Pamela Rheinfrank v. Abbott Laboratories, Inc., et al

Filing

OPINION filed : AFFIRMED the district court's grant of summary judgment and its denial of a nrew trial, decision not for publication. Martha Craig Daughtrey, Circuit Judge; John M. Rogers, Circuit Judge AUTHORING and Deborah L. Cook, Circuit Judge.

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NOT RECOMMENDED FOR PUBLICATION
File Name: 17a0116n.06

FILED

No. 16-3347

Feb 21, 2017
DEBORAH S. HUNT, Clerk

UNITED STATES COURT OF APPEALS
FOR THE SIXTH CIRCUIT
PAMELA RHEINFRANK, individually, and as
Parent and Natural Guardian of M.B.D.,
Plaintiff-Appellant,
v.
ABBOTT LABORATORIES, INC.; ABBVIE, INC.,
Defendants-Appellees.

BEFORE:

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ON APPEAL FROM THE
UNITED STATES DISTRICT
COURT FOR THE SOUTHERN
DISTRICT OF OHIO

DAUGHTREY, ROGERS, and COOK, Circuit Judges.

ROGERS, Circuit Judge. This state-law product liability case arose from birth defects in
the form of serious physical and cognitive disabilities suffered by plaintiff Rheinfrank’s child.
The defects were allegedly caused by the antiepileptic drug Depakote, manufactured by
defendant Abbott Laboratories, and taken by Rheinfrank while pregnant with the child.
Rheinfrank contended that the labeling on the drug was not adequate. The district court held that
Rheinfrank’s Ohio law failure-to-warn claim—to the extent that it was based on Abbott’s failure
to warn of the risk of developmental delays—was preempted by federal drug labeling law
because the Food and Drug Administration had rejected label changes containing such warnings
even well after Rheinfrank’s pregnancy. A jury found for Abbott on several remaining claims,
and Rheinfrank appeals the overall judgment for defendant. Each of Rheinfrank’s contentions on
appeal is not sufficient to warrant reversal. The district court’s preemption analysis was correct.

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With respect to the jury verdict, the district court did not abuse its discretion in putting limits on
expert testimony related to the scope of the experts’ respective expertise, or by rejecting
requested jury instructions that were repetitive, confusing, or both.
I.
For nearly her entire life Rheinfrank has suffered from epilepsy. In 1988, after a relapse
of her epileptic seizures, she began taking two antiepileptic drugs, one of them Depakote. She
continued that course of treatment over the next fifteen years, including the years she was
pregnant with each of her first four children. Late in 2003, while she was still on her daily
regimen of the two drugs, Rheinfrank became pregnant with her fifth child, M.B.D. While she
was carrying M.B.D. she continued to take both antiepileptic drugs daily.

In July 2004

Rheinfrank gave birth to M.B.D., who was later diagnosed with physical deformities and
cognitive disabilities, including Fetal Valproate Syndrome. Those disabilities Rheinfrank now
blames on her daily use of Depakote.
The Food and Drug Administration (FDA) first approved Depakote in early 1983, and, by
the time Rheinfrank was first prescribed the drug in 1988, it had also been designated a
Pregnancy Category D drug by the FDA. As of 2003, the drug’s label accordingly included a
“Black Box Warning” cautioning about the risks the drug posed to developing fetuses:
TERATOGENICITY:
VALPROATE CAN PRODUCE TERATOGENIC EFFECTS SUCH AS
NEURAL TUBE DEFECTS (E.G., SPINA BIFIDA). ACCORDINGLY, THE
USE OF DEPAKOTE TABLETS IN WOMEN OF CHILDBEARING
POTENTIAL REQUIRES THAT THE BENEFITS OF ITS USE BE WEIGHED
AGAINST THE RISK OF INJURY TO THE FETUS. THIS IS ESPECIALLY
IMPORTANT WHEN THE TREATMENT OF A SPONTANEOUSLY
REVERSIBLE CONDITION NOT ORDINARILY ASSOCIATED WITH
PERMANENT INJURY OR RISK OF DEATH (E.G., MIGRAINE) IS
CONTEMPLATED. SEE WARNINGS, INFORMATION FOR PATIENTS. AN
INFORMATION SHEET DESCRIBING THE TERATOGENIC POTENTIAL
OF VALPROATE IS AVAILABLE FOR PATIENTS.
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The “Usage and Pregnancy” section of the same label further underlined these risks:
Usage in Pregnancy
ACCORDING TO PUBLISHED AND UNPUBLISHED REPORTS,
VALPROIC ACID MAY PRODUCE TERATOGENIC EFFECTS IN THE
OFFSPRING OF HUMAN FEMALES RECEIVING THE DRUG DURING
PREGNANCY. THERE ARE MULTIPLE REPORTS IN THE CLINICAL
LITERATURE WHICH INDICATE THAT THE USE OF ANTIEPILEPTIC
DRUGS DURING PREGNANCY RESULTS IN AN INCREASED INCIDENCE
OF BIRTH DEFECTS IN THE OFFSPRING. ALTHOUGH DATA ARE MORE
EXTENSIVE
WITH
RESPECT
TO
TRIMETHADIONE,
PARAMETHADIONE, PHENYTOIN, AND PHENOBARBITAL, REPORTS
INDICATE A POSSIBLE SIMILAR ASSOCIATION WITH THE USE OF
OTHER ANTIEPILEPTIC DRUGS. THEREFORE, ANTIEPILEPSY DRUGS
SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING
POTENTIAL ONLY IF THEY ARE CLEARLY SHOWN TO BE ESSENTIAL
IN THE MANAGEMENT OF THEIR SEIZURES.
THE INCIDENCE OF NEURAL TUBE DEFECTS IN THE FETUS MAY BE
INCREASED IN MOTHERS RECEIVING VALPROATE DURING THE
FIRST TRIMESTER OF PREGNANCY. THE CENTERS FOR DISEASE
CONTROL (CDC) HAS ESTIMATED THE RISK OF VALPROIC ACID
EXPOSED WOMEN HAVING CHILDREN WITH SPINA BIFIDA TO BE
APPROXIMATELY 1 TO 2%. OTHER CONGENITAL ANOMALIES (E.G.,
CRANIOFACIAL DEFECTS, CARDIOVASCULAR MALFORMATIONS
AND ANOMALIES INVOLVING VARIOUS BODY SYSTEMS),
COMPATIBLE AND INCOMPATIBLE WITH LIFE, HAVE BEEN
REPORTED. SUFFICIENT DATA TO DETERMINE THE INCIDENCE OF
THESE CONGENITAL ANOMALIES IS NOT AVAILABLE. THE HIGHER
INCIDENCE OF CONGENITAL ANOMALIES IN ANTIEPILEPTIC DRUGTREATED WOMEN WITH SEIZURE DISORDERS CANNOT BE
REGARDED AS A CAUSE AND EFFECT RELATIONSHIP. THERE ARE
INTRINSIC METHODOLOGIC PROBLEMS IN OBTAINING ADEQUATE
DATA ON DRUG TERATOGENICITY IN HUMANS; GENETIC FACTORS
OR THE EPILEPTIC CONDITION ITSELF, MAY BE MORE IMPORTANT
THAN DRUG THERAPY IN CONTRIBUTING TO CONGENITAL
ANOMALIES.

