Digital technologies used in clinical trial recruitment and enrollment including application to trial diversity and inclusion: A systematic review.

Background: Many clinical trials fail because of poor recruitment and enrollment which can directly impact the success of biomedical and clinical research outcomes. Options to leverage digital technology for improving clinical trial management are expansive, with potential benefits for improving access to clinical trials, encouraging trial diversity and inclusion, and potential cost-savings through enhanced efficiency. Objectives: This systematic review has two key aims: (1) identify and describe the digital technologies applied in clinical trial recruitment and enrollment and (2) evaluate evidence of these technologies addressing the recruitment and enrollment of racial and ethnic minority groups. Methods: We conducted a cross-disciplinary review of articles from PubMed, IEEE Xplore, and ACM Digital Library, published in English between January 2012 and July 2022, using MeSH terms and keywords for digital health, clinical trials, and recruitment and enrollment. Articles unrelated to technology in the recruitment/enrollment process or those discussing recruitment/enrollment without technology aspects were excluded. Results: The review returned 614 results, with 21 articles (four reviews and 17 original research articles) deemed suitable for inclusion after screening and full-text review. To address the first objective, various digital technologies were identified and characterized, which included articles with more than one technology subcategory including (a) multimedia presentations (19%, n = 4); (b) mobile applications (14%, n = 3); (c) social media platforms (29%, n = 6); (d) machine learning and computer algorithms (19%, n = 4); (e) e-consenting (24%, n = 5); (f) blockchain (5%, n = 1); (g) web-based programs (24%, n = 5); and (h) virtual messaging (24%, n = 5). Additionally, subthemes, including specific diseases or conditions addressed, privacy and regulatory concerns, cost/benefit analyses, and ethnic and minority recruitment considerations, were identified and discussed. Limited research was found to support a particular technology's effectiveness in racial and ethnic minority recruitment and enrollment. Conclusion: Results from this review illustrate that several types of technology are currently being explored and utilized in clinical trial recruitment and enrollment stages. However, evidence supporting the use of digital technologies is varied and requires further research and evaluation to identify the most valuable opportunities for encouraging diversity in clinical trial recruitment and enrollment practices.

Adjudication of a primary trial outcome: Results of a calibration exercise and protocol for a large international trial.

Background: Ascertainment of the severity of the primary outcome of upper gastrointestinal (GI) bleeding is integral to stress ulcer prophylaxis trials. This protocol outlines the adjudication process for GI bleeding events in an international trial comparing pantoprazole to placebo in critically ill patients (REVISE: Re-Evaluating the Inhibition of Stress Erosions). The primary objective of the adjudication process is to assess episodes submitted by participating sites to determine which fulfil the definition of the primary efficacy outcome of clinically important upper GI bleeding. Secondary objectives are to categorize the bleeding severity if deemed not clinically important, and adjudicate the bleeding site, timing, investigations, and treatments. Methods: Research coordinators follow patients daily for any suspected clinically important upper GI bleeding, and submit case report forms, doctors' and nurses' notes, laboratory, imaging, and procedural reports to the methods center. An international central adjudication committee reflecting diverse specialty backgrounds conducted an initial calibration exercise to delineate the scope of the adjudication process, review components of the definition, and agree on how each criterion will be considered fulfilled. Henceforth, bleeding events will be stratified by study drug, and randomly assigned to adjudicator pairs (blinded to treatment allocation, and study center). Results: Crude agreement, chance-corrected agreement, or chance-independent agreement if data have a skewed distribution will be calculated. Conclusions: Focusing on consistency and accuracy, central independent blinded duplicate adjudication of suspected clinically important upper GI bleeding events will determine which events fulfil the definition of the primary efficacy outcome for this stress ulcer prophylaxis trial. Registration: NCT03374800 (REVISE: Re-Evaluating the Inhibition of Stress Erosions).

The application of Phase 0 and microtracer approaches in early clinical development: past, present, and future.

Phase 0 microdosing studies were introduced to the drug development community approximately 20 years ago. A microdose is defined as less than 1/100th of the dose calculated based on animal data to yield a pharmacological effect in humans, with a maximum of 100 µg, or 30 nmoles for protein products. In our experience, Phase 0 microdose studies have not been fully embraced by the pharmaceutical industry. This notion is based on the number of Phase 0 studies that we have been involved in. Thus, we conducted at least 17 Phase 0 microdose studies in the Zero's (on average, two per year), but in the years beyond this, it was only 15 studies (1.4 per year); in these latter years, we did conduct a total of 23 studies which employed an intravenous (i.v.) microdose for absolute bioavailability (ABA) assessments (two per year on average), which are the most used and potentially informative type of clinical study using a microdose, albeit they are formally not microdose studies. In the current review, we summarize the past use of and experience with Phase 0 microdose designs in early clinical development, including intravenous 14C microdose ABA studies, and assess what is needed to increase the adoption of useful applications of Phase 0/microdose studies in the near future.

