Nancy Kline Leidy

Recommendations on health-related quality of life research to support labeling and promotional claims in the United States

Health-related quality of life (HRQL) outcomes evaluation is becoming an important component of clinical trials of new pharmaceuticals and medical devices. HRQL research provides patients, providers, and decision makers with important information on the impact of disease and treatment on physical, psychological, and social functioning and well-being. These outcomes are also useful to the pharmaceutical and device industries as they attempt to understand and communicate product value to physicians, patients, health insurers and others. HRQL labeling and promotional claims in the US are likely to increase over the next few years. The evidentiary requirements to make such a claim should be based on accepted scientific standards of HRQL evaluation and consistent with the regulatory requirements for clinical efficacy. This report outlines the scientific practices that should be considered in the evaluation of evidence for an HRQL claim, including the selection of appropriate domains, evidence to support the reliability and validity of HRQL measurement, considerations in research design and statistical analyses, and the issue of clinical significance. Representatives from the pharmaceutical and device industries, regulatory agencies, and the HRQL scientific community should work together to make certain the use of HRQL in labeling and promotion are based on sound scientific evidence, and that these messages are clearly and accurately reported to the consumers.

Health-related quality of life assessment in euthymic and depressed patients with bipolar disorder: Psychometric performance of four self-report measures

The purpose of this study was to evaluate the psychometric properties of selected health-related quality of life (HRQL) self-report measures in 62 euthymic and depressed patients diagnosed with bipolar disorder. Patients completed the Quality of Life in Depression Scale (QLDS), Mental Health Index-17 (MHI-17), Cognitive Function Scale, and Medical Outcomes Study Short Form-36 (SF-36) at baseline and 8 weeks following treatment. Hamilton and Young Rating Scales were used to assess clinical status and validate the HRQL measures. The MHI-17, Cognitive Function Scale, QLDS, and SF-36 social function, vitality, role limitations-emotional, and mental health scales have good reliability and validity, and are responsive to changes in clinical status in patients with bipolar disorder. Although the small sample size limits generalizablity, euthymic and depressed outpatients with bipolar disorder appear to contribute reliable self reports on selected aspects of their quality of life.

Development and preliminary validation of the multiattribute Rhinitis Symptom Utility Index.

The Rhinitis Symptom Utility Index (RSUI) was developed as a preference-based measure of rhinitis symptoms. The RSUI consist of ten questions on the severity and frequency of stuffy or blocked nose, runny nose, sneezing, itching, watery eyes and itching nose or throat over a 14 day period. A cross-sectional survey of 100 adults with allergic rhinitis was completed, with data collected on rhinitis history and severity, physician-rated rhinitis severity, the Rhinitis Quality of Life Questionnaire (RQLQ) and the Health Utilities Index Mark 2 (HUI2). The mean age of the patients was 37±11 years and 60% were female and 38% had a diagnosis of asthma. A multiplicative multiattribute utility function was developed from patient-derived preferences for different rhinitis-related symptom states. The mean RSUI score for this sample was 0.72±0.23, with a range of 0.15–1.0. Two week reproducibility of the RSUI was weak (ICC=0.40). The index differentiated patients by physician-rated severity (p<0.05) and was correlated 0.35 (p<0.001) with the HUI2 and −0.67 (p<0.001) with the RQLQ total score. The RSUI is brief and easy to administer and the results of this study support its reliability and validity. The modest reproducibility reflects the day to day variability of rhinitis. The RSUI may be a useful patient outcome for clinical trials and for cost-effectiveness studies comparing medical treatments for rhinitis.

A comparative trial of paper-and-pencil versus computer administration of the Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire.

Background .Although most health-related quality of life questionnaires are self-administered by means of paper and pencil, new technologies for automated computer administration are becoming more readily available. Novel methods of instrument administration must be assessed for score equivalence in addition to consistency in reliability and validity. Objectives .The present study compared the psychometric characteristics (score equivalence and structure, internal consistency, and reproducibility reliability and construct validity) of the Quality of Life in Reflux And Dyspepsia (QOLRAD) questionnaire when self-administered by means of paper and pencil versus touch-screen computer. The influence of age, education, and prior experience with computers on score equivalence was also examined. Research Design .This crossover trial randomized 134 patients with gastroesophageal reflux disease to 1 of 2 groups: paper-and-pencil questionnaire administration followed by computer administration or computer administration followed by use of paper and pencil. To minimize learning effects and respondent fatigue, administrations were scheduled 3 days apart. A random sample of 32 patients participated in a 1-week reproducibility evaluation of the computer-administered QOLRAD. Results .QOLRAD scores were equivalent across the 2 methods of administration regardless of subject age, education, and prior computer use. Internal consistency levels were very high (&agr; = 0.93–0.99). Interscale correlations were strong and generally consistent across methods (r = 0.75–0.87). Correlations between the QOLRAD and Short Form 36 (SF-36) were high, with no significant differences by method. Test-retest reliability of the computer-administered QOLRAD was also very high (ICC = 0.93–0.96). Conclusions.Results of the present study suggest that the QOLRAD is reliable and valid when self-administered by means of computer touch-screen or paper and pencil.

