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Quality of Life Measures in Clinical Trials

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Title: Quality of Life Measures in Clinical Trials


1
Quality of Life Measures in Clinical Trials
  • George A Wells
  • Department of Epidemiology and Community Medicine
  • University of Ottawa

2
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

3
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

4
Statistical Aspects
  • Levels of Measurement
  • nominal, ordinal, interval
  • discrete, continuous

5
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

6
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

7
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)

8
Identifying the best endpoints
  • influence physicians decision
  • combination of outcomes thats most practical and
    useful
  • hard measurement
  • change in endpoint that would be clinically
    significant

9
Identifying the best endpoints
  • References to quality of life
  • 1966-74 40 references
  • 1986-99 gt10,000 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

10
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

11
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

12
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 Presidents Commission on National
    Goals in the United States (1960)
  • to examine the quality of individuals lives
  • Elkington (1966)
  • Editorial Medicine and the Quality of Life
  • a single definition of quality of life
    remains elusive

13
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 individuals
    ability to live a fulfilling life

14
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

15
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

16
Domains Important in Measuring Quality of Life
  • Schipper Levitt
  • physical / occupational functioning
  • psychological functioning
  • sociability
  • somatic comfort

17
Domains Important in Measuring Quality of Life
  • Aaronson
  • disease, symptoms and treatment s/e
  • psychological functioning
  • sociability
  • somatic comfort

18
Domains Important in Measuring Quality of Life
  • Bonomi et al
  • physical
  • independence
  • social
  • psycological
  • spiritual
  • environmental

19
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

20
Consensus Domains in Measuring Quality of Life
  • Physical function
  • Emotional / psychological function
  • Social
  • Symptoms of disease and treatment

21
Influences on Quality of Life
  • 1) gender
  • 2) culture
  • 3) disease specific
  • 4) spiritual
  • 5) age

22
Properties of Quality of Life
  • 1) multi-factorial / dimensions
  • 2) subjective
  • 3) time sensitive
  • 4) patient centred
  • 5) patients as their own control

23
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
  • Wares community centred concept
  • QOL is defined by the ripple effect of health
    events and interventions on the patients

24
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
  • Calmans principle
  • gap between patients expectations and
    achievements
  • gap between patients actual achievements and
    potential

25
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

26
Health Measurement
  • Reliability
  • Validity
  • Sensitivity to Change

27
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

28
Reliability
The reliability coefficient expresses the
proportion of the total variance in the
measurements (denominator), which is due to true
differences between subjects (numerator)
29
Reliability
  • Reproducibility
  • Test-retest reliability
  • Intra-rater reliability
  • Inter-rater reliability
  • Internal consistency of a scale (correlation
    among items composing an instrument)

30
Reliability Reproducibility
  • Intra-class correlation (ICC)
  • (based on ANOVA)
  • Pearsons r
  • Kendalls index of concordance
  • Kappa coefficient
  • Bland and Altman

31
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

32
Reliability Reproducibility
  • Other considerations (contd)
  • 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

33
Reliability Reproducibility
  • Other considerations (contd)
  • multiple observations k
  • multiple items on questionnaire
  • multiple observers
  • repeated use of an instrument

34
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

35
Reliability Internal Consistency
  • Item-total correlation
  • checks homogeneity of scale
  • correlation of individual item with scale score
    omitting that item
  • Pearson correlation (working rule gt0.2)
  • Split-half reliability
  • splits scale in half, each half is correlated
    with the other
  • Spearman-Brown
  • Kuder-Richardson 20
  • scales with dichotomous items
  • Cronbachs aplha
  • scales with ordinal items
  • should be gt0.70 but lt0.90 (item redundancy)

36
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

37
Validity
  • Determine the degree of confidence we can place
    on inferences made based on the scores from the
    scale

38
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

39
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

40
Validity
  • Construct (contd)
  • 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

41
Validity
  • Evaluation using
  • Correlations
  • Receiver operator characteristic (ROC) curves
  • 2x2 tables (sensitivity and specificity)

42
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

43
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
  • ROC
  • Evaluate how a given change score can
    discriminate between patients who improve from
    those who do not

44
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

45
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

46
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)

47
Generic versus Specific
  • SIP
  • behaviourally based measure of health status
  • 136 items
  • 12 categories

48
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

49
Generic versus Specific
  • QL and EORTC-QLQ
  • cancer

50
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

51
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

52
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

53
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

54
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

55
Advantages and Disadvantages in Clinical Trial
Research
  • Advantages (cond)
  • 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

56
Advantages and Disadvantages in Clinical Trial
Research
  • Advantages (contd)
  • Standardized tool for comparison with other
    studies
  • Improve likelihood of uptake by decision makers
    and health care providers

57
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

58
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?)

59
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

60
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

61
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)
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