Clinical Trial Literature Research Articles

Sex Disparity in Extracorporeal Membrane Oxygenation Clinical Trial Enrollment

Objectives: Multiple studies have shown that extracorporeal membrane oxygenation (ECMO) is used clinically more often in men than women. Because clinical trials provide the basis for identifying patients who are likely to benefit from medical therapies, we hypothesized that sex-based imbalances in ECMO trial enrollment may both reflect and perpetuate these observed disparities. Our objective was to determine whether sex-based enrollment imbalances exist within the published ECMO clinical trial literature. Design: Cross-sectional analysis. Setting: Randomized controlled trials published between 2003 and 2023 that either tested ECMO as a treatment modality or tested another intervention among patients receiving ECMO. Patients: Not applicable Interventions: None. Measurements and Main Results: We used the Cochrane Highly Sensitive Search Strategy to search PubMed for eligible trials. Data on participant demographics, trial characteristics, and journal information were abstracted for each publication. The primary outcome of interest was the proportion of male and female participants in each published trial. The initial literature search identified 774 articles. Of these, 31 were eligible for inclusion, and 28 provided data on the sex of study participants. Twenty-six of these 28 trials (93%) enrolled more men than women, and in aggregate women comprised 28% (95% CI, 26–30%) of all trial participants (551/1956 subjects). Trials involving extracorporeal cardiopulmonary resuscitation (ECPR) exhibited the largest sex-based enrollment differences (83% men) followed by venoarterial ECMO for cardiogenic shock (73% men). Among trials published in journals with impact factors of ten or higher 74% (95% CI, 72–76%) of participants were men. Only two trials (7%) provided data on the race or ethnicity of study participants. Conclusions: Substantial sex-based disparity exists in published ECMO clinical trials. Underrepresentation of women relative to disease prevalence is most significant among trials utilizing venoarterial ECMO for cardiogenic shock and ECPR for cardiac arrest, limiting the applicability of findings from these trials for women.

Assessment of readability of gynecologic cancer clinical trials literature at NCI-designated comprehensive cancer centers

Assessment of readability of gynecologic cancer clinical trials literature at NCI-designated comprehensive cancer centers

Chasing Shadows: How Implausible Assumptions Skew Our Understanding of Causal Estimands

The ICH E9 (R1) addendum on estimands, coupled with recent advancements in causal inference, has prompted a shift towards using model-free treatment effect estimands that are more closely aligned with the underlying scientific question. This represents a departure from traditional, model-dependent approaches where the statistical model often overshadows the inquiry itself. While this shift is a positive development, it has unintentionally led to the prioritization of an estimand’s ability to perfectly answer the key scientific question over its practical learnability from data under plausible assumptions. We illustrate this by scrutinizing assumptions in the recent clinical trials literature on principal stratum estimands, demonstrating that some popular assumptions are not only implausible but often inevitably violated. We advocate for a more balanced approach to estimand formulation, one that carefully considers both the scientific relevance and the practical feasibility of estimation under realistic conditions.

Gender, Racial, and Academic Authorship Diversity in the Otolaryngology Clinical Trial Literature.

To investigate the state and trajectory of gender, racial, and academic authorship diversity in the otolaryngology clinical trial literature over the past 2 decades. Bibliometric analysis. Otolaryngology clinical trial literature. Clinical trials published in the 9 major otolaryngology journals between 2000 and 2020 were included. The gender, race, and academic seniority of the first, senior, and corresponding authors were recorded for each trial. Multivariable regression models assessed the temporal trajectory of authorship diversity over time and the disparity in citations across author characteristics. Models adjusted for relevant confounders pertaining to publication environment and study design. Among 2117 trials, first, senior, and corresponding authors have been predominantly White (60%-64%), male (76%-80%), and attending physicians (63%-69%). Trials led by Black (<1%) and Hispanic (<5%) authors were severely underrepresented. Over time, the representation of female (adj. β 0.8%, 95% CI [0.5%, 1.1%] per year), Asian (1.0% [0.7%, 1.3%] per year), and MD resident (0.4% [0.1%, 0.7%] per year) first authorship increased, but representation of female (0.2% [-0.1%, 0.5%] per year), Black (0% [-0.03%, 0.02%] per year), Hispanic (-0.2% [-0.33%, -0.02%] per year) senior authorship remained persistently low. Asian-led trials were cited significantly less compared to White-led trials even after adjusting for study design and publication year (aIRR 0.82 [0.73, 0.92]). Despite promising signs of improving authorship diversity over time, persistent underrepresentation of female, Black, Hispanic senior authorship underscore the need for additional efforts to diversify the otolaryngology clinical science workforce.

