Journal of Medical Economics

ISSN: 1369-6998 (Print) 1941-837X (Online) Journal homepage: https://www.tandfonline.com/loi/ijme20

Estimating health state utilities associated with a

rare disease: familial chylomicronemia syndrome
(FCS)

Louis S. Matza, Glenn A. Phillips, Timothy A. Howell, Nicole Ciffone & Zahid
Ahmad

To cite this article: Louis S. Matza, Glenn A. Phillips, Timothy A. Howell, Nicole Ciffone
& Zahid Ahmad (2020) Estimating health state utilities associated with a rare disease:
familial chylomicronemia syndrome (FCS), Journal of Medical Economics, 23:9, 978-984, DOI:
10.1080/13696998.2020.1776719

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JOURNAL OF MEDICAL ECONOMICS
2020, VOL. 23, NO. 9, 978–984
https://doi.org/10.1080/13696998.2020.1776719
Article 0034-RT.R1/1776719

ORIGINAL RESEARCH

Estimating health state utilities associated with a rare disease: familial

chylomicronemia syndrome (FCS)
Louis S. Matzaa, Glenn A. Phillipsb, Timothy A. Howella, Nicole Ciffonec and Zahid Ahmadd
a
Patient-Centered Research, Evidera, Bethesda, MD, USA; bValue & Evidence Generation, Rhythm Pharmaceuticals, Boston, MA, USA;
c
Arizona Center for Advanced Lipidology, Tucson, AZ, USA; dDepartment of Internal Medicine, University of Texas Southwestern Medical
Center, Dallas, TX, USA

ABSTRACT ARTICLE HISTORY

Aims: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder with no currently approved Received 25 February 2020
therapies. Treatments are in development, and cost-utility analyses will be needed to examine their Revised 30 April 2020
value. These models will require health state utilities representing FCS. Therefore, the purpose of this Accepted 21 May 2020
study was to estimate utilities for FCS and an associated episode of acute pancreatitis (AP).
KEYWORDS
Methods: Because it is not feasible to gather a large enough sample of patients with this extremely Utility; familial
rare condition to complete standardized preference-based measures, vignette-based methods were chylomicronemia syndrome;
used to estimate utilities. In time trade-off interviews, general population participants in the UK and FCS; rare disease; acute
Canada valued health state vignettes drafted based on literature review, clinician input, and interviews pancreatitis; time trade-off
with patients. Four health states described variations of FCS. A fifth health state, describing AP, was
added to one of the other health states to evaluate its impact on utility. JEL CLASSIFICATION CODES
Results: A total of 308 participants provided utility data (208 UK; 100 Canada). Mean utilities for FCS I10; I19
health states ranged from 0.46 to 0.83, with higher triglycerides, more severe symptoms, and a history
of AP associated with lower utility values. The disutility (i.e. utility decrease) of AP ranged from –0.17
to –0.25, with variations depending on the health state to which it was added. Utility means were
similar in the UK and Canada.
Conclusions: The vignette-based approach is useful for estimating utilities of a rare disease. The
health state utilities derived in this study would be useful in models examining cost-effectiveness of
treatments for FCS.

Introduction Despite these challenges, cost-effectiveness analyses are

In recent years, there has been significant growth in develop-
ment of medications for treatment of rare diseases1–9.
Economic modeling, including cost-utility analysis (CUA), is
often needed to examine the value of these treatments10.
These models require utilities, which are values representing
the strength of preference for health states, to calculate
quality-adjusted life years (QALYs). Health technology assess-
ment (HTA) reviewers often prefer that utilities are derived
from generic preference-based measures such as the EQ-5D
completed by patients.11–15 However, to derive utilities from
patient-completed instruments, a sufficiently large sample of
patients is needed to represent health states included in eco-
nomic models. For rare diseases, it may not be feasible to
recruit a large enough sample of patients living in the rele-
vant health states. It can also be difficult to gather a sample
of patients with rare conditions to validate generic instru-
ments for use in the target population16,17.
needed to inform resource allocation decisions for treatment
of rare diseases, and these analyses often require health state
utilities. Therefore, alternative methods for estimating utilities
should be considered. Vignette-based methodology is one
approach that can be used to estimate utilities for rare dis-
eases when it is not feasible to collect preference-based data
from a large enough sample of patients. Health state descrip-
tions (often called vignettes or health states) can be drafted
based on the best available information, possibly including
input from patients, to ensure that the health states accur-
ately represent the typical patient experience. Then, utilities
can be estimated in a valuation study with general popula-
tion respondents.
One rare disease that will soon require economic model-
ing is familial chylomicronemia syndrome (FCS). This genetic
disorder is most commonly linked to mutations in the gene
encoding lipoprotein lipase (LPL), an enzyme that breaks
down chylomicron lipoprotein particles. It can also be linked
to mutations in genes which encode other proteins that are

