McGuire v. Secretary of Health and Human Services ( 2015 )

In the United States Court of Federal Claims
OFFICE OF SPECIAL MASTERS
*************************
NICOLETTE MCGUIRE, *
* No. 10-609V
Petitioner, * Special Master
* Christian J. Moran
*
v. * Filed: September 18, 2015
*
SECRETARY OF HEALTH * Entitlement; human
AND HUMAN SERVICES, * papillomavirus (“HPV”)
* vaccine; headaches; cytokines.
Respondent. *
*************************
Ronald C. Homer, Sylvia Chin-Caplan, and Meredith Daniels, Conway, Homer &
Chin-Caplan, P.C., Boston, MA, for Petitioner;
Debra A. Filteau Begley, U. S. Dep’t of Justice, Washington, DC, for Respondent.
PUBLISHED DECISION DENYING COMPENSATION1
Nicolette McGuire alleges that the human papillomavirus vaccinations she
received when she was 20 years old caused her to develop headaches, resulting in
great pain. Ms. McGuire seeks compensation pursuant to the National Childhood
Vaccine Injury Compensation Program, codified at 42 U.S.C. § 300aa–10 through
34 (2012).
To support her claim, Ms. McGuire filed her medical records. Because the
records were inconsistent about when Ms. McGuire started having significant
headaches after the vaccination, she provided her recollections during a hearing
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.
held on November 4, 2011. Revised Findings of Fact, issued October 12, 2012,
determined that Ms. McGuire started experiencing prolonged headaches on
October 25-28, 2007, and these headaches became constant approximately one
week later.2
After the Revised Findings of Fact were issued, the parties presented
opinions from experts retained for the litigation. In due course, a hearing was held
during which the four experts testified.
The undersigned has considered the entire record. After weighing the
evidence, the undersigned finds that Ms. McGuire has not met her burden of
establishing that the HPV vaccination caused her headaches. The simplest
explanation is that Ms. McGuire failed to present a reliable basis for concluding,
on a more-likely-than-not basis, that the HPV vaccination can cause headaches that
last for months and years.
The remainder of the decision elaborates on this basic finding. The
background of the experts are set forth initially because their experience provides a
context for understanding Ms. McGuire’s medical history, which is set forth in the
following section. Collectively, those sections are the foundation for the analysis
section that explains why the evidence does not preponderate in Ms. McGuire’s
favor.
Biographies
The parties rely upon the doctors whom they retained as expert witnesses to
explain the respective positions regarding Ms. McGuire’s illness. Ms. McGuire
retained Dr. Spencer Weig, an expert in child neurology, and Dr. Sahar Swidan, a
PharmD who specializes in headache treatment. The Secretary retained Dr. David
2
The parties disagreed, for a time, about the type of headache Ms. McGuire suffered.
Ms. McGuire proposed chronic daily headaches (CDH) and the Secretary proposed new daily
persistent headaches (NDPH). However, before the hearing, the parties concluded that
classifying Ms. McGuire’s headaches as either CDH or NDPH would not affect the outcome of
the claim that the HPV vaccination caused Ms. McGuire’s headaches. Resp’t’s Status Rep., filed
Mar. 11, 2015.
2
Alexander, a neurologist, and Dr. Andrew Saxon, an immunologist.3 The
following sections provide some context for the opinions discussed throughout this
decision.
Dr. Weig
Background. After completing his education in medical school in 1983, Dr.
Weig practiced pediatric neurology from 1987-2011. Tr. 174. His patients were
younger than 19 years old. Tr. 168. If a potential patient were older than 20 years,
Dr. Weig referred the person to an adult neurologist. Tr. 209.
Dr. Weig treated children with a variety of neurologic disorders. Some of
these disorders, such as acute disseminated encephalomyelitis, limbic encephalitis,
NDA receptor encephalitis, multiple sclerosis, transverse myelitis, acute
inflammatory demyelinating polyneuropathy or Guillain-Barré Syndrome, chronic
inflammatory demyelinating polyneuropathy, dermatomyositis, and myasthenia
gravis, involve the immune system. Tr. 173; exhibit 30 (Dr. Weig’s report) at 5-6.
For these patients, he sometimes, but not always, consulted a colleague who
specialized in immunology. Tr. 212. His knowledge of how diseases originate
was an essential part of his ability to practice as a pediatric neurologist. Tr. 176.
In Dr. Weig’s practice, approximately one-third of his patients suffered from
some type of headache. Tr. 148-49. For CDH, Dr. Weig cared for 20-30 people in
his practice and more during hospital rounds. Tr. 271-72. For NPDH, Dr. Weig
estimated that he saw two or three people who satisfied the formal diagnostic
criteria. Tr. 210. He most recently saw a patient suffering from CDH in May
2011, shortly before he retired. Tr. 277.
Although Dr. Weig retired from practicing pediatric neurology, he has
continued his teaching duties, which began in 1990. Currently, he advises medical
school students during rounds at a hospital. Tr. 148, 276. He does not see any
patients outside of hospital rounds. Tr. 275. To maintain his license, he attends
conferences with other doctors approximately twice per month. Annually, he
spends about 20-30 hours at these conferences. Tr. 276.
3
The Secretary retained Dr. Saxon after her original immunologist, Burton Zweiman,
died. Resp’t’s Status Rep., filed Jan. 2, 2014. At the Secretary’s suggestion, Dr. Zweiman’s
report and curriculum vitae were struck from the record. Order, issued Mar. 6, 2015.
3
Dr. Weig’s education, training, and experience qualified him as an expert in
pediatric neurology. Tr. 175-76. However, the Secretary raised two arguments
about Dr. Weig’s experience that reduced the value of his opinion. The lesser
point is Dr. Weig’s background as a pediatric neurologist does not perfectly fit Ms.
McGuire’s case because her headaches began when she was 20 years old. Tr. 165-
70. Special masters have sometimes found the differences between pediatric
neurology and adult neurology to be significant. See, e.g., Milik v. Sec'y of Health
& Human Servs., No. 01-64V, 2014 WL 6488735, at *12 (Fed. Cl. Spec. Mstr.
Oct. 29, 2014) (crediting a pediatric neurologist’s opinion regarding childhood
developmental delays), mot. for rev. denied, 121 Fed. Cl. 68 (Fed. Cl. Apr. 29,
2015); Deribeaux v. Sec'y of Health & Human Servs., No. 05-306V, 2011 WL
6935504, at *38 (Fed. Cl. Spec. Mstr. Dec. 9, 2011) (crediting a pediatric
neurologist’s interpretation of an MRI performed on a child), mot. for rev. denied,
105 Fed. Cl. 583 (Fed. Cl. 2012), aff’d, 717 F.3d 1363 (Fed. Cir. 2013). However,
the Secretary did not present any evidence, such as testimony from the neurologist
that she retained, that established CDH in the pediatric population differs from
CDH in the adult population. Thus, despite his pediatric focus, Dr. Weig’s opinion
remains relevant. See Hall v. Sec'y of Health & Human Servs., No. 02-1052V,
2009 WL 3423036, at *30 (Fed. Cl. Spec. Mstr. Oct. 6, 2009) (stating, in the
context of awarding attorneys’ fees and costs, that “the fact that someone else may
have better qualifications does not mean that [a retained doctor] was entirely
unqualified”); cf. Sullivan v. Sec'y of Health & Human Servs., No. 10-398V, 2015
WL 1404957, at *20 (Fed. Cl. Spec. Mstr. Feb. 13, 2015) (stating “the possibility
of a better study is not an effective critique of an existing, otherwise valid study”).
The Secretary’s second criticism of Dr. Weig is more meaningful. The
Secretary argued that Dr. Weig lacked the training in immunology to offer a theory
of how the HPV vaccine causes CDH via the immune system. Tr. 171-73. Dr.
Weig admitted that his formal training in immunology came in medical school
from which he graduated in 1973. Tr. 145-46, 172. He is not board-certified in
immunology. Tr. 149-50. In addition, after Dr. Weig presented his first report and
the Secretary countered with a neurologist plus an immunologist (first Dr.
Zweiman, then Dr. Saxon), Ms. McGuire announced a plan to retain an
immunologist to support Dr. Weig.4
4
Ms. McGuire did not present testimony from an actual immunologist. She presented
testimony from Dr. Swidan, whose qualifications are reviewed below.
4
Although Dr. Weig’s working knowledge of immunology suffices as a basis
to explain a general theory, Dr. Weig lacked any detailed understanding of
immunology. For example, Dr. Weig’s knowledge of the function and working of
cytokines was limited. He was unable to discuss how cytokines like tumor
necrosis factor alpha (“TNF”) are produced, stating instead that he would have to
defer to an immunologist. Tr. 279. Dr. Weig’s lack of specialization in
immunology makes his opinion on immunologic topics less valuable than the
opinion of Dr. Saxon, who is an immunologist. Locane v. Secʼy of Health &
Human Servs., 685 F.3d 1375, 1380 (Fed. Cir. 2012) (finding that special master
was not arbitrary in considering the backgrounds of experts and crediting the
expert with a more specific specialization).
Opinion. Dr. Weig expressed his opinions in four reports. Exhibits 28, 30,
37, and 40. He categorized Ms. McGuire’s headaches as chronic daily headaches.
He opined that the HPV vaccine can cause CDH by stimulating the production of
cytokines, particularly TNF. For this proposition, he relied primarily upon a paper
whose lead author is Ligia Pinto. Dr. Weig also opined that increased levels of
TNF contribute to the pathology of CDH and for this proposition, Dr. Weig
primarily relied upon a paper co-written by Todd Rozen and Sahar Swidan. In his
January 12, 2015 report, Dr. Weig expressed the opinion that expected interval
between vaccination and the onset of headaches is 5 days to 6 weeks. Dr. Weig
also defended Dr. Swidan’s qualifications.
Dr. Alexander
Background. Dr. Alexander completed medical school in 1979, and a
residency in neurology in 1983. Exhibit A, tab 1 (C.V. of Dr. Alexander). In
1984, he started private practice in Los Angeles, California. He started teaching at
UCLA in 2002, and became a full-time professor there in 2008. Tr. 304-06. He
holds board-certifications in three areas: neurology, spinal cord medicine, and
strokes. Tr. 306.
As a practicing neurologist, he has treated hundreds of patients with CDH.
Tr. 414. However, he has not diagnosed any patient with the rare form of CDH,
NDPH. Tr. 310, 404.
5
His current responsibilities include three duties. He treats patients at a
hospital with 11 beds.5 Very few of his current patients suffer from CDH. Tr. 309.
He teaches neurologic topics, particularly disorders of the spinal cord and strokes.
Tr. 313. He also has administrative responsibilities, including serving on one of
UCLA’s institutional review boards, which authorizes research projects involving
human beings. Tr. 311.
The Secretary requested that Dr. Alexander be recognized as an expert in
adult neurology. Ms. McGuire did not object. Tr. 314-15.
Although Dr. Alexander qualifies as an expert in neurology, his background
does not match the subject of Ms. McGuire’s case perfectly. She suffers from
some form of CDH and Dr. Alexander specializes in treating other neurologic
maladies that afflict adults. Thus, much like Dr. Weig, there appears to be a small,
yet noticeable, gap between the doctor’s specialty and Ms. McGuire’s illness. This
gap does not disqualify Dr. Alexander from offering a reliable opinion, but if Ms.
McGuire’s case required expertise specifically on headaches, then it was not
apparent that Dr. Alexander would be of much assistance.
