In this case, none of the pertinent studies were designed to reveal
whether bromocriptine could cause ICH, and none so concluded. Some
studies involved almost poisonous doses; some involved animals that had a
steel rod injected down their spinal cords so the animals had no intact
nervous systems; some involved bromocriptine's reaction locally (e.g., in
a single isolated vein of an animal) as opposed to a systemic
administration; and some were poorly documented.
Plaintiffs' experts cannot identify any animal study showing that
Parlodel causes ICH or any other stroke or hypertension or injury
purportedly secondary to cerebral vasospasm. Hrg. II:340 (Petro).
Moreover, when the animal studies conflict with his hypothesis, Dr. Kulig
opines that the studies "ha[ve] nothing to do with the human situation
where the dose may be different. It's a different species, it's a
different indication, et cetera, et cetera." Hrg. I:153-54.
To the extent that the opinions of Drs. Kulig and Petro are based on
animal studies, this Court does not believe the "fit" requirement has
been met in this case, because "there is simply too great an analytical
gap between the data and the opinion proffered." General Electric Co. v.
Joiner, 522 U.S. 136, 146 (1997) (expert offering animal studies showing
one type of cancer in mice to establish causation of another type of
cancer in humans). While researchers might reliably extrapolate from
animal studies sometimes, see Glastetter, 252 F.3d at 991 n. 5 ("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."), the type of
extrapolations Drs. Kulig and Petro divine from these particular animal
studies require giant analytical leaps between the data and the opinions
Therefore, this Court rejects the plaintiffs' experts' opinions
inasmuch as they rely on animal studies. Accord Glastetter, 252 F.3d at
991 ("We are convinced that the animal studies relied on by [plaintiff's
expert physicians are insufficient to prove that bromocriptine causes
ICHs."); Glastetter, 107 F. Supp.2d at 1041 (same); Siharath, 131 F.
Supp.2d at 1357 ("After careful review of the animal studies at issue in
this case, the court concludes that Plaintiffs have not met the necessary
standard for reliability."); Hollander, 95 F. Supp.2d at 1238 ("The court
also rejects the plaintiffs' experts' attempt to extrapolate from animal
studies to show that Parlodel causes strokes. The studies relied upon
involved different drugs, did not test the systemic effect of the drug,
some of the animals were anesthesitized, and they were neither pregnant
nor post-partum. . . . [T]he animal studies on which the plaintiffs'
experts rely are too dissimilar to the facts presented in this litigation
to be reliable.").
E. EFFECTS OF OTHER ERGOT ALKALOIDS
The plaintiffs' experts rely on various data indicating that other
ergot alkaloid derivatives have vasoconstrictive effects (Petro Aff.,
¶ A10). They rely on the general notion that ergots can cause
"ergotism." "Ergotism" is a term that has been used synonymously with
vasospasm from ergots and the delirious effects that vasospasm cause
(e.g., hypertension, seizures, stroke, myocardial infarction, and
ischemia in other parts of the body from decreased blood supply).
In this case, the plaintiffs' experts assert that bromocriptine is an
ergot alkaloid and that some, even many, ergot alkaloids have been known
to cause vasoconstriction/vasospasm.
Drs. Kulig and Petro hypothesize that it is likely that bromocriptine, a
member of the ergot alkaloid family, behaves like its chemical cousins.
However, using this "guilt by association" inference in their
methodology is of questionable scientific reliability, inasmuch as (1) a
structural difference between bromocriptine and other ergots is the
addition of a bromine atom (Hrg. I:105); and (2) even small structural
changes at the molecular level can radically change a particular
substance's properties. BERDE, ERGOT ALKALOIDS AND RELATED COMPOUNDS
(EX. D-14). Using this inference as part of their methodology of
determining the complicated comparative molecular effects of two
structurally different substances is particularly questionable given Dr.
Kulig's inability to articulate how bromocriptine would operate
differently (or how it operates at all) on a molecular level (Hrg. I:
105-08). The plaintiffs' experts' "generic assumption that bromocriptine
behaves like other ergot alkaloids carries little scientific value." See
Glastetter, 252 F.3d at 990.
