Quality of Life Assessment
in Clinical Trials
Elizabeth Garrett-Mayer
Some slides adapted from www.biostat.wisc.edu/training/courses/542slides/09-
qol.pdf
Aside: MIXED procedure “Mixed” effects model in SAS Includes both fixed and random effects Fixed effects
Time Treatment
Random effects Person-specific coefficients
Commonly seen Estimate a common slope over time Allow each individual to has his/her own intercept
0 5 10 15 20
-50
51
01
5
TIME
RE
SP
ON
SE
Why are we interested in Quality of Life (QOL)?
The FDA has stated that efficacy with respect to overall survival and/or improvements in QOL might provide the basis for drug approval.
Shaughnessy JA, Wittes RE, Burke G et al.Commentary concerning demonstration of safety and efficacy ofInvestigational anticancer agents in clinical trials.Journal of Clinical Oncology 1991 (9) 2225-32
Measuring QOL
Happy Miserable
How are you feeling today?
What is QoL? WHO: “Health is not only the absence of
infirmity and disease, but also a state of physical, mental and social well-being.”
Multiple domains include: Physical, cognitive, emotional and social functioning, pain, sexual functioning, health perceptions, and symptoms about nausea and fatigue
Fundamental Principle: QoL IS ASSESSED BY THE PATIENT
QoL Definition depends on context:
Cancer vs. MI vs. hypertension Early instruments for measuring QoL were
disease-specific Later instruments, “general health status”
POMS = Profile of Mood SIP = Sickness Impact Profile
Difficulties with concept No agreement on definition Lack of standardized measures
QoL One definition (Levine and Croog) has two components:
Functioning Social (major component): get along with family and
friends Physical: perform daily activities Emotional: stability and self-control Intellectual: decision-making ability
Perceptions Life satisfaction: sense of well-being Health Status: compared to others
Factors influencing QoL Interventions/Treatment Disease Processes Labeling: diagnosis brings on ‘change’ Concomitant Care Non-related life events (e.g. death in the
family)
Rationale in Clinical Trials
QOL assesses effect of intervention/treatment Primary response (treatment improves symptoms?) Side effects (treatment toxic?) Economic aspects (low risk/cost of treatment but high
benefit?) Another setting: Treatment for pain
Primary response (pain lessened?) Side effects (interact with disease? Other side effects?) Economic aspects
Data Collection Data collection can add measurement error or
bias Mode: self-administered vs. interview
Self-admin: Reading ability, fine-motor skills Interview: Hearing problems, age/gender/ethnicity
sensitivity, training of interviewer Either: language
Content Instrument validity, sensitivity, specificity Sensitivity of questions Frame of reference (cognitive skills, privacy, cultural
background) Source(s)
Patient vs family vs health care provider
Assessing QoL Hardest part! Determine QoL objective Choose instrument to measure QoL
Reliable, valid, responsive, feasible Global measures, disease-specific measures,
symptom checklists Select assessment time points Develop analysis plan
Choosing your instrument Off-the-shelf (i.e. general) instruments
Designed to distinguish sickness from wellness May not be sensitive to particular aspect of a
given trial May not be validated or “normed” in
population being tested May ask silly questions for trial population May take long time to complete May impact negatively on compliance
Choosing your instrument “Tailor Made” Instruments
Quick and simple Standardized but targeted to disease Validated, normed to trial population Select subsets of off-the-shelf instruments
Home-Made Instruments Often designed by graduate student or
comparable Often too long Often not validated or ‘normed’ or field tested
in the patient population of interest
a. CARES-SF (Schag 1991) - 59 item scale which measures rehabilitation and quality of life in patients with cancer. This has been modified to the HIV Overview of Problems Evaluation Systems (HOPES, Schag 1992)
b. City of Hope Quality of Life, Cancer Patient Version (Ferrell 1995) – a 41 item ordinal scale representing the four domains of quality of life including physical well being, psychological well being, and spiritual well being.
c. Daily Diary Card-QOL (Gower 1995) - a self-administered card for use in cancer clinical trials that has been shown to demonstrate short-term changes in quality of life related to symptoms induced by chemotherapy.
d. EORTC QOL-30 (Aaronson 1993) - this instrument is composed of modules to assess quality of life for specific cancers in clinical trials. The current instrument is 30 items with physical function, role function, cognitive function, emotional function, social function, symptoms, and financial impact.
e. FACT-G (Cella 1993) – a 33 item scale developed to measure quality of life in patients undergoing cancer treatment.
f. FLIC (Finkelstein 1988) – a 22 item instrument which measures quality of life in the following domains: physical/occupational function, psychological state, sociability, and somatic discomfort. This scale was originally proposed as an adjunct measure to cancer clinical trials.
g. Southwest Oncology Group Quality of Life Questionnaire (Moinpour 1990) – a scale developed for cancer patients incorporating questions from various function, symptoms, and global quality of life measures.
