Quality of Life Assessment in Clinical Trials:

Methodologic Issues
Neil K. Aaronson, PhD
The Netherlands Cancer Institute, Amsterdam, The Netherlands

ABSTRACT: Historically, health-related quality of life research has been carried out at a de-
scriptive level, providing rich data regarding the impact of disease and treatment on
the physical, functional, psychologic, and social health of varying patient populations.
More recently, there has been growing interest in incorporating psychosocial or "qual-
ity of life" outcome measures into clinical trials of medical interventions, particularly
in the chronic diseases. This article reviews a number of the central methodologic
issues surrounding the development or selection of quality of life measures appropriate
for use in clinical trials. Topics discussed include the following:
1. Who should assess quality of life?
2. What should be assessed?
3. What means of data collection should be used, e.g., interviews, questionnaires or
diaries?
4. Should the focus of the quality of life measures be generic or disease specific?
5. What are some of the considerations for response scales and for the time frame of
questions addressing the quality of life?
6. What psychometric properties should be considered in evaluation of a questionnaire
assessing quality of life?
Additional attention is directed toward research design and implementation issues in
clinical trial-based quality of life studies.

KEY WORDS: Quality of life, clinical trials, methodology

INTRODUCTION
In the late 1940s several i m p o r t a n t articles w e r e p u b l i s h e d that signaled a
shift in the w a y in w h i c h w e w o u l d c o m e to conceptualize health a n d evaluate
o u r medical interventions. In 1947, the World H e a l t h O r g a n i z a t i o n i n t r o d u c e d
a b r o a d e n e d definition of health as "a state of c o m p l e t e physical, m e n t a l a n d
social well-being, a n d not m e r e l y the absence of disease a n d infirmity" [1].
Several years later, K a r n o f s k y a n d Burchenal [2] outlined the basic criteria
n e c e s s a r y for the evaluation of n e w c h e m o t h e r a p e u t i c agents. These included
not only the classical indicators of therapeutic success such as length of sur-

Address reprint requests to: NeiI K. Aaronson, The Netherlands Cancer Institute, Department of
Psychosocial Research, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Received July 5, 1989.

Controlled Clinical Trials 10:195S-208S(1989) 195S

© ElsevierSciencePublishing Co., Inc. 1989 0197-2456/1989/$3.50
655 Avenue of Americas,New York, New York10010
196S N.K. Aaronson

vival and objective response, but also more qualitative parameters such as
performance status, reduction in symptom level, improved mood, and sense
of well-being, parameters that today would be classified under the heading
"quality of life."
Some 40 years later, Campbell and his colleagues, prominent workers in
population-based quality of life research, were still grappling with problems
of definition: "Quality of life is a vague and ethereal entity, something that
many people talk about, but which nobody clearly knows what to do about"
[3]. Despite the lack of conceptual agreement, however, "quality of life" vari-
ables have been incorporated into a wide range of health services and clinical
research, particularly in patients with chronic diseases. Quality of life as-
sessments have been used to do the following:
1. Describe the nature and extent of functional and psychosocial problems
confronting patients at various stages in the disease trajectory.
2. Establish norms for psychosocial morbidity among specific patient groups.
3. Monitor the quality of care, with an eye toward improving the way in
which treatment is delivered.
4. Evaluate the efficacy of competing medical interventions.
5. Screen individual patients for possible psychosocial intervention (e.g., psy-
chotherapy).
During the last decade, particular attention has been directed toward the
feasibility of incorporating quality of life parameters in clinical trial evalua-
tions. Quality of life data have played a prominent role in recent prospective,
randomized clinical trials in operable [4-6] and advanced breast cancer [7],
soft-tissue sarcoma [8], coronary artery disease [9,10[, hypertension [11], and
rheumatoid arthritis [12]. Yet, such applications remain the exception rather
than the rule. For example, in a recent literature review covering the period
1981-1986, only 3 of 99 published studies of surgical trials included quality
of life evaluations [13].
The hesitancy to incorporate psychosocial parameters into clinical trials
would appear to result, in part, from a basic lack of familiarity on the part of
clinicians and social scientists with each other's conceptual frames of reference
and research traditions. More importantly, there are a number of key method-
ologic issues that must be resolved before one can seriously recommend the
routine introduction of quality of life outcome measures in the rigorous con-
fines of the clinical trial.
This article provides a brief overview of some of the more salient meth-
odological considerations involved in developing or selecting quality of life
measures for use in clinical trials, in choosing an appropriate research design,
and in research implementation. Topics to be addressed include the following:
1. Who should assess quality of life?
2. What should be assessed?
3. What means of data collection should be used, e.g., interviews, question-
naires, or diaries?
4. Should quality of life measures be generic or disease specific?
5. What are some of the considerations for response scales and for the time
frame of questions addressing the quality of life?
Quality of Life Assessment in Clinical Trials 197S

