Cheryl Koehn, as Mother and Next Friend of Vanessia Koehn v. Secretary of Health and Human Services

In the United States Court of Federal Claims

OFFICE OF SPECIAL MASTERS

**********************

CHERYL KOEHN, *

as mother and next friend of * No. 11-355V

VANESSIA KOEHN, * Special Master Christian J. Moran

*

Petitioner, * Filed: May 30, 2013

*

v. *

* Entitlement, HPV vaccine (Gardasil),

SECRETARY OF HEALTH * systemic juvenile idiopathic arthritis

AND HUMAN SERVICES, * (sJIA)

*

Respondent. *

**********************

P. Leigh O’Dell, Beasley, Allen, et al., Montgomery, AL, for petitioner;

Darryl R. Wishard, United States Dep’t of Justice, Washington, DC, for

respondent.

PUBLISHED DECISION DENYING COMPENSATION1

Cheryl Koehn alleges that two doses of the human papillomavirus (“HPV”)

vaccine given to her daughter, Vanessia, caused her to suffer from systemic

juvenile idiopathic arthritis (“sJIA”).2 Ms. Koehn seeks compensation from the

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.

2

The Secretary recognized the HPV vaccine as a vaccine covered in the

Vaccine Program on April 20, 2007. National Vaccine Injury Compensation

(. . . continued)

National Childhood Vaccine Injury Compensation Program. 42 U.S.C. § 300aa-10

et seq. (2012). To establish that she is entitled to compensation, Ms. Koehn must

fulfill the three-pronged test set forth in Althen v. Sec’y of Health & Human

Servs., 418 F.2d 1274, 1278 (Fed. Cir. 2005).

Ms. Koehn relies primarily upon the opinion of Michael McCabe, Ph.D. Dr.

McCabe presents an innovative theory involving cytokines to explain how an HPV

vaccine can cause sJIA. The Secretary, however, undermined the persuasive value

of Dr. McCabe’s hypothesis by presenting a contrary opinion from Carlos Rose,

M.D., a board-certified rheumatologist. As detailed in section IV below, Dr.

McCabe’s theory has not been tested, has not been the subject of peer-review, is

not generally accepted in the relevant medical community, and is inconsistent with

epidemiological studies.

The flaws in Ms. Koehn’s evidence extend from the first prong of Althen to

the remaining two prongs. Ms. Koehn has not established that the onset of her

sJIA occurred in a temporal interval that Dr. McCabe’s theory would predict. See

section V. Additionally, Ms. Koehn’s case lacks a “logical sequence of events”

that connects her disease to the HPV vaccination as required by the second prong

of Althen. See section VI.

Consequently, Ms. Koehn has not established that she is entitled to

compensation. A full discussion follows.

I. Procedural History

Ms. Koehn filed her petition on June 6, 2011, and medical records on June

14, 2011. These medical records are summarized in section II.C, below. Ms.

Koehn filed a report from Dr. McCabe on August 24, 2011. Exhibit 9. Due to

concerns about the adequacy of the disclosure regarding Althen prong one, Ms.

Program: Addition of Meningococcal and Human Papillomavirus (HPV) Vaccines

to the Vaccine Injury Table, 72 Fed. Reg. 19937. Although many petitioners have

claimed that the HPV vaccine harmed them, this may be the first instance in which

a claim has reached a special master for resolution. (Other HPV vaccine cases

have been resolved when petitioners acknowledged that they were not likely to

prevail or when the parties reached a settlement.)

2

Koehn filed a supplemental report from Dr. McCabe on October 3, 2011. Exhibit

27. As discussed more extensively below, in sections II.D.1.b and c, Dr. McCabe

opined that the HPV vaccine caused Vanessia’s sJIA. Ms. Koehn also filed the

articles on which Dr. McCabe relied.

After Ms. Koehn made these submissions, the Secretary evaluated the

evidence. The Secretary recommended that compensation be denied because Ms.

Koehn had not satisfied any of the three elements set forth in Althen. In addition

to identifying perceived flaws in Dr. McCabe’s opinion, the Secretary also relied

upon an opinion presented by Dr. Rose. Resp’t Rep’t, filed Nov. 14, 2011. The

gist of Dr. Rose’s opinion is that there is not adequate evidence to support the

theory that the HPV vaccine can cause sJIA. See sections II.D.2.b and c, below.

The parties did not succeed in resolving the case through a settlement. Thus,

the case was set for a hearing. In advance of the hearing, the parties filed briefs

and additional medical literature. Dr. McCabe and Dr. Rose testified at a hearing

held on June 21, 2012. Following the hearing, the parties submitted additional

articles and briefs.

Ms. Koehn’s claim that the HPV vaccine caused Vanessia’s sJIA is ready for

adjudication. The foundational elements—the HPV vaccine and sJIA—are

discussed first. The following sections review Vanessia’s medical history as well

as the qualifications, reports, and testimony of the experts. After a short recitation

of the legal standards, this decision separately analyzes Ms. Koehn’s evidence for

each of the Althen prongs. Section VII provides the conclusion.

II. Background

To provide context to Vanessia’s medical history and the opinions of the

parties’ experts on the issue of vaccine causation, found below in sections II.C and

D, respectively, it is helpful first to review some preliminary information

concerning the vaccine Vanessia received and the condition from which she

suffers. Thus, sections II.A and B provide a brief overview of human

papillomavirus, HPV vaccine, and JIA.

3

A. Human Papillomaviruses and Human Papillomavirus Vaccines

1. Human Papillomaviruses

There are more than 130 different types of human papillomaviruses. These

viruses tend to be found in cutaneous or mucosal epithelial surfaces. Some strains

of human papillomavirus are relatively benign, causing warts. Other strains, in

particular HPV 16 and HPV 18, cause cervical cancer. Exhibit 16 (Margaret

Stanley, Immunobiology of HPV and HPV vaccines, 109 Gynecologic Oncology

S15 (2008)) at S15-16.

Because of the cells that it infects, a human papillomavirus “is practically

invisible to the host who remains ignorant of the pathogen for long periods of

time.” A human papillomavirus does not cause cytolysis,3 necrosis,4 or

inflammation. Without exposure to the host’s immune system, “there is little or no

release into the local milieu of pro-inflammatory cytokines.” Id. at S16. This is

part of the virus’s strategy for survival.

Given enough time, “most [human papillomavirus] infections resolve.” But,

approximately 10-20 percent of infected individuals develop persistent infections.

One reason appears to be that humans produce relatively few antibodies in

response to the human papillomavirus. Id. at S17.

2. Vaccines against Human Papillomaviruses

Developing an effective vaccine against human papillomaviruses was

challenging, in part, because of the need to generate a robust response from the

person’s immune system. Exhibit 16 (Stanley) at S17-18. Researchers eventually

succeeded in creating an HPV vaccine that induces “high concentrations of

neutralizing antibodies.” Id. at S18. An HPV vaccine can cause the host to

produce more antibodies than the human papillomavirus because, in part, the

vaccine is given intramuscularly, close to the lymph nodes. This delivery system

3

Cytolysis is the “destruction of a cell by rupture of the cell membrane with

loss of cytoplasm.” Dorland’s Illustrated Medical Dictionary 466 (32nd ed. 2012).

4

Necrosis is “the sum of morphological changes indicative of cell death.”

Dorland’s at 1235.

4

“circumvent[s] the immune avoidance strategies of the viral intraepithelial

infectious cycle.” Id.

a) HPV Vaccine Composition

Another advance in the creation of vaccines against the human

papillomavirus was the reproduction of a portion of the virus known as the L1

protein. The resulting virus-like particle (VLP) stimulates the immune system to

produce antibodies and the antibodies confer immunity to the particular strand of

the human papillomavirus. Exhibit 17 (Margaret Stanley, HPV- immune response

to infection and vaccination, 5 Infectious Agents & Cancer 19 (2010)) at 2-3.

There are two different vaccines against human papillomavirus. One, known as

Cervarix, contains the L1 VLP for two strands, 16 and 18. The other, known as

Gardasil, contains the L1 VLP for four strands, 6, 11, 16, and 18. Id. at 3. In

addition to the difference in strands, Cervarix and Gardasil contain different

adjuvants.5 Cervarix uses an adjuvant known as AS04, which is comprised of a

lipid and an aluminum salt. Exhibit E (Thomas Verstraeten et al., Analysis of

adverse events of potential autoimmune aetiology in a large integrated safety

database of AS04 adjuvanted vaccines, 26 Vaccine 6630 (2008)) at 6631. On the

other hand, Gardasil uses amorphous aluminum hydroxyphosphate sulfate to

increase antibody production. Transcript (“Tr.”) 154; Physician’s Desk Reference

at 1828 (66th ed. 2012).

b) HPV Vaccine Effectiveness

Experiments on HPV vaccines have shown that “the peak geometric mean

antibody concentrations achieved are at least two [logarithmic] higher than those

after natural seroconversion”6 and for “the majority of vaccinated subjects, serum

antibody levels remain at concentrations greater than those found in natural

infection.” Exhibit 16 at S18. One article commented that “[i]t is fairly

uncommon that a vaccine will produce an immune response greater than that

5

An adjuvant is a stimulator of a more robust immune response. See

Dorland’s at 32

6

Seroconversion is “the change of a patient’s serologic test from negative to

positive, indicating the development of antibodies in response to infection or

immunization.” Dorland’s at 1698.

5

achieved by natural infection.” Exhibit 21 (Villa et al., Immunologic responses

following administration of a vaccine targeting human papillomavirus Types 6, 11,

16, and 18, 24 Vaccine 5571 (2006)) at 5581.7

The amount of time to generate the antibody response was discussed in

several articles. For example, one article reported that “vaccination induced a

marked immune response, beginning approximately 1 month after the initial dose,

peaking at approximately month 7, and thereafter declining to a stable plateau for

2.5 years after the last vaccine dose.” Exhibit 25 (Ian Frazer, Correlating

immunity with protection for HPV infection, 11 Int’l J. Infectious Diseases S10

(2007)) at S13; see also exhibit 22 (Elmar Joura et al., HPV antibody levels and

clinical efficacy following administration of a prophylactic quadrivalent HPV

vaccine, 26 Vaccine 6844 (2008)) at 6849; exhibit 28 (Alfonso García-Piñeres et

al., Cytokine and Chemokine Profiles following Vaccination with Human

Papillomavirus Type 16 L1 Virus-Like Particles, 14 Clinical & Vaccine

Immunology 984 (2007)) at 986; exhibit 29 at 331.

In addition to looking at the production of antibodies in response to an HPV

vaccine, researchers have also investigated the cytokine response. E.g., exhibit 28

(García-Piñeres), exhibit 32 (Rebecca T. Emeny et al., Priming of Human

Papillomavirus Type 11-Specific Humoral and Cellular Immune Responses in

College-Aged Women with a Virus-Like Particle Vaccine, 76 J. Virology 7832

(2002)), exhibit 30 (Thomas G. Evans et al., A Phase 1 Study of a Recombinant

Viruslike Particle Vaccine against Human Papillomavirus type 11 in Healthy Adult

Volunteers, 183 J. Infectious Diseases 1485 (2001)). At the hearing, relatively

little attention was paid to the García-Piñeres article, Emeny article, or the Evans

article because Dr. McCabe and Dr. Rose primarily discussed an article by Pinto.

See, e.g., Tr. 119-20.

7

Other studies that also reported that the vaccine produces a stronger

antibody response include exhibit 29 (Ligia A. Pinto et al., Cellular Immune

Responses to Human Papillomavirus (HPV)—16 L1 in Health Volunteers

Immunized with Recombinant HPV-16 L1 Virus-Like Particles, 188 J. Infectious

Diseases 327 (2003)) at 336; exhibit 35 (Purnima Bhat et al., Regulation of

immune responses to HPV infection and during HPV-directed immunotherapy,

239 Immunological Revs. 85 (2011)) at 87; and exhibit 18 (Luciano Mariani &

Aldo Venuti, HPV vaccine: an overview of immune response, clinical protection,

and new approaches for the future, 8 J. Translational Med. 105 (2010)) at 107.

6

Dr. McCabe bases much of his opinion on the Pinto article, which, according

to Dr. McCabe, is “an important paper in vaccinology, the study of vaccines.” Tr.

100. The Pinto study is “a technical tour de force.” Tr. 100, 103. Therefore, due

to its complexity and its significance, the Pinto article is reviewed in detail.

When this study was conducted, vaccines against human papillomavirus

were being developed. Dr. Pinto and colleagues designed an experiment “to better

characterize the innate and acquired immune system cytokine response elicited by

L1 VLP vaccination.” Exhibit 26 (Ligia A. Pinto et al., HPV-16 L1 VLP vaccine

elicits a broad-spectrum of cytokine responses in whole blood, 23 Vaccine 3555

(2005)) at 3556. The vaccination referenced in the Pinto article contained one

protein present in Gardasil. Tr. 100.

Twenty-four women participated in the study. Blood specimens were

collected before the initial injection, known as month zero. Twenty women, then,

received a 50 µg dose of vaccination without adjuvant and four women received a

placebo of sterile saline solution. One month later, all women were given a second

injection of the same substance (either the vaccination or a placebo). At month

two, more blood was drawn. At six months, the women received a third injection.

At seven months, more blood was drawn. Exhibit 26 at 3556.

The researchers determined the level of cytokines for each of the three blood

samples after different types of stimulation. Exhibit 26 at 3557. This process was

done “in vitro,” id. at 3562, meaning in glass, like a test tube. Dorland’s at 956.

The blood from women who received the vaccine and women who received the

placebo was evaluated in the context of four substances. In the first, the blood was

not stimulated at all. The researchers refer to this as the “media.” In the second,

the blood was stimulated with 10 µg of the virus-like particle present in the

vaccine. In the third, the blood was stimulated with 1.0 µg of the virus-like

particle. In the fourth, the blood was stimulated with a control known as PHA.

Exhibit 26 at 3557, § 3.1; see also Tr. 292-93. The stimulation was for “24 [hours]

in the absence or presence of L1 VLP or PHA.” Exhibit 26 at 3559 (caption to

figure 1).

As discussed below in section IV.B.3, the researchers obtained different

results depending upon whether there was any stimulation. For cells in the

media—meaning no stimulation—the cytokine levels stayed relatively similar

from month zero to month two to month seven. “As shown in Fig. 1D,

spontaneous secretion of cytokines in the absence of any stimuli (media control)

7

did not show any significant increases following vaccination.” Exhibit 26 at 3560.

For blood that was stimulated either with 10 µg or 1.0 µg of the virus-like particle,

cytokines increased. “Stimulation of cells from vaccine recipients with L1 VLP

(10 µg/ml) induced significant increases in the median levels of inflammatory . . .

cytokines.” Id. at 3557-59. “Similar patterns of cytokine production to the ones

seen in response to L1 VLP at 10 µg/ml were observed when L1 VLP was tested at

1.0 µg/ml.” Id. at 3559.

c) HPV Vaccine Safety

Dr. McCabe and Dr. Rose each referenced one epidemiological study that

investigated the safety of an HPV vaccine.8 One was an article by Chun Chao.

