

reconsideration of the district court’s July 2012 order

granting summary judgment to GSK. GSK asserts that, as

Plaintiffs’ opening brief does not challenge the district court’s

underlying grant of summary judgment to GSK, Plaintiffs

See Greater L.A. Council on Deafness, Inc. v. Zolin, 812 F.2d 1103, 1107

& n.5 (9th Cir. 1987), superceded by statute on other grounds.

9

Briefly, Teva argues that we should affirm on each of the following

four bases: (1) it had no duty to warn about the alleged risk of HSTCL

arising from an off-label use of Purinethol; (2) it had no duty to warn

about alleged risks from use of a competitor’s product; (3) Plaintiffs

cannot maintain a failure to warn claim because Dr. Rich had already

received the information; and (4) because Plaintiffs cannot prove that

Maxx developed HSTCL after May 2006, they cannot prove that an

alleged failure to warn by Teva was the proximate cause of Maxx’s

injuries.

WENDELL V. GLAXOSMITHKLINE 25

abandoned their argument that the district court erroneously

granted summary judgment to GSK.

GSK’s argument is unpersuasive. As to GSK, Plaintiffs

are challenging only the district court’s denial of its motion

for leave to file a motion for reconsideration. A challenge to

a denial of a motion for leave to file a motion for

reconsideration brings up just the denial of that motion, not

the underlying merits. Cf. Molloy v. Wilson, 878 F.2d 313,

315 (9th Cir. 1989) (“An appeal from a denial of a Rule 60(b)

motion brings up only the denial of the motion for review, not

the merits of the underlying judgment.”). Plaintiffs did raise

this argument in their Opening Brief, asserting that because

the district court’s rulings regarding the admissibility of

expert testimony and causation were erroneous, “the ruling on

Plaintiffs’ motion likewise should be vacated so that it can be

decided on its merits on remand.”

We agree with Plaintiffs. The district court denied their

motion “as moot” because “Plaintiffs cannot prevail on their

claims against [GSK] for the same reasons they cannot

prevail on their claims against Teva”: lack of admissible

causation evidence, and lack of evidence showing Dr. Rich’s

reliance on warnings. Because we reverse the district court

on those issues, we also reverse the district court’s denial of

Plaintiffs’ motion for reconsideration.

REVERSED AND REMANDED.