The opinion of the court was delivered by: DONALD LEE, Senior District Judge.
FINDINGS OF FACT AND
This pharmaceutical products liability action was originally
filed by the plaintiff, Lisa A. Soldo, in the United States
District Court for the District of New Jersey which transferred
the action to this Court because the plaintiff is a resident of
Pennsylvania and also because Pennsylvania is the situs where she
allegedly suffered an intracerebral hemorrhage as a result of her
ingestion of Parlodel ®, a drug manufactured and marketed by
the defendant and also where she received most of her medical
The Court has jurisdiction based on diversity of citizenship
and the amount in controversy pursuant to 28 U.S.C. § 1332.*fn1
The plaintiff is a citizen of the Commonwealth of Pennsylvania,
residing at 101 West Lake Road, Transfer, Pennsylvania 16154.
The defendant, Sandoz Pharmaceuticals Corporation, now Novartis
Pharmaceutical Corporation ("NPC"), is organized and existing
under the laws of the State of Delaware, with its principal place
of business located at 59 Route 10, East Hanover, New Jersey
Before the Court for disposition is the defendant's Motion for
Summary Judgment on Issues of Medical Causation (Document No.
77), to which plaintiff responded in Plaintiff's Memorandum of
Law in Opposition to Defendant's Motion for Summary Judgment on
Issues of Medical Causation (Document No. 84).
NPC moves the Court to enter judgment in its favor as a matter
of law on the basis that plaintiff's evidence of general and
specific causation fails to meet the test of scientific
reliability set out in Daubert v. Merrell Dow Pharmaceuticals,
509 U.S. 579, 113 S.Ct. 2786, 125 L.Ed.2d 469 (1993) and followed
by the Court of Appeals for the Third Circuit in In re Paoli
Railroad Yard PCB Litig., 35 F.3d 717 (3d Cir. 1994) and Heller
v. Shaw Indus., Inc., 167 F.3d 146 (3d Cir. 1999).
Pursuant to NPC's Motion for Evidentiary Hearing Regarding
NPC's Motion for Summary Judgment on Issues of Medical Causation
(Document No. 63), the Court conducted a Daubert hearing during
which medical expert witnesses testified on behalf of the parties
and exhibits were introduced into the record. At various other
times, on motions of the parties, other extensive exhibits,
including medical treatises, were also introduced into the
Following the Daubert hearing, with the assistance of the Duke
of Law Registry of Independent Scientific and Technical Advisors,
the Court appointed three medical experts who were directed to
opine as to whether the methodology or technique employed by the
plaintiff's medical experts in opining that Parlodel ® can
cause stroke and did cause plaintiff's intracerebral hemorrhage
is scientifically reliable.
Those three experts are:
(i) David A. Savitz, Ph.D. Epidemiology
(ii) William J. Powers, M.D. Neurology/Radiology
(iii) David A. Flockhart, M.D., Ph.D. Pharmacology
Additionally, both before and after the Daubert hearing, the
parties submitted proposed findings of fact and conclusions of
law, and, after receipt of the reports of the court-appointed
experts, the parties were invited to file and did file
supplemental proposed findings of fact and conclusions of law.
Based on the record before it, the Court enters the following
Findings of Fact and Conclusions of Law.*fn2
A. Findings of Fact Regarding the History of Parlodel ®
1. Parlodel ® is a prescription drug formulated and sold by
Novartis Pharmaceutical Corporation f/k/a Sandoz Pharmaceuticals
Corporation ("NPC") since 1978. The active ingredient of Parlodel
® is bromocriptine mesylate ("bromocriptine").
2. In November 1976, NPC submitted a New Drug Application
("NDA") for Parlodel ® for treatment of
amenorrhea/galactorrhea. [Summary for Basis of Approval:
Amenorrhea/Galactorrhea] (Att. 61).
3. Parlodel ® has been approved by the Food and Drug
Administration ("FDA") since 1977 for treatment of
amenorrhea/galactorrhea associated with hyperprolactinemia.
[Summary for Basis of Approval: Amenorrhea/Galactorrhea]
4. In 1980, after reviewing extensive submissions from NPC's
predecessor Sandoz Pharmaceuticals Corporation ("SPC"), the FDA
approved Parlodel ® for the indication prevention of
physiological lactation ("PPL"). Parlodel ® was found to be
"both effective and safe" for the prevention of lactation.
[Summary for Basis for Approval of Parlodel ®: Prevention of
Physiological Lactation, at 9] (Att. 62).
5. The FDA approved the use of Parlodel ® to treat
individuals with Parkinson's Disease and also to treat
infertility associated with hyperprolactinemia in 1981. [Summary
for Basis for Approval of Parlodel ®: Parkinson's Disease]
(Att. 63); [Summary for Basis for Approval of Parlodel ®:
Agromegaly] (Att. 64).
6. The FDA approved Parlodel ® for the treatment of
acromegaly in 1984. [Summary for Basis for Approval of Parlodel
®: Female Infertility] (Att. 65).
7. The FDA approved Parlodel ® for the treatment of
Prolactin-Secreting Adenomas. [Summary Basis of Approval of
Parlodel ®: Prolactin-Secreting Adenomas] (Att. 66).
8. In 1990, an approved indication for Parlodel ® was the
PPL. 1990 PDR, (Att. 68).
9. At all times relevant to this case, Parlodel ® was
FDA-approved for the indication PPL. [Summary for Basis for
Approval of Parlodel ®: Prevention of Physiological
Lactation] (Att. 63).
10. In its 1984 FDA Drug Bulletin, FDA noted that though the
labeling of Parlodel ® was being revised to reflect reports
of adverse reactions, "[a] cause and effect relationship has not
been established." FDA Drug Bulletin, April, 1984 (Ex. 19). The
1984 Drug Bulletin expressly referenced dechallenge and
11. The 1988 FDA Advisory Committee concluded that there was
insufficient "evidence to indicate a causal relationship between
the use of Parlodel ® and postpartum stroke/seizure." See
1988 Summary Minutes (Ex. 20).
12. The 1989 FDA Advisory Committee concluded that there was no
"need" for pharmaceutical treatment of postpartum breast
engorgement, but did not present or review any new data on
safety, did not review any new data on efficacy, and did not vote
on the safety and efficacy of Parlodel ® for the PPL. See
1989 Summary Minutes (Ex. 21).
13. Subsequent to the 1989 Advisory Committee meeting, Dr.
Solomon Sobel prepared an internal memorandum to the Commissioner
of the FDA concerning the Advisory Committee's recommendation
that notes, inter alia, that "Ms. Ann Witt in the General
Counsel's office reports that we have a case for a NOOH [Notice
of Opportunity for a Hearing] based on updated prrceptions of
efficacy and safety, `but it won't be easy' since we can raise
doubts about safety but we cannot prove that risks exist." See
Memorandum from Solomon Sobel to The Commissioner, June 27, 1989
at 4 (Ex. 22) (emphasis added.)
14. SPC voluntarily withdrew the Parlodel ® indication for
PPL on August 18, 1994. [Letter from Thomas Koestler to Solomon
Sobel, 8/18/94] (Att. 89).
15. FDA's August 1994 Notice of Opportunity for Hearing
("NOOH") which was a proposal to withdraw the indication
PPA did not conclude that there was a causal connection between
Parlodel ® and stroke in general, or ICH in particular. See
59 Fed. Reg. 43347 (August 23, 1994).
16. FDA's August 1994 NOOH states only that the information on
adverse events raises safety questions, and seeks consideration
of those issues. See 59 Fed. Reg. 43347, 43351 (August 23,
17. The FDA Notice of Opportunity for Hearing was based on
FDA's receipt of reports of adverse experiences, and the Notice
articulated the FDA's perception that no pharmaceutical
intervention was needed, though it confirmed that FDA could not
prove that Parlodel ® was not both "effective and safe," as
it had determined in 1980. The Notice, in this regard, also
confirmed the FDA's internal assessment in 1989 (when the FDA
requested voluntary withdrawal of all lactation prevention drugs)
that FDA could "raise doubts about safety but [FDA] cannot prove
that risks exist." Memorandum from Solomon Sobel to The
Commissioner, June 27, 1989, at 4 (Att. 90).
18. SPC's voluntary withdrawal of the indication PPL from
Parlodel ® mooted the administrative hearing process, and
thus no hearing or formal proceeding was held.
19. Notwithstanding SPC's withdrawal of the indication PPL from
Parlodel ®, on January 17, 1995, the FDA formally withdrew
the indication PPL from Parlodel ®. 60 Fed. Reg. 3404-03
(January 17, 1995), (Att. 94).
20. At least 10,000,000 (ten million) women in the United
States are estimated to have used Parlodel ® for PPL between
1980 and 1994. Iffy/Revels Dep. at 58 (Att.1C); Iffy Dep. at 137
21. Parlodel ® remains FDA approved today for the treatment
of Parkinson's Disease, amenorrhea and galactorrhea, and
pituitary and Prolactin disorders, such as acromegaly.
B. Use of FDA Proceedings in Assessing the Effects of Parlodel
® Use in Postpartum Women
22. The current FDA-approved labeling for Parlodel ® states
that "a causal relationship between Parlodel ® (bromocriptine
mesylate) administration and hypertension, seizures, strokes, and
myocardial infarction in postpartum women has not been
established." Physicians' Desk Reference, Aug. 1, 1998 (bold
emphasis in original), Ex. RB.
23. The WARNINGS section of the current package labeling for
Parlodel ® states that a causal relationship between Parlodel
® and the adverse events of stroke, seizure, and hypertension
has not been established:
Symptomatic hypotension can occur in patients treated
with Parlodel ® (bromocriptine mesylate) for any
indication. In postpartum studies with Parlodel ®
(bromocriptine mesylate), decreases in supine
systolic and diastolic pressures of greater than 20
mm and 10 mm Hg, respectively, have been observed in
almost 30% of patients receiving Parlodel ®
(bromocriptine mesylate). On occasion, the drop in
supine systolic pressure was as much as 50-59 mm of
Hg. While hypotension during the start of therapy
with Parlodel ® (bromocriptine mesylate) occurs
in some patients, in postmarketing experience in the
U.S. in postpartum patients 89 cases of hypertension
have been reported, sometimes at the initiation of
therapy, but often developing in the second week of
therapy; seizures have been reported in 72 cases
(including 4 cases of status epilepticus), both with
and without the prior development of hypertension; 30
cases of stroke have been reported mostly in
postpartum patients whose prenatal and obstetric
courses had been uncomplicated. Many of these
patients experiencing seizures and/or strokes
reported developing a constant and often
progressively severe headache hours to days prior to
the acute event. Some cases of strokes and seizures
were also preceded by visual disturbances (blurred
vision, and transient cortical blindness). Nine cases
of acute myocardial infarction have been reported.
Although a causal relationship between Parlodel ®
(bromocriptine mesylate) administration and
hypertension, seizures, strokes, and myocardial
infarction in postpartum women has not been
established, use of the drug for prevention of
physiological lactation, or in patients with
uncontrolled hypertension is not recommended.
Physicians' Desk Reference, Aug. 1, 1998 (bold emphasis in
original), Ex. RB.
24. In the sub-section entitled "Adverse Events Observed in
Other Conditions, Postpartum Patients" of the ADVERSE REACTIONS
section, the current package labeling further states:
In postmarketing experience in the U.S. serious
adverse reactions reported include 72 cases of
seizures (including 4 cases of status epilepticus),
30 cases of stroke, and 9 cases of myocardial
infarction among postpartum patients. Seizure cases
were not necessarily accompanied by the development
of hypertension. An unremitting and often
progressively severe headache, sometimes accompanied
by visual disturbance, often preceded by hours to
days many cases of seizure and/or stroke. Most
patients had shown no evidence of any of the
hypertensive disorders of pregnancy including
eclampsia, preeclampsia or pregnancy induced
hypertension. . . . The relationship of these adverse
reactions to Parlodel ® (bromocriptine mesylate)
administration has not been established.
Physicians' Desk Reference, Aug. 1, 1998, Ex. RB (emphasis
25. This language appeared on the Parlodel ® label in March
1995, just two months after FDA published in the Federal Register
its notice of the withdrawal of the prevention of PPL. See Ex.
26. At the Daubert hearing in Railey v. Sandoz Pharmaceuticals
Corporation, Dr. Kenneth William Kulig agreed with Judge McDade
that FDA, being a prudent agency, would err on the side of
caution if there were even a possibility that an adverse effect
outweighed the benefit of a drug. 11/9 Tr. at 124-25; see also
Ex. SR (Kulig/Railey Tr. at 118).
27. In his testimony at the Daubert hearing in Railey v. Sandoz
Pharmaceuticals Corp., Dr. Kulig admitted that the December 1994
FDA Federal Register notice regarding Parlodel ® was not
proof that Parlodel ® causes strokes. Ex. SR (Kulig/Railey
Tr. at 119).
C. Findings of Fact Regarding the Pharmacology of Parlodel ®
28. Like dozens of other drugs, bromocriptine is derived from
ergot, a naturally-occurring substance. The drugs deriving from
ergot are known as "ergot alkaloids." Berde and Strumer,
"Introduction to the Pharmacology of Ergot Alkaloids and Related
Compounds as a Bases of Their Therapeutic Application," Ergot
Alkaloids and Related Compounds (hereinafter "Berde"), (Att. 23).
29. Bromocriptine differs physically from the other ergot
alkaloids in several respects, the most notable of which is that
a bromine atom has been added. Clark, et al, "Actions on the
Heart and Circulation," Ergot Alkaloids and Related Compounds 321
(1978), (Att. 67).
30. Slight differences in molecular structure can cause
seemingly similar compounds to have radically different
biological effects. Berde p. 2, (Att. 23).
31. For example, bromocriptine inhibits uterotonic activity,
whereas methlyergotamine has potent uterotonic activity in the
rabbit. Berde p. 4, (Att. 23).
