Use of existing patient-reported outcome (PRO) instruments and their modification: the ISPOR Good Research Practices for Evaluating and Documenting Content Validity for the Use of Existing Instruments and Their Modification PRO Task Force Report.

BACKGROUND: Patient-reported outcome (PRO) instruments are used to evaluate the effect of medical products on how patients feel or function. This article presents the results of an ISPOR task force convened to address good clinical research practices for the use of existing or modified PRO instruments to support medical product labeling claims. The focus of the article is on content validity, with specific reference to existing or modified PRO instruments, because of the importance of content validity in selecting or modifying an existing PRO instrument and the lack of consensus in the research community regarding best practices for establishing and documenting this measurement property. METHODS: Topics addressed in the article include: definition and general description of content validity; PRO concept identification as the important first step in establishing content validity; instrument identification and the initial review process; key issues in qualitative methodology; and potential threats to content validity, with three case examples used to illustrate types of threats and how they might be resolved. A table of steps used to identify and evaluate an existing PRO instrument is provided, and figures are used to illustrate the meaning of content validity in relationship to instrument development and evaluation. RESULTS & RECOMMENDATIONS: Four important threats to content validity are identified: unclear conceptual match between the PRO instrument and the intended claim, lack of direct patient input into PRO item content from the target population in which the claim is desired, no evidence that the most relevant and important item content is contained in the instrument, and lack of documentation to support modifications to the PRO instrument. In some cases, careful review of the threats to content validity in a specific application may be reduced through additional well documented qualitative studies that specifically address the issue of concern. CONCLUSION: Published evidence of the content validity of a PRO instrument for an intended application is often limited. Such evidence is, however, important to evaluating the adequacy of a PRO instrument for the intended application. This article provides an overview of key issues involved in assessing and documenting content validity as it relates to using existing instruments in the drug approval process.

Psychometric properties of a single-item scale to assess sleep quality among individuals with fibromyalgia.

BACKGROUND: Sleep disturbances are a common and bothersome symptom of fibromyalgia (FM). This study reports psychometric properties of a single-item scale to assess sleep quality among individuals with FM. METHODS: Analyses were based on data from two randomized, double-blind, placebo-controlled trials of pregabalin (studies 1056 and 1077). In a daily diary, patients reported the quality of their sleep on a numeric rating scale ranging from 0 ("best possible sleep") to 10 ("worst possible sleep"). Test re-test reliability of the Sleep Quality Scale was evaluated by computing intraclass correlation coefficients. Pearson correlation coefficients were computed between baseline Sleep Quality scores and baseline pain diary and Medical Outcomes Study (MOS) Sleep scores. Responsiveness to treatment was evaluated by standardized effect sizes computed as the difference between least squares mean changes in Sleep Quality scores in the pregabalin and placebo groups divided by the standard deviation of Sleep Quality scores across all patients at baseline. RESULTS: Studies 1056 and 1077 included 748 and 745 patients, respectively. Most patients were female (study 1056: 94.4%; study 1077: 94.5%) and white (study 1056: 90.2%; study 1077: 91.0%). Mean ages were 48.8 years (study 1056) and 50.1 years (study 1077). Test re-test reliability coefficients of the Sleep Quality Scale were 0.91 and 0.90 in the 1056 and 1077 studies, respectively. Pearson correlation coefficients between baseline Sleep Quality scores and baseline pain diary scores were 0.64 (p < 0.001) and 0.58 (p < 0.001) in the 1056 and 1077 studies, respectively. Correlations between the Sleep Quality Scale and the MOS Sleep subscales were statistically significant (p < 0.01), except for the MOS Snoring subscale. Across both studies, standardized effect sizes were generally moderate (0.46 to 0.52) for the 300 mg group and moderate (0.59) or moderate-to-large (0.70) for the 450 mg group. In study 1056, the effect size for the 600 mg group was moderate-to-large (0.73). In study 1077, the effect size for the 600 mg group was large (0.82). CONCLUSION: These results provide evidence of the reproducibility, convergent validity, and responsiveness to treatment of the Sleep Quality Scale and provide a foundation for its further use and evaluation in FM patients.

What do we know about quality of life in dementia? A review of the emerging evidence on the predictive and explanatory value of disease specific measures of health related quality of life in people with dementia.