6. What psychometric properties should be considered in evaluation of a

questionnaire assessing quality of life?
7. How frequently and in response to what events should quality of life be
assessed?
8. What biases exist in recruitment of patients for collection of quality of life
data?
9. What is the potential impact of missing follow-up data for the assessment
of the quality of life of patients?

MEASUREMENT ISSUES
Who Should Measure the Patient's Quality of Life?
The quality of life of patients can be assessed by a health care provider,
by the patient, or by someone close to the patient such as a partner or other
family member. Historically, it has most often been the physician who has
provided such assessments, albeit in a limited way. Thus, for example, in
oncologic clinical trials clinicians are asked routinely to rate the performance
status of their patients and the side effects of the treatment. More recently,
physician-based rating systems have been developed that address a broader
set of quality of life dimensions, including psychologic and social well-being
[141.
The principal advantages associated with such clinician-based observation
techniques are of a practical nature. Typically, it requires much less time and
effort to complete a rating form oneself than it does to arrange for patients
to be interviewed or to be assisted in filling out a questionnaire. Further, in
those cases where the patient is unable to provide quality of life ratings (e.g.,
due to neuropsychiatric symptoms), physicians' ratings may, with caution,
be used as a proxy quality of life measure.
Nevertheless, the available evidence suggests that methodologic limitations
associated with certain physician rating scales may outweigh their practical
advantages. For example, several studies of performance status measures
have documented low levels of interphysician reliability and, perhaps more
importantly, low levels of agreement between ratings provided by physicians
and those of patients [15,16]. It should be noted that the reliability of clinician-
based rating scales can be improved significantly by introducing standardized
instructions and by providing training in their use [17,18]. Additionally, data
suggest that nurses and other ancillary health care personnel may provide
more reliable ratings than do physicians [19].
In light of these considerations, it is increasingly argued that it is desirable,
and often necessary, to ask patients directly about the impact of disease and
treatment on their daily lives. This is clearly the case w h e n one is interested
in assessing such subjective experiences as pain, fatigue, or psychologic dis-
tress. Yet, even in the case of more readily observable symptoms (e.g., alo-
pecia among chemotherapy patients; diminished grip strength among rheu-
matoid arthritis patients) patient feedback may provide important insights
into their meaning and impact on daily living.
Feedback provided by a family member can also yield useful information
regarding the patient's quality of life. In studies involving children, the parent
198S N.K. Aaronson

may serve as the primary source of such data. Even in the case of the adult
patient, however, the partner may provide a unique perspective regarding
such issues as mood state, functional capacity, and level of sexual interest.

What Should Be Assessed?

As suggested earlier, quality of life is an elusive concept that defies precise
definition. As Feinstein [20] puts it: "the idea has become a kind of umbrella
under which are placed many different indexes dealing with whatever the
user wants to focus on." One way of circumventing the problem of concept
definition is to leave the task to the individual patient. For example, Gough
and his coworkers [21] suggest that one need only field a single question to
evaluate cancer patients' quality of life: "How would you rate your quality of
life today?" They support this position by demonstrating a relatively strong
correlation between scores on this single item and scores derived from more
elaborate assessment batteries. Unfortunately, such statistical evidence begs
the issue of utility. Although it may be useful to have a summary quality of
life score for certain tasks (e.g., for calculating quality-adjusted life years),
more specific information is required in order to interpret such global ratings.
H o w are we to interpret a patient reporting a low quality of life? Does it imply
limitations in functional capacity, intolerable symptoms levels, depression,
social isolation, or a combination of such factors?
A review of the literature [22] suggests that quality of life is most often
approached as multidimensional construct composed minimally of the follow-
ing four domains:

