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Patient Reported Outcomes

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Title: Patient Reported Outcomes


1
Patient Reported Outcomes
  • Lowell E. Schnipper, M.D.
  • Berenson Professor of Medicine
  • Harvard Medical School
  • Chief, Hematology-Oncology
  • Beth Israel Deaconess Medical Center

2
Question
  • PROs and HRQoL is of diminishing importance in
    the era of emerging targeted therapies?
  • True?
  • False?

3
Patient Reported OutcomesWhy?
  • Cancer often an incurable illness
  • Improvement in patients HRQoL is an expectation
    of appropriate therapy
  • Palliation is often the goal
  • HRQoL is the product of Patient Reported Outcomes

4
Value to the Clinical Trials Process
  • Provide information about toxicity
  • Symptom relief
  • These often are primary or secondary clinical
    trial endpoints
  • In the clinical setting HRQoL assessments can
    have predictive value for survival

5
Subjectivity and Objectivity
  • HRQoL is not subjective in the usual sense of the
    term
  • It can be measured accurately in an individual,
    and in a group
  • It is subjective in that it derives from the
    human subject of research or clinical practice

6
Health-Related Quality of Life (HRQOL) Assessment
1. What is HRQOL? 2. What Should You Measure? 3.
How Should You Measure it? 4. How is it
incorporated into clinical research
7
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8
Health Related Quality of Life (HRQoL)
  • Includes a number of domains
  • Physical functioning ranges from normal to
    complete impairment
  • Psychological well-being (depression, anxiety,
    fear of recurrence)
  • Social functioning

9
P. Ganz, personal communicationt
10
HRQoL Dimensions
  • Physical Functioning Spirituality
  • Occupational/Role Functioning FutureOrientation
  • Social Functioning Sexuality/Intimacy
  • Emotional Well-being
    Health Concerns
  • Symptom Status Family Well-Being
  • Financial Concerns Satisfaction w/Care
  • Global/Overall Perception of Quality of Life

11
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12
HRQOL Assessment
What Should You Measure?
13
Definitions
  • Instrument Questionnaire
  • Item Question
  • Domain Dimension Area of Behavior or
    Experience
  • Cross-Sectional DesignCompares 2 or More
    Populations at One Point in Time
  • Longitudinal DesignAssesses Changes in HRQOL
    Over Time in 1 or More Populations

14
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15
Types of QOL Instruments
  • Health profiles-descriptive questionnaires-measure
    s by a simple metric different aspects of HRQoL
    across multiple domains
  • Generic, multi-dimensional
  • Disease-specific, multi-dimensional
  • Condition-specific, multi-dimensional

16
Functional Status
  • Measure of Functioning

Focus May be Generic or Disease-Specific
17
Domain Specific
Linear Analog Self-Assessment
Place an X at a point on the line that best
represents how you have felt over the past two
weeks.
X
18
Aggregated Scores
Simple Average
Sum or Mean of Item or Subscale Scores to Yield a
Global Score This Approach Weights each Item
Proportional to its Variance in the Population
Under Study Example Quality of Life Index
19
Quality of Life Index
20
Quality of Life Index
21
HRQOL
Functional Status
Symptoms
Global Ratings
22
Symptoms
  • Focus
  • Disease (e.g., asthma, CHF, cancer, lung cancer)
  • Type of symptom (e.g., pain)
  • Dimension(s)
  • Frequency
  • Severity
  • Distress
  • Interference with activities

23
HRQOL
Functional Status
Symptoms
Global Ratings
24
Global Ratings
Single Assessment of Overall Health or HRQOL
Example E-V-G-F-P
How would you describe your overall state of
health CHECK ONE? Excellent Very Good
Good Fair Poor
25
HRQOL Assessment
Why Should You Measure It?
26
HRQOL Value Added
Operational Definition
HRQOL Assessment Adds Value IF HRQOL Data Can
Influence Overall Conclusions of the Study
27
Study Goals
Nature of the Value Added Depends on Overall
Study Goals
  • evaluating the effectiveness of interventions
  • characterizing treatment-specific outcomes for
    use in shared decision making
  • characterizing the burden of illness
  • predicting patient outcomes
  • quality-adjusting survival for resource
    allocation and other policy decisions

