quality of life (qol) results from clinical trials · brief history . 1979: ncic (now ccsri)...
TRANSCRIPT
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Quality of Life (QOL)Results from Clinical Trials
(A primer for New Investigators)
M. Brundage MD MSc FRCPCQueen’s Cancer Research InstituteCancer Care and Epidemiology Division
Quality of Life Committee Co-ChairCanadian Cancer Trials Group
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Overview: Objectives
• Be familiar with the CCTG structure re: QOL Committee
• Understand the nature of QOL data• Philosophy• Source Questionnaires• Data collection
• Become familiar with Scale/instrument interpretation issues• Reliability, validity, responsiveness
• Become familiar with clinical utility of QOL data
• New Directions of CCTG QOL Committee
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Brief History
1979: NCIC (now CCSRI) decides to have a formal cooperative clinical trials group
1980: NCIC Clinical Trials Group established at Queen’s University (Dr. Pater)
1982: First Phase III Trial with QOL (BR.5)
1989: Establishment of a QOL committee (Dr. J. Pater)• Dr. David Osoba and Dr. Benny Zee• Dr. Andrea Bezjak• Drs. Jolie Ringash/Michael Brundage
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Brief History
1979: NCIC (now CCSRI) decides to have a formal cooperative clinical trials group
1980: NCIC Clinical Trials Group established at Queen’s University (Dr. Pater)
1982: First Phase III Trial with QOL (BR.5)
1989: Establishment of a QOL committee (Dr. J. Pater)• Dr. David Osoba and Dr. Benny Zee• Dr. Andrea Bezjak• Drs. Jolie Ringash/Michael Brundage
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Brief History
Historical Example: NCIC BR.5
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BR.5 QOL
• Shortly after the trial started, centres were asked to participate in the QOL component of the trial– They were given the option to use both Sickness
Impact Profile (SIP) and Functional Living Index –Cancer (FLIC) questionnaires, only FLIC, or not participate
• Almost all centres agreed to participate and most chose to use both instruments
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After BR.5
• Low compliance (<25%) with QOL collection in BR.5 was due to many factors
• It was evident that adequate QOL data collection would not just happen
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Clinical Trials Committee (CTC)
DSMC Disease Site Committees
CanadianCancer Trials Group
Other Supporting Committees
IND Committee
Lay Representatives
Endpoint Committees
Central Office Kingston
BreastGIGU
GyneLungBrainH&N
SarcomaSymptom Control
MelanomaHematology
Quality of Life
Working Group in Economics
Correlative Biology and
Tumour Banking
SCIENTIFIC COMMITTEES
SUPPORTING COMMITTEES
OVERSIGHTCOMMITTEE
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Clinical Trials Committee (CTC)
DSMC Disease Site Committees
Other Supporting Committees
IND Committee
Lay Representatives
Endpoint Committees
Central Office Kingston
BreastGIGU
GyneLungBrainH&N
SarcomaSymptom Control
MelanomaHematology
Quality of Life
Working Group in Economics
Correlative Biology and
Tumour Banking
SCIENTIFIC COMMITTEES
SUPPORTING COMMITTEES
OVERSIGHTCOMMITTEE
Clinicians (8)Radiation OncologyMedical OncologySurgical Oncology
CRA Representative (1)
Psychosocial Scientists (3)
Liaison
Lay Representative (1)Central Office Statistician (1)Central Office Staff (SC and PC) (2)
CanadianCancer Trials Group
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0100200300400500600700800900
Randomized Trials with QOL Published Results
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PROs and HRQoL
Patient-Reported Outcomes (PROs):
Provide a standardized method of measuring the patient perspective on “any outcome based on data provided by patients or patient proxies as opposed to data provided by other sources”
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First – A Brief Bit of Background
Patient-Reported Outcomes (PROs):
Provide a standardized method of measuring the patient perspective on “any outcome based on data provided by patients or patient proxies as opposed to data provided by other sources”
Health-related quality of life (HRQoL):
“The extent to which one’s usual or expected physical, emotional, and social well-being is affected by a medical condition and/or treatment.”
