Neurotherapeutics (2017) 14:934–944
DOI 10.1007/s13311-017-0571-6
REVIEW
Evolution of Patient-Reported Outcomes and Their
Role in Multiple Sclerosis Clinical Trials
Cindy J. Nowinski 1 & Deborah M. Miller 2 & David Cella 1
Published online: 14 September 2017
# The American Society for Experimental NeuroTherapeutics, Inc. 2017
Abstract Patient-reported outcomes (PROs) are playing an Keywords Patient-reported outcomes . Health-related quality
increasing role in multiple sclerosis (MS) research and practice, of life . Multiple sclerosis . Clinical trials
and are essential for understanding the effects that MS and MS
treatments have on patients’ lives. PROs are captured directly
from patients and include symptoms, function, health status, Patient-reported outcomes (PROs) refer to direct patient re-
and health-related quality of life. In this article, we review dif- ports of their experience with a disease and its treatment.
ferent categories (e.g., generic, targeted, preference-based) of PROs are a subset of the broader concept of Bpatient-generat-
PRO measures and considerations in selecting a measure. The ed outcomes^ that refer to the full range of health information
PROs included in MS clinical research have evolved over time, provided by patients about themselves, which can include
as have the measures used to assess them. We describe findings demographic information, prior history, and so on. PROs are
from recent MS clinical trials that included PROs when evalu- obtained via Breport of the status of a patient’s health condition
ating Food and Drug Administration-approved disease-modify- that comes directly from the patient, without interpretation of
ing therapies (e.g., daclizumab, teriflunomide). Variation in the the patient’s response by a clinician or anyone else^ [1]. PROs
measures used in these trials makes it difficult to draw any include symptoms, functional level, health status, health util-
conclusions from the data. We therefore suggest a standardized ity, and health-related quality of life (HRQoL). By their very
approach to PRO assessment in MS research and describe 2 nature, PROs are patient-centered and their addition to tradi-
generic, National Institutes of Health-supported measurement tionally collected anatomical, biological, and clinical data has
systems [Neuro-QoL and the Patient-Reported Outcomes resulted in a fundamental shift in how research and clinical
Measurement Information System (PROMIS)] that would fa- practice are conducted. This article presents an overview of
cilitate such an approach. The use of PROs in MS care and PRO assessment, how its inclusion in multiple sclerosis (MS)
research is expanding beyond clinical trials, as is demonstrated clinical research has evolved over time, and directions for the
by examples from comparative effectiveness and other patient- future.
centered research. The importance of PRO assessment is ex- MS is a chronic progressive disease that usually manifests
pected to continue to grow in the future. in young adulthood. It has limited impact on life expectance.
There is no typical course to disease progression and MS
Electronic supplementary material The online version of this article produces a myriad of symptoms that can occur at any time
(https://doi.org/10.1007/s13311-017-0571-6) contains supplementary and in different combinations. MS is not a curable disease;
material, which is available to authorized users. treatment tends to focus on symptom management, limiting
disease progression with the use of disease-modifying drugs
* Cindy J. Nowinski (DMDs), and maximizing quality of life. MS research, then,
must include evaluation of how well interventions achieve
these goals. As patients appreciate the totality of their disease
1
Northwestern University Feinberg School of Medicine, Chicago, IL, experience, these goals can best be defined with their input. In
USA addition, patient perceptions frequently differ from those of
2
Mellen Center, Cleveland Clinic, Cleveland, OH, USA clinicians [2–5]. Assessment of patient functioning in the
, Evolution of Patient-Reported Outcomes and Their Role in Multiple Sclerosis Clinical... 935
treatment setting, however well measured, may not accurately Multidimensional, or profile measures, typically provide separate
reflect their functioning at home [6]. Thus, PROs are generally scores for each dimension rather than a summary score. Some,
accepted as important to assess in clinical research for most such as the FAMS, provide both individual dimension scores and
chronic conditions [7, 8], including MS (see the proceedings a total summary score.