Exhibit 34 (Chao et al., Surveillance of autoimmune conditions following routine

use of quadrivalent human papillomavirus vaccine, 271 J. Intern. Med. 193

(2012)). The other was an article by Thomas Verstraeten. Exhibit E.

(1) Chao Article

Dr. Chao and colleagues used a database to look at the medical history of

nearly 190,000 women. Their goal was to determine whether women who

received a dose of a quadrivalent human papillomavirus vaccine developed

autoimmune diseases within 180 days after the vaccination. Exhibit 34 at 193.

The researchers selected 180 days “to accommodate lag time for clinical work”

necessary for the treating doctor to arrive at the correct diagnosis. Id. at 201.

The article says that the researchers looked for cases of “juvenile rheumatoid

arthritis (JRA).” Id. at 194. The article explained how the researchers looked for

various diseases:

8

Dr. Rose also reproduced a portion of the package insert (also known as the

manufacturer’s label). See exhibit A at 3-4. The Secretary, however, did not

submit the package insert as an exhibit, did not ask any questions about the

package insert during direct examination of Dr. Rose, and did not cite it in her

post-hearing brief. Although Ms. Koehn asked some questions about the package

insert during the cross-examination of Dr. Rose, Tr. 252-60, the package insert

does not affect the outcome of this case.

8

The method for case identification was designed to be highly sensitive

to capture any potential cases, to address potential undercoding or

miscoding in the early course of an autoimmune condition. To this

end, ICD-9 diagnosis codes, abnormal laboratory results or pharmacy

prescriptions possibly indicative of autoimmune conditions . . . were

captured.

Id. at 194-95. Information about the specific ICD-9 codes was contained in

Appendix A-C. Id. at 195. However, the copy of the Chao article that was filed as

exhibit 34 did not contain the appendices. See exhibit 34.

After the scope of the case ascertainment became an issue at the hearing, see

Tr. 248, Dr. Rose was permitted to file the relevant appendix and a report

commenting on the ICD-9 code. As a preliminary matter, Dr. Rose explained what

an ICD-9 code is:

The ICD-9 is a complex and evolving international coding system

utilized by patient care providers to identify the condition or

conditions suffered by their patients. The codes have a multiplicity of

uses including retrospective identification of cases for public health

projects (like the one in question), utilization of resources, quality

assurance and adequacy of charges for rendered services.

Exhibit I (Dr. Rose’s supplemental report, dated Nov. 1, 2012) at 2.9 Dr. Rose next

stated that under the ICD-9, the relevant code is 714.3, juvenile rheumatoid

arthritis. Id. The Chao researchers used this code. See exhibit H (reproduction of

Appendix A-1 from the Chao article). In addition, the Chao researchers also

searched for medications commonly prescribed for sJIA. Exhibit I at 3. Thus, Dr.

Rose concluded that “almost certainly all cases of JRA within the study population

would have been detected with the methodology utilized by the investigators.” Id.

at 4.

Given this understanding of what the researchers did, the results can be

stated. In the category of juvenile rheumatoid arthritis, the researchers found three

9

For more information about ICD-9 codes, see Fresco v. Sec’y of Health &

Human Servs., No. 06-469V, 2013 WL 364723, at *9 n.40 (Fed. Cl. Spec. Mstr.

Jan. 7, 2013).

9

cases arising after vaccination. Exhibit 34 at 197 (table 1, column E, line 6).

Among people who were not vaccinated, the researchers estimated that there were

43 cases. Id. at 199 (table 3, third column, line 6). The incidence rate ratios

(“IRR”) was 0.48 with a 95% confidence interval of 0.26-0.91. Id. (table 3,

columns 4-5, line 6). Dr. Rose explained that because the confidence interval was

below 1.0, there was “no increase in risk of developing new onset of JRA after

HPV vaccination.” Exhibit I at 3. Although Dr. Chao and colleagues did not make

a specific finding for juvenile rheumatoid arthritis, their overall conclusion was

similar. They stated that “this observational surveillance study offers some

assurance that amongst a large and likely generalizable female population, no

safety signal for autoimmune conditions was found following HPV4 vaccination in

routine clinical use.” Id. at 202.

(2) Verstraeten Article

The Verstraeten article collects several studies about the safety of vaccines

containing an adjuvant known as AS04. AS04 is the adjuvant in Cervarix, not the

adjuvant used in Gardasil. Exhibit E at 6631; Tr. 240 (Dr. Rose).

Dr. Verstraeten’s and colleagues’ goal was “to evaluate the safety of AS04

adjuvanted vaccines with regard to rates of AEs [adverse events] of potential

autoimmune aetiology.” Exhibit E at 6631. To address the problem that small

studies may not detect rare events, Dr. Verstraeten and colleagues collected “[a]ll

completed or ongoing controlled, randomised studies of ASO4 adjuvanted HPV-

16/18, HSV and HBV vaccines conducted by GSK Biologicals [GlaxoSmithKline,

the manufacturer of those vaccines] or collaborators,” with one exception. Id.

Forty-two studies were included. Id. at 6632 (table 1). More than 36,000 people

received a vaccine and more than 30,000 people served as controls. Id. In regard

to the number of people, Dr. Rose stated that the Verstraeten article was

“the closest that we can be to an epidemiological study” because it studied “about

60,000 individuals . . . [and] covered two years of followup.” Tr. 232. Dr.

McCabe did not address this article.

Using a database, Dr. Verstraeten and colleagues looked for adverse events

following the vaccination using terms in the Medical Dictionary for Regulatory

Activities. Exhibit E at 6631. One of the terms was “juvenile arthritis,” which,

10

according to Dr. Rose, encompasses sJIA. Id. at 6633 (table 2); Tr. 287.10 The

authors’ general conclusion was their study “did not show evidence of an overall

increase in relative risks for autoimmune disorders in participants receiving

vaccines containing AS04 compared with controls.” Exhibit E at 6633.

B. Juvenile Idiopathic Arthritis

1. Basic Information11

The term “juvenile idiopathic arthritis” encompasses several different

diseases. The form affecting Vanessia is known as sJIA.12 The diagnostic criteria

10

Another term was “rheumatoid arthritis,” an autoimmune disease that Dr.

Rose stated does not encompass sJIA. Exhibit E at 6634 (table 3); Tr. 287; see

also Tr. 186, 197-98. Among the vaccine recipients, there were 12 cases of

rheumatoid arthritis. Among the controls, there were nine cases. Exhibit E at 6634

(table 3). The relative risk was 1.17 and the 95 percent confidence interval ranged

from 0.47 to 2.86. Id. at 6635 (table 4). When asked about this article, Dr.

McCabe explained that a relative risk of greater than one means that the risk is

increased and a relative risk of less than one means that the risk is decreased. Tr.

188.

11

Dr. McCabe, who is not a medical doctor, testified that he learned more

about sJIA by reading articles about the disease in the course of preparing his

expert report. Tr. 164; see also Tr. 65 (discussing exhibit 12), 75-80 (discussing

exhibit 13). Dr. Rose, who is a pediatric rheumatologist with experience in

treating sJIA, generally did not challenge the accuracy of information provided

about the disease. Thus, the source of information about sJIA is the set of articles

filed as exhibits as well as the testimony.

12

Other names for this same entity include Still’s disease, systemic arthritis,

systemic-onset juvenile rheumatoid arthritis, and systemic-onset juvenile chronic

arthritis. Exhibit C (Fabrizio De Benedetti & Rayfel Schneider, Chapter 14:

Systemic Juvenile Idiopathic Arthritis, in Textbook of Pediatric Rheumatology

(“Textbook”) (James T. Cassidy et al. eds., 6th ed. 2011)) at 236. Exhibit G

contains a photocopy of the cover of this textbook, the book’s publication

information, and the first page (page 236) of chapter 14. For ease, all citations to

this textbook will be made to exhibit C.

11

include: arthritis and a quotidian fever13 for at least two weeks, plus a rash,

lymphadenopathy, enlargement of the liver or spleen, or serositis. Exhibit C at 236

(relying upon the criteria set by the International League of Associations for

Rheumatology).

The disease manifests in different parts of the body. Characteristically more

than one joint is affected. During active inflammation, a person often experiences

muscle pain, a fever and rash. The disease also causes problems in the person’s

spleen and lymph nodes. Less common features include problems in the heart,

liver and (more rarely) the central nervous system. Exhibit C at 238-41.

“The acute manifestations of sJIA are variable in duration and last from

weeks to months.” Id. at 246. While approximately 40 percent of patients nearly

completely recover after one course of the disease, more than half of the people

afflicted “have a persistent disease course.” Id. In the United States, less than 0.5

percent of people with sJIA die from it. Id. at 247.

Treatments for sJIA include “medications to minimize joint inflammation.”

Id. at 244. Prednisone is recommended.14 Other drugs that have some

effectiveness include anti-tumor necrosis factor,15 anti-interleukin 6 receptors, anti-

interleukin 1, methotrexate,16 intravenous immunoglobulin, cyclosporine-A, and

thalidomide. Exhibit C at 244-46.

13

A quotidian fever is one that “recurs every day.” Dorland’s at 693. The

fever in sJIA is also sometimes referred to as a “hectic fever,” which also means

recurring each day. Id. at 692.

14

Prednisone is a medication against inflammation and suppresses the

immune system. Dorland’s at 1509.

15

An example of a pharmaceutical that inactivates tumor necrosis factor is

etanercept. Dorland’s at 650. Enbrel is a trademarked name for etanercept. Id. at

612.

16

Methotrexate is a “folic acid inhibitor” used for many conditions,

including “severe rheumatoid and psoriatic arthritis.” Dorland’s at 1151.

12

Studies from Europe suggest that sJIA has an annual incidence of between

0.3 and 0.8 per 100,000 children less than 16 years of age.17 Although the onset

peaks among children 1-5 years old, adolescents and adults can also develop the

disease. Males and females are affected equally. Id. at 236.

2. Causes

The term name of the disease—systemic idiopathic juvenile arthritis—

provides information about what is known about the cause of the disease.

According to a medical dictionary, “idiopathic” means “of unknown cause or

spontaneous origin.” Dorland’s at 912. “Idiopathic” does not mean that there is no

cause. While the cause or causes of sJIA have not been found, “there is substantial

evidence of a dysregulated innate immune response with consequent increased

production of inflammatory cytokines.” Exhibit G at 237.18

Cytokines are “nonantibody proteins released by one cell population . . . on

contact with specific antigen, which act as intercellular mediators, as in the

generation of an immune response.” Dorland’s at 466. Cytokines are “the ways

we tell one cell to the other what to do.” Tr. 279 (Dr. Rose). Cytokines are “very

ubiquitous” and the cytokine response is “almost . . . universal.” Id. After a

person encounters an antigen, the immune system responds with the production of

cytokines within hours. Tr. 281-82 (Dr. Rose), 295, 300 (Dr. McCabe).

17

The incidence rate refers to the number of new cases in a population over

a period of time. See Dorland’s 1595.

18

An autoinflammatory disease differs from an autoimmune disease. See

Dorland’s at 181 (defining autoimmune and autoinflammatory). Autoimmune

diseases, about which special masters often hear testimony, are caused by

autoantibodies and autoreactive T cells. However, in sJIA, autoantibodies and

autoreactive T cells are not involved. Thus, sJIA is not an autoimmune disease.

Exhibit 13 (Elizabeth D. Mellins et al., Pathogenesis of systemic juvenile

idiopathic arthritis: some answers, more questions, 7 Nature Revs. Rheumatology

416 (2011)) at 417-18.

While rheumatologists such as Dr. Mellins, distinguish autoimmune diseases

from autoinflammatory diseases, Dr. Chao and Dr. Verstraeten (two

epidemiologists) did not maintain this precision. Although both articles discuss

“autoimmune diseases,” that phrase is broad enough to include sJIA. See section

II.A.2.c.

13

Human beings produce a finite number of types of cytokines, with perhaps

as many as 40 different cytokines being identified so far. Tr. 290; see also Tr. 172

(Dr. McCabe stating he “accept[s] to a certain extent that there is a commonality in

immune effector functions”). Depending on the context, cytokines have different

purposes. Some cytokines promote inflammation while other cytokines are anti-

inflammatory. See Tr. 78. Dr. McCabe stated that ordinarily, pro-inflammatory

cytokines can act on multiple tissues and can lead to (a) increased vascular

permeability, (b) fever, and (c) increased synovial inflammation. Tr. 77-78; see

also exhibit 13 (Mellins) at 418-21, reproduced as exhibit 38 (PowerPoint slides) at

5.

The specific pro-inflammatory cytokines that have been implicated in the

development of sJIA include interleukin (“IL”) 1, IL-6, IL-7, IL-8, IL-18,

macrophage inhibitory factor, and tumor necrosis factor. Exhibit C (Textbook) at

237; Tr. 66 (Dr. McCabe), 280 (Dr. Rose). “Many features of sJIA seem to be

explained by the known effects of innate proinflammatory cytokines, IL-1 and IL-6

in particular.” Exhibit 13 at 418.

How any of these cytokines contribute to sJIA is unknown.19 As one

textbook stated, “[t]he role of each one of these mediators is far from being

clarified.” Exhibit C at 237. At the hearing, Dr. McCabe recognized that the

medical community did not understand what the cytokines were doing at the

cellular level. Tr. 299.

Even accepting the proposition that pro-inflammatory cytokines contribute

to the course of sJIA, this observation does not identify the causes of the disease

because something must initiate the increase in cytokines. Hence, one of the

articles cited by Dr. McCabe asks “What are the initial triggers of sJIA?” Exhibit

13 (Mellins) at 423. As Dr. Rose explained, medical researchers are generating

19

The production of pro-inflammatory cytokines does not always result in

disease. In fact, as Dr. McCabe and Dr. Rose recognize in their expert reports, the

production of pro-inflammatory cytokines is a protective response that vaccines are

designed to elicit. See exhibit 9 (Dr. McCabe) at 3 and exhibit A (Dr. Rose) at 6;

see also exhibit 26 (Pinto). The production of these pro-inflammatory cytokines,

however, is associated with diseases, including diseases other than sJIA, such as

sarcoidosis and systemic lupus erythematosus. Tr. 279.

14

hypotheses to explain the development of pro-inflammatory cytokines. See Tr.

217.

Dr. McCabe identified three articles in which the authors stated that

infections or vaccinations could be the initial cause for sJIA. Tr. 136, 142-43,145-

46. One article stated, “in juvenile idiopathic arthritis (JIA) a temporal relationship

between disease onset, childhood vaccination, remissions and flares hint[s] at a

possible relation of JIA disease activity and vaccinations or infections.” Exhibit 15

(Arash Ronaghy et al., Vaccination leads to an aberrant FOXP3 T-cell response in

non-remitting juvenile idiopathic arthritis, 70 Ann. Rheum. Dis. 2037 (2011)) at

120 (footnote deleted without notation). Another article asserted that “[o]ne

scenario is that infectious agents that are typically encountered in childhood initiate

sJIA; no single environmental trigger has been identified, although this lack of an

obvious candidate could point to multiple common agents being capable of

initiating sJIA.” Exhibit 13 (Mellins) at 417. A third article stated “[i]n juvenile

idiopathic arthritis, infections and vaccinations have been suggested as two

candidate triggers.” Exhibit 12 (Berent Prakken et al., Juvenile idiopathic arthritis,

377 Lancet 2138 (2011)) at 2141. This article continued, “but neither has been

confirmed as a trigger because of a scarcity of proper controlled, prospective

studies.” Id.

