C. K., as Mother and Next Friend of V.K. v. Secretary of Health and Human Services

In the United States Court of Federal Claims

No. 11-355V

(Originally Filed: December 3, 2013)

(Reissued: December 19, 2013)*

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

C. K., as Mother and Next

Friend of V. K.,

Vaccine case; off-table

claim; Althen; petitioner’s

Petitioner,

challenge to the Special

Master’s decision; HPV

v.

vaccine; Gardasil;

systemic juvenile

SECRETARY OF HEALTH AND

idiopathic arthritis

HUMAN SERVICES,

Respondent.

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

OPINION

Currently before the court is petitioner’s motion for review of the

Special Master’s ruling of May 30, 2013 denying compensation for an injury

allegedly caused by a vaccine. The matter is fully briefed, and oral argument

was held on October 18, 2013. For the reasons explained below, we deny

petitioner’s motion for review.

On June 6, 2011, petitioner, C. K., filed a petition for compensation

under the National Childhood Vaccine Injury Act, 42 U.S.C. §§ 300aa-1 to-34

(2006) (“Vaccine Act”), on behalf of her minor daughter, V. K. (“V”). The

petition alleges that V developed systemic juvenile idiopathic arthritis

(“SJIA”) because she received two doses of the human papillomavirus

*

This opinion was initially withheld from publication to provide the

parties with a period of time to propose redactions. The court adopted the

parties’ proposed redactions, which were made to protect petitioner’s identity.

The opinion is now prepared for release.

(“HPV”) vaccine. Specifically, petitioner’s theory of the case was that the

HPV vaccine causes an increase in particular cytokines, the same cytokines are

implicated in SJIA, and therefore the HPV vaccine can be a significant factor

in causing SJIA. After conducting a hearing, reviewing epidemiological

studies, and weighing the evidence provided by the experts, the Special Master

concluded that petitioner had failed to establish a persuasive theory of

causation and denied petitioner’s request for compensation. See Koehn v.

Sec’y of Health & Human Servs., No. 11-355V, 2013 WL 3214877 (Fed. Cl.

Spec. Mstr. May 30, 2013) (hereinafter “Decision”).

BACKGROUND1

I. Facts

V was born in 1995. She was generally healthy throughout childhood.

She had no remarkable medical events for the first twelve years of her life

other than asthma. Dr. Elena R. Regala, V’s routine physician, administered

the first dose of the HPV2 vaccine in February of 2008 during a regular check-

up. The brand of HPV vaccine given to V was Gardasil, which is

manufactured by Merck.3 Gardasil provides immunization against four strands

of virus: HPV-6, HPV-11, HPV-16, and HPV-18, and is therefore referred to

as a quadrivalent HPV vaccine.

The HPV vaccine contains virus-like particles (“VLP”) that were

created from the L1 protein of the human papillomavirus. In order to generate

a robust immune response sufficient to generate long term immunity, the

1

The facts are derived from the Special Master’s decision.

2

There are over 130 strands of HPV. Some of these strands cause

warts. Two strains of the virus, HPV 16 and HPV 18, are known to cause

cancer. For a more thorough description of symptoms caused by an HPV

infection, see Decision at *2.

3

The other brand of HPV vaccine discussed in some of the studies

considered by the Special Master is Cervarix, which provides immunity against

HPV strands 16 and 18. Cervarix differs from Gardasil in that it provides

immunity against only two strains of HPV and contains a lipid and aluminum

salt adjuvant known as AS04.

2

vaccine contains an adjuvant4 and is delivered intramusculary. This vaccine

can cause the host to produce more antibodies than he or she would have

produced in response to a natural infection.

The second dose of Gardasil was given to V on April 18, 2008. On or

around June 21, 2008, V experienced a rash all over her body. This caused her

on June 24, 2008 to visit Dr. Regala, who prescribed Benadryl and prednisone

for what Dr. Regala believed to be an allergic reaction. Within three days, V’s

rash had disappeared. After V stopped taking the prednisone, she developed

pain in multiple places including her knees, thighs, and calves. V was admitted

to Marian Medical Center on June 28, 2008, for severe joint pain and high

fever. While at the hospital, V received medical tests, saw a Rheumatologist,

and was prescribed prednisone. On July 2, 2008, she was discharged from the

hospital with a presumptive discharge diagnosis of juvenile idiopathic arthritis.

At the time she was discharged, V no longer had a fever or joint pain but still

had a rash.

The cause of SJIA is unknown. The annual incidence rate of this

disease in children less than 16 years of age is between 0.3 and 0.8 out of every

100,000. Children with SJIA exhibit symptoms of arthritis and a recurring

fever for at least two weeks as well as a rash, enlargement of the liver or

spleen, lymphadenopathy, or serositis. When a child with SJIA has active

inflamation, commonly referred to as a flare, he or she may experience muscle

pain, pain in more than one joint, a fever, and a rash. SJIA may also cause

problems with the heart, liver, or in rare cases, the central nervous system.

Many of the symptoms described above are associated with a

dysfunction of the innate immune response and a corresponding increase in the

production of pro-inflammatory cytokines. A cytokine is a protein which is

released almost immediately by certain cells when they come into contact with

a specific antigen. When the cytokine is released it signals other cells to

generate an immune response. In short, cytokines are like smoke signals

which cells send out to indicate the presence of an invasion and to elicit a

defensive response. Respondent’s expert testified that the cytokine response

4

The particular adjuvant contained in Gardasil is amorphous aluminum

hydroxyphosphate sulfate, which stimulates antibody production.

3

is almost universal.5 There are, however, specific cytokines which are

recognized as being either anti-inflammatory or pro-inflammatory. Pro-

inflammatory cytokines can lead to fever, increased vascular permeability, and

increased synovial inflammation. “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 [(“TNF”)].” Decision at *8. Because of the involvement of

these cytokines, which are part of the innate immune system, SJIA is classified

as an autoinflammatory disease as opposed to an autoimmune disease.6

SJIA is treated by medications which minimize inflamation, including

some combination of the following: any nonsteroidal anti-inflammatory

pharmaceutical such as ibuprofen or naproxen; intravenous immunoglobulin;

cyclosporine-A; thalidomide; prednisone, which reduces inflamation and

generally suppresses the immune system; etanercept, which targets and inhibits

TNF; methotrexate, which is a folic acid inhibitor; tocilizumab, which inhibits

IL-6 production; and anakinra, which is a IL-1 inhibitor.