Critical Appraisal of Clinical Trials Evaluating Physical Therapy Treatments for Temporomandibular Disorders: AScoping Review.

Physical therapy seems the most promising treatment for temporomandibular disorders (TMD), although their effectiveness is controversial in general, due to high heterogeneity regarding study designs, applied treatments and outcomes measures. The aim of this scoping review is to analyse the methodological characteristics of clinical trials evaluating physical therapy treatments in subjects with TMD. A systematic search was conducted in Medline/PubMed, SPORTDiscus, Scopus, Web of Science, SciELO, Cochrane, ScienceDirect and EMBASE databases on 31 October 2023. Clinical trials evaluating physical therapy interventions in patients older than 18 years with TMD, published in English or Spanish languages. Data regarding content reporting of study designs, sample characteristics, interventions and outcome measures was extracted. Descriptive summary statistics were reported. The search retrieved 15 322 records, and 136 were included. There were 107 randomised clinical trials, 5 non-randomised controlled trials and 24 non-controlled trials. Most studies had moderate to high risk of bias, small sample sizes (median, 44 subjects) and short follow-up periods (1-3 months). The most common diagnostic criteria used was the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) (48.9%). The most reported experimental interventions were manual therapy (40.4%), exercise (30.2%) and electrotherapy modalities (27.2%), and the most common outcome measure domains were pain (83.8%), range of movement (61.8%), disability (45.6%) and mechanosensitivity (29.4%). There was poor content reporting of experimental interventions. Current literature of clinical trials of physical therapy interventions for TMD has moderate to high risk of bias, poor content reporting, small sample size and short-term follow-ups which limit internal and external validity, as well as applicability into clinical practice.

Hyaluronic Acid/Platelet-Rich Plasma Mixture Improves Temporomandibular Joint Biomechanics: A Systematic Review.

Hyaluronic acid (HA) is the main component of the temporomandibular joint (TMJ) synovial fluid. Arthritis in temporomandibular disorders (TMDs) disrupts HA metabolism, resulting in shorter polymeric chain predominance and increased friction. Intra-articular injections of HA supplement the larger molecules of this glycosaminoglycan, and the platelet-rich plasma (PRP) delivered in this way releases growth factors, suppressing inflammation. This PRISMA-compliant PROSPERO-registered (CRD42024564382) systematic review aimed to assess the validity of mixing HA with PRP in the injectable treatment of TMJ disorders. We searched the medical literature for eligible randomized clinical trials using BASE, Google Scholar, PubMed and Scopus engines on 9 May 2024, with no time frame limit. Selected reports were assessed for risk of bias using the Cochrane RoB2 tool. Numerical data were collected on articular pain and mandibular mobility. We provided mean differences from baseline and between study and control groups at each observation point. The efficacy of TMD treatment with HA/PRP versus HA or PRP alone was assessed meta-analytically. Of 171 identified records, we selected 6 studies. In the 6-month follow-up, the mean advantage of PRP supplementation with HA was 2.52 (SE = 2.44; d = 0.83) mm and the benefit of adding PRP to HA was 1.47 (SE = 2.68; d = 0.34) mm in mandibular abduction. The pain-improvement scores were -1.33 (SE = 1.02; d = -1.05) and -1.18 (SE = 0.92; d = 0.80), respectively. Presumably, the HA/PRP range of therapeutic efficiency includes cases non-respondent to HA or PRP alone.

Benefit-Risk Trade-offs and Patient Preferences for Therapy Selection in Ulcerative Colitis: a Multicountry Preference Study.