In the context of discussing vaccination as a possible trigger, Prakken cited

two articles that were filed into the record. Exhibit 12 (Prakken) at 2141 nn. 46,

47. In both studies, the people given the vaccine already suffered from juvenile

idiopathic arthritis and the researchers were examining whether the patient’s

disease worsened after the vaccination. One study involved the mumps, measles,

and rubella (“MMR”) vaccine. In a retrospective analysis of 207 patients with

juvenile idiopathic arthritis (of which 17 had systemic arthritis), the researchers

found “no changes in disease activity, flare occurrence or medication use after the

MMR vaccination.” Exhibit 43 (Marloes W. Heijstek et al., Safety of measles,

mumps and rubella vaccination in juvenile idiopathic arthritis, 66 Ann. Rheum.

Dis. 1384 (2007)) at 1386. Thus, the researchers concluded that the “MMR

vaccination appears to be safe in JIA.” Id.

20

This article, as submitted, does not have the same pagination as originally

published in the Annals of Rheumatic Diseases.

15

The other study used the meningococcal C vaccination. The total number of

participants was 234, including 34 with systemic arthritis. The researchers “did

not detect any worsening of disease activity within 6 months after MenC

vaccination.” Exhibit 47 (Evelien Zonneveld-Huijssoon et al., Safety and Efficacy

of Meningococcal C Vaccination in Juvenile Idiopathic Arthritis, 56 Arthritis &

Rheumatism 639 (2007)) at 644.

The parties did not submit any case reports linking the Gardasil vaccine and

JIA.

C. Vanessia’s Medical History before and after her sJIA Diagnosis21

Vanessia was born in February 1995. She was generally healthy for the first

12 years of her life. In February 2008, Vanessia saw her regular doctor, Dr. Elena

R. Regala for a routine check-up. Dr. Regala noted Vanessia’s history of asthma.

Exhibit 3 at 11. Dr. Regala’s office administered the first dose of the HPV vaccine

to Vanessia on this date. Id.; exhibit 2 at 3. Vanessia received the second dose of

the HPV vaccine on April 18, 2008. Exhibit 2 at 3; exhibit 3 at 8.

On approximately June 21, 2008, Vanessia developed a rash all over her

body. She reported to Dr. Regala on June 24, 2008, that she had this rash for “3

days.” Exhibit 3 at 8. Dr. Regala suspected an allergic reaction and prescribed

Benadryl and prednisone. Id. The rash disappeared in three days. Id. at 26 (notes

dated July 2, 2008).

Vanessia stopped taking the prednisone and, on June 27, 2008, she

developed pain in many places including her knees, thighs, and calves. Exhibit 4

at 14.22 Dr. Regala’s impression included juvenile rheumatoid arthritis. Exhibit 3

at 27.

On June 28, 2008, Vanessia was admitted to Marian Medical Center for

“high fever accompanied by severe joint pains of the knees and ankles,” which

21

The parties accept the accuracy of the medical records.

22

Given that Dr. Regala prescribed prednisone on June 24, 2008, and

Vanessia reported, on June 27, 2008, that she had stopped taking prednisone, it

appears that Vanessia actually took prednisone for fewer than three days.

16

started on June 25, 2008. Exhibit 3 at 26. While in the hospital, various laboratory

tests were done. Exhibit 3 at 12-21; exhibit 4 at 6. Dr. Frank Scott, a

rheumatologist, saw Vanessia. Dr. Scott’s impression was that she had “probable

Still’s disease (systemic onset juvenile arthritis).” Exhibit 4 at 11-12. Vanessia

was prescribed prednisone. By the day on which she was discharged (July 2,

2008), she had started to feel better, no longer had a fever, and was not suffering

from joint pains. However, she still had a rash. When she left the hospital, her

presumptive discharge diagnosis was JIA. Exhibit 4 at 6. At discharge, Dr. Regala

referred Vanessia to a pediatric rheumatologist. Exhibit 3 at 11.

On July 8, 2008, Vanessia saw Dr. Deborah McCurdy, a pediatric

rheumatologist at the University of California at Los Angeles Health System. Dr.

McCurdy recorded that Vanessia’s vaccinations were up-to-date, including a

second dose of the HPV vaccine. Dr. McCurdy also noted that Vanessia’s family

history included JIA. Exhibit 5 at 51. Dr. McCurdy stated that Vanessia’s

symptoms made “sJIA very likely.” Id. at 55. Dr. McCurdy continued the

prescriptions for prednisone and was waiting for the results of pending laboratory

studies to add methotrexate and Enbrel. Id. Dr. McCurdy sent a letter

summarizing her findings to Dr. Regala on July 8, 2008. Exhibit 5 at 20-26. Dr.

McCurdy’s letter mentioned that Vanessia had “just received the second of three

HPV vaccines.” Id. at 21.

Vanessia saw Dr. Regala again on August 19, 2008. Exhibit 3 at 6. Dr.

Regala knew that Vanessia was suffering from JIA from the previous

correspondence with Dr. McCurdy. See exhibit 5 at 20, 24 (Dr. McCurdy’s letter

to Dr. Regala dated July 8, 2008). Dr. Regala administered the third dose of the

HPV vaccine to Vanessia on August 19, 2008. Exhibit 3 at 6; see also exhibit 2

at 3.

On August 27, 2008, a physical therapist associated with a local public

health department, Sylvia Medinger, saw Vanessia in response to a referral from

Dr. McCurdy. In her history, Ms. Medinger recorded that Vanessia’s dose of

prednisone had ended on August 18, 2008. Vanessia was still receiving Enbrel.

On August 25, 2008, Vanessia had a “flare-up . . . with fever, rash and increase in

pain.” Ms. Medinger evaluated Vanessia and recommended that she have physical

therapy twice a week. Exhibit 8 at 48-50.

Vanessia returned to Dr. McCurdy on September 3, 2008. Vanessia

recounted that she was having some symptoms after stopping prednisone. Dr.

McCurdy recorded that Vanessia had “some improvement with Enbrel.” Vanessia

17

was also taking methotrexate. Dr. McCurdy examined Vanessia and found that she

had swollen knees and ankles. Dr. McCurdy’s impression was that she was

“improved but still [had evidence of] active [disease]” and was “better.” Exhibit 5

at 45-46.

Dr. McCurdy continued to care for Vanessia and follow-up appointments

were held in December 2008, 2009 (two appointments), and 2010. At these visits,

Vanessia, despite her JIA, was generally “doing well.” The doctors recommended

that she receive the influenza vaccine and H1N1 vaccine. Exhibit 5 at 32, 41, 44,

60.

Another follow-up appointment occurred on January 12, 2011, at UCLA.

This time, Vanessia saw Dr. Alice Hoftman, another pediatric rheumatologist. Dr.

Hoftman’s record states that Vanessia was “currently pursuing lawsuit against

Gardasil. [Received] Gardasil #2, 4/08. [Diagnosed] 7/08.” Exhibit 5 at 27.

During this visit, Dr. Hoftman apparently recommended that Vanessia receive the

flu vaccine. Despite having previously accepted the doctor recommendation that

Vanessia receive a flu vaccine in 2008-2010, Ms. Koehn refused at this visit. See

exhibit 5 at 28, 32 (H1N1 vaccine), 44, 60. Regarding her refusal, Dr. Hoftman

wrote: “[patient’s] mother refused flu vaccine this year. Discussed [with] mom

the importance of this vaccine. Mom hesitant [because] Gardasil. [Discussed

with] mom – no data but all vaccines and infections can trigger autoimmune

response.” Id. at 28.

D. Experts’ Qualifications, Reports and Testimony

1. Petitioner’s Expert, Michael J. McCabe, Ph.D.

a) Qualifications

Dr. McCabe earned a Ph.D. in microbiology and immunology from Albany

Medical College in 1991. He worked at the Karolinska Institute in Stockholm,

Sweden as a postdoctoral research associate from 1990 to 1992. In 1992, he joined

the faculty of Wayne State University as a research assistant professor at the

Institute of Chemical Toxicology. His research explored how chemicals, metals

and other contaminants from the environment affect the immune response. He also

held various other positions at Wayne State University until 2000. Exhibit 10

(curriculum vitae); Tr. 12-14, 50-53.

18

From 2000 to 2009, Dr. McCabe worked, first as an assistant professor and

then as an associate professor, in the Department of Environmental Medicine at the

University of Rochester School of Medicine and Dentistry. Dr. McCabe’s duties

included research, a small amount of teaching, and administration. While

supervising approximately 25 scientists “working on lab-based and

epidemiological research projects,” Dr. McCabe’s research focused on

“mechanistic metal toxicology and immunotoxicology.” Exhibit 10; see also Tr.

15-17, 35-37 (detailing teaching responsibilities).

In 2009, Dr. McCabe started working at Robson Forensic, Inc. as an

associate. In that capacity, Dr. McCabe provides “reports and testimony toward

the resolution of . . . personal injury litigation of toxicology and human health

assessments involving environmental and occupational exposures to agents such as

metals.” Exhibit 10; see also Tr. 33-34.

Dr. McCabe has written about 40 articles that appear in peer-reviewed

publications and about 12 book chapters. Most, but not all, of Dr. McCabe’s

publications relate to the toxicity of metals. Tr. 15, 37-39.

Dr. McCabe has contributed to select committees exploring causation. For

example, Dr. McCabe participated on a National Academy of Science committee

exploring beryllium alloy exposure. He reviewed proposals about Gulf War

injuries for the Department of Defense. He was a co-author of a white paper about

the role of the environment in developing autoimmune diseases for the National

Institute of Environmental Health Sciences. Exhibit 10; Tr. 22-29.

In response to questions asked by the Secretary’s counsel during voir dire,

Dr. McCabe stated that he is not a medical doctor and does not treat patients. Tr.

33. He has not researched sJIA. Tr. 41. However, Dr. McCabe has been involved

in a small pilot study, examining how “lead-intoxicated girls” responded to

Gardasil. Tr. 42.

His current position at Robson Forensics, Inc. requires him to “review legal

cases, produce reports, and testify as needed.” Tr. 33. Dr. McCabe estimated that

activities related to litigation provide more than 95 percent of his income with most

of his work for plaintiffs. Tr. 33-34.

Ms. Koehn offered Dr. McCabe as an expert in the field of immunology to

which the Secretary did not interpose an objection. Tr. 31, 50. Dr. McCabe was

recognized as an expert in immunology. Tr. 53.

19

b) Report23

Dr. McCabe’s report begins with a review of Vanessia’s medical history.

Dr. McCabe’s recitation is consistent with the information presented above.

Dr. McCabe describes “juvenile rheumatoid arthritis.”24 He emphasizes that

this disease is an autoinflammatory process “driven by dysregulation of the innate

immune system as evidenced by a role for pro-inflammatory cytokines (e.g. IL-6,

IL-1 and TNF-α).” Exhibit 27 at 2. He states, “[m]uch as the same with most

human autoimmune diseases, the cause of Juvenile Rheumatoid Arthritis is thought

to be multifactorial – with genetic susceptibility factors and environmental triggers

working together in complex ways to initiate and perpetuate adaptive and innate

immune activities resulting in tissue damage.” Id. at 2-3. “[T]he basis for the

argument for a causative role for these environmental triggers [referring to

infections and vaccinations] comes from mechanistic considerations.” Id. at 3.

Dr. McCabe also describes the HPV vaccine. Citing an article by Pinto, Dr.

McCabe asserts that “[i]n individuals immunized with [HPV vaccines], high levels

of both adaptive and innate immune cytokines are produced.” Id. at 3. “Notably,

many of these same vaccine-elicited cytokines are the pro-inflammatory cytokines

that have been implicated in the etiology of JRA.” Id. As made clear during the

hearing, this is the essence of Dr. McCabe’s theory: an HPV vaccine elicits a

certain cytokine pattern (particularly IL-6) and these cytokines cause sJIA. Tr.

123.

Dr. McCabe’s report also elaborates on the topic of the temporal interval that

is medically appropriate for causation. Dr. McCabe cites studies that showed that

within seven months of Gardasil vaccination, more than 99 percent of people have

seroconverted. Exhibit 27 at 4-6. This discussion implies that it was appropriate

to infer that development of a disease within seven months of a vaccination was

caused by the vaccination.

23

Dr. McCabe’s supplemental report encompasses his original report.

Therefore, citations will be only to the report dated October 1, 2011 (Exhibit 27).

24

Dr. Rose pointed out that “juvenile rheumatoid arthritis” is not the

currently preferred term. Exhibit A at 4-5.

20

c) Testimony25

After presenting his qualifications, Dr. McCabe discussed Gardasil. Tr. 54-

55. He summarized Vanessia’s medical history, Tr. 55-61, and his synopsis is in

accord with the findings of fact set forth above. Dr. McCabe premised his opinion

on Vanessia’s diagnosis of sJIA. Tr. 60.26

Dr. McCabe’s next topic was explaining how Gardasil can cause sJIA. Dr.

McCabe began by explaining a prevailing theory of how sJIA originates. As

mentioned above in section II.B., sJIA is mediated by pro-inflammatory cytokines,

such as TNF, interleukin 1, interleukin 6, and interleukin 18. The role of these pro-

inflammatory cytokines leads to a classification of sJIA as an autoinflammatory

disease. Tr. 65-66. According to Dr. McCabe, when a person with a genetic

susceptibility encounters an environmental trigger, the person’s innate immune

system falls out of balance. The result of this imbalance, for some people, is sJIA.

Tr. 66-69, 92-93.

Dr. McCabe testified about the Bradford Hill criteria for causation.27 In Dr.

McCabe’s view, several of these criteria supported finding that Gardasil can cause

sJIA. Supporting criteria include the temporal sequence, the dose-response

relationship, and biological plausibility. Tr. 97-99. Another factor, experimental

evidence, was the springboard into a lengthy discussion about how human beings

respond to a vaccine against some types of human papillomavirus.

25

This section of the decision and the section on Dr. Rose’s testimony

summarize pertinent portions of their testimony without necessarily discussing

each page of the transcript. However, the entire transcript has been reviewed.

26

If Dr. McCabe had disagreed with the diagnosis from Vanessia’s treating

doctors, his testimony about an alternative diagnosis might have been problematic

because Dr. McCabe is not a medical doctor.

27

After the hearing, Ms. Koehn filed the article in which the Bradford Hill

criteria appear. Exhibit 48 (Sir Austin Bradford Hill, The Environment and

Disease: Association or Causation?, 7 Proc. of the Royal Society of Medicine 295

(1965)).

21

Dr. McCabe spoke extensively about a 2005 article written by Dr. Pinto and

colleagues. Tr. 100-04; see Exhibit 26. Dr. McCabe interpreted this study as

showing that a vaccine against a particular strand of human papillomavirus caused

the production of various pro-inflammatory cytokines. Tr. 103-04, 110-11.

