VICP Registry Case Source Bundle Canonical URL: https://vicp-registry.org/case/USCOURTS-cofc-1_10-vv-00251 Package ID: USCOURTS-cofc-1_10-vv-00251 Petitioner: Emily Tarsell, as the Executrix of the Estate of Christina Tarsell Filed: 2010-04-19 Decided: 2018-03-26 Vaccine: HPV Vaccination date: 2007-08-22 Condition: cardiac arrhythmia resulting in her death Outcome: compensated Award amount USD: 310130 AI-assisted case summary: Emily Tarsell, as executrix of the estate of her daughter Christina Tarsell, filed a petition on April 19, 2010, alleging that Christina's HPV Gardasil vaccine caused an autoimmune reaction in the nervous tissue of her heart, resulting in cardiac arrhythmia and her sudden death. Christina was born in 1986 and received three doses of the HPV quadrivalent vaccine: August 22, 2007 (dose 1), November 20, 2007 (dose 2), and June 3, 2008 (dose 3). She died on June 21, 2008, eighteen days after dose 3. The key temporal facts were as follows: approximately three weeks after dose 1, on September 12, 2007, Christina had a pre-participation physical at Bard College that recorded her pulse at 72 and showed her cardiovascular system to be normal, with no racing or skipping heartbeat. However, on the same day she received dose 2 (November 20, 2007), her internist Dr. Lafferman detected an irregular pulse. An EKG showed premature ventricular contractions. A subsequent echocardiogram on February 12, 2008, found normal heart structure. Following dose 3 on June 3, 2008, Christina experienced dizziness and faintness from June 7-12, 2008, and died on June 21, 2008. Medical examiner Dr. Kari Reiber determined that both the cause and manner of death were undetermined. Heart tissue sent to the CDC showed no conspicuous inflammatory cell infiltrates on microscopic examination. Petitioner's theory was that the HPV vaccine caused an autoimmune reaction targeting the beta adrenergic receptors and/or L1 calcium channels of the heart, triggering fatal arrhythmia. Petitioner's experts were Dr. Yehuda Shoenfeld, an immunologist, and Dr. Michael Eldar, a cardiologist. Respondent's experts were Dr. Scott Yeager, a cardiologist, and Dr. S. Michael Phillips, an immunologist. An entitlement hearing was held on November 13-14, 2014. Special Master Moran denied compensation on February 16, 2016, finding that Ms. Tarsell had not established by preponderant evidence that Christina's arrhythmia arose after the first HPV dose; that even if it had, the proposed mechanism contained too many leaps and unsupported assumptions; and that the CDC's finding of no inflammatory infiltrates in the heart tissue contradicted what the autoimmune theory would have predicted. The Court of Federal Claims, Judge Williams, vacated the decision and remanded on June 30, 2017 (133 Fed. Cl. 782), directing the special master to apply different legal standards in analyzing the challenge-rechallenge evidence. On remand, Special Master Moran issued a ruling on September 25, 2017, finding entitlement under the Court-directed standards. The normal cardiac findings on September 12, 2007 (three weeks after dose 1) followed by the arrhythmia detected on November 20, 2007 (three months after dose 1) constituted challenge-rechallenge evidence that was sufficiently probative to carry petitioner's burden of proof on the logical sequence prong, despite Dr. Phillips's contrary evidence. On February 26, 2018, respondent filed a proffer for damages to which petitioner agreed: $250,000.00 for vaccine-related death, $60,000.00 for past pain and suffering, and $130.00 for past unreimbursable expenses, for a total of $310,130.00. Respondent reserved the right to seek review of the September 25, 2017 entitlement ruling. Interim attorneys' fees of $173,107.70 had been awarded on May 13, 2015. Theory of causation field: HPV Gardasil (3 doses: Aug 22, 2007; Nov 20, 2007; June 3, 2008) → cardiac arrhythmia → sudden death June 21, 2008. Theory: HPV vaccine → autoimmune reaction targeting beta adrenergic receptors/L1 Ca channels → arrhythmia. Dr. Shoenfeld (immunologist) + Dr. Eldar (cardiologist). CDC autopsy: no inflammatory infiltrates. SM Moran Feb 16, 2016: DENIED (onset unclear; too speculative; no infiltrates). CFC Williams June 30, 2017 (133 Fed.Cl. 782): VACATED, REMANDED (different legal standards). SM Moran Sept 25, 2017: ENTITLEMENT on remand (challenge-rechallenge: normal heart 3 wks post-dose 1 → arrhythmia 3 months post-dose 1). Damages Feb 26, 2018: $310,130 ($250K death + $60K pain/suffering + $130 expenses). All DB dates correct. Public staged source text: ================================================================================ DOCUMENT 1: USCOURTS-cofc-1_10-vv-00251-0 Date issued/filed: 2015-06-11 Pages: 3 Docket text: PUBLIC DECISION (Originally filed: 05/13/2015) regarding 165 DECISION Interim Fees Stipulation. Signed by Special Master Christian J. Moran. (tpj) Copy to parties. -------------------------------------------------------------------------------- Case 1:10-vv-00251-MCW Document 169 Filed 06/11/15 Page 1 of 3 In the United States Court of Federal Claims OFFICE OF SPECIAL MASTERS * * * * * * * * * * * * * * * * * * * * * EMILY TARSELL, * No. 10-251V as the Executrix of the Estate of, * Special Master Christian J. Moran CHRISTINA TARSELL, * * Filed: May 13, 2015 Petitioner, * * v. * Attorneys’ fees and costs; interim * award; amount which is not disputed. SECRETARY OF HEALTH * AND HUMAN SERVICES, * * Respondent. * * * * * * * * * * * * * * * * * * * * * * Mark T. Sadaka., Mark T. Sadaka, LLC, Englewood, NJ, for petitioner; Ann D. Martin., United States Dep’t of Justice, Washington, D.C., for respondent. UNPUBLISHED DECISION ON INTERIM ATTORNEYS’ FEES AND COSTS1 Emily Tarsell claims that human papillomavirus quadrivalent (“HPV”) vaccines administered to her daughter, Christina, on August 22, 2007, November 20, 2007, and June 3, 2008, caused an autoimmune reaction in the nervous tissue of Christina’s heart that caused cardiac arrhythmia resulting in her death. Ms. Tarsell seeks compensation pursuant to the National Childhood Vaccine Injury Act, 42 U.S.C. §§ 300aa-10 through 34 (2012). Her case remains pending. Ms. Tarsell is now awarded, on interim basis, attorneys’ fees and costs in the total amount of $173,107.70. See Avera v. Sec’y of Health & Human Servs., 515 F.3d 1343, 1352 (Fed. Cir. 2008). 1 The E-Government Act of 2002, Pub. L. No. 107-347, 116 Stat. 2899, 2913 (Dec. 17, 2002), requires that the Court post this decision on its website. Pursuant to Vaccine Rule 18(b), the parties have 14 days to file a motion proposing redaction of medical information or other information described in 42 U.S.C. § 300aa-12(d)(4). Any redactions ordered by the special master will appear in the document posted on the website. Case 1:10-vv-00251-MCW Document 169 Filed 06/11/15 Page 2 of 3 On May 6, 2015, Ms. Tarsell filed a motion for interim attorneys’ fees and costs, seeking a total of $173,107.70. This request includes work performed by Ms. Tarsell’s attorney, Mark T. Sadaka, in the near five years from the filing of Ms. Tarsell’s petition through February 17, 2015. This time period includes the preparation for, and participation in, a two-day hearing held in November 2014, as well as Ms. Tarsell’s prehearing and posthearing briefs. On May 12, 2015, respondent filed a revised stipulation stating that respondent will not object to an award of $173,107.70, for Ms. Tarsell’s interim attorneys’ fees and costs.2 Regardless of whether they are entitled to compensation, petitioners who bring their petition in good faith and who have a reasonable basis for the petition may be awarded attorneys’ fees and costs. See 42 U.S.C. § 300aa–15(e)(1). Respondent does not contend that Ms. Tarsell fails to satisfy this standard. Thus, Ms. Tarsell is eligible for an award of attorneys’ fees and costs.3 After a determination that Ms. Tarsell is eligible for an award of attorneys’ fees and costs, the next question is to decide the reasonable amount. A review of the materials offered in support of the motion for interim attorneys’ fees and costs indicates that the requested amount is reasonable. Therefore, Ms. Tarsell is awarded the amount to which respondent did not object. This decision awards Ms. Tarsell all the attorneys’ fees and costs through February 17, 2015. There is no just reason to delay the entry of judgment on interim attorneys’ fees and costs. Therefore, in the absence of a motion for review filed under RCFC Appendix B, the clerk of court shall enter judgment in petitioner’s favor. Those fees and costs are awarded as follows: A lump sum of $173,107.70, in the form of a check made payable to petitioner, Emily Tarsell, and petitioner’s attorney, Mark T. Sadaka, for interim attorneys’ fees and other litigation costs available under 42 U.S.C. § 300aa-15(e). 2 Respondent originally filed the stipulation on May 6, 2015, this original stipulation incorrectly listed the amount requested in petitioner’s motion for interim fees, and was stricken. 3 The finding that the petition was supported by good faith and reasonable basis is not intended to suggest whether Ms. Tarsell is entitled to compensation. 2 Case 1:10-vv-00251-MCW Document 169 Filed 06/11/15 Page 3 of 3 The Clerk shall enter judgment accordingly.4 The court thanks the parties for their cooperative efforts in resolving this matter. IT IS SO ORDERED. s/ Christian J. Moran Christian J. Moran Special Master 4 Pursuant to Vaccine Rule 11(a), the parties can expedite entry of judgment by each party filing a notice renouncing the right to seek review by a United States Court of Federal Claims judge. 3 ================================================================================ DOCUMENT 2: USCOURTS-cofc-1_10-vv-00251-1 Date issued/filed: 2016-03-08 Pages: 30 Docket text: PUBLIC DECISION (Originally filed: 02/16/2016) regarding 174 DECISION of Special Master. Signed by Special Master Christian J. Moran. (SP) Copy to parties. -------------------------------------------------------------------------------- Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 1 of 30 In the United States Court of Federal Claims OFFICE OF SPECIAL MASTERS * * * * * * * * * * * * * * * * * * * * * EMILY TARSELL, as the Executrix * of the Estate of CHRISTINA * No. 10-251V TARSELL, * Special Master Christian J. Moran Petitioner, * * Filed: February 16, 2016 v. * * Entitlement; human papillomavirus SECRETARY OF HEALTH * (“HPV”) vaccine; sudden AND HUMAN SERVICES, * death * Respondent. * * * * * * * * * * * * * * * * * * * * * * Mark T. Sadaka, Mark T. Sadaka, LLC, Englewood, NJ, for petitioner; Ann D. Martin, United States Dep’t of Justice, Washington, D.C., for respondent. PUBLISHED DECISION DENYING COMPENSATION1 Emily Tarsell alleges that the human papillomavirus (“HPV”) vaccine caused her daughter, Christina, to die unexpectedly. Ms. Tarsell, acting as the executrix of Christina’s estate, is seeking compensation pursuant to the National Childhood Vaccine Injury Compensation Program, codified at 42 U.S.C. § 300aa−10 through 34 (2012). After Christina received the first dose of the HPV vaccine, she was diagnosed with a heart problem, known as arrhythmia. The arrhythmia is likely to have caused Christina’s death. 1 The E-Government, 44 U.S.C. § 3501 note (2012) (Federal Management and Promotion of Electronic Government Services). Pursuant to Vaccine Rule 18(b), the parties have 14 days to file a motion proposing redaction of medical information or other information described in 42 U.S.C. § 300aa-12(d)(4). Any redactions ordered by the special master will appear in the document posted on the website. Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 2 of 30 To connect the HPV vaccination and Christina’s arrhythmia, Ms. Tarsell relies upon the opinion of an immunologist, Yehuda Shoenfeld, and a cardiologist, Michael Eldar.2 Dr. Shoenfeld asserted that the arrhythmia developed after the first HPV vaccination. Dr. Shoenfeld and Dr. Eldar opined that the HPV vaccine caused the arrhythmia, which led to Christina’s death. The Secretary disagreed with Ms. Tarsell’s claim. The Secretary presented the opinions of cardiologist Scott Yeager and immunologist S. Michael Phillips.3 Dr. Yeager opined that the onset of Christina’s arrhythmia is unknown. Dr. Yeager and Dr. Phillips opined that evidence did not support the causal mechanism proposed by Ms. Tarsell’s two experts. Ms. Tarsell has not met her burden of establishing her case with preponderant evidence. Ms. Tarsell has not persuasively established a basic proposition of her claim, that Christina did not experience an arrhythmia until after the first dose of the HPV vaccine. Without this foundation, the rest of Ms. Tarsell’s claim cannot stand. In addition, even if Christina’s arrhythmia did arise after the vaccination, the proposed theory contains too many leaps and unsupported assumptions to be persuasive. Furthermore, a study of Christina’s heart tissue that pathologists at the Centers for Disease Control and Prevention (“the CDC”) conducted showed that Christina did not experience damage in the way her experts’ theories predicted. Consequently, despite the sympathetic position of Ms. Tarsell as the mother of a woman who died far too early, Ms. Tarsell is not entitled to compensation. I. Background The relevant facts include information from Christina’s life as well as the way that she died – suddenly and unexpectedly. 2 Dr. Shoenfeld, whose curriculum vitae spans over 120 pages, has nearly 40 years of researching autoimmune response, writing numerous articles on the subject. Exhibit 37. Dr. Shoenfeld has testified previously before the Vaccine Program. Dr. Eldar also has nearly 40 years of experience authoring over 170 articles. Exhibit 137. 3 Dr. Yeager has written more than 90 peer-reviewed reports, abstracts, book chapters, and presentations in cardiology over his 40-year career. Exhibit GG. Dr. Phillips’s 50 years of research experience has produced more than 130 original papers, editorials, reviews, chapters, and books. Exhibit B. 2 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 3 of 30 A. Christina’s Medical History In May 2008, Christina had just completed her third year of college, where she was studying art and playing tennis. Athletics had been part of Christina’s life for many years. She played tennis even though during one sports physical, a doctor detected an irregular pulse. After Christina’s end-of-the-semester college exams in 2008, and before starting a job at a museum, Christina visited her parents in Maryland. While visiting her parents, Christina received the third dose of the HPV vaccine on June 3, 2008. Exhibit 3 at 99. On June 5, 2008, 2 to 12 dots appeared on Christine’s neck near her right ear. Exhibit 15 ¶ 4. On June 7, 2008, Christina felt dizzy and faint. Findings of Fact, issued Mar. 30, 2012, at 7. Christina returned to her college apartment on June 12, 2008. In the following week, Christina worked at an art museum four days, including Thursday, June 19, 2008. Exhibit 22 at 277. Later that day, Christina ate dinner with her apartment mates. They talked until the early morning on Friday, June 20, 2008. Exhibit 6 at 152. On Monday, June 23, 2008, Christina did not report for work. One of her apartment mates investigated and found Christina in her bed, unresponsive. Exhibit 6 at 152. The undersigned found that Christina had died on Saturday, June 21, 2008 at approximately noon. Findings of Fact at 9. A medical examiner, Keri Reiber, performed an autopsy on June 24, 2008. Dr. Reiber found that the cause of Christina’s death was cardiac arrest of an undetermined cause. Exhibit 8 at 158. Knowing that Christina had received the HPV vaccine in the days prior to her death, Dr. Reiber reported the death to VAERS and sent tissue to the CDC for further examination. Id.; exhibit 10. The CDC’s Infectious Disease Pathology Branch performed a microscopic examination of Christina’s heart tissue. The results showed that the heart tissue exhibited no “conspicuous inflammatory cell infiltrates.” Exhibit 10 at 170. Christina’s mother holds the opinion that the cause of her beloved daughter’s death was the HPV vaccine. Ms. Tarsell talked about Christina’s life and her death with local media. Exhibit 23, 26. The emotion apparent in those videotapes is consistent with the demeanor Ms. Tarsell presented during her testimony. Tr. 19- 24. There is no doubt that Christina was a wonderful young adult, whom Bard College honored with an honorary degree the year after her premature death. Tr. 3 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 4 of 30 20. Ms. Tarsell is certainly entitled to sympathy for having endured the loss of her only child at a premature age. But, sympathy is not a basis for awarding compensation in the Vaccine Program. 42 U.S.C. § 300aa–13; Hodges v. Secʼy of Health & Human Servs., 9 F.3d 958, 961 (Fed. Cir. 1993) (noting that special masters are responsible for “the unenviable job of sorting through these painful cases”). Setting aside emotion, what is the basis for concluding that the HPV vaccine caused Christina’s death? Some reasons lie in Christina’s early medical history. Christina was born in 1986. Her early medical history contains typical illnesses. Exhibit 1 at 15-40. As mentioned earlier, Christina played sports. Tr. 21. Her participation in sports required her to have physical examinations at which her pulse was measured periodically. The list of measurements is presented in the following chart: Date Context Pulse Citation 8/14/01 Routine assessment. Age 14, 9 72 Exhibit 1 at 19 months. 7/18/02 Routine assessment. Age 15, 8 60 Exhibit 1 at 18 months. 11/29/02 Pulled muscle 70 Exhibit 1 at 17 2/28/05 Motor vehicle accident 76 Exhibit 1 at 8 6/16/05 Physical for college 104 Exhibit 2 at 78 6/23/06 Routine preventative medicine 84 Exhibit 1 at 5 visit 8/22/07 Annual gynecologist visit. First Not noted but Exhibit 3 at 109 dose of HPV vaccine given. cardiovascular is marked negative 9/12/07 Pre-participation Physical 72; heart, Exhibit 2 at 87-88 evaluation murmurs, and pulses marked normal 11/20/07 Dr. Lafferman. Second dose of Irregular Exhibit 4 at 136 HPV vaccine given. 4 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 5 of 30 Dr. Lafferman’s detection of an irregular pulse on November 20, 2007, was the first time a doctor discovered an irregularity in Christina’s cardiac rhythm.4 This discovery occurred approximately three months after Christina received the first dose of the HPV vaccine. Exhibit 3 at 109-10. This discussion about Christina’s irregular heartbeat requires a brief (and simplified) digression about regular heartbeats. The heart pumps blood by contracting. Tr. 42-43; Dorland’s Illus. Med. Dictionary, at 825-26 (32d ed. 2012). A normal rate of contraction is typically around 60 beats per minute, but the rate can range from 40 to 200. Tr. 44. The rate of contraction is controlled by the autonomic nervous system. Tr. 45; Dorland’s at 1859. The autonomic nervous system sends electrical current throughout the heart. Tr. 45-49. These electrical signals initiate a process known as polarization, depolarization, and repolarization. Tr. 52-58; Dorland’s at 495 (depolarization), 1484 (polarization), 1625 (repolarization). The polarization-depolarization- repolarization cycle involves the passage of different ions through channels, such as sodium channels. Another type of channel involved in the cycle is a calcium channel. Dorland’s at 337; Tr. 54. The polarization-depolarization-repolarization process is depicted in electrocardiograms. Dorland’s at 599; Tr. 62.5 When the heart functions normally, the heart follows an expected rhythm. When not normal, the person suffers from “arrhythmia.” Tr. 61; Dorland’s at 133. One type of arrhythmia is known as “bigeminy,” which means the second beat is abnormal. Tr. 495-96; Dorland’s at 214. Dr. Lafferman detected an irregular heartbeat on November 20, 2007. She described it as “bigeminy.” Exhibit 4 at 136. Dr. Lafferman ordered an electrocardiogram, which was also conducted on November 20, 2007. The EKG was abnormal. The report stated “[p]remature ventricular complexes.” Id. at 142. Dr. Lafferman also administered the second dose of the HPV vaccine on November 20, 2007. Exhibit 3 at 124. 