Glastetter v. Novartis Pharmaceuticals Corp. , 252 F.3d 986 ( 2001 )

. United States Court of Appeals
FOR THE EIGHTH CIRCUIT
___________
No. 00-3087 & No. 00-3467
___________
Tina M. Glastetter, Steven J. Glastetter, *
*
Appellants, *
* Appeal from the United States
v. * District Court for the
* Eastern District of Missouri
Novartis Pharmaceuticals Corporation, *
formerly known as Sandoz *
Pharmaceuticals Corp.; Novartis AG, *
formerly known as Sandoz AG, * [TO BE PUBLISHED]
*
Appellees. *
___________
Submitted: April 9, 2001
Filed: June 8, 2001 (Corrected-July 5, 2001)
___________
Before HANSEN and BYE, Circuit Judges, and MELLOY, 1 District Judge.
___________
PER CURIAM.
Tina Glastetter suffered a stroke two weeks after she gave birth to her third
child. She blamed her stroke on medication called Parlodel, which she had taken to
suppress postpartum lactation. Glastetter sued Parlodel’s manufacturer, Novartis
1
The Honorable Michael J. Melloy, United States District Judge for the Northern
District of Iowa, sitting by designation.
Pharmaceuticals Corporation, in federal court under a state-law products liability
theory. The district court2 excluded Glastetter’s expert medical testimony that
Parlodel caused her stroke, holding that it lacked scientific reliability. Glastetter v.
Novartis Pharms. Corp., 107 F. Supp. 2d 1015 (E.D. Mo. 2000). Because the court’s
ruling was fatal to Glastetter’s proof of causation, the court granted Novartis summary
judgment and assessed costs. Glastetter now appeals, and we affirm.
I
Glastetter suffered from occasional migraines, she was overweight, and she had
smoked heavily for several years. At age 36, she delivered her third child by caesarean
section on August 2, 1993. Her pregnancy and delivery were uneventful. After
childbirth, Glastetter chose not to breast-feed her child. Her doctor prescribed a two-
week dose of Parlodel to suppress lactation. Glastetter had taken Parlodel for the
same reason following a prior pregnancy. On August 16, Glastetter complained of a
severe headache. The pain became intense, and she was later taken to a local hospital.
At the hospital, doctors performed a CT scan, which revealed an intracerebral
hemorrhage (ICH)3 in the right frontoparietal area of Glastetter’s brain. She
experienced left-side paralysis and slurred speech. Doctors were unable to identify the
cause of Glastetter’s stroke.
Novartis introduced Parlodel in 1978. In 1980, the Food & Drug Administration
approved Parlodel for use in preventing postpartum lactation. Parlodel blocks the
body’s production of the hormone prolactin, which acts upon the breasts to induce
2
The Honorable E. Richard Webber, United States District Judge for the Eastern
District of Missouri.
3
An ICH is a “wet stroke,” in which too much blood enters the brain. An ICH
may be contrasted with an ischemic stroke, or “dry stroke,” in which blood flow to
the brain is restricted.
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secretion of milk in postpartum women. Parlodel’s active ingredient is a chemical
substance called “bromocriptine mesylate” (bromocriptine). 4 About six months after
Glastetter suffered her stroke, the FDA proposed to revoke its earlier approval of
Parlodel for inhibiting postpartum lactation. The FDA concluded that the possible
harm from using Parlodel (including the possibility of seizures and strokes in certain
at-risk women) outweighed its limited benefit as a lactation suppressant. 59 Fed. Reg.
43,347 (Aug. 23, 1994). The FDA later revoked its approval of Parlodel after Novartis
waived a formal hearing. 60 Fed. Reg. 3404, 3404-3405 (Jan. 17, 1995).
Glastetter brought an action against Novartis in 1997. She alleged that her
ingestion of Parlodel caused her ICH. Glastetter’s husband, Steven, joined a claim for
loss of consortium. Following extensive discovery, Novartis moved in limine to
exclude Glastetter’s two expert witnesses on medical causation, Dr. Kenneth Kulig and
Dr. Denis Petro. The district court received testimony from Drs. Kulig and Petro, and
from Novartis’s own medical experts, during a four-day evidentiary hearing in March
2000. On August 14, 2000, the district court excluded Glastetter’s proposed expert
testimony, holding that it was not scientifically valid, a prerequisite for admission under
Fed. R. Evid. 702. See Daubert v. Merrell Dow Pharms., Inc., 509 U.S. 579 (1993).
Because Glastetter relied upon her experts to prove causation, and because causation
was an essential element of her state-law products liability theory, the district court
granted Novartis summary judgment. The district court later awarded Novartis some
of its costs in conducting the Daubert hearing. Glastetter then filed the instant appeal
challenging both the district court’s Daubert ruling as well as its award of costs to
Novartis.
