Psychometric evaluation of an electronic Asthma Symptom Diary for young children.

BACKGROUND: Patient-reported outcome measures that facilitate self-report by children are needed to reduce the bias of proxy report. We previously developed an electronic Pediatric Asthma Symptom Diary (ePASD) to assess the severity of daily asthma symptoms and proximal impacts in children aged 6-11 years with mild to severe asthma. The ePASD, administered via a digital application with visuals, sounds, and text, is uniquely designed to minimize the importance of reading skills on children's ability to self-report accurately. Here, we describe the ePASD's psychometric properties. METHODS: Ninety-one children aged 6-11 years with mild to severe asthma and their caregivers participated in 2 study visits, which consisted of training on the provisioned device and completing asthma-specific clinical outcome assessment (COA) questionnaires. The children self-completed the ePASD at home twice daily for 8 consecutive days. The scoring of the ePASD was guided by factor analyses, inter-item correlations, and internal consistencies. Reliability, discriminating ability, construct validity, and responsiveness were evaluated for ePASD items and candidate scores. RESULTS: All COAs included in the study-the ePASD, Asthma Control Questionnaire (ACQ), Childhood Asthma Control Test, Pediatric Asthma Quality of Life Questionnaire-Standardized (PAQLQ[S]), and global ratings-demonstrated that the children exhibited few asthma-related symptoms and impacts at all timepoints, and consequently, showed little change over time. Internal consistencies (all Cronbach's alphas ≥ 0.52) and test-retest reliabilities (all intraclass correlation coefficients ≥ 0.60) were largely satisfactory. Patterns of convergent and divergent correlations supported the construct validity of ePASD scores. The ePASD symptom scores correlated moderately to strongly with PAQLQ(S) Symptom scores (all correlations ≥ - 0.46) and with ACQ scores (all correlations ≥ 0.42), as predicted. Evidence of the discriminating ability of ePASD items and composite scores was demonstrated by known-groups analyses. CONCLUSIONS: The ePASD is a reliable and valid measure of asthma symptoms and proximal impacts in children aged 6-11 years with mild, moderate, or severe asthma. These results lay the psychometric groundwork for use of the ePASD in future clinical trials for the management of pediatric asthma. An ongoing pediatric asthma treatment trial is anticipated to provide evidence of the ePASD's responsiveness to change.

Content Validation of Patient-Reported Sleep Measures and Development of a Conceptual Model of Sleep Disturbance in Patients with Moderate-to-Severe, Uncontrolled Asthma.

Purpose: Sleep disturbance is common in patients with asthma and can lead to subsequent impacts on health-related quality of life (HRQOL). Fit-for-purpose patient-reported outcome measures (PROMs) assessing asthma-related sleep disturbance and next-day HRQOL impact (next-day impact) are needed to evaluate disease burden and treatment effects. Patients and Methods: Adults (18-65 years) from three US clinics were recruited for semistructured interviews. Concept elicitation (CE) identified how asthma affects participants' sleep and how asthma-related sleep disturbances impact their daily lives, which informed conceptual model development. Cognitive debriefing (CD) of the Asthma Sleep Disturbance Questionnaire (ASDQ), Sleep Diary, and Patient-Reported Outcomes Measurement Information System Sleep-Related Impairment Short Form 8a (PROMIS SRI SF8a) was completed to assess each measure's content validity. Results: Twelve individuals participated in two interview rounds (6 individuals per round). Participants most frequently reported asthma-related nighttime awakening and decreased sleep quality and duration. Negative impacts of a poor night's sleep due to asthma symptoms included feeling tired/fatigue/lack of energy and subsequent negative impacts on physical functioning, emotions and mood, mental functioning, work or volunteerism, and social functioning. Across both rounds of CD interviews, participants generally found the Sleep Diary and PROMIS SRI SF8a items relevant and easy to complete with no modifications. The ASDQ was modified for clarity and consistency. Conclusion: As described in the conceptual model, asthma affects multiple aspects of sleep that can cause next-day fatigue and other subsequent negative HRQOL impacts. This study demonstrates that the ASDQ, Sleep Diary, and PROMIS SRI SF8a items are comprehensive, relevant, and appropriate for patients with moderate-to-severe, uncontrolled asthma. Evaluation of psychometric properties for the ASDQ, Sleep Diary, and PROMIS SRI SF8a based on clinical trial data in patients with moderate-to-severe, uncontrolled asthma will further support their use.