from the annual meetings of the International Society for
Quality of Life Research) [9–11]. Further, PROs are increas-
ingly seen as supporting every aspect of the healthcare con- Health Utility Measures
tinuum from research to clinical practice (including clinical
decision-making and quality reporting) through to public Health utility measures are a special type of PRO derived from
health [12–16]. economic and decision theory. Utility measures cover multiple
health domains but provide a single summary score. This score
reflects patient preferences for different health states, with higher
Approaches to PRO Assessment preferences signifying greater value or desirability. Scores typi-
cally range from 0 (death) to 1 (perfect health), although negative
Most PRO measures are categorized as either generic or targeted. numbers (states worse than death) are possible. Utility scores
Generic measures include questions that are general enough for can be used to compute quality-adjusted survival, measured in
use with both healthy and clinical populations. Generic measures quality-adjusted life years (QALYs), by supplying the Bquality^
used in MS include the Medical Outcomes Study Short Form-36 component of the equation. QALYs combine both mortality
(SF-36) [17], the Sickness Impact Profile [18], and versions of (survival) and morbidity (HRQoL) into a single index [35,
the Health Utilities Index [19]. Targeted measures are comprised 36], applicable across diseases and interventions. QALYs are
of questions aimed towards specific diseases (e.g., MS), domains frequently used in cost-effectiveness and similar analyses to
(e.g., cognition, fatigue), or interventions (e.g. use of biological help guide resource allocation. Commonly used generic utility
response modifiers). Examples of symptom-focused, domain- measures include the EQ-5D [37], the Quality of Well-Being
specific measures include the Brief Pain Inventory [20], and the scale [38], and the Health Utility Index [39, 40]. However,
pain, fatigue, depression, sleep, and other symptom measures generic health utility measures have been criticized for being
included in the Patient-Reported Outcomes Measurement insensitive to treatment effects and/or failing to adequately cov-
Information System (PROMIS) and the Neurology Quality of er all relevant dimensions for a given condition [41]. This has
Life (Neuro-QoL) measurement system. Disease-specific mea- led to efforts to develop disease- or condition-specific utility
sures for MS are numerous, and include the Multiple Sclerosis measures such as the 15D [42] and the Multiple Sclerosis
International Quality of Life (MusiQoL) [21], the Multiple Impact Scale – Eight Dimensions [43, 44].
Sclerosis Quality of Life-54 (MSQOL-54) [22], the Functional
Assessment of Multiple Sclerosis (FAMS) [23], the Multiple
Sclerosis Impact Scale (MSIS-29) [24], the Patient Reported Item Response Theory and PRO Assessment
Impact of Multiple Sclerosis (PRIMUS) [25], the Hamburg
Quality of Life Questionnaire in Multiple Sclerosis [26], the In recent years, PROs have begun to incorporate modern mea-
MS Quality of Life Inventory [27], the Multiple Sclerosis surement science [e.g., item response theory (IRT)] into their
Impact Profile [28], the Leeds Multiple Sclerosis Quality of development. Utilization of IRT provides the instruments with
Life scale [29], the Disability and Impact Profile [30], and the certain advantages, including the ability to be brief while remain-
RAYS scale [31]. Some PRO measures, like the Disability and ing precise and valid [45]. Using IRT methodology, sets of ques-
Impact Profile, also incorporate patients’ perceptions of how im- tions (items) are calibrated along a continuum that covers the full
portant each effect of MS is on their lives. Generic PROs, usually range of the construct to be measured. Once calibrated, any or all
normed against general/healthy populations, are appropriate for items in this Bbank^ can be used to generate a score. Users can
cross-disease comparisons, and are useful in resource allocation select specific items to create Bshort forms^ (SFs), typically
and cost-effectiveness analyses. In contrast, targeted measures consisting of 6 to 8 questions that meet their measurement needs.