4 Ms. Tarsell argues that this detection in November 2007 implies that the irregularity developed shortly before November 2007. However, as discussed in section IV below, the Secretary disagrees with this reasoning. 5 “Electrocardiogram” is abbreviated both ECG and EKG. Tr. 59; Dorland’s at 599. 5 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 6 of 30 Approximately one month later, on December 27, 2007, Christina had a follow-up appointment. Her heartbeat was again irregular. Exhibit 4 at 135. An EKG showed the same pattern as the November 20, 2007 EKG. Exhibit 4 at 141; Tr. 83 (Dr. Eldar), 504 (Dr. Yeager).6 Dr. Lafferman recommended an echocardiogram. Christina had an echocardiogram on February 12, 2008. The heart structure was found to be normal. Exhibit 4 at 139; see also Tr. 146 (Dr. Eldar), 510-11 (Dr. Yeager). In Dr. Yeager’s opinion, Christina did not have an irregular heart rhythm when the echocardiogram was performed. Tr. 511-12. Christina’s doctors did not recommend a Holter monitor or periodic follow-up. Consequently, Christina’s next medical appointment was on June 3, 2008, when, as noted above, she received the third dose of the HPV vaccine. Christina’s death on June 21, 2008, was both sudden and unexpected. After an autopsy, the medical examiner, Dr. Reiber, determined that both the cause of Christina’s death and the manner of her death were “undetermined.” Exhibit 8 at 158. In this litigation, Ms. Tarsell’s experts offer a cause for Christina’s death: the HPV vaccinations. However, before discussing the theory by which the vaccination could have led to Christina’s death, it is worthwhile to place Christina’s death in the context of other sudden unexplained deaths. B. Sudden Unexplained Deaths The unrebutted evidence is that in 2008, Christina was not the only American woman who received the HPV vaccine and then died suddenly and unexpectedly. Statistical information suggests that approximately 159 other young women also unexpectedly died after receiving the HPV vaccine. The source of this estimate was Dr. Phillips. Tr. 342-48; see also Tr. 518 (Dr. Yeager). Dr. Phillips was qualified to explain epidemiological studies. Tr. 335-38. Ultimately, Dr. Phillips’s opinion was that the HPV vaccination did not cause Christina’s death. Tr. 338-39. In the absence of a causal relationship, a 6 The report from the December 27, 2007 EKG stated Christina had “atrial fibrillation.” The finding that Christina’s premature contractions came from her atria was mistaken. The testifying cardiologists agreed that the contractions actually originated from Christina’s ventricles. Tr. 67-68 (Dr. Eldar), 502 (Dr. Yeager). 6 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 7 of 30 connection between the vaccination and Christina’s death is coincidental. See Capizzano v. Secʼy of Health & Human Servs., 440 F.3d 1317 (Fed. Cir. 2006); Grant v. Secʼy of Health & Human Servs., 956 F.2d 1144 (Fed. Cir. 1992). Several epidemiological studies did not find an increased rate of sudden and unexplained deaths after HPV vaccination. Two epidemiological studies that looked for numerous adverse effects of an HPV vaccine were exhibit 109 (Chun Chao et al., Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine, 271 J. Intern. Med. 193 (2012)) and exhibit 95 (Barbara A. Slade et al., Postlicensure Safety Surveillance for Quadrivalent Human Papillomavirus Recombinant Vaccine, 302 JAMA 750 (2009)). The Chao study evaluated medical records of over 189,000 women after receipt of each dose of the HPV vaccine for new onset of autoimmune conditions. The researchers compared their health to that of the control group of unvaccinated women. The study found no evidence linking the HPV vaccine to autoimmune conditions. Exhibit 109 at 1. The Slade group of researchers investigated HPV VAERS reports from June 1, 2006 to December 31, 2008. There were 32 reported deaths following vaccination with six being cardiac-related. The researchers performed a clinical review of medical records and autopsy reports determining that the deaths reported were attributable to causes other than the vaccine. Exhibit 95 at 6. Other studies focused on any evidence of an increased rate of death following HPV vaccine. In Dr. Phillips’s estimation, the strongest study was reported by the Australian government. Tr. 471. In Australia, nearly seven million doses of the HPV vaccine were distributed between 2007 and 2013. There were no reports of “deaths directly linked to the vaccine.” Exhibit PP (Austl. Gov’t Dep’t of Health Therapeutic Goods Admin., Gardasil (quadrivalent human papillomavirus vaccine), update 1 (Apr. 25, 2014), http://www.tga.gov.au/safety/alerts-medicine- gardasil-130516.htm.) at 2. Ms. Tarsell’s experts did not challenge the Australian report, leaving Dr. Phillips’s testimony unrebutted. One of Ms. Tarsell’s experts, Dr. Shoenfeld, dismissed the findings from Chao because of a potential conflict of interest. Tr. 213. Dr. Shoenfeld appeared to approve the work by Slade as Dr. Shoenfeld cited that study in connection with his opinion on the appropriate temporal relationship. Tr. 255-58. In addition to criticizing some (but not all) of the epidemiological studies upon which the Secretary relied, Dr. Shoenfeld also attempted to draw support 7 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 8 of 30 from a study authored by Eva Vanamee and colleagues. When the authors submitted the manuscript for publication, two peer reviewers rejected it. Tr. 250. In their work, Vanamee and colleagues re-analyzed data that the manufacturer of the HPV vaccine, Merck & Co., Inc., presented to the Food and Drug Administration. They found that in the first month after vaccination, four vaccinees died. See exhibit 38 (Eva Vanamee et al., An independent review of the Gardasil clinical trial data: Do the benefits outweigh the risks (unpublished manuscript) (on file with the clerk’s office)) at 4-6. From this piece of datum, Vanamee concluded that the HPV vaccine may be contributing to an increased risk of deaths. Dr. Phillips opined that the Vanamee study was not reliable. Tr. 352. Vanamee appeared to ignore additional details about the context of the deaths. For example, one death was attributed to a trauma that followed a car accident. See exhibit 81 (Memorandum from Nancy B. Miller, Medical Officer, Food and Drug Administration (June 8, 2006) (on file with the clerk’s office)) at 190. Dr. Shoenfeld’s opinion was that the vaccination was still the reason for the death either because the reporter of information manipulated the data or because the vaccination impaired the person’s ability to operate a car. Tr. 262-65. Dr. Shoenfeld’s opinion on this point is not credible as he had no foundation for his charges.7 Instead, Dr. Phillips’s opinion that the Vanamee study was not reliable is more persuasive.8 Without the Vanamee study, all the epidemiological evidence points in one direction. As Dr. Phillips explained, some epidemiological studies are designed well and others are not designed well. The particular strengths and weaknesses of any particular epidemiologic study are relatively unimportant because the findings 7 Dr. Shoenfeld appears to be developing a propensity for selective ad hominem attacks. When researchers such as Dr. Chao find no evidence that a vaccine is causing an increased incidence of disease, Dr. Shoenfeld attacks the integrity of the researcher. However, Dr. Shoenfeld readily accepts the reports of a vaccination preceding the onset of various diseases without considering the bias or prejudice of those reporters. 8 After the hearing, Ms. Tarsell did not cite the Vanamee study in her brief. The Secretary argued that Ms. Tarsell “has abandoned any reliance on it.” Resp’t’s Posth’g Br. at 17. In her reply brief, Ms. Tarsell did not respond to this contention and also did not cite the Vanamee paper. 8 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 9 of 30 that HPV vaccination has not caused an increase in the rate of death in the relevant population are consistent across many studies. Tr. 349-51. The Secretary “is permitted to offer evidence to demonstrate the inadequacy of the petitioner’s evidence on a requisite element of the petitioner’s case-in- chief.” Bazan v. Sec’y of Health & Human Servs., 539 F.3d 1347, 1353 (Fed. Cir. 2008). In a case from the beginning of the Vaccine Program, the Federal Circuit stated “epidemiological studies are probative medical evidence relevant to causation.” Grant, 956 F.2d at 1149 (Fed. Cir. 1992). On the other hand, a special master may not deny compensation simply because a petitioner has failed to introduce epidemiologic studies. Capizzano, 440 F.3d at 1325 (Fed. Cir. 2006). The Secretary’s epidemiologic evidence in this case is comparable to the approach the Secretary took in the Omnibus Autism Proceeding. There, the special masters considered a multitude of epidemiologic studies that investigated whether various vaccinations caused autism and found no causal relationship. The special masters found that the epidemiologic evidence was one reason --- but not the only reason --- for finding that the petitioners failed to carry their burden in those cases. See, e.g., Cedillo v. Secʼy of Health & Human Servs., No. 98-916V, 2009 WL 331968, at *84-93 (Fed. Cl. Spec. Mstr. Feb. 12, 2009), mot. for rev. denied, 89 Fed. Cl. 158 (2009), aff’d, 617 F.3d 1328 (Fed. Cir. 2010); Hazlehurst v. Secʼy of Health & Human Servs., No. 03-654V, 2009 WL 332306, at *34-39 (Fed. Cl. Spec. Mstr. Feb. 12, 2009), mot. for rev. denied, 88 Fed. Cl. 473 (2009), aff’d, 604 F.3d 1343 (2010). However, after resolution of the test cases in the Omnibus Autism Proceeding, the Federal Circuit issued Koehn v. Sec'y of Health & Human Servs., 773 F.3d 1239 (Fed. Cir. 2014). In the underlying case, a special master denied compensation, in part, because the epidemiologic evidence was against the petitioner’s claim. Koehn v. Sec'y of Health & Human Servs., No. 11-355V, 2013 WL 3214877, at *25-26 (Fed. Cl. Spec. Mstr. May 30, 2013), mot. for rev. denied, 113 Fed. Cl. 757 (2013), aff’d, 773 F.3d 1239 (Fed. Cir. 2013). At the Federal Circuit, two members of the panel stated that the special master erred in evaluating the evidence relating to the first prong of Althen. Although the Federal Circuit did not specify the actual errors the special master made, the broad language in Koehn at least raises a question about relying upon epidemiologic evidence. 773 F.3d at 1244 n.1. But, this interpretation of Koehn might itself be problematic because several other Federal Circuit cases have endorsed a special master’s reliance on epidemiologic studies. See Hunt v. Sec'y of Health & Human Servs., No. 12-232V, 2015 WL 1263356, at *17 n.18 (Fed. Cl. Spec. Mstr. Feb. 23, 2015), mot. for rev. denied, 123 Fed. Cl. 509 (2015); Holt v. Secʼy of Health & Human 9 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 10 of 30 Servs., No. 05-136V, 2015 WL 4381588 at *30 n.84 (Fed. Cl. Spec. Mstr. June 24, 2015), mot. for review filed (July 23, 2015). Regardless of any questions about how special masters may rely upon epidemiological studies, it is clear that some young women die suddenly, unexpectedly, and without any known cause. These deaths shock the affected family and broader community. The deaths of apparently healthy and thriving young people for no reason are “not the way life is supposed to be.” Tr. 518 (Dr. Yeager). Yet, they happen regardless of whether the women received any vaccination. Tr. 137 (Dr. Eldar). When researchers have looked to see whether these senseless deaths occur more frequently after the decedent received the HPV vaccination, they have not detected any increase. Thus, the epidemiological studies teach either that the HPV vaccine has not increased the rate of death or if the HPV vaccine is increasing the rate of death, then the increase happens so rarely that multiple studies have not found it. II. Overview of Ms. Tarsell’s Arguments and the Secretary’s Responses Ms. Tarsell claims that Christina’s case is not one of these tragic events that statistics would unemotionally predict. She claims Christina’s case is an example of the very rare case that statistics cannot detect. Ms. Tarsell presents opinions from two experts. Dr. Shoenfeld, but not Dr. Eldar, asserts that Christina’s arrhythmia began after the first dose of the HPV vaccine. From this assumption, Dr. Shoenfeld then opines that the HPV vaccine caused Christina to develop arrhythmia. Dr. Shoenfeld begins the explanation for how HPV vaccine can cause a sudden death. His primary theory is that the HPV vaccine causes the body to produce antibodies that are misdirected against a part of the heart, known as an L1 calcium channel. Dr. Eldar finishes Ms. Tarsell’s theory. The cumulative damage to the L1 calcium channel impairs the heart’s functioning leading to arrhythmia, and arrhythmia caused Christina’s death. The Secretary also presented the opinions of two experts. Dr. Phillips, as just discussed, presented information about epidemiology. He also responded to the immunologic aspects of Dr. Shoenfeld’s theory. Dr. Yeager is a cardiologist. Like Dr. Eldar, he did not know when Christina’s arrhythmia began. These experts presented their opinions in a series of reports. Exhibits 36, 94, 101, 108, 138 (all Dr. Shoenfeld); 100, 107, 140 (all Dr. Eldar); A, UU, XX (all 10 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 11 of 30 Dr. Phillips); FF, VV, ZZ, OOO (all Dr. Yeager).9 They and Ms. Tarsell testified at a hearing. Following the hearing, the parties submitted briefs, making the case ripe for adjudication. III. Standard for Adjudication A petitioner is required to establish her case by a preponderance of the evidence. 42 U.S.C. § 300aa–13(1)(a). The preponderance of the evidence standard requires a “trier of fact to believe that the existence of a fact is more probable than its nonexistence before [he] may find in favor of the party who has the burden to persuade the judge of the fact’s existence.” Moberly v. Sec’y of Health & Human Servs., 592 F.3d 1315, 1322 n.2 (Fed. Cir. 2010) (citations omitted). Proof of medical certainty is not required. Bunting v. Sec’y of Health & Human Servs., 931 F.2d 867, 873 (Fed. Cir. 1991). Distinguishing between “preponderant evidence” and “medical certainty” is important because a special master should not impose an evidentiary burden that is too high. Andreu v. Sec’y of Health & Human Servs., 569 F.3d 1367, 1379-80 (Fed. Cir. 2009) (reversing special master’s decision that petitioners were not entitled to compensation); see also Lampe v. Sec’y of Health & Human Servs., 219 F.3d 1357 (Fed. Cir. 2000); Hodges v. Sec’y of Health & Human Servs., 9 F.3d 958, 961 (Fed. Cir. 1993) (disagreeing with dissenting judge’s contention that the special master confused preponderance of the evidence with medical certainty). The elements of Ms. Tarsell’s case are set forth in the often cited passage from the Federal Circuit’s decision in Althen: “(1) a medical theory causally connecting the vaccination and the injury; (2) a logical sequence of cause and effect showing that the vaccination was the reason for the injury; and (3) a showing of a proximate temporal relationship between vaccination and injury.” Althen v. Sec’y of Health & Human Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005). IV. Analysis The three prongs of the Althen test are evaluated in separate sections below. The order of presentation begins with timing because a gap in Ms. Tarsell’s evidence is most readily apparent in the context of attempting to identify when 9 Relatively early in the case, Ms. Tarsell filed a report from Dr. Werner Spitz. Exhibit 32. However, his opinions do not advance Ms. Tarsell’s case. 11 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 12 of 30 Christina started to suffer arrhythmia. The next issue is the theory or theories that Ms. Tarsell and her experts presented. The last factor is the “logical sequence of cause and effect.” Each section analyzes the evidence (medical records, testimony and medical literature) in relation to the relevant precedent. A. Timing Ms. Tarsell’s first challenge is establishing when Christina’s arrhythmia began. When a petitioner cannot establish the onset of the injury the vaccine allegedly caused, the petitioner cannot fulfill the third Althen prong. See Hopkins v. Secʼy of Health & Human Servs., 84 Fed. Cl. 517, 524-27 (2008) (denying motion for review). Here, the most persuasive evidence indicates that the onset of Christina’s arrhythmia is unknown. The arrhythmia could have begun either before or after the vaccination. When Dr. Eldar, Ms. Tarsell’s cardiologist, was asked when Christina’s arrhythmia began, he stated “I cannot say exactly when it started.” Tr. 120. Similarly, when Dr. Yeager, the respondent’s cardiologist, was asked when Christina’s arrhythmia began, he stated “I don’t think I can date when she began having cardiac arrhythmia.” Tr. 493. Given their expertise in treating heart problems, Dr. Eldar and Dr. Yeager are credible when their answer essentially is “I don’t know when the arrhythmia began.” Ms. Tarsell has no effective response. A close reading of her post-hearing brief reveals that Ms. Tarsell has not proposed any specific date of onset. See Pet’r’s Posth’g Br., filed Feb. 17, 2015, at 15-18. Here, Ms. Tarsell states “Christina was a healthy young woman prior to her first [HPV] vaccine. She developed new-onset arrhythmia which did not resolve.” The order of these two sentences implies that the vaccination preceded the onset of her arrhythmia. In making this argument, Ms. Tarsell appears to be following the reasoning of her immunologist, Dr. Shoenfeld. When Dr. Shoenfeld was asked when Christina’s cardiac symptoms started, he answered “November 20, 2007,” which was the day her irregular pulse was first detected. Tr. 286. When asked to explain the basis for his opinion, Dr. Shoenfeld noted that before the vaccination, none of Christina’s treating doctors had found an irregular pulse. Dr. Shoenfeld reasoned “if you don’t have an evidence [of an irregular pulse], and then if you have an evidence that the first time was after the second vaccine, it was after the second vaccine.” Tr. 287. 