Regulatory and HTA Considerations for Development of Real-World Data Derived External Controls.

Regulators and Health Technology Assessment (HTA) bodies are increasingly familiar with, and publishing guidance on, external controls derived from real-world data (RWD) to generate real-world evidence (RWE). We recently conducted a systematic literature review (SLR) evaluating publicly available information on the use of RWD-derived external controls to contextualize outcomes from uncontrolled trials submitted to the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and/or select HTA bodies. The review identified several key operational and methodological aspects for which more detailed guidance and alignment within and between regulatory agencies and HTA bodies is necessary. This paper builds on the SLR findings by delineating a set of key takeaways for the responsible generation of fit-for-purpose RWE. Practical methodological and operational guidelines for designing, conducting, and reporting RWD-derived external control studies are explored and discussed. These considerations include: (i) early engagement with regulators and HTA bodies during the study planning phase; (ii) consideration of the appropriateness and comparability of external controls across multiple dimensions, including eligibility criteria, temporality, population representation, and clinical evaluation; (iii) ensuring adequate sample sizes, including hypothesis testing considerations; (iv) implementation of a clear and transparent strategy for assessing and addressing data quality, including data missingness across trials and RWD; (v) selection of comparable and meaningful endpoints that are operationalized and analyzed using appropriate analytic methods; and (vi) conduct of sensitivity analyses to assess the robustness of findings in the context of uncertainty and sources of potential bias.

Effectively Leveraging RWD for External Controls: A Systematic Literature Review of Regulatory and HTA Decisions.

Real-world data (RWD)-derived external controls can be used to contextualize efficacy findings for investigational therapies evaluated in uncontrolled trials. As the number of submissions to regulatory and health technology assessment (HTA) bodies using external controls rises, and in light of recent regulatory and HTA guidance on the appropriate use of RWD, there is a need to address the operational and methodological challenges impeding the quality of real-world evidence (RWE) generation and the consistency in evaluation of RWE across agencies. This systematic review summarizes publicly available information on the use of external controls to contextualize outcomes from uncontrolled trials for all indications from January 1, 2015, through August 20, 2021, that were submitted to the European Medicines Agency, the US Food and Drug Administration, and/or select major HTA bodies (National Institute for Health and Care Excellence (NICE), Haute Autorité de Santé (HAS), Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), and Gemeinsamer Bundesausschuss (G-BA)). By systematically reviewing submissions to regulatory and HTA bodies in the context of recent guidance, this study provides quantitative and qualitative insights into how external control design and analytic choices may be viewed by different agencies in practice. The primary operational and methodological aspects identified for discussion include, but are not limited to, engagement of regulators and HTA bodies, approaches to handling missing data (a component of data quality), and selection of real-world endpoints. Continued collaboration and guidance to address these and other aspects will inform and assist stakeholders attempting to generate evidence using external controls.

Patient-reported outcomes with cemiplimab monotherapy for first-line treatment of advanced non-small cell lung cancer with PD-L1 of ≥50%: The EMPOWER-Lung 1 study.

BACKGROUND: In the EMPOWER-Lung 1 trial (ClinicalTrials.gov, NCT03088540), cemiplimab conferred longer survival than platinum-doublet chemotherapy for advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50%. Patient-reported outcomes were evaluated among trial participants. METHODS: Adults with NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned cemiplimab 350 mg every 3 weeks or platinum-doublet chemotherapy. At baseline and day 1 of each treatment cycle, patients were administered the European Organization for Research and Treatment of Cancer Quality of Life-Core 30 (QLQ-C30) and Lung Cancer Module (QLQ-LC13) questionnaires. Mixed-model repeated measures analysis estimated overall change from baseline for PD-L1 ≥50% and intention-to-treat populations. Kaplan-Meier analysis estimated time to definitive deterioration. RESULTS: In PD-L1 ≥50% patients (cemiplimab, n = 283; chemotherapy, n = 280), baseline QLQ-C30 and QLQ-LC13 scores showed moderate-to-high functioning and low symptom burden. Change from baseline favored cemiplimab on global health status/quality of life (GHS/QOL), functioning, and most symptom scales. Risk of definitive deterioration across functioning scales was reduced versus chemotherapy; hazard ratios were 0.48 (95% CI, 0.32-0.71) to 0.63 (95% CI, 0.41-0.96). Cemiplimab showed lower risk of definitive deterioration for disease-related (dyspnea, cough, pain in chest, pain in other body parts, fatigue) and treatment-related symptoms (peripheral neuropathy, alopecia, nausea/vomiting, appetite loss, constipation, diarrhea) (nominal p < .05). Results were similar in the intention-to-treat population. CONCLUSIONS: Results support cemiplimab for first-line therapy of advanced NSCLC from the patient's perspective. Improved survival is accompanied by improvements versus platinum-doublet chemotherapy in GHS/QOL and functioning and reduction in symptom burden.