5

Scientists have identified approximately 40 specific cytokines thus far.

6

The distinction between an autoimmune and an autoinflammatory

disease is made based on the part of the immune system that is dysregulated

or out of balance. The immune system is comprised of two systems: the

adaptive and innate. These two systems interact continuously to maintain

balance. Hr’g Tr. 67-70, June 21, 2012. When the adaptive immune system

is dysregulated, the autoantibodies and autoreactive T cells do not function as

they would in a healthy individual and the resultant state is called an

autoimmune disease. Rheumatoid arthritis is typically understood to be an

autoimmune disease. When the innate immune system, which involves

cytokine production by monocytes and neutrophils, functions abnormally, then

the resulting state is known as an autoinflammatory disease. See Elizabeth D.

Mellins et al., Pathogenesis of systemic juvenile idiopathic arthritis: some

answers, more questions, 7 Nature Revs. Rheumatology 416 (2011)

(hereinafter “Mellins”). Before this distinction was made between

autoimmune and autoinflammatory diseases, most forms of arthritis were

generally referred to as autoimmune disorders. SJIA was only recently

classified as an autoimmune disease. Some scholars continue to broadly

characterize arthritis as an autoimmune disease and include SJIA in this

characterization.

4

After being discharged from the hospital, V saw a pediatric

rheumatologist, Dr. Deborah McCurdy, on July 8, 2008, who noted that V’s

family history included juvenile idiopathic arthritis and concluded that SJIA

was a likely diagnosis in this case. Dr. McCurdy recorded that V’s

vaccinations were up to date and that V had received two of three courses of

the HPV vaccine. Dr. McCurdy communicated these findings to Dr. Regala.

When Dr. Regala saw V again on August 19, 2008, she administered the third

dose of HPV vaccine. At the time that V received the third course of Gardasil,

she was no longer taking prednisone but had started etanercept. A physical

therapist recorded that on August 25, 2008, V experienced a flare with

symptoms of fever, rash, and increased joint pain. Dr. McCurdy saw V again

on September 3, 2008. Dr. McCurdy noted that V complained of having some

symptoms after stopping prednisone and that V had swollen ankles and knees.

Dr. McCurdy concluded that V had improved but still showed signs of active

disease while being treated with methotrexate and etanercept.

Dr. McCurdy continued to care for V through 2010. On January 12,

2011, V visited another pediatric rheumatologist, Dr. Alice Hoftman. During

this visit, Dr. Hoftman recommended that V receive the influenza vaccine.

Although V had received the influenza vaccine during the previous three years,

C. K. refused this treatment for her daughter. Dr. Hoftman recorded that C. K.

was hesitant about giving V the vaccine because of Gardasil. Dr. Hoftman

explained that there was “‘no data but all vaccines and infections can trigger

autoimmune response.’” Decision at *10 (quoting Ex. 5 at 28).

II. Expert Opinions

A. Petitioner’s Expert

Petitioner offered the testimony of Dr. Michael J. McCabe, Jr., an

expert in the field of immunology. Dr. McCabe is not a medical doctor and

does not treat patients. In his report, Dr. McCabe wrote that the cause of

arthritis is multi-factorial. Genetic susceptibility and environmental triggers

such as infections and vaccinations are possible causative factors. Dr.

McCabe’s theory is essentially that the HPV vaccine, which Dr. McCabe

characterized as a potent immunogen, was the environmental trigger that

caused V’s immune system to fall out balance resulting in her SJIA. The

evidence of this is that the vaccine elicited a strong cytokine response which

involved the same cytokines that are associated with SJIA.

5

In support of his theory, Dr. McCabe provided “‘scientific and medical

literature that implicates pro[-]inflammatory cytokines and inflammatory

responses and innate immunity in the pathogenesis of systemic juvenile

arthritis.’” Decision at *12 (quoting Hr’g Tr. 123). One such article was Ligia

A. Pinto et al., HPV-16 L1 VLP vaccine elicits a broad-spectrum of cytokine

responses in whole blood, 23 Vaccine 3555 (2005) (hereinafter “Pinto”),

which Dr. McCabe interpreted as showing an increase in the production of

particular cytokines in response to the HPV vaccine.7 The Special Master

summarized the Pinto study as follows:

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.

The researchers determined the level of cytokines for

each of the three blood samples after different types of

stimulation. This process was done “in vitro,” meaning in glass,

like a test tube. 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. The

stimulation was for 24 hours in the absence or presence of L1

VLP or PHA.

7

The HPV vaccine used in the Pinto study provides immunity against

just one strand of HPV, HPV-16, and did not contain an adjuvant. By contrast,

the vaccine that V received, Gardasil, provided immunity against four strands

of HPV, including HPV-16, and contained an adjuvant.

6

. . . . [T]he 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.

. . . [S]pontaneous secretion of cytokines in the absence of any

stimuli (media control) did not show any significant increases

following vaccination. 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. 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.

Decision at *4 (citations and quotations omitted). The Pinto study included a

graph that Dr. McCabe used to show how levels of pro-inflammatory cytokines

like IL-1 beta, IL-6, and TNF alpha increased in response to direct stimulation

with the L1 VLP.8 Pinto at 3558; see Hr’g Tr. 104. According to Dr.

McCabe, the particular cytokines that increased in response to the HPV L1

VLP are the same cytokines, IL-1, IL-6, and TNF, that are dysregulated in

SJIA. This commonality of cytokines present in response to the HPA vaccine

and involved in SJIA is the foundation and mechanistic support for Dr.

McCabe’s theory of causation.

Dr. McCabe also presented the Special Master with an epidemiological

study, which evaluated a database of the medical history of approximately

189,000 women to determine whether these women developed autoimmune

conditions within 180 days of receiving the quadrivalent HPV vaccine. Chun

Chao et al., Surveillance of autoimmune conditions following routine use of

quadrivalent human papillomavirus vaccine, 271 J. Intern. Med. 193 (2012)

8

This was not the only study Dr. McCabe relied on to show an increase

in pro-inflammatory cytokines in response to stimulation with the HPV

vaccine. Dr. Pinto participated in a more recent study which also showed “that

various cytokines increased after the administration of a vaccine against

human papillomavirus.” Decision at *12; see 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) (hereinafter “García-Piñeres”).

