Opinion
A1204223
01-22-2014
SHERRY L. ADAMS, et. al., Plaintiffs, v. THE PROCTOR & GAMBLE DISTRIBUTING, LLC, et. al., Defendants
Frank C. Woodside, III, Esq., Eric K. Combs, Esq., Mary-Jo Pullen, Esq., Counsel for Defendants The Proctor & Gamble Distributing LLC, and The Proctor & Gamble Company, and The Proctor & Gamble Manufacturing Company. Raymond C. Silverman, Esq., Counsel for Plaintiffs.
Frank C. Woodside, III, Esq., Eric K. Combs, Esq., Mary-Jo Pullen, Esq., Counsel for Defendants The Proctor & Gamble Distributing LLC, and The Proctor & Gamble Company, and The Proctor & Gamble Manufacturing Company.
Raymond C. Silverman, Esq., Counsel for Plaintiffs.
ENTRY GRANTING DEFENDANTS' MOTION TO EXCLUDE OPINIONS OF DRS. ASKARI, GRAINGER, GREENBERG, LAUTENBACH, AND SMITH
Ethna M. Cooper, Judge
This case is before the Court on Defendants The Proctor & Gamble Distributing LLC, The Proctor & Gamble Company and the Proctor & Gamble Manufacturing Company's Motion to Exclude the Opinions of Drs. Askari, Grainger, Greenberg, Lautenbach and Smith, Plaintiffs' Memorandum in Opposition to Defendants' Motion to Exclude the Opinions of Drs. Askari, Grainger, Greenberg, Lautenbach and Smith, and Defendants' Reply thereto. Oral argument was held on Thursday, December 19, 2013 at which time the Court heard extensive arguments of counsel with respect to Defendants' Motion.
II. BACKGROUND
This case arises from Plaintiffs' allegations that Sherry Adams' (" Adams") chronic use of Fixodent resulted in neurological injuries. Plaintiffs contend that when Fixodent is swallowed and exposed to the gastrointestinal tract in excess amounts, the zinc in Fixodent is subsequently absorbed by the body, causing depleted copper levels ultimately resulting in the development of a " constellation of neurological symptoms generally referred to as neuropathy as well as other hematologic complications."
--------- Notes: Complaint, ¶ 8. [2] Valentine v. PPG Industries, et. al. , 158 Ohio App.3d 615, 2004-Ohio-4521, 821 N.E.2d 580, aff'd by Valentine v. Conrad , 110 Ohio St.3d 42, 2006-Ohio-3561, 850 N.E.2d 683. [3] Valentine , 158 Ohio App.3d 615, 2004-Ohio-4521 at ¶ 17, 821 N.E.2d 580. [4] Newman v. The Farmacy Natural & Specialty Foods , 168 Ohio App.3d 630, 2006-Ohio-4633 at ¶ 11, 861 N.E.2d 559. [5] Daubert v. Merrell Dow Pharmaceuticals, Inc. (1993), 509 U.S. 579, 113 S.Ct. 2786, 125 L.Ed.2d 469. [6] Id. at 593-94. [7] Id. at 595. [8] Valentine , 158 Ohio App.3d 615, 2004-Ohio-4521 at ¶ 34, 821 N.E.2d 580. [9] Valentine , 158 Ohio App.3d 615, 2004-Ohio-4521 at ¶ 27, 821 N.E.2d 580quoting ( Bragdon v. Abbott (1998), 524 U.S. 624, 653, 118 S.Ct. 2196, 141 L.Ed.2d 540) [10] Id. quoting Daubert , 509 U.S. at 592. [11] Id at ¶ ¶ 37-41 quoting Daniel J. Capra, The Daubert Puzzle , 32 Ga. L. Rev 699, 705 (1988)(" In deciding the question of admissibility, trial judges must consider the degree to which the accuracy of scientific information has been established. The less certain the scientific community is about information, the less willing courts should be to receive it.") [12] Miller , 80 Ohio St.3d at 613 citing Daubert , 509 U.S. at 593-94; see also Turker v. Ford Motor Company , (8th Dist 2007), 2007-Ohio-985 at ¶ 19. [13 ] 293 F. 1013, 1014 (D.C.App. 1923) [14] Valentine , 158 Ohio App.3d 615, 2004-Ohio-4521 at ¶ 38, 821 N.E.2d 580. [15] In re Meridia Prods. Liab. Litig. , 328 F.Supp.2d 791, 800 (N.D. Ohio 2004), quoting Conde v. Velsicol Chem. Corp. , 804 F.Supp. 972, 1025-26 (S.D. Ohio 1992). [16]Ebbing Lautenbach, M.D., M.P.H., M.S.C.E., et. al., Practical Healthcare Epidemiology, 30, 3rd Ed. 2010 (" Lautenbach Book"). [17]Deposition of Martyn Smith (1/12/12) at 127:22-129:10; Deposition of Ebbing Lautenbach (5/11/11) at 25:16-26:12; Deposition of Steven Greenberg (9/28/12) at 63:9-64:9, 65:3-21, 66:24-68:2. [18] In re Denture Cream Prods. Liab. Litig. , 795 F.Supp.2d at 1356. [19]Smith Dep. (4/26/13) 120:6-121:4. [20] Id. at 1355, citing Michael D. Greene, et. al., Reference Guide on Epidemiology , in Reference Manual On Scientific Evidence (Federal Judicial Center, 2d Ed. 2000) at 336. [21] Valentine , 158 Ohio App.3d 615, 2004-Ohio-4521 at ¶ 34, 821 N.E.2d 580. [22]CDC, Office of Surveillance Epidemiology and Laboratory