Both before and during her pregnancy with M.B.D. in 2003 and 2004, Rheinfrank had received
her prescription for Depakote from Dr. Dagmar Lemus, then a resident of internal medicine at
Cincinnati’s Good Samaritan Hospital. Although Lemus claimed that she did not remember

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prescribing Depakote to Rheinfrank, she nevertheless insisted that she would have relayed the
information on the Black Box warning before prescribing the drug. Lemus further explained that
she would never have relied on any promotional or other materials when deciding to prescribe
the drug to Rheinfrank.
In April 2005, Abbott Laboratories1 sent a letter to Dr. Russell Katz of the FDA to
propose an update to the already-approved label for Depakote. Abbott had learned of some of
the early results of a study then being led by Dr. Kimford Meador, investigating the
neurodevelopmental effects of antiepileptic drugs like Depakote on young children (the “NEAD
study”). That study uncovered preliminary evidence of “possible developmental delay in some
children exposed to [Depakote] in utero.” In response to these reports Abbott put together a
Prior Approval Supplement (“PAS”) that proposed changing Depakote’s label to “provid[e]
revised information related to teratogenicity and additional information for developmental delay
and include revisions to the WARNINGS—Usage in Pregnancy and the Patient Information
Leaflet sections.” Accompanying that supplement were two additional changes: “[a]n outline of
safety-related changes for teratogenicity/developmental delay and DDI with topiramate” and
“[n]ew information concerning the use of valproate in women of childbearing potential:
teratogenicity and developmental delay.”
Also among the revisions Abbott proposed for Depakote’s label was the inclusion of new
language under its “Usage in Pregnancy” section, reading in relevant part:
THERE ARE DATA THAT SUGGEST AN INCREASED INCIDENCE OF
CONGENITAL MALFORMATIONS ASSOCIATED WITH THE USE OF
VALPROIC ACID DURING PREGNANCY WHEN COMPARED WITH SOME
OTHER ANTIEPILEPTIC DRUGS. THEREFORE, VALPROIC ACID SHOULD
BE CONSIDERED FOR WOMEN OF CHILDBEARING POTENTIAL ONLY
1

Abbott Laboratories separately incorporated its pharmaceutical business as “AbbVie” in 2013. Both are named
defendants, and for convenience we refer to them as “Abbott Laboratories” or “Abbott” in this opinion.

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AFTER THE RISKS HAVE BEEN THOROUGHLY DISCUSSED WITH THE
PATIENT AND WEIGHED AGAINST THE POTENTIAL BENEFITS OF
TREATMENT.
...
THERE HAVE BEEN REPORTS OF DEVELOPMENTAL DELAY IN THE
OFFSPRING OF WOMEN WHO HAVE RECEIVED VALPROIC ACID DURING
PREGNANCY.
Abbott further proposed new language under the “Information for Women Who Could Become
Pregnant” section of its Patient Information Leaflet:
These medications have also been associated with other birth defects such as
defects of the heart, the bones, and other parts of the body. Information suggests
that birth defects may be more likely to occur with these medications than some
other drugs that treat your medical condition. In addition, there have been reports
of developmental delay in children born to women taking these medications.
In support of these modifications Abbott attached to its PAS a “White Paper” discussing some of
the scientific literature relating to developmental delay in children exposed in utero to
antiepileptic drugs, including some of the results of the NEAD study.

In February 2006,

however, the FDA responded to Abbott’s PAS by email, notifying Abbott that the proposed
sentence discussing developmental delay should not be added to Depakote’s labeling:
The sentence “There have been reports of developmental delay in the offspring of
women who have received valproic acid during pregnancy” is based on two recent
publications (Gaily E et al. Neurology 62(1):28-32, 2004 and Vinten J et al.
Neurology 64(6): 949-54, 2005) that attempted to correlate children’s
performance on IQ assessments with maternal prenatal use of valproate but which
did not adequately control for maternal IQ and maternal educational attainment.
Maternal IQ and maternal educational attainment are known to strongly correlate
with children’s performance on IQ assessments and thus would confound any
attempt to draw a correlation to maternal prenatal valproate use. Given the
studies’ inability to establish this correlation, the proposed sentence should not be
incorporated into labeling. A similar proposed sentence in the Patient Information
Leaflet was removed in the Approval Letter for S-032 (January 11, 2006).
In May 2007, after Dr. Meador released additional data from the NEAD study, Abbott
sent another letter to Dr. Katz, this time bearing the subject-line, “General Correspondence –
Request for Advice regarding Developmental Labeling.” The letter’s purpose was to give the
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FDA “an updated analysis of the occurrence of developmental delay in the attached white paper,
which now includes more compelling data from the [NEAD] study.” Attached to that letter was
also a 2007 white paper discussing a recently published abstract from Dr. Meador’s NEAD
study, which the letter claimed provided “the first data with adequate control for maternal IQ
using a standard IQ measure and showed a significant developmental delay in 185 two-year-old
children exposed to valproic acid during pregnancy.” Pointing to those data, Abbott proposed
new language to the “WARNINGS – Usage in Pregnancy” section of Depakote’s label: “There
have been reports of developmental delay in the offspring of women who have received
valproate during pregnancy.”
In March 2008, according to an internal contact report prepared by Abbott, the company
held a teleconference with Dr. Katz and another representative of the FDA Division of
Neurology Products “to discuss teratogenesis associated with valproic acid treatment.” The
report indicated that “Dr. Katz stated they cannot approve this labeling change at this time,” as
the data was “not ‘ripe’ for inclusion in labeling since it [was] based on interim data from Dr. K.
Meador and the Neurodevelopment Effects of Antiepileptic Drugs (NEAD) Study group.” The
report went on to state that:
[the] FDA feels that the sample size with VPA compared to other agents is small,
some of the data for the 2 year old IQ evaluation was imputed, and there are too
many confounding factors to believe the data is reliable at this time point in the
study. Dr. Katz stated that they want to wait until the study is complete at the sixyear time point. Dr. Embrescia then commented that there have been a number of
cases of developmental delay reported through our [p]ost-marketing safety
surveillance program, and asked whether that might not warrant the change in
labeling. Dr. Katz asked for the number of cases we have, and Jim responded that
at the time we submitted the proposed labeling change we had 240 reported cases,
although many of those cases are confounded by other congenital abnormalities
the patients have or other medications they were on. Dr. Katz indicated he thought
these cases were probably too confounded to assess and that he believes this is the
type of event where they want investigation in a formal setting to confirm.

