Court Opinion

ID: 2827175
Source: CourtListenerOpinion
Date Created: 2015-08-13 19:04:16.140117+00
Date Added: 2024-06-11T11:31:24.153828
License: Public Domain

Filed 7/16/15; pub. order 8/13/15 (see end of opn.)

              IN THE COURT OF APPEAL OF THE STATE OF CALIFORNIA

                                  SECOND APPELLATE DISTRICT

                                             DIVISION THREE

NANCY COOPER, Individually and as                        B250163
Successor, etc.,
                                                         (Los Angeles County
         Plaintiffs and Appellants,                      Super. Ct. No. CGC-12-518535)

         v.

TAKEDA PHARMACEUTICALS
AMERICA, INC., et al.,

         Defendants and Respondents.

         APPEAL from a judgment of the Superior Court of Los Angeles County,
Kenneth R. Freeman, Judge. Reversed and remanded with directions.
         Esner Chang & Boyer, Stuart B. Esner; The Miller Firm, Michael J. Miller and
Jeffrey A. Travers for Plaintiffs and Appellants.
         Sidley Austin and Catherine Valerio Barrad for Defendants and Respondents.
                                      _________________________
                                     INTRODUCTION

       The defendants are Takeda Pharmaceuticals America, Inc., Takeda
Pharmaceuticals U.S.A., Inc. (formerly Takeda Pharmaceuticals North America, Inc.),
and Takeda Pharmaceutical Company Limited, referred to collectively as “Takeda.”1 In
coordinated litigation, numerous plaintiffs have sued Takeda, manufacturers of the
prescription drug Actos® (the trade name for pioglitazone HCl tablets), which is used to
treat type 2 diabetes mellitus. Jack Cooper and Nancy Cooper are plaintiffs in one of the
coordinated cases and alleged that Jack Cooper developed bladder cancer from ingesting
the drug.2
       The matter was tried to a jury in early 2013. The jury found Takeda liable on
causes of action for strict liability failure to warn, negligent failure to warn, and loss of
consortium. Specifically, the jury found that Takeda failed to adequately warn Jack
Cooper’s treating physician of the risk of bladder cancer, and that this failure to warn was
a substantial factor in causing his harm. The jury awarded damages to Jack Cooper of $5
million, and to Nancy Cooper in the amount of $1.5 million for loss of consortium.
       Before, during, and after trial, Takeda challenged the admissibility of causation
testimony by the Coopers’ expert urologic oncologist. At trial, the trial court permitted
the expert to testify that, based on his performance of a differential diagnosis, he believed
Actos® was a substantial factor in causing Jack Cooper’s bladder cancer. However, the
court later ordered the expert’s testimony stricken, concluding that the testimony was
speculative and lacking in foundation, and granted Takeda’s motion for judgment

1      Plaintiffs did not challenge on appeal the judgment in favor of defendant Takeda
California, Inc. (formerly Takeda San Diego, Inc.).
2     The trial court granted a preference trial in October 2012, due to the poor state of
Jack Cooper’s health. This court also granted plaintiffs’ motion for calendar preference.
Regrettably, Jack Cooper died in July 2014, and we have granted the motion to substitute
Nancy Cooper, as successor-in-interest, in place of appellant and decedent Jack Cooper.

                                               2
notwithstanding the verdict. The trial court also granted Takeda’s alternative motion for
new trial on the grounds that without the testimony of plaintiffs’ expert, Dr. Smith, the
evidence was insufficient to support the verdict, and that the trial court should not have
instructed the jury regarding concurrent causation.
       In this appeal by the Coopers, we conclude that the trial court erred in striking the
expert’s testimony. By requiring that the expert rule out all other possible causes for Jack
Cooper’s bladder cancer, even where there was no substantial evidence that other such
causes might be relevant, the court exceeded the proper boundaries of its gatekeeping
function in determining the admissibility of the complex scientific testimony. We also
conclude that the evidence supported giving a jury instruction on multiple causation.
Accordingly, we reverse the judgment notwithstanding the verdict and the order granting
a new trial, as well as the subsequent judgment entered in favor of Takeda, and remand
the matter to the trial court with directions to enter a new judgment based on the jury’s
verdict.

                  PROCEDURAL AND FACTUAL BACKGROUND

       Takeda, a pharmaceutical company headquartered in Japan, manufactures
pioglitazone, a prescription drug used to treat type 2 diabetes, marketed in the United
States since 1999 under the brand name Actos®. In 2006, plaintiff Jack Cooper was
prescribed Actos® to treat his type 2 diabetes. He took Actos® continuously until he
was diagnosed with bladder cancer in November 2011.
       Jack and Nancy Cooper filed the present lawsuit against Takeda, alleging that
Actos® caused Jack Cooper’s bladder cancer, and that Takeda failed to adequately warn
of this risk. Cooper and his wife (hereafter referred to collectively and in the singular as
Cooper) asserted claims for negligent failure to warn and strict liability failure to warn,
negligent misrepresentation, fraudulent concealment, and loss of consortium, and also
sought punitive damages.

                                              3
       Because the issues on appeal revolve around the causation testimony by Cooper’s
expert witness, Dr. Norm Smith, we primarily focus our summary of the evidence on that
testimony, supplemented by the testimony of one other expert.
I.     Cooper’s Expert Evidence
       A. Dr. Alfred Neugut
       Dr. Alfred I. Neugut, an epidemiologist and oncologist, testified that to a
reasonable degree of medical certainty, “Actos . . . contribute[s] to or cause[s] the
development of bladder cancer.” His opinion was based primarily on his review of 15
epidemiological studies (the same studies relied on by Dr. Norm Smith, the expert whose
testimony is in issue in this appeal). Regarding those studies, Dr. Neugut stated that any
single study can be criticized in isolation. But when, as here, most studies consistently
reach a similar result, an epidemiologist can be confident that the consistent result is
correct. Regarding Actos®, most of the studies gave a positive result (meaning Actos®
contributed to bladder cancer), and most of the studies with negative results “leaned in
the positive direction.”
       Dr. Neugut explained that studies use a “hazard ratio,” which compares the
number of cases in which a disease actually occurs to the number of cases in which it was
expected to occur. Thus, if the disease occurred in 30 cases when it was expected to
occur in only 10, the hazard ratio would be three (30 actual cases divided by 10 expected
cases). As relevant to studying whether a particular drug causes a particular disease, a
hazard ratio of three suggests that in the population studied a person who ingested the
drug would be three times as likely to develop the disease than people who did not ingest
the drug.
       Among the studies involving Actos®, the “Mamtani Study,” published in 2012 in
one of the best peer-reviewed journals, produced a hazard ratio of 6.97 for people
exposed to the drug for five years or more. According to Dr. Neugut, a risk ratio of seven
(the ratio of the Mamtani Study rounded off) is “uncommonly high.”

                                              4
       B. Dr. Norm Smith
          1. Qualifications
       Dr. Smith is a urologic oncologist (a surgeon who specializes in cancers of the
urinary tract), and is the codirector of the urologic oncology section at the University of
Chicago. He is certified by the American Board of Urology, and was selected to
participate in the American Urology Association Leadership Program, designed to train
surgeons to be leaders in that organization. Dr. Smith treats patients, 80 percent of his
practice being devoted to treating patients with bladder cancer, and he also teaches
medical students. He is cochair of a working group within the Bladder Cancer Advocacy
Network that awards research grants in the field of bladder cancer. He has served as a
reviewer to determine the merit of other scientists’ research studies and their suitability
for publication for such publications as the Journal of the American Medical Association,
Cancer, the Journal of Urology, the European Urology Journal, Urologic Oncology
Seminars and Investigations, the British Journal of Urology International, and the
American Journal of Pathology. He serves as an editor for the online journal, Advances
in Urology. He was the lead author of an article published in the peer-reviewed journal,
Urologic Oncology Seminars and Investigations, called “Bladder Cancer Risk from
Occupational and Environmental Exposures,” (Urol Oncol. 2012 Mar-Apr; 30(2): 199-
211)3 and has published over 56 articles in the peer-reviewed literature dealing with
causes and origins of bladder cancer. He also conducts his own clinical research trials.
          2. Dr. Smith’s General Causation Testimony
       As of mid-2011 when Dr. Smith finished cowriting the Kiriluk paper on bladder
cancer risk from occupational and environment exposures, there was limited data
available regarding the association between Actos® use and bladder cancer, and therefore
that subject only covered one paragraph in the Kiriluk paper. By the time of his second
deposition in this case, Dr. Smith had reviewed 15 epidemiological and clinical studies

3      The paper Dr. Smith co-authored was referred to at trial as the Kiriluk paper.

                                              5
showing an increased risk of bladder cancer among patients taking Actos® for diabetes.
Among the studies Dr. Smith had reviewed were confidential materials provided by
Takeda regarding the association between Actos® and bladder cancer. Dr. Smith stated
that since completing his paper in July 2011, a large volume of data had been revealed
that in his opinion constituted “very powerful data” regarding the risk of bladder cancer
associated with Actos®. Dr. Smith testified it was his opinion that, to a reasonable
degree of medical certainty, Actos® causes bladder cancer. His opinion was based on his
review of the 15 epidemiological studies which, particularly when taken as a whole,
indicate that Actos® use is associated with a significantly increased risk of bladder
cancer. Many of the studies he reviewed found that this biological effect was greatest
among long-term users and those with a larger cumulative dose. Asked if the studies on
which he relied took into account diabetes and older white male subjects, Dr. Smith
answered in the affirmative, saying that many of the studies that found a relationship
between Actos® and bladder cancer had “adjusted for sex, race, smoking, hemoglobin[]
A1C, et cetera, yes.”4
       For example, among the eight Takeda-funded studies, the Second Interim Kaiser
Cohort from 2007 found, after adjusting for age and sex, a statistically significant
association between the incidence of bladder cancer and increasing levels of exposure to
Actos® (among patients who started Actos® 18 to 36 months prior, those who had 12 to
24 months of use, and those with between 7,000 mg and 18,000 mg of cumulative dose)
as compared with patients that never used Actos®. Adjusting for smoking, diabetes
duration, and baseline glycosylated hemoglobin concentration (HbA1c, a measure of the
severity of diabetes) diminished the risk estimates although the patterns remained the
same. The Takeda meta-analysis, which combined the results of numerous previous
studies with both positive and negative findings, found a hazard ratio of 2.642, i.e., a

4     Dr. Smith testified that hemoglobin A1C is a measure of the severity of diabetes;
some of the studies he reviewed adjusted for that factor.

                                              6
statistically significant increased risk for bladder cancer among subjects treated with
Actos®. The Second Interim Nested Case Control study found use of Actos® was
associated with a 2.5 times increased risk of bladder cancer, which Dr. Smith described
as “very alarming.” That number increased slightly to 2.6 after adjusting for race,
smoking history, high risk occupations, urinary tract infections, and HbA1c
concentration.
       Among the seven independent, peer-reviewed studies Dr. Smith reviewed, the
Piccinni study found the hazard ratio for Actos® use to be 4.3. The Neumann study
(published in 2012), a study performed in France involving 1.4 million people, though
criticized for its methodology, also found that Actos® exposure was significantly
associated with an increased risk of bladder cancer. Dr. Smith opined that study was
significant, aside from its methodological shortcomings, because of the very large sample
size. The Colmers meta-analysis also showed a significant increased risk of bladder
cancer with Actos®, as did the Bosetti article, which is a meta-analysis involving 17
studies, both positive and negative.
       Takeda acknowledged to the FDA in an e-mail sent in May 2012 that the potential
development of bladder cancer is now an identified risk of Actos®.5

5      We granted Cooper’s request to take judicial notice of the fact that in April 2014,
the Office of Environmental Health Hazard Assessment added pioglitazone to the list of
chemicals known to the State of California to cause cancer for the purposes of the Safe
Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65).

