Real-world Evidence Research Articles

Factors associated with the initiation of high-efficacy disease-modifying agents over moderate-efficacy disease-modifying agents in multiple sclerosis

BackgroundWith multiple treatment options, choosing the initial disease-modifying agent (DMA) could be crucial to managing multiple sclerosis (MS). Common treatment strategies recommend starting patients with moderate-efficacy disease-modifying agents (meDMAs), while others advocate initiating high-efficacy disease-modifying agents (heDMAs). However, limited real-world evidence exists regarding the factors associated with utilizing differing treatment strategies in the MS. ObjectiveThis study evaluated the factors associated with the initiation of heDMAs in comparison to meDMAs among patients with MS. MethodsA retrospective cohort study was conducted using the Merative MarketScan Commercial Claims Database. Adult (18–64 years) MS patients with ≥1 DMA prescription were identified from 2016 to 2019. Patients were classified as incident heDMA or meDMA users based on their earliest DMA prescription, with a 12-month washout period. All covariates were measured during the 12-month baseline before the index DMA date. A multivariable logistic regression model, guided by the Andersen Behavioral Model, was applied to examine the predisposing, enabling, and need factors associated with using heDMAs over meDMAs. ResultsThere were 10,003 eligible MS patients, with the majority of users being female (74.92 %), middle-aged adults (35–54 years, 58.97 %), and enrolled in the Preferred Provider Organization (PPO, 53.10 %) healthcare plan. Overall, 2293 (22.92 %) MS patients initiated heDMAs. The multivariable logistic regression model revealed that male patients (adjusted odds ratio [aOR]: 1.46, 95 % Confidence Interval [CI]: 1.30–1.64) had higher odds of initiating heDMAs. Meanwhile, patients with bladder dysfunction medications (aOR: 1.39, 95% CI: 1.21-1.61), fatigue medications (aOR: 1.77, 95 %CI: 1.44–2.17), and impaired walking (aOR: 1.62, 95 %CI: 1.42–1.86) were more likely to initiate treatment with heDMAs. In contrast, patients with higher Elixhauser comorbidities scores, sensory symptoms (aOR: 0.47, 95 %CI: 0.42–0.53), visual symptoms (aOR: 0.63, 95 %CI: 0.54–0.73), and brainstem symptoms (aOR: 0.81, 95 %CI: 0.67–0.97) were less likely to be prescribed with heDMAs. ConclusionThe study found that approximately one in four MS patients initiated heDMAs. Both demographic and clinical factors influenced the selection of heDMA. More work is needed to understand the differential value of selecting heDMAs over meDMAs for personalizing DMA treatment.

Is Canada Moving towards a More Agile Regulatory Approval and Reimbursement Process with a Shifting Role for Real-World Evidence (RWE) for Oncology Drugs?

Canada is known to have a complex pathway for new drug approval and reimbursement, resulting in delayed access for patients with serious and life-threatening diseases, such as cancer. Several recent publications from key stakeholders, including patients, physicians and policymakers, highlight patient helplessness, physician frustrations and policymakers entangled in a massive network of bureaucracy unable to make headway. Several quantitative and qualitative assessments using time from regulatory approvals to successful reimbursements confirm long review times and high rejection rates for oncology drugs, especially those receiving conditional approvals. A consensus forum of 18 Canadian oncology clinicians recently voiced frustration with the process and inability to deliver guideline-supported efficacious therapies to their patients. This manuscript compares data extracted from publicly available data sources from 2019 to June 2024 to previous publications. Methods: Public databases from Health Canada, the Canadian Agency for Drugs and Technologies in Health (CADTH), which is in the process of changing to Canada's Drug Agency, and the pan-Canadian Pharmaceutical Alliance (pCPA) were reviewed and the data collected were analyzed with descriptive statistics. Results: From the data, three trends emerge, (i) an increasing number of oncology drugs are receiving conditional approvals from Health Canada, (ii) the percentage of conditionally approved oncology drugs receiving positive reimbursement recommendations from CADTH is still low but appears to be improving, but delays in access are now contingent upon pCPA deciding whether to negotiate price and then the duration of any negotiation, and (iii) real-world evidence is no longer part of the decision-making for conditional approvals. A slight increase in the positive endorsement of RWE used to support CADTH recommendations was observed. Conclusions: The lack of timely access to oncology drugs hurts Canadian patients. While a small trend of improvement appears to be emerging, longer-term data collection is required to ensure sustained patient benefits.