7

(hereinafter “Chao”). One of the diseases that the researchers targeted was

juvenile rheumatoid arthritis9 (“JRA”). In order to identify JRA within the

population, the researchers looked for a diagnostic code which included JRA

and searched for medications commonly prescribed to treat JRA. While the

researchers did not reach any statistically relevant findings regarding JRA, they

concluded, “no safety signal for autoimmune conditions was found following

HPV4 vaccination in routine clinical use.” Id. at 202. Dr. McCabe used this

study to show that, despite the large population involved in this study, it was

not large enough to detect any increase in the rate of SJIA following HPV

vaccination because SJIA is such a rare disease. During the hearing, Dr.

McCabe explained that there is an absence of epidemiological studies in

support of his theory because the disease is too rare for scientists to be able to

generate statistically relevant data. Hr’g Tr. 134-35. Dr. McCabe testified that

“there is ‘no epidemiology that’s meaningful enough to inform us’ as to

whether the HPV vaccine causes sJIA.” Decision at *13 (quoting Hr’g Tr.

141-42).

The additional literature which Dr. McCabe relied on in his report to

support the connection between vaccines and SJIA was summarized by the

Special Master in the following manner:

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 1 [(hereinafter “Roghany”)] . . . . 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

9

The researchers did not search for SJIA in particular. However, Dr.

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

population would have been detected with the methodology utilized by the

investigators.” Decision at *5 (citations and quotations omitted).

8

candidate could point to multiple common agents being capable

of initiating sJIA.” [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 [(hereinafter “Prakken”)]. This article

continued, “but neither has been confirmed as a trigger because

of a scarcity of proper controlled, prospective studies.” Id.

Decision at *8 (underlining in original). These articles speculate that there

might be a link between vaccination in general and the development of SJIA,

but Dr. McCabe suggested that V was most likely predisposed to develop SJIA

and that V’s environmental trigger, which substantially caused her to develop

the disease, was Gardasil. Hr’g Tr. 162, 197.

Dr. McCabe applied the Bradford-Hill criteria for causation to lend

credence to his theory. See Sir Austin Bradford Hill, The Environment and

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

295 (1965) (hereinafter “Bradford-Hill”). Dr. McCabe believes that the

temporal sequence, the dose-response relationship, biological plausibility, and

experimental evidence, all of which are indicative of causation under the

Bradford-Hill assessment, showed that Gardasil could cause SJIA. Dr.

McCabe acknowledged that some of the Bradford-Hill criteria, such as

strength of association and analogy, were not necessarily supportive of his

theory of causation.

Regarding the dose-response correlation, Dr. McCabe pointed to

evidence that V experienced a flare after receiving the third dose of HPV

vaccine. While acknowledging that V was receiving anti-inflammatory

treatments when she received the third dose, which made the causation of this

flare less than clear, Dr. McCabe suggested that the worsening of symptoms

such as fever, rash, and joint pain during this flare showed that V was

generating pro-inflammatory cytokines in response to the third dose of

vaccination.

Dr. McCabe also noted that studies showed that almost all of the

patients who received the HPV vaccine seroconverted, or developed sufficient

antibodies for immunity, within seven months. Based on that data, Dr.

McCabe concluded that development of disease within seven months after

receiving an HPV vaccine was evidence of a proximate temporal relationship.

9

B. Respondent’s Expert

Dr. Carlos Rose, an expert in the field of pediatric rheumatology,

testified on behalf of the Secretary of Health and Human Services. As a

pediatric rheumatologist, Dr. Rose routinely treats children with SJI–Dr. Rose,

however, is not an immunologist, he has not done any research on the HPV

vaccine, and he has not researched the role of pro-inflammatory cytokines in

SJIA. After reviewing the literature and Dr. McCabe’s report, Dr. Rose

concluded that it was mere coincidence that V developed SJIA shortly

following her second dose of HPV vaccine. Although Dr. Rose acknowledged

that there is some overlap in the cytokines, particularly IL-1 and IL-6,10 present

in those recently vaccinated against HPV and those who have SJIA, Dr. Rose

concluded that this overlap was more likely due to the limited number of

cytokines that are involved in the stereotypical inflammatory response rather

than due to a causal relationship with the vaccine.

In response to the research cited by Dr. McCabe regarding the

connection between the HPV vaccine and SJIA, Dr. Rose opined that these

articles were simply hypothesis-generating and did not represent a scientific

consensus based on evidence and testing. Instead, Dr. Rose explained that, in

his experience, pediatric rheumatologists generally discuss the safety of HPV

vaccine for their patients and are not asserting links between SJIA and

vaccines.

Dr. Rose also provided his interpretation of the relevance of the Pinto

study. The media group, i.e. the group not stimulated in vitro, was the most

relevant to Dr. Rose because it showed a lack of sustained cytokine response

one month after each dose of vaccination. Dr. Rose observed that the cytokine

response in this media group remained relatively consistent at months zero,

two, and seven. This, according to Dr. Rose, is “‘very suggestive that the

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

sustained.’” Decision at *17 (quoting Hr’g Tr. 225). By contrast, patients with

SJIA experience a pattern of up-regulated cytokines, which is why they are

treated with medications that inhibit these specific cytokines. Dr. Rose

10

“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.” Decision at *16.

10

disagreed that the Pinto or García-Piñeres studies showed how a vaccine,

which may trigger a temporary cytokine response, can cause permanent

cytokine dysregulation resulting in disease.

In support of his assertion that SJIA is not caused by the HPV vaccine,

Dr. Rose cited an epidemiological study of roughly 60,000 individuals that

found no “evidence of an overall increase in relative risks for autoimmune

disorders in participants receiving vaccines containing AS04.” Thomas

Verstraeten et al., Analysis of adverse events of potential autoimmune

aetiology in a large integrated safety database of AS04 adjuvant vaccines, 26

Vaccine 6630, 6633 (2008) (hereinafter “Verstraeten”) (comparing the

development of autoimmune diseases in recipients of three different vaccines,

only one of which was an HPV vaccine known as Cevarix, containing the

adjuvant AS04 against a control group of recipients of vaccines that did not

contain AS04 and finding that there was no greater risk of autoimmune disease

in the population exposed to AS04).11 Dr. Rose believed that this study would

have shown a connection between SJIA and the HPV vaccine if one existed.