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In April 2009, Abbott once again requested advice from the FDA about adding
developmental delay warnings to the Depakote label. In its letter Abbott noted that since its
2005 and 2007 requests, Dr. Meador had published further results from the NEAD study in the
New England Journal of Medicine, and other researchers had begun publishing the results of
other studies relating to developmental delay in children exposed to Depakote. Abbott therefore
requested that the FDA “provide advice on the acceptability of these data for use to support an
amendment to the current label regarding the risk of developmental delay and/or autism/autism
spectrum disorder with intrauterine exposure to valproate.”
In September 2009, the FDA Division of Neurology Products held another teleconference
with Abbott in response to its latest request for advice. According to Abbott’s internal report of
that meeting, the FDA “had expressed concerns with Dr. Meador’s data” and had “plans to
conduct an independent review.” Dr. Katz reportedly stated that the FDA’s “statisticians have
raised concerns with the [NEAD] study and the methodology for the collection of data,” so that
“before taking regulatory actions with labeling, they needed time to evaluate the data.” Dr. Katz
accordingly “stated that they were not yet ready to ‘sign off on labeling language’” concerning
developmental delay. Moreover, in reply to an inquiry by Abbott as to whether the FDA “would
be open to [Abbott’s] proposal for labeling language in the interim while the [FDA] completes
its review,” Dr. Katz noted that Abbott “would be within [its] rights to submit a [“changes being
effected,” or CBE supplement],” but added that the FDA “would not take action until the review
of the data was complete.” Two months later, Abbott submitted a CBE labeling supplement to
add developmental delay warnings to Depakote’s label. In October 2011, years after Abbott’s
initial request, the FDA approved the addition of a warning about developmental delay on the
Depakote label.

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In 2013 Rheinfrank brought this suit in diversity against Abbott, on behalf of herself and
M.B.D., asserting several Ohio state statutory claims of strict liability based on design defect,
inadequate warning, and nonconformance with representations, as well as a number of state
common law claims. Abbott responded with a number of motions, including one for summary
judgment on Rheinfrank’s failure-to-warn claim with respect to the risks of developmental delay
and her request for punitive damages under the Ohio Product Liability Act.
As to the failure-to-warn claim, Abbott contended that because the FDA had twice
rejected its proposed modifications to Depakote’s label warning of new evidence of development
delay, there was “clear evidence” under Wyeth v. Levine, 555 U.S. 555 (2009), that the agency
would not have approved a developmental-delay warning before M.B.D.’s conception and birth
ten years earlier. The district court accepted Abbott’s argument, reasoning that:
because there is clear evidence the FDA would not have approved a change to the
Depakote label adding a developmental delay warning prior to M.B.D.’s injury.
The Court finds the FDA’s February 2006 decision that developmental delay
warnings “should not be incorporated into [Depakote] labeling” and the FDA’s
2008 belief that “the data do not provide sufficient evidence to support
[Depakote] labeling changes at this time” constitute “clear evidence” that when
confronted by the issue in 2003, the FDA would have rejected an attempt to add a
developmental delay warning.
Although the district court thus determined that Rheinfrank’s particular claim that Abbott had
failed to warn of the risk of developmental delay was preempted, the court nevertheless denied
summary judgment on Rheinfrank’s broader failure-to-warn claim because other questions of
material fact remained.

The court did grant summary judgment for Abbott, however, on

Rheinfrank’s request for punitive damages, ruling that she was “barred from recovering for
punitive damages because the FDA has not made a finding of either fraud or misrepresentation.”
Before trial, the district court also entered an order limiting in various respects the
testimony of several of Rheinfrank’s experts.
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The first of those limitations involved the

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testimony of Drs. Michael Privitera (a neurologist), Howard Saal (a geneticist), and C. Ralph
Buncher (an epidemiologist), restricting all three from giving any opinion as to what warnings or
information should have been included in Depakote’s label. As to Dr. Privitera, the court
concluded that:
Dr. Privitera is not qualified to opine on the regulatory aspects of the case,
including whether Abbott was required to send a patient package leaflet directly
to patients or whether Abbott’s submissions to the FDA should have included
certain materials. Similarly, testimony about what Defendants should have
included in the label or what materials should have been submitted to the FDA
falls outside the scope of his expertise, as it falls under the regulatory component
and is speculative. Thus, Dr. Privitera also may not testify about whether
Depakote should have been contraindicated for all women of childbearing years.
On the other hand, testimony in which Dr. Privitera opines on the medical facts
and science regarding the risks and benefits of Depakote and compares that
knowledge with what was provided in the text of the labeling is admissible.
As for Dr. Saal, the court determined that, although he was “well-qualified . . . to testify as to the
medical facts and science and compare that information and data with the language of the 2003
Depakote label,” he was “not an expert in FDA regulations,” and thus “lack[ed] the requisite
expertise to opine as to the regulatory aspects of the case, including what ‘should’ have been in
the 2003 label and whether the drug ‘should’ have been contraindicated for women of
childbearing years, as this assumes regulatory knowledge.” The court concluded much the same
about Dr. Buncher: despite being “qualified to opine on the medical facts and science regarding
Depakote and compare that data to a Depakote label,” the court found that he lacked “specialized
knowledge or expertise in the regulatory field, as he has never worked for the FDA, nor is he an
expert on FDA labeling regulations.” The court concluded that Dr. Buncher “lack[ed] the
requisite expertise to opine as to the regulatory aspects of the case, including what ‘should’ have
been in the 2003 Depakote label and whether Depakote ‘should’ have been contraindicated for
women of childbearing years, as this assumes regulatory knowledge.”

