Risperdal and Invega Cases ( 2020 )

Filed 5/8/20; Certified for Partial Publication 6/3/20 (order attached)
IN THE COURT OF APPEAL OF THE STATE OF CALIFORNIA
SECOND APPELLATE DISTRICT
DIVISION THREE
RISPERDAL AND INVEGA B284315, B284002,
CASES B284317
(Los Angeles County
Super. Ct. Nos. BC562540,
BC583302, BC604937)
(JCCP No. 4775)
APPEALS from judgments of the Superior Court of Los
Angeles County, William E. Highberger, Judge. Affirmed in part
and reversed in part.
Bernstein Liebhard and Daniel C. Burke for Plaintiff and
Appellant C.S.
Law Office of Martin N. Buchanan, Martin N. Buchanan;
Engstrom, Lipscomb & Lack and Ann Howitt for Plaintiffs and
Appellants J.D. and J.T.
Drinker Biddle & Reath, Rodney M. Hudson, William A.
Hanssen; Faegre Drinker Biddle & Reath and Rodney M. Hudson
for Defendants and Respondents.
——————————
C.S., J.D., and J.T. (collectively plaintiffs) were adolescents
who were prescribed the antipsychotic drug risperidone after it
was approved by the Food and Drug Administration (FDA) to
treat behavioral symptoms in children with autism. They allege
that risperidone caused them to develop gynecomastia, a
condition characterized by the enlargement of male breast tissue.
Plaintiffs sued risperidone’s manufacturers and distributors,
Janssen Pharmaceuticals, Inc.; Janssen Research and
Development, LLC; Johnson & Johnson; and McKesson
Corporation (collectively and interchangeably, Janssen) for
failure to adequately warn of the risk of gynecomastia on the
drug’s label. Janssen moved for summary judgment on federal
preemption grounds against plaintiffs. Janssen also moved for
summary judgment against the individual plaintiff, C.S., on the
ground that he could not raise a triable issue of fact under New
York’s proximate cause standard, which requires the patient to
show that the treating physician would have changed her
prescribing behavior had she had an adequate warning. The trial
court granted both motions. For the reasons set forth below, we
affirm the summary judgment against C.S., but reverse the
summary judgment decided on preemption grounds.
BACKGROUND
I. Janssen researches a pediatric indication for risperidone
Risperidone1 is an antipsychotic medication that was first
approved by the FDA in 1993 for managing manifestations of
psychotic disorders in adults. Risperidone elevates blood levels of
prolactin, a hormone produced by the pituitary gland. Elevated
1 Risperdal is the brand name for risperidone.
2
levels of prolactin (hyperprolactinemia) are associated with
gynecomastia.
After risperidone was approved for use in adults, Janssen
sought a pediatric indication to treat irritability associated with
autism in children. Before it sought FDA approval for pediatric
use, Janssen conducted five studies of prolactin levels and
prolactin-related side effects in 592 children who took risperidone
for disruptive behavior disorders. The combined results of these
five studies showed that the prolactin levels of children elevated
quickly after being put on risperidone, peaked during weeks four
through seven, then gradually declined. At weeks four through
seven, 70.5 percent of children had elevated prolactin levels.
Thirty of the 592 children, or five percent, developed prolactin-
related side effects, with gynecomastia being the most common.
The largest of the pediatric studies was an open label
risperidone only use study known as RIS-INT-41 (study 41).
(Croonenberghs et al., Risperidone in Children With Disruptive
Behavior Disorders and Subaverage Intelligence: A 1-Year, Open-
Label Study of 504 Patients (Jan. 2005) 44 Journal of the
American Academy of Child and Adolescent Psychiatry 64.) It
followed 504 children between the ages of five and 14 who used
risperidone over the course of one year. The results of study 41
showed that 5.5 percent of the boys in the study developed
gynecomastia. Janssen also conducted an extension study of
study 41 that followed 48 of the children who continued to take
risperidone for a second year known as RIS-INT-70 (study 70).
(Reyes et al., Long-Term Use of Risperidone in Children with
Disruptive Behavior Disorders and Subaverage Intelligence:
Efficacy, Safety, and Tolerability (2006) 16 Journal of Child and
3
Adolescent Psychopharmacology 260.) Study 70 showed that 14.3
percent of the children developed gynecomastia.
The pooled results of the five pediatric studies were
published in a 2003 article in the Journal of Clinical Psychiatry.
(Findling et al., Prolactin Levels During Long-Term Risperidone
Treatment in Children and Adolescents (Nov. 2003) 64 Journal of
Clinical Psychiatry 1357.) The purpose of the article was to
investigate prolactin levels in children taking risperidone and to
explore any relationship to “side effects hypothetically
attributable to prolactin” or “SHAP”, which included
gynecomastia.2 For the article, Janssen commissioned a
statistical analysis of the five pediatric studies that generated a
number of tables. One of those tables was table 21, which
compared subjects with elevated prolactin levels and those with
normal prolactin levels for different study time periods. For
children prescribed risperidone for a period of eight to 12 weeks,
table 21 showed that those with elevated prolactin levels were 2.8
times more likely to have suffered prolactin-related side effects,
particularly gynecomastia.
A July 2002 draft manuscript of the article circulated
internally within Janssen referred to the statistically significant
association between elevated prolactin in risperidone users and
prolactin related adverse events during weeks eight through 12.
In internal emails, Janssen officials expressed concerns about
how to deal with the table 21 statistics. One Janssen
representative stated, “I think we need to include the lack of
association between . . . [prolactin] level or SHAP, as our advisors
tell us that this is one serious concern about prolactin. If we can
2 SHAP is an acronym invented by Janssen. Gynecomastia
is the only prolactin-related side effect in males.