1. Physical functional status

2. Disease-related and treatment-related physical symptoms
3. Psychologic functioning
4. Social functioning

Beyond this core set of domains, additional psychosocial topics are often
included in assessment batteries that are of relevance to particular patient
populations (e.g., sexuality and body image, cognitive impairment, fear of
disease recurrence, etc.).
Working within such a multidimensional framework, the researcher must
strike a balance between breadth and depth of coverage. Instruments de-
signed to measure a wide spectrum of quality of life dimensions can typically
address each topic only on a relatively superficial level. Other measures
focusing on a narrower range of issues can offer greater depth of inquiry
per topic. Ware [23] suggests that it may be appropriate to cast a fairly wide
assessment "net," given our limited knowledge of the impact of disease and
treatment on the lives of patients, and the uncertainty surrounding the rel-
ative importance of any particular quality of life dimension. If, however, the
expected difference in event rates between the treatment arms in a clinical
trial is small, it may be necessary to employ a more detailed instrument that
is highly sensitive to either intraindividual change or intergroup differences
in selective quality of life domains.
Quality of Life Assessment in Clinical Trials 199S

Interviews, Questionnaires, or Diaries?

Interviews represent perhaps the most flexible means of collecting patient-
based quality of life data. They can be applied to the broadest range of patients,
including those who would otherwise be unable to complete a self-admin-
istered questionnaire (e.g., the elderly, the poorly educated, the physically
handicapped). Interviews also facilitate sophisticated question branching and
can minimize the problem of missing data by incorporating probes for clari-
fication or amplification of patients' responses. Offsetting these advantages
is the fact that interviews require more commitment of staff time than is
typically available in clinical settings. Particularly in multicenter clinical trials,
it cannot be expected that sufficient resources will be available to permit
interviewing as the standard means of data collection.
Although self-administered questionnaires sacrifice some of the richness
of detail derived from interviews, they represent the most practical, efficient,
and inexpensive method of obtaining patient-based information. A particu-
larly important advantage of questionnaires is that, if designed with simplicity
in mind, they can be administered frequently during the course of a clinical
trial. Although some patients may need assistance in completing a question-
naire, this is often the case only with the first administration. Even for those
patients who need repeated assistance, however, it is always possible to use
a questionnaire in the form of an interview. The reverse is seldom the case.
Interviews are rarely designed or formated in such a way that they can be
used in a self-administered form. It should be cautioned, however, that vary-
ing the mode of administration of a questionnaire (i.e., self-completed versus
interviewer-assisted) may introduce bias in the study results.
Patient diaries are particularly useful if one is interested in frequent (e.g.,
daily) assessment of changes in symptom experience. For example, the British
Medical Research Council has developed a diary card for use among patients
receiving chemotherapy or radiotherapy that includes ratings of nausea and
vomiting, activity level, mood state, anxiety, and overall health [24]. The major
limitation of diaries is that, due to the frequency of administration, the number
of questions asked must remain quite limited. Further, patient compliance
can be a significant problem that may remain undetected if patients complete
the diary retrospectively (e.g., for an entire week). This, of course, would
defeat the purpose of the diary approach.

Generic Versus Disease-Specific Measures

Quality of life measures can be organized along a continuum reflecting
their intended spectrum of application:
1. Generic measures designed for use across a broad range of chronic disease
populations.
2. Disease-cluster instruments that have a somewhat narrower focus, while
still maintaining a generic element (e.g., measures designed for use with
cardiovascular disease or for cancer populations, in general).
3. Disease-specific measures (e.g., designed for primary breast cancer patients,
essential hypertension patients, etc.).
4. Ad hoc measures designed for a specific study.
200S N.K. Aaronson

The principal advantage associated with the more generic class of measures
is that they permit comparison of results across studies, a feature that is of
particular relevance in this age of meta-analysis. Broad coverage of important
psychosocial domains also facilitates a stepwise process of instrument de-
velopment, validation and revalidation in a variety of research settings. It is
no accident that reports of the psychometric performance of such generic
measures as the Sickness Impact Profile [25], the Nottingham Health Profile
[26], and the Quality of Well-Being Scale [27] appear regularly in the research
literature.
The major limitation of such generic measures is that they may not address
topics of particular relevance for a given disease or treatment (e.g., specific
disease symptoms or treatment side effects). Conversely, although more dis-
ease-oriented measures (cf. refs. 28 and 29) offer a greater degree of specificity,
this is often achieved at the expense of generalizability.
In order to balance the tradeoffs inherent in choosing between generic and
disease-specific measures, it may be possible to synthesize these approaches
in a single modular assessment strategy [30,31]. By this is meant the devel-
opment of a set of short, multiple-item measures reflecting the basic quality
of life dimensions outlined earlier (i.e., the functional status, physical symp-
toms common to a range of related diseases, psychologic functioning, and
social functioning). These modules, combined into a core quality of life ques-
tionnaire, could then be supplemented by additional disease-specific and/or
treatment-specific modules. Such a modular system is currently being field
tested by the European Organization for Research and Treatment of Cancer
(EORTC) [32]. If successful, this approach would facilitate cross-study com-
parison, while permitting a level of specificity necessary to address those
issues of particular relevance in a given clinical trial setting.