The discussion about the 2005 Pinto article flowed into testimony about a

more recent article in which Dr. Pinto appears as the senior author. Exhibit 28

(García-Piñeres). Again, the authors used a vaccine against one strand, type 16, of

the human papillomavirus. This study also showed that various cytokines

increased after the administration of a vaccine against human papillomavirus. Tr.

117-19.

Dr. McCabe summarized his opinion why Gardasil can cause sJIA. His

opinion is based, in part, upon “the scientific and medical literature that implicates

proinflammatory cytokines and inflammatory responses and innate immunity in the

pathogenesis of systemic juvenile arthritis.” His opinion is also based, in part,

upon the “scientific and medical literature that demonstrates that HPV vaccine is a

strong and potent immunogen that stimulates the production of these same

proinflammatory cytokines.” Tr. 123.

At this point, Dr. McCabe moved to explain why Gardasil caused Vanessia’s

sJIA. Dr. McCabe saw evidence that Vanessia was generating pro-inflammatory

cytokines in her clinical presentation, including a fever, rash and joint pain. Tr.

123. Dr. McCabe also maintained that when Vanessia was given medications

intended to reduce pro-inflammatory cytokines, such as Enbrel, methotrexate, and

prednisone, her disease improved. Tr. 124-25. Dr. McCabe also suggested that

Vanessia’s sJIA worsened after she received the third dose of Gardasil on August

19, 2008. Dr. McCabe, however, cautioned that when Vanessia received this dose,

she was on anti-inflammatory therapies. Thus, whether the third dose of Gardasil

caused Vanessia’s sJIA to flare was “not necessarily clear.” Tr. 126.

The next topic of Dr. McCabe’s direct testimony was the medically

appropriate interval between vaccination and the onset of symptoms. Dr. McCabe

stated that any adverse consequence of the vaccination is likely to arise in “the

time period that measurable changes in the immune response are known to be

elicited by the vaccine.” Tr. 128. Relying upon various studies, Dr. McCabe

stated, by reference, that the medically appropriate immune response range would

extend to approximately seven months after the vaccination. Tr. 127-29; see also

exhibit 25 at S13.

22

Dr. McCabe’s final topic was to address a study by Chun Chao and others.

Exhibit 34. Despite involving approximately 189,000 people, Dr. McCabe

asserted that the size of the study was not sufficiently large to detect any increase

in the number of cases involving sJIA because sJIA is a rare disease. Tr. 133-34.

Therefore, Dr. McCabe agrees with Berent Prakken, the author of another article

on juvenile idiopathic arthritis, who recommended that “much larger studies . . .

will be needed to define the role of environmental triggers in JIA.” Tr. 136

(quoting exhibit 12 at 4).

For all these reasons, Dr. McCabe concluded, to a reasonable degree of

scientific certainty, that the first two doses of the Gardasil vaccine caused Vanessia

to develop sJIA. 28 Tr. 136-38.

On cross-examination, Dr. McCabe acknowledged that the Prakken article

states “‘Infections and vaccinations have been suggested as two candidate triggers,

but neither has been confirmed because of the scarcity of proper control

perspective studies.’” Tr. 140 (quoting exhibit 12 at 2141). The studies that

looked for a connection between vaccination and juvenile idiopathic arthritis

concerned the meningococcal vaccine and the MMR vaccine. Id.

Dr. McCabe stated that clinicians and basic researchers have been

investigating the causes of sJIA for a long time. But, they have not identified the

cause because it is a “multifactorial disease.” Tr. 143-44. In this regard, Dr.

McCabe stated that there is “no epidemiology that’s meaningful enough to inform

us” as to whether the HPV vaccine causes sJIA. Tr. 141-42. Dr. McCabe also

acknowledged that he had not located any case reports describing an association

between HPV vaccine and sJIA. Id. Dr. McCabe is not aware of anyone

conducting a case control study of whether HPV vaccine causes sJIA. Tr. 147.

Counsel for the Secretary probed Dr. McCabe’s reliance on medical articles.

For example, counsel noted the 2005 Pinto article does not mention any type of

arthritis, including sJIA, does not propose any theory to connect an HPV vaccine to

sJIA, and does not report that anyone who received the vaccination developed any

28

Ms. Koehn’s counsel asked Dr. McCabe if he held his opinions “to a

reasonable degree of scientific certainty,” and Dr. McCabe answered affirmatively.

Tr. 137. Dr. McCabe could have testified if he held his opinions only to a

reasonable degree of scientific probability.

23

symptoms. Tr. 147-48. For the last point, Dr. McCabe pointed out that because

the study did not report any consequence, it is impossible to know whether any test

subjects experienced any adverse events. Tr. 148-49. Government counsel and

Dr. McCabe reviewed similar limitations to other articles, including the García-

Piñares article. Tr. 149-50.

In regard to the Chao article, Dr. McCabe stated that the researchers

considered juvenile rheumatoid arthritis. Tr. 155 (citing exhibit 34 (Chao) at 197).

The abstract of this article states “No autoimmune safety signal was found in

women vaccinated with HPV-4.”29 Tr. 156 (quoting exhibit 34 at 193).

In Vanessia’s medical history, none of her treating doctors expressed any

opinion as to whether the HPV vaccine caused her to develop sJIA. Dr. McCabe

did not see any indication that Vanessia’s treating doctors were concerned about

giving her the third dose of Gardasil after she had developed sJIA. Tr. 156-57. Dr.

McCabe recognized that it appears that shortly before the third dose of Gardasil,

Vanessia had stopped taking prednisone but was improving on Enbrel. Tr. 158

(citing exhibit 5 at 45-46).

Dr. McCabe stated that hypothetically, if Vanessia had not received Gardasil

and still developed sJIA, then he would not know what caused her to develop the

disease. Tr. 160. His opinion that Gardasil caused Vanessia to develop sJIA is

based, in part, upon the timing and also upon the immunobiology of what is known

about sJIA. Tr. 161.

Dr. McCabe also answered questions the undersigned asked. Dr. McCabe

stated that after Ms. Koehn’s counsel first contacted him, there was a hypothesis

that Gardasil caused Vanessia’s sJIA. He investigated whether “there was a

tenable scientific argument” by conducting a scientific undertaking. He learned

about sJIA. Tr. 164. He also looked for data to support the proposition that

Gardasil causes an increase in pro-inflammatory cytokines. He also drew upon his

experience and background. Tr. 164-65.

Dr. McCabe testified that the limited number of cytokines does not detract

from his opinion that Gardasil causes a production of pro-inflammatory cytokines

and these cytokines caused Vanessia’s sJIA. He stated that although a tool box

29

Gardasil is the vaccine against four strands of the human papillomavirus.

24

may have many tools, it is likely that a hammer was used to pound a nail. Tr. 172-

73.

Dr. McCabe recognized that some of the Bradford Hill criteria do not

support a finding of causation. For example, the “strength of association” is not

supportive. In addition, the criteria of “analogy” would either be not supportive or

not relevant. The studies involving juvenile idiopathic arthritis and either the

MMR vaccine or the meningococcal vaccine do not link the disease with the

vaccine. If the MMR vaccine and/or the meningococcal vaccine were analogous to

Gardasil, then those studies would counter the hypothesis that Gardasil can cause

sJIA. However, Dr. McCabe suggested that the MMR vaccine and the

meningococcal vaccine differed from Gardasil. See Tr. 179-83.

Additionally, Dr. McCabe agreed that Gardasil is not the only cause of sJIA.

This fact is easily recognized because sJIA existed before Gardasil. Tr. 173-74,

190-91.

In regard to Vanessia’s case specifically, the undersigned asked how Dr.

McCabe could distinguish a case of sJIA caused by Gardasil from a case of sJIA

caused by something else. Dr. McCabe’s response was relatively weak. Although

not phrased in these terms, he essentially stated that among all the things to which

Vanessia was exposed, the only possible cause for sJIA was Gardasil. See Tr. 191-

94.

After a short redirect examination, Dr. McCabe confirmed that his opinion

remained unchanged. He stated that Gardasil caused Vanessia’s sJIA. Tr. 195-97.

2. Respondent’s Expert, Carlos Rose, M.D.

a) Qualifications

Dr. Rose graduated from Argentina’s University of Buenos Aires in 1977.

He passed his boards for rheumatology while still in Argentina in 1983. By 1987,

Dr. Rose was living in the United States, participating in an internship in pediatrics

at the Medical Center of Delaware. He had successive fellowships in pediatric

rheumatology, first at the Children’s Hospital of Philadelphia and then at Alfred I.

duPont Institute in Delaware. He has held a board certification in pediatrics with a

specialty in rheumatology since 1998. Dr. Rose estimated that there are 216

pediatric rheumatologists in the United States. Exhibit B (curriculum vitae) at 1-5;

Tr. 199-200.

25

He has worked as a staff physician in pediatric rheumatology at the Alfred I.

duPont Institute since 1991. In 1994, he became chief of the rheumatology

division. He has taught pediatrics at the Jefferson Medical College of Thomas

Jefferson University since 1991, and he became a full professor at that school in

2002. Exhibit B at 6-7.

He has served on international committees and lectured to audiences in

foreign countries. Dr. Rose has written more than 70 peer-reviewed articles. He

also has written more than 25 book chapters or monographs. Some publications

relate to juvenile idiopathic arthritis, but not specifically to sJIA. Exhibit B at 13-

20; Tr. 202-03.

As part of voir dire, Ms. Koehn’s counsel elicited the following points about

Dr. Rose’s qualifications. He is not an immunologist and he has not researched the

role of pro-inflammatory cytokines in causing sJIA. He has not done any research

on any human papillomavirus vaccine, including Gardasil. Tr. 204.

Dr. Rose stated that he has worked for the Department of Health and Human

Services in the Vaccine Program for 21 years. Over that span, Dr. Rose estimated

that he has reviewed approximately 60 cases. He recommended compensation in

one case. Tr. 205-07.

The Secretary offered Dr. Rose as an expert in the field of pediatric

rheumatology. After Ms. Koehn did not object, he was recognized in that field.

Tr. 207.

b) Reports

In Dr. Rose’s first report, he begins with a summary of Vanessia’s medical

history. Dr. Rose agrees that she suffers from sJIA. Exhibit A at 1.

He states that sJIA is an “auto-inflammatory disease[] likely associated with

dis-regulation [sic] of cytokine networks likely IL-1 and IL-6 networks rather than

the adaptive immune system.” For this particular form of arthritis, Dr. Rose states

that he is not familiar with any infections being associated with sJIA, although

some infections have been associated with “transient self-limiting arthritis.” In

regard to the human papillomavirus, Dr. Rose states that that organism does not

produce any arthritis and “no syndrome even remotely reminiscent of sJIA is seen

in association with the infection.” Id. at 2.

26

Dr. Rose rejects the idea that HPV vaccine can cause sJIA. Relying on a

study that integrated many clinical trials, Dr. Rose states there was “no statistically

significant difference in the event rates between vaccine and control groups.” Id.

at 3, 8 (citing exhibit E (Verstraeten)). Dr. Rose also reviewed the literature that

Dr. McCabe cited.

Dr. Rose’s first report concludes that “more likely than not Vanessia’s

disease emerged as the result of chance and it was not causally related to the

immunizations she received.” Id. at 7. Dr. Rose’s supplemental report makes a

similar point: “the temporal association between vaccine and disease onset is

coincidental.” Exhibit F at 1.

The supplemental report presents Dr. Rose’s opinion regarding Dr.

McCabe’s cytokine theory. Dr. Rose asserts that “[t]he cytokine response is

complex and cytokines that in certain circumstances are pro-inflammatory, in

others are anti-inflammatory, depending on the combination of signals, the tissue

in question and even perhaps the age of the individual.” He maintains that “[t]he

fact that similar cytokines are found in serum of sJIA patients and in vaccine

response is more a reflection of the somewhat limited and stereotypical

inflammatory response repertoire in mammals than a suggestion for a link

[between] vaccine [and] sJIA.” Id.

c) Testimony

After Dr. Rose was accepted as an expert in pediatric rheumatology, he

summarized the material that he reviewed in this case. He offered his opinion that

the Gardasil vaccinations were not related to Vanessia’s development of sJIA. Tr.

208.

Dr. Rose agreed that Vanessia suffers from sJIA. SJIA, as set forth above, is

not an autoimmune condition. It is an autoinflammatory condition. Dr. Rose

explained that the treatment for sJIA is different medications, including

corticosteroids (methotrexate). The purpose of some drugs is to inhibit cytokines

such as interleukin 1, interleukin 6, and TNF. The way Vanessia’s doctors treated

her was typical. Tr. 210-14.

Dr. Rose elaborated on cytokines and sJIA. He stated that interleukin 6 may

be a cause of sJIA. Even if it is not a cause, interleukin 6 influences the course of

the disease. For example, peaks in interleukin 6 preceding a rise in temperature

27

and a hectic fever are a defining characteristic of sJIA. Interleukin 1 has also been

linked causally to arthritis. Dr. Rose stated that his experience as a clinician who

has seen some (but not all) patients with sJIA improve after taking drugs that

control interleukin 1 and interleukin 6 informs his belief that these cytokines play a

role in the disease. Tr. 215-17.

Dr. Rose disputed the relevance of Dr. McCabe’s citation to the Prakken

(exhibit 12), Mellins (exhibit 13), and Rongahy (exhibit 15) articles. According to

Dr. Rose, although these articles mention that infections could cause juvenile

idiopathic arthritis, the articles were merely generating hypotheses that could be

tested. To Dr. Rose, the articles did not report any evidence supporting Dr.

McCabe’s theory. See Tr. 217-18. According to Dr. Rose, pediatric

rheumatologists are not discussing whether an HPV vaccine can cause sJIA.

Instead, pediatric rheumatologists are discussing how safe the vaccines are for

patients with sJIA. Tr. 219.

Dr. Rose testified that one way to look at the safety of vaccines is to give

vaccines to people who have a disease and to see what happens. For juvenile

idiopathic arthritis, there were studies involving the MMR vaccine and the

meningococcal vaccine. Those studies showed that the MMR vaccine and the

meningococcal vaccine did not affect people with juvenile idiopathic arthritis

adversely. Tr. 221-23.

Dr. Rose is not aware of any epidemiological data connecting the HPV

vaccine and sJIA. He also has not seen any case reports on this topic. Tr. 220.

Dr. Rose discussed some of the articles on which Dr. McCabe relied. For

the Pinto article (exhibit 26), Dr. Rose examined whether cytokines remained

elevated. Constancy in elevation was important to Dr. Rose because, as a clinician,

he sees patients with a pattern of continually elevated cytokines. When Dr. Rose

stops medications that inhibit the production of cytokines, the patients flare. But,

when Dr. Rose looked at the data presented in the Pinto article, he did not see

much difference in the amount of cytokines produced at zero months, two months,

and seven months. To Dr. Rose, the Pinto data is “very suggestive that the

response that this vaccine elicited in these normal people has not been sustained,”

and thus the vaccine-elicited cytokine response differs from the sustained pattern

of “upregulation” he sees in his patients with sJIA. Tr. 223-26.