CONTACT Louis S. Matza louis.matza@evidera.com Patient-Centered Research, Evidera, 7101 Wisconsin Avenue, Suite 1400, Bethesda, 20814, MD, USA
Supplemental data for this article is available online at https://doi.org/10.1080/13696998.2020.1776719.
ß 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
www.tandfonline.com/ijme

necessary for proper LPL function. This leads to an increase
in triglyceride levels18,19. Patients with FCS often experience
acute pancreatitis (AP) episodes, fatty deposits on the skin
(eruptive xanthomas), abdominal pain, fatigue, impaired cog-
nition, and enlargement of the liver or spleen. FCS is
extremely rare, occurring in about one in one million peo-
ple20,21. Until recently, there were no approved therapies for
FCS, and most patients attempt to manage the condition
through an extremely restrictive diet18,22. A novel treatment
called volanesorsen has recently been authorized for use in
the European Union23, and it has been shown to reduce tri-
glyceride levels in phase II and III trials24,25. In the phase III
trial, 77% of patients with FCS had triglycerides less than
750 mg/dL at three months of treatment25. As treatments are
introduced, utilities are needed for economic modeling to
examine their value.
The purpose of this study was to estimate health state
utilities representing FCS using vignette-based methodology.
To ensure that the health state vignettes were a reasonably
accurate representation of the patient experience, patients
with FCS and physicians who treat FCS were interviewed to
support the development of health state content. The health
states were valued in time trade-off (TTO) interviews with
general population respondents in the UK and Canada.
Methods
Health state development
Five health state descriptions were drafted and refined based
on published literature, interviews with FCS patients, and
interviews with clinicians specializing in FCS. The literature
search was performed to inform development of the patient
and clinician interview guides and identify characteristics of
FCS that should be included in the health states. This litera-
ture search focused on hypertriglyceridemia,26–28 FCS case
studies providing descriptions of patients,29–32 impact of
FCS18,33, the FCS diet22,34, and pancreatitis.35–38
Multiple rounds of telephone interviews were conducted
with three clinicians specializing in lipidology (endocrinolo-
gist, cardiologist, nurse practitioner). As FCS is a rare disease,
the clinicians saw relatively few patients with the condition,
but all reported that they had sufficient experience to
describe the typical patient experience of the disease, its
treatment, its impact, pancreatitis, and the restrictive diet.
The endocrinologist, cardiologist, and nurse practitioner
reported seeing approximately 10, five, and four patients
with FCS per year, respectively. The three clinicians were
located in Texas, Arizona, and New York.
The first interview with each clinician included a series of
open-ended questions designed to elicit descriptions of
patients’ typical experience with FCS, its impact, the FCS
diet, treatment, and AP. Descriptions of these patient experi-
ences were generally consistent across the three clinicians,
and no contradictory information emerged from the inter-
views. Clinician’s responses were used to inform the develop-
ment of the first draft of the health states. During
subsequent follow-up discussions, each clinician reviewed
the health states and suggested edits as necessary. These
JOURNAL OF MEDICAL ECONOMICS 979
discussions continued until all three clinicians agreed that
the health states provided clear and accurate representations
of the typical patient experience. In addition, the three clini-
cians agreed that, taken together, these five health states
provided reasonable coverage of the range of patient experi-
ences with FCS. Given their professional experience and the
state of the research on this rare disease, they did not
believe that additional health states with finer distinctions
among triglyceride levels and associated symptoms could be
supported by available data or clinician input.
Interviews with three patients (two female, one male;
ages 47, 56, and 57; all living in the US) were conducted to
confirm that the health state descriptions were consistent
with their personal experience of FCS. All three patients
reported that they could comment on health states with
high or low triglycerides because their triglyceride levels and
associated symptoms had varied during their lifetime with
FCS. In addition, all had experienced AP, and they were
therefore able to comment on the AP health state. One of
the patients had experienced only one episode of AP, while
the others had experienced multiple episodes. These inter-
views began with discussion of their personal experience
with FCS, including symptoms, diet, impact, and pancreatitis.
Then, the patients reviewed draft health states and provided
feedback on clarity, accuracy, and relevance of the health
state descriptions. Edits were made based on patient input.
All three patients agreed that the health states were consist-
ent with their personal experience of FCS.
Five health state vignettes were developed for valuation
in this study. Four of these health states were chronic (i.e.
unchanging over time, valued with a 10-year time horizon),
describing FCS varying by triglyceride levels and history of
AP: low triglycerides and no AP history (Health State A); high
triglycerides and no AP history (B); low triglycerides and his-
tory of AP that had resolved (C); and high triglycerides and
history of AP that had resolved (D). Key differences between
the four chronic health states include symptom severity, con-
cerns about recurring pancreatitis, and the amount of missed
work due to symptoms. The fifth health state described an
AP attack (E) as a temporary event including symptoms, dur-
ation, hospitalization, and treatment. The FCS diet was
described in an introductory information page that applied
to all health states.
In the health states and the introductory information
page, FCS was described in simple language so that the
information would be easily comprehensible to general
population participants. When medical terminology was
used, it was defined in simple terms. For example, triglycer-
ides were defined as “fats.” In addition, all health states
included descriptions of symptom severity and impact so
that respondents could form impressions and preferences
based on the description of patient experience, rather than