Real-world effectiveness of casirivimab and imdevimab among patients diagnosed with COVID-19 in the ambulatory setting: a retrospective cohort study using a large claims database.

OBJECTIVE: To assess the real-world effectiveness of casirivimab and imdevimab (CAS+IMD) versus no COVID-19 antibody treatment among patients diagnosed with COVID-19 in the ambulatory setting, including patients diagnosed during the Delta-dominant period prior to Omicron emergence. DESIGN: Retrospective cohort study. SETTING: Komodo Health closed claims database. PARTICIPANTS: 13 273 128 patients diagnosed with COVID-19 (December 2020 through September 2021) were treated with CAS+IMD or untreated but treatment eligible under the Emergency Use Authorization (EUA). Each treated patient was exact and propensity score matched without replacement to up to five untreated EUA-eligible patients. INTERVENTIONS: CAS+IMD. PRIMARY AND SECONDARY OUTCOME MEASURES: Composite endpoint of 30-day all-cause mortality or COVID-19-related hospitalisation. Kaplan-Meier estimators were used to calculate outcome risks overall and across subgroups: age, COVID-19 vaccination status, immunocompromised status, and timing of diagnosis (December 2020 to June 2021, and July to September 2021). Cox proportional hazards models were used to estimate adjusted HRs (aHRs) and 95% CIs. RESULTS: Among 75 159 CAS+IMD-treated and 1 670 338 EUA-eligible untreated patients, 73 759 treated patients were matched to 310 688 untreated patients; matched patients were ~50 years, ~60% were women and generally well balanced across risk factors. The 30-day risk of the composite outcome was 2.1% and 5.2% in the CAS+IMD-treated and CAS+IMD-untreated patients, respectively; equivalent to a 60% lower risk (aHR 0.40; 95% CI, 0.38 to 0.42). The effect of CAS+IMD was consistent across subgroups, including those who received a COVID-19 vaccine (aHR 0.48, 95% CI, 0.41 to 0.56), and those diagnosed during the Delta-dominant period (aHR 0.40, 95% CI, 0.38 to 0.42). CONCLUSIONS: The real-world effectiveness of CAS+IMD is consistent with the efficacy for reducing all-cause mortality or COVID-19-related hospitalisation reported in clinical trials. Effectiveness is maintained across patient subgroups, including those prone to breakthrough infections, and was effective against susceptible variants including Delta. .

Patient-reported outcomes labeling for oncology drugs: Multidisciplinary perspectives on current status and future directions.

Introduction: Regulatory agencies encourage the incorporation of the patient voices throughout clinical drug development. Patient-Reported Outcomes (PROs) offer one way of doing this and their use has markedly increased in many therapeutic areas, particularly oncology, in recent years. However, few oncology drug labels include PRO data and those which do, offer little consistency. Objective: To provide multidisciplinary perspectives (patient, pharmaceutical industry, PRO researcher, regulatory expert) on PRO data in oncology drug labels. Methods: PRO data in the labels of drugs approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for oncology indications between 2010 and 2020 were critically reviewed by authors who provided their insights on the advantages and disadvantages/gaps. Results: Forty-six oncology drugs included PRO data in their labels. Differences were observed between FDA and EMA PRO labeling (e.g., PRO concept, use of tables and graphs to display PROs or reference to clinical meaningfulness). In providing their perspectives on the number and nature of PROs in labels, authors noted limitations including: the low proportion of oncology drugs with PRO labeling, limited PRO information in labels, lack of patient-friendly language, and potential bias towards positive outcomes. Lack of consistency within- and between-agencies was noted. Conclusion: Despite regulatory agencies' commitment to incorporate patient voices in regulatory decisions, availability of PRO information is limited in oncology drug labels. While several PRO guidance documents are available from regulatory and Health Technology Assessment agencies, harmonization of PRO guidance for labeling inclusion around the world is needed to better inform prescribers and consequently their patients in the process of shared medical decisions.