32. Bromocriptine acts on dopamine receptors in the brain and
elsewhere to produce its clinically useful effects. "Parlodel
®." Physicians' Desk Reference, (Medical Economics Data 1990)
(hereinafter "1990 PDR"), (Att. 68). Most of these effects occur
due to the drug's action on dopamine receptors in the pituitary
gland, a midbrain structure that controls many hormonal
functions. Id. Bromocriptine blocks the secretion of the hormone
Prolactin, which acts on the breasts to induce secretion of milk.
Bromocriptine thus prevents lactation from occurring by blocking
the hormone that causes it. Id. Because it prevents the secretion
of Prolactin, bromocriptine has traditionally been used (and is
still used today) for a number of disorders characterized by
hyperprolactinemia, or excess prolactin secretion: amenorrhea,
galactorrhea, some types of female infertility, hypogonadism, and
Prolactin-secreting adenoma.*fn4 Id. In addition, bromocriptine is
used for acromegaly and Parkinson's disease.*fn5
33. For PPL, Parlodel ® is typically taken for 14 days, but
hyperprolactinemia, acromegaly, and Parkinson's patients may take
the drug every day for years. Id.
D. Findings of Fact Regarding the Medical History Giving Rise to
34. Plaintiff was admitted to the hospital and delivered her
second child on December 26, 1990. 12/26/90, Labor and Delivery
Summary, Sentara Norfolk General Hospital, (Att. 69).
35. Plaintiff was normotensive (that is, did not have elevated
blood pressure) before or during her pregnancy or during or
immediately after her delivery. 8/3/89 and 4/5/90, Office Notes,
Dr. Shawne R. Bryant, (Att. 70); 6/4/90 to 12/26/90, Prenatal
Flow Sheet, Dr. Gad E. Brosch, (Att. 71); 12/26/90, Labor Record,
Sentara Norfolk General Hospital, (Att. 72); 12/26/90, Anesthesia
Record, Sentara Norfolk General Hospital, (Att. 73); 12/26/90,
Recovery Room Record, Sentara Norfolk General Hospital, (Att.
74); 12/26/90 to 12/27/90, Postpartum Nurses' Records, (Att.
36. Plaintiff elected not to breast feed. 12/26/90, Assessment
Screening Room Form, Sentara Norfolk General Hospital, (Att. 76).
37. On December 26, 1990, plaintiff's treating OB-GYN, Dr. Gad
E. Brosch, dictated a 15-day order for Parlodel ®, 5 mg/day,
to be taken in two 2.5 mg doses per day. 12/26/90, Physician's
Post Partum Orders Form, Sentara Norfolk General Hospital,
38. The hospital medication administration records reflect
Parlodel ® was not administered while plaintiff was in the
hospital. 12/26/90, Medication Administration Record, Sentara
Norfolk General Hospital, (Att. 78).
39. Plaintiff was discharged from the hospital on December 27,
1990. 12/27/90, Physician's Order Form, Sentara Norfolk General
Hospital, (Att. 79).
40. There are no records of any prescription for Parlodel ®
being filled after plaintiff left the hospital on December 27,
41. Plaintiff does not recall when she started taking Parlodel
®. Deposition of Lisa Soldo ("Soldo Dep."), p. 121, (Att.8).
42. Plaintiff does not remember how often she took Parlodel
®. Soldo Dep. p. 121-22, (Att.8).
43. Plaintiff does not remember how many pills of Parlodel
® per day she took. Soldo Dep. p. 121-22, (Att.8).
44. Plaintiff testified that she took Parlodel ® while she
was visiting her parents in Transfer, Pennsylvania. Soldo Dep. p.
45. Plaintiff recalls that she discarded her empty Parlodel
® bottle "about one or two days" before her stroke. Soldo
Dep. p. 128, (Att.8).
46. Plaintiff's experts credit plaintiff's deposition testimony
that she did not follow her prescription and instead completed
her Parlodel ® regimen "one or two days" before her
intracerebral hemorrhage ("ICH"). (11/8 Tr. at 73); 11/15 Tr. at
47. Plaintiff's experts cannot state, given plaintiff's
deposition testimony, when plaintiff took her last dose of
Parlodel ®. 11/15 Tr. at 57.
48. There is no evidence other than plaintiff's deposition
testimony regarding the frequency and duration of plaintiff's
Parlodel ® usage.
49. There is no scientific method to determine when plaintiff
took her last dose of Parlodel ®. 11/15 Tr. at 62.
50. A 15-day prescription for Parlodel ®, started on
December 27, 1990, would have been completed on or around January
51. On January 18, 1991, 23 days after her discharge, while
still in Pennsylvania, plaintiff complained of a very severe
headache, and laid down in a room at her mother's house. Soldo
Dep., pp. 132-33, (Att.8).
52. When awakened several hours later, plaintiff was
53. Plaintiff was taken to Sharon General Hospital, where a
CT-scan of the brain revealed an ICH. 1/18/91, Head CT-scan
Report, Sharon General Hospital, (Att. 80).
54. Plaintiff's Emergency Room admission form, completed with
information provided by her family, lists possible aspirin use,
but not Parlodel ®. 1/18/91, Emergency Room Record, Sharon
General Hospital, (Att. 52).
55. Shortly after admission to Sharon General Hospital, at
11:12 p.m., a urine sample was collected for a toxicology screen.
The drug screen results indicated the presence of salicylate
(aspirin) and "large amount present" of amphetamines. 1/18/91,
Laboratory Report, Sharon General Hospital, (Att. 81).
56. On January 19, 1991, plaintiff was transferred to Saint
Elizabeth Hospital Medical Center for further treatment. While
there, she was given a four-vessel cerebral arteriogram to help
diagnose her condition. 1/19/91, Arteriogram Report, Saint
Elizabeth Hospital Medical Center, (Att. 82). Plaintiff also
underwent a craniotomy to evacuate a large hematoma that had
built up as the result of her cerebral bleed. 1/20/91 Operation
Report, Saint Elizabeth Hospital Medical Center (incorrectly
dated 1/21/91), (Att. 83). Fragments of the hematoma were
examined and found consistent with an acute hemorrhage. 1/20/91,
Pathology Report, Saint Elizabeth Hospital Medical Center, (Att.
57. Plaintiff's highest recorded blood pressure in the Sharon
General emergency room was 130/70. 1/18/91, Emergency Room
Record, Sharon General Hospital, (Att. 52); 1/18/91 1/19/91,
frequent Vital Signs Form, Sharon General Hospital, (Att. 91).
Plaintiff's highest recorded blood pressure at Saint Elizabeth
Hospital Medical Center, prior to her craniotomy was a single
reading of 150/90. Most readings at Saint Elizabeth Hospital
Medical Center averaged in the 110/80 range. 1/19/91, Critical
Care 24 Hour Flowsheet, Saint Elizabeth Hospital Medical Center,
58. On January 20, 1991, plaintiff was again screened for
substances in her blood. The results were negative for most
substances, including salicylates, acetaminophen, and
amphetamine. The test also found "substance present consistent
with sympathomimetic amine." 1/20/91, Laboratory Report, Saint
Elizabeth Hospital Medical Center, (Att. 86).
59. There were no objective measurements made of the amount of
Parlodel ®, if any, in plaintiff's blood or tissue at the
time of plaintiff's ICH. 11/8 Tr. at 91-92.
60. Plaintiff's experts testified that the half-life of
Parlodel ® in the blood may be as short as three hours and
may be a high as 100 hours. 11/15 Tr. at 58.
61. Plaintiff's experts assume that plaintiff had "a
substantial amount" of Parlodel ® in her system at the time
of her ICH. 11/15 Tr. at 20.
62. If plaintiff took her last dose of Parlodel ® only one
day (24 hours) before her ICH, based on a three-hour serum half
life the Parlodel ® in plaintiff's system would have gone
through eight half-lives prior to the event. After eight
half-lives, only 1/256th of the amount of Parlodel ®
initially in plaintiff's blood stream would be present. 11/15 Tr.
63. If plaintiff took her last dose of Parlodel ® only two
days (48 hours) before her ICH, based on a three-hour serum half
life only 1/65,000th of the amount of Parlodel ® initially in
plaintiff's blood stream would have been present at the time of
the event. 11/15 Tr. at 61.
64. If plaintiff last took Parlodel ® as much as 60 hours
prior to her stroke, a possibility recognized by plaintiff's
experts (11/15 Tr. at 57), based on a three-hour serum half-life
her blood levels of bromocriptine would be reduced by a factor of
2 20 from their initial, therapeutic level, i.e., would be less
than one two-millionth of their starting levels at the time of
65. If plaintiff took her last dose of Parlodel ® only one
day (24 hours) before her stroke, a possibility recognized by
plaintiff's experts (11/15 Tr. at 58), based on a 100-hour
half-life, her blood levels at the time of the stroke would be
only barely lower than they were when last at therapeutic
66. Given the uncertainties in the timing of plaintiff's last
dose and uncertainties with respect to the half-life of
bromocriptine articulated by plaintiff's experts, it is unknown
whether the level of bromocriptine in plaintiff's blood stood at
the therapeutic level at one extreme or 1/2,000,000 of the
therapeutic level at the other extreme or somewhere in between.
67. Plaintiff has not demonstrated a scientifically valid basis
to conclude that she was taking Parlodel ® one or two days
before her ICH.
68. Plaintiff has not demonstrated that she had a substantial
amount of Parlodel ® in her system at the time of her ICH.
69. Plaintiff has not demonstrated that she had an amount of
Parlodel ® in her system at the time of her ICH sufficient to
cause any biological effect.
70. At the time of her stroke, plaintiff smoked between half a
pack and a pack of cigarettes per day. 1/19/91, History and
Physical, Saint Elizabeth Hospital Medical Center, (Att. 52).
71. At her deposition, plaintiff could not remember the date of
her stroke. Soldo Dep. p. 129, (Att.8).
72. Plaintiff has testified that her stroke keeps her from
remembering facts about her Parlodel ® usage. Soldo Dep. p.
E. Findings of Fact Regarding Epidemiology
73. Stroke is a relatively common and widespread disease in the
United States; there are 700,000 new stroke cases a year in the
United States, and it is the third leading cause of death in the
United States. 11/16 Tr. at 69.
74. A background risk for stroke exists in all age groups.
11/17 Tr. at 56.
75. Dr. Kulig conceded that he does not know the annual
incidence of stroke in the United States. 11/8 Tr. at 169.
76. Dr. Kulig conceded that he does not know whether stroke is
more common than breast cancer in the United States. 11/8 Tr. at
77. Dr. Kulig conceded that he does not know whether stroke is
the third leading cause of death in the United States after
diseases of the heart and all cancers combined. 11/8 Tr. at
78. Dr. Kulig conceded that he does not know what percentage of
stroke victims in the United States is persons under age 65. 11/8
Tr. at 170.
79. Differential diagnosis alone cannot establish causation to
a degree of medical certainty in a case involving a disease as
common as stroke. 11/16 Tr. at 99; see also Ex. SQ (In re New
York State Silicone Breast Implant Litigation Brusch v. Cooper
Companies, No. 128115/93, Tr. (9/29/97)) at 859 ("a cause and
effect relationship" cannot be shown with a disease as common as
breast cancer in humans "by a process of differential diagnosis")
(discussed in 11/8 Tr. at 179-80).
80. Roughly one-third of all strokes, despite careful
evaluation, go undiagnosed as to their cause. 11/15 Tr. at 174.
81. Strokes exist for which a particular cause cannot be
ascertained, even after extensive investigation. 11/10 Tr. at
82. There are strokes in persons of any age for which we do not
have a mechanism to explain their causality. 11/10 Tr. at 214.
83. "In the absence of an understanding of the biological and
pathological mechanisms by which disease develops,
epidemiological evidence is the most valid type of scientific
evidence of toxic causation." Federal Judiciary Center, Reference
Manual on Scientific Evidence ("Ref. Man. Sci. Evid.") at 126.
84. Regardless of whether the mechanism is known, given the
existence of a background risk of stroke, the scientific way to
determine whether bromocriptine increases the risk of stroke in
humans is through a proper controlled clinical or epidemiologic
study. 11/15 Tr. at 181-82; 11/17 Tr. at 56; Ex. SQ at 859 (Dr.
Kulig agrees controlled study is required to establish a cause
and effect relationship between a substance and a disease as
common as breast cancer).
85. For example, because of the background risk of birth
defects, it was necessary to conduct epidemiologic studies to
determine whether Bendectin use raises the risk of developing
birth defects. Ultimately, epidemiology demonstrated that there
was a negative association between Bendictin and an increased
risk of birth defects, or, put another way, Bendectin use did not
raise the odds of having a child with a birth defect. 11/17 Tr.
86. A particular epidemiologic study's measurement of relative
risk has no meaning by itself but must be interpreted in
conjunction with its statistical degree of confidence. Ref. Man.
Sci. Evid. at 152-55. Relative risk is always expressed with
"confidence intervals" that indicate a range of relative risk
values in which the "true" relative risk is very likely to fall.
Id. at 154-55. A confidence interval that includes 1.0 means that
the relative risk estimate in
a particular study is not statistically significant. Id. at
154-55. See generally Ref. Man. Sci. Evid. at 147-49, 154-55.
Relative risk is the ratio of the incidence of disease in exposed
individuals to the incidence in unexposed individuals. A relative
risk of 1.0 means that the incidence in each group is the same,
i.e., the exposure has no association with the disease. A
relative risk significantly below 1.0 means that the exposure is
associated with the absence of the disease, whereas a relative
risk significantly above 1.0 means that exposure is associated
with an increased risk of the disease.
87. During the postpartum period, women are at an increased
risk of many types of cerebrovascular accidents, including
cerebral infarction, ICH, and subarachnoid hemorrhage. See The
Kittner Study; see also 11/15 Tr. at 168-71.
88. Indeed, postpartum stroke is a common serious complication
of pregnancy. 11/15 Tr. at 168; 11/16 Tr. at 24; see also
Kulig/Roberts Tr. at 44-45 (pregnancy and delivery are risk
factors for stroke; probably increased incidence of postpartum
stroke;) see generally Lanska and Kryscio, Peripartum Stroke and
Intracranial Venous Thrombosis in the National Hospital Discharge
Survey, 89 Obstetrics & Gynecology 412 (1997), Ex. GT; see
also 11/16 Tr. at 73-74.
