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SOLDO v. SANDOZ PHARMACEUTICALS CORP.

January 13, 2003

LISA A. SOLDO, PLAINTIFF,
v.
SANDOZ PHARMACEUTICALS CORPORATION, DEFENDANT.



The opinion of the court was delivered by: Lee, District Judge.

FINDINGS OF FACT AND CONCLUSIONS OF LAW

Introduction

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 treatment.

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 07936.

Procedural Background

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 record.

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

Findings of Fact

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] (Att.61).

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 rechallenge data.

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 perceptions 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, 1994).

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 (Att.1A).*fn3

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 added).

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. RP

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 This Lawsuit

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.75).

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, (Att.77).

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, 1990.

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. 129, (Att.8).

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 38, 57.

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 9, 1991.

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 unresponsive.

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.84).

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, (Att.85).

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. at 60-61.

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 her event.

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 levels.

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. 122, (Att.8).

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 171.

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 170-71.

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 212.

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. at 57-58.

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 non-pregnancy; 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 to stroke").

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 reg; 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?

A. Yes.

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 pregnancy. Correct?

A. Yes, we could use your formula.

Q. And that would yield a relative risk estimate of 11.9, roughly?

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 pregnancy. Correct?
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 that.
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. 6566 (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 (Att.1A).

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.

(i) Study 60

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 171-72.

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.

(ii) Hand Vein Study

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 119.

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 ® PPL indication.

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 vasoconstriction.

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 doses.

(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 case-control 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. Id.

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) (Att. 2D).

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 77-78.

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.") (Att.9).

157. The HCIA study does not support plaintiff's hypothesis that bromocriptine use increases the risk of stroke in postpartum women.

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 lactation.

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.

F. Scientific Method

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 35.

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.

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 (Att.2C).

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 plaintiff's 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?

A. No.

Q. Can it be shown with case reports?

A. No.

Q. Can it be shown with case series, multiple case reports?

A. No.

Q. Can it be shown by a process of differential diagnosis?

A. No.

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 studies:

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 are raising.
Q. And when you use the term, sir, weight of evidence, that is not a scientific methodology, is it?
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 opinion offered in a publication in the medical or scientific literature?

A. Correct.

Iffy/Kuhn Dep. 121 (Att. ID). 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) (Att.15).

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 criteria).

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 ICH.

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 cerebral vasospasm.

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. at 50.

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 136-39.

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 ICH.

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, testability.

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 causation.

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 (Att.2).

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. at 38.

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) (Att.44).

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 (Att.25).

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 (Att.25).

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) (Att.37).

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 (Att.3)

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).

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 63-65.

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 testable.

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 animal studies:

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 chemicals.
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).

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 54.

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.

(i) The hind limb study

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 177, 187.

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 17879.

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 limb test?

A. No, that's really not necessary.

Q. You have not attempted to do any such correlation, correct?
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 be productive?
Q. The answer is, no, you have not attempted to do a correlation, correct?

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. at 169-70.

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 study.

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 (Att.2H).

(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 161-62.

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 cerebral vasoconstriction.

304. The dog study does not support plaintiff's hypothesis that a person taking Parlodel ® at therapeutic doses could develop ICH.

305. Extrapolating from the Parlodel ® doses given in the dog study to postpartum women taking Parlodel ® does not comport with the fundamental principle of dose response. Cf. 11/17 Tr. at 42-43.

(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. at 163-64.

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 fermentation tanks.

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 treasure-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 activity. Id.

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. Id.

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. Id.

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 75.

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 FDA-approved.

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 Kulig

(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 (Att.2J).

343. Dr. Kulig knows of no epidemiologic or other study showing that Parlodel ® significantly increases the risk of either vasospasm or stroke. Kulig/Railey 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

(a) Epidemiology

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) (Att.2I).

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); ...


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