Apart from the slight discordance in background, another flaw in Dr.
Alexander’s presentation was a series of missteps in his reports. In his reports, Dr.
Alexander suggested that various factors other than the HPV vaccine, such as her
use of SSRI,6 oral contraceptives, and analgesics, caused Ms. McGuire’s
headaches. Exhibit A at 10-12; exhibit C at 8-9. However, in response to
information presented during cross-examination, Dr. Alexander modified or
retreated from some of his earlier written statements. Tr. 361-91. Thus, Dr.
Alexander is encouraged to use more care in how he writes his reports in the
future.
Opinion. Dr. Alexander wrote three reports. Exhibits A, C, E. A significant
topic was the assertion that Ms. McGuire’s headaches were new daily persistent
headaches. As noted in footnote 2 above, the dispute over CDH or NDPH turned
5
UCLA is building a new rehabilitative facility with 138 beds and Dr. Alexander will be
the director of that facility when it opens. Tr. 312.
6
SSRI is defined as “selective serotonin reuptake inhibitor.” Dorland’s Illustrated
Medical Dictionary 1759 (32d ed. 2012).
6
out to be academic because Ms. McGuire’s TNF theory could explain how the
HPV vaccine would cause either CDH or NDPH.
Dr. Alexander disagreed with the assertion that the HPV vaccination can
cause prolonged headaches of any type and he disagreed with the assertion that the
HPV vaccination caused Ms. McGuire’s headaches. He noted that the cause of
these headaches is unknown.
Dr. Saxon
Background. Dr. Saxon described himself as a “physician-scientist.” Tr.
567. He graduated from medical school in 1972. He completed a post-doctorate
fellowship in immunology at UCLA in 1977, and became a professor at UCLA.
While at the institution, he started the division of immunology within the
department of medicine. Tr. 577.
He is board-certified in internal medicine, immunology, and diagnostic
laboratory immunology. Tr. 569. His research has focused on immunologic
concepts and he has written nearly 200 articles that have appeared in peer-
reviewed publications. Tr. 578. In the 1970s, as part of the litigation involving the
swine flu vaccine, judges appointed him to advise them. Tr. 582, 678-79.
Dr. Saxon currently spends about 15 percent of his time on medical-legal
matters. Tr. 571. Most of his time is spent on biomedical research for companies.
Since his retirement from UCLA in 2006, he rarely sees any patients and the
patients whom he sees have severe immunologic diseases. Tr. 570.
Dr. Saxon was qualified as an expert in immunology and diagnostic
immunology. His testimony demonstrated that among the people who testified, he
was the most knowledgeable about immunology and diagnostic immunology. The
precision with which he answered questions suggested that he understood and
could explain subtle points about immunology. His presentation was thoughtful
and engaging.
The one place where Dr. Saxon arguably went awry concerns the disclosure
of his opinions. In his testimony, Dr. Saxon described how he investigated the
reference levels reported in the Rozen and Swidan article discussed below. Dr.
Saxon did not disclose his opinions in a report before trial and he should have
given Ms. McGuire’s attorney and Dr. Swidan an opportunity to prepare for this
testimony. However, Ms. McGuire did not move to strike the testimony during the
hearing and neither Ms. McGuire’s attorney nor Dr. Swidan requested an
opportunity to respond after the hearing. Thus, any procedural deficiencies
7
associated with a lack of notice are considered waived. Nevertheless, Dr. Saxon is
instructed to be mindful about the requirement to disclose opinions in advance of
the trial.
Opinion. Dr. Saxon wrote three reports. Exhibits D, F, I. The first report
was a general response to Dr. Weig’s opinion that the HPV vaccine can cause
prolonged headaches. Dr. Saxon asserted that the HPV vaccinations did not
contribute to Ms. McGuire’s headaches. Dr. Saxon addressed two aspects of Dr.
Weig’s opinion: the potential role of TNF in headaches as reported in the Rozen
and Swidan article and the HPV vaccine’s ability to prompt the production of TNF
as discussed in the Pinto article. Exhibit D.
Dr. Saxon’s next two reports addressed more narrow topics. In exhibit F, he
challenged Dr. Swidan’s qualifications to opine on immunology. This topic is
explored in more detail below. In Dr. Saxon’s last report, he responded to Dr.
Weig’s opinion regarding timing. Exhibit I.
Dr. Swidan
Background. The final expert is Dr. Swidan. Because her background is
unusual for an expert who testifies in the Vaccine Program, her education, training,
and experience is described in a bit more detail.
After starting her college education at Eastern Michigan University, Dr.
Swidan completed four years of study at the University of Michigan, where she
received a Doctorate of Pharmacy degree. Exhibit 39 (C.V.) at 1; Tr. 433. A
doctorate in pharmacy is not the same as a Ph.D. in pharmaceutical sciences. Tr.
450-52.7 In obtaining her doctorate in pharmacy, Dr. Swidan studied
pharmacology. Tr. 434. Pharmacology is “the science that deals with the origin,
nature, chemistry, effects, and uses of drugs; it includes pharmacognosy,
pharmacokinetics, pharmacodynamics, pharmacotherapeutics, and toxicology.”
Dorland’s Illustrated Medical Dictionary 1425 (32d ed. 2012); accord Tr. 460-62.
Dr. Swidan also learned about immunology, including “antibiotics, antivirals, [and]
vaccines.” Tr. 435.
7
The Secretary’s cross-examination of Dr. Swidan brought out the distinction between a
doctorate of pharmacy and a Ph.D. in pharmacology. Ms. McGuire’s counsel’s error in
characterizing Dr. Swidan’s degree appears inadvertent. See Tr. 433-34, 449.
8
Dr. Swidan’s training to earn a doctorate in pharmacy emphasized clinical
aspects of pharmacology. (In contrast, people pursuing a Ph.D. in pharmaceutical
sciences conduct more research in laboratories.) Tr. 451. Clinical pharmacology,
in turn, concerns “help[ing] the physicians make smarter decisions about drug
therapy.” Tr. 469. Clinical pharmacologists provide this assistance by knowing
about the individual patient, confirming that the correct drug was prescribed at the
correct dose, and “monitoring for any adverse effects.” Id.After graduating with her doctorate in pharmacy, Dr. Swidan completed a
fellowship in biopharmaceutics. Exhibit 39 at 1; Tr. 435. In that position, Dr.
Swidan designed clinical trials and wrote reports about the results. Tr. 435-37;
exhibit 39 at 11-12 (listing articles).
After Dr. Swidan completed her post-graduate training, she became the
clinical coordinator at Chelsea Community Hospital. This hospital is located in a
town of about 5,000 people and is affiliated with the larger University of Michigan
Health System. Tr. 437-38, 453. Within the Chelsea Community Hospital, an
inpatient unit treated people with head and general pain. Dr. Swidan described this
as a tertiary care center to which people with refractory headaches from around the
world are referred. Tr. 447-48.
Dr. Swidan joined the team who made daily rounds. Tr. 438. When going
on rounds, “the physicians taught more disease and diagnosis and neurological
type syndromes.” Tr. 446. As discussed during cross-examination, Dr. Swidan
worked under supervision of a doctor and could not diagnose a patient. Tr. 452,
475. On rounds, Dr. Swidan taught “the pharmacology, treatment of pain
syndromes, head pain, some of the reactions, [and] some of the
pharmocogenetics.” Tr. 446.
Dr. Swidan described “head pain and pain management” as her “clinical
interest and love.” Tr. 443. Dr. Swidan, as part of a team, has written articles and
book chapters about head pain and headache management. Tr. 445, 458; see also
exhibit 39 at 11-13. Dr. Swidan’s co-authorship of a paper about TNF and chronic
headaches led to her retention as an expert witness in this case and there is
extensive discussion about that paper in section I.B.3(a), below.
Dr. Swidan stated that she “do[es] 60 to 100 lectures a year in general
around the country and internationally in mainly pain management, head pain and
neurological conditions,” Tr. 444, although her curriculum vitae lists considerably
fewer “invited presentations.” Her curriculum vitae indicates that she has made
9
presentations to the Michigan Pharmacists’ Association about CDH and to the
American Academy of Neurology. Exhibit 39 at 6, 8; see also Tr. 543-44.
In 2007, she stopped working at Chelsea Community Hospital and opened a
business called Pharmacy Solutions. She attempts to bring her experience as a
clinical pharmacist in a hospital to a larger audience. Tr. 441.
In addition to operating Pharmacy Solutions, Dr. Swidan is also a clinical
associate professor of pharmacy at the College of Pharmacy at the University of
Michigan. Exhibit 39 at 2. Her teaching focuses on neurology and pain
management. Tr. 441-42. In the context of asking Dr. Swidan about her
responsibilities as a professor, Ms. McGuire inquired about Dr. Swidan’s teaching
about pathophysiology. Tr. 442-43.
Dr. Swidan’s knowledge about how diseases, particularly headaches, arise is
a point of particular controversy. Dr. Swidan explained that as a professor, she
teaches pharmacology students “the physiology, how does the body normally work
because it’s hard to understand what goes wrong if you don’t understand how the
body normally works.” She continued that she reviews “pathophysiology . . . what
happens to the body in disease state and then how can we treat the disease.” Tr.
443.
When Ms. McGuire attempted to build on this foundation by asking Dr.
Swidan to explain how vaccines can cause persistent headaches, the Secretary
argued that Dr. Swidan lacked the qualifications to offer an opinion about the
cause of headaches. Tr. 474-75. The Secretary maintained that although Dr.
Swidan was on a team that treated headache patients, Dr. Swidan did not have the
knowledge to comment on the cause of the headaches:
[Dr. Swidan] always makes her determination with the
assistance of a medical doctor with specialized
knowledge in the condition. And they inform her of the
diagnosis. They inform her of the pathophysiology and
then ask her for treatments -- recommendations on
treatments.
So, she constantly uses the term “we” and then she
assumes the entire knowledge of the team that she is on,
despite the fact that she plays a particular role on that
team. So, that, I think, is where we’re starting to cross
over to impute on Dr. Swidan the entire knowledge of the
10
teams that she works on, despite the fact that she doesn’t
have their qualifications or expertise. And that’s what
I’m trying… to explain there’s a difference between the
two.
Tr. 477-78.
After the Secretary raised this objection, Dr. Swidan further elaborated upon
her training and experience. She stated “it’s very important for us [professionals
with a doctor of pharmacy degree] to understand the pathophysiology” of diseases
such as asthma. Tr. 485. The Secretary did not present any testimony suggesting
that clinical pharmacists are not trained in pathophysiology.
In responding to the Secretary’s challenge to Dr. Swidan’s testimony, Ms.
McGuire asserted that Dr. Swidan is qualified to provide opinions because of her
“listening to her colleagues, from her education, her training and her background
and her specialized knowledge, and it’s based on review of the medical literature.”
Tr. 489-90. In Ms. McGuire view, the Secretary’s objection is “not a basis to
exclude her testimony, but it’s more a question of the weight that [the special
master], as a fact finder, assign to that testimony.” Tr. 490.
Dr. Swidan was permitted to present her opinions about the causes of
headaches and how a vaccination can contribute to the cause of headache. Tr. 491.
This evidentiary ruling to admit the opinion was based, in part, on her background
in headache pain. See Tr. 471.8
The Secretary’s argument regarding Dr. Swidan’s lack of qualifications
raised during the hearing echo an argument presented in a pre-hearing motion.