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Examples of Patient-Reported Outcomes
Health-related QOL
Functional Status
Health Status
Satisfaction
Adherence
Utilities
Symptom Scales
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What is QOL?
• “the goodness of life” or person’s overall well-being• Influenced by:
• patient’s perspective (subjectivity)• multi-dimensional (many dimensions of life experience
relating to specific “domains”)• Sociocultural context (culture and value systems)
• As related to health (not housing, income, environment, etc)
Overall QOL?
Health-related QOL?
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What is health-related QOL?
• “Optimum levels of physical, role and social function, including relationships, and the perception of health, fitness, life satisfaction and well-being.”
Bowling, 1995
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• Indicator of patient status• Measurement method is familiar• Measurement scale is familiar• Clinical interpretation is familiar
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• Indicator of patient status• Measurement method is less familia• Measurement scale is less familiar• Clinical interpretation challenging
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• EORTC QLQ-C30+3 Instrument• Domain: Global quality of life
How would you rate your overall health during the past week?1 2 3 4 5 6 7
Very poor Excellent
How would you rate your overall quality of life during the past week?1 2 3 4 5 6 7
Very poor Excellent
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HQL Measurement and Epidemiology
Quality ofLife Data
Toxicity Data /Performance Status
Self-reported HCP/RA-reported
Multi-dimensional Tabulated items
More complex/Unfamiliar Less complex/More familiar
Response-shift? Rater issues?
Correct dimensions? Sufficient?
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HRQL vs. Toxicity
0.0%
20.0%
40.0%
60.0%
80.0%
100.0%
Mood
Weakne
ss
Fatigue
Cough Pain
Dysph
agia
Nause
a
Vomitin
g
Prop
ortio
n Sy
mpt
om R
epor
ted
Savage et al, ASCO 2005
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Measuring QOL
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HQL Measurement and Epidemiology
Aaronson, JNCI 1993
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•Do you have any trouble doing strenuous activities like carrying a heavy shopping…
•Do you have any trouble taking a long walk
•Do you have to stay in bed or a chair for most of the day
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•Do you have any trouble concentrating on things, like reading a newspaper or watching television?
•Have you had difficulty remembering things?
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•Has your physical condition or medical treatments interfered with your family life?
•Has your physical condition or medical treatments interfered with your social activities?
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•Reliability: Does the questionnaire produce reproducible results?
• Internal – e.g. Chronbach’s alpha• Test-retest – repeatability• Longer questionnaires generally with higher reliability
• Validity: Does the questionnaire really measure QOL?
• Face / Content• Construct
HQL Measurement and Epidemiology
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Why QOL is important
• Different treatments have similar survival • Treatment improves survival but has severe
side effects • Treatment has no effect on survival but may
improve QOL • Cure is not possible • Chronic diseases with high survival rates
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Clinical Example: Symptomatic Locally Advanced NSCLC (SC.15)
Disease too extensive for curative therapy
With or without metastases beyond the thorax
2000 cGy in 5 fractions vs 1000 cGy in 1 fraction
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NCI Canada SC15
Single 18 weeksFractionated 26 weeksp = 0.0492
Survival according to treatment
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-10
-8
-6
-4
-2
0
2
4
6
8
10
QLQ-C30 Change Scores (Baseline score to 5 weeks)
*p < 0.05
*
Five Fractions (N=89)
Single Fraction (N=87)
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0
100
Before During After
QOL Score
Treatment Intent: Improve QOL
Mean 60.8Mean 71.2
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0
100
Before During After
QOL Score
Treatment Intent: Improve QOL
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-10
-8
-6
-4
-2
0
2
4
6
8
10
QLQ-C30 Change Scores (Baseline score to 5 weeks)
*p < 0.05
*
Five Fractions (N=89)
Single Fraction (N=87)
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0
100
Before During After
QOL Score
Treatment Intent: Improve QOL
Mean 60.8Mean 71.2
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0
100
Before During After
QOL Score
Treatment Intent: Improve QOL
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0
100
Before During After
QOL Score
Treatment Intent: Improve QOL
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0
100
Before During After
QOL Score
Treatment Intent: Improve QOL
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0
100
Before During After
QOL Score
Treatment Intent: Improve QOL
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0%
100%
After
"Improved"
"Unchanged"
"Worse"
Percent of
Patients
Treatment Intent: Improve QOL
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0
100
"Improved" "Unchanged" "Worse"
Percent of
Patients
Treatment Intent: Improve QOL
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What magnitude of change is significant?