12 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 13 of 30 Dr. Shoenfeld’s conclusion is based on superficial logic and is, ultimately, not persuasive. Dr. Shoenfeld is correct that Dr. Lafferman detected an irregular pulse in Christina for the first time on November 20, 2007. In other appointments, Christina’s pulse was measured but no irregularity was detected. For a detailed list of when those appointments occurred, see the table in section I, above. Dr. Shoenfeld assumes that if Christina were suffering from an irregular pulse on the days she was examined, the doctors would have detected it. Contrary to Dr. Shoenfeld’s assumption, people who suffer from arrhythmia do not suffer the arrhythmia continuously. Dr. Yeager explained that a person can have 20 minutes of bigeminy and then a few hours of normal rhythm. Tr. 540. In one study, patients with severe symptomatic arrhythmia wore Holter monitors and, in these patients, abnormal beats were found approximately 17 percent of the time. Exhibit 106 (Takashi Noda et al., Malignant Entity of Idiopathic Ventricular Fibrillation and Polymorphic Ventricular Tachycardia Initiated by Premature Extrasystoles Originating from the Right Ventricular Outflow Tract, 46(7) J. Amer. Coll. Cardiology 1288 (2005)); Tr. 496-97. When the Noda article was brought to Dr. Eldar’s attention, he did not dispute Dr. Yeager’s opinion. See Tr. 564-65. Because people with arrhythmia have periods in which their heart beats in normal rhythm, it is not possible to conclude that a doctor’s failure to detect an irregular pulse necessarily means that the patient was not suffering from arrhythmia at other times during the day of examination. Tr. 495-96; exhibit OOO (Dr. Yeager Supp’l Rep.) at 3 (“I have no confidence that an unremarkable physical exam tells us anything other than the patient was probably not having a significant arrhythmia during those few seconds of auscultation”). This means that there is no good evidence about when Christina first started to experience the arrhythmia. The lack of evidence is damaging to Ms. Tarsell’s claim for compensation. She bears the burden of establishing when Christina’s disease began. See Bazan, 539 F.3d at 1353-54 (Fed. Cir. 2008); Hopkins, 84 Fed. Cl. at 524-27. When there is no persuasive evidence on a particular point, the special master should rule against the party with the burden of proof. See Knudsen v. Secʼy of Health & Human Servs., 35 F.3d 543, 550 (Fed. Cir. 1994) (when the evidence is in equipoise, the party with the burden of proof has failed to carry the burden of persuasion); In re Claims for Vaccine Injuries Resulting in Autism Spectrum Disorder or a Similar Neurodevelopmental Disorder, Master Autism File, 2004 WL 1660351, at *8 (Fed. Cl. Spec. Mstr. July 16, 2004) (“in legal factfinding if there is no evidence, the factual issue simply is resolved against the party having 13 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 14 of 30 the ‘burden of proof’”). Here, the evidence is not in equipoise. Ms. Tarsell has no persuasive evidence of onset. While the failure to establish on a more-likely-than-not basis the onset of Christina’s arrhythmia is a sufficient basis to resolve Ms. Tarsell’s claim that the HPV vaccination caused the arrhythmia that led to Christina’s death, this is not the only problem with Ms. Tarsell’s case.10 Accordingly, the other Althen prongs will be analyzed. B. Theory If Ms. Tarsell had established that Christina’s arrhythmia began after her first HPV vaccination, then, as a matter of logic, the HPV vaccination could have possibly caused the arrhythmia. Cf. Locane v. Sec’y of Health & Human Servs., 685 F.3d 1375, 1381 (Fed. Cir. 2012) (stating that when a disease arises before the vaccination, the “Althen inquiry is inapplicable”). Part of Ms. Tarsell’s burden would be to establish, with preponderant evidence, a “causal theory connecting the vaccination to the injury.” Althen, 418 F.3d at 1278. To satisfy her burden under the first prong of Althen, to present a theory causally connecting the HPV vaccine to Christina’s death, Ms. Tarsell has advanced the theory of molecular mimicry involving the L1 calcium channels. In addition, she may also be advancing a theory involving beta adrenergic receptors. Because the beta adrenergic theory is more easily addressed, it is considered first. 1. Beta Adrenergic Receptors Procedurally, whether Ms. Tarsell is proceeding on the beta adrenergic theory is not entirely clear. Dr. Shoenfeld’s fourth report disclosed an opinion that a possible defect in Christina’s beta adrenergic receptors could have caused her arrhythmia. Exhibit 108 at 9; see also exhibit 36 at 6 (mentioning adrenergic 10 Conceptually, if the evidence persuasively showed that Christina was suffering from an irregular heartbeat before vaccination, Ms. Tarsell could argue that the vaccination significantly aggravated the pre-existing arrhythmia. Although Ms. Tarsell referenced this theory of recovery in her pre-hearing brief, Pet’r’s Preh’g Br. at 17 n.1, 19, Ms. Tarsell did not assert this theory in her posthearing brief or her posthearing reply. If Ms. Tarsell intended to pursue a significant aggravation theory, it was incumbent on her to present evidence that Christina's arrhythmia would not have progressed as it did. See Locane v. Sec’y of Health & Human Servs., 99 Fed. Cl. 715, 732-33 (2011), aff’d, 685 F.3d 1375 (Fed. Cir. 2012). 14 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 15 of 30 stimulation but not in the context of Christina’s history). However, Ms. Tarsell’s pre-trial brief did not reference this theory at all. See Pet’r’s Br., filed Sept. 26, 2014, at 13 (“Christina Tarsell died from molecular mimicry and subsequent cross- reactivity between HPV 16 L1 and L-type calcium channel”). Nevertheless, Dr. Eldar and Dr. Shoenfeld discussed beta adrenergic receptors in their testimony and Dr. Yeager responded. Ms. Tarsell included the beta adrenergic theory in her initial brief after the hearing. Pet’r’s Posth’g Br. at 12. After the Secretary raised challenges, see Resp’t’s Posth’g Br., filed Apr. 17, 2015, at 13-14, Ms. Tarsell’s reply did not defend the theory at all. Under these circumstances, Ms. Tarsell may have relinquished this theory. But, any potential waiver is academic because Ms. Tarsell has failed to establish the persuasiveness of the beta adrenergic theory. The beta adrenergic theory focuses on the wiring leading to and existing in the heart. As mentioned earlier, the autonomic nervous system controls the rate at which the heart beats. The autonomic nervous system includes a set of receptors known as beta adrenergic receptors. Dorland’s at 33, 1603-04. One group of researchers investigated whether people suffering from different types of arrhythmias had autoantibodies directed against their beta adrenergic receptors. These researchers found that slightly more than one-half the people with ventricular arrhythmias had anti-beta adrenergic receptor antibodies. The prevalence in the control group was approximately 15 percent. Exhibit 128 (Pablo A. Chiale et al., High Prevalence of Antibodies Against Beta - and Beta - 1 2 Adrenoceptors in Patients With Primary Electrical Cardiac Abnormalities, 26 J. Am. Coll. Cardiol. 864 (1995)) at 864. Dr. Eldar’s opinion was that the difference between the two groups “make[s] you think that there is . . . maybe a cause and effect between the one and the other.” Tr. 171. From this foundation, Dr. Shoenfeld extended the association to causation, opining that the autoantibodies can cause arrhythmias. Tr. 235; see also Tr. 189 (“pathogenic autoantibodies”). In addition, Dr. Shoenfeld also asserted that the HPV vaccine can induce the creation of antibodies to the beta adrenergic receptors. Tr. 270. For this proposition, Ms. Tarsell’s case rests nearly entirely on the simple assertion of Dr. Shoenfeld. When pressed to explain the basis for his belief that the HPV vaccine can lead to the production of antibodies directed against beta adrenergic receptors, Dr. Shoenfeld relied on a series of articles suggesting that the HPV vaccine caused a different disease, postural orthostatic tachycardia syndrome (POTS). Tr. 279. Dr. Yeager persuasively explained why relying upon a putative connection between 15 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 16 of 30 HPV vaccination and POTS cannot serve as a reliable foundation for HPV vaccination and arrhythmia. Tr. 523-27. Unlike the situation with respect to the L1 calcium channel discussed below, there is no reliable evidence that the HPV vaccine causes the body to produce antibodies to the beta adrenergic receptors in the heart. The only evidence was Dr. Shoenfeld’s opinion. Ms. Tarsell has failed to demonstrate that this aspect of his opinion is reliable. See Caves v. Sec’y of Health & Human Servs., 100 Fed. Cl. 119, 134 (2011) (“it should be obvious to petitioner that a scientific theory that lacks any empirical support will have limited persuasive force”), aff’d without opinion, 463 F. App’x 932 (Fed. Cir. 2012). Dr. Shoenfeld’s assertion, by itself, is not persuasive. Doyle v. Sec’y of Health & Human Servs., 92 Fed. Cl. 1, 8 (2010) (“Mere conclusory opinions - or ones that are nearly so as unaccompanied by elaboration of critical premises - will not suffice as proof of causation, no matter how vaunted or sincere the offeror”); see also Cedillo v. Sec’y of Health & Human Servs., 617 F.3d 1328, 1339 (Fed. Cir. 2010) (a special master may find an analytic gap in the opinion of a petitioner’s expert that precludes compensation). Because the beta adrenergic theory does not satisfy Ms. Tarsell’s burden on the first Althen prong, her other theory involving the L1 calcium channel will be discussed. The L1 calcium channel is a theory separate from the beta adrenergic theory. See Tr. 150-55 (Dr. Eldar discussing differences between the two theories), 292-93 (Dr. Shoenfeld). 2. Molecular Mimicry with the L1 Calcium Channel a) Introduction to Molecular Mimicry and Homology Ms. Tarsell’s primary theory is based upon molecular mimicry. Tr. 238. Molecular mimicry posits that the molecular structure of an antigen (like a vaccine) resembles the molecular structure of human tissue. When the body’s immune system responds to the antigen, the immune system mistakenly attacks the host. Tr. 193; see also Tr. 375, 418. The term for a similarity in molecular structure is “homology.” See Dorland’s at 868. Dr. Shoenfeld states that only genetically prone individuals will develop molecular mimicry. Tr. 305. Dr. Shoenfeld has identified a specific basis for the molecular mimicry between the HPV vaccine and the heart. He relies upon research of computer 16 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 17 of 30 databases that identified a particular sequence of amino acids present in both the HPV vaccination and calcium channels found in the heart.11 Tr. 278-79. The evidence showing a relevant homology derives from four articles in which Darja Kanduc is either the author or co-author. In the earliest article, Dr. Kanduc stated that her colleagues and she wanted to investigate the belief that “an autoimmune reaction is mostly caused by a host receiving an antigen that has amino acid homology/similarity with amino acid sequences in self-antigens of the host.” Exhibit LLL (Darja Kanduc et al., Massive peptide sharing between viral and human proteomes, 29 Peptides 1755 (2008)) at 1755. Dr. Kanduc used a consistent methodology in the four articles. The foundation for her experiments was that “[p]rotein sequences of the human proteome [12] as well as a number of viral proteomes have become available in databanks.” Id. The proteins may contain thousands of amino acids and the relevant calcium channel contains more than 2500 amino acids. Tr. 387, 392 (discussing exhibit FFF (Charles Antzelevitch et al., Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST- Segment Elevation, Short QT Intervals, and Sudden Cardiac Death, 115 Circulation 442 (2007))). With computers, Dr. Kanduc searched for sequences of amino acids that appear both in the human proteome and in invasive organisms, such as bacteria and viruses. See Tr. 301 (Dr. Shoenfeld), 375 (Dr. Phillips), see also exhibit LLL at 1756-57 (detailed description of methodology). The length of the sequence varied from five amino acids to nine amino acids.13 Dr. Kanduc and colleagues tried to identify homologies because “the mathematical quantification of peptide overlap extent between viruses and humans is essential to understand the role of structural viral similarity in the pathogenesis of autoimmunity.” Exhibit LLL at 1756. In the earliest experiment reported, the computerized screening found “a massive, indiscriminate, unexpected pentapeptide overlapping between viral and human proteomes.” Id. at 1755. Part of the reason 11 There are 20 amino acids and each amino acid has been assigned a letter. For example, “L” stands for leucine. Dorland’s at 60-61, Tr. 377, 389. 12 A proteome is “the complete set of proteins produced from the information encoded in a genome.” Dorland’s at 1535. 13 A sequence of five amino acids is known as a pentamer. See Dorland’s at 1407; Tr. 375. 17 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 18 of 30 for the overlap is that sequence of amino acids repeat. Mathematically, a sequence of five amino acids contains more than three million combinations. (520 = 3,200,000.) However, less than 10 percent of the pentamers actually appear in either the viral or human proteome. Id. at 1756. The researchers concluded “the mathematical redundancy present in the protein world is not stochastic (i.e. is not pure random chance), but rather reflects strong peptide usage bias since certain peptides are repeatedly used (and shared) in (and among) viral and human proteins.” Id. at 1762. A premise of molecular mimicry is that when invading organisms have a structure similar to the molecular structure of human beings, the body’s response to the bacteria or virus can produce an autoimmune reaction. Because Kanduc’s 2008 research found “massive” overlap between viruses and humans, “autoimmune diseases should theoretically approach a 100% real incidence.” Id. at 1765. However, autoimmune diseases are not that common. Thus, Dr. Kanduc and colleagues stated that their datum “call into question the possibility of a direct causal association between virus-host sharing of amino acid motifs and incitement of autoimmune reactions.” Id. at 1755. In 2009, Dr. Kanduc, writing alone, reported on an experiment using the HPV 16 proteome. She discovered a perfect sequence of seven amino acids 82 times in the human proteome. Exhibit 75 (Darja Kanduc, Quantifying the possible cross-reactivity of an HPV16 vaccine, 8 J. Experimental Therapeutics and Oncology 65 (2009)) at 66. The abstract to the article concluded that “[a]ny antigen-based vaccine needs to be carefully and thoroughly designed and critically screened for potential side effects by comparing sequence similarity at the molecular level.” Id. at 65. Dr. Kanduc, again writing alone, reported about a more specific experiment in 2010. She looked for similarities between a particular portion of the HPV 16 virus known as the L1 capsid and “human proteins that, when altered, are associated with cardiovascular diseases and arrthythmogenic disorders.” Exhibit 74 (Darja Kanduc, Potential cross-reactivity between HPV16 L1 protein and sudden death-associated antigens, 9(2) J. Experimental Therapeutics and Oncology, 159 (2010)) at 1. One of these sequences of five amino acids, LQAGL, occurs in the L-type calcium channel. Defects in the L-type calcium channel cause Timothy syndrome and Brugada syndrome. Id. at 5. Dr. Kanduc stated that her finding “suggests that possible immune cross-reactions deriving from utilization of HPV L1 in vaccination might be a source of cardiac implications.” Id. at 6. 18 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 19 of 30 The final article to which Dr. Kanduc contributed was also published in 2010. A group of researchers, including Dr. Kanduc, compared 40 bacteria with the human genome, looking for matches of nine amino acids. They found more than 47,000 perfect matches, comprising about one-third of the human proteome. Exhibit KKK (Brett Trost et al., Bacterial peptides are intensively present throughout the human proteome, 1 Self/Nonself 71 (2010)) at 71; see also Tr. 376- 79 (Dr. Phillips’s description of Trost experiment). The authors stated that their findings called into question the molecular mimicry theory. They wrote: According to the molecular mimicry hypothesis, the widespread overlap between viral and bacterial proteomes and the human proteome (see Table 1 and ref 5) would predict that autoimmune diseases should have a much higher incidence than actually observed, both in the total number of individuals affected and the number of autoimmune pathologies per individual. Thus, it is difficult to reconcile the enormous number of viral and bacterial peptides disseminated throughout the human proteins with a fundamental role for molecular mimicry in the etiology of certain autoimmune conditions. Id. at 73. To some, Dr. Shoenfeld’s invocation of molecular mimicry plus an identified homology would constitute a persuasive medical theory.14 However, the evidence persuasively showed that the LQAGL homology Kanduc discovered in 2009 is not an adequate basis for finding that a cross-reaction actually occurs. Dr. Phillips explained that it is not entirely unexpected for a particular sequence of amino acids to reappear. Tr. 378-79. Dr. Shoenfeld concurred, stating that there is “a lot of molecular mimicry.” Tr. 227. To Dr. Phillips, “showing a homology at a pentameric level — that is, five amino acids — is many steps from showing that that [homology] is causally related to an autoimmune disease.” Tr. 375. 14 Dr. Shoenfeld refrained from describing his theory as “more likely than not.” In his view, the theory was “plausible,” meaning that it is a “mechanism which is understood [that] can occur.” Tr. 268. 19 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 20 of 30 b) From Homology to Autoimmune Reaction Ms. Tarsell did not rest her case simply upon Dr. Kanduc’s identification of the LQAGL pentamer in both the HPV16 L1 capsid and the calcium channel. Ms. Tarsell developed a specific application of molecular mimicry by presenting testimony from Dr. Shoenfeld and Dr. Eldar that explains how a homology can lead to a fatal arrhythmia. It appears that the theory contains several discrete assertions. These include the following: 1. The HPV vaccine contains a sequence of amino acids, known as LQAGL. The Secretary agrees with this assertion. 2. The body responds to the HPV vaccine by producing antibodies against the LQAGL sequence. 3. The anti-LQAGL antibodies are produced in large quantities that remain present at meaningful concentrations in the serum. 4. The heart, specifically the L1 calcium channel, contains the LQAGL sequence. The Secretary agrees with this assertion with a caveat, discussed at length below. 5. The antibodies produced in response to the LQAGL sequence in the HPV vaccine cross-react with the LQAGL sequence in the L1 calcium channel of the heart. 