Before the hearing, the Secretary had filed a motion to exclude Dr. Swidan’s
opinion as unreliable pursuant to Daubert. To support this motion, the Secretary
relied, in part, on an opinion from Dr. Saxon that Dr. Swidan “does not have the
required scientific expertise to address the issues at hand and failed to employ the
8
Although Dr. Swidan was admitted as an expert in pharmacology, she was not admitted
as an expert in immunology. Dr. Swidan does not have any advanced degree in immunology.
Tr. 457. She also could not respond to some questions about immunologic concepts. Tr. 458-59.
Dr. Saxon later described this knowledge as “basic” enough that a “first-year graduate student”
would have. Tr. 648. The ruling that Ms. McGuire had not shown that Dr. Swidan was qualified
in immunology did not prevent Ms. McGuire from asking Dr. Swidan any questions. Dr. Swidan
answered every question that Ms. McGuire asked. In other words, no testimony was excluded.
11
proper scientific approach and methodology in reaching her conclusions.” Exhibit
F at 1-2. While that motion was pending, the Federal Circuit indicated that a
special master should not give less weight to a person with a Ph.D. in immunology
than a person who graduated from medical school. Koehn v. Secʼy of Health &
Human Servs., 773 F.3d 1239, 1244 (Fed. Cir. 2014). In accord with Koehn, the
Secretary’s motion to exclude Dr. Swidan’s testimony was denied. Order, issued
Feb. 19, 2015.
Now, having heard Dr. Swidan’s testimony, the undersigned may comment
that Dr. Swidan’s opinion was not very helpful. Dr. Swidan delivered much less
than was promised. Ms. McGuire retained Dr. Swidan to counter the opinion of
Dr. Saxon, the immunologist whom the Secretary retained, and to present
information about the paper she co-authored with Dr. Rozen. On immunology, the
contest between Dr. Swidan and Dr. Saxon was not close. Dr. Saxon possesses
expertise in immunology, as reflected in his status as a board-certified internist,
clinical immunologist and diagnostic immunologist, that Dr. Swidan lacks. Tr.
569. Dr. Saxon explained relatively sophisticated immunologic concepts in a way
that is consistent with someone who has practiced medicine as an immunologist
and taught immunology for more than 35 years. In contrast, Dr. Swidan’s
testimony was often conclusory. The lack of support was particularly glaring when
Dr. Swidan attempted to demonstrate that her education (a Ph.D. in
pharmacology), and her experience (20 years as a clinical pharmacist) qualified her
to opine on the causes of diseases. Although Dr. Swidan and Ms. McGuire’s
attorney consistently pressed the idea that Dr. Swidan’s responsibilities as a
clinical pharmacist require her to understand the pathogenesis of diseases, they
failed to persuade me, the trier of fact, that Dr. Swidan possesses sufficient
knowledge about the causes of relevant diseases that would make her testimony
useful.9
Dr. Swidan’s relative lack of knowledge carried over to the other topic about
which she was expected to possess some mastery --- the article about TNF and
headaches. Dr. Swidan could not answer many questions about the article that she
co-authored, repeatedly saying that Dr. Rozen was responsible for that section. To
9
Given that the Secretary had filed a motion to exclude Dr. Swidan’s testimony before
the hearing, it was incumbent on Ms. McGuire’s attorney to establish a solid foundation for Dr.
Swidan’s expertise. Ms. McGuire’s attorney’s examination into Dr. Swidan’s background left
many topics unexplained.
12
some degree, Dr. Saxon’s failure to disclose his specific criticisms about the Rozen
and Swidan article in advance of the hearing placed Dr. Swidan at a disadvantage.
Nevertheless, Dr. Swidan should have been prepared to talk in-depth about the
article because (a) the article was one of the two articles most important to Ms.
McGuire’s case, and (b) Dr. Swidan was retained specifically because she co-wrote
that article.
In short, although Dr. Swidan contributed some meaningful information as
the citations to her testimony demonstrate, Dr. Swidan fell significantly short in
testifying on the topics critical to Ms. McGuire’s claim. In the future, an attorney
representing a petitioner should consider the strengths and weaknesses in Dr.
Swidan’s background before retaining her to testify in the Vaccine Program.
Opinion. Dr. Swidan wrote two reports. Exhibit 38 set forth her basic
opinion – that the HPV vaccination caused an inflammatory response in Ms.
McGuire and this inflammatory response caused her to have headaches. Dr.
Swidan emphasized the role of TNF in headaches. In her second report, Dr.
Swidan, after reviewing Dr. Saxon’s criticism of both her background and her
opinion, confirmed her opinion that the HPV vaccination caused Ms. McGuire’s
headache. Exhibit 41.
Ms. McGuire’s Medical Background
The October 12, 2012 Revised Findings of Fact resolved one critical aspect
of this case: when Ms. McGuire’s headaches began. During most of the litigation,
the details about Ms. McGuire’s headaches seemed important because Dr. Weig
stated that she suffered from NDPH and Dr. Alexander, in contrast, opined that she
suffered from CDH. Exhibit 28 (Dr. Weig); exhibit A (Dr. Alexander). However,
this dispute about diagnosis turned out to be insignificant because Ms. McGuire’s
experts presented a theory through which the HPV vaccine can cause either NDPH
or CDH. See Resp’t’s Status Rep., filed Mar. 11, 2015. Eliminating the arguments
about diagnosis simplifies Ms. McGuire’s case. Many of the details about the
quality, duration, location, and intensity of her headaches are not material.
Consequently, this decision discusses Ms. McGuire’s medical records relatively
summarily, although the medical records themselves have been reviewed
thoroughly.
Health before Vaccination
Ms. McGuire was born in 1987. Exhibit 2 at 1. Her father suffered from
cluster headaches at least once. Exhibit 4 at 1; Tr. 85, 99. Dr. Alexander asserted
13
that Ms. McGuire’s genetic background may have contributed to her headaches.
Tr. 325.
In 2003, Ms. McGuire sought treatment for a panic disorder. She was
prescribed Zoloft. Exhibit 22 at 130-31, 126; see also Tr. 34-35. Ms. McGuire
continued to take Zoloft until the summer 2004. But, after she stopped taking
Zoloft, her anxiety returned and she resumed the prescription. Exhibit 22 at 118-
22.
In August 2006, Ms. McGuire saw Robert M. Levenson, her pediatrician.
Ms. McGuire reported that she had returned from a cruise to Bermuda slightly
more than two weeks earlier. After coming home, Ms. McGuire had a sudden
onset of frontal headaches, tiredness, malaise and an achy neck and shoulders for
two weeks. Dr. Levenson prescribed Fioricet and recommended therapeutic
massages. Exhibit 1 at 107-08; see also Tr. 30-31, 54 (Ms. McGuire’s testimony
that a medical record ostensibly referring to a headache in December 2006 was
actually referring to her August 2006 headache); cf. Tr. 328-29, 370-71, 472.
Approximately one year later in August 2007, Ms. McGuire went to an
urgent care center for anxiety and panic attacks. She also reported symptoms of
depression after stopping Zoloft in January that year. The doctor prescribed
lorazepam. Exhibit 1 at 93-94.
In September 2007, Ms. McGuire was working as a medical assistant for
Harvard Vanguard Medical Associates. Exhibit 21 (employment records) at 1; see
also Tr. 9, 103 (describing duties). She was also attending nursing school in the
evening. Exhibit 20 (school records). She described herself as “healthy and
active.” Exhibit 17 (affidavit) at 1; accord Tr. 9-10.
On September 20, 2007, Ms. McGuire saw Laura Tremblay, her primary
care physician, for a complete physical examination. Ms. McGuire said that she
was having various gastrointestinal and gynecological complaints, but after Dr.
Tremblay’s review, she said all other systems were negative. At this appointment,
Ms. McGuire received the first dose of the HPV vaccine. Exhibit 1 at 88-89; see
also Tr. 36.10
10
Ms. McGuire averred that after receiving the vaccination, she left work because she felt
ill. Specifically, she had a fever and headache, was nauseated, and vomited. Exhibit 17 at 1; Tr.
(continued…)
14
Health after Vaccination
Between October 25 and October 28, 2007, Ms. McGuire began having
headaches that were initially intermittent. One week after the headaches began,
Ms. McGuire’s headaches became constant. Revised Findings, issued Oct. 12,
2012. Ms. McGuire took over-the-counter medications, which did not help.
Nonetheless, she continued to work and to attend school. Tr. 11-12.
On November 14, 2007, Ms. McGuire received the second dose of the HPV
vaccine. Exhibit 1 at 86. Approximately four months later, Ms. McGuire told her
neurologist that there “was no change in her headache after the second vaccine.”
Id. at 54; see also Tr. 73; cf. Tr. 222.11 On November 20, 2007, Ms. McGuire had
a nutrition assessment. Exhibit 1 at 86; Tr. 47.12
Ms. McGuire recalled that after having a headache for many weeks, she
became concerned that her headache had not stopped. In addition, the severity was
increasing. Tr. 14-15, 52. Therefore, on December 9, 2007, she went to seek
assistance at an urgent care facility associated with her employer, Harvard
Vanguard Medical Associates. Tr. 15. She stated that she had been having
headaches for six weeks before her appointment. Exhibit 1 at 83-84; see also Tr.
47-48. In terms of a more recent history, Ms. McGuire’s report appears to be
11, 37-39, 119. She made similar statements to doctors treating her months later. See exhibit 1
at 54 (Mar. 20, 2008); exhibit 3 at 77 (Apr. 23, 2008).
Ms. McGuire’s experts did not mention her illness on September 20, 2007. Exhibit 28
(Dr. Weig’s rep.) at 1; exhibit 38 (Dr. Swidan’s rep.) at 3. However, Dr. Swidan did briefly
testify that Ms. McGuire “was sick with a febrile illness” and that the blood-brain barrier can be
leaky in sick patients. Tr. 526.
11
Ms. McGuire testified that about a week and a half after the second dose of HPV
vaccination, her headaches changed from intermittent to constant. Tr. 13, 43-44, 91-92, 123-24.
However, her recollection is not consistent with several medical records that do not mention a
change in her headache quality or frequency after the second dose of the HPV vaccine. See
exhibit 1 at 46 (record dated May 17, 2008), 54 (record from March 20, 2008); exhibit 3 at 73-76
(record dated June 17, 2008); see also Tr. 222-24, 340-43; but see exhibit 11 at 12 (record dated
Aug. 31, 2009); Tr. 299.
12
Ms. McGuire did not discuss her headaches with the dietician. In Dr. Alexander’s
opinion, this omission is inconsistent with a claim that she was suffering from severe headaches.
Tr. 335-36, 402. In contrast, Dr. Weig did not perceive any inconsistency because people would
not normally talk to a dietician about their headaches. Tr. 423.
15
inconsistent. At one place, Ms. McGuire said that, “for the past two weeks” (that
is, starting around Thanksgiving), she was feeling frontal pressure. Exhibit 1 at 83;
see also Tr. 51-52; cf. exhibit 3 at 3 (a Dec. 23, 2007 emergency department record
suggesting frontal headaches started four weeks earlier); Tr. 60-61 (Ms. McGuire’s
testimony about the Dec. 23, 2007 record); Tr. 215. Yet, later within the same
paragraph, Ms. McGuire stated that “Symptoms have not accelerated, and there
was no change in location or quality in the past 2 weeks.” Exhibit 1 at 83; see also
Tr. 219, 337.
While hospitalized, Ms. McGuire underwent many tests, including a lumbar
puncture and MRIs. Exhibit 1 at 72-74. After the lumbar puncture, her headaches
worsened. Id. at 73; see also Tr. 218-19 (Dr. Weig), 340 (Dr. Alexander).
