Non-interventional Studies Research Articles

Simulation effect on medical sciences students' motivation: A systematic review study.

Simulation is an educational technology that can facilitate learning, improve performance, and develop critical thinking and self-confidence in students. Motivation is an effective factor in the level of efficiency and the use of individual talent, ability, and satisfaction. The aim of this study was to determine the effect of simulation on students' motivation based on existing studies. This systematic review was conducted using a full systematic search strategy based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for the identification of relevant literature in Cochrane, PubMed, Embase, Scopus, Web of Science, and ERIC electronic databases up to April 2023, utilizing search terms in the titles and abstracts. Finally, 21 articles were selected after being screened in accordance with our inclusion and exclusion criteria. Of 21 articles related to the study's aim, 19 articles (91%) were interventional studies (three randomized controlled trials (RCTs) and 16 non-RCTs) and two articles (9%) were noninterventional studies (cohort and cross-sectional). The results revealed that in 17 studies (77%), simulation studies had a positive effect on motivation, and in 19% of studies, simulation had no significant effect on motivation. Most of the studies improved students' learning motivation using different simulation methods. Simulation methods require appropriateness in three areas: comprehensiveness, the subjects of training, and the allocation of appropriate facilities.

The creation of an adaptable informed consent form for research purposes to overcome national and institutional bottlenecks in ethics review: experience from rare disease registries.

The lack of harmonization of evaluation criteria by Ethics Committees in the European Union (EU) has led to inconsistent ethics reviews received by research sites participating in multicenter non-interventional studies. The European General Data Protection Regulation (GDPR) appears to be implemented at national level with a substantial degree of variance in interpretation. The European Reference Networks (ERNs) were struggling in setting an Informed Consent Form (ICF) for registries, allowing reuse of data for research purposes. The aim of this work is to develop an adaptable ICF for research purposes to be used in ERN registries. To work on this challenge, a team was established within the European Joint Programme on Rare Diseases (EJP RD) to develop a patients' registry ICF template allowing easy adaptation to ERNs, country, and site-level specificities. ERN and patients' representatives validated the choice of developing a GDPR-compliant template for research purposes. The feedback received from 34 Ethics Committees on the Clinical Patient Management System ICF, including the submission of patients' data to the ERN registries and the EU consent regulatory framework were analyzed along with existing ontologies for data access and reuse. An adaptable ICF was developed following iterative cycles of consultation and review by clinicians, research experts, ethics and regulatory advisors, and patients' representatives. The development of pediatric material for minor participants was also undertaken. Research oriented ICF templates for adults and for parents/legal representatives of patients were released in 26 national languages. This adaptable ICF aims to foster, according to patients' preferences, the reuse of registries data for research purposes in compliance with the applicable laws and standards. Pediatric material is being finalized to collect minors' assent. ICF machine-readability is also progressing to enhance data discovery and facilitate its access and reuse conditions.

TAURUS-MS II: real-world use of teriflunomide in Germany and changes in treatment patterns over time.

Teriflunomide is a once-daily oral disease-modifying therapy (DMT) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Only limited information is available about its real-world use and changes over time. To collect real-world data on teriflunomide use in clinical routine (and comparison to the previously conducted study TAURUS-MS). National, open, non-interventional, prospective, multicenter study. TAURUS-MS II was conducted at 220 German sites between July 2017 and March 2022, including RRMS patients treated with teriflunomide. Data on patient demographics, MS history, previous treatment, therapy satisfaction, and safety were collected. In total, 752 patients were included (65% female) with a mean age (±standard deviation) of 43 ± 11 years. Sixty-six percent had DMT before, and 46% had discontinued their last pretreatment ≤6 months prior to study entry. Among the latter, previous DMTs were interferon (21%), glatiramer acetate (11%), and dimethyl fumarate (9%), and reasons for discontinuation were adverse events (AEs; 55%) and insufficient efficacy (16%). Over 24 months, the mean treatment Satisfaction Questionnaire for Medication scores improved by 6 ± 29 points on effectiveness, 8 ± 20 on convenience, and 12 ± 25 on global satisfaction. The mean number of MS relapses decreased from 0.81 ± 0.81 in the 24 months prior to 0.27 ± 0.57 within 24 months after study entry. Non-serious AEs occurred in 423 patients (56%) and serious AEs in 49 patients (7%). Most reported AEs were alanine aminotransferase increase (11%), hypertension (8%), and alopecia (7%). Compared to TAURUS-MS, patients in TAURUS-MS II were younger, had a higher employment rate, and a higher share of treatment-naïve patients. Mean number of relapses was significantly reduced. Patient satisfaction was significantly improved compared to previous DMT. Tolerability was comparable to previous trials. Bundesinstitut für Arzneimittel und Medizinprodukte public database for non-interventional studies, number 7138.