A Review of Patient-Reported Outcome Considerations in Oncologic Drugs Advisory Committee Meetings (2016-2021).

PURPOSE: The purpose of this project was to gain insight into the role of patient-reported outcome (PRO) data in US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) reviews and recommendations by documenting PRO-related considerations that appear in transcripts of ODAC meetings over a 6-year period (2016-2021). METHODS: ODAC meeting transcripts were reviewed for any mention of PRO-related concepts. Meetings that reviewed biosimilars and meetings that discussed conceptual matters were excluded. For each identified transcript, the meeting date, brand and generic names of the drug, and indication were collected from the meeting minutes. Comments by ODAC members, FDA reviewers, and study sponsors on PRO data were captured during the review. Qualitative review of transcripts included both reading and searching for key terms, including PROs, quality of life, and health-related quality of life. Discussion of PRO-related topics was captured verbatim, organized thematically, and analyzed by two independent reviewers. RESULTS: Twenty-seven transcripts of reviews were identified for 2016-2021. Topics related to PROs were included in 12 of those 27 reviews. The ODAC was satisfied with PROs included in 2 of those 12 reviews. Reasons for dissatisfaction in 10 of the 12 reviews included key concepts not assessed (5/12), missing data (5/12), and disagreement with sponsors' interpretation (3/12). The ODAC also expressed dissatisfaction with the lack of PRO data in 6 of 15 reviews that did not include PROs. CONCLUSION: Less than half of ODAC reviews in 2016-2021 included PROs, and reviewers expressed frustration at the lack of PRO data. Even when included, evidence on the basis of PROs was rarely deemed adequate for benefit-risk assessments.

Development and content validation of a self-completed, electronic Pediatric Asthma Symptom Diary.

BACKGROUND: Childhood asthma is an important unmet need. To date, patient-reported outcome measures (PROMs) for children with asthma have used a combination of caregiver or proxy-reported and self-reported measures. No comprehensive measure is available to assess the severity and impact of daytime and nighttime asthma symptoms and rescue medication use for self-completion by children aged 6-11 years. This study aimed to develop a novel, interactive, electronic Pediatric Asthma Symptom Diary (ePASD) measuring self-reported key symptom severity and proximal impacts of asthma in young children with varying reading ability and disease severity, consistent with US Food and Drug Administration (FDA) PRO guidance and the International Society for Health Economics and Outcomes Research (ISPOR) good research practices. METHODS: A targeted literature review and clinician interviews were undertaken to characterize symptoms and impacts experienced by children with mild-to-severe asthma. Concept elicitation interviews (CEIs) were conducted with 44 children and their caregivers (30 US; 14 UK). Following item and digital application development, the ePASD was assessed for relevance, understanding, and interpretability through cognitive debriefing interviews (CDIs) with 21 US children. Face validity/translatability assessments were also performed. RESULTS: Key measurement concepts included cough, wheeze, difficulty breathing, chest tightness/discomfort, nighttime awakening, and daytime activity limitations. Concept saturation was reached during CEIs for primary asthma-related daytime and nighttime symptoms and core impacts. Most CDI participants found the ePASD items clear, understandable, and comprehensive. Standardized training is anticipated to facilitate reliable child self-report. CONCLUSION: The ePASD, a novel PROM for children aged 6-11 years with asthma, uses an innovative multimedia approach and has been developed in accordance with FDA PRO guidance and ISPOR good research practices, directly capturing the child's self-reported asthma symptoms, impacts on daily activities and nighttime awakening, and rescue medication use.

Assessing the impact on caregivers caring for patients with rare pediatric lysosomal storage diseases: development of the Caregiver Impact Questionnaire.