4
demonstrate that the transient rise in [prolactin] does not result
in abnormal maturation or SHAP, this would be most reassuring
to clinicians.” Another Janssen representative stated, “Key
message—prolactin rise is transient and not related to side
effects hypothetically attributed to prolactin.” Janssen then
commissioned a revised statistical analysis, which excluded all
findings of prolactin-related side effects in males 10 years or
older. With the revised data set, Janssen created a new table,
which was similar to table 21; however, it no longer showed any
statistical significance for prolactin-related side effects at weeks
eight through 12.
In October 2002, Janssen prepared another draft of the
article based on the revised statistics. The draft manuscript
claimed that there “was no statistical difference in the percentage
of patients who reported SHAP for any analysis time period,
whether or not prolactin levels were normal or above the ULN
[upper limit of normal] (range).” The final published version of
the article again omitted all prolactin-related side effects in boys
10 years of age or older, and did not mention or include the
original analysis results for weeks eight through 12. Table 21
was not disclosed by Janssen to the outside authors of the article.
II. The FDA approves risperidone’s label and pediatric
indication
In 2003, Janssen submitted a supplemental new drug
application seeking a pediatric indication for risperidone to treat
children with autism. Janssen submitted the pooled pediatric
safety data to the FDA. Janssen described the data pooling
portion of Janssen’s proposed statistical analysis plan, which
included data from autism studies as well as data from pediatric
5
disruptive behavior disorder studies. Janssen did not submit
table 21 as part of its application.
In July 2006, the FDA sent Janssen an approvable letter
for its application and attached proposed labeling that included
language describing the method for pooling pediatric safety
data.3 The FDA requested that Janssen specify the number of
pediatric patients in the studies. Janssen responded with two
proposals for calculating the number of patients for adverse event
purposes. The FDA found discrepancies in Janssen’s calculation,
noting that the “proposed labeling uses 1348 as the denominator
for the calculation of the rate of . . . ( . . . adverse events) in
pediatric clinical trials” while the other events observed during
the premarketing evaluation of risperidone section states that
risperidone was studied in 1,923 children. The FDA asked
Janssen to clarify the total number of patients exposed to
risperidone and to provide an updated percentage for
gynecomastia.
Janssen explained that the number of risperidone-treated
subjects across all studies of children and adolescents with
autism or disruptive behavior disorders was 1,348. The FDA
asked Janssen to include any new serious adverse events
experienced by children to the list of events observed during
premarketing evaluation and to include all pediatric studies
beyond autism and disruptive behavior disorders. These
3 An approvable letter is a written communication to an
applicant from the FDA stating that the agency will approve the
application if specific additional information or material is
submitted or specific conditions are met. (21 C.F.R. § 314.110(a)
(2019); see id. § 814.44(e)(2019) [describing approvable letters for
medical devices].)
6
additional studies brought the total number of risperidone-
treated subjects to 1,923.
The FDA’s revised label included 1,923 patients as a
denominator and a proposed calculation for the reported incident
rate specific to gynecomastia in the label. The FDA revised the
reported rate of gynecomastia from .03 percent to 2.7 percent.
Janssen responded to the FDA’s proposal by explaining that
1,923 pediatric patients was an accurate number; however,
38 patients were in an ongoing clinical study and full safety data
were not yet available. Janssen proposed a rate based on 1,885
patients, excluding the 38 patients from the ongoing study. This
brought the rate of gynecomastia to 2.3 percent. The 2.3 percent
rate included the results from studies 41 and 70.
In October 2006, the FDA approved the pediatric use of
risperidone for irritability associated with autistic disorder with
an updated label. Under the precautions section for pediatric
use, the label stated, “The efficacy and safety of [risperidone] in
the treatment of irritability associated with autistic disorder
were established in two 8-week, placebo-controlled trials in
156 children and adolescent patients, aged 5 to 16 years. . . .
Additional safety information was also assessed in a long-term
study in patients with autistic disorder, or in short- and long-
term studies in more than 1200 pediatric patients with other
psychiatric disorders who were of similar age and weight, and
who received similar dosages of [risperidone] as
patients . . . treated for irritability associated with autistic
disorder.”
The precautions section also contained a section on
hyperprolactinemia, stating, “As with other drugs that
antagonize dopamine D2 receptors, risperidone elevates prolactin
7
levels and the elevation persists during chronic administration.
Risperidone is associated with higher levels of prolactin elevation
than other antipsychotic agents. [¶] . . . [G]ynecomastia . . . ha[s]
been reported in patients receiving prolactin-elevating
compounds.” The label went on to state that “[r]isperidone has
been shown to elevate prolactin levels in children and adolescents
as well as in adults (see PRECAUTIONS—Hyperprolactinemia).
In double-blind, placebo-controlled studies of up to 8 weeks
duration in children and adolescents (aged 5 to 17 years), 49% of
patients who received risperidone had elevated prolactin levels
compared to 2% of patients who received placebo. [¶] In clinical
trials in 1885 children and adolescents with autistic disorder or
other psychiatric disorders treated with
risperidone, . . . gynecomastia was reported in 2.3% of risperidone
treated patients. [¶] The long-term effects of risperidone on
growth and sexual maturation have not been fully evaluated.”
Under adverse reactions and other events observed during the
premarketing of risperidone, the label stated that during
premarketing assessment, risperidone was administered to 2,607
adult patients and 1,923 pediatric patients. That same section
listed gynecomastia as “rare” and defined rare events to mean
those occurring in fewer than one in 1,000 patients.
III. Citizens petition
In July 2012, Sheller P.C. (Sheller), a law firm representing
hundreds of individuals who had taken risperidone, petitioned
the FDA to immediately revoke the pediatric indication for
risperidone unless and until the long-term safety of the drug
could be demonstrated, or in the alternative, require that the
risperidone label include a box warning based on the lack of
8
sufficient safety data (citizens petition).4 The citizens petition
alleged that the risperidone label did not reflect the long-term
safety data used to support risperidone’s pediatric indications
and it did not reflect the true risks posed by the drug. The
citizens petition alleged that the portion of the risperidone label
stating that gynecomastia was reported in 2 to 3 percent of
risperidone-treated patients was misleading and that the actual
rate of gynecomastia was five percent. The citizens petition also
alleged that the risperidone label failed to recommend that
physicians should closely monitor their adolescent patients’
prolactin levels, routinely examine them for abnormal breast
growth, and discontinue risperidone use at the first sign of any of
those symptoms.
