Knowledge Base Prototype Creating with Using Interdisciplinary Metathesaurus.

This article presents our experience in development an ontological model can be used in clinical decision support systems (CDSS) creating. We have used the largest international biomedical terminological metathesaurus the Unified Medical Language System (UMLS) as the basis of our model. This metathesaurus has been adapted into Russian using an automated hybrid translation system with expert control. The product we have created was named as the National Unified Terminological System (NUTS). We have added more than 33 million scientific and clinical relationships between NUTS terms, extracted from the texts of scientific articles and electronic health records. We have also computed weights for each relationship, standardized their values and created symptom checker in preliminary diagnostics based on this. We expect, that the NUTS allow solving task of named entity recognition (NER) and increasing terms interoperability in different CDSS.

Excellence in the management of Advanced Hybrid Closed-Loop Systems: Lessons from the Polish cohort.

BACKGROUND: The aim of the study was to analyze the real-world performance of MiniMed 780G (MM780G) Advanced Hybrid Closed Loop (AHCL) system users from Poland (PL) and compare it to the European region excluding Poland (EU-PL) in order to identify factors contributing to potential differences. The former achieved some of the best Time in Range (TIR) results globally using this technology. METHODS: CareLink Personal data uploaded by MM780G system users from August 2020 to December 2022 were analyzed. RESULTS: The Polish users (N=1304) on average reached to TIR of 79.1 ± 8.7 % (vs 73.0 ± 10.0 % for EU-PL, N=55659), a TBR<54 mg/dL of 0.6 ± 0.7 % (vs 0.4 ± 0.6 %) and a TBR<70 mg/dL of 2.9 ± 2.1 % (vs 2.1 ± 1.8 %). The adoption rate of optimal settings (i.e, GT=100 mg/dL, AIT=2hr) in PL was high (19.7 % vs 6.3 %), and filtering on optimal setting users led to less pronounced differences in glycemic control between PL and EU-PL. A univariable analysis with post-AHCL TIR showed that geography itself (PL vs EU-PL) is not a significant contributor to a high post-AHCL TIR (p = 0.15), and that much of the Polish post-AHCL TIR can be explained by the high pre-AHCL TIR. CONCLUSION: The Polish MM780G users achieved better glycemic control than the general European population (excluding Poland). This is largely attributable to the adoption of optimal settings in Poland and the already high glycemic outcomes at system start. As these characteristics can be implemented elsewhere, we believe this outstanding result can be obtained in other countries as well.

Novel and Proven Models of Public, Private, and Public-Private Partnerships in Healthcare: An Update.

Initiatives to share assets in the life science sector through dedicated partnerships had and still have a multitude of different aspects in the past few decades. The range goes from industry partners, small and big companies, in bilateral agreements with academic institutions up to large privately and publicly funded consortia. In general, the term public-private partnership (PPP) is used when at least one public (non-profit, academic, and/or government) part and one or more private for-profit partners are involved. A Public-Private Partnership is often driven by a public body, i.e. a ministry or a public agency. Their synergism has been described 10 years ago (Dearing, Science 315(19):344-347, 2007; Casty and Wieman, Ther Innov Regul Sci 47(3):375-383, 2013; Stevens et al., Biotechnol Law Rep 34(4):153-165, 2015). So why view this synergism again today? It will be shown that the situation in life science has changed: novel partners acting digital, data expertise being involved on many levels and novel partnering models arising. Success and challenges will be described in this chapter.

Comorbidities and survival of multiple myeloma patients diagnosed in Finland between 2000 and 2021.