For the remainder of December 2007 and continuing into January 2008, Ms.
McGuire saw many doctors for her headaches and those doctors prescribed a
variety of pharmaceuticals. The attempted interventions did not provide any
lasting relief. See exhibit 1 at 63-81; exhibit 3 at 17-18 (admission to the
emergency room), 80-81 (discharge); Tr. 16-21, 53-68.13
Throughout 2008, Ms. McGuire visited several more doctors but they did
not help alleviate her symptoms. Some of these histories indicate that Ms.
McGuire’s first HPV vaccination preceded the onset of her headaches in October
2007. However, none of these doctors stated that the vaccination caused her
headaches. See exhibit 1 at 54-55; exhibit 3 at 78-79; exhibit 5 at 2; exhibit 1 at
46-47, 36-37; exhibit 3 at 32-34; exhibit 9 at 8; exhibit 3 at 66-67; see also Pet’r’s
Preh’g Br. at 34-36 (quoting medical records).
During a hospitalization in 2008, a doctor prescribed a short course of
prednisone. Exhibit 1 at 41, 46-47; see also Tr. 196, 355, 474. Prednisone is a
“synthetic glucocorticoid… [used] as an antiinflammatory and immunosuppressant
in a wide variety of disorders.” Dorland’s at 1508. Ms. McGuire later informed
her doctors that the course of prednisone did not help her headaches and may have
made them worse. Exhibit 3 at 70 (Dr. Klein’s letter, dated July 30, 2008); exhibit
13
Ms. McGuire’s (over)use of medication likely contributed to the continuation of her
headaches. Tr. 206, 269, 322-25, 393. Because Ms. McGuire started taking medication after her
headaches became chronic, the Secretary has not argued that Ms. McGuire’s use of medication
caused her headaches. Tr. 394.
16
12 at 3 (report, dated Dec. 10, 2008); exhibit 13 at 1 (Dr. Herzog’s letter, dated
Aug. 16, 2010).
On January 15, 2009, Ms. McGuire went to the Osher Clinical Center for
Complementary and Integrated Medical Therapies, where she saw Donald Levy,
M.D. Dr. Levy stated that because Ms. McGuire “never had headaches before the
HPV vaccination,” there was a causal connection between the vaccination and the
headache. Exhibit 12 at 9; see also Tr. 191-92, 268, 411-13.
In the remainder of 2009, Ms. McGuire saw doctors less frequently. Exhibit
2 at 2; exhibit 8 at 4; exhibit 11 at 3, 12-13; exhibit 16 at 13-15.
On July 13, 2010, Ms. McGuire saw Andrew Herzog, M.D. at the
Neuroendocrine Associates at Harvard Medical School. She stated that her
headaches started “within 2 hours of the [HPV vaccine] injection.” Exhibit 13 at
12. She also said that before the vaccination, she had never had headaches. Dr.
Herzog stated that although headaches have been reported to follow HPV
vaccinations, a long-lasting headache would be unusual. He suggested an
evaluation for an immune-mediated process. Id. at 13; see also Tr. 190. However,
this investigation did not reveal any abnormalities that would cause headaches.
Exhibit 13 at 5-11; see also Tr. 266, 412-13.
Despite the continuing problems with headaches, Ms. McGuire graduated
from nursing school in December 2010. She passed her examinations in March
2011, and became a registered nurse. Exhibit 35 (Ms. McGuire’s affidavit,
describing her employment history) at 1; Tr. 22. She worked as a registered nurse
for approximately two years, but then her headaches prevented her from working.
Exhibit 35 at 2; see also Tr. 23, 107.
Standards for Adjudication
A petitioner is required to establish her case by a preponderance of the
evidence. 42 U.S.C. § 300aa–13(1)(a). The preponderance of the evidence
standard requires a “trier of fact to believe that the existence of a fact is more
probable than its nonexistence before [he] may find in favor of the party who has
the burden to persuade the judge of the fact’s existence.” Moberly v. Sec’y of
Health & Human Servs., 592 F.3d 1315, 1322 n.2 (Fed. Cir. 2010) (citations
omitted). Proof of medical certainty is not required. Bunting v. Sec’y of Health &
Human Servs., 931 F.2d 867, 873 (Fed. Cir. 1991).
Distinguishing between “preponderant evidence” and “medical certainty” is
important because a special master should not impose an evidentiary burden that is
17
too high. Andreu v. Sec’y of Health & Human Servs., 569 F.3d 1367, 1379-80
(Fed. Cir. 2009) (reversing special master’s decision that petitioners were not
entitled to compensation); see also Lampe v. Sec’y of Health & Human Servs., 219
F.3d 1357 (Fed. Cir. 2000); Hodges v. Sec’y of Health & Human Servs., 9 F.3d
958, 961 (Fed. Cir. 1993) (disagreeing with dissenting judge’s contention that the
special master confused preponderance of the evidence with medical certainty).
The elements of Ms. McGuire’s case are set forth in the often cited passage
from the Federal Circuit’s decision in Althen: “(1) a medical theory causally
connecting the vaccination and the injury; (2) a logical sequence of cause and
effect showing that the vaccination was the reason for the injury; and (3) a showing
of a proximate temporal relationship between vaccination and injury.” Althen v.
Sec’y of Health & Human Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005).
Analysis
The three prongs of the Althen test are evaluated in separate sections below.
The order of presentation begins with theory, which outlines petitioner’s proposed
theory and the relevant evidence and case law. The next issue is the timing and the
last factor is the “logical sequence of cause and effect.” Each section analyzes the
evidence (medical records, testimony and medical literature) in relation to the
relevant precedent.
I. Theory
The first Althen prong requires “a medical theory causally connecting the
vaccination and the injury.” 418 F.3d at1278. Because Ms. McGuire’s injury is
chronic headaches, basic information about headaches is provided as a foundation.
Against this backdrop, Ms. McGuire bears the burden of presenting a theory to
explain how the HPV vaccine can cause chronic headaches. Veryzer v. Sec'y of
Health & Human Servs., 100 Fed. Cl. 344, 355 (2011), aff'd per curiam, 475 F.
App'x 765 (Fed. Cir. 2012).
Ms. McGuire attempted to meet her burden in two ways. As explained in
section B below, Ms. McGuire presented evidence – testimony from Dr. Weig and
Dr. Swidan. In addition, as explained in section C below, Ms. McGuire presented
an argument based on a recent case from the Federal Circuit.
18
A. Overview of Primary Headaches
Medical science does not know the cause of primary headaches.14 See
exhibit 38, tab U (Rozen and Swidan) at 1053 (stating the “pathogenesis of NDPH
is unknown”), exhibit 40, tab C (Sanjay Prakash & Nilima Shah, Post‐infectious
New Daily Persistent Headache May Respond to Intravenous Methylprednisolone,
J. Headache Pain 2010; 11:59‐66) at 59 (stating that for NDPH, the
“pathophysiology is largely unknown”), Tr. 317.
However, there are some generally accepted beliefs about the pathogenesis
of primary headaches. A vastly simplified summary is that a headache begins with
some irritant to the trigeminal nerve.15 Once the trigeminal nerve is disturbed, the
body produces various substances, including calcitonin gene-related peptide
(CGRP), that perpetuate a cycle. Tr. 317-18, 476, 491-93.
Many aspects about the etiology of chronic headaches are undetermined.
For example, scientists have not identified the initial trigger (or triggers).
Scientists have recognized that infections, surgery, and stressful life events
sometimes precede the onset of chronic headaches. Exhibit 38, tab U (Rozen and
Swidan) at 1053; exhibit 40, tab C (Prakash) at 59 (abstract). However, these
preceding factors have not been determined to be causes of the headaches. Tr.
682-83 (Saxon).
In addition to the uncertainty about the cause of headaches, there are
questions about why a headache is prolonged. Commonly, headaches resolve after
a few hours and/or after medications. The headaches that Ms. McGuire suffers
differ in that they are chronic and refractory to treatment. The factor or factors
contributing to the headache’s chronicity and resistance to treatment are
undetermined. Tr. 495-96.
A current theory is that CGRP is part of a cycle with the cytokine TNF.
Cytokines are proteins that a cell releases to communicate with another cell during
14
Primary headaches are not the same as secondary headaches. Secondary headaches are
headaches associated with another disorder, such as meningitis. Tr. 153, 316, 602-03.
15
The trigeminal nerve, which is also known as the fifth cranial nerve, is a sensory nerve
for the face, teeth, mouth, and nasal cavity. It is also the motor nerve for chewing. Dorland’s at
1260; see also Dorland’s at 1246 (illustration).
19
the generation of an immune response. Dorland’s at 466; see also Tr. 179, 350,
606. Although Dr. Weig characterized TNF as a proinflammatory cytokine, Tr.
179, Dr. Saxon disagreed. Dr. Saxon asserted that TNF is used in more than 100
biologic activities. Tr. 606. Dr. Saxon supported his view that TNF is not always
a proinflammatory cytokine by pointing to the Pinto article, which is discussed in
more detail below. Tr. 631-35, citing exhibit D, tab 16 (Ligia Pinto et al., HPV-16
L1 VLP Vaccine Elicits a Broad-Spectrum of Cytokine Responses in Whole
Blood, 23 Vaccine 3555 (2005)).16
B. Evidence relating to HPV Vaccines Causing Headaches
Ms. McGuire presented testimony from Dr. Weig and Dr. Swidan that the
HPV vaccine can cause headaches. Tr. 177, 509-11. The theory Ms. McGuire
proposes seems to contain at least three distinct steps. First, the HPV vaccine
promotes the production of various cytokines, including TNF. Second, from the
body’s periphery, TNF crosses the blood brain barrier to reach the central nervous
system. Third, in the central nervous system, TNF causes inflammation producing
headaches. See Pet’r’s Preh’g Br. at 17-18.
1. Does the HPV Vaccine Promote the Production of TNF?
The first step in the petitioner’s theory is the administration of the HPV
vaccine increases the level of TNF. For this proposition, Dr. Weig and Dr. Swidan
rely upon the Pinto article. Exhibit 28 (Dr. Weig) at 4; Tr. 179, 253 (Dr. Weig),
516 (Dr. Swidan).
In the Pinto experiment, blood from women was drawn and tested to set
baseline measuring points. Then, some women received a dose of a vaccine
against some strains of the human papillomavirus (but not the same vaccine as Ms.
McGuire received) and some women received a placebo. The participants received
another dose or placebo one month later; one month after the second dose, the
researchers drew a second sample of the women’s blood. The women received a
third dose of the vaccine (or placebo) and after waiting another month, the
researchers drew a third sample. Exhibit D, tab 16 (Pinto) at 3556.
16
In addition to the literature, another reason for crediting Dr. Saxon over Dr. Weig is
that Dr. Saxon specializes in immunology. Dr. Weig stated that he would defer to an
immunologist. Tr. 279.
20
The blood samples were cultured in vitro for 24 hours and then the amount
of cytokines was measured. The testing showed that the women who received the
vaccine produced higher amounts of TNF than the women who did not. Tr. 632-41
(Dr. Saxon). This result is not surprising because the vaccine is designed to
prompt a response from the immune system. Tr. 511 (Dr. Swidan). Thus, the
Pinto experiment supports one aspect of the petitioner’s theory: HPV vaccine
elevates the amount of TNF.