C. Additional Studies the Special Master Considered

Part of the Bradford-Hill criteria referenced by Dr. McCabe is causation

judged by analogy, i.e. whether similar vaccines cause results that are similar

to those alleged by petitioner. Bradford-Hill at 299. To explore this criteria

of causation, the Special Master looked at analogous studies which evaluated

whether there was a connection between SJIA and the meningococcal C

vaccine or the measles, mumps, and rubella (“MMR”) vaccine. Decision at

*22; see Marloes W. Heijstek et al., Safety of measles, mumps, and rubella

vaccination in juvenile idiopathic arthritis, 66 Ann. Rheum. Dis. 1384 (2007)

(hereinafter “Heijstek”); Evelien Zonneveld-Huijssoon et al., Safety and

Efficacy of Meningococcal C Vaccination in Juvenile Idiopathic Arthritis, 56

Arthritis & Rheumatism 639 (2007) (hereinafter “Zonneveld-Huijssoon”). The

subjects of these studies already had juvenile idiopathic arthritis or SJIA and

11

At the hearing, the weaknesses of this study were discussed, including

the fact that the study did not involve Gardasil or the adjuvant contained in

Gardasil and that the researchers looked for JRA rather than SJIA. Hr’g Tr.

240-44. Dr. Rose also conceded that a proper epidemiological study of SJIA

would have to test at least 100,000 individuals because of the rarity of the

disease. Hr’g Tr. 245-46.

11

the researchers sought to determine whether the subjects’ disease symptoms

worsened after receiving either the meningococcal C or the MMR vaccine.

The conclusion was the same in each study: the researchers did not observe

any flares or worsening of disease activity in the subjects with SJIA or juvenile

idiopathic arthritis following vaccination.

According to Dr. Rose, these studies show that the meningococcal

vaccine and the MMR vaccine are safe for use in patients with SJIA. Because

of this record of safety, Dr. Rose added that Pediatric Rheumatologists

recommend that their patients receive all vaccines, except those containing live

viruses. Hr’g Tr. 222.

III. The Special Master’s Analysis

In order to receive compensation for an injury caused by a vaccine

other than those injuries listed on the Vaccine Injury Table,12 a petitioner must,

show by preponderant evidence that the vaccination brought

about her 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.

Althen v. Sec’y of Health & Human Servs., 418 F.3d 1274, 1278 (Fed. Cir.

2005); see 42 U.S.C. § 300aa-13(a)(1)(A). Petitioner “must provide a

reputable medical or scientific explanation that pertains specifically to the

petitioner’s case, although the explanation need only be ‘legally probable, not

medically or scientifically certain.’”13 Moberly v. Sec’y of Health & Human

12

See 42 U.S.C. § 300aa-14(a) (injury table); W.C. v. Sec’y of Health

& Human Servs., 704 F.3d 1352, 1356 (Fed. Cir. 2013) (explaining that “[i]n

a table claim, the petitioner benefits from a statutory presumption of causation

upon showing that the injury is listed in the Vaccine Injury Table for the

vaccine received and occurred within the time period in the table” but that “[i]f

the injury is not listed in the table, the petitioner must prove actual causation

by a preponderance of the evidence”).

13

“[A] finding of causation in the medical community may require a

(continued...)

12

Servs., 592 F.3d 1315, 1322 (Fed. Cir. 2010) (quoting Knudsen v. Sec’y of

Health & Human Servs., 35 F.3d 543, 548-49 (Fed. Cir. 1994)). The theory

presented by petitioner need only be more likely than not and “close calls

regarding causation are resolved in favor of injured claimants.” Althen, 418

F.3d at 1280. “Nonetheless, the petitioner must do more than demonstrate a

‘plausible’ or ‘possible’ causal link between the vaccination and the injury; he

must prove his case by a preponderance of the evidence.” W.C., 704 F.3d at

1356.

If petitioner establishes a prima facie case under the Althen elements,

then the burden shifts to the government to show “‘also by a preponderance of

evidence, that the injury was in fact caused by factors unrelated to the

vaccine.’” Id. (quoting Knudsen v. Sec’y of Health & Human Servs., 35 F.3d

543, 547 (Fed. Cir. 1994)).

The Special Master analyzed each prong of Althen in turn. Pursuant to

prong one of Althen, the Special Master considered whether petitioner

presented a reliable scientific theory under the framework of Daubert v.

Merrell Dow Pharmaceutical, Inc., 509 U.S. 579, 592-95 (1993), whether

petitioner’s theory originated within the scientific community or arose for the

purposes of litigation, and whether the epidemiological evidence supported

petitioner’s theory.

First, the Special Master assessed the reliability of Dr. McCabe’s theory

by applying three14 of the following Daubert factors:

(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

13

(...continued)

much higher level of certainty than that required by the Vaccine Act to

establish a prima facie case.” Broekelschen v. Sec’y of Health & Human

Servs., 89 Fed. Cl. 336, 343 (2009), aff’d 618 F.3d 1339 (Fed. Cir. 2010).

14

The third Daubert factor was not considered by the Special Master

because neither party introduced evidence regarding the potential rate of error.

13

community.

Terran v. Sec’y of Health & Human Servs., 195 F.3d 1302, 1316 (Fed. Cir.

1999) (citing Daubert, 509 U.S. at 592-95).