4
We employ the terms “bromocriptine” and “Parlodel” interchangeably
throughout this opinion.
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II
A party may present expert medical testimony if the expert’s opinion is
scientifically valid and it will assist the jury. Daubert, 509 U.S. at 589-93. Daubert
described the district court as a gatekeeper. In exercising its gatekeeping function, a
district court must make “a preliminary assessment of whether the reasoning or
methodology underlying the testimony is scientifically valid and of whether that
reasoning or methodology properly can be applied to the facts in issue.” Id. at
592-593. An expert opinion “must be supported by appropriate validation—i.e.,
‘good grounds,’ based on what is known.” Id. at 590. In sum, the district court’s
gatekeeping role separates expert opinion evidence based on “good grounds” from
subjective speculation that masquerades as scientific knowledge. See Globetti v.
Sandoz Pharms. Corp., 111 F. Supp. 2d 1174, 1177 (N.D. Ala. 2000). We review a
district court’s decision to exclude expert testimony for an abuse of discretion.
General Elec. Co. v. Joiner, 522 U.S. 136, 141-43 (1997).
A
Each of Glastetter’s experts conducted a “differential diagnosis,” which
concluded that Parlodel caused her ICH. In performing a differential diagnosis, a
physician begins by “ruling in” all scientifically plausible causes of the plaintiff’s injury.
The physician then “rules out” the least plausible causes of injury until the most likely
cause remains. The final result of a differential diagnosis is the expert’s conclusion
that a defendant’s product caused (or did not cause) the plaintiff’s injury. See
generally Westberry v. Gislaved Gummi AB, 178 F.3d 257, 262-66 (4th Cir. 1999).
In Turner v. Iowa Fire Equip. Co., we held that “a medical opinion about
causation, based upon a proper differential diagnosis, is sufficiently reliable to satisfy
Daubert.” 229 F.3d 1202, 1208 (8th Cir. 2000). Because a differential diagnosis is
presumptively admissible, see id., a district court may exercise its gatekeeping function
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to exclude only those diagnoses that are scientifically invalid. In the present case, the
district court excluded the differential diagnoses performed by Glastetter’s expert
physicians because they lacked a proper basis for “ruling in” Parlodel as a potential
cause of ICH in the first place. Glastetter, 107 F. Supp. 2d at 1045 & nn.28-29
(“[T]he data and methods of plaintiffs’ experts are not scientifically valid bases for the
conclusion that Parlodel can cause an ICH in a human.”). We agree with the district
court’s conclusion.
B
Glastetter’s experts articulated a theory to explain how Parlodel might cause an
ICH. They theorized that Parlodel causes arteries to constrict (vasoconstriction),
resulting in elevated blood pressure. High blood pressure is itself a recognized risk
factor for ICHs. Thus the experts opined that Parlodel’s vasoconstrictive properties
likely caused Glastetter’s ICH. Although this chain of medical reasoning appears
sound, its major premise remains unproven. Glastetter’s experts failed to produce
scientifically convincing evidence that Parlodel causes vasoconstriction. Her experts
relied on various types of scientific data—published case reports; medical treatises;
human rechallenge/dechallenge data; animal studies; internal Novartis documents; and
the FDA’s revocation of Parlodel’s indication for suppressing lactation—to establish
that Parlodel acts as a vasoconstrictor. We agree with the district court’s conclusion
that this data does not demonstrate to an acceptable degree of medical certainty that
Parlodel can cause an ICH. See Daubert, 509 U.S. at 590 n.9 (“In a case involving
scientific evidence, evidentiary reliability will be based upon scientific validity.”)
(emphases in original).
Much of the evidence relied upon by Drs. Kulig and Petro has been culled from
case reports in which doctors reported patient strokes following their ingestion of
Parlodel. A case report is simply a doctor’s account of a particular patient’s reaction
to a drug or other stimulus, accompanied by a description of the relevant surrounding
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circumstances. Case reports make little attempt to screen out alternative causes for
a patient’s condition. They frequently lack analysis. And they often omit relevant
facts about the patient’s condition. Hence, “[c]ausal attribution based on case studies
must be regarded with caution.” Reference Manual on Scientific Evidence 475 (Fed.
Judicial Ctr. 2000); see Turner, 229 F.3d at 1209 n.5 (collecting cases). Though case
reports demonstrate a temporal association between Parlodel and stroke, or stroke-
precursors, that association is not scientifically valid proof of causation.
Glastetter’s experts referred to several medical texts that suggest that
bromocriptine acts as a vasoconstrictor. Each of these texts suffers from one or more
infirmities that prevented the district court from accepting its conclusions. Some of
the texts were largely grounded upon case reports and other anecdotal information.