Measurement Look for measures that are proven to be
VALID RELIABLE
Validity: does measure actually measure the construct it is intended to measure?
Reliability: how much close is does our measure get to the “true” score? (ranges from 0 to 1)
Measurement RELIABILITY AND VALIDITY DEPEND ON THE
SAMPLE TO WHICH YOUR MEASURE IS APPLIED! Example:
the FACT-G has been shown to have reliability of in 0.87 in Americans undergoing chemotherapy (Cella)
Is it still a reliable measure in Japanese men with esophageal cancer?
Is it a reliable measure in Korean women with breast cancer?
If a measure is to be applied to a different population from which it has been validated on, it needs to be re-assessed.
Measurement What is the big deal if the reliability is lower in my
sample? Low reliability = Poor measure Low reliability also implies poor validity. Think of these scales as “surrogate markers” of
quality of life Would you use surrogate markers that you KNEW
were only weakly related to the true outcome of interest?
If reliability is low, then you are not measuring what you are trying to measure.
Look for reliabilities above 0.75
Measurement What about validity in new population?
The same items/questions may mean different things to different patient populations or cultures
For some latent variables (e.g. mental disorders), the variable of interest manifests itself differently in different cultures or population subgroups.
Translations into different languages can affect results dramatically
If there are items in the scale that are irrelevant for your patient population, then you are compromising your validity by including them.
Analytic Issues
“Measurement” QOL measured by multiple indicators Need validated overall ‘score’ Or, can use fancier multivariate methods
Usually, treat ‘score’ as observed level of QoL and proceed with analysis.
Problems: ‘score’ is often not a valid measure of QoL in
the patient population Score tends to be fraught with measurement
error (reliability tells you about this)
Analytic Issues ATAC study:
Used FACT-G and FACT-B. Simply added up the responses to each item
(but that is shown to be valid and reliable) Treats each item as “exchangeable:” assumes
each item is equally sensitive to changes in QoL
Alternative: develop model to weight each item relative to how informative it is about QoL (latent variable methods…..).
Latent Variables QoL is, by definition, a “latent variable:” it cannot
be directly measured. We measure it using “symptoms” of QoL Statistical methods help us make inference about
state of QoL via the symptoms. Develop models/scales for measuring QoL We can maximize reliability and evaluate validity.
Issues to consider: What if our “symptoms” are not tapping into QoL like we
think? What if patients’ perceptions of the questions we ask are
different? How can we find out about these things????
QualityOf
Life
Have you felt
nauseated?
Have you hadproblemssleeping?
Have you had pain?
Have you lacked
appetite?
Have you felt
depressed?
Latent Variable Depiction
Other latent variables in medical research
Pain Mental disorders
Depression Schizophrenia Autism
Mobility/Function (gerontology) Arthritis
Other QOL issues Often interested in whether or not survival with
poor quality of life is better than death without suffering.
“QALY”= Quality Adjusted Life Years Example:
Cancer: many patients would rather not get toxic therapies and have more enjoyable end of life
The general idea is to down-weight time spent in periods of poor quality of life.
Methodologically challenging: How to determine the weights? Different settings might need different weights.
QTWIST: Quality-Adjusted Time Without Symptoms of disease and Toxicity.
Quality Adjusted Survival
Evaluate therapies based on both quantity and quality of life through survival analysis
Based on QALYs. Define QOL health states, including
one with good health (minimal symptoms).
Patients progress through health states and never back-track.
Partition the area under the Kaplan-Meier Curve and calculate the average time spent in each clinical health state.
Compare treatment regimens using weighted sums durations, weights are utility based.
Example: 5 year survival
0 6 1 0 8 2 0 6 1 0 2 1 3. . . . 3 adjusted years of life
Compare the average QTWIST in two treatment groups.Could be that on treatment A, people live longer, but QOL is worse.
Quality of Life for Individual
References: www.biostat.wisc.edu/training/courses/542slides/09-qol.pdf
Fairclough and Gelber, “Quality of Life: Statistical Issues and Analysis.” From Quality of Life and Pharmacoeconomics in Clinical Trials, Second Edition, ed. B. Spiker. 1996.
Top Related