89. "There are a number of physiological changes that occur in
the transformation from pregnancy back to the non-pregnant state.
These take place in what's known as the postpartum period, which
is defined as the first six weeks post-delivery. During that time
there's a major decrease in blood volume; there are hormonal
changes, as the woman shifts from the hormonal state of pregnancy
to nonpregnancy; there are changes in coagulation of the blood
that are thought to create a hypercoagulable state, that is a
state in which blood clots more easily in some women in this
period. Those are some of the mechanisms that have been put forth
to account for the rise in stroke in the postpartum period."
11/15 Tr. at 170.
90. Data on pregnancy and the postpartum period gathered for
the past five decades reflect that postpartum stroke is a common
serious complication of pregnancy. Douglas J. Lanska, M.D., M.S.,
M.P.H., and Richard J. Kryscio, Ph.D., "Stroke and intracranial
venous thrombosis during pregnancy and puerperium," 51 Neurology
1622, 1627 (1998) (table 3 citing epidemiologic studies of
stroke), Ex. GU; see also 11/15 Tr. at 168-70.
91. Plaintiff concedes that no epidemiology exists that
demonstrates that a woman taking Parlodel ® postpartum is
more than twice as likely to have a stroke than a woman who has
not taken Parlodel ®, i.e., statistically-significant
epidemiology demonstrating a relative risk greater than 2.0. 11/8
Tr. at 9, 10.
92. Plaintiff cannot present any statistically significant
study demonstrating an association between any ergot alkaloid and
stroke in human beings. 11/9 Tr. at 132.
93. Plaintiff cannot cite any study showing that the rate of
postpartum stroke increased significantly starting in 1980 when
Parlodel ® was introduced for the prevention of postpartum
lactation in the United States. 11/15 Tr. at 70.
94. Plaintiff cannot cite any article that indicates that the
risk of postpartum stroke significantly decreased after 1994 when
the Parlodel ® PPL indication was withdrawn in the United
States. 11/15 Tr. at 71.
95. There is no prospective, doubleblind, randomized,
placebo-controlled study published or unpublished that shows
that bromocriptine causes stroke. 11/10 Tr. at 187.
96. Epidemiology has methods and standards and, as such, is by
its very nature "testable." Epidemiologists express study results
in terms of a relative risk.
97. Plaintiff's experts, Drs. Kenneth Kulig and Dennis Petro,
disregard the express conclusion of the studies that eclampsia is
not a sufficient explanation for the increased risk of postpartum
stroke. E.g., id.; Kulig/Hollander Dep. 117 (Att.2A); Petro Dep.
225, 227 (Att.3E); Petro/Rider Dep. 242-43 (Att.3A).
98. Drs. Kulig and Petro both concede that there is no
statistically-significant epidemiologic study showing that
Parlodel ® increases the risk of stroke. See Petro/B/G/Q Dep.
290 (Att.3C); Iffy/NJC Dep. 46-52, 143 (Att.1A); Kulig/Hollander
Dep. 108-09 (Att.2A).
99. At his deposition in Brasher v. Sandoz Pharmaceuticals
Corporation, 160 F. Supp.2d 1291 (N.D.Ala. 2001) Dr. Petro,
plaintiff's expert, acknowledged that the postpartum period
itself is a risk factor for stroke. Petro/Brasher Dep. at 322.
100. Notwithstanding the existence of compelling evidence of an
elevated risk of stroke in the postpartum period, Dr. Petro
offered no basis to rule out the postpartum period in performing
his differential diagnosis for plaintiff's stroke. E.g., 11/10
Tr. at 105 ("there's no reason to believe that just having a
child three weeks prior will in fact make that person susceptible
101. Plaintiff designated, but declined to call to testify, Dr.
George Macones, an expert epidemiologist.
102. Dr. Macones rejects Dr. Kulig's hypothesis. Dr. Macones
previously testified that the epidemiology clearly showed an
increased risk of stroke in the postpartum period, even excluding
preeclampsia and eclampsia. In an unrelated Parlodel ® case,
Dr. Macones testified regarding the Kittner Study:
Q. So postpartum stroke can clearly occur in women
who up to that point have had normal pregnancies and
are deemed healthy. Correct?
Q. Now, focusing on figures one and two, if we
excluded all strokes associated with preeclampsia and
eclampsia, we could apply the formula that we
discussed earlier to make a relative risk estimation
for the postpartum period compared to the balance of
A. Yes, we could use your formula.
. . .
Q. And that would yield a relative risk estimate of
A. 11.9, good job.
Q. So using that estimate that would indicate that if
one excludes preeclampsia and eclampsia, there still
seems to be substantial increased risk of stroke in
the postpartum period compared to the balance of
A. . . . [A]gain, using person weeks is one way of
doing it. And if you look at it in terms of weeks
like that and weeks at risk, then your 11 relative
risk is right. I think another legitimate way to look
at it is just to look at pregnancy and postpartum and
not count the number of weeks. . . . [T]he relative
risk would be whatever, 1.8, 1.9, something like
Q. . . . [E]ven if we did it your way, . . . one
still finds roughly twice as many postpartum strokes
as strokes during pregnancy. Correct?
A. Yeah, that's absolutely what they found.
Q. Even if you exclude preeclampsia and eclampsia?
A. Yeah, that's correct.
Macones/B/G/Q Dep. 94-95 (Att.4A). Thus, Dr. Macones testified
that he had no basis to disagree with the conclusion of Kittner
that "[a] causal role for preeclampsia and eclampsia does not
fully explain the much stronger associations in stroke found for
the postpartum state than for pregnancy itself."
Macones/B/G/Q Dep. 101 (citing Kittner) (Att.4A).
103. Dr. Macones admits that the epidemiologic data do not
support the conclusion that Parlodel ® increases the risk for
postpartum stroke: "Based on the epidemiological data that I have
reviewed, not having reviewed anything else, the answer would be
that I can't say either way." Macones/NJC Dep. 41-42 (Att. 43).
104. Dr. Macones has testified that it is unknown whether there
is a positive or a negative association between Parlodel ®
and stroke. Macones/Hernandez Dep. 65-66 (Att.9).
105. Plaintiff's experts are similarly unable to point to any
clinical trial for any indication of Parlodel ® in which
there was a statistically-significant increased risk of stroke.
Petro/B/G/Q Dep. 311 (Att.3C). Nor can plaintiff's experts point
to any treatises or textbooks stating that bromocriptine causes
stroke. Petro/B/G/Q Dep. 337 (Att.3C); Iffy/NJC Dep. 181-83
106. Plaintiff's experts do not rely on any clinical trial that
demonstrated stroke associated with any use of Parlodel ®.
11/9 Tr. at 74.
107. Dr. Kulig testified that the Sandoz Study 60 shows that
"at least one case of hypertension was caused by the drug
[Parlodel ®] using the drug company's own causation
assessment." 11/9 Tr. at 78.
108. The investigators/authors of Sandoz Study 60 do not state
anywhere in the report that hypertension was demonstrated in any
participant in the study. Ex. LG (Study 60).
109. Indeed, the authors of Sandoz Study 60 stated that
"Parlodel ® was safe and relatively well tolerated, although
a blood pressure lowering effect was noted." Ex. LG at 6.
110. Dr. Kulig does not recall whether he reviewed the actual
blood pressure data from any of the patients in Sandoz Study 60
to see whether the data supported his assertion that at least one
case of hypertension during the clinical trial was caused by
Parlodel ®. 11/9 Tr. at 83.
111. In Sandoz Study 60, one trial participant-Patient
62 exhibited a single diastolic hypertensive blood pressure
reading during a second 24-week phase of a three-phase clinical
trial. 11/16 Tr. at 165-66.
112. As plaintiff's expert Dr. Petro testified, a single
reading of elevated blood pressure is insufficient to support a
finding of hypertension. 11/10 Tr. at 195-97.
113. In any event, Patient 62 in the Sandoz Study 60 was
hypertensive prior to participating in the Parlodel ®
clinical trial. 11/16 Tr. at 171.
114. After her 72-week involvement in the Sandoz Study 60,
Patient 62's measured blood pressure was significantly lower than
it had been before her participation in Study 60. 11/16 Tr. at
115. The Sandoz Study 60 did not demonstrate that Parlodel
® treatment causes hypertension or elevated blood pressure.
116. There is no evidence that the Sandoz Study 60 raw data was
"sanitized" in any way, at any time. 11/17 Tr. at 14-15.
117. Plaintiff presented no factual evidence that Sandoz Study
60 was terminated prematurely or "sanitized" in any way.
118. Plaintiff has not demonstrated that the Sandoz Study 60
supports her hypothesis that Parlodel ® taken in therapeutic
doses causes cerebral vasoconstriction or vasospasm.
119. Plaintiff has not demonstrated that the Sandoz Study 60
raw data supports her hypothesis that Parlodel ® taken in
therapeutic doses causes cerebral vasoconstriction or vasospasm.
120. Plaintiff has not demonstrated that the Sandoz Study 60 or
its raw data supports her hypothesis that Parlodel ® taken in
therapeutic doses causes ICH.
121. Dr. Kulig testified that the Sandoz "hand vein study"
demonstrates that "Parlodel ®, like the other ergot
alkaloids, is a vasoconstrictor, and in this case the blood
vessel that was examined was the hand veins [sic] of human
beings." 11/8 Tr. at 145-46.
122. At his deposition in Siharath v. Sandoz Pharmaceuticals
Corp., Dr. Kulig stated that he does not know whether the hand
vein study results can be extrapolated to cerebral veins. 11/9
Tr. at 114; see also Kulig/Siharath Dep. at 199 (Att. 10).
123. Dr. Kulig conceded that he also does not know whether the
results of the hand vein study can be extrapolated to cerebral
arteries, 11/9 Tr. at 114-19.
124. Dr. Kulig did not attempt to compare the doses and blood
levels of bromocriptine in Sandoz' experiment against those seen
in women receiving oral doses of Parlodel ®. 11/9 Tr. at
125. A woman would have to take 5,000 Parlodel ® 2.5 mg
tablets in a single dose to place the same amount of
bromocriptine in her bloodstream as was used in the "hand vein
study." 11/16 Tr. at 154-55.
126. The hand vein study is a dose response study in which no
effect was noted except at the highest of the test infusion
doses, which was many times the dose and blood level of
bromocriptine ingested under prescription for the Parlodel ®
127. The hand vein study does not demonstrate that any person
taking Parlodel ® at therapeutic doses would develop any of
the outcomes which Dr. Kulig asserts based on his interpretation
of the hand vein study.
128. The hand vein study does not demonstrate that any person
taking Parlodel ® at therapeutic doses would develop cerebral
129. Extrapolation from the massive Parlodel ® doses given
in the hand vein study to postpartum women taking Parlodel ®
does not comport with the fundamental principle of dose response.
Cf. 11/17 Tr. at 42-43.
130. Plaintiff's experts, Drs. Kulig and Petro, do not use a
scientifically valid methodology in relying on the results of the
hand vein study as support for their opinion that Parlodel ®
can cause ICH in postpartum women when taken at therapeutic
(iii) Epidemiological Studies re: Parlodel ® and Stroke
131. Among the epidemiologic studies concerning Parlodel ®
and stroke are the ERI Study, the HCIA Study, the Kittner Study
and the Witlin-Sibai Study. In the first study, investigators
reviewed hospital databases with information about 280,096 women
delivering babies. Kenneth Rothman, An Epidemiologic Evaluation
of the Possible Relation Between Bromocriptine, Puerperal
Seizures and Strokes, (Sept. 30,
1988) ("ERI Study") (Att. 14). (The casecontrol model of
epidemiologic studies is explained in detail in the Ref. Man.
Sci. Evid. at 136-38.) Out of a total of 10 postpartum strokes in
this population, only one occurred in a woman who had taken
Parlodel ®. The resulting relative risk calculation (8.4) was
not statistically-significant, and the study was deemed "not
informative." ERI Study (Att. 14) at 2.
132. Dr. Rothman found that, at the 90% confidence level, the
lower confidence interval for the risk of stroke due to Parlodel
® use was only 0.40, consistent with a negative association.
133. Plaintiff's experts state that this single occurrence of a
stroke among more than 280,000 women is evidence of general
causation, though they nonetheless agree that it lacks
statistical significance. Petro/B/G/Q Dep. 409 ("the sample size
was inadequate to appropriately address the question [whether
Parlodel ® causes stroke]") (Att.3C); Iffy/NJC Dep. 48 (ERI
study did not reach statistical significance) (Att.1A); Kulig/NJC
Dep. 83 ("I don't believe it's a very reliable study. . . .")
(Att.2B); Kulig/Daubert Hearing Transcript in Nussel (Railey v.
Novartis Pharms. Corp., Case No. 94-1440 (C.D. Ill., Peoria
Div.)), Apr. 6, 1999, Vol. I, at 79-80 ("I'm not claiming that
[the ERI] study shows that the drug Parlodel ® causes
stroke") (Att.2C); Kulig/O'Connor Dep. 35-39 (admission that he
is bound by investigator's statement that study is inconclusive)
134. Dr. Kulig testified that the ERI study is the only
epidemiologic study on which he relies as support for his opinion
that Parlodel ® causes ICH in the postpartum period. 11/8 Tr.
at 206; see Ex. KW.
135. Dr. Kulig concedes that the confidence interval for the
stroke data in the ERI study crossed the number one and therefore
could not exclude the possibility that the calculated relative
risk of stroke in women using Parlodel ® was due to chance.
11/8 Tr. at 207, 212-13.
136. The results of the ERI study concerning stroke are
negative in terms of the hypothesis that Parlodel ® causes
stroke. 11/15 Tr. at 183.