However, there are two problems with how Ms. McGuire seeks to employ
the Pinto article. The first, and less significant, issue is that the Pinto experiment
was conducted in vitro, not in vivo. Tr. 258, 643. An extrapolation from a petri
dish to human beings may be reasonable, but there needs to be some basis for the
extrapolation. “As a general matter, it may be that in vitro tests are not reliably
predictive of human safety.” Bristol-Meyers Squib Co. v. Teva Pharma. USA,
Inc., 769 F.3d 1339, 1355 n.5 (Fed. Cir. 2014) (Taranto, J.) (dissenting from denial
of reh’g en banc) (citing Reference Manual on Scientific Evidence). In other
cases, special masters have commented on the problems with using in vitro studies.
See Kolakowski v. Sec'y of Health & Human Servs., No. 99-625V, 2010 WL
5672753, at *85-86 (Fed. Cl. Spec. Mstr. Nov. 23, 2010); Dwyer v. Sec'y of Health
& Human Servs., No. 03-1202V, 2010 WL 892250, at *131-32 (Fed. Cl. Spec.
Mstr. Mar. 12, 2010). Ms. McGuire did not provide a reliable reason for making a
jump of this kind.
The second and more significant issue concerns the amount of TNF
produced in the Pinto experiment. As Dr. Saxon pointed out, the Pinto authors did
not conclude that the amount of cytokine produced was pathologic. Tr. 643-44.
Some evidence regarding the amount of TNF produced as part of a normal reaction
to a vaccine compared to an adverse reaction to a vaccine would have been helpful
because Dr. Weig’s theory asserts that the HPV vaccine caused an “excessive”
amount of TNF. Tr. 281. This assertion is particularly unsupported because Dr.
Weig admitted that he did not know the amount of TNF that was required to cause
a disease. Tr. 247.
While the lack of support for Dr. Weig’s opinion is problematic for Ms.
McGuire, the Secretary introduced evidence contradicting the assertion that the
amount of cytokines produced was pathologic. This evidence was the most recent
report on vaccines and adverse reactions from the Institute of Medicine (“IOM”).
Exhibit D, tab 4 (Kathleen Stratton et al., Adverse Effects of Vaccines: Evidence
and Causality, Institute of Medicine (2012)). Due to the credentials and expertise
of the members of the Institute of Medicine, special masters have consistently
placed great weight on their reports and appellate courts have consistently found
21
the crediting of these reports not arbitrary. See Porter v. Sec'y of Health & Human
Servs., 663 F.3d 1242, 1252–54 (Fed. Cir. 1993) (2002 report); Cucuras v. Sec'y of
Health & Human Servs., 993 F.2d 1525, 1529 (Fed. Cir. 1993) (1991 report); Isaac
v. Sec'y of Health & Human Servs., 108 Fed. Cl. 743, 768–74 (2013), aff’d, 540 F.
App’x 999 (Fed. Cir. 2013) (2011 pre-publication report); Terran v. Sec’y of
Health & Human Servs., 41 Fed. Cl. 330, 337 (1998) (1991 report and different
1994 report), aff’d, 195 F.3d 1302, 1317 (Fed. Cir. 1999); Kelley v. Sec’y of
Health & Human Servs., 68 Fed. Cl. 84, 91 n.11 (2005) (1994 report); Kuperus v.
Sec’y of Health & Human Servs., No. 01–60V, 2003 WL 22912885, at *10 (Fed.
Cl. Spec. Mstr. Oct. 23, 2003) (1994 report). In its most recent report, the IOM
found “no evidence that directly or indirectly supports the oversecretion of
cytokines as an operative mechanism.” Exhibit D, tab 4 (Stratton) at 76 [pdf 3].
Ms. McGuire introduced no persuasive evidence to rebut the IOM’s conclusion
that no evidence supports a conclusion that cytokines cause a disease.
2. Does TNF Cross the Blood Brain Barrier?
Because the HPV vaccine is given intramuscularly (exhibit 19 at 2), the
initial reaction whereby the cytokine TNF is recruited occurs near the site of
injection. Exhibit 38 (Dr. Swidan’s report) at 9. To reach the brain, the TNF must
enter the bloodstream and cross the blood brain barrier. The blood brain barrier
separates the vital parts of the central nervous system from the blood and contains
anatomical and physiological components. Dorland’s at 201. The mechanism by
which TNF penetrates the blood brain barrier is unclear. Exhibit 28 (Dr. Weig’s
report) at 4.
The Secretary’s cross-examination of Dr. Swidan revealed that the crossing
of the blood brain barrier was a second step in her theory. Tr. 525-26. However,
how TNF would cross the blood brain barrier was not explained very well. Dr.
Weig admitted that TNF would not easily cross the blood brain barrier. Tr. 181.
Dr. Swidan proposed that a rise in TNF in the body’s periphery could cause
the blood brain barrier to become leaky. Tr. 562. She further asserted that the
fever Ms. McGuire experienced within two days of the vaccination was evidence
of a systemic reaction. Tr. 526.
However, the medical doctors did not agree with Dr. Swidan. Dr. Weig, as
noted above, asserted that the TNF does not easily cross the blood brain barrier.
Even after hearing Dr. Swidan’s testimony, Dr. Weig acknowledged that he did not
know whether TNF creates permeability in the blood brain barrier. Tr. 709.
22
Likewise, Dr. Saxon stated that he had never heard of a leaky blood brain barrier.
Tr. 692-93.
Whether cytokines can cross the blood brain barrier appears to be a topic on
which medical doctors, especially a neurologist like Dr. Weig, would have more
training and experience than a pharmacologist. Dr. Swidan presented no support
for her assertion that TNF can cross the blood brain barrier. Thus, her opinion on
this point lacks reliability, undermining Ms. McGuire’s proof on prong one.
3. Does TNF Contribute to Headaches?
The final step in Ms. McGuire’s theory concerns what happens after TNF
crosses the blood brain barrier and enters the central nervous system. On this
point, Dr. Weig’s and Dr. Swidan’s opinions were unclear. At times, they seemed
to suggest that TNF caused the headache. Exhibit 28 at 4 (Dr. Weig’s Rep.) (TNF
increases production of peptide (CGRP) implicated in migraine pathogenesis);
exhibit 30 at 5 (Dr. Weig’s Supp’l Rep.) (“Elevated TNF alpha appears to be a
causative agent for multiple forms of headache.”); exhibit 38 at 12 (Dr. Swidan’s
Rep.) (TNF induces CGRP, a known factor in migraine pathogenesis); Tr. 516-17
(Dr. Swidan). At other times, they seemed to suggest that TNF only made a
headache worse (either in duration or severity). Tr. 704-05 (Dr. Swidan) (TNF
“amplifies” CGRP production; Tr. 202-04 (Dr. Weig) (headaches “substantially…
worsened” after second HPV vaccine); see also Tr. 614-17 (Dr. Saxon).
Ms. McGuire’s pre-trial brief identified an article whose authors are Dr.
Rozen and Dr. Swidan as the primary basis for the theory that TNF contributes to
headaches. Pet’r’s Preh’g Br. at 26 (stating “the two articles of utmost importance
to [Ms. McGuire’s] theory [are] the Pinto article… and the Rozen and Swidan
article”). However, for the reasons explained below, Ms. McGuire’s reliance on
the Rozen and Swidan article is misplaced. Nevertheless, this problem is not fatal
to Ms. McGuire’s case because other evidence, including a study by Dr. Durham
and the testimony of Dr. Saxon, support a finding that TNF contributes to
headaches.
a) Rozen and Swidan
Background. Dr. Rozen and Dr. Swidan designed a study to determine
whether their patients with refractory headaches were experiencing inflammation.
After Dr. Rozen diagnosed the patients, he ordered a spinal tap. Dr. Rozen sent the
cerebrospinal fluid and a blood sample to a laboratory, ARUP Laboratories, for
23
testing. Dr. Rozen and Dr. Swidan were looking for evidence of pro-inflammatory
cytokines. Tr. 495-500, 527-30.
ARUP Laboratories determined the reference range for the presence of
cytokines in the blood and the reference range for the presence of cytokines in the
cerebrospinal fluid by testing 36 volunteers. For both substances, the reference
range was less than 8.2 picograms per milliliter (pg/mL). In the published article,
Dr. Rozen stated that ARUP Laboratories disclosed the reference ranges via a
“personal communication.” Exhibit 38, tab U (Todd Rozen and Sahar Swidan,
Elevation of CSF Tumor Necrosis Factor α Levels in New Daily Persistent
Headache and Treatment Refractory Chronic Migraine, 47 Headache 1050 (2007))
at 1051. Dr. Swidan testified that ARUP Laboratories provided the information
about reference ranges to Dr. Rozen only, not to her. Tr. 531-32.
Dr. Rozen and Dr. Swidan compared the amount of TNF in their 38 patients
with refractory headaches with the amount of TNF in 36 normal individuals as
determined by ARUP Laboratories. The amount of TNF in the serum was similar
in both groups. However, the cerebrospinal fluid from patients with refractory
headaches contained more TNF than the cerebrospinal fluid from volunteers at
ARUP Laboratories. Exhibit 38, tab U at 1051-52. Dr. Rozen and Dr. Swidan
wrote: “TNF [alpha] levels are elevated in various forms of [CDH].” Id. at 1053.
From this observation, Dr. Rozen and Dr. Swidan hypothesized that
“[p]ersistent elevation of TNF [alpha] could lead to persistent elevation of CGRP,
and thus daily head pain.” Id. Similarly, they asserted that “an increase in TNF
[alpha] levels in the CSF may play a true role in the pathogenesis of CDH.” Id. at
1054. If so, pharmaceuticals that inhibit the production of TNF [alpha] could have
“an important role in the treatment of NDPH and refractory chronic migraine.” Id.
at 1055. However, Dr. Rozen and Dr. Swidan cautioned that their work “is an
initial observation, which must be substantiated by future studies.” Id. at 1054.
Both Dr. Weig and Dr. Swidan relied upon the Rozen and Swidan study.
See exhibit 28 (Dr. Weig) at 3-4; exhibit 38 (Dr. Swidan) at 11.
Criticisms. Through Dr. Saxon, the Secretary raised several arguments
against the usefulness of the Rozen and Swidan article.
24
First, Dr. Saxon challenged the way ARUP Laboratories determined the
reference range for TNF in cerebrospinal fluid --- testing 36 healthy volunteers.17
A reference range is a set of values in which 95 percent of people fall. Tr. 624; see
also Dorland’s at 2021 (defining reference values). Dr. Saxon argued that a
reference range for a laboratory test should involve at least a few hundred
participants. Tr. 625-26. Dr. Saxon’s opinion was based upon his qualification as
a board-certified expert in internal medicine, clinical immunology and diagnostic
immunology. His opinion was not challenged at all.
Second, Dr. Saxon questioned the values in ARUP Laboratories’ reference
ranges for TNF in the serum and in the cerebrospinal fluid. Dr. Saxon indicated
that having the same reference range (< 8.2 pg/ML) is “most unusual.” Tr. 609-10.
In his experience, Dr. Saxon has never before encountered a pair of tests in which
the normal levels were the same in the blood and cerebrospinal fluid. Tr. 625.18
Dr. Swidan’s experience was similar. When asked whether she was aware of any
test in which the reference range was the same for CSF and serum, Dr. Swidan
answered: “I don’t know if I can answer that with my knowledge because that’s a
pathologist’s training. . . . And, so, there may be, but I do not know of any.” Tr.
535.