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The court also placed several limitations on the testimony of Rheinfrank’s regulatory
expert, Dr. Suzanne Parisian. As relevant here, the court ruled that, although a medical doctor
and former “FDA Medical Officer,” Parisian was nevertheless “unqualified to opine that as of
2003, Depakote was known to be the most teratogenic drug,” as she is “not a teratologist and
does not have any specialized knowledge or experience in evaluating [antiepileptic drugs].” Her
opinion testimony was thus limited to “what actions Abbott could have taken and/or was
required to take with respect to communicating risks to healthcare professionals,” as well to
“regulatory requirements relating to the development, testing, marketing, and surveillance of
prescription drugs.”
Before the case went to the jury on the four remaining causes of action—strict liability
under Ohio law for failure to warn and failure to conform to representations, and negligent
failure to warn and negligent design—Rheinfrank requested a number of jury instructions.
Among those were requests for instructions concerning the manufacturer’s standard of care and
knowledge (No. 7), federal requirements for drug labeling (No. 8) and for adding safety
warnings (No. 11), as well as an instruction concerning strict liability for an inadequate postmarket warning (No. 14). The district court refused to offer the first three of these instructions
separately (Nos. 7, 8, and 11), “but incorporated aspects of those proposed instructions where
appropriate.” As the court later explained when denying Rheinfrank’s motion for a new trial:
As Plaintiffs acknowledged in their Proposal for Supplemental Jury Instructions
in Response to [Jury] Question #4, the majority of their Requested Jury
Instruction No. 7 was incorporated into page 30 of the Civil Jury Instructions
under Claim One: Strict Product Liability – Defect Due to Inadequate Warning.
The Court rejected Requested Jury Instruction No. 8, because Plaintiffs cited no
Ohio authority in support of the instruction and because the Court was concerned
that an instruction on misbranding would confuse the Jury. The Court
incorporated the first sentence of Plaintiff’s Requested Jury Instruction No. 11
into the instruction on Compliance with Regulations. The Court rejected the
remainder of the requested instruction because it found no reason to deviate from
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the Ohio pattern instructions and that superfluous instructions would be
burdensome and confusing to the Jury.
The court also excluded an instruction Rheinfrank had proposed on post-market warnings
(No. 14). Rheinfrank had in fact asked for two instructions, Nos. 13 and 14, both dealing with
her strict liability failure-to-warn claim. As proposed, Instruction No. 13 would have read:
STRICT LIABILITY – INADEQUATE WARNINGS/INSTRUCTIONS
M.B.D. claims that Defendants’ drug Depakote was defective due to inadequate
warnings or instructions, and as a result caused M.B.D.’s harm, injuries, and
losses.
You must find for M.B.D. on her claim that Depakote was defective based on
inadequate warnings or instructions if the greater weight of the evidence
demonstrates that:
(A) At the time Depakote left Defendants’ control, Defendants knew or should
have known, in the exercise of reasonable care as an expert in the field, that
Depakote posed increased risks of harm to unborn children; and
(B) Defendants failed to provide the warnings or instructions that a manufacturer
exercising reasonable care would have provided concerning Depakote’s increased
risks of harm to unborn children; and
(C) As a result of Defendants’ failure to provide adequate warnings or
instructions, Pamela Rheinfrank’s doctor prescribed and Pamela Rheinfrank used
Depakote, which resulted in M.B.D.’s harm, injuries, and losses.
Rheinfrank’s proposed Instruction No. 14, on the other hand, would have added:
STRICT LIABILITY – INADEQUATE POST MARKET
WARNINGS/INSTRUCTIONS
M.B.D. claims that Defendants’ drug Depakote was defective due to inadequate
post-market warnings or instructions, and as a result caused M.B.D.’s harm,
injuries, and losses.
You must find for M.B.D. on her claim that Depakote was defective based on
inadequate warnings or instructions if the greater weight of the evidence
demonstrates that:
(A) After Depakote left Defendants’ control, Defendants knew or should have
known, in the exercise of reasonable care as an expert in the field, that Depakote
posed increased risks of harm to unborn children; and

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(B) Defendants failed to provide the post-market warnings or instructions that a
manufacturer exercising reasonable care would have provided concerning
Depakote’s increased risks of harm to unborn children; and
(C) As a result of Defendants’ failure to provide adequate post-market warnings
or instructions, Pamela Rheinfrank’s doctor prescribed and Pamela Rheinfrank
used Depakote, which resulted in M.B.D.’s harm, injuries, and losses.
The court ultimately decided to exclude the requested Instruction No. 14, citing two reasons.
First, the court was “concerned that two, separate strict liability instructions back-to-back would
be confusing and inconsistent with Plaintiffs’ other proposed instructions and interrogatories.”
As the court explained in rejecting Rheinfrank’s motion for a new trial:
For example, [Rheinfrank’s] Requested Jury Instruction No. 15 (Presumption
Based on Inadequate Warnings) did not distinguish warning and instruction from
post-marketing warning and instruction. [Rheinfrank’s] Proposed Interrogatory
No. 1 did not distinguish between warning and instruction and post-marketing
warning or instruction.
The court reasoned, moreover, that Rheinfrank “did not justify why [she] proposed two separate
instructions on the strict liability failure to warn claim, as opposed to one merged instruction.”
On those grounds the court had instead decided to provide a single “Compliance with
Regulations in its Civil Jury Instruction,” which explained that “a drug manufacturer bears the
ultimate responsibility for the content of its label at all times. It is charged both with drafting an
adequate label and with ensuring that its warning remain adequate as long as the drug is on the
market.” The court further noted that, before the charge conference, it had circulated its
Annotated Civil Jury Instructions to both Rheinfrank and Abbott—instructions that did not
include Rheinfrank’s requested instruction No. 14. During the later charge conference with both
sides’ counsel—a meeting that lasted more than three hours—Rheinfrank raised no objection to
the court’s exclusion of Instruction No. 14.

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After an 11-day trial, the jury began deliberations on the four remaining claims, during
which they submitted to the court a question (Jury Question No. 4) about the merged inadequatewarning instruction:
Page 30 of the Civil Jury Instructions, under the Claim One, paragraph two,
sentence one states “a prescription drug is defective due to inadequate warning or
instruction if at the time the prescription drug left the control of the manufacturer .
. .”
Question: What does “left the control of the manufacturer” mean? When its
approval was granted or when it left the factory?
According to the district court, as related in its later opinion rejecting Rheinfrank’s motion for a
new trial:
When the Court received Jury Question No. 4 and read it to counsel, discussion
immediately followed about whether “left the control of the manufacturer” is a
defined phrase in case law or statute. [Rheinfrank’s] counsel proposed that she
believed the correct answer to be “when it left the factory.” Jury Question No. 4
then took on a life of its own when counsel submitted briefs to the Court on the
question. [Rheinfrank] argued that the Jury must be confused about whether
Depakote may be defective due to inadequate post-marketing warning or
instruction. They contended that the Court should submit not only their
Requested Jury Instruction No. 14, but also Nos. 7, 8, and 11, and direct the Jury
to refer to the Court’s Civil Jury Instruction on Compliance with Regulations.
[Abbott] disagreed and argued that when something leaves the control of the
manufacturer is a fact question for the Jury and that additional instructions would
be improper. The Court agreed with [Abbotts’] interpretation of Jury Question
No. 4 and instructed the Jury that “left the control of the manufacturer” was an
issue for them, as Jury, to decide based on their assessment of the evidence and
instructions that were previously provided.
After the jury returned a complete verdict for Abbott, Rheinfrank moved for a new trial,
arguing, among other things, that the court’s rulings limiting the expert testimony of Drs.
Privitera, Saal, Buncher, and Parisian were in error and had unfairly prejudiced her case, and that
her case had been further prejudiced by the court’s erroneous exclusion of her four requested
jury instructions (Nos. 7, 8, 11, and 14). Rheinfrank contended, in addition, that the court’s
response to Jury Question No. 4 was improper, and urged the court to reconsider its earlier ruling
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granting partial summary judgment to Abbott on its federal preemption and punitive damages
claim.
The district court, however, stood by its earlier rulings as to the expert testimony, its
exclusion of the first three jury instructions (Nos. 7, 8, and 11), and its earlier grant of summary
judgment to Abbott on Rheinfrank’s failure-to-warn claim about the risks of developmental
delay and her request for punitive damages. As to the requested Instruction No. 14, the court
concluded that, by failing to object to the exclusion of the proposed instruction during the charge
conference, Rheinfrank had waived any objection.