Services, www.cdc.gov/excite/classroom/outbreak/steps.htm. [23] Id. [24]Lautenbach Report (4/30/12) at ¶ 23 (" Anemia and neutropenia are commonly seen in copper deficiency and often accompany the neurologic symptoms."); see also Neeraj Kumar, M.D., Copper Deficiency Myelopathy , 61(5) Arch. Neurol., 762, 765 (2004)(" [t]he recognized hematologic manifestations of acquired copper deficiency in humans include anemia, neutropenia, sideroblastosis, and megaloblastic changes."). [25]Neeraj Kumar, M.D., Copper Deficiency Myelopathy (Human Swayback ), 81(10) Mayo Clinic Proc., 1371, 1382 (2006); Alemaychu A. Gabreyes, et. al., Hypocupremia Associated Cytopenia and Myelopathy, A National Retrospective Review , 90 Euro J. Haema. 1 (2012). [26] In re Denture Cream Prods. Liab. Litig. , 795 F.Supp.2d at 1347, n 3. [27]Reference Manual On Scientific Evidence at 379 (Federal Judicial Center, 2d Ed. 2000) " A study that finds that an agent is associated with many different diseases should be examined skeptically." [28] Id. at 1361. [29] Valentine , 158 Ohio App.3d 615, 2004-Ohio-4521 at ¶ 47, 821 N.E.2d 580, citing Rider v. Sandoz Pharmaceuticals Corp. , 295 F.3d 1194, 1198 (11th Cir. 2002); see also Haggerty v. Upjohn Co. , 950 F.Supp. 1160, 1165 (S.D. Fla. 1996)(" [W]hile case reports may provide anecdotal support, they are no substitute for a scientifically designed and conducted inquiry."). [30] Baker v. Chevron USA Inc. , 680 F.Supp.2d 865 (S.D. Ohio 2010), citing McClain c. Metabolife Int'l, Inc. , 401 F.3d 1233. 1240 (11th Cir. 2005); see also Allison v. McGhan Medical Corp. , 184 F.3d 1300, 1316 (11th Cir. 1999)(case reports and case studies are " universally regarded as insufficient to establish causation because they lack controls). [31]Lautenbach Book, at 33; Lautenbach Dep. (5/11/11) at 28:5-13. [32]See Defendants' Motion to Exclude, Ex. 5, Sharon S. Nations, et. al., Denture Cream: An Unusual Source of Excess Zinc, Leading to Hypocupremia , 71. Journal Of Neurology 639, 642 (2008); Ex. 47, Marco Spinazzi, et. al., Mylo-optico-neurology in copper deficiency occurring after partial gastrectomy , 254 J Neurol 1012, 1015 (2007); Ex. 48, Zhaleh Khaleeli, et. al., Copper deficiency as a treatable cause of poor balance, 340 BMJ 864, 865 (2010); Ex. 41, R. Brian Sommerville, et. al., Anema. Paresthesias, and Gait Ataxia in a 57-Year Old Denture Wearer , 57:8 Clinical Chemistry 1103, 1105 (2011); Ex. 49, K. Doherty, et. al., Zinc-containing denture adhesive: a potential source of excess zinc resulting in copper deficiency myelopathy , 210 British Dental Journal, 523, 525 (2011); Ex. 50, Joanne Wu, MD, MPH, et. al., Copper Deficiency as a Cause of Unexplained Hematologic and Neurologic Deficits in Patient with Prior Gastrointestinal Surgery , 19(2) J Am Board of Fam. Med, 191, 192 (2006); Ex. 51, N. Kumar, Myelopolyneuropathy Due to Copper Deficiency or Zinc Excess? , 61 Arch Neurol, 604, 605 (2004). [33]Lautenbach Dep. (1/27/12) at 96:5-14. [34]Lautenbach Dep. (6/4/13) at 38-39. [35] In re Accutane Products Liability , Middle District of Florida MDL 1626, No. 8:04-MD-2523-T-30TBM (May 2, 2007). [36] Jacoby v. Rite Aid Corporation (Pa. Super. 2013), 2013 WL 6556743 at *6, n.5, citing Lautenbach Report 12/1/11, at 8. [37]Lautenbach Dep. (6/4/13) at 86:19-87:13; 90:3-22. [38]Lautenbach Dep. (10/3/12) at 62:16-63:14. [39]Lautenbach R. (4/15/13) at ¶ 19. [40] Id. at ¶ ¶ 47, 60-61. [41]Nelson Report (6/27/13) at 9; Lautenbach Dep. (6/4/13) at 143:18-144:7. [42]Motion to Exclude, Scottish Trace Element & Micronutrient Reference Laboratory Annual Reports, (" STEMRL. R."), Years 4/2004-3/2005 (Ex. 67), 4/2005-3/2006 (Ex. 68), 4/2006-3/2007 (Ex. 69), 4/2007-3/2008 (Ex. 70), 4/2010-3/2011 (Ex. 71); Nelson Report (6/27/13) at 10; Lautenbach Dep. (6/4/13) at 180:21-182:2; Report of Douglas Weed (6/26/13) at 12; Nelson Report (6/27/13) at 18-12. [43]Discovery Responses of co-author Dr. Ian Morrison at PG 001113779; Nelson Report (6/27/13 at 13-14; Report of Matthew E. Fink (6/28/13) at 2. [44]Morrison Discovery Responses at PG 001113778-3779; Nelson Report (6/27/13) at 16-17; Fink Report (6/28/13) at 2-3. Id. pp. 29-30. [45]Lautenbach Dep. (6/4/13) at 164:7-166:3. [46]Lautenbach Dep. (6/4/13) at 27:11-19. [47]See Valentine , 158 Ohio App.3d 615, 2004-Ohio-4521 at ¶ 27, 821 N.E.2d 