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DELUCA v. MERRELL DOW PHARMS.

April 29, 1992

AMY DELUCA, an infant by her guardian ad litem, CINDY DELUCA and CINDY DELUCA and RONALD DELUCA, Plaintiffs,
v.
MERRELL DOW PHARMACEUTICALS, INC., et al., Defendants.



The opinion of the court was delivered by: GARRETT E. BROWN, JR.

 BROWN, District Judge

 This action arises out of birth defects suffered by the plaintiff Amy DeLuca. Amy DeLuca brought suit through her mother and guardian ad litem, Cindy DeLuca, who with her husband, joined as plaintiffs in their individuals capacities. Plaintiffs allege that the birth defects (limb reduction) suffered by Amy DeLuca were caused by her mother's exposure to Bendectin, an anti-nausea drug produced by the Defendant Merrell Dow Pharmaceuticals, Inc. ("Merrell Dow").

 PROCEDURAL HISTORY

 By Memorandum and Order dated June 7, 1990, this Court granted defendant Merrell Dow's motion for summary judgment. *fn1" This Court held that the testimony of Dr. Alan Done, who was offered as an expert in pediatric pharmacology, was inadmissible because it was not based on data of a type reasonably relied upon by experts in the relevant fields as is required by Federal Rule of Evidence 703. Because Dr. Done's testimony was the only evidence offered by plaintiffs to show a causal link between Bendectin exposure and birth defects, the Court entered summary judgment in favor of Merrell Dow. DeLuca v. Merrell Dow Pharmaceuticals, Inc., 131 F.R.D. 71 (D.N.J. 1990).

 Plaintiffs appealed and the Court of Appeals reversed and remanded the action for further proceedings. DeLuca by DeLuca v. Merrell Dow Pharmaceuticals, Inc., 911 F.2d 941 (3d Cir. 1990). The issues presently before this Court are three: (1) whether Dr. Done's testimony should be excluded under Rule 703 because the data upon which he relies are not of a type that experts in the field of epidemiology would rely upon, id. at 952-54; (2) whether Dr. Done's testimony should be excluded from evidence under Rule 702 on the grounds that (a) his methodology is unreliable, or (b) it would overwhelm, confuse or mislead the jury, id. at 954-57; and (3) if Dr. Done's testimony is admissible, whether under applicable New Jersey law the evidence relevant to causation would permit a jury finding that Amy DeLuca's birth defects were caused by her mother's exposure to Bendectin. Id. at 957-59.

 Consistent with that opinion, this Court conducted a hearing held on five separate days, followed by extensive post-hearing submissions of the parties, in order to determine whether Dr. Done's testimony is admissible under the criteria set forth in United States v. Downing, 753 F.2d 1224 (3d Cir. 1985). The record before this Court consists of written direct testimony submitted by the parties and oral cross-examination and re-direct examination of the witnesses. Plaintiffs' experts were Dr. Alan K. Done, M.D. and Dr. Shanna Swan, Ph.D. Defendants submitted the expert testimony of Dr. Richard R. Monson, M.D., Sc.D, Dr. Nicholas H. Wright, M.D., M.P.H., Dr. Steven H. Lamm, M.D., Dr. Gerald A. Faich, M.D., M.P.H., Dr. Pauline Brenholz, M.D. and Dr. Paul Stanley Lietman, M.D., Ph.D. This Opinion constitutes my Findings of Fact and Conclusions of Law.

 FACTUAL FINDINGS

 I. Causes and Incidence of Birth Defects

 A. Causes of Birth Defects

 1. The majority (approximately 65%) of birth defects in general are of unknown origin. Brenholz Direct at 3; Done Test., Tr. 7/10/91, at 29.

 2. Possible causes of birth defects include genetic factors (chromosomal abnormalities or mutant genes) and environmental factors (diet, drug exposure, infections, x-rays and the like). Malformations may be multifactorial, meaning they are likely caused by a combination of genetic and environmental factors. Brenholz Direct at 4.

 3. Genetic factors are etiological agents that initiate mechanisms of malformation by biochemical or other means at the subcellular level. Genetic factors typically are inherited or arise as a new gene mutation or new chromosomal abnormality, but do not necessarily manifest themselves in each pregnancy or in every generation. Brenholz Direct at 4.

 4. Environmental factors, or teratogenic agents, may induce congenital malformations when the tissues and organs are developing. Brenholz Direct at 4.

 5. The fact that a chromosomal study is normal does not rule out genetic defects. Medical science has not yet developed tests for most genetic defects. Brenholz Test., Tr. 9/19/91, at 78-79.

