Quality of Life Measures in Clinical Trials

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Quality of Life MeasuresinClinical Trials

• George A Wells
• Department of Epidemiology and Community Medicine
• University of Ottawa

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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

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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

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Statistical Aspects

• Levels of Measurement
• nominal, ordinal, interval
• discrete, continuous

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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

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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

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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)

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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

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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

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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

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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

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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

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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

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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

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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

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Domains Important in Measuring Quality of Life

• Schipper Levitt
• physical / occupational functioning
• psychological functioning
• sociability
• somatic comfort

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Domains Important in Measuring Quality of Life

• Aaronson
• disease, symptoms and treatment s/e
• psychological functioning
• sociability
• somatic comfort

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Domains Important in Measuring Quality of Life

• Bonomi et al
• physical
• independence
• social
• psycological
• spiritual
• environmental

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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

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Consensus Domains in Measuring Quality of Life

• Physical function
• Emotional / psychological function
• Social
• Symptoms of disease and treatment

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Influences on Quality of Life

• 1) gender
• 2) culture
• 3) disease specific
• 4) spiritual
• 5) age

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Properties of Quality of Life

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

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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

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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

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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

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Health Measurement

• Reliability
• Validity
• Sensitivity to Change

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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

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Reliability
The reliability coefficient expresses the
proportion of the total variance in the
measurements (denominator), which is due to true
differences between subjects (numerator)
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Reliability

• Reproducibility
• Test-retest reliability
• Intra-rater reliability
• Inter-rater reliability
• Internal consistency of a scale (correlation
  among items composing an instrument)

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Reliability Reproducibility

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

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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

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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

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Reliability Reproducibility

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

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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

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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)

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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

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Validity

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

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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

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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

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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

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Validity

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

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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

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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

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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

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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)

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Generic versus Specific

• SIP
• behaviourally based measure of health status
• 136 items
• 12 categories

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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

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Generic versus Specific

• QL and EORTC-QLQ
• cancer

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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

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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

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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

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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

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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

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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

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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?)

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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

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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

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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)