Trial Design Research Articles

Exercise for Prostate Cancer-Worthy Goals but Suboptimal Trial Designs.

Exercise for Prostate Cancer-Worthy Goals but Suboptimal Trial Designs.

Innovative approaches for vaccine trials as a key component of pandemic preparedness - a white paper.

WHO postulates the application of adaptive design features in the global clinical trial ecosystem. However, the adaptive platform trial (APT) methodology has not been widely adopted in clinical research on vaccines. The VACCELERATE Consortium organized a two-day workshop to discuss the applicability of APT methodology in vaccine trials under non-pandemic as well as pandemic conditions. Core aspects of the discussions are summarized in this article. An "ever-warm" APT appears ideally suited to improve efficiency and speed of vaccine research. Continuous learning based on accumulating APT trial data allows for pre-planned adaptations during its course. Given the relative design complexity, alignment of all stakeholders at all stages of an APT is central. Vaccine trial modelling is crucial, both before and in a pandemic emergency. Various inferential paradigms are possible (frequentist, likelihood, or Bayesian). The focus in the interpandemic interval may be on research gaps left by industry trials. For activation in emergency, template Disease X protocols of syndromal design for pathogens yet unknown need to be stockpiled and updated regularly. Governance of a vaccine APT should be fully integrated into supranational pandemic response mechanisms. A broad range of adaptive features can be applied in platform trials on vaccines. Faster knowledge generation comes with increased complexity of trial design. Design complexity should not preclude simple execution at trial sites. Continuously generated evidence represents a return on investment that will garner societal support for sustainable funding. Adaptive design features will naturally find their way into platform trials on vaccines.

A randomized, embedded, pragmatic, Bayesian clinical trial examining clinical decision support for high flow nasal cannula management in children with bronchiolitis: design and statistical analysis plan

BackgroundHigh flow nasal cannula (HFNC) has been increasingly adopted in the past 2 decades as a mode of respiratory support for children hospitalized with bronchiolitis. The growing use of HFNC despite a paucity of high-quality data regarding the therapy’s efficacy has led to concerns about overutilization. We developed an electronic health record (EHR) embedded, quality improvement (QI) oriented clinical trial to determine whether standardized management of HFNC weaning guided by clinical decision support (CDS) results in a reduction in the duration of HFNC compared to usual care for children with bronchiolitis.MethodsThe design and summary of the statistical analysis plan for the REspiratory SupporT for Efficient and cost-Effective Care (REST EEC; “rest easy”) trial are presented. The investigators hypothesize that CDS-coupled, standardized HFNC weaning will reduce the duration of HFNC, the trial’s primary endpoint, for children with bronchiolitis compared to usual care. Data supporting trial design and eventual analyses are collected from the EHR and other real world data sources using existing informatics infrastructure and QI data sources. The trial workflow, including randomization and deployment of the intervention, is embedded within the EHR of a large children’s hospital using existing vendor features. Trial simulations indicate that by assuming a true hazard ratio effect size of 1.27, equivalent to a 6-h reduction in the median duration of HFNC, and enrolling a maximum of 350 children, there will be a > 0.75 probability of declaring superiority (interim analysis posterior probability of intervention effect > 0.99 or final analysis posterior probability of intervention effect > 0.9) and a > 0.85 probability of declaring superiority or the CDS intervention showing promise (final analysis posterior probability of intervention effect > 0.8). Iterative plan-do-study-act cycles are used to monitor the trial and provide targeted education to the workforce.DiscussionThrough incorporation of the trial into usual care workflows, relying on QI tools and resources to support trial conduct, and relying on Bayesian inference to determine whether the intervention is superior to usual care, REST EEC is a learning health system intervention that blends health system operations with active evidence generation to optimize the use of HFNC and associated patient outcomes.Trial registrationClinicalTrials.gov NCT05909566. Registered on June 18, 2023.

Oxylipin Dynamics Following A Single Bout of Yoga Exercise: A Pilot Randomized Controlled Trial Secondary Analysis.