To help navigate the complex treatment landscape of ulcerative colitis (UC), we quantified the benefit-risk trade-offs that patients were willing to make when choosing treatment. Patients completed an online discrete choice experiment. Eligible patients had a UC diagnosis for ≥6 months, were aged ≥18 years, and resided in France, Germany, Italy, Spain, or the UK. Patients chose between 2 hypothetical treatments set up to ensure trade-offs were made. Clinical trial data, literature review, and patient interviews identified treatment attributes. Relative attribute importance (RAI) scores and maximum acceptable risks were generated. A patient-centric benefit-risk assessment of 200mg of filgotinib was conducted as an example to show how measured trade-offs can be used. Overall, 631 patients participated; patients had a mean age of 42.2 years and were predominantly male (75.3%). Achieving and maintaining clinical remission was the most important factor for patients (RAI 32.4%); to achieve this, patients were willing to accept slightly higher risks of blood clots, serious infections, and malignancies compared with lower risk treatment profiles. Patients also valued the convenience of oral treatments, avoiding steroids, and the ability to attend school/work. The patient-centric benefit-risk assessment suggested patients are significantly more likely to prefer Janus kinase 1 preferential inhibitor filgotinib over placebo. Achieving clinical remission was the highest treatment priority for patients. To attain this, patients were willing to accept some slightly higher risk treatment profiles. Patient choices in the benefit-risk assessment suggested patients were significantly more likely to prefer filgotinib over placebo.

Abstract PO1-01-04: The optimal neoadjuvant treatment regimen for HR+/HER2+ breast cancer: a network meta-analysis

Abstract Background In patients with the HR+/HER2+ breast cancer (BC) subtype, it can be more challenging to achieve pathological complete response (pCR) after neoadjuvant therapy compared with the HR-/HER2+ subtype. The importance of neoadjuvant therapy and the association of pCR with long-term clinical benefits have been widely demonstrated in HER2+ BC. This network meta-analysis aimed to identify the optimal anti-HER2 regimen, the role of endocrine therapy, and the better chemotherapy choice for the neoadjuvant treatment of HR+/HER2+ BC patients. Methods Literature for neoadjuvant clinical trials in HR+/HER2+ breast cancer was searched in Medline, EMBASE, Cochrane Library, and Web of Science for publications released before June 2023. Single-arm trials, retrospective studies, and observational studies were excluded, as well as studies containing no neoadjuvant phase and/or no anti-HER2 drugs. A network meta-analysis with the fixed-effect model in a Bayesian framework was performed. Odds ratios (ORs) with 95% confidence intervals (CI) for pathological complete response (pCR) analysis and hazard ratios (HRs) with 95% CI for event-free survival (EFS) were calculated. A ranking of treatment patterns was performed using SUCRA. (Registered in PROSPERO: CRD42023385644 Results 2,844 records were identified by the literature search, 60 trials were included after the screening, and valid data were extracted. 19 trials and 2,883 patients were included in the primary analysis of pCR. Compared with trastuzumab + chemotherapy (CT), three treatment regimens showed significantly higher pCR rates, T-DM1 based treatment (T-DM1, OR: 2.83, 95% CI: 1.90, 4.27; which includes T-DM1 alone, T-DM1 + pertuzumab or T-DM1 + endocrine therapy), trastuzumab + pertuzumab + CT (PH, OR: 2.57, 95% CI: 1.70, 3.94), and trastuzumab + tyrosine kinase inhibitor (TKI)+ CT (H+TKI, OR: 1.60, 95% CI: 1.22, 2.09; TKI includes lapatinib, neratinib and pyrotinib). The SUCRA ranking of pCR showed that T-DM1 was ranked first (SUCRA: 0.94), followed by PH (SUCRA: 0.85) and H+TKI (SUCRA: 0.60). PH came first in the SUCRA ranking of EFS (SUCRA: 0.74) as well as cumulative SUCRA combining pCR and EFS (SUCRA: 0.79). For chemotherapy strategies, platinum-containing regimens showed no significant increase in pCR rate compared to no platinum regimens (OR: 1.27, 95% CI: 0.95, 1.69), regimens with anthracycline also had no statistical difference from those without anthracycline (OR: 0.74, 95% CI: 0.51, 1.07). When assessing the impact of endocrine therapy, no significant difference in pCR rate was observed with or without endocrine therapy (OR: 1.18, 95% CI: 0.80, 1.73). Conclusions The PH regimen remains the best neoadjuvant treatment choice for HR+/HER2+ early BC patients considering pCR and EFS outcomes simultaneously. H+TKI did not show significant benefits, so it is not recommended to be given priority in clinical practice. The platinum-containing regimen’s potential benefit compared to the non-platinum regimen is uncertain and needs more clinical investigation. The necessity of adding endocrine therapy is not proven due to limited data availability. Funding: This study was sponsored by Shanghai Roche Pharmaceuticals Ltd. Disclosure: Hao Tang, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Yajing Feng, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Xin Yu, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Citation Format: Hao Wang, Shiwei Liu, Miao Yu, Kun Mi, Exian Mou, Li Xia, Weimin Xie, Hao Tang, Yajing Feng, Xin Yu. The optimal neoadjuvant treatment regimen for HR+/HER2+ breast cancer: a network meta-analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-04.