580, quoting Daubert , 509 U.S. at 590 (" The proposed expert testimony must be supported by appropriate validation....") [48]George J. Brewer, Metals in the Causation and Treatment of Wilson's Disease and Alzheimer's Disease, and Copper Lowering Therapy in Medicine , 393 Inorganica Chimica Acta 135, 136 (2012); see also Johnson Report(7/29/12) a 2.; Deposition of Joseph Prohaska (9/25/12) at 54:16-56:5. [49]795 F.Supp.2d at 1356. [50]Askari Report (4/14/13) at 14; Smith Report (4/15/13) at ¶ ¶ 124-128. [51]Askari Dep. (6/20/13) at 115:13-116:12; Askari Dep. (6/21/13) 164:25-165:4. In the study, 12 human subjects were dosed with 12 grams of Fixodent, 6 dosed with zinc acetate and 6 with a placebo, each day for 30 days. [52]Askari Dep. (7/9/13) at 346:3-11; 347:8-12. [53] In re Denture Cream Prods. Liab. Litig. , 795 F.Supp.2d at 1353, n. 20. [54]Deposition of Hongkun Wang (8/13/13) at 25:4-14, 77:4-24, 84:19-5:4, 103:8-104:17, 105:3-7; Askari Dep. (6/20/13) at 42:19-43:25; 46:22-47:1; Askari Dep. (6/21/13) at 241:3-242:7; Expert Report of Diane Jorkasky (6/27/13) at 18-20. Dr. Askari admits that " unblinding" a study potentially introduces bias which is sometimes difficult to detect. Askari Dep. (7/9/13) at 407:10-19. Deposition of Salim Shah (6/5/13) at 180:14-181:5; Shah Dep. (6/13/13) at 507:7-12. [55]Askari Dep. (6/21/13) at 229:23-233:11; Jorkasky Dep. (6/27/13) at 33; Expert Report of Robert Gibbons (6/27/13) at 4-5; David L. Sackett, Bias in Analytic Research, 32 J, Chron Dis., Appendix A (1979)(defining " post-hoc significance bias" as " [w]hen decision levels ... are selected after the data have been examined, conclusions may be biased.") Motion to Exclude, FN 152, 154, 159, 161. [56] E.I. du Pont de Nemours & Co. V. Robinson (Tex 1995), 923 S.W.2d549, 559; Daubert v. Merrell Dow Pharmaceuticals, Inc. (9th Cir. 1995), 43 F.3d 1311, 1317 (" One very significant fact to be considered is whether. . .they have developed their opinions expressly for the purpose of testifying, ") [57] Baker, et. al. v. Chevron U.S.A., Inc., et. al. , (6th Cir. 2013), Case Nos. 11-4369; 12-3995, 533 Fed.Appx. 509, at * 31, citing Pluck v. BP Oil Pipeline Co. (6th Cir. 2011), 640 F.3d 671, 680 (" the district court acted within its discretion when it discounted studies that contained statistically insignificant results."). [58]Askari Dep. (7/9/12) at 394:9-23; Wang Dep. (8/13/13) at 66:24-67:4. The serum zinc measurements for all but one subject remained within normal reference range and no participant had a serum copper level below the normal range. Shah Dep. (6/5/13) at 218:22-219:9. [59]Askari Dep. (6/21/13) at 262:15-263-7; 69:21-24; Johnson Report (6/28/13) at 9; Askari Dep, (7/9/13) at 384:25-385:19. The study's statistician, Dr. Wang, acknowledged that such a limited comparison, as opposed to a comparison of data for the entire study period, was an improper way to analyze the data. Wang Dep. (8/13/13) at 49:19-50:24. [60] In re Denture Cream Prods. Liab. Litig. , 795 F.Supp.2d at 1356. [61]Greenberg Dep. (6/13/13) at 89:9-23. [62]Askari Dep. (1/20/12) at 46:23-47:8. [63]Greenberg Dep. (6/13/13) at 89:24-90:10. [64]Smith Report (4/15/13) at ¶ 101. [65] Kilpatrick v. Breg, Inc. (11th Cir. 2010), 613 F.3d 1329, 1335; Ballard v. Keen Transp., Inc. (S.D. Ga. 2011), No. 4:10=CV-54, Allen v. Pennsylvania Eng'g Corp. (5th Cir. 1996), 102 F.3d 194, 198. [66]Grainger Report (4/9/13) at 6. [67]Vick's Research Center, Inter-Department Memo: " Zinc Dissociation: Repeat Experiment, " dated August 22, 1989, produced at PG 000214047 (Motion to Exclude, Ex. 93). [68]Grainger Dep. (1/24/12) at 65:20-66:1; 67:6-11, 67:22-68:10. [69]Askari Dep. (1/20/12) at 194:5-195:3. [70] Valentine , 158 Ohio App.3d 615, 2004-Ohio-4521 at ¶ 17, 821 N.E.2d 580 citing Wiley, Expert Witness Update: New Developments in Personal Injury Litigation (2000), Section 1:04, at 18-19 and Section 1.05 (C), a 28 (stating that " the dose makes the poison.") [71] In re Denture Cream Prods. Liab. Litig. , 795 F.Supp.2d 1345, n. 20. [72]Askari Dep. (7/9/13) at 346:3-347:12. [73]Smith Report (4/15/13) at ¶ 119. [74]Motion to Exclude, Ex. 94, P& G 6/1/11 Safety Assessment at 6. [75] Id., Ex.28, Smith Report (4/15/13) at¶ ¶ 110-113; Ex. 10, Johnson Report (7/29/12) at 18-19. However, when