Background: Yoga may promote health via a complex modulation of inflammation. Little is known about oxylipins, a class of circulating mediators involved in inflammation resolution. Objective: To explore the acute effects of yoga exercise on systemic levels of oxylipins. Methods: This is a secondary analysis of a three-arm (high-intensity-yoga: HY, n = 10); moderate-intensity-yoga: MY, n = 10; and no-intervention-control: CON, n = 10) pilot randomized controlled trial employing a single bout of yoga exercise. Blood samples (baseline and 4-timepoint post-intervention) were used for an unbiased metabolipidomic profiling analysis. Net Areas Under the Curve per oxylipin were evaluated for each group. Results: Lipoxin(LX)B4, prostaglandin(PG)D2, and resolvin(Rv)D3 exhibited a greater magnitude of change in HY compared with MY and CON. Conclusion: Findings inform the design of future trials exploring the acute effects of yoga exercise on oxylipins' systemic levels.

Personalized care in dilated cardiomyopathy: Rationale and study design of the activeDCM trial.

Dilated cardiomyopathy (DCM) is a leading cause of heart failure, particularly in younger individuals. Low physical strength is a global risk factor for cardiovascular mortality, and physical activity and a healthy lifestyle have been shown to improve outcomes in patients with heart failure. However, inappropriate exercise may increase the risk of arrhythmias in certain individuals with DCM. The determinants for predicting individual risks in this setting are poorly understood, and clinicians are hesitant to recommend sports for cardiomyopathy patients. The activeDCM trial aims to assess the safety and efficacy of a personalized exercise and activity programme for individuals with DCM. The activeDCM trial is a prospective, randomized, interventional trial with a 12month follow-up. Three hundred patients, aged 18-75years with DCM, left ventricular ejection fraction (LVEF)≤50% and New York Heart Association (NYHA) classes I-III, will be enrolled. The intervention includes a personalized exercise and activity programme. The primary outcome is the increase in peak oxygen uptake (VO2max, mL/kg/min) from baseline to 12months. Secondary endpoints include adherence to personalized activity programmes, freedom from clinically relevant arrhythmia, unplanned hospitalization for heart failure and changes in NYHA class, quality of life scores, 6min walk distance, muscular strength, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) levels and cardiac function. Advanced research questions include high-density phenome and omics analysis combined with digital biomarkers derived from Apple Watch devices. The activeDCM trial will provide valuable insights into the safety and efficacy of personalized exercise training in DCM patients, inform clinical practice and contribute to the development of heart failure management programmes. The study will generate data on the impact of exercise on various aspects of cardiovascular disease, including genetic, metabolic, phenotypic and longitudinal aspects, facilitating the development of future digital tools and strategies, including the incorporation of smart wearable devices.

Older Adults with Cancer and Common Comorbidities-Challenges and Opportunities in Improving Their Cancer Treatment Outcomes.

The older American population is rapidly increasing, and millions of older adults will be cancer survivors with comorbidities. This population faces specific challenges regarding treatment and has unique clinical needs. Recognizing this need, the National Cancer Institute (NCI), in collaboration with the National Institute on Aging (NIA), hosted a webinar series, entitled "Cancer, Aging, and Comorbidities." This commentary provides a reflection of five thematic areas covered by the webinar series, which was focused on improving cancer treatment for older adults with cancer and comorbidities: i) the impact of comorbidities on treatment tolerability and patient outcomes; ii) the impact of comorbidities on cancer clinical trial design; iii) the development of wearable devices in measuring comorbidities in cancer treatment; iv) the effects of nutrition and the microbiome on cancer therapy and; v) the role of senescence and senotherapy in age-related diseases. While advances have been made in these areas, many gaps and challenges exist and are discussed in this commentary. To improve cancer survivorship in older populations with comorbidities, aging and comorbidities must be jointly considered and incorporated across the spectrum of cancer research. This includes more basic research of the mechanisms linking comorbidities and cancer development and treatment response, building critical resources and infrastructure (eg, preclinical models and patient samples), conducting clinical trials focused on the older population, integrating geriatric assessment into cancer treatment, and incorporating novel technologies, such as wearable devices into clinical trials and cancer care.

Dose prescription for stereotactic body radiotherapy: general and organ-specific consensus statement from the DEGRO/DGMP Working Group Stereotactic Radiotherapy and Radiosurgery.