the triglyceride level.
The health states were formatted as a series of bullet
points on individual cards. The bullet points were organized
into categories with headings intended to facilitate compre-
hension. For example, the headings for health state A were
disease and diet; physical symptoms; cognitive symptoms; and
980 L. S. MATZA ET AL.
impact on usual activities and quality of life. For health states
C and D, the section describing lingering symptoms from pre-
vious pancreatitis was titled “previous experience.” See
Supplementary Appendix A for the introductory information
page and Supplementary Appendix B for the full text of the
final health state vignettes.
Participants
Participants were required to be at least 18 years old; reside in
the UK or Canada; and be able to give informed consent and
complete protocol requirements. Inclusion criteria did not spe-
cify clinical criteria because interviews were intended to yield
utilities that may be used in cost-utility analyses for submis-
sion to HTA agencies, which often prefer that utilities repre-
sent general population values11,14,15. Participants in this
general population sample were recruited via newspaper and
online advertisements. Potentially interested participants who
responded to the advertisements were screened by telephone
to assess eligibility prior to attending their study interview,
and eligibility was confirmed at the beginning of the inter-
view. During screening, an effort was made to recruit a sam-
ple that was similar to the general populations of the UK and
Canada with regard to age, gender, and racial/background. In
addition, employment status was monitored to ensure that
the rate of unemployed individuals was roughly comparable
to that of the general population of each country.
Pilot study
Methods were tested in a pilot study with 20 participants in
London (10 women; mean age ¼ 41.75 years; age range
19–52 years). Health states were valued in a TTO task, and
then revised based on feedback from pilot participants.
Revisions affected formatting and organization, rather than
content. For example, information common to all the health
states (e.g. FCS diet) was removed from each health state
and presented in a background information page that
applied to all health states. Participants had no difficulty
using the 10-year time horizon for the four chronic states,
followed by the one-year time horizon for AP.
Utility interview procedures and scoring
After the pilot study, the TTO valuation study was performed
in the UK (Edinburgh and London) in April 2018 and Canada
(Montreal and Quebec City) in August 2018. The strengths
and limitations of TTO methods, as well as comparisons to
other approaches for valuing health states, have been dis-
cussed extensively in previous literature39. All participants
provided written informed consent, and the study was
approved by an independent institutional review board
(Ethical & Independent Review Services, Study 18016). In
Canada, participants were given the choice of English or
French for the interview and study materials.
First, participants reviewed the introductory information
page. Then, they ranked the four chronic health states (A, B,
C, D) from most preferable to least preferable to familiarize
themselves with the health state content. After the ranking
task was completed, these four health states were valued in
a TTO utility elicitation task with a 10-year time horizon, fol-
lowing commonly used methodology39. For each health
state, participants were offered a series of choices between
spending 10 years in the health state or spending varying
amounts of time in full health. Full health was described as
“You are healthy. You do not have any health problems. You
can perform your usual activities without difficulty (getting
around the community, work, school, social, family, and
physical activities).” Choices were presented in six-month
(5%) increments, with time in full health alternating between
longer and shorter durations (i.e. 10 years, 0 [dead], 9.5, 0.5,
9.0, 1.0, 8.5, 1.5 … ). The utility value was calculated based on
the point of indifference between y years in the health state
being valued and x years in full health (utility ¼ x/y).
When respondents perceived a health state to be worse
than dead, the task and scoring procedures were altered as
described in previous literature40. Participants were offered a
choice between dead (choice 1) and a 10-year life span
(choice 2) beginning with varying amounts of time in the
health state being rated, followed by full health for the
remainder of the 10-year life span. The negative utility scores
were calculated with a scoring approach commonly used to
avoid highly skewed distributions (utility ¼ –x/10, where x is
the number of years in full health, and 10 is the number of
years in the total life span of choice 2).
To estimate disutility associated with an attack of AP,
respondents rated a sequence of two health states in a TTO
task with a one-year time horizon with one-month trading
increments. Each participant first rated either C or D, followed
by the identical health state with the addition of an attack of
AP (health state E) occurring in the middle of the one-year
time period. The one-year time horizon was used to assess the
impact of this temporary event because the addition of a brief
event is unlikely to have a measurable impact on preference
for a 10-year time horizon. Because the time horizon was
exactly one year, the utility decrease associated with the add-
ition of health state E to either C or D represents the QALY
decrement associated with AP. Participants were randomized
as to whether health state C or D was used as the context for
AP. The one-year TTO follows the same procedures and scor-
ing as those described above for the 10-year TTO.
Interviewers were trained to identify illogical responses in
order to maintain data quality. For example, ranking a health
state with an attack of AP as preferable to the same health
state without an attack of AP would be illogical. When
respondents provided unexpected preferences in the ranking
or TTO task, the interviewer would query the response to
ensure that the respondent understood the task and the
health state and was stating their preferences accurately.
Interviewers were trained to avoid biasing any responses or
suggesting that any response was correct or incorrect.
Statistical analysis procedures
Statistical analyses were completed using SAS version 9.2
(SAS Institute, Cary, NC). Continuous variables were
 JOURNAL OF MEDICAL ECONOMICS 981

