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Background Real-world evidence (RWE) generated using real-world data (RWD) presents the potential to contextualize and/or supplement traditional clinical trials for regulatory approval of rare diseases (RDs). This systematic review evaluated the use of RWD for non-oncologic RD therapies with orphan drug designation (ODD) to support efficacy outcomes in regulatory application packages to the US Food and Drug Administration (FDA). New drug applications (NDAs) and biologic license applications (BLAs) submitted between January 2017 and October 2022 were obtained from publicly available FDA drug approval websites. NDAs and BLAs of non-oncologic RD therapies were screened, and manually reviewed using RWE-related keywords. Quantitative summary of number/proportion of study types was provided, whereas qualitative synthesis focused on key categories of output assessing the use of RWD in overall drug approval process, including agency’s feedback on its strengths and key challenges. Results A total of 868 NDAs and BLAs were identified, of which 243 were screened for non-oncologic RDs with ODD, and 151 were subsequently reviewed for the RWD used to support efficacy outcomes. Twenty (12 NDAs, 8 BLAs) applications met the review inclusion criteria. Most (19; 95%) applications used only retrospective RWD, while one (5%) collected RWD both retrospectively and prospectively. RWD studies included natural history including registry-based/retrospective historical controls (14; 70%), retrospective medical chart-reviews (4; 20%), and external RWD controls from other studies (2; 10%). The FDA generally accepted RWD studies demonstrating a large effect size despite the noted concerns and criticisms. However, the agency expressed concerns about overall quality and comparability of RWD with trial data for some applications, including RWD study designs with respect to differences in patients’ baseline characteristics, missing information, and potential bias and measurement errors. Conclusions This systematic review highlights potential benefits of appropriately conducted RWE studies in RD, which can strengthen the clinical evidence for efficacy comparison and contextualization to support product approval efforts, particularly when a large magnitude of effect is observed for the new intervention. Nonetheless, quality and completeness of RWD and its comparability with trial data remain areas of concern that can serve as valuable learnings for advancing future science and regulatory approvals.

Untreated attention-deficit/hyperactivity disorder (ADHD) can lead to substantial adverse social, economic, and emotional outcomes for patients. The effectiveness of current pharmacologic treatments is often reduced, due to low treatment adherence and medication discontinuation. This current systematic literature review analyzes the current state of knowledge surrounding ADHD medication discontinuation, focusing on: 1) the extent of patient persistence; 2) adherence; and 3) the underlying reasons for patients' treatment discontinuation and how discontinuation rates and reasons vary across patient subgroups. We selected 91 original studies (67 with persistence/discontinuation results, 26 with adherence results, and 41 with reasons for discontinuation, switching, or nonadherence) and 36 expert opinion reviews on ADHD medication discontinuation, published from 1990 to 2013. Treatment persistence on stimulants, measured by treatment duration during the 12-month follow-up periods, averaged 136 days for children and adolescents and 230 days for adults. Owing to substantial study heterogeneity, comparisons across age or medication type subgroups were generally inconclusive; however, long-acting formulations and amphetamines were associated with longer treatment duration than short-acting formulations and methylphenidates. The medication possession ratio, used to measure adherence, was <0.7 for all age groups and medication classes during a 12-month period. Adverse effects were the most commonly cited reason for discontinuation in all studies. Original research studies reported the lack of symptom control as a common discontinuation reason, followed by dosing inconvenience, social stigma associated with ADHD medication, and the patient's attitude. In summary, although there was a lack of consistency in the measurement of adherence and persistence, these findings indicate that drug adherence and persistence are generally poor among patients with ADHD. Clinicians may be able to help improve adherence and persistence to ADHD treatment by educating caregivers and patients on treatment goals, administering long-acting medications, and following-up with patients to verify if medication is still effective and well-tolerated.