Long-term impact of ivacaftor on mortality rate and health outcomes in people with cystic fibrosis

BackgroundIvacaftor (IVA) has been shown to improve lung function and other clinical outcomes in people with cystic fibrosis (CF). A decade of real-world IVA availability has enabled the examination of...

Outcomes of a patient support programme for subcutaneous immunoglobulin therapy in patients with primary or secondary immunodeficiencies or chronic inflammatory demyelinating polyneuropathy.

Subcutaneous immunoglobulin (SCIg) therapy is important in the treatment of primary (PID) and secondary immunodeficiencies (SID) and chronic inflammatory demyelinating polyneuropathy (CIDP). Patient support programmes (PSPs) help patients self-administer medication regimens and play a more active role in the self-management of their medical conditions. To describe the effectiveness of the CSL Behring CARES PSP in optimising the quality use of SCIg in a hospital-free environment. This retrospective, observational study analysed records of patients enroled in the CSL Behring CARES PSP. Key outcomes were accessibility and effectiveness. Data were extracted from the patient database and analysed using descriptive methods. Seven hundred eighty-nine patients with PID (30.8%), SID (53.4%) and CIDP (15.8%) were enroled in the CARES PSP, 92.8% of whom were referred from public hospitals and the remaining from private hospitals. Of the total patient population, 697 (88.3%) received the nurse-led SCIg self-administration training and education (COACH), out of which 656 (94.1%) completed training and achieved competency after an average of 2.3 training sessions. The proportions of patients who achieved competency were similar across age groups and prior SCIg hospital education status. This is the largest real-world evidence study that describes the effectiveness of SCIg PSPs across three therapeutic disease states. These PSPs can optimise hospital resources such as infusion nurse time and allocation of infusion chairs that were once used for intravenous immunoglobulin infusions, improve patient access to SCIg therapy and enable patients self-administer SCIg outside a hospital environment.

Analysis of Baseline Molecular Factors Associated With the Risk of Central Nervous System Progression Among Alectinib-Treated Patients With ALK–Positive NSCLC

IntroductionDespite receiving alectinib therapy, patients with ALK-rearranged NSCLC remain at risk of central nervous system (CNS) progression. Our retrospective study aimed to identify baseline clinical and molecular factors associated with the risk of CNS progression in this patient subset. MethodsWe analyzed the clinical, molecular, and imaging data of 318 patients with ALK-positive advanced NSCLC who received alectinib as first-line (1L-alectinib) or second-line (2L-alectinib) therapy at baseline (1L, n = 183; 2L, n = 135) and at disease progression (1L, n = 57; 2L, n = 75). ResultsThe incidence rates of CNS progression were 12.3% after 1L-alectinib treatment and 30.7% after 2L-alectinib treatment. Compared with patients who received 1L-alectinib, CNS progression was significantly higher in patients who received 2L-alectinib (p = 0.04), particularly those who had oligoprogression (p = 0.01). Oligoprogression was detected in 55.0% (44 of 80) of patients who progressed after first-line alectinib, with the remaining 45.0% (36 of 80) having nonoligoprogression. Univariate and multivariate analyses and stepwise regression analyses consistently identified a higher likelihood of CNS progression among (1) patients who received 2L-alectinib than 1L-alectinib, (2) patients with non-3a/b variant ALK fusion than those with echinoderm microtubule-associated protein-like 4–ALK variant 3a/b, and (3) patients with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of 50% or higher than PD-L1 TPS of less than 50%. ConclusionsOur study provided real-world evidence that patients who harbored PD-L1 TPS of 50% or higher were more likely to experience CNS progression during alectinib therapy. The association between CNS progression and breakpoint variants warrants further investigation. Our findings suggest that close monitoring and prompt intervention are crucial in prolonging the quality of life of this patient subset.

External Controls to Study Treatment Effects in Rare Diseases: Challenges and Future Directions.

