Sheri Fehnel

Interpreting patient-reported outcome results: US FDA guidance and emerging methods.

In recent years, the US FDA has become more critical of instruments used to measure patient-reported outcomes (PROs) in clinical trials. To facilitate decisions related to the approval of drugs, labels and promotional claims based on PROs, the FDA created the Study Endpoints and Label Development (SEALD) group. SEALD has developed a PRO guidance related to the use of PRO measures used to support drug approvals and label claims, including recommendations for establishing thresholds for meaningful change at the individual level (i.e., defining a responder). This article examines in detail the FDA-recommended methodology for defining a responder and analyzing responder-based PRO measure results. We also present other responder analysis approaches for consideration in furthering the precision and interpretation of this methodology.

Gastrointestinal side effects in chronic opioid users: results from a population-based survey.

Background  Gastrointestinal side effects are commonly associated with opioid treatment for pain.

Frequency and severity of vasomotor symptoms among peri- and postmenopausal women in the United States

Objective To describe characteristics of vasomotor symptoms, specifically daily frequency and severity, among women 40–65 years old in the United States (US). Design A survey was completed by a nationally representative sample of 4402 US women aged 40–65 years old. A questionnaire focusing on menopausal symptoms was administered online in April 2005. Results The prevalence of vasomotor symptoms was 79% in peri- and 65% in postmenopausal women. Women with daily vasomotor symptoms had an average of 2.5 very mild/mild, 2.6 moderate, 2.5 severe, and 1.4 very severe daytime hot flushes in a typical day. Women with night sweats every night had an average of 2.4 moderate, 3.2 severe, and 2.7 very severe night sweats in a typical night. Overall, 9% of peri- and 7% of postmenopausal women reported 7+ moderate to very severe vasomotor symptoms in a typical day. Although some women reported that symptoms were worse in the evening and in the summer, many women reported they were consistent, both throughout the day and throughout the seasons of the year. Conclusions The Menopause Epidemiology Study builds upon existing literature by providing data on daily frequency and severity of vasomotor symptoms. There are many women with frequent and severe vasomotor symptoms who may benefit from treatment.

Prevalence and impact of antidepressant-associated sexual dysfunction in three European countries: replication in a cross-sectional patient survey

Sexual dysfunction is a common but often unrecognized side effect of many antidepressants. Building upon the results of a previous investigation, this study aimed to assess the prevalence and impact of antidepressant-associated sexual dysfunction (AASD) in three European countries. A cross-sectional survey of 704 adults in Germany, Spain, and The Netherlands was used in the study. All participants had recently started taking a selective serotonin reuptake inhibitor or serotonin— noradrenaline reuptake inhibitor. Information about other medications and conditions known to impair sexual functioning was gathered, and changes in sexual functioning and the impact of such changes were assessed. The SF-12 and Arizona Sexual Experience Scale (ASEX) were administered to measure health status and sexual functioning. AASD was defined using ASEX scores and information regarding changes in sexual functioning. ASEX scores generally exceeded the threshold defining sexual dysfunction: 67.2% in the German, 79.4% in the Spanish, and 73.3% in the Dutch samples. The prevalence of AASD was conservatively estimated to be between 37.1% (German sample) and 61.5% (Spanish sample). Overall, 46.4% of male and 52.1% of female participants were classified with AASD. Patients classified with AASD reported significantly worse quality of life (QoL), self-esteem, mood, and relationships with partners, compared with non-AASD patients. There were significant differences between patients with and without AASD in SF-12 Mental Component scores, with AASD patients displaying poorer mental well-being. Sexual dysfunction is a frequent occurrence during antidepressant treatment, and is associated with reduced QoL and self-esteem, and negative effects on mood and relationships.