Background Patients with propionic acidemia (PA) may face recurrent metabolic decompensation events (MDEs) and multisystemic complications. This study compared characteristics and clinical outcomes of patients with PA and matched non-PA controls by age stratum. Methods Patients with PA from the US IQVIA PharMetrics Plus claims database (10/2015‒6/2022) had their follow-up time partitioned into age strata (0‒2, 3‒6, 7‒12, 13‒17, ≥ 18 years) and were matched 1:1 to randomly selected non-PA controls within each stratum. MDEs were identified as hospitalizations with claims for hyperammonemia and/or metabolic acidosis. Hospitalizations with claims for PA signs and symptoms were evaluated. Results Among 191 patients with PA and 230 matched non-PA controls (median follow-up: 2.7 years), patients with PA had more comorbidities (neurologic/nervous system, cytopenias, growth, metabolism, cardiac system; listed in order of frequency) across all age strata. The overall MDE rate for patients with PA was 0.5 per patient-year (PPY) while hospitalizations with various PA signs and symptoms ranged from 0.3 to 0.6 PPY. MDE rates were highest in those aged 3‒6 years (1.4 PPY), lowest in the 13‒17 years stratum (0.1 PPY), and rose again in adults (0.2 PPY). Patients with MDEs (31.4%) had a significantly higher burden of PA-related symptoms and comorbidities than those without; both groups showed even greater differences when compared to controls. Conclusions Patients with PA across all age strata, with and without MDEs, experience a substantial burden of disease-related comorbidities, complications, and healthcare visits compared with matched non-PA controls, which highlights the need for improved clinical outcomes in these patients.

Background There is currently no prior literature evaluating the economic burden of propionic acidemia (PA) in the US. This study evaluated the healthcare resource utilization (HRU) and expenditures associated with PA, overall and stratified by age. Methods The IQVIA PharMetrics ® Plus Claims database was used to identify patients with PA and matched (1:1) non-PA control individuals, who were stratified into 0–2, 3–6, 7–12, 13–17, and 18 + years age strata. All-cause HRU and costs were compared between the 2 cohorts by age stratum; PA-related HRU/costs were described for patients with PA. Results Among 230 paired observations across age strata, patients with PA had significantly higher all-cause HRU per-person-year (PPY) than control individuals. Patients with PA had 0.47–2.31 inpatient admissions PPY compared to 0.00-0.17 for control individuals (rate ratio: 10.36–78.55, all p  < 0.001). Patients with PA had 2.23–4.46 times more emergency room visits and 1.89–8.21 times more outpatient visits than control individuals as assessed by rate ratios. Patients with PA incurred significantly higher annualized all-cause total healthcare costs than control individuals, with the highest difference in the 0–2 year old ($205,883) and the lowest in the 7–12 year old age stratum ($20,168; both p  < 0.001). Among patients with PA, annualized mean PA-related total medical costs were $38,724 overall; inpatient admissions accounted for most costs ($33,575). Patients with PA who experienced metabolic decompensation events (MDEs) had higher HRU and costs than those without MDEs. Conclusions Patients with PA, with or without MDEs, had significantly increased HRU and costs than matched controls without PA. Economic burden, largely driven by hospitalizations, was significantly higher among patients with PA than control individuals across all pediatric and adult age strata.

Background Adhesions are fibrous bands of scar tissue, often a result of surgery, that form between internal organs and tissues, joining them together abnormally. Postoperative adhesions frequently occur following abdominal surgery, and are associated with a large economic burden. This study examines the inpatient burden of adhesiolysis in the United States (i.e., number and rate of events, cost, length of stay [LOS]). Methods Hospital discharge data for patients with primary and secondary adhesiolysis were analyzed using the 2005 Healthcare Cost and Utilization Project's Nationwide Inpatient Sample. Procedures were aggregated by body system. Results We identified 351,777 adhesiolysis-related hospitalizations: 23.2% for primary and 76.8% for secondary adhesiolysis. The average LOS was 7.8 days for primary adhesiolysis. We found that 967,332 days of care were attributed to adhesiolysis-related procedures, with inpatient expenditures totaling $2.3 billion ($1.4 billion for primary adhesiolysis; $926 million for secondary adhesiolysis). Hospitalizations for adhesiolysis increased steadily by age and were higher for women. Of secondary adhesiolysis procedures, 46.3% involved the female reproductive tract, resulting in 57,005 additional days of care and $220 million in attributable costs. Conclusions Adhesiolysis remain an important surgical problem in the United States. Hospitalization for this condition leads to high direct surgical costs, which should be of interest to providers and payers.