The Impact of Antifungal Stewardship on Clinical and Performance Measures: A Global Systematic Review.

Antimicrobial stewardship programs (ASP) have been proposed as an opportunity to optimize antifungal use. The antifungal resistance is a significant and emerging threat. The literature on antifungal stewardship (AFS) and its influence on performance and clinical outcome measures is scarce. This study aimed to examine global evidence of the impact of AFS on patients and performance measures. The "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) was used for the flow of identification, screening, eligibility, and inclusion. PubMed and MEDLINE were searched using the term ''antifungal stewardship'' on 15 February 2023. Search terms included antifungal stewardship, antimicrobial stewardship, candida, candidemia, candiduria, and invasive fungal disease. Of the 1366 records, 1304 were removed since they did not describe an antifungal stewardship intervention. Among the 62 full texts assessed, 21 articles were excluded since they were non-interventional studies and did not include the outcome of interest. Thus, 41 articles were eligible for systematic review. Eligible studies were those that described an AFS program and evaluated clinical or performance measures. Of the 41 included studies, the primary performance measure collected was antifungal consumption (22 of 41), and mortality (22 of 41), followed by length of stay (11 of 41) and cost (9 of 41). Most studies were single-center, quasi-experimental, with varying interventions across studies. The principal finding from most of the studies in this systematic review is a reduction in mortality expressed in different units and the use of antifungal agents (13 studies out of 22 reporting mortality). Antifungal consumption was significantly blunted or reduced following stewardship initiation (10 of 22). Comparing studies was impossible due to a lack of standard units, making conducting a meta-analysis unfeasible, which would be a limitation of our study. It has been shown that AFS interventions may improve antifungal consumption and other performance measures. According to available published studies, antifungal consumption and mortality appear to be the possible performance measures to evaluate the impact of AFS.

Literature Review of Safety Event Reporting in Observational Studies: Challenges Extrapolating across Comparable Products

Nirmatrelvir/ritonavir (PAXLOVIDTM, Pfizer) is an anti-infective inhibiting CYP3A4 indicated for the treatment of COVID-19 in adults at increased risk of severe COVID-19. As a newly approved product, PAXLOVID has limited safety information regarding rare events and serious adverse events (SAEs). This review describes the characterization of the real-world safety profile of products with similar pharmacological properties to PAXLOVID and aims to understand the impact of any drug interaction on the concomitantly prescribed products. A literature search of articles in PubMed published between 2018 and 2023 was conducted to assess the real-world frequency of safety outcomes of interest, specifically those meeting the criteria of serious adverse reaction. The review was restricted to observational, noninterventional studies and included CYP3A4 inhibitors prescribed for short-term treatment of infections in the outpatient setting. Twenty-one articles were included in the review. Most focused on a small, predefined list of safety outcomes and did not provide insight into the broader range of safety outcomes that might occur for the evaluated products with similar pharmacological properties to PAXLOVID or the impact of any interaction on the concomitant product. The findings highlight the challenges in obtaining proxy safety outcomes characteristics via a review of products with comparable pharmacological properties and underscore the need to have large, rapidly accessible data sources that can contribute to the safety profile of newly authorized products in the real world.

Abstract A085: A comparison of the recruitment and enrollment of racially and ethnically minoritized patients in two non-interventional genetic testing studies in Florida