summarized in terms of means and SDs, and categorical vari- final sample consists of 308 participants (n ¼ 208 in the UK
ables were summarized as frequencies and percentages. and n ¼ 100 in Canada; demographic results presented in
Subgroups were compared with independent t-tests, and Table 1). The most common health conditions were anxiety
health state utilities were compared with paired t-tests. (n ¼ 57, 18.5%), depression (n ¼ 45, 15.9%), and hypertension
(n ¼ 33, 10.7%). No participants reported a diagnosis of FCS.
One participant reported knowing somebody with FCS.
Results
Sample characteristics Health state utilities
A total of 318 participants attended interviews. Ten partici-
In the introductory ranking task with health states A through
pants were unable to complete the interview procedures,
D, there was little variation in rank order. In the UK, 203 of
including three in Canada and seven in the UK (i.e. difficulty
the 208 participants (97.6%) ranked the health states from
understanding the TTO task or health states). Therefore, the
most preferable to least preferable in the order A, C, B, D.
The other five UK participants ranked the health states as A,
Table 1. Sample characteristics.
Characteristics UK Canada B, C, D. In Canada, all 100 participants ranked the health
(N ¼ 208) (N ¼ 100) states as A, C, B, D.
Age (Mean, SD) 44.8 (15.23) 47.4 (17.35) Mean utilities of the four chronic states (Table 2) followed
Gender (n, %) logical patterns with more severe FCS associated with lower
Male 104 (50.0%) 50 (50.0%)
Female 104 (50.0%) 50 (50.0%)
utilities. Values ranged from 0.46 to 0.80 in the UK and 0.47
Racial/Ethnic Background (n, %) to 0.83 in Canada. There were no statistically significant dif-
White 148 (71.2%) 88 (88.0%) ferences between the UK and Canada on any of these util-
Mixed 13 (6.3%) 3 (3.0%)
Asian 18 (8.7%) 0 (0.0%) ities. All pairwise comparisons between mean health state
Black 28 (13.5%) 3 (3.0%) utilities (e.g. comparing A to B) were statistically significant
Othera 1 (0.5%) 6 (6.0%) in both the UK and Canada (all p < .0001).
Marital status (n, %)
Single 137 (65.9%) 57 (57.0%) The purpose of the one-year TTO was to estimate the dis-
Married/cohabitating/living with partner 69 (33.2%) 38 (38.0%) utility of an episode of AP, described in health state E (Table
Otherb 2 (1.0%) 5 (5.0%)
Employment status (n, %)
2). An AP episode resulted in disutilities of –0.25 and –0.20
Full-time work 83 (39.9%) 52 (52.0%) when added to health states C and D, respectively. There
Part-time work 57 (27.4%) 10 (10.0%) were no significant differences between the UK and Canada
Otherc 68 (32.7%) 38 (38.0%)
Education level (n, %) on the one-year valuations of health state D with or without
University degree 95 (45.7%) 35 (35.0%) E. The one-year utilities of C were significantly greater in
No university degree 113 (54.3%) 65 (65.0%)
Canada than the UK, both without the addition of E
a
Other self-reported racial/ethnic background in the UK was Persian (n ¼ 1).
Other in Canada included Arab (n ¼ 1), Haitian (n ¼ 1), and unspeci-
(t ¼ –2.17, p ¼ .03) and with E (t ¼ –2.52, p ¼ .01). However,
fied (n ¼ 4). there were no significant differences between the UK and
b
Other self-reported marital status in the UK was engaged (n ¼ 2). Other in Canada in disutilities associated with AP, regardless of
Canada included civil union (n ¼ 1), couple (n ¼ 1), and free union (n ¼ 3).
c
Other self-reported employment status in the UK included apprentice whether C or D was used as the baseline state. All disutilities
(n ¼ 11), business owner (n ¼ 1), care for disabled child (n ¼ 1), disabled were statistically significant (all p < .0001). For example, in
(n ¼ 4), ESA (n ¼ 1), retired (n ¼ 22), self-employed (n ¼ 5), student (n ¼ 18),
the UK, the one-year utility of 0.71 for health state C was sig-
unemployed (n ¼ 14), and 0 h contract (n ¼ 1). Other in Canada included
autonomous (n ¼ 1), business owner (n ¼ 2), disabled (n ¼ 1), homemaker nificantly greater than the value of C with the addition of an
(n ¼ 2), retired (n ¼ 25), student (n ¼ 5), and unemployed (n ¼ 2). AP episode (0.46).