Background Anemia is a frequent complication of chronic kidney disease (CKD) that negatively affects patients’ health-related quality of life. Methods We conducted qualitative concept elicitation (CE) and cognitive debriefing (CD) interviews to assess the frequency, duration, and severity of symptoms and impacts associated with anemia of CKD and to facilitate the development of a new patient-reported outcome (PRO) measure. We interviewed 36 patients with CKD and hemoglobin levels ≥8.0 to <12.0 g/dL using a semi-structured interview guide developed specifically for this study until saturation was reached. We used MAXQDA to perform qualitative analysis of interview transcripts to determine the most relevant symptoms and impacts (based on the frequency of concept mentions) experienced by participants. Results Most participants had stage 4/5 CKD (81%) and were being treated with an erythropoietin stimulating agent (69%). Spontaneously reported symptoms included feeling tired (79%), shortness of breath (39%), and weak/lacking strength (36%). We developed the Chronic Kidney Disease and Anemia Questionnaire (CKD-AQ), which includes 23 items assessing frequency and severity of the most relevant symptoms and impacts identified by patients with anemia of CKD. The CD interviews confirmed the clarity and relevance of the concepts identified in the CE phase. Conclusion The CKD-AQ is a novel PRO measure that captures the frequency and severity of the most relevant symptoms and impacts associated with anemia of CKD. Future studies will evaluate its psychometric properties and its potential utility in anemia management.

Introduction For many, atopic dermatitis (AD) is not adequately controlled with topical regimens. This analysis examined treatment using advanced therapies and associated costs. Methods The IQVIA Health Plan Claims data set was analyzed. Patients aged ≥ 12 years with AD who newly initiated advanced therapy after the availability of dupilumab (March 28, 2017) and had ≥ 6 months continuous enrollment before and after their first advanced therapy claim (index date) were included. Advanced therapies included dupilumab, systemic corticosteroids (SCSs), systemic immunosuppressants (SISs), and phototherapy. A multivariate regression model was used to predict annualized follow-up healthcare costs. Results In total, 1980 patients were included (61.1% female; mean age, 41.2 years [SD, 17.4]; 11.3% < 18 years). Pre-index date, 65.2% of patients used topical corticosteroids (TCSs; 40.7% and 32.1% used medium and high potency, respectively). The most common advanced therapy was SCSs ( N  = 1453 [73.4%]; 69.2% prednisone) followed by dupilumab ( N  = 265 [13.4%]), SISs ( N  = 99 [5.0%]; 47.5% methotrexate), and phototherapy ( N  = 163 [8.2%]). Of patients treated with dupilumab, SISs, and phototherapy, 17.4%, 26.3%, and 14.1%, respectively, were prescribed SCSs post-index date. Overall, 62.6% of patients initiating SCSs, 49.1% initiating dupilumab, 64.6% initiating SISs, and 36.2% initiating phototherapy were prescribed TCSs post-index date. Mean annualized total costs (SD) post-index date were $20,722 ($47,014): $11,196 ($41,549) in medical costs ($7973 [$35,133] in outpatient visit costs) and $9526 ($21,612) in pharmacy costs. Mean annualized total cost (SD) varied significantly ( P  < 0.05) by index treatment: dupilumab, $36,505 ($14,028); SCSs, $17,924 ($49,019); SISs, $24,762 ($47,583); phototherapy, and $17,549 ($57,238). Conclusions Switching to combination therapy with SCSs and TCSs was common within 6 months of initiating advanced therapy in patients with AD. Patients also incurred significant pharmacy and outpatient costs. These results highlight the difficulty of managing AD with these existing treatment options.

Background Vitiligo is an autoimmune disorder in which the immune system targets melanocytes, manifesting in patches of lost skin pigmentation. Objectives To characterize the occurrence of autoimmune/autoinflammatory and/or nonautoimmune comorbid conditions in patients with vitiligo. Methods Adults representative of the 2017 US Census population were recruited for an online, cross‐sectional survey. Based on responses to vitiligo screening questions, participants were categorized into one of three groups: diagnosed vitiligo, undiagnosed vitiligo and no vitiligo. Participants reported clinical‐diagnosed conditions from prespecified lists of 13 autoimmune/autoinflammatory conditions and 21 nonautoimmune conditions. Results A total of 40,888 adults participated in the online survey; 315 (0.8%) were categorized as diagnosed vitiligo, 249 (0.6%) as undiagnosed vitiligo and 40,325 (98.6%) as no vitiligo. The percentage of participants with at least one autoimmune/autoinflammatory comorbidity was 2.65 times greater in the diagnosed vitiligo group than in the no vitiligo group. Psoriasis, rheumatoid arthritis and multiple sclerosis had the greatest difference in the percentage of participants between the diagnosed vitiligo and no vitiligo groups. The percentage of participants with nonautoimmune comorbidities was higher in the diagnosed vitiligo group than in the no vitiligo group. Vision changes, arthritis, back pain, anxiety, depression and sudden hearing loss had the greatest difference in the percentage of participants between the diagnosed vitiligo group and the no vitiligo group. Conclusions This large survey found that both autoimmune/autoinflammatory and nonautoimmune conditions were more common among adults with vitiligo. The greater percentage of autoimmune/autoinflammatory conditions in participants with vitiligo suggests that screening for such comorbidities may be beneficial and may indicate important opportunities for early intervention.