One text reported Parlodel’s propensity to cause diseases other than ICH, such as
coronary vasospasm and heart attack. Still other texts relied upon generic
comparisons between bromocriptine and related chemical compounds. At least one
text ventured a hesitant conclusion that Parlodel causes vasoconstriction, but the
explanation made clear that more research was needed before causation could be
firmly established.
Like the district court, Glastetter, 107 F. Supp. 2d at 1032-35, we find that these
texts do not present persuasive scientific evidence that Parlodel causes
vasoconstriction. Indeed, we regard the experts’ claims with some suspicion since
one leading treatise on medical toxicology concludes that bromocriptine has no
vasoconstrictive properties. See Matthew J. Ellenhorn, Ellenhorn’s Medical
Toxicology: Diagnosis and Treatment of Human Poisoning 1879, table 74-23 (2d ed.
1997). “[N]othing in either Daubert or the Federal Rules of Evidence requires a district
court to admit opinion evidence that is connected to existing data only by the ipse dixit
of the expert.” Joiner, 522 U.S. at 146.
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The experts pointed out that bromocriptine belongs to a class of medicinal
substances called ergot alkaloids. Some, perhaps many, ergot alkaloids are known to
cause vasoconstriction and vasospasm. Dr. Kulig hypothesized that bromocriptine
may behave like its chemical cousins—as a vasoconstrictor. But this generic
assumption that bromocriptine behaves like other ergot alkaloids carries little scientific
value. Even minor deviations in molecular structure can radically change a particular
substance’s properties and propensities. Schudel v. General Elec. Co., 120 F.3d 991,
996-97 (9th Cir. 1997).
Glastetter’s experts also cite a handful of “rechallenge” and “dechallenge”
events involving Parlodel. Rechallenge occurs when a doctor re-exposes a patient to
a drug believed to have caused an earlier adverse reaction; dechallenge removes that
exposure. See Glastetter, 107 F. Supp. 2d at 1031 n.9. Rechallenge and dechallenge
data are substantially more valuable than run-of-the-mill case reports because a
patient’s reactions are measured against his own prior reactions. Measuring the
patient’s reaction bears some similarity to a controlled experiment. Of course,
rechallenge and dechallenge events usually involve individual patients only (rather than
study groups), and are not often subject to routine testing controls. The district court
discounted Glastetter’s rechallenge and dechallenge data because the paucity of
examples presented statistically insignificant results. Further, a portion of the
rechallenge and dechallenge data involved artery spasms and heart attacks, conditions
which are quite distinct from Glastetter’s ICH. Although we believe that this evidence
is more potent proof of causation than the district court believed it to be, we
nevertheless conclude that the court did not abuse its considerable discretion in
rejecting the rechallenge and dechallenge data as proof that Parlodel acts as a
vasoconstrictor.
Glastetter’s experts rely upon animal studies to prove that bromocriptine causes
vasoconstriction, which, in turn, could have caused an ICH. But during the Daubert
hearing, Dr. Petro admitted that not a single animal study had ever concluded that ICH
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was associated with bromocriptine. Glastetter, 107 F. Supp. 2d at 1041. Moreover,
none of the pertinent animal studies were designed to reveal whether bromocriptine
could cause ICHs. See id. Both Dr. Kulig and Dr. Petro also acknowledged the
difficulty in reliably extrapolating from the results of studies on small animals to effects
on much larger humans. We are convinced that the animal studies relied upon by
Glastetter’s expert physicians are insufficient to prove that bromocriptine causes
ICHs.5
Glastetter argues that Novartis’s internal documents admit that Parlodel causes
hypertension and strokes. She points to three or four statements excerpted from
company memoranda. See Glastetter, 107 F. Supp. 2d at 1036-38. Glastetter lifted
these statements out of context from longer memoranda between Novartis doctors.
Placed in proper context, it is apparent that Novartis doctors simply expressed a
desire to perform further testing to determine whether Parlodel might be associated
with certain types of seizures and strokes. These statements do not “admit” that
Parlodel can cause an ICH.
Glastetter also relies upon the FDA’s 1994 action which rescinded its earlier
approval of Parlodel to suppress postpartum lactation. She argues that the FDA’s
action is strong evidence that Parlodel can cause ICHs. We disagree.
The FDA evaluates pharmaceutical drugs using a different standard than the
causation standard at issue in the present case. The FDA evaluated the medical
literature and concluded that Parlodel might cause seizures or strokes in women
already susceptible to disease. The FDA decided that “the potential risks associated
with the use of bromocriptine for the prevention of physiological lactation outweigh
5
A cautionary note is appropriate at this juncture. We do not discount the value
of animal studies per se. Rather, we find that the particular animal studies submitted
in this case do not present scientifically compelling evidence of causation.
