Review ArticleRecommended methods for determining responsiveness and minimally important differences for patient-reported outcomes
Introduction
Patient-reported outcomes (PROs) are frequently incorporated in clinical trials comparing health interventions for chronic diseases. These PROs include measures of health-related quality of life (HRQL), symptoms, and treatment satisfaction. PROs provide the patient's perspective and help us understand the effects of disease and treatment on symptoms, functioning, and other outcomes [1], [2], [3]. For many chronic diseases, PROs represent one of the most important health outcomes for evaluating the effectiveness of treatments and changes in disease trajectory. As far back as Hippocrates, listening to the patient has been considered an integral part of medical science [4]. Therefore, the patient's perspective of her health is integral to understanding health outcomes. The application of relevant and psychometrically sound PROs in clinical trials assists patients, their family members, and clinicians in understanding the comprehensive impact of treatment on patient symptoms, functioning, treatment preferences, and general well being.
To be useful in clinical trials evaluating new health interventions, PROs, similar to other health outcomes, must have acceptable reliability and validity [1], [2], [5], [6]. Responsiveness is an aspect of construct validity [7] and is determined by evaluating the relationship between changes in clinical and patient-based endpoints and changes in the PRO scores over time, or based on the application of a treatment of known and demonstrated efficacy [2], [5], [8]. Responsiveness can be evaluated based on observational studies or in clinical trials. Evidence supporting responsiveness and for interpreting PRO results is critical for clinical trial settings. Information on the interpretation of changes or differences in PRO scores is based on the minimal important difference (MID). Demonstrating a MID is also important evidence for achieving successful PRO claims through regulatory agencies [9], [10]. Nonetheless, virtually all instruments found to differentiate among clinically distinct groups are also found to be responsive to change.
Although responsiveness and interpretation of PRO measures have been discussed for the past 15 years or more [2], [5], [7], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], recommendations about the best approach for evaluating responsiveness and determining MIDs for PRO instruments are still needed. For example, the FDA requested further information and guidance on methods for determining responsiveness and MID [9]. Although there is an evolving consensus as to the best approach to evaluating responsiveness and MID [25], [26], [29], there is no clear statement about the recommended methods and about important issues underlying responsiveness and MID.
This report focuses on issues and recommendations for evaluating responsiveness and MID for PRO measures in chronic disease. These issues are especially germane given that for most chronic diseases cure is not feasible, and that the main objective of treatment is to maintain or improve patient functioning and well being. The remainder of this report will cover (1) conceptual issues and definitions; (2) methods for evaluating responsiveness and MID; (3) recommended decision criteria for determining MID; and (4) summary and conclusions. We will illustrate methods and concepts using published health outcomes literature.
Section snippets
Interpretation of PROs: conceptual issues and definitions
PROs require the patient to assign a response to questions (or statements) about their perceptions or activities, such as symptoms, capabilities, or performance of roles or responsibilities. These responses are typically combined in some way to create summary scores that can be used to measure concepts such as physical, psychological, or social functioning and well being, or symptom burden or severity. Symptoms can be rated based on frequency, severity, duration, degree of bother, or impact on
Methods of evaluating responsiveness and clinical significance
Longitudinal studies are needed to determine whether a PRO instrument is responsive to changes or differences. These studies may be randomized clinical trials comparing treatments of known efficacy or observational studies where patients are treated with usual medical care and followed over relevant periods of time. For clinical trial designs, there needs to be some evidence that the treatment is effective and that the expected changes in clinical status are linked to expected changes in the
Recommended decision criteria for determining MID
The application of multiple methods to determine the MID for a PRO instrument in a specific patient population will almost always result in a range of values for the MID. This is the essence of triangulation, that is, examining multiple values from different approaches and hopefully converging on a small range of values (or one single value). It is recommended that the different MID estimates be graphed to visually depict the range of estimates. Figure 1 provides a summary of MID estimates from
Summary and conclusions
For PRO endpoint data to be accepted as evidence of treatment efficacy there must be evidence documenting the instrument's conceptual framework, content validity, and psychometric qualities. For responsiveness, it is necessary to demonstrate that the PRO scores are sensitive to actual changes in health status. Although demonstrating responsiveness is a key component to establishing an instrument's construct validity, it is also important to determine the MID to assist in interpreting
Acknowledgments
This paper was supported in part by Genentech, South San Francisco, California, the UCLA/DREW Project EXPORT, National Institutes of Health, National Center on Minority Health & Health Disparities, (P20-MD00148-01), the UCLA Center for Health Improvement in Minority Elders/Resource, Centers for Minority Aging Research, National Institutes of Health, National Institute of Aging, (AG-02-004), and the National Institute of Aging (AG20679-01).
References (52)
- et al.
Recommendations for evaluating the validity of quality of life claims for labeling and promotion
Value Health
(1999) - et al.
Measuring change over time: assessing the usefulness of evaluative instruments
J Chronic Dis
(1987) - et al.
Measurement of health status. Ascertaining the minimal clinically important difference
Contr Clin Trials
(1989) - et al.
Group vs individual approaches to understanding the clinical significance of differences or changes in quality of life
Mayo Clin Proc
(2002) - et al.
Methods to explain the clinical significance of health status measures
Mayo Clin Proc
(2002) - et al.
Defining clinically meaningful change in health-related quality of life
J Clin Epidemiol
(2003) - et al.
Clinical significance of patient-reported questionnaire data: another step toward consensus
J Clin Epidemiol
(2005) - et al.
Minimally important differences were estimated for the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) instrument using a combination of distribution- and anchor-based approaches
J Clin Epidemiol
(2005) - et al.
Combining anchor and distribution based methods to derive minimal clinically important differences on the Functional Assessment of Cancer Therapy anemia and fatigue scales
J Pain Symptom Manage
(2002) - et al.
Assessing meaningful changes in quality of life over time: a user's guide for clinicians
Mayo Clin Proc
(2002)
Determining a minimal important chance in the disease-specific quality of life questionnaire
J Clin Epidemiol
Impact of omalizumab on quality-of-life outcomes in patients with moderate-to-severe allergic asthma
Ann Allergy Asthma Immunol
Further evidence supporting an SEM-based criteria for identifying meaningful intra-individual changes in health-related quality of life
J Clin Epidemiol
Recommendations on health-related quality of life research to support labeling and promotional claims in the United States
Qual Life Res
Measuring treatment impact: a review of patient-reported outcomes and other efficacy endpoints in approved product labels
Contr Clin Trials
Reliability and validity (including responsiveness)
Quality of life: Assessment, analysis and interpretation
Responsiveness to change: an aspect of validity, not a separate dimension
Qual Life Res
Guidance for industry—patient-reported outcome measures: Use in medical product development to support labeling claims
Reflection paper on the regulatory guidance for the use of health-related quality of life (HRQL) measures in the evaluation of medicinal products
Clinical significance: a statistical approach to defining meaningful change in psychotherapy research
J Clin Consult Psychol
Evaluating measurement responsiveness
J Rheumatol
Interpretation of quality of life changes
Qual Life Res
Interpreting pharmacoeconomic and quality-of-life clinical trial data for use in therapeutics
Pharmacoeconomics
Interpreting the significance of changes in health-related quality of life scores
J Clin Oncol
Cited by (1603)
Minimal clinically important differenceof fatigue severity scale in patients with chronic stroke
2024, Journal of Stroke and Cerebrovascular DiseasesMinimal clinically important difference in maxillofacial trauma patients: a prospective cohort study
2024, British Journal of Oral and Maxillofacial Surgery