Abstract Objectives: To compare participation rates of minority individuals in two non-interventional genetic studies. Background: Enrollment of participants into non-interventional studies is important in understanding cancer development in minority patients. Black, Hispanic, and Latin men and women are diagnosed with aggressive forms of cancer at more advanced stages however, the underlying mechanisms leading to poor outcomes of disease is still not well understood. To understand disease development, two studies were launched. Study 1 focused on the recruitment of mutation carriers not yet diagnosed with cancer. Participants of this study were of any race and consented to the collection of fresh tissue. Participants were physician-referred and approached by the study team on the day of surgery. The patients received an explanation of the objectives and conditions of participation. Study 2 was focused on recruiting minority participants in clinic with a confirmed diagnosis of breast or prostate cancer. Participants consented to the collection of archival tissue and participants were called prior to their clinic visit and explained the objectives and conditions of participation. We compared the rates of enrollment of minority patients into these non-interventional genetic studies. Methods: Participants were Black, Hispanic/Latino(a), or White, Non-Hispanic who were mutation carriers without cancer or had an active diagnosis of ovarian, breast, or prostate cancer. The study team was composed of Latin, South, and Central American Spanish-speakers and African American Caribbeans Haitian-Creole speakers. All study materials were available in English, Haitian Creole, and Spanish. Matched recruitment was completed between the patient population and study team members who spoke English, Haitian Creole, and Spanish. The studies were assessed and compared for their methods of recruitment, participation rates, and demographics of their enrolled patient populations between December 2022 and May 2023. Results: A total of 121 men and women are included in this data analysis. 81.8% of patients approached for both studies consented to participate. 92.9% of those who consented were minorities. In Study 1, 68.6% eligible patients agreed to participate (24/35). Of the 24 patients enrolled, 41.7% (10/24) were White Hispanic/Latina, 20.8% (5/24) were Black Hispanic and non-Hispanic, 29.2% (7/24) were White non-Hispanic, and 2.7% (2/36) declined race. Of those who rejected participation, 63.6% were Black non-Hispanic. In Study 2, 87.2% (75/86) of the 86 eligible patients consented to the study. 72% (54/75) were female and 28% (21/75) were male. Of the female participants, 31.5% (17/54) were Black non-Hispanic and 68.5% (37/54) were White Hispanic/Latino. Of the male participants, 47.6% (10/21) were Black and 52.3% (11/21) were Hispanic/Latino. 63.6% of those who rejected participation were White Hispanic. Conclusions: Our results indicate that study acceptance by racially and ethnically minoritized individuals is dependent on recruitment approach and current health status. Citation Format: Destiny B. Burnett, Sandy St-Hilaire, Melissa N. Castillo, Daniela M. Zuniga Carlier, Osmaray Morales Casanova, Ashlee J. Sealy, Alex P. Sanchez, Matthew P. Schulmbrecht, Camille Ragin, Sophia George, Judith Hurley, Janaki Sharma, Alejandra Perez. A comparison of the recruitment and enrollment of racially and ethnically minoritized patients in two non-interventional genetic testing studies in Florida [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A085.

Enhancing the Retention of Healthcare Workers in Rural Areas: A Systematic Review

Introduction: Rural areas globally face significant challenges in retaining healthcare workers, impacting the delivery of essential health services and exacerbating health disparities. This systematic review aimed to evaluate the effectiveness of various strategies implemented over the last 15 years to enhance healthcare worker retention in rural settings, with the goal of identifying evidence-based interventions that can inform policy and practice to improve rural healthcare delivery. Methods: The review focused exclusively on interventional studies and clinical trials published from 2007 to 2022. A comprehensive search of multiple databases, including PubMed, MEDLINE, Embase, CINAHL, and the Cochrane Library, was conducted using specific search terms related to healthcare worker retention in rural areas. Inclusion criteria targeted studies evaluating quantifiable outcomes of retention strategies, with exclusion criteria set to omit non-interventional studies, research focused on urban settings, and non-English publications. The study selection, data extraction, and quality assessment processes were rigorously conducted to ensure the reliability of the findings. Results: Twelve studies met the inclusion criteria, revealing a broad range of interventions from financial incentives and educational programs to supportive workplace interventions and community engagement strategies. Financial incentives demonstrated a notable positive impact on retention, with risk ratios ranging from 1.2 to 1.75, indicating a 20% to 75% increase in retention rates. Supportive workplace interventions also showed effectiveness, with a risk ratio of up to 1.4. However, the results for educational and community engagement strategies were more variable, suggesting the need for tailored approaches. Conclusions: The review highlights the effectiveness of targeted interventions in enhancing the retention of healthcare workers in rural areas, particularly financial incentives and supportive workplace interventions. These findings underscore the importance of implementing multifaceted, evidence-based strategies tailored to the unique challenges of rural healthcare settings to improve workforce stability and healthcare delivery.