can provide more in-depth and comprehensive coverage of a For example, a user wishing to assess upper extremity function in
specific domain or area, are thought to be more sensitive to a group of patients who tended to have poor or very poor fine
changes in health status or function, and questions may seem motor abilities could create a custom SF primarily comprised of
more relevant and therefore more acceptable to patients [32]. those items targeting lower levels of upper motor function that
This has led to recommendations for using a combined approach cluster near the lower end of that bank. Item banks are also the
(generic and targeted) when feasible [33, 34]. The MSQOL-54, basis for computerized adaptive testing (CAT). This is a special-
for example, includes the generic SF-36 along with 18 MS- ized type of computer-based testing in which, after the initial item
specific questions. PROs also differ in whether they measure a is presented, the test administration algorithm selects each item to
single dimension of health or multiple dimensions. be presented based on the response to the previous
DOI 10.1007/s13311-017-0571-6
REVIEW
Evolution of Patient-Reported Outcomes and Their
Role in Multiple Sclerosis Clinical Trials
Cindy J. Nowinski 1 & Deborah M. Miller 2 & David Cella 1
Published online: 14 September 2017
# The American Society for Experimental NeuroTherapeutics, Inc. 2017
Abstract Patient-reported outcomes (PROs) are playing an Keywords Patient-reported outcomes . Health-related quality
increasing role in multiple sclerosis (MS) research and practice, of life . Multiple sclerosis . Clinical trials
and are essential for understanding the effects that MS and MS
treatments have on patients’ lives. PROs are captured directly
from patients and include symptoms, function, health status, Patient-reported outcomes (PROs) refer to direct patient re-
and health-related quality of life. In this article, we review dif- ports of their experience with a disease and its treatment.
ferent categories (e.g., generic, targeted, preference-based) of PROs are a subset of the broader concept of Bpatient-generat-
PRO measures and considerations in selecting a measure. The ed outcomes^ that refer to the full range of health information
PROs included in MS clinical research have evolved over time, provided by patients about themselves, which can include
as have the measures used to assess them. We describe findings demographic information, prior history, and so on. PROs are
from recent MS clinical trials that included PROs when evalu- obtained via Breport of the status of a patient’s health condition
ating Food and Drug Administration-approved disease-modify- that comes directly from the patient, without interpretation of
ing therapies (e.g., daclizumab, teriflunomide). Variation in the the patient’s response by a clinician or anyone else^ [1]. PROs
measures used in these trials makes it difficult to draw any include symptoms, functional level, health status, health util-
conclusions from the data. We therefore suggest a standardized ity, and health-related quality of life (HRQoL). By their very
approach to PRO assessment in MS research and describe 2 nature, PROs are patient-centered and their addition to tradi-
generic, National Institutes of Health-supported measurement tionally collected anatomical, biological, and clinical data has
systems [Neuro-QoL and the Patient-Reported Outcomes resulted in a fundamental shift in how research and clinical
Measurement Information System (PROMIS)] that would fa- practice are conducted. This article presents an overview of
cilitate such an approach. The use of PROs in MS care and PRO assessment, how its inclusion in multiple sclerosis (MS)
research is expanding beyond clinical trials, as is demonstrated clinical research has evolved over time, and directions for the
by examples from comparative effectiveness and other patient- future.
centered research. The importance of PRO assessment is ex- MS is a chronic progressive disease that usually manifests
pected to continue to grow in the future. in young adulthood. It has limited impact on life expectance.
There is no typical course to disease progression and MS
Electronic supplementary material The online version of this article produces a myriad of symptoms that can occur at any time
(https://doi.org/10.1007/s13311-017-0571-6) contains supplementary and in different combinations. MS is not a curable disease;
material, which is available to authorized users. treatment tends to focus on symptom management, limiting
disease progression with the use of disease-modifying drugs
* Cindy J. Nowinski (DMDs), and maximizing quality of life. MS research, then,
must include evaluation of how well interventions achieve
these goals. As patients appreciate the totality of their disease
1
Northwestern University Feinberg School of Medicine, Chicago, IL, experience, these goals can best be defined with their input. In
USA addition, patient perceptions frequently differ from those of
2
Mellen Center, Cleveland Clinic, Cleveland, OH, USA clinicians [2–5]. Assessment of patient functioning in the
, Evolution of Patient-Reported Outcomes and Their Role in Multiple Sclerosis Clinical... 935
treatment setting, however well measured, may not accurately Multidimensional, or profile measures, typically provide separate
reflect their functioning at home [6]. Thus, PROs are generally scores for each dimension rather than a summary score. Some,
accepted as important to assess in clinical research for most such as the FAMS, provide both individual dimension scores and
chronic conditions [7, 8], including MS (see the proceedings a total summary score.