Advances in treatment have improved the survival of multiple myeloma (MM) patients, but the disease remains incurable. Here, in this nationwide retrospective real-world evidence (RWE) study, we report the patient characteristics, incidence, overall survival outcomes, comorbidities, and healthcare resource utilization (HCRU) of all adult MM patients diagnosed between 2000 and 2021 in Finland. A total of 7070 MM patients and their 21,210 age-, sex- and region-matched controls were included in the analysis. The average MM incidence doubled from 4.11 to 8.33 per 100,000 people during the follow-up. The average age-standardized incidence also showed a significant increase over time (2.51 in 2000 to 3.53 in 2021). An increase in incidence was particularly seen in older population, indicative of improved diagnosis praxis. The median overall survival (mOS) of the MM patients and their matched controls was 3.6 and 15.6 years, respectively. The mOS of all MM patients increased significantly from 2.8 years (2000-2004) to 4.4 years (2017-2021) during the follow-up period. Distinctively, in patients who received autologous stem cell transplantation (ASCT), the mOS was 9.2 years, while in patients who did not receive ASCT, the mOS was only 2.7 years. MM patients showed more comorbidities at index and increased HCRU than their matched controls. The longer median survival and decreased risk of death indicate improved treatment outcomes in MM patients in Finland.

[CAR T-cell therapy for malignant lymphoma].

Advances in understanding of the pathogenesis of B-cell lymphoma have led to development of various novel targeted therapies. Among them, CD19-targeted chimeric antigen receptor (CAR) T-cell therapies for relapsed and refractory B-cell lymphomas have shown remarkable efficacy in clinical trials, and three CAR T-cell products are now available in Japan. Real-world evidence (RWE) has shown that these products can provide comparable efficacy to clinical trials in clinical practice, where CAR T-cells were administered in patients with wider range of backgrounds. This finding will certainly broaden the role of CAR T-cell therapies in the treatment of B-cell lymphoma. However, since about half of the patients treated with CAR T-cell therapy progress thereafter, there is an urgent need for risk stratification and optimized management of refractory cases. Here, we review the results of clinical trials and RWE of CAR T-cell therapy in B-cell lymphoma.

A Comprehensive Framework for Evaluating the Value Created by Real-World Evidence for Diverse Stakeholders: The Case for Coordinated Registry Networks.

OBJECTIVES: This manuscript presents a comprehensive framework for the assessment of the value of real-world evidence (RWE) in healthcare decision-making. While RWE has been proposed to overcome some limitations of traditional, one-off studies, no systematic framework exists to measure if RWE actually lowers the burden. This framework aims to fill that gap by providing conceptual approaches for evaluating the time and cost efficiencies of RWE, thus guiding strategic investments in RWE infrastructure. METHODS: The framework consists of four components: (114th Congress. 21st Century Cures Act.; 2015. https://www.congress.gov/114/plaws/publ255/PLAW-114publ255.pdf .) identification of stakeholders using and producing RWE, (National Health Council. Glossary of Patient Engagement Terms. Published 2019. Accessed May 18. 2021. https://nationalhealthcouncil.org/glossary-of-patient-engagement-terms/ .) understanding value propositions on how RWE can benefit stakeholders, (Center for Drug Evaluation and Research. CDER Patient-Focused Drug Development. U.S. Food & Drug Administration.) defining key performance indicators (KPIs), and (U.S. Department of Health and Human Services - Food and Drug Administration: Center for Devices and Radiological Health and Center for Biologics Evaluation and Research. Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices - Guidance for Industry and Food and Drug Administration Staff. 2017. http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida .) establishing metrics and case studies to assess value. KPIs are categorized as 'better, faster, or cheaper" as an indicator of value: better focusing on high-quality actionable evidence; 'faster,' denoting time-saving in evidence generation, and 'cheaper,' emphasizing cost-efficiency decision compared to methodologies that do not involve data routinely collected in clinical practice. Metrics and relevant case studies are tailored based on stakeholder value propositions and selected KPIs that can be used to assess what value has been created by using RWE compared to traditional evidence-generation approaches and comparing different RWE sources. RESULTS: Operationalized through metrics and case studies drawn from the literature, the value of RWE is documented as improving treatment effect heterogeneity evaluation, expanding medical product labels, and expediting post-market compliance. RWE is also shown to reduce the cost and time required to produce evidence compared to traditional one-off approaches. An original example of a metric that measures the time saved by RWE methods to detect a signal of a product failure was presented based on analysis of the National Cardiovascular Disease Registry. CONCLUSIONS: The framework presented in this manuscript offers a comprehensive approach for evaluating the value of RWE, applicable to all stakeholders engaged in leveraging RWE for healthcare decision-making. Through the proposed metrics and illustrated case studies, valuable insights are provided into the heightened efficiency, cost-effectiveness, and improved decision-making within clinical and regulatory domains facilitated by RWE. While this framework is primarily focused on medical devices, it could potentially inform the determination of RWE value in other medical products. By discerning the variations in cost, time, and data utility among various evidence-generation methods, stakeholders are empowered to invest strategically in RWE infrastructure and shape future research endeavors.