 6. Family history is similarly not determinative, as recessive genes can be inherited from generation to generation, but do not manifest themselves unless there is a union with a partner who also carries the same recessive gene. There is a one in four chance that such a condition will appear. Brenholz Test., Tr. 9/19/91, at 79-80.

 B. Incidence of Birth Defects

 7. Congenital malformations are as old as recorded medical history. There have been countless instances of similar limb defects reported prior to Bendectin's first having been sold in this country in 1957. Since the time that Merrell Dow ceased the marketing of Bendectin, limb defects of the type suffered by Amy DeLuca have continued to be observed and reported. Brenholz Direct at 8. *fn2"

 8. An analysis comparing the incidence of birth defects to the sale of Bendectin has shown that there is no association between the two. Lamm Direct at 5-6; Defendant's Ex. 50. *fn3"

 9. Data collected by the Centers for Disease Control ("CDC") in Atlanta, Georgia show that after Bendectin ceased to be marketed (when Bendectin had been off the market for about three years) there was a slightly greater increase in birth defects than when Bendectin was prescribed in approximately 25% of all pregnancies. Wright Direct at 48; Defendant's Ex. 45. *fn4"

 C. Evaluation of Possible Teratogens

 10. Geneticists use the Catalog of Teratogenic Agents, written by Thomas H. Shepard, M.D., as a source of reference when consulting patients as to the probable outcome of a pregnancy. In the Catalog, Dr. Shepard characterizes substances as "proven", "possible" or "unlikely" teratogens. Bendectin is listed as "unlikely" to be a teratogen. Cigarette smoking is listed as a "possible teratogen." The question of whether an induced abortion affects subsequent pregnancies has been debated. Brenholz Direct at 5-6; Defendant's Ex. 51. *fn5"

 11. Geneticists also use Reprotox, a computerized teratogen registry of the Reproductive Toxicology Center in Washington, D.C. Reprotox contains accurate, objective, comprehensive information regarding potential teratogenic agents and offers summaries of relevant and important articles. The registry states that animal and epidemiologic studies demonstrate no association between Bendectin and adverse pregnancy outcomes in general, and limb defects specifically. Brenholz Direct at 7; Defendant's Ex. 53. *fn6"

 12. Dr. Done has offered no materials on teratogenicity which state to the contrary. *fn7"

 13. Dr. Done has failed to explain how he himself ruled out Mrs. DeLuca's prior abortion and cigarette smoking as possible causes of Amy DeLuca's birth defects. Done Aff.; Done Test., Tr. 7/10/91; Brenholz Direct at 6-7.

 14. Dr. Brenholz testified that pregnancy and smoking are always factors to be considered in determining the etiology of a birth defect. She also testified that a prior recent abortion and cigarette smoking could not be linked with a definite birth defect. Brenholz Test., Tr. 9/19/91, at 66-69.

 II. Epidemiologic Studies on Bendectin

 A. Principles of Epidemiology

 15. Dr. Done placed emphasis in this case on epidemiologic studies, as there is almost universal agreement that the effects of drugs in human beings can best be evaluated by studying data concerning how those drugs did in fact affect persons who ingested them.

 16. Plaintiffs originally relied secondarily on animal studies as well as epidemiologic studies. However, Magistrate Judge John Devine entered an order, which this Court affirmed on appeal, excluding from evidence all in vivo and in vitro animal studies. Plaintiffs have not challenged that ruling. Dr. Done also stated in his affidavit that he relied on structural activity considerations as well. His direct testimony, however, did not address this theory, but instead exclusively treated epidemiologic studies.

 17. Epidemiologic studies typically express their results in terms of relative risks or odds ratios. The relative risk or odds ratio compares the rate of disease in the exposed population to the rate of disease in the unexposed population. If the two rates are the same, then the ratio is one. Where there is no association between exposure and disease, one would expect to find studies yielding relative risks grouped around the number 1.0 -- some less than 1.0 and some more than 1.0. Monson Direct at 20-22; Wright Direct at 11-12.

 18. The size of a study is one measure of its stability and power; thus, other things being equal, the larger the study, the greater its strength. Monson Direct at 22-24.

 19. A confidence interval is a statistical calculation which provides information as to the stability of a relative risk calculation. A 95% confidence interval means that there is a 95% probability that the "true" relative risk falls within the interval. Monson Direct at 25; Wright Direct at 18. Most epidemiologists use a 95% interval; some use a 90% interval. Wright Direct at 21.