In the absence of studies that directly tested petitioner’s theory, the

Special Master explored the Bradford-Hill causation criteria of analogy. The

Special Master considered two types of analogous studies: those that were

conducted on animals and those that involved other vaccines. As for the first

type, neither party identified a study conducted with animals even though an

animal model for macrophage activation syndrome exists, which is similar to

SJIA. Dr. Rose explained that the lack of animal studies on this issue was

likely attributable to the fact that researchers were pursuing more productive

theories. Then the Special Master considered the Heijstek and Zonneveld-

Huijssoon studies, which belonged to the second type. These studies showed

no disease aggravation when the test subjects who had JIA or SJIA were

vaccinated with the meningococcal C or the MMR vaccination. The Special

Master wrote that these “studies suggest that when researchers have explored

whether vaccinations affect juvenile idiopathic arthritis, they have not found

that the vaccine worsens the disease.” Decision at *22. The Special Master

acknowledged that these studies contained some factual differences from the

present case, but concluded that “[b]ecause they are studies, the Heijstek and

Zonneveld-Huijssoon findings are entitled to more weight than speculative

passages in other articles.” Id. The Special Master concluded that the

analogous evidence weighed against petitioner’s case, or was, at best, neutral.

Next, the Special Master observed that Dr. McCabe’s theory was

unprecedented and had not been published or peer reviewed, although the

Special Master noted that Dr. McCabe relied on peer reviewed and published

articles in support of his theory. Specifically, the Special Master discussed Dr.

McCabe’s reliance on the Pinto experiment to show an increase in cytokines

seven months after vaccination. Dr. McCabe had drawn that result from the

part of the experiment in which researchers had stimulated blood samples from

vaccinated individuals with VLP. Dr. Rose agreed with Dr. McCabe that an

increase in the cytokine response would follow from direct stimulation with

the VLP. However, Dr. Rose opined that the most relevant part of the Pinto

study to the present case was the “media” column, which showed that the level

of cytokines present in the blood is relatively stable when it is left alone

following vaccination. The Special Master found Dr. Rose’s interpretation of

the Pinto experiment more persuasive. According to the Special Master, this

14

evidence did not weigh in favor of finding that petitioner’s theory is more

likely than not.

While the Special Master acknowledged that petitioner had provided the

Prakken article, which shows that some scientists may be hypothesizing about

a possible link between vaccination and SJIA, the Special Master noted that

one equivocal article did not constitute “evidence that the relevant scientific

community generally accepts the theory that Gardasil can cause sJIA.”

Decision at *24. Given that Dr. Rose is the head of pediatric rheumatology at

the Alfred I. DuPont Hospital for Children, the Special Master believed that

Dr. Rose would know if pediatric rheumatologists were discussing a possible

link between Gardasil and SJIA. However, Dr. Rose testified that pediatric

rheumatologists were not discussing whether Gardasil caused SJIA. Rather,

pediatric rheumatologists, including Dr. Rose, generally recommend that their

patients receive all vaccines except those that contain a live virus. The Special

Master found that the relevant scientific community, at this time, does not

accept the theory that Gardasil can cause SJIA.

Next, the Special Master analyzed the epidemiological studies provided

by respondent. One of these articles, authored by Chao, studied the effects of

Gardasil in upwards of 189,000 young women. The Special Master noted that

the researchers in this study did not find a cluster of autoimmune disease onset

in relation the vaccine. The Special Master then turned to the Verstraeten

article, which, although he found to be somewhat weak because of the small

sample size and because the researchers tested Cervarix instead of Gardasil,

“[t]aken 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.” Decision at *26.

Lastly, the Special Master noted that Dr. McCabe developed his theory

of causation for the purpose of litigation. The Special Master weighed this

fact against petitioner’s theory under the Althen prong-one analysis, which

considers whether petitioner has put forth a medical theory causally connecting

the vaccination and the injury. After reviewing the totality of petitioner’s

theory, the Special Master found it problematic that, even if he accepted “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.” Decision at *8. Ultimately, the

Special Master found that Dr. McCabe’s theory of causation contained

sufficient gaps to make it unpersuasive and petitioner therefore failed to prove

15

a medical theory that more likely than not the vaccination was causally

connected to the injury.

Although the Special Master was not required to reach conclusions

about the remaining Althen prongs after holding that petitioner had failed to

prove prong one, he noted that the record did not support a finding that

development of SJIA within a seven-month interval was sufficient to establish

a proximate temporal relationship. Specifically, the Special Master found that

the Pinto experiment undermined Dr. McCabe’s proposed seven-month

interval for the onset of SJIA symptoms because the cytokine response to

stimulation with VLP was immediate in the Pinto experiment. While Dr.

McCabe attempted to explain the delay between vaccination and symptom

onset with a theory of amplification, the Special Master saw the media portion

of the Pinto study as contradictory because cytokines in this group remained

relatively constant over time. Additionally, the Special Master deduced that

the evidence provided about V did not persuasively show that she developed

SJIA because of the HPV vaccine. After reviewing Dr. McCabe’s theory, Dr.

Rose’s contradictory opinion, and the evidence presented by each expert, the

Special Master concluded that petitioner’s theory “contain[ed] sufficient gaps

to make it unpersuasive.” Decision at *26.

DISCUSSION

This court has jurisdiction to review decisions of the special masters in

accordance with 42 U.S.C. § 300aa-12. We review the special master’s

decision under the standard articulated in 42 U.S.C. § 300aa-12(e) and can

only set aside “findings of fact or conclusion of law” that were “arbitrary,

capricious, an abuse of discretion, or otherwise not in accordance with law.”

42 U.S.C. § 300aa-12(e)(2); see Carson v. Sec’y of Health & Human Servs.,

727 F.3d 1365, 1368 (Fed. Cir. 2013) (describing how the reviewing court

should “give no deference to the . . . Special Master’s determinations of law,

but uphold the Special Master’s findings of fact unless they are arbitrary or

capricious”). “The arbitrary and capricious standard of review is difficult for

[a petitioner] to satisfy with respect to any issue, but particularly with respect

to an issue that turns on the weighing of evidence by the trier of fact.” Lampe

v. Sec’y of Health & Human Servs., 219 F.3d 1357, 1360 (Fed. Cir. 2000).

“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 v. Sec’y of Health & Human Servs., 592 F.3d 1315, 1325

16

(Fed. Cir. 2010). Special masters have discretion to weigh the evidence and

“reversible error is ‘extremely difficult to demonstrate’” unless the special

master has failed to consider the relevant evidence of record, drawn

implausible inferences or failed to articulate a rational basis for the decision.

