1
Introduction

Summary

A key methodology for the evaluation of therapies is the randomised controlled trial (RCT). These clinical trials traditionally considered relatively objective clinical outcome measures, such as cure, biological response to treatment, or survival. Later, investigators and patients alike have argued that subjective indicators should also be considered. These subjective patient-reported outcomes are often regarded as indicators of quality of life. They comprise a variety of outcome measures, such as emotional functioning (including anxiety and depression), physical functioning, social functioning, pain, fatigue, other symptoms and toxicity. A large number of questionnaires, or instruments, have been developed for assessing patient-reported outcomes and quality of life, and these have been used in a wide variety of circumstances. This book is concerned with the development, analysis and interpretation of data from these quality of life instruments.

1.1 Patient-reported outcomes

This book accepts a broad definition of quality of life, and discusses the design, application and use of single- and multi-item, subjective, measurement scales. This encompasses not just 'overall quality of life' but also the symptoms and side effects that may or may not reflect - or affect - quality of life. Some researchers prefer to emphasise that we are only interested in health aspects, as in health-related quality of life (HRQoL or HRQL), while others adopt the terms patient-reported outcomes (PROs) or patient-reported outcome measures (PROMs), because those terms indicate interest in a whole host of outcomes, such as pain, fatigue, depression through to physical symptoms such as nausea and vomiting. But not all subjects are 'patients' who are ill; it is also suggested that PRO could mean person-reported outcome. Health outcomes assessment has also been proposed, which emphasises that the focus is on health issues and also avoids specifying the respondent: for young children and for the cognitively impaired we may use proxy assessment for cognitive reasons. And for many years some questionnaires have focused on health status or self-reported health (SRH), with considerable overlap to quality of life.

From a measurement perspective, this book is concerned with all the above. For simplicity we will use the now well-established overall term quality of life (QoL) to indicate (a) the set of outcomes that contribute to a patient's well-being or overall health, or (b) a summary measure or scale that purports to describe a patient's overall well-being or health. Examples of summary measures for QoL include general questions such as 'How good is your overall quality of life?' or 'How do you rate your overall health?' that represent global assessments. When referring to outcomes that reflect individual dimensions, we use the acronym PROs. Examples of PROs are pain or fatigue; symptoms such as headaches or skin irritation; function, such as social and role functioning; issues such as body image or existential beliefs; and so on. Mostly, we shall assume the respondent is the patient or person whose experience we are interested in (self-report), but it could be a proxy.

The measurement issues for all these outcomes are similar. Should we use single- or multi-item scales? Content and construct validity - are we measuring what we intend? Sensitivity, reliability, responsiveness - is the assessment statistically adequate? How should such assessments be incorporated into clinical studies? And how do we analyse, report and interpret the results?

1.2 What is a patient-reported outcome?

The definition of patient-reported outcome is straightforward, and has been described as "any report of the status of a patient's health condition that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else" (US FDA, 2009). A PRO can be measured by self-report or by interview provided that the interviewer records only the patient's response. The outcome can be measured in absolute terms (e.g. severity of a symptom, sign or state of a disease) or as a change from a previous assessment.

1.3 What is quality of life?

In contrast to PRO, the term Quality of life is ill defined. The World Health Organization (WHO, 1948) declares health to be 'a state of complete physical, mental and social well-being, and not merely the absence of disease'. Many other definitions of both 'health' and 'quality of life' have been attempted, often linking the two and, for QoL, frequently emphasising components of happiness and satisfaction with life. In the absence of any universally accepted definition, some investigators argue that most people, in the Western world at least, are familiar with the expression 'quality of life' and have an intuitive understanding of what it comprises.

However, it is clear that 'QoL' means different things to different people, and takes on different meanings according to the area of application. To a town planner, for example, it might represent access to green space and other facilities. In the context of clinical trials we are rarely interested in QoL in such a broad sense, and instead are concerned only with evaluating those aspects that are affected by disease or treatment for disease. This may sometimes be extended to include indirect consequences of disease, such as unemployment or financial difficulties. To distinguish between QoL in its more general sense and the requirements of clinical medicine and clinical trials the term health-related quality of life (HRQoL) is frequently used in order to remove ambiguity.

Health-related QoL is still a loose definition. What aspects of QoL should be included? It is generally agreed that the relevant aspects may vary from study to study but can include general health, physical functioning, physical symptoms and toxicity, emotional functioning, cognitive functioning, role functioning, social well-being and functioning, sexual functioning and existential issues. In the absence of any agreed formal definition of QoL, most investigators circumvent the issues by describing what they mean by QoL, and then letting the items (questions) in their questionnaire speak for themselves. Thus some questionnaires focus upon the relatively objective signs such as patient-reported toxicity, and in effect define the relevant aspects of QoL as being, for their purposes, limited to treatment toxicity. Other investigators argue that what matters most is the impact of toxicity, and therefore their questionnaires place greater emphasis upon psychological aspects, such as anxiety and depression. Yet others try to allow for spiritual issues, ability to cope with illness and satisfaction with life.

Some QoL instruments focus upon a single concept, such as emotional functioning. Other instruments regard these individual concepts as aspects, or dimensions, of QoL, and therefore include items relating to several concepts. Although there is disagreement about what components should be evaluated, most investigators agree that a number of the above dimensions should be included in QoL questionnaires, and that QoL is a multidimensional construct. Because there are so many potential dimensions, it is impractical to try to assess all these concepts simultaneously in one instrument. Most instruments intended for health-status assessment include at least some items that focus upon physical, emotional and social functioning. For example, if emotional functioning is accepted as being one aspect of QoL that should be investigated, several questions could evaluate anxiety, tension, irritability, depression and so on. Thus instruments may contain many items. Although a single global question such as 'How would you rate your overall quality of life?' is a useful adjunct to multi-item instruments, global questions are often regarded as too vague and non-specific to be used on their own. Most of the general questionnaires that we describe include one or more global questions alongside a number of other items covering specific issues. Some instruments place greater emphasis upon the concept of global questions, and the EQ-5D questionnaire (Appendix E4) asks a parsimonious five questions before using a single global question that enquires about 'your health'. Even more extreme is the Perceived Adjustment to Chronic Illness Scale (PACIS) described by Hürny et al. (1993). This instrument consists of a single, carefully phrased question that is a global indicator of coping and adjustment: 'How much effort does it cost you to cope with your illness?' This takes responses ranging between 'No effort at all' and 'A great deal of effort'.

One unifying and non-controversial theme throughout all the approaches is that the concepts forming these dimensions can be assessed only by subjective measures, PROs, and that they should be evaluated by asking the patient. Proxy assessments, by a relative or other close observer, are usually employed only if the patient is unable to make a coherent response, for example...