Many advances in the treatment and care of cancer patients have been
closely linked to the availability of more effective pharmaceutical
agents. As research continues to develop new and improved
chemotherapeutic agents, it is heartening that the FDA maintains a
flexible approach to the drug approval process and will consider an
array of indicators of drug efficacy, including patient self-reports
of health-related quality of life. Dr. Beitzs article provides
an overview of some of the issues related to study design and data
analysis and interpretation that emerge when health-related quality
of life is used as an end point in such trials.
The article includes a number of helpful suggestions for the
development of strategies in drug evaluation. It also raises some
additional questions. I will focus on two issues: (1) the
interpretation of multiple end points, and (2) the meaning of
Multiple Indicators of Health-Related Quality of Life
Dr. Beitz cites studies that included multiple indicators of drug
efficacy. For example, studies examining the effects of mitoxantrone
(Novantrone) plus prednisone in patients with hormone-refractory
prostate cancer included patient-reported changes in pain scores and
analgesia, in addition to standard assessments of tumor response.
Studies comparing gemcitabine (Gemzar) and fluorouracil used the
outcome of clinical benefit response, a composite of both
patient self-reports (ie, pain intensity, analgesic use), observer
ratings (ie, Karnofsky performance status), and physical data (ie,
weight change). Whether a patient was rated as having a clinical
benefit response was specified by a complex algorithm.
When multiple indicators of health-related quality of life are used,
the investigator is faced with the possibility that the measures will
yield inconsistent results. For example, Malia Wilson and I recently
reviewed the use of quality-of-life assessment in cancer clinical
trials. We identified three randomized, placebo-controlled studies
comparing well-being in patients with advanced nonsmall-cell
lung cancer (NSCLC) or colorectal cancer who received treatment with
hydrazine sulfate or placebo.[2-4] All three studies included
survival, toxicity, and quality-of-life end points.
The findings of our review indicated inconsistent interrelationships
among outcomes: For example, toxicity and quality of life yielded a
similar pattern of results in the two NSCLC studies[2,4] that was not
upheld in the colorectal study. Also, decrements in survival
correlated with decrements in quality of life in the colorectal study
by Loprinzi et al but not in the same groups NSCLC study.
In these three studies, the interpretation was facilitated because
hydrazine sulfate did not result in better outcomes, regardless of
indicator. However, what if an agent led to better survival but worse
toxicity and quality of life? Moreover, is it possible that patients
might experience more toxicity but better quality of life?
In the case of the studies of gemcitabine vs fluorouracil discussed
by Dr. Beitz, an analysis of individuals who could complete two
cycles of therapy indicated comparable reductions in pain intensity
in the two groups but lower analgesic use and higher Karnofsky status
in the gemcitabine group. It is somewhat difficult to reconcile these
findings, which raise a number of questions: For example, is there
something about gemcitabine that lowers analgesic use, or,
alternatively, something about fluorouracil that increases its use?
Is a physicians perception of how well a patient is doing
affected by how many prescriptions are being written? Thus, could
Karnofsky ratings have been affected by whether a patient was taking
analgesics? If patients had been asked about their satisfaction with
treatment, would pain intensity have been a more powerful predictor
than analgesic use or physician ratings, thus indicating equivalent
effects of both agents on health-related quality of life from the
patients perspective? Clearly, relationships among study
outcomes are complex and warrant further study.
Meaning of Effectiveness
Throughout Dr. Beitzs paper, health-related quality of life is
referred to as providing evidence of drug effectiveness
that will lead to drug approval. Effectiveness is also
the theme of the FDA documents cited at the end of the article.
However, Dr. Beitz and her FDA colleagues appear to be using this
term somewhat differently than it is being applied in much of the
health services literature. For example, Hays et al define
efficacy as what is possible, as compared to
effectiveness, which is what happens under existing
The studies described by Dr. Beitz seem more relevant to establishing
what is possibleie, whether a drug can confer patient
benefitthan to determining how a drug performs outside of the
setting of controlled research. This inference is supported by Dr.
Beitzs recommendation of phase III clinical trials as the
preferred design to assess health-related quality of life outcomes.
Advantages and Disadvantages of Phase III Trials
There are distinct advantages to a phase III design. For example,
phase III studies control for many biases that threaten the
interpretation of study results: Patient selection biases are largely
eliminated, and exposure to the experimental condition (eg, drug
administration) can be specified precisely.
At the same time, phase III design is subject to other biases,
particularly those related to external validity: Patients in clinical
trials are often highly selected, and settings in which clinical
trials are conducted may have standards of care that differ
significantly from those in nonresearch settings.
In fact, only a small percentage of cancer patients participate in
clinical trials; this percentage has been estimated to be 6%. Most
clinical trial participants are unrepresentative of typical cancer
patients in a number of ways. For example, trial participants are
likely to be younger: An analysis of Southwest Oncology Group
therapeutic registrations over a 4-year period indicated that
individuals over 65 years of age constituted only 23% of trial
participants, whereas 54% of cancer cases are diagnosed in patients
who fall into this age group.
Beyond Phase III Trials
Thus, to provide adequate examination of the full effectiveness of
cancer drugsie, how these drugs work in the patients and
setting typically found in oncology clinical practiceone may
need to go beyond phase III clinical trials. In fact, phase IV,
postmarketing trials provide an ideal opportunity to
examine how approved drugs actually perform in the context of patient
and environmental factors that may influence acceptance, tolerance,
and adherence to therapy. These factors can include comorbidity and
intercurrent disease, availability of supportive and symptomatic
care, transportation to treatment centers, economic factors
(including health insurance and systems of health care), and patient
and family preferences. Factors such as these can have a major
influence on the effectiveness of drug therapies in the real
world and can be examined through a variety of study designs.
Multiple kinds of assessments can yield useful information about
health-related quality of life in cancer patients, and various
experimental and analytic designs may be appropriate, depending on
the objectives of a particular study. Dr. Beitzs paper clearly
communicates the FDAs flexible approach to evaluating new
agents so that they will be available to cancer patients. It is hoped
that the FDA will encourage continued evaluation of how these
pharmaceuticals affect health-related quality of life as they are
used in everyday clinical practice.
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