Regulators increasingly rely on real-world evidence generated from routine-care health data to evaluate novel therapies. Particularly, external control arms are increasingly used to supplement and contextualize efficacy and safety claims of single arm clinical trials for rare disease therapies. However, there are a number of methodological issues that may affect the validity of results derived from such comparisons. In this mini-review, we briefly summarize frequently used approaches and outline some of the most important criticisms and paths forward.

Real-World Evidence of the Safety and Effectiveness of Atogepant Added to OnabotulinumtoxinA for the Preventive Treatment of Chronic Migraine: A Retrospective Chart Review.

Combination use of atogepant and onabotulinumtoxinA has the potential to be more effective than either alone for the preventive treatment of chronic migraine (CM) due to their complementary mechanisms of action. This analysis collected real-world data to evaluate the safety, tolerability, and effectiveness of adding atogepant to onabotulinumtoxinA as a combination preventive treatment for CM. This retrospective, longitudinal, multicenter chart review included adults with CM who received ≥ 2 consecutive cycles of onabotulinumtoxinA before ≥ 1month of onabotulinumtoxinA and atogepant combination treatment. Charts at atogepant prescription (index date) and two subsequent onabotulinumtoxinA treatment visits (~ 3 and ~ 6 months post-index) were reviewed for change from baseline in monthly headache days (MHDs), ≥ 50% reduction in MHDs, discontinuation rates, and adverse events (AEs). Of the 55 charts that met safety analysis criteria, 31 had data on headache days at index and first post-index visit and were eligible for effectiveness analysis (mean age 46.7years, 94.5% female). For those with data available prior to onabotulinumtoxinA treatment (n = 25), the mean MHD was 24.0 days, reduced by 8.15 days after onabotulinumtoxinA treatment. After atogepant was added, MHD was incrementally reduced by 4.53 days and 8.75 days from index date to the first (N = 31) and second (N = 23) post-index onabotulinumtoxinA treatment visit, respectively. A ≥ 50% reduction in MHDs was achieved by 45.2% of patients ~ 3months post-index. Atogepant and onabotulinumtoxinA were discontinued by 16.1% and 6.5% of patients, respectively. In the safety population, 32.7% of patients experienced ≥ 1 AE. No serious AEs were reported. This real-world study of patients with CM demonstrated that adding atogepant to onabotulinumtoxinA as a combination preventive treatment for CM was effective by providing an additional reduction in MHDs over ~ 3 and ~ 6months of combination treatment. Safety results were consistent with the known safety profiles of onabotulinumtoxinA and atogepant, with no new safety signals identified.

Impact of Disease Factors of Patients with Psoriasis and Psoriatic Arthritis on Biologic Therapy Switching: Real-World Evidence from the CorEvitas Psoriasis Registry.

Patients with psoriasis (PSO) and psoriatic arthritis (PsA) may frequently switch biologic therapies over the course of treatment because of symptom variability and individual responses. Real-world studies analyzing patient characteristics and clinical factors associated with biologic switching are limited. This longitudinal cohort study used real-world data from the CorEvitas Psoriasis Registry to evaluate the relationship between associated disease factors and biologic switching among patients with PSO and PsA in the United States (US) and Canada following initiation of a biologic. Patients were evaluated between April 2015-August 2022. Combinations of disease severity (as measured by Psoriasis Area Severity Index [PASI]) and Dermatology Life Quality Index (DLQI) as a measure of health-related quality of life (HRQoL) were assessed, and the association with time to switching was calculated using Cox proportional hazards regression modeling. Among 2580 patient-initiations (instances of patients initiating a biologic), 504 (19.5%) switched biologics within 30months of initiation. Switching was more frequent when either PASI > 10 or DLQI > 5 compared with PASI ≤ 10 or DLQI ≤ 5 at follow-up. Patients with higher skin involvement (PASI > 10) and impact on HRQoL (DLQI > 5) were 14 times more likely to switch (hazard ratio = 14.2, 95% confidence interval: 10.7, 18.9) than those with lower skin involvement (PASI ≤ 10) and HRQoL (DLQI ≤ 5). Patients with PSO and PsA treated in a real-world dermatology setting with substantial disease factors following biologic initiation were more likely to switch therapies. Those with PASI > 10 and DLQI > 5 switched more frequently than those with PASI ≤ 10 and DLQI ≤ 5.