According to Dr. Rose, the García-Piñares article from 2007 (exhibit 28) in

which Dr. Pinto appears as the senior author makes the same point. These

28

experiments showed that a vaccine can stimulate the production of cytokines when

administered. But, in Dr. Rose’s view, these experiments do not show how a

single incidence of cytokine production can cause a disease. See Tr. 227-28.

Dr. Rose also discussed the Verstraeten (exhibit E) article, which he cited in

his expert report. Exhibit A at 3, 8. Dr. Rose stated that “this is the closest that we

can get to an epidemiologic study. This is a study of about 60,000 individuals.”

Tr. 232. Dr. Rose stated that if the vaccine were “a significant trigger[,] I would

expect to see one or two cases of sJIA in the vaccinees.” Id. However, Verstraeten

and his colleagues found “no evidence of an overall increase in relative risks for

autoimmune disorders in participants receiving vaccines containing AS04

compared with controls.” Exhibit E at 6633.

In regard to Vanessia, Dr. Rose said that he did not see any evidence that her

treating doctors believed that the HPV vaccination caused her sJIA. Dr. Rose said

that according to the standard of practice, even after Vanessia was diagnosed as

having sJIA following the second dose of Gardasil, she still should receive the

third dose. Dr. Rose said that he recommends that his patients with sJIA receive

the HPV vaccine. For Vanessia, although she had a rash and increased joint pain

after the third dose of Gardasil, Dr. Rose stated that this flare was due to the

discontinuation of corticosteroids. Dr. Rose said that this pattern of stopping the

medication and worsening of the condition happened earlier. Tr. 232-34.

On cross-examination, Ms. Koehn’s counsel elicited the following testimony

from Dr. Rose. The Verstraeten article did not involve Gardasil and involved a

vaccine that had a different adjuvant from the adjuvant in Gardasil. There was

some question about whether the Verstraeten article was looking for cases of sJIA.

Tr. 240-44.

Dr. Rose stated that the incidence (new cases per year) of sJIA is between

0.3 and 0.8 per 100,000 people. Tr. 244. This fact was the starting point for a

discussion between counsel and Dr. Rose about how large a population sample

would be needed to power an epidemiological study involving sJIA. This colloquy

did not provide especially helpful testimony in that Dr. Rose said, “I really need a

calculator or somebody to help me to really calculate it. . . . So maybe you need

100,000. I don’t really know the answer. . . . At least you need 100,000.” Tr.

245-46.

Dr. Rose stated that in the Chao article, the researchers were looking for

cases of “juvenile rheumatoid arthritis.” Tr. 248 (discussing exhibit 34 at 194).

29

Dr. Rose maintained that, although the article was published in 2011, the

researchers were using an out-of-date term. Dr. Rose believed that the term

“juvenile rheumatoid arthritis” would capture cases of sJIA. Tr. 248-52.

Ms. Koehn’s counsel also inquired about the Gardasil package insert, which

Dr. Rose had cited in his expert report. Ms. Koehn’s counsel raised two issues.

First, whether the phase 3 or phase 4 clinical trials would have identified cases of

sJIA that followed the administration of Gardasil. Dr. Rose said that if there were

any cases, then they would have been reported. Second, whether the number of

subjects in the clinical trials would have detected any changes in the incidence of

sJIA. Dr. Rose stated that although there were about 10,000 vaccinees and a

similar number of controls, if the vaccine caused sJIA, there would be some cases

reported. Tr. 252-60.

d) Post-Hearing Report

Due to questions about the scope of the Chao research that arose during the

hearing, Dr. Rose was permitted to file a brief supplemental report. It explained the

process of identifying diseases in women who had received Gardasil. Exhibit F.

III. Standards for Adjudication

To receive compensation under the Program, Ms. Koehn must prove either:

(1) that Vanessia suffered a “Table Injury”—i.e., an injury listed on the Vaccine

Injury Table—corresponding to a vaccine that she received, or (2) that Vanessia

suffered an injury that was actually caused by Gardasil. See 42 U.S.C. §§ 300aa-

13(a)(1)(A) and 11(c)(1); Capizzano v. Sec’y of Health & Human Servs., 440

F.3d 1317, 1319-20 (Fed. Cir. 2006). Here, Ms. Koehn is not claiming an injury

listed on the Vaccine Table. Therefore, she must prove causation-in-fact.

When a petitioner proceeds on a causation-in-fact theory, a petitioner must

establish three elements. The petitioner=s

burden is to show by preponderant evidence that the vaccination

brought about [the] injury by providing: (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.

30

Althen, 418 F.3d at 1278.

In this passage, Althen indicates that petitioner’s burden of proof is a

preponderance of the evidence. Accord 42 U.S.C. § 300aaB13(a)(1). The

preponderance of the evidence standard, in turn, has been interpreted to mean that

a fact is more likely than not. Moberly v. Sec’y of Health & Human Servs., 592

F.3d 1315, 1322 n.2 (Fed. Cir. 2010). 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 judgment that petitioners were not entitled to

compensation); see also Lampe v. Sec’y of Health & Human Servs., 219 F.3d

1357 (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). In this regard,

“close calls regarding causation are resolved in favor of injured claimants.”

Althen, 418 F.3d at 1280.

Ms. Koehn argues she has provided preponderant evidence to meet her

burden under Althen to prove Vanessia’s sJIA was caused in fact by her Gardasil

vaccinations. An evaluation of each prong follows.

IV. Prong One from Althen – Medical Theory

The starting point for analysis is the theory proposed by the expert that

“causally connect[s] the vaccination and the injury.” Althen, 418 F.2d at 1278.

This element of petitioner’s case is sometimes referred to as answering the “can

it” question. Pafford v. Sec’y of Health & Human Servs., No. 01-165V, 2004 WL

1717359, at *4, 9 (Fed. Cl. Spec. Mstr. July 16, 2004), mot. for review denied, 64

Fed. Cl. 19 (2005), aff’d, 451 F.3d 1352 (Fed. Cir. 2006).

To explain how Gardasil harmed Vanessia, Ms. Koehn presents a theory

dependent upon relatively complex medical knowledge. Special masters have

been instructed in how to evaluate this type of evidence. See section IV.A below.

The evidence is analyzed in section IV.B.

31

A. Considerations of Scientific and Medical Evidence

As Congress authorized, the judges of the Court of Federal Claims have

collectively issued the Vaccine Rules. 42 U.S.C. § 300aaB12(d)(2). The Vaccine

Rules, in turn, provide that the special master “must consider all relevant and

reliable evidence governed by principles of fundamental fairness to both parties.”

Vaccine Rule 8(b)(1); see Cedillo v. Sec’y of Health & Human Servs., 617 F.3d

1328, 1339 (Fed. Cir. 2010) (stating “Vaccine Rule 8(b)(1) necessarily

contemplates an inquiry into the soundness of scientific evidence to be considered

by special masters”).

The reliability of expert testimony is a topic on which the Federal Circuit has

guided special masters. The leading case is Terran v. Sec’y of Health & Human

Servs., 195 F.3d 1302 (Fed. Cir. 1999). In Terran, the special master “examined”

the expert’s opinion “in the light of the four guideposts enumerated in Daubert,”

and “conclude[d] that petitioner’s theory of causation is not based on reliable

scientific evidence.” Terran v. Sec’y of Health & Human Servs., No. 95-451V,

1998 WL 55290, at *11 (Fed. Cl. Spec. Mstr. Jan. 23, 1998) (citing Daubert v.

Merrell Dow Pharma., Inc., 509 U.S. 579 (1993)). When Ms. Terran’s appeal

reached the Federal Circuit, she argued that “the Special Master improperly

applied the Daubert factors to the expert’s testimony.” The Federal Circuit

rejected this argument and indicated that the special master reasonably used

“Daubert’s questions as a tool or framework for conducting the inquiry into the

reliability of the evidence.” Terran, 195 F.3d at 1316.

After Terran, decisions from judges of the Court of Federal Claims have

consistently cited to the Daubert criteria as useful in assessing an opinion that a

vaccine can cause an injury. See, e.g., Snyder v. Sec’y of Health & Human

Servs., 88 Fed. Cl. 706, 742-45 (2009); Cedillo v. Sec’y of Health & Human

Servs., 89 Fed. Cl. 158, 181-82 (2009), aff’d, 617 F.3d at 1338; Bazan v. Sec’y of

Health & Human Servs., 70 Fed. Cl. 687, 699 n.12 (2006) (“A special master

assuredly should apply the factors enumerated in Daubert in addressing the

reliability of an expert witness’s testimony regarding causation.”), rev’d on other

grounds, 539 F.3d 1347 (Fed. Cir. 2008); Campbell v. Sec’y of Health & Human

Servs., 69 Fed. Cl. 775, 781 (2006); Piscopo v. Sec’y of Health & Human Servs.,

66 Fed. Cl. 49, 54 (2005).

The reliability of the expert’s theory is not presumed. A “special master is

entitled to require some indicia of reliability to support the assertion of the expert

witness.” Moberly, 592 F.3d at 1324 (citing Terran, 195 F.3d at 1316).

32

Furthermore, the reliability of an expert=s theory affects the persuasiveness of the

evidence. Special masters may “inquir[e] into the reliability of testimony from

expert witnesses. 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.” Moberly, 529 F.3d at 1325 (citing Terran,

195 F.3d at 1316). 30

The mere proffer of a theory does not satisfy petitioners’ burden on this

prong. If the special master finds that the expert’s theory is supported by only an

“ipse dixit,” then the special master may reject this opinion. Snyder, 88 Fed. Cl. at

745 n.66 (2009) (quoting Gen. Elec. Co. v. Joiner, 522 U.S. 136, 146 (1997)); see

also Cedillo, 617 F.3d at 1339 (also quoting Joiner, 522 U.S. at 146).

To avoid presenting just an unadorned statement from an expert, petitioners

typically present medical articles on which the expert relies. When the petitioner

30

In her post-hearing brief, Ms. Koehn consistently described Dr. McCabe’s

theory as “biologically plausible.” Pet’r Br., filed Sept. 21, 2012, at 8, 12 (citing

Doe 93 v. Sec’y of Health & Human Servs., 98 Fed. Cl. 553, 566-67 (2011)). The

Secretary argued that Ms. Koehn was using the wrong standard. Resp’t Br., filed

Nov. 19, 2012, at 5 (citing Pet’r Br. at 8). Nevertheless, Ms. Koehn continued to

assert that she has advanced a “biologically plausible theory of causation.” Pet’r

Reply Br., filed Dec. 4, 2012, at 4 (capitalization changed without notation).

As discussed in the text, Moberly establishes that the correct standard of

proof in evaluating a petitioner’s theory is the preponderance of the evidence.

Moberly, 592 F.3d at 1322. Although Ms. Koehn is accurate in citing Doe 93 in

support of a plausibility standard, another Court of Federal Claims opinion

respectfully disagreed with Doe 93. Caves v. Sec’y of Health & Human Servs.,

100 Fed. Cl. 119, 144 n.18 (2011). Rather than use a plausibility standard, Caves

used a preponderance of the evidence standard. Id. at 132 (stating “each of [the

Althen] requirements must be proven by a preponderance of the evidence”). When

the Federal Circuit reviewed Caves, it affirmed without opinion pursuant to

Federal Circuit Rule 36. 463 F. Appx. 932 (Fed. Cir. 2012). The Federal Circuit’s

Rule 36 adjudication indicates that “a judgment or decision has been entered

without an error of law.” Thus, the precedential authority supports the

preponderance of the evidence standard.

33

presents medical articles, the special master may evaluate those articles.31 Andreu,

569 F.3d at 1379-80 (“[T]he special master can consider [medical literature or

epidemiological evidence] in reaching an informed judgment as to whether a

particular vaccination likely caused a particular injury.”) (citing Daubert, 509 U.S.

at 593-97). The Secretary, too, may offer articles that contradict a petitioner’s

theory. Stone v. Sec’y of Health & Human Servs., 676 F.3d 1373, 1379-80, reh’g

en banc denied, 690 F.3d 1380 (Fed. Cir. 2012), cert. denied, --- S.Ct. ---, 2013

WL 328557 (2013); Bazan, 539 F.3d at 1353 (stating “[t]he government, like any

defendant, is permitted to offer evidence to demonstrate the inadequacy of the

petitioner’s evidence on a requisite element of the petitioner’s casein-chief [sic].”).

In evaluating expert testimony and scientific literature, special masters

should analyze scientific literature “not through the lens of the laboratorian, but

instead from the vantage point of the Vaccine Act=s preponderant evidence

standard.” Andreu, 569 F.3d at 1380. “In other words, a finding of causation in

the medical community may require a much higher level of certainty than that

required by the Vaccine Act to establish a prima facie case. The special master

must take these differences into account when reviewing the scientific evidence.”

Broekelschen v. Sec’y of Health & Human Servs., 89 Fed. Cl. 336, 343 (2009),

aff’d, 618 F.3d 1339 (Fed. Cir. 2010).

When an expert’s opinion is not supported, the special master may find

petitioner’s proof was inadequate. Althen, 418 F.3d at 1278 (“A persuasive

medical theory is demonstrated by ‘proof of a logical sequence of cause and

effect’ . . . supported by ‘reputable medical or scientific explanation[,]’ i.e.,

‘evidence in the form of scientific studies or expert medical testimony.’”) (quoting

Grant v. Sec’y of Health & Human Servs., 956 F.2d 1144, 1148 (Fed. Cir. 1992));

see also Shapiro v. Sec’y of Health & Human Servs., 105 Fed. Cl. 353, 360 n.5

(2012) (denying motion for review and stating “the Special Master merely

required that the theories be reliable and meet the preponderance of the evidence

standard. He found each of [petitioner’s expert’s] explanations lacking in this

regard, based upon major gaps and flaws in those theories, and instead was

persuaded by [respondent’s expert’s] contradicting testimony.”), aff’d mem., 2013

WL 1896173 (Fed. Cir. 2013).

31

The special master, however, may not require medical literature. Althen,

418 F.3d at 1280.

34

These standards will be used to determine whether Ms. Koehn has met her

burden of proof for the first prong of Althen.

B. Evidence Related to Prong One of Althen

1. Overview

Dr. McCabe’s theory includes two distinct propositions: first, the

production of inflammatory cytokines can cause sJIA, and, second, Gardasil can

cause inflammatory cytokines. See Pet’r Br., filed Sept. 21, 2012, at 8-12

(organizing petitioner’s prong one evidence around these two points). As

previously summarized, Dr. McCabe relied primarily upon articles authored by

Prakken, Mellins, Ronaghy, and Pinto. Exhibits 12, 13, 15 and 26.

Dr. Rose questioned the reliability of using cytokines to link Gardasil and

sJIA. The formulation that: (1) Gardasil can cause an increase in particular

cytokines; (2) those cytokines can contribute to sJIA; and, therefore, (3) Gardasil

can be a significant factor in causing sJIA is oversimplified. The generation of

cytokines is “very ubiquitous and [is] almost a universal response.” Tr. 279.

Further, people produce a finite number of cytokines, with perhaps as many as 40

being identified so far. Tr. 290; see also Tr. 172 (Dr. McCabe stating he “accept[s]

to a certain extent that there is a commonality in the immune effector functions”).