6. The damage to the L1 calcium channel in the heart causes arrhythmia. As noted, the Secretary agrees with two of the six propositions: that the LQAGL sequence appears in the HPV vaccine and this pentamer appears in the L1 calcium channel. This basic homology, as explained above, does not mean that there is a cross-reaction. For the remaining four assertions, the Secretary has challenged the reliability of the theory. See id. at 11-16. Dr. Phillips stated that Dr. Shoenfeld is not “incorrect,” but that he has presented a theory with no evidence. Tr. 380. c) Response to LQAGL After an administration of the HPV vaccine, which contains the HPV 16 L1 capsid, the petitioner’s theory indicates that the body will respond to the particular sequence of amino acids LQAGL. Dr. Phillips explained why the presence of amino acids L-Q-A-G-L in the HPV vaccine does not necessarily mean that the body actually reacts to that pentamer. He began by explaining that a “protein is a very complex structure. . . [with] primary, secondary, and tertiary structure.” Tr. 386. The primary structure refers to a linear sequence, the secondary structure 20 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 21 of 30 refers to shapes that the protein can form, and the tertiary structure refers to a three-dimensional configuration. Id. at 386-87. The immune system responds to the antigen in a three-dimensional form. Id. at 387. Thus, the body must break down the HPV vaccine in exactly the correct way to release the LQAGL peptide. See Tr. 386. Quoting Dr. Phillips’s testimony, the Secretary argued that “‘there’s no guarantee that this short pentamer is going to contribute to that structure.’” Resp’t’s Posth’g Br. at 10, quoting Tr. 387-88. In reply, Ms. Tarsell did not cite any evidence to refute Dr. Phillips’s opinion about how the immune system responds to proteins. See Pet’r’s Reply Br., filed May 15, 2015, at 5-6 (stating that Dr. Shoenfeld stated that the LQAGL peptide is contained in the HPV vaccine, but not addressing whether the body would respond to that sequence). d) Concentration Assuming that the body produces an immune response to the LQAGL pentamer, the body must produce a sufficient quantity of antibodies that the antibodies can cause damage. Although some Vaccine Program cases have considered issues about dose response curves, see, e.g., Kolakowski v. Secʼy of Health & Human Servs., No. 99-625V, 2010 WL 5672753 at *17-21 (Fed. Cl. Spec. Mstr. Nov. 23, 2010), Snyder v. Secʼy of Health & Human Servs., No. 01- 162V, 2009 WL 332044 at *65 (Fed. Cl. Spec. Mstr. Feb. 12, 2004), mot. for rev. denied, 88 Fed. Cl. 706 (2009), the parties did not elicit any testimony about this aspect of petitioner’s theory. Because the Secretary did not raise any direct challenge to the amount of antibodies, Ms. Tarsell’s lack of evidence is not held against her. e) Location of the Calcium Channel in Heart In Dr. Kanduc’s 2009 article, she identified the LQAGL pentamer as part of the “[v]oltage-dependent L-type calcium channel subunit alpha-1C.” Exhibit 74 at 5. Dr. Kanduc did not provide any additional information about where the protein appears in the heart cells. The LQAGL pentamer is located on an intra-cellular portion of the calcium channel. See exhibit FFF at 446 (figure D); exhibit 120 (Victor A. McKusick, Calcium Channel, Voltage-Dependent, L-Type, Alpha-1C Subunit; CACNA1C, Online Mendelian Inheritance in Man, OMIM. Johns Hopkins Univ., Baltimore, MD. 114205 (March 19, 2014) http://www.omim.org/); see also Tr. 392-96. Ms. 21 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 22 of 30 Tarsell did not dispute this evidence.15 See exhibit 138 (Dr. Shoenfeld’s post- hearing report) at 1. The Secretary argues that the location of the LQAGL pentamer makes Ms. Tarsell’s theory less likely. Usually, antibodies react with material located outside of the cell membrane. See Tr. 397. The extra-cellular location allows antibodies, which circulate through the blood stream, to bind to the cognate antigen. In contrast, the relevant pentamer is located on an intra-cellular portion of the channel – behind the cell membrane. The cell membrane generally prevents antibodies from reaching the calcium channel to cross-react with the LQAGL pentamer. Tr. 7; Resp’t’s Posth’g Br. at 11-12. To ameliorate the prejudice associated with the late disclosure of exhibit NNN and the late raising of an argument based on the intracellular location of LQAGL, Ms. Tarsell was allowed to file supplemental reports from Dr. Shoenfeld and Dr. Eldar that addressed whether antibodies can penetrate the cell membrane. Tr. 9, 400-01, 571; order, issued Nov. 21, 2014. Ms. Tarsell filed those reports as exhibits 138 and 140. f) Penetrating Cell Membrane After the Secretary asserted that any antibodies produced in response to the HPV vaccine could not react with the LQAGL pentamer in the calcium channels of the heart, the parties elicited testimony from the experts about this issue. In addition, Ms. Tarsell was permitted to submit supplemental reports. Usually, antibodies bind to the outside of a cell, where the antibodies start their attack against an invading organism. See Tr. 397 (Dr. Phillips: “the vast majority of antibodies bind to conformational determinants on the surface of cells”). But, as discussed above, this typical process is not relevant to petitioner’s 15 At the hearing, the Secretary presented one more article locating the pentamer as behind the cell wall. See Tr. 5, exhibit NNN (The Universal Protein Resource (“UniProt”), UniProtKB - Q13936 (CAC1C_HUMAN) Voltage-dependent L-type calcium channel subunit alpha-1C, http://www.uniprot.org/uniprot/Q13936 (last visited Nov. 13, 2014)). Ms. Tarsell, appropriately, objected to the late disclosure of this evidence. Tr. 7-9, 400-01. Substantively, it is not clear that the UniProt article added anything more to the information contained in exhibit 120 and exhibit FFF, which were in the record before the hearing. Nonetheless, the Secretary is expected to be more diligent about disclosing evidence before the hearing. 22 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 23 of 30 experts’ opinions here because the calcium channel is inside the cell, protected by the cell’s membrane. Tr. 398. When Dr. Shoenfeld was asked whether antibodies can penetrate a cell’s membrane, he asserted that they could. He spontaneously referenced a conference devoted to this topic and offered to produce papers on the topic. Tr. 273-75. Then, after the hearing, he identified specific articles discussing the process of endocytosis. Exhibit 138 (Dr. Shoenfeld’s Nov. 25, 2014 report). In the hearing, Dr. Phillips stated that certain antibodies can penetrate the cell membrane and when there is penetration, the antibodies may damage the cell. Tr. 398; see also Tr. 461. Although Dr. Phillips did not raise this point in this context, Christina’s autopsy did not show any damage to the cells in her heart. Exhibit 10 at 170; Tr. 481-82. When the Secretary responded to the post-hearing supplemental reports from Dr. Shoenfeld and Dr. Eldar, the Secretary presented a report from Dr. Yeager. Dr. Yeager recognized that Dr. Shoenfeld relied upon endocytosis, but argued that Dr. Shoenfeld did “not offer any animal or human model of cardiac disease mediated through this mechanism.” Exhibit OOO at 2. It seems telling that the Secretary’s response about endocytosis came from a cardiologist, not an immunologist (Dr. Phillips). The evidence, therefore, demonstrates that antibodies can penetrate a cell’s membrane. The Secretary’s complaint that Ms. Tarsell’s evidence on this point is not robust is misdirected because she raised arguments about the intracellular location of the pentamer at the hearing. Compare Resp’t’s Preh’g Br., filed Oct. 20, 2014, with Tr. 400 (statement from respondent’s counsel that Dr. Phillips’s report did not disclose an opinion about intracellular antibodies). A more timely presentation by the Secretary would have allowed both parties to develop evidence on this point more thoroughly. Dr. Phillips stated: “I’m not making a statement that [molecular mimicry] . . . is totally disproven by the fact that [the calcium channel is] intracellular, but I did want to make the point that since it is intracellular, it makes it more difficult for these antibodies . . . to penetrate.” Tr. 401-02. The undersigned finds his analysis on this point persuasive. g) Type of Disease Assuming that antibodies produced in response to the LQAGL pentamer of the HPV vaccine reach the calcium channel, the final step is to consider how the 23 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 24 of 30 antibodies would affect the functionality of that channel. Because the calcium channel is a tube (Tr. 236), the two obvious possibilities are that damage to the tube either lets too much or too little calcium pass or lets too little calcium pass. Tr. 99 (Dr. Eldar), 532 (Dr. Yeager). The 2009 Kanduc paper on which Ms. Tarsell relies to establish homology provides some guidance as to what happens when the relevant calcium channel is damaged. Dr. Kanduc associated defects in the gene for the LQAGL pentamer with causing two diseases: Timothy’s syndrome and Brugada syndrome. Exhibit 74 (Kanduc) at 5; see also Tr. 389. Brugada’s syndrome is very distinctive and Christina’s electrocardiogram was not consistent with Brugada’s syndrome. Tr. 97-98, 529-30; see also Dorland’s at 1823. There was also no testimony that Christina suffered from Timothy’s syndrome. See Tr. 299-300; see also Tr. 558- 59. After Dr. Shoenfeld disclosed his reliance on the 2009 Kanduc article, Dr. Yeager discussed the implication of relying upon a genetic defect associated with Brugada’s syndrome. If we are speculating that a hypothetical antibody is stimulating the phenotypic expression of Brugada- associated sudden death, how are we to explain the lack of the electrocardiographic manifestations of the underlying calcium channel disorder? The only electrocardiographic abnormality identified in Christina was her ventricular ectopy, and Brugada Syndrome is not typically associated with increased baseline ventricular ectopy. Exhibit AAA at 2. Thus, before the experts testified orally, there was a problem in Ms. Tarsell’s evidence. Her experts were proposing a theory that appeared to lead to either Brugada’s syndrome or Timothy’s syndrome. Yet, Christina did not suffer from either of those problems. See Hibbard v. Sec’y of Health & Human Servs., 698 F.3d 1355, 1364 (Fed. Cir. 2012) (finding that special master was not arbitrary in denying compensation when petitioner’s theory involved the vaccine causing dysfunction in the autonomic nervous system and the petitioner did not display any problems in her autonomic nervous system); Ricci v. Sec’y of Health & Human Servs., 101 Fed. Cl. 385 (2011) (finding that special master was not arbitrary in denying compensation when petitioner’s theory proposed that a vaccine caused 24 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 25 of 30 inflammation in the central nervous system and the vaccinee did not show signs of such an injury). However, Dr. Eldar testified about how problems in the calcium channel would present. He stated that the flow of calcium has been linked to ventricular tachycardia through catecholamines. Tr. 103-04, 568-69; see also Pet’r’s Posth’g Br. at 11. He developed this opinion in his report filed after the hearing. Exhibit 140. Like the Secretary’s introduction of exhibit NNN during the hearing, the initial presentation of an opinion involving catecholamines during the hearing caught the opposing party off guard. See Tr. 570. Although the parties did not flesh out this issue fully, there appears to be a reliable basis for finding that if the calcium channel were damaged, the consequence could be a form of ventricular tachycardia. Thus, on this limited point, Ms. Tarsell's case was persuasive. h) Summary: Theory The Federal Circuit has stated that petitioner’s burden of proof is “more likely than not,” not mere plausibility. Moberly, 592 F.3d 1315, 1322 (Fed. Cir. 2010). Decisions from the Court of Federal Claims have followed Moberly. M.S.B. by Bast v. Sec’y of Health & Human Servs., 117 Fed. Cl. 104, 123 (2014), appeal dismissed, 579 F. App’x 1001 (Fed. Cir. 2014); Taylor v. Sec’y of Health & Human Servs., 108 Fed. Cl. 807, 819 (2013).16 Here, Dr. Shoenfeld described his theory as “plausible,” meaning that it can occur. Tr. 268. It is true that the Secretary has not presented evidence to show that the molecular mimicry theory is impossible. Yet, the Secretary has raised sufficient challenges to the theory that Ms. Tarsell has not met her burden of proof. These challenges include: 16 Ms. Tarsell argues that her burden is only to present a “‘viable’ medical theory.” Pet’r’s Reply Br., at 5, quoting Contreras v. Sec’y of Health & Human Servs., 121 Fed. Cl. 230, 246 (2015), appeal docketed, No. 2015-5097 (Fed. Cir. June 22, 2015). At the Federal Circuit, the Secretary has argued that the formulation of a petitioner’s burden on prong 1 set forth in Contreras is not consistent with Moberly. Brief for Respondent-Appellee at 36, Contreras v. Sec’y of Health & Human Servs., No. 2015-5097 (Fed. Cir. Oct. 2, 2015), 2015 WL 5971936, at *36. 25 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 26 of 30 • The likelihood that LQAGL homology could be an inconsequential coincidence in light of the relative commonness of pentamer level homology between invasive organisms and the human proteome, • The likelihood that a human’s immune system would recognize and respond to the five particular amino acids LQAGL when the HPV 16 contains thousands of amino acids, • The likelihood that any antibodies produced in response to the LQAGL pentamer would cross the cell membrane, • The likelihood that antibodies to LQAGL would inflict autoimmune damage to the calcium channel that would appear as bigeminy, not Brugada syndrome or Timothy’s syndrome as genetic studies would predict. In finding that Ms. Tarsell has not presented reliable evidence to make her theory persuasive, the undersigned does not intend to suggest that either Dr. Shoenfeld or Dr. Eldar were insincere. To the contrary, all the experts generally appeared to express their honestly held opinions about the theoretical basis for the HPV vaccine to cause a fatal arrhythmia and generally expressed those opinions respectfully. Ms. Tarsell’s case falls short of the preponderance of evidence standard due to a lack of support. See Caves, 100 Fed. Cl. at 134. The experts, themselves, recognized that much of the theory remains untested and unexamined. For example, Dr. Shoenfeld stated that the Kanduc article “didn’t finish the whole work.” Tr. 269. Dr. Shoenfeld asserted that he could continue Kanduc’s work by isolating the calcium channels to see if they react with antibodies. See Tr. 271; see also Tr. 300-02. With respect to his opinion that a defect in the calcium channel would manifest differently from Brugada’s syndrome or Timothy’s syndrome, Dr. Shoenfeld said “We will not know it. We will have to test it.” Tr. 300. Dr. Phillips testified that “showing a homology at a pentameric level . . . is many steps away from showing that that [similarity] is causally related to an autoimmune disease.” Tr. 375. He also stated: “I'm not saying that -- that the theory is incorrect, but I'm saying it's an inadequate explanation, and there's no evidence that it was an explanation in this case.” Tr. 380. This assessment is accurate. In stating that (a) the theory is unpersuasive and (b) additional testing could make the theory more persuasive, the undersigned could be viewed as requiring scientific certainty. The undersigned is aware that Ms. Tarsell does not have to 26 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 27 of 30 prove her case to that degree. Andreu v. Sec’y of Health & Human Servs., 569 F.3d 1367, 1380 (Fed. Cir. 2009), Bunting, 931 F.2d at 873. The undersigned recognizes the difference in proof between the preponderance of evidence standard and a beyond a reasonable doubt standard. See Hodges, 9 F.3d at 962 (the “fact that the opinion of petitioner’s doctors was rejected does not mean that the Special Master was demanding scientific certainty; he might simply have been demanding some degree of acceptable scientific support”). Here, Ms. Tarsell’s evidence does not meet even the simpler more-likely-than-not standard. V. Logical Sequence If Ms. Tarsell had established that the HPV vaccine can, as a theoretical matter, cause arrhythmia and if she had established that Christina’s arrhythmia arose in a time interval for which an inference of causation is appropriate, then Ms. Tarsell would also be required to present preponderant evidence that “a logical sequence of cause and effect” linked the HPV vaccine to Christina’s death. In the absence of this predicate showing, an Althen prong 2 analysis is not needed. See Caves, 100 Fed. Cl. at 134. Nevertheless, a brief overview of the evidence particularly relevant to prong 2 is conducted to demonstrate that all the evidence has been reviewed. A. Prong 2 standards The Federal Circuit has identified several factors that may be probative with respect to the petitioner’s burden on the second prong of Althen. These include, among other things, the opinions of treating physicians, expert testimony, challenge-rechallenge, and pathological markers. See Capizzano, 440 F.3d at 1322. B. Factors 1. Treating Doctors The doctor who performed Christina’s autopsy, Kari Reiber, was aware that Christina received a third dose of the HPV vaccine a few days before she died.17 17 Dr. Reiber’s date of vaccination (June 8, 2008) is not the correct date, which was June 3, 2008. Exhibit 3 at 99. 27 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 28 of 30 Dr. Reiber submitted information about Christina’s death to the Vaccine Adverse Event Reporting Service (VAERS). The submission of a VAERS report is not necessarily evidence that the doctor considers the vaccination to have caused the injury being reported. La Londe v. Sec’y of Health & Human Servs., 110 Fed. Cl. 184, 206 n. 37 (2013), aff’d, 746 F.3d 1334 (Fed. Cir. 2014), Vig v. Secʼy of Health & Human Servs., No. 01-198V, 2013 WL 6596683, at *17 (Fed. Cl. Spec. Mstr. Nov. 14, 2013). In addition, Ms. Tarsell did not present any argument based upon either the VAERS report or Dr. Reiber’s notation that the HPV preceded Christina’s death. See Pet’r’s Posth’g Br.; Pet’r’s Posth’g Reply Br. Under these circumstances, the opinions of treating doctors do not favor a finding of causation. 