Targeting Pivotal Hallmarks of Cancer for Enhanced Therapeutic Strategies in Triple-Negative Breast Cancer Treatment-In Vitro, In Vivo and Clinical Trials Literature Review.

This literature review provides a comprehensive overview of triple-negative breast cancer (TNBC) and explores innovative targeted therapies focused on specific hallmarks of cancer cells, aiming to revolutionize breast cancer treatment. TNBC, characterized by its lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), presents distinct features, categorizing these invasive breast tumors into various phenotypes delineated by key elements in molecular assays. This article delves into the latest advancements in therapeutic strategies targeting components of the tumor microenvironment and pivotal hallmarks of cancer: deregulating cellular metabolism and the Warburg effect, acidosis and hypoxia, the ability to metastasize and evade the immune system, aiming to enhance treatment efficacy while mitigating systemic toxicity. Insights from in vitro and in vivo studies and clinical trials underscore the promising effectiveness and elucidate the mechanisms of action of these novel therapeutic interventions for TNBC, particularly in cases refractory to conventional treatments. The integration of targeted therapies tailored to the molecular characteristics of TNBC holds significant potential for optimizing clinical outcomes and addressing the pressing need for more effective treatment options for this aggressive subtype of breast cancer.

The overlap between randomised evaluations of recruitment and retention interventions: An updated review of recruitment (Online Resource for Recruitment in Clinical triAls) and retention (Online Resource for Retention in Clinical triAls) literature.

The Online Resource for Recruitment in Clinical triAls (ORRCA) and the Online Resource for Retention in Clinical triAls (ORRCA2) were established to organise and map the literature addressing participant recruitment and retention within clinical research. The two databases are updated on an ongoing basis using separate but parallel systematic reviews. However, recruitment and retention of research participants is widely acknowledged to be interconnected. While interventions aimed at addressing recruitment challenges can impact retention and vice versa, it is not clear how well they are simultaneously considered within methodological research. This study aims to report the recent update of ORRCA and ORRCA2 with a special emphasis on assessing crossover of the databases and how frequently randomised studies of methodological interventions measure the impact on both recruitment and retention outcomes. Two parallel systematic reviews were conducted in line with previously reported methods updating ORRCA (recruitment) and ORRCA2 (retention) with publications from 2018 and 2019. Articles were categorised according to their evidence type (randomised evaluation, non-randomised evaluation, application and observation) and against the recruitment and retention domain frameworks. Articles categorised as randomised evaluations were compared to identify studies appearing in both databases. For randomised studies that were only in one database, domain categories were used to assess whether the methodological intervention was likely to impact on the alternate construct. For example, whether a recruitment intervention might also impact retention. In total, 806 of 17,767 articles screened for the recruitment database and 175 of 18,656 articles screened for the retention database were added as result of the update. Of these, 89 articles were classified as 'randomised evaluation', of which 6 were systematic reviews and 83 were randomised evaluations of methodological interventions. Ten of the randomised studies assessed recruitment and retention and were included in both databases. Of the randomised studies only in the recruitment database, 48/55 (87%) assessed the content or format of participant information which could have an impact on retention. Of the randomised studies only in the retention database, 6/18 (33%) assessed monetary incentives, 4/18 (22%) assessed data collection location and methods and 3/18 (17%) assessed non-monetary incentives, all of which could have an impact on recruitment. Only a small proportion of randomised studies of methodological interventions assessed the impact on both recruitment and retention despite having a potential impact on both outcomes. Where possible, an integrated approach analysing both constructs should be the new standard for these types of evaluations to ensure that improvements to recruitment are not at the expense of retention and vice versa.