In addition to requests for a box warning and revocation of
the pediatric indication, the citizens petition indicated that
Janssen was in possession of documents that substantiated the
allegations. However, those documents were subject to
confidentiality orders in other risperidone litigation and
petitioners were unable to supply those documents to the FDA.
The petition requested that the FDA obtain the documents
directly from Janssen or to release petitioners from the
confidentiality orders. In response, the FDA requested Janssen
to submit any data in its possession relevant to the use of
risperidone in children and adolescents that it had not previously
provided. Janssen responded that it had not identified any data
4 The FDA generally requires special problems with a drug,
particularly those that may lead to death or serious injury, to be
placed in a prominently displayed box on the label. (21 C.F.R.
§ 201.80(e) (2019).)
9
that it was required to submit pursuant to its statutory and
regulatory obligations.
The FDA denied the citizens petition, disagreeing with the
assertion that a lack of long-term safety data is a basis for either
revoking the pediatric indications for risperidone or adding a new
boxed warning. The FDA was concerned that revoking
risperidone’s pediatric indications until long-term safety could be
demonstrated “would be tantamount to a long-term or permanent
withdrawal, thereby removing an important and beneficial
therapeutic option for many children and adolescents with these
disorders.” The FDA stated that based on reviews of clinical data
submitted by Janssen, published literature, and postmarketing
surveillance, there was no evidence that risperidone was unsafe
or anything else that warranted revoking the pediatric indication
of the drug. The FDA also stated, “Gynecomastia is a common
clinical manifestation of hyperprolactinemia, regardless of
cause,[fn. omitted] and does not represent a serious adverse
event” as defined in 21 Code of Federal Regulations,
section 312.32 (a) (2019).5
5 “An adverse event . . . is considered ‘serious’ if . . . it
results in any of the following outcomes: Death, a life-
threatening adverse event, inpatient hospitalization or
prolongation of existing hospitalization, a persistent or
significant incapacity or substantial disruption of the ability to
conduct normal life functions, or a congenital anomaly/birth
defect. Important medical events that may not result in death,
be life-threatening, or require hospitalization may be considered
serious when, based upon appropriate medical judgment, they
may jeopardize the patient or subject and may require medical or
surgical intervention to prevent one of the outcomes listed in this
definition.” (21 C.F.R. § 312.32 (a) (2019).)
10
Further, the FDA found no basis for requiring a box
warning about the lack of long-term safety data associated with
pediatric use of risperidone. In response to the petitioner’s box
warning request, the FDA noted that risperidone is “known to
elevate blood levels of prolactin, a naturally occurring hormone
produced by the pituitary gland in the brain. Elevated levels of
prolactin (hyperprolactinemia) from any cause can be associated
with a number of clinical effects, including breast enlargement
(also called gynecomastia).” “The risk of hyperprolactinemia
associated with certain antipsychotics has been basic textbook
knowledge in psychiatry for many years.”
In its denial, the FDA noted that it was not responding to
any labeling requests other than the request for a box warning
and the revocation of the pediatric indication. “Although your
petition includes an extensive discussion of the current labeling
of [risperidone], you do not make specific labeling requests other
than . . . that FDA require a new boxed warning for Risperdal
and all generic versions of risperidone. We therefore do not
respond to your specific contentions regarding the current
labeling of these products.”
IV. C.S.
C.S. is a New York resident who was diagnosed with
autism and attention deficit hyperactivity disorder as a child. He
exhibited aggressive behavior including screaming, tantrums,
and physical aggression. C.S. and his mother consulted a child
psychiatrist to treat these behavioral symptoms. The
psychiatrist prescribed risperidone to C.S. from April 2009 to
July 2010.
Before prescribing a particular medication, the
psychiatrist’s practice was to review the risks and benefits with
11
her patients. At the time she prescribed risperidone to C.S., her
custom was to mention gynecomastia in “passing” but she did not
“delve into” it the way she would have with other side effects.
When presented with the results of study 70 which showed a
gynecomastia rate of 12.5 percent, the psychiatrist stated she
would have emphasized gynecomastia as a side effect to C.S.’s
mother and would have included it as part of her risk-benefit
analysis. She currently informs her patients that gynecomastia
is a potential side effect of risperidone use, but still emphasizes
other side effects more.
The psychiatrist’s records do not indicate that she
mentioned gynecomastia to C.S.’s mother or observed the
condition in C.S. The psychiatrist would have noted
gynecomastia in C.S.’s medical records if she had observed the
condition, or if either C.S. or his mother had mentioned it.
Indeed, C.S.’s medical records do not mention gynecomastia,
breast growth, or elevated prolactin during risperidone use. A
few months after C.S. stopped using risperidone, another
physician examined C.S. and found his chest to be “ ‘normal
contour, normal shape and expansion, clear to auscultation’ ” and
made the same observation five months later.
Two months after discontinuing risperidone, C.S. was
prescribed, haloperidol, another antipsychotic associated with
elevated prolactin. Haloperidol’s prescribing information in effect
at the time stated, “[a]ntipsychotic drugs elevate prolactin levels;
the elevation persists during chronic administration.” C.S. used
haloperidol from September 2010 through 2016. In November
2011, over a year after C.S. discontinued risperidone, a physician
noted C.S. had abnormal breast growth. In February 2015, C.S.
was diagnosed with idiopathic gynecomastia.
12
V. Procedural history
Plaintiffs, along with thousands of other individuals sued
Janssen, alleging that they developed gynecomastia from their
use of risperidone and that Janssen failed to adequately warn of
the risk. The complaints were coordinated and assigned to a
single trial court.
