Quality of Life Measures
in
Clinical Trials
George A Wells
Department of Epidemiology
and Community Medicine
University of Ottawa
Outcome Measures
• Hard vs soft outcomes
• Ranges of outcomes and their assessment
• Statistical aspects
• Criteria for development and selection of
outcomes
• Choosing efficacy parameters: types of
endpoints
Patients desire the following…
1) to live as long as possible [death]
2) to be normally functioning [disability]
3) to be free of pain, psycological,
physical, social and other
symptoms [discomfort]
4) to be free of iatrogenic
problems from treatments [drug s/e]
5) to remain solvent [destitution]
Statistical Aspects
Levels of Measurement
– nominal, ordinal, interval
– discrete, continuous
… Statistical Aspects
Relating two numbers (x,y)
– incremental change x-y
– proportional change (x-y)/y
– percent change 100 (x-y)/y
– proportion (of baseline) x/y
– percent (of baseline) 100 x/y
Criteria for Development and Selection
of Outcomes
Comprehensive (content validity)
- includes appropriate components of health
Credibility (face validity)
- appears sensible and interpretable
Accuracy (criterion validity)
- consistently reflects true clinical status of patients
Sensitivity to change (discriminant validity)
- detects smallest clinically important difference
Biological sense (construct validity)
- matches hypothesized expectations when compared
with other indirect measures
Choosing Efficacy Parameters: Types
of Endpoints
• objective measurements (validated and accepted to
represent appropriate efficacy criteria)
• reduced or reversed disease progression
• improved quality of life
• reduced mortality
• clinical global impression (physician, patient)
• improved symptomatology of patient
• biochemical measures (assessing underlying disease state)
Identifying the best endpoints …
• influence physicians‟ decision
• combination of outcomes that‟s most practical
and useful
• hard measurement
• change in endpoint that would be clinically
significant
Identifying the best endpoints …
• References to quality of life
– 1966-74 40 references
– 1986-99 >10,000 references
• FDA has 2 requirements for approving anticancer
drugs:
– improve survival
– increase quality of life
• Quality of life has been the focus of
– numerous questionnaires and measurement instruments
– many articles and conferences
– policy
– (increasingly) outcome in clinical trials
Quality of Life Endpoints in Clinical
Trials
• What is quality of life
• Health measurement scales and
quality of life
• Generic versus specific quality of life
• Advantages and disadvantages of
quality of life measures
What is quality of life …
Aristotle
“… when it comes to saying in what happiness consists,
opinions differ and the account given by the generality of
mankind is not at all like that of the wise. The former take it
to be something obvious and familiar, like pleasure or
money or eminence and there are various other views, and
often the same person actually changes his opinion. When
he falls ill he says that it is health and when he is hard up
he says it is money.”
Pigou
first coined the term QOL in 1920 in a book on economics
and welfare
What is quality of life …
World Health Organization (1948)
Redefined health … “state of complete physical, mental and
social well-being and not merely the absence of disease”
Report on the President‟s Commission on
National Goals in the United States (1960)
“… to examine the quality of individual‟s lives”
Elkington (1966)
Editorial: Medicine and the Quality of Life
… a single definition of quality of life remains elusive
What is quality of life …
Kaplan
“… impact of disease and treatment on disability and daily
functioning …”
Greer
“… physical, emotional, social well-being after disease and
treatment … ”
Burlinger
”… impact of perceived health on an individual‟s ability to
live a fulfilling life …”
What is quality of life …
Cella and Tulsky
“… patients appraisal of and satisfaction with their current
level of functioning compared to what they perceive to be
possible or ideal…”
Spilker
“… the functional effect of an illness and its consequent
therapy upon a patient as perceived by the patient …”
Patrick and Erickson
”… the value assigned to opportunity, perceptions,
functional states, impairment and death, associated with
events or conditions as influenced by disease, injuries,
treatment or policy …”
What is quality of life …
Williams
“… individuals perceptions of their position in life in the
context of culture and value systems in which they live and
in relations to their goals, expectations, standards and
concerns …”
Common theme:
Patient centred and subjective
Domains Important in Measuring
Quality of Life
Schipper & Levitt
– physical / occupational functioning
– psychological functioning
– sociability
– somatic comfort
…Domains Important in Measuring
Quality of Life
Aaronson
– disease, symptoms and treatment s/e
– psychological functioning
– sociability
– somatic comfort
…Domains Important in Measuring
Quality of Life
Bonomi et al
– physical
– independence
– social
– psycological
– spiritual
– environmental
…Domains Important in Measuring
Quality of Life
Cella & Tulsky
– physical concerns
– functional ability
– family well being
– emotional well-being
– spirituality
– social functioning
– treatment satisfaction
– future orientation (planning, hope)
– sexuality / intimacy
– occupational functioning
Consensus Domains in Measuring
Quality of Life
– Physical function
– Emotional / psychological function
– Social
– Symptoms of disease and treatment
Influences on Quality of Life
1) gender
2) culture
3) disease specific
4) spiritual
5) age
Properties of Quality of Life
1) multi-factorial / dimensions
2) subjective
3) time sensitive
4) patient centred
5) patients as their own control
Approaches / Concepts Used in
Defining Quality of Life
• Psychological approach
• QOL reflects patients‟ perceived illness side of
the distinction between illness and disease (eg.,
hypertension)
• Time-trade off utility concept
• QOL is defined by patients‟ willingness to trade-
off years of life for suboptimal life
• does not account for concepts such as
adaptation
• Ware‟s community centred concept
• QOL is defined by the „ripple‟ effect of health
events and interventions on the patients‟
…Approaches / Concepts Used in
Defining Quality of Life