To develop expert consensus statements on multiparametric dose prescriptions for stereotactic body radiotherapy (SBRT) aligning with ICRU report91. These statements serve as afoundational step towards harmonizing current SBRT practices and refining dose prescription and documentation requirements for clinical trial designs. Based on the results of aliterature review by the working group, atwo-tier Delphi consensus process was conducted among 24physicians and physics experts from three European countries. The degree of consensus was predefined for overarching (OA) and organ-specific (OS) statements (≥ 80%, 60-79%, < 60% for high, intermediate, and poor consensus, respectively). Post-first round statements were refined in alive discussion for the second round of the Delphi process. Experts consented on atotal of 14OA and 17OS statements regarding SBRT of primary and secondary lung, liver, pancreatic, adrenal, and kidney tumors regarding dose prescription, target coverage, and organ at risk dose limitations. Degree of consent was ≥ 80% in 79% and 41% of OA and OS statements, respectively, with higher consensus for lung compared to the upper abdomen. In round2, the degree of consent was ≥ 80 to 100% for OA and 88% in OS statements. No consensus was reached for dose escalation to liver metastases after chemotherapy (47%) or single-fraction SBRT for kidney primaries (13%). In round2, no statement had 60-79% consensus. In 29of 31statements ahigh consensus was achieved after atwo-tier Delphi process and one statement (kidney) was clearly refused. The Delphi process was able to achieve ahigh degree of consensus for SBRT dose prescription. In summary, clear recommendations for both OA and OS could be defined. This contributes significantly to harmonization of SBRT practice and facilitates dose prescription and reporting in clinical trials investigating SBRT.

Risk Prediction for Clonal Cytopenia: Multicenter Real-World Evidence

Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 CCUS patients investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count <100×109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the Clonal Cytopenia Risk Score (CCRS), which stratified patients into low- (score <2.5 points), intermediate- (score 2.5-<5), and high-risk (score ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high- (37.2%) risk groups, respectively, by Gray’s test (P <.0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P =.005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.

Lower or higher oxygenation targets in the intensive care unit: an individual patient data meta-analysis.

Optimal oxygenation targets for patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are not clearly defined due to substantial variability in design of previous trials. This study aimed to perform a pre-specified individual patient data meta-analysis of the Handling Oxygenation Targets in the ICU (HOT-ICU) and the Handling Oxygenation Targets in coronavirus disease 2019 (COVID-19) (HOT-COVID) trials to compare targeting a partial pressure of arterial oxygen (PaO2) of 8-12kPa in adult ICU patients, assessing both benefits and harms. We assessed 90-day all-cause mortality and days alive without life support in 90days using a generalised mixed model. Heterogeneity of treatment effects (HTE) was evaluated in 14 subgroups, and results graded using the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN). At 90days, mortality was 40.4% (724/1792) in the 8kPa group and 40.9% (733/1793) in the 12kPa group (risk ratio, 0.99; 95% confidence interval [CI] 0.92-1.07; P = 0.80). No difference was observed in number of days alive without life support. Subgroup analyses indicated more days alive without life support in COVID-19 patients targeting 8kPa (P = 0.04) (moderate credibility), and lower mortality (P = 0.03) and more days alive without life support (P = 0.02) in cancer-patients targeting 12kPa (low credibility). This study reported no overall differences comparing a PaO2 target of 8-12kPa on mortality or days alive without life support in 90days. Subgroup analyses suggested HTE in patients with COVID-19 (moderate credibility) and cancer (low credibility).

Variable Duration Trial as an Alternative Design for Continuous Endpoints.

Clinical trials with continuous primary endpoints typically measure outcomes at baseline, at a fixed timepoint (denoted Tmin), and at intermediate timepoints. The analysis is commonly performed using the mixed model repeated measures method. It is sometimes expected that the effect size will be larger with follow-up longer than Tmin. But extending the follow-up for all patients delays trial completion. We propose an alternative trial design and analysis method that potentially increases statistical power without extending the trial duration or increasing the sample size. We propose following the last enrolled patient until Tmin, with earlier enrollees having variable follow-up durations up to a maximum of Tmax. The sample size at Tmax will be smaller than at Tmin, and due to staggered enrollment, data missing at Tmax will be missing completely at random. For analysis, we propose an alpha-adjusted procedure based on the smaller of the p values at Tmin and Tmax, termed . This approach can provide the highest power when the powers at Tmin and Tmax are similar. If the power at Tmin and Tmax differ significantly, the power of is modestly reduced compared with the larger of the two powers. Rare disease trials, due to the limited size of the patient population, may benefit the most with this design.

