Diane Wild

Multinational Trials—Recommendations on the Translations Required, Approaches to Using the Same Language in Different Countries, and the Approaches to Support Pooling the Data: The ISPOR Patient‐Reported Outcomes Translation and Linguistic Validation Good Research Practices Task Force Report

OBJECTIVES With the internationalization of clinical trial programs, there is an increased need to translate and culturally adapt patient-reported outcome (PRO) measures. Although guidelines for good practices in translation and linguistic validation are available, the ISPOR Patient-Reported Outcomes Translation and Linguistic Validation Task Force identified a number of areas where they felt that further discussion around methods and best practices would be beneficial. The areas identified by the team were as follows: 1) the selection of the languages required for multinational trials; 2) the approaches suggested when the same language is required across two or more countries; and 3) the assessment of measurement equivalence to support the aggregation of data from different countries. METHODS The task force addressed these three areas, reviewed the available literature, and had multiple discussions to develop this report. RESULTS Decision aid tools have also been developed and presented for the selection of languages and the approaches suggested for the use of the same language in different countries. CONCLUSION It is hoped that this report and the decision tools proposed will assist those involved with multinational trials to 1) decide on the translations required for each country; 2) choose the approach to use when the same language is spoken in more than one country; and 3) choose methods to gather evidence to support the pooling of data collected using different language versions of the same tool.

A Comparative Review of Health-Related Quality-of-Life Measures for Use in HIV/AIDS Clinical Trials

With the advent of highly active antiretroviral therapy (HAART), HIV-infected patients are living longer and are concerned not only with a treatment’s ability to extend their life but also with the quality of the life they are able to lead. Regulatory authorities are also paying closer attention to the use of health-related quality-of-life (HR-QOL) measures in clinical trials and to the subsequent claims that are made based on the results. This paper reviews existing HR-QOL measures reported in the HIV/AIDS literature since 1990 and identifies those most worthy of consideration for use in future clinical trials.A comprehensive review following predefined selection criteria was conducted. Generic and HIV-targeted measures were assessed for content and practicality for the clinical trial setting. The generic measures were additionally reviewed for the ability to produce preference-based index scores and for the existence of normative general population data. Three generic and six HIV-targeted measures met these selection criteria and were then assessed more fully in terms of their development (HIV-targeted measures), psychometric properties and appropriateness for use in clinical trials.It was determined that each of the selected generic measures (i.e. Medical Outcomes Study [MOS] 36-Item Short Form Survey Instrument [SF-36], EQ-5D, Health Utilities Index [HUI]) could serve as a useful adjunct to an HIV-targeted measure in a trial. The Functional Assessment of HIV Infection (FAHI) and MOS-HIV health survey were deemed the two most appropriate HIV-targeted measures. Each of the measures can be self-administered in ≤10 minutes and there was ample evidence of their excellent psychometric properties. However, they would not be optimal in all HIV-infected subgroups (e.g. treatment naive vs advanced; adolescents vs older adults) targeted for clinical trial interventions.Although there is no one best HR-QOL measure for use in HIV/AIDS clinical trials, based on our review criteria we identified three generic and two HIVtargeted candidate measures. However, these measures have their limitations and it is clear that greater consensus needs to develop regarding more effective and efficient approaches to HR-QOL measurement in HIV/AIDS clinical trials. Along with the increasingly complex HR-QOL measurement task resulting from changes in the HIV-infected population and shifts in the HR-QOL burden associated with HIV infection and its treatment over the past 25 years, it is increasingly important that HR-QOL outcomes become viable endpoints in HIV/AIDS clinical trials.

Assessing and demonstrating data saturation in qualitative inquiry supporting patient-reported outcomes research.