Effectiveness of Subcutaneous Casirivimab and Imdevimab in Ambulatory Patients with COVID-19.

INTRODUCTION: Data on real-world effectiveness of subcutaneous (SC) casirivimab and imdevimab (CAS+IMD) for the treatment of coronavirus disease 2019 (COVID-19) are limited. The objective of this study was to assess the effectiveness of SC CAS+IMD versus no antibody treatment among patients with COVID-19. METHODS: This retrospective cohort study linked Komodo Health and CDR Maguire Health and Medical data. Patients diagnosed with COVID-19 in ambulatory settings (August 1-October 30, 2021) treated with SC CAS+IMD were exact- and propensity score-matched to fewer than five untreated treatment-eligible patients and followed for the composite endpoint of 30-day all-cause mortality or COVID-19-related hospitalization. Kaplan-Meier estimators were used to calculate outcome risk overall and across subgroups. Cox proportional-hazards models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). RESULTS: Of 13,522 patients treated with CAS+IMD, 12,972 were matched to 41,848 untreated patients. The 30-day composite outcome risk was 1.9% (95% CI 1.7-2.2) and 4.4% (95% CI 4.2-4.6) in the treated and untreated cohorts, respectively; treated patients had a 49% lower relative risk of the composite outcome (aHR 0.51; 95% CI 0.46-0.58) and a 67% relative risk of 30-day mortality (aHR 0.33, 95% CI 0.18-0.60). Effectiveness was consistent across vaccination status and various subgroups. DISCUSSION: Patients with COVID-19 benefitted from treatment with SC CAS+IMD versus untreated patients. The results were consistent across subgroups of patients, including older adults, immunocompromised patients, and patients vaccinated against COVID-19. Results were robust across numerous sensitivity analyses. CONCLUSION: SC CAS+IMD is effective in reducing 30-day COVID-19-related hospitalization or mortality in real-world outpatient settings during the Delta-dominant period.

Reliability and Validity of an Instrument of COVID-19 Patient-Reported Symptoms in Outpatients.

Importance: Patient-reported outcome instruments are key in assessing COVID-19-related symptoms and associated burden. However, a valid and reliable instrument to assess symptom severity and progression among outpatients with COVID-19 is not yet available. Objectives: To assess the extent to which the Symptoms Evolution of COVID-19 (SE-C19) instrument is valid, reliable, and able to detect symptom changes in outpatients with COVID-19, as well as to establish a definition of symptom resolution. Design, Setting, and Participants: In this diagnostic/prognostic study, psychometric properties of SE-C19 were assessed in participants recruited into an ongoing, adaptive, phase 1/2/3, randomized, double-blind, placebo-controlled clinical trial, during 2020 to 2022. Adult outpatients with symptomatic COVID-19 were randomized 1:1:1 to receive 2.4 g or 8.0 g intravenous casirivimab and imdevimab or placebo, in outpatient centers at 114 sites, from 2 countries (US and Mexico). Main Outcomes and Measures: Reliability, validity, and sensitivity to change of the SE-C19 were assessed. SE-C19 and Patient Global Impression of Severity (PGIS) were administered daily from predose at day 1 to day 29. Results: Analysis was conducted on 657 adult outpatients (342 female patients [52.1%], 562 White patients [85.5%]), and 337 non-Hispanic patients [51.3%]. At baseline, patients reported a mean (SD) of 6.6 (3.9) symptoms (ie, rated as at least mild) with a mean (SD) of 3.8 (3.3) of these symptoms being rated as moderate or severe. Stable patients according to PGIS showed scores with intraclass correlation values indicating moderate-to-good test-retest reliability (ie, 0.50-0.90). At baseline, 20 item scores (87%) varied significantly across PGIS-defined groups, supporting the validity of the SE-C19. A symptom-resolution end point was defined after excluding the item sneezing due to its low ability to discriminate severity levels, and excluding confusion, rash, and vomiting, due to their low prevalence in this population. Symptom resolution required complete absence of all remaining items, except cough, fatigue, and headache, which could be mild or moderate in severity. A total of 19 of 23 items from the SE-C19 instrument were identified as valid and reliable to measure disease-related symptoms in outpatients with COVID-19. Conclusions and Relevance: This study identified 19 items that are valid and reliable to measure disease-related symptoms in outpatients with COVID-19, and proposed a definition of symptom resolution for potential use in future clinical trials.