Impact of Disease Burden of Patients with Psoriasis on Biologic Therapy Switching: Real-World Evidence from the CorEvitas Psoriasis Registry.

Due to variable psoriasis symptoms, disease progression, and individual responses to therapy, patients may start, stop, or switch biologic therapies. Real-world data on the associated disease burden of patients with psoriasis who do and do not switch biologics are incomplete. This study compared disease burden among patients from the CorEvitas Psoriasis Registry (July 2017-December 2021) who switched biologics and those who did not within 4-12months following initiation. Disease-related patient-reported outcomes (PROs) were recorded, including skin pain, itching, activity impairment, and effects on health-related quality of life (HRQoL). Disease severity was measured by body surface area (BSA) and Psoriasis Area and Severity Index (PASI). Unadjusted and adjusted regression models were used to compare study outcome measures between the two groups. This study included 2145 patients, with 159 classified as switchers and 1986 as non-switchers. The most common reason for switching therapy was failure to maintain initial response (51.7%; n = 78). Moderate-to-severe disease (BSA ≥ 3) was found among 83.0% (n = 132) of switchers versus 26.1% (n = 516) of non-switchers. PASI > 5 was reported among 49.7% (n = 79) of switchers versus 8.6% (n = 171) of non-switchers. Differences in skin pain, itching, and effects on HRQoL between switchers and non-switchers were larger in magnitude for bio-experienced patients. Patients who switched biologic therapy experienced a greater disease burden of psoriasis across PROs than non-switchers. Patient-centered factors may be important drivers of biologic switching. Our findings suggest the association between switching and disease burden may be stronger among patients with prior biologic therapy experience.

Classical chemotherapy, immunotherapy, or adjuvant radiotherapy-how to improve the oncologic outcome of radical cystectomy?

According to current guidelines, patients with muscle-invasive urothelial carcinoma (pT2-pt4a pN0) should be offered neoadjuvant cisplatin-containing chemotherapy before radical cystectomy. If not used neoadjuvantly, chemotherapy can be administered in the adjuvant setting (for > pT3 or pN+ disease). Both neoadjuvant and adjuvant therapy lead to improved overall survival. In the adjuvant setting, the checkpoint inhibitor nivolumab has also been approved for treatment of PD-L1-positive tumors (tumor proportion score [TPS] ≥ 1%). On the one hand, real-world evidence shows that cisplatin-fit patients often do not receive chemotherapy and, on the other hand, that arelevant proportion of patients are also not suitable for cisplatin-based chemotherapy. Further multimodal therapeutic strategies are hence urgently needed to improve the prognosis of affected patients. In particular, the use of antibody-drug conjugates and combination strategies involving checkpoint inhibitors are currently being intensively researched.

Regulatory Development, Adoption, and Perseverance of Real-world Evidence with global health authorities

Real-world evidence (RWE) has gained significant attention as a valuable source of evidence in healthcare decision-making. This article provides a comprehensive analysis of the regulatory development, adoption, and perseverance of RWE with global health authorities, as well as a synopsis of the major trends and practices among global health authorities. The aim is to shed light on the current landscape, and prospects of utilizing RWE in regulatory processes. Globally, many health authorities are drafting guidelines for RWE and implementing various regulations. Implementation is in the initial stages because RWE has certain limitations. This article examines the experiences of selected global health authorities in the development and implementation of RWE strategies. It also examines regulatory guidelines, pilot programmes, and collaborations designed to establish a solid foundation for the use of RWE. However, despite all challenges and limitations, RWE is widely being used in drug approval and commercial sense.

Effectiveness of ulinastatin in critical care patients in real world: a retrospective multi-center study