137. In his deposition in O'Connor v. Sandoz Pharmaceuticals
Corp., Dr. Kulig testified: "[The ERI study] doesn't prove
anything basically if you want to use proof in a very scientific
sense of the word, it doesn't prove that Parlodel ® causes
strokes or seizures, it's suggested that it does, but it doesn't
prove it, and I think we need to prove it one way or the other in
order to call this drug safe or effective." Kulig/O'Connor Dep.
at 38 (Att. 7).
138. In an affidavit submitted in the case Railey v. Sandoz
Pharmaceuticals Corporation, Dr. Kulig wrote, "This [ERI] study
is inherently unreliable and is not relied upon. . . ." 11/8 Tr.
191; see also Ex. SP (Railey Affidavit).
139. Dr. Kulig concedes that the basis for his opinion in
Railey v. Sandoz Pharmaceuticals Corporation is the same as the
basis for his opinion in this case. 11/8 Tr. at 209.
140. Dr. Kulig testified that he relies on the ERI study as
support for his opinion that Parlodel ® causes ergotism. 11/9
Tr. at 8-9.
141. As Dr. Kulig concedes, the ERI study nowhere concludes or
states that Parlodel ® causes ergotism. 11/9 Tr. at 10.
142. Indeed, the ERI study does not make findings about a link
between Parlodel ® and ergotism. 11/15 Tr. at 184.
143. Dr. Petro testified that he is not relying on the ERI
study for any portions of his opinion. 11/10 Tr. at 99.
144. Dr. Petro nevertheless cites the ERI study as evidence
that Parlodel ® used in the postpartum period was a
significant risk factor for stroke. 11/15 Tr. at 71.
145. Dr. Macones admits that the ERI study on Parlodel ®
and postpartum stroke, upon which plaintiff's other experts rely,
is "uninformative" on that issue and does not even begin to
address the question. Macones/Hernandez Dep. at 65 (Att.9).
146. Dr. Macones admits that, if additional stroke cases had
been found in the ERI study, it is entirely speculative as to
whether such stroke cases would have been women who used Parlodel
® or women who did not. Macones/B/G/Q Dep. at 78-80 (Att. 42).
Similarly, Dr. Macones admits that, if additional stroke cases
had been found, additional controls would have been selected and
it is entirely speculative as to whether such controls would have
been women who used Parlodel ® or women who did not. Id.
147. The ERI study stroke results are not statistically
significant and may not be used in a scientifically valid manner
to support an expert's opinion that bromocriptine causes stroke.
148. The Witlin-Sibai study, "Postpartum Stroke: A Twenty-Year
Experience," examined the incidence of stroke in postpartum
women. Ex. OE.
149. When the underlying study data were examined for the
possible role of Parlodel ® use in postpartum stroke, the
Witlin-Sibai study results supported the hypothesis that
bromocriptine use in the postpartum period was protective of
stroke, or, to put it another way, the study showed that women
taking bromocriptine were eight times less likely than women not
taking bromocriptine to develop stroke in the postpartum period
(Odds Ratio 0.12). This result is statistically significant.
11/17 Tr. at 67-68.
150. Dr. Sibai reliably obtained the 40,000 Parlodel ® user
figure used in the Witlin-Sibai study by asking Roberta Rogers, a
Pharm.D., to review the hospital pharmacy records to determine
how many Parlodel ® prescriptions were written over a
two-year period. This figure was then extrapolated and applied
over the entire period when Parlodel ® was used for
postpartum lactation at Dr. Sibai's hospital. 11/17 Tr. at
151. Even if the number of bromocriptine users in the
Witlin-Sibai study were overstated by 33% (of which there is no
evidence), the results of the study would not fundamentally
change; the study results would still reflect that women taking
bromocriptine were five times less likely than women not taking
bromocriptine to develop stroke. This result would still be
statistically significant. 11/17 Tr. at 70.
152. The Witlin-Sibai study was peer reviewed and initially
accepted for publication. 11/17 Tr. at 73.
153. After plaintiff's counsel contacted the journal editor by
telephone and in writing, the journal editor "knuckled under" and
declined to publish the study. 11/17 Tr. at 73.
154. Dr. Laura Carolyn Green relied upon Dr. Sibai's affidavit
regarding the Witlin-Sibai study, an affidavit with a higher
degree of reliability than the kinds of explanatory information
she would normally have access to in assessing the scientific
validity of a study. 11/17 Tr. at 65.
155. Although Dr. Kulig characterizes the Witlin-Sibai study as
"litigation science," Dr. Witlin was not an expert witness for
NPC when the manuscript was written and Dr. Sibai was not an
expert witness for NPC when the data on which
the manuscript is based was collected. 11/9 Tr. at 21.
156. A third epidemiologic study analyzed 533,816 delivery
records from 128 hospitals and tracked postpartum complications,
correlating these complications with Parlodel ® use. HCIA,
Postpartum Complications and Parlodel ® (October 1995), Ex.
DZ. This study estimated a relative risk for stroke associated
with bromocriptine use of 1.088 with a confidence interval ("CI")
from 0.448 to 2.643. Because the CI included 1, this result was
not statistically-significant. Id.; see also 11/9 Tr. at 14-15
(dismissing results from HCIA study); Kulig/NJC Dep. 78 (" . . .
overall I think the [HCIA] study is not reliable in answering the
questions that need to be answered.") (Att.8); Macones/Hernandez
Dep. 76-77 ("the confidence intervals are extremely wide which
suggest . . . huge amounts of uncertainty in the data.")
157. The HCIA study does not support plaintiff's hypothesis
that bromocriptine use increases the risk of stroke in postpartum
158. The Kittner study determined that the risk of ICH during
the postpartum period is 28.3 times higher than in similarly aged
women who are not postpartum. 11/15 Tr. at 173.
159. Plaintiff's ICH falls in the postpartum time frame
identified by the Kittner study as a period of significantly
increased risk for stroke. 11/15 Tr. at 176-77.
160. The results of the Kittner study are consistent with the
long-standing literature and studies that support the hypothesis
that the postpartum period is a risk factor for stroke. 11/17 Tr.
at 137-38; 11/16 Tr. at 73-76.
161. Because of the different baseline risk for stroke between
European and African-American women, and the differing baseline
risks of stroke depending on age, the Kittner study was age and
race adjusted to minimize these possible biases in the study
data. 11/16 Tr. at 16.
162. Although the Kittner study population included both
European and African-American women, there is no reason to
believe that the elevated relative risk for stroke in the
postpartum period is different for white women and black women,
even though white women and black women have different baseline
risks for stroke. 11/16 Tr. at 15, 18.
163. Plaintiff's experts suggest that Parlodel ® perhaps
accounted for the significant increased risk documented in the
Kittner study. The suggestion is based on at least two critical
assumptions for which no evidence was presented:
that Parlodel ® was in fact in regular use at
the hospitals involved in the Kittner study during
the two years of that study;
that some or all of the women identified in the
Kittner study with postpartum stroke had been (a)
bottle-feeding, and (b) using a drug to suppress
164. In Dr. Kulig's own hospital, Parlodel ® was taken off
of the preprinted standing orders in the mid-1980's, i.e., before
the time frame of the Kittner study. 11/8 Tr. at 32.
165. After the Kittner study was published, Dr. Kittner engaged
in a case-control study examining the potential risk factors for
ischemic stroke in the same geographic area. 11/15 Tr. at 179-80;
Ex. GB. The case-control study did seek information concerning
drug use within one month of an incident stroke, and none of the
seven postpartum women who had a stroke in that study indicated
usage of Parlodel ®. These facts were set forth in
a letter from Dr. Kittner published in the New England Journal of
Medicine. 11/15 Tr. at 178-80; Ex. GB.
166. The facts support an inference that Parlodel ® may not
have been available in the hospitals covered by the Kittner
study. In any event, there was no evidence whatsoever presented
to support plaintiff's experts supposition that Parlodel ®
may have played a role in the Kittner study.
167. Parlodel ® is not a scientifically probable confounder
for the increased risk of stroke in postpartum women reported in
the Kittner study. 11/15 Tr. at 180-81.
168. The Kittner Study specifically evaluates the role of
eclampsia and concludes that eclampsia does not account for the
findings of significant increased risk of stroke (for example,
the 28-times increased risk of ICH). Ex. GA at 773.
169. In still another epidemiologic study, investigators
compared hospital admissions and drug use to identify women who
experienced ischemic heart disease, hypertension, or
cerebrovascular events (such as stroke) before, during, and after
Parlodel ® for PPL. No women were admitted to hospitals for
these conditions during the presumed exposure period or in the
two months following. Herings and Stricker, Bromocriptine and
Suppression of Postpartum Lactation, 17 Pharmacy World &
Sci., 133-37 (1995), Ex. EA.
170. The Herings and Stricker study does not support
plaintiff's hypothesis that bromocriptine use increases the risk
of stroke in postpartum women.
171. The only two patients documented in the Herings and
Stricker study to have had cerebrovascular disease, which
includes stroke, were not users of Parlodel ®.
Macones/Colangelo at 66-67.
172. The definition of science is being able to test a
hypothesis in a manner which is valid that is, controlled,
unbiased, blinded whenever possible, significant in its
conclusions by statistically valid techniques, and where the
conclusions are supported by the data. 11/8 Tr. at 182; see also
11/10 Tr. at 182.
173. The scientific method is the naming of a hypothesis, the
careful testing of that hypothesis, and the use of scientific
judgment to evaluate the results of those tests. 11/17 Tr. at
174. The hallmark of the scientific method is the generation of
testable hypotheses which are then subjected to the real world
crucible of experimentation, validation, and replication. Daubert
v. Merrell Dow Pharm., 509 U.S. 579, 593, 113 S.Ct. 2786,
125 L.Ed.2d 469 (1993) (citing K. Popper, Conjectures and
Refutations: The Growth of Scientific Knowledge, at 37 (5th ed.
1989) ("the criterion of the scientific status of a theory is its
. . . testability")). The Daubert Court went on to note that
"`scientific methodology is based on generating hypotheses and
testing them to see if they can be falsified; indeed, this
methodology is what distinguishes science from other fields of
human inquiry.'" Id. (citations omitted).
175. To "falsify" a hypothesis in this context means to prove
that the "null hypothesis" that Parlodel ® has no effect on
the risk of postpartum stroke is false, i.e., that Parlodel
® in fact significantly increases the risk of postpartum
stroke. The failure of plaintiff's experts to show any study
proving that the null hypothesis has been falsified demonstrates
that their causal hypothesis has not been tested or verified by
the means of science.
176. Plaintiff's experts acknowledge that epidemiologic studies
are the best evidence
of medical causation. See Kulig/Nussel Hearing Transcript, Apr.
6, 1999, Vol. II, at 168-70 (Att.2C) (well performed
epidemiologic study generally strongest evidence of causation);
Iffy/Globetti Dep. 89-90 (case reports are "much less suitable"
than epidemiology for proving medical causation) (Att.1B).
177. In the following dialogue, which occurred between Dr.
Kulig and Chief Judge McDade in an evidentiary Daubert hearing,
Dr. Kulig conceded that epidemiologic studies are the best
evidence of causation:
THE COURT: If you had a choice between that type of
study [epidemiologic study] and adverse event
reporting sheet, which would you choose?
THE WITNESS: Well, if it was the only choice?
THE COURT: Yes, if that was the only choice.
THE WITNESS: And the epidemiologic study was a good
one. I would obviously choose that.
THE COURT: You would choose it in every case when
it's matched against something else, wouldn't you?
THE WITNESS: If it was well performed.
THE COURT: Yes.
THE WITNESS: Yes.
Kulig/Nussel Hearing Transcript, Apr. 6, 1999, Vol. II at 170
178. Dr. Kulig testified that he uses "exactly the same"
scientific methodology in assessing whether a substance causes a
potential adverse event in both his Parlodel ® litigation
work on behalf of plaintiffs and his breast implant litigation
work on behalf of defendants. 11/8 Tr. at 36-37 (Kulig). He
testified to his scientific methodology in the breast implant
litigation as follows:
Q. Doctor, on a more general level, can a cause and
effect relationship be established with a disease as
common as breast cancer in humans without first
showing an association through a controlled study?
Q. Can it be shown with case reports?
Q. Can it be shown with case series, multiple case
Q. Can it be shown by a process of differential
Ex. SQ (In re New York State Silicone Breast Implant Litigation,
Brusca v. Cooper Companies, No. 128115/93, Tr. (9/29/97)) at 859
(discussed at 11/8 Tr. at 172-81) (emphasis added).
179. In assessing medical causation, the scientific method
requires valid scientific proof first that a drug can cause the
effect in question and then valid scientific proof that the drug
did cause the effect in a particular individual. For example:
Dr. Kulig agrees that he would not offer an expert
opinion as to causation in a specific case with one
patient unless he thought as a matter of science that
both general causation and specific causation had
been established in a scientifically reliable way.
11/9 Tr. at 140.
Dr. Petro testified that he must know whether
bromocriptine can cause ICH before being able to
state that a particular individual suffered an ICH
caused by bromocriptine. 11/10 Tr. at 181-82;
Petro/Brasher Dep. at 107 (Att.2).
G. Toxicologic Principles of Dose Response and Threshold
180. The principle of dose response is fundamental to the
scientific method, the
toxicological method, and the medical method. 11/17 Tr. at 42;
11/10 Tr. at 158.
181. The principle of dose response states that the possibility
of an effect increases as the amount of substance to which a
living being is exposed is increased. 11/10 Tr. at 158.
182. The principle of threshold is fundamental to toxicology.
11/10 Tr. at 158.
183. The principle of threshold states that no effects are seen
in a living being until they are exposed to a certain i.e.,
threshold level of a substance. 11/10 Tr. at 158-59.
184. Bromocriptine, the parent compound, does not accumulate in
the human body even after multiple doses. 11/15 Tr. at 133.
185. In this Court's judgment, plaintiff's experts abandon the
scientific method as they themselves define it in this case.
For example, Dr. Petro acknowledged that the scientific method
requires the formulation and testing of hypotheses. Petro/B/G/Q
Dep. 348 (Att.3C). To test the hypothesis that a particular drug
causes a particular adverse event, Dr. Petro admitted that the
scientific method would require one to (1) conduct a prospective,
double-blind, randomized, placebo-controlled study, id. at 351;
(2) utilize a single patient trial design, id. at 356-57; or (3)
establish through epidemiology that an overwhelming number of
people experience the adverse event when given the drug compared
to those who experience the event in its absence, id. at 368-69.