The trial court divided the cases into four separate groups:
individuals who used risperidone as children before the October
2006 label change; individuals who used risperidone as children
after the October 2006 label change; individuals who used
risperidone as children before and after the October 2006 label
change; and individuals who used Invega, but not risperidone.6
Plaintiffs are from the second group of individuals who used
risperidone after the October 2006 label change.
Janssen moved for summary judgment against six of the
plaintiffs who took risperidone after the 2006 label change,
including J.D., J.T., and C.S. Janssen asserted that their claims
were preempted by federal law governing prescription
medication. Janssen also moved for summary judgment on
nonpreemption grounds against C.S, arguing that C.S. could not
raise a triable issue of fact under New York’s proximate cause
standard. The trial court granted both motions.
J.D., J.T., and C.S. filed individual appeals. We
consolidated the appeals, ordered J.D. and J.T. to file joint
briefing on the preemption issue, and allowed C.S. to join in that
briefing and to file separate briefing on the nonpreemption issues
raised in the case-specific motion for summary judgment. After
6Invega is a risperidone-related drug. Individuals who
took Invega are not the subject of this appeal.
13
the appeals were fully briefed, the United States Supreme Court
decided Merck Sharp & Dohme Corp. v. Albrecht (2019) ___ U.S.
___, ___ [139 S. Ct. 1668] (Merck Sharp), addressing the same
preemption question at issue here. Janssen, J.D., and J.T. filed
supplemental briefs discussing Merck Sharp.
DISCUSSION
As noted above, there are two motions for summary
judgment at issue: one entered against a group of plaintiffs who
used risperidone after the FDA approved the 2006 label and
another on case-specific grounds against C.S. Regarding the
preemption issue, the parties dispute whether the trial court had
authority to determine the preemption question as matter of law
or whether it was required to submit underlying factual disputes
to a jury. On the merits, the parties contest whether Janssen
met its burden to show that plaintiffs’ claims were preempted.
With respect to the case-specific summary judgment against C.S.,
the parties dispute whether there is a triable issue of fact that
risperidone’s label proximately caused C.S. to develop
gynecomastia. We address each issue in turn.
I. Preemption
A. Preemption is decided as a matter of law
The parties’ first dispute is whether the trial court had
authority to decide the preemption issue as a matter of law.
Plaintiffs argue that the trial court overstepped its authority by
deciding the preemption issue in the face of underlying factual
disputes that should have been submitted to a jury. However,
the United States Supreme Court in Merck Sharp, supra,
139 S. Ct. 1668 rejected this argument. “[J]udges, rather than lay
juries, are better equipped to evaluate the nature and scope of an
14
agency’s determination. Judges are experienced in ‘[t]he
construction of written instruments,’ such as those normally
produced by a federal agency to memorialize its considered
judgments. [Citation.] And judges are better suited than are
juries to understand and to interpret agency decisions in light of
the governing statutory and regulatory context. [Citations.] To
understand the question as a legal question for judges makes
sense given the fact that judges are normally familiar with
principles of administrative law.” (Id. at p. 1680.) Merck Sharp
acknowledged that “brute facts will prove relevant to a court’s
legal determination about the meaning and effect of an agency
decision”; however, these factual questions are “subsumed within
an already tightly circumscribed legal analysis.” (Ibid.) They do
not “warrant submission alone or together with the larger pre-
emption question to a jury.” (Ibid.) Accordingly, the trial court
was correct to decide the issue without submitting any purported
underlying factual questions to a jury.
B. Plaintiffs’ claims are not preempted
Although the trial court had authority to decide the issue,
in light of Merck Sharp, it came to the wrong conclusion. Janssen
did not meet its burden to establish its preemption defense.
To understand plaintiffs’ theory of the case and Janssen’s
preemption defense, we provide an overview of FDA regulations
and the process followed by drug manufacturers to appropriately
label their drugs. “The FDA regulates the safety information
that appears on the labels of prescription drugs that are
marketed in the United States. [Citation.] Although we
commonly understand a drug’s ‘label’ to refer to the sticker
affixed to a prescription bottle, in this context the term refers
more broadly to the written material that is sent to the physician
15
who prescribes the drug and the written material that comes
with the prescription bottle when the drug is handed to the
patient at the pharmacy. [Citation.] These (often lengthy)
package inserts contain detailed information about the drug’s
medical uses and health risks.” (Merck Sharp, supra, 139 S.Ct.
at pp. 1672–1673.)
Federal regulations set out the requirements for the
content, format, and order of the safety information on a drug’s
label. (21 C.F.R. § 201.57(c) (2019).) The labels must include:
“(1) prominent ‘boxed’ warnings about risks that may lead to
death or serious injury; (2) contraindications describing any
situation in which the drug should not be used because the risk of
use outweighs any therapeutic benefit; (3) warnings and
precautions about other potential safety hazards; and (4) any
adverse reactions for which there is some basis to believe a causal
relationship exists between the drug and the occurrence of the
adverse event.” (Merck Sharp, supra, 139 S.Ct. at p. 1673.) The
section where a particular risk appears on a drug label is an
indicator of the likelihood and severity of the risk, ensuring that
less important information does not overshadow more important
information. (Ibid.) It prevents over exaggeration of risk and
excludes speculative or hypothetical risks such that appropriate
use of an otherwise beneficial drug is discouraged. (Ibid.)
A “central premise of federal drug regulation [is] that the
manufacturer bears responsibility for the content of its label at
all times.” (Wyeth v. Levine (2009) 555 U.S. 555, 570–571.) While
drug manufacturers work with the FDA to develop an
appropriate label when they apply for approval of a new drug, the
drug manufacturer, not the FDA, is responsible for crafting an
adequate label and ensuring that the warnings remain adequate
16
while the drug is on the market. (Ibid.; 21 U.S.C.S. § 355(a), (b),
& (d); 21 C.F.R. § 314.125(b)(6) (2019).) The drug manufacturer
has a duty to conduct postmarket surveillance and revise the
label as soon as there is reasonable evidence of an association of a
serious hazard with a drug. (21 C.F.R. §§ 201.80(e) (2019),
314.80(b) (2019).)