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its limited benefits and bromocriptine is no longer shown to be safe for use in
preventing physiological lactation.” 59 Fed. Reg. at 43351. In effect, the FDA
balanced Parlodel’s possible harm against its limited beneficial use. Such balancing
is irrelevant in determining the threshold question posed in this appeal: whether
Glastetter’s experts properly “ruled in” Parlodel as a cause of ICHs.
The FDA’s approach differs from ours in another critical aspect. The FDA will
remove drugs from the marketplace upon a lesser showing of harm to the public than
the preponderance-of-the-evidence or more-likely-than-not standards used to assess
tort liability. “The methodology employed by a government agency ‘results from the
preventive perspective that the agencies adopt in order to reduce public exposure to
harmful substances.’” Hollander v. Sandoz Pharms. Corp., 95 F. Supp. 2d 1230,
1234 n.9 (W.D. Okla. 2000) (quoting Mitchell v. Gencorp Inc., 165 F.3d 778, 783 n.3
(10th Cir. 1999)). The FDA’s 1994 decision that Parlodel can cause strokes is
unreliable proof of medical causation in the present case because the FDA employs
a reduced standard (vis-a-vis tort liability) for gauging causation when it decides to
rescind drug approval.
Viewed in isolation, Glastetter’s different pieces of scientific evidence do not
substantiate her experts’ conclusion that Parlodel can cause ICHs. Likewise, we do
not believe that the aggregate of this evidence presents a stronger scientific basis for
Glastetter’s supposition that Parlodel can cause ICHs. We do not discount the
possibility that stronger evidence of causation exists, or that, in the future, physicians
will demonstrate to a degree of medical certainty that Parlodel can cause ICHs. Such
evidence has not been presented in this case, however, and we have no basis for
concluding that the district court abused its discretion in excluding Glastetter’s expert
evidence. See Joiner, 522 U.S. at 141-43.
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C
Finally, Glastetter contends that the district court erred by ruling that
epidemiological proof must be submitted to establish that a drug caused a particular
medical condition. If her contention were accurate, we would likely reverse, for a
plaintiff need not introduce epidemiological evidence of causation in order to satisfy
Daubert’s threshold for admission of expert medical testimony. But our review of the
court’s opinion and the voluminous record in this case convinces us that the court did
not make such a ruling.
Epidemiology is the branch of science that studies the etiology, or cause, of
disease. Reference Manual at 335. Understandably, epidemiological studies and
reports are much desired by litigants in cases involving medical causation. In this
case, Glastetter and Novartis generally agree that no reliable epidemiological evidence
links Parlodel and ICHs. Conversely, no study has refuted a link between Parlodel and
ICHs. Cf. Siharath v. Sandoz Pharms. Corp., 131 F. Supp. 2d 1347, 1356-59 (N.D.
Ga. 2001) (criticizing the limited epidemiological evidence associated with Parlodel due
to various statistical and conceptual flaws). This is hardly surprising. The statistical
pool of childbearing women who suffer strokes is quite limited. And epidemiologists
cannot perform controlled experiments because it would be unconscionable to induce
strokes in postpartum women simply to advance the medical community’s
understanding of Parlodel. Globetti, 111 F. Supp. 2d at 1179 n.13.
The absence of epidemiological evidence did not doom Glastetter’s case, as the
district court indicated. Cf. Glastetter, 107 F. Supp. 2d. at 1044 & n.27. Of course,
epidemiological evidence might have assisted Glastetter in establishing causation, and
thus its absence limited the available tools with which she could prove causation.
Having carefully considered the record in this case, we are convinced that the district
court did not require Glastetter to present epidemiological evidence in order to prove
that Parlodel caused her ICH. We find no error of the type she posits.
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We affirm the district court’s decision to exclude Glastetter’s expert evidence,
and the court’s resulting grant of summary judgment in favor of Novartis.
III
After granting summary judgment in favor of Novartis, the district court
awarded Novartis $15,525.26 in costs associated with the Daubert hearing. These
costs included certain fees and travel reimbursements for witnesses, transcripts,
deposition fees, and limited photocopying charges. The court did not award all the
costs that Novartis sought, and, in several instances, the court drastically reduced
Novartis’s requested award. On appeal, Glastetter argues against the court’s award
of fees for expert witnesses and for the preparation of daily transcripts. We agree with
the district court’s fee award for the reasons stated in its opinion, and therefore affirm
the award of costs. See 8th Cir. R. 47B.
IV
We affirm the judgment of the district court in all respects.6
A true copy.
Attest:
CLERK, U.S. COURT OF APPEALS, EIGHTH CIRCUIT.
6
We grant appellants’ motion to correct and supplement the record on appeal.
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