Persistence to edoxaban treatment in patients with atrial fibrillation: Analysis from the Global ETNA-AF program

Abstract Background/Introduction Direct oral anticoagulants (DOACs) are now the standard treatment for stroke prevention in most patients with atrial fibrillation (AF). However, many studies have reported suboptimal adherence and persistence to DOAC treatment. Data collected in routine care, such as in the Global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF program, may provide insight into factors associated with treatment persistence. Purpose Evaluate the persistence to edoxaban treatment in a large, unselected, real-world population using 2-year data from the Global ETNA-AF study. Methods The Global ETNA-AF program is a predefined integration of prospective, observational, non-interventional regional studies from Europe, Japan, and other Asian countries to evaluate the safety and effectiveness of edoxaban in patients with AF. Demographic and clinical characteristics were collected at baseline. In this analysis, patients were stratified by persistence to edoxaban treatment during a 2-year follow-up period (ie, persistence [PERS], suspension [SUS], permanent discontinuation [PERD], and suspension with later permanent discontinuation [SUS+PERD]). Results Overall persistence was high, with 87.1% of patients under edoxaban treatment at 2 years considering both groups that discontinued edoxaban at any time (PERD and SUS+PERD). Mean patient age, creatinine clearance, CHA2DS2-VASc, and HAS-BLED score were similar between the PERS (n = 20,053), SUS (n = 3088), PERD (n = 2936), and SUS+PERD (n = 503) groups (Table). In the PERS group, there were slightly fewer patients who received previous anticoagulation (vitamin K antagonist or DOAC) and were concomitantly using anti-platelet drugs at baseline. A larger proportion of SUS+PERD vs all other patients had a history of ischaemic stroke and/or major bleeding. Overall mortality was lower in patients in the PERS and SUS groups (0.79% [95% confidence interval {CI} 0.70–0.89] and 1.85% [95% CI 1.53–2.24], respectively) compared with patients who discontinued the treatment (PERD: 22.50% [95% CI 21.12–23.98]; SUS+PERD: 13.05% [95% CI 10.73–15.88]). Notably, persistence in the Global ETNA-AF program was generally higher than reported in GLORIA-AF at 2 years (70.9%) and XANTUS at 1 year (77.4%), despite a more compromised health profile especially considering the advanced patient age. Conclusions Treatment with edoxaban in routine clinical practice is associated with high persistence (87%) at 2 years in elderly patients with AF and multiple comorbidities. Persistence to edoxaban treatment was associated with better survival during the 2-year follow-up period. Further investigation is ongoing to determine the specific causes and consequences of edoxaban suspension and discontinuation to improve personalization of thromboembolic prophylaxis in patients with AF.Table 1

Outcomes of Patients with Extramedullary Disease in Triple-Class Exposed Relapsed/Refractory Multiple Myeloma from the LocoMMotion + MoMMent Studies

Introduction: Patients (pts) with triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM) represent a particularly difficult-to-treat population. A pooled analysis of the prospective, non-interventional, multinational LocoMMotion (NCT04035226) and MoMMent (NCT05160584) studies previously demonstrated suboptimal outcomes in pts with TCE RRMM. Extramedullary disease (EMD) is an aggressive feature of multiple myeloma characterized by the presence of plasmacytomas that have spread beyond the bone marrow. A recent systematic literature review (Bladé et al, 2022) found that the prognosis of pts with EMD is poor, as most current treatment (tx) options are notably less efficacious in pts with EMD than in those without EMD. The review also found that there are few prospective studies evaluating tx approaches in pts with EMD. Additional prospective data are needed to better understand current txs and outcomes for pts with EMD. In this analysis, we describe current txs and outcomes in pts with TCE RRMM with EMD over the past 3 years in LocoMMotion and MoMMent. Methods: Data were pooled from LocoMMotion (median follow-up [mFU], 26.4 months [mo; range, 0.1-35.0]; enrolled Aug 2019-Oct 2020; N=248) and MoMMent (mFU, 9.3 mo [range, 0.4-15.3]; enrolled Nov 2021-Jul 2022; N=54). Both studies have similar designs; eligible pts received ≥3 prior lines of therapy (LOT; LocoMMotion allowed <3 prior LOT if pts were double refractory to a proteasome inhibitor and immunomodulatory drug), were TCE, had measurable disease and documented progressive disease since their last LOT, and had an ECOG performance status (PS) of 0 or 1 at screening. EMD was defined as extramedullary plasmacytoma reported by the investigator. The assessment of plasmacytoma was not mandated but, per protocol, it was anticipated that extramedullary plasmacytomas would be prospectively assessed by clinical examination or radiologic imaging at baseline (BL) for all pts with a history of plasmacytomas, or if clinically indicated prior to the first dose of standard-of-care (SOC) therapy. If an assessment was not performed, the pt was considered not to have BL plasmacytoma. Responses were evaluated per IMWG criteria by a response review committee. A Cox proportional hazards model and Kaplan-Meier methodology were used to estimate medians, 95% CIs, and survival curves (unadjusted and adjusted for potential confounders) for progression-free survival (PFS) and overall survival (OS). Results: The pooled analysis included 302 pts with mFU of 24.3 mo (95% CI, 21.0-25.6; data cut-off, Oct 27, 2022 [LocoMMotion], Mar 13, 2023 [MoMMent]). 30 pts had EMD at BL and 272 did not. Anatomical locations of plasmacytomas in these pts included vertebra, liver, pelvis, skin, and lymph nodes, suggesting a mix of purely extramedullary (harder to treat) and bone-related plasmacytomas. Duration of study follow-up was similar for pts with EMD (26.5 mo [95% CI 17.3-31.9]) and those without (24.3 mo [95% CI 20.3-25.6]). BL demographics and disease characteristics were generally comparable, with ≥10% difference in ISS stage III, LDH >245 U/L, and ECOG PS of 1 observed in pts with EMD. A greater proportion of pts with EMD than those without EMD were penta-drug exposed (56.7% vs 45.2%) and had received prior autologous stem cell transplant (76.7% vs 62.5%). Pts with EMD received 21 unique SOC tx regimens, primarily chemotherapy based (Table). The ORR was lower for pts who had EMD vs those who did not (7/30; 23.3% [95% CI 9.9-42.3] vs 89/272; 32.7% [27.2-38.6]). Pts with EMD also had a shorter median PFS (2.3 mo [95% CI 1.6-4.4] vs 5.1 mo [4.4-6.0]) and median OS (7.2 mo [95% CI 5.4-18.6] vs 15.1 mo [12.0-18.5]) compared with those without EMD (Figure). The adjusted survival curves have similar patterns to the unadjusted. Among the 30 pts with EMD, there were 23 and 21 PFS and OS events, respectively; conclusions based on time-to-event data should therefore be interpreted with caution due to a small sample size. Conclusions: These results indicate that there is a significant unmet medical need for better tx options in this population of pts with TCE RRMM, specifically in pts with EMD. This need is illustrated by the poor outcomes observed with existing txs and the absence of an effective established SOC for this condition. Conducting clinical trials with innovative therapies, using clearly defined criteria for EMD, is essential to address the unmet medical needs of these pts.