FDA regulations account for changes to drug safety
information changing over time that necessitate revisions to a
drug’s label. (21 C.F.R. §§ 314.80(c) (2019), 314.81(b)(2)(i)
(2019).) Substantive label changes generally require advance
FDA approval. However, an FDA regulation called the “ ‘changes
being effected’ ” or “ ‘CBE’ ” regulation permits drug
manufacturers to change a label without advanced approval if the
change is designed to add or strengthen a warning where there is
“ ‘newly acquired information’ ” about the “ ‘evidence of a causal
association’ ” between the drug and a risk of harm. (Merck
Sharp, supra, 139 S.Ct. at p. 1673; 21 C.F.R. § 314.70(c)(6)(iii)(A)
(2019).) “Newly acquired information is data, analyses, or other
information not previously submitted to the Agency, which may
include (but is not limited to) data derived from new clinical
studies, reports of adverse events, or new analyses of previously
submitted data (e.g., meta-analyses) if the studies, events, or
analyses reveal risks of a different type or greater severity or
frequency than previously included in submissions to FDA.”
(21 C.F.R. § 314.3(b) (2019).) Manufacturers cannot propose a
label change that is not based on newly acquired information and
supported by reasonable evidence of a causal association with the
drug. (21 C.F.R. §§ 314.70(c)(6)(iii)(A) (2019), 201.57(c)(6)(i)
(2019).) The FDA reviews CBE submissions and can reject label
17
changes even after the manufacturer has made them. (See
21 C.F.R. § 314.70(c)(6), (7) (2019).)
The FDA, however, has limited resources and
“manufacturers have superior access to information about their
drugs, especially in the postmarketing phase as new risks
emerge.” (Wyeth v. Levine, supra, 555 U.S. at pp. 578–579.) To
fill the void, “[s]tate tort suits uncover unknown drug hazards
and provide incentives for drug manufacturers to disclose safety
risks promptly.” (Id. at p. 579.) These lawsuits are a
complementary form of drug regulation and offer an important
layer of consumer protection. They also support the premise that
manufacturers always bear ultimate responsibility for their drug
labeling. (Ibid.)
In Wyeth v. Levine, supra, 555 U.S. at page 572, a patient
sued a drug manufacturer for a failure-to-warn claim after she
developed gangrene and her arm had to be amputated as a result
of her use of an antinausea drug. A physician’s assistant
administered the drug using the “IV-push method” whereby the
drug is injected directly into the patient’s vein. Using this
method greatly increased the risk that the drug could enter a
patient’s artery and cause irreversible gangrene. (Id. at p. 559.)
The drug manufacturer argued that the patient’s state-law
claims were preempted because it would have been impossible to
comply with both its state-law duties and federal labeling duties,
which require FDA approval of the exact text of a drug label. (Id.
at p. 568.) The United States Supreme Court observed, however,
that while typically, a manufacturer may only change a drug
label after it gets FDA approval for the change, the CBE
regulation makes an exception, permitting a manufacturer to
make certain changes to its label before receiving the FDA’s
18
approval. (Ibid.) For example, a manufacturer can “add or
strengthen a contraindication, warning, precaution, or adverse
reaction” without waiting for the FDA to approve the change.
(21 C.F.R. § 314.70(c)(6)(iii)(A) (2019).) Therefore, a drug
manufacturer can be held liable for a state law failure-to-warn
claim if it could have revised its label using the CBE process but
failed to do so. (See Merck Sharp, supra, 139 S.Ct. at pp. 1677–
1678.) Levine concluded that state-law failure-to-warn claims
concerning prescription drugs are preempted only where there is
clear evidence that the FDA would have rejected the proposed
label change. (Levine, at pp. 571–572.)
“ ‘[C]lear evidence’ is evidence that shows the court that the
drug manufacturer fully informed the FDA of the justifications
for the warning required by state law and that the FDA, in turn,
informed the drug manufacturer that the FDA would not approve
a change to the drug’s label to include that warning.” (Merck
Sharp, supra, 139 S.Ct. at p. 1672.) In this context clear evidence
is not a typical standard of proof. (Id. at p. 1679.) “Standards of
proof, such as preponderance of the evidence and clear and
convincing evidence, have no place in the resolution of this
question of law.” (Id. at p. 1685 (conc. opn. of Alito, J.).) “The
underlying question . . . is whether federal law (including
appropriate FDA actions) prohibited the drug manufacturer from
adding any and all warnings to the drug label that would satisfy
state law. And, of course, in order to succeed with that defense
the manufacturer must show that the answer to this question is
yes.” (Id. at p. 1678.)
This type of impossibility preemption is a demanding
defense. (Wyeth v. Levine, supra, 555 U.S. at p. 573.) Because
the CBE regulation permits changes, “a drug manufacturer will
19
not ordinarily be able to show that there is an actual conflict
between state and federal law such that it was impossible to
comply with both.” (Merck Sharp, supra, 139 S.Ct. at p. 1679.)
“[T]he very idea that the FDA would bring an enforcement action
against a manufacturer for strengthening a warning pursuant to
the CBE regulation is difficult to accept.” (Levine at p. 570.)
Plaintiffs assert that Janssen could have used the CBE
process to revise the risperidone label by: (1) warning of a direct
correlation between risperidone use and gynecomastia; (2) adding
a recommendation for regular monitoring of prolactin levels and
physical examinations of children taking the drug; (3) deleting
language on the label referring to gynecomastia as a rare event
occurring in fewer than 1/1000 patients; and (4) disclosing the
results of studies 41 and 70.