Table 2. Health state utilitiesa.

Mean (SD) utilities Disutility of acute pancreatitis

FCS health states UK Canada Difference between UK Canada
(N ¼ 208) (N ¼ 100) UK and Canada
10-year health states
A: Low TG, no AP 0.80 (0.21) 0.83 (0.18) –0.03 (0.20)
B: High TG, no AP 0.60 (0.33) 0.61 (0.33) –0.02 (0.33)
C: Low TG, previous AP 0.74 (0.23) 0.78 (0.19) –0.04 (0.22)
D: High TG, previous AP 0.46 (0.42) 0.47 (0.36) –0.01 (0.40)
1-year health states
Subgroup rating E relative to C N ¼ 107 N ¼ 48
C without E 0.71 (0.30) 0.80 (0.17) –0.08 (0.27)
C with E (adding an AP event to health 0.46 (0.40) 0.60 (0.28) –0.14 (0.37) –0.25 (0.28) –0.20 (0.20)
state C)
Subgroup rating E relative to D N ¼ 101 N ¼ 52
D without E 0.53 (0.38) 0.57 (0.35) –0.04 (0.37)
D with E (adding an AP event to health state D) 0.33 (0.43) 0.40 (0.34) –0.07 (0.40) –0.20 (0.23) –0.17 (0.16)
Abbreviations. AP, Acute pancreatitis; FCS, Familial chylomicronemia syndrome; SD, Standard deviation; TG, Triglycerides.
a
TTO utilities are on a scale anchored to 0 representing dead and 1 representing full health.
982 L. S. MATZA ET AL.
Most participants were willing to trade time to avoid liv-
ing in the four chronic health states. Only three participants
(1.4%) in the UK and two participants (2.0%) in Canada were
unwilling to trade time to avoid any of the chronic
health states.
In the UK, negative utility scores were rare for health
states A (1.0%), B (3.8%), and C (1.4%). Rates of negative
scores were somewhat higher for health states D (9.6%) and
the valuations of C and D with the addition of AP (9.3% and
14.9%, respectively). Rates of negative utilities were lower in
Canada: A (0%), B (3.0%), C (0%), D (5.0%), C with E (2.1%),
and D with E (7.7%).
Discussion
Results followed expected patterns, with lower utilities for
health states representing more severe FCS as indicated by
higher triglycerides, more severe symptoms, and history of
AP. Utilities and differences between utility scores were simi-
lar in the UK and Canada. There are no previously published
utilities for FCS that can be used for comparison, but the
utility values appear to be in a reasonable range based on
comparison to EQ-5D utilities reported for type 2 diabetes,
another endocrine-related condition41. The higher utilities for
FCS with low triglycerides are in a similar range to previously
published utilities for type 2 diabetes without complications,
while the lower utilities for FCS with high triglycerides are
similar to those of type 2 diabetes with more severe compli-
cations such as peripheral neuropathic pain or retinopathy.
When using the resulting utilities in a CUA, modelers
should be aware of the difference between chronic and tem-
porary health states. Because the four chronic states did not
change over time, the utilities can be applied for any dur-
ation in a model (consistent with constant proportional
trade-off, a key assumption of the QALY model). In a CUA,
these utilities would have to be applied to the proportion of
patients who can be categorized as having either high or
low triglycerides, with or without a history of AP. These pro-
portions will likely vary across models, depending on the
clinical trial or real-world data used as the source of
information.
Unlike the utilities of the four chronic health states, the
disutility of AP is tied to the time horizon of the task
because the AP attack was described as temporary event
that changed over time. These utility decreases associated
with AP represent the impact of AP on a one-year period,
and the disutility should be applied in a model as a QALY
decrement. The AP episode was applied to two health states
(C and D). Anecdotal evidence from previous studies has
suggested that temporary medical events have more impact
on utility when added to milder health states, rather than