Role of Artificial Intelligence in Pharmaceutical Drug Development

: One of the most popular sectors in the tech and healthcare industries right now is artificial intelligence. In the search and development of new drugs, artificial intelligence is essential. Drug design using computer-assisted design (CADD) has supplanted the traditional approach. Artificial intelligence is assisting businesses in the development of new drugs in a faster, more affordable, and more efficient manner, saving money and manpower in the process of creating new drug molecules to treat any disease. Quantitative structure-activity relationship (QSAR) analysis, activity scoring, in silico testing, biomarker development, and mode of action identification are all aided by artificial intelligence. It is revolutionizing these sectors by swiftly identifying potential drug candidates, efficiently conducting clinical trials, and customizing patient care. AI optimizes drug manufacturing processes, augments safety monitoring, and streamlines market analysis. In clinical trials, AI streamlines patient recruitment and ensures more precise trial designs, leading to faster and more efficient research. AI empowers personalized medicine by tailoring treatment plans and drug dosages to individual patient characteristics. AI also optimizes pharmaceutical manufacturing processes, amplifies safety monitoring by analyzing real-time data for adverse events, and supports market analysis and sales strategies. AI in the pharmaceutical industry is a multifaceted tool. Artificial Intelligence (AI) has the potential to streamline complex pharmaceutical regulatory matters. Regulatory processes like audits and dossier completion can be automated with AI tools.

Molecular profiling of 888 pediatric tumors informs future precision trials and data-sharing initiatives in pediatric cancer

To inform clinical trial design and real-world precision pediatric oncology practice, we classified diagnoses, assessed the landscape of mutations, and identified genomic variants matching trials in a large unselected institutional cohort of solid tumors patients sequenced at Dana-Farber / Boston Children’s Cancer and Blood Disorders Center. Tumors were sequenced with OncoPanel, a targeted next-generation DNA sequencing panel. Diagnoses were classified according to the International Classification of Diseases for Oncology (ICD-O-3.2). Over 6.5 years, 888 pediatric cancer patients with 95 distinct diagnoses had successful tumor sequencing. Overall, 33% (n = 289/888) of patients had at least 1 variant matching a precision oncology trial protocol, and 14% (41/289) were treated with molecularly targeted therapy. This study highlights opportunities to use genomic data from hospital-based sequencing performed either for research or clinical care to inform ongoing and future precision oncology clinical trials. Furthermore, the study results emphasize the importance of data sharing to define the genomic landscape and targeted treatment opportunities for the large group of rare pediatric cancers we encounter in clinical practice.

Application of Novel Biomarkers in MASLD: Precision Medicine Based Approach.

The new nomenclature of metabolic dysfunction-associated steatotic liver disease (MASLD) emphasizes a positive diagnosis based on cardiometabolic risk factors (CMRFs). This definition is not only less stigmatizing but also allows for subclassification and stratification, thereby addressing the heterogeneity of what was historically referred to as non-alcoholic fatty liver disease (NAFLD). The heterogeneity within this spectrum is influenced by several factors which include but are not limited to; demographic/dietary factors, the amount of alcohol use and drinking patterns, metabolic status, gut microbiome, genetic predisposition together with epigenetic factors. The net effect of this dynamic and intricate system-level interaction is reflected in the phenotypic presentation of MASLD. Therefore, the application of precision medicine in this scenario aims at complex phenotyping with consequent individual risk prediction, development of individualized preventive strategies, and improvements in the clinical trial designs. In this review, we aim to highlight the importance of precision medicine approaches in MASLD, including the use of novel biomarkers of disease, and its subsequent utilization in future study designs.

Cope PPA—Adaptation of the Biographic-Narrative Approach for Persons with Primary Progressive Aphasia: Protocol for Clinical Trial Design

Cope PPA—Adaptation of the Biographic-Narrative Approach for Persons with Primary Progressive Aphasia: Protocol for Clinical Trial Design

Science Pulse: Management of cardiogenic shock and trial design - time for a paradigm shift! Insights from the 3CT Meeting.

Science Pulse: Management of cardiogenic shock and trial design - time for a paradigm shift! Insights from the 3CT Meeting.

Eligibility of Asian and European registry patients for phase III trials in heart failure with reduced ejection fraction.