taking into consideration the relative dose correction and the fact that every person has a baseline level of zinc, the study report indicates that less than 10% of the zinc from Fixodent is bioavailable. [76] In re Denture Cream Prods. Liab. Litig. , 795 F.Supp.2d at 1353; Johnson Report (7/29/12) at 23 (" The absorption of zinc in from the gastrointestinal tract is not linear with the amount of zinc ingested; that is, twice as large a dose of zinc does not result in twice as much zinc absorption.") [77]Johnson Report (7/9/12) at 3. [78] Id. [79] Id. [80] Id. at 17. [81]Smith Dep. (9/25/12) at 74:16-77:12. [82] Id. at 66:17-24. [83] Id. at 77:20-79:4. [84]Smith Dep. (1/12/12) at 86:12-17. [85]See Baker , 680 F.Supp.2d at 880, citing Nelson v. Tennessee Gas Pipeline Co. (6th Cir. 2001), 243 F.3d 244, 252-53. [86] Brecount v. The Proctor & Gamble Co. (1957), 166 Ohio St.477, ¶ 3, 144 N.E.2d 189. [87] Terry v. Caputo (2007), 115 Ohio St.3d 351, 2007-Ohio-5023, 875 N.E.2d 72. [88] Valentine , 158 Ohio App.3d 615, 2004-Ohio-4521 at ¶ 53, 821 N.E.2d 580 citing Cavallo v. Star Enterprise (E.D.Va. 1995), 892 F.Supp. 756, 761. [89] Id. [90] Valentine v. Conrad (2006), 110 Ohio St.3d 42, 2006-Ohio-3561 at ¶ 22, 850 N.E.2d 683 citing Hardyman v. Norfolk & W.Ry. Co. (6th Cir. 2001), 243 F.3d 255, 260. [91] Kerns , 2008-Ohio-2242 at ¶ 94. [92]Valentine, at ¶ 53. [93]Lautenbach Dep. (5/11/11) 77:17-22-78:12-19; Smith Dep. (1/12/12) 162:24-163:23-24; Greenberg Dep. (6/13/13) 42:24-43:19, 44:18-45:5-10;; Brewer Dep. (4/15/11) 25:5-26:3; Jan-Philipp Bach, Copper deficiency associated with sever neurological disorder- A genetic work-up of possible mutations in copper transport proteins , 291 J. Neurol. Sci. 95, 96 (2010).. [94]Greenberg Report (5/30/13) at 9, citing Rebecca J. Spain, When metals compete: a case of copper-deficiency myeloneuropathy and anemia , 5(2) Nat. Clin. Pract. Neurol 106, 108, 109 (2009); Greenberg Dep. (6/13/13) 125:24-126:11, 128:25-129:18 [95]Report of Robert A. Sacher, M.D. (6/26/13) at 3-4. [96]Greenberg Report (5/30/13) at 9. [97]Simpson Report (6/27/13) at 6. Adams Dep. (3/13/13) at 46:14-17; Koch Report (6/26/13) at 15; Greenberg Report (5/30/13) at 8. [98] Valentine v. Conrad , at ¶ 34. [99]Greenberg Dep. (6/13/13) at 59:9-53:21 [100] Id. [101]Adams Dep. (3/13/13) at 53:11-54:14. [102] Id. at 54:23-56:18. [103] Terry , 115 Ohio St.3d 351, 2007-Ohio-5023 at ¶ 2, 875 N.E.2d 72 of syllabus; Marcus v. Rusk Heating & Cooling Inc. (12th Dist. 2013), 2013-Ohio-528. [104] Herzner v. Fischer Attached Homes, Ltd. (12th Dist. 2008), 2008-Ohio-2261. [105] Id. ; see also Rose v. Truck Centers, Inc. (N.D. Ohio 2009), 611 F.Supp.2d 745, 750. ---------
Plaintiffs have submitted the reports of several experts in support of their theories of both general and specific causation. Defendants seek to exclude the opinions of Plaintiffs' expert as unreliable under Valentine v. PPG Industries.
III. ANALYSIS
In order for Plaintiffs to succeed on their claims, they must establish that: 1) Fixodent is capable of causing Adams' condition (general causation); and 2) Fixodent in fact caused Adams' medical condition (specific causation). Ohio Rule of Evidence 702 sets forth that,
" A witness may testify as an expert if all of the following apply: (A) The witness' testimony either relates to matters beyond the knowledge or experience possessed by lay persons or dispels a misconception common among lay persons;
(B) The witness is qualified as an expert by specialized knowledge, skill, experience, training, or education regarding the subject matter of the testimony;
(C) The witness' testimony is based on reliable scientific, technical, or other specialized information. To the extent that the testimony reports the result of a procedure, test, or experiment, the testimony is reliable only if all of the following apply:
(1) The theory upon which the procedure, test, or experiment is based is objectively verifiable or is validly derived from widely accepted knowledge, facts, or principles;
(2) The design of the procedure, test, or experiment reliably implements the theory;
(3) The particular procedure, test, or experiment was conducted in a way that will yield an accurate result."
It is Plaintiffs' burden to show that its expert evidence is admissible.