ABSTRACT Objectives Ulinastatin has been applied in various diseases associated with inflammation, but its effectiveness lacks real-world evidence. We aimed to evaluate the effectiveness of ulinastatin based on a real-world database in the intensive care unit (ICU) patients. Methods This was a retrospective cohort study. ICU patient data from multi-centers in China were collected. Propensity score matching (PSM) was applied. The effectiveness of ulinastatin was evaluated by mortality, length of stay in the ICU and mechanical ventilation duration. Kaplan-Meier method was used to estimate the hazard ratio and plot the survival curve. Results A total of 2036 patients were analyzed after PSM. Mortality was significantly lower in the ulinastatin group than in the non-ulinastatin group (hazard ratio for death: 0.77; 95% confidence interval: 0.62–0.96; p = 0.018). Ulinastatin significantly reduced mortality at 28 days (10.0% vs. 13.6%), 60 days (13.9% vs. 18.2%) and 90 days (14.7% vs. 18.5%), length of stay in the ICU (median 8.0 d vs. 13.0 d), and mechanical ventilation duration (median 24.0 h vs. 25.0 h; p < 0.05). Conclusions Ulinastatin was beneficial for patients in the ICU, mainly by reducing mortality, length of ICU stay, and mechanical ventilation duration. This study provides evidence of the clinical effectiveness of ulinastatin.

Long-Term Treatment for Unspecified Anxiety Disorders with Cannabidiol: A Retrospective Case Series from Real-World Evidence in Colombia

Introduction: Preclinical and clinical evidence has elucidated that cannabis-based medical formulations (CBMFs) may display anxiolytic, antidepressive, and neuroprotective properties. CBMFs are often considered as novel therapeutic anxiolytic agents that can be prescribed as pharmacotherapy for symptomatic domains in anxiety disorders (ADs). Our aim was to explore effectiveness and tolerability of enriched cannabidiol (CBD) oil extract formulations in adults with anxiety symptoms in an outpatient mental health program in Colombia during the COVID-19 pandemic. Methods: We conducted an observational, retrospective, real-world evidence case series from electronic health records at Zerenia Clinic in Bogotá, Colombia between June 2021 and December 2022. Our convenience sample consisted of people searching for CBMFs for the treatment of anxiety symptoms. A cohort of 24 adults was prescribed with enriched CBD in the form of non-sterile oral liquids suspended in sesame seed oil extracts for DSM-5 unspecified anxiety disorder and followed throughout the first year of treatment. CBMFs were prepared by dissolving full-spectrum cannabis extracts in sesame seed oil to a standardized concentration of active ingredients which is CBD-enriched. The oil extract contained 100 mg/mL of CBD and less than 1.9 mg/mL of THC. Primary outcome measures established were the anxiety subscale in the Hospital Anxiety and Depression Scale (HADS-A), and the clinical global impression scale with regard to severity (CGI-S) and improvement (CGI-I) at baseline, 6 months, and 12 months during follow-up. Secondary outcome measures established were HADS depression subscale (HADS-D) and the Epworth Sleepiness Scale (ESS), respectively. Participants also completed the patient-reported outcome measures (PROMs) during each visit throughout the 12-month follow-up. PROMs documented both participantʼs subjective improvement experience and progressive adverse effects. Results: After 6 months of treatment with sublingually administered enriched CBD oil extracts in a median dosage of 100 mg, more than half (54.17%) of the sample continued to report significant anxiety symptoms. After 12 months, only 37.50% persisted with significant anxiety symptoms with a median dose of 120 mg of enriched CBD oil extracts. Similar subjective improvements were reported with regard to sleep disturbances (SDs) as a secondary outcome. At baseline, less than half (46.83%) of the sample reported significant daytime sleepiness. After 6 months of enriched CBD oil extract treatment, less than one third (29.17%) continued to report SDs. At end point, a high proportion of the sample (87.50%) were considered to have normal daytime sleepiness. The cohort showed no clinically relevant depressive symptoms at baseline based on HADS-D scores; therefore, no improvement could be reported throughout the 12-month follow-up. Minimal gender differences with regard to HADS-D scores may be attributed to modifying effects of menopause-related symptoms. No significant adverse drug reactions or deaths were reported during the 12-month follow-up. Conclusions: Further research should determine the long-term efficacy, safety, and appropriate dosages of enriched CBD oil extracts in treating specific ADs rather than broad and unspecified anxiety symptoms. The state of the art of CBMFs for ADs should be warranted by future randomized controlled trials. The next stage for cannabis research should be focused in performing head-to-head trials comparing enriched CBD extracts or capsules versus first-line treatments proven to be effective in ADs.

Ultrasonography led multimodal diagnostic pathway for giant cell arteritis.