Traditional approaches to designing clinical trials for heart failure (HF) have historically relied on expertise and past practices. However, the evolving landscape of healthcare, marked by the advent of novel data science applications and increased data availability, offers a compelling opportunity to transition towards a data-driven paradigm in trial design. This research aims to evaluate the scope and determinants of disparities between clinical trials and registries by leveraging natural language processing for the analysis of trial eligibility criteria. The findings contribute to the establishment of a robust design framework for guiding future HF trials. Interventional phase III trials registered for HF on ClinicalTrials.gov as of the end of 2021 were identified. Natural language processing was used to extract and structure the eligibility criteria for quantitative analysis. The most common criteria for HF with reduced ejection fraction (HFrEF) were applied to estimate patient eligibility as a proportion of registry patients in the ASIAN-HF (N=4868) and BIOSTAT-CHF registries (N=2545). Of the 375 phase III trials for HF, 163 HFrEF trials were identified. In these trials, the most frequently encountered inclusion criteria were New York Heart Association (NYHA) functional class (69%), worsening HF (23%), and natriuretic peptides (18%), whereas the most frequent comorbidity-based exclusion criteria were acute coronary syndrome (64%), renal disease (55%), and valvular heart disease (47%). On average, 20% of registry patients were eligible for HFrEF trials. Eligibility distributions did not differ (P=0.18) between Asian [median eligibility 0.20, interquartile range (IQR) 0.08-0.43] and European registry populations (median 0.17, IQR 0.06-0.39). With time, HFrEF trials became more restrictive, where patient eligibility declined from 0.40 in 1985-2005 to 0.19 in 2016-2022 (P=0.03). When frequency among trials is taken into consideration, the eligibility criteria that were most restrictive were prior myocardial infarction, NYHA class, age, and prior HF hospitalization. Based on 14 trial criteria, only one-fifth of registry patients were eligible for phase III HFrEF trials. Overall eligibility rates did not differ between the Asian and European patient cohorts.

A phase 2 study of a brachyury-targeting vaccine in combination with radiation therapy for the treatment of advanced chordoma.

This was a single-arm, phase 2 clinical trial of Bavarian Nordic (BN)-Brachyury vaccine plus radiotherapy (RT) designed to determine the objective response rate (ORR), progression-free survival (PFS), and safety of the combination in chordoma. A total of 29 adult patients with advanced chordoma were treated with two subcutaneous priming vaccine doses of modified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury and one vaccine dose of fowlpox virus (FPV)-Brachyury before RT. After RT, booster vaccinations were given with FPV-Brachyury every 4 weeks for 4 doses, then every 12 weeks (week 110). A minimum RT dose of >8 Gy in one fraction for each target was required. Response was evaluated by modified Response Evaluation Criteria in Solid Tumors 1.1 (mRECIST), where only radiated lesions were considered targets, and by standard RECIST 1.1 in a subset of patients. Two of 26 evaluable patients experienced durable partial response (PR) (ORR of 7.7%; 90% confidence interval [CI], 2.6-20.8]) by mRECIST 1.1. A total of 21 patients (80.8%; 90% CI, 65.4-90.3) had stable disease, and three patients (11.5%; 90% CI, 4.7-25.6) had progressive disease as best response per mRECIST 1.1. Median PFS was not reached during the study. This trial confirms the safety of BN-Brachyury and RT. Although the study did not meet the predefined study goal of four responses in 29 patients, we did observe two PRs and a PFS of greater than 2 years. For a vaccine-based study in chordoma, an ultra-rare disease where response rates are low, a randomized study or novel trial designs may be required to confirm activity.

A phase 2 study of a brachyury-targeting vaccine in combination with radiation therapy for the treatment of advanced chordoma.