Symptomatic treatment of cough in children

Cough is one of the most common symptoms in paediatric practice. Cough nature, duration, intensity, frequency, time and cause of occurrence should be considered in the differential diagnosis of its causes. Sputum evacuation disorders and changes in its rheological properties are indications for the prescription of mucoactive drugs. Despite the fact that the drugs included in this group have different mechanisms of action, all of them restore mucociliary clearance and lead to effective evacuation of secretions from the respiratory tract. Herbal medicinal products can be used along with classic mucoactive drugs (mucolytics, mucopegulators and mucokinetics). Ivy leaves are an example of a well-known and meticulously researched source of phytopharmaceutical products, they are included in the ESCOP monograph and entered into the positive list of the German Commission E. The efficacy and safety of ivy leaf products have been demonstrated in various controlled clinical studies. The authors presented a review of published clinical studies and non-interventional studies involving a total of 65,383 patients suffering from both acute and chronic respiratory diseases. The studies demonstrated the efficacy of ivy leaf extract preparations as achievement of a higher level of bronchodilation and surfactant production, which led to bronchospasmolytic, secretolytic, expectorant and, in turn, antitussive action. Herbal medicinal products are now actively used in the treatment of new coronavirus infection. Hedelix is one of the ivy leaf extract pharmaceutical preparations approved for use in children over the age of two years.

Applying health behavior theories that explain elderly’ deprescribing behavior: a systematic review

Abstract Deprescribing is a strategy to optimize medication use. Despite the fact that behavioral theories have shown to be useful in explaining health behaviors, the literature on deprescribing relies almost exclusively on attitudes as an explanatory factor for this behavior. This systematic review aimed to assess the capacity of health behavior theories and concepts to explain patient's and caregivers’ deprescribe behavior. Two independent reviewers performed a search on Medline, Embase, Scopus, Psycinfo, Cochrane, and the grey literature, using the key words: older adults, informal caregivers, deprescribing, behavioral models, health belief model, theory of planned behavior, social cognitive theory, nudge, and health literacy, Interventional and non-interventional studies that applied at least one health behavior theory or at least one concept from these theories to older adults’ or their caregivers’ intention or deprescribing behavior were included. Quality screening of the identified records was done using the JBI critical appraisal tool. Ten non-interventional studies and twelve interventional studies were identified. Social Cognitive Theory was most often used to explain deprescribing intention, whereas self-efficacy was used most often to explain deprescribing behavior. Higher health literacy also predicted deprescribing intention, whereas internal locus of control was a barrier to deprescribing behavior. One study applied nudging to deprescribing but showed no significant effect. The only study involving informal caregivers revealed that the belief that relatives experienced side effects was a reason to support deprescribing. It is concluded that health behavior theories and concepts involved in these theories explain deprescribing intentions and behaviors more effectively than only relying on attitudes toward deprescribing. Key messages • Deprescribing behavior requires complexes changes to established patters of behaviors. • Health behavior theories and concepts from these theories can explain deprescribing intentions and behaviors more effectively than relying only on widely studied attitudes toward deprescribing.