Lampe 219 F.3d at 1360 (quoting Hines v. Sec’y Health & Human Servs., 940

F.2d 1518, 1528 (Fed. Cir. 1999)). The reviewing court does “not reweigh the

factual evidence, assess whether the special master correctly evaluated the

evidence, or examine the probative value of the evidence or the credibility of

the witnesses–these are all matters within the purview of the fact finder.”

Porter v. Sec’y of Health & Human Servs., 663 F.3d 1242, 1249 (Fed. Cir.

2011).

Petitioner makes four challenges to the Special Master’s decision. We

address each allegation in turn.

I. Whether the Special Master failed to consider the record as a

whole

Petitioner claims that the Special Master failed to consider the whole

record in his decision. See Dickerson v. Sec’y of Health & Human Servs., 35

Fed. Cl. 593, 601 (1996) (“[F]ailure to examine the full record and provide

sufficient findings constitutes error.”). Petitioner believes that, if the Special

Master had considered the entire record, he would have seen that petitioner

presented a plausible theory supported by the scientific evidence and research.

Respondent replies that the Special Master did not exclude any

evidence and that he considered “all ‘relevant and reliable evidence governed

by principles of fundamental fairness to both parties’” as evidenced by the

thoroughness of his decision. Resp’t’s Resp. to Pet’r’s Mot. for Review 10

(quoting RCFC, App. B, Rule 8(b)(1)). Once the Special Master thoroughly

considered the record, he was entitled to weigh the evidence and conclude that

he was not persuaded by petitioner’s theory of the case.

We agree that the Special Master was careful to consider all relevant

evidence, particularly those pieces on which petitioner relied to support her

case. The Special Master discussed the literature that Dr. McCabe cited to

show that medical experts were considering whether there is a connection

between SJIA and vaccination, and he found these articles to be equivocal.

See Decision at *8. The Special Master reviewed the content of the Pinto

study at length and concluded that Dr. Rose’s interpretation of the significance

17

of the study was more persuasive. Decision at *23-24. Additionally, the

Special Master engaged each part of Dr. McCabe’s expert opinion in the

analysis of his decision. The Special Master also considered relevant evidence

and testimony provided by Dr. Rose. The fact that the Special Master found

Dr. Rose’s expert opinion more persuasive in light of Dr. Rose’s testimony and

scientific evidence is simply a function of the Special Master’s role as fact

finder. So long as the Special Master considered the relevant evidence, and we

conclude that he did, we cannot disturb his findings on this ground.

II. Whether petitioner’s burden of proof was erroneously elevated

A. Whether the Special Master required petitioner to

provide epidemiological proof

Petitioner asserts that the Special Master erred by requiring

epidemiological proof of petitioner’s theory. See Cappizzano v. Sec’y of

Health & Human Servs., 440 F.3d 1317, 1325 (Fed. Cir. 2006) (“[R]equiring

either epidemiological studies, rechallenge, the presence of pathological

markers or genetic disposition, or general acceptance in the scientific or

medical communities to establish a logical sequence of cause and effect . . . .

impermissibly raises a claimant’s burden.”). Petitioner acknowledges that,

throughout the Special Master’s decision, he asserted that he was not requiring

epidemiological proof. Nevertheless, petitioner alleges that, instead of

accepting Dr. McCabe’s explanation for why there is an absence of

epidemiological and animal studies connecting Gardasil and the development

of SJIA, the Special Master turned to and placed “inordinate emphasis” on

epidemiological studies provided by respondent that were not squarely on

point. Pet’r’s Mot. for Review 25. In sum, petitioner believes that the Special

Master de facto required epidemiological evidence by pointing to the Chao

article, which did not find any statistically relevant increase in the development

of JRA following vaccination with Gardasil, and the Verstraeten article, which

involved a different HPV vaccine, a different adjuvant, and did not target SJIA

within the studied pool of individuals.

Respondent argues that the Special Master did not raise the burden of

proof. Rather, throughout his decision, the Special Master maintained that

petitioner must prove her case by a preponderance of the evidence. See, e.g.,

Decision at *18, *20, *28. Respondent states, and we agree, that under the

preponderance of the evidence standard, simply positing a theory is not

enough. Petitioner must provide a theory that is persuasive. See W.C., 704

18

F.3d at 1356.

The Special Master has discretion to assess the reliability of expert

testimony when weighing the persuasiveness of the evidence. Moberly, 592

F.3d at 1325. While the special master may not require epidemiological proof

of petitioner’s theory, Cappizzano, 440 F.3d at 1325, he may evaluate

contradictory evidence provided by respondent, 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, 133 S. Ct. 2022 (2013), and he may consider the

presence or absence of peer reviewed scientific studies in the context of

applying the Daubert framework for analyzing whether an expert’s theory is

persuasive, Terran, 195 F.3d at 1316 (upholding the special master’s approach

of “using Daubert’s questions as a tool or framework for conducting the

inquiry into the reliability of the evidence”); see Cedillo v. Sec’y of Health &

Human Servs., 617 F.3d 1328, 1339 n.3 (Fed. Cir. 2010) (listing the case law

in which the Court of Appeals for the Federal Circuit upheld the special

master’s application of the Daubert factors).

In this case, the Special Master considered epidemiological and other

medical articles in the context of assessing the persuasiveness of the expert

opinions using the first Daubert factor, which is whether the theory has been

or can be tested. See 509 U.S. at 593. Throughout his analysis the Special

Master considered the evidence presented by both experts. After considering

the lack of animal studies, the articles that posited about a connection between

SJIA and vaccination, and the studies that showed no worsening of symptoms

in subjects with JIA and SJIA after receiving the MMR or the meningococcal

C vaccine, the Special Master found that the latter evidence was more

persuasive than the former and, therefore, this Daubert factor was either

neutral or balanced against petitioner. While the Special Master may not

require petitioner to prove his case with epidemiological studies, that does not

mean that scientific evidence that tends to contradict petitioner’s theory must

be ignored. The Special Master was squarely within his role as a fact-finder

when he weighed the evidence presented to him. Because we are not tasked

with reweighing the evidence, and the Special Master’s conclusion about the

first Daubert factor was neither arbitrary nor capricious, we find no error. See

Hulbert v. Sec’y of Health & Human Servs., 49 Fed. Cl. 485, 490 (2001), aff’d,

35 F. App’x 899 (Fed. Cir. 2002) (deferring to the Special Master’s

determination that the petitioner’s expert did not present an opinion that was

as credible as the opinion given by the respondent’s expert when analyzed

under the Daubert framework).