• Reintegration concept
• reorganization of physical, psychological and
social characteristics of an individual into a
harmonious whole so that well adjusted living
can be resumed after incapacitating illness /
trauma
• Calman‟s principle
• gap between patients‟ expectations and
achievements
• gap between patients actual achievements and
potential
Quality of Life Endpoints in Clinical
Trials
• What is quality of life
• Health measurement scales and
quality of life
• Generic versus specific quality of life
• Advantages and disadvantages of
quality of life measures
Health Measurement
• Reliability
• Validity
• Sensitivity to Change
Reliability
Reflection of the amount of error, both
random (mechanical inaccuracy,
measurement mistakes) and
systematic, inherent to any
measurement
Determines how reproducible is the scale
under different conditions
Reliability
Reliabilit y
Subject variabilit y
Subject variabilit y Measuremen error
t
2
σs
2 2
σ s σε
The reliability coefficient expresses the proportion
of the total variance in the measurements
(denominator), which is due to true differences
between subjects (numerator)
Reliability
• Reproducibility
• Test-retest reliability
• Intra-rater reliability
• Inter-rater reliability
• Internal consistency of a scale
(correlation among items composing
an instrument)
Reliability: Reproducibility
• Intra-class correlation (ICC)
• (based on ANOVA)
• Pearson‟s r
• Kendall‟s index of concordance
• Kappa coefficient
• Bland and Altman
Reliability: Reproducibility
• Other considerations:
• Observations as fixed factor
• test always done by same observers
• same items completed by all
• Observations as random factor
• observer varies
2
R 2
pat
pat 2
obs err
2
Reliability: Reproducibility
• Other considerations (cont‟d):
• Observer nested within subject
• several subjects evaluated by several observers
• no observer common to more than one subjects
• One-way ANOVA
• subject as grouping factor
• multiple observations within each cell as
„within-subject‟ factor
Reliability: Reproducibility
• Other considerations (cont‟d):
• multiple observations k
• multiple items on questionnaire
• multiple observers
• repeated use of an instrument
2
R
pat
pat err / k
2 2
Reliability: Internal Consistency
• Represents the average of the
correlations among all items in the
measure
• All the items should be „tapping‟
different aspects of the same attribute
• items should be moderately correlate with
each other
• each should correlate with the total scale
score
Reliability: Internal Consistency
• Item-total correlation
• checks homogeneity of scale
• correlation of individual item with scale score
omitting that item
• Pearson correlation (working rule: >0.2)
• Split-half reliability
• splits scale in half, each half is correlated with the
other
• Spearman-Brown
• Kuder-Richardson 20
• scales with dichotomous items
• Cronbach‟s aplha
• scales with ordinal items
• should be >0.70 but <0.90 (item redundancy)
Reliability: Improving IT
• Reduce error variance
• observer training
• elimination of extreme observers
• improve scale design
• Increase true variance
• introduce items resulting in performance
nearer middle of scale
• modify descriptors on the scale
• Increase number of items
• as long as items not perfectly correlated
Validity
Determine the degree of confidence we
can place on inferences made based
on the scores from the scale
Validity
• Content
• cover all domains of interest
• sufficient number of items
• inferred from experts
• Criterion
• test against a „gold‟ standard
• Concurrent
• gold standard and the new instrument are
applied at the same time
• Predictive
• Gold standard is applied in the future
Validity
• Construct
• if no gold standard exists
• based on conceptual definition of construct to be
measured
• defines hypotheses of what should or should not
correlate
• Correlational
Convergent
• instrument tested should correlate with other
methods that measure same concept
Divergent
• instrument should not correlate with other
methods that measure different themes
Validity
• Construct (cont‟d)
• Factorial analysis
– examines how items measure one or more
common themes
– analysis forms the questions into groups or
factors that appear to measure common themes
with each factor distinct from the others
• Multi-trait multi-method analysis
– method for considering convergent and
discriminant validity simultaneously
Validity
• Evaluation using:
• Correlations
• Receiver operator characteristic (ROC)
curves
• 2x2 tables (sensitivity and specificity)
Sensitivity to Change
Ability of an instrument to detect small
but clinically important clinical
Particularly important where subjective
reports of health status is one of the
primary outcomes of the trial
Sensitivity to Change
• t-test
• compares means at baseline and follow-up
• Effect-size
• relates changes in mean score (from baseline to
follow-up) to the standard deviation of baseline
score
mean baseline- mean follow - up
Effect size
SD baseline
• ROC
• Evaluate how a given change score can
discriminate between patients who improve from
those who do not
Quality of Life Endpoints in Clinical
Trials
• What is quality of life
• Health measurement scales and
quality of life
• Generic versus specific quality of life
• Advantages and disadvantages of
quality of life measures
Generic versus Specific
Generic
Instrument designed to assess health related
quality of life in a broad range of
populations
Specific
Instrument designed for specific disease
condition
Generic versus Specific
Examples: Generic
Sickness Impact Profile (SIP)
Rand-36 Item Health Status Profile (SF-36)
Examples: Specific
Spitzer Quality of Life Index (QL)
European Organization for Research and Treatment of
Cancer Quality of Life (EORTC-QLQ)
Generic versus Specific
• SIP
• behaviourally based measure of health
status
• 136 items
• 12 categories
Generic versus Specific
• SF-36
• 36 items
• 8 domains (health concepts):
• Physical functioning
• Bodily pain
• Role limitation due to physical problems
• Role limitation due to emotional problems
• General mental health
• Social functioning
• Energy / fatigue
• General health perception
• 2 component scores:
• Physical component score
• Mental component score
Generic versus Specific
• QL and EORTC-QLQ
• cancer
Generic versus Specific
Why use Generic or specific?