Malignant melanoma in Portuguese adult population: a scoping review of the real-world evidence.

PURPOSE: Malignant melanoma is an aggressive cancer, and there is a notable dearth on epidemiology, clinical and treatment characterization within the Portuguese population. We performed a scoping review to identify real-world evidence studies focused in Portuguese adult patients with malignant melanoma. METHODS: A comprehensive search was conducted. After screening, we described the studies by design, sample size, geographics, setting, population, and outcomes reported. RESULTS: The search yielded 54 studies, mainly retrospective (79.6%). The population assessed was heterogeneous varying from patients with melanoma in general to specific types of melanoma, or even more restricted to patients with specific conditions. The evidence found was mostly concerning clinical outcomes (n=46), patients' clinical profile (n=44) and demographic characterization (n=48). Treatment information was described in 30 studies whereas only 18 reported epidemiological parameters. Studies were mainly performed by the major oncology centers in Lisbon, Oporto and Coimbra, and only two evaluated the entire Portuguese population. To allow comparability, only studies including patients with cutaneous malignant melanoma were considered (13 of the 54) for outcomes evaluation analysis. Median OS varied from 18 to 36 months, assessed after melanoma treatment. Incidence was the most reported epidemiological parameter, confirming the increasing number of cutaneous malignant melanoma patients over the years. Only one study reported prevalence and four reported mortality rates. CONCLUSIONS: The evidence found confirms the lack of information about malignant melanoma in Portugal, highlighting the need of real-world studies to assess melanoma prevalence and incidence rates, current treatment approaches, and clinical characterization of these patients.

Suicidal Ideation in Medicinal Cannabis Patients: A 12-Month Prospective Study.

OBJECTIVE: To document the prevalence and correlates of suicidal ideation (SI) among individuals seeking cannabis-based medicinal products (CBMPs); to test whether SI declines or intensifies after three months of CBMP treatment and to document 12-month trajectories of depression in those reporting SI and other patients. METHOD: Observational data were available for 3781 patients at entry to treatment, 2112 at three months and 777 for 12 months. Self-reported depressed mood and SI were assessed using items from the PHQ-9. Additional data included sociodemographic characteristics and self-reported well-being. RESULTS: 25% of the sample reported SI at treatment entry and those with SI had higher levels of depressed mood (mean = 17.4 vs. 11.3; F(1,3533) = 716.5, p < .001) and disturbed sleep (mean = 13.8 vs. 12.2, F(1,3533) = 125.9, p < .001), poorer general health (mean = 43.6 vs. 52.2, F(1,3533) = 118.3, p < .001) and lower quality of life (mean = 0.44 vs. 0.56 (F(1,3533) = 118.3, p < .001). The prevalence of SI reduced from 23.6% to 17.6% (z = 6.5, p < .001) at 3 months. Twelve-month follow-up indicated a substantial reduction in depressed mood with this reduction being more pronounced in those reporting SI (mean (baseline) = 17.7 vs. mean (12 months) = 10.3) than in other patients (mean (baseline) = 11.1 vs. mean (12 months) = 7.0). CONCLUSIONS: SI is common among individuals seeking CBMPs to treat a range of chronic conditions and is associated with higher levels of depressed mood and poorer quality of life. Treatment with CBMPs reduced the prevalence and intensity of suicidal ideation.

Suicidal ideation is common among individuals seeking CBMPs for chronic conditionsIt is associated with higher levels of depressed mood and poorer quality of lifeTreatment with CBMPs reduced the prevalence and intensity of suicidal ideation.

Implications of therapy interruption on monthly migraine days and modified migraine disability assessment in patients treated with erenumab for chronic and episodic migraine: SQUARE study interim results.