Landscape review of global real-world data sources for studying medication use in pregnancy and lactation that support regulatory decision making.

Most pregnant people take at least one medication during gestation or while breastfeeding, however data are lacking on the safety of medication use in these populations. We conducted a landscape review of real-world data sources specific to medication use in pregnancy and breastfeeding populations that have met, or have potential to meet, health authorities' requirements for post-authorization safety studies. A 2-phase approach identified data sources from literature, publicly available registers of non-interventional post-authorization studies of pregnant women, existing database inventories, and emerging data sources known to the authors. Required key attributes were assessed according to current regulatory guidance, resulting in selection of 49 suitable data sources. All global regions were represented, with North America (37%) and Europe (33%) most common; 12% of the data sources included pregnancy information from low-to middle-income countries. Administrative healthcare claims (25%) and electronic healthcare records (21%) comprised the largest types of data sources. Across data sources, 53% were managed by national or regional governments, 27% by industry, and 20% by academic institutions. Maternal age, diagnoses, prenatal care, and reproductive history were available in most, whereas fewer included demographic data (e.g., race/ethnicity). Breastfeeding data were collected in 37% of the final data sources. We conducted a systematic approach to data source evaluation of pregnancy and breastfeeding to be used as a resource for investigators to consider when designing pregnancy-related research studies to satisfy regulatory requirements.

Dravet syndrome: A systematic literature review of the illness burden.

We performed a systematic literature review and narrative synthesis according to a pre-registered protocol (Prospero: CRD42022376561) to identify the evidence associated with the burden of illness in Dravet syndrome (DS), a developmental and epileptic encephalopathy characterized by drug-resistant epilepsy with neurocognitive and neurobehavioral impairment. We searched MEDLINE, Embase, and APA PsychInfo, Cochrane's database of systematic reviews, and Epistemonikos from inception to June 2022. Non-interventional studies reporting on epidemiology (incidence, prevalence, and mortality), patient and caregiver health-related quality of life (HRQoL), direct and indirect costs and healthcare resource utilization were eligible. Two reviewers independently carried out the screening. Pre-specified data were extracted and a narrative synthesis was conducted. Overall, 49 studies met the inclusion criteria. The incidence varied from 1:15 400-1:40 900, and the prevalence varied from 1.5 per 100 000 to 6.5 per 100 000. Mortality was reported in 3.7%-20.8% of DS patients, most commonly due to sudden unexpected death in epilepsy and status epilepticus. Patient HRQoL, assessed by caregivers, was lower than in non-DS epilepsy patients; mean scores (0 [worst] to 100/1 [best]) were 62.1 for the Kiddy KINDL/Kid-KINDL, 46.5-54.7 for the PedsQL and 0.42 for the EQ-5D-5L. Caregivers, especially mothers, were severely affected, with impacts on their time, energy, sleep, career, and finances, while siblings were also affected. Symptoms of depression were reported in 47%-70% of caregivers. Mean total direct costs were high across all studies, ranging from $11 048 to $77 914 per patient per year (PPPY), with inpatient admissions being a key cost driver across most studies. Mean costs related to lost productivity were only reported in three publications, ranging from approximately $19 000 to $20 000 PPPY ($17 596 for mothers vs $1564 for fathers). High seizure burden was associated with higher resource utilization, costs and poorer HRQoL. The burden of DS on patients, caregivers, the healthcare system, and society is profound, reflecting the severe nature of the syndrome. Future studies will be able to assess the impact that newly approved therapies have on reducing the burden of DS.

Effectiveness and Tolerability of 12-Month Brivaracetam in the Real World: EXPERIENCE, an International Pooled Analysis of Individual Patient Records.