                                             7
           3. Dr. Smith’s Specific Causation Testimony
              a. Differential Diagnosis in General 6
       Dr. Smith testified that the way bladder cancer presents in a patient’s body does
not indicate what caused it. He said that the relevant factors in creating a differential
diagnosis for bladder cancer fall into two broad categories: smoking history and exposure
history. Smith stated that smoking is the “most important risk factor in the development
of bladder cancer” and that time since the patient stopped smoking is critical in assessing
the risk because of the long latency period (“several decades”) between tobacco exposure
and emergence of cancer. He testified that other important factors are “exposure
history,” such as “past medical treatments like radiation exposures” and “environmental
exposures,” age, gender, race, diabetic condition, past medical history, surgeries,
medication history (including dose and duration of Actos®), allergies, and family history.
       Dr. Smith was later asked to explain to the jury “what differential diagnosis
means,” and responded in a manner that describes differential diagnosis as a means of
considering a patient’s physical symptoms and determining from those symptoms the
disease most likely to be the cause of those symptoms, rather than considering a patient’s
known disease and determining the most likely cause or causes of the disease. He said,
“Differential diagnosis is a concept that, when you see a patient for whatever problem it
might be, one of the common ones in urology is blood in the urine. You say to yourself
what are all the possible causes of blood in the urine, and it generates this long list. Then
you go through a process of eliminating them one by one to the best of your ability to say
well, this is my best guess as to what the problem is. And then you proceed with testing
and/or diagnostics to figure out exactly the cause to the best of your ability.” Cooper’s

6       “Differential diagnosis” is defined as “the determination of which of two or more
diseases with similar symptoms is the one from which the patient is suffering, by a
systematic comparison and contrasting of the clinical findings.”
(http://www.medilexicon.com/medicaldictionary.php?t=24388, citing Stedman’s Medical
Dictionary (2006).)

                                              8
counsel continued, “And in the real world practice of bladder cancer surgery in the last
year, have you put Actos on your differential diagnosis as a cause of bladder cancer?”
Dr. Smith replied, “Yes,” impliedly acknowledging that the differential diagnosis method
is also used to determine the likely cause of a disease.
        Dr. Smith stated that the differential diagnosis he performed regarding Cooper was
dissimilar from one he would conduct with a patient he was treating in that with his own
patient he would review all outside medical records and could also talk to the patient. He
said he often does not have a detailed discussion with every patient about cause because
the treatment is the same regardless of the cause. He discusses with the patient those
“modifiable factors” that the patient can change to improve their outcome, such as
cessation of smoking. Dr. Smith stated that he did not speak to or examine Cooper at any
time.
              b. Dr. Smith’s Differential Diagnosis Regarding the Cause of Cooper’s
              Bladder Cancer
        Dr. Smith said he based his specific causation opinion on his own paper regarding
potential exposure-related causes of bladder cancer; on a particular table from an
epidemiology study relating to Actos®; and a combination of all the published literature,
the Takeda studies, his experience taking care of bladder cancer patients, and his
experience in having written on exposures and risks for bladder cancer.
        Dr. Smith also reviewed about 1,000 pages of Cooper’s medical records. He noted
that Cooper had taken over 50,000 milligrams of Actos® over the course of slightly more
than five years. Dr. Smith had also reviewed Cooper’s deposition and had reviewed 15
epidemiological and clinical studies examining the relationship between bladder cancer
and ingestion of Actos®.
        Cooper was described in the medical records as being in generally good health,
with no history of kidney stones. There were incongruent references in the records to
diabetes, borderline diabetes, and type II diabetes. Cooper had “transitional cell” bladder
cancer, also referred to as “urothelial” cancer. It was a high grade cancer, meaning that it
was biologically aggressive and spread rapidly. Dr. Smith’s best estimate was that the

                                              9
cancer was present for about six months before Cooper was diagnosed in November
2011.
        The medical records indicated that Cooper had no family history of bladder
cancer, and that he was a retired construction supervisor and “has had no occupational
exposure.” Cooper did not use alcohol. He was described both as a former smoker and
as a “never smoker,” with benign essential hypertension, type 2 diabetes mellitus, and
chronic kidney disease, stage 3. He had a history of basal cell carcinoma of the face.
Cooper was White, and his date of birth was August 28, 1933.
        Regarding Cooper’s history of smoking, Dr. Smith testified that there were
discrepancies in the medical records. Some records stated he never smoked, and
elsewhere it was reported that he quit smoking in 1992 or 1994. A form completed by
Cooper in December 2011, after he was diagnosed with bladder cancer, indicated he had
a 40-year history, ending in 1994, of smoking one pack per week. Whenever the records
stated he smoked, however, it was described as less than one pack per week, or about
three to four cigarettes per day.7
        In performing the differential diagnosis, Dr. Smith considered as factors to rule in
Cooper’s race, his sex, his smoking history (including secondhand smoke), and his
occupation as a construction supervisor. Cooper had been a construction supervisor for
15 years, and had been retired for over 13 years thereafter. Dr. Smith reviewed the
records prepared by Dr. Xavier, Cooper’s medical oncologist, and the records from all of
his doctors. Dr. Xavier reported that there was no history of any occupational cause of
Cooper’s bladder cancer. Dr. Smith stated that there is “a very long list of occupations”
associated with the development of bladder cancer and cited some examples. Despite
there being “a long, long list,” however, he stated that “none of those, to my opinion and
review, fit Mr. Cooper.” He “evaluated all the potential occupations on this list and felt

7      Cooper testified at trial, as did his family members, that he stopped smoking
cigarettes and a pipe in 1974, because he promised his daughter he would do so if she
won a national skating competition, which she did that year.

                                             10
that it [occupational exposure] did not substantially apply to Mr. Cooper.” During the
section 402 hearing, Dr. Smith stated he was not aware of any literature that would
indicate a retired Pacific Phone supervisor would have a risk of developing bladder
cancer of even half of the risk posed by his Actos® exposure.
       Based on Cooper’s medical records, Dr. Smith ruled out radiation exposure,
chemotherapy, infections, immunosuppression, the pain medication phenacetin,
aristolochia fungi, arsenic exposure, HPV virus, chlorinated or fluoridated water, and
vitamin D deficiency. Dr. Smith noted that Cooper had two bouts of skin cancer, in 2002
and 2009, apparently due to prolonged sun exposure. From that fact he concluded that
there was no likelihood of a vitamin D deficiency, a known cause of bladder cancer. He
acknowledged that direct contact with gasoline or diesel, which contain polycyclic
aromatic hydrocarbons (PAH), can cause skin cancer, and are also known to be bladder
cancer carcinogens. He considered Cooper’s skin cancer to be sun related rather than
caused by direct contact with gasoline or diesel fuel. He stated that he did not rule in
occupational exposure to PAH and then investigate further in order to rule it out. There
was no mention made in the medical record that Cooper worked around diesel and
gasoline engines during the 40 years he worked at construction sites which could have
exposed him to polycyclic aromatic hydrocarbons.
       Asked if the fact Cooper had diabetes was a risk factor for bladder cancer,
Dr. Smith stated there were some papers indicating a slight risk associated with diabetes,
while other studies found no elevated risk. The former studies found a relative risk in
only the 1.2 range, i.e., a low range.8

8      Another of Cooper’s experts, Dr. Neugut, testified that he had not seen any
persuasive evidence that diabetes itself causes bladder cancer, and that in virtually every
study regarding Actos®, all study subjects were diabetic (or the study controlled for
diabetes) to avoid the concern that it was diabetes that was the underlying cause of the
bladder cancer.

                                             11
       Dr. Smith stated that there was no discussion in his Kiriluk paper about whether
diabetes is a risk factor for bladder cancer because “we considered it and didn’t put it in
because we didn’t think that it warranted it.” He and his colleagues determined that
although there was some conflicting data on diabetes as a cause of bladder cancer, there
was not enough data to comment on it in their paper.
       Dr. Smith acknowledged that Dr. Brunsting (Cooper’s primary care physician),
told Cooper in May 2004, two years before prescribing Actos® to Cooper, that he was
borderline diabetic. Dr. Smith stated that kidney disease is a known complication of
diabetes and could be an indication of worsening diabetes, but could also be caused by
hypertension. Eight months before being diagnosed with bladder cancer, Cooper’s doctor
stated in a medical record that Cooper had a history of chronic kidney disease, stage 3.
Dr. Smith’s opinion was that there was no relevant difference in determining whether
Cooper’s kidney disease was caused by worsening diabetes or hypertension. He agreed it
would be relevant if one accepted the proposition that the severity of diabetes may itself
be a cause of bladder cancer, but of course Dr. Smith’s opinion was to the contrary.
       Importantly, Dr. Smith stated that all of the epidemiological studies he reviewed
had adjusted for age, sex, and race. Asked more specifically if the studies on which he
relied took into account diabetes and older, white, male subjects, Dr. Smith answered in
the affirmative. He said that the studies that found a relationship between Actos® and
bladder cancer had “adjusted for sex, race, smoking, hemoglobin[] A1C, et cetera, yes.”
Dr. Smith also acknowledged the hypothesis that renal insufficiency and albuminuria
directly contribute to the incidence of bladder cancer, but he disagreed with that theory.
He also said there was no data to support the association between exposure to
electromagnetic power lines and bladder cancer.9

9      Defendants’ expert, Dr. Schoenberg, mentioned the hypotheses that
electromagnetic fields such as Cooper might have encountered in being a telephone
lineman, and diabetes, might be associated with development of bladder cancer. He
described the literature on these specific issues as being “hypothesis generating, but by no
means offering proof.” He opined he would apply the same description to the papers
                                             12
       Dr. Smith summarized that he concluded that occupational exposure “went into
the rule out category and [he] was really left with trying to evaluate smoking versus
Actos as the most substantial risk factors.”
       Several studies involving the causation of bladder cancer by Actos® that
Dr. Smith had reviewed accounted for the effect of smoking in their analysis. Dr. Smith
stated that, compared to the issue under study, i.e., Actos®, smoking proved to be not as
important a factor as Actos® in causing bladder cancer. The studies indicated that use of
Actos® for more than five years resulted in a 600 percent increased risk of getting
bladder cancer. Dr. Smith was asked if anything about Cooper’s history of being a
former smoker “remotely comes close to having that degree of association.” He
answered that in general looking at all of the exposures evaluated, the only factor that
would approach a similar hazard ratio would be a person’s being a current, heavy smoker.
He noted that Cooper was not a current smoker, and was never a heavy smoker.
       The Takeda meta-analysis indicated that being on Actos® for more than 24
months resulted in a hazard ratio of 4.4 and having been exposed to a cumulative dose
greater than 28 milligrams resulted in a hazard ratio of 4.6. Considering that Cooper was
taking Actos® for about 62 months and his cumulative dose was 55,000 milligrams,
Dr. Smith stated, “my concern would be that these numbers would be higher in his
specific case.” Asked, “So whatever his risk may be for being Caucasian, for smoking,
or even if he was in a high risk occupation, or even if he had a severe A1C, that’s been
accounted for when we talk about this increased risk?” Dr. Smith replied in the
affirmative with regard to the Takeda meta-analysis.
       Dr. Smith testified that the risk of bladder cancer associated with being a smoker
decreased by 40 percent the first four years after cessation of smoking. Recent studies
indicated that if one smoked any amount but quit by the age of 40, one avoided
practically all risk of smoking-related death. If a person quit smoking at a later age, he or

hypothesizing that Actos® causes bladder cancer, that is, generating a hypothesis but not
constituting proof.