28
Question
  • HRQoL is relevant to which type(s) of clinical
    trials
  • Phase I
  • Phase Ib/II
  • Randomized phase II trial
  • Prospective randomized trial
  • All of the above

29
Evaluating Effectiveness
Depends On
1. Phase of the Trial 2. Natural History of
Disease
30
Type of Clinical Trial and PRO
  • Phase I not critical-goal is primarily to define
    MTD or optimal biologic dose
  • Phase II can be used but not essential
  • An opportunity to collect pilot data for use in
    phase III trial
  • Phase III-HRQOL data is essential in this context

31
Tailoring study design to the natural history of
the disease
  • 3 paradigms
  • Chronic and/or recurrent, non-lethal diseases
  • Lethal but curable diseases
  • Lethal, incurable diseases

32
Chronic and/or recurrent, non-lethal diseases
  • Effectiveness
  • relief of disease-related symptoms
  • minimal treatment-related toxicity

33
Chronic and/or recurrent, non-lethal diseases
  • What outcomes do you need?
  • Primary
  • Disease-related symptoms
  • Secondary
  • Treatment-related symptoms
  • Global rating
  • Functional status
  • Utilities (if CEA is planned)

34
Lethal but curable diseases
  • Effectiveness
  • cure rates
  • minimize toxicity

35
Lethal but curable diseases
  • What outcomes do you need?
  • Primary
  • Survival
  • Secondary
  • Utilities (if CEA analysis is planned)
  • treatment-related symptoms, functional status

36
Lethal, incurable diseases
  • Effectiveness
  • palliation
  • prolongation of survival

J. Weeks July 2006
37
Lethal, incurable diseases
  • What outcomes do you need?
  • Primary
  • Survival
  • Functional status
  • Disease-related symptoms
  • Global rating
  • Secondary
  • Utilities (if CEA is planned)

J. Weeks July 2006
38
Supporting SharedDecision Making
Information Patients Need
Nature of Alternative TreatmentsLikely Outcomes
from Treatments Descriptive Information forEach
of the Possible Outcomes simple, transparent
measures
39
Characterizing theBurden of Illness
To Benchmark Study Population generic health
status measures To Identify Patient
Needs domain-specific measuressymptom-specific
measures
40
Predicting Outcomes
Baseline HRQoL has been Shown to be an
Independent Predictor for survival response to
therapy Breast Cancer Lung Cancer functional
status resource use (chronic illness)
41
HRQoL Assessment
How Should You Measure It?
Identify the Respondent patientsurrogateprovider
(MD, RN, other)
42
HRQoL Assessment
How Should You Measure It?
  • Identify the Respondent

Choose the Domains to be Measured disease or
domain-specific instrumentgeneric
instrumentglobal assessment of QoL
43
HRQoL Assessment
How Should You Measure It?
  • Identify the Respondent
  • Choose the Domains to be Measured

Consider the Need for Interpretability health
state descriptionstranslating numeric into
clinical differences
44
HRQoL Assessment
How Should You Measure It?
  • Identify the Respondent
  • Choose the Domains to be Measured
  • Consider Need for Interpretability

Choose a Mode of Administration in person, by
phone, mailedcomputer assisted (in person or
phone)self-administered (forms, computer)
45
HRQoL Instruments
  • Multi-dimensional HRQoL instruments are available
    that cover the basic HRQoL domains
  • Generic
  • Cancer-specific
  • Domain-specific

46
HRQoL Instruments
  • Generic types
  • Intended for use across broad chronic disease
    populations
  • Allow comparisons across these groups
  • Disadvantage may not permit adequate
    cancer-specific focus
  • Disease caused symptoms
  • Treated related symptoms

47
HRQoL Instruments
  • Generic types-examples
  • Medical Outcome Study Short Form Health Survey
    (SF-36) Ware, JE, Med Care (1992)30473-83.
  • EuroQoL (EQ-5D) Health Policy (1990)16199-208.