This was a single-arm, phase 2 clinical trial of Bavarian Nordic (BN)-Brachyury vaccine plus radiotherapy (RT) designed to determine the objective response rate (ORR), progression-free survival (PFS), and safety of the combination in chordoma. A total of 29 adult patients with advanced chordoma were treated with two subcutaneous priming vaccine doses of modified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury and one vaccine dose of fowlpox virus (FPV)-Brachyury before RT. After RT, booster vaccinations were given with FPV-Brachyury every 4 weeks for 4 doses, then every 12 weeks (week 110). A minimum RT dose of >8 Gy in one fraction for each target was required. Response was evaluated by modified Response Evaluation Criteria in Solid Tumors 1.1 (mRECIST), where only radiated lesions were considered targets, and by standard RECIST 1.1 in a subset of patients. Two of 26 evaluable patients experienced durable partial response (PR) (ORR of 7.7%; 90% confidence interval [CI], 2.6-20.8]) by mRECIST 1.1. A total of 21 patients (80.8%; 90% CI, 65.4-90.3) had stable disease, and three patients (11.5%; 90% CI, 4.7-25.6) had progressive disease as best response per mRECIST 1.1. Median PFS was not reached during the study. This trial confirms the safety of BN-Brachyury and RT. Although the study did not meet the predefined study goal of four responses in 29 patients, we did observe two PRs and a PFS of greater than 2 years. For a vaccine-based study in chordoma, an ultra-rare disease where response rates are low, a randomized study or novel trial designs may be required to confirm activity.

Eligibility of Asian and European registry patients for phase III trials in heart failure with reduced ejection fraction.

Traditional approaches to designing clinical trials for heart failure (HF) have historically relied on expertise and past practices. However, the evolving landscape of healthcare, marked by the advent of novel data science applications and increased data availability, offers a compelling opportunity to transition towards a data-driven paradigm in trial design. This research aims to evaluate the scope and determinants of disparities between clinical trials and registries by leveraging natural language processing for the analysis of trial eligibility criteria. The findings contribute to the establishment of a robust design framework for guiding future HF trials. Interventional phase III trials registered for HF on ClinicalTrials.gov as of the end of 2021 were identified. Natural language processing was used to extract and structure the eligibility criteria for quantitative analysis. The most common criteria for HF with reduced ejection fraction (HFrEF) were applied to estimate patient eligibility as a proportion of registry patients in the ASIAN-HF (N=4868) and BIOSTAT-CHF registries (N=2545). Of the 375 phase III trials for HF, 163 HFrEF trials were identified. In these trials, the most frequently encountered inclusion criteria were New York Heart Association (NYHA) functional class (69%), worsening HF (23%), and natriuretic peptides (18%), whereas the most frequent comorbidity-based exclusion criteria were acute coronary syndrome (64%), renal disease (55%), and valvular heart disease (47%). On average, 20% of registry patients were eligible for HFrEF trials. Eligibility distributions did not differ (P=0.18) between Asian [median eligibility 0.20, interquartile range (IQR) 0.08-0.43] and European registry populations (median 0.17, IQR 0.06-0.39). With time, HFrEF trials became more restrictive, where patient eligibility declined from 0.40 in 1985-2005 to 0.19 in 2016-2022 (P=0.03). When frequency among trials is taken into consideration, the eligibility criteria that were most restrictive were prior myocardial infarction, NYHA class, age, and prior HF hospitalization. Based on 14 trial criteria, only one-fifth of registry patients were eligible for phase III HFrEF trials. Overall eligibility rates did not differ between the Asian and European patient cohorts.

Gender-Specific Medicine in the European Society of Cardiology Guidelines from 2018 to 2023: Where Are We Going?

Background/Objectives: Evidence-based medicine (EBM) shapes most clinical guidelines. Although the advent of EBM marked a significant advancement, failure to include sex differences in the study design and analysis of most trials leads to an under-representation of gender-specific medicine (GM) in EBM-directed guidelines. In this review, we evaluated how the topic of GM was developed in the guidelines produced by the European Society of Cardiology (ESC) from 2018 to 2023. Methods: Two independent reviewers evaluated 24 ESC guidelines. Significant mentions of GM were counted and divided between epidemiology, diagnosis, and therapeutics. The qualitative and semi-quantitative analysis of information relating to GM was performed. Data on the number of citations of papers with a title concerning GM and the prevalence and role of women in guidelines’ authorship were also analyzed. Results: Less than 50% of guidelines had a section dedicated to GM. Only nine guidelines were led by a woman, and 144/567 authors were female. In the most recent guidelines and in those with at least 30% of female authors, there was an increased mention of GM. On average, guidelines had four significant mentions of GM regarding epidemiology, two regarding diagnosis, and one regarding therapy. Articles with titles concerning GM made up, on average, 1.5% of the total number of citations. Conclusions: Although sex differences play a significant role in most clinical scenarios, ESC guidelines still do not sufficiently account for this. The problem does not seem to solely lie in the guidelines, but in the lack of attention to GM in research needed for their preparation.