Linda S. Deal

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.

Development and psychometric evaluation of the Endometriosis Treatment Satisfaction Questionnaire

PurposeTo develop and psychometrically evaluate the Endometriosis Treatment Satisfaction Questionnaire, a patient-reported assessment of satisfaction with endometriosis treatment.MethodsThe Endometriosis Treatment Satisfaction Questionnaire was developed based on the results of five focus groups and three iterative sets of cognitive interviews along with expert opinion and a review of the literature. The psychometric properties were assessed using data collected during a multicenter, randomized, proof-of-concept trial. The development and validation processes followed the guidance recommended by the United States FDA for patient-reported outcome instruments.ResultsThe Endometriosis Treatment Satisfaction Questionnaire’s reliability, validity, and utility as a measure of patient satisfaction with their endometriosis treatment were supported. The results of the item-level analyses showed no evidence of distributional anomalies or response scale biases. The Endometriosis Treatment Satisfaction Questionnaire is unidimensional, has excellent internal consistency reliability, and discriminates well between known groups. Scores correlated well with other patient-reported outcome measures of endometriosis without being redundant.ConclusionsThe Endometriosis Treatment Satisfaction Questionnaire has utility for assessing patient satisfaction with endometriosis treatment and may be useful in clinical trials that are assessing new treatments for endometriosis, especially when deciding between competing treatments or regimens that are found to have similar tolerability and efficacy.

Development of an Electronic Daily Uterine Fibroid Symptom Diary

AbstractBackground: In some women, uterine fibroids are associated with severe, disabling symptoms. There is a lack of high-quality evidence supporting the effectiveness of most interventions for symptomatic uterine fibroids. In part, this is due to the lack of available disease-specific instruments with comprehensive validation evidence that measure treatment benefit from the patient perspective. Objective: The aim of this study was to develop an electronic patient-reported outcomes (PRO) instrument that measures treatment benefit from the patient’s perspective that is easily administered and practical for use in clinical trials. Rigorous methods that are consistent with the US FDA’s PRO Guidance to Industry were employed. Methods: The study took place in two phases: a content development phase (eight focus groups; three sets of cognitive interviews) and a prospective nonintervention usability pilot phase. Both phases were conducted in the US.The study population comprised women diagnosed with symptomatic uterine fibroids. A total of 68 women (mean age 40 years) participated in the eight focus groups; 27 women (mean age 41 years) who were not part of the focus groups participated in the cognitive interviews. Fourteen additional women (mean age 39 years) participated in a usability pilot. Efforts were made to recruit a diverse population with respect to race and education. Results: After completing eight focus groups, no new symptom concepts or severity-level measurement ideas were introduced, indicating that concept saturation was achieved. Fourteen draft items were developed during the focus groups for testing in the cognitive interviews. Every symptom represented by the draft items was endorsed by at least two-thirds of the participants in the cognitive interviews. After completing three rounds of cognitive interviews, the Fibroid Symptom Diary© (FSD) contained eight items that assessed bleeding severity, menstrual cramping, and fibroid-related fatigue. An open-field item, tailored to each participant, was also included to assess the most bothersome fibroid-related pain. However, to accommodate electronic administration of the diary this item was replaced, prior to the usability pilot, with three pain-specific items (i.e. abdominal pain, low back pain, and pain during intercourse) that were most commonly expressed during the development phase. The final FSD includes 11 items: five addressing menstrual bleeding or spotting; one each relating to cramping (distinct from other pain), fatigue, and bloating; and three that address other fibroid-related pain. The average time for completing the diary was 1–2 minutes per day.A total of 118 daily diary records were collected from 14 participants (average of nine daily diary completions per participant; range 5–18 days) in the usability pilot. Seven participants completed the diary every day. Most participants experienced the majority of the symptoms included in the FSD. Conclusions: The FSD captures the concepts most important to women with uterine fibroids and has strong evidence of content validity as required by the FDA PRO Guidance to Industry. Once fully validated, the FSD may replace other measures for assessing changes in symptoms and treatment benefit that are both burdensome to patients and cumbersome to trial sponsors.