48
HRQoL Instruments
  • Cancer-specific instruments
  • Responsive to disease-related changes
  • Cannot be used across populations with chronic
    disease
  • Several are in common use because they are
    reliable and have been validated
  • Functional Living Index-Cancer ShipperJCO
    (1984) 2427-483
  • Modular instruments combine a generic or core
    instrument applicable to a broad range of cancer
    patients with cancer-type specific questions
  • FACT-C Gunnars, Acta Oncologica (2001)40175-84.
  • EORTC QLQ-C30, Aaronson JNCI (1993)85365-367.

49
HRQoL Instruments
  • Domain Specific Instruments
  • Designed to address one specific aspect of HRQoL
  • Examples
  • Multi-dimensional Fatigue Inventory (MFI)
  • McGill Pain Questionnaire

50
Uses of HRQoL Instruments
  • Outcome measure
  • RCT evaluating treatment outcomes
  • To qualify quantity of survival
    (e.g.,cost-effectiveness)
  • Assess late physical/psychological problems
  • Predictor
  • Intervention

51
HRQOL Assessment
Other Considerations
  • Is the proposed analysis too taxing for the
    subject?
  • must questionnaire be completed serially in light
    of possible attrition
  • Is a proxy needed?
  • will population include children, low literacy,
    non-English speaking, visually impaired, or
    cognitively impaired adults?

52
HRQOL Assessment
Other Considerations (contd)
  • timing of assessments
  • consistency across patients/groups critical
  • responses influenced by recent experiences
  • missing data
  • avoid at all costs
  • generally cannot be assumed to be at random
  • specify methods for dealing in advance!
  • multiple comparisons
  • specify primary endpoints in advance

53
HRQOL Assessment
Make Your Final Choice
  • Psychometric (responsive, valid, reproducible)
    properties
  • validated in your population
  • known and used in your field

54
Patient Reported Outcomes Methodological
Challenges
  • The variety of questionnaires available
  • Choice of time points
  • Incomplete data (data attrition)
  • Lack of pre-defined endpoints
  • Response-shift over time of patient perceptions
    of HRQoL
  • Psychological defenses tend to conserve
    perception of good HRQoL

55
Question
  • In a longitudinal study the best way to deal
    with response shift is to
  • Increase the sample size to dilute this effect
  • Anticipate it by changing the scales used at
    longitudinal time points when making HRQoL
    measurements
  • Use a pre-test (then test) and post-test set of
    questions at a follow-up visit to assess the
    degree of change (shift) in baseline attitude of
    HRQoL
  • None of the above

56
Examples from Completed Trials
57
Developing a HRQoL instrument PrinciplesPhase
III Breast Ca Trial
  • 1. Dimensions Physical, emotional and social
    well-being
  • 2. Importance items (questions) must reflect
    importance to patients
  • 3. Quantifiable summary scores must be amenable
    to statistical analysis
  • 4. Validity the instrument should be a true
    measurement of HRQoL
  • 5. Reproducibility the instrument should yield
    similar results in comparable patients
  • 6. Responsiveness the instrument should detect
    clinically important changes
  • 7. Simplicity the questionnaire should be short
  • JCO 61798-1810, 1988

58
Developing a HRQoL instrument Principles
  • Item selection
  • Interview patients and determine what issues are
    important
  • Winnow redundancies
  • Breast cancer Questionnaire (BCQ) hair loss,
    emotional dysfunction, physical symptoms, trouble
    and inconvenience associated with treatment,
    fatigue, nausea, positive well-being
  • BCQ contained 30 questions,
  • Likert scale administered by an interviewer, and
    took 10-15 minutes 7 points-patients asked to
    recall how they had been feeling over a defined
    period (2 weeks in this case). Maximum score on
    scale equates with most minimal deficit
  • Final score expressed as mean of the score on the
    30 questions
  • JCO 61798-1810, 1988