In support of their labeling contentions, plaintiffs argue
that table 21, studies 41 and 70 constitute newly acquired
information for purposes of the CBE regulation.
As an initial matter, we do not agree with plaintiffs that
studies 41 and 70 constitute newly acquired information. By
definition, newly acquired information is “information not
previously submitted to the [FDA].” (21 C.F.R. § 314.3(b)(4)
(2019).) The plaintiffs do not dispute that Janssen submitted the
results of both studies to the FDA as part of its application for a
pediatric indication. Thus, because the FDA had the results of
studies 41 and 70, they cannot serve as the basis for a CBE
submission. Further, to the extent plaintiffs argue that the
results of these studies demonstrated a higher rate of
gynecomastia than the 2.3 percent indicated on the label, the
FDA made clear in its discussions with Janssen during the
labeling process that it wanted adverse events, such as
20
gynecomastia, to be calculated from all sources and pooled to
ensure that all events across multiple studies were captured.
Because the FDA had studies 41 and 70, and it expressly asked
for the rate of gynecomastia to be calculated using pooled results
from all studies (not just the select few identified by plaintiffs),
there is clear evidence that the FDA was fully informed and
required Janssen describe the risk of gynecomastia in the
manner that it did.
Plaintiffs’ argument that the risperidone label was
inadequate because a section listed gynecomastia as a rare event
occurring in less than one in 1,000 patients, thus contradicting
the results of the pediatric studies, is also without merit. The
term “rare” appears in the section, other events observed during
the premarketing evaluation of Risperdal which states that
Risperdal was administered to 2,607 adult patients and
1,923 pediatric patients. The section goes on to state that events
are categorized by body system and listed in order of decreasing
frequency according to the following definitions: “frequent
adverse events are those occurring in at least 1/100 patients (only
those not already listed in the tabulated results from placebo–
controlled trials appear in this listing); infrequent adverse events
are those occurring in 1/100 to 1/1000 patients; rare events are
those occurring in fewer than 1/1000 patients.” Thus, it appears
this gynecomastia rate was in reference to all patients, not just
children. Plaintiffs have cherrypicked this language as well as
the pediatric studies to create a purported discrepancy in the
reported rate of gynecomastia on the risperidone label.
We are thus left with table 21 as a basis to support a
potential label change via the CBE regulation. It is undisputed
that Janssen did not submit table 21 during the application or
21
labeling process.7 Nevertheless, Janssen offers several
arguments why table 21 does not preclude its preemption
defense. First, table 21 is not newly acquired information
because it did not reveal risks of a different type or greater
severity or frequency and the analysis was based on the studies
submitted to the FDA. Janssen argues that the label warned of
the exact type of risk, gynecomastia, and table 21 does not change
the 2.3 percent rate. While it is true that table 21 does not
change the rate of gynecomastia reported on the label, Janssen’s
position overlooks the fact that table 21 provided additional
information with respect to elevated prolactin levels during
different time periods. Specifically, table 21 tended to show that
children who had elevated prolactin after taking risperidone for
eight to 12 weeks were 2.8 times more likely to develop prolactin-
related side effects, including gynecomastia. As the risperidone
label made no mention of the likelihood of developing side effects
related to elevated prolactin levels for different time periods, this
information demonstrated a risk of greater frequency then
reported on the label.
Second, Janssen argues that table 21 is not new and does
not support a label change because the FDA confirmed that
Janssen submitted all the necessary data and information to
conclude that risperidone was appropriately labeled. In support,
Janssen refers to the FDA’s statement in a reply brief filed in a
separate litigation between the FDA and Sheller, the law firm
that filed the citizens petition. The statement is of little value
here. Sheller sued the FDA, asserting it had to expend
unnecessary resources in various forums where it was suing
Janssen for risperidone-related injuries. The primary issue in
7 The FDA did not receive table 21 until October 2015.
22
the brief cited by Janssen was whether the law firm had standing
to sue the FDA for denying the citizens petition. This statement
is not clear evidence that the FDA would have rejected a CBE
submission based on table 21. Not only was it made in a wholly
different context, but “the only agency actions that can determine
the answer to the pre-emption question, . . . are agency actions
taken pursuant to the FDA’s congressionally delegated
authority.” (Merck Sharp, supra, 139 S.Ct. at p. 1679.) The FDA
can communicate its disapproval of a warning by means of notice-
and-comment rulemaking setting forth labeling standards, (see,
e.g., 21 U.S.C.S. § 355(d); 21 C.F.R. §§ 201.57 (2019), 314.105
(2019)); by formally rejecting a warning label that would have
been adequate under state law, (see, e.g., 21 C.F.R. §§ 314.110(a)
(2019), 314.125(b)(6) (2019)); or with other agency action carrying
the force of law (cf., e.g., 21 U.S.C.S. § 355(o)(4)(A)). The FDA’s
reference in a reply brief filed in a separate lawsuit in which the
agency is seeking to avoid liability, is not the type of official
action required by Merck Sharp.
Third, Janssen contends that, to the extent table 21
supports a monitoring recommendation, the CBE process does
not allow Janssen to unilaterally change an FDA-approved label
to make a monitoring recommendation. Janssen reasons that,
because monitoring recommendations are included in the
highlights section of a drug label (21 C.F.R. § 201.57(b)(2)(v)(C)
(2019)) and a change to that section requires prior approval from
the FDA, Janssen could not make that change via the CBE
process. Janssen’s argument misses the mark. Although the
highlights section may indicate certain “recommendations for
patient monitoring that are critical to safe use of the drug”
(21 C.F.R. § 201.57(a)(10) (2019)), it does not have to include all
23
of the same monitoring recommendations contained in the full
prescribing information, which need only be “helpful in following
the patient’s response or in identifying possible adverse
reactions.” (21 C.F.R. § 201.57(c)(6)(iii) (2019).) The highlights
section includes warnings and precautions and adverse reactions.