A China-Based Cost-Effectiveness Analysis of Novel Oral Anticoagulants versus Warfarin in Patients with Left Ventricular Thrombosis.

This study aims to conduct a comprehensive cost-effectiveness comparison between novel oral anticoagulants (NOACs) and warfarin in Chinese patients with left ventricular thrombosis (LVT). By incorporating the impact of volume-based procurement (VBP) policy for pharmaceuticals in China, this analysis intends to provide crucial insights for informed healthcare decision-making. A Markov model was employed to simulate the disease progression of LVT over a 54-week time horizon, using weekly cycles and six mutually exclusive health states. The model incorporated transition probabilities between health states calculated based on clinical trial data and literature sources. Various cost and utility parameters were also included. Additionally, a series of sensitivity analyses were conducted to address parameter variations and associated uncertainties. The study finding suggest that from the perspective of Chinese healthcare, the majority of brand-name drug (BND) NOACs generally lack cost-effectiveness when compared to warfarin. However, when considered the VBP policy, NOACs, particularly rivaroxaban, prove to be more cost-effective than warfarin. Rivaroxaban provided an additional 0.0304 quality-adjusted life years (QALYs) per patient and reduced overall medical costs by 9095.73 CNY, resulting in an incremental cost-effectiveness ratio (ICER) of -298,786.20 CNY/QALY. Sensitivity analysis indicated a 78.4% probability of any NOACs being more cost-effective compared to warfarin. However, specifically considering NOACs under the VBP policy, the likelihood of them being more cost-effective approached 90%. Taking into account Chinese pharmaceutical procurement policies, the findings highlight the superior efficacy of NOACs, especially rivaroxaban, in enhancing both the quality of life and economic benefits for Chinese LVT patients. NOACs present a more cost-effective treatment option, improving patient quality of life and healthcare cost efficiency compared to warfarin.

Automatic categorization of self-acknowledged limitations in randomized controlled trial publications

Objective:Acknowledging study limitations in a scientific publication is a crucial element in scientific transparency and progress. However, limitation reporting is often inadequate. Natural language processing (NLP) methods could support automated reporting checks, improving research transparency. In this study, our objective was to develop a dataset and NLP methods to detect and categorize self-acknowledged limitations (e.g., sample size, blinding) reported in randomized controlled trial (RCT) publications. Methods:We created a data model of limitation types in RCT studies and annotated a corpus of 200 full-text RCT publications using this data model. We fine-tuned BERT-based sentence classification models to recognize the limitation sentences and their types. To address the small size of the annotated corpus, we experimented with data augmentation approaches, including Easy Data Augmentation (EDA) and Prompt-Based Data Augmentation (PromDA). We applied the best-performing model to a set of about 12K RCT publications to characterize self-acknowledged limitations at larger scale. Results:Our data model consists of 15 categories and 24 sub-categories (e.g., Population and its sub-category DiagnosticCriteria). We annotated 1090 instances of limitation types in 952 sentences (4.8 limitation sentences and 5.5 limitation types per article). A fine-tuned PubMedBERT model for limitation sentence classification improved upon our earlier model by about 1.5 absolute percentage points in F1 score (0.821 vs. 0.8) with statistical significance (p<.001). Our best-performing limitation type classification model, PubMedBERT fine-tuning with PromDA (Output View), achieved an F1 score of 0.7, improving upon the vanilla PubMedBERT model by 2.7 percentage points, with statistical significance (p<.001). Conclusion:The model could support automated screening tools which can be used by journals to draw the authors’ attention to reporting issues. Automatic extraction of limitations from RCT publications could benefit peer review and evidence synthesis, and support advanced methods to search and aggregate the evidence from the clinical trial literature.