In the patient-reported outcomes (PROs) field, strict regulatory requirements must be met for qualitative research that contributes to labeling claims for medicinal products. These requirements not only emphasize the importance of reaching saturation but also of providing documentary evidence that saturation has been reached. This paper reviews qualitative literature for useful definitions of the concept and for practical approaches for assessing saturation. The paper considers approaches in light of the rigorous regulatory requirements for PRO research that are used to support labeling claims for medicinal products and the wider requirements for flexibility and creativity in qualitative research in general. This assessment is facilitated by the use of examples from our past qualitative PRO studies. Based on conclusions from this assessment, we offer preliminary recommendations for future qualitative PRO studies for assessing and documenting saturation.

Impact of schizophrenia and schizophrenia treatment-related adverse events on quality of life: direct utility elicitation

ObjectiveTo examine the impact of schizophrenia, its treatment and treatment-related adverse events related to antipsychotics, on quality of life from the perspective of schizophrenia patients and laypersons.MethodsHealth state descriptions for stable schizophrenia, extra pyramidal symptoms (EPS), hyperprolactinemia, diabetes, weight gain and relapse were developed based on a review of the literature and expert opinion. The quality of life impact of each health state was elicited using a time trade-off instrument administered by interview to 49 stable schizophrenia patients and 75 laypersons. Regression techniques were employed to examine the importance of subject characteristics on health-related utility scores.ResultsPatients and laypersons completed the interview in similar times. Stable schizophrenia had the highest mean utility (0.87 and 0.92 for laypersons and patients respectively), while relapse (0.48 and 0.60) had the lowest mean utility. Of the treatment-related adverse events, EPS had the lowest mean utility (0.57 and 0.72, respectively). Age, gender and PANSS score did not influence the utility results independently of health state. On average, patient utilities are 0.077 points higher than utilities derived from laypersons, although the ranking was similar between the two groups.ConclusionEvents associated with schizophrenia and treatment of schizophrenia can bring about a significant detriment in patient quality of life, with relapse having the largest negative impact. Results indicate that patients with stable schizophrenia are less willing to trade years of life to avoid schizophrenia-related symptoms compared to laypersons. Both sets of respondents showed equal ability to complete the questionnaire.

Validation of a patient‐administered questionnaire to measure the severity and bothersomeness of lower urinary tract symptoms in uncomplicated urinary tract infection (UTI): the UTI Symptom Assessment questionnaire

To develop and validate a self‐administered questionnaire to assess the ‘severity’ and ‘bothersomeness’ of the most frequently reported signs and symptoms of uncomplicated urinary tract infection (uUTI).

Patient perspectives on taking vitamin K antagonists: a qualitative study in the UK, USA and Spain

Aim: Limitations of vitamin K antagonists (VKAs) include frequent monitoring, dietary restrictions and drug interactions. This study conducted an indepth exploration of perspectives of VKA therapy in respondents with atrial fibrillation or venous thromboembolism. Methods: A total of 60 respondents, recruited from the UK, USA and Spain, were interviewed on their experiences and views of VKA therapy. Thematic analysis was conducted on the data. Results: Although there were some differences between the countries and some small differences between atrial fibrillation and venous thromboembolism respondents, many respondents found various aspects of VKA to be burdensome, including the international normalized ratio monitoring and dietary considerations. Conclusion: Atrial fibrillation and venous thromboembolism respondents accept the limitations of VKAs and the adjustments to their lifestyles, but recognize a lack of alternative treatment.

Patient Reported Outcome (PRO) assessment in epilepsy: a review of epilepsy-specific PROs according to the Food and Drug Administration (FDA) regulatory requirements