2. Challenge-Rechallenge “A rechallenge event occurs when a patient who had an adverse reaction to a vaccine suffers worsened symptoms after an additional injection of the vaccine.” Capizzano, 440 F.3d at 1322. The basic chronology may appear to support a challenge-rechallenge argument. According to Ms. Tarsell’s perspective, the following events happened: (1) Christina did not suffer from arrhythmia until she received the first HPV vaccination, (2) the first HPV vaccination caused Christina to suffer arrhythmia, which was detected on the date of the second HPV vaccination, (3) the second HPV vaccination worsened Christina’s arrhythmia, and (4) the third HPV vaccination, on June 3, 2008, made Christina’s arrhythmia so much worse that she died from it on June 25, 2008. However, Ms. Tarsell has not presented any argument based upon challenge- rechallenge. The concept does not appear in Ms. Tarsell’s pre-trial brief, initial post-hearing brief, or post-hearing reply brief. In addition, Dr. Shoenfeld mentioned challenge-rechallenge only fleetingly. See Tr. 245-46, 257-58, 328-30. Even if Ms. Tarsell had directly argued challenge-rechallenge, it is not clear that Christina’s case fulfills the challenge-rechallenge paradigm. See Nussman v. Sec’y of Health & Human Servs., 83 Fed. Cl. 111, 119-20 (finding special master did not err in rejecting petitioner’s argument regarding rechallenge). To start, as discussed extensively in section IV, the onset of Christina’s arrhythmia is unknown. She may have had an undetected arrhythmia for many years. If so, the first dose of the HPV vaccination did not cause the arrhythmia. In addition, patients who have an arrhythmia do not follow one clinical course. As Dr. Eldar explained, “somebody has a problem, he lives with it or she lives with it for a 28 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 29 of 30 month or years, and then one day, that’s it.” Tr. 138. In other words, a seemingly benign arrhythmia can become fatal for completely unknown reasons. 3. Response as Predicted by the Causal Theory The essence of the theories Ms. Tarsell presented is that the HPV vaccination prompted an autoimmune attack on some part of the heart, either the beta adrenergic receptors or the L1 calcium channel. Dr. Phillips explained the implications of these theories: If, in fact, it was a significant autoimmune reaction going on, one would expect to see cellular infiltrates in various organs, and if the autoimmune reaction was going on of significance in the heart, you would expect that the myocardium would be infiltrated with lymphocytes. If there was a cytotoxic antibody there which had been attacking these channels, that cytotoxic antibody would also cause pathologic changes, with secondary infiltration of other cell populations which were inflammatory in nature, including polymorphonuclear cells or mononuclear cells. Tr. 407-08. However, what the theories predicted was not found. Doctors from the CDC examined tissue taken during Christina’s autopsy. Upon microscopic examination, they reported: “Sections of myocardium show no conspicuous inflammatory cell infiltrates.” Exhibit 10 at 170. Ms. Tarsell had no persuasive evidence for this discrepancy. Consequently, even if Ms. Tarsell had demonstrated the reliability of any theory causally connecting the HPV vaccinations to fatal arrhythmia as an abstract proposition, there is little persuasive evidence that this theory played out in Christina’s case. At the end, we have very little solid information about Christina’s unfortunate death. We know that she was Ms. Tarsell’s beloved daughter, whose future was bright. We know that her death was entirely shocking and caused Ms. Tarsell a terrible kind of grief. 29 Case 1:10-vv-00251-MCW Document 175 Filed 03/08/16 Page 30 of 30 But, sudden unexpected deaths happen with a greater frequency than may be commonly appreciated. See section I. We do not know the reason why apparently healthy young people die and, in the context of Ms. Tarsell’s claim in the Vaccine Program, the Secretary does not bear the burden of supplying a reason for Christina’s senseless death. See LaLonde, 746 F.3d at 1340. VI. Conclusion Ms. Tarsell claimed that the HPV vaccinations caused Christina’s arrhythmia, which led to her death. The evidence was not sufficient to establish the causal relationship between the vaccination and the arrhythmia. Consequently, Ms. Tarsell is not entitled to compensation. The Clerk’s Office is instructed to enter judgment in accord with this decision. IT IS SO ORDERED. s/ Christian J. Moran Christian J. Moran Special Master 30 ================================================================================ DOCUMENT 3: USCOURTS-cofc-1_10-vv-00251-4 Date issued/filed: 2017-10-13 Pages: 27 Docket text: PUBLIC ORDER/RULING (Originally filed: 9/25/17) regarding 198 Ruling on Entitlement. Signed by Special Master Christian J. Moran. (MRG) Copy to parties. -------------------------------------------------------------------------------- Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 1 of 27 In the United States Court of Federal Claims OFFICE OF SPECIAL MASTERS * * * * * * * * * * * * * * * * * * * * * EMILY TARSELL, as the Executrix * of the Estate of CHRISTINA * No. 10-251V TARSELL, * Special Master Christian J. Moran Petitioner, * * Filed: September 25, 2017 v. * * Entitlement; human papillomavirus SECRETARY OF HEALTH * (“HPV”) vaccine; sudden AND HUMAN SERVICES, * death; plausible medical theory; * onset of arrhythmia; challenge- Respondent. * rechallenge * * * * * * * * * * * * * * * * * * * * * Mark T. Sadaka, Mark T. Sadaka, LLC, Englewood, NJ, for petitioner; Ann D. Martin, United States Dep’t of Justice, Washington, D.C., for respondent. PUBLISHED RULING ON REMAND FINDING ENTITLEMENT1 Emily Tarsell alleges that the human papillomavirus (“HPV”) vaccine caused her daughter, Christina, to die unexpectedly. Ms. Tarsell, acting as the executrix of Christina’s estate, is seeking compensation pursuant to the National Childhood Vaccine Injury Compensation Program, codified at 42 U.S.C. § 300aa−10 through 34 (2012). The undersigned previously found that Ms. Tarsell had not met her burden of proof. Decision, 2016 WL 880223 (Fed. Cl. Spec. Mstr. Feb. 16, 2016). However, the Court of Federal Claims vacated the decision and remanded for additional consideration under different legal standards. Opinion and Order, 2017 1 The E-Government, 44 U.S.C. § 3501 note (2012) (Federal Management and Promotion of Electronic Government Services). Pursuant to Vaccine Rule 18(b), the parties have 14 days to file a motion proposing redaction of medical information or other information described in 42 U.S.C. § 300aa-12(d)(4). Any redactions ordered by the special master will appear in the document posted on the website. Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 2 of 27 WL 3837363 (Fed. Cl. June 30, 2017). Under the Court-directed legal standards, the undersigned finds that Ms. Tarsell is entitled to compensation. I. Facts2 The previous actions from judicial officers set forth the facts of Christina’s medical history in detail. See Opinion and Order, 2017 WL 3837363; Decision, 2016 WL 880223; and Findings of Fact, 2012 WL 1608741 (Fed. Cl. Spec. Mstr. March 30, 2012). Thus, this Ruling recounts only the most important events in Christina’s history. Christina was born in 1986. In 2004, she was seen for weight gain, fatigue, and potential hypothyroidism. Exhibit 1 at 9-13. In February 2005, tests of Christina’s thyroid were normal. Id. at 53. She played sports and, according to the testimony of her mother, she had physical exams to participate in athletics. Tr. 21- 22. During her periodic visits with a doctor, her pulse was recorded. For a list of 30 visits in which her pulse was recorded, see Opinion and Order, 2017 WL 38373636, at *17, Appendix A. On August 22, 2007, Christina saw an internist, Dr. Lafferman. The record from this visit does not record a pulse. However, a review-of-symptoms checkbox for cardiovascular symptoms is marked negative. During this visit, Christina received the first dose of the HPV vaccine. Exhibit 3 at 109-10. Approximately three weeks later, on September 12, 2007, Christina had a Pre-Participation Physical Evaluation at Bard College, where she was studying. The record indicates that Christina’s pulse was 72. The record also includes prompts regarding heart, murmurs, and pulses, which were all marked normal. The record further indicates that Christina reported that her heart does not race or skip beats during exercise. Exhibit 2 at 87-88. On November 20, 2007, Christina received the second dose of the HPV vaccine in the office of her gynecologist, Julie Jacobsen. Exhibit 3 at 124. On 2 After the Court’s remand, the undersigned has reviewed Christina’s medical records, the reports from Dr. Shoenfeld, Dr. Eldar, Dr. Yeager, and Dr. Phillips, the transcript (“Tr.”) of the hearing from November 13-14, 2014, the parties’ briefs (before hearing, after hearing, in conjunction with the motion for review, and on remand), and the transcript of the August 18, 2016 oral argument (“Oral Arg. Tr.”). The undersigned has also reviewed the literature that the parties cited. Although the undersigned has considered all this evidence and all the arguments, the undersigned does not necessarily cite all the evidence and all the arguments. 2 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 3 of 27 November 20, 2007, Christina also returned to Dr. Lafferman. Dr. Lafferman detected an irregular pulse. Exhibit 4 at 136. This discovery occurred approximately three months after Christina received the first dose of the HPV vaccine. Exhibit 3 at 109-10. Christina underwent an electrocardiogram (“EKG”) that showed her heart beat was not normal -- she was having a premature second beat. Id. at 142; see also Tr. 62-68, 501-02. In the following month, Christina again returned to see Dr. Lafferman. The record indicates that once more Christina’s pulse was irregular. Exhibit 4 at 135. Dr. Lafferman sent Christina for another EKG and this second EKG showed the same pattern as the first EKG. Exhibit 4 at 141; Tr. 83 (Dr. Eldar), 504 (Dr. Yeager).3 Dr. Lafferman recommended an echocardiogram. On the same day as the appointment with Dr. Lafferman, Christina saw Karl Diehn, a specialist in ears, nose and throat. Christina was complaining about chronic nasal congestion and the doctor recommended trying nasal steroids and possibly seeing an allergist. As part of the examination, Dr. Diehn recorded that “The carotid pulses are intact.” Exhibit 5 at 144. Christina was diagnosed with an episode of gastritis on February 6, 2008. Exhibit 2 at 74. On February 12, 2008, Christina underwent a transthoracic echocardiogram. The heart structure was found to be normal. Exhibit 4 at 139; see also Tr. 146 (Dr. Eldar), 510-11 (Dr. Yeager). In Dr. Yeager’s opinion, Christina did not have an irregular heart rhythm when the echocardiogram was performed. Tr. 511-12. Christina’s doctors did not recommend a Holter monitor or periodic follow-up. Christina’s next medical appointment was on June 3, 2008, when she received the third dose of the HPV vaccine. Exhibit 3 at 99. On June 5, 2008, Christina developed 2-12 dots on the right side of her neck under her ear. Findings of Fact, 2012 WL 1608741, at *4, citing exhibit 15 (affidavit of Tommie Tarsell) ¶ 4. These dots persisted until June 19, 2008. Id., 3 The report from the December 27, 2007 EKG stated Christina had “atrial fibrillation.” The finding that Christina’s premature contractions came from her atria was mistaken. The testifying cardiologists agreed that the contractions actually originated from Christina’s ventricles. Tr. 67-68 (Dr. Eldar), 502 (Dr. Yeager). 3 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 4 of 27 citing exhibit 16 (emails between Christina and her father). These dots were not noted in Christina’s autopsy. See exhibit 8. Christina was feeling both dizzy and faint from June 7, 2008 to June 12, 2008. Findings of Fact, 2012 WL 1608741, at *4. While she may have been “tired,” no evidence indicates that any fatigue interfered with her activities. Id. at 5. After returning to her apartment in New York City on June 12, 2008, Christina pursued her routine activities such as working. She died on June 21, 2008, at approximately noon. Findings of Fact, 2012 WL 1608741, at *6. A medical examiner, Kari Reiber, performed an autopsy. She determined that both the cause of Christina’s death and the manner of her death were “undetermined.” Exhibit 8 at 158. Dr. Reiber transmitted tissue samples to the Centers for Disease Control and Prevention (the “CDC”). The CDC’s Infectious Disease Pathology Branch performed a microscopic examination of Christina’s heart tissue. The results showed that the heart tissue exhibited no “conspicuous inflammatory cell infiltrates.” Exhibit 10 at 170. Dr. Reiber submitted a vaccine adverse event report to the Vaccine Adverse Event Report Service (VAERS). See exhibit 8 at 158. Other people and the manufacturer of the HPV vaccine (Merck & Co.) submitted additional information to VAERS. See, e.g., exhibit 20; exhibit 3 at 104, 105, 107, 108, and 113; exhibit 11; exhibit 21. Although the undersigned has considered this material, a belabored discussion of this correspondence is not needed as the Court did not specifically direct an analysis of this correspondence. II. Procedural History Ms. Tarsell initiated this action by filing a petition on April 19, 2010. She periodically filed medical records and affidavits from Christina’s family and friends. Due to some uncertainties in this evidence, the undersigned found various facts about Christina’s life and death. Findings of Fact, 2012 WL 1608741, at *3-6. The Findings of Fact served as a predicate for the parties to retain expert witnesses. Ms. Tarsell currently relies upon opinions of Yehuda Shoenfeld, an immunologist, and Michael Eldar, a cardiologist. Dr. Shoenfeld’s reports are exhibits 36, 94, 101, 108, 138. The reports from Dr. Eldar are exhibits 100, 107, 140. The Secretary has countered those opinions by retaining Stanley M. Phillips, 4 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 5 of 27 an immunologist with training in epidemiology, and Scott Yeager, a cardiologist. Dr. Phillips’s reports are exhibits A, UU, and XX. The reports from Dr. Yeager are exhibits FF, VV, ZZ, and OOO. These four experts as well as Ms. Tarsell testified during a hearing on November 13-14, 2014. The undersigned presided at the hearing and had an opportunity to assess the witnesses during their testimony. These observations contributed to the undersigned’s assessment of the relative value of particular points of testimony. See Moberly v. Sec'y of Health & Human Servs., 592 F.3d 1315, 1325 (Fed. Cir. 2010) (“Weighing the persuasiveness of particular evidence often requires a finder of fact to assess the reliability of testimony, including expert testimony, and we have made clear that the special masters have that responsibility in Vaccine Act cases”). The parties filed briefs after the hearing. With respect to the discovery of an arrhythmia in Christina, Ms. Tarsell asserted that Dr. Lafferman’s detection of an irregular heartbeat on November 20, 2007, was the first time an irregular heartbeat was found. Pet’r’s Posthear’g Br., filed Feb. 17, 2015, at 3, 16-17. Ms. Tarsell also cited to corroborating testimony from Dr. Eldar, who discussed six instances between 2001 and 2006 in which Christina’s pulse was measured. Id. at 17, citing Tr. 87 and 165-70. Ms. Tarsell argued that the initial detection of the irregular heartbeat on November 20, 2007, meant that the arrhythmia must have started relatively recently, after the first dose of the HPV vaccine. See id. at 15 (“Christina was a healthy young woman prior to her first Gardasil vaccine. She developed new-onset arrhythmia which did not resolve”). In his brief, the Secretary did not contest the assertion that Dr. Lafferman’s November 20, 2007 detection was the first time a doctor detected an irregular heartbeat. However, the Secretary disagreed with the petitioner’s reasoning that emphasized the significance of this discovery. Citing testimony from both Dr. Yeager and Dr. Eldar, the Secretary commented that asymptomatic ventricular premature contractions would involve periods of time throughout the day when the patient is in abnormal rhythm and periods when the patient is in normal rhythm. Resp’t’s Posthear’g Br., filed April 17, 2015, at 19-20. Therefore, this condition could well have predated its discovery. The undersigned issued a decision on February 16, 2016, finding that Ms. Tarsell had failed to meet her burden of proof for all three prongs set forth in Althen v. Sec’y of Health & Human Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005). The lynchpin of the analysis was that Ms. Tarsell had failed to establish, on a more 5 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 6 of 27 likely than not basis, that Christina’s arrhythmia started after the first dose of the HPV vaccine. 2016 WL 880223, at *7-8. Ms. Tarsell filed a motion for review. The judge to whom the case was assigned heard oral argument on August 18, 2016. Later, the case was transferred to a different judge. The judge issued an Opinion and Order on June 30, 2017, granting the motion for review. 