Rheinfrank countered that she had not

waived her right to argue that the requested instruction should be given, because the jury’s
Question No. 4 had called into doubt a “key instruction” during deliberations that required
correction, as in Reynolds v. Green, 184 F.3d 589 (6th Cir. 1999). But the court rejected that
argument and its analogy to Reynolds, reasoning that:
The language the Jury expressed its confusion over – “left the control of the
manufacturer” – was in both of [Rheinfrank’s] Requested Instruction Nos. 13 and
14. Belatedly charging the Jury in the middle of its deliberations with
[Rheinfrank’s] Requested Jury Instruction No. 14 would not have answered
[Rheinfrank’s] question. Further, the proposed scenarios by the Jury – “[w]hen its
approval was granted” or “left the factory” provided insight into the mindset of
the Jury, demonstrating that they were proposing definitions for the “left the
control of the manufacturer,” none of which included any prodding into “postmarket” scenarios. The Court viewed [Rheinfrank’s] argument – a belated
attempt to bootstrap several additional jury instructions to an answer to Jury
Question No. 4 – as inappropriate, unhelpful, and likely to cause greater
confusion.
The court further noted that, because the instruction the court gave already “covered the
differences between [Rheinfrank’s] Requested Jury Instructions Nos. 13 and 14 and cured any
deficiencies,” its instructions “read as a whole” were appropriate. And even if they were not, the
court concluded, “based on the evidence and the Jury’s total defense verdict, there would have
been no difference in the outcome of the case.”
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The district court accordingly denied Rheinfrank’s motion for a new trial, and she now
appeals.
II.
The first of Rheinfrank’s several claims on appeal is that the district court prejudiced her
case by erroneously limiting the testimony of several of her expert witnesses, allegedly entitling
her to a new trial. But because each of those rulings was based on the district court’s reasonable
assessment as to the limits of those experts’ respective expertise, and all were consistent with the
rulings of other courts, the district court could reasonably have limited the testimony as it did
without exceeding the “great latitude” this court must afford such evidentiary rulings, see
Taulbee v. Wal-Mart Stores, Inc., 5 F. App’x 361, 363 (6th Cir. 2001) (quoting Rye v. Black
& Decker Mfg. Co., 889 F.2d 100, 101-02 (6th Cir. 1989)). Those rulings therefore did not
amount to an abuse of the district court’s discretion, the standard for this court’s review here,
Decker v. GE Healthcare Inc., 770 F.3d 378, 391 (6th Cir. 2014).
Rheinfrank first argues that the district court erroneously limited the testimony of several
of her medical experts— Drs. Privitera, Saal, and Buncher—to the medical facts about Depakote
and how they compared to the details contained on its label, because, Rheinfrank claims, those
experts were also qualified to opine as to the “adequacy” of that label. But as the district court
explained, the expertise of each of those witnesses—neurology in Privitera’s case, genetics and
dysmorphology in Saal’s, and epidemiology in Buncher’s—did not extend to regulatory
questions like the ones Rheinfrank proposed for them to answer: “what ‘should’ have been in the
2003 Depakote label and whether Depakote ‘should’ have been contraindicated for women of
childbearing years.” None of them, after all, had ever worked for the FDA—unlike Dr. Parisian,
who did testify for Rheinfrank on the regulatory aspects of Depakote’s label. None had any

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specialized training or expertise in FDA labeling regulations. Under the standard set forth in
Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579 (1993), and its progeny, the district
court need only have decided, by a preponderance, that the expert witness was qualified to
proffer her testimony, see Decker, 770 F.3d at 391. In this case, given that several other courts
have similarly limited the testimony of medical experts to questions within their specialized
medical ken, see In re Gadolinium-Based Contrast Agents Prods. Liab. Litig., No. 1:08 GD
50000, MDL No. 1909, 2010 WL 1796334, at *19 (N.D. Ohio May 4, 2010); In re Diet Drugs
(Phentermine, Fenfluramine, Dexfluramine) Prods. Liab. Litig., No. MDL 1203, 2000 WL
876900, at *11 (E.D. Pa. June 20, 2000), the court could reasonably have found that
Rheinfrank’s experts were likelier than not unqualified under Daubert to opine on regulatory
areas in which they had neither specialized training nor professional experience—including
opinions as to what ‘should’ have appeared on Depakote’s label, subject as that must be to an
essentially technical, regulatory judgment. The district court consequently did not abuse its
discretion by so limiting their testimony.
Rheinfrank’s arguments to the contrary, moreover, are without merit.

Rheinfrank

appears to contend that the district court’s ruling excessively limited these experts’ testimony by
making the question of “adequacy” into a “regulatory matter,” thus prejudicially excluding their
other opinions as to the “adequacy” of Depakote’s label in a wider, non-regulatory sense. But
that is a misstatement of what the district court ruled. As the district court explained in limiting
Privitera’s testimony:
Dr. Privitera is not qualified to opine on the regulatory aspects of the case,
including whether Abbott was required to send a patient package leaflet directly
to patients or whether Abbott's submissions to the FDA should have included
certain materials. Similarly, testimony about what Defendants should have
included in the label or what materials should have been submitted to the FDA
falls outside the scope of his expertise, as it falls under the regulatory component
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and is speculative. Thus, Dr. Privitera also may not testify about whether
Depakote should have been contraindicated for all women of childbearing years.
The court placed much the same limitation, moreover, on Saal’s and Buncher’s testimony, ruling
that they could not testify as to “what ‘should’ have been in the 2003 Depakote label and
whether Depakote ‘should’ have been contraindicated for women of childbearing years, as this
assumes regulatory knowledge.” In no case, that is, did the court exclude these experts’ opinions
as to the “adequacy” of Depakote’s label from the point of view of their respective medical
expertise, but only from the point of view of the label’s regulatory adequacy. In fact, Privitera
was allowed to “opin[e] on the medical facts and science regarding the risks and benefits of
Depakote” and was likewise able to “compar[e] that knowledge with what was provided in the
text of the labeling,” and he did so. Similarly, both Saal and Buncher were allowed to “testify as
to the medical facts and science” and likewise were able to “compare that information and data
with the language of the 2003 Depakote label,” and they did so. Thus the limitation the district
court placed on each of these experts’ testimony as to the “adequacy” of Depakote’s label was
itself limited, and only to the regulatory aspects of the labeling. As explained, that limitation
was reasonable enough to fall within the “considerable leeway” of discretion that has been
confided to the district court when making such rulings, see Meridia Prods. Liab. Litig. v. Abbott
Labs., 447 F.3d 861, 868 (6th Cir. 2006) (quoting Kumho Tire Co. v. Carmichael, 526 U.S. 137,
152 (1999)).
Rheinfrank also challenges the limitation placed on her regulatory expert, Dr. Parisian,
who was not permitted to testify “that as of 2003, Depakote was known to be the most
teratogenic drug.”