The Patient Matters in the End(point).

Digital health technologies such as wearable sensors are increasingly being used in clinical trials. However, the endpoints created from these useful tools are wide and varied. Often, digital health technologies such as wearable sensors are used either to collect a raw metric like "step count" or with artificial intelligence algorithms to define a biomarker for improvement. In the case of the former, improvements in such a raw metric is difficult to attribute to the patient health in a meaningful way. In the case of the latter, despite the potential predictive accuracies of machine learning and artificial intelligence approaches, the resulting biomarkers are a black box, which has limited direct interpretability to the patient's specific health concerns. The paper represents a call to arms to really place the patient at the heart of the endpoint. By designing trial endpoints which are measured by digital health technologies using a patient centered approach from the outset, the patient benefits from understanding the implications of approved medication for their life.

Development and content validation of the Symptoms Evolution of COVID-19: a patient-reported electronic daily diary in clinical and real-world studies.

BACKGROUND: At the onset of the COVID-19 pandemic, there was limited understanding of symptom experience and disease progression. We developed and validated a fit-for-purpose disease-specific instrument to assess symptoms in patients with COVID-19 to inform endpoints in an interventional trial for non-hospitalized patients. METHODS: The initial drafting of the 23-item Symptoms Evolution of COVID-19 (SE-C19) Instrument was developed based on the Centers for Disease Control and Prevention symptom list and available published literature specific to patients with COVID-19 as of Spring 2020. The measurement principles outlined in the Food and Drug Administration (FDA) Patient-Reported Outcomes (PRO) guidance and the FDA's series of four methodological Patient-Focused Drug Development guidance documents were also considered. Following initial development, semi-structured qualitative interviews were conducted with a purposive sample of 30 non-hospitalized COVID-19 patients. Interviews involved two stages: (1) concept elicitation, to obtain information about the symptoms experienced as a result of COVID-19 in the patients' own words, and (2) cognitive debriefing, for patients to describe their understanding of the SE-C19 instructions, specific symptoms, response options, and recall period to ensure the content of the SE-C19 is relevant and comprehensive. Five clinicians treating COVID-19 outpatients were also interviewed to obtain their insights on symptoms experienced by patients and provide input on the SE-C19. RESULTS: Patients reported no issues regarding the relevance or appropriateness of the SE-C19 instructions, including the 24-h recall period. The comprehensiveness of the SE-C19 was confirmed against the conceptualization of the patient experience of symptoms developed in the qualitative research. Minor conceptual gaps were revealed to capture nuances in the experience of nasal and gustatory symptoms and systemic manifestations of sickness. Almost all items were endorsed by patients as being appropriate, well understood, and easy to respond to. The clinicians largely approved all items, response options, and recall period. CONCLUSIONS: The qualitative research provided supportive evidence of the content validity of the SE-C19 to assess the symptoms of outpatients with COVID-19, and its use in clinical trials to evaluate the benefit of treatment. Minor changes may be considered to improve conceptual clarity and ease of responding.

Patient experience of symptoms and impacts of COVID-19: a qualitative investigation with symptomatic outpatients.

OBJECTIVES: There is little in-depth qualitative evidence of how symptoms manifest themselves in outpatients with COVID-19 and how these in turn impact outpatients' daily lives. The objective of the study was therefore to explore the experience of outpatients with COVID-19 qualitatively, concerning the symptomatic experience and its subsequent impact on daily life. SETTING: Qualitative research study comprising virtual in-depth, open-ended interviews with outpatients and clinicians. PARTICIPANTS: Thirty US adult patients with COVID-19 were interviewed within 21 days of diagnosis. Patients were 60% female and 87% white, who had to self-report one of the following: fever, cough, shortness of breath/difficulty breathing, change/loss of taste/smell, vomiting/diarrhoea or body/muscle aches. Five independent clinicians were also interviewed about their experience treating outpatients. PRIMARY AND SECONDARY OUTCOME MEASURES: Transcripts were analysed thematically to organise symptoms and impacts of daily life into higher-order overarching categories, and subsequently propose a conceptual model. The adequacy of the sample size was assessed by conceptual saturation analysis. RESULTS: Patient-reported concepts were organised into six symptom themes (upper respiratory, lower respiratory, systemic, gastrointestinal, smell and taste, and other) and seven impact themes (activities of daily living, broad daily activities, leisure/social activities, and physical, emotional, professional and quarantine-specific impacts). Symptom type, severity, duration and time of onset varied by patient. Clinicians endorsed all patient-reported symptoms. CONCLUSIONS: The manifestation of symptoms in outpatients is heterogeneous and affects all aspects of daily life. Outpatients offered new detailed insights into their symptomatic experiences, including heterogeneous experiences of smell and taste, and the impacts that symptoms had on their daily lives. Findings of this research may be used to supplement existing knowledge of the outpatient experience of mild-to-moderate COVID-19, to further inform treatment guidelines and to provide an evidence base for evaluating potential treatment benefits.