However, when asked whether such studies had ever been conducted
showing that bromocriptine causes stroke, Dr. Petro admitted that
they had not. Id. at 351-52 (no prospective, double-blind,
randomized, placebo-controlled study); id. at 360 (no single
patient trial design); id. at 369 (no epidemiology).
186. Dr. Petro admitted that one could not show general
causation using scientific methodology in the absence of such
Q. In the absence of such studies, is there a
particular methodology that tests the hypothesis that
substance A causes effect B?
A. Well, again, the observation of the effect in an
uncontrolled manner does not meet the standard you
Q. And when you use the term, sir, weight of
evidence, that is not a scientific methodology, is
A. Well, in certain situations, you can't do any of
these other tests, so you make a judgment. Again,
it's more subjective than scientific methodology.
Q. All right.
A. But again, I would suggest that that has a certain
merit in scientific research in the absence of the
other type of study designs, but it's not conclusive,
et cetera. I mean I it does not rise to the
standard you are suggesting.
Id. at 369-70. Thus, plaintiff's experts' methodology in this
case is subjective in the words of her own expert as
opposed to scientific.
187. Similarly, Dr. Leslie Iffy described the scientific method
as requiring "controlled studies [that] . . . show . . .
significant evidence for [a] certain effect. . .". Iffy/Revels
Dep. 75-76 (Att.1C); see also Iffy/Globetti Dep. 58 (causation
established through epidemiology or "[s]etting up controlled and
blinded investigations in order to test a certain premise")
(Att.1B). Nevertheless, he abandons these scientific requirements
in litigation generally:
Q. It's your understanding of the law that the
causation opinion in the context of litigation does
not need to be as strong or rigorous as a causation
offered in a publication in the medical or scientific
Iffy/Kuhn Dep. 121 (Att. 1D). Accordingly, Dr. Iffy opined that
Parlodel ® can cause stroke, even though he conceded that the
necessary studies have not been conducted. See, e.g., Iffy/NJC
Dep. 46-52, 143 (Att.1A). Dr. Iffy testified that there are no
objective requirements necessary to satisfy the scientific method
and that "we have to satisfy ourselves with less than ideal
scientific approaches." Iffy/Globetti Dep. 274 (Att.1B).
188. Dr. Kulig likewise discards the scientific method. Upon
questioning by Chief Judge McDade at an evidentiary Daubert
hearing, Dr. Kulig agreed that the scientific method can be
described as follows:
Scientists employ an approach to gathering
information known as the scientific method. Although
this approach is as varied as scientists themselves,
there are still certain processes that can be
identified as typical of these scientific methods:
First, accumulate scientific data used to formulate
the hypothesis, observations, and experiments; test
the hypothesis; the new data allows researchers to
come to a general conclusion about the phenomenon
being studied; and then you may repeat that process
again and again as you get more information, as you
get closer to perhaps a true relationship.
Kulig/Nussel Hearing Transcript, Apr. 6, 1999, Vol. II, at 173-74
(Att.2C). Dr. Kulig has admitted that the testing of hypotheses
has not been conducted with respect to bromocriptine and stroke.
See, e.g., Kulig/Hollander Dep. 108-09 (Att.2A).
189. In prior deposition testimony, Dr. Kulig testified that
pregnancy and delivery are risk factors for the development of
stroke. Kulig/Roberts Dep. at 44-45 (Att.5).
190. In his deposition testimony, Dr. Macones agreed that the
postpartum period, by itself, is a risk factor for stroke. Dr.
Macones testified that he had no basis to disagree with the
conclusion of the Kittner study that "[a] causal role for
preeclampsia and eclampsia does not fully explain the much
stronger associations in stroke found for the postpartum state
than for pregnancy itself." Macones/B/G/Q Dep. 101 (citing
Kittner) (Att. 42).
191. Plaintiff's experts do not rely on any epidemiologic
studies regarding Parlodel ® when used for any indication
other than postpartum lactation. 11/9 Tr. at 24.
192. Although Dr. Kulig testified at the hearing that the
postpartum period is not a high risk period for stroke if
eclampsia is excluded, 11/9 Tr. at 157, his testimony is not
based on affirmative evidence but instead is based upon
criticisms of the epidemiologic studies showing the increased
risk. Id. at 157-58.
193. Dr. Kulig is not an expert in epidemiology. Kulig/Warren
Dep. 54 (does not consider himself an expert in epidemiology)
194. The existing epidemiology regarding postpartum stroke and
Parlodel ® does not support plaintiff's experts' hypothesis
that Parlodel ® can cause ICH.
195. There is no scientifically reliable evidence that
bromocriptine, taken in therapeutic doses in humans, causes
either generalized or cerebral vasoconstriction or vasospasm.
E.g., 11/16 Tr. at 32, 33.
196. There is no scientifically reliable evidence that
bromocriptine caused plaintiff to suffer either generalized or
cerebral vasoconstriction or vasospasm.
197. There is no scientifically reliable evidence that
bromocriptine, taken in therapeutic
doses in humans, causes ICH. E.g., 11/16 tr. at 41-42.
198. There is no scientifically reliable evidence that
bromocriptine caused plaintiff's ICH
199. Dr. Kulig testified that he relied on the Bradford Hill
criteria in making causality assessments. 11/8 Tr. at 57.
200. However, application of the Bradford Hill criteria depends
first upon an association by epidemiology between a disease and
an exposure to an agent. The association must rule out chance.
Ex. EB; see also 11/8 Tr. at 188-89 (discussing Bradford Hill
201. There is no epidemiology that rules out chance and
supports a link between ICH and exposure to Parlodel ®.
202. Dr. Kulig is not aware of any peer reviewed published
papers in which the Bradford-Hill criteria have been applied to
the question of whether Parlodel ® causes vasoconstriction of
cerebral arteries, ICH, or stroke. 11/8 Tr. at 199-200.
203. Dr. Kulig improperly used the Bradford-Hill criteria to
attempt to support his opinion that Parlodel ® can cause
204. Dr. Kulig did not demonstrate that any
statistically-significant epidemiology exists that supports the
hypothesis that the use of Parlodel ® can cause ICH.
H. Parlodel ® Pharmacology and the Alleged Mechanism by Which
Parlodel ® Can Cause ICH
205. Plaintiff's experts hypothesize that plaintiff's
therapeutic use of Parlodel ® caused cerebral
vasoconstriction or vasospasm that led to ICH. 11/8 Tr. at 103;
11/15 Tr. at 5.
206. Plaintiff's experts cannot identify to a reasonable degree
of medical certainty the specific mechanism by which Parlodel
® allegedly causes cerebral vasoconstriction in humans. 11/9
Tr. at 88-89; see also 11/16 Tr. at 103 (no proven mechanism).
207. Plaintiff introduced no evidence of published
peer-reviewed studies that state as a matter of scientific
knowledge that bromocriptine causes cerebral vasoconstriction or
208. Bromocriptine causes a reduction in blood pressure via
peripheral dilation of blood vessels in intact, normotensive
animal models. 11/17 Tr. at 50.
209. Bromocriptine has either no effect or causes a reduction
in blood pressure in spontaneously hypertensive rats. 11/17 Tr.
210. Bromocriptine also causes reductions in blood pressure via
vasodilation in intact anesthetized cats. 11/17 Tr. at 50.
211. Bromocriptine in very small doses has been demonstrated to
inhibit the known vasoconstrictive effects of much larger doses
of serotonin, which is naturally produced by the human body.
11/16 Tr. at 157.
212. The human body itself naturally produces vasoconstrictive
substances, such as hormones, norepinephrine, epinephrine, and
serotonin. 11/16 Tr. at 146-47; 11/15 Tr. at 24.
213. These endogenous (naturally produced) vasoconstrictors are
far more potent than bromocriptine at causing peripheral
vasoconstrictive events. 11/16 Tr. at 150; see also Ex. G.
214. The most recent edition of Ellenhorn's Medical Toxicology,
which plaintiff herself introduced into evidence as plaintiff's
exhibit 1406, lists the vasoconstrictive properties of
bromocriptine as zero. Ex. CI at Table 41-37; 11/9 Tr. at
215. Plaintiff has characterized Ellenhorn's Medical Toxicology
as a "well recognized
authoritative toxicology textbook." 11/8 Tr. at 44.
216. Other than a theory of individual "sensitivities" for
which he offered no basis, 11/10 Tr. at 49, Dr. Petro did not
offer any methodology or mechanism for explaining how or why a
patient taking Parlodel ® will develop vasoconstriction or
vasospasm rather than the expected vasodilation.
217. Dr. Petro states that studies of active metabolites of
bromocriptine have not been done to test whether any metabolites
have any vasoconstrictive effects. 11/10 Tr. at 177-78.
218. Plaintiff has not demonstrated that metabolites of
bromocriptine have vasoconstrictive effects.
219. Plaintiff has not demonstrated that the pharmacology of
bromocriptine supports the hypothesis that Parlodel ® in
therapeutic doses causes vasoconstriction or vasospasm.
220. Plaintiff has not demonstrated the mechanism by which
Parlodel ® in therapeutic doses allegedly causes
vasoconstriction or vasospasm.
221. Where a vasospasm has been shown to cause stroke, i.e.,
vasospasm secondary to a subarachnoid hemorrhage causing stroke,
the strokes caused are ischemic strokes rather than hemorrhagic
strokes. 11/16 Tr. at 39.
222. Plaintiff has not demonstrated that the pharmacology of
bromocriptine supports the hypothesis that bromocriptine causes
223. Plaintiff has not demonstrated the mechanism by which
Parlodel ® in therapeutic doses causes ICH.
224. The causal hypothesis of plaintiff's experts that
bromocriptine causes stroke has never been borne out by
statistically-valid testing or otherwise shown by scientifically
reliable means. Plaintiff's epidemiologist, Dr. Macones, opines
that there is no evidence that Parlodel ® increases the risk
of postpartum stroke. Macones/Hernandez Dep. 86 (Att.4C).
Accordingly, plaintiff's experts' hypotheses cannot pass muster
under the first, and most important, Daubert factor,
I. Findings of Fact Regarding Case Reports and Adverse Drug
Experience Reports ("ADEs")
225. Case reports, which may or may not be published in the
scientific or medical literature, describe isolated and
uncorroborated instances of medical events occurring coincident
with the use of a prescription drug. They tend to be brief
recitals of events which do not consider potential alternate
causes or attempt to investigate or to explain methods of
226. Case reports do not use control groups, are not
susceptible to statistical analysis of risk, and are not
verifiable through meaningful peer review. 11/10 Tr. at 205-06.
227. Case reports often fail to address the individual's prior
medical history, risk factors, use of other medications or drugs,
family medical history, and other individual factors necessary to
assess a cause-and-effect relationship between the use of the
drug and the reported adverse effect. See, e.g., Kulig/B/G/Q Dep.
431-35, 532 (Att. 11); Kulig/Siharath Dep. 142-43 (Att. 10);
Petro/Rider Dep. 181-82 (Att. 12); Petro/B/G/Q Dep. 428-29
228. Case reports are not controlled studies. 11/10 Tr. at 206;
Petro/Brasher Dep. at 428.
229. Standing alone, a case report does not establish
causation. 11/9 Tr. at 36-37.
230. For any given case report, no scientifically probable
conclusion can be
drawn that the suspect drug caused the reaction. 11/9 Tr. at 38.
231. The event reported in a case report may have been related
to an underlying disease for which the drug was given. 11/9 Tr.
232. The event reported in a case report may have occurred by
chance at the same time that the suspected drug was taken. 11/9
Tr. at 39.
233. One can have a temporal relationship between the use of a
drug and an effect without there being a causal relationship.
11/10 Tr. at 204.
234. Case reports cannot be used to determine relative risk.
11/10 Tr. at 205.
235. According to Dr. Kulig, when one addresses "people
studies," one should "tak[e] it from the most important to the
least important, epidemiology studies being the most important,
case series, case reports being the least important."
Kulig/Oregon Breast Implant Tr. at 705 (Att. 28); 11/8 Tr.
at 186; 11/9 Tr. at 26-27.
236. As Dr. Kulig has written, "case reports are traditionally
viewed as the least vigorous form of proof of a hypothesis or
validation of a therapy." 11/9 Tr. at 27; see also Brent, Kulig
and Rumack, "Analysis of the Types of Papers Presented at the
Annual Toxicology Meetings," 32 Vet. Hum. Toxicol. (April 1990)
237. In a Daubert hearing in Railey v. Sandoz Pharmaceuticals
Corporation, Dr. Kulig testified that dechallenge and rechallenge
case reports are "hardly proof that the drug caused the effect."
11/9 Tr. at 48; Ex SR (Kulig/Railey hearing at 149).
238. The Larrazet "re-challenge" relied upon by plaintiff's
experts is a case report. 11/16 Tr. at 195.
239. The Larrazet case report did not address cerebral
arteries. 11/16 Tr. at 196.
240. In Larrazet, a patient with previous coronary vasospasm
was instructed to stop taking antispasm medications 36 hours
prior to the so-called "re-challenge." 11/16 Tr. at 196.
241. The Larrazet case report did not involve any controls,
i.e., catheterizing to visualize coronary artery prior to the
so-called "re-challenge." 11/16 Tr. at 197.
242. The Larrazet case report did not show that Parlodel ®
caused vasoconstriction because, inter alia, it did not
demonstrate lack of vasoconstriction prior to the co-called
"re-challenge," i.e., it was uncontrolled. 11/17 Tr. at 17.
243. ADRs are a form of case report compiled by drug
manufacturers which are submitted to the FDA and describe "any
adverse event associated with the use of a drug in humans,
whether or not considered drug related."