19

B. Whether the Special Master impermissibly held against

petitioner the fact that Dr. McCabe’s theory had not been

published or peer reviewed

Petitioner asserts the Special Master heightened her burden to

something close to scientific certainty by holding against her the fact that Dr.

McCabe’s theory had not been published and subject to peer review. Rather,

plaintiff claims that she met her burden of preponderant evidence by

presenting a theory that was in line with published and peer reviewed scientific

literature.

Respondent responds that it was permissible for the Special Master to

ask whether Dr. McCabe’s theory had been published and subject to peer

review because it is the second factor of the Daubert framework for assessing

the reliability of an expert opinion. See 509 U.S. at 593. While we agree that

it would be problematic if the Special Master had required petitioner uniquely

to present a theory that had been tested and peer reviewed, that is not what

happened in this case. The Special Master sought indicia of reliability through

the use of the Daubert framework, and he noted that, “until [V]’s case, there

was not even one case report published in the medical journals showing even

a temporal sequence in which a Gardasil vaccination preceded sJIA.”

Decision at *23 (citation omitted). The Special Master did not end his analysis

of the second Daubert factor there, however. He proceeded to consider the

peer reviewed medical evidence presented by petitioner and, after weighing it,

concluded, “the evidence relating to peer review and publication does not

assist in finding that Dr. McCabe’s theory is probable.” Decision at *24. The

Special Master’s finding was not arbitrary or capricious, and it did not

impermissibly raise petitioner’s burden because it occurred within a larger

framework and was not the Special Master’s sole reason for concluding that

petitioner’s theory was unpersuasive.

C. Whether it was in error and raised petitioner’s burden

when the Special Master considered if rheumatologists

generally accept Dr. McCabe’s theory

When the Special Master inquired about whether rheumatologist

generally accept the theory that Gardasil can cause SJIA, petitioner claims that

he impermissibly raised her burden by requiring a theory that is generally

accepted within the scientific community. Petitioner cites Graves v. Secretary

20

of Health and Human Services, 101 Fed. Cl. 310, 323 (2011) (reciting that

general acceptance of the theory within the medical community is not

required). According to petitioner, the Special Master arbitrarily and

capriciously relied on Dr. Rose’s statement that he did not recall hearing

discussion amongst his colleagues about Gardasil causing SJIA.

Respondent contends, and we agree, that the Special Master’s inquiry

into whether there is general acceptance of Dr. McCabe’s theory within the

scientific community is permissible as part of the Daubert analysis. See 509

U.S. at 594. In his analysis of this factor, the Special Master noted that

petitioner provided articles, such as Berent Prakken et al., Juvenile idiopathic

arthritis, 377 Lancet 2138, 2141 (2011), that showed that the scientific

community was hypothesizing that vaccinations or infections might trigger

SJIA. Decision at *24. Also, the Special Master noted that Dr. Rose testified

that pediatric rheumatologists did not accept the theory that Gardasil can cause

SJIA and that the general practice of pediatric rheumatologists is to

recommend that their patients receive all vaccinations except those that contain

a live virus. As between these indications of what the relevant medical

community believes about a connection between Gardasil and SJIA, the

Special Master found that the relevant scientific community does not generally

accept Dr. McCabe’s theory. This inquiry, as part of the Daubert framework,

did not impermissibly raise petitioner’s burden of proof

III. Whether the Special Master misinterpreted the Pinto article

Petitioner asserts that the Special Master’s findings regarding the Pinto

study were contrary to the evidence. First, petitioner alleges that the Special

Master was confused in thinking that the Pinto study involved a live strand of

HPV. Petitioner points out that there is no evidence of a live human

papillomavirus being involved in either V’s case or in the Pinto study. The

Special Master’s statement regarding the live human papillomavirus appeared

in the context of the following paragraph in the Special Master’s decision:

Despite contrary testimony from Dr. McCabe . . . , 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 [V] in the sense that no medical record suggests

that she was exposed to a living strand of the human

papillomavirus. If [V] encountered the human papillomavirus

21

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.

Decision at *23. This paragraph, when considered with the Special Master’s

earlier description of the Pinto study, Decision at *4, shows that the Special

Master understood that only VLP was used in the Pinto study. The Special

Master’s comparison of the reaction of the blood samples when stimulated

with VLP to show how the body would react to a natural HPV infection was

made to illustrate Dr. Rose’s opinion that a robust cytokine response would be

expected in response to stimulation. However, the distinction in this case is

that V never experienced a stimulant such as a live human papillomavirus or

a concentrated dose of VLP as was administered in the Pinto study. This is the

reason why Dr. Rose thought that the media group in the Pinto study was more

relevant than the stimulated groups. The Special Master’s agreement with

that analysis was neither erroneous or illogical.

Second, petitioner argues that the Special Master’s reliance on Dr.

Rose’s interpretation of the Pinto study was arbitrary and capricious because

Dr. Rose is not an immunologist and has not conducted research involving

vaccines or pro-inflammatory cytokines. Dr. Rose was accepted as an expert

in pediatric rheumatology and, as such, was qualified to opine about medical

studies. The Special Master did not exclude Dr. McCabe’s interpretation of

the Pinto study, but instead found Dr. Rose’s interpretation to be more reliable.

Moberly, 592 F.3d at 1325-26 (“Assessments as to the reliability of expert

testimony often turn on credibility determinations, particularly in cases . . .

where there is little supporting evidence for the expert’s opinion.”).

Respondent asserts, and we agree, that, in light of all of the evidence, the

Special Master’s reliance on Dr. Rose’s interpretation of the significance of

the Pinto study was within his discretion as the fact-finder.

IV. Whether the Special Master arbitrarily and capriciously weighed

the evidence against petitioner

A. Petitioner provided scientific support for her theory,

which the Special Master arbitrarily dismissed

Petitioner claims that the Special Master erroneously dismissed

scientific support for petitioner’s theory. Specifically, in the Special Master’s

Althen prong-one analysis, he “neither cites not considers the Mellins,

22

Roghany, Prakken, or Emeny articles.”15 Pet’r’s Mot. for Review 20.