Integrated analysis of a phase 2 study of cemiplimab in advanced cutaneous squamous cell carcinoma: extended follow-up of outcomes and quality of life analysis.

BACKGROUND: To provide pooled longer term data from three groups of a phase 2 study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC), and to determine duration of response (DOR) and impact on quality of life (QoL). METHODS: Patients received cemiplimab 3 mg/kg every 2 weeks (group 1, metastatic CSCC [mCSCC], n=59; group 2, locally advanced CSCC, n=78) or cemiplimab 350 mg every 3 weeks (group 3, mCSCC, n=56). Primary endpoint was objective response rate (ORR) per independent central review (ICR). QoL was repeatedly measured at day 1 of each treatment cycle (groups 1 and 2: 8 weeks; group 3: 9 weeks). RESULTS: Median duration of follow-up was 15.7 months. Overall, ORR per ICR was 46.1% (95% CI: 38.9% to 53.4%). Complete response (CR) rates were 20.3%, 12.8%, and 16.1% for groups 1, 2, and 3, respectively. Median time to CR was 11.2 months. Among patients with partial response or CR, the estimated proportion of patients with ongoing response at 12 months from the first objective response was 87.8% (95% CI: 78.5% to 93.3%), with median DOR not reached. Kaplan-Meier estimated probability of overall survival (OS) was 73.3% (95% CI: 66.1% to 79.2%) at 24 months, with median OS not reached. Global Health Status (GHS)/QoL improvements were observed as early as cycle 2 and were significantly improved and durable until last assessment. Kaplan-Meier estimate of median time to first clinically meaningful improvement for pain was 2.1 (95% CI: 2.0 to 3.7) months and was significantly improved in responders versus non-responders (p<0.0001). CONCLUSIONS: This is the largest (n=193) clinical dataset for a programmed cell death-1 inhibitor against advanced CSCC, confirming the sustained substantial clinical activity of cemiplimab in these patients, including new findings of improved CR rates over time, increasing DOR, and durable pain control and GHS/QoL improvement. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02760498), https://clinicaltrialsgov/ct2/show/NCT02760498.

Real-world persistence with dupilumab among adults with atopic dermatitis.

BACKGROUND: The real-world persistence with dupilumab therapy for atopic dermatitis (AD) is unknown. OBJECTIVE: To characterize adults with AD who initiated dupilumab and evaluate persistence with dupilumab therapy. METHODS: This retrospective cohort study used the IBM MarketScan Commercial and Medicare database. Adults with AD who initiated dupilumab (first dispensation = index date) between March 28, 2017, and March 31, 2018, were identified and followed up until September 30, 2018, or disenrollment. Twelve months of continuous preindex enrollment were required to characterize baseline treatment history and comorbidities. Kaplan-Meier analysis was used to estimate dupilumab persistence at 6 and 12 months, assuming a 14-day injection frequency and a 30-day grace period. RESULTS: A total of 1963 adults were identified who initiated dupilumab (mean [SD] age 42.1 [15.7] years; 50.7% women; 49.8% with ≥1 atopic comorbidity). Baseline AD treatments included topical corticosteroids (81.6%), systemic corticosteroids (72.5%), and systemic immunosuppressants (22.8%). Dupilumab persistence (95% confidence interval) at 6 and 12 months was 91.9% (90.7%-93.2%) and 77.3% (75.0%-79.7%), respectively. Among 329 patients who discontinued dupilumab, the risk of reinitiation was 78.8% (95% confidence interval: 75.8%-81.7%) within an average of 4 months. CONCLUSION: Dupilumab persistence at 12 months was high, suggesting patient satisfaction with effectiveness, tolerability, and treatment regimen.