Distribution-method approach
Anchor-based approach
Conjoint approach
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E.g.: Osoba et al, JCO 1998 • Minimal change: 5-10 points
• Moderate change: 10-20 points
• Large change: >20 points
What “difference” is clinically significant?
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Cumulative Distribution FunctionPhysical Function:
Cumulative Percent of Patients Changed at 9 monthsPe
rcen
t of P
atie
nts
Chan
ged
“Cut-point” for change at 9 months:
Improved at 9 months0=no change
Worsened at 9 months
p=0.03
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Some Concerns….
• The biggest problem with analyzing QOL information from clinical trials is missing data• are pts whose QOL data are missing different from
pts supplying QOL data? • Or is QOL data missing because pts are sicker that
those providing info?
• Analysis can try to account for missing data but it is best trying to prevent missing data
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0
100
Before During After
QOL Score
Treatment Intent: Improve QOL
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0
100
Before During After
QOL Score
Treatment Intent: Improve QOL
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0
100
Before During After
QOL Score
Treatment Intent: Improve QOL
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Expert Consensus Panel
1. What are the characteristics of the population of interest?
2. Is the QOL questionnaire relevant, reliable, valid, and responsive to change?
3. Are the timing and frequency of assessment adequate?
4. Is the study adequately powered?
5. How are multiple QOL outcomes addressed in the analyses?
6. How are multiple time points handled?
7. Can alternative explanations account for observed scores?
8. Are missing data handled adequately?
9. Is an observed survival difference accounted for?
10. Was response shift (change in patient’s perspective of QOL) taken into account?
11. Is clinical significance addressed?
Spranger et al, Mayo Clin Proc, 2002; 77: 561-571
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Added value of HRQL in Cancer Clinical Trials
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Minimising waste and maximising benefits…..
Capturing what
matters
Designing a high quality
study
Obtaining data and
protecting patients
Ensuring that data are analysed
and reported appropriately
Providing high quality evidence to
inform patient-
centred care.
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Capturing what
matters
Designing a high quality
study
Obtaining data and
protecting patients
Ensuring that data are analysed
and reported appropriately
Providing high quality evidence to
inform patient-
centred care.
CONSORT
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JAMA. 2013;309(8):814-822
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Original Consort Statement Consort PRO Extension
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Capturing what
matters
Designing a high quality
study
Obtaining data and
protecting patients
Ensuring that data are analysed
and reported appropriately
Providing high quality evidence to
inform patient-
centred care.
CONSORTSYSAQOL
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• Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data
• International
• Multi-stakeholder
• Shared interest in improving the standards of PRO analysis in cancer RCTs in order to improve patient outcomes
61
What is SISAQOL
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Capturing what
matters
Designing a high quality
study
Obtaining data and
protecting patients
Ensuring that data are analysed
and reported appropriately
Providing high quality evidence to
inform patient-
centred care.
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6083 abstracts screened
Review 1
100 articles
Framework was developed to classify factors associated with missing PRO data
5 components and 46 categories, each with sub-categories
Review 2
117 articles
Strategies were organized to reduce instance and impact of missing PRO data
2000+ strategies for study design, implementation, reporting
184 unique manuscripts
Informed the development of an Integrative Review. Strategies for study design and implementation were mapped to the Classification Framework.
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http://bmjopen.bmj.com/content/6/6/e010938
Clinical Trials 2018;15(1):95-106
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Capturing what
matters
Designing a high quality
study
Obtaining data and
protecting patients
Ensuring that data are analysed
and reported appropriately
Providing high quality evidence to
inform patient-
centred care.