21 C.F.R. § 314.80(a) (Att. 37).
244. "[B]ecause of incomplete data and the uncertainty caused
by the underlying illness, indication, or other drug exposures,
adverse experience reports may be attributed to a drug or
biological product even though it may not necessarily have caused
the adverse experience." Final Rule, Department of Health and
Human Services, Food and Drug Administration, "Postmarketing
Expedited Adverse Experience Reporting for Human Drug and
Licensed Biological Products; Increased Frequency Reports," 62
Fed. Reg. 34166, 34167 (1997) (to be codified at 21 C.F.R.
Chapters 310, 314, and 600) (Att. 46).
245. Over a decade ago, FDA's Surveillance and Data Processing
Branch of the Division of Epidemiology and Surveillance published
a "Brief Description [of Adverse Reaction Reporting System
("ARRS") with Caveats of [the] System." According to FDA, "[t]he
primary purpose of maintaining the [ARRS] data base is to serve
as an early warning or signaling system. . . ." Brief Description
with Caveats of System, Surveillance and Data Processing Branch
of the Division of Epidemiology and Surveillance, Division of
Epidemiology & Surveillance, Dec. 1988, at p. 1 ("FDA
Caveats"), Ex. RN; see also Nov. 1991 FDA Caveats, at p. 1
246. These FDA Caveats further state that:
"for any given case report, there is no certainty
that the suspect drug caused the reaction. This is
because physicians are encouraged to report all
suspected drug events, not just those that are known
to have been caused by the drug. The event reported
in a case report may have been related to an
underlying disease for which the drug was given, to
other drugs being taken concurrently, or may have
occurred by chance at the same time the suspected
drug was taken."
Dec. 1988 FDA Caveats, at p. 1 ¶ 1, Ex. RN; see also Nov. 1991
FDA Caveats, at p. 1 ¶ 1 (Att. 25). Thus, "[a]ccumulated case
reports cannot be used to calculate incidence or estimates of
drug risk. They must be carefully interpreted as reporting rates
and not occurrence or incidence rates. Comparisons of drug safety
cannot be made from these data." Dec. 1988 FDA Caveats, at p. 2
¶ 2, Ex RN; see also Nov. 1991 FDA Caveats, at p. 2 ¶ 2
247. A reporting physician may report an alleged adverse effect
which occurred while an individual was taking multiple
prescription drugs. See, e.g. Kulig/B/G/Q Dep. 431-35, 532
(Att. 11); Kulig/Siharath Dep. 142-43 (Att. 10); Petro/Rider Dep.
181-82 (Att. 12); Petro/B/G/Q Dep. 428-29 (Att.2).
248. The reports serve as a tracking system, and do not
"reflect a conclusion by the applicant or the FDA that the report
or information constitutes an admission that the drug caused or
contributed to an adverse effect." 21 C.F.R. § 314.80(k)
249. Dr. Kulig testified that he relies upon third-party
"causality assessments" as an example of the appropriate
methodology for assessing causation. 11/9 Tr. at 105.
250. NPC did not perform these "causality assessments."
251. The "causality assessments" were prepared by the Drug
Monitoring Centre ("DMC") (part of Sandoz Pharma AG ("Pharma"), a
Swiss corporation that is not a party to this case). 11/8 Tr. at
12 (opening statement of plaintiff's counsel Kristal); 11/8 Tr.
at 111-12; see also Ex. PR, Complaint (naming only Sandoz
Pharmaceuticals Corporation as defendant).
252. Dr. Kulig has conceded that such "causality assessments"
could not be published in a peer-reviewed publication because the
methodology for making "causality assessments" is not adequately
described therein. Kulig/Hollander Dep. 115-16 (Att.3).
253. Dr. Kulig does not know if the DMC's "methodology,"
whatever it was, was created and applied for regulatory purposes
rather than scientific ones. E.g., Kulig/Hollander Dep. 114
254. In filling out "causality assessments," DMC employees
evaluated an ADR or case report and checked off "yes" or "no" as
responses to a pre-set list of questions. See, e.g., 11/8 Tr. at
115-16 (discussing box-checking on form).
255. Plaintiff has referred to "causality assessments" showing
that the DMC attributed "probable causation" in certain case
reports of digital vasospasm to Parlodel ®. No such
"causality assessments" showed the DMC attributing "probable
causation" in a case of ICH to Parlodel ®.
See 11/15 Tr. at 51 (concession by Dr. Petro that digital
vasospasm is not the same as ICH); 11/17 Tr. at 47-48
(unchallenged testimony of Dr. Green that "it is well-known in
medicine and science that the body has different vascular beds[;]
[and that] [t]here are different sorts of receptors, populations
of receptors on the peripheral vasculature that serves our
fingers and toes than there are for major vessels, such as
coronary arteries or cerebral arteries").
256. As with any other ADR or case report, the data are not
controlled or subject to statistical evaluation and the
"assessment" is necessarily based on the self-selected and
limited information provided. 11/9 Tr. at 67.
257. European authorities require "causality assessments" for
regulatory purposes. Krupp/NJC Dep. at 185 (Att. 19). FDA has no
comparable requirement. Id.
258. Dr. Maurice Nelson Graham Dukes, who styles himself as the
world's foremost "adverse drug reaction scientist," states that
causality assessments are subjective and unreliable:
An outcome grading employing such terms as `not
possible,' `unlikely,' `possible' and `probable' is
currently used in some adverse reaction monitoring
agencies, primarily to determine which reports of
suspected adverse reactions contribute to the total
evidence, which do not, and which deserve further
consideration. However, these useful scales have no
objective reliability which would render them useful
in a wider environment. At the very least, a court
considering evidence based on the use of formalized
causality assessment should require evidence that its
dependability in the type of case under consideration
has previously been demonstrated. . . .
M.N.G. DUKES, RESPONSIBILITY FOR DRUG-INDUCED INJURY: A REFERENCE
BOOK FOR LAWYERS, THE HEALTH PROFESSIONS AND MANUFACTURERS, 46
(2d ed. Dec. 1998) (emphasis added) (Att. 21); cf. 11/9 Tr. at
259. Plaintiff has not shown that DMC "causality assessments"
are based on the comprehensive or otherwise scientific review of
all facts giving rise to the reported adverse event. 11/9 Tr. at
66 (admission by Dr. Kulig that he did not know how "causality
assessments" were done at DMC and, in particular, whether DMC had
"received everything" at the time DMC made such assessments).
Among other things, incomplete medical records would preclude DMC
from adequately considering whether there were confounding
factors in the patients addressed by the "causality assessments,"
e.g., concomitant use of other drugs. Id. at 67 ("causality
assessments" may not take into account confounding factors.).
260. Plaintiff has not shown that DMC "causality assessments"
are based on objectively reliable data or are otherwise
261. Plaintiff has not shown, or even argued, that the
regulatory "causality assessment" methodology is one that is
generally accepted in medical or scientific fields for purposes
of reliably establishing medical causation.
262. Plaintiff has not shown an acceptable error rate (or any
error rate) for this methodology.
263. DMC causality assessments have not been demonstrated to
form part of a scientifically reliable methodology for testing
the hypothesis that Parlodel ® causes cerebral
vasoconstriction or ICH.
J. Animal Evidence Re: Effects of Parlodel ®
264. The use of animal studies to prove causation in human
beings has "two significant disadvantages," which "are almost
always fraught with considerable, and currently unresolvable,
uncertainty." Federal Judicial Center, Reference Manual on
Scientific Evidence, at 130 (1994). First, extrapolating from
animals to humans is difficult because "differences in
absorption, metabolism, and other factors may result in
interspecies variation in responses." Id. A second difficulty is
that "the high doses customarily used in animal studies requires
consideration of the dose-response relationship and whether a
threshold no-effect dose exists." Id.
265. Dr. Kulig has previously testified that in the absence of
evidence of an association between an exposure in humans and a
common human disease, causation cannot be established using
Q. . . . I want to jump down to the experimental
category, the experimental criteria, and ask you
whether, in the absence of evidence of an association
between an exposure in humans and a common human
cancer such as breast cancer, whether causation can
be established by studies in rodents?
A. No, it cannot.
Q. Why not?
A. There are many problems with animal
experimentation in trying to apply that data to the
human situation, particularly in rodents, and I think
I have prepared a list of those problems.
* * * * *
There is significant interspecies and gender
variation in animals. For example, a chemical may
cause cancer in rats but not mice. It may cause it in
guinea pigs but not monkeys. Risk assessors
frequently assume that, if it's caused in any
species, it's a positive test, even if other animals
do not demonstrate the same effect. Likewise, some
chemicals cause cancer in males and not females, or
vice-versa. Some risk assessors generally assume any
positive is a positive test even if there are many
more negative experiments on the same subject.
Other species, especially rodents, may not be
relevant for humans because they absorb, distribute,
metabolize and excrete chemicals quite differently
than we do. They may not be able to activate a
chemical in the same way.
Animals used in experiments are deliberately inbred
for generic susceptibility to cancer, and that
frequently results in a pretty high baseline rate of
cancers, even when they are not exposed to the test
MTDs are the maximum tolerated doses used in risk
assessment of animal experimentation where the
highest dose possible without making the animals
clinically sick is used, and frequently these doses
are very, very high and they are usually not relevant
to humans. Humans are not exposed to the same
chemicals in doses that ever approach doses used in
these experiments. At these high doses, the chemicals
may cause cellular damage, and that results in
neoplasms because there is an increased cell turnover
in an attempt to repair the damage. You would not see
the same affect (sic) at lower doses where there is
no tissue damage.
Ex. SQ, Kulig/Brusca 9/29/97 Daubert hearing Tr. at 862-63;
863-65 (referenced at 11/9 Tr. at 122-23).
266. Dr. Laura Carolyn Green, NPC's expert in toxicology has
reviewed hundreds of human and animal studies, both
published and unpublished, all of which support her scientific
conclusion that Parlodel ® taken at therapeutic doses did not
cause cerebral vasoconstriction or vasospasm. 11/17 Tr. at
267. Plaintiff's experts do not rely on any animal studies
where an animal was given Parlodel ® and suffered a stroke.
11/10 Tr. at 83.
268. Toxicologic methods to assist with the testing and
affirming or refuting the hypothesis of whether a substance
causes cerebral vasoconstriction have been available since at
least 1950, if not the 1930s. 11/17 Tr. at 39.
269. An abundance of animal models exist to assist with testing
the hypothesis that a foreign substance can induce
cerebrovascular accidents. 11/17 Tr. at 52-53.
270. For example, the combination of PPA and caffeine has been
reproducibly shown to cause stroke in animal models. 11/17 Tr. at
271. As of November 17, 1999, the Medline research database, a
recognized source of scientific literature, has classified 115
articles as pertaining to the topic of chemically-induced ICH in
animal models. 11/17 Tr. at 53; see also Ex. TO.
272. Dr. Petro, without alluding to these data and articles,
testified that there are no good animal models for inducing
stroke with a drug. 11/10 Tr. at 85.
273. Plaintiff's experts rely on the "hind limb" study as
support for their opinion that Parlodel ® has "amphoteric"
properties, meaning that the drug is both a vasodilator and a
vasoconstrictor, not dependent on dose, and that these properties
are classic properties of ergot alkaloids. 11/8 Tr. at 142-43;
11/10 Tr. at 90-91.
274. The hind limb study is the only Parlodel ® study that
plaintiff's experts say shows such an "amphoteric action" in
bromocriptine. 11/10 Tr. at 169.
275. The hind limb study was a dose response study that
measured effects of Parlodel ® infused in an isolated animal
extremity in three doses: 1 microgram/kilogram; 5
micrograms/kilogram; and 25 micrograms/kilogram. 11/16 Tr. at
276. The methodology used in the hind limb study was designed
to eliminate any effects of bromocriptine on the nervous system
of the dog. 11/10 Tr. at 178. Systemic or oral administration of
Parlodel ® would lead to both local effects as studied in the
hind limb study and central nervous system effects of
bromocriptine, and it is not known what effects would have been
observed in the hind limb study if the drug had been administered
systemically instead of injected locally. 11/10 Tr. at 178-79.
277. The control animals presented with up to seven percent
constriction, according to the methodology protocol as
documented in a German article reviewed (in English translation)
only by defense expert Karl Engelman. 11/16 Tr. at 185-87.
278. In the hind limb study, when vehicle controls were taken
into account, Parlodel ® had no effect in the isolated animal
extremity at the two lower doses; it showed an effect only at the
25 microgram/kilogram dose. 11/16 Tr. at 187. Thus, the hind limb
study demonstrates that Parlodel ® exhibits a threshold below
which it does not cause vasoconstriction even in the isolated
limb. 11/16 Tr. at 187.
279. Only about five percent of an oral dose of Parlodel ®
actually enters the bloodstream, compared with 100 percent of the
drug when it was injected directly into the hind limb of the dogs
in the hind limb
study. 11/10 Tr. at 175-76. Thus, a woman taking standard 2.5 mg
Parlodel ® tablets would need to take 1,250 tablets at a time
to place the same amount of Parlodel ® in her bloodstream as
was used in the 25 microgram/kilogram assay of the hind limb
study. 11/16 Tr. at 187-88.
280. None of the animals in the hind limb study developed ICH.
Cf. 11/10 Tr. at 83.
281. In his deposition in the case Brasher v. Sandoz
Pharmaceuticals Corporation, Dr. Kulig testified that he did not
know whether the hind limb methodology had been compared with
outcomes in animal studies to determine if they are predictive of
whole animal toxicity. Kulig/Brasher Dep. at 49 (Att. 11).
282. Dr. Kulig does not know how the dog artery resistance
measured in the hind limb study compares to human artery
resistance. 11/9 Tr. at 111-12.
283. For example, when questioned about the "perfused hind limb
of the dog" study, Dr. Kulig testified:
Q. Have you attempted to compare what the
concentration of bromocriptine is after a 2.5
milligram dose for PPL with the concentration of
bromocriptine that would have resulted in this hind
A. No, that's really not necessary.
. . .
Q. You have not attempted to do any such correlation,
A. It's not necessary. It would not be productive to
make that correlation.