Defendants do not take issue with the first two requirements under Rule 702. Rather Defendants contend that Plaintiffs' experts' opinions are " methodically flawed and scientifically unreliable, " thus implicating the third requirement under Rule 702. The U.S. Supreme Court in Daubert set forth several factors to aid in the determination of whether an expert's opinion is reliable. These factors are: 1) whether the theory or technique has been tested; 2) whether it has been subjected to peer review; 3) whether there is a known or potential rate of error; and 4) whether the methodology has gained general acceptance. While the " inquiry is flexible, " the focus remains " solely on principles and methodology, not on the conclusions that they generate."
Ohio law on the admissibility of expert mirrors, the Supreme Court's holding in Daubert. Under Valentine , Plaintiffs' experts must proceed in a " stepwise fashion" to: 1) establish the characteristic of the alleged medical condition; 2) carefully define the nature and amount of the alleged toxic exposure; 3) demonstrate that the medical and scientific literature provides reliable evidence that in some circumstances the exposure can cause the outcome, and 4) reach a reasonable conclusion applying general knowledge to the specific circumstances of the case, taking into account mitigating circumstances and competing causes.
Plaintiffs have offered the opinions of five experts to establish that Fixodent caused Adams' myelopathy. Defendants argue that Plaintiffs' experts' opinions are flawed because they: " 1) are based upon hypothesis-generating case reports and unsupported extrapolation; 2) lack any reliable epidemiological data demonstrating a causal relationship between Fixodent and neurological injuries; 3) fail to establish the characteristics of the medical condition at issue (i.e. there is no case definition); and 4) fail to establish the amount and duration of exposure necessary to cause the alleged injury (i.e. the dose/response relationship)."
Under Ohio law, " scientific evidence and expert testimony must have traceable, analytic basis in objective fact before it may be considered." It is the Court's function to determine whether the proposed expert testimony has a " reliable basis in the knowledge and experience of the discipline." To do this, there must be a valid connection between an expert's opinion regarding causation and the scientific research.
Plaintiffs do not dispute the applicable legal standard but rather, spend much of their time arguing that the scientific principles relied upon by its experts are " generally accepted." However, as Defendants point out, in Ohio, " general acceptance" of a methodology is only one factor for a court to consider in determining reliability, but it is not a prerequisite to admissibility. In this respect, Ohio does not follow the standard announced in Frye v. United States , which held that an expert's opinion is inadmissible unless it has gained " general acceptance" in the relevant scientific community.
Epidemiological Evidence
Epidemiology explores " the causes of diseases in humans as inferred from observations of humans." Epidemiological studies are therefore the " primary generally accepted methodology for demonstrating a causal relation between the chemical compound and a set of symptoms or disease." According to Dr. Lautenbach, before identifying the possible causes of a disease, " one must first quantify the frequency with which the disease occurs... the most commonly used measures of disease frequency in epidemiology are prevalence and incidence." None of Plaintiffs' experts have identified, or are able to identify, the incidence of myelopathy or neuropathy in the general population in order to form a baseline (or background risk) for such. As the court in Chapman opined,
Some people use denture cream and some people have a myelopathy; it is possible (and depending on the incidence of myelopathies, likely) that some denture-cream users have an idiopathic myelopathy simply due to the background distribution of that disease. Without a baseline, any incidence may be coincidence. Accordingly, the absence of this data is a substantial weakness in Plaintiffs' experts' causal reasoning.
There has been no baseline offered with respect to the disorders which comprise CDM and there is no available data with respect to the incidence of elevated zinc in the blood or copper deficiency within the general population, denture users or Fixodent users. Indeed Dr. Smith admits that this data is unavailable. Moreover, no other expert has produced such data. As a result, there is no reliable way to establish whether Fixodent use increases the risk of neurological disorders. According to the court in Chapman , the lack of a baseline is just one of the analytical gaps which, standing alone, mandates the exclusion of Plaintiffs' experts.
Case Definition
Under Valentine , in order to show that a chemical substance can cause a specific medical condition, the expert " must establish the characteristics of the medical condition. This is commonly referred to as a " case definition." According to the Center for Disease Control (" CDC"), a case definition includes " information on symptoms, laboratory findings, and limitations of time, place and person." A case definition allows an investigator to exclude individuals with illnesses unrelated to the potential toxic substance. Copper deficiency myeloneuropathy (" CDM") has never been defined by a specific set of signs or symptoms. It's been described in various publications as a " myelopathy with peripheral neuropathy of varying severity." Of particular note is that symptoms allegedly resulting from copper deficiency commonly manifest themselves through blood abnormalities such as anemia and neutropenia. However, some case studies have occasionally linked CDM to MRI findings. Once again, the court in Chapman , noted that " [a] number of different terms have been used -- more or less as synonyms, regardless whether that is medically accurate -- in the course of the litigation to refer to the constellation of neurological injuries allegedly caused by long-term use of Fixodent. Those terms include myelopathy, myeloneuropathy, myelopolyneuropathy, copper-deficiency myelopathy, peripheral neuropathy, CNS demyelination, axonal polyneuropathy and others." Thus, it is clear that there is no universal case definition for CDM. Plaintiffs' experts have not set forth an agreed required list of clinical, laboratory or diagnostic findings in order for an individual to be diagnosed with CDM. The court in Chapman , relying on Greene, Reference Manual On Scientific Evidence, found that the inconsistencies in case definition limit the evidentiary value of the case reports with respect to causation because it is uncertain whether all the case subjects had copper-deficiency myelopathy.