Therefore, this Court rejects the plaintiffs' experts' opinions
inasmuch as they rely on the ergot alkaloid inference. See id. (noting
that even small structural changes at the molecular level "can radically
change a particular substance's properties"); Glastetter, 107 F. Supp.2d
at 1034 ("Like the Court in Hollander, this Court does not find, based on
all the evidence, that plaintiffs' experts, and plaintiffs' evidence,
establishes that `bromocriptine and the other ergots have sufficiently
similar physiological effects to warrant comparison.'"); Hollander,
95 F. Supp.2d at 1238 ("The plaintiffs have failed to demonstrate that
bromocriptine and the other ergots have sufficiently similar
physiological effects to warrant comparison."); Brumbaugh, 77 F. Supp.2d
at 1157 ("Testimony extending general conclusions about similar drugs
does not meet Daubert's requirement of reliability. . . . [Plaintiff's
expert's] unsupported suspicion may be correct but it is not a reliable
scientific opinion based on the record before me."); Siharath,
131 F. Supp.2d at 1363 (finding that plaintiffs' experts' reliance on the
generalized ergot alkaloid inference "raises serious questions of
F. MEDICAL TEXTS
The plaintiffs' experts cite clippings from various scientific
literature. First, Dr. Petro relies on two cardiac treatises, noting
bromocriptine's potential ability to cause coronary vasospasm and
attendant myocardial infarction. The first, HURST'S THE HEART, states:
"[t]hree newly recognized associations and/or causes of coronary spasm
include general anesthesia, `allergic angina' (histamine-induced), and
postpartum bromocriptine usage. . . . In postpartum women receiving
bromocriptine in the presence of pregnancy-induced hypertension acute
myocardial infarction has occurred" (Doc. 245, Pls.' Ex. 1450, at p. 3).
The second, BRAUNWALD'S HEART DISEASE, states:
Peripartum AMI [acute myocardial infarction] is often
associated with normal coronary angiographic
findings; this suggests a decrease in coronary
perfusion, possibly due to spasm or in situ thrombosis
[clotting within a blood vessel which may cause
infarction of tissues supplied by the vessel], as a
relatively common etiological factor in this patient
population. Although the cause of the spasm is not
clear, it has often been associated with
pregnancy-induced hypertension and in some instances
with the use of ergot derivatives to suppress
(Doc. 245, Pls.' Ex. 2511, at p. 2).
Second, Dr. Petro relies on a stroke treatise, in which Parlodel's
to cause cerebral arterial vasoconstriction is noted. BARNETT'S STROKE:
PATHOLOGY, DIAGNOSIS AND MANAGEMENT (1998) states: "The physiopathology
and cause of reversible angiopathy is focal arterial vasoconstriction,
which may be due to sympathomimetic [exhibiting a mutual relation
between two organs, systems or parts of the body] drugs such as ergot
derivatives, crack cocaine, methyl amphetamine, and phenylpropanolamine"
(Doc. 245, Pls.' Ex. 2512, at pp. 2-3).
Third, Dr. Petro relies on Sandoz Medical Research Department Dr.
Robert Griffith's 1978 contribution to the book, DOPAMINERGIC ERGOT
DERIVATIVES AND MOTOR FUNCTION, in which he stated, under the heading
"Bromocriptine Toxicity," that "[d]igital vasospasm in cold weather
occurs with high doses [of bromocriptine], especially in patients who
have previously reported Raynaud's phenomenon" (Pls.' Ex. 219).
In this case, a fair reading of the majority of plaintiffs' medical
texts indicates that there is an association between bromocriptine and
vasospasm, which is quite different from drawing the conclusion of
causation between therapeutic doses of bromocriptine and ICH. Moreover,
the plaintiffs' experts would agree that medical texts provide no more
support than the evidence upon which they rely.
Therefore, this Court rejects the plaintiffs' experts' opinions
inasmuch as they rely on these medical texts. Accord Glastetter, 252 F.3d
at 990 (observing that "[s]ome of the texts referred to by plaintiffs'
experts were "largely grounded upon case reports and other anecdotal
information"); Glastetter, 107 F. Supp.2d at 1034 n. 18 (observing that
"all the texts, treatises, and journals cited by plaintiffs appear based
upon the accumulated case reports or individual case reports" and
rejecting the argument "that texts and treaties that draw an
`association' between Parlodel and vasoconstriction based upon case
reports make such texts and treatises any more reliable than the case
reports on which they rely").
G. DEFENDANT'S INTERNAL DOCUMENTS
Dr. Petro relies on statements extracted from internal Sandoz
documents/correspondence (Petro Aff., ¶ A6). This Court, however,
does not believe that Sandoz' statements, taken in context, actually
"admit" that Parlodel can cause IHC. Rather, placed in context, these
statements merely express a desire to perform further testing. See
Glastetter, 252 F.3d at 990. Therefore, this Court rejects the
plaintiffs' experts' opinions inasmuch as they rely on Sandoz documents
and statements. Accord Glastetter, 252 F.3d at 990 ("Glastetter argues
that [Sandoz'] internal documents admit that Parlodel causes hypertension
and strokes. She points to three or four statements excerpted from
company memoranda. . . . 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.").