Q. Have you attempted to do such a correlation?
A. Why would I attempt to do something that wouldn't
Q. The answer is, no, you have not attempted to do a
A. That's correct.
Kulig/B/G/Q Dep. 80, 84 (Att.2H).
284. Dr. Petro concedes that comparing a mongrel ten kilogram
dog, such as that used in the hind limb study, to a postpartum
woman, "is a stretch." 11/10 Tr. at 175.
285. Dr. Petro has not even attempted to determine the vascular
resistance in human beings to compare it to the vascular
resistance of the dogs studied in the hind limb study. 11/10 Tr.
286. The hind limb study does not support plaintiff's
hypothesis that a person taking therapeutic doses of Parlodel
® could develop vasoconstriction as observed in the hind limb
287. The hind limb study does not support plaintiff's
hypothesis that a person taking Parlodel ® at therapeutic
doses could develop cerebral vasoconstriction.
288. The hind limb study does not support plaintiff's
hypothesis that a person taking Parlodel ® at therapeutic
doses could develop ICH.
289. Extrapolating from the massive Parlodel ® doses given
in the hind limb study to postpartum women taking Parlodel ®
does not comport with the fundamental principle of dose response.
Cf. 11/17 Tr. at 42-43.
290. With respect to the dog "hind limb" study in particular,
plaintiff's experts do not have any experience in using this type
of animal model in their own laboratory research. E.g.,
Kulig/Rider Dep. 226 (Att.2J). They do not know whether this
animal model in dogs has ever been validated in other
laboratories. E.g., Kulig/B/G/Q Dep. 48 (Att.2H). There is no
federal or foreign regulatory body that has ever adopted the
methodology or approved the methodology used in this study and
the methodology of this dog hind limb study has never been
compared to outcomes in
intact animals to show whether it predicts what happens in whole
animals. Kulig/B/G/Q Dep. 49, 151 (Att.2H). Further,
bromocriptine was administered in such a way that it had no
systemic effects it was not allowed to affect the brain, and it
was not allowed to affect the nervous system, Kulig/Siharath Dep.
148-49 (Att.2I), but plaintiff's experts do not know whether the
results would have been the same, similar, or different if
systemic effects had been allowed. E.g., Kulig B/G/Q Dep. 43
(ii) The 62-week oral toxicity study in dogs
291. Dr. Petro finds the 62-week oral toxicity study in dogs to
be significant to his causation opinions because it resulted in
ear necrosis in some tested animals, suggesting vasoconstriction.
11/10 Tr. at 82.
292. Neither of plaintiff's causation expert witnesses
presented evidence that demonstrated a scientifically valid
methodology for translating ear necrosis to cerebral vasospasm.
293. Neither Dr. Kulig nor Dr. Petro presented evidence that
receptors in peripheral blood vessels such as those found in the
ears are sufficiently similar to those found in cerebral blood
vessels to support the hypothesis that reactions in peripheral
blood will also occur similarly in cerebral blood vessels.
294. In the dog study, animals received bromocriptine for 62
weeks, whereas plaintiff took Parlodel ® for at most three
weeks. 11/10 Tr. at 161.
295. In the dog study, the study animals, at the lowest dose (1
mg/kg/day), received roughly 14 times the daily dose of Parlodel
® prescribed to plaintiff for PPL. 11/10 Tr. at 160.
296. No ear necrosis was observed at the lowest dose level.
11/10 Tr. at 161.
297. Viewed over the full length of the study, the dogs
ingesting Parlodel ® at the lowest study dose ingested more
than 280 times the Parlodel ® that plaintiff ingested while
she was taking Parlodel ®. 11/10 Tr. at 161.
298. The animals in the dog study being administered 280 times
the amount of Parlodel ® that plaintiff ingested demonstrated
no evidence of any vasoconstrictive effects. 11/10 Tr. at
299. The dogs that were administered three milligrams/kilogram
per day for 62 weeks ingested approximately 840 times more
Parlodel ® than plaintiff ingested while she was taking
Parlodel ® for PPL. 11/10 Tr. at 162.
300. The dogs that were administered ten milligrams/kilogram
per day for 62 weeks ingested approximately 2,800 times more
bromocriptine on a body weight basis than plaintiff ingested
while she was taking Parlodel ® for PPL. 11/10 Tr. at 162.
301. None of the animals in the dog study developed ICH. 11/10
Tr. at 165.
302. The dog study does not support plaintiff's hypothesis that
a person taking therapeutic doses of Parlodel ® could develop
any vasoconstriction as observed in the ear necrosis study.
303. The dog study does not support plaintiff's hypothesis that
a person taking Parlodel ® at therapeutic doses could develop
304. The dog study does not support plaintiff's hypothesis that
a person taking Parlodel ® at therapeutic doses could develop
305. Extrapolating from the Parlodel ® doses given in the
dog study to postpartum women taking Parlodel ® does not
with the fundamental principle of dose response. Cf. 11/17 Tr. at
(iii) The 53-week oral toxicity study in rats
306. Dr. Petro finds a 53-week oral toxicity study in rats to
be significant to his causation opinions because it resulted in
ear necrosis in some tested animals, suggesting vasoconstriction.
11/10 Tr. at 82.
307. In the 53-week oral toxicity study, rats who received five
milligrams of Parlodel ® per kilogram of body weight per day
for 53 weeks demonstrated no vasoconstrictive effects. This daily
dose is roughly 70 times the daily dose that plaintiff was
prescribed for the prevention of postpartum lactation. 11/10 Tr.
308. In the 53-week oral toxicity study, rats demonstrated no
vasoconstrictive effects in the tail tip until they ingested 20
milligrams of Parlodel ® per kilogram of body weight, or
roughly 280 times the daily dose that plaintiff was taking for
the prevention of postpartum lactation. 11/10 Tr. at 165.
309. Rats in the 53-week oral toxicity study that developed
blue discoloration of the tail tip did not exhibit this effect
until the 37th week of their ingestion of 280 times the daily
dose plaintiff was taking for PPL. 11/10 Tr. at 165.
310. Plaintiff, at most, took Parlodel ® for three weeks.
311. Regardless of the dose, none of the rats in the 53-week
oral toxicity study developed ICH. 11/10 Tr. at 165.
312. The 53-week oral toxicity study in rats does not
demonstrate that a person taking therapeutic doses of Parlodel
® could develop vasoconstriction.
313. The 53-week oral toxicity study in rats does not
demonstrate that a person taking Parlodel ® at therapeutic
doses could develop cerebral vasoconstriction.
314. The 53-week oral toxicity study in rats does not
demonstrate that a person taking Parlodel ® at therapeutic
doses could develop ICH.
315. Extrapolating from the Parlodel ® doses given in the
rat study to postpartum women taking Parlodel ® does not
comport with the fundamental principle of dose response. Cf.
11/17 Tr. at 42-43.
K. Findings of Fact Regarding Other Ergot Alkaloids
316. Parlodel ®, or bromocriptine mesylate as it is known
by its generic name, is a member of the ergot alkaloid group of
compound a group composed of many hundreds of chemicals. Ergot
alkaloids are compounds which have molecular structures that
include several carbon, hydrogen, and nitrogen atoms configured
into interconnecting rings, with most of the rings being
six-sided rings and at least one being a five-sided ring, and
which can be obtained by extraction of different strains of the
fungus claviceps which is grown on rye or cultivated in
317. Parlodel ® is a product that has been marketed for
over 20 years in the United States. There is a vast body of
pharmacologic, clinical, and other evidence about the drug. See,
e.g., B. Berde and E. Strumer, "Introduction to the Pharmacology
of Ergot Alkaloids and Related Compounds as a Basis of Their
Therapeutic Application" (Ch. 1), in B. Berde and H.O. Schild,
Ergot Alkaloids and Related Compounds, 49 Handb. Exp. Pharmacol.
(1978), at 1 (Att. 23); Clark et al, "How Does Bromocriptine
Work?," Triangle 17(1): 21-31 (1978) (Att. 24); Lahlou &
Demenge, "Contribution of Spinal Dopamine Receptors to the
Hypotensive Action of Bromocriptine in Rats," J. Cardiovasc.
Pharmacol. 18(3):317-25 (1991) (Att. 25).
318. It is well settled in this and comparable peer-reviewed
literature that the members of the ergot alkaloid group contain
an extraordinarily diverse range of characteristics and effects.
For example, in Ergot Alkaloids and Related Compounds, recognized
as an authoritative publication on ergot alkaloids, the authors
compare the characteristics of several members of the ergot
alkaloid group. Based on numerous laboratory experiments, the
authors state that "there are few chemical groups which comprise
substances with such diversified actions." B. Berde and E.
Sturmer, supra, at 2 (Att. 23). Due to the diversity of
characteristics and effects among the ergot alkaloids, the
authors state that "ergot has been of the nature of a treasure
chest to pharmacologists, . . . and has become a treasture-house
for drugs." Id. at 2 (internal quotations omitted). "The wide
field of therapeutic application of ergot alkaloids and related
compounds corresponds to their chemical and pharmacological
diversity." Id. at 10. Thus, not only do ergot alkaloids have a
wide diversity of characteristics and effects, but also so do the
drugs derived from ergot alkaloids.
319. To illustrate the diversity of the ergot alkaloids, the
Ergot Alkaloids authors provide a table which compares the effect
of seven different ergot alkaloids in ten categories of
biological activity. Id. 2, 4 (Bromocriptine mesylate is a
derivative of bromocriptine.) In the table, the relative effects
of the compounds are listed, with the effect of the most active
compound in each category arbitrarily characterized with the
value 1000. As the authors intended, a quick review of this table
clearly reveals the disparate effects of ergot alkaloids. The
table also demonstrates that the characteristics of bromocriptine
vary widely from other ergot alkaloids. Id.
320. For example, in a comparison of the level of uterotonic
activity the characteristic of giving tone to the uterine
muscle produced in rabbits, four of the alkaloids produce
various levels of uterotonic activity, whereas three of the
alkaloids (including bromocriptine) actually inhibit this
321. Likewise, in a comparison of the effect on body
temperature in rabbits, five alkaloids increase body temperature
whereas two decrease it, and although lysergic acid diethylamide
("LSD") and bromocriptine both increased body temperatures, LSD's
effect on body temperature was 400 times that of bromocriptine.
322. Similarly, in a comparison of stereotypical dopaminergic
effect the effect on tissues and organs by dopamine, a compound
produced within animals and people that causes heightened
responsiveness of certain nerve endings, three alkaloids produce
various levels of effect, which were all more than 300 times
greater than the negligible effects of the other four alkaloids.
323. Finally, for inhibiting fertility in rats, only
bromocriptine produces a comparatively significant effect. Id.
324. There is no statistically-significant epidemiologic study
showing that any ergot increases the risk of stroke. Even if for
argument's sake another member of the ergot alkaloid group could
be shown to contribute to strokes, a proposition which NPC does
not concede, it would be irrelevant to whether bromocriptine
contributes to strokes.
325. Bromocriptine differs from other ergot alkaloids. For
example, it prevents coronary artery vasoconstriction by blocking
alpha adrenergic receptors. By contrast, many other ergot
alkaloids directly act on these alpha adrenergic receptors to
cause coronary artery vasoconstriction. 11/17 Tr. at 55.
326. Also by way of example, Parlodel ® pressor activity is
5000 times less potent than that of the ergot alkaloid
ergotamine. 11/17 Tr. at 26. Pressor activity relates to a
compound's ability to cause vasoconstriction. 11/17 Tr. at 26.
327. Dr. Kulig testified that he does not rely on the fact that
other ergot alkaloids cause vasoconstriction as proof that
Parlodel ® causes vasoconstriction. 11/9 Tr. at 130.
328. In contrast, Dr. Petro testified that because LSD and
bromocriptine are both ergot alkaloids, it is significant to him
that LSD can cause vasospasm and hallucinations. 11/10 Tr. at
329. Dr. Petro also relies on a published case report by Senter
and Lieberman regarding use of the drug ergotamine as support for
the hypothesis that Parlodel ® causes vasoconstriction. E.g.,
11/10 Tr. at 46-48, 65, Exhibit 1404.
330. Plaintiff did not experience hallucinations or any symptom
identified in the Senter case report. 11/15 Tr. at 39-41.
331. In contrast to his reliance on evidence from other ergots
to support his hypothesis that Parlodel ® can cause ICH, when
discussing sympathomimetic amines, Dr. Petro testified that it is
improper to "lump together" all the drugs in the sympathomimetic
class, because there is a "whole range of drugs" within that
class. 11/15 Tr. at 17.
332. The Court finds in conclusion that given the documented
diversity of this chemical group, any reliance on general rules
or principles purportedly associated with ergot alkaloids as a
group would be particularly inappropriate.
L. Findings of Fact Regarding Other Injuries Not Alleged by
Plaintiff and Parlodel ® Use for Other Indications
333. Plaintiff's experts rely in part on evidence of injuries
other than ICH that are allegedly related to Parlodel ® use.
334. Plaintiff's experts rely in part on evidence gathered from
Parlodel's ® use for other indications for which it is
335. Evidence of so-called "other injuries" includes
allegations that Parlodel ® when used for the PPL indication
caused myocardial infarction, seizures, or ischemic stroke.
336. Evidence of so-called "other indications" includes either
clinical studies or anecdotal reports and other allegations
regarding Parlodel ® when used for the PPL indication. Some
other indications include acromegaly, amenorrhea, galactorrhea,
pituitary tumors, and treatment of Parkinson's Disease.
337. The issue in this case is whether Parlodel ® caused
plaintiff's ICH, a specific type of stroke involving bleeding
into the brain. Other injuries allegedly associated with Parlodel
®, such as myocardial infarction, seizures, hypertension,
headaches, and non-hemorrhagic strokes are each distinct kinds of
injuries with a multitude of different causal mechanisms.
338. The Court finds that plaintiff has not demonstrated that
other injuries allegedly associated with the use of Parlodel
® are similar in causal mechanism to plaintiff's ICH.