BACKGROUND: There are limited real-world data in Switzerland examining the impact of erenumab, a fully human IgG2 monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor, on migraine-related quality of life. OBJECTIVE: This 18-month interim analysis of 172 patients with episodic or chronic migraine from the SQUARE study provides first prospective insights on the impact of mandatory erenumab treatment interruption, following Swiss-reimbursement requirements, in a real-world clinical setting in Switzerland. FINDINGS: Recruited patients receiving 70 or 140 mg erenumab underwent treatment interruption on average 11.2 months after therapy onset with a mean duration of 4 months. There were sustained improvements in mean monthly migraine days (MMD) and migraine disability (mMIDAS) during initial treatment with erenumab. Treatment interruption was associated with a temporary worsening of condition. Symptoms ameliorated upon therapy reuptake reaching improvements similar to pre-break within 3 months. CONCLUSIONS: Treatment interruption was associated with a temporary worsening of condition, which improved again after therapy restart.

Real-world safety and effectiveness of radium-223 in patients with metastatic castration-resistant prostate cancer: Interim analyses of the prospective, observational RAPIT study.

Several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC) are available, including radium-223 dichloride (223Ra), which was approved based on phase 3 data demonstrating improved overall survival (OS) and a favorable safety profile. To date, real-world evidence for 223Ra use in Taiwan is from three studies of <50 patients. This observational study (NCT04232761) enrolled male patients with histologically/cytologically confirmed mCRPC with bone metastases from centers across Taiwan. 223Ra was prescribed as part of routine practice by investigators. Patients with prior 223Ra treatment were excluded. The primary objective was to assess 223Ra safety; secondary objectives evaluated efficacy parameters, including OS. Overall, 224 patients were enrolled. Most patients had an Eastern Cooperative Oncology Group performance status of 0/1 (79.0%) and ≤20 bone metastases (69.2%); no patients had visceral metastases. 223Ra was first- or second-line therapy in 23.2% and 47.7% of patients, respectively. The total proportion of patients who received 5-6 223Ra cycles was 68.8%; this proportion was greater with first-line use (84.3%) than second- (65.7%) or third-/fourth-line use (64.1%). More chemotherapy-naïve patients (61.9%) completed the 6-cycle 223Ra treatment than chemotherapy-exposed patients (56.7%). Any-grade treatment-emergent adverse events (TEAEs) and serious TEAEs occurred in 54.0% and 28.6% of patients, respectively, while 12% experienced 223Ra-related adverse events. Median OS was 15.7 months (95% confidence interval 12.13-19.51); patients receiving 5-6 223Ra injections and earlier 223Ra use had longer OS than those receiving fewer injections and later 223Ra use. 223Ra provides a well-tolerated and effective treatment for Taiwanese patients with mCRPC and bone metastases.

Effectiveness and Safety of the MVA-BN Vaccine against Mpox in At-Risk Individuals in the United States (USMVAc).

The mpox 2022 outbreak was declared a public health emergency in July 2022. In August 2022, the MVA-BN vaccine received emergency use authorization in the United States (US) to target at-risk groups. This study (EUPAS104386) used HealthVerity's administrative US healthcare data to generate real-world evidence for MVA-BN vaccine effectiveness and safety to prevent mpox disease in men who have sex with men (MSM) and transgender women, the most affected population during the 2022 mpox outbreak. Fully vaccinated subjects (two doses ≥ 28 days apart) were initially matched with five unvaccinated subjects on calendar date, age, US region, and insurance type. Subjects were followed from index date (14 days after the second dose) until death or data end to ascertain mpox occurrence. After propensity score adjustment, the MVA-BN vaccine effectiveness against mpox disease was 89% (95% CI: 12%, 99%) among those fully vaccinated; attenuated to 64% (95% CI: 40%, 78%) among those with any dose and 70% (95% CI: 44%, 84%) for those with only a single dose. One pericarditis adverse event of special interest was observed when the risk window was extended to 28 days. These results contribute to the totality of evidence supporting the favorable benefit/risk profile of the MVA-BN vaccine.

Data Science Methods for Real-World Evidence Generation in Real-World Data.