59
Developing a HRQoL instrument Principles
  • Co-administration of several additional
    questionnaires, e.g., Spitzer QoL, Rand Physical
    and Emotional Status, Karnofsky score (by
    physician)
  • Each questionnaire was administered at intervals
    throughout study treatment period and up to 72
    weeks.
  • JCO 61798-1810, 1988

60
Developing a HRQoL instrument Principles
  • BCQ had the best correlations with the Rand
    Physical and Emotional surveys and the Spitzer
    QoL instrument (Correlation coefficients approx.
    0.6)
  • Not surprisingly the prolonged treatment
    demonstrated a significant dip in QoL using the
    BCQ and Karnofsky scores during the extended
    treatment period. The BCQ correlated better with
    the patients assessments of her QoL.
  • JCO 61798-1810, 1988

61
Prednisone /- Mitoxantrone in Hormone Resistant
Prostate Cancer
  • Randomized controlled trial
  • Palliation as an end points 2 point reduction in
    the McGill-Melazak Pain questionnaire
  • Approval of Mitoxantrone for this indication
    based upon positive QoL findings

Tannock, JCO (1996)141756-64
62
Prednisone /- Mitoxantrone in Hormone Resistant
Prostate Cancer
  • Instruments employed
  • Prostate Cancer-Specific QoL Instrument with 9
    linear self-assessment scales (pain, physical
    activity, appetite, constipation, etc.)
  • EORTC/QLQ-C30 contains multi-item domains for
    physical function, emotional function, pain,
    global QoL

Tannock, JCO (1996)141756-64
63
Prednisone /- Mitoxantrone in Hormone Resistant
Prostate Cancer
  • Results
  • Favored MP for pain (38 reduction), physical
    activity, constipation and mood
  • QoL parameters (PS, pain intensity and serum alk
    Phos) significant predictors of OS---PSA was not!
  • Could be expanded to include cost effectiveness
    (cost per quality adjusted life year gained)

Tannock, JCO (1996)141756-64
64
Question
  • In the mitoxantrone/Prednisone trial just
    discussed, how would do you account for missing
    data?

65
Question
  • a. Anticipate attrition, identify a proxy at the
    point at which the patient is unavailable b. the
    sample size should be large enough to dilute the
    effect of missing data
  • c. anticipate loss of patient availability and
    identify proxies at the start of the study
  • d. use of a proxy will never provide validated
    data in a study in which HRQoL is an important
    endpoint

66
SWOG 8894 Hormonal Therapy of Advanced
Metastatic Prostate Cancer
Bilateral Orchiectomy Flutamide
Bilateral Orchiectomy Placebo
Within one week of registration.
JNCI 1998 90 1537-44
67
SWOG 9039 QOL Companion to S8894Activation
History
  • Therapeutic trial, S8894, opened 12/89
  • QOL Companion study, S9039, opened 10/90
  • 290/1387 patients registered to therapeutic
    trial
  • QOL sample size 500 patients
  • Both studies closed to accrual 9/94

68
S9039 Primary Quality of Life Endpoints
  • Treatment-specific symptoms
  • Diarrhea
  • Gas Pain
  • Body Image
  • Emotional Functioning
  • Physical Functioning

69
HRQOL Results
  • Placebo arm significantly better
  • Emotional status
  • Less diarrhea
  • Consistent picture
  • Placebo arm patients reported better HRQOL
  • Flutamide not palliative
  • Appears to worsen HRQOL relative to placebo
  • Could have missed an important outcome if just
    measured symptoms

70
Median Emotional Well-Being Scores
100
90
Minor Med Cond
Orch Placebo
CHF
80
Orch Flutamide
COPD Hyperten
70
60
///
General Population Patientswith Medical
Conditions
0
S9039 Patients at 6 Months
71
CONCLUSIONS
1. Integration of QOL outcomes in cancer clinical
trials is challenging 2. Anticipation of design,
data collection, and analysis will decrease some
problems 3. Additional resources are required to
incorporate QOL outcomes successfully-budget for
them!
72
Despite the Uphill Climbwere getting there
73
Acknowledgements
  • Dr. Jane Weeks
  • Dr. Patricia Ganz
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