Petitioner argues that, instead of affording proper weight to the

aforementioned studies provided by petitioner which were relevant, from

respected journals, and peer-reviewed, the Special Master arbitrarily favored

analogous, but off-topic, studies authored by Heijstek and Zonneveld-

Huijssoon. Petitioner distinguishes the Heijstek and Zonneveld-Huijssoon

studies because they involved the meningococcal C and the MMR vaccines,

which lack the potency of Gardasil, and involved patients who had already

developed SJIA and may have been taking pharmaceuticals to control the

disease. Additionally, Dr. McCabe testified that he would expect the

meningococcal C vaccine, which is a vaccine against a bacterial infection, to

elicit a different cytokine response than the HPV vaccine, which immunizes

against a virus. Hr’g Tr. 183-84. These differences between the Heijstek and

Zonneveld-Huijssoon studies and the facts of this case, according to petitioner,

make the Special Master’s reliance on them arbitrary and capricious.

By contrast, respondent argues that the Special Master considered the

Prakken, Mellins, Roghany, and Emeny articles but found that they did not

support petitioner’s theory. While the Special Master did not evaluate each of

these articles specifically in the context of prong one, he did reference them

throughout his decision and found that the statements that petitioner relied on

from these articles were ambiguous. In his decision, the Special Master

described the scientific support that petitioner gleaned from the Prakken,

Mellins, and Roghany articles and found it to be unpersuasive due to the

equivocation in the findings. Decision at *8-9, *13, *16, *22, *24. While the

Special Master only briefly mentioned the Emeny article in his decision, he did

write that, “[a]t 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.” Decision at *3. As fact-

finder, it is within the province of the Special Master to weigh the evidence

and determine whether it is reliable. He plainly was aware of all the articles

and was not obligated to unpack them in detail. His treatment of the Prakken,

Mellins, Roghany, and Emeny articles was not arbitrary or capricious.

15

The “Emeny” article referred to in the quotation above is Rebecca T.

Emeny 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, 336 (2003) (hereinafter “Emeny”).

23

B. Whether the Special Master arbitrarily and capriciously

disregarded Dr. McCabe’s testimony

According to petitioner, the Special Master erred by disregarding Dr.

McCabe’s testimony on prong two because he does not treat patients.

Petitioner asserts that Dr. McCabe is qualified to testify about causation even

though he would not be qualified to testify about treatment. Petitioner also

opines that, while Dr. McCabe was uniquely qualified to testify about the

causal connection between Gardasil and SJIA based on his research as an

immunologist, Dr. Rose has never focused on causation but instead specializes

in treating children with SJIA.

Respondent replies that the Special Master fully considered Dr.

McCabe’s testimony, including Dr. McCabe’s testimony concerning whether

V’s flare following the third Gardasil dose was indicative of specific

causation. Respondent points out that it is the Special Master’s prerogative

under the law to examine the qualifications and expertise of the witnesses

when weighing their opinions, citing Locane v. Secretary of Health and

Human Services, 685 F.3d 1375, 1380 (Fed. Cir. 2012). Here, the Special

Master found more reliable Dr. Rose’s opinion that V’s vaccination with

Gardasil and development of SJIA were unrelated events. This finding is

sound under the law and was not arbitrary or capricious given the divergent

expert opinions.

Finally, petitioner contends that the Special Master erred by

disregarding Dr. McCabe’s testimony about the temporal relationship between

vaccination and disease. Dr. McCabe explained that a cytokine response may

take months to cycle through a period of amplification to eventually manifest

as SJIA. Dr. McCabe testified that development of SJIA within seven months

of vaccination therefore would be a medically appropriate period for causation

because that is the time period when the immune system works to create

antibodies against HPV in response to the HPV vaccine. See Decision at *27.

Timing was thus indicative of causation in V’s case, according to Dr. McCabe,

because she developed SJIA within four months of her first dose and two

months of the second dose.

The Special Master was not persuaded by Dr. McCabe’s explanation of

the amplification process. “[S]pecifically, 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.” Decision at *28. The Special

24

Master found that Dr. McCabe failed to explain how a seven month period is

appropriate for causation based on a theory involving the cytokine response

when both experts agree the response is almost immediate to an antigen or

trigger. The Special Master wrote that “[t]he body’s rapid cytokine response

appears inconsistent with Dr. McCabe’s assertion that the onset of disease

could take many months.” Decision at *28.

Respondent argues that the Special Master was entitled to find

persuasive Dr. Rose’s opinion regarding timing, which was that the medically

appropriate period for causation should be short if the cause is cytokine

related. Dr. Rose’s opinion was not the only scientific evidence that suggested

a shorter window for causation than Dr. McCabe proposed. The Special

Master also drew from data in the Pinto study showing increased cytokines in

response to stimulation and compared it to data that demonstrated a low and

consistent level of cytokines in the absence of stimulation. The Special Master

found that “[t]he Pinto experiment [] undermines the cohesiveness of Dr.

McCabe’s theory, particularly in regard to timing both for onset of symptoms

and duration of symptoms.” Decision at *23.

After considering the evidence and testimony from both experts, the

Special Master asserted that a finding on Althen prong-three was not necessary

because petitioner had failed to establish prong-one. Nevertheless, the Special

Master noted the following: “In the absence of evidence, it is difficult to find

that [petitioner] has met her burden of proof. Even two months is probably too

long an interval for a cytokine-driven reaction.” Decision at *28. We will not

disturb this finding because it was not arbitrary or capricious in light of the

evidence.

CONCLUSION

It is not our role to “reweigh the factual evidence, assess whether the

special master correctly evaluated the evidence, or examine the probative value

of the evidence or the credibility of the witnesses.” Porter, 663 F.3d at 1249.

Because the Special Master’s decision was not arbitrary, capricious, or

otherwise not in accordance with the law, we affirm his decision. For the

reasons set forth above, we deny petitioner’s motion for review. The clerk is

directed to enter judgment accordingly. No costs.

25

s/Eric G. Bruggink

ERIC G. BRUGGINK

Judge

26