Despite collection of patient reported outcome (PRO) data in clinical trials of antiepileptic drugs (AEDs), PRO results are not being routinely reported on European Medicines Agency (EMA) and Food and Drug Administration (FDA) product labels. This review aimed to evaluate epilepsy-specific PRO instruments against FDA regulatory standards for supporting label claims. Structured literature searches were conducted in Embase and Medline databases to identify epilepsy-specific PRO instruments. Only instruments that could potentially be impacted by pharmacological treatment, were completed by adults and had evidence of some validation work were selected for review. A total of 26 PROs were reviewed based on criteria developed from the FDA regulatory standards. The ability to meet these criteria was classified as either full, partial or no evidence, whereby partial reflected some evidence but not enough to comprehensively address the FDA regulatory standards. Most instruments provided partial evidence of content validity. Input from clinicians and literature was common although few involved patients in both item generation and cognitive debriefing. Construct validity was predominantly compromised by no evidence of a-priori hypotheses of expected relationships. Evidence for test-retest reliability and internal consistency was available for most PROs although few included complete results regarding all subscales and some failed to reach recommended thresholds. The ability to detect change and interpretation of change were not investigated in most instruments and no PROs had published evidence of a conceptual framework. The study concludes that none of the 26 have the full evidence required by the FDA to support a label claim, and all require further research to support their use as an endpoint. The Subjective Handicap of Epilepsy (SHE) and the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) have the fewest gaps that would need to be addressed through additional research prior to any FDA regulatory submission, although the NDDI-E was designed as a screening tool and is therefore unlikely to be suitable as an instrument for capturing change in a clinical trial and the SHE lacks the conceptual focus on signs and symptoms favoured by the FDA.

Patient-reported treatment satisfaction measures for long-term anticoagulant therapy

A comprehensive literature search identified seven instruments, of which three had psychometric data available. These were the ‘Sawicki instrument’, the Duke Anticoagulation Satisfaction Scale (DASS) and Deep Vein Thrombosis Quality of Life (DVTQoL). Sawicki assessed five domains with acceptable internal reliability. The six DVTQoL domains had good internal consistency, construct validity and reliability, although test–retest reliability and responsiveness have not been published. The DASS instrument covers three dimensions: limitations, burdens (i.e., negative impacts) and positive impacts. The burdens dimension correlated with short form-36 generic scales. The DASS had good internal consistency and item variability, and acceptable test–retest reliability and scale structure. DASS has the potential to help identify reasons for dissatisfaction and poor compliance across multiple models of care. Oral anticoagulation with vitamin K antagonists affects patients’ quality of life, and is further complicated by variations in compliance and ability to self-manage anticoagulation. This paper reviews instruments designed specifically to assess treatment satisfaction in patients receiving oral anticoagulation.

Reimbursement agency requirements for health related quality-of-life data: a case study.

A review was undertaken to identify relevant and appropriate heath-utility estimates for patients with atrial fibrillation who had stroke and to appraise them against the published requirements for several countries’ Health Technology Assessment agencies: Australia (Pharmaceutical Benefits Advisory Committee), Canada (Common Drug Review), England and Wales (NICE), Germany (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen), Scotland (Scottish Medicines Consortium) and Sweden (Tandvårds–och läkemedelsförmånsverket). National agencies have created guidelines to support economic evaluations for their own countries but these guidelines differ. It may be more appropriate for agencies to be concerned primarily with the methodological quality of studies that report utilities rather than identifying local values. As such, we recommend some steps that could be considered when assessing the quality of utility studies in a systematic review or meta-analysis. These steps include considering the methods of utility estimation, model needs, generalizability, sample size and the use of large databases. This may, thus, facilitate consistent and rational Health Technology Assessment decision making.

PIN25 ASSESSMENT OF HEALTH-RELATED QUALITY OF LIFE MEASURES IN HIV AND AIDS

depression (3.5%) was mostly unchanged (Baseline-Wk8; P = 0.059). Clinical depression (patient-reported) was associated with increased bothersomeness of other symptoms (fatigue, loss of appetite, nervousness) at Baseline & Wk8 (P < 0.05). CONCLUSIONS: Patient-reported depression outcomes should be valued during HIV treatment, as more patients who were virologically controlled but experiencing Grade 2 PI/NNRTIassociated side effects self-reported signs of clinical depression than were diagnosed by physicians. Prevalence of clinical depression was reduced following substitution to LPV/r.