A review of empirical research related to the use of small quantitative samples in clinical outcome scale development

IntroductionThere has been a notable increase in the advocacy of using small-sample designs as an initial quantitative assessment of item and scale performance during the scale development process. This is particularly true in the development of clinical outcome assessments (COAs), where Rasch analysis has been advanced as an appropriate statistical tool for evaluating the developing COAs using a small sample.MethodsWe review the benefits such methods are purported to offer from both a practical and statistical standpoint and detail several problematic areas, including both practical and statistical theory concerns, with respect to the use of quantitative methods, including Rasch-consistent methods, with small samples.ConclusionsThe feasibility of obtaining accurate information and the potential negative impacts of misusing large-sample statistical methods with small samples during COA development are discussed.

Challenges of Developing an Observable Parent-Reported Measure: A Qualitative Study of Functional Impact of ADHD in Children

BACKGROUND Informant-reported outcome measures, usually completed by parents, are often administered in pediatric clinical trials with the intention of collecting data to support claims in a medical product label. Recently, there has been an emphasis on limiting these measures to observable content, as recommended in the US Food and Drug Administration guidance on patient-reported outcomes. This qualitative study explores the concept of observability using the example of childhood attention deficit/hyperactivity disorder (ADHD). METHODS Concept elicitation interviews were conducted with children (aged 6-12 years) diagnosed with ADHD and parents of children with ADHD to identify concepts for a potential parent-reported measure of functional impact of childhood ADHD. The observability of each concept was considered. RESULTS Of the 30 parents (90% females; mean age = 42.0 years), 24 had a child who was also interviewed (87.5% males; mean age = 9.6 years). Areas of functional impact reported by parents and/or children included the following: 1) functioning within the home/family, 2) academic performance, 3) school behavior, 4) social functioning, 5) emotional functioning, and 6) decreased self-efficacy. Parents cited many examples of direct observation at home, but opportunities for observation of some important areas of impact (e.g., school behavior and peer relationships) were limited. CONCLUSIONS Findings illustrate the substantial functional impairment associated with childhood ADHD while highlighting the challenges of developing informant-reported outcome measures limited to observable content. Because ADHD has an impact on childrens functioning in a wide range of contexts, a parent-report measure that includes only observable content may fail to capture important aspects of functional impairment. Approaches for addressing this observability challenge are discussed.

Development of the 7-Item Binge-Eating Disorder Screener (BEDS-7)

OBJECTIVE Develop a brief, patient-reported screening tool designed to identify individuals with probable binge-eating disorder (BED) for further evaluation or referral to specialists. METHODS Items were developed on the basis of the DSM-5 diagnostic criteria, existing tools, and input from 3 clinical experts (January 2014). Items were then refined in cognitive debriefing interviews with participants self-reporting BED characteristics (March 2014) and piloted in a multisite, cross-sectional, prospective, noninterventional study consisting of a semistructured diagnostic interview (to diagnose BED) and administration of the pilot Binge-Eating Disorder Screener (BEDS), Binge Eating Scale (BES), and RAND 36-Item Short-Form Health Survey (RAND-36) (June 2014-July 2014). The sensitivity and specificity of classification algorithms (formed from the pilot BEDS item-level responses) in predicting BED diagnosis were evaluated. The final algorithm was selected to minimize false negatives and false positives, while utilizing the fewest number of BEDS items. RESULTS Starting with the initial BEDS item pool (20 items), the 13-item pilot BEDS resulted from the cognitive debriefing interviews (n = 13). Of the 97 participants in the noninterventional study, 16 were diagnosed with BED (10/62 female, 16%; 6/35 male, 17%). Seven BEDS items (BEDS-7) yielded 100% sensitivity and 38.7% specificity. Participants correctly identified (true positives) had poorer BES scores and RAND-36 scores than participants identified as true negatives. CONCLUSIONS Implementation of the brief, patient-reported BEDS-7 in real-world clinical practice is expected to promote better understanding of BED characteristics and help physicians identify patients who may have BED.