Abstract 2315: AI-enabled precision oncology era: Advanced and interactive interpretation of next-gneneration sequencing (NGS) reports

Abstract Background: Next-generation sequencing (NGS) has been widely adopted in clinical practice, but there are still unmet needs among physicians regarding the interpretation and application of NGS reports. These needs include selecting multi-targeted and combination therapies, keeping up with evolving treatment options and clinical trial results, and incorporating personalized medicine based on real clinical cases. Methods: To address these challenges, we propose using large language model (LLM) to analyze and interpret clinical questions, perform semantic searches in a high-quality database, and provide customized prompts and logical outputs. Our knowledge base includes diagnostic and treatment details for 600+ tumor subtypes, 620,000+ entries, 2,000+ drug details, and 440,000+ clinical trials. The database is updated automatically using a fact engine and medical literature sources. Personalized gene interpretation is incorporated using pretraining, cosine similarity, and context learning prompts. Results: Our tool, named "SmartMTB", enables personalized interpretation of genomic testing reports for precision oncology. Users input the latest clinical features using a selection-based or question-and-answer approach. The tool identifies the treatment stage and genomic variations, provides information on mutation frequencies, sensitivity and resistance of targeted and immunotherapies, and priority selection strategies for multi-gene mutations. It matches similar clinical cases and provides real-time updates on treatment options and clinical trial literature. It also facilitates patient matching for clinical trials and considers economic factors. Conclusion: We present a groundbreaking artificial intelligence (AI) tool in cancer care that revolutionizes precision oncology. This AI system, trained on extensive datasets, swiftly and accurately analyzes and interprets complex genomic and clinical data. It enables clinicians to make informed decisions about personalized treatment strategies, significantly improving patient outcomes in cancer therapy. Citation Format: Hui Chen, Zanmei Xu, Lijuan Chen, Mingmin Wang, Peng Zhang, Fei Pang, Kai Wang. AI-enabled precision oncology era: Advanced and interactive interpretation of next-gneneration sequencing (NGS) reports [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2315.

Effect of Needle Gauge Size on Pain During Intravitreal Anti-VEGF Injection: A Systematic Review and Network Meta-Analysis.

Concerns related to pain from intravitreal injections are one of the key factors mentioned by patients when asked about therapy. In this systematic review and network meta-analysis, we evaluate the literature of comparative clinical trials on the relationship between needle gauge size and pain experience during intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy. We searched 12 literature databases on 14 October 2023 for comparative studies of gauge sizes for intravitreal anti-VEGF injections. The primary outcome of interest was the reported pain experience immediately after the injection. All outcomes of pain were transformed into standardized effect sizes using Cohen's d. Using a network meta-analysis approach, we were able to compare all gauge sizes and rank them according to the reported pain experience. We identified nine eligible studies with data on a total of 998 patients and 1004 eyes. Needle sizes studied were 26-gauge, 27-gauge, 29-gauge, 30-gauge, 32-gauge, 33-gauge, and 34-gauge. A complete network was present, which allowed for a network meta-analysis. We used the thickest (26-gauge) needle as the reference group and observed a clear trend of lower pain experience with thinner gauge sizes (d: -0.4, d: -2.7, d: -3.8, d: -4.8, d: -4.5, and d: -5.3; respectively, for 27-gauge, 29-gauge, 30-gauge, 32-gauge, 33-gauge, and 34-gauge). A gauge size of 30 or thinner may minimize patient discomfort related to intravitreal anti-VEGF therapy.

Policy instruments for the governance of the social drivers of health data in clinical and research settings: a policy mapping brief.

This paper maps policy instrument use for the social drivers of health (SDoH) data governance in clinical and research settings. In the United States, Centers for Medicare and Medicaid Services (CMS) and National Institutes of Health (NIH) advocate for standardized data capture. Yet, challenges persist, including limited adoption of CMS-issued SDoH risk codes and gaps in reporting SDoH in clinical trial literature. The mapping across clinical and research SDoH reporting emerges as a comprehensive solution that requires policy support. Specifically, the findings presented in this paper support future policy development through regulatory instruments, fiscal incentives, and knowledge exchange. Actionable recommendations for the United States and international contexts include convening interdisciplinary taskforces, developing agency guidelines for process evaluation, and establishing ethical principles for SDoH data use.

Aceso-DSAL: Discovering Clinical Evidences from Medical Literature Based on Distant Supervision and Active Learning.