Thus, to Dr. Rose, “similarities in cytokine patterns . . . do not mean much in terms

of causality.” Tr. 219.

Given this dispute between the experts, the special master’s responsibility is

“to assess the reliability of testimony, including expert testimony” Moberly, 592

F.3d at 1325. One accepted method for evaluating the persuasiveness of an

expert’s opinion is to conduct an analysis using Daubert. Id. at 1324, citing Terran

195 F.3d at 1316.

The Supreme Court listed several non-exclusive factors that trial

courts may consider in evaluating an expert’s opinion:

(1) whether a theory or technique can be (and has been) tested; (2)

whether the theory or technique has been subjected to peer review and

publication; (3) whether there is a known or potential rate of error and

whether there are standards for controlling the error; and, (4) whether

the theory or technique enjoys general acceptance within a relevant

scientific community.

35

Terran, 195 F.3d at 1316 n.2 (citing Daubert, 509 U.S. at 592-95). These factors

will be used here.

2. Whether a Theory or Technique can be (and has been)

Tested

One way to test the theory that Gardasil can cause sJIA is to administer

Gardasil to people and see how many people develop the disease. These

epidemiological studies are discussed separately below.

In lieu of that type of testing, scientists (including Dr. McCabe) look to

criteria listed by Sir Austin Bradford Hill. See exhibit 48; see also Tr. 97

(testimony from Dr. McCabe about the Bradford Hill criteria). Two criteria that

are potentially useful here are responses to other vaccines and animal models.

a) Other Vaccines

Dr. McCabe recognized that one way of inquiring was to “study

exacerbation in individuals who have already been diagnosed and have the

disease.” Tr. 134. Dr. McCabe also stated that considering studies with other

vaccines would be “a reasonable hypothesis . . . to consider with a few caveats.”

Tr. 181. Exploring how vaccinations affect people with a disease can inform the

assessment of whether the vaccinations cause the disease. Tr. 222; see also W.C.

v. Sec’y of Health & Human Servs., No. 07-456V, 2011 WL 4537877, at *14-15

(Fed. Cl. Spec. Mstr. Feb. 22, 2011) (considering three studies about flu

vaccination given to people with multiple sclerosis), mot. for review denied in

relevant part and granted in non-relevant part, 100 Fed. Cl. 440 (2011), aff’d 704

F.3d 1352 (Fed. Cir. 2013).

The record contains the results of two studies involving vaccines and

juvenile idiopathic arthritis. In both studies, the people given the vaccine already

suffered from juvenile idiopathic arthritis and the researchers were studying

whether the patient’s disease worsened after the vaccination. See generally,

exhibit 43 (Heijstek) and exhibit 47 (Zonneveld-Huijssoon). One study involved

MMR vaccine. In a retrospective analysis of 207 patients with juvenile idiopathic

arthritis (of which 17 had sJIA), the researchers found “no changes in disease

activity, flare occurrence or medication use after the MMR vaccination.” Thus, the

36

researchers concluded that the “MMR vaccination appears to be safe in JIA.”

Exhibit 43 (Heijstek) at 1386.32 The other study used the meningococcal C

vaccination. The total number of participants was 234, including 34 with sJIA.

Exhibit 47 (Zonneveld-Huijssoon) at 641. The researchers “did not detect any

worsening of disease activity within 6 months after MenC vaccination.” Id. at 644.

Analogizing between how other vaccines affect patients with juvenile

idiopathic arthritis and how Gardasil affects patients with sJIA, Dr. Rose stated

that “these two vaccines seem to have a wonderful record of safety in patients with

JIA.” Tr. 222. Dr. Rose added, that all vaccines, except live viral vaccines, are

recommended to those who have JIA. Id.

Dr. McCabe pointed out that Gardasil induces a stronger response from the

immune system than the natural infection. Tr. 181-82. Dr. McCabe also did not

know whether the MMR vaccine or the meningococcal C vaccination induced the

same type of cytokines as Gardasil induces. Tr. 183. Thus, the analogy between,

on the one hand, either MMR vaccine or the meningococcal vaccine, and, on the

other hand, Gardasil, is not perfect.

To the extent that some differences can be overlooked, the Heijstek and

Zonneveld-Huijssoon studies suggest that when researchers have explored whether

vaccinations affect juvenile idiopathic arthritis, they have not found that the

vaccine worsens the disease. Because they are studies, the Heijstek and

Zonneveld-Huijsoon findings are entitled to more weight than speculative passages

in other articles. For example, a group of researchers, including Dr. Zonneveld-

Huijsoon, stated “in juvenile idiopathic arthritis (JIA) a temporal relationship

between disease onset, childhood vaccination, remissions and flares, hint at a

possible relation of JIA disease activity and vaccinations or infections.” Exhibit 15

(Ronaghy) at 1. As the Secretary argued, this language (“hint”) is “equivocal.”

Resp’t Br. at 6.

b) Animal Models

Another way to test whether a substance causes a disease is to substitute

animals for people. If the animals develop the disease, then people might, too. See

32

Dr. Heijstek and colleagues added a caveat that the statistical power of

their study was limited and recommended a prospective trial. Id.

37

Tr. 176 (Dr. McCabe’s testimony that if he had unlimited funding to study the

causes of sJIA, he would “possibly look for some changes in animal models”).

Here, there are no animal models for sJIA. However, animal models do

exist for a related disease, macrophage activation syndrome. Dr. McCabe and Dr.

Rose agreed that macrophage activation syndrome is similar to, although not

exactly the same as, sJIA. Tr. 76 (Dr. McCabe), 219 (Dr. Rose), 285 (Dr. Rose),

297-98 (Dr. McCabe); see also exhibit C (Textbook) at 241 (discussing

macrophage activation syndrome within a chapter on sJIA). While Dr. Rose

suggested that a worsening of symptoms after injecting MAS-afflicted mice with

specific vaccines would give us clues about the effects of certain vaccines

compared to others, Tr. 219, 285, there was no evidence showing that this

experiment was conducted.33

Dr. Rose further indicated that, in his opinion, this experiment is unlikely to

be conducted. Dr. Rose explained that researchers are pursuing hypotheses around

sJIA that are more likely to produce advancements than the theory that Gardasil

can cause sJIA. Tr. 220-22.

Overall, the evidence relating to testing does not assist Ms. Koehn. From

her perspective, the most favorable interpretation is that this factor is neutral

(neither supporting nor discounting) because the most on-point testing has not been

done. Another interpretation is that this factor is against Ms. Koehn’s theory

because the testing that has been done with other vaccines and sJIA has refuted a

connection between those vaccines and sJIA.

3. Whether the Theory or Technique has been Subjected to

Peer Review and Publication

The theory that Gardasil can cause sJIA has not been subject to peer review

or publication. Dr. McCabe’s attempt to combine two ideas— (1) that pro-

inflammatory cytokines can cause sJIA and (2) that Gardasil can cause pro-

inflammatory cytokines—appears to be unprecedented. As the Secretary points

out, until Ms. Koehn’s case, there was not even one case report published in the

33

Neither party introduced any articles discussing the extent of experiments

on animals with macrophage activation syndrome.

38

medical journals showing even a temporal sequence in which a Gardasil

vaccination preceded sJIA. Resp’t Br. at 9.

The peer-reviewed article on which Dr. McCabe most heavily relied was

Pinto. Dr. McCabe saw Pinto as supporting his theory because Pinto demonstrates,

in some circumstances, increased levels of cytokines are present seven months

after vaccination. The specific part of the Pinto experiment on which Dr. McCabe

relied was when blood from a vaccinated person was stimulated with the virus-like

particle. See Tr. 104-12.

Dr. Rose opined that a different part of the experiment was more

meaningful. He stated that for purposes of evaluating a possible connection

between HPV vaccination and sJIA, the relevant portion is the media. To Dr.

Rose, this part of the experiment showed how the cells “are before and after

vaccination, how the cells behave when you leave them alone.” Tr. 224. When

Dr. Rose analyzed the data regarding the media, he saw that “for almost no

cytokine there’s a spontaneous release of cytokines that is different at time zero

compared to time two and time seven.” Tr. 225. The researchers came to the same

conclusion: “As shown in Fig. 1D, spontaneous secretion of cytokines in the

absence of any stimuli (media control) did not show any significant increases

following vaccination.” Exhibit 26 (Pinto) at 3560. In other words, each

successive administration of HPV vaccine did not produce any increase in

cytokines. Cytokine levels increased only when researchers reintroduced the agent

against which the vaccine was designed to protect.

Dr. Rose was less interested in the data showing the production of cytokines

after the blood cells were stimulated with more of the L1 virus-like particle. He

stated: “[o]f course, when you stimulate with an antigen you get more” cytokines

released. Tr. 265.

Despite contrary testimony from Dr. McCabe (see Tr. 293-96, 301-03), Dr.

Rose’s focus on the media column is logical. The blood in the media encountered

the L1 virus-like particle only in the context of the three doses of vaccination. This

pattern resembles what happened to Vanessia in the sense that no medical record

suggests that she was exposed to a living strand of the human papillomavirus. If

Vanessia encountered the human papillomavirus after the vaccination, the Pinto

article predicts that she would produce a robust immune response like the ones

reported for 10 µg and 1.0 µg of the virus-like particle.

39

The Pinto experiment also undermined the cohesiveness of Dr. McCabe’s

theory, particularly in regard to timing both for onset of symptoms and duration of

symptoms. To review, after human beings are exposed to an antigen, they produce

cytokines immediately. Tr. 281-82 (Dr. Rose’s testimony that “from stimulus to

response is a question of hours”). But, in Dr. McCabe’s theory, the onset of

disease can occur as long as seven months after vaccination. Tr. 127-29 (citing

exhibit 25 (Frazer) at S13).

Dr. McCabe explained that the delay could be due to the time needed to

amplify the immune system’s response. Tr. 300-01; see also Tr. 295. However,

the media portion of the Pinto experiment contradicts Dr. McCabe’s speculation

about an amplification process. In Pinto, the cytokines increased only when the

blood was restimulated. When the blood was left alone, the cytokine level stayed

relatively constant. This lack of continued elevation in pro-inflammatory

cytokines was inconsistent with how sJIA persists. In Dr. Rose’s experience in

treating people with sJIA, those patients constantly need to receive medications to

prevent development of pro-inflammatory cytokines. When the medication stops,

the person has a flare in her (or his) disease. Tr. 224. Dr. McCabe, who is not a

medical doctor, agreed that “cytokine disregulation in sJIA isn’t a transient event.”

Tr. 305. But, when he was asked about why sJIA is a chronic disease, Dr. McCabe

did not provide a persuasive explanation. Tr. 305.

Overall, the evidence relating to peer review and publication does not assist

in finding that Dr. McCabe’s theory is probable. The peer-reviewed articles about

epidemiology are taken up separately.

4. Whether There is a Known or Potential Rate of Error and

Whether There are Standards for Controlling the Error

No evidence was introduced on this topic. An error rate for Dr. McCabe’s

theory cannot be calculated. Thus, this factor does not constitute affirmative or

negative evidence.

40

5. Whether the Theory or Technique Enjoys General

Acceptance within a Relevant Scientific Community34

Except for the portion of the Prakken article discussed above, Ms. Koehn

has not presented any evidence that the relevant scientific community generally

accepts the theory that Gardasil can cause sJIA. See Pet’r Reply Br. at 14-15. The

Secretary has presented evidence (the opinion of Dr. Rose) that shows that the

theory is not generally accepted.

Dr. Rose is the head of pediatric rheumatology at the Alfred I. DuPont

Hospital for Children. Exhibit B (curriculum vitae); Tr. 200. He conducts

research on juvenile rheumatoid arthritis, although not on sJIA. Tr. 202. He

attends conferences held by associations of rheumatologists. Tr. 283-84. He

serves as an editor for Clinical Rheumatology. Exhibit B at 9. Given this

background, it seems likely that if rheumatologists were considering whether

Gardasil can cause sJIA, then Dr. Rose would have heard some discussion about

this theory. However, Dr. Rose testified that he did not recall hearing about this

idea. Tr. 284.

Furthermore, Dr. Rose stated that the general practice among

rheumatologists is to recommend vaccinations for their patients with sJIA. See

Tr. 219, 222. This practice reflects a belief that the benefits from vaccination

outweigh the potential harm from vaccination. Although, conceivably, at some

future time, rheumatologists will generally accept the theory that Gardasil can

cause sJIA, the evidence in this case is that they do not.

6. Additional Considerations

In defining how district court judges should determine whether expert

opinion is admissible, the Supreme Court has emphasized that the approach should

be “flexible.” Kumho Tire Co., Ltd. v. Carmichael, 526 U.S. 137, 150 (1999)

(citing Daubert, 509 U.S. at 594). Thus, the analysis of whether the theory that

34

Citing Capizzano, 440 F.3d at 1325, Ms. Koehn argues that a petitioner is

not required to show a particular theory has general acceptance. Pet’r Br. at 15. It

is correct that special masters may not require general acceptance. However,

pursuant to Terran, special masters may consider whether a particular theory has

general acceptance as one factor in the overall analysis. 195 F.3d at 1316.

41

Gardasil can cause sJIA may consider more than just the four factors explicitly

listed in Daubert. Two other factors are the origins of the theory and

epidemiological studies.

a) Genesis of the Expert’s Theory

One consideration is why the expert came up with the opinion. On remand

from the Supreme Court, the Ninth Circuit stated:

One very significant fact to be considered is whether the experts are

proposing to testify about matters growing naturally and directly out

of research they have conducted independent of the litigation, or

whether they have developed their opinions expressly for purposes of

testifying. That an expert testifies for money does not necessarily cast

doubt on the reliability of his testimony, as few experts appear in

court merely as an eleemosynary gesture. But in determining whether

proposed expert testimony amounts to good science, we may not

ignore the fact that a scientist’s normal workplace is the lab or the

field, not the courtroom or the lawyer’s office.

Daubert v. Merrell Dow Pharm., Inc., 43 F.3d 1311, 1317 (9th Cir. 1995).

Here, Dr. McCabe developed his theory for the purpose of litigation. From

his initial consultation, he understood that petitioner was hypothesizing that

Gardasil caused Vanessia’s sJIA. From that starting point, Dr. McCabe

investigated whether “there was a tenable scientific argument” and produced his

report accordingly. Tr. 164. This factor, although not decisive, weighs against Dr.

McCabe’s theory.

b) Epidemiological Studies

The Federal Circuit has endorsed consideration of epidemiological studies as

one factor in the special master’s analysis. See W.C. v. Sec’y of Health & Human

Servs., 704 F.3d 1352, 1361 (Fed. Cir. 2013) (holding that the special master was

not arbitrary in denying compensation and summarizing epidemiological studies

cited by the special master); Lampe, 219 F.3d at 1365 (stating “[a]n

epidemiological study may be probative medical evidence relevant to a causation

determination”). The special master may not find against a petitioner solely

because the petitioner did not introduce supporting epidemiology. Capizzano, 440

F.3d at 1325.

42

Ms. Koehn acknowledges that she has not presented any epidemiology.