BACKGROUND: Capturing the impact of caring for patients with debilitating rare disease is important for understanding disease burden. We aimed to develop and validate an instrument to measure the impact on caregivers of caring for children with three lysosomal storage diseases (LSDs): metachromatic leukodystrophy (MLD), neuronopathic mucopolysaccharidosis type II (MPS II) and mucopolysaccharidosis type IIIA (MPS IIIA). METHODS: A draft instrument was developed based on targeted literature searches and revised through sequential qualitative interviews with caregivers of patients first with MLD (n = 16), then with MPS II (n = 22), and finally with MPS IIIA (n = 8). The instrument, which covered domains of physical, emotional, social and economic burden, was refined at each stage of development based on caregiver feedback. Saturation of major concepts was reached during concept elicitation (MLD and MPS II). RESULTS: It was confirmed that caring for a patient with an LSD impacts social functioning, emotional/psychological functioning, physical functioning, daily activities, and finances/work productivity. Results from cognitive debriefing of the draft questionnaires were considered during each round of interviews, resulting in a final set of items that caregivers found clear and easy to understand. The Caregiver Impact Questionnaire (CIQ) has 30 items in five domains: (1) social functioning (7 items); (2) impact on daily activities (5 items); (3) emotional/psychological functioning (10 items); (4) physical functioning (6 items); and (5) financial impact (2 items). CONCLUSIONS: These findings demonstrate that the content of the CIQ is relevant for determining the impact of caring on caregivers of patients with MLD, MPS II and MPS IIIA.

Nosebleeds in hereditary hemorrhagic telangiectasia: Development of a patient-completed daily eDiary.

OBJECTIVE: A prospective, qualitative study was conducted to develop a patient-reported outcome measure (PROM) for daily administration via electronic diary (eDiary) to assess the severity of nosebleeds in patients with hereditary hemorrhagic telangiectasia (HHT), in accordance with Food and Drug Administration (FDA) PROM guidance criteria. METHODS: Three expert clinicians who treat patients with HHT provided input during instrument development, which comprised: 1) Peer-reviewed literature and instrument review; 2) Development of draft Nosebleed Diary items; 3a) Three rounds of qualitative interviews (two with a paper-based diary, one with an eDiary) with patients with documented severe epistaxis related to HHT, for concept elicitation and cognitive debriefing; 3b) Face validity and translatability assessment; 3c) Patient evaluation of the usability and acceptability of the eDiary device; and 4) Preparation of the final Nosebleed eDiary and conceptual framework. RESULTS: No existing instruments were identified that evaluate HHT-related nosebleed severity daily and meet FDA PROM guidance criteria. Frequency, duration, and/or speed of flow (i.e., intensity) were reported by most participants with HHT when asked to describe their nosebleed severity. The Nosebleed eDiary was refined based on 17 patient interviews, clinical expert input and the face validity and translatability assessment. The final four-item eDiary was acceptable to patients with HHT. CONCLUSION: The Nosebleed eDiary is "fit for purpose" to assess the severity of HHT-related nosebleeds, and has established face and content validity. Further adaptation may be required for use in mild or moderate HHT populations. Psychometric testing to evaluate construct validity and reliability are recommended next steps. LEVEL OF EVIDENCE: 2c "Outcomes research".

Impact of Measuring Patient-Reported Outcomes in Dermatology Drug Development.

Although some symptoms of dermatologic diseases, such as pruritus and pain, can be subjectively assessed only by patients, the most commonly used endpoints in dermatology drug research traditionally have been clinician-reported outcomes. Research has found that patient-reported outcomes (PROs) were included in only one-quarter of 125 trials conducted between 1994 and 2001. Our objective was to characterize the impact of PROs in dermatology drug development from the patient, prescriber, regulator, payer, and manufacturer perspectives using a case study approach. We conducted a structured literature review for pivotal clinical trials using PROs for six dermatologic products (MAS063DP, onabotulinumtoxinA, calcipotriene hydrate plus betamethasone dipropionate, pimecrolimus, tacrolimus, and ustekinumab). We also searched regulatory websites to identify product labeling and the UK National Institute for Health and Care Excellence website to identify submissions for the products of interest. A total of 32 articles illustrating the various perspectives were selected for inclusion. Clinical trials that include PROs allow patients to differentiate among treatments based on the experience of other patients participating in trials and enable prescribers to understand the benefit-risk profile of new treatments. The inclusion of PROs enables regulators to evaluate product benefits with a patient-centered perspective; five of the products of interest obtained eight total product labeling statements. PRO data supported manufacturers' dissemination of product benefits in the form of publications and PRO labeling for the product. For payers, PRO data were used in an analysis of cost effectiveness of new treatments. Inclusion of PROs in dermatology drug development programs benefits patients, prescribers, regulators, manufacturers, and payers.

Cognitive dysfunction and work productivity in major depressive disorder.