In the healthcare landscape, data science (DS) methods have emerged as indispensable tools to harness real-world data (RWD) from various data sources such as electronic health records, claim and registry data, and data gathered from digital health technologies. Real-world evidence (RWE) generated from RWD empowers researchers, clinicians, and policymakers with a more comprehensive understanding of real-world patient outcomes. Nevertheless, persistent challenges in RWD (e.g., messiness, voluminousness, heterogeneity, multimodality) and a growing awareness of the need for trustworthy and reliable RWE demand innovative, robust, and valid DS methods for analyzing RWD. In this article, I review some common current DS methods for extracting RWE and valuable insights from complex and diverse RWD. This article encompasses the entire RWE-generation pipeline, from study design with RWD to data preprocessing, exploratory analysis, methods for analyzing RWD, and trustworthiness and reliability guarantees, along with data ethics considerations and open-source tools. This review, tailored for an audience that may not be experts in DS, aspires to offer a systematic review of DS methods and assists readers in selecting suitable DS methods and enhancing the process of RWE generation for addressing their specific challenges.

Initiating GLP-1 Therapy in Combination with FreeStyle Libre Provides Greater Benefit Compared with GLP-1 Therapy Alone.

Background and Aim: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) therapy provides glycemic benefits to individuals with type 2 diabetes (T2D). However, the effects of GLP-1 RA therapy in combination with FreeStyle Libre systems (FSL) are unknown. This study aimed to compare changes in hemoglobin A1c (HbA1c) between people acquiring GLP-1 with FSL (GLP-1+FSL) versus GLP-1 without FSL (GLP-1). Methods: This real-world study used Optum's de-identified Market Clarity Data, a linked electronic health records (EHR)-claims database, and included adults with T2D and HbA1c ≥8% who acquired their first GLP-1 RA medication between 2018 and 2022. GLP-1+FSL subjects acquired their first FSL within ±30 days of their first GLP-1 acquisition. Cohorts were matched 1:5 on baseline insulin therapy, age, sex, baseline HbA1c, and GLP-1 type. Paired changes in HbA1c were compared between unmatched and matched groups at 6 months. Results: The study included 24,724 adults in the unmatched cohort (GLP-1+FSL, n = 478; GLP-1, n = 24,246). The matched cohort included 478 GLP-1+FSL users and 2,390 GLP-1 users: mean age 53.5 ± 11.8 and 53.5 ± 11.3 years, HbA1c 10.25 ± 1.68% and 10.22 ± 1.69%, respectively. HbA1c reduction was greater in the GLP-1+FSL group compared with the GLP-1 group in the unmatched cohort (-2.43% vs. -1.73%, difference 0.70%, P < 0.001, respectively) and in the matched cohort (-2.43% vs. -2.06%, difference 0.37%, P < 0.001). GLP-1+FSL vs. GLP-1 treatment was associated with greater HbA1c reduction in the intensive insulin (-2.32% vs. -1.50%), nonintensive insulin (-2.50% vs. -1.74%), and noninsulin group (-2.46% vs. -1.78%), as well as in patients using semaglutide (-2.73% vs. -1.92%) and dulaglutide (-2.45% vs. -1.71%) GLP-1 RA, all P < 0.001. Conclusions: Adults with suboptimally controlled T2D, initiating GLP-1 RA with FreeStyle Libre, had greater improvement in HbA1c compared with those treated with GLP-1 RA only. These results suggest an additional glycemic benefit of FSL when used with a GLP-1 RA in T2D treatment.

Incorporating external real-world data (RWD) in confirmatory adaptive design.

Adaptive designs, such as group sequential designs (and the ones with additional adaptive features) or adaptive platform trials, have been quintessential efficient design strategies in trials of unmet medical needs, especially for generating evidence from global regions. Such designs allow interim decision making and making adjustment to study design when necessary, meanwhile maintaining study integrity and operating characteristics. However, driven by the heightened competitive landscape and the desire to bring effective treatment to patients faster, innovation in the already functional designs is still germane to further propel drug development to a more efficient path. One way to achieve this is by leveraging external real-world data (RWD) in the adaptive designs to support interim or final decision making. In this paper, we propose a novel framework of incorporating external RWD in adaptive design to improve interim and/or final analysis decision making. Within this framework, researchers can prespecify the decision process and choose the timing and amount of borrowing while maintaining objectivity and controlling of type I error. Simulation studies in various scenarios are provided to describe power, type I error, and other performance metrics for interim/final decision making. A case study in non-small cell lung cancer is used for illustration on proposed design framework.