Real-world evidence studies of brivaracetam (BRV) have been restricted in scope, location, and patient numbers. The objective of this pooled analysis was to assess effectiveness and tolerability of brivaracetam (BRV) in routine practice in a large international population. EXPERIENCE/EPD332 was a pooled analysis of individual patient records from multiple independent non-interventional studies of patients with epilepsy initiating BRV in Australia, Europe, and the United States. Eligible study cohorts were identified via a literature review and engagement with country lead investigators, clinical experts, and local UCB Pharma scientific/medical teams. Included patients initiated BRV no earlier than January 2016 and no later than December 2019, and had ≥6 months of follow-up data. The databases for each cohort were reformatted and standardised to ensure information collected was consistent. Outcomes included ≥50% reduction from baseline in seizure frequency, seizure freedom (no seizures within 3 months before timepoint), continuous seizure freedom (no seizures from baseline), BRV discontinuation, and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Patients with missing data after BRV discontinuation were considered non-responders/not seizure free. Analyses were performed for all adult patients (≥16 years), and for subgroups by seizure type recorded at baseline; by number of prior antiseizure medications (ASMs) at index; by use of BRV as monotherapy versus polytherapy at index; for patients who switched from levetiracetam to BRV versus patients who switched from other ASMs to BRV; and for patients with focal-onset seizures and a BRV dose of ≤200mg/day used as add-on at index. Analysis populations included the full analysis set (FAS; all patients who received at least one BRV dose and had seizure type and age documented at baseline) and the modified FAS (all FAS patients who had at least one seizure recorded during baseline). The FAS was used for all outcomes other than ≥50% seizure reduction. All outcomes were summarised using descriptive statistics. Analyses included 1644 adults. At baseline, 72.0% were 16-49 years of age and 92.2% had focal-onset seizures. Patients had a median (Q1, Q3) of 5.0 (2.0, 8.0) prior antiseizure medications at index. At 3, 6, and 12 months, respectively, ≥50% seizure reduction was achieved by 32.1% (n=619), 36.7% (n=867), and 36.9% (n=822) of patients; seizure freedom rates were 22.4% (n=923), 17.9% (n=1165), and 14.9% (n=1111); and continuous seizure freedom rates were 22.4% (n=923), 15.7% (n=1165), and 11.7% (n=1111). During the whole study follow-up, 551/1639 (33.6%) patients discontinued BRV. TEAEs since prior visit were reported in 25.6% (n=1542), 14.2% (n=1376), and 9.3% (n=1232) of patients at 3, 6, and 12 months, respectively. This pooled analysis using data from a variety of real-world settings suggests BRV is effective and well tolerated in routine clinical practice in a highly drug-resistant patient population.

Studies to Assess the Utility of Serum Neurofilament Light Chain as a Biomarker in Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common and disabling dose-limiting toxicities of chemotherapy. We report here the results of two separate non-interventional studies (49 patients), which evaluated blood neurofilament light chain (NfL) as a biomarker of CIPN in breast cancer patients treated with paclitaxel. All patients underwent a standard treatment protocol that was established independently of the present studies. NfL was measured in serum using an ultrasensitive single-molecule array and compared with the self-administered European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN twenty-item scale (CIPN20) and Total Neuropathy Score clinical version (TNSc), a clinician-reported measure of neuropathy progression. The TNSc increased with cumulative dose compared with baseline, and the NfL concentrations were also strongly associated with the cumulative dose of chemotherapy. The analysis showed a correlation between TNSc and NfL. Both TNSc and NfL showed weak to moderate associations with CIPN20 subscores, with a better association for the CIPN20 sensory compared with motor and autonomic subscores. Data from the two studies provide evidence that serum NfL has the potential to be used as a biomarker to monitor and mitigate CIPN. However, studies with additional patients planned in the ongoing clinical trial will determine the universal application of NfL as a biomarker in CIPN.

BENEFITS OF THE EFFICACY AND SAFETY OF VITAMIN AND MINERAL COMPLEX "VITRUM PRENATAL FORTE" IN THE PREVENTION OF HYPOVITAMINOSIS AND MINERAL DEFICIENCY IN PREGNANCY

Non-interventional (observational) studies, which are of great medical and social importance, are one of the methods to assess the effectiveness and safety of pharmaceutical products in routine clinical practice, to clarify the risk profile and benefits of certain therapies. The aim of this study was to evaluate the efficacy and safety of vitamin and mineral complex "Vitrum Prenatal Forte" in the prevention of hypovitaminosis and mineral deficiency in pregnancy to improve maternal and perinatal outcomes. One of the important aims of the large-scale study was to evaluate the efficacy of the drug Vitrum Prenatal Forte in the prevention and treatment of anaemia in pregnant women. This article reviews the epidemiology of iron deficiency, features of iron metabolism, etiology and pathogenesis of iron deficiency in pregnant women and maternity women, approaches to the diagnosis of iron deficiency anaemia and iron deficiency, methods of prevention and treatment of iron deficiency states.