INTRODUCTION: Major depressive disorder (MDD) is strongly associated with poor work-related outcomes. Cognitive dysfunction is prevalent in MDD, and research supports a correlation between greater depression severity and more pronounced cognitive deficits, which frequently persist after remission. AREAS COVERED: Given the prevalence of cognitive dysfunction, and the humanistic and economic impact of occupational impairments in individuals with MDD, the relationship between cognitive dysfunction in MDD and work-related outcomes requires characterization. A selective review of the literature was conducted to better understand and further highlight this relationship. Expert commentary: Although current evidence is limited, MDD-related cognitive dysfunction may have a direct negative impact on work productivity. Presenteeism is the key outcome impacted by cognitive deficits in MDD. Additional well-designed prospective observational research may clarify how cognitive dysfunction influences the MDD-work productivity relationship. Use of reliable, valid, and sensitive measures of cognitive functioning and work productivity in MDD is warranted.

Patient-Reported Outcomes Labeling for Products Approved by the Office of Hematology and Oncology Products of the US Food and Drug Administration (2010-2014).

PURPOSE: To review the use of patient-reported outcome (PRO) data in medical product labeling granted by the US Food and Drug Administration (FDA) for new molecular entities and biologic license applications by the FDA Office of Hematology and Oncology Products (OHOP) between January 2010 and December 2014, to elucidate challenges faced by OHOP for approving PRO labeling, and to understand challenges faced by drug manufacturers to include PRO end points in oncology clinical trials. METHODS: FDA Drug Approval Reports by Month were reviewed to obtain the number of new molecular entities and biologic license applications approved from 2010 to 2014. Drugs approved by the FDA OHOP during this period were selected for further review, focusing on brand and generic name; approval date; applicant; indication; PRO labeling describing treatment benefit, measures, end point status, and significant results; FDA reviewer feedback on PRO end points; and study design of registration trials. First in class, priority review, fast track, orphan drug, or accelerated approval status was retrieved for selected oncology drugs from 2011 to 2014. Descriptive analyses were performed by using Microsoft Excel 2010. RESULTS: Of 160 drugs approved by the FDA (2010-2014), 40 were approved by OHOP. Three (7.5%) of the 40 received PRO-related labeling (abiraterone acetate, ruxolitinib phosphate, and crizotinib). Compared with nononcology drugs (2011-2014), oncology drugs were more likely to be orphan and first in class. The majority of oncology drug reviews by FDA were fast track, priority, or accelerated. CONCLUSION: Although symptoms and functional decrements are common among patients with cancer, PRO labeling is rare in the United States, likely because of logistical hurdles and oncology study design. Recent developments within the FDA OHOP to capture PROs in oncology studies for the purpose of product labeling are encouraging.

Measurement properties of an asthma symptom and rescue medication use diary.

INTRODUCTION: Assessment of symptoms and rescue medication use are well-established endpoints for clinical trials evaluating asthma treatment. OBJECTIVE: To evaluate the measurement properties of an asthma symptom and rescue medication use (ASRMU) diary for clinical trials involving asthma patients aged ≥12 years. METHODS: Interviews with 35 patients were conducted to confirm the importance of key concepts in the ASRMU diary. Scores of symptom and rescue medication use were converted to symptom-free days (SFD) and rescue-free days (RFD). Test-retest reliability and equivalence (based on intra-class correlation coefficients [ICCs]) between paper-and-pencil and electronic (eDiary) versions were evaluated in a prospective study in 47 patients. Responsiveness of the ASRMU diary was evaluated through differences in percentage of SFD and of RFD by treatment group in eight asthma clinical trials that assessed inhaled corticosteroids (ICS) and long-acting ß2-agonists (LABA), alone or in combination. A ninth placebo-controlled study calculated effect sizes. Minimal important differences (MID) were determined using anchor-based methods from two trials and by interviewing 11 patients. RESULTS: Patient interviews supported content validity for the ASRMU diary. Test-retest reliability was acceptable for SFD (ICC:0.70-0.75), but varied for RFD (ICC:0.58-0.78). Paper-and-pencil and eDiary modes of administration were equivalent (SFD, ICC=0.84; RFD, ICC=0.70). ICS/LABA had the largest percentage of SFD and RFD, followed by monotherapy and then placebo. MIDs were 7.7-14.7% for SFD and 8.4-15.6% for RFD. CONCLUSIONS: The ASRMU diary captures the disease-specific concepts of greatest importance to asthma patients and provides important information for asthma diagnosis and treatment evaluation.