A third question of the ARUP Laboratories’ reference ranges concerned the
current reference ranges. Dr. Saxon stated that shortly before trial, he called
ARUP Laboratories to ask about the reference range for TNF. Tr. 688-89. ARUP
Laboratories told him that the reference range for TNF from the serum was less
than 22 pg/ML. Tr. 610, 625. Assuming that normal TNF levels are the same in
blood as they are in cerebrospinal fluid, then an expected CSF level would be 22
pg/ML. If this is also correct, then Dr. Rozen and Dr. Swidan did not discover
anything significant because the TNF level in all the patients was less than 22
pg/ML. In other words, the patients would fall within the reference range. Tr.
538, 627-28.
17
While healthy people may provide blood samples for testing routinely, healthy people
do not undergo spinal taps usually. See Tr. 550 (Dr. Swidan: “we can’t just spinal tap people
without valid reason”), 630 (Dr. Saxon wondering whether an internal review board would
approve a study subjecting healthy people to spinal taps).
18
Dr. Saxon’s background in diagnostic immunology gives him expertise in determining
whether tests have clinical value. Tr. 586-87.
25
Assessment. Overall, these criticisms diminish the reliability of the Rozen
and Swidan article.19 Before the hearing, Dr. Swidan’s authorship of this paper
was a stated basis for Ms. McGuire’s decision to retain her to testify about the
immunologic etiologies for chronic headaches. See Pet’r’s Preh’g Br. at 25 (“Dr.
Swidan’s testimony is offered as that of an expert in . . . specifically, the
aforementioned medical article she co-authored”). However, it is now evident that
Dr. Swidan’s role in conducting the experiments and preparing the results for
publication was limited. She did not communicate with ARUP Laboratories. Tr.
531-32. Therefore, she could not defend (or even explain) the lab’s reference
ranges. Her reliance on the work of Dr. Rozen underscored her relative lack of
experience.
Apart from these concerns about the foundations for the Rozen and Swidan
paper, there are additional problems. Dr. Rozen and Dr. Swidan recommended
that future studies substantiate their findings. Exhibit 38, tab U (Rozen & Swidan)
at 1054. However, neither Dr. Saxon nor Dr. Swidan was aware of any work that
also found elevations in TNF in patients’ CSF.20 Tr. 350-52, 699 (Dr. Saxon); Tr.
546 (Dr. Swidan). Thus, substantiation remains lacking.
Consistent with the lack of confirmation for the novel finding in the Rozen
and Swidan paper, the authors’ recommendation that doctors prescribe TNF
inhibitors to patients suffering from chronic headaches has not been followed. Dr.
Weig (Ms. McGuire’s expert) does not prescribe TNF inhibitors to his patients
19
Although Dr. Saxon had prepared reports addressing the Rozen and Swidan article (see
exhibit F at 8), he had not disclosed any criticism of the reference ranges from the ARUP
Laboratories. See exhibits D, F, I.
At hearing, when an expert attempts to present an opinion not disclosed before hearing,
the opposing party may seek to strike that testimony. E.g. Childers v. United States, 116 Fed. Cl.
486, 596-99 (2013) (granting motion to strike testimony). However, Ms. McGuire’s attorney did
not attempt to strike Dr. Saxon’s opinion during the hearing when any perceived prejudice could
have been mitigated. Consequently, Ms. McGuire’s failure to move to strike the testimony
constitutes a waiver of the argument that the Secretary had failed to disclose Dr. Saxon’s
opinions in advance of the hearing. See Vaccine Rule 8(f).
20
Dr. Saxon recognized that other articles published in peer-reviewed journals have cited
the Rozen and Swidan article. Tr. 698. While these sources have cited the Rozen and Swidan
article, these investigators have not independently verified that people who suffer from chronic
headaches have elevated TNF in the cerebrospinal fluid. Id.; Tr. 628.
26
with chronic headaches. Tr. 264. Dr. Alexander similarly does not prescribe TNF
inhibitors. Tr. 414.
Collectively, these factors undermine the value of the Rozen and Swidan
article. Although Ms. McGuire characterized this article as “peer-reviewed,
published, and well-accepted,” Pet’r’s Preh’g Br. at 26, Ms. McGuire did not
present any persuasive evidence that the article is “well-accepted.”21 In another
place, Ms. McGuire described the Rozen and Swidan article as “[r]eliable.” Id. at
17. But, Dr. Saxon’s testimony with respect to the reference ranges has called into
question the reliability of the findings in the Rozen and Swidan article. Dr. Swidan
could not answer these challenges.
b) Other Evidence
Although Ms. McGuire’s pre-hearing brief emphasized the Rozen and
Swidan article, this article provides very little, if any, support for the claim that
TNF contributes to headaches. The evidence that more persuasively assists Ms.
McGuire in connecting TNF and headaches comes from one of the Secretary’s
experts, Dr. Saxon.
Based primarily on experiments reported by Dr. Paul Durham (exhibit 28,
tab G (Paul Durham, Calcitonin gene‐related peptide (CGRP) and migraine, 46
Headache S3 (2006))), Dr. Saxon testified that TNF is part of an amplification
process. He stated that the irritation of the trigeminal nerve and associated
production of CGRP is the equivalent of placing a car key in the ignition and
turning it. Tr. 614. Both start a process. Dr. Saxon continued the analogy by
saying that increasing TNF is like stepping on the gas pedal. Tr. 614, 702-03.22
This testimony from Dr. Saxon is sufficient to find that Ms. McGuire has
established the third step in her three-part theory. It is more-probable-than-not that
21
Ms. McGuire’s submission of the article from the journal Headache established that it
was “published.” Although Ms. McGuire did not present any evidence that Headache subjects
articles to a peer-review process, the undersigned assumes that there was a peer-review process.
22
Dr. Weig asserted that the Perini article complements the Durham article. Tr. 183,
citing exhibit 38, tab Q (Francesco Perini et al., Plasma Cytokine levels in Migraineurs and
Controls, 45 Headache 926 (2005)). Although Dr. Saxon raised some questions about methods
of specimen collection and statistical analysis of the Perini article (Tr. 617-20), Perini still
supports an argument that elevations in TNF contribute to chronic headaches.
27
the addition of exogenously produced TNF would cause a person to suffer
headaches that are more severe or more prolonged than otherwise.23
However, Ms. McGuire’s evidence on the first two steps of her three-part
theory falls short of being persuasive. In particular, the following questions
undermine the persuasiveness of the theory causally connecting the HPV vaccine
and chronic headaches:
 Is the amount of TNF produced after vaccination an amount sufficient to
cause a disease?
 Is there a reliable basis for extrapolating the Pinto experiment from in
vitro to in vivo?
 Is there a reliable basis for finding that TNF crosses the blood brain
barrier?
On these points, Ms. McGuire has produced a measure of evidence,
consisting of the testimony of Dr. Weig and Dr. Swidan, but did not shore up their
opinions by referring to any literature. As an abstract legal principle, petitioners
may establish that they are entitled to compensation without presenting any
medical literature. Althen, 418 F.3d at 1274. “However, it should be obvious to
petitioner that a scientific theory that lacks any empirical support will have limited
persuasive force.” Caves v. Secʼy of Health & Human Servs., 100 Fed. Cl. 119,
134 (2011), aff’d per curiam, 463 F. App’x 932 (Fed. Cir. 2012). Special masters
are not required to accept the opinion of any expert, particularly one who expresses
opinions without support. Cedillo v. Secʼy of Health & Human Servs., 617 F.3d
1328, 1347-48 (Fed. Cir. 2010).
C. Argument based upon Precedent
Despite the evidentiary shortcomings in her presentation, Ms. McGuire
draws support from the Federal Circuit’s opinion in Koehn. Ms. McGuire states
23
The finding that the evidence supports Ms. McGuire’s assertions on the third step fully
makes up for any prejudice that she may have suffered with respect to the undisclosed criticisms
of the Rozen and Swidan article. Any mistakes of Ms. McGuire’s attorney in not objecting to
Dr. Saxon’s criticisms as undisclosed or in failing to request rebuttal testimony from Dr. Swidan
did not harm Ms. McGuire. Ms. McGuire achieved the result she wanted – a finding that TNF
can worsen headaches – by a different path without relying solely on the Rozen and Swidan
article.
28
that in Koehn the Federal Circuit upheld a theory that is “profoundly similar” to
her own. Ms. McGuire appears to be implying that the similarities between her
case and Koehn support a similar outcome in her case. Pet’r’s Preh’g Br. at 20.
To assess the comparability of the cases, the facts of Koehn are set forth.
In Koehn, the petitioner’s expert presented a two-step theory. The first
proposition was that inflammatory cytokines can cause systemic juvenile
idiopathic arthritis and the second proposition was that the HPV vaccine prompts
the induction of inflammatory cytokines. Koehn v. Sec'y of Health & Human
Servs., No. 11-355V, 2013 WL 3214877, at *21 (Fed. Cl. Spec. Mstr. May 30,
2013), mot. for rev. denied, 113 Fed. Cl. 757 (2013), aff’d, 773 F.3d 1239 (Fed.
Cir. 2014).
Pursuant to Terran v. Secʼy of Health & Human Servs., 195 F.3d 1302, 1316
(Fed. Cir. 1999), the undersigned special master evaluated this theory according to
the factors that the Supreme Court articulated in Daubert v. Merrell Dow Pharma.,
Inc., 509 U.S. 579 (1993), and found that the theory was not persuasive. Koehn,
2013 WL 3214877, at *22-26. Separately, the undersigned also found that the
petitioner did not establish the third prong of Althen, which concerns timing. Id. at
*26-29. The Court of Federal Claims denied a motion for review, finding that the
special master’s findings for both Althen prong 1 and Althen prong 3 were not
arbitrary. C.K. v. Sec'y of Health & Human Servs., 113 Fed. Cl. 757, 772-73
(2013). Consequently, the judgment denied the petitioner compensation.
The Federal Circuit affirmed this judgment. The basis for the affirmance
was the finding that the petitioner had failed to establish an appropriate timing.
Koehn, 773 F.3d at 1243-44. This is the holding of the Federal Circuit. Godfrey v.
Sec'y of Health & Human Servs., No. 10-565V, 2015 WL 4972882 at *4-5 (Fed.
Cl. Aug. 19, 2015) (granting motion for review for additional consideration of
Koehn).
However, with respect to Althen prong 1, the Federal Circuit panel split.
Two members stated “the Special Master committed several errors in the
assessment of the first and second Althen prongs.” Id. at 1243. The majority
expanded on their reasoning in a footnote, stating “Had the Special Master
29
properly evaluated the evidence, we believe the Special Master would have likely
found that Koehn met her burden under the first Althen prong.” Id. at 1244 n.1.24
In the case at hand, Ms. McGuire relies upon this footnote. Pet’r’s Preh’g
Br. at 19-20 n.12. However, the views of the panel majority expressed in the
footnote are dicta and do not constitute a holding requiring that all special masters
credit any theory relying upon the Pinto article. See Highmark, Inc. v. Allcare
Health Mgmt. Sys., Inc., 701 F.3d 1351, 1354 n.2 (Fed. Cir. 2012) (en banc) (per
curiam) (discussing what panel opinions constitute binding precedent); see also
Bristol-Meyers, 769 F.3d at 1353 (Taranto, J.) (dissenting from denial of reh’g en
banc) (“[S]tatements in opinions must be read in context, considering their role in
the decision and the facts of the case. Nevertheless, advocates often ignore this
principle, relying on phrases and sentences found through database word searches
without reading the whole opinion, and arguing for a precedential effect that is
unwarranted.”); Godfrey, 2015 WL 4972882 at *7 (“the circuit’s criticisms of the
special master’s decision in Koehn with regard to causation are dicta”).