Question Time-Frame and Response Scales

Although there are a number of technical issues involved in questionnaire
construction, two which deserve particular attention are the time frame of
the questions and the response scales employed. When assessing the physical
and psychosocial health status of patients, researchers have employed time
frames ranging from "at this moment" to 1 month. Often the time frame of
the questions is left completely undefined. In clinical trial evaluations, it may
be essential to limit the time frame to a relatively short period. For example,
in chemotherapy clinical trials two periods can typically be distinguished: a
period during which the immediate effects of the drug are at hand (e.g.,
nausea, fatigue), and a rest period during which a patient recovers from these
short-term effects. If the question time frame is too long or is left undefined,
patients may be confused as to which period to report.
A more general consideration favoring a short time frame has to do with
memory effects. People are generally better able to report their symptom
experience accurately over a relatively short time period than over longer
intervals. Finally, short question time frames can be advocated in order to
avoid confounding specific symptom experience with a more generalized
tendency to complain [33].
Quali~ ofLife Assessmentin ClinicalTrials 201S
Not At A Quite Very
a. All Little A Bit Much

No Extreme
b. Pain Pain
(I0 cm.)

No Extreme
c. Pain Pain
1 2 3 4 5 6 7

Figure 1 Questionnaire response scales, a. Likert-type (categorical) scale, b. Linear

(visual) analogue scale, c. Hybrid scale.

A related issue concerns the use of questions that require patients to com-
pare their current health status with that at some point in the past. A typical
example is the following question: "Do you tire more easily now than you
used to?" Although a healthy adult may be able to provide an interpretable
answer to such a question, for the chronically ill it is unclear as to what the
appropriate reference point should be: the period prior to treatment, prior to
diagnosis, or prior to the onset of symptoms. Thus, unless the reference point
is made explicit, such comparative questions are best avoided.
Choosing an appropriate question response format also invites careful con-
sideration. The two principal alternatives available are Likert-type scales and
visual analogue scales. The Likert-type scale is categorical in nature, providing
the patient with a set number of closed-ended response choices (Fig. la). In
contrast, a visual analogue scale is composed typically of a 10cm line with
descriptive anchors at each end (Fig. lb). The patient is asked to mark the
point on the line that corresponds most closely to his or her experience, and
the distance from the anchor points is subsequently measured. A hybrid form
of response scale combines the categorical guides of the Likert-scale with the
anchoring system employed in linear analogue scales (Fig. lc).
In theory, liner analogue scales carry with them certain statistical advan-
tages in that they more closely approximate true interval level measures than
do Likert-type scales. Yet, practical limitations may outweigh these more
formal considerations. Although a number of investigators report successful
use of the linear analogue method with chronic disease patients [34,35], others
argue that the level of abstraction required by the technique is too great for
many patients [24,36]. Further, the need to physically measure each response
for purposes of coding and analysis mitigates against its use in large scale
clinical trials.
Although the hybrid scale illustrated in Figure lc appears to combine the
best features of two traditional response formats, a recent study indicates that
most patients do not treat the response line as a linear analogue scale (i.e.,
do not use a slash mark), but rather circle one of the numbers along the line
[36]. Thus, despite certain advantages associated with linear analogue scales,
the Likert-type scale seems most appropriate to ensure that patients under-
stand the task and can complete it without assistance.
202S N.K. Aaronson