                                               13
she reverted to the risk that would be seen in a person who smoked less than 10 cigarettes
per week. Those studies, published in the New England Journal of Medicine by Jha and
Thun, examined deaths from all causes. In accordance with those studies, if Cooper had
stopped smoking in the 1970’s, he still had a 20 percent increased risk of death from
smoking-related causes. If someone smoked until they were 55 to 64 years of age, the
hazard ratio would be 1.7, i.e., a 70 percent increased risk of death from smoking-related
causes over somebody who never smoked.
       Dr. Smith said that in reaching his differential diagnosis, he considered Cooper’s
history of smoking, environmental exposures, and occupational exposures. He noted that
it was sometimes hard to define a single agent to which a patient might have been
exposed. “But if you look once again at all of that, you don’t really get hazard ratios out
of the ones whereas in the Mamtani article, that seems to fit Mr. Cooper very well with
his . . . 50-plus thousand milligrams cumulative dose greater than five years that has a
hazard ratio of almost seven. So I think in his case when you try to weigh that all in,
that’s really what is formative of the opinion that Actos caused bladder cancer for
Mr. Cooper.” Cooper’s counsel asked Dr. Smith, “Let’s go with half as risky as Actos.
Actos, Mamtani, five years, 700 percent increased risk—odds ratio of 7. Is there
anything in Mr. Cooper’s history that’s even half as risky scientifically? Former
smoking?” Dr. Smith answered, “the relative risks of that go down to the ones, and this
new article would suggest maybe even lower than that if you quit at age 40.” He
testified, “[I]f you looked at people that quit smoking, all comers, the odds ratios are
usually in the 1’s, and they approach that of nonsmokers when one has quit for many,
many years and was a light smoker like Mr. Cooper.”
       Dr. Smith definitively stated: “[A]fter review of all the potentials, differential
diagnosis, ruling in, ruling out, carefully evaluating the occupational, environmental, and
smoking, that it’s my opinion that the most substantial causative factor for Mr. Cooper
was his length of Actos and cumulative dose of Actos.”

                                              14
II.    The Jury Verdict
       The jury returned a 9-3 verdict for Cooper on the strict liability failure to warn
claim and a 10-2 verdict for Cooper on the negligent failure to warn and loss of
consortium claims. Specifically, the jury found that Takeda failed to adequately warn
Cooper’s treating physician of the risk of bladder cancer, and that this failure to warn was
a substantial factor in causing Cooper’s harm. Similarly, the jury found that Takeda
negligently failed to adequately warn Cooper’s treating physician of the risk of bladder
cancer, and that this failure to warn was a substantial factor in causing Cooper’s harm.
The jury returned a verdict for Takeda on the claims for negligent misrepresentation (12-
0), intentional concealment (11-1), and punitive damages (12-0). The jury awarded
Cooper $5 million in compensatory damages and $1.5 million in damages for loss of
consortium.
III. Post Verdict Rulings
       The procedural history contesting the admissibility of Dr. Smith’s testimony that
Actos® was a substantial factor in causing Cooper’s bladder cancer is lengthy and
complicated. By various procedural mechanisms -- motion in limine, motion to strike,
motion for nonsuit, motion for directed verdict, and finally motion for judgment
notwithstanding the verdict (JNOV) -- Takeda sought to exclude Dr. Smith’s testimony
or have it stricken. In large part, the procedural particulars are not material to this appeal.
To the extent they are, we summarize them.
       Throughout the proceedings, the trial court expressed the same concern about Dr.
Smith’s testimony: that without a competent differential diagnosis based on Cooper’s
history and medical condition that accounted for all potential causes, and ruled out each
potential cause except Actos®, Dr. Smith’s specific causation opinion was unreliable.
Nonetheless, the court permitted Dr. Smith to testify, making clear that his testimony
could later be stricken.
       After the verdict, the court, which had deferred ruling on Takeda’s motion in
limine, motion to strike, and motion for nonsuit, ruled on those motions. In a lengthy
ruling (which we examine in more detail below, in the Discussion section of this

                                              15
opinion), the court concluded that Dr. Smith’s differential diagnosis was speculative and
unreliable. Therefore, the court struck the testimony on causation, and purported to grant
Takeda’s motion for nonsuit. Later, the court vacated the order granting nonsuit, and
considered instead Takeda’s motions for JNOV and for new trial.
       Takeda’s JNOV motion argued, as here relevant, that Cooper’s two failure to warn
claims and the loss of consortium claim failed because there was no evidence that
Actos®, as opposed to some other factor or factors, caused Cooper’s bladder cancer. The
court adopted the reasoning of its prior ruling striking Dr. Smith’s testimony, and
concluded: (1) without Dr. Smith’s testimony, evidence of causation was lacking, and
(2) even if the testimony were not stricken, it did not constitute substantial evidence of
causation. Therefore, the court granted JNOV.
       Takeda had also moved in the alternative for a new trial, pursuant to Code of Civil
Procedure section 657, subdivisions (1), (6) and (7), on Cooper’s claims for failure to
warn and loss of consortium. The trial court granted the motion on two independent
grounds. First, it concluded the evidence was insufficient to support the jury’s verdict on
the three claims because “there is no evidence of specific causation in this case” for the
reasons in the court’s order striking Dr. Smith’s testimony, and therefore plaintiffs “could
not have met their burden of showing that any failure to warn was a substantial factor in
causing harm” to Cooper.
       Second, the trial court concluded that it was error to give a multiple causation
instruction. The court held that the instruction was not supported by substantial evidence,
since neither side introduced evidence of multiple causation. The court further held that
(1) “the CACI 431 instruction was prejudicial and probably affected the jury verdict,
given the lack of evidence of concurrent causation” because “[w]ithout the instruction,
the jury would not have been in a position to consider multiple concurrent causes”; and
(2) it was not supported by substantial evidence at trial. The court entered judgment for
Takeda on all causes of action on July 18, 2013. This timely appeal followed.

                                             16
                                        DISCUSSION

     I. JNOV
     Cooper contends that the trial court erred in granting Takeda’s JNOV motion. For the
reasons explained below, we agree.10
     A. The Standard of Review
        “Typically, if a defendant believes that the plaintiff has not presented substantial
evidence to establish a cause of action, the defendant may move for a nonsuit if the case
has not yet been submitted to the jury, a directed verdict if the case is about to be
submitted, or a judgment notwithstanding the verdict (jnov) following an unfavorable
jury verdict.
        “While made at different times, the three motions are analytically the same and
governed by the same rules. (See Beavers v. Allstate Ins. Co. (1990) 225 Cal. App. 3d
310, 327 [‘. . . different aspects of the same judicial function and have long been held to
be governed by the same rules’].) The function of these motions is to prevent the moving
defendant from the necessity of undergoing any further exposure to legal liability when
there is insufficient evidence for an adverse verdict. (E.g., Reynolds v. Willson (1958)
51 Cal. 2d 94, 99.) Put another way, the purpose of motions for nonsuit, directed verdicts
and jnovs is to allow a party to prevail as a matter of law where the relevant evidence is
already in.
        “And naturally, given the constitutional right to jury trial and a policy of judicial
economy against willy-nilly disregarding juries’ hard work (even, in the case of a motion

10     As we have explained, after the verdict, the trial court initially struck Dr. Smith’s
testimony and purported to grant Takeda’s motion for nonsuit. Thereafter, it vacated the
grant of nonsuit, and granted JNOV in favor of Takeda. Cooper argues that the trial court
erred procedurally by granting JNOV while also finding inadmissible Dr. Smith’s
testimony regarding specific causation, where the trial court had failed to rule on the
motion to strike that testimony before the jury rendered its verdict. Because we find the
court’s substantive error in granting JNOV dispositive, it is unnecessary to discuss the
alleged procedural error.

                                              17
for nonsuit, the work of the jury in listening to the case up to that point), the basic rules
regarding these motions are predictably strict. Conflicts in the evidence are resolved
against the moving defendant and in favor of the plaintiff; all reasonable inferences to be
drawn from the evidence are drawn against the moving defendant and in favor of the
plaintiff. (See, e.g., Nally v. Grace Community Church (1988) 47 Cal. 3d 278, 291 [for
nonsuit, ‘ “ ‘every legitimate inference which may be drawn from the evidence’ ” ’
should be drawn in plaintiff’s favor, and the evidence should be evaluated ‘ “in the light
most favorable to the plaintiff” ’]; CC-California Plaza Associates v. Paller & Goldstein
(1996) 51 Cal. App. 4th 1042, 1050-1051 [‘ “A nonsuit or a directed verdict may be
granted ‘only when, disregarding conflicting evidence and giving to plaintiff’s evidence
all the value to which it is legally entitled, herein indulging in every legitimate inference
which may be drawn from that evidence, the result is a determination that there is no
evidence of sufficient substantiality to support a verdict in favor of the plaintiff if such a
verdict were given.’ ” ’ (italics omitted)]; Hansen v. Sunnyside Products, Inc. (1997)
55 Cal. App. 4th 1497, 1510 [for judgments notwithstanding the verdict, ‘ “ ‘ “[i]f there is
any substantial evidence, or reasonable inferences to be drawn therefrom, in support of
the verdict, the motion should be denied” ’ ” ’].)” (Fountain Valley Chateau Blanc
Homeowner’s Assn. v. Department of Veterans Affairs (1998) 67 Cal. App. 4th 743, 750-
751.)
        An order granting JNOV is reviewed de novo. A reviewing court determines
whether substantial evidence supports the verdict, considering the evidence in the light
most favorable to the party obtaining the verdict. (Tognazzini v. San Luis Coastal
Unified School Dist. (2001) 86 Cal. App. 4th 1053, 1057-1058.)
   B. The Trial Court’s Ruling
        In granting Takeda’s JNOV motion, the court adopted its reasoning from the prior
order striking Dr. Smith’s testimony. Thus, it is necessary to examine the ruling striking
the testimony in some detail.
        The court examined the foundation for Dr. Smith’s testimony from his deposition,
section 402 hearing, trial testimony, and applicable admitted exhibits and concluded that,

                                              18
although Dr. Smith identified many possible causes of bladder cancer, he did not
“sufficiently consider [them] and then rule them out as to Mr. Cooper specifically.” The
trial court therefore excluded from evidence Dr. Smith’s specific causation opinion,
stating, “[I]t is evident to the Court that the manner in which Dr. Smith conducted his
differential diagnosis is based on speculation, is not reliable, not done with the
intellectual rigor expected of an expert, and is therefore inadmissible under prevailing
California law.”
       The court acknowledged that Dr. Smith testified that he performed a differential
diagnosis and ruled out “smoking, environmental exposures, occupational exposure.”
But the court concluded that Dr. Smith did not have a foundation for ruling out these
potential causes of Cooper’s bladder cancer. For instance, as to environmental and
occupational exposures, the court stated that Dr. Smith, at his deposition, when asked
what Cooper did for a living, testified that he could not recall. When asked whether he
knew if Cooper had any exposures at his workplace that had any sort of association with
bladder cancer, Dr. Smith testified that it was “ ‘a difficult question to answer because
. . . we don’t understand all the exposures.’ Absent a foundational basis for ruling in, and
then ruling out, these occupational and environmental exposures (potential exposures
which Dr. Smith identifies as belonging to a ‘huge list’), Dr. Smith could not reliably
perform a differential diagnosis to arrive at his specific causation opinion. [Fn.]” The
court noted that “the fact that Dr. Smith did not examine or interview Mr. Cooper does
not, by itself, render his specific causation inadmissible. However, Dr. Smith was
required to otherwise establish a reliable foundation for his differential diagnosis, which
he did not do as to Mr. Cooper. Dr. Smith’s testimony that Dr. Xavier mentioned ‘no
history of occupational exposures’, and his reliance on that mere statement, is not
sufficient, from a foundational standpoint, to rule in, and rule out, such potential
exposures to reach a differential diagnosis as to the specific cause of Mr. Cooper’s
bladder cancer.” Dr. Smith could not testify whether Cooper was exposed to secondhand
smoke at work, whether he may have had any exposures at his work associated with
bladder cancer, and “whether he may have had exposure to anything during his Army