Even if the footnote in Koehn were not dicta, however, it is unclear whether
the views of the panel majority in that case could determine the outcome in Ms.
McGuire’s case. A “special master’s task is to make a factual determination of
causation based on the evidence in a particular case. A study of many individual
cases may be useful evidence as to causation, but it does not compel the finder of
fact to find causation in a particular case.” Lampe v. Secʼy of Health & Human
Servs., 219 F.3d 1357, 1366 (Fed. Cir. 2000). The mandate to consider the
evidence in each case carries particular force because the evidence in Koehn differs
from the evidence in this case.
Concededly, Ms. McGuire’s theory shares the basic structure of the theory
advanced in Koehn: the HPV vaccine induces the production of cytokines and the
produced cytokines cause a disease. But, the theory in Ms. McGuire’s case adds
the step of crossing the blood brain barrier. The blood brain barrier is not trivial.
In evaluating a theory, special masters may consider whether petitioners have
presented a reliable basis for finding that a vaccine, which is administered in the
body’s periphery, can cause adverse effects in the part of the body protected by the
blood brain barrier. See Moberly, 592 F.3d at 1324; Taylor v. Secʼy of Health &
24
The remaining member of the panel did not believe that the errors regarding prong 1
and prong 2 presented “adequate grounds for reversal given the highly deferential standard of
review.” Koehn, 773 F.3d at 1245 (Moore, J., concurring).
30
Human Servs., 108 Fed. Cl. 807, 819 (Fed. Cl. 2013) (denying motion for review
because, in part, petitioner failed to present evidence of a breach in the blood brain
barrier).
In addition, the evidence surrounding the theory in Ms. McGuire’s case
differs from the evidence surrounding the theory in Koehn. For example, in this
case, the Secretary presented the 2012 IOM report that found no evidence that
cytokines cause a disease. Exhibit D, tab 4 (Stratton) at 76 [pdf 3]. This evidence
was not offered in Koehn.
Another difference between Ms. McGuire’s case and Koehn is the disease
afflicting the petitioner. In Koehn, the disease was a form of arthritis. Here, the
disease is chronic headaches. While in Koehn two members of the Federal Circuit
appeared to conclude that the petitioner’s evidence supported a finding that
cytokines cause a type of arthritis, their conclusion would not necessarily mean
that cytokines can cause headaches.
In this case, a finding that the HPV vaccine can cause chronic headaches
depends upon the evidence introduced in this case. Althen, 418 F.3d at 1281. For
the reasons discussed above, the Secretary has controverted Ms. McGuire’s
evidence to such a degree that the evidence does not preponderate in Ms.
McGuire’s favor on this point.
II. Timing
Although timing is the third factor from Althen, it is easier to assess the
evidence immediately after the discussion of the theory. The causal theory largely
influences the amount of time that is consistent with an inference of causation.
Langland v. Secʼy of Health & Human Servs., 109 Fed. Cl. 421, 434 (2013).
As part of her case-in-chief, the petitioner bears the burden of establishing
that the onset of her disease occurred within an acceptable time. Bazan v. Sec’y of
Health & Human Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008). This formulation
implies that the third prong from Althen actually contains two parts. First, there
must be a showing that a range of time is “acceptable” to infer causation. Second,
there must be a showing that the petitioner’s disease arose in this acceptable time.
Shapiro v. Secʼy of Health & Human Servs., 101 Fed. Cl. 532, 542-43 (2011),
recons. denied after remand on other grounds, 105 Fed. Cl. 353 (2012), aff’d per
curiam, 503 F. App’x 952 (Fed. Cir. 2013).
31
For Ms. McGuire, there is no dispute about the second part of the third
prong. The time when her headaches arose was determined in the Revised
Findings: sometime between October 25 and October 28, 2007. Because she
received the first dose of the HPV vaccine on September 20, 2007, the interval
between vaccination and onset of headaches for Ms. McGuire is 35 to 38 days.
Consequently, her burden is to establish that approximately 38 days is an
acceptable period for inferring causation.
With respect to the first part of the timing prong, the parties presented
relatively little evidence. Actually, Ms. McGuire failed to present any opinion
from Dr. Weig regarding the appropriate temporal interval until after an order
directed her to review Dr. Weig’s first two reports. Order, issued Dec. 15, 2014.
His ensuing written opinion regarding the appropriate temporal relationship relied
upon a 1994 report from the Institute of Medicine. Exhibit 40 at 1. In his oral
testimony, Dr. Weig again cited the 1994 IOM report and the Prakash and Shaw
article. Tr. 199-202.
The 1994 IOM report found that acute disseminated encephalomyelitis
(ADEM) and Guillain-Barré syndrome (GBS) “generally occur after an interval of
5 days to 6 weeks following . . . injection of antigen.” Exhibit 40, tab B (Kathleen
Stratton et al., Adverse Events Associated with Childhood Vaccines: Evidence on
Causality, Institute of Medicine (1994)) at 47. ADEM and GBS are demyelinating
conditions. Tr. 265. Special masters have found the period of 5 days to 6 weeks is
an acceptable interval for diseases mediated through an autoimmune process such
as molecular mimicry. Lilly v. Secʼy of Health & Human Servs., No. 09-31V,
2009 WL 3320518, at *3 (Fed. Cl. Spec. Mstr. Sept. 28, 2009).
A problem for Ms. McGuire is that she did not present any evidence that
suggests the time for a demyelinating disease matches the time for cytokines to
produce headaches. Dr. Weig conceded that TNF is “not [causing] an autoimmune
attack in the way that that term is typically used, which would mean like an attack
to destroy . . . cells or myelin.” Tr. 283. An admission that the process Dr. Weig
has advanced involving TNF differs from the process of demyelination essentially
makes an analogy to the 1994 IOM unpersuasive.
As discussed in the preceding section, Dr. Weig’s theory contains at least
three steps, beginning with the production of TNF in response to the vaccine.
However, even for this foundational step, Dr. Weig did not know how long the
body takes to produce pathogenic levels of cytokines. Tr. 265. Dr. Weig’s
inability even to estimate the time required casts doubt on his opinion regarding
timing.
32
Dr. Swidan provided little assistance. She asserted that TNF in the serum
might remain elevated during a chronic migraine attack. Tr. 546. But, in the
Rozen and Swidan experiment, the TNF levels in serum was the same in controls
and in people suffering headaches. The more meaningful substance is the
cerebrospinal fluid. See Tr. 462 (Dr. Swidan noting that pharmacologists study
whether a substance crosses the blood brain barrier). For the cerebrospinal fluid,
Dr. Swidan acknowledged that there are no studies measuring TNF in the
cerebrospinal fluid during a chronic migraine. Tr. 546. In addition, Dr. Swidan
did not provide any testimony about the time required to produce TNF initially.
Questions were also posed to Dr. Saxon about the duration of cytokines. He
stated that on the intracellular level, which is the relevant metric, most cytokines
“work in minutes” and they last for hours. Tr. 690-91. If Dr. Saxon is correct,
then Ms. McGuire would need to show that the short duration of cytokines is
consistent with an onset of her headaches approximately 35 days later. See Koehn,
773 F.3d at 1244 (holding that special master was not erroneous in finding that a
cytokine-driven reaction would not explain an onset approximately 60 days
later).25
In commenting upon the appropriate temporal relationship, Dr. Saxon
emphasized the weakness in the underlying theory. Dr. Saxon stated that Dr.
Weig’s theory for how the HPV vaccine can cause headaches “doesn’t fit with any
logic principles.” “[B]ecause [the theory] doesn’t fit an immunologic paradigm,”
“you don’t need immunologic time frames.” Tr. 645.
This criticism fits. Dr. Weig offered a theory involving cytokines, but his
testimony revealed that he did not know the time needed to produce cytokines or
the duration of cytokines. Therefore, Dr. Weig could not persuasively offer an
explanation of the temporal interval that would be appropriate. His resort to the
1994 IOM appears to be a desperate reach for a straw. Ms. McGuire has not
established the temporal interval between the HPV vaccination and the onset of
25
As discussed in section I.C. above, the Federal Circuit’s holding in Koehn was to rule
the special master’s analysis on timing was not arbitrary or capricious. Ms. McGuire would have
been better served to pay attention to this analysis because the latency between the vaccination
and the onset of headaches was multiple weeks, which is similar to the period of latency for
arthritis in Koehn.
If Ms. McGuire’s reliance on Koehn to establish prong one were correct, then it would
seem to follow that Ms. McGuire would also be bound by Koehn on prong three.
33
chronic headaches that is appropriate for causation. Therefore, she has not
established Althen prong three.
III. Logical Sequence of Cause of Effect
Because Ms. McGuire has not presented a persuasive theory explaining how
the HPV vaccine can cause chronic headaches (prong 1) and she has not
established the appropriate temporal relationship (prong 3), it follows, as a matter
of logic, that she cannot establish “a logical sequence of events” beginning with
the vaccination and ending with her chronic headaches. Caves, 100 Fed. Cl. at
134. Nevertheless, the evidence most closely related to this prong is also discussed
to demonstrate that the entire record has been considered.
The Federal Circuit has identified several factors that may be probative with
respect to the petitioner's burden on the second prong. These include, among other
things, the opinions of a petitioner's treating physicians, expert testimony,
challenge-rechallenge, and pathological markers. See Capizzano, 440 F.3d at
1322.
A. Treating Doctors
The order for briefs before hearing instructed Ms. McGuire to identify
statements of treating doctors in which they expressed an opinion that the HPV
vaccine caused Ms. McGuire’s headaches. Order, issued Jan. 15, 2015. In
response, Ms. McGuire identified seven doctors. Pet’r’s Preh’g Br. at 34-36.
However, as Ms. McGuire conceded during the pre-trial conference, in most of the
quoted passages, the doctor is presenting only a chronological account of events.
A sequence is not the same as a statement of causation. Cedillo v. Secʼy of Health
& Human Servs., 617 F.3d 1328, 1347-48 (2010); La Londe v. Secʼy of Health &
Human Servs., 110 Fed. Cl. 184, 206 (2013), aff’d on other ground, 746 F.3d 1334(Fed. Cir. 2014); Langland v. Sec'y of Health & Human Servs., 109 Fed. Cl. 421,
439 (2013) (stating that the special master was not arbitrary in finding that the
records from treating doctors “reflect no more than intake histories or temporal
associations”); Caves, 100 Fed. Cl. at 127.
When these reports are set aside, Ms. McGuire is left with few useful
statements from treating doctors. The potentially most useful statement comes
from Dr. Herzog, the endocrinologist who saw Ms. McGuire nearly three years
after the HPV vaccination. Dr. Herzog stated that “headache is reported as quite
common after [Gardasil] vaccination (11-12%) but long lasting headache is
unusual. . . . In the absence of response to standard migraine and muscle tension
34
headache treatments, the possibility of an immunologically mediated process could
be considered.” Exhibit 13 at 13.
On its face, Dr. Herzog’s report that he could consider an immune mediated
process a “possibility” does not satisfy the preponderant evidence standard.
Paterek v. Secʼy of Health & Human Servs., 527 F. App’x 875, 879 (Fed. Cir.