Principles for Good Practice in the Conduct of Non-interventional Studies: The View of Industry Researchers

This reflection paper presents a consolidated view of EFPIA on the need for principles for good practice in the generation and use of non-interventional studies (NIS), including overarching principles such as the registration of hypothesis evaluating treatment effect (HETE) studies. We first define NIS and the important adjacencies to clinical trials and relationship with real-world evidence (RWE). We then outline the principles for good practice with respect to appropriate research design, study protocol, fit-for-purpose variables and data quality, analytical methods, bias reduction, transparency in conduct and use, privacy management and ethics review. We conclude with recommendations for action for the research community to promote trust and credibility in the use of NIS.

Real-world effectiveness of golimumab in adult patients with rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis and an inadequate response to initial TNFi therapy in Greece: the GO-BEYOND prospective, observational study.

The impact of golimumab (GLM) on remission or low disease activity (LDA) was evaluated in patients with moderate-to-severe rheumatoid arthritis (RA), progressive psoriatic arthritis (PsA), or severe axial spondyloarthritis (axSpA), who failed previous treatment for their rheumatic disease with one initial tumor necrosis factor α inhibitor (TNFi). This is a multicenter, prospective, real-world observational 18-month study, conducted in Greece. The primary endpoint, assessed at 6 months, included the proportion of patients attaining LDA and/or remission (Disease Activity Score for 28 joints based on C-reactive protein [DAS28-CRP] ≤ 3.2), minimal disease activity (MDA; MDA criteria), and moderate disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] score 4-7), respectively. Other endpoints evaluated the persistence to GLM treatment and its impact on patients' work productivity (Work Productivity and Activity Impairment [WPAI] instrument) and quality of life (QoL; EuroQoL5 dimensions 3 levels [EQ-5D-3L] questionnaire). Descriptive statistics, the Wilcoxon signed-rank test, and Kaplan-Meier method were used for analyses. At 6 months, LDA was achieved by 46.4% of patients with RA, MDA by 57.1% of patients with PsA, and BASDAI 4-7 by 24.1% of patients with axSpA. For all study patients, persistence rates on GLM were high (85.1-93.7%) over 18months; all WPAI domain scores and the EQ-5D-3L index score improved significantly (p < 0.001) from baseline to 18months. GLM treatment was effective in patients with RA, PsA, or axSpA who had failed previous treatment with one TNFi and led to significant WPAI and QoL improvements. Persistence rates were high. Trial registration number and date of registration: As per the local regulations the study has been registered at the national registry for non-interventional studies https://www.dilon.sfee.gr/studiesp_d.php?meleti_id=MK8259-6995 .

Is There Any Association between Nutrition and Myopia?: A Systematic Review.

This systematic review indicates that the current evidence shows no association of nutrition with myopia. We systematically reviewed the outcomes of the studies that previously investigated the association between nutrition and myopia. Embase, MEDLINE, and PubMed were searched by two independent authors to identify cross-sectional, cohort, retrospective, or interventional studies that assessed the association of nutrition with myopia from inception to the year 2021. Further, the reference list of the included articles was screened. The data from the included studies were extracted and qualitative analysis was performed. Quality assessment for non-interventional studies and interventional trials was performed using the Newcastle-Ottawa scale and Cochrane RoB 2 respectively. Twenty-seven articles were included in the review. Most of the nutrients and dietary elements investigated in non-interventional studies showed inconsistencies in their association with myopia with the majority indicating no association. Nine studies showed a significant association of diverse nutrients and dietary elements with either an increase (Odds ratio: 1.07) or a decrease (Odds ratio: 0.5 to 0.96) in the risk of myopia development. However, the majority of these studies have minimal odds ratios with wider or overlapping confidence intervals, implicating weaker associations. All three nutrients and dietary elements assessed in the interventional trial had implications for myopia control, with two trials indicating a clinically minimal effect. This review implies that there is some evidence to indicate a potential influence of specific nutrients and dietary elements in myopia development which are supported by several theories. However, given the vast, diverse, and complex nature of nutrition, more systematic investigation is warranted to comprehend the extent to which these specific nutrients and dietary elements are associated with myopia through longitudinal studies by subduing the limitations in the existing literature.

The evolution of the concept of non-interventional clinical studies

The evolution of the concept of non-interventional clinical studies