A novel patient-reported outcomes instrument assessing the side effects of peanut oral immunotherapy.

BACKGROUND: Patients treated with peanut oral immunotherapy (OIT) may experience adverse reactions, particularly during up-dosing. OBJECTIVE: To develop the Side Effects of Peanut Oral Immunotherapy Diary (SEPOD), an electronic questionnaire assessing the daily side effects of peanut OIT in clinical trials. METHODS: Content and design of the SEPOD were informed by empirical literature review and meetings with 3 allergy-immunology experts. Interviews to confirm content and inform revisions were conducted in 24 pediatric patients with peanut allergy (14 treated with peanut OIT) aged 6 to 17 years; children aged 6 to 11 years were interviewed with their caregiver. RESULTS: The SEPOD was drafted after literature review and expert interviews; the initial measurement approach comprised 2 SEPOD versions, a patient-reported outcome (PRO) version for children aged 12 to 17 years, and a caregiver-administered PRO version for children aged 6 to 11 years with instructions for caregiver questionnaire administration. Pediatric patients were expected to respond independently on both versions. Patient interviews indicated that some younger children (ie, aged 6-8 years) had difficulty understanding questions, even when reading aloud; therefore, a caregiver-administered outcome version, identical in content to the caregiver-administered PRO version, was developed for this age group. The final electronic SEPOD covered 23 peanut OIT side effects within the following 7 domains: gastrointestinal, dermatologic, itching, nasal, and respiratory, swelling (eyelid or periorbital, lip, tongue, and throat), pain (tongue, mouth, and throat), and dizziness. CONCLUSION: This study yielded the SEPOD, a new clinical outcome assessment instrument with various methods of administration that can be used to assess the side effects of peanut OIT experienced by pediatric patients in a clinical trial setting.

Dupilumab improves patient-reported symptoms of atopic dermatitis, symptoms of anxiety and depression, and health-related quality of life in moderate-to-severe atopic dermatitis: analysis of pooled data from the randomized trials SOLO 1 and SOLO 2.

Background: Atopic dermatitis (AD) profoundly affects quality of life (QoL). Dupilumab significantly improves clinical outcomes, is well tolerated, and approved to treat inadequately controlled moderate-to-severe AD in adults; however, its effect on patient-reported outcomes (PROs) is not fully characterized.Objective: To evaluate the impact of dupilumab on patient-reported AD symptoms and QoL.Methods: Pooled data were analyzed from two identically designed phase 3 studies, LIBERTY AD SOLO 1 (NCT02277743) and SOLO 2 (NCT02277769), assessing the following PROs: Peak Pruritus Numerical Rating Scale (NRS), Pruritus Categorical Scale, SCORing AD (SCORAD), Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), Hospital Anxiety and Depression Scale (HADS), five-dimension EuroQoL questionnaire (EQ-5D), and patient-assessed disease status and treatment effectiveness.Results: Dupilumab rapidly improved (vs. placebo) Peak Pruritus NRS scores by day 2 (p < .05), anxiety and depression (HADS), and QoL (DLQI) by week 2, and maintained through week 16 (p < .0001). At week 16, more dupilumab-treated than placebo-treated patients reported improvement in SCORAD itch and sleep, and no pain/discomfort (EQ-5D) (p < .0001).Limitations: Cultural differences of translated PROs.Conclusion: Dupilumab had a significant, positive impact on AD symptoms, including itch, sleep, pain, anxiety and depression, and QoL in adults with moderate-to-severe AD.

Dupilumab improves symptoms, quality of life, and productivity in uncontrolled persistent asthma.