Psychometric Properties
A central consideration in choosing among candidate quality of life mea-
sures is the extent to which psychometric standards of reliability, validity,
and sensitivity are met. Within the context of clinical trials, reliability is often
best determined by internal consistency estimates. This correlational tech-
nique indicates the extent to which the hypothesized scales are free of random
error. Internal consistency can be estimated using data from a single admin-
istration of a questionnaire, although it is desirable to replicate such reliability
estimates using subsequent questionnaire administrations. Other approaches
to reliability testing such as the test-retest method and interrater comparisons
may be less useful in examining the performance characteristics of question-
naires used in clinical trials.
Although calculating scale reliability is principally a technical matter, es-
tablishing scale validity involves perhaps as much art as it does science. At
the most basic level, careful examination of the form and content of questions
can provide invaluable information regarding the face validity of a measure
(e.g., Are the questions open to multiple interpretation? Do they cover ad-
equately the full range of relevant topics?). Although examination of the face
validity of scale items does not involve any formal statistical procedures, it
represents one of the most important steps in the validation process. In order
to maximize the face validity of quality of life measures, it is useful to include
a range of individuals (e.g., physicians, social scientists, methodologists, and
patients) both at the stage of item construction and during pretesting [37].
Criterion validity involves testing a scale against some other empirical stan-
dard. Unfortunately, in quality of life research it is often difficult to identify
criterion measures that are themselves valid and reliable (e.g., for assessing
psychologic or social dysfunctioning).
Construct validity refers to a family of procedures that has as a common
denominator the examination of the pattern of correlations within and be-
tween various scales. To establish construct validity one looks for evidence
of convergence among indicators of the same or similar theoretical constructs,
and of discrimination among indicators of unrelated constructs. The multi-
trait-multimethod approach developed by Campbell and Fiske [38], as well
as cluster and factor analytic models, is useful in examining the construct
validity of measures.
The sensitivity of an instrument to either intraindividual change over time
or interindividual differences is an essential consideration in clinical trial-
based quality of life research. In comparative studies, the degree of sensitivity
demanded of an instrument is inversely related to the expected effect size
(i.e., the magnitude of change or differences in quality of life parameters that
one is interested in detecting). Unfortunately, very few available quality of
life measures provide sensitivity data. However, evidence of low scale score
variability may signal problems with instrument sensitivity as well.
It should be emphasized that the psychometric properties of an instrument
cannot be assumed to hold across various populations. It is generally rec-
ognized that a quality of life measure validated in the general population may
perform poorly when used with chronic disease populations. Similarly, a
measure that is well validated for a specific patient population (e.g., cancer
Quality of Life Assessment in Clinical Trials 203S

patients) will not necessarily perform adequately when used among other
patient groups (e.g., cardiovascular disease patients). However, when used
in a population similar to that on which the original validation work was
carried out, instrument performance may not measure up to expectations.
For example, in a recent clinical trial in metastatic lung cancer [36], the psy-
chometric performance of the cancer-specific quality of life measure employed
(the Functional Living Index--Cancer [FLIC]) fell far short of what had been
expected based on the original validation study. It was hypothesized that
differences in the sociodemographic characteristics and functional impairment
levels of the study samples might have accounted for these disappointing
results. This suggests the need for a period of pretesting before deciding
whether a candidate quality of life measure is the best choice for a given
clinical trial.

RESEARCH DESIGN A N D IMPLEMENTATION

Undoubtedly, lack of confidence in the ability to measure quality of life in
a valid and reliable manner represents a major obstacle to introducing such
evaluations as an integral part of clinical trials. However, our experience
within the EORTC has taught us that research design and implementation
problems are often of equal importance. In fact, one cannot help suspecting
that the paucity of published reports of clinical trial-based quality of life
research reflects not only a hesitancy to undertake such studies in the first
place, but also a failure to generate sufficient publishable data from those
studies that have been initiated.
Although there are a range of research design issues relevant to the suc-
cessful implementation of quality of life studies, two worthy of particular
attention are the frequency and timing of data collection, and the problem of
patient accrual bias and differential loss to follow-up.

When and H o w Frequently Should Quality of Life Be Assessed?