The Impact of Asthma on Health-Related Quality of Life

Although a substantial body of epidemiological and economic literature on asthma exists, relatively little is known about the impact of asthma on health-related quality of life (HRQL). The purpose of this review was to synthesize results from recent studies, profile the factors influencing HRQL in asthmatics, discuss the impact of treatment on HRQL outcomes, and offer recommendations for further research. The results of this review support the premise that asthma can adversely affect the physical, psychological, and social domains of HRQL. Published data suggest that females, those from lower socioeconomic groups, and ethnic minorities experience poorer quality of life as a result of their asthma symptoms. Results of published clinical trials indicate treatment regimens can have a significant impact on HRQL outcomes. Pharmacological interventions appear to effect change primarily in the physical domain and behavioral interventions lead to improvements in both physical and psychosocial domains. Future research should focus on precise a priori delineation of research hypotheses, including the selection of primary and secondary endpoints, the clarification and consistent application of criteria for defining asthma severity, thoughtful selection of HRQL instruments appropriate for the research hypotheses and target population, and careful delineation of clinically meaningful change scores of asthma-specific outcome measures.

Characterizing and Quantifying the Symptomatic Features of COPD Exacerbations

BACKGROUND There is a need for a standardized, valid, and reliable instrument for quantifying exacerbations of COPD. The objective of this study was to identify symptom items that characterize COPD exacerbations to form a new patient diary for evaluating exacerbation frequency, severity, and duration. METHODS Twenty-three symptom items identified from patient interviews were administered to 410 patients with COPD aged (mean ± SD) 65 ± 10 years with stable FEV(1) of 51% predicted ± 20% predicted and 1.8 ± 1.8 exacerbations in the preceding 12 months. A total of 222 patients had a physician-diagnosed exacerbation; 188 were stable. Item-level analyses (floor and ceiling effects, criterion keying, item-total correlation) were used in the first stage of item reduction. Further reduction was conducted using Rasch model and descriptive item analyses. Exploratory factor analysis was performed on the items that survived the exclusion process. RESULTS No item behaved differently between stable and exacerbation conditions. One item was removed after item-level analysis, and eight were removed following Rasch analysis. Together, the surviving 14 items met the criteria for a unidimensional measure of exacerbation severity. Internal consistency (person separation index) was excellent at 0.92. Post hoc exploratory factor analysis revealed one dominant factor, with three domains (breathlessness, cough and sputum, and chest symptoms) that accounted for 68% of the variance. CONCLUSIONS An exacerbation appears to be a quantitative rather than qualitative change from the stable state. This analysis identified a range of symptoms that form a unidimensional construct of overall exacerbation severity. The 14 items identified form the Exacerbations of Chronic Pulmonary Disease Tool (EXACT), a daily diary for detecting and quantifying exacerbation severity in COPD.

Does epoetin alfa improve health-related quality of life in chronically ill patients with anemia? Summary of trials of cancer, HIV/AIDS, and chronic kidney disease.

OBJECTIVES Anemia, defined as having low levels of hemoglobin (HGB), is caused by disease-related (e.g., bone marrow suppression, nutritional deficiency) or treatment-related (e.g., chemotherapy, antiretroviral therapy) factors. Although epoetin alfa has been shown to improve HGB outcomes in cancer, HIV/AIDS, and chronic kidney disease (CKD), these results have been viewed in isolation, rather than across populations. The purpose of this article is to review findings from trials that evaluated the impact of epoetin alfa on HGB and health-related quality of life (HRQL) across various populations with different underlying causes of anemia. METHODS A review of clinical trials published in English between January 1993 and September 2005. Searches were conducted using MEDLINE and EMBASE. Between- and within-group changes in HGB and HRQL were examined. RESULTS One hundred ten articles were retrieved and 18 were reviewed. Statistically significant improvements in HGB were generally seen (1) between groups for cancer patients receiving epoetin alfa compared with those receiving placebo or standard of care (SOC) (between-group differences in changes from baseline to end point ranging from 1.2 to 1.9 g/dl); and (2) within groups for HIV/AIDS and CKD patients receiving epoetin alfa (changes from baseline to end point of 2.5 and 2.9 g/dl and 2.7 g/dl, respectively). Statistically and clinically significant improvements in HRQL, particularly with regard to fatigue, were seen across chronic conditions based on the Linear Analog Scale Assessment energy scale; where improvements of at least 8 mm-considered clinically relevant-were generally seen (1) between groups for cancer patients receiving epoetin alfa compared with those receiving placebo or SOC (differences in changes from baseline to end point from 0.8 to 19.8 mm); and (2) within groups for HIV/AIDS and CKD patients receiving epoetin alfa (changes from baseline to end point of 23 and 25 mm and 28 mm, respectively). CONCLUSIONS Results of published clinical trials suggest that treatment of anemia associated with cancer, HIV/AIDS and CKD can have a significant impact on HRQL, particularly fatigue, and that this impact is both statistically and clinically significant.