                                             19
service.” Rather, Dr. Smith merely reviewed Cooper’s medical record and did not take a
history from Cooper. The court said, “[R]uling in, and ruling out, potential causes of
Mr. Cooper’s bladder cancer is critical for purposes of establishing a foundation as to
Dr. Smith’s specific causation opinion by way of a differential diagnosis.”
       As to Cooper’s history of smoking, the court stated that “without knowing the date
Mr. Cooper ceased smoking, Dr. Smith could not (and did not) properly rule out smoking
as a potential cause of Mr. Cooper’s bladder cancer in conducting his differential
diagnosis” given Dr. Smith’s testimony that smoking is a significant risk factor and the
time since cessation of smoking is important in assessing smoking as a risk factor. The
court continued, “An expert physician, evaluating a patient’s medical records, would
thoroughly study them, noting anything of significance, and follow up on every detail
necessary to come up with an accurate diagnosis. Since the date Mr. Cooper stopped
smoking and his level of tobacco consumption is a critical fact in the diagnosis, an expert
would do all he or she could to resolve any ambiguities. Pursuant to Sargon,[11] Dr.
Smith was required to ‘employ[] in the courtroom the same level of intellectual rigor that
characterizes the practice of an expert in the relevant field.’ Sargon, supra, 55 Cal.4th at
772 (emphasis added).” The court said, “Yet, Dr. Smith, not having noticed the multiple
medical record entries indicating smoking cessation in the 1992-4 timeframe or
Mr. Cooper’s history of moderate emphysema, steadfastly continued to use as [a] basis
for his opinion the statement of Mr. Cooper’s attorney that Mr. Cooper stopped smoking
in the 1970s.”
       The court further stated that Dr. Smith did not consider Cooper’s history of
chronic kidney disease or his various episodes of skin cancer. There was no evidence
that Dr. Smith reviewed these records in reaching his differential diagnosis. The court
indicated that, “These records in particular are important because if diabetes is a risk

11    Sargon Enterprises, Inc. v. University of Southern California (2012) 55 Cal. 4th
747 (Sargon).

                                             20
factor for bladder cancer, they are a measure of the seriousness of Mr. Cooper’s
diabetes.”
       The court also found that Dr. Smith had changed his position as to whether age,
race and gender were risk factors without citing any basis for eliminating these factors,
and ruled out diabetes as a risk factor without providing support for doing so. The court
noted that “the very epidemiological studies upon which Dr. Smith relies for his Actos
causation opinion treat the level of the underlying diabetes as a cause of bladder cancer.”
       The court then examined the epidemiological studies upon which Dr. Smith relied
and pointed out specific problems and “flaws” in each of them, questioning whether
epidemiological studies can generally be used as a basis for a differential diagnosis. The
court concluded that the studies did not serve as reasonable bases for Dr. Smith’s specific
causation opinion, and “do not ‘actually support’ Dr. Smith’s reasoning.” Furthermore,
the court rejected Cooper’s assertion that Dr. Smith’s general causation opinion rendered
his specific causation opinion reliable, stating, “There is nothing in Dr. Smith’s
deposition transcript, nor anything stated at the §402 hearing or during his trial testimony,
which demonstrates that Dr. Smith could disregard the identified risk factors as they
specifically relate to Mr. Cooper. Again, a differential diagnosis is a patient-specific
process. It is evident to the Court that Dr. Smith did no patient-specific analysis that
satisfies the admissibility standards under Evidence Code §§ 801 and 802. [¶]
Moreover, instead of his differential diagnosis being patient specific, based upon a review
[of] the patient’s medical history, clinical tests, biological and physiological markers, and
physical examination of the patient, Dr. Smith rendered a diagnosis based upon
speculation, conjecture and leaps of logic. His sole remaining risk factor is not patient-
specific, but is instead based upon statistical studies. Dr. Smith’s diagnosis would
virtually apply to any male, non-smoker who took Actos for more than five years, since
he has no physiological or biological markers to distinguish Mr. Cooper’s bladder cancer
from the myriad of bladder cancer patients he treats with no known causes.” The court
emphasized that it was not ruling on the weight of Dr. Smith’s opinion, but only its
admissibility.

                                             21
     C. The Trial Court Erred
     As we explain, in finding Dr. Smith’s testimony inadmissible, the trial court’s
reasoning is inconsistent with California law on the acceptable bounds of expert
testimony regarding causation, as well as on the trial court’s gate keeping function of
excluding unreliable expert testimony.
        1. Standards for Admission of Expert Testimony
        “Trial judges have a substantial gatekeeping responsibility when it comes to expert
testimony. (Sargon, [supra,] 55 Cal. 4th 747 at p. 769.) In particular, courts are to ensure
that opinions are not speculative, based on unconventional matters or grounded in
unsupported reasoning. (Id., at pp. 771-772.) We review a court’s execution of these
gatekeeping duties for an abuse of discretion. ([City of San Diego v.] Sobke [(1998)]
65 Cal.App.4th [379] at p. 396.)” (People ex rel. Dept. of Transportation v. Dry Canyon
Enterprises, LLC (2012) 211 Cal. App. 4th 486, 493.)
        Based on the provisions of Evidence Code sections 801 and 80212, “the trial court
act[s] as a gatekeeper to exclude expert opinion testimony that is (1) based on matter of a
type on which an expert may not reasonably rely, (2) based on reasons unsupported by

12      Evidence Code section 801 provides that, “If a witness is testifying as an expert,
his testimony in the form of an opinion is limited to such an opinion as is: [¶] (a) Related
to a subject that is sufficiently beyond common experience that the opinion of an expert
would assist the trier of fact; and [¶] (b) Based on matter (including his special
knowledge, skill, experience, training, and education) perceived by or personally known
to the witness or made known to him at or before the hearing, whether or not admissible,
that is of a type that reasonably may be relied upon by an expert in forming an opinion
upon the subject to which his testimony relates, unless an expert is precluded by law from
using such matter as a basis for his opinion.”
        Evidence Code section 802 states: “A witness testifying in the form of an opinion
may state on direct examination the reasons for his opinion and the matter (including, in
the case of an expert, his special knowledge, skill, experience, training, and education)
upon which it is based, unless he is precluded by law from using such reasons or matter
as a basis for his opinion. The court in its discretion may require that a witness before
testifying in the form of an opinion be first examined concerning the matter upon which
his opinion is based.”

                                             22
the material on which the expert relies, or (3) speculative.” (Sargon Enterprises, Inc. v.
University of Southern California (2013) 215 Cal. App. 4th 1495, 1504-1505 (Sargon II).)
“ ‘[E]ven when the witness qualifies as an expert, he or she does not possess a carte
blanche to express any opinion within the area of expertise. [Citation.] For example, an
expert’s opinion based on assumptions of fact without evidentiary support . . . or on
speculative or conjectural factors . . . has no evidentiary value . . . and may be excluded
from evidence. [Citations.]’ (Jennings v. Palomar Pomerado Health Systems, Inc.
(2003) 114 Cal. App. 4th 1108, 1117; see also Bushling v. Fremont Medical Center (2004)
117 Cal. App. 4th 493, 510 [‘expert opinion may not be based on assumptions of fact that
are without evidentiary support or based on factors that are speculative or conjectural
. . . ’].) ‘Therefore, an expert’s opinion that something could be true if certain assumed
facts are true, without any foundation for concluding those assumed facts exist in the case
before the jury, does not provide assistance to the jury because the jury is charged with
determining what occurred in the case before it, not hypothetical possibilities.’ (Jennings
v. Palomar Pomerado Health Systems, Inc., supra, 114 Cal.App.4th at p. 1117.)” (Dee v.
PCS Property Management, Inc. (2009) 174 Cal. App. 4th 390, 404.)
       Here, the trial court considered Dr. Smith’s testimony regarding specific causation
to be speculative, unreliable, and “not done with the intellectual rigor expected of an
expert, and [] therefore inadmissible under prevailing California law.”
       2. The Court’s Misapplication of the Substantial Factor Test
       In part, the court found Dr. Smith’s testimony unreliable and inadmissible because
Dr. Smith did not adequately consider and definitively rule out potential causes of
Cooper’s bladder cancer other than Actos® . The court’s reasoning misapprehended the
substantial factor test of causation.
       “The law is well settled that in a personal injury action causation must be proven
within a reasonable medical probability based upon competent expert testimony. Mere
possibility alone is insufficient to establish a prima facie case. [Citations.] That there is a
distinction between a reasonable medical ‘probability’ and a medical ‘possibility’ needs
little discussion. There can be many possible ‘causes,’ indeed, an infinite number of

                                              23
circumstances which can produce an injury or disease. A possible cause only becomes
‘probable’ when, in the absence of other reasonable causal explanations, it becomes more
likely than not that the injury was a result of its action. This is the outer limit of inference
upon which an issue may be submitted to the jury. [Citation.]” (Jones v. Ortho
Pharmaceutical Corp. (1985) 163 Cal. App. 3d 396, 402-403.)
       “With cancer the question of causation is especially troublesome. . . . Under the
present state of scientific knowledge . . . it is frequently difficult to determine the nature
and cause of a particular cancerous growth. . . . [¶] The fact that a determination of
causation is difficult to establish cannot, however, provide a plaintiff with an excuse to
dispense with the introduction of some reasonably reliable evidence proving this essential
element of his case. Although juries are normally permitted to decide issues of causation
without guidance from experts, ‘the unknown and mysterious etiology of cancer’ is
beyond the experience of laymen and can only be explained through expert testimony.
[Citation.] Such testimony, however, can enable a plaintiff’s action to go to the jury only
if it establishes a reasonably probable causal connection between an act and a present
injury.” (Jones v. Ortho Pharmaceutical Corp., supra, 163 Cal.App.3d at p. 403.)
       “[P]roffering an expert opinion that there is some theoretical possibility the
negligent act could have been a cause-in-fact of a particular injury is insufficient to
establish causation. (Saelzler v. Advanced Group 400 (2001) 25 Cal. 4th 763, 775-776
[expert testimony positing a ‘ “mere possibility of such causation is not enough; and
when the matter remains one of pure speculation or conjecture, or the probabilities are at
best evenly balanced, it becomes the duty of the court to direct a verdict for the
defendant” ’]; accord, Leslie G. v. Perry & Associates (1996) 43 Cal. App. 4th 472, 487.)
Instead, the plaintiff must offer an expert opinion that contains a reasoned explanation
illuminating why the facts have convinced the expert, and therefore should convince the
jury, that it is more probable than not the negligent act was a cause-in-fact of the
plaintiff’s injury.” (Jennings v. Palomar Pomerado Health Systems, Inc., supra,
114 Cal.App.4th at p. 1118.)