(21 C.F.R. § 201.57(a)(10), (11) (2019).) Thus, if the CBE process
could not be used to add any information that could conceivably
be included in the highlights section, the CBE process could
never be used to add any new warning, precaution, or adverse
reaction without FDA approval. This is contrary to the purpose
of the CBE process and the holdings in Wyeth v. Levine, supra,
555 U.S. 555.
We also reject Janssen’s assertion that the denial of the
citizens petition was clear evidence the FDA would have rejected
a proposed label change based on the evidence presented in
table 21. As stated above, the FDA did not have table 21 when it
denied the citizens petition. Impossibility preemption requires
the drug manufacturer to show that it fully informed the FDA.
Janssen did not. Nevertheless, Janssen argues that, because the
FDA rejected similar allegations in the citizens petition, the FDA
would have also rejected plaintiffs’ claims here. But the citizens
petition made a much broader request, asking the FDA to
essentially take risperidone off the market or include the risk of
gynecomastia in the box warning, the most serious type of
warning on the label. (See 21 C.F.R. § 201.57(c)(1) (2019)
[requiring contraindications leading to death or serious injury be
included in boxed warning].) In contrast, here, plaintiffs’
argument is that table 21 could have supported a label change
that included a recommendation to monitor prolactin levels at
certain periods while a patient was taking risperidone. The fact
24
that the allegations in the citizens petition were similar and
partly based on some of the evidence presented here does not
change our conclusion that the claims are distinct. Hypothetical
labeling changes and speculative future rejections are not clear
evidence of an impossibility preemption defense. (See Merck
Sharp, supra, at p. 1682 (conc. opn. of Thomas, J.).)
Accordingly, Janssen did not meet its burden to show by
clear evidence that it fully informed the FDA and, in turn, the
FDA rejected a proposed label change. Plaintiffs’ claims based on
the information in table 21 are not preempted.
II. C.S. cannot establish causation
Turning to the merits of Janssen’s case-specific summary
judgment against C.S., we find Janssen’s argument persuasive.
C.S. failed to raise a triable issue of fact with respect to causation
because there is no evidence that C.S.’s treating physician would
have changed her prescribing behavior had she been given a
different warning.
Summary judgment is proper when there are no triable
issues of material fact and the moving party is entitled to
judgment as a matter of law. (Code Civ. Proc., § 437c, subd. (c).)
“The purpose of the law of summary judgment is to provide
courts with a mechanism to cut through the parties’ pleadings in
order to determine whether, despite their allegations, trial is in
fact necessary to resolve their dispute.” (Aguilar v. Atlantic
Richfield Co. (2001) 25 Cal. 4th 826, 843.)
“A defendant who moves for summary judgment bears the
initial burden to show the action has no merit—that is, ‘one or
more elements of the cause of action, even if not separately
pleaded, cannot be established, or that there is a complete
defense to [that] cause of action.’ [Citation.] Once the defendant
25
meets this initial burden of production, the burden shifts to the
plaintiff to demonstrate the existence of a triable issue of
material fact. [Citation.] ‘From commencement to conclusion,
the moving party defendant bears the burden of persuasion that
there is no triable issue of material fact and that the defendant is
entitled to judgment as a matter of law.’ [Citation.] We review
the trial court’s ruling on a summary judgment motion de novo,
liberally construing the evidence in favor of the party opposing
the motion and resolving all doubts about the evidence in favor of
the opponent. [Citation.] We consider all of the evidence the
parties offered in connection with the motion, except that which
the court properly excluded.” (Grotheer v. Escape Adventures,
Inc. (2017) 14 Cal. App. 5th 1283, 1292–1293.)
Under New York law,8 a pharmaceutical “manufacturer’s
duty is to warn of all potential dangers in its prescription drugs
that it knew, or, in the exercise of reasonable care, should have
known to exist.” (Martin v. Hacker (1993) 83 N.Y.2d 1, 8.) This
duty to warn applies to the prescribing medical professional, not
the individual patient. (Id. at p. 9.) The basis for this rule is that
the physician acts as a learned intermediary between the
manufacturer and the patient, evaluating the patient’s needs,
assessing the risks and benefits of available drugs, and
supervising their use. (Glucksman v. Halsey Drug Co., Inc.,
(1990) 553 N.Y.S.2d 724, 726.) A plaintiff must demonstrate that
the warning was inadequate and that the failure to adequately
warn of the dangers of the drug was a proximate cause of his or
her injuries. (Ibid.) To establish proximate cause, “a plaintiff
must demonstrate that had a different, more accurate warning[ ]
8As C.S. is a New York resident, the parties do not dispute
that New York law applies.
26
been given, his physician would not have prescribed the drug in
the same manner.” (Alston v. Caraco Pharm., Inc. (S.D.N.Y.
2009) 670 F. Supp. 2d 279, 285.) A defendant is entitled to
summary judgment if the evidence establishes “that any given
warning would have been futile—either because any such
warnings would not have been heeded or because the injury
would have occurred, regardless of the given warnings.” (Bee v.
Novartis Pharms. Corp. (E.D.N.Y. 2014) 18 F. Supp. 3d 268, 284.)
C.S. argues that he is entitled to a heeding presumption,
i.e., had Janssen given an adequate warning, C.S.’s physician
would have followed it. Janssen counters that New York does not
recognize a heeding presumption. The only New York case that
is directly on point and contains a lengthy discussion of the
heeding presumption is Castorina v. A.C. & S. (2017) 49 N.Y.S.3d
238, a decision by the Supreme Court, New York County.
Castorina at pages 242 and 243 found that the heeding
presumption has not been unequivocally recognized as part of
New York law and, even if there were a presumption required by
state decisional law, there is authority that has restricted its use
to where the individual who would have heeded the warnings is
not available to testify. As Castorina is the only New York case
on point, we adopt its rule that where, as here, the physician was
available to and actually did testify, plaintiff must prove that an
adequate warning would have been heeded.