H. FDA's 1994 ACTION
Plaintiffs' experts also rely on the FDA's 1994 action that rescinded
its earlier approval of Parlodel to suppress PPL. They argue that the
FDA's action is evidence that Parlodel can cause ICH. On August 24,
1994, the FDA issued the following statement:
Since approval of bromocriptine for use in preventing
physiological lactation, FDA has received a number of
of serious and life-threatening adverse
experiences (hypertension, seizures, and CVA's
[cardiovascular accidents]) associated with the use of
bromocriptine for this indication. FDA believes that
the number of women experiencing such adverse
experiences may well be greater than those reported to
the FDA. The above evidence, in aggregate, calls into
question bromocriptine's safety for use in postpartum
women given that bromocriptine may be responsible for
hypertension, seizures, and CVA's in a small but
significant number of patients. Moreover,
bromocriptine may be an additional risk factor in
patients who are already at risk for seizures and
stroke. In addition, a possible mode of action exists
for these adverse events. In the general population, a
risk factor for hypertensive crises and spasms is
exposure to ergot alkaloids. Bromocriptine is a
semi-synthetic ergot alkaloid.
FDA now has new information suggesting that
therapeutic use of bromocriptine for the prevention of
physiological lactation may lead to serious adverse
experiences, including death and paralysis, in a small
but significant number of patients. Patients at high
risk of experiencing these serious adverse experiences
cannot be adequately predetermined. In light of the
limited benefit of using bromocriptine for the
prevention of lactation, and the effectiveness and
lack of serious adverse effects of conservative
treatments such as breast binding with or without mild
analgesics, the risk that bromocriptine may cause a
serious adverse effect in a postpartum woman is
unacceptable. Accordingly, the Director concludes that
the potential risks associated with the use of
bromocriptine for the prevention of physiological
lactation outweigh its limited benefits and
bromocriptine is no longer shown to be safe for use in
preventing physiological lactation.
59 Fed.Reg. 43347, 43351 (Aug. 24, 1994). Notably, the Order does not
state that the FDA has determined that there is a causal connection
between bromocriptine and ICH. Rather, the Order merely indicates the
FDA's conclusion that "the limited benefit of using bromocriptine" for
the prevention of physiological lactation is outweighed by the "potential
risks associated with the use of bromocriptine."
Plaintiffs' experts' contention that the FDA's order directly supports
their opinions ignores the fact that the agency determination is based on
risk-benefit analysis, a standard lower than the one this Court must now
apply. See Glastetter, 252 F.3d at 991, Siharath, 131 F. Supp.2d at 1336.
Therefore, this Court rejects the plaintiffs' experts' opinions inasmuch
as they rely on actions taken by the FDA.
I. TOTALITY OF THE EVIDENCE
Each of plaintiffs' experts' bits of evidence in this case suffers from
reliability and/or relevance deficiencies such that an opinion based on
it fails Daubert. And, plaintiffs' experts have not suggested that they
would hold the same opinions (or hold them to the requisite degree of
probability) if they were foreclosed from relying on one category of
evidence, such as case reports. Nevertheless, the Court has gone on to
consider whether, in aggregate, the evidence cited supports an inference
that would enable plaintiffs' experts to offer an admissible causation
opinion. The Court concludes that it does not. In this particular case,
the data points pulled from each "type" of evidence are too limited, too
disparate and too inconsistent. It amounts to a hollow whole of hollow
parts. See Siharath, 131 F. Supp.2d at 1371.
Mrs. Caraker has plainly suffered a great loss, and will undoubtedly be
to shoulder considerable suffering in the future, as a result of
her traumatic ICH. This Court understands Mrs. Caraker's belief that the
timing in this case points a finger at Parlodel. As a matter of fact,
Parlodel might have indeed been the cause of her injury. This Court,
however, is not now in the position of a finder of fact, and this ruling
makes no determination about the cause of Mrs. Caraker's injury.
Rather, the only issue before the Court is whether the testimony of
Drs. Kulig and Petro is reliable under the Daubert standard discussed
above. Under Daubert, the Courts are forbidden from allowing expert
testimony that is scientifically unreliable, and this Court has attempted
to faithfully apply that standard in this case. After careful
consideration of the testimony, exhibits and arguments of the parties,
the Court has concluded that the expert testimony of Drs. Kulig and Petro
is scientifically unreliable.
Therefore, for the reasons discussed above and in accordance with this
Court's September 12, 2001, Order, IT IS ORDERED that the plaintiffs'
experts' opinions are inadmissible in their entirety and Sandoz' motion
to exclude their testimony (Doc. 212) is GRANTED.
This shall serve as this Court's final ruling on this issue. This Court
hereby GRANTS the defendant forty-five (45) days from the date that this
order is issued to file a summary judgment motion. For the purposes of
this summary judgment motion only, the parties are hereby relieved of the
motion packet serving and filing requirements in Local Rule 7.1.
IT IS SO ORDERED.