                                              24
       In the instant case, the trial court’s reasoning concerning the flaws in Dr. Smith’s
differential diagnosis held Cooper’s expert to a more rigid standard than is required to
prove causation in civil cases. Under the applicable substantial factor test, it is not
necessary for a plaintiff to establish the negligence of the defendant as the proximate
cause of injury with absolute certainty so as to exclude every other possible cause of a
plaintiff’s illness, even if the expert’s opinion was reached by performance of a
differential diagnosis. The jury here was required to determine whether there was any
substantial evidence that other known risk factors for bladder cancer acted on plaintiff
and provided an alternative explanation for his disease. But only if the existence of an
alternative explanation, supported by substantial evidence and not mere speculation, as a
matter of law defeated the explanation proffered by Cooper (i.e., Actos®) would JNOV
be appropriate.
       The decision in Sarti v. Salt Creek Ltd. (2008) 167 Cal. App. 4th 1187 (Sarti) is
instructive. In Sarti, a restaurant patron sued the restaurant for breach of warranty after
developing food poisoning shortly after eating at the restaurant. The jury entered a
verdict in favor of the plaintiff, but the trial court granted JNOV in favor of the
restaurant. On the plaintiff’s appeal, the appellate court reinstated the verdict in the
plaintiff’s favor.
       The evidence at trial showed that plaintiff ate raw tuna at the restaurant, then
developed a serious illness due to the ingestion of a particular bacteria found in raw
chicken but not in raw tuna. However, the evidence also demonstrated that the
restaurant’s specific practices could have led to cross-contamination of raw food
consumed by the plaintiff. Plaintiff’s expert testified that anything that might have
touched something that touched raw chicken would be cross-contaminated. The
restaurant’s dishwasher did not adequately sterilize dishes, the waiter frequently used an
unsterilized rag to wipe various surfaces, and raw chicken juice may have leaked onto
some of the vegetables stored beneath it. The appellate court concluded that a reasonable
jury could infer that a rag used to wipe down a raw chicken board was used to wipe down

                                              25
a vegetable or tuna board, or that raw chicken juice could have dripped onto food later
consumed raw.
       Important for our purposes here, the court in Sarti noted that “[t]here was plenty of
substantial evidence on which the jury could have found the restaurant not liable.” (Sarti,
supra, 167 Cal.App.4th at p. 1191.) Plaintiff’s friend who ate the same food did not get
sick, the restaurant took other careful measures to separate its raw tuna from its raw
chicken, and plaintiff herself “worked as a supermarket checker the day she became ill,
and could, at least in theory, have picked up campylobacter from a leaking bag of raw
chicken she might have scanned.” (Id. at pp. 1191-1192.) The trial court commented
that although such evidence was presented, it would have voted with the jury in finding
the restaurant liable. However, the court felt constrained to enter JNOV based on its
reading of the case of Minder v. Cielito Lindo Restaurant (1977) 67 Cal. App. 3d 1003
(Minder) as setting forth a black-letter rule of law that food poisoning cases have
heightened causation requirements. The trial court read Minder as establishing “ ‘that the
concept of inferences, which are otherwise permitted in civil cases, apparently play little
or no role in food poisoning cases. And remember, an inference is not evidence itself, an
inference is the result of reasoning based upon collateral evidence.’ ” (Sarti, supra, at
p. 1192.)
       As observed by the Sarti court, however, “The Minder court never expressly said
that it thought that defendants in food poisoning cases deserved a break from ordinary
rules of tort causation, but that thought permeated the court’s analysis, and it was
certainly picked up by the trial judge in our own case, who described Minder as
enunciating a ‘heightened’ standard of causation. [¶] We cannot agree, however, with
the strong implication in the Minder analysis that food poisoning cases are somehow
unique in tort law.”13 (Sarti, supra, 167 Cal.App.4th at pp. 1201-1202.) The Sarti court

13     The Sarti court closely analyzed the Minder case, and concluded that the real issue
precluding a finding of liability was that there simply was not enough of a specific link
demonstrated between the particular kind of food poisoning involved and any particular
                                             26
concluded that “[t]o the degree that the Minder opinion does indeed suggest a no-
inference rule (or, at least, a presumption against inferences different from other tort
cases), it contradicted established precedent in existence at the time.” (Id. at p. 1203.)
For example, the court held in Dougherty v. Lee (1946) 74 Cal. App. 2d 132 (Dougherty),
that “ ‘ “It is not necessary in the trial of civil cases that the circumstances shall establish
the negligence of the defendant as the proximate cause of injury with such absolute
certainty as to exclude every other conclusion. It is sufficient if there is substantial
evidence upon which to reasonably support the judgment. (Ley v. Bishopp [(1928)]
88 Cal. App. 313, 316.)” ’ (Dougherty, supra, 74 Cal.App.2d at p. 136, italics added
[quoting from Barham v. Widing (1930) 210 Cal. 206, 215.])” (Sarti, supra, at pp. 1203-
1204.)
         In addition, the Sarti court observed that the Minder opinion strongly suggested
the existence of a requirement that the plaintiff rule out all other causes of the illness.
The restaurant argued “for an ‘all alternatives must be ruled out’ approach” as being
required by California law. (Sarti, supra, 167 Cal.App.4th at p. 1205.) The Sarti court,
relying on Mitchell v. Gonzales (1991) 54 Cal. 3d 1041, flatly rejected the assertion that
exclusion of alternatives with absolute certainty is required. (Sarti , supra, at p. 1205.)
Suffice it to say that we agree with the Sarti court that Mitchell, in endorsing a jury
instruction telling the jury to determine “ ‘whether the defendant’s conduct was a
substantial factor in bringing about the injury’ ” (Mitchell at p. 1049, italics added),
“plainly demonstrated that California law on causation is ‘substantial factor.’ And, as the
prior Dougherty opinion expressly stated, a plaintiff need not ‘ “exclude every other
conclusion” ’ than the defendant’s negligence. (Dougherty, supra, 74 Cal.App.2d at
p. 136.)” (Sarti, supra, at p. 1210.)
         Thus, because California has rejected the notion that a plaintiff must definitively
“exclude all ‘possibilities’ ” (Sarti, supra, 167 Cal.App.4th at p. 1210) other than the

unsanitary condition at the restaurant. The testimony from the plaintiffs’ treating
physician came close but did not actually connect the offending pathogen to the
unsanitary conditions found at the restaurant. (Sarti, supra, 167 Cal.App.4th at p. 1195.)

                                               27
defendant’s conduct or product as the cause of plaintiff’s harm, clearly an expert, in
reaching a specific causation opinion, need not exclude all other possibilities before he or
she can express an opinion that defendant’s conduct or product caused the plaintiff’s
harm.
        As recognized by the Sarti court, something more than bare conceivability or
plausibility of other causes must be required before another cause of injury, as a matter of
law, must be chosen as the cause in fact over the defendant’s conductor, by extension,
before an expert’s opinion is held inadmissible as being speculative or lacking in
foundation. “For example, in a food poisoning case, how could the plaintiff disprove that
she didn’t pick up some nasty bacteria (here, campylobacter) because she touched a
doorknob that had been previously touched by someone who had been handling raw
chicken or who had changed a diaper, and hadn’t washed his or her hands? Well, yes,
one might reason, it is conceivable that that might have happened. It is ludicrous, though,
to suggest that such bare conceivability must, as a matter of law, defeat a food poisoning
claim. [¶] The relevant question is this one: Was there any substantial evidence that
someone who had just handled raw chicken (or changed a diaper or whatever) and who
hadn’t washed his or her hands, touched something that the plaintiff soon touched, and
then the plaintiff, say, ate a hamburger or a sandwich without washing her hands, after
which she became sick within a time frame consistent with the illness that she, indeed,
contracted?” (Sarti, supra, 167 Cal.App.4th at pp. 1210-1211.) The court found that the
restaurant had “cited no substantial evidence requiring a finding that Sarti picked up the
campylobacter from handling a leaky package of chicken while working at a checkstand,
or handling a cat, or somehow being exposed to a baby in the house, or eating in the
lunchroom with the employees from the meat department,” and thus the court was
“spared the tough problem of whether the existence of an alternative ‘explanation’
supported by substantial evidence competing with the finding the jury actually chose
might somehow defeat, as a matter of law, the jury’s finding of food poisoning from the
restaurant meal.” (Id. at p. 1211.) The court continued, “One must remember, it is the
winning party after a jury trial, not the losing party, who gets the benefit of reasonable

                                             28
inferences from the evidence. Under classic rules of appellate review, we are required to
accept the inference, if reasonable, that Salt Creek got sloppy with its wipe-down rags
over the inference that Sarti ran a leaky bag of chicken through a checkout scanner and
then didn’t wash her hands before touching some food she ate.” (Ibid.)
       Just as food poisoning cases are not unique in California tort law, cases in which
expert physicians perform a differential diagnosis to “rule in” and “rule out” other
possible causes of a disease are not unique; the substantial factor rule of causation still
applies in such cases. Thus, Dr. Smith was not required to rule out all other possible
causes of bladder cancer before his testimony could be deemed admissible. The trial
court’s ruling to the contrary contravened California law.
       The trial court rejected Dr. Smith’s opinion because, in the court’s view, he did
not have sufficient foundation to rule in and rule out other causes of Cooper’s cancer.
Specifically, the court faulted Dr. Smith for not conducting further investigation into
other possible causes, saying that although Dr. Smith identified many possible causes of
bladder cancer, he did not “sufficiently consider [them] and then rule them out as to
Mr. Cooper specifically.” The court said, “Differential diagnosis is ‘the patient-specific
process of elimination that medical practitioners use to identify the “most likely” cause of
a set of signs and symptoms from a list of possible causes’ and is ‘undoubtedly important
to the question of specific causation.’ See Matthew Bender, Drug Product Liability,
§5.01(b)(2012) (emphasis added). [¶] ‘Differential diagnosis is a standard scientific
technique of identifying the cause of a medical problem by eliminating the likely causes
until the most probable one is isolated. It is typically performed after taking physical
examinations and medical histories, and reviewing clinical tests.’ Id. (Emphasis added.)
[¶] . . . [¶] Importantly, ‘[m]ost courts require that a reliable differential diagnosis at
least consider other factors that could have been the sole cause of the plaintiff’s injury.
Nevertheless, the expert need not rule out every conceivable cause for his or her
differential-diagnosis-based opinion to be admissible.’ Id.” The trial court nonetheless
concluded that, “instead of his differential diagnosis being patient specific, based upon a
review [of] the patient’s medical history, clinical tests, biological and physiological

                                              29
markers, and physical examination of the patient, Dr. Smith rendered a diagnosis based
upon speculation, conjecture and leaps of logic. His sole remaining risk factor is not
patient-specific, but is instead based upon statistical studies. Dr. Smith’s diagnosis would
virtually apply to any male, non-smoker who took Actos for more than five years, since
he has no physiological or biological markers to distinguish Mr. Cooper’s bladder cancer
from the myriad of bladder cancer patients he treats with no known causes.”
       The court found that Dr. Smith did not have a foundation for ruling out
occupational and environmental exposures because at trial Dr. Smith did not recall
Cooper’s profession, and acknowledged it was difficult to know if Cooper had any
exposures at his workplace that had any sort of association with bladder cancer,
“ ‘because . . . we don’t understand all the exposures.’ ” The trial court found
Dr. Smith’s reliance on Cooper’s treating physician’s statement that Cooper had “ ‘no
history of occupational exposures’ ” was “not sufficient, from a foundational standpoint,
to rule in, and rule out, such potential exposures to reach a differential diagnosis as to the
specific cause of Mr. Cooper’s bladder cancer.” The trial court said that Dr. Smith could
not testify whether Cooper was exposed to secondhand smoke at work, whether he may
have had any exposures at his work associated with bladder cancer, and whether he may
have had exposure to anything during his Army service. The court said, “[R]uling in, and
ruling out, potential causes of Mr. Cooper’s bladder cancer is critical for purposes of
establishing a foundation as to Dr. Smith’s specific causation opinion by way of a
differential diagnosis.”
       As to Cooper’s history of smoking, the court stated that “without knowing the date
Mr. Cooper ceased smoking, Dr. Smith could not (and did not) properly rule out smoking
as a potential cause of Mr. Cooper’s bladder cancer in conducting his differential
diagnosis” given Dr. Smith’s testimony that smoking is a significant risk factor and the
time since cessation of smoking is important in assessing smoking as a risk factor.
However, Dr. Smith did not rule out smoking as a potential cause of Cooper’s bladder
cancer. He plainly admitted that smoking “could be a cause of his bladder cancer.”