Biological Anti-IL-5/IL-5R Therapeutics for Chronic Obstructive Pulmonary Disease (COPD) with Specific Treatable Traits: A Real-World Retrospective Analysis.

Introduction: We describe the use of anti-IL-5 monoclonal antibodies from a COPD clinic, a source other than traditional clinical trials. The objectives were to characterize the patient subgroup prescribed anti-IL-5 monoclonal antibodies and to report potential benefits. Methods: This is a retrospective case series study of 17 patients treated in a COPD subspecialty clinic. All patients had a diagnosis of COPD (post-bronchodilator FEV1/FVC <0.7) and had been prescribed an anti-IL-5 biologic for at least 8 months. Acute exacerbations of COPD (AECOPDs) were collected as reported in electronic medical records. Results: All patients (17) enrolled were treated with biologics for ≥8 months, and 13 (76%) for ≥1 year. Patients were characterized by severe disease traits, FEV1 <50% predicted, recurrent exacerbations (3.5 moderate-to-severe AECOPDs in the year before treatment), high peripheral blood eosinophil counts (≥250 cells/µL in the previous year), all on inhaled triple therapy, and only 1 patient with a diagnosis of asthma prior to smoking. There was a statistically significant decrease in the exacerbation rate compared with baseline after 8 and 12 months of anti-IL-5 treatment, respectively, yielding the equivalent of a 2-3x reduction in exacerbation rate. Absolute FEV1 decreased, and the decline in FEV1 % of predicted reached statistical significance (p<0.05); CAT score improved (p<0.05). Discussion: This real-world evidence data aligns with existing studies suggesting the potential benefit of anti-IL-5 treatment for specific patients with COPD and therefore advocates for further investigation of RCTs on the use of anti-IL-5 biologics for well-characterized patients with COPD.

Real-world Data and Evidence to support a switch in status from Prescription drug to Over the Counter drug as applied by the EMA, the US FDA, the MHRA, and the BfArM.

PURPOSE: We studied under which circumstances and to what extent Real-World Data (RWD) and Real-World Evidence (RWE) were used in regulatory decisions when switching products from Prescription-only (Rx) to Over-the-Counter (OTC) status with the aim of extracting learnings that could be applied in future switches. METHODS: Sanofi commissioned Clarivate Analytics to identify switches from Rx to OTC in the European Union (centrally by the European Medicines Agency [EMA] and in Germany by the Bundesinstitut für Arzneimittel und Medizinprodukte [BfArM]), in the United States by the Food and Drug Administration (FDA), and in the United Kingdom by the Medicines and Healthcare products Regulatory Agency (MHRA) as far back as data were available in the public domain, mainly Health Authority webpages. They covered the period from and including 2022 and went as far back as they could find data in their proprietary database or in the public domain; for the EMA back to 2008, the US FDA back to 2001, the UK MHRA back to 1991, and the German BfArM for the period 2013-2022. We also asked Clarivate to investigate the nature of acceptance of RWD and RWE, and to what extent they are accepted by the different regulators in their decision-making and approval processes. FINDINGS: We found that the number of drugs available in the OTC segment is higher in regulatory jurisdictions where OTC policies are clear and supplemented by guidelines and transparent decision-making processes at the regulator level. A wide range of different data sources, many of which can be regarded as RWD/RWE in their broadest definitions, have been used to support switches. The data required by regulators to support a switch from Rx-only to OTC availability primarily centers on drug safety-both the drug's intrinsic safety and the safety associated with consumer usage. IMPLICATIONS: Clear and transparent regulatory switch frameworks are conducive to growing the number of medicines available to consumers willing to self-manage their conditions. Transparent disclosure of the RWD and RWE data sets that regulators have found acceptable in historic switch applications is desirable because it would help sponsors to facilitate and increase prospective switches, thereby benefiting patients and society.