OBJECTIVE: Given its complexity, there is growing consensus on the need to measure patient-rated broad outcomes like health-related quality of life (HRQL) as well as discrete functions like cognition and behaviour in dementia. This review brings together current data on the distribution, determinants and course of HRQL in dementia to investigate the predictive and explanatory value of measures of HRQL in people with dementia. DESIGN: A systematic review of papers in English published up to October 2007 to identify data on the use of disease-specific measures of HRQL in dementia. RESULTS: There are no clear or consistent associations between socio-demographic variables and HRQL. There is no convincing evidence that lower cognition or greater activity limitation is associated with lower HRQL. There is a strong suggestion that depression is consistently associated with decreased HRQL in dementia. However, the magnitude of the associations observed is moderate only and the proportion of variance explained is low suggesting that depression and HRQL are different constructs. We currently know almost nothing about the natural history of HRQL in dementia or what attributes or interventions promote or inhibit HRQL life for people with dementia. CONCLUSIONS: While in other illnesses there may be simple association between HRQL and an easily measurable clinical variable, in dementia this is not so. There are now instruments available with which to measure disease-specific HRQL directly in clinical trials and other studies that can yield informative data.

Moving Towards Accountability for Reasonableness - A Systematic Exploration of the Features of Legitimate Healthcare Coverage Decision-Making Processes Using Rare Diseases and Regenerative Therapies as a Case Study.

BACKGROUND: The accountability for reasonableness (A4R) framework defines 4 conditions for legitimate healthcare coverage decision processes: Relevance, Publicity, Appeals, and Enforcement. The aim of this study was to reflect on how the diverse features of decision-making processes can be aligned with A4R conditions to guide decision-making towards legitimacy. Rare disease and regenerative therapies (RDRTs) pose special decision-making challenges and offer therefore a useful case study. METHODS: Features operationalizing each A4R condition as well as three different approaches to address these features (cost-per-QALY-focused and multicriteria-based) were defined and organized into a matrix. Seven experts explored these features during a panel run under the Chatham House Rule and provided general and RDRT-specific recommendations. Responses were analyzed to identify converging and diverging recommendations. RESULTS: Regarding Relevance, recommendations included supporting deliberation, stakeholder participation and grounding coverage decision criteria in normative and societal objectives. Thirteen of 17 proposed decision criteria were recommended by a majority of panelists. The usefulness of universal cost-effectiveness thresholds to inform allocative efficiency was challenged, particularly in the RDRT context. RDRTs raise specific issues that need to be considered; however, rarity should be viewed in relation to other aspects, such as disease severity and budget impact. Regarding Publicity, panelists recommended transparency about the values underlying a decision and value judgements used in selecting evidence. For Appeals, recommendations included a life-cycle approach with clear provisions for re-evaluations. For Enforcement, external quality reviews of decisions were recommended. CONCLUSION: Moving coverage decision-making processes towards enhanced legitimacy in general and in the RDRT context involves designing and refining approaches to support participation and deliberation, enhancing transparency, and allowing explicit consideration of multiple decision criteria that reflect normative and societal objectives.

The Economic Impact of New Therapeutic Interventions on Neuropsychiatric Inventory (NPI) Symptom Scores in Patients with Alzheimer Disease.

BACKGROUND/AIMS: Few studies have modeled individual Neuropsychiatric Inventory (NPI) symptom scores for Alzheimer disease (AD) patients and assessed the value of therapeutic interventions that can potentially impact them. The main objective of this study was to evaluate the impact of new AD symptomatic treatments on relevant health economic outcomes via their potential effects on cognition and neuropsychiatric symptoms such as depression, irritability, anxiety, and sleep disorder. METHODS: We enhanced the previously published AHEAD model (Assessment of Health Economics in Alzheimer's Disease) by including new variables and functional relations to capture the NPI's individual neuropsychiatric symptoms in addition to the total NPI score. This update allowed us to study the longitudinal effect of improvements in specific NPI subscale scores and the downstream impact on outcomes such as psychiatric medication use, survival, and institutional placement. RESULTS: The model base-case results showed that a hypothetical treatment with symptomatic effects on anxiety, depression, and irritability NPI subscales was not cost-effective; however, the treatment's cost-effectiveness was improved once a direct link between NPI subscales and mortality was explored or under relatively stronger treatment effects. CONCLUSION: Treatments that influence specific symptoms within the overall NPI have the potential to improve patient outcomes in a cost-effective way. This model is a useful tool for evaluating target product profiles of drugs with effect on NPI symptoms in early stages of development.

The association between Alzheimer's disease symptom severity and caregiver outcomes: a cross-sectional study.