To establish the sensitivity and negative predictive value of a multimodal pathway incorporating ultrasonography, 18-fluorodeoxyglucose labelled positron emission tomography computed tomography and temporal artery biopsy for the diagnosis of giant cell arteritis. 1000 consecutive referrals for a new diagnosis of giant cell arteritis were analysed. All patients had a protocolized examination. Patients with a negative ultrasonography and a C-reactive protein of ≥ 20 mg/l received an extended ultrasound examination. If that was negative, and there was no other explanation for their presentation, a second test in the form of either a temporal artery biopsy or an 18-fluorodeoxyglucose labelled positron emission tomography computed tomography was offered. We calculated the sensitivity and negative predictive value of the interventions for diagnosing giant cell arteritis. 279/1000 patients had positive ultrasonography for giant cell arteritis. 202 had bilateral superficial temporal arterial involvement. Ultrasonography of the axillary artery and other head/neck arteries increased the yield by 53 and 24 patients respectively. 181 patients were referred for a second test. 24/139 temporal artery biopsies and 7/42 18-fluorodeoxyglucose labelled positron emission tomography computed tomography scans were positive. The sensitivity and negative predictive value rise from 62.3% and 84.7% respectively for imaging superficial temporal arteries alone, to 95.7% and 98.0% respectively for extended ultrasonography plus a second test. This is the first real world evidence of the utility of ultrasonography for the diagnosis of giant cell arteritis as part of a multimodal diagnostic pathway.

Real-World Evidence of 3D Printing of Personalised Paediatric Medicines and Evaluating Its Potential in Children with Cancer: A Scoping Review.

Personalised medicine, facilitated by advancements like 3D printing, may offer promise in oncology. This scoping review aims to explore the applicability of 3D printing for personalised pharmaceutical dosage forms in paediatric cancer care, focusing on treatment outcomes and patient experiences. Following the Joanna Briggs Institute (JBI) methodology, a comprehensive search strategy was implemented to identify the relevant literature across databases including PubMed, Embase, and Web of Science. Three independent reviewers conducted study selection and data extraction, focusing on studies involving paediatric patients under 18 years old and pharmaceutical dosage forms manufactured using 3D printing technology. From 2752 records screened, only six studies met the inclusion criteria, none of which specifically targeted paediatric cancer patients. These studies examined aspects of acceptability, including swallowability, taste, and feasibility of 3D-printed formulations for children. While the studies demonstrated the potential benefits of 3D printing in paediatric medication, particularly in personalised dosing, there is a notable lack of evidence addressing its acceptability in paediatric cancer patients. Further interdisciplinary collaborative research is needed in this area to fully assess preferences and acceptability among children with cancer and their parents or caregivers.

The impact of different censoring methods for analyzing survival using real-world data with linked mortality information: a simulation study

BackgroundEvaluating outcome reliability is critical in real-world evidence studies. Overall survival is a common outcome in these studies; however, its capture in real-world data (RWD) sources is often incomplete and supplemented with linked mortality information from external sources. Conflicting recommendations exist for censoring overall survival in real-world evidence studies. This simulation study aimed to understand the impact of different censoring methods on estimating median survival and log hazard ratios when external mortality information is partially captured.MethodsWe used Monte Carlo simulation to emulate a non-randomized comparative effectiveness study of two treatments with RWD from electronic health records and linked external mortality data. We simulated the time to death, the time to last database activity, and the time to data cutoff. Death events after the last database activity were attributed to linked external mortality data and randomly set to missing to reflect the sensitivity of contemporary real-world data sources. Two censoring schemes were evaluated: (1) censoring at the last activity date and (2) censoring at the end of data availability (data cutoff) without an observed death. We assessed the performance of each method in estimating median survival and log hazard ratios using bias, coverage, variance, and rejection rate under varying amounts of incomplete mortality information and varying treatment effects, length of follow-up, and sample size.ResultsWhen mortality information was fully captured, median survival estimates were unbiased when censoring at data cutoff and underestimated when censoring at the last activity. When linked mortality information was missing, censoring at the last activity date underestimated the median survival, while censoring at the data cutoff overestimated it. As missing linked mortality information increased, bias decreased when censoring at the last activity date and increased when censoring at data cutoff.ConclusionsResearchers should consider the completeness of linked external mortality information when choosing how to censor the analysis of overall survival using RWD. Substantial bias in median survival estimates can occur if an inappropriate censoring scheme is selected. We advocate for RWD providers to perform validation studies of their mortality data and publish their findings to inform methodological decisions better.