The development and psychometric evaluation of the motivation and energy inventory (MEI)

Because depressed patients commonly experience reductions in motivation and energy, both as symptoms of their disorder and as side effects of pharmacotherapy, it is important to identify interventions that can restore their vitality. The Motivation and Energy Inventory (MEI) was recently developed to facilitate the evaluation of such efforts both in depression research, as well as in other therapeutic areas where vitality is an important issue. The constructs addressed by the MEI were identified through a combination of literature review, consultation with experts, and patient focus groups. Potential problems identified during cognitive testing and addressed in subsequent revisions related to the instructions, reference period, response scale sizes, and response scale labels, as well as a number of item-specific issues. Most recently, the data from two randomized, placebo-controlled clinical trials were utilized to evaluate the psychometric properties of the new questionnaire. In general, the data collected during the first and second trial were used for exploratory and confirmatory analysis, respectively. Consistent with the measurement model of the MEI, the psychometric results confirm that the instrument has three factors generally addressing physical energy, mental energy, and social motivation. Furthermore, these results provide evidence for the internal consistency, construct validity, and responsiveness of all three MEI subscales. Additional work is currently underway to examine test–retest reliability and establish minimal clinically important difference values for the MEI subscales.

Reasons for rejection of patient-reported outcome label claims: a compilation based on a review of patient-reported outcome use among new molecular entities and biologic license applications, 2006-2010.

OBJECTIVES Previous analyses of patient-reported outcome (PRO) label claims concentrated only on successful label claims. The goal of this research was to explore the reasons why PRO label claims were denied and to compile regulatory feedback regarding the use of PROs in clinical trials. METHODS By using the Food and Drug Administrations Drug Approval Report Web page, all new molecular entities and biologic license applications approved between January 2006 and December 2010 were identified. For identified drug products, medical review sections from publicly available drug approval packages were reviewed to identify PRO end-point status and any Study Endpoints and Label Development team comments. RESULTS Of the 116 new molecular entities and biologic license applications with accompanying drug approval packages identified and reviewed, 44.8% of the products included PROs as part of the pivotal studies; however, only 24.1% received PRO label claims. Primary reasons for denial included issues of fit for purpose, issues of study design, data quality or interpretation, statistical issues, administrative issues, and lack of demonstrated treatment benefit. CONCLUSIONS Based on drug approval packages, nearly half (45%) of new molecular entitity/biologic license application products in the years 2006 to 2010 included PROs in the clinical trials supporting their approval, yet this rate is not reflected by claims granted. Understanding the nature of PRO claims granted under the current regulatory guidance is important. In addition, a clear understanding of denied claims yields valuable insight into where sponsors may improve implementation of PROs in clinical trials and submission of PRO evidence to increase the likelihood of obtaining PRO label claims.

US FDA patient-reported outcome guidance: great expectations and unintended consequences

Release of the US FDA patient-reported outcome (PRO) guidance raised expectations within the pharmaceutical industry for the use of PRO measures in support of labeling claims. The FDA developed the guidance with admirable intent, and the recommendations within this document are based on sound scientific principles. However, implementation of the guidance has been somewhat inconsistent within the Study Endpoints and Label Development (SEALD) and across the various FDA-reviewing divisions. Industry and regulatory bodies need to work toward gaining common ground to best support registration of treatments that could extend patients’ lives, reduce symptoms, and/or improve health-related quality of life. PROs are valuable tools in communicating these messages, and realistic implementation of the FDA PRO Guidance may truly facilitate this process.

Development and preliminary validation of the Menopause Symptoms Treatment Satisfaction Questionnaire (MS-TSQ)

Objective: The Menopause Symptoms Treatment Satisfaction Questionnaire, an eight-item questionnaire with a 4-week recall period, was developed to assess womens satisfaction with treatment for symptoms associated with menopause. We describe the development and initial testing of the scale. Design: Following standard instrument-development procedures, focus groups were conducted with menopausal women experiencing hot flushes to generate potential constructs. Multiple items were drafted to address each construct. An iterative process of cognitive testing, item revision, and item reduction was followed to identify the most appropriate items and optimal response scales. The psychometric validation of the questionnaire used data collected through a multicenter, randomized, double-blind, placebo-controlled study including 543 postmenopausal women. Psychometric analyses were conducted to explore potential item reduction and to address questionnaire scaling and scoring. Internal consistency reliability, construct validity, and discriminant validity of the new scale were also examined. Results: The questionnaire includes items addressing the control of daytime and nighttime hot flushes; effects of treatment on sleep, mood, libido, and cognition; medication tolerability; and overall satisfaction. Correlation analyses indicated that the items are related to each other without being overly redundant and that the item set is best described using a one-factor model. The subsequent scale score demonstrated sound internal consistency reliability, strong construct validity, and good discriminant validity. Conclusions: The results of the development and initial validation are favorable. It is expected that the questionnaire will prove to be a worthwhile tool for assessing womens satisfaction with treatment for menopausal symptoms.