Development of the Impact of Juvenile Metachromatic Leukodystrophy on Physical Activities scale

BackgroundMetachromatic leukodystrophy (MLD) is a rare disease with three forms based on the age at onset of signs and symptoms. The objective of this study was to develop a caregiver-reported clinical outcome assessment that measures impairments in physical functioning related to activities of daily living in patients with juvenile MLD.MethodsA targeted literature review and exploration of proprietary research, including a conceptual model, were conducted. Concept elicitation interviews were conducted to elicit additional concepts related to impairments in patients’ physical functioning with caregivers of five individuals with juvenile MLD. Based on the research review and concept elicitation interviews, the conceptual model was updated and the Impact of Juvenile Metachromatic Leukodystrophy on Physical Activities (IMPA) scale draft items were created. Cognitive debriefing interviews were conducted with six additional caregivers to finalize the conceptual model and to refine the IMPA scale.ResultsInitially, 17 potentially important concepts were identified and addressed in the draft IMPA scale. Following the cognitive debriefing interviews, 15 activities/items remained: brush teeth, comb/brush hair, bathe/shower, dress self, eat, drink, use pencil/crayon, sit upright, use toilet, get on/off toilet, walk, use stairs, get in/out of bed, get in/out of chair/wheelchair, and get in/out of vehicle. Items that did not uniquely contribute to the purpose of the instrument were removed.ConclusionThe IMPA scale, developed according to regulatory standards, provides a means of detecting changes in activities of daily living in individuals with juvenile MLD and can hence be used in future studies to measure benefits of therapeutic interventions.

Patient Voice in Rare Disease Drug Development and Endpoints

While planning for a successful clinical trial in a prevalent condition is no trivial orchestration, even more complicated is the coordination of novel, delicate and critical operational components necessary for the successful conduct of clinical trials of rare disease (RD). We highlight some of the inherent and practical challenges to conducting clinical trials and selecting or developing endpoints for RD and the importance of including the patient voice or perspective. These challenges include the lack of regulatory precedent for proposed endpoints, a void of available measures, little or no published literature or natural history information, the practicalities of obtaining access to patients, and the appropriateness of placebo-controlled trials. As part of our review, we include practical considerations for addressing these issues along with a regulatory perspective regarding potential logistic and methodologic challenges. We conclude that the patient perspective is a critical component in defining treatment benefit and in interpreting the meaningfulness of a change (or lack thereof). Engaging with patients is needed at multiple steps along the long road of drug discovery.

Development of the Observable Behaviors of Autism Spectrum Disorder Scale

Background: The objective of this research was to develop a caregiver-reported clinical outcome assessment (COA) measure designed to assess observable behaviors of children, ages 4 to 12 years, with autism spectrum disorder (ASD) for supporting labeling claims of treatment benefit. Methods: Development of the measure included a review of the literature and existing instruments, conceptual disease model development, concept elicitation focus groups, item generation, and cognitive debriefing interviews. Results: Predominant characteristics and behaviors of ASD identified by the literature and instrument reviews included sociability, communication deficits, stereotypy, inattention and hyperactivity, irritability, anxiety, and familial impact. In each of the 10 instruments reviewed, evidence of content validity was limited or nonexistent. Predominant themes arose across 8 major categories during concept elicitation. A total of 27 concepts were identified through focus group feedback and formed the basis for item development and cognitive pre-testing. Revisions to the items yielded a final version of a daily diary containing 21 items assessing observable behaviors and characteristics of ASD in children 4 to 12 years old. Conclusions: The Observable Behaviors of ASD Scale (OBAS) was developed as a self-administered, caregiver-reported measure containing 8 predominant themes. Items are scored on one of two 5-point ordinal categorical response scales, and the recall period for each item is “the past 24 hours.” This research provides evidence that the OBAS is content valid for assessing treatment benefit, which was found to be lacking in other instruments.