• developed for appropriate population
• differential weights given to each category
• differential selection of categories
Consequence:
• specific indices are more responsive to
change
• generic indices give importance on overall
well-being
Generic versus Specific
The use of generic and specific quality of life measures
in hemodialysis patients treated with erythropoietin
(Laupacis & Wong, Cont Clin Trials, 1991)
Instruments
• Generic: SIP and Time Trade Off
• Specific: Kidney Disease Questionnaire (KDQ)
Methods
• interview with patients
• ranked by 50 hemodialysis patients
Results
• KDQ was most responsive to change (especially
fatigue, physical symptoms)
• SIP improved a little (aggregate global, physical; not
psychosocial)
• Time Trade Off no improvement
Generic versus Specific
The MACTAR Patient Preference Disability
Questionnaire – an individualized
functional priority approach for assessing
improvements in physical siability in
clinical trials of rheumatoid arthritis
(Tugwell et al, J Rheum, 1987)
“Comparison against global improvement
suggests that this instrument has the
potential to detect small clinically
important changes in function”
Quality of Life Endpoints in Clinical
Trials
• What is quality of life
• Health measurement scales and
quality of life
• Generic versus specific quality of life
• Advantages and disadvantages of
quality of life measures
Advantages and Disadvantages in
Clinical Trial Research
Advantages:
• Applicable to all phases of trial assessment
• screening
• planning therapy / decision making
• longitudinal monitoring
• quality of care
• Allows for a broader assessment of
intervention impact on study subject
• well being
• emotional function
• physical function
• sleep
• sexual function
• side effects
Advantages and Disadvantages in
Clinical Trial Research
Advantages (con‟d):
• Involves subject in study
• empowerment and sense of contribution will
enhance adherence to protocol
• help create a sense of participation instead of
„guinea pig‟ role
• longitudinal monitoring
• quality of care
• Ease of administration
• cost
• patient administered
Advantages and Disadvantages in
Clinical Trial Research
Advantages (cont‟d):
• Standardized tool for comparison with
other studies
• Improve likelihood of uptake by
decision makers and health care
providers
Advantages and Disadvantages in
Clinical Trial Research
Disadvantages:
• Investigator resistance
• patient generated data may not be accepted by
investigators
• subjective nature of data may inspire skepticism
• contrary to „dichotomous process‟ of physicians
• Implementation
• burden of data collection
• time and frequency
• costs
• lack of training
• selection of appropriate questionnaire
• administration
Advantages and Disadvantages in
Clinical Trial Research
Disadvantages:
• Utility of Questionnaire
• formalized data collection for health status not a
guarantee that impact on quality of life will truly
be determined
• selection of components which provide will
provide false reflection of interventions impact
• collected data may not provide information that
can be acted on
• measures for specific disease may not be
available to investigator (Is it appropriate to use
generic scales?)
Advantages and Disadvantages in
Clinical Trial Research
Disadvantages:
• Interpretation
• output not user friendly
• scores (CES-D)
• norms
• are results accurate / comparable between
populations
• language, age, race, education etc.
• analysis issues
• what difference is clinically important
• non-linearity
Advantages and Disadvantages in
Clinical Trial Research
“The choice of a quality of life assessment instrument
is often limited by considerations of time, money
and expertise. In the clinical trial setting, for
example, the decision of whether or not to include
a „quality component‟ in the investigation often
boils down to such issues as implementation cost,
brevity of the elicitation process, ease of self-
administration, and required degree of interveiwer
training.”
(Paltiel and Stinnett, In: Quality of Life and
Pharmacoeconomics in Clinical Trials, Second
edition, B. Spilker (editor)) important changes in
function”
Some Suggestions
• Identify an operational definition
• Identify instrument based on relevant domains which
reflect quality of life not just health status
• Require baseline estimates since each patient is their
own control
• Change is important, not just the absolute value
• Quality of life is dynamic and has many influences on
it including time (differentiate intervention from time
dependent changes)