 B. The Bendectin Studies

 20. Bendectin is one of the most extensively studied drugs in history. Dr. Done listed forty-two entries on Table 1 included as part of Exhibit B to his affidavit. That list contained thirty-one published studies or reports on Bendectin, six studies that did not address Bendectin, one unpublished re-analysis of an existing work, two unpublished preliminary drafts, one additional unpublished report, and one unpublished analysis of Food & Drug Administration ("FDA") "adverse drug reaction reports" or "drug experience reports" ("ADRs" or "DERs") conducted by Dr. Done himself. Done Aff., Ex. B.

 21. Dr. Done conceded that there are no published studies showing a statistically significant association between Bendectin exposure and the development of limb reduction defects. Done Test., Tr. 7/10/91, at 27.

 22. Dr. Done conceded that in the medical literature there is no established association to a statistically significant degree between exposure to Bendectin and an increased incidence of the specific type of Amy DeLuca's birth defects. Done Test., Tr. 7/10/91, at 29.

 23. None of the authors of the thirty-one published studies included by Dr. Done on his chart concluded that a causal association between Bendectin ingestion and birth defects had been shown, and none of the published literature found any statistically significant association between Bendectin and the type of birth defects suffered by Amy DeLuca. See Plaintiffs' Exs. 1-43.

 24. Dr. Done conceded that the authors of the published epidemiologic literature have concluded that their studies failed to demonstrate an association between Bendectin and limb reduction defects. Done Test., Tr. 7/10/91, at 27.

 25. In 1982 and 1983, the FDA conducted a detailed review of Bendectin and released a report, continuing to approve the sale of Bendectin. The FDA concluded: "We do not however, believe available information supports a conclusion that Bendectin is teratogenic in humans." Defendant's Ex. 20, at 34.

 26. In 1984, the court-appointed expert in the multi-district Bendectin litigation concluded that there was no evidence upon which to conclude that Bendectin caused birth defects. Lamm Direct at 4-5.

 27. In the Notice of Proposed Rulemaking included in the Federal Register at Volume 52, No. 163 (August 24, 1987), the FDA concluded: "The agency has reviewed extensive data concerning the possible teratogenicity of doxylamine succinate and concludes that it is unlikely that this ingredient is a teratogen." Defendant's Ex. 19, at 31905.

 28. Dr. Done concluded, based on his methodology, that a grouping of the data from all studies conclusively established that there was in fact an association between Bendectin and birth defects. Done Aff. at 2-3.

 III. The Done Methodology: Dr. Done's Reanalysis of Epidemiologic Studies

 29. In his affidavit, Dr. Done stated the bases for his conclusion that Bendectin caused the congenital limb defect suffered by Amy DeLuca were his "knowledge of the properties of Bendectin, the compatibility of the timing of Bendectin exposure in this case with the particular defect, the fact that the defect is of the type for which there is substantial evidence of Bendectin causation, the absence of another more likely cause in this case, evidence of teratogenicity of Bendectin from animal teratogenicity and in-vitro mechanistic studies, and the ample evidence of human teratogenicity of Bendectin from the epidemiologic studies analyzed in Exhibit "B"." Done Aff. at 2. With the exception of epidemiologic studies, Dr. Done provided no supporting data or explanations for the other bases upon which he relied. *fn8"

 30. In his affidavit, Dr. Done stated: "Proof of causation can never come from epidemiologic studies, even with extensive replication." Done Aff. at 3.

 A. Dr. Done's Data Sheets

 31. Dr. Done purports to have taken the numbers he entered in the boxes on his chart from either the underlying studies themselves, or in the articles where no calculations were made, Dr. Done claims to have calculated the numbers himself. In many cases, this is simply not true.

 32. Dr. Shanna Swan, plaintiffs' other expert, did not independently verify the data included on Dr. Done's chart, did not check his calculations and did not check to see if Dr. Done correctly extracted the data from the articles as to which he made no calculations. Swan Test., Tr. 7/12/91, at 7-14. *fn9" Dr. Swan merely commented on Dr. Done's methodology as he described it and "took as a given that he did what he said he did." Swan Test., Tr. 7/12/91, at 9-21.

 B. Dr. Done's Methodology of Calculation

 33. The calculation of a relative risk is a simple arithmetic calculation of the rate of occurrence in the exposed population compared to the rate of occurrence in the unexposed population. Done Test., Tr. 7/10/91, at 142; Wright Direct at 11; Monson Direct at 21-22. Relative risk calculations are not subject to variations other than those attributable to round-off techniques, provided the correct data is selected. Monson Direct at 11. The calculation of confidence intervals, on the other hand, is a more difficult calculation and may vary depending on the type of computer program used. Monson Direct at 11; Done Aff., Ex. B.