2013). In addition, as Dr. Weig acknowledged on cross-examination, Dr. Herzog
looked for evidence of immune-mediated diseases such as lupus that could have
caused headaches as a consequence of that disease but did not find any evidence of
an immune-mediated process. Tr. 267. Thus, Dr. Herzog’s report does not lend
much assistance to the theory that the HPV vaccine caused Ms. McGuire’s primary
headaches.
After Dr. Herzog’s report, Dr. Levy’s 2009 report received the most
attention at the hearing. To recap, Dr. Levy practices alternative medicine and he
saw Ms. McGuire on January 15, 2009, which was approximately two years after
her headaches became permanent. According to the history Dr. Levy received,
Ms. McGuire “never had headaches before the HPV vaccination.” Exhibit 12 at 5.
He stated that “It seems reasonable that there is a causal connection. Headache is a
known side effect of HPV vaccine but studies show its frequency is similar in
controls and vaccinees.” Id.26 He recommended various non-traditional
interventions.
An initial problem with Dr. Levy’s report is that the history he obtained is
not accurate. Before the vaccination, Ms. McGuire did have at least one headache.
See Tr. 412-13. An incorrect history may lead a doctor to incorrect reasoning. See
Paterek, 527 F. App’x at 884 (holding that special master was not arbitrary in
rejecting the opinion of a doctor who obtained an inaccurate history).
Another issue is that Dr. Levy practices, according to Dr. Weig, “alternative
medicine.” Tr. 268. No information suggests that Dr. Levy has sufficient
expertise in either immunology or neurology to explain in a reliable fashion how
the vaccine can lead to headaches. See Tr. 268-69.
26
Dr. Levy took the additional step of postulating that the immune system, including
“proinflammatory cytokines,” might affect the “trigemino-vascular system.” He cited three
articles. Exhibit 12 at 5. However, neither party submitted those articles.
35
These two points weaken the value of Dr. Levy’s opinion that there is a
causal connection between the HPV vaccination and Ms. McGuire’s headaches. In
addition, Dr. Levy’s statement must be considered in the context of the many other
doctors who knew Ms. McGuire received the first dose of her HPV vaccination
before she started having recurring headaches in October 2007, but did not suggest
that the vaccination caused the headaches. See 42 U.S.C. § 300aa–13(a)(1)
(stating that special master must consider the record as a whole). From this
perspective, Dr. Levy’s opinion appears to be one not shared by his colleagues in
the medical profession.
B. Rechallenge
The Federal Circuit recognizes “rechallenge” as a factor that may be relevant
to considering whether a logical sequence of events supports the claim that a
vaccine caused an injury. Capizzano, 440 F.3d at 1322 (finding that a re-challenge
means “a patient who had an adverse reaction to a vaccine suffers worsened
symptoms after an additional injection of the vaccine”); see also Tr. 650.
In accord with the Federal Circuit’s instruction regarding rechallenge,
petitioners who demonstrate rechallenge may prevail in the Vaccine Program. Hall
v. Sec'y of Health & Human Servs., No. 02-1052V, 2007 WL 3120284, at *7-8
(Fed. Cl. Spec. Mstr. Sept. 12, 2007). However, petitioners must actually establish
that they fulfill the challenge-rechallenge paradigm. Shapiro v. Sec'y of Health &
Human Servs., No. 99-552V, 2012 WL 273686, at *12 (Fed. Cl. Spec. Mstr. Jan.
10, 2012), recons. denied after remand on other grounds, 105 Fed. Cl. 353 (2012),
aff’d per curiam, 503 F. App’x 952 (Fed. Cir. 2013); Nussman v. Sec'y of Health
& Human Servs., No. 99-500V, 2008 WL 449656, at *9-10 (Fed. Cl. Spec. Mstr.
Jan. 31, 2008), mot. for rev. denied, 83 Fed. Cl. 111 (2008).
The reverse of challenge-rechallenge is challenge-dechallenge.
“Dechallenge” refers to a situation in which removing the agent that supposedly
incites an adverse reaction leads to an improvement. Rider v. Sandoz Pharm.
Corp., 295 F.3d 1194, 1199-200 (11th Cir. 2002); Glastetter v. Novartis Pharm.
Corp., 252 F.3d 986, 990 (8th Cir. 2001). If removing the allegedly harm-causing
agent does not help, then the agent may not have actually caused the injury.
In this case, Ms. McGuire claims “challenge-rechallenge” and, at the same
time, the Secretary has invoked “challenge-dechallenge.” These disparate
arguments are based upon different aspects of Ms. McGuire’s medical history.
36
A succinct chronology to highlight only the events relevant to the challenge-
rechallenge-dechallenge arguments begins with Ms. McGuire’s receipt of the first
dose of the HPV on September 20, 2007. Exhibit 1 at 88-89. Her headaches began
between October 25 and October 28, 2007, and became constant one week later.
Revised Findings, issued Oct. 12, 2012. On November 14, 2007, Ms. McGuire
received the second dose of the HPV vaccine. Exhibit 1 at 86. The parties do not
dispute these events.
The parties, however, contest the next event in this sequence. To support
her argument in support of rechallenge, Ms. McGuire asserts that approximately
two weeks after receiving the second dose, her headaches became worse. See Tr.
204-05 (Dr. Weig’s testimony).27 The Secretary does not agree with the contention
that Ms. McGuire’s headaches worsened about two weeks after the second dose.
See Tr. 416-18 (Dr. Alexander). Different portions of the medical records support
each party’s interpretation. See exhibit 1 at 80 (Ms. McGuire reported on
December 10, 2007, that “her headache has progressively worsened”); exhibit 1 at
54 (Ms. McGuire told her neurologist on March 20, 2008, that there “was no
change in her headache after the second vaccine.”)
Determining whether Ms. McGuire’s headaches truly worsened at the end of
November or beginning of December 2007 is not necessary for this decision. Even
if her headaches did worsen, the worsening would not necessarily be a result of the
November 14, 2007 vaccination. This is because for CDH, “there are good times
and there are bad times.” Tr. 417. In other words, the severity of the headaches
fluctuates for a variety of unknown reasons. Thus, the possibility of worsening
does not point, even on a more-likely-than-not standard, to the vaccine as the cause
of any worsening. Thus, Ms. McGuire’s reliance on the challenge-rechallenge
theory is not persuasive.
This leaves the Secretary’s challenge-dechallenge argument. Ms. McGuire
and her experts maintain that the HPV vaccine provoked the production of an
excessive amount of TNF, which, in turn, caused the headache. Part of Ms.
McGuire’s support for the assertion that high amounts of TNF cause headaches is
the Prakash and Shaw study, which reported that people with headaches who
27
Although Ms. McGuire presented the challenge-rechallenge argument through Dr.
Weig, Ms. McGuire did not raise this contention in her pre-trial brief.
37
received high doses of steroids, which counter the production of TNF, improved.
Exhibit 40 (Dr. Weig report) at 1; Pet’r’s Preh’g Br. at 18.
From this foundation, the Secretary argues that Ms. McGuire does not fulfill
the challenge-dechallenge paradigm. See Resp’t’s Preh’g Br. at 22-23. In May
2008, Ms. McGuire received a course of steroids. Exhibit 1 at 41, 46-47.
However, the steroids either did not affect Ms. McGuire or they made her worse.
Exhibit 12 at 3; exhibit 13 at 1; exhibit 3 at 66, 70-71. Dr. Saxon and the
Secretary, thus, conclude that the lack of improvement indicates that TNF was not
responsible for Ms. McGuire’s headaches. Exhibit D at 11, Resp’t’s Preh’g Br. at
23.
Ms. McGuire effectively rebutted the Secretary’s reliance on challenge-
dechallenge. She showed that the amount of steroids used in the Prakash and Shaw
study exceeded by a large margin the amount of steroids prescribed to Ms.
McGuire. Tr. 196-98. Whether a stronger dose of steroids could have improved
Ms. McGuire’s headaches is uncertain and the dosages used by Prakash and Shaw
are not typically prescribed. Tr. 687.
Overall, neither Ms. McGuire’s challenge-rechallenge argument nor the
Secretary’s challenge-dechallenge is particularly persuasive.
C. Expected Response
A final way to consider whether Ms. McGuire presented preponderant
evidence that the sequence of events logically points to the vaccine as the cause for
her headaches is to evaluate whether she responded in a way predicted by her
expert’s theory. Both the Federal Circuit and the Court of Federal Claims have
accepted this method of analysis. Hibbard v. Secʼy of Health & Human Servs.,
698 F.3d 1355, 1364 (Fed. Cir. 2012); Dodd v. Secʼy of Health & Human Servs.,
114 Fed. Cl. 43, 57 (2013) (special master did not err in finding that the facts of the
vaccinee’s injury did not fit the theory offered by the petitioner); La Londe v.
Secʼy of Health & Human Servs., 110 Fed. Cl. 184, 205 (2013) (special master did
not err in rejecting the petitioner’s argument regarding prong 2 when the medical
records did not support the theory being offered), aff’d, 746 F.3d 1334 (Fed. Cir.
2014).
Here, Dr. Weig wrote that the vaccinations produced “a state of chronic
CNS inflammation with resulting headache.” Exhibit 28 at 4; accord Tr. 246.
People suffering from inflammation in their brains – as the term inflammation is
usually used – have “confusion, seizures, aphasia, coma, cranial nerve palsies, CSF
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pleocytosis, or systemic signs of inflammatory disease with fevers, elevated
sedimentation rate.” Exhibit A (Dr. Alexander’s report) at 12-13. Furthermore,
inflammation would be evident on MRIs and CT scans. Dr. Alexander was quite
blunt in rejecting Dr. Weig’s assertion that Ms. McGuire had inflammation in her
central nervous system. Dr. Alexander stated that “there is not a shred of evidence
that she has chronic CNS inflammation producing headaches.” Id. at 12. At the
hearing, Dr. Weig, essentially, agreed that Ms. McGuire did not have any of the
signs or symptoms of CNS inflammation as conventionally understood. See Tr.
178, 246, 289, 708-09. In his rebuttal testimony, Dr. Weig acknowledged that his
use of the term “inflammation” “would not correspond to the standard definition of
the term . . . in the general medical community.” Tr. 708.
Rather, Dr. Weig introduced a concept that was not discussed in his reports.
He stated that Ms. McGuire suffered from “sterile inflammation.” Tr. 177. Dr.
Weig said that “sterile” means “there’s no evidence of inflammatory cells in the
spinal fluid.” Tr. 177-78. Dr. Saxon clarified that Dr. Weig’s “sterile
inflammation” occurs at the molecular level. Tr. 604.
It would help a petitioner to show “evidence in the record suggesting that the
proposed mechanism was at work” in her case. Moberly, 592 F.3d at 1324. But,
this type of showing appears not to be possible because doctors do not routinely
order cerebrospinal fluid to be tested for TNF. See exhibit 30 (Dr. Weig) at 5; Tr.
550. Thus, Ms. McGuire is unable to present any evidence that she reacted in a
way that Dr. Weig’s theory would predict.
Overall, Ms. McGuire’s evidence regarding prong 2 was not of sufficient
quality or persuasiveness to compensate for the deficiencies in prongs 1 and 3.
Taken as a whole, Ms. McGuire did not meet her burden of proof on this prong.
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Conclusion
Ms. McGuire claimed that the HPV vaccine caused her to suffer headaches
and presented evidence, including opinions from Dr. Weig and Dr. Swidan, to
support her allegation. However, the evidence does not preponderate in her favor.
The Clerk’s Office is instructed to enter judgment in accord with this
decision.
IT IS SO ORDERED.
s/ Christian J. Moran
Christian J. Moran
Special Master
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