The question of how frequently, and at what points in time, the quality of
life of clinical trial patients should be assessed is closely related to the issue
of patient and staff burden. Many clinicians express concern with the burden
that quality of life assessments will place on their patients. Although this
concern may be justified in some cases, the available evidence suggests that
the majority of patients welcome the opportunity to report how their disease
and treatment is affecting their daily lives [38]. Nevertheless, an overly fre-
quent data collection schedule will typically result in unacceptable levels of
either patient or staff noncompliance.
For example, in one of the first EORTC phase III clinical trials in which an
attempt was made to incorporate quality of life assessment, w o m e n receiving
combination chemotherapy for advanced breast cancer were asked to com-
plete a questionnaire on day 1, day 10, and day 22 of each treatment cycle.
Given that patients continued to receive treatment until progression or relapse
(thus resulting, in some cases, in 20 or more treatment cycles), it is not
surprising that the data collection broke down at a relatively early stage in
the trial.
204S N.K. Aaronson

Centers Participating in Medical Trial

Center Center Center CenterD Center

IE
A B C
",,, ,/ I I
Centers Agreeing to
Collect QL Data
] I Centers Not ^greeing1
To Collect QL Data

I
Patients [
I
Patients
Not Recruited Recruited
I I
' Patients Did
I
Patients
Colpleted Not Complete
QL Study QL Study

Figure 2 Patient recruitment bias and differential loss to follow-up.

This case illustrates, albeit in a negative sense, the need for keeping the
research design as simple as possible. The absolute frequency of questionnaire
administration is necessarily dependent on the overall research design. In
clinical trials where there is primary interest in the short-term or acute effects
of treatment, relatively frequent questionnaire administration during the in-
tensive treatment phase (e.g., once per treatment cycle) may be appropriate.
In long-term clinical trials, it is common to gradually lengthen the period
between questionnaire administrations.
In addition to frequency of administration, the timing of questionnaires
can be of critical importance, particularly if one is interested in capturing acute
treatment effects. For example, lack of precision in distributing questionnaires
intended to be completed by patients at the end of a cycle of chemotherapy
may result in serious underreporting of symptoms. In all cases, it can be
recommended that quality of life data collection be planned around regularly
scheduled medical visits. It is the rare hospital administrator (or patient, for
that matter) who would accept additional clinic appointments only for the
purpose of such data collection.

Patient Recruitment Bias and Differential Loss to Follow-Up

At each stage of the clinical trial process bias can be introduced that may
compromise the representativeness of the study sample and, in extreme cases,
may render the quality of life results uninterpretable. Figure 2 outlines the
possible sources of such bias.
The first source of bias can be found at the institutional level. In many
large-scale, multicenter clinical trials quality of life assessment is an optional
component of the research design. Often, the institutions that are willing to
undertake quality of life investigations have academic affiliations or can oth-
erwise be regarded as centers of "research excellence." Such institutions may
Quality of Life Assessment in Clinical Trials 205S

have patient populations that are quite different from the more typical regional
hospital. Thus, one runs the risk of accruing patients into quality of life studies
who are not representative of the sample of patients accrued into the medical
trial as a whole, let alone of the larger patient population of interest.
One way of eliminating this form of bias would be to integrate quality of
life studies as a mandatory component of clinical trials. It is questionable,
however, whether study coordinators would be willing to risk the loss of
potential institutional participation because of an unwillingness or inability
to collect psychosocial data. More realistic measures for maximizing partici-
pation in quality of life studies include the following:
1. Assuring that the purpose and value of collecting quality of life data are
clearly presented.
2. Employing simple quality of life study designs that make minimal demands
on medical staff.
3. Where feasible and appropriate, offering additional incentives (financial
or professional) for participation in such studies.
In principle, once a center has agreed to collect quality of life data in a
given clinical trial, it is expected that such data will be obtained from all
patients accrued onto that trial. In practice, however, this is rarely the case.
More typically, one finds that only a percentage of the patients are included
in the quality of life study. When queried, physicians will most often attribute
this to administrative mistakes, hectic outpatient clinics, and other such ex-
ternal factors. However, one cannot help suspecting that some patients are
excluded from quality of life investigations for more substantive reasons (e.g.,
the physician feels that the doctor-patient relationship would be affected
adversely). If such systematic selection takes place, the representativeness of
the quality of life sample is further compromised.
Again, use of a realistic data collection scheme that minimizes the disrup-
tion of normal clinic routine can eliminate many of the administrative prob-
lems surrounding quality of life data collection. Use of certain data manage-
ment tools such as study calenders and flagging of patient charts can also
facilitate smoother study administration. Exclusion of patients from study
participation on a priori grounds is a more intransigent problem. Although
the evidence suggests that the vast majority of patients are willing to partic-
ipate in qualify of life studies, it is only through experience that the individual
physician can be convinced of the relatively benign (and often beneficial)
nature of patient participation in such research.
The final and most serious form of bias occurs when patients are lost to
follow-up. Frequently, as patients become more ill and symptomatic, they
will be incapable of completing a questionnaire or unwilling to do so. Yet it
is precisely at this point of disease progression that we are most interested
in assessing changes in quality of life. It may be possible to lengthen the
period that patients remain on-study by assuring that assistance is available
for completing questionnaires, or that questionnaires can be administered in
the form of a brief interview. Ultimately, of course, concern with the well-
being of the patient must outweigh considerations surrounding the metho-
dologic integrity of a study.
206S N.K. Aaronson