 34. During cross-examination, Dr. Done explained how he obtained the data he used in making the calculations he entered on the chart. Done Test., Tr. 7/10/91, at 114-34. With respect to the Newman and Greenberg studies, Dr. Done admitted that the numbers were transposed. Done Test., Tr. 7/10/91, at 130.

 35. Defense experts, Drs. Monson, Wright and Lamm, have itemized numerous errors made by Dr. Done in the calculation of the "data sets" *fn10" he included on his chart. *fn11" Monson Direct at 10-28; Wright Direct at 4-28; Lamm Direct at 15-18. The defense experts as well as Dr. Swan testified that the precise method used by Dr. Done in making some of his calculations was a mystery and was not in conformance with any known methodology.

 36. Drs. Monson, Wright, Lamm and Swan, all qualified epidemiologists, in many cases could not replicate Dr. Done's recalculations. Monson Direct at 27-28; Wright Direct at 33; Lamm Direct at 15-18; Swan Test., Tr. 7/12/91, at 12, 20, 25-26, 28-29 & 33.

 37. Dr. Done's chart listed a relative risk of 8.8 with confidence intervals of 2.0 to 3.9 with respect to limb reduction defects for the Jick '80 study (fourth entry on Dr. Done's chart). Done Aff., Ex. B. This is incorrect since the relative risk must fall between the confidence limits. Done Test., Tr. 7/10/91, at 93-95; Swan Test., Tr. 7/12/91, at 11-12.

 38. The Shapiro and Heinonen publications of the same study presented a standardized relative risk of 1.15 for musculoskeletal malformations. Plaintiffs' Ex. 13, Table 2, at 482; Plaintiffs' Ex. 14, Table 23.5, at 327. Dr. Done's chart listed two separate non-standardized *fn12" relative risks of 1.4 and 1.6, calculations which are at odds with his claimed procedure of using the authors' calculations where possible. Dr. Swan could not explain how Dr. Done calculated two different relative risks when the data from the underlying studies were the same. Swan Test., Tr. 7/12/91, at 33.

 39. Dr. Done calculated the 1.6 figure in the Shapiro '77 study by adding club feet to the author's category of musculoskeletal defects. Done Test., Tr. 7/10/91, at 122-25; Monson Direct at 14.

 40. Although Dr. Swan listed a relative risk of 0.67 to 1.0 in her reanalysis for women under the age of thirty who ingested the same two-ingredient Bendectin as did Mrs. DeLuca, Dr. Done listed a relative risk of 2.4 on his chart. Compare Done Aff., Ex. B. with Plaintiffs' Ex. 28. Dr. Swan admitted that she would not place much weight on this portion of her reanalysis because the numbers are so small. Swan Test., Tr. 7/12/91, at 44.

 41. The Bannister study did not contain adequate information on control subjects to calculate a relative risk. Wright Direct at 37. Even if one were to make certain assumptions regarding the data, there is no known methodology which could yield a relative risk of 13, the number which Dr. Done entered on his chart. Monson Direct at 12; Lamm Direct at 16. Dr. Done testified that he calculated the relative risk of 13 by taking 3/23 as the numerator and dividing by 1/28. Done Test., Tr. 7/10/91, at 116-18. Simple arithmetic reveals, however, that 3/23 divided by 1/28 equals 3.65, not 13. Possible relative risks are either 1.2 or 1.4. Monson Direct at 12-13. Dr. Done previously testified in another trial that the relative risk was 1.4. Done Test., Tr. 7/10/91, at 118-19.

 42. Dr. Swan could not explain how Dr. Done calculated a relative risk of 13 for the Bannister study. Swan Test., Tr. 7/12/91, at 20-26.

 43. For the Saxen study, Dr. Done listed a relative risk of 4.6 for all defects. Done Aff., Ex. B; Plaintiffs' Ex. 8. The data for all defects were not presented in the underlying study. Lamm Direct at 16; Defendant's Ex. 48. Dr. Done explained, however, that the "all" category included all defects of other kinds occurring in people who also had cleft lip or palate. Done Test., Tr. 7/10/91, at 97.

 45. Dr. Swan could not give an opinion as to whether Dr. Done used an accepted methodology in calculating his relative risk of 11.4. ...


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