SATURN: assessing the feasibility of utilising existing registries for real-world evidence data collection to meet patients, regulatory, health technology assessment and payer requirements

BackgroundSATURN (Systematic Accumulation of Treatment practices and Utilisation, Real world evidence, and Natural history data) for the rare condition osteogenesis imperfecta (OI) has the objective to create a common core dataset by utilising existing, well-established data sources to meet the needs of the various stakeholders (physicians, registry/dataset owners, patients and patient associations, OI community leaders, European [EU] policymakers, regulators, health technology assessments [HTA]s, and healthcare systems including payers). This paper describes the steps taken to assess the feasibility of one existing OI registry (i.e., the Registry of OI [ROI]) as a candidate for SATURN. The same methodology will be applied to other existing OI registries in the future and this same concept could be utilised for other rare disease registries.MethodsThe approach to assessing the feasibility of the ROI registry consisted of three steps: (1) an assessment of the registry characteristics using the Registry Evaluation and Quality Standards Tool (REQueST); (2) a gap analysis comparing SATURN required Core Variables to those being captured in the registry’s Case Report Form (CRF); and (3) a compliance check on the data exchange process following the Title 21 of Code of Federal Regulations (CFR) Part 11/EudraLex Annex 11 Compliance Checklist. The first registry that SATURN has assessed is the ROI database at the Istituto Ortopedico Rizzoli (IOR) in Italy.ResultsThe results from the ROI REQueST have demonstrated satisfactory complete responses in terms of methodology, essential standards, interpretability, and interoperability—readiness for data linkage, data sources, and ethics to meet the needs of data customers. However, the ROI data is from a tertiary referral centre which may limit the ability to understand the full patient journey. The gap analysis has revealed that an exact or logical match between SATURN requested variables and the ROI current variables exists for the following items: patient characteristics, treatment of OI (medical and surgical) and treatment of pain (with the exception of frequency of treatment and reasons for discontinuation), fracture history and bone density. However, data on safety was missing. The compliance check has implied that the ROI implemented appropriate controls for the web-based platform (i.e., Genotype–phenotype Data Integration Platform [GeDI]) that is involved in processing the electronic patient data, and GeDI is a validated/compliant application that follows relevant 21 CFR Part 11/EudraLex Annex 11 regulations.ConclusionsThis robust feasibility process highlights potential limitations and opportunities to develop and to refine the collaboration with the ROI as the SATURN programme moves forward. It also ensures that the existing datasets in the rare condition OI are being maximised to respond to the needs of patients, data customers and decision-makers. This feasibility process has allowed SATURN to build a compliant methodology that aligns with the requirements from the European Medicines Agency (EMA) and HTAs. More data variables will continue to be developed and refined along the way with more registries participating in SATURN. As a result, SATURN will become a meaningful and truly collaborative core dataset, which will also contribute to advancing understanding of OI diagnosis, treatment, and care.

Patients’ health care resources utilization and costs estimation across cardiovascular risk categories: insights from the LATINO study

BackgroundAtherosclerotic Cardiovascular Disease (ASCVD) is a global public health concern. This study aimed to estimate the healthcare resource utilization (HRU) and costs stratified by cardiovascular disease (CVD) risk categories using real-world evidence, in a regional population in Portugal.MethodsThis is a retrospective observational study, using data from Electronic Health Records between 2017 and 2021. Patients aged ≥ 40 years, and with at least one general practitioner (GP) appointment in the 3 years before 31st of December 2019, were included. CVD risk categories were determined based on 2021 ESC prevention guidelines. HRU encompassed hospital data (hospitalizations, outpatient and emergency room visits) and GP appointments. Total direct costs per patient were calculated based on the reference cost of the Portuguese legislation for payment methodology on Diagnosis-Related Groups (DRGs).ResultsAnalysis of 3 122 695 episodes, revealed consistent HRU and costs across the five years. Very high-risk patients, showed higher HRU, particularly in hospital admissions. Costs tended to rise with higher CVD risk level. Very high-risk patients with ASCVD had higher costs for hospital admissions, while low-to-moderate risk patients had higher costs for GP visits. Despite a smaller proportion, very high-risk patients with prior ASCVD represent the highest costs per patient across healthcare settings (from 115€ in emergency visits to 2 673€ in hospitalizations), followed by very high-risk patients without prior ASCVD (ASCVD-risk equivalents).ConclusionThis study revealed a substantial HRU and costs by patients with very high CVD risk, particularly those with prior ASCVD. Moreover, ASCVD-risk equivalents emerge as notable consumers, emphasizing the importance of risk assessment and preventive measures in cost-effective management of these patients.