M. Findings of Fact Regarding Plaintiff's Expert Dr. Kenneth
(i) Dr. Kulig's Qualifications
339. Dr. Kulig has never prescribed Parlodel ® for any
indication. Kulig Dep. 80 (Att.2K).
(ii) Scientific Knowledge
340. Dr. Kulig opines that plaintiff "had an ergot-induced
vasospasm of a cerebral artery that subsequently ruptured,
resulting in a large intracerebral hemorrhage in her brain."
Kulig Dep. 48 (Att.2K).
341. Dr. Kulig is not an epidemiologist, or a neurologist, or
an ob/gyn. Kulig/NJC Dep. at 63 (not an epidemiologist) (Att.8);
11/8 Tr. at 169 (not board certified in neurology); Kulig/Brasher
Dep. at 456 (not an ob/gyn) (Att. 11).
342. Dr. Kulig's essential opinion is that bromocriptine
(Parlodel ®) is an ergot derivative and that ergots are known
to cause stroke by inducing vasospasm, i.e., a constriction of
arteries. Kulig Expert Report (Att.2M); cf. Kulig/Rider Dep. 209
343. Dr. Kulig knows of no epidemiologic or other study showing
that Parlodel ® significantly increases the risk of either
vasospasm or stroke. Kulig/Roiley Dep. 42 (Att.2E);
Kulig/Simonson Dep. 129 (Att.2Q).
344. Dr. Kulig cannot testify to a reasonable degree of medical
certainty how Parlodel ® allegedly causes vasospasm.
Kulig/B/G/Q Dep. 202 (Att.2H).
(iii) The Testing or Testability of Dr. Kulig's Opinions
345. Dr. Kulig concedes that, to test the hypothesis that
bromocriptine or Parlodel ® can cause a particular adverse
effect in a human being, one needs some type of experimental
method. Kulig/B/G/Q Dep. 262-63 (Att.2H).
346. Dr. Kulig admits that such experiments or testing of
hypotheses have not been conducted with respect to bromocriptine
and stroke. See, e.g., Kulig/Hollander Dep. 108-09 (Att.2A); see
Kulig Siharath Dep. 105-06 (does not recall if he relies on any
studies that state bromocriptine causes vasospasm in humans)
347. Dr. Kulig concedes that no epidemiologic study in the
peer-reviewed medical literature shows a
statistically-significant association between Parlodel ® and
stroke. Kulig/Warren Dep. 243 (Att.2G). Therefore, he agrees that
there is no statistically-significant epidemiologic study showing
that Parlodel ® increases the risk of stroke. See
Kulig/Hollander Dep. 108-09 (Att.2A)
348. Dr. Kulig admits that the only way to calculate a relative
risk is through an epidemiologic study of some type.
Kulig/Hernandez Dep. 55 (Att.2R).
349. Dr. Kulig opines, however, that epidemiologic calculations
of relative risk can be used to support a causation opinion
without regard to statistical significance. See, e.g.,
Kulig/Railey Dep. 42 (ERI study not statistically significant but
is nevertheless a "strong piece of evidence") (Att.2E).
350. Dr. Kulig attempts to rely on the single occurrence of a
stroke in the ERI Study among more than 280,000 women as evidence
of general causation, notwithstanding the admitted lack of
statistical significance. Kulig/NJC Dep. 83 ("I don't believe
it's a very reliable study. . . .") (Att.2B); Kulig/Nussel
Hearing Transcript, April 6, 1999, Vol. I, at 79-80 ("I'm not
claiming that [the ERI] study shows that the drug Parlodel ®
causes stroke") (Att.2C); Kulig/O'Conner Dep. 35-39 (admission
that he is bound by investigator's statement that study is
inconclusive) (Att. 2D).
(b) The Bradford Hill Criteria
351. In Dr. Kulig's opinion, the only epidemiologic study of
Parlodel ® and stroke was the ERI study. Kulig/Hollander
Dep. 108 ("A. Okay. In my opinion, there's only one epidemiology
study on Parlodel ® use in the postpartum period, and that's
the ERI study. The ERI study, in my opinion, is . . . a red flag,
if you will, for stroke development.") (Att.2A)
352. However, in his affidavit filed in the Nussel case, Dr.
Kulig stated that the ERI study "is inherently unreliable and is
not relied upon for [his] opinions." Kulig/Nussel Aff. p. 9
¶ 7(i) (Oct. 20, 1998) (Att.2N).
353. Nevertheless, Dr. Kulig relies on the ERI study as
evidence that Parlodel ® causes stroke. E.g., Kulig/Nussel
Aff., p. 11 ¶ 10(a) (using ERI to satisfy first Hill
criterion, "strength") (Att.2N).
354. Regarding HCIA, another study failing to show a
relationship between Parlodel ® and a risk of postpartum
stroke, Dr. Kulig stated that, "overall I think the [HCIA] study
is not reliable in answering the questions that need to be
answered." Kulig/NJC Dep. 78 (Att.2B).
(c) Dr. Kulig's Reliance on Anecdotal Human Data
355. Dr. Kulig relies heavily on ADEs and anecdotal case
356. Dr. Kulig admits, however, that case reports are
traditionally the least rigorous form of proof of a hypothesis.
Kulig/Warren Trial Transcript 187 (Att. 20).
357. Dr. Kulig acknowledges that case reports are not
epidemiologic studies. Kulig/Anderson Dep. 232 (Att.2F);
Kulig/Warren Dep. 104 (Att.2G). Dr. Kulig acknowledges that case
reports are not blinded or controlled and that one cannot
calculate a relative risk from case reports. Kulig/B /G /Q Dep.
271-72 (Att.2H); Kulig/Siharath Dep. 141 (Att.2I); Kulig/Anderson
Dep. 232 (Att.2F). Further, Dr. Kulig admits that one cannot
derive any confidence intervals for determining statistical
significance from case reports. Kulig/Anderson Dep. 232
358. Dr. Kulig admits that one cannot scientifically attribute
causation based on case reports. Kulig/B /G /Q Dep. 431-35, 532
(Att.2H); Kulig/Siharath Dep. 142-43 (Att.2I).
359. Dr. Kulig concedes that epidemiologic studies obviously
trump case reports. Kulig/Nussel Hearing Transcript, Apr. 6,
1999, Vol. II, at 170 (Att.2C).
360. Dr. Kulig agrees that: "A claim by a physician that a
particular product caused a plaintiff's injury based on the
observation that the plaintiff developed a disease after exposure
may amount to nothing more than a description of two events,
exposure and disease, that are sequentially but not causally
connected." Kulig/B /G /Q Dep. 272-73 (Att.2H).
361. Dr. Kulig concedes that a temporal relationship standing
alone does not prove causation. Kulig/Coleman Dep. 64 (Att.2P).
(iv) Dr. Kulig's Opinion on Mechanism
362. Not only are vasoconstriction and hypertension absent in
the women who take Parlodel ® for PPL, but also they are
absent as well in the patients around the world who take Parlodel
® in much higher doses and for longer periods of time for
other indications, such as Parkinson's disease. See, e.g.,
Kulig/Warren Trial Transcript 127-28 (Att. 20).
363. Dr. Kulig does not describe the mechanism by which
Parlodel ® supposedly causes vasoconstriction in some
undefined, unpredictable, and unknowable tiny segment of the
postpartum population, in the face of admitted evidence that the
expected effect of Parlodel ® is exactly the opposite. For
example, Dr. Kulig has no theory to explain the extreme rarity of
vasoconstrictive phenomenon he hypothesizes. He offers only the
speculation that unspecified "ergots" are unusual drugs that can
sometimes, even in the same person, have different effects,
Kulig/NJC Dep. 192 (Att.2B), but adds, "I don't know why that
happens." Id. at 193.
364. Dr. Kulig does not endorse any mechanism by which Parlodel
® may cause vasoconstriction or stroke as a matter of
reasonable medical certainty. Kulig/B /G /Q Dep. 202 (Att.2H);
Kulig/Siharath Dep. 121-25, 136, 203 (Att.2I).
(v) Dr. Kulig's Methodology
365. Dr. Kulig has published case reports concerning Parlodel
®, but he has never set forth in those reports or in any
other published data susceptible of peer review the definitive
causation opinions he offers in court. Dr. Kulig's one published
report presented two cases of headache. Kulig, et al,
"Bromocriptine-associated headache: Possible life-threatening
sympathomimetic interaction," Obstet. Gynecol, 78(5) Part
2:941-43 (1991) (Att. 10).
366. The report states that Parlodel ® "has been postulated
to be a vasoconstrictor," id. at 943, and concludes, "[a]lthough
causation cannot be proven, the use of sympathomimetics to treat
bromocriptine-induced headache may exacerbate the adverse effects
of bromocriptine in some patients," id.
367. Dr. Kulig's methodology reasons from anecdotal data, the
error rate of which is impossible to know or establish. He admits
that case reports are not controlled, blinded, capable of
yielding statistical significance, or capable of ruling out other
alternative causes of the events noted therein. See, e.g.,
Kulig/B /G /Q Dep. 271-72 (Att.2H); Kulig/Anderson Dep. 232
368. The probable error rate accompanying any use of case
reports is manifest where, as here, the epidemiology finds no
statistically-significant association between Parlodel ® and
369. Dr. Kulig does not address the concept of the rate of
error that is inherent in his methodology. See, e.g.,
Kulig/Anderson Dep. 208-09 (does not know rate of error and does
not agree that the concept has any significance to reliability of
his opinions). (Att.2F); Kulig/Hernandez Dep. 220-21 (cannot
quantify rate of error) (Att.2R); Kulig/Rider Dep. 226 (same)
(Att.2J); Kulig/Siharath Dep. 187-88 (same) (Att.2I).
370. The methodology of Dr. Kulig and his conclusions
concerning bromocriptine has not attracted support in the
scientific community. Kulig Dep. 107 (unable to cite any treatise
in neurology stating that bromocriptine causes stroke) (Att.2K).
(viii) Dr. Kulig's Reliance on Animal and Other Studies
371. Dr. Kulig relies on animal studies in support of his
causation opinion. Kulig Dep. 218 ("I've got a whole pile of
animal studies behind me.") (Att.2K).
372. Dr. Kulig relies upon discrete parts of two or three
animal studies in which the drug was not administered orally, as
in plaintiff's case. See, e.g., Kulig/B /G /Q Dep. 32-43, 80-88,
98-118, 121-22, 128-29, 175-91, 207-08 (Att.2C); Kulig/Rider Dep.
99-100 (Att.2J); Kulig/Siharath Dep. 99-102, 152-53 (Att.2I). Dr.
Kulig acknowledges the weakness of such evidence. Kulig Dep. 196
("If you give an intraperitoneal drug to a mouse, there's very
little human corollary to that because we don't give drugs to
people that way, for
instance.") (Att.2K); Kulig/Nussel Hearing Transcript, Apr. 6,
1999, Vol. II, at 129-34 (testifying that he was not "hanging his
hat" on animal studies to prove that bromocriptine is a
373. Dr. Kulig cannot cite any animal study showing cerebral
hypertension to have been caused by bromocriptine. Kulig/Warren
Trial Transcript 64 (Att. 20).
374. Dr. Kulig cannot cite any animal experiments in intact
animals in which bromocriptine has been shown to have a
hypertensive effect. Kulig/Warren Dep. 431 (Att. 20).
375. In the animal studies relied upon by Dr. Kulig, doses of
bromocriptine vastly in excess of those used for PPL were
injected into animals whose nervous systems had first been
destroyed to prevent compensating mechanisms, see Kulig/B /G /Q
Dep. 118-19, 178 (Att.2H), or enormous doses of bromocriptine
were injected into in vitro "preparations" involving not a live
animal, but an isolated strip of an artery. Kulig/B /G /Q Dep.
376. The investigators in these studies on which Dr. Kulig
relies studied parts of the animal that may have different
receptors from the cerebral arteries of the same animal and may
have been different receptors from the cerebral arteries of
humans. See Kulig/Siharath Dep. 204 (Att.2I); Kulig/Hollander
Dep. 89-91 (Att.2A).
377. These studies do not provide a scientifically valid link
with the live, intact human being at issue in this case. See.
e.g., Kulig/B /G /Q Dep. 43, 56-57, 72, 74-75, 80-84, 174-75,
188-91, 223 (Att.2H); Kulig/Rider Dep. 99-101, 228-30
(bromocriptine is not administered to humans intra-arterially, as
it was in study) (Att.2J); id. at 232-36 (does not know amount of
bromocriptine that would have to be administered orally to a
human to achieve a level comparable to 25 micrograms injected
into a dog's femoral artery, as in this study); Kulig/Siharath
Dep. 103-04, 209 (Att.2I); id. at 204 (limitations of using
animal studies to predict effects in humans include different
reactivity, pharmacokinetics, and pharmacodynamics among species;
the fact that animals are often tested in overdose quantities;
and differences between animals and humans in size, receptors,
and receptor activity); Kulig/Warren Dep. 43, 149 (Att.2G).
378. No one has ever established a dose-response relationship
with respect to bromocriptine and stroke. See Kulig/B /G /Q Dep.
116-17, 123 (failing to take dose-response into account in human
379. Dr. Kulig is not aware of any studies in intact animals
showing that bromocriptine causes high blood pressure or stroke.
Kulig/B /G /Q Dep. 207-08 (no studies showing high blood pressure
or stroke) (Att.2H); See Kulig/Siharath Dep. 210 (Att.2I).
380. Dr. Kulig refers to an "inversion point" in the animal
data, a point at which the vasodilatory effect of bromocriptine
allegedly changes over to vasoconstriction in the "hind limb
`study,'" but he does not know either whether there is such an
inversion point in human beings, or whether any experimental
methodology shows the existence of inversion points in human
beings. Kulig/B /G /Q Dep. 61 (Att.2H). Dr. Kulig admits that, if
there are inversion points in humans, they may be at entirely
different levels than for the dog. Kulig/B /G /Q Dep. 58
381. Dr. Kulig admits that the whole concept of an inversion
point does not make any sense unless an artery is artificially
isolated from the rest of the body. Kulig//B /G /Q Dep. 61-62
("Q. Are you familiar with any ...