                                              30
       Dr. Smith testified further that regardless of when Cooper stopped smoking,
Actos® ingestion was, in his opinion, still more likely to have been the most substantial
factor in causing Cooper’s bladder cancer than his smoking history. Based on a study
examining all smoking-related deaths by duration and age of cessation of smoking,
Dr. Smith agreed that if someone quit smoking at 35 to 44 years of age, he or she would
have a 20 percent increased risk of dying of cancer compared to someone who never
smoked. If a person smoked until they were 55 to 64 years of age, he or she would have
a 70 percent increased risk of dying of cancer compared to someone who never smoked.
Another source Dr. Smith reviewed, the Brennan paper, indicated that if Cooper smoked
for 20 years, until 1974, he had a 100 percent increased risk of developing bladder
cancer. If he smoked for 40 years, until 1994, he had perhaps a 300 percent increased
risk for bladder cancer. If he stopped in 1994, 17 years would have passed before he was
diagnosed with bladder cancer. He would not have reached the risk level of a
nonsmoker, but he was always a light smoker and his risk declined the longer it had been
since he stopped smoking. Dr. Smith opined, “even in the time frame of 17 years, the
risk of . . . smoking-related cancers and diseases goes down significantly in that time
frame.” He concluded: “[A]fter review of all the potentials, differential diagnosis, ruling
in, ruling out, carefully evaluating the occupational, environmental, and smoking, that it’s
my opinion that the most substantial causative factor for Mr. Cooper was his length of
Actos and cumulative dose of Actos.”
       In essence, Dr. Smith was presented with two hypotheticals, one in which Cooper
stopped smoking in 1974, and one in which he stopped smoking around 1994, and
testified regarding both. Asked, “Doctor, you will agree, would you not, sir, that
Mr. Cooper’s history of smoking, whether it be 20 years or 40 years, certainly could be a
cause of his bladder cancer?” He replied in the affirmative, and said that it was one of
the things he ruled in. This testimony was entirely adequate to illuminate the subject for
the jury, without further investigation or clarification by Dr. Smith of the discrepancy in
the medical records. “Expert testimony has its own rules given its issues of reliability
because the expert is not testifying to percipient facts, but instead relies on a multitude of

                                              31
materials, including hearsay, in forming his or her opinion. Further, the expert is not
bound by actual facts in rendering an opinion, but may opine on hypothetical situations
. . . .” (Sargon II, supra, 215 Cal.App.4th at p. 1505.) It is the jury’s role and function to
determine whether the hypothetical fact pattern is supported by the evidence, and whether
to credit the expert’s opinion. (People v. Vang (2011) 52 Cal. 4th 1038, 1050.) The jury
here could decide based on the testimony when they believed Cooper stopped smoking,
and evaluate the persuasiveness of Dr. Smith’s testimony on that basis.
       In evaluating Cooper’s medical records that were provided to him, Dr. Smith was
not required to “follow up on every detail necessary to formulate an accurate diagnosis,”
and “do all he . . . could to resolve any ambiguities,” before he could offer an opinion on
causation. Dr. Smith was not required to affirmatively negate every other possible cause
by engaging in further investigation and evaluation of Cooper and his medical history, in
order for his causation opinion to meet the threshold of reliability required for
admissibility. In our view, the trial court’s condemnation of Dr. Smith’s review of
Cooper’s medical records did not point out any critical information that Dr. Smith
overlooked. Rather, the trial court appeared to be speculating that some unknown
exposure could be lurking in the unexamined records. But as we have said, Dr. Smith
was not required to search for evidence that even Takeda’s counsel failed to find and
present to the jury. Takeda also did not point out any relevant evidence regarding other
causes that Dr. Smith overlooked, whether in Cooper’s medical records or in the
deposition testimony of other witnesses. Nor was Dr. Smith obliged to “perform physical
examinations” or do clinical testing to investigate the matter further. The court cited
those things as typically being involved in the performance of a differential diagnosis, by
definition, not accounting for the fact that differential diagnoses most frequently occur in
a clinical setting and are aimed at identifying the disease from which a patient suffers in
order to provide treatment (rather than identifying the cause of a disease for forensic
purposes). There is no indication here that any physical examination or clinical tests
would have shed any further light on the cause of Cooper’s bladder cancer. The court’s
implicit criticism of Dr. Smith in that regard was therefore inapt.

                                              32
       The court indicated that Dr. Smith did not consider Cooper’s history of chronic
kidney disease or his various episodes of skin cancer, which was important because if
diabetes is a risk factor for bladder cancer, those things are measures of the seriousness of
Cooper’s diabetes. However, Dr. Smith opined, based on research he did when co-
authoring the Kiriluk paper and the fact that many of the epidemiological studies
controlled for the presence and severity of the test subjects’ diabetes, that he did not
consider diabetes to be a risk factor for bladder cancer. Therefore, his relative disregard
of information on those topics was warranted. Similarly, the court was critical of
Dr. Smith’s apparently overlooking a radiographic report for Cooper indicating a finding
on x-ray of moderate emphysema, which could indicate a severe extent of lung damage
from smoking. However, Dr. Smith testified that, although he was not an emphysema
expert, he could authoritatively state that a radiographic finding was not the same thing as
a clinical diagnosis. Indeed, Dr. Smith pointed out that the same radiologist who made
the observation of moderate emphysema on the x-ray interpreted a CT scan performed on
Cooper after the x-ray as finding “No visible pulmonary or pleural disease.”
       Dr. Smith did consider other possible causes of bladder cancer suggested by
Cooper’s medical records. Dr. Smith ruled out radiation exposure, chemotherapy,
infections, immunosuppression, the pain medication phenacetin, aristolochia fungi,
arsenic exposure, HPV virus, chlorinated or fluoridated water, and vitamin D deficiency.
He noted that vitamin D deficiency was unlikely because Cooper had two bouts of skin
cancer, probably due to sun exposure, so he inferred Cooper was not vitamin D deficient.
Dr. Smith acknowledged that direct contact with gasoline or diesel, which contain
polycyclic aromatic hydrocarbons (PAH), can cause skin cancer, and are also known to
be bladder cancer carcinogens. As already noted, he considered Mr. Cooper’s skin
cancer to be sun related rather than caused by direct contact with gasoline or diesel fuel,14

14     Indeed, one or both of the episodes of skin cancer occurred on his face, not a
location where he was likely to have had prolonged skin contact with diesel or gasoline.

                                             33
and there was nothing in the medical record indicating that Cooper worked around diesel
and gasoline engines during the 40 years he worked at construction sites which could
have exposed him to polycyclic aromatic hydrocarbons. Takeda introduced no
substantial evidence to indicate that he had; it only raised the speculation that he might
have.
         That is the critical point: Takeda cannot point to any substantial evidence to
indicate that another cause of bladder cancer, other than Actos®, was ignored by
Dr. Smith, such that his opinion was unreliable.15 In order to accept Dr. Smith’s opinion
as being sufficiently intellectually rigorous, and before finding admissible his opinion on
specific causation, the trial court would have had Dr. Smith investigate beyond the
medical records and evidence made available to him by Cooper—and Takeda—in search
of substantial evidence that other causes of bladder cancer operated on Cooper. That is
not the standard of admissibility for expert opinion on medical causation. Bare
conceivability that other causes of bladder cancer might have affected Cooper, raised by
Dr. Smith’s acknowledgement that there are so many possible causes and so much still
unknown about the causation of bladder cancer, in the absence of any substantial
evidence to support the notion that Cooper was in fact affected by those causes, was not a
proper basis for the court to exclude Dr. Smith’s testimony. California has rejected the
notion that an expert must “exclude all ‘possibilities’ ” in reaching a specific causation
opinion. (Sarti, supra, 167 Cal.App.4th at p. 1210.) Bare conceivability of another
possible cause does not defeat a claim; the relevant question is whether there is
“substantial evidence” of an alternative explanation for the disease. (Id. at pp. 1210-
1211.)
         In purporting to assess the admissibility of Dr. Smith’s testimony and disavowing
that it was ruling on the weight of Dr. Smith’s opinion, the trial court altogether excluded

15      As stated above, Dr. Smith acknowledged that smoking presented a significant
risk to Cooper of developing bladder cancer, but opined that on balance Actos® played a
more substantial role in Cooper’s development of the disease.

                                              34
Dr. Smith’s testimony essentially because he failed to demonstrate that Actos® was the
exclusive factor in causing Cooper’s bladder cancer. The trial court held Dr. Smith to a
standard by which he was required to present for consideration every possible alternative
cause of Cooper’s cancer, demonstrate that he had personally conducted a comprehensive
investigation into the evidence supporting and refuting each other cause as a possible
causative factor in Cooper’s cancer, and testify that based on that evidence he concluded
that Actos® was the exclusive factor in causing Cooper’s bladder cancer. California law
certainly does not require that rigorous standard as a threshold test for the admissibility of
an expert’s opinion regarding causation. To be admissible, an expert physician’s
testimony, even in the context of the physician’s performance of a differential diagnosis,
need not rule out the applicability of all other possible causes of disease where there is no
substantial evidence that other known risk factors for bladder cancer acted on Cooper and
provided an alternative explanation for his disease. Perhaps Cooper inhaled too much
secondhand smoke from coworkers over 15 years ago, was exposed to PAH’s by having
direct skin contact with diesel fuel, or was exposed to other myriad possible causes of
bladder cancer, but it was entirely speculative for Takeda to assert that other known risk
factors could have played a role where it presented no substantial evidence to support
such notions.
       Dr. Smith freely acknowledged that smoking also played an important role in the
development of bladder cancer, and that older white men were at higher risk of
developing the disease. But the jury was free to give weight to Dr. Smith’s testimony
that, to a reasonable degree of medical probability, Actos® was the most substantial
factor in causing Cooper’s bladder cancer, based in part on the fact that the studies upon
which he relied in forming that opinion controlled for smoking and demographic
factors.16 To paraphrase Sarti, because after a jury trial the winning party gets the benefit

16      The trial court criticized Dr. Smith for changing his testimony from the time of his
first deposition when he said that age, race, and sex are risk factors, to saying at trial that
these factors are simply the demographic of people who tend to get bladder cancer,
                                              35
of reasonable inferences from the evidence (Sarti, supra, 167 Cal.App.4th at p. 1211),
and because we have concluded that the trial court erred in excluding plaintiff’s expert
testimony regarding specific causation, we are required to accept the inference, if
reasonable, that Actos® was a substantial factor in causing Cooper’s bladder cancer, if
the foundation for that causation is reliable.
       Of course here, the trial court condemned Dr. Smith’s reliance on many of the
studies he cited in support of his opinions. We therefore turn next to examining whether
the trial court erred in concluding that the materials cited by Dr. Smith were not a reliable
basis upon which to form the opinion that Actos® causes bladder cancer, and caused it in
Cooper’s case.
       3. The Epidemiological Studies
       In finding Dr. Smith’s testimony unreliable, the court examined the
epidemiological studies upon which Dr. Smith relied and pointed out specific problems
and “flaws” in each of them, questioning whether epidemiological studies can generally
be used as a basis for a differential diagnosis. The court concluded that the studies did
not serve as reasonable bases for Dr. Smith’s specific causation opinion, and “do not
‘actually support’ Dr. Smith’s reasoning.” In doing so the trial court was substituting its
opinion for the opinion of Dr. Smith and the opinions of the authors of the studies. This
is not the proper function of the trial court.
       Specifically, the trial court noted that the authors of the KPNC nested case control
study cautioned against use of the data in the study for making risk assessment. The trial
court categorically found unreliable the studies upon which Dr. Smith relied based on the
study’s “secondary endpoint” data because Dr. Smith admitted that secondary endpoint
data must be viewed with caution. The court pointed out that Dr. Smith had reviewed the

without citing any basis for eliminating these factors. However, we find adequate
Dr. Smith’s explanation that describing these things as risk factors or demographics is a
matter of semantics. Importantly, however, Dr. Smith stated that all of the
epidemiological studies upon which he relied had adjusted for age, sex, and race. Thus,
the trial court’s criticism that he eliminated those factors without any basis is factually
incorrect.