An exploration into CTEPH medications: Combining natural language processing, embedding learning, in vitro models, and real-world evidence for drug repurposing.

In the modern era, the growth of scientific literature presents a daunting challenge for researchers to keep informed of advancements across multiple disciplines. We apply natural language processing (NLP) and embedding learning concepts to design PubDigest, a tool that combs PubMed literature, aiming to pinpoint potential drugs that could be repurposed. Using NLP, especially term associations through word embeddings, we explored unrecognized relationships between drugs and diseases. To illustrate the utility of PubDigest, we focused on chronic thromboembolic pulmonary hypertension (CTEPH), a rare disease with an overall limited number of scientific publications. Our literature analysis identified key clinical features linked to CTEPH by applying term frequency-inverse document frequency (TF-IDF) scoring, a technique measuring a term's significance in a text corpus. This allowed us to map related diseases. One standout was venous thrombosis (VT), which showed strong semantic links with CTEPH. Looking deeper, we discovered potential repurposing candidates for CTEPH through large-scale neural network-based contextualization of literature and predictive modeling on both the CTEPH and the VT literature corpora to find novel, yet unrecognized associations between the two diseases. Alongside the anti-thrombotic agent caplacizumab, benzofuran derivatives were an intriguing find. In particular, the benzofuran derivative amiodarone displayed potential anti-thrombotic properties in the literature. Our in vitro tests confirmed amiodarone's ability to reduce platelet aggregation significantly by 68% (p = 0.02). However, real-world clinical data indicated that CTEPH patients receiving amiodarone treatment faced a significant 15.9% higher mortality risk (p<0.001). While NLP offers an innovative approach to interpreting scientific literature, especially for drug repurposing, it is crucial to combine it with complementary methods like in vitro testing and real-world evidence. Our exploration with benzofuran derivatives and CTEPH underscores this point. Thus, blending NLP with hands-on experiments and real-world clinical data can pave the way for faster and safer drug repurposing approaches, especially for rare diseases like CTEPH.

Timing of sodium-glucose cotransporter 2 inhibitor initiation and post-discharge outcomes in acute heart failure with diabetes: A population-based cohort study.

Results from randomized trials suggest benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitor initiation in clinically stable acute heart failure. We aim to examine the real-world effectiveness of early versus delayed post-discharge SGLT2 inhibitor initiation in people with acute heart failure and type 2 diabetes. Using linkable administrative databases in Ontario, Canada, individuals aged 66 years or older with type 2 diabetes who were discharged to the community from acute care hospitals for heart failure between 1 July 2016 and 31 March 2020 were included in this retrospective, population-based cohort study. The primary outcome was hospitalization for heart failure (HHF) or cardiovascular mortality as a composite. Follow-up started from discharge for maximum 1 year. We compared outcomes between post-discharge SGLT2 inhibitor initiation within 3 days, 4-90 days, or 91-180 days, versus delayed initiation for at least 180 days. The 'clone-censor-weight' approach with a target trial emulation framework was used to address time-related biases. There were 9641 eligible individuals. After cloning and artificial censoring, there were 38 564 clones, 12 439 person-years, and 7584 events. Compared to delayed initiation for at least 180 days, initiation within 3 days post-discharge was associated with a lower 1-year risk of HHF or cardiovascular mortality (risk ratio [RR] 0.65, 95% confidence interval [CI] 0.45-0.83), while initiation 4-90 days (RR 0.83, 95% CI 0.72-0.93) or 91-180 days (RR 0.89, 95% CI 0.79-0.97) showed smaller risk reduction. Real-world evidence supports early SGLT2 inhibitor initiation to reduce HHF or cardiovascular mortality in acute heart failure and type 2 diabetes.