Patient-reported outcome labeling claims and measurement approach for metastatic castration-resistant prostate cancer treatments in the United States and European Union.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) and its treatment significantly affect health-related quality of life (HRQOL). Our objectives were to evaluate and compare patient-reported outcome (PRO) claims granted by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for 5 recently approved mCRPC treatments and to examine key characteristics, development, and measurement properties of the PRO measures supporting these claims against current regulatory standards. METHODS: Five products approved for treatment of mCRPC by the FDA and the EMA (2010-2013) were examined: enzalutamide, abiraterone, sipuleucel-T, cabazitaxel, and radium Ra 223 dichloride. United States (US) drug approval packages and European Public Assessment Reports were reviewed. PRO claims in the US labels and European Summaries of Product Characteristics and supporting measures were identified. For PRO measures supporting claims, a targeted literature review was conducted to identify information on key characteristics and measurement properties; this information was compared against FDA PRO guidance criteria. RESULTS: Nine PRO "claims" were granted across 4 of 5 products reviewed. The EMA granted more claims (7 claims-4 for pain, 3 for HRQOL) than the FDA (2 claims, both for pain). The Brief Pain Inventory-Short Form (BPI-SF) worst pain item supported most pain claims and was the only measure supporting US claims. EMA pain claims were supported by BPI-SF worst pain (n = 2) and average pain (n = 1) items and the McGill Pain Questionnaire Present Pain Intensity component (n = 1). EMA HRQOL claims were supported by the Functional Assessment of Cancer Therapy-Prostate Module (n = 2) and the EuroQol 5 Dimensions with visual analogue scale (n = 1). Pain and prostate cancer-specific HRQOL measures supporting claims met US regulatory standards for construct validity, reliability, and responsiveness; these properties were strongest for the BPI-SF worst pain item. Only the BPI-SF worst pain item has documented content validity in mCRPC. CONCLUSIONS: PRO label claims were commonly granted across the mCRPC products reviewed. Among the measures reviewed, only the BPI-SF worst pain item supported US label claims. The BPI-SF worst pain item is recommended for pain assessment for the evaluation of new mCRPC treatments.

Assessment of PRO label claims granted by the FDA as compared to the EMA (2006-2010).

BACKGROUND: The US Food and Drug Administration (FDA) provides formal guidance for the use of patient-reported outcomes (PROs) in support of labeling claims, whereas the European Medicines Agency (EMA) offers insight in a reflection paper relating to health-related quality of life in lieu of formal guidance. OBJECTIVES: PRO label claims granted for new molecular entities and biologic license applications from 2006 through 2010 were reviewed to evaluate consistencies and discrepancies in PRO label claims granted by the FDA and the EMA and to highlight trends in the acceptance of PRO claims across agencies. METHODS: Products approved by both the FDA and the EMA were identified. By using US Drug Approval Packages and European Public Assessment Reports packages, any PRO label claims made for the same product by the same company were compared. RESULTS: Both agencies approved a total of 75 products. Of these, 35 (47%) had at least one EMA-granted PRO label claim compared with 14 (19%) by the FDA. Most FDA-grated claims focused on symptoms; however, EMA-granted claims were more likely to include higher order concepts. Few (~12%) were granted the same label claims. Despite this discordance between the two agencies, where PRO label claims were granted by both the FDA and the EMA, there was similarity in the type of label claim. CONCLUSIONS: The EMA is more likely than the FDA to grant PRO claims and for higher order constructs. On a macro level, there appears to be poor concordance between claims granted by both agencies. On close examination, however, there appears to be greater concordance than previously recognized, which may be instructive in formulating future PRO strategies. Further research to create strategic alignment across agencies may be beneficial.

Potential of patient-reported outcomes as nonprimary endpoints in clinical trials.