                                                 36
PROactive study, the Lewis paper in 2011, and the Piccinni paper, prior to his retention
as an expert in this case, and at that time found the data in those studies was insufficient
for him to reach the opinion that Actos® can cause bladder cancer. The trial court also
discounted the reliability of two studies upon which Dr. Smith relied that found a
statistically significant association between Actos® and bladder cancer in the primary
endpoint data, the Azoulay and Neumann studies. The court dismissed the results of the
Neumann study because its authors changed methodology after beginning the study, and
the positive association in the study came only after the authors excluded 250,000 of the
original patients; in the study as originally conceived, no significant association was
found. In addition, the court found the study to be seriously flawed because the primary
endpoint studied the association between “ever and never users” of Actos®. The authors
themselves also noted several key limitations in their study, including that it “ ‘lack[ed]
data on tobacco use, know[n] to be the third main risk factor for bladder cancer after age
and male sex” and that it did not “ ‘report data on the duration of diabetes.’ ”
       The court also concluded that the Azoulay study “suffers from fundamental flaws”
in that the Azoulay authors admitted the research database they used lacked data on other
occupational exposures, race, and family history of bladder cancer. The Azoulay study
also did not control for smoking based on the number of years the subject smoked, when
they smoked, or how much they smoked. In short, the court concluded that “neither the
Neumann study nor the Azoulay study (which, again, were the only two studies relied on
by Dr. Smith whose primary endpoints were statistically significant) serve as ‘reasonable
[bases]’ for Dr. Smith’s specific causation opinion. Sargon, supra, 55 Cal.4th at 772.”
       To the extent the trial court found inadmissible Dr. Smith’s opinions based on its
conclusion that the epidemiological studies on which Dr. Smith relied lacked scientific
validity, the court abused its discretion. In briefing filed in the trial, Cooper set forth
detailed information refuting the criticisms of the epidemiological studies leveled by
Takeda and later by the trial court. This material demonstrates that the trial court’s
rejection of these studies was too simplistic, because it did not take into account the
varied scientific principles involved in determining the validity of the studies.

                                              37
       As an example, Cooper pointed out that Takeda’s experts said of the protocol for
the KPNC study, which they authored, that “Although the primary analysis will examine
‘ever exposure’ to Actos, we will conduct additional analyses that account, one at a time,
for these two aspects of exposure [ever exposure and dose response]. We hypothesize
that a true biological effect would be greatest among long-term users and expect to see a
greater effect in patients who began the medications longest ago.” In other words, the
study was designed to look first at “ever exposure” to Actos® as the primary endpoint
and then at length of exposure (“dose response”) as the secondary endpoint. The study
authors anticipated that the secondary endpoint would be essential to help determine if
Actos® functions as a cancer initiator, in which case brief exposures might be crucial, or
if Actos® functions as a promoter, such that the amount of exposure might be more
important.
       As to the Neumann study, Dr. Smith testified that the study was significant, aside
from its methodological shortcomings, because of the very large sample size involved. In
addition, the study’s author explained that the study was altered after its initiation so the
maximum age of participants was 79 because “[t]he misclassification of bladder cancer
cases in this age group is such that it did not appear feasible to draw any valid
conclusions, which is why we decided to limit our analysis to results obtained in patients
aged 40 to 79 years.” The author also pointed out countervailing factors mitigating the
absence of covariates such as history of diabetes and smoking (i.e., diabetes duration was
in fact estimated by other means, and the study result viewed in relation to smoking
suggested a possible underestimation of the risk of bladder cancer related to exposure to
Actos®).
       Regarding the Azoulay study, published in the British Medical Journal, the authors
acknowledged the database they used lacked information on risk factors for bladder
cancer such as arsenic, occupational exposures, race/ethnicity, and family history of
bladder cancer. They continued, “However, it is unlikely that these variables were
differentially distributed between ever users of pioglitazone and ever users of other oral
hypoglycaemic agents. Thus we do not believe that the absence of these variables

                                              38
affected the internal validity of the study, although residual confounding may still be
present.” (Italics added.) The database did contain information on several important
confounders, such as body mass index, excessive alcohol use, and smoking. In addition,
the study had the distinct strength of relying on a large cohort of patients with type 2
diabetes, followed for up to 22 years, enabling the identification of a large number of
bladder cancer cases with varying durations of diabetes. The database also contained
prerecorded information on prescriptions, thus eliminating the possibility of recall bias.
       From the foregoing discussion we mean to illustrate and emphasize that the
validity of these studies, and both their strengths and their weaknesses, are subject to
considerable scientific interpretation and debate. The trial court abused its discretion by
essentially stepping in and resolving the debate over the validity of the studies. In
particular, the trial court’s piecemeal rejection of individual studies was inappropriate and
ignored the testimony by Drs. Neugut and Smith that the results of the individual studies
considered as a whole, including in the meta-analyses, was what really persuaded them
that Actos® causes bladder cancer. All studies have limitations and flaws, and it is
entirely valid to interpret each study’s results by taking into account these limitations and
flaws. However, it is essential that the results of other studies conducted by other
scientists on the same subject, that aim to correct for the limitations and flaws in prior
studies, be taken into account, and the body of studies be considered as a whole.17 As
Dr. Neugut testified, any one study can be criticized, but if most studies consistently
reach a similar answer, that gives confidence to an epidemiologist that the answer is
correct.
       As recognized by the trial court here, “courts must also be cautious in excluding
expert testimony. The trial court’s gatekeeping role does not involve choosing between
competing expert opinions. The high court warned that the gatekeeper’s focus ‘must be

17     For example, the Colmers meta-analysis showed a significant increased risk of
bladder cancer with Actos®, as did the Bosetti article, which was a meta-analysis
involving 17 studies that had both positive and negative findings.

                                             39
solely on principles and methodology, not on the conclusions that they generate.’
(Daubert v. Merrell Dow Pharmaceuticals, Inc. [(1993)] 509 U.S. [579,] 595.) The
advisory committee on the 2000 amendments to Federal Rules of Evidence, rule 702
(28 U.S.C.), which codified the rule established in Daubert, noted that the trial court’s
task is not to choose the most reliable of the offered opinions and exclude the others:
‘When a trial court, applying this amendment, rules that an expert’s testimony is reliable,
this does not necessarily mean that contradictory expert testimony is unreliable. The
amendment is broad enough to permit testimony that is the product of competing
principles or methods in the same field of expertise.’ (Advisory Com. Notes to Fed.
Rules Evid., rule 702, 28 U.S.C.)
       “The trial court’s preliminary determination whether the expert opinion is founded
on sound logic is not a decision on its persuasiveness. The court must not weigh an
opinion’s probative value or substitute its own opinion for the expert’s opinion. Rather,
the court must simply determine whether the matter relied on can provide a reasonable
basis for the opinion or whether that opinion is based on a leap of logic or conjecture.
The court does not resolve scientific controversies. Rather, it conducts a ‘circumscribed
inquiry’ to ‘determine whether, as a matter of logic, the studies and other information
cited by experts adequately support the conclusion that the expert’s general theory or
technique is valid.’ [Citation.] The goal of trial court gatekeeping is simply to exclude
‘clearly invalid and unreliable’ expert opinion. [Citation.] In short, the gatekeeper’s role
‘is to make certain that an expert, whether basing testimony upon professional studies or
personal experience, employs in the courtroom the same level of intellectual rigor that
characterizes the practice of an expert in the relevant field.’ [Citation.]” (Sargon, supra,
55 Ca1.4th at p. 772; italics added.)
       Indeed, the court purported to be following the dictates of Sargon. It stated in its
order: “As part of the Court’s duties under Evidence Code §802, as set forth in Sargon,
the Court ‘may inquire into . . . not only the type of material on which an expert relies,
but also whether that material actually supports the expert’s reasoning. “A court may
conclude that there is simply too great an analytical gap between the data and the opinion

                                             40
proffered.” ’ Sargon, 55 Cal.4th at 771[-772] (citing General Electric Co. v. Joiner
(1997) 522 U.S. 136, 146) (emphasis added).”
       We find that the trial court erred in excluding Dr. Smith’s opinion testimony
regarding specific causation as being clearly speculative, unreliable, lacking in
intellectual rigor, and based only on studies that did not actually support his reasoning.
Dr. Smith is one of the foremost experts in the world on bladder cancer, and provided
helpful and appropriate expert testimony to assist the jury in deciding the complicated
issue of whether Cooper’s cancer was caused by Actos®.
       The expert testimony rejected by the Supreme Court in Sargon provides a distinct
and illustrative contrast to the testimony wrongfully deemed inadmissible in the case
before us. In Sargon, the manufacturer of a novel dental implant brought an action for
breach of contract against a university with which it contracted to perform clinical testing
of the device. In support of the manufacturer’s claim for lost profits, an expert testified
that the small manufacturer, that had annual net profits of $101,000, would have become
a worldwide leader in the dental implant industry and would have earned profits ranging
from $200 million to $1 billion if the university had not breached its contract. The trial
court excluded that expert’s opinion as speculative and unreliable, and the Supreme Court
affirmed that ruling. The expert’s market share approach to computing lost profits was
based upon a comparison of Sargon to six large, multinational dental implant companies
that were the dominant market leaders in the industry. (Sargon, supra, 55 Cal.4th at
p. 756.) Unlike the comparator companies, Sargon had no meaningful marketing or
research and development organization, and no parent company to assist it. The expert
testified that the product was so innovative and superior that within 10 years Sargon
would have become the market leader. (Id. at p. 757.) He acknowledged that he had no
expertise in the dental implant field or in determining how innovative Sargon’s device
was, and that the damages calculation depended on the innovativeness of the product, as
well as his assumption that the market share of each of the six comparator companies
reflected its degree of innovativeness. The trial court deemed inadmissible the expert’s
testimony, finding “ ‘[t]o the extent that this ranking of “innovativeness,” . . . rests on the

                                              41
fact that some [dental implant companies] have larger market shares, it rests on nothing
more than a tautology. As there is no evidentiary basis that equates the degree of
innovativeness with the degree of difference in market share, the question posed to the
jury—to rank innovativeness and assign a market share, the sine qua non of [the expert’s]
opinion—has no rational basis.’ ” (Id. at pp. 763-764.) The expert testified that if there
had been no breach of contract, Sargon would have gone from a three-person operation to
sharing industry leadership with a multi-million dollar international corporation, and
would have done so in part by investing in research and development that would have
produced new products. (Id. at pp. 765-766.) The trial court found this to be
“ ‘absolutely devoid of any factual basis about an industry where he has no expertise.’ ”
(Id. at p. 766.)
       After the Court of Appeal reversed the trial court’s ruling, the Supreme Court
granted review and found that the trial court had not erred in excluding the expert’s
testimony. The high court concluded, “An accountant might be able to determine with
reasonable precision what Sargon’s profits would have been if it had achieved a market
share comparable to one of the ‘Big Six.’ The problem here, however, is that the expert’s
testimony provided no logical basis to infer that Sargon would have achieved that market
share. The lack of sound methodology in the expert’s testimony for determining what the
future would have brought supported the trial court’s ruling.” (Sargon, supra, 55 Cal.4th
at p. 781.)
       The Court observed, “The trial court’s preliminary determination whether the
expert opinion is founded on sound logic is not a decision on its persuasiveness. The
court must not weigh an opinion’s probative value or substitute its own opinion for the
expert’s opinion. Rather, the court must simply determine whether the matter relied on
can provide a reasonable basis for the opinion or whether that opinion is based on a leap
of logic or conjecture. The court does not resolve scientific controversies. Rather, it
conducts a ‘circumscribed inquiry’ to ‘determine whether, as a matter of logic, the studies
and other information cited by experts adequately support the conclusion that the expert’s
general theory or technique is valid.’ [Citation.] The goal of trial court gatekeeping is