2017 WL 3837363. In short, the judge required a reanalysis of all three Althen prongs, setting forth additional legal principles to be considered under Althen prongs 1 and 3. After remand, the parties were given an opportunity to file briefs that were restricted to prong 3. The Secretary filed his remand brief on August 11, 2017, and Ms. Tarsell responded on August 18, 2017. The filing of those submissions makes the case ready for adjudication again. III. Analysis The Court’s Opinion and Order requires a re-examination of the evidence for each of the Althen prongs. For each prong, the pertinent portion of the February 16, 2016 Decision is briefly summarized for context. Then, the Court’s correction and instructions are noted. Finally, the parties’ evidence along with their arguments is evaluated. A. Prong 1: Medical Theory Citing Moberly, 592 F.3d at 1322; M.S.B. by Bast v. Sec’y of Health & Human Servs., 117 Fed. Cl. 104, 123 (2014), appeal dismissed, 579 F. App’x 1001 (Fed. Cir. 2014); and Taylor v. Sec’y of Health & Human Servs., 108 Fed. Cl. 807, 819 (2013), the undersigned stated that Ms. Tarsell’s burden with respect to the first prong of Althen is to present a theory that is “more likely than not.” Decision, 2016 WL 880223, at *15. The undersigned noted that Dr. Shoenfeld described his theory as “plausible.” Id. at *16, quoting Tr. 268. For this reason and for other reasons set forth in the Decision, the undersigned found that Ms. Tarsell had not satisfied her burden of proof. The Court disagreed with the Decision’s description of the burden of proof. Citing Andreu v. Sec’y of Health & Human Servs., 569 F.3d 1367, 1375 (Fed. Cir. 2009); Doe/11 v. Sec’y of Health & Human Servs., 87 Fed. Cl. 1, 5 (2009), aff’d, 601 F.3d 1349 (Fed. Cir. 2010); and Doe 93 v. Sec'y of Health & Human Servs., 98 Fed. Cl. 553, 566-67 (2011), the Court held that a petitioner satisfies her obligation to present a medical theory by presenting a theory that is “plausible.” Opinion and Order, 2017 WL 3837363, at *10. This interpretation of the law is 6 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 7 of 27 binding in this case. Hanlon v. Sec'y of Health & Human Servs., 40 Fed. Cl. 625, 630 (1998), aff’d in non-relevant part, 191 F.3d 1344 (Fed. Cir. 1999). The ensuing question is: what does “plausible” mean? Because the Court held that obligating the petitioner to establish a theory that is more likely than not imposed too high a burden, “plausible” must mean something less than more likely than not. Some guidance can be found in the Supreme Court’s interpretation of Federal Rule of Civil Procedure 8(a)(2). In determining that a well-pleaded complaint must “state a claim to relief that is plausible on its face,” the Supreme Court stated that “[t]he plausibility standard is not akin to a ‘probability requirement,’ but it asks for more than a sheer possibility that a defendant has acted unlawfully.” Ashcroft v. Iqbal, 556 U.S. 662, 678 (2009). The Federal Circuit, in turn, has cited the plausibility standard in evaluating complaints alleging patent infringement. See McZeal v. Sprint Nextel Corp., 501 F.3d 1354, 1357 (Fed. Cir. 2007); see also Hibbard v. Sec’y of Health & Human Servs., 698 F.3d 1355, 1366 (Fed. Cir. 2012) (noting that “[i]n the recent en banc decision in Cloer v. Secretary of Health & Human Services [654 F.3d 1320, 1333 n.4 (Fed. Cir. 2010) (en banc)] the court once again made clear that Althen does not lessen the ultimate burden of proof on a petitioner to show actual causation by a preponderance of the evidence. In Cloer, the court characterized Althen as setting forth ‘three pleading requirements for a non-Table injury petition’”). Additional guidance about the meaning of the term “plausible” might be found by consulting dictionaries. See Hervey v. Sec’y of Health & Human Servs., 88 F.3d 1001, 1002 (Fed. Cir. 1996) (using a dictionary to define a term in the Vaccine Act). Unfortunately, dictionary entries for “plausible” include definitions offering both positive and negative connotations, suggesting that a plausible proposition may reasonably be met with either credulity or incredulity. For example, The American Heritage Dictionary defines plausible both as “seemingly or apparently valid, likely or acceptable,” and as “given a deceptive impression of truth, acceptability, or reliability.” The American Heritage Dictionary 950 (2nd Coll. Ed.). In one prior Vaccine Act case, a special master faced precisely this difficulty. See Hargrove v. Sec’y Health & Human Servs., No. 05-0694V, 2009 WL 1220986, at *28 (Fed. Cl. Spec. Mstr. April 14, 2009) (noting that in both its positive and negative connotations, plausible “does not mean anything close to certain; it does not even mean probable”). In that case, the special master rejected as disingenuous one expert’s statement that “anything is plausible.” Id. at *28. Instead, the special master concluded that “plausibility’s import is carried in the ‘could’ proposition.” Id. This is consistent with the presiding Judge’s instruction 7 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 8 of 27 in this case that the undersigned “assess whether Petitioner provided a biologically plausible theory without requiring Petitioner to demonstrate that particularized manifestations of this theory actually occurred.” Opinion and Order, 2017 WL 3837363, at *12. Under a legal standard in which a petitioner must present a “plausible” theory, Ms. Tarsell has met her burden of proof. Her theory, jointly presented by Dr. Shoenfeld and Dr. Eldar, is conceivably true. Indeed, as previously noted, respondent’s experts conceded a number of significant points, including inter alia, that molecular mimicry is itself plausible (Tr. 421 (Dr. Phillips)), that the HPV vaccine contains the same LQAGL pentamer as located in the L-type calcium channel (Tr. 389-90, 394-97 (Dr. Phillips)), that increased amounts of intracellular calcium can lead to arrhythmia (Tr. 556 (Dr. Yeager)), and that arrhythmia can be caused by autoantibodies (Tr. 556 (Dr. Yeager)). Opinion and Order, 2017 WL 3837363, at *11; Decision, 2016 WL 880223, at *10-16. While the Secretary’s experts, Dr. Phillips and Dr. Yeager, presented several reasons why the theory was unlikely to be probable,4 the Secretary does not argue that the theory is impossible. See Oral Arg. Tr. 103. B. Prong 3: Timing 1. Preliminary Comments Citing Bazan v. Sec'y of Health & Human Servs., 539 F.3d 1347, 1353-54 (Fed. Cir. 2008), and Hopkins v. Sec'y of Health & Human Servs., 84 Fed. Cl. 517, 524-27 (2008), the undersigned stated that Ms. Tarsell “bears the burden of establishing when Christina’s disease began.” Decision, 2016 WL 880223, at *8. To elaborate, in Bazan, “the proximate temporal relationship prong requires preponderant proof that the onset of symptoms occurred within a timeframe for which, given the medical understanding of the disorder’s etiology, it is medically acceptable to infer causation-in-fact.” 539 F.3d at 1352. Citing the testimony of both Dr. Eldar and Dr. Yeager, the undersigned found that the onset of Christina’s arrhythmia was unknown. Decision, 2016 WL 880223, at *7-8. Dr. Eldar stated: 4 The February 16, 2016 Decision set forth those reasons. However, the Court indicated that these reasons “do not go to the biological plausibility of Petitioner’s theory.” Opinion and Order, 2017 WL 3837363, at *12. Thus, a recitation of the previously rejected reasons in a decision on remand would be inappropriate. See Contreras v. Sec’y of Health & Human Servs., 844 F.3d 1363, 1369 (Fed. Cir. 2017) (noting that the undersigned “maintained an erroneous viewpoint throughout this case, despite instructions to the contrary”). 8 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 9 of 27 “I cannot say exactly when [Christina’s arrhythmia] started.” Tr. 120. Similarly, Dr. Yeager testified “I don’t think I can date when she began having cardiac arrhythmia.” Tr. 493. The Court also disagreed with this interpretation. Relying primarily upon W.C. v. Sec'y of Health & Human Servs., 704 F.3d 1352, 1359 (Fed. Cir. 2013), the Court determined that the undersigned should have first determined whether it was “‘more likely than not’” that “Christina’s cardiac arrhythmia” “predated her first Gardasil vaccine.” Opinion and Order, 2017 WL 3837363, at *8-9. The undersigned respectfully submits that the Court’s formulation of prong 3 may alter the burden of proof. Cf. Resp’t’s Post-Remand Br., filed Aug. 11, 2017, at 3 (advising “not to alleviate petitioner of her burden under prong three, as that would be contrary to law”). Respondent persuasively cautions against giving “undue weight to the absence of evidence and improperly reliev[ing] petitioner of proving her case by a preponderance of the evidence.” Id.; see also Doyle v. Sec'y of Health & Human Servs., 92 Fed. Cl. 1, 4 (2010) (denying a motion for review where a special master found that petitioner had not satisfied Althen prong 3 because petitioner’s expert admitted that onset of petitioner’s condition was insidious and he could not determine whether onset was prior to vaccination). Regardless, the undersigned is obligated to implement the Court’s instruction. Hanlon, 40 Fed. Cl. at 630; see also Strickland v. United States, 423 F.3d 1335, 1338 & n. 3 (Fed. Cir. 2005) (noting that when the Court of Federal Claims believes a Federal Circuit case is inconsistent with an intervening Supreme Court case, the Court of Federal Claims is obligated to note the conflict but follow the Federal Circuit case). 2. Etiology of Arrhythmia The Court directed the undersigned to consider the “etiology” of arrhythmia. Etiology means the science of studying the cause of a disease. The parties provided no commentary on this aspect of the Court’s order in their post-remand briefs. The undersigned’s review of the testimony has identified relatively little testimony from the experts about the cause of arrhythmia. Some arrhythmias are associated with structural defects of the heart, such as a heart after a myocardial infarction or a diseased myocardium. Tr. 159-60 (Dr. Eldar). However, Christina’s heart did not have any obvious structural defects. See exhibit 4 at 139 (echocardiogram), exhibit 8 at 158 (autopsy) and exhibit 10 at 170 (CDC testing). Thus, these structural causes to arrhythmias are not relevant. 9 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 10 of 27 Non-structural causes for arrhythmias include antibodies attacking the channel of the heart. Tr. 91-94 (Dr. Eldar). These antibodies typically arise in the context of autoimmune disease, such as lupus, type 1 diabetes, and Chagas’ disease. Exhibit ZZ (Dr. Yeager’s report) at 1. Dr. Eldar and his team discovered another type of arrhythmia that is not caused by a channelopathy. Tr. 31-32, 160. Two other diseases, Brugada syndrome and Timothy syndrome, also cause disturbed rhythms and the origins of Brugada syndrome and Timothy syndrome are genetic.5 Due to the need to glean information about the causes of arrhythmia from testimony on other topics, the foregoing list of known causes to arrhythmia is probably incomplete. Cf. Tr. 115 (Dr. Eldar’s testimony that research is likely to discover more genetic causes for arrhythmia in the future), 514 (Dr. Yeager also indicating that channelopathies are “yet to be discovered”). Although the “etiology” of a disease is distinct from the disease’s presentation, the Court also directed the undersigned to consider how arrhythmias present. The incidence of arrhythmias increases as the person ages as part of the aging process. Tr. 500-01 (Dr. Yeager). Newborns are very unlikely to have any arrhythmias. Tr. 500 (Dr. Yeager); see also exhibit 36 (Dr. Shoenfeld’s report) at 5. Nearly all octogenarians have arrhythmias. Tr. 500. Between these groups and most similar to Christina are teen-agers. Approximately one-third or more of teen- agers “have some ventricular ectopy, some fairly impressive ventricular ectopy, even though they are perfectly healthy.” Tr. 500; accord exhibit OO (M.E. Alexander and C.I. Berul, “Ventricular Arrhythmias: When to Worry,” 21 Pediatr. Cardiol. 532 (2000)) at 532 (“Without apparent heart disease, isolated premature ventricular contractions (PVCs) are seen in . . . 20% to 35% of adolescents”).6 5 Both Dr. Eldar and Dr. Yeager recommended testing Christina’s surviving relatives for potential genetic causes to her arrhythmia. Tr. 159, 506-07, 517. However, this genetic testing was not done. 6 Dr. Yeager disclosed his opinion that adolescents frequently experience arrhythmias in his first report, filed May 2, 2014. Exhibit FF at 5-6. Dr. Eldar, in his response to Dr. Yeager, concurred with a caveat. Quoting Dr. Yeager’s assertion that patients with ventricular premature complexes are “‘usually felt to be at quite low risk, and may even be cleared for competitive athletics,’” Dr. Eldar stated that the claim that Christina’s type of arrhythmia (a ventricular premature complex originating from the right ventricular outflow tract) is common in adolescents “is true for many cases of RVOT VPCs [but] definitely not true for all of them.” Exhibit 100 at 6 (quoting exhibit FF at 6); accord Tr. 74. 10 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 11 of 27 Dr. Yeager aptly summarized the challenge in determining when arrhythmia starts. He stated: So, sometime between infancy and adulthood and as you get older, there tends to be more and more ventricular ectopy discovered. Obviously, in everybody, it starts sometime. They’re not aware . . . and we’re [doctors are] not aware of it, generally it doesn’t even get documented in their medical records. . . . So, there’s a lot of ventricular ectopy in the background of healthy, normal people, and in general it’s impossible for us to say exactly when it starts. Tr. 500. On cross-examination, Dr. Yeager emphasized that arrhythmia is not an “all or nothing” condition. Tr. 538. A person can have 20 minutes of bigeminy and then a few hours of normal rhythm. Tr. 540. In one study, patients with severe symptomatic arrhythmia wore Holter monitors and, in these patients, abnormal beats were found approximately 17 percent of the time. Tr. 496-97 (Dr. Yeager) (interpreting exhibit 106 (Takashi Noda et al., Malignant Entity of Idiopathic Ventricular Fibrillation and Polymorphic Ventricular Tachycardia Initiated by Premature Extrasystoles Originating from the Right Ventricular Outflow Tract, 46(7) J. Amer. Coll. Cardiology 1288 (2005)). When the Noda article was brought to Dr. Eldar’s attention, he did not dispute Dr. Yeager’s opinion. See Tr. 564-65. The variation in heart rhythm among people who are known to have arrhythmia is demonstrated in Christina’s case. On December 27, 2010, which was the day Dr. Lafferman detected a second irregular heart beat (exhibit 4 at 135) and Christina’s second EKG was abnormal (exhibit 4 at 141), Christina also saw Dr. Diehn. As part of his physical examination, Dr. Diehn noted that her “carotid pulses are intact.” Exhibit 5 at 144. Dr. Shoenfeld and Dr. Eldar were adamant that anyone with medical training should be able to detect Christina’s type of arrhythmia when taking a pulse. Tr. 89, 165, 169. Dr. Yeager concurred. Tr. 541. Thus, a reasonable inference from the lack of notation from Dr. Diehn is that Christina was not having an irregular pulse when he tested her. A second example from Christina’s life is her echocardiogram. Dr. Yeager presented persuasive testimony, which Dr. Eldar did not challenge, that instances of irregular rhythm would normally be noted during an echocardiogram. Tr. 511, 11 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 12 of 27 552-53. Again, the lack of a notation on the report of the echocardiogram tends to show that Christina was not experiencing arrhythmia during the echocardiogram. The variation in heart rates is an important factor in trying to determine when Christina’s arrhythmia began. A notation that a person had a normal pulse simply shows that “the patient probably was not having a significant arrhythmia during those few seconds of auscultation.” Exhibit OOO (Dr. Yeager) at 3 (emphasis added); accord Tr. 496 (Dr. Yeager). As Dr. Shoenfeld stated, albeit in a different context, one should not start with the “absence of evidence” and conclude that there is “evidence of absence.” Exhibit 36 at 4. Without citing any evidence, Ms. Tarsell argues what the standard of care dictates for Christina’s treating doctors. Pet’r’s Br. on Remand, filed Aug. 18, 2017, at 2. The gist of the argument seems to be that because Christina’s pulse was recorded as normal, her heart rate was always normal. Otherwise, the doctors would have acted differently. The undersigned accepts the proposition that when doctors detect an abnormal pulse, the doctors are likely to refer the patient for additional testing. After all, Dr. Lafferman followed this practice when she detected an abnormal pulse in Christina. However, a doctor’s ability to respond to an abnormal pulse depends upon the doctor’s ability to detect an abnormal pulse. Here, the persuasive evidence indicates that doctors have a relatively small opportunity to catch abnormal pulses.7 Dr. Eldar or Dr. Yeager could have explained why people in doctor’s offices record pulses when the recording provides information about the patient’s heart rate for a short amount of time, probably one minute or less. In the undersigned’s view, Ms. Tarsell overstates the weight that should be given to the series of normal pulse readings. 3. The Court’s First Question: Is It Likely That Christina’s Arrhythmia Began before the First HPV Vaccination? The undersigned’s February 2, 2016 decision found that it was not possible to determine when Christina’s arrhythmia started because the testifying cardiologists could not say when it started. Decision, 2016 WL 880223, at *7-8. Upon further review, the evidence about the relative commonness of arrhythmia 7 Conceivably, if a patient reported feeling a racing heart, a doctor might investigate this symptom through methods longer than taking a pulse. However, there is no record of Christina complaining about her heart even after Dr. Lafferman detected her abnormal pulse. 12 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 13 of 27 among adolescents has some value in suggesting that Christina’s arrhythmia actually started years before the vaccination. The undersigned realizes that Christina generally did not complain about symptoms associated with arrhythmia, such as dizziness or fatigue. But, many people with arrhythmia do not report any problems. Tr. 329 (Dr. Shoenfeld: “you can have arrhythmia and be asymptomatic”). Christina was one of those people because even after she was detected to have an irregular heartbeat, she did not report problems to medical personnel. Tr. 120 (Dr. Eldar), 496 (Dr. Yeager). Despite the potential value of the evidence that adolescents often experience arrhythmia, the undersigned feels constrained by the initial finding. Having found that the onset of Christina’s arrhythmia could not be determined on a more-likely- than-not basis, the undersigned believes that finding (a) the onset is ascertainable, and (b) the onset occurred before vaccination would be fundamentally unfair to Ms. Tarsell. Such a switch in position might suggest a bias against Ms. Tarsell. The undersigned has considered the list of medical appointments during which Christina’s pulse was recorded. As previously noted, Dr. Shoenfeld and Dr. Eldar repeatedly stated that when a doctor or nurse takes a pulse, he or she would be able to detect the irregular heart beat if Christina were experiencing arrhythmia. The assertion is accepted. But, Ms. Tarsell and her experts appear to overlook the condition: “if Christina were experiencing arrhythmia” when her pulse was being checked. Because the evidence persuasively shows that people with arrhythmia experience the irregular heart beat for only a small percent of the time, the likelihood of detecting an irregular heartbeat that is not associated with any symptoms is small.8 Dr. Yeager added an additional complication in trying to draw an inference from a doctor’s or nurse’s notation of a normal pulse. While a doctor or a nurse could feel an irregular pulse when the doctor or nurse touched the patient or listened to the patient’s heart, Dr. Yeager explained that many doctor’s offices obtain blood pressure and pulse by using a machine called Dynamaps. Tr. 494-95. According to Dr. Yeager, the machine can present the information about the pulse 8 Petitioner argues that “[a]s the number of tests increase the chance of finding Christina’s arrhythmia, if it existed at all, goes up” and that “as the number of physical evaluations increase, the risk of non-detection of an arrhythmia falls markedly.” Pet. Post- Remand Br., filed Aug. 18, 2017, at 2-3. However, petitioner based this argument on the proportion of arrhythmia sufferers that are symptomatic rather than on the proportion of the day that any given arrhythmia sufferer is symptomatic. 