BACKGROUND: The purpose of this research was to fully explore the impact of endpoint type (primary vs. nonprimary) on decisions related to patient-reported outcome (PRO) labeling claims supported by PRO measures and to determine if nonprimary PRO endpoints are being fully optimized.This review examines the use of PROs as both primary and nonprimary endpoints in support of demonstration of treatment benefit of new molecular entities (NMEs) and biologic license applications (BLAs) in the United States in the years 2000 to 2012. METHODS: All NMEs and BLAs approved by the Food and Drug Administration (FDA) between January 2000 and June 2012 were identified using the FDA Drug Approval Reports Web page. Generic products granted tentative approvals were excluded. For all identified products, medical review sections from publicly available drug approval packages were reviewed to identify PRO endpoint status. Product labels (indication, clinical trials sections) were reviewed to determine the number and type of PRO claim. RESULTS: A total of 308 NMEs/BLAs were identified. Of these, 70 NMEs/BLAs (23%) were granted PRO claims. The majority of product claims were for disease- or condition-specific signs and symptoms. Of the 70 products with PRO claims, a PRO was a primary endpoint for the vast majority (57 [81%]). A total of 19 of the 70 products were granted a PRO claim based on a nonprimary endpoint. While nonprimary endpoints were used most often to support claims of improved signs or symptoms, nonprimary endpoints were much more likely to support claims of higher order impacts. CONCLUSIONS: Successful PRO labeling claims are typically based on primary endpoints assessing signs and symptoms. Based on this research, studies with PROs as primary endpoints are far more likely to facilitate positive regulatory review and acceptance of PROs in support of labeling claims. Although inclusion of PROs as nonprimary endpoints in clinical trials has its challenges, recent PRO labels granted by the FDA show that they can indeed be candidates for PRO labeling claims as long as they are supported by evidence.

Proxy-reported questionnaires for young children with asthma: a structured review.

Which proxy-reported outcome measures have been developed for use with children aged 6 years and younger to assess asthma symptoms, asthma control, and asthma-specific health-related quality of life, and do these questionnaires' measurement properties support their use as end-points in clinical trials? A two-phase literature search was conducted: 1) studies describing relevant questionnaires were identified, and the questionnaires were assessed against predefined criteria; 2) studies providing information on the measurement properties of questionnaires meeting the predefined inclusion criteria were identified. Literature sources included PubMed and EMBASE databases, scientific conference proceedings, a clinical trial registry, and a quality of life instrument database. The initial search of literature databases and conference abstracts identified 631 records. 20 paediatric asthma proxy-reported outcome instruments were identified; seven met the inclusion criteria: Childhood Asthma Control Test, Control de Asma en Niños Questionnaire, Pediatric Asthma Caregiver Diary, Pediatric Asthma Control Tool, PedsQL 3.0 Short-Form 22 Asthma Module, PedsQL Asthma Symptoms Scale, and Test for Respiratory and Asthma Control in Kids. Three proxy-reported outcome instruments were considered suitable for use as end-points in paediatric asthma clinical trials; the Pediatric Asthma Caregiver Diary possesses the strongest measurement properties of the three.

Role of Patient-Reported Outcome Measures in the Assessment of Central Nervous System Agents.

This work aimed to provide an understanding of the current use and regulatory acceptability of patient-reported outcome (PRO) measures in labeling claims for central nervous system (CNS) agents. A subset of CNS agents was identified from all New Drug Approvals and Biologic License Applications for new drugs approved in the US from January 2006 to June 2012. Clinician-reported outcomes (ClinROs) (62%) and PROs (38%) were the most widely used primary outcome measures. The PROs were frequently used in combination with ClinROs. Twelve PRO claims were granted across 41% of CNS drug approvals: 83%, symptoms; 17%, functioning. The PROs are frequently utilized as primary and secondary end points in CNS agents, and labeling claims are granted at higher levels than for non-CNS agents (41% vs 24%, respectively). These claims are granted at a lower rate than expected, given that direct patient input may lend valuable insight to treatment impacts in most CNS diseases.

A review of patient-reported outcome labels in the United States: 2006 to 2010.

OBJECTIVE: In 2004, Willke and colleagues reviewed the efficacy endpoints reported in the labels of new drugs approved in the United States from 1997 through 2002 to evaluate the use of patient-reported outcome (PRO) endpoints. Of the labels reviewed, 30% included PROs. Our study aimed to build on this work by describing the current state of PRO label claims granted for new molecular entities (and biologic license applications since February 2006 after the release of the US Food and Drug Administration (FDA) draft PRO guidance. METHODS: All new molecular entities and biologic license applications approved by the FDA from January 2006 through December 2010 were identified by using the Web page of the FDA Drug Approval Reports. For all identified products, drug approval packages and approved product labels were reviewed to identify PRO endpoint status and to determine the number and type of PRO claims. RESULTS: Of the 116 products identified, 28 (24%) were granted PRO claims; 24 (86%) were for symptoms, and, of these, 9 (38%) claims were pain related. Of the 28 products with PRO claims, a PRO was a primary endpoint for 20 (71%), all symptom related. CONCLUSIONS: The FDA continues to approve PRO claims, with 24% of new molecular entities and biologic license applications being granted. Successful PRO label claims over the past 5 years have generally supported treatment benefit for symptoms specified as primary endpoints.