Automatic extraction of valuable, structured evidence from the exponentially growing clinical trial literature can help physicians practice evidence-based medicine quickly and accurately. However, current research on evidence extraction has been limited by the lack of generalization ability on various clinical topics and the high cost of manual annotation. In this work, we address these challenges by constructing a PICO-based evidence dataset PICO-DS, covering five clinical topics. This dataset was automatically labeled by a distant supervision based on our proposed textual similarity algorithm called ROUGE-Hybrid. We then present an Aceso-DSAL model, an extension of our previous supervised evidence extraction model - Aceso. In Aceso-DSAL, distantly-labelled and multi-topic PICO-DS was exploited as training corpus, which greatly enhances the generalization of the extraction model. To mitigate the influence of noise unavoidably-introduced in distant supervision, we employ TextCNN and MW-Net models and a paradigm of active learning to weigh the value of each sample. We evaluate the effectiveness of our model on the PICO-DS dataset and find that it outperforms state-of-the-art studies in identifying evidential sentences.

Survival, treatment patterns, and costs of HER2+ metastatic breast cancer patients in Ontario between 2005 to 2020.

To enable the integration of novel therapies, it is critical to understand current long-term outcomes in HER2-positive metastatic breast cancer (mBC), including survival, treatment patterns, and costs. We sought to define these outcomes among patients with mBC in Ontario. We conducted a retrospective population-level study in Ontario women diagnosed with breast cancer of any stage between January 1, 2005 and December 31, 2019, with follow-up until December 31, 2020. HER2-positivity was based on receipt of a HER2-targeted therapy (HER2-TT) in the first line (1L) metastatic setting. Administrative databases at ICES were used to assess outcomes. In Ontario, 2557 patients were diagnosed with mBC and received a HER2-TT, and of these 1606 were diagnosed with early-stage (stage I-III) that became metastatic (recurrent), while 951 were diagnosed with late stage/de novo mBC (stage IV). The average age of all patients was 54.8years ± 12.7years. Treatment regimens that included pertuzumab and trastuzumab (cohort name: pert_tras) were the most frequently used HER2-TT for 1L mBC (51.4%), while T-DM1 was the most frequent therapy (87.5%) in second line (2L). The median overall survival (mOS) from initiation of 1L pert_tras was not reached, whereas mOS from initiation of T-DM1 in 2L was 18.7months. The overall mean cost per patient on pert_tras during 1L was $267,282. The main cost drivers were the cost of systemic therapy, followed by cancer clinic visits, with a mean cost per patient at $158,961 and $73,882, respectively. The baseline characteristics and treatment patterns for patients who received HER2-TT in our study align with previously reported results. However, the mOS observed for 2L T-DM1 was shorter than that found in pivotal, clinical trial literature. As expected, anti-cancer systemic therapy costs were the main contributor to the over quarter-million dollar mean cost per patient on pert_tras in 1L.

Abstract A133: Mapping the legal estrangement theory onto known barriers in recruiting diverse participants to clinical trials

Abstract Lack of diversity in clinical trials research has significant health consequences because medications and treatments have varying effects on people based on their demographic, socio-economic, and geographic characteristics. This study uniquely adopts the legal estrangement theory to explain the causes for limited diversity in federally funded clinical trials and offers multi-level strategies that researchers, institutions, the US Department of Health &amp; Human Services (HHS), and Congress can take to increase diversity in clinical trials. Legal estrangement is a theory that represents detachment and alienation from those who created the law. From February to March 2023, researchers reviewed legal and medical literature, news stories, and federal regulations to identify barriers contributing to limited diversity in clinical trials. Using the legal estrangement theory as an overarching guide, three broad themes across the clinical trials literature (i.e., procedural injustice, vicarious marginalization, and structural exclusion) were identified. Procedural injustice refers to when people perceive not being treated with dignity and respect. Vicarious marginalization refers to negative experiences that collectively contribute to feelings of alienation. Structural exclusion refers to the way policies that seem to be race or class-neutral have disproportionate effects on marginalized communities. We found that researcher implicit bias and stereotyping contribute to procedural injustice and vicarious marginalization by discouraging prospective people from joining clinical trials. Structural barriers like inaccessibility to participant-friendly educational materials, ambiguity in grant reporting requirements, lack of strong substantive grant standards, exclusion of LGBTQI+ individuals from grant enrollment reports, and budgetary constraints limit efforts to increase participant diversity in clinical trials. To improve diversity in clinical trials, we recommend improving transparency and communication, building meaningful partnerships with community leaders, requiring cultural competency training for researchers, incorporating automatic and non-autonomic recruitment strategies to circumvent bias, strengthening substantive NIH grant standards, adding gender identities to grant enrollment reports, and requesting greater Congressional funding for clinical trials research. Thus, to improve diversity in federally funded clinical trials, a multi-faceted approach that involves researchers, academic institutions, community members, HHS, and Congress are recommended to reduce procedural injustice, vicarious marginalization, and structural exclusion. Future research is needed to explore the connection between structural barriers to access to clinical trials and disparities in cancer care management and patient outcomes. Citation Format: Cilgy M. Abraham, Denalee M. O'Malley. Mapping the legal estrangement theory onto known barriers in recruiting diverse participants to clinical trials [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 A133.