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Systematic evaluation of Patient-Reported Outcome protocol content and reporting in
cancer trials - EPiCDr Derek Kyte, PhD
Centre for Patient-Reported Outcomes Research (CPROR)University of Birmingham [email protected]
NCRI Psychosocial Oncology & Survivorship Clinical Studies Group
On behalf of the EPiC study group: Derek Kyte, Ameeta Retzer, Khaled Ahmed, Thomas Keeley, Jo Armes, Julia M Brown, Lynn Calman, Anna Gavin, Adam W Glaser, Diana M Greenfield, Anne Lanceley,
Rachel M Taylor, Galina Velikova, Michael Brundage, Fabio Efficace, Rebecca Mercieca-Bebber, Madeleine T King, Grace Turner, Melanie Calvert.
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Objective: review the rigour with which PROs are incorporated into cancer clinical
trials
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METHODS• Systematic evaluation of 1,141 cancer trials on the NIHR Portfolio 2001-2014.
Excluding non-randomised trials or those that terminated early.
CHECKLISTS
GENERAL PRO-SPECIFIC
SPIRIT 2013 PRO CHECKLIST
CONSORT 2010 CONSORT PRO
We reviewed:
1. PRO protocol content
3. Availability of PRO trial results
5. Quality of PRO reporting
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EPiC Study Results - PRO protocol content• Trial protocols (n=101) included a mean of 32/51 (range 11–43, SD 6) SPIRIT
2013 recommendations
• 10/33 (range 2–19, SD 4) PRO protocol checklist items.
66%32%
SPIRIT 2013PRO…
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EPiC Study Results - PRO protocol content
Recommended Protocol Item Protocol Coverage
Detail regarding the rationale for PRO collection missing in 68%
Description of PRO-specific objectives missing in 83%
Justification of the choice of PRO instrument with regard to the study hypothesis missing in 66%
Questionnaire measurement properties missing in 49%
Information regarding PRO data collection plans missing in 41%
Methods to reduce avoidable missing PRO data missing in 61%
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Capturing what
matters
Designing a high quality
study
Obtaining data and
protecting patients
Ensuring that data are analysed
and reported appropriately
Providing high quality evidence to
inform patient-
centred care.
CONSORTSYSAQOL
SPIRIT
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“Added Value”
10. HRQL results of interest for descriptive purposes
• Head and neck cancer patients
• Women five-years post breast cancer treatment
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“Added Value”
9. HRQL as a prognostic factor
• Repeatedly illustrated in multiple study contexts
• Stratification / statistical adjustment
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“Added Value”
8. HRQL in Phase I/II trials
• Detect toxicity or response
• Estimate effect size for phase III
• “Pick the winner”
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“Added Value”
7. HRQL results that support primary outcome
• Palliative chest radiotherapy for locally advanced lung cancer
• Improvement in nausea and vomiting with effective anti-emetics
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“Added Value”
6. HRQL results that “conflict” with primary outcome
• Pre-operative vs. post-operative radiotherapy for limb soft-tissue sarcoma
• Wound healing – post-op favoured• Long-term functioning – pre-op favoured
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“Added Value”
5. Quantification of treatment-related toxicity
• Adjuvant chemotherapy for early-stage lung cancer
• Significant survival difference• Some impact of treatment on HRQL • Recovery of HRQL after treatment
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“Added Value”
4. Demonstration of reduced treatment-related toxicity
• Palliative chemotherapy for advanced-stage lung cancer
• No significant difference in global HRQL• Differences seen in treatment tolerance
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“Added Value”
3. Measurement of response to treatment
• Mitoxantrone and prednisone for patients with metastatic prostate cancer
• No significant survival difference• improved symptoms and HRQL
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“Added Value”
2. Industry / FDA
• Claims for new drug labelling
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“Added Value”
2. Industry / FDA
• Claims for new drug labelling
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“Added Value”
1. Patient Preferences
• Medical decision making
• Other elements of patient education
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Preference Ratings
More useful or helpful
Less useful or helpful
0 2 4 6 8 10
Survival Information
Acute Toxicity
Late Toxicity
Global HRQL
Physical Functioning
Emotional Functiong
Cognitive Functioning
Brundage et al, ISOQOL 2005
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Time for Questions….Over to you!