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 Administration's 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.

Item reduction and psychometric validation of the Oily Skin Self Assessment Scale (OSSAS) and the Oily Skin Impact Scale (OSIS).

INTRODUCTION: Developed using focus groups, the Oily Skin Self Assessment Scale (OSSAS) and Oily Skin Impact Scale (OSIS) are patient-reported outcome measures of oily facial skin. OBJECTIVE: The aim of this study was to finalize the item-scale structure of the instruments and perform psychometric validation in adults with self-reported oily facial skin. METHODS: The OSSAS and OSIS were administered to 202 adult subjects with oily facial skin in the United States. A subgroup of 152 subjects returned, 4 to 10 days later, for test­retest reliability evaluation. RESULTS: Of the 202 participants, 72.8% were female; 64.4% had self-reported nonsevere acne. Item reduction resulted in a 14-item OSSAS with Sensation (five items), Tactile (four items) and Visual (four items) domains, a single blotting item, and an overall oiliness item. The OSIS was reduced to two three-item domains assessing Annoyance and Self-Image. Confirmatory factor analysis supported the construct validity of the final item-scale structures. The OSSAS and OSIS scales had acceptable item convergent validity (item-scale correlations >0.40) and floor and ceiling effects (<20%). Cronbach's alpha coefficients ranged from 0.83 to 0.89 for the OSSAS and 0.82 to 0.87 for the OSIS, demonstrating excellent internal consistency. The a priori test­retest reliability criterion (intraclass correlation [ICC] ≥0.7) was met for one of the three OSSAS domains and one of the two OSIS domains. OSSAS and OSIS domains distinguished among groups that differed in patient-reported facial oily skin severity (P < 0.0001), and bother associated with oily skin (P < 0.0001). CONCLUSIONS: The OSSAS and OSIS versions tested in this study have been found to have strong psychometric properties in this patient sample (adults with self-reported oily facial skin), as assessments of self-reported oily facial skin severity and its emotional impact, respectively.

Patient experiences with oily skin: the qualitative development of content for two new patient reported outcome questionnaires.

OBJECTIVE: To develop the content for two new patient reported outcome (PRO) measures to: a) assess the severity of symptoms; and b) the impact of facial skin oiliness on emotional wellbeing using qualitative data from face to face, and internet focus groups in Germany and the US. METHODS: Using input from initial treatment satisfaction focus groups (n = 42), a review of relevant literature and expert clinicians (n = 3), a discussion guide was developed to guide qualitative inquiry using Internet focus groups (IFGs). IFGs were conducted with German (n = 26) and US (n = 28) sufferers of oily skin. Questionnaire items were generated using coded transcript data from the focus groups. Cognitive debriefing was conducted online with 42 participants and face to face with an additional five participants to assess the comprehension of the items. RESULTS: There were equal numbers of male and female participants; mean age was 35.4 (SD 9.3) years. On average, participants had had oily skin for 15.2 years, and 74% (n = 40) reported having mild-moderate acne. Participants reported using visual, tactile and sensory (feel without touching their face) methods to evaluate the severity of facial oiliness. Oily facial skin had both an emotional and social impact, and was associated with feelings of unattractiveness, self-consciousness, embarrassment, irritation and frustration. Items were generated for a measure of oily skin severity (Oily Skin Self-Assessment Scale) and a measure of the impact of oily skin on emotional well-being (Oily Skin Impact Scale). Cognitive debriefing resulted in minor changes to the draft items and confirmed their face and content validity. CONCLUSION: The research provides insight into the experience of having oily skin and illustrates significant difficulties associated with the condition. Item content was developed for early versions of two PRO measures of the symptoms and emotional impact of oily facial skin. The psychometric validation of these measures reported elsewhere.