BACKGROUND: In a pivotal, phase 2b study (NCT01854047) in patients with uncontrolled persistent asthma, despite using medium-to-high-dose inhaled corticosteroids plus long-acting ß2 agonists, dupilumab improved lung function, reduced severe exacerbations, and showed an acceptable safety profile. OBJECTIVE: To assess the impact of dupilumab on asthma control, symptoms, quality of life (QoL), and productivity. METHODS: Data are shown for the intention-to-treat population receiving dupilumab 200/300 mg every 2 weeks (doses being assessed in phase 3; NCT02414854), or placebo. Predefined analyses of total scores were conducted at week 24 for the 5-item Asthma Control Questionnaire (ACQ-5), patient-reported morning/evening (AM/PM) asthma symptoms, Asthma Quality of Life Questionnaire (AQLQ), and asthma-related productivity loss. Responder rate analyses for these measures, subgroup analyses by baseline characteristics, and asthma-related productivity loss analyses were conducted post hoc. RESULTS: Data from 465 patients were analyzed (158 placebo; 307 dupilumab). Both dupilumab doses significantly improved scores through week 24 (all outcomes, overall population). The proportion of patients meeting or exceeding the minimal clinically important difference for the overall population were significantly greater vs placebo (P < .05) for ACQ-5 (range, 72.6%-76.7% vs 61.4%), for AM/PM asthma symptoms score (48.7%-54.1% vs 34.2% and 52.7%-53.5% vs 34.2%, respectively) and for AQLQ (64.0%-65.0% vs 51.3%). The effect of dupilumab was consistent across most subgroups. Productivity loss was significantly higher in placebo- vs dupilumab-treated patients (P < .0001). CONCLUSION: Dupilumab produced significant, clinically meaningful improvements in asthma control, symptoms, QoL, and productivity. REGISTRATION: ClinicalTrials.gov Identifier: NCT01854047.

Association of Inadequately Controlled Disease and Disease Severity With Patient-Reported Disease Burden in Adults With Atopic Dermatitis.

Importance: Real-world data are limited on the patient-reported burden of adult atopic dermatitis (AD). Objective: To characterize the patient-reported burden of AD with regard to impact of disease severity and inadequate control in adults from clinical settings. Design, Setting, and Participants: In this cross-sectional study using data from 6 academic medical centers in the United States collected by a self-administered internet-based questionnaire, 1519 adult patients with AD were stratified by AD severity as mild or moderate/severe using the Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD). Patients with moderate/severe disease using systemic immunomodulators/phototherapy were further stratified as having adequate or inadequate disease control. Strata were compared for all outcomes. Main Outcomes and Measures: Outcomes included validated measures and stand-alone questions assessing itch (pruritus numerical rating scale; PO-SCORAD itch visual analog scale), pain (numerical rating scale), sleep (PO-SCORAD sleep visual analog scale; sleep interference with function), anxiety and depression (Hospital Anxiety and Depression Scale), and health-related quality of life (Dermatology Life Quality Index). Results: Among the 1519 adult patients with AD, relative to mild AD (n = 689, 64% women; mean [SD] age, 46.5 [18.0] years), patients with moderate/severe AD (n = 830, 66.8% women; mean [SD] age, 45.1 [16.9] years) reported more severe itching and pain, greater adverse effects on sleep, higher prevalence of anxiety and depression (417 [50.2%] vs 188 [27.3%]), and greater health-related quality-of-life impairment. The 103 patients with moderate/severe AD with inadequate disease control despite treatment with systemic immunomodulators or phototherapy (55.7%) reported higher burdens of itch and sleeping symptoms vs patients with controlled disease including more days per week with itchy skin (5.7 vs 2.7) and higher proportions with itch duration greater than half a day (190 [22.8%] vs 20 [2.9%]). Sleep symptoms included trouble sleeping (3.9 vs 1.1 on the PO-SCORAD VAS), longer sleep latency (38.8 vs 21.6 minutes), more frequent sleep disturbances (2.6 vs 0.4 nights in past week), and greater need for over-the-counter sleep medications (324 [39%] vs 145 [21%]). Conclusions and Relevance: Inadequate disease control was common among patients with moderate/severe AD, and was associated with a higher patient-reported burden than patients with controlled disease. Regardless of disease control, the burden of moderate/severe AD was higher than mild AD, suggesting a need for more effective therapies for moderate/severe disease.

Economic Evaluation of Dupilumab for the Treatment of Moderate-to-Severe Atopic Dermatitis in Adults.