13 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 14 of 27 “irrespective of heart rhythm.” Tr. 495. Dr. Eldar disagreed, stating that the electronic devices in his hospital will read “error,” when the pulse is irregular. Tr. 566. Dr. Yeager’s point would be stronger if two questions had been explored. First, how did Christina’s doctors and nurses obtain the information about her pulse? Did they use a stethoscope or touch Christina? Or, did they use an automated machine. Second, if a machine were used, would the machine indicate a person was having an irregular pulse? Although the undersigned has considered the entire record, the most valuable evidence is the testimony from the two cardiologists that the onset of Christina’s arrhythmia is not known. Nonetheless, Christina’s routine medical care consistent with her age and condition failed to detect any evidence of arrhythmia before the vaccination and her arrhythmia was indisputably discovered after vaccination. In this situation, the answer to the Court’s question is: It is not more-likely-than-not that Christina’s arrhythmia started before the vaccination.9 4. The Court’s Second Question: Did Christina’s Arrhythmia and Cardiac Arrest Occur within a Medically Appropriate Time after her Vaccines? Logically, because the undersigned does not find that preponderant evidence supports a finding that Christina’s arrhythmia started before the vaccination, Christina’s arrhythmia must have started after vaccination. This deduction leads to the Court’s second instruction set forth in the heading above. The Court’s direction actually contains two sub-parts: what is a medically appropriate time after vaccination for arrhythmia and/or cardiac arrest to occur, and when did Christina’s arrhythmia and/or cardiac arrest occur? See Shapiro v. Sec’y of Health & Human Servs., 101 Fed. Cl. 532, 542-43 (2011), recons. denied after remand on other grounds, 105 Fed. Cl. 353 (2012), aff’d without op., 503 Fed. App’x 952 (Fed. Cir. 2013). 9 The Court’s wording of the question affects the outcome. If the Court had alternatively directed the undersigned to determine the opposite, i.e. “Whether it is more-likely-than-not that Christina’s arrhythmia started after the vaccination,” the undersigned likewise would have been compelled by evidence, taken as a whole, to say “No.” 14 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 15 of 27 a) Medically Appropriate Interval Compared to the question of when Christina’s arrhythmia began, the question of the medically appropriate interval received much less attention from the parties and their experts. Because the first reports from Dr. Shoenfeld did not discuss this topic, the undersigned directed Ms. Tarsell to file a supplemental report from him “on the topic of a medically acceptable timeframe between vaccination and the onset of cardiac arrhythmia.” Order, issued Jan. 27, 2014. Dr. Shoenfeld’s ensuing report from February 21, 2014 is, therefore, important because he was specifically directed to answer a question that the Court eventually posed in the Opinion and Order. Relying in part upon the Slade article, Dr. Shoenfeld stated that to be proximately related to a vaccination, a death following vaccination should occur within approximately one month. Exhibit 94 at 1-2. A close reading of Dr. Shoenfeld’s report indicates that he, intentionally or unintentionally, did not directly answer the question about the medically appropriate interval between vaccination and arrhythmia. In his testimony on direct examination, Dr. Shoenfeld was also not clear about the medically acceptable interval between vaccination and the onset of arrhythmia. He stated that at least after an initial vaccination, the immune response comes “between two to three weeks.” Tr. 211. He stated that “two weeks is too early” for a vaccination to cause arrhythmia. Dr. Shoenfeld also stated that for a booster vaccination that elicits a recall response, the reaction can take place more quickly – “a week or ten days.” Tr. 210-11. Dr. Shoenfeld further stated: “sometimes, after the first vaccine, you don’t expect autoimmune disease. It’s usually after the second and the third.” Tr. 242- 43. He continued: “You may get sometimes allergic reaction, and sometimes you can get already the autoimmune disease. . . . So, not necessarily after the first vaccine we should get it. Usually, it will be, I would say, in proximity, which might be between two, three weeks to one month, two months, that we will get the high titers of if [sic] autoantibodies were produced.” Tr. 243-44. Later, he added: “the diagram that represents the production of the immunoglobulin is usually three weeks. . . . So, for an immunologist, the three weeks is, I would say, the optimal. I can explain shorter or longer periods by different schedules of immunization, by different ways, but the three weeks is, I believe, optimal.” Tr. 249. On redirect examination, which occurred the following day, Dr. Shoenfeld again testified that his proposed mechanism for inducing arrhythmia “takes at least 15 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 16 of 27 three weeks, but you need to mount a high titer.” Tr. 328. He also stated that for a booster dose of the vaccine, the reaction takes place in fewer days. Tr. 329-30. As part of Dr. Phillips’s testimony, the undersigned asked about the timing for molecular mimicry. Dr. Phillips responded: You know, honestly, I don't think I can give you an accurate measurement. I think it could be all over the place. I mean, if you induce an experimental autoimmune reaction, say, in an experimental animal using adjuvants and so on, you can have manifestations in as short a period of time as seven to ten days. If you suggest that the autoimmune manifestations are related to the maximum titer, then there’s been studies in the test tube which will show that you can start making antibodies in as short a period of time as four to five days, but that’s IgG, and then Ig -- or M, and then IgG, within a week to ten days, and that in vivo the antibodies will tend to peak around six weeks to three months after you've been exposed. Tr. 465. The undersigned finds Dr. Phillips’s testimony that an autoimmune reaction can take place in as short as seven days persuasive. The undersigned specifically rejects Dr. Shoenfeld’s statement that his proposed mechanism takes at least three weeks. The undersigned has heard from many immunologists – including Dr. Shoenfeld -- that an appropriate time for an adverse reaction via molecular mimicry is 5-42 days. E.g. Simanski v. Sec'y of Health & Human Servs., No. 03- 103V, 2010 WL 2292200, at *17 (Fed. Cl. Spec. Mstr. May 13, 2010)) (Dr. Shoenfeld acknowledging in a case where he raised molecular mimicry that the appropriate interval for Guillain-Barre Syndrome is between 5 and 21 days and opining that a four day onset was “conceivable”), mot. for rev. den’d, 96 Fed. Cl. 588 (2010), vacated and remanded on other grounds, 671 F.3d 1368 (Fed. Cir. 2012). Indeed, Dr. Shoenfeld has previously offered opinions that effectively suggest that timing does not even matter at all. See Johnson v. Sec’y of Health & Human Servs., No. 10-578V, 2016 WL 4917548, at *10 (Fed. Cl. Spec. Mstr. Aug. 18, 2016) (explaining that “[p]etitioner attempts to point to Dr. Shoenfeld’s 16 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 17 of 27 argument that the timing does not matter so long as it occurred after the vaccine.”); see also Hennessy v. Sec’y of Health & Human Servs., 91 Fed. Cl. 126, 142 (2010) (observing that Dr. Shoenfeld’s theory would nullify Althen prong 3 by encompassing “nearly any conceivable timing” from immediately after vaccination until years later). If Dr. Shoenfeld were correct that three weeks is not a medically-appropriate amount of time to form an autoimmune reaction via molecular mimicry, then petitioners whose autoimmune disease became manifest within three weeks of an initial vaccination would not prevail in those other cases. The undersigned’s experience informs the determination that Dr. Shoenfeld is not credible when he limits autoimmune reactions after the first dose of a vaccination to starting after three weeks. Although the undersigned credits Dr. Phillips testimony that a molecular mimicry reaction may take place after seven days, the outer limit for the medically appropriate interval is less clear. Dr. Shoenfeld seems to say that antibodies might be produced for “two months.” Tr. 244. Dr. Phillips extends the time for antibody production to “six weeks to three months.” Tr. 465. Neither expert explained the basis for their assertion. While Dr. Phillips’s estimate of three months seems long in the undersigned’s experience, the undersigned will accept that range in this case. b) When Did Christina’s Arrhythmia and Cardiac Arrest Occur? Having found that the medically appropriate interval is between seven days and three months from the date of an initial (not booster) dose of a vaccine, the undersigned next must determine whether the onset of Christina’s arrhythmia occurred in this window. The undersigned finds that it did because, and only because, the previous finding indicates that preponderant evidence does not support the finding that the arrhythmia started before the vaccination. Starting from the assumption that Christina’s arrhythmia started after the August 22, 2007 vaccination, her arrhythmia must have begun by November 20, 2007, when Dr. Lafferman first detected the arrhythmia. This is a period of 90 days, which almost entirely overlaps with the medically acceptable range of seven days to three months. In reaching this finding, the undersigned has considered that Christina’s pulse was recorded without any notation of any abnormality on September 12, 2007. Exhibit 2 at 82, 87-88. According to Dr. Shoenfeld’s logic, the lack of a 17 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 18 of 27 notation of an irregular heartbeat means that Christina was not suffering from arrhythmia. From the undersigned’s observation of Dr. Shoenfeld during his testimony, Dr. Shoenfeld appeared to construct an unpersuasive reason to justify the lack of arrhythmia 21 days after vaccination. See Tr. 210-11. However, the undersigned has already rejected this reasoning. The recording of Christina’s pulse on September 12, 2007, provides information about her pulse while her pulse was being checked. The medical record does not say what her pulse was at other hours of September 12, 2007. Even Christina’s report that she does not feel her heart racing during exercise provides little information because, as Dr. Yeager explained, people can have arrhythmia without symptoms. Tr. 547; accord Tr. 119 (Dr. Eldar). Under the assumption that Christina’s arrhythmia started after the vaccination only, the undersigned finds that her arrhythmia began within a time that is medically appropriate to infer causation. Thus, the remaining question concerns the timing of her cardiac arrest. Here, the sequence of events is clearer. Christina received the third dose of the HPV vaccination on June 3, 2008. The undersigned found that she died on June 21, 2008. Findings of Fact, 2012 WL 1608741, at *6. The interval is 18 days. This interval fits within the medically acceptable range. 5. Summary of Prong Three After following the Court’s instructions with regard to the method of analyzing the issues, the undersigned finds that Ms. Tarsell has met her burden with respect to prong three. C. Prong 2: Logical Sequence of Cause and Effect Finding that Ms. Tarsell has met her burden with respect to prongs 1 and 3 does not end the analysis because to receive compensation, Ms. Tarsell also must establish that the second prong of Althen: “a logical sequence of cause and effect showing that the vaccination was the reason for the injury.” Althen, 418 F.3d at 1278. The Federal Circuit has stated that the second prong “is not without meaning.” Capizzano v. Sec’y of Health & Human Servs., 440 F.3d 1317, 1327 (Fed. Cir. 2006). The February 16, 2016 Decision found that Ms. Tarsell did not meet her burden of proof on this issue. The undersigned determined because of the lack of knowledge about when Christina’s arrhythmia began, Ms. Tarsell did not establish 18 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 19 of 27 that Christina’s case met the challenge-rechallenge paradigm. The undersigned also credited Dr. Phillip’s testimony that there was no evidence that Christina reacted in a way that Dr. Shoenfeld’s and Dr. Eldar’s theory predicted. Finally, the undersigned did not see support from treating doctors. 2016 WL 880223, at *17- 18. The Court’s Opinion and Order ruled that the undersigned did not consider all the evidence of record because the Decision did not cite all the evidence. 2017 WL 3837363, at *13. Thus, the Court required an explicit analysis of all the evidence. Id., at *16. Upon reconsideration of all the evidence on remand, the undersigned finds that a logical sequence of cause and effect supports Ms. Tarsell’s claim. The absolutely essential reason for the undersigned’s change in course concerns challenge-rechallenge. For sake of completeness, the undersigned will also address the other aspects of the record required by the Opinion and Order. 1. Challenge-Rechallenge The Federal Circuit has noted that challenge-rechallenge can help a petitioner establish the second prong of Althen. Capizzano, 440 F.3d at 1322. The February 12, 2016 Decision recognized this guidance but found that the facts that could be established by preponderant evidence did not fit the paradigm. 2016 WL 880223, at *17. Now, as explained above, due to the Court’s instruction and sequence of questions, the undersigned has found that Christina’s arrhythmia developed within a medically appropriate time after the first HPV vaccination. This finding satisfies the “challenge” aspect of challenge-rechallenge. The undersigned has also found that Christina’s death occurred within a medically appropriate time after the third HPV vaccination.10 This event constitutes the “re-challenge” aspect of challenge-rechallenge. In addition, upon further reflection, the undersigned recognizes that the initial Decision may not have given appropriate weight to the findings that she felt 10 The parties have not presented any arguments based upon the second HPV vaccination. Ms. Tarsell has not explained the lack of explicit symptoms from Christina. The Secretary has not argued the lack of explicit symptoms after the second vaccination undermines the challenge- rechallenge paradigm. 19 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 20 of 27 dizzy and faint from June 7, 2008 to June 12, 2008. See Findings of Fact, 2012 WL 1608741, at *4. Feeling faint and feeling dizzy can be symptoms of arrhythmia. Tr. 248 (Dr. Shoenfeld), 328 (same), 550 (Dr. Yeager). However, feeling faint and feeling dizzy can be symptoms of other problems. Tr. 549-50. Given the general finding that Christina experienced challenge-rechallenge, her reports of feeling faint and feeling dizzy help fill in the picture that she was reacting adversely to the third dose of the HPV vaccination. In other words, Christina’s feeling faint and feeling dizzy provide ancillary support for the challenge-rechallenge phenomena. However, if the challenge-rechallenge paradigm were not valid, then the feeling faint and feeling dizzy could not carry Ms. Tarsell’s burden. While Christina’s feeling faint and feeling dizzy provide some circumstantial evidence of an adverse reaction, the presence of 2-12 red dots from June 5, 2008 until June 19, 2008 does not. See Findings of Fact, 2012 WL 1608741, at *4. Dr. Shoenfeld assumed that the presence of red dots meant that Christina broke out in a rash and Dr. Shoenfeld further asserted that a rash is a manifestation of an autoimmune reaction. Tr. 201, 247. However, Dr. Phillips persuasively rebutted these points. Tr. 402-06. Among other comments, Dr. Phillips explained that allergic reactions and autoimmune reactions follow different immunologic pathways. The undersigned credits Dr. Phillips’s opinion.11 But, the finding that the presence of 2-12 red dots does not signify an autoimmune reaction does not weigh against Ms. Tarsell. Ms. Tarsell can prevail – and does prevail – based upon the challenge-rechallenge paradigm. Nevertheless, to ensure compliance with the Opinion and Order, the undersigned will address other points potentially relevant to prong 2. 2. Christina’s Medical History, including Hypothyroidism In May 2004, Christina saw Renee Howard, her pediatrician, who completed a form for 16-19 year olds. Dr. Howard noted Christina was a well adolescent but who also had experienced fatigue and gained weight. Dr. Howard ordered lab tests to check on Christina’s thyroid level. Exhibit 1 at 14. After a few months of tests (see exhibit 1 at 58-59), the doctor placed Christina on Synthroid on September 20, 2004. Exhibit 1 at 13. 11 Likewise, Christina’s history of being allergic to Cefzil and Augmentin (see exhibit 11 at 214) does not make her pre-disposed to having an autoimmune reaction. Although Dr. Shoenfeld made this assertion (Tr. 205, 246-47), Dr. Phillips effectively rebutted it. Tr. 402-06. 