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					Quality of Life Measures
     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

• Choosing efficacy parameters: types of
        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
 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
   – 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

• 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 …

  “… 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.”

  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 …

 “… impact of disease and treatment on disability and daily
 functioning …”

 “… physical, emotional, social well-being after disease and
 treatment … ”

 ”… 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…”

  “… 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 …

 “… 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

 – 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.,

•    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

•    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 /

•   Calman‟s principle
      •   gap between patients‟ expectations and
      •   gap between patients actual achievements and
   Quality of Life Endpoints in Clinical

• 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

Reflection of the amount of error, both
   random (mechanical inaccuracy,
   measurement mistakes) and
   systematic, inherent to any

Determines how reproducible is the scale
   under different conditions

   Reliabilit y
                  Subject variabilit y
       Subject variabilit y  Measuremen error
      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)

•   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       2
                              obs     err
        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


                     pat   err / k
                      2       2
    Reliability: Internal Consistency

•    Represents the average of the
     correlations among all items in the

•    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
    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
     •   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

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

•   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

•   Construct
           •   if no gold standard exists
           •   based on conceptual definition of construct to be
           •   defines hypotheses of what should or should not

    •   Correlational

           • instrument tested should correlate with other
              methods that measure same concept

           • instrument should not correlate with other
              methods that measure different themes

•   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

•   Evaluation using:

    •   Correlations

    •   Receiver operator characteristic (ROC)

    •   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

                        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

• 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


   Instrument designed to assess health related
      quality of life in a broad range of


   Instrument designed for specific disease
        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
    •   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

• specific indices are more responsive to
• generic indices give importance on overall
       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)

   •    Generic: SIP and Time Trade Off
   •    Specific: Kidney Disease Questionnaire (KDQ)
   •    interview with patients
   •    ranked by 50 hemodialysis patients
   •    KDQ was most responsive to change (especially
        fatigue, physical symptoms)
   •    SIP improved a little (aggregate global, physical; not
   •    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

• 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

  •   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
   Advantages and Disadvantages in
       Clinical Trial Research

  •   Investigator resistance
        •   patient generated data may not be accepted by
        •   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

  •   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

  •   Interpretation
        •   output not user friendly
            • scores (CES-D)
            • norms

        •   are results accurate / comparable between
             • 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

    (Paltiel and Stinnett, In: Quality of Life and
    Pharmacoeconomics in Clinical Trials, Second
    edition, B. Spilker (editor)) important changes in
            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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