Pet’r Br. at 15. The Secretary, on the other hand, relies upon the results of two

studies that looked for but did not find an increased incidence of disease after

vaccines against human papillomavirus. Resp’t Br. at 7-8 (citing exhibit 34 (Chao)

and exhibit E (Verstraeten)).

Ms. Koehn’s cross-examination of Dr. Rose brought out two weaknesses in

this reliance on the Verstraeten article. First, as mentioned above, Gardasil is not

the same as Cervarix. Tr. 240. Logically, it is possible that a component of

Gardasil that is not in Cervarix could cause unintended side effects that would not

be identified in studies about Cervarix. Second, the size of the Verstraeten study,

despite including more than 60,000 people, is still not large enough to discover an

increased risk of sJIA. This argument derives from the incidence of sJIA, which is

approximately 0.3 to 0.8 per 100,000 people in the United States. Tr. 244-45; but

see Tr. 133 (Dr. McCabe’s testimony that the incidence of sJIA is between 2 and

20 cases per 100,000 people). Given the frequency with which new cases develop,

Dr. Rose was reluctant to estimate the size of an adequately powered study,

although he speculated the size might be 100,000 people. Tr. 245-46.

In addition to the Verstraeten study, the other epidemiological study was

authored by Chun Chao. Ms. Koehn reasonably could not repeat the attacks used

against the Verstraeten article in response to the Chao article. Unlike the

population Verstraeten analyzed, the Chao study subjects received Gardasil.

Compare exhibit E (Verstraeten) at 6631 with exhibit 34 (Chao) at 193 and Tr. at

132 (Dr. McCabe noting that HPV-4, referred to in the Chao study, is Gardasil). In

addition, Chao looked at more than twice as many women. Compare exhibit 34

(Chao) at 193 (n = 189,629) with exhibit E (Verstraeten) at 6630 (n = 68,512).

Instead, Ms. Koehn called into question the supposition that Chao researchers

would have identified cases of sJIA. See Pet’r Reply Br. at 14.

Based on the population analyzed by Chao and her colleagues and the

incidence of sJIA, the study appears to be robust. According to the results,

however, “no cluster of disease onset in relation to vaccination timing, dose

sequence or age was found for any autoimmune condition.” Exhibit 34 at 193. In

other words, “[n]o autoimmune safety signal was found in women vaccinated with

HPV4.” Id. While an epidemiological study cannot prove that Gardasil does not

cause autoimmune diseases as an absolute proposition, the results suggest that

Gardasil causes an autoimmune disease extremely rarely, if it causes an

autoimmune disease at all.

43

Taken together, the Verstraeten and the Chao articles are an additional (but

not decisive) reason for finding that Dr. McCabe’s theory that a vaccine against

human papillomavirus can cause sJIA to be unlikely. The same result would have

occurred even if the epidemiological studies were not part of the record.

C. Summary

The Supreme Court has recognized that a novel theory that is relatively

unexamined by the relevant scientific community may not be as persuasive as a

theory that has been thoroughly peer-reviewed. This is so because “submission to

the scrutiny of the scientific community . . . increases the likelihood that

substantive flaws in methodology will be detected.” Daubert, 509 U.S. at 593-94.

The Daubert Court added, however, that the lack of publication is a “relevant,

though not dispositive, consideration in assessing . . . scientific validity.” Id. at

594. Special masters, too, have recognized that a theory’s novelty is not

dispositive in determining its scientific validity. Cedillo v. Sec’y, Health &

Human Servs., No. 98-916V, 2009 WL 331968, at *111 (Fed. Cl. Spec. Mstr.

Feb. 12, 2009) (“At times novel theories can be persuasive.”), mot. for review

denied, 89 Fed. Cl. 158, aff’d, 617 F.3d 1328. Ultimately, however, it is

petitioner’s burden to support her theory with “sufficient supportive evidence to

justify the adoption of a proffered new theory.” Cedillo, 2009 WL 331968, at

*111.

With respect to the first prong of Althen, Ms. Koehn’s burden is to establish

that Gardasil can cause sJIA. Her proof does not need to be scientifically certain;

preponderant evidence suffices.

Here, the evidence does not weigh in Ms. Koehn’s favor. Dr. McCabe, a

Ph.D. immunologist, has pieced together a theory that, although not entirely

impossible, contains sufficient gaps to make it unpersuasive. See Joiner, 522 U.S.

at 146 (affirming exclusion of an expert’s report when the trial court “conclude[d]

that there [was] simply too great an analytic gap between the data and the opinion

proffered”). Consequently, Ms. Koehn has not met her burden of proof.

44

V. Prong Three from Althen – Timing35

Petitioners are required to establish a “showing of a proximate temporal

relationship between vaccination and injury.” Althen, 418 F.3d at 1278. The

Federal Circuit has elaborated that the third prong of the Althen test requires

“preponderant proof that the onset of symptoms occurred within a timeframe

which, given the medical understanding of the disorder’s etiology, it is medically

acceptable to infer causation.” Bazan, 539 F.3d at 1352. “Under this test,

petitioner [is] first required to establish the timeframe for which it is medically

acceptable to infer causation, that is, the timeframe in which symptoms would be

expected to arise if the [disease] was caused by the vaccination. Then, she [is]

obliged to show that the onset of her [disease] occurred during this causation

period.” Shapiro v. Sec’y of Health & Human Servs., 101 Fed. Cl. 532, 542

(2011), recons. denied after remand, 105 Fed. Cl. 353 (2012), aff’d mem., 2013

WL 1896173 (Fed. Cir. 2013).

These two aspects are separately considered, beginning with findings related

to when Vanessia’s sJIA began. After the relevant time for Vanessia is

established, the next section reviews whether her onset date falls within a

medically acceptable timeframe.

A. What happened to Vanessia

Vanessia received the first dose of Gardasil on February 18, 2008, and the

second dose on April 18, 2008. Exhibit 2 at 3. The experts agree that Vanessia’s

sJIA became manifest in late June 2008. See Tr. 129 (Dr. McCabe stating “the

disease emerged manifest in June of 2008”); Exhibit A (Dr. Rose’s report) at 1.36

As the Secretary points out, the interval between vaccination and onset is

approximately four months (using the date of the first dose) and approximately two

months (using the date of the second dose). See Resp’t Br. at 14.

35

Since the third prong of Althen ties directly to Dr. McCabe’s theory, this

decision discusses the third prong now. The second prong of Althen is discussed

in section VI.

36

Facts supporting the onset include: On June 21, 2008, Vanessia reported

she had a rash all over her body. Exhibit 3 at 8. While hospitalized, Vanessia was

diagnosed with systemic onset juvenile arthritis. Exhibit 4 at 11-12.

45

For Ms. Koehn to prevail, she must establish that two months (or four

months) falls within the medically acceptable timeframe. Bazan, 539 F.3d at 1352;

Shapiro, 101 Fed. Cl. at 542.

B. Time Expected by Medical Science

The Court of Federal Claims has recognized that petitioners’ proof of the

medically acceptable time for an injury to appear after vaccination depends upon

the petitioners presenting, pursuant to Althen prong one, a “reputable theory as to

how the vaccination could cause the injury.” Langland v. Sec’y of Health &

Human Servs., 109 Fed. Cl. 421, 443 (2013). This linkage makes sense. If

medical science understands how an injury might occur, then there would be some

basis for understanding when the injury would occur. Conversely, if there is little

understanding about the cause of a disease, then it is difficult to say when the

disease should begin.37 See Veryzer v. Sec’y of Health & Human Servs., 100 Fed.

Cl. 344, 356 (2011) (“[T]he ‘etiology’ of the disorder determines the appropriate

temporal relationship.”), aff’d without opinion, 475 Fed. Appx. 765 (Fed. Cir.

2012). Moreover, analyzing the medically appropriate time from prong three in

terms of the medical theory from prong one is in accord with the observation that

evidence from one prong may overlap with another prong. Capizzano, 440 F.3d at

1326.

To Dr. McCabe, the “expected interval between vaccination . . . and the

onset of the autoinflammatory disease is predicted by the time period that

measurable changes in the immune response are known to be elicited by the

vaccine.” Tr. 128. As discussed above, people receiving Gardasil produce

antibodies against the human papillomavirus within seven months. See exhibit 25

(Frazer) at S13. Therefore, Dr. McCabe implies that an appropriate timeframe in

which an individual can first exhibit symptoms of sJIA caused by Gardasil extends

to up to seven months. See Pet’r Reply Br. at 16 (“[I]t follows that the interval

37

Dr. Rose expressed this idea when he stated “two months is as good as

two hours or as good as six months since we really don’t know what’s going on.”

Tr. 308.

46

during which sJIA could be said to have a temporal association with Gardasil is the

same 3-dose time frame, or within 7 months.”).38

Dr. Rose questioned why a theory involving cytokines could produce an

injury after a delay of several months. As discussed in reference to Althen prong

one, Dr. Rose stated, and Dr. McCabe agreed, that the immune system produces

cytokines very quickly after it encounters an antigen. Tr. 281-82 (Dr. Rose); Tr. at

295 (Dr. McCabe). Thus, Dr. Rose expected that if vaccine-triggered cytokines

contributed to the pathogenesis of sJIA, then symptoms of sJIA would “start[] right

away.” Tr. 282.

Dr. McCabe’s theory holds that cytokines that are produced in response to

the vaccination could lead to sJIA. He acknowledged that sJIA has genetic factors,

“meaning that certain susceptible members of the population likely exist and

develop this disease with or without environmental triggers.” Tr. 76. He then

added that cytokines, activated by the vaccine, act on multiple tissues causing fever

and the release of acute phase reactive proteins. Tr. 77-80. In his PowerPoint, he

also acknowledged increased vascular permeability and increased synovial

inflammation in response to cytokine activation. Exhibit 38 at slide 5 (reproducing

figure 1 from exhibit 13 (Mellins) at 419). When asked to explain how the

vaccine-stimulated cytokines cause the disease, Dr. McCabe referred to these

consequences. Tr. 299. He also expected that “cytokine-mediated interactions

between cells of the adaptive immune system and the innate immune system . . .

are somehow playing a role in the disease,” but more sophisticated information

was lacking. Tr. 299-300.

The lack of specificity in Dr. McCabe’s theory creates a gap in Ms. Koehn’s

case. The consequences of cytokine production that Dr. McCabe identifies, such

as fever, are usually apparent very quickly. The body’s rapid cytokine response

appears inconsistent with Dr. McCabe’s assertion that the onset of disease could

take many months.

Dr. McCabe attempted to answer this conundrum by opining that the onset

of sJIA could be delayed because “there’s an amplification process.” Tr. 301.

However, Dr. McCabe did not explain persuasively what he meant by that term.

38

As discussed below, Dr. McCabe did not directly discuss the interval in

Vanessia’s case, which is two months.

47

see also Tr. 295. And specifically, Dr. McCabe did not explain why the immune

system’s production of cytokines would be amplified for weeks and months

without a stimulant being present.

In sum, the record does not support a finding that the medically appropriate

interval for a cytokine-mediated theory would extend out to seven months as Dr.

McCabe proposed. Seven months might be appropriate for a different theory.39

And seven months might be appropriate for a cytokine-mediated theory if there

were some reliable evidence about how the cytokines start a lengthy process. But,

because cytokines exist for a short duration, a preponderance of evidence does not

support the finding that seven months is an appropriate medical interval.

More important for Ms. Koehn’s case is whether a preponderance of the

evidence establishes that two months is a medically appropriate interval because

Vanessia’s sJIA symptoms were recognized approximately two months after the

second dose of Gardasil. See section V.A above. There was no testimony from

either Dr. McCabe or Dr. Rose saying that two months is medically appropriate. In

the absence of evidence, it is difficult to find that Ms. Koehn has met her burden of

proof. Even two months is probably too long an interval for a cytokine-driven

reaction. See James v. Sec’y of Health & Human Servs., No. 09-284V, 2010 WL

4205699, at *6 (Fed. Cl. Spec. Mstr. Sept. 30, 2010) (summarizing testimony of

the petitioner’s expert that a child’s death 14 hours after vaccination was consistent

with release of cytokines); Doe/11 v. Sec’y of Health & Human Servs., No.

99-212V, 2008 WL 4899356, at *28-30 (Fed. Cl. Spec. Mstr. Oct. 29, 2008)

(discussing whether a cytokine storm can arise in four hours), mot. for review

denied, 87 Fed. Cl. 1 (2009), aff’d, 601 F.3d 1349 (Fed. Cir. 2010).40

39

For example, in other cases, petitioners have proposed that a vaccine

caused an autoimmune response involving either antibodies or T-cells. Ms. Koehn

has not proposed a theory involving antibodies or T-cells because neither appears

to be involved in the pathogenesis of sJIA. See Exhibit C (Textbook) at 236.

40

These cases are consulted because (a) petitioner did not introduce any

evidence about whether two months is a medically appropriate time and (b) special

masters may use their “accumulated expertise” in evaluating the cases. Lampe,

219 F.3d at 1362 (quoting Hodges v. Sec’y of Health & Human Servs., 9 F.3d 958,

961 (Fed. Cir. 1993)).

48

Ultimately, a finding on Althen prong three is not needed. Even if Ms.

Koehn had established that there was a proper temporal sequence, timing does not

entitle her to compensation. Grant, 956 F.2d at 1148. She is also required to

establish a persuasive medical theory. Althen, 418 F.3d at 1278. As explained

above, she has not met the first element and the failure to meet this element means

that she cannot be compensated. See Hibbard v. Sec’y of Health & Human Servs.,

698 F.3d 1355, 1364-65 (Fed. Cir. 2012) (holding special master did not err in

resolving the case pursuant to prong two when respondent conceded that petitioner

met prong three).

VI. Prong Two from Althen – Logical Sequence of Cause and Effect

The remaining Althen prong is “a logical sequence of cause and effect

showing that the vaccination was the reason for the injury.” 418 F.3d at 1278.

Given the finding that Ms. Koehn has not established a persuasive theory to

explain how Gardasil can cause sJIA, as a matter of logic, she cannot show that

Gardasil did cause her sJIA. See Caves, 100 Fed. Cl. at 145. Nevertheless, the

evidence particularly relevant to this factor is discussed for the sake of

completeness.41

A. Factors to Consider in regard to Prong Two from Althen

While the first prong from Althen is sometimes shortened to “can it?,” the

second prong can be summarized as asking “did it?” See Pafford, 2004 WL

1717359, at *4-5, 9. Evidence relevant to this prong “tends to be evidence specific

for the petitioner.” Viscontini v. Sec’y of Health & Human Servs., No. 98-619V,

2011 WL 5842577, at *20 (Fed. Cl. Spec. Mstr. Oct. 21, 2011), mot. for review

denied, 103 Fed. Cl. 600 (2012). This focus on the petitioner particularly reflects

the separate inquiries into the question of general causation (Althen prong one) and

question of specific causation (Althen prong two). Veryzer, 100 Fed. Cl. at 353.

41

As part of her argument regarding Althen prong two, the Secretary argues

that the two (or four) month delay between vaccination and onset of symptoms

makes the logical sequence of events questionable. See Resp’t Br. at 10. Because

section V.B above discussed the timing issue, the analysis of Vanessia’s

chronology is not repeated here.