                                            42
simply to exclude ‘clearly invalid and unreliable’ expert opinion. [Citation.]” (Sargon,
supra, 55 Cal.4th at p. 772.)
       The nature and reliability of Dr. Smith’s testimony in this case bears no
resemblance to the expert testimony in Sargon. In Sargon, the expert had no reasonable
basis for his opinion on lost profits, and reached his conclusions only by speculating and
making readily discernible leaps of logic. The same cannot be said about Dr. Smith’s
testimony. Although the trial court denied doing so, it did in fact weigh the probative
value of Dr. Smith’s opinion, and the studies upon which he relied, and substituted its
own opinion for Dr. Smith’s. The court did engage in settling a scientific controversy
when it looked piecemeal at a large body of epidemiological studies before finding the
expert’s opinion based on those studies wholly lacking in foundation, when it engaged in
an analysis of whether studies reporting secondary endpoints were inherently unreliable,
and when it disregarded other studies because it found the methodology, which was fully
explained to the scientific community in peer-reviewed journals, to be misleading. “The
courts’ evidentiary gatekeeping function is . . . not a warrant for judicial intervention in
genuine scientific debates over substantive principles.” (People v. Superior Court (Vidal)
(2007) 40 Cal. 4th 999, 1014.) The flaws in the study methodologies were explored in
detail through cross-examination and with the defense expert witnesses, and constituted
evidence that went to the weight and not the admissibility of Dr. Smith’s opinion
testimony based on those studies. Those were matters for the jury to decide. Fortunately
the trial court allowed the jury to weigh those criticisms and explanations, and permitted
the jury to render a verdict which we may now restore.
       Even if the court had not found that Dr. Smith could not reasonably rely on the
epidemiological studies and that his opinion was unsupported by the materials, the trial
court questioned what other basis Dr. Smith had for his differential diagnosis, other than
ruling in Actos® based on the studies. The court noted that the studies showing an
increased risk of bladder cancer in people taking Actos®, “appeare[d] to be the one thing
that is ruled in,” but the court wanted an explanation of what, “in addition to the study,
does he have to show that Mr. Cooper got bladder cancer because of that? Because

                                              43
Dr. Smith says that he has a lot of patients in this age group who have bladder cancer, and
he can find no cause. So the question is what, in addition to these studies, is Dr. Smith
basing his differential diagnosis on.”
       The epidemiological studies relied on by Dr. Smith indicated exposure to Actos®
resulted in hazard ratios for developing bladder cancer ranging from 2.54 to 6.97.18 By
demonstrating a relative risk greater than 2.0 that a product causes a disease,
epidemiological studies thereby become admissible to prove that the product at issue was
more likely than not responsible for causing a particular person’s disease. “When
statistical analyses or probabilistic results of epidemiological studies are offered to prove
specific causation . . . under California law those analyses must show a relative risk
greater than 2.0 to be ‘useful’ to the jury. [Daubert v. Merrell Dow Pharmaceuticals Inc.
(9th Cir. 1995) 43 F.3d 1311, cert. den. 516 U.S. 869 [116 S. Ct. 189, 133 L. Ed. 2d 126]
Daubert II, at p. 1320. This is so, because a relative risk greater than 2.0 is needed to
extrapolate from generic population-based studies to conclusions about what caused a
specific person’s disease. When the relative risk is 2.0, the alleged cause is responsible
for an equal number of cases of the disease as all other background causes present in the
control group. Thus, a relative risk of 2.0 implies a 50% probability that the agent at
issue was responsible for a particular individual’s disease. This means that a relative risk
that is greater than 2.0 permits the conclusion that the agent was more likely than not
responsible for a particular individual’s disease. [Reference Manual on Scientific
Evidence (Federal Judicial Center 2d ed. 2000) (“Ref. Manual”),] Ref. Manual at 384,
n. 140 (citing Daubert II).” (In re Silicone Gel Breast Impl. Prod. Liab. Lit. (C.D.Cal.
2004) 318 F. Supp. 2d 879, 893; italics added.) Thus, having considered and ruled out

18      For example, the second Interim Nested Case Analysis of the Kaiser Permanente
study demonstrated that long-term users of Actos® had a relative risk for bladder cancer
of 4.6. Takeda’s own meta-analysis of its clinical trials showed a statistically significant
hazard ratio of 2.642. In Azoulay, the authors found a statistically significant hazard
ratio of 2.54 for patients exposed to more than 28,000 mg of Actos®.

                                             44
other background causes of bladder cancer based on his medical records, Dr. Smith could
conclude based on the studies that it was more likely than not that Cooper’s exposure to
Actos® caused his bladder cancer. In other words, because the studies, to varying
degrees, adjusted for race, age, sex, and smoking, as well as other known causes of
bladder cancer, Dr. Smith could rely upon those studies to make his differential diagnosis
ruling in Actos®—as well as smoking—and concluding that Actos® was the most
probable cause of Cooper’s disease.
       4. Materials Reviewed After First Deposition
       We briefly note that the trial court also ruled that Dr. Smith could not rely for his
opinion at trial on the Mamtani study or Cooper’s deposition testimony, because he had
not reviewed those documents before his deposition. We conclude that this was error.
       Evidence Code section 801, subdivision (b) states an expert may base his or her
opinion on any reliable information “perceived by or personally known to the [expert]
witness or made known to him [or her] at or before the hearing.” The cases cited by the
court indeed held that an expert cannot state at trial undisclosed opinions. (See
Kennemur v. State of California (1982) 133 Cal. App. 3d 907, 919; Bonds v. Roy (1999)
20 Cal. 4th 140, 141, 148.) However, those cases are entirely distinguishable from the
one before us. In Kennemur, the court merely held that an expert must disclose the
general substance of his or her opinions through a designation or a deposition. In Bonds,
the court excluded an expert’s testimony where the proffered opinion was one the expert
had expressly disavowed at his deposition, also citing the rule that a party must disclose
“the general substance of an expert’s expected testimony.” (Bonds, supra, at p. 148.)
       Here, Dr. Smith’s expert designation, served on December 7, 2012, stated
“Dr. Smith will explain that Mr. Cooper’s distant history of smoking is far less likely
than Actos® to have contributed to his bladder cancer. Mr. Cooper smoked fewer than
three cigarettes per day before quitting in 1974.” He further stated he had performed a
differential diagnosis, and “ha[d] given careful consideration to, and ruled out other
confounding factors in causing Jack Cooper’s bladder cancer.” Dr. Smith was deposed
on December 7, 2012, and then again on February 12, 2013. At the second deposition, he

                                             45
stated that he had by then also reviewed the Mamtani article, and Takeda’s counsel
thoroughly examined Dr. Smith regarding the Mamtani study. Dr. Smith had also read
Cooper’s deposition transcript prior to his second deposition. In any event, Takeda never
pointed to any relevant information in the deposition which was not contained in the
medical records. We conclude that Dr. Smith was entitled to rely on both documents for
his opinion at trial. He had previously disclosed the general substance of his opinion, he
did not disavow that opinion at any time, and in any event, Takeda had the opportunity to
examine his opinion on those matters before trial.
II.    The Motion for New Trial Based on Instructional Error
       A.     Factual Background and Jury Instructions on Causation
       In addition to granting JNOV, the trial court also granted Takeda’s motion for new
trial, on two independent grounds. First, it concluded the evidence was insufficient to
support the jury’s verdict because “there is no evidence of specific causation in this
case,” the court having struck Dr. Smith’s testimony in that regard, and therefore
plaintiffs “could not have met their burden of showing that any failure to warn was a
substantial factor in causing harm” to Cooper. In view of the foregoing discussion, we of
course conclude that the court erred in granting the motion for new trial on this basis.
The evidence was clearly sufficient to support the jury’s finding that Actos® was a
substantial factor in causing Cooper’s bladder cancer.
       Second, the trial court concluded that it was error to have given what it had termed
in the jury instructions a “multiple causation” instruction. The court granted the motion
for new trial on the basis that the instruction should not have been given because it was
not supported by substantial evidence, since neither side introduced evidence of multiple
causation. The court further held that “the CACI 431 instruction was prejudicial and
probably affected the jury verdict, given the lack of evidence of concurrent causation”
because “[w]ithout the instruction, the jury would not have been in a position to consider
multiple concurrent causes.” This ruling was premised on the court’s perception that
there was no evidence offered that Actos® combined with some other cause resulting in

                                             46
Cooper’s development of cancer, and that Dr. Smith had specifically ruled out smoking
as a factor in causing Cooper’s bladder cancer.
       The court had also instructed the jury based on a version of CACI 430, entitled
“Causation: Substantial Factor,” as follows: “You have heard me mention the
requirement that conduct be a substantial factor in causing harm. A substantial factor in
causing harm is a factor that a reasonable person would consider to have contributed to
the harm. It must be more than a remote or trivial factor. It does not have to be the only
cause of the harm. [¶] Conduct is not a substantial factor in causing harm if the same
harm would have occurred without that conduct.”
       At Cooper’s request and over Takeda’s repeated objections, the court also gave the
“multiple causation instruction” (a version of CACI 431). As given, that instruction
stated that: “A person’s negligence may combine with another factor to cause harm. If
you find that Takeda’s negligence was a substantial factor in causing Mr. Cooper’s harm,
then Takeda is responsible for the harm. Takeda cannot avoid responsibility just because
some other person, condition, or event was also a substantial factor in causing
Mr. Cooper’s harm.”
       Takeda contends on appeal, as it did in the trial court in discussing jury
instructions and in its motion for new trial, that the instruction on multiple causation
should not have been given because neither Cooper nor Takeda presented evidence that
some other factor combined with Actos® to cause Cooper’s bladder cancer.
       B.     Discussion
       Based on our review of the record, we find that there was substantial evidence to
support the giving of the challenged instruction, and therefore the trial court committed
error in granting the motion for new trial on the ground that it should not have been given
and resulted in prejudice to Takeda.
       Dr. Smith did not rule out smoking as a potential cause of Cooper’s bladder
cancer. He said in conducting his differential diagnosis, after ruling out other exposures,
he “was really left with trying to evaluate smoking versus Actos as the most substantial
risk factors.” Dr. Smith stated that, compared to Actos®, smoking proved to be not as

                                             47
important a factor as Actos® in causing bladder cancer. He candidly admitted that
smoking “could be a cause of his bladder cancer.” When asked, “Doctor, you will agree,
would you not, sir, that Mr. Cooper’s history of smoking, whether it be 20 years or 40
years, certainly could be a cause of his bladder cancer?” He unambiguously replied in
the affirmative, and said that it was one of the things he ruled in.
       Dr. Smith testified that regardless of when Cooper stopped smoking, Actos®
ingestion was, in his opinion, more likely to have been the most substantial factor in
causing Cooper’s bladder cancer than his smoking history. He concluded: “[A]fter
review of all the potentials, differential diagnosis, ruling in, ruling out, carefully
evaluating the occupational, environmental, and smoking, that it’s my opinion that the
most substantial causative factor for Mr. Cooper was his length of Actos and cumulative
dose of Actos.” (Italics added.)
       From this testimony, it is evident that Cooper did not argue that he developed
bladder cancer only because he was exposed to Actos®. He allowed for the possibility
that his smoking history played a role as well. He sought, however, to convince the jury
that the effect of Actos® was more pronounced, that it played a significantly more
prominent role in his development of bladder cancer than did smoking. As such, we
conclude the jury was properly instructed.

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                                       DISPOSITION

       The trial court’s order granting Takeda’s judgment notwithstanding the verdict and
in the alternative its motion for new trial, filed June 27, 2013, and the trial court’s order
granting judgment in favor of Takeda, filed July 18, 2013, are reversed. The trial court is
ordered to enter judgment for Cooper in accordance with the jury verdict of April 26,
2013, without further proceedings. Plaintiff Cooper is to recover his costs on appeal.

                                                   ALDRICH, J.

We concur:

              EDMON, P. J.

              KITCHING, J.

                                              49
Filed 8/13/15
                           CERTIFIED FOR PUBLICATION

                IN THE COURT OF APPEAL OF THE STATE OF CALIFORNIA

                            SECOND APPELLATE DISTRICT

                                     DIVISION THREE

NANCY COOPER, Individually and as                       B250163
Successor, etc.,
                                                        (Los Angeles County
        Plaintiffs and Appellants,                      Super. Ct. No. CGC-12-518535)

        v.
                                                        ORDER CERTIFYING OPINION
TAKEDA PHARMACEUTICALS                                  FOR PUBLICATION
AMERICA, INC., et al.,                                  [NO CHANGE IN JUDGMENT]

        Defendants and Respondents.

THE COURT:
       The opinion in the above-entitled matter filed on July 16, 2015, was not certified
for publication in the Official Reports. For good cause it now appears that the opinion
should be published in the Official Reports and it is so ordered.
       [There is no change in the Judgment.]