Case Reports
The bulk of Plaintiffs' experts' opinions rely, at some point, on case reports linking denture cream to neurologic disorders. Under Valentine , case reports are not considered to be reliable as to causation because they merely record data and do not reflect any scientific methodology. Because they lack control groups, these case reports and studies are of limited reliability. Indeed, despite Plaintiffs' primary reliance upon case reports and case studies, Dr. Lautenbach concurs that " since a case report or case series does not include a comparison group, one cannot determine which characteristic in the description of the cases are unique to the illness." Notably, many of the publications which Plaintiffs' experts relied upon offered their conclusions as hypotheses and speculation. Dr. Lautenbach has testified that the case reports merely suggest a possible association between denture cream and neurological symptoms rather than actual causation. Indeed, Plaintiffs have identified only four case reports which purport to link excessive Fixodent use to the alleged related neurological symptoms. Only one case report identifies a patient who reportedly solely used Fixodent. The remainder of the cases relates to a product with a different chemical structure than that of Fixodent and one with more than two times the amount of zinc as contained in Fixodent.
Additionally, the case studies do not contain complete information regarding the patients' use of denture cream, such as when it started, how long it continued, the brand that was used, how much was used and how often. Moreover, the case reports fail to follow one standard case definition and do not contain sufficient differential diagnoses. Thus, the information resulting from these case reports are merely inferential hypotheses requiring validation or invalidation through further testing.
Dr. Lautenbach's use of the Naranjo scale to validate the case reports is likewise unreliable as the scale has not been recognized by courts or scientists as a reliable method for making a determination of causation. According to Dr. Lautenbach, " [t]he Naranjo adverse drug reaction probability scale has been used widely to classify the probability that an adverse event (often reported in a case report) is related to drug exposure." However, due to Dr. Lautenbach's vague case definition, it cannot be determined which condition (myelopathy, myeloneuropathy, or neuropathy, or a combination thereof) was required in order to support the finding of a probable relationship with denture cream use. Dr. Lautenbach testified that the methodology for selecting the ten Naranjo criteria is not known, nor is the basis for assigning the various weights to each criterion. He also acknowledged that there was no time limit set between exposure to the toxic substance and the occurrence of an adverse event under the Naranjo scale. Lastly, it is worthy to note that the highest ranking which Dr. Lautenbach gave any case report was " probable" with respect to demonstrating causation. Dr. Lautenbach specifically stated that, " [w]hen the Naranjo criteria are applied to all reported cases of myelopathy in individuals using denture cream, the likelihood that myelopathy was related to denture cream exposure is categorized as " probable" in all but three cases."
Following the Chapman decision excluding Dr. Lautenbach's expert opinion, Dr. Lautenbach conducted a " cohort study" which Plaintiffs contend provides evidence of the incidence rate of CDM in denture adhesive users in particular and non-denture adhesive users in Scotland. However, the authors of this study, who claim to have reviewed all reported cases of copper deficiency in Scotland during a five year period, excluded 6 of the 22 identified patients due to insufficient available data; excluded all cases where serum copper was between 6 and 10 mmol/L, despite the fact that these values were below normal, because they believed that cases below 6 mmol/L would be able to " detect all relevant clinical cases." The study also failed to identify the number of Scottish citizens with low copper levels who had no symptoms or were identified by other Scottish labs performing copper serum testing. Additionally, neither the study authors nor the diagnosing physicians provided a case definition for CDM. The study provides no information pertaining to the amount, length or frequency of denture cream use, the timeframe between use and onset of symptoms, or even whether the use of denture cream preceded the neurological symptoms. Moreover, no mention is made as to whether the diagnosing physicians undertook complete differential diagnoses prior to settling on CDM. Most importantly, Dr. Lautenbach acknowledged that he possess no data reflecting the general incidence of myelopathy, myeloneuropathy, or neuropathy in the Scottish population.
Dr. Lautenbach's study has not been published, subjected to peer review or replicated. Without such validation, Dr. Lautenbach's proposed testimony is merely an opinion based upon a subjective belief.
Mechanism of Injury
Plaintiffs' experts have proposed two theories with respect to the mechanism of injury: 1) the mechanism whereby zinc becomes bioavailable from the Fixodent chemical polymer in the stomach; and 2) the mechanism whereby excess zinc blocks the absorption of copper in the body. Both theories are untested and are contradicted by other evidence. Indeed, Plaintiffs' experts have acknowledged that the previous theory holding that excess zinc blocked the absorption of copper through intestinal cell metallothionein induction has been called into doubt and that the scientific community is still investigating this hypothesis. This theory also does not explain how the zinc in Fixodent becomes available (or bioavailable) for absorption in the body. Moreover, as the court in Chapman noted, this theory does not address how long copper in the body must be blocked before the body becomes copper deficient and, in turn, how long the body must be copper deficient before producing neurological injury.
Following the Chapman court's decision, Dr. Askari designed and funded a study to prove the hypothesis that copper blockage by excess zinc in Fixodent causes copper deficiency myeloneuropathy. Both Drs. Askari and Smith rely upon this study to infer that Fixodent can causes copper deficiency myeloneuropathy. However, the results of this study disprove the hypothesis that Fixodent blocks the absorption of copper. The study failed to determine if the test subjects became copper deficient, suffered neurological injury, or developed negative copper balance as a result of exposure to zinc. The study failed to identify whether a particular dose of Fixodent would result in a specific type of neurological injury. Most importantly, the study failed to consider actual Fixodent usage patterns which the Chapman court considered to be a critical component in understanding Fixodent's effect on copper balance. The study was also methodically flawed as the company conducting the study and the company carrying out the research failed to adhere to study protocol, failed to consult a statistician during the design phase, failed to maintain a blind study, modified the manner in which the endpoint was measured after the study data was " unblinded, " and changed the level of statistical significance for the endpoint post hoc.