CONCLUSION
There is currently a great deal of interest in incorporating quality of life
assessments into clinical trials. This interest can be seen as a logical extension
of the growing concern with the cost-benefit of n e w medical technologies.
In order to maximize the likelihood that quality of life data will attain a
legitimate place in the clinical research process, care must be taken in devel-
oping brief, well-designed instruments that meet rigorous scientific standards.
At the same time, quality of life research designs m u s t reflect an appreciation
of the practical constraints operating in the typical clinical setting. Underlying
these technical issues is the continuing n e e d to refine our u n d e r s t a n d i n g of
the relationship b e t w e e n disease as a biologic process and illness as a social
phenomenon. Ultimately, the goal is to develop evaluation models that achieve
a sophisticated balance b e t w e e n qualitative and quantitative definitions of
therapeutic success.

REFERENCES
1. World Health Organization: The constitution of the World Health Organization.
WHO Chron 1:29, 1947
2. Karnosky DA, Burchenal JH: Clinical evaluation of chemotherapeutic agents in
cancer. In: Evaluation of Chemotherapeutic Agents, McLeod CM, Ed. New York:
Columbia University Press, 1949
3. Campbell A, Converse PE, Rogers WL: The Quality of American Life. New York:
Sage, 1976
4. Schain W, Edwards BK, Rice Gorrel C, et al: Psychosocial and physical outcomes
of primary breast cancer therapy: Mastectomy versus excisional biopsy and irra-
diation. Breast Cancer Res Treat 3:377-382, 1983
5. de Haes JCJM, van Oostrom MA, Welvaart K: The effect of radical and conserving
surgery on the quality of life of early breast cancer patients. Eur J Surg Oncol
12:337-342, 1986
6. Gelber RD, Goldhirsch A: A new endpoint for the assessment of adjuvant therapy
in postmenopausal women with operable breast cancer. J Clin Oncol 4:1772-1779,
1986
7. Coates A, Gebski V, Bishop JF et al: Improving the quality of life during chemo-
therapy for advanced breast cancer. N Engl J Med 317:1490-1495, 1987
8. Sugarbaker PH, Barofsky I, Rosenberg SA, and Gianola FJ: Quality of life assess-
ment of patients in extremity sarcoma clinical trials. Surgery 91:17-23, 1982
9. CAAS Principal Investigators and their Associates: Coronary Artery Surgery Study
(CASS): A randomized trial of coronary artery bypass surgery. Circulation 68:951-
960, 1983
10. Olsson G, Lubsen J, van Es GA, and Rehnqvist N: Quality of life after myocardial
infarction: Effect of long term metoprolol on mortality and morbidity. Br Med J
292:1491-1493, 1986
11. Croog SH, Levine S, Testa MA, et al: The effects of antihypertensive therapy on
the quality of life. N Engl J Med 314:1657-1664, 1986
12. Bombardier C, Ware J, Russel IJ, Larson M, Chalmers A, Leighton Read J: Au-
ranofin therapy and quality of life in patients with rheumatoid arthritis. Am J Med
81:565-578, 1986
13. O'Young J, McPeek B: Quality of life variables in surgical trials. J Chron Dis 40:513-
522, 1987
Quality of Life Assessment in Clinical Trials 207S