The development and validation of the daily electronic Endometriosis Pain and Bleeding Diary

BackgroundThe objective of this study was to develop and validate a daily electronic Endometriosis Pain and Bleeding Diary (EPBD) for assessing treatment-related changes in endometriosis symptoms from the patients perspective in a clinical trial setting.MethodsThe EPBD items were developed based on clinician input and the results of 5 focus groups (N = 38) and 3 iterative sets of cognitive interviews (N = 22). The psychometric properties were evaluated using data collected in a usual-practice, non-intervention study conducted at 4 sites in the United States. Existing questionnaires were also administered to explore the construct validity of the EPBD. The development and validation processes were consistent with the recommendations in the 2009 FDA Patient Reported Outcomes Guidance to Industry.ResultsFocus group participants described 2 distinct types of pain (intermittent and continuous), which they felt were relevant and important to monitor. Participants also indicated that pain and bleeding/spotting associated with intercourse were important symptoms related to endometriosis. Cognitive interviews with additional endometriosis patients served to optimize item content, wording, and response options. Psychometric analyses found the EPBD items to behave as expected, for example, item-level means for subjects with severe endometriosis symptoms were higher (i.e., worse) compared with subjects with mild symptoms. Item-total correlations for the EPBD pain items (range 0.40-0.89) indicated that the items were related but not redundant. EPBD pain ratings correlated highly with the modified Brief Pain Inventory-Short Form Pain Intensity score (range 0.46-0.61). Women with severe endometriosis symptoms reported significantly higher intermittent and continuous dysmenorrhea and intermittent and continuous pelvic pain ratings and greater interference with daily activities compared with women with mild symptoms (all p < 0.01).ConclusionsThe results of this study show that the 17-item EPBD reliably and validly characterizes the types of pain that endometriosis patients identified as being important. As a daily patient-reported assessment, it overcomes the significant potential for intra- and inter-rater variability and rater and recall bias that is inherent in the Biberoglu and Behrman Scale. Additional studies are required to confirm the dimensionality and optimal scoring of the EPBD, to corroborate the present results, and to assess other important measurement properties, such as responsiveness.

Patient-centered assessment of cognitive symptoms of depression.

OBJECTIVE To identify and explore concepts important to patients with cognitive symptoms of major depressive disorder (MDD) and adapt an existing patient-reported outcome (PRO) measure to assess these symptoms. METHODS Four focus groups were conducted with MDD patients (n = 33) to elicit relevant concepts and determine whether one of several PRO scales could be used to assess cognitive symptoms of depression. Following selection and minor modification of the Perceived Deficits Questionnaire (PDQ), cognitive debriefing interviews were conducted with additional patients (n = 17) to further refine and adapt this measure for use in MDD. Minor revisions based on patient input yielded the PDQ for Depression (PDQ-D). RESULTS Focus group participants reported a variety of cognitive symptoms that were classified into 7 general categories: lack of focus and clear thought, memory problems, difficulty with lexical access, difficulty with divided attention, difficulty with decision making, difficulty thinking quickly, and difficulty learning new things. Limitations in work productivity were the most commonly reported impacts of cognitive symptoms. While suggesting a few modifications, focus group participants reacted positively to the PDQ based on the breadth, specificity, and relevance of the items. Cognitive debriefing participants indicated that the modified PDQ items were generally easy to understand and relevant to their experiences with MDD. CONCLUSION Because cognitive symptoms are burdensome to patients with MDD, their assessment is important to optimize treatment outcomes. The PDQ-D has the potential to supplement existing assessment methods, providing unique information important for both comprehensive evaluation of individuals with MDD and evaluation of new treatments.