Dr. Askari's study was clearly conducted for the purpose of the present litigation coming as it did on the heels of the court's decision in Chapman. Carefully scrutinizing the deviations from standard methodologies, as well as the lack of statistical significance in the study hypothesis' primary measure, the Court should find little evidentiary value in this study's results. Indeed, Drs. Askari and Wang's hypothesis that zinc from Fixodent blocks copper absorption was not borne out by the study data. Moreover the data failed to show an increase in copper fecal elimination and Dr. Askari's reliance solely on the ratio of fecal Copper 65 to Copper 63 values between the Fixodent and placebo groups for merely three days was acknowledged by the study statistician as an incorrect means of analyzing the data.
It is important to note that Plaintiffs' experts admit that the mechanism by which copper deficiency results in neurological injury is unknown. When viewed in conjunction with the experts' statements that copper deficiency appears in a variety of ways , in only susceptible persons , and that it is impossible to predict when such deficiency will lead to neurological issues , this lack of a mechanism renders the reliability of the experts' causation theories suspect. Thus, the mechanistic evidence does not support the experts' opinions as to general causation.
Likewise, the mechanism which supports Plaintiffs' alternative theory whereby zinc dissociates from the Fixodent polymer, thereby becoming bioavailable, is unknown. As Dr. Smith acknowledges in his report, to become bioavailable, zinc must disassociate. Plaintiffs cite to Dr. Grainger's Report to support their theory on how zinc becomes bioavailable in the body. Unfortunately, Dr. Grainger's opinion that some amount of zinc dissociates from the polymer in Fixodent while in the stomach is based upon inferences drawn from in vitro dissociation. Several courts have held that experts who rely upon in vitro experiments must state how the test results translate to the operation within the human body. Without such an explanation, Dr. Grainger's opinion is of little evidentiary value. Moreover, Dr. Grainger's opinion is based on in vitro data regarding the dissociation of zinc in the stomach acidic environment as opposed to the small intestine where zinc absorption occurs. For this reason, data concerning the dissociation of zinc from stomach acid, real or simulated, is irrelevant to support theories of the mechanism of bioavailability. Indeed, Defendant's in vitro data shows very little zinc is dissociated from Fixodent in a simulated intestinal environment. It is also notable that, upon cross examination, Dr. Grainger testified that he: 1) has no opinion as to the amount of zinc that will ultimately become available in the body from ingested Fixodent; 2) failed to consider the body's homeostasis in forming his opinions ; and 3) failed to consider the conditions under which Fixodent may be ingested by the body. Dr. Askari likewise, testified that it is not known how zinc enters the bloodstream through the gastrointestinal tract. For these reasons, Plaintiffs have failed to support their mechanistic theories to support an inference of causation.
Dose-Response Relationship
Under Ohio law, Plaintiffs must show that Adams " was exposed to the toxic substance and that the level of exposure was sufficient to induce the complained-of-medical condition (commonly called a 'dose-response relationship')." " In order to obtain a reliable understanding of Fixodent's actual effect on copper balance, the product's actual usage patterns should be modeled in tests to determine if it is capable of delivering zinc in a way that will cause a negative copper balance and, within ethical limits, a copper deficiency." No such study has been performed which simulates the extreme usage reported by Plaintiff and the case reports.
Dr. Smith attempts to set forth a dose-response relationship by relying upon several P& G studies to formulate a " bioavailability multiplier." Dr. Smith concludes that nearly 75% of the zinc in Fixodent will be ingested regardless of how much is applied and for how long the patient wears it on their dentures. However, Dr. Smith's multiplier fails to account for variables such as: 1) the frequency of application of Fixodent; 2) the duration of wear before reapplication; 3) whether excess product is removed or swallowed by the user; 4) whether food consumption affects the bioavailability of the product; and 5) the fact that zinc preferentially remains on the denture device over the course of wear time. Dr. Smith also relied upon the raw data rather than the final reported data which resulted in an overstatement of the bioavailability of zinc. Dr. Smith does not address the data in P& G study indicating that a 6g dose of Fixodent delivered only slightly more bioavailable zinc than the 3g dose, which suggests that some other limiting factor was at work. Lastly, Dr. Smith erroneously applied his dose calculation to the Institutes of Medicine's (" IOM") Tolerable Upper Limit (" UL") for zinc, which is 40 mg/day. However, there is no evidence that this UL is the limit above which neurological injury will occur. The 40 mg/day figure is calculated from the " Lowest Observable Adverse Effect Level." The Lowest Observable Adverse Effect Level figure for zinc is 60 mg/day. To arrive at a recommended upper limit, the IOM applied a 1.5 safety margin to the Lowest Observable Adverse Effect Level of 60 mg/day and arrived at 40mg/day. Thus, 40 mg/day is, in actuality, a daily level which the IOM believes will not cause adverse consequences.