But this limitation also was reasonable and therefore not an abuse of

discretion. The district court concluded that Parisian was not qualified to give that testimony
because even though she had an extensive background as an FDA Medical Officer and is a
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medical doctor, she is “not a teratologist and does not have any specialized knowledge or
experience in evaluating [antiepileptic drugs],” id. The court concluded that such a specific
opinion as to the teratogenic effects of Depakote relative to other antiepileptic drugs therefore
“falls outside the scope of her expertise,” limited as that is by her regulatory background with the
FDA and as a physician without any specialized understanding or expertise in antiepileptic
drugs. As Rheinfrank appears to concede, Parisian is no specialist in teratology and therefore
has no more specialized or expert understanding of antiepileptic drugs than any other licensed
physician. The court could therefore reasonably conclude that her opinion about the relative
teratogenicity of Depakote exceeded her expertise. As that is all we have required to uphold a
ruling like the one the district court made here, see Rye, 889 F.2d at 101, that decision was not an
abuse of discretion.
But even if the district court did err by so limiting Parisian’s testimony, that error was
harmless. First, Rheinfrank was in fact able to elicit testimony at trial from Parisian that covered
the relative teratogenicity of Depakote, the very testimony the exclusion of which Rheinfrank
now claims prejudiced her case:
Q: And as of this time on August 30, 2002, did the Depakote label contain
information that the risk of malformations was higher with Depakote than with
other AEDs?
A: No.
Q: And is that what information was included in the report from Dr. Holmes to
Abbott?
A: Yes.
Even apart from Parisian’s testimony, moreover, Rheinfrank was able to elicit the same
testimony from her other two experts, Privitera and Buncher, who each testified to the higher
teratogenicity associated with Depakote relative to other AEDs. This court has indicated that
where “the substance of the excluded testimony [is] furnished by other witnesses,” that exclusion

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is not prejudicial. Hines v. Joy Mfg. Co., 850 F.2d 1146, 1153 (6th Cir. 1988). Thus, even if the
district court erroneously limited Parisian’s testimony, that error would not have been
prejudicial. Nor, as a result, would it warrant reversal. See McCombs v. Meijer, Inc., 395 F.3d
346, 358 (6th Cir. 2005).
III.
Rheinfrank next contends that she is entitled to a new trial because the district court erred
in rejecting four jury instructions that she requested, resulting in confusion for the jury and
prejudice to her case. But because the instructions that the court did give either substantially
covered Rheinfrank’s requested instructions or did not prejudice Rheinfrank’s case in any event,
the court’s refusal to provide those four instructions does not amount to reversible error, see
Decker, 770 F.3d at 396.2 Those rulings, reviewed for an abuse of discretion, Cummins v. BIC
USA, Inc., 727 F.3d 506, 510 (6th Cir. 2013), therefore do not warrant a new trial.
Rheinfrank argues that the district court erred by refusing to give her three instructions
relating to the manufacturer’s standard of care and knowledge (No. 7) and requirements for drug
labeling (No. 8) and adding safety warnings (No. 11) under federal law, because all three were
correct, and their omission confused and misled the jury and thus were prejudicial. But as the
district court explained as to Rheinfrank’s requested Instructions No. 7 and 11, both were
partially incorporated into the instruction the court actually gave. Moreover, at least two of the
three differences that Rheinfrank cites between the given instruction and the two she requested
(Nos. 7 and 11)—that the given instruction failed to explain what would make a label inadequate
under federal law and did not identify the procedures by which the manufacturer would update
2

Under this court’s standard for reviewing a district court’s refusal of a jury instruction, such a decision is
“reversible error if (1) the omitted instruction is a correct statement of the law, (2) the instruction is not substantially
covered by other delivered charges, and (3) the failure to give the instruction impairs the requesting party's theory of
the case.” Decker, 770 F.3d at 396 (internal quotation marks and citation omitted).

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its labels—do not amount to substantial departures from the given instructions, which made clear
the gist of those procedures, and explained what would make a prescription drug warning
adequate.

Although Rheinfrank believes those explanations were deficient, for not having

indicated “what ability Abbott had to change its label should it become inadequate,” in fact the
given instruction made that ability clear, at least implicitly:
a drug manufacturer bears the ultimate responsibility for the content of its label at
all times. It is charged both with drafting an adequate label and with ensuring that
its warning remain adequate as long as the drug is on the market.
Abbott could hardly bear the duty of maintaining the adequacy of its label if it lacked the power
to effect those changes. Moreover, the same compliance instruction explained, in relation to
Depakote’s Black Box warning, that “[t]he manufacturer may make suggestions, but the FDA
makes the ultimate determination regarding the content of the Black Box warning”—implying,
once again, that Abbott had at least some ability under federal law to amend its labeling. As the
given instructions substantially covered Rheinfrank’s requested Instructions No. 7 and 11, the
district court did not err by excluding them as separate instructions, see Decker, 770 F.3d at 396.
Furthermore, Rheinfrank’s requested instruction on the federal requirements for drug
labeling (No. 8), which would have further defined the “adequacy” of a “label” under federal
law, also substantially overlapped with the given instruction on the adequacy of prescription drug
warnings. Indeed, if anything, the adequacy instruction given by the court was more detailed
than the one Rheinfrank herself proposed.3 Ultimately, the only substantive differences between

3

The “Adequacy of Prescription Drug Warning” instruction reads:
You may find a warning to be unreasonable, hence inadequate, in its factual content, its expression
of the facts, or the method or form in which it is conveyed. The adequacy of such warnings is
measured not only by what is stated, but also by the manner in which it is stated. A reasonable
warning not only conveys a fair indication of the nature of the dangers involved, but also warns
with the degree of intensity demanded by the nature of the risk. A warning may be found to be
unreasonable in that it was unduly delayed, reluctant in tone or lacking in a sense of urgency.

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the requested Instruction No. 8 and those the court gave come down to the omitted definition of a
“label” and Rheinfrank’s proposed definition of “misbranding.”

But as the district court

explained, including those details—which were not supported by any Ohio authorities—would
only have confused the jury, especially as misbranding did not appear to be a focus of the
testimony at trial. In any event, Rheinfrank has given no reason to believe that the exclusion of
the definition of a “label” from the court’s instructions prejudiced her case. On the contrary,
even though the proposed definition would have made clear that promotional and other
marketing materials were also “labelling,” in addition to the label that was clearly addressed at
trial, Rheinfrank’s own physician explained that those materials did not figure in her decision to
prescribe Depakote to Rheinfrank. Given, then, that Rheinfrank’s requested Instruction No. 8
either overlapped in large measure with instructions given by the court or was otherwise not
prejudicially excluded, the district court did not err by rejecting it as a separate instruction, see
Decker, 770 F.3d at 396.
Rheinfrank also contends that the district court erred by refusing to give her requested
Instruction No. 14, which would have provided a separate strict liability charge for “post-market
warning/instruction,” because, Rheinfrank claims, the instruction given by the court failed to
explain adequately that “the manufacturer’s duty is the same both before and after the product
leaves its control.” But there are two independently fatal flaws in Rheinfrank’s claim. First, as
with the other instructions Rheinfrank requested, the instructions given by the district court
Rheinfrank’s requested Instruction No. 8 reads, in relevant part:
Directions for use and warnings are inadequate if they are misleading based on what the
manufacturer said, how the manufacturer said it, or what the manufacturer did not say. If the
labeling for a prescription drug does not contain such adequate directions for use and warnings,
the drug is misbranded. Similarly, if a drug is dangerous to health when used in the dosage,
manner, frequency, or duration prescribed, recommended, or suggested in the labeling, the drug is
misbranded.
The sale of misbranded prescription drugs is unlawful.