INTRODUCTION: Dupilumab significantly improves signs and symptoms of atopic dermatitis (AD), including pruritus, symptoms of anxiety and depression, and health-related quality of life versus placebo in adults with moderate-to-severe AD. Since the cost-effectiveness of dupilumab has not been evaluated, the objective of this analysis was to estimate a value-based price range in which dupilumab would be considered cost-effective compared with supportive care (SC) for treatment of moderate-to-severe AD in an adult population. METHODS: A health economic model was developed to evaluate from the US payer perspective the long-term costs and benefits of dupilumab treatment administered every other week (q2w). Dupilumab q2w was compared with SC; robustness of assumptions and results were tested using sensitivity and scenario analyses. Clinical data were derived from the dupilumab LIBERTY AD SOLO trials; healthcare use and cost data were from health insurance claims histories of adult patients with AD. The annual price of maintenance therapy with dupilumab to be considered cost-effective was estimated for decision thresholds of US$100,000 and $150,000 per quality-adjusted life-year (QALY) gained. RESULTS: In the base case, the annual maintenance price for dupilumab therapy to be considered cost-effective would be $28,770 at a $100,000 per QALY gained threshold, and $39,940 at a $150,000 threshold. Results were generally robust to parameter variations in one-way and probabilistic sensitivity analyses. CONCLUSION: Dupilumab q2w compared with SC is cost-effective for the treatment of moderate-to-severe AD in US adults at an annual price of maintenance therapy in the range of $29,000-$40,000 at the $100,000-$150,000 per QALY thresholds. FUNDING: Sanofi and Regeneron Pharmaceuticals, Inc.

Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial.

BACKGROUND: Dupilumab (an anti-interleukin-4-receptor-α monoclonal antibody) blocks signalling of interleukin 4 and interleukin 13, type 2/Th2 cytokines implicated in numerous allergic diseases ranging from asthma to atopic dermatitis. Previous 16-week monotherapy studies showed that dupilumab substantially improved signs and symptoms of moderate-to-severe atopic dermatitis with acceptable safety, validating the crucial role of interleukin 4 and interleukin 13 in atopic dermatitis pathogenesis. We aimed to evaluate the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids versus placebo with topical corticosteroids in adults with moderate-to-severe atopic dermatitis. METHODS: In this 1-year, randomised, double-blinded, placebo-controlled, phase 3 study (LIBERTY AD CHRONOS), adults with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids were enrolled at 161 hospitals, clinics, and academic institutions in 14 countries in Europe, Asia-Pacific, and North America. Patients were randomly assigned (3:1:3) to subcutaneous dupilumab 300 mg once weekly (qw), dupilumab 300 mg every 2 weeks (q2w), or placebo via a central interactive voice/web response system, stratified by severity and global region. All three groups were given concomitant topical corticosteroids with or without topical calcineurin inhibitors where inadvisable for topical corticosteroids. Topical corticosteroids could be tapered, stopped, or restarted on the basis of disease activity. Coprimary endpoints were patients (%) achieving Investigator's Global Assessment (IGA) 0/1 and 2-point or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week 16. Week 16 efficacy and week 52 safety analyses included all randomised patients; week 52 efficacy included patients who completed treatment by US regulatory submission cutoff. This study is registered with ClinicalTrials.gov, NCT02260986. FINDINGS: Between Oct 3, 2014, and July 31, 2015, 740 patients were enrolled: 319 were randomly assigned to dupilumab qw plus topical corticosteroids, 106 to dupilumab q2w plus topical corticosteroids, and 315 to placebo plus topical corticosteroids. 623 (270, 89, and 264, respectively) were evaluable for week 52 efficacy. At week 16, more patients who received dupilumab plus topical corticosteroids achieved the coprimary endpoints of IGA 0/1 (39% [125 patients] who received dupilumab plus topical corticosteroids qw and 39% [41 patients] who received dupilumab q2w plus topical corticosteroids vs 12% [39 patients] who received placebo plus topical corticosteroids; p<0·0001) and EASI-75 (64% [204] and 69% [73] vs 23% [73]; p<0·0001). Week 52 results were similar. Adverse events were reported in 261 (83%) patients who received dupilumab qw plus topical corticosteroids, 97 (88%) patients who received dupilumab q2w, and 266 (84%) patients who received placebo, and serious adverse events in nine (3%), four (4%), and 16 (5%) patients, respectively. No significant dupilumab-induced laboratory abnormalities were noted. Injection-site reactions and conjunctivitis were more common in patients treated with dupilumab plus topical corticosteroids-treated patients than in patients treated with placebo plus topical corticosteroids. INTERPRETATION: Dupilumab added to standard topical corticosteroid treatment for 1 year improved atopic dermatitis signs and symptoms, with acceptable safety. FUNDING: Sanofi and Regeneron Pharmaceuticals Inc.