OBJECTIVE: To determine the association between Alzheimer's disease (AD) symptom severity and caregiver outcomes. METHOD: This was a database analysis of the Alzheimer's Disease Caregiver Study, a cross-sectional, caregiver-reported study conducted in 2007. Data were collected nationwide via the Internet and in 8 cities: Detroit, Michigan; Knoxville, Tennessee; Los Angeles, California; Miami, Florida; Philadelphia, Pennsylvania; Phoenix, Arizona; St Louis, Missouri; and Washington, DC. Participants were unpaid adult caregivers of AD patients (N = 1,077). Symptom severity was measured using the Revised Memory and Behavioral Problem Checklist (RMBPC). Caregiver outcomes included the Caregiver Burden Scale, diagnosis of anxiety and depression, use of the emergency room, hospitalization, number of physician visits, and missed workdays in the past 6 months. Linear and logistic regression models were developed to assess effects of AD symptom severity on outcomes. Covariates included caregiver and patient characteristics and interactions of AD symptom severity with covariates based on previous analyses. RESULTS: Of the 1,077 respondents, 1,034 had valid RMBPC overall symptom severity scores. AD symptom severity was a significant (P < .01) predictor of all caregiver outcomes except physician visits. Each unit increase in RMBPC severity score corresponded with an increase of 0.328 (95% CI, 0.101-0.554) units in caregiver burden. Each unit increase in severity resulted in increases in physician visits (b = 0.343; 95% CI, 0.052-0.635) and absenteeism (b = 1.722; 95% CI, 0.694-2.749). For each unit increase in RMBPC severity score, caregivers had greater likelihood of emergency room use (odds ratio = 1.506; 95% CI, 1.230-1.845), hospitalization (OR = 1.393; 95% CI, 1.091-1.777), anxiety (OR = 1.506; 95% CI, 1.257-1.805), and depression (OR = 1.811; 95% CI, 1.505-2.179). CONCLUSIONS: AD symptom severity is significantly associated with poorer caregiver outcomes. Therefore, treatments that slow AD symptom progression may be beneficial to caregiver outcomes.

Measurement properties of the Medical Outcomes Study Sleep Scale in patients with fibromyalgia.

OBJECTIVE: Sleep problems are a common symptom of fibromyalgia (FM). The objective of this study was to evaluate the Medical Outcomes Study (MOS) Sleep Scale as a measure of FM-related sleep problems. METHODS: Analyses were based on data from the 1056 and 1077 studies, two randomized, double-blind, placebo-controlled trials of pregabalin for adults with FM. MOS Sleep Scale scores of study patients were compared with United States normative scores using a one-sample Z test. Subscale structure of the MOS was evaluated by confirmatory factor analyses, internal consistency was evaluated using Cronbach's alpha reliability coefficients. Estimated clinically important differences (CID) in MOS Sleep Disturbance subscale scores were evaluated using mixed-effects models of change in subscale scores as a function of the Patient Global Impression of Change (PGIC). RESULTS: 1056 and 1077 included 748 and 745 patients, respectively. Most patients were female (1056: 94.4%, 1077: 94.5%) and white (1056: 90.2%, 1077: 91.0%). Mean ages were 48.8 years (1056) and 50.1 years (1077). Baseline MOS Sleep Scale scores were statistically (P<0.001) and substantially poorer than general population values. The MOS subscale structure was confirmed in both studies at each assessment except at baseline in the 1056 study. Cronbach's alpha coefficients were acceptable, at least 0.70, for all multi-item scales at baseline and end-of-study assessments in both studies, with the exception of the Sleep Adequacy subscale at baseline. The estimated CID for the MOS Sleep Disturbance subscale was 7.9. CONCLUSIONS: The MOS Sleep Scale is an appropriate measure of FM-related sleep problems. These analyses provide the foundation for further use and evaluation of the MOS Sleep Scale in FM patients.

Effects of an oral growth hormone secretagogue in older adults.

CONTEXT: GH secretion declines with age, possibly contributing to reduced muscle mass, strength, and function. GH secretagogues (GHS) may increase muscle mass and physical performance. OBJECTIVES/DESIGN: We conducted a randomized, double-masked, placebo-controlled, multicenter study to investigate the hormonal, body composition, and physical performance effects and the safety of the orally active GHS capromorelin in older adults with mild functional limitation. INTERVENTION/PARTICIPANTS: A total of 395 men and women aged 65-84 yr were randomized for an intended 2 yr of treatment to four dosing groups (10 mg three times/week, 3 mg twice a day, 10 mg each night, and 10 mg twice a day) or placebo. Although the study was terminated early according to predetermined treatment effect criteria, 315 subjects completed 6 months of treatment, and 284 completed 12 months. RESULTS: A sustained dose-related rise in IGF-I concentrations occurred in all active treatment groups. Each capromorelin dose prompted a rise in peak nocturnal GH, which was greatest with the least frequent dosing. At 6 months, body weight increased 1.4 kg in subjects receiving capromorelin and decreased 0.2 kg in those receiving placebo (P = 0.006). Lean body mass increased 1.4 vs. 0.3 kg (P = 0.001), and tandem walk improved by 0.9 sec (P = 0.02) in the pooled treatment vs. placebo groups. By 12 months, stair climb also improved (P = 0.04). Adverse events included fatigue, insomnia, and small increases in fasting glucose, glycosylated hemoglobin, and indices of insulin resistance. CONCLUSIONS: In healthy older adults at risk for functional decline, administration of the oral GHS capromorelin may improve body composition and physical function.