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already covered, not just substantially but entirely, her requested Instruction No. 14. As noted,
the court gave an instruction that made clear that “a drug manufacturer bears the ultimate
responsibility for the content of its label at all times,” and that it must “ensur[e] that its warning
remain[s] adequate as long as the drug is on the market.” Indeed, the given instruction on the
strict product liability failure-to-warn claim further explained that “[t]he manufacturer has the
duty to remain reasonably current with scientific knowledge, development, research, and
discoveries concerning the product,” and that, consequently, it “must communicate its superior
knowledge to those who, because of their own limited knowledge and information, would
otherwise be unable to protect themselves.” Read as a whole, as jury instructions must be, see
Pivnick v. White, Getgey & Meyer Co., LPA, 552 F.3d 479, 488 (6th Cir. 2009), these
instructions made clear that what Rheinfrank had proposed in her requested Instruction No. 14
was already covered by the instructions given by the court: Abbott had a duty to maintain the
accuracy of its label at all times, even after Depakote had gone on the market and after the doses
of the drug that Rheinfrank took had left the factory. That overlap is enough to clear the district
court of any accusation of error, see Decker, 770 F.3d at 396. But even if the district court had
erred in rejecting Rheinfrank’s Instruction No. 14, she confronts still another difficulty with her
claim: by failing to object during the charge conference and before jury deliberations, that
objection is now forfeited, Howe v. City of Akron, 723 F.3d 651, 660-61 (6th Cir. 2013) (citing
Fed. R. Civ. P. 51(c)(1)). In either case, then, Rheinfrank cannot succeed on her claim that the
district court abused its discretion by refusing to give her requested instruction.
The question submitted by the jury during deliberations does not alter this conclusion.
Rheinfrank contends that once the jury asked about the meaning of “left the control of the
manufacturer,” it became clear that the jury had mistakenly believed that “the timing of when

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Depakote’s label left Abbott’s control” bore on the company’s liability. Thus, Rheinfrank
argues, once the jury expressed its confusion on this “key instruction,” under Reynolds v. Green,
184 F.3d 589, 594 (6th Cir. 1999), her right to raise an objection was revived and her original
requested Instruction No. 14 became proper. As the district court explained, however, the same
fact that distinguished Reynolds also made Rheinfrank’s proposed instruction inappropriate as a
substitute: the very language apparently at the root of the confusion over the court’s instruction
(“left the control of the manufacturer”) also appeared, nearly verbatim, in Rheinfrank’s requested
Instruction No. 14 (“[a]fter Depakote left Defendants’ control”).

Thus the district court

concluded not only that Reynolds was inapplicable, but, more importantly, that swapping in
Rheinfrank’s instruction would add nothing but more confusion for the jury, failing as it did to
answer the question they posed in the first place. Even assuming that Rheinfrank’s objection
was not waived, then, her proposed instruction would still have failed to cure the jury’s
confusion and would arguably have compounded it. It was therefore not error—and thus not an
abuse of discretion—for the district court not to give Rheinfrank’s requested Instruction No. 14
even in the face of the jury’s question.
IV.
Rheinfrank further contends that the district court erred in granting summary judgment on
Abbott’s preemption defense against Rheinfrank’s failure-to-warn claim, because genuine issues
of material fact remained as to whether the FDA would have approved a developmental delay
warning prior to M.B.D.’s suffering the injuries she did in utero. This error, Rheinfrank argues,
also entitles her to a new trial. But because the evidence in the record reveals that the FDA twice
rejected Abbott’s attempts to strengthen Depakote’s label to add a developmental delay warning,
there was clear enough evidence under Wyeth that the FDA would not have approved any such

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change in Depakote’s label.

The district court’s grant of summary judgment on Abbott’s

preemption defense, reviewed de novo, see Int’l Union v. Cummins, Inc., 434 F.3d 478, 483 (6th
Cir. 2006), was therefore proper.
Because the FDA twice refused Abbott’s attempts to strengthen Depakote’s label, based
on its own review of the evidence that the drug adversely affected the development of children
exposed to it in utero, Rheinfrank’s failure-to-warn claim is preempted by federal drug labeling
law. In Wyeth, the Supreme Court reaffirmed the “central premise of federal drug regulation that
the manufacturer bears responsibility for the content of its label at all times,” requiring the
manufacturer to “craft[] an adequate label” and to “ensur[e] that its warnings remain adequate as
long as the drug is on the market.” 555 U.S. at 570-71. However, because the FDA also has the
authority to reject any labeling changes—under both its unilateral “Changes Being Effected”
(CBE) and its “Prior Approval Supplement” (PAS) regimes4—the Court also indicated that the
manufacturer could “show by ‘clear evidence’ that the FDA would have rescinded any change in
the label and thereby demonstrate that it would in fact have been impossible to do under federal
law what state law required.” PLIVA, Inc. v. Mensing, 564 U.S. 604, 624 n.8 (2011) (citing
Wyeth, 555 U.S. at 571). But the only way the FDA can “rescind” a proposed label change is
either by rejecting it after it has been added through a CBE supplement, see 21 C.F.R.
4

As this court has explained these two labeling-modification regimes:
After initial approval of a drug, branded-drug companies may seek modification of their labeling
in two ways: first, through a “Prior Approval Supplement,” which requires submission to and
approval by the FDA prior to distribution of the product, and applies to most labeling and other
changes with “potential to have an adverse effect on the identity, strength, quality, purity, or
potency of the drug product,” 21 C.F.R. § 314.70(b), and second, through a “Changes Being
Effected” (CBE) supplement, which must be submitted 30 days before distribution, but does not
require prior FDA approval. 21 C.F.R. § 314.70(c). Label changes “[t]o add or strengthen a
contraindication, warning, precaution, or adverse reaction” may be made through the CBE
process. 21 C.F.R. § 314.70(c)(6)(iii)(A). Branded-drug companies, therefore, are free to update
their labeling, subject only to subsequent FDA disapproval. Wyeth, 555 U.S. at 569.

Fulgenzi v. PLIVA, Inc., 711 F.3d 578, 581 (6th Cir. 2013) (footnote omitted).

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§§ 314.70(c)(6)(iii)(A)-(C), (c)(7), or by declining it in the first place, under the PAS regime, see
id. at 314.70(b). Together Wyeth and Mensing therefore indicate that “a court cannot order a
drug company to place on a label a warning if there is ‘clear evidence’ that the FDA would not
approve it.” Robinson v. McNeil Consumer Healthcare, 615 F.3d 861, 873 (7th Cir. 2010). That
evidence would be clear enough, moreover, in cases where the FDA has rejected a proposed
label modification in a “submission to which the agency was responding”—such as in response
to a PAS. Id. That makes sense, as the Seventh Circuit concluded in Robinson, for “it would be
odd to think” that a manufacturer “had a legal duty to guarantee against a risk that the FDA
thought not worth warning against.” Id.
In this case, because Abbott has produced precisely that kind of evidence Abbott has met
its burden under Wyeth’s clear-evidence standard. In its email response to Abbott’s 2005 PAS
submission, the FDA made clear that a developmental delay warning “should not be incorporated
into [Depakote’s] labeling”—a response that even Rheinfrank has characterized as a rejection by
the FDA of the proposed labeling. Two years later, moreover, in response to another request for
advice from Abbott, the FDA’s Dr. Katz once again explained that “the data do not provide
sufficient evidence to support [Depakote] labeling changes at this time.” Indeed, the FDA would
only approve Abbott’s proposed developmental delay warnings in 2011—some six years after
Abbott first suggested them. Given, then, that as of 2008 the FDA did not believe the state of the
data supported a developmental delay warning, it stands to reason that as of 2003, with even less
data to go on, the FDA would similarly have rejected a developmental delay warning—even a
CBE, judged as that is by the same standard as a PAS, see 21 C.F.R § 314.70(c)(6)(iii)(A).5 It
5