The complexity of treatment adherence in adults with asthma: challenges and opportunities.

The therapeutic program for persons with asthma includes recommendations for altering the environment and a drug regimen designed to alleviate symptoms, minimize exacerbations, and improve quality of life. Unfortunately, patients can have difficulty adhering to these recommendations, which contributes to treatment failure and increased costs. This paper provides a comprehensive review of the challenge of adherence in adults with asthma, including the costs and benefits, optimal adherence levels, assessment methods commonly used in research and practice, factors believed to predict poor adherence, and tested and untested strategies for improving adherence. Opportunities for further research are discussed throughout the paper.

Measuring functional performance in patients with COPD: a discussion of patient-reported outcome measures

ABSTRACT Background: Chronic obstructive pulmonary disease (COPD) is a chronic condition and a major public health concern. Moreover, its prevalence is increasing. COPD commonly affects patient performance of daily activities that people perform in order to meet basic needs, fulfill usual roles, and maintain their health and well-being. What types of activities are affected and to what degree≟ How do these effects change over time? What impact, positive or negative, do various treatments have on the capacity of patients to perform activities? To address these questions, the concept of activity performance must be defined and appropriately measured. Methods: This paper presents a model of function that defines functional performance as distinct but related to physiological impairments and functional capacity. A systematic review of the literature was conducted to locate patient-reported outcome (PRO) instruments that have been used to capture functional performance in clinical studies of COPD and have been validated with patients with COPD. The content of each measure was reviewed to assess depth and breadth of coverage. Results: The systematic review yielded nine validated PROs used to capture functional performance in clinical studies of COPD: three are generic; six were designed specifically for use in patients with COPD. Variability in content coverage occurred across the PROs, with some sacrificing depth for breadth. Few of the PROs covered the full range of content as defined in the model. Limiting selected PROs to those that have been used with patients with COPD, while relevant to this population, may preclude other PRO instruments that can measure functional performance. The relevance of another instrument would, however, need to be confirmed with patients with COPD. Conclusions: Selection of endpoints and instruments for clinical studies of COPD and its treatment must be driven by a clear definition of concepts of interest and the relevance of content areas to patients. Some existing instruments may provide adequate coverage of endpoints or content areas under investigation. Others clearly will not.

Performance of the EXAcerbations of Chronic Pulmonary Disease Tool Patient-reported Outcome Measure in Three Clinical Trials of Chronic Obstructive Pulmonary Disease

RATIONALE The EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) is a patient-reported outcome measure to standardize the symptomatic assessment of chronic obstructive pulmonary disease exacerbations, including reported and unreported events. The instrument has been validated in a short-term study of patients with acute exacerbation and stable disease; its performance in longer-term studies has not been assessed. OBJECTIVES To test the EXACTs performance in three randomized controlled trials and describe the relationship between resource-defined medically treated exacerbations (MTEs) and symptom (EXACT)-defined events. METHODS Prespecified secondary analyses of data from phase II randomized controlled trials testing new drugs for the management of chronic obstructive pulmonary disease: one 6-month trial (United States) (n = 235) and two 3-month, multinational trials (AZ 1 [n = 749], AZ 2 [n = 597]). In each case, the experimental drugs were found to be ineffective, permitting assessment of the EXACTs performance in three independent studies of moderate to severe high-risk patients on maintenance therapies. MEASUREMENTS AND MAIN RESULTS The mean age of subjects was 62 to 64 years; 48 to 76% were male. Mean FEV1 % predicted was 42 to 59%. EXACT scores exhibited internal consistency (Cronbachs α ≥ 0.90), reproducibility (intraclass correlation ≥ 0.70), correlation with St. Georges Respiratory Questionnaire (Spearman rho [rs] = 0.62, 0.46, 0.46 in the three trials; P < 0.001), and Breathlessness Cough and Sputum Scale (AZ 1, rs = 0.83; AZ 2, rs = 0.83; P < 0.001). EXACT-defined events had a high correspondence with alternative indicators of worsening (94, 88, and 93%). In each trial, unreported events were similar in severity (mean EXACT score, 56, 57, 61 vs. 53, 54 [P < 0.05], 57 [P < 0.05], respectively; 100-point scale) and longer (median, 9, 8, 7 vs. 8, 7 [P < 0.01], 6 days, respectively) than moderate MTEs. CONCLUSIONS Data generated through the EXACT offers insight into the symptomatic nature of MTEs and the frequency, severity, and duration of unreported symptom-defined events. Clinical trials registered with www.clinicaltrials.gov (MPEX: NCT00739648; AZ 1: NCT00949975; AZ 2: NCT01023516).