Increase coverage of HIV and AIDS services in Myanmar.

Myanmar is experiencing an HIV epidemic documented since the late 1980s. The National AIDS Programme national surveillance ante-natal clinics had already estimated in 1993 that 1.4% of pregnant women were HIV positive, and UNAIDS estimates that at end 2005 1.3% (range 0.7-2.0%) of the adult population was living with HIV. While a HIV surveillance system has been in place since 1992, the programmatic response to the epidemic has been slower to emerge although short- and medium-terms plans have been formulated since 1990. These early plans focused on the health sector, omitted key population groups at risk of HIV transmission and have not been adequately funded. The public health system more generally is severely under-funded.By the beginning of the new decade, a number of organisations had begun working on HIV and AIDS, though not yet in a formally coordinated manner. The Joint Programme on AIDS in Myanmar 2003-2005 was an attempt to deliver HIV services through a planned and agreed strategic framework. Donors established the Fund for HIV/AIDS in Myanmar (FHAM), providing a pooled mechanism for funding and significantly increasing the resources available in Myanmar. By 2006 substantial advances had been made in terms of scope and diversity of service delivery, including outreach to most at risk populations to HIV. More organisations provided more services to an increased number of people. Services ranged from the provision of HIV prevention messages via mass media and through peers from high-risk groups, to the provision of care, treatment and support for people living with HIV. However, the data also show that this scaling up has not been sufficient to reach the vast majority of people in need of HIV and AIDS services.The operating environment constrains activities, but does not, in general, prohibit them. The slow rate of service expansion can be attributed to the burdens imposed by administrative measures, broader constraints on research, debate and organizing, and insufficient resources. Nevertheless, evidence of recent years illustrates that increased investment leads to more services provided to people in need, helping them to obtain their right to health care. But service expansion, policy improvement and capacity building cannot occur without more resources.

Daily process methodology for measuring earlier antidepressant response.

OBJECTIVE: Rapid onset of therapeutic action for antidepressant medication represents a major area of unmet medical need, and any such effects have been difficult to detect using standard study designs and measurement strategies. We conducted a randomized, open-label study with blinded raters using daily process assessment vs. standard weekly assessment to answer the following study questions: 1) is it possible to detect an antidepressant response more rapidly with daily assessment than with standard assessment approaches? 2) what is the burden of daily assessment on participants relative to standard clinical assessments? and 3) does the process of completing daily assessments have any effect on clinic-based assessments such as the Hamilton Depression Rating Scale (HAM-D)? METHOD: Seventy-eight outpatients with major depressive disorder who received open-label fluoxetine were randomized to standard weekly clinic assessment or standard weekly clinic assessment plus daily assessment, and were followed for 28 days. Data were collected between September, 2002 and August, 2003. RESULTS: Daily assessment appeared to have no effect on 17-item HAM-D or MADRS scores obtained in the clinic. Survival analyses revealed that daily diaries detected therapeutic effects more quickly than did standard weekly clinic assessments, across most endpoints. Perceived burden of study participation was not significantly increased by daily diary completion, nor reflected in higher dropout rates. CONCLUSION: Daily process assessment improves the ability to detect an early antidepressant response.

Select plant tannins induce IL-2Ralpha up-regulation and augment cell division in gammadelta T cells.

Gammadelta T cells are innate immune cells that participate in host responses against many pathogens and cancers. Recently, phosphoantigen-based drugs, capable of expanding gammadelta T cells in vivo, entered clinical trials with the goal of enhancing innate immune system functions. Potential shortcomings of these drugs include the induction of nonresponsiveness upon repeated use and the expansion of only the Vdelta2 subset of human gammadelta T cells. Vdelta1 T cells, the major tissue subset, are unaffected by phosphoantigen agonists. Using FACS-based assays, we screened primary bovine cells for novel gammadelta T cell agonists with activities not encompassed by the current treatments in an effort to realize the full therapeutic potential of gammadelta T cells. We identified gammadelta T cell agonists derived from the condensed tannin fractions of Uncaria tomentosa (Cat's Claw) and Malus domestica (apple). Based on superior potency, the apple extract was selected for detailed analyses on human cells. The apple extract was a potent agonist for both human Vdelta1 and Vdelta2 T cells and NK cells. Additionally, the extract greatly enhanced phosphoantigen-induced gammadelta T cell expansion. Our analyses suggest that a tannin-based drug may complement the phosphoantigen-based drugs, thereby enhancing the therapeutic potential of gammadelta T cells.