more severe states. Current results support this hypothesis.
In both countries, the AP disutility was larger when added to
the milder health state (C) than to the more severe state (D).
Limitations of vignette-based methodology should be
acknowledged. Like most medical conditions, FCS symptoms
range from mild to severe, and utilities derived from
vignettes cannot represent every level of severity. Instead,
the utilities represent preferences for discrete health states
as described in the vignettes, which were drafted to repre-
sent typical patient profiles. The extent to which these util-
ities might differ from values derived from patient-
completed measures such as the EQ-5D or Health Utilities
Index13,42 is unknown. However, methodology was selected
to maximize comparability to standardized utility valuation
methods. For example, chronic health states were valued by
general population participants in a TTO task with a 10-year
time horizon, similar to methods used to derive the original
EQ-5D scoring tariffs43.
One potential risk with some health state vignettes is that
it may be necessary to provide more information than would
be included in health states derived from generic preference-
based instruments. For example, whereas a health state
based on the EQ-5D would have five bullet points, the
length of health states in the current study ranged from five
bullet points to 13 bullet points. Although efforts were made
to keep the health states as brief as possible, more informa-
tion was necessary to capture the ongoing impact of AP in
health states C (10 bullet points) and D (13 bullet points). It
is possible that these longer health states could have intro-
duced reading comprehension and memory difficulties for
some participants. To mitigate these challenges, interviewers
carefully reviewed each bullet point with the respondents to
ensure that they understood and attended to all details. In
addition, illogical rankings and TTO valuations were queried
to ensure that they were based on good comprehension and
actual preference, rather than a misunderstanding of health
state content. In general, it appears that these efforts were
effective because the resulting utilities followed logical pat-
terns. Still, it is possible that some participants may not have
considered or remembered all parts of the two longer health
states when performing the TTO task.
Another methodological limitation is that the health state
vignettes were drafted and refined based on input from a
relatively small number of clinicians and patients. Because
FCS is extremely rare, it is difficult to recruit a large sample
of patients and clinicians with relevant experience.
Furthermore, the patients and clinicians were based in the
US, rather than the UK and Canada, which were the locations
of the subsequent utility valuation study. Because of differen-
ces between the healthcare systems, it is possible that treat-
ment approaches for FCS may vary across these three
countries. In sum, although health states were drafted based
on the best available information, a larger and more geo-
graphically diverse sample of patients and clinicians could
have led to slightly different health states and utility values.
Generalizability of the sample may also be a limitation.
Although efforts were made to avoid over-representing any
group with regard to age, gender, ethnic/racial background,
or employment status, the sample was not recruited to be
nationally representative in either the UK or Canada. Future
research with a larger sample could be conducted to elicit
utilities for FCS that are truly nationally representative.
Despite limitations, this study demonstrates that the
vignette-based approach can be useful for estimating utilities
of rare diseases. This methodology may be considered when