from the annual meetings of the International Society for
Quality of Life Research) [9–11]. Further, PROs are increas-
ingly seen as supporting every aspect of the healthcare con- Health Utility Measures
tinuum from research to clinical practice (including clinical
decision-making and quality reporting) through to public Health utility measures are a special type of PRO derived from
health [12–16]. economic and decision theory. Utility measures cover multiple
health domains but provide a single summary score. This score
reflects patient preferences for different health states, with higher
Approaches to PRO Assessment preferences signifying greater value or desirability. Scores typi-
cally range from 0 (death) to 1 (perfect health), although negative
Most PRO measures are categorized as either generic or targeted. numbers (states worse than death) are possible. Utility scores
Generic measures include questions that are general enough for can be used to compute quality-adjusted survival, measured in
use with both healthy and clinical populations. Generic measures quality-adjusted life years (QALYs), by supplying the Bquality^
used in MS include the Medical Outcomes Study Short Form-36 component of the equation. QALYs combine both mortality
(SF-36) [17], the Sickness Impact Profile [18], and versions of (survival) and morbidity (HRQoL) into a single index [35,
the Health Utilities Index [19]. Targeted measures are comprised 36], applicable across diseases and interventions. QALYs are
of questions aimed towards specific diseases (e.g., MS), domains frequently used in cost-effectiveness and similar analyses to
(e.g., cognition, fatigue), or interventions (e.g. use of biological help guide resource allocation. Commonly used generic utility
response modifiers). Examples of symptom-focused, domain- measures include the EQ-5D [37], the Quality of Well-Being
specific measures include the Brief Pain Inventory [20], and the scale [38], and the Health Utility Index [39, 40]. However,
pain, fatigue, depression, sleep, and other symptom measures generic health utility measures have been criticized for being
included in the Patient-Reported Outcomes Measurement insensitive to treatment effects and/or failing to adequately cov-
Information System (PROMIS) and the Neurology Quality of er all relevant dimensions for a given condition [41]. This has
Life (Neuro-QoL) measurement system. Disease-specific mea- led to efforts to develop disease- or condition-specific utility
sures for MS are numerous, and include the Multiple Sclerosis measures such as the 15D [42] and the Multiple Sclerosis
International Quality of Life (MusiQoL) [21], the Multiple Impact Scale – Eight Dimensions [43, 44].
Sclerosis Quality of Life-54 (MSQOL-54) [22], the Functional
Assessment of Multiple Sclerosis (FAMS) [23], the Multiple
Sclerosis Impact Scale (MSIS-29) [24], the Patient Reported Item Response Theory and PRO Assessment
Impact of Multiple Sclerosis (PRIMUS) [25], the Hamburg
Quality of Life Questionnaire in Multiple Sclerosis [26], the In recent years, PROs have begun to incorporate modern mea-
MS Quality of Life Inventory [27], the Multiple Sclerosis surement science [e.g., item response theory (IRT)] into their
Impact Profile [28], the Leeds Multiple Sclerosis Quality of development. Utilization of IRT provides the instruments with
Life scale [29], the Disability and Impact Profile [30], and the certain advantages, including the ability to be brief while remain-
RAYS scale [31]. Some PRO measures, like the Disability and ing precise and valid [45]. Using IRT methodology, sets of ques-
Impact Profile, also incorporate patients’ perceptions of how im- tions (items) are calibrated along a continuum that covers the full
portant each effect of MS is on their lives. Generic PROs, usually range of the construct to be measured. Once calibrated, any or all
normed against general/healthy populations, are appropriate for items in this Bbank^ can be used to generate a score. Users can
cross-disease comparisons, and are useful in resource allocation select specific items to create Bshort forms^ (SFs), typically
and cost-effectiveness analyses. In contrast, targeted measures consisting of 6 to 8 questions that meet their measurement needs.
can provide more in-depth and comprehensive coverage of a For example, a user wishing to assess upper extremity function in
specific domain or area, are thought to be more sensitive to a group of patients who tended to have poor or very poor fine
changes in health status or function, and questions may seem motor abilities could create a custom SF primarily comprised of
more relevant and therefore more acceptable to patients [32]. those items targeting lower levels of upper motor function that
This has led to recommendations for using a combined approach cluster near the lower end of that bank. Item banks are also the
(generic and targeted) when feasible [33, 34]. The MSQOL-54, basis for computerized adaptive testing (CAT). This is a special-
for example, includes the generic SF-36 along with 18 MS- ized type of computer-based testing in which, after the initial item
specific questions. PROs also differ in whether they measure a is presented, the test administration algorithm selects each item to
single dimension of health or multiple dimensions. be presented based on the response to the previous