Background No head-to-head clinical trials have been published comparing guanfacine extended release (GXR) and atomoxetine (ATX): two nonstimulants approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). However, other study designs or methods could be used to indirectly compare these two medications. Matching-adjusted indirect comparison (MAIC) is a recent methodology that utilizes individual patient data (IPD) from clinical trials for one treatment and published aggregate data from another treatment to estimate the relative efficacy of both, providing rapid, reliable comparative efficacy results. Objective The aim of this study was to compare the efficacy of GXR and ATX for the treatment of ADHD using MAIC. Study Design A systematic literature search was conducted to identify ATX and GXR trials published through December 2012. Studies were selected for MAIC analyses on the basis of having comparable trial characteristics and study designs. Summary data from selected ATX trials and IPD from selected GXR trials were used. MAIC methodology ensured comparable populations: target doses for the ‘base case’ comparison were selected on the basis of maximum effective dosage ranges from the US FDA-approved product labels (GXR 0.09–0.12 mg/kg/day, ATX 1.2 mg/kg/day for children and adolescents weighing ≤70 kg). Individuals from GXR trials were selected if they matched inclusion/exclusion criteria from selected ATX trials; selected GXR IPD were then re-weighted to match the published ATX trial mean baseline characteristics and placebo outcomes. Sensitivity analyses were conducted, examining different dosage ranges and repeating the analysis in a larger number of trials, allowing for larger and more heterogeneous trial populations. Main Outcome Measure The primary outcome measure was change in ADHD Rating Scale IV (ADHD-RS-IV) total score. Results Using MAIC in the base case comparison, significantly greater reductions in mean (standard error; SE) ADHD-RS-IV total scores from baseline to end of study were observed in patients treated with GXR relative to ATX [−7.0 (2.2); p  < 0.01]. Significantly greater reductions for GXR over ATX were also demonstrated for hyperactivity/impulsivity [−3.8 (1.2); p  < 0.01] and inattention [−3.2 (1.3); p  < 0.05] subscales of the ADHD-RS-IV. Similar results were observed in MAIC sensitivity analyses evaluating other dosage ranges and using more heterogeneous trial populations (e.g., larger randomized sample, broader subject weight range, additional trials). Mean (SE) decreases in ADHD-RS-IV total scores were greater for GXR relative to ATX when including IPD for those administered GXR at lower than target dosage (0.075–0.090 mg/kg/day) compared with ATX at target dosage (1.2 mg/kg/day), with a relative improvement of −6.0 (2.7) ( p  < 0.05). Reductions in ADHD-RS-IV total scores were also greater for GXR in another MAIC examining GXR at target dosage (0.09–0.12 mg/kg/day) and a broader range of ATX dosages (including three additional trials evaluating ATX ≥1.2 mg/kg/day); relative improvement for GXR versus ATX administered at target dosage or higher was −7.6 (1.4) ( p  < 0.01). Conclusion After adjusting for difference in baseline trial characteristics using MAIC, GXR appears to be more efficacious than ATX for the treatment of ADHD. Results were consistent in a variety of dosage range comparisons and within increasingly heterogeneous trial populations.

Propionic acidaemia is a rare disorder caused by defects in the propionyl-coenzyme A carboxylase α or β (PCCA or PCCB) subunits that leads to an accumulation of toxic metabolites and to recurrent, life-threatening metabolic decompensation events. Here we report interim analyses of a first-in-human, phase 1/2, open-label, dose-optimization study and an extension study evaluating the safety and efficacy of mRNA-3927, a dual mRNA therapy encoding PCCA and PCCB. As of 31 May 2023, 16 participants were enrolled across 5 dose cohorts. Twelve of the 16 participants completed the dose-optimization study and enrolled in the extension study. A total of 346 intravenous doses of mRNA-3927 were administered over a total of 15.69 person-years of treatment. No dose-limiting toxicities occurred. Treatment-emergent adverse events were reported in 15 out of the 16 (93.8%) participants. Preliminary analysis suggests an increase in the exposure to mRNA-3927 with dose escalation, and a 70% reduction in the risk of metabolic decompensation events among 8 participants who reported them in the 12-month pretreatment period. Interim data from a clinical trial of mRNA-3927—an mRNA therapeutic for propionic acidaemia—provide early indications of the safety and efficacy of the treatment, and suggest that this approach might be applicable to other rare diseases.