it is not feasible to recruit a large enough patient sample to
derive utilities necessary for economic modeling. The utilities
estimated in this study can be used in models examining the
cost-effectiveness of new treatments for FCS.
Transparency
Declaration of funding
This study was funded by Akcea Therapeutics.
Declaration of financial/other relationships
Louis Matza and Timothy Howell are employees of Evidera, a company
that received funding from Akcea for time spent conducting this
research. Glenn Phillips was an employee of Akcea Therapeutics at the
time this study was conducted, including the time when this manuscript
was drafted. Nicole Ciffone and Zahid Ahmad received funding from
Akcea for time spent on this research.
A peer reviewer on this manuscript has disclosed that they have
been involved in clinical trials of volanesorsen sponsored by Akcea and
that their institution has received payments for their attendance at
advisory board meetings. The peer reviewers on this manuscript have
no other relevant financial relationships or otherwise to disclose.
Author contributions
LM and GP co-directed the study including study design, health state
development, data analysis, and data interpretation. TH directed proto-
col development and the data collection, while assisting with health
state development. NC and ZA provided clinical input to help shape the
study design, health states, methods, protocol, and interpretation. LM
and TH drafted the manuscript, and all other authors provided input
and approval.
Acknowledgements
The authors would like to thank Hayley Karn and Gordon Parola for
assistance with the pilot study; Haylee Andrews, Ella Brookes,
Christopher Langelotti, and Natalie Taylor for assistance with participant
recruitment; Kristen Deger, Meredith Hoog, Christopher Langelotti,
Haylee Andrews, Melissa Garcia, and Ella Brookes for assistance with the
UK data collection; Beenish Nafees, Carole Charland, Karen Hofman, and
Matthew Sparks for assistance with the Canadian data collection;
Benjamin Arnold and the FACITtrans team for performing the transla-
tions; Ray Hsieh and Christine Thompson for statistical programming;
and Amara Tiebout for editorial support.
Ethics compliance
Ethical Approval/Informed Consent: All procedures performed in this
study were in accordance with the ethical standards of the institutional
and/or national research committee and with the 1964 Helsinki declar-
ation and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included
in the study.
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