Rheinfrank contends, based on one of Abbott’s FDA contact reports dating from November 2005, that the FDA
had in fact approved a CBE adding a developmental delay warning. But as the district court explained, the FDA
contact report in question—stating that the “FDA was in agreement with the latest wording provided to them
regarding . . . developmental delay”—appears to have been referring to a revision that Abbott made to its 2005 PAS

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would accordingly have been impossible for Abbott, prior to M.B.D.’s injury in 2003-2004, to
comply with Ohio’s product liability law to provide warnings about developmental delay while
respecting the FDA’s apparent unwillingness—and their authority not—to accept them. Under
Wyeth, that is enough for federal law to preempt a failure-to-warn claim raised under state law.
Rheinfrank raises a series of objections to this conclusion, but none is persuasive.
Rheinfrank first contends that the evidence Abbott provided showing that the FDA would have
rejected any change to Depakote’s label was too informal to be binding, and thus, under Wyeth,
was too little and too “fleeting” to constitute clear evidence that the FDA would not have
accepted a proposed label change, under either the CBE or PAS regime for label modification.6
But the Court in Wyeth did not say that for evidence to be clear it must result from a formal
procedure of approval or disapproval. Indeed, to require as much would appear to require
rewriting the Court’s chosen test—from whether “the FDA would not have approved a change”
to a drug’s label under a CBE or PAS to whether the FDA had not approved it. Wyeth, 555 U.S.
at 572 (emphasis added). As the Court has since clarified, given the FDA’s authority to rescind
any unilateral CBE, all that Abbott need have done—and did do here—is show that “the FDA
would have rescinded any change in the label,” Mensing, 564 U.S. at 624 n.8, a showing that
does not appear to exclude the kind of informal communications from FDA higher-ups that
Abbott provided.

earlier that summer at the FDA’s request. Indeed, the next sentence makes that clear: “[The FDA officials] noted
that we [Abbott] had removed a sentence about developmental delay from the Patient Information Leaflet, and said
that was OK.”
6

Rheinfrank questions the admissibility of Abbott’s internal contact reports with the FDA, which supply the only
evidence that Dr. Katz had twice made clear that the FDA did not think labelling about developmental delay was
appropriate in 2008 or 2009. But Rheinfrank does not appear to have raised the evidentiary challenge below or in
her opening brief, nor was it considered by the district court. As a result, those arguments must be deemed forfeited,
at least absent some showing of a “gross miscarriage of justice.” Wiley v. United States, 20 F.3d 222, 226 (6th Cir.
1994). Rheinfrank has not made that showing here.

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Furthermore, Rheinfrank misreads Wyeth for her claim that unless communications
between a drug manufacturer and the FDA occur under formal channels, they would be too
“fleeting” and insufficiently “final” to qualify as “clear evidence.”

As the Court instead

explained, the real problem with Wyeth’s claim—that “the FDA intended to prohibit it from
strengthening the warning about” its pharmaceutical—was that there was “no evidence in [the]
record that the FDA or the manufacturer gave more than passing attention to the issue”
surrounding the proposed warning.
quotation marks omitted).

Wyeth, 555 U.S. at 572 (emphasis added and internal

Here, by contrast, there is considerable evidence in the record

showing that Abbott followed up on new data surrounding developmental delay and Depakote,
that Abbott contacted the FDA multiple times to propose modifications to reflect that data, and
that each time officials from the FDA unit responsible for reviewing those modifications
unequivocally stated that they were inappropriate at the time. As these communications reveal
more than the “passing attention” that the Court agreed left Wyeth’s claim wanting, and as all
make clear that the FDA would have rejected the proposed change to Depakote’s label, they are
clear enough to satisfy Wyeth’s standard.
Rheinfrank nevertheless contends that, even if the FDA signaled that it would not have
approved a stronger developmental delay warning on Depakote’s label, a finding of “clear
evidence” would still be precluded, either because Abbott misrepresented the state of the
evidence to the FDA in its communications about its proposed labelling changes, or because
there was evidence about Depakote’s effects on developmental delay that Abbott should have
known but failed to obtain. Each of these arguments, however, is unavailing. First, even if the
evidence that Abbott submitted was as misleading or incomplete as Rheinfrank alleges, the
evidence in the record establishes that the FDA undertook its own review of the relevant

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empirical literature apart from Abbott’s various analyses.7 It was that review, moreover, that
ultimately led Dr. Katz to conclude “that [the FDA was] not yet ready to ‘sign off on labeling
language’” concerning developmental delay,” and that the FDA “would not take action [on
Abbott’s submitted CBE] until the review of the data was complete.” Thus, whatever may have
been Abbott’s omissions or misrepresentations in its communications with the agency, the FDA
clearly explained that, in its own view of the data, the developmental delay warning that Abbott
had proposed was not yet warranted. As explained, that evidence is also clear enough to satisfy
Wyeth’s standard.
Rheinfrank further argues that Wyeth makes relevant to a “clear evidence” inquiry not
just what Abbott knew but also what it should have known, and that under that standard Abbott
fell well short of its responsibility under federal labeling law by refusing to fund or conduct
studies probing Depakote’s effects on developmental delay. But this argument is too conjectural
to defeat preemption. As the Court has explained, speculation as to what “a third party or the
Federal Government might do” that would “make[] it lawful for a private party to accomplish
under federal law what state law requires of it” cannot thwart a claim of preemption, as evidence
of that kind would make “most conflicts between state and federal law illusory,” and thus
“render[] conflict pre-emption all but meaningless.”

Mensing, 564 U.S. at 620-21.

That,

however, is exactly what Rheinfrank asks this court to accept: a series of speculations as to what
the FDA could have done with different evidence that Abbott might have collected if it had run
its own studies. Because such speculations are not enough to undermine the clear evidence that

7

Rheinfrank also challenges the admissibility of this evidence, but she does not appear to have raised this objection
below or in her opening brief, nor was it considered by the district court. As a result, this challenge, too, must be
deemed waived. See Wiley, 20 F.3d at 226; Kuhn v. Washtenaw County, 709 F.3d 612, 624-25 (6th Cir. 2013).

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the FDA would have rejected a strengthened warning on Depakote’s label prior to M.B.D.’s
injury, Rheinfrank’s failure-to-warn claim is preempted by federal law.8
V.
We therefore affirm the district court’s grant of summary judgment and its denial of a
new trial.

8

Because the district court properly denied Rheinfrank’s motion for a new trial, we need not reach her claim for
punitive damages.

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