Repeated Levosimendan Infusions in the Management of Advanced Heart Failure: Review of the Evidence and Meta-analysis of the Effect on Mortality.

In the latest years, several studies described the impact of repetitive/intermittent i.v. levosimendan treatment in the management of advanced heart failure. For this updated review, we systematically searched the literature for clinical trials, registries , and real-world data and identified 31 studies that we commented in a narrative review: 3814 patients were described, of whom 1744 were treated repetitively with levosimendan. On the basis of the nature of the study protocols and of the end points, out of those studies, we further selected 9 that had characteristics, making them suitable for a meta-analysis on mortality. This short list describes data from 680 patients (of whom 399 received repeated doses of levosimendan) and 110 death events (of which 50 occurred in the levosimendan cohort). In the meta-analysis, repetitive/intermittent therapy with i.v. levosimendan was associated with a significant reduction in mortality at the longest time point available: 50 of 399 (12.5%) versus 60 of 281 (21.4%) in the control arms, with a risk ratio of 0.62 (95% confidence interval, 0.42-0.90; P < 0.01). In a sensitivity analysis, removing each trial and reanalyzing the remaining data set did not change the trend, magnitude, or significance of the results. A visual inspection of the funnel plot did not suggest publication bias. The results provide a very strong rationale for continuing to investigate the repetitive use of levosimendan in patients with advanced heart failure by properly powered regulatory clinical trials. Meanwhile, it seems that the use of repetitive/intermittent i.v. levosimendan infusions has become one of the few effective options for preserving the hemodynamic and symptomatic balance in such patients.

Evaluation of the Loss of Strength, Resistance, and Elasticity in the Different Types of Intraoral Orthodontic Elastics (IOE): A Systematic Review of the Literature of In Vitro Studies.

Intraoral orthodontic elastics (IOE), typically referred to as rubber bands, are important tools for correcting malocclusion, and they are classified into latex and synthetic (elastomeric-based) elastics. They have different strengths and sizes, depending on their intended use, that provide clinicians with the ability to correct both anteroposterior and vertical discrepancies. Clinical use, together with saliva, alters the physical characteristics of both latex and synthetic elastics, causing declines in strength over time. The aim of the study was to assess, through a systematic review of in vitro studies, the properties of intraoral elastics. The primary goal was to evaluate how IOEs behave in terms of tension strength and duration. The secondary goal was to investigate the force loss during the first hours of wear. The tertiary goal was to assess how these forces decayed. The following electronic databases were searched from December 2020 to April 2021: Medline Full Text, PubMed, Cochrane Clinical Trials Register, Science Direct, and Literature Review. Out of 8505 initial articles, 10 were selected for the systematic review. The force-degradation property was found in all types of IOEs. The loss of strength was directly proportional to time, with the highest value during the first 3 h after extension, regardless of the elastic band size and manufacturer. The forces generated by the latex bands were higher than in those of the elastomeric-based elastics, but they did not consistently correspond to the loads specified by the manufacturers. The retention forces in the latex IOEs were significantly higher than those in the nonlatex bands, suggesting that elastomeric-based bands need to be changed more frequently and at regular intervals throughout a 24 h period. This systematic review indicates that intraoral orthodontic elastics have the greatest loss of force during the first 3 h, that latex rubber bands have the highest strength during the first hour, that the forces generated are not always consistent with the manufacturer's specifications, and that nonlatex (elastomeric-based) IOEs need to be changed frequently and regularly during a 24-h cycle.