20 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 21 of 27 Christina appears to have taken Synthroid for a few months. See Tr. 240 (Dr. Shoenfeld: Christina was on Synthroid “for a short time”). On February 2, 2005, Christina reported that she had been off Synthroid for 5-6 weeks. Exhibit 1 at 9. The ensuing labs showed that Christina’s T4 was on the low end of normal. Exhibit 1 at 53. Laboratory work from June 2005 showed that Christina’s TSH was normal. Exhibit 1 at 50. Approximately one year later, Christina’s TSH remained normal. Id. at 48. From this information, Dr. Shoenfeld opined that Christina had an autoimmune thyroid disease such as Hashimoto thyroiditis. Tr. 240-41 (discussing hypothyroidism, characterized by counsel as Hashimoto). He also predicted that if Christina had lived, she would have required more Synthroid. Tr. 241. Dr. Shoenfeld also asserted that because Christina had one autoimmune disease, she was predisposed to suffering another autoimmune disease. See Tr. 192-93, 204-05. Dr. Phillips disagreed. He stated that “we don’t even know that she has hypothyroidism, and second, there were no tests done, such as measuring . . . antithyroglobulin antibody or antithyroperoxidase antibody, which are necessary to make that diagnosis.” Tr. 405. He added “it’s totally speculative whether she had Hashimoto’s and even if she had Hashimoto’s, that’s usually a limited, not systemic, autoimmune disease.” Id. From the undersigned’s perspective managing the case, the issue about Christina’s hypothyroidism was not significant. Dr. Shoenfeld’s first report mentions Christina’s thyroid only in two places and his discussion in those two places was limited to one sentence. See exhibit 36 at 4 (before the vaccination, Christina was “diagnosed with possible mild hypothyroidism”), 14 (Christina was “diagnosed with mild hypothyroidism”). Dr. Shoenfeld did not use the term “Hashimoto” at all in the first report. Dr. Shoenfeld’s second and third reports do not mention thyroid problems at all. See exhibits 94 and 101. Dr. Shoenfeld’s fourth report mentions thyroid antibodies as an example of how antibodies can affect organs. Exhibit 108 at 6. Consistent with her expert’s limited development of this point, Ms. Tarsell’s pre-trial brief makes no mention of Christina’s thyroid problem. See Pet’r’s Prehear’g Br., filed Sept. 26, 2014, at 4 (omitting any discussion of a thyroid problem from petitioner’s recitation of facts). Furthermore, from the undersigned’s observation of the witnesses during the testimony, Dr. Shoenfeld discussion of thyroid problems was also relatively unsubstantial. After the hearing, Ms. Tarsell’s briefs seemed to confirm the undersigned’s assessment that Christina’s thyroid was not a very important issue. Her primary brief did not discuss Christina’s thyroid at all. See Pet’r’s Posthear’g Br., filed 21 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 22 of 27 Feb. 17, 2015, especially at 2-3 (omitting facts about thyroid testing). She did not cite Dr. Shoenfeld’s argument that Christina’s hypothyroidism made her predisposed to suffering another autoimmune disease. See id. Likewise, Ms. Tarsell’s reply brief did not discuss Christina’s thyroid at all. See Pet’r’s Reply, filed May 15, 2015. Under these circumstances, the undersigned concluded that petitioner had not actively prosecuted the issue of Christina’s thyroid condition and determined that the issue did not require discussion. The undersigned, however, had acknowledged Christina’s history of thyroid problem in an earlier adjudication. Findings of Fact, 2012 WL 1608741, at *3. However, after Ms. Tarsell’s motion for review, the Court directed an evaluation of Christina’s thyroid. Opinion and Order, 2017 WL 3837363, at *13. The undersigned finds that this argument has very little persuasive value. First, Christina’s experience with a thyroid problem seems temporary. She took Synthroid for a few months, but then her thyroid levels returned to normal. Ms. Tarsell has not persuasively explained why Christina’s experience of low thyroid in 2004 has long-lasting consequences. Second, the undersigned has not identified any treating doctor that diagnosed Christina as having an autoimmune disease. The lack of diagnosis from a treating doctor tends to suggest that Christina was not suffering from an autoimmune disease. See Capizzano, 440 F.3d at 1326 (indicating that reports of treating doctors are favored). While Dr. Shoenfeld diagnosed her as having an autoimmune disease in his testimony, Dr. Phillips disagreed. See Tr. 404-05 (“she really didn’t have any evidence of clinical autoimmune disease”), 481 (“there’s no evidence that [Christina] has any of these autoimmune diseases”). Third, even assuming that Christina suffered from an undiagnosed autoimmune disease, the significance is not clear. Dr. Shoenfeld may be correct (on a more likely than not basis) that a person with one autoimmune disease is prone or predisposed to develop another autoimmune disease. But, if this is true, why does the vaccination contribute to the onset of the second autoimmune disease? It would seem that if Christina developed an autoimmune thyroid problem approximately three years before the HPV vaccination, then an expected course of this autoimmune problem would be to develop another autoimmune problem. Dr. Shoenfeld has not persuasively explained why the HPV vaccine would be a substantial factor in the progression from one autoimmune 22 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 23 of 27 disease to another.12 For these reasons, Ms. Tarsell has not established that Christina’s temporary hypothyroidism supported her claim that the HPV vaccine caused Christina’s arrhythmia. 3. Statements from Treating Doctors The Court directed the undersigned to consider statements from treating doctors. The Court specifically listed “internist Christine Lafferman, pediatrician Renee Howard, gynecologist Julie Jacobstein, otolaryngologist Karl Diehn, and various physicians at Bard College student health services.” Opinion and Order, 2017 WL 3837363, at *14. The Court distinguished this group of doctors from Kari Reiber, the pathologist who performed Christina’s autopsy, because the former treated Christina while she was alive. Id.; but see Nordwall v. Sec’y of Health & Human Servs., 83 Fed. Cl. 477, 488 (2008) (stating that although autopsy reports “may not have been created in the context of diagnosing and treating a patient, they are contemporaneous records made by a health care professional outside the context of litigation, and should be given the same probative weight as other medical records”), app. dismissed voluntarily, 331 Fed. App’x 720 (Fed. Cir. 2009). The undersigned has reviewed the records. The undersigned has not identified any statement from a treating doctor that suggested that the HPV vaccine caused Christina’s arrhythmia and/or her death. While all the physicians who treated Christina commented about different aspects of her health, the undersigned focused on the specific question of the treating doctor’s opinions, if any, about the role, if at all, of the vaccination. Because Ms. Tarsell bears the burden of proving her case with preponderant evidence, the silence from these doctors does not help Ms. Tarsell meet her burden. The Court also corrected a factual matter in that the undersigned incorrectly stated that Dr. Lafferman administered the second dose of the HPV vaccine. Actually, as the Court pointed out, Kim Buerhaus from Dr. Jacobstein’s office administered the second dose at an unknown time on November 20, 2007. See exhibit 3 at 107 (VAERS report). Dr. Lafferman appears to have seen Christina later in the day on November 20, 2007, because the EKG strip is labeled: “Nov/20/2007 14:36:15.” Exhibit 4 at 142. Thus, it appears that Dr. Jacobstein’s 12 In other cases, petitioners’ experts have proposed that the evolution from one autoimmune disease to another autoimmune disease requires a trigger. However, Dr. Shoenfeld appears not to have offered this opinion in this case. 23 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 24 of 27 decision to order the second dose of the HPV vaccine occurred before Christina’s arrhythmia was detected. Finally, the undersigned has considered that Dr. Jacobsen filed a VAERS report. However, Ms. Tarsell requested that Dr. Jacobsen inform appropriate people that Christina died after receiving the HPV vaccine. See exhibit 3 at 113. Dr. Jacobsen did submit a report to VAERS. However, as the February 16, 2016 decision stated, a doctor’s decision to file a report to VAERS does not necessarily indicate that the doctor believed that the vaccine caused the injury. 4. Response Predicted by Causal Theory The February 16, 2016 Decision also found that Ms. Tarsell had not established that Christina showed signs or symptoms of an adverse reaction that was in accord with the theory her experts had presented. Decision, 2016 WL 880223, at *18. The Court required a re-examination of this issue. Opinion and Order, 2017 WL 3837363, at *16. Essentially, Dr. Shoenfeld posited that the HPV vaccination can lead to an autoimmune attack on the heart, specifically on the calcium channels contained within the cell membrane. Dr. Eldar continued the theory by explaining how damage to a calcium channel can cause a fatal arrhythmia. Dr. Phillips questioned whether this process occurred in Christina. He stated: If, in fact, it was a significant autoimmune reaction going on, one would expect to see cellular infiltrates in various organs, and if the autoimmune reaction was going on of significance in the heart, you would expect that the myocardium would be infiltrated with lymphocytes. If there was a cytotoxic antibody there which had been attacking these channels, that cytotoxic antibody would also cause pathologic changes, with secondary infiltration of other cell populations which were inflammatory in nature, including polymorphonuclear cells or mononuclear cells. Tr. 407-08. Dr. Phillips later expressed a similar idea: 24 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 25 of 27 [I]f it’s thought that this is an arrhythmia caused by an antibody doing something to the conduction system of the heart, then it -- if it's a tissue-specific autoimmune reaction, it will be in the heart, and then you should see some abnormalities in the heart vis-à-vis histologic changes, and there weren't any. Tr. 482. Dr. Phillips’s testimony carries a fair amount of weight. Under Dr. Shoenfeld’s theory, the antibodies must break through the cell membrane to reach the calcium channel before damaging the calcium channel. Therefore, it seems to make some sense that such a destructive process would leave some tell-tale signs as Dr. Phillips indicated. Instead of looking at this part of Dr. Phillips’s testimony, the Court cited another portion. [Q.] Have you ever -- in your career or in your research, have you ever -- have you ever encountered a cross-reactivity that doesn't produce cell damage? A. We see cross-reactivities all the time, and many of them don't. Tr. 433. As the transcript indicates, the undersigned believed that the attorney asking the question and the witness answering the question were understanding the term “cross-reactive” differently.13 In any event, the questions and answers following this exchange show that Dr. Phillips expected to see detectable changes. See Tr. 434-37. Moreover, to the extent that Dr. Phillips suggested on page 433, that some autoimmune reactions would not produce cell damage, his testimony about the specific autoimmune reaction in this case – an antibody attack on the L-1 calcium channels of the heart – is that it would be detectable. Dr. Phillips expected that the damage would be visible on the organ that was being attacked – the heart. Although, as the Court pointed out, Dr. Shoenfeld 13 Specifically, the undersigned interjected that it appeared that petitioner’s counsel was using “cross-reactivity” differently than respondent’s counsel had upon previous questioning of the witness. Tr. 433. After that, counsel rephrased his question and Dr. Phillips provided a longer explanation. Tr. 433-434. 25 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 26 of 27 explained that doctors did not look for antibodies, Dr. Phillips was looking at the heart.14 After additional reflection, the undersigned believes that Dr. Phillips presented several strong points weakening Ms. Tarsell’s case. See Bazan, 539 F.3d at 1353-54 (recognizing that the Secretary may introduce evidence to controvert petitioner’s case). If Ms. Tarsell could not establish that Christina’s case fit within the challenge-rechallenge paradigm, then the undersigned would likely find Dr. Phillips’s opinion strong enough to outweigh Ms. Tarsell’s evidence on prong 2. However, the undersigned finds that the challenge-rechallenge evidence is sufficiently probative that this presentation carries Ms. Tarsell’s burden of proof. See Doe 11 v. Sec’y of Health & Human Servs., 601 F.3d 1349, 1355 (Fed. Cir. 2010) (recognizing that the presence of some contrary evidence does not make a special master’s fact-finding arbitrary or capricious). Ultimately, because of the finding that Christina began to experience arrhythmia after her HPV vaccination, Ms. Tarsell has presented preponderant evidence of a logical sequence of cause and effect, connecting the HPV vaccination to the ensuing arrhythmia. IV. Conclusion The Court’s Opinion and Order required additional consideration consistent with the legal principles articulated by the Court for analyzing the evidence in this tragic case about a woman, Christina Tarsell, who died much too young. Under the approach dictated by the Court, Ms. Tarsell is entitled to compensation. The parties should anticipate that a separate order regarding damages will issue shortly. Pursuant to Vaccine Rule 28.1(a), the Clerk’s Office is instructed to notify the Court of this ruling. 14 Similarly, the finding in one article that trace amounts of the DNA of the human papillomavirus have been found in people who have received the HPV vaccine seems irrelevant to the question of whether Christina cross-reacted. 26 Case 1:10-vv-00251-MCW Document 200 Filed 10/13/17 Page 27 of 27 IT IS SO ORDERED. s/ Christian J. Moran Christian J. Moran Special Master 27 ================================================================================ DOCUMENT 4: USCOURTS-cofc-1_10-vv-00251-5 Date issued/filed: 2018-03-26 Pages: 5 Docket text: PUBLIC DECISION (Originally filed: 2/26/2018) regarding 212 DECISION on Remand Stipulation/Proffer. Signed by Special Master Christian J. Moran. (MRG) Service on parties made. -------------------------------------------------------------------------------- Case 1:10-vv-00251-MCW Document 213 Filed 03/26/18 Page 1 of 5 In the United States Court of Federal Claims OFFICE OF SPECIAL MASTERS * * * * * * * * * * * * * * * * * * * * * EMILY TARSELL, as the Executrix * of the Estate of CHRISTINA * No. 10-251V TARSELL, * Special Master Christian J. Moran Petitioner, * * Filed: February 26, 2018 v. * * Damages; decision on proffer; SECRETARY OF HEALTH * human papillomavirus AND HUMAN SERVICES, * (“HPV”) vaccine; sudden * death. Respondent. * * * * * * * * * * * * * * * * * * * * * * Mark T. Sadaka, Mark T. Sadaka, LLC, Englewood, NJ, for petitioner; Ann D. Martin, United States Dep’t of Justice, Washington, D.C., for respondent. UNPUBLISHED DECISION AWARDING DAMAGES1 On April 19, 2010, Emily Tarsell, as executrix of Christina Tarsell’s Estate, filed a petition seeking compensation under the National Vaccine Injury Compensation Program, 42 U.S.C. §§ 300aa-1 through 34, alleging that the human papillomavirus (“HPV”) vaccine caused Christina to die suddenly and unexpectedly. Initially, the undersigned found that Ms. Tarsell had not met her burden of proof. Decision, 2016 WL 880223 (Fed. Cl. Spec. Mstr. Feb. 16, 2016). However, the Court of Federal Claims vacated the decision and remanded for additional consideration under different legal standards. Opinion and Order, 133 Fed. Cl. 782 (2017). Under the Court-directed legal standards, the undersigned found that Ms. Tarsell was entitled to compensation. Ruling, 2017 WL 4583233 (Fed. Cl. Spec. Mstr. Sep. 25, 2017). 1 The E-Government Act, 44 U.S.C. § 3501 note (2012) (Federal Management and Promotion of Electronic Government Services), requires that the Court post this decision on its website. Pursuant to Vaccine Rule 18(b), the parties have 14 days to file a motion proposing redaction of medical information or other information described in 42 U.S.C. § 300aa-12(d)(4). Any redactions ordered by the special master will appear in the document posted on the website. Case 1:10-vv-00251-MCW Document 213 Filed 03/26/18 Page 2 of 5 On February 20, 2018, respondent filed a Proffer on Award of Compensation, to which petitioner agrees. Respondent, nonetheless, maintains his position that petitioner has not established entitlement under the legal standard adopted by the Federal Circuit and denies that Christina Tarsell’s arrhythmia and death were caused by vaccination. Based upon the record as a whole, the special master finds the Proffer reasonable and that petitioner is entitled to an award as stated in the Proffer. Pursuant to the attached Proffer—in the form of a check payable to petitioner as the legal representative of Christina Tarsell’s estate—the court awards petitioner: 1. A lump sum payment of $250,000.00 for Christina Tarsell’s vaccine- related death; 2. A lump sum payment of $60,000.00 for past pain and suffering for Christina Tarsell’s vaccine-related injury; and, 3. A lump sum payment of $130.00 for past unreimbursable expenses related to Christina Tarsell’s vaccine-related injury. These amounts reflect all elements of compensation to which petitioner would be entitled under 42 U.S.C. §300aa-15(a). In the Proffer, the parties note that they have waived their right to seek review of this damages decision. However, the Secretary has reserved his right to seek review of the September 25, 2017 ruling finding entitlement. The Clerk’s Office is instructed: (1) To enter judgment in case 10-251V according to this decision and the attached Proffer; (2) To provide this decision to the presiding judge pursuant to Vaccine Rule 28.1(a). Any questions may be directed to my law clerk, Matthew Ginther, at (202) 357-6360. IT IS SO ORDERED. s/Christian J. Moran Christian J. Moran Special Master 2 Case 1:10-vv-00251-MCW Document 213 Filed 03/26/18 Page 3 of 5 IN THE UNITED STATES COURT OF FEDERAL CLAIMS OFFICE OF SPECIAL MASTERS ____________________________________ ) EMILY TARSELL, as the Executrix ) of the Estate of CHRISTINA TARSELL, ) ) Petitioner, ) No. 10-251V ) Special Master Moran v. ) ECF ) SECRETARY OF HEALTH AND ) HUMAN SERVICES, ) ) Respondent. ) ____________________________________) RESPONDENT’S PROFFER ON AWARD OF COMPENSATION On September 25, 2017, in a decision on remand, the Special Master determined that petitioner is entitled to compensation under the National Childhood Vaccine Injury Act of 1986 (“Vaccine Act”), as amended, 42 U.S.C. §§300aa-1 to -34, after applying the “Court-directed legal standards” articulated by Judge Williams in her June 30, 2017, Opinion and Order, which vacated and remanded the Special Master’s February 16, 2016, decision denying compensation. Maintaining his position that petitioner has not established entitlement to compensation under Althen v. HHS, 418 F.3d 1274 (Fed. Cir. 2005), and denying that Christina Tarsell’s arrhythmia and death were caused by vaccination, respondent nevertheless proffers an award of compensation based on the Special Master’s finding of entitlement. The parties have no objection to the amount of proffered damages. Assuming the Special Master issues a damages decision in conformity with this proffer, the parties waive their right to seek review of such damages decision, recognizing that respondent reserves his right, pursuant to 42 U.S.C. § 300aa-12(f), to seek review of the September 25, 2017, decision finding petitioner entitled to an award under the Vaccine Act. This right accrues following entry of judgment. Case 1:10-vv-00251-MCW Document 213 Filed 03/26/18 Page 4 of 5 I. Items of Compensation For purposes of this proffer, the term “vaccine-related” is as described in the Special Master’s September 25, 2017, decision finding petitioner entitled to an award under the Vaccine Act. Based upon the evidence of record, respondent proffers that petitioner, as legal representative of the estate of Christina Tarsell, should be awarded the following items of compensation, pursuant to 42 U.S.C. § 300aa-15(a): A. $250,000.00 for Christina Tarsell’s vaccine-related death; B. $60,000.00 for past pain and suffering for Christina Tarsell’s vaccine-related injury; and, C. $130.00 for past unreimbursable expenses related to Christina Tarsell’s vaccine- related injury. These amounts represent all elements of compensation to which petitioner would be entitled under 42 U.S.C. §300aa-15(a). Petitioner agrees. II. Form of the Award Respondent recommends that the compensation should be made through a lump sum payment of $310,130.00 in the form of a check payable to petitioner as the legal representative of the estate of Christina Tarsell. Petitioner agrees. No payment shall be made until petitioner provides respondent with documentation that she has been appointed the legal representative of Christina Tarsell’s estate. Respectfully submitted, CHAD A. READLER Acting Assistant Attorney General C. SALVATORE D’ALESSIO Acting Director Torts Branch, Civil Division 2 Case 1:10-vv-00251-MCW Document 213 Filed 03/26/18 Page 5 of 5 CATHARINE E. REEVES Deputy Director Torts Branch, Civil Division GABRIELLE M. FIELDING Assistant Director Torts Branch, Civil Division s/ Ann D. Martin by s/ Traci R. Patton ANN D. MARTIN Senior Trial Attorney Torts Branch, Civil Division U.S. Department of Justice P.O. Box 146 Benjamin Franklin Station Washington D.C. 20044-0146 Tel: (202) 307-1815 E-mail: Ann.Martin @usdoj.gov Dated: February 20, 2018 3