14. Spitzer WO, Dobson AJ, Hall J, Chesterman E, Levi J, Shepherd R, Battista RN,
Catchlove BR: Measuring the quality of life of cancer patients: A concise QL-index
for use by physicians. J Chron Dis 34:585-597, 1981
15. Hutchinson TA, Boyd NF, Feinstein AR: Scientific problems in clinical scales as
demonstrated by the Karnofsky index of performance status. J Chron Dis 32:661-
666, 1979
16. Schag CC, Heinrich RL, Ganz PA: Karnofsky performance status revisited: Reli-
ability, validity and guidelines. J Clin Oncol 2:187-193, 1984
17. Grieco A, Long CJ: Investigations of the Karnofsky performance status as a mea-
sure of quality of life. Health Phys 3:129-142, 1984
18. Mor V, Laliberte L, Morris JN: The Karnofsky performance status scale: An ex-
amination of its reliability and validity in a research setting. Cancer 53:2002-2007,
1984
19. Yates JW, Chalmer B, McKegney FP: Evaluation of patients with advanced cancer
using the Karnofsky performance status. Cancer 45:2220-2224, 1980
20. Feinstein AR: Clinimetric perspectives. J Chron Dis 40:635-640, 1987
21. Gough IR, Furnival CM, Schilder L, Grove W: Assessment of the quality of life
of patients with advanced cancer. Eur J Cancer Clin Oncol 19:1161-1165, 1983
22. de Haes JCJM, van Knippenberg FCE: The quality of life of cancer patients: A
review of the literature. Soc Sci Med 20:809-817, 1985
23. Ware JE Jr: Methodological considerations in the selection of health status pro-
cedures. In: Assessment of Quality of Life in Clinical Trials of Cardiovascular
Therapies, Wenger NK, Mattson ME, Furberg CD, Elinson J, Eds. New York: Le
Jacq Publishing, 1984
24. Fayers PM, Jones SDR: Measuring and analyzing the quality of life in cancer clinical
trials: A review. Stat Med 2:429-446, 1983
25. Bergner M, Bobbitt RA, Carter WB, Gilson BS: The Sickness Impact Profile: De-
velopment and final revision of a health status measure. Med Care 19:787-805,
1981
26. Hunt SM, McEwen J: The development of a subjective health indicator. Sociol
Health Ill 2:231-246, 1980
27. Andersen JP, Bush JW, Berry CC: Classifying function for health outcome and
quality of life evaluation: Self versus individual models. Med Care 25:470-479,
1987
28. Schipper H, Clinch J, McMurray A, Levitt M: Measuring the quality of life of
cancer patients: The Functional Living Index--Cancer. J Clin Oncol 2:472-483,
1984
29. Selby PJ, Chapman JA, Etazadi-Amoli J, DaUey D, Boyd NF: The development of
a method of assessing the quality of life for cancer patients. Br J Cancer 50:13-22,
1984
30. Aaronson NK: Methodological issues in psychosocial oncology with special ref-
erence to clinical trials. In: Assessment of Quality of Life and Cancer Treatment,
Ventafridda V, Ed. Amsterdam: Excerpta Medica, 1986
31. Katz S: The science of quality of life. J Chron Dis 40:459-463, 1987
32. Aaronson NK, Bullinger M, Ahmedzai S: A modular approach to quality of life
assessment in cancer clinical trials. Rec Results Cancer Res 111:231-249, 1988
33. Huisman SJ, van Dam FSAM, Aaronson NK, Hanewald GJFP: On measuring
complaints of cancer patients: Some remarks on the time span of the question.
In: The Quality of Life of Cancer Patients, Aaronson NK, Beckmann J, Eds. New
York: Raven, 1987
34. Priestman TJ, Baum M: Evaluation of quality of life in patients receiving treatment
for advanced breast cancer. Lancet 1:899-900, 1976
208S N.K. Aaronson

35. Padilla GV, Presant C, Grant MM, Metter G, Lipsett J, Heide F: Quality of life
index for patients with cancer. Res Nurs Health 6:117-126, 1983
36. Ganz PA, Haskell CM, Figlin RA, La Soto N, Siaus J: Estimating the quality of
life in a clinical trial of patients with metastatic lung cancer using the Karnofsky
performance status and the Functional Living Index--Cancer. Cancer 61:849-856,
1988
37. Lomas J, Pickard L, Mohide A: Patient versus clinician item generation for quality
of life measures. Med Care 25:764-769, 1987
38. Campbell DT, Fiske DW: Convergent and discriminant validation by the multitrait-
multimethod matrix. Psychol Bull 56:81-105, 1959
39. Fallowfield L: Do psychological studies upset patients? In: Syllabus of the Post-
Graduate Course: Current Concepts in Psycho-Oncology and AIDS, Holland JC,
Ed. New York: Memorial Sloan-Kettering Cancer Center, 1987