Additionally, the Lowest Observable Adverse Effect Level was the result of testing which showed changes in a certain enzyme level when exposed to 60 mg of zinc per day. Dr. Smith opined that decreases in this enzyme activity (erythrocyte CU, Zn-superoxide dismutase), was a sensitive biomarker of copper status. Dr. Smith holds this opinion despite the IOM's Dietary Reference Intake Report which states that the clinical significance of changes in this enzyme is not known. Moreover, Dr. Smith cannot pinpoint the length of time a reduction in copper must exist before a patient would develop myelopathy. Lastly, it is immaterial to the issue of causation whether an individual has been exposed to zinc levels in excess of those levels which a regulatory agency has determined places a person at risk. For these reasons, Dr. Smith's dose-response theory is therefore merely an " inference based upon inference, " something which is prohibited under Ohio law.
Specific Causation
Plaintiffs' expert evidence must also establish specific causation in addition to general causation to establish a prima facie case of toxic exposure. A valid differential diagnosis presumes that general causation has been established and is the only reliable method of establishing specific causation. Pursuant to Valentine , if Plaintiffs' experts cannot " rule-in" the alleged toxic substance, use of the differential diagnosis is not a reliable means of establishing specific causation. Because Plaintiffs' expert evidence fails to establish general causation, the Court need not reach the issue of specific causation. However, in an abundance of caution, Defendants proceed to argue the deficiencies in Plaintiffs' proof with respect to such.
Differential diagnosis is " appropriate only when considering potential causes that are scientifically known." Use of the differential diagnosis, pursuant to Ohio law, " requires that the expert be able to discern all potential causes of a particular injury before being able to isolate the single cause of a patient's symptoms." Indeed, " [w]here other causes are unknown, there is nothing to eliminate and thus, no increase in the likelihood of causation by the toxic agent."
Plaintiffs' experts have acknowledged that there exist unknown causes for copper deficiency, hyperzincemia, hypocupremia, neuropathies, and myelopathies, which cannot be eliminated. Therefore, under Ohio law, use of the differential diagnosis to conclude that Fixodent caused Plaintiffs' neurological condition is precluded.
Specifically, Dr. Greenberg admitted that he did not conduct the diagnostic testing to identify copper deficiency myeloneuropathy outlined in an article which he referenced in his report. Dr. Greenberg simply relied upon Adams' abnormal blood testing to opine that copper deficiency was the cause of Adams' neurological condition, despite her lack of history of hematologic abnormalities (such as anemia, leukopenia or neutropenia) which are commonly associated with copper deficiency. Dr. Greenberg erroneously eliminated possible hereditary causes based upon his assumption that Adams' condition improved after ceasing her use of Fixodent and supplementing with copper. However, Plaintiffs' medical records indicate that her neurological disorder continued to progress and her ability to function deteriorated despite ceasing her use of Fixodent and supplementing with copper. Most notably, Dr. Greenberg's exam performed two years after Adams stopped using Fixodent, showed the most abnormal neurological findings in her medical history.
Lastly, under Valentine , an expert must carefully define the nature and amount of the exposure to the toxic substance. However, because there is no reliable methodology which would permit the calculation of Adams' exposure to bioavailable zinc, specific causation cannot be established. Dr. Greenberg's calculation of Adams' estimated daily exposure reflected the amount of zinc in the Fixodent which Adams testified she applied to her dentures daily, not necessarily the amount which was bioavailable. Dr. Greenberg made no mention of Dr. Smith's " bioavailable multiplier" nor does he compare Adams' use to any purported threshold which would demonstrate that such exposure could cause neurological disease. Dr. Greenberg fails to consider how often Adams applied Fixodent, how well she cleaned her dentures before reapplication, whether she applied it at meal times, the amount of Fixodent she actually ingested or the amount of zinc absorbed through her gastrointestinal tract. Dr. Greenberg further fails to address Adams' specific testimony wherein she stated that she " often removed the excess from her mouth rather than swallowing it." Adams also testified that every time she removed her dentures, excess denture cream remained on the device, which she cleaned off before re-applying. In light of these deficiencies in Dr. Greenberg's assessment, his opinion cannot be considered reliable with respect to Adams' actual exposure to Fixodent as a specific cause of her neurological condition.
Under Ohio law, expert testimony is required which demonstrates that a plaintiff was exposed to levels of the alleged toxic substance which are sufficient to cause the alleged injury. Where the analytical gap between the data relied upon and the expert's opinion as to exposure is too great, Rule 702(C) dictates exclusion of the opinion. The expert evidence in this matter fails to consider Adams' actual usage of the product and as such, is merely speculative. Such speculation is, therefore, properly excluded.
IV. CONCLUSION
In order for Plaintiffs to succeed on their claims, they must establish that: 1) Fixodent is capable of causing Adams' condition (general causation); and 2) Fixodent in fact caused Adams' medical condition (specific causation).
As discussed above, Plaintiffs' experts have failed to provide a sound basis to support a conclusion that Fixodent could cause neurological injuries. Plaintiffs' experts' opinions are flawed in several respects, but specifically because they: 1) are based on unreliable case reports; 2) lack reliable epidemiological data indicating a causal relationship between use of Fixodent and neurological injuries; 3) lack a case definition; and 4) fail to establish the dose/response relationship. Given the flaws in the methodology and the scientific unreliability of the experts' opinions, the Court finds that the opinions of Drs. Askari, Grainger, Greenberg, Lautenbach and Smith should be, and are, excluded.
With respect to specific causation, Dr. Greenberg fails to consider Adams' actual usage of the product and as such, his opinion is merely speculative. Moreover, Dr. Greenberg's differential diagnosis is not reliable in light of his admission that there are unknown causes for Adams' neurological conditions and his failure to exclude other viable causes for Adams' condition. Based upon these methodological flaws, exclusion of Dr. Greenberg's opinion with respect to specific causation is appropriate.
IT IS SO ORDERED.