This leads us to Janssen’s argument that C.S. failed to
raise a triable issue with respect to whether his treating
physician would have heeded a different warning and not
prescribed risperidone in the same manner. According to
Janssen, C.S. must show that his psychiatrist would not have
prescribed risperidone had she been given a different warning.
27
C.S., on the other hand, suggests that any alteration to his
psychiatrist’s prescribing behavior is enough. Based on the
authorities relied on by both parties, the answer lies somewhere
in between.
In another risperidone case, Chandler v. Janssen Pharms.,
Inc. (E.D.N.Y. 2018) 322 F. Supp. 3d 314, the trial court granted
summary judgment in favor of Janssen. The plaintiff’s treating
physician testified that he was not sure he would have changed
his decision even if he knew the risk of gynecomastia was higher
than the rate on the drug label. (Id. at p. 328.) Just as testified
here, the physician stated he would have done a risk-benefit
analysis and considered gynecomastia as a potential risk and
weighed it against the potential benefits of keeping his patient on
the drug. (Ibid.) These statements were not enough to defeat
summary judgment.
In contrast, in Bee v. Novartis Pharms. Corp., supra,
18 F. Supp. 3d 268, the trial court found genuine issues of material
fact existed as to whether the patient’s prescribing and treating
physicians would have acted differently if the drug manufacturer
had provided a different warning. There, the patient alleged that
he developed osteonecrosis of the jaw (bone death caused by poor
blood supply) because the drug manufacturer failed to warn
about the risk that tooth extraction, or other forms of invasive
dental work, would trigger the condition. (Id. at pp. 273, 286.)
The physician testified that, since he learned of the drug’s side
effects, he distributes handouts about the drug, informs his
patients about the benefits of the drug, discusses the risk of
developing the condition, provides patients with instructions for
their dental providers, and warns patients not to undergo dental
work until they have stopped taking the drug unless it is an
28
absolute emergency. (Id. at pp. 293–294.) This testimony was
sufficient to raise a triable issue of fact with respect to proximate
cause as there was a question of whether a different label altered
the treating physician’s behavior.
In Davids v. Novartis Pharms. Corp. (E.D.N.Y. 2012)
857 F. Supp. 2d 267, a case involving the same drug as Bee, the
trial court found a genuine issue of material fact as to whether
the patient’s treating physician would have prescribed the drug
had she been given a different warning. Again, the treating
physician testified that she would have referred the patient to a
dental specialist to evaluate his dental health before making her
prescribing decision. (Davids, at p. 288.)
In McDowell v. Eli Lilly and Co. (S.D.N.Y. 2014) 58
F. Supp. 3d 391, the trial court granted summary judgment in
favor of the drug manufacturer finding that the discontinuation
warning on the label of an antidepressant was not the proximate
cause of the plaintiff’s injuries. The plaintiff’s treating physician
stated that he preferred that particular antidepressant over other
medications used to treat the same conditions. He also testified
that knowing incident rates of certain withdrawal symptoms
would not have changed his decision to prescribe the drug. The
only thing that the doctor would have changed was that he would
have emphasized the withdrawal symptoms. This was not
enough to raise a triable issue under New York’s proximate cause
standard.
We find the above district court cases instructive and
conclude that the psychiatrist’s testimony dooms C.S.’s claim.
When presented with the results of the individual studies that
showed a higher rate of gynecomastia among pediatric patients,
the psychiatrist did not indicate whether her decision to prescribe
29
risperidone would have changed. Rather, the psychiatrist
equivocated, stating that, while she would include the higher rate
in her risk-benefit analysis, risperidone may have still been the
best choice for C.S. At the time, there were only two medications
on the market approved to treat C.S.’s symptoms. The
psychiatrist stated that she would still have to balance the side
effects of risperidone with the only other available drug that had
the side effect of making “kids feel[ ] like they’re jumping out of
their skin.” When presented with the results of study 70, the
psychiatrist said, “[i]t may or may not have changed the choice of
medicine.” The psychiatrist acknowledged that she “was treating
a really sick kid and I felt I did right by that kid, so I just don’t
want to mix things up. I didn’t know—I didn’t know this
information at the time. But I was aware that gynecomastia
could be a side effect.” The psychiatrist’s statements are not
enough to raise a triable issue of fact with respect to whether she
would have altered her behavior. C.S. had to show something
more than the psychiatrist’s ambiguous statements that she may
have still prescribed risperidone and would have spent more time
explaining gynecomastia as a side effect.
C.S. failed to carry his burden to establish that his
physician would have heeded the warning. Therefore, summary
judgment was correctly entered against C.S.
30
DISPOSITION
The judgments entered against J.D. and J.T. are reversed.
The judgment entered against C.S. is affirmed. The parties are
to bear their own costs on appeal.
DHANIDINA, J.
We concur:
LAVIN, Acting P. J.
EGERTON, J.
31
Filed 6/3/20
CERTIFIED FOR PARTIAL PUBLICATION*
IN THE COURT OF APPEAL OF THE STATE OF CALIFORNIA
SECOND APPELLATE DISTRICT
DIVISION THREE
RISPERDAL AND INVEGA B284315, B284002,
CASES B284317
(Los Angeles County
Super. Ct. Nos. BC562540,
BC583302, BC604937)
(JCCP No. 4775)
CERTIFICATION AND
ORDER FOR PARTIAL
PUBLICATION
The opinion in the above-entitled matter filed May 8, 2020,
was not certified for publication in the Official Reports. For good
cause it now appears that the opinion should be partially published
in the Official Reports and it is so ordered.
DHANIDINA, J. LAVIN, Acting P. J. EGERTON, J.
* Pursuant to California Rules of Court, rules 8.1105 and 8.1110,
this opinion is certified for publication with the exception of part IV
of the Background and part II of the Discussion.