49

According to the Federal Circuit, the petitioner might present preponderant

evidence on this prong by submitting evidence from treating doctors and/or

evidence demonstrating challenge / rechallenge. Capizzano, 440 F.3d at 1325-26.

This type of evidence focuses on the overriding issue in this case—whether

Gardasil was a substantial factor in causing Vanessia’s sJIA. See Shyface v. Sec’y

of Health & Human Servs., 165 F.3d 1344, 1352 (Fed. Cir. 1999). Although Ms.

Koehn argued that Vanessia’s presentation was consistent with pro-inflammatory

cytokines, see Pet’r Br. at 13-14 (citing Tr. 123-25), this showing merely

establishes that Vanessia suffered from sJIA. It does not show that the pro-

inflammatory cytokines resulted from Gardasil. To be entitled to compensation,

Ms. Koehn must present additional evidence. See Moberly, 592 F.3d at 1323

(holding that an appropriate temporal onset and “a simplistic elimination of other

potential causes of the injury” does not meet petitioner’s burden) (quoting Althen,

418 F.3d at 1278).

B. Evidence Related to Prong Two from Althen

1. Statements of Treating Doctors

To demonstrate the “logical sequence of cause and effect,” the Federal

Circuit has identified statements of treating doctors as probative evidence.

Capizzano, 440 F.3d at 1326. Their views, however, are not necessarily

“sacrosanct.” Snyder, 88 Fed. Cl. at 745 n.67.

Here, Ms. Koehn acknowledges that “Vanessia’s treating physicians did not

express any opinion as to whether Gardasil was a cause of her development of

sJIA.” Pet’r Br. at 14 (citing Tr. 157). Although this lack of connection from a

treating doctor tends to make her claim less likely, Ms. Koehn points to a statement

from one of Vanessia’s rheumatologists, Dr. Hoftman.

Dr. Hoftman worked within the University of California at Los Angeles

(UCLA) Health System. Exhibit 5 at 28. Vanessia had been seen at UCLA since

July 2008. Exhibit 3 at 11; exhibit 5 at 51. Dr. Hoftman saw her on January 12,

2011, as part of a periodic follow up. Exhibit 5 at 28. In the context of presenting

a plan until Vanessia’s next appointment in three months, Dr. Hoftman wrote “Pt

mother refused flu vaccine this year. Discussed [with] mom importance of this

vaccine, risk < benefit. Mom hesitant b/c Gardasil. [Discussed with] mom – no

50

data but all vaccines and infections can trigger autoimmune response.” Exhibit 5

at 28.42

Dr. Hoftman does not express any agreement with Ms. Koehn’s concern

about Gardasil. Dr. Hoftman actually appears to have recommended that Vanessia

receive the flu vaccination and Vanessia would have been vaccinated against the

flu at the January 12, 2011 appointment except that Ms. Koehn “refused flu

vaccine this year.” In other years after Vanessia was diagnosed with sJIA, doctors

had recommended, and Ms. Koehn had accepted their recommendation, that

Vanessia receive a flu vaccination. See exhibit 5 at 32, 44, 60.

2. Challenge / Rechallenge

The advice to receive a flu vaccination is not necessarily inconsistent with a

theory that Gardasil caused Vanessia’s sJIA because the flu vaccine is not the same

as Gardasil. The more relevant inquiry is whether the doctors recommended an

additional dose of Gardasil.

When patients encounter a putative causative agent a second time, they are

considered to be facing a “rechallenge.” See Capizzano, 440 F.3d at 1322 (stating

“[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”).

The challenge-rechallenge paradigm is relevant to determining whether petitioners

have demonstrated a “logical sequence of cause and effect.” Capizzano, 440 F.3d

at 1326.

When the vaccinee’s medical history supports challenge-rechallenge, special

masters have accepted this evidence as persuasive. Freeman v. Sec’y of Health &

Human Servs., No. 04-1528V, 2009 WL 5103594, at *12 (Fed. Cl. Spec. Mstr.

Dec. 9, 2012); Hall v. Sec’y of Health & Human Servs., No. 02-1052B, 2007 WL

312084, at *7 (Fed. Cl. Spec. Mstr. Oct. 4, 2007). On the other hand, petitioners

have sometimes fallen short of demonstrating that their case truly fits the

42

To the extent that Dr. Hoftman expressed an opinion that “all vaccines . . .

can trigger [an] autoimmune response,” Dr. Hoftman’s statement provides a

modicum of support for Ms. Koehn’s prong one argument. It does not weigh very

heavily in that regard because, as Dr. Hoftman states in that same sentence, there is

“no data” for the proposition.

51

challenge-rechallenge model. Doe 70 v. Sec’y of Health & Human Servs., 95 Fed.

Cl. 598, 608 (2010) (denying motion for review when the special master did not

arbitrarily find that “the facts of petitioner’s case did not fit the challenge-

rechallenge model”), aff’d sub nom., Rickett v. Sec’y of Health & Human Servs.,

468 Fed. Appx. 952 (Fed. Cir. 2011); Locane v. Sec’y of Health & Human Servs.,

No. 99-589V, 2011 WL 3855486, at *11 (Fed. Cl. Spec. Mstr. Feb. 17, 2011), mot.

for review denied, 99 Fed. Cl. 715, 732 (2011), aff’d, 685 F.3d 1375 (Fed. Cir.

2012).

Here, the parties draw different conclusions from how Vanessia fared after

her third vaccination. The relevant chronology shows:

Date Event Citation

7/1/08 Dr. Scott diagnoses Vanessia with probable sJIA while Exhibit 4 at

she was hospitalized 11-12.

7/2/08 Dr. Regala, Vanessia’s pediatrician, refers Vanessia to Exhibit 3 at

UCLA / Dr. McCurdy 11.

7/8/08 Vanessia’s first appointment with Dr. McCurdy. The Exhibit 5 at

history notes that Vanessia had received two doses of the 51-55.

HPV vaccine.

Dr. McCurdy continued the prescriptions for prednisone,

methotrexate, Enbrel.

8/19/08 Dr. Regala administers the third dose of Gardasil Exhibit 3 at

6; see also

exhibit 3 at

3-4.

8/25/08 During physical therapy, Vanessia had rash, chills, and Exhibit 8 at

joint pain. 48-50.

9/3/08 Vanessia returns to Dr. McCurdy. Her current Exhibit 5 at

medication was Enbrel. By history, Vanessia had “some 45-46.

improvement [with] Enbrel,” although she had “swollen

knees [and] ankles.” Also, by history, after Vanessia

“stop[ped] prednisone, [her] rash returned.”

The doctor’s plan included continuing Enbrel and

starting methotrexate. The doctor also ordered laboratory

tests and if there were an increase in “inflammatory

markers[,] may need prednisone.”

Relying upon Dr. Rose’s testimony, the Secretary interprets this sequence as

contrary to the challenge-rechallenge paradigm. According to the Secretary, “if the

52

HPV vaccine caused or substantially contributed to Vanessia’s sJIA, then it would

seem logical that a third dose of it on August 19, 2008 would have significantly

exacerbated her symptoms.”43 The Secretary argues that the third dose of Gardasil

did not make Vanessia worse because the rash was associated with stopping

prednisone, not with the administration of the vaccine. Resp’t Br. at 12.

Dr. McCabe’s response is to emphasize a medication that Vanessia was

taking—Enbrel. When Vanessia received the third dose of Gardasil, she was also

taking an “anti-inflammatory therapy.” Tr. 126. Enbrel is a confounding factor.

As Dr. McCabe explained: “If there were no changes, part of that would be I

would suspect or wonder and consider whether well, the reason that there’s no

change is because at the same time that a stimulus is given an inhibitor is present.”

Tr. 126.

In this context, Dr. McCabe stated that trying to determine whether the third

dose of Gardasil made Vanessia worse is “difficult to say” because there are “[t]oo

many variables.” Tr. 127. Any worsening could have been due to her stopping

prednisone. Her continued use of Enbrel could have prevented any worsening that

Gardasil would have caused absent the use of Enbrel.44 In addition, there is the

normal waxing and waning of sJIA.

The many confounding factors make reliance on Vanessia’s experience after

the third dose of Gardasil difficult in either respect. While it cannot be said that

the Secretary has proven the absence of rechallenge, Ms. Koehn has not met her

burden of proving that Vanessia’s case constitutes an example of rechallenge.45

43

Dr. McCabe indicated that on an abstract level, this logic is an appropriate

way to explore a cause and effect relationship. Tr. 125-26.

44

Enbrel appears to help Vanessia cope with her disease. See exhibit 8 at 43

(noting, on February 25, 2009, that her hand hurt after she missed one dose of

Enbrel).

45

In its most recent report addressing whether vaccines cause injuries, the

Institute of Medicine discussed the value of the rechallenge paradigm.

It is possible that one or more of the ‘challenges’ in an individual case

patient reporting is related to coincidental exposure; thus, the

committee looked for other information. . . . The value for the

(. . . continued)

53

3. Relative Qualifications of Experts46

In weighing the persuasiveness of opinion testimony, special masters may

consider the relative expertise of the witness. Locane v. Sec’y of Health & Human

Servs., 685 F.3d at 1380 (stating “[t]he Special Master found Dr. Warner’s

testimony more persuasive than Dr. Bellanti’s because of their different

backgrounds and specialties and because the medical literature supports Dr.

Warner’s theory. . . . We find nothing arbitrary or capricious.”); Stone, 676 F.3d at

1382 (noting “[t]he special master found the respondent’s experts’ testimony on

that issue to be more reliable than Dr. Kinsbourne’s in view of their more extensive

and more recent experience”).

Dr. McCabe is not a medical doctor. Tr. 33. While Dr. McCabe’s lack of

training and experience as a medical doctor could decrease the value of his opinion

for any of the Althen prongs, see Resp’t Br. at 4-5 (discussing Dr. McCabe’s

committee of rechallenge cases is much greater for monophasic

conditions (events that typically happen only once, e.g., vasculitis)

than for relapsing-remitting conditions, such as multiple sclerosis or

rheumatoid arthritis.

Institute of Medicine, Adverse Effects of Vaccines: Evidence and Causality

(Kathleen Stratton et al., eds. 2012). Although reports from the Institute of

Medicine have informed decisions of special masters, see, e.g., Terran, 1998 WL

55290, at *10-12, mot. for review denied, 41 Fed. Cl. 330, 337 (1998), aff’d 195

F.3d 1302 (Fed. Cir. 1999), the decision in Ms. Koehn’s case does not depend

upon the views of the Institute of Medicine.

46

In addition to the relative qualifications of the experts, both sides suggest

that the other side’s expert may be biased. Neither of these arguments found their

targets because both Dr. McCabe and Dr. Rose appeared to offer sincerely held

opinions.

Nevertheless, Dr. McCabe derives more than 95 percent of his income from

participating in litigation. Tr. 34. In Ms. Koehn’s words, his “professional

activities revolve in large measure around participation in litigation.” Pet’r Reply

Br. at 3. This concentration leaves Dr. McCabe open to a challenge that he is

simply a professional witness.

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credentials and background), the Secretary makes a particular argument for prong

two. The Secretary contends that he “is not qualified to independently provide

medical testimony and evidence on this issue.” 47 Resp’t Br. at 13.

Ms. Koehn replies that Dr. McCabe’s opinion should be given “substantial

weight.” Pet’r Reply Br. at 3. Ms. Koehn notes that Dr. McCabe earned a Ph.D in

microbiology and immunology. Id. While an assistant professor at Wayne State

University, he researched cytokines. Tr. 21-22. When he moved to the University

of Rochester School of Medicine and Dentistry, he led researchers who were

exploring how vaccines “modulate the immune response.” Tr. 20-21. Ms. Koehn

argues that Dr. McCabe’s specific training in immunology makes him “more

qualified” than Dr. Rose “to discuss the effects of vaccines on cell biology.” Pet’r

Reply Br. at 2-3.

Dr. McCabe is qualified to discuss immunologic principles and that

expertise naturally fits in the discussion of theory under prong one of Althen.

However, when those principles are applied to Vanessia specifically as part of the

prong-two analysis, Dr. McCabe’s inexperience with diagnosing diseases in human

beings becomes more problematic. Dr. McCabe does not have the experience of

Dr. Rose, who has diagnosed and treated 150-200 patients with sJIA. Tr. 278.

Thus, when it comes to evaluating their opinions, Dr. Rose’s opinion is given more

weight.

Dr. Rose’s opinion is that Gardasil did not cause Vanessia’s sJIA. To him,

Vanessia’s Gardasil vaccinations and her development of sJIA were “unrelated

events.” Tr. 208. This opinion is persuasive.

4. Summary

The Althen prong two analysis is necessary only if it is found (or assumed)

that the petitioner met the burden regarding Althen prong one. In the present case,

Ms. Koehn’s evidence on prong one was not persuasive. Hence, the foregoing

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Despite this argument, the Secretary did not file a Daubert-type motion to

exclude his testimony. Such a motion to exclude testimony is relatively rare in the

Vaccine Program. Fresco, 2013 WL 364723, at *21; Garcia v. Sec’y of Health &

Human Servs., No. 05-720V, 2010 WL 2507793, at *2 (Fed. Cl. Spec. Mstr. May

19, 2010).

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analysis about Vanessia’s case was undertaken for the sake of completeness and to

ensure that the entire record was considered.

The evidence about Vanessia does not persuasively show that she developed

sJIA because of Gardasil. Her treating doctors gave her the third dose of Gardasil

after she had been diagnosed with sJIA and the treating doctors continued to

recommend other vaccinations to her. These vaccinations did not clearly

exacerbate Vanessia’s sJIA as might be expected if the Gardasil vaccine were

causative.

As discussed in the context of Althen prong three, a sequence in which the

vaccination preceded the development of the disease does not establish causation.

In some cases, the disease followed the vaccination only as a matter of

coincidence. See Capizzano, 440 F.3d at 1327 (recognizing the possibility of

coincidence).

Dr. Verstraeten anticipated that coincidence and causation might be

confused. He wrote:

Bearing in mind the background incidence of autoimmune disorders

in adolescents and young adult population, it seems likely that, with

broader use of HPV vaccines or other vaccines targeting this age

group, autoimmune disorders will be reported in temporal association

with vaccine administration even in the absence of a causal

relationship.

Exhibit E (Verstraeten) at 6633. Vanessia’s case fits this description. Ms. Koehn

has accurately reported that Vanessia’s sJIA started after the vaccination but she

has not established the necessary “causal relationship.”

VII. Conclusion

Through the testimony of Dr. McCabe, Ms. Koehn has presented some

evidence on each of the Althen prongs. However, Dr. McCabe’s opinions are not

persuasive. Ms. Koehn has not established, under a more likely than not standard,

that the two doses of Gardasil caused Vanessia to suffer sJIA.

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She is not entitled to compensation. The Clerk’s Office is instructed to enter

judgment in accord with this decision unless a motion for review is filed.

IT IS SO ORDERED.

s/Christian J. Moran

Christian J. Moran

Special Master

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