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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

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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 that’s 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 >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


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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 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


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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 individual’s 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

  • Ware’s 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

  • Calman’s 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)

    • Pearson’s r

    • Kendall’s 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 (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


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    Reliability: Reproducibility

    • Other considerations (cont’d):

      • 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: >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)


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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 (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


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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


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    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


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    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


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    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


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    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


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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)


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