Recent Advances in the Treatment and Management of Alzheimer's Disease: A Precision Medicine Perspective.

About 60% to 70% of people with dementia have Alzheimer's Disease (AD), a neuro-degenerative illness. One reason for this disorder is the misfolding of naturally occurring proteins in the human brain, specifically ß-amyloid (Aß) and tau. Certain diagnostic imaging techniques, such as amyloid PET imaging, tau PET imaging, Magnetic Resonance Imaging (MRI), Comput-erized Tomography (CT), and others, can detect biomarkers in blood, plasma, and cerebral spinal fluids, like an increased level of ß-amyloid, plaques, and tangles. In order to create new pharma-cotherapeutics for Alzheimer's disease, researchers must have a thorough and detailed knowledge of amyloid beta misfolding and other related aspects. Dolopezil, rivastigmine, galantamine, and other acetylcholinesterase inhibitors are among the medications now used to treat Alzheimer's disease. Another medication that can temporarily alleviate dementia symptoms is memantine, which blocks the N-methyl-D-aspartate (NMDA) receptor. However, it is not able to halt or re-verse the progression of the disease. Medication now on the market can only halt its advance-ment, not reverse it. Interventions to alleviate behavioral and psychological symptoms, exhibit an-ti-neuroinflammation and anti-tau effects, induce neurotransmitter alteration and cognitive en-hancement, and provide other targets have recently been developed. For some Alzheimer's pa-tients, the FDA-approved monoclonal antibody, aducanumab, is an option; for others, phase 3 clinical studies are underway for drugs, like lecanemab and donanemab, which have demonstrat-ed potential in eliminating amyloid protein. However, additional study is required to identify and address these limitations in order to reduce the likelihood of side effects and maximize the thera-peutic efficacy.

Implementation Science to Achieve Equity in Heart Failure Care: A Scientific Statement From the American Heart Association.

Guideline-directed medical therapies and guideline-directed nonpharmacological therapies improve quality of life and survival in patients with heart failure (HF), but eligible patients, particularly women and individuals from underrepresented racial and ethnic groups, are often not treated with these therapies. Implementation science uses evidence-based theories and frameworks to identify strategies that facilitate uptake of evidence to improve health. In this scientific statement, we provide an overview of implementation trials in HF, assess their use of conceptual frameworks and health equity principles, and provide pragmatic guidance for equity in HF. Overall, behavioral nudges, multidisciplinary care, and digital health strategies increased uptake of therapies in HF effectively but did not include equity goals. Few HF studies focused on achieving equity in HF by engaging stakeholders, quantifying barriers and facilitators to HF therapies, developing strategies for equity informed by theory or frameworks, evaluating implementation measures for equity, and titrating strategies for equity. Among these HF equity studies, feasibility was established in using various educational strategies to promote organizational change and equitable care. A couple include ongoing randomized controlled pragmatic trials for HF equity. There is great need for additional HF implementation trials designed to promote delivery of equitable guideline-directed therapy.

Utilizing Quality of Life Adjusted Days Alive and Out of Hospital in Heart Failure Clinical Trials.

BACKGROUND: In heart failure (HF) trials, there has been an emphasis on utilizing more patient-centered outcomes, including quality of life (QoL) and days alive and out of hospital. We aimed to explore the impact of QoL adjusted days alive and out of hospital as an outcome in 2 HF clinical trials. METHODS: Using data from 2 trials in HF (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT] and Study of Dietary Intervention under 100 mmol in Heart Failure [SODIUM-HF]), we determined treatment differences using percentage days alive and out of hospital (%DAOH) adjusted for QoL at 18 months as the primary outcome. For each participant, %DAOH was calculated as a ratio between days alive and out of hospital/total follow-up. Using a regression model, %DAOH was subsequently adjusted for QoL measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score. RESULTS: In the GUIDE-IT trial, 847 participants had a median baseline Kansas City Cardiomyopathy Questionnaire Overall Summary Score of 59.0 (interquartile range, 40.8-74.3), which did not change over 18 months. %DAOH was 90.76%±22.09% in the biomarker-guided arm and 88.56%±25.27% in the usual care arm. No significant difference in QoL adjusted %DAOH was observed (1.09% [95% CI, -1.57% to 3.97%]). In the SODIUM-HF trial, 796 participants had a median baseline Kansas City Cardiomyopathy Questionnaire Overall Summary Score of 69.8 (interquartile range, 49.3-84.3), which did not change over 18 months. %DAOH was 95.69%±16.31% in the low-sodium arm and 95.95%±14.76% in the usual care arm. No significant difference was observed (1.91% [95% CI, -0.85% to 4.77%]). CONCLUSIONS: In 2 large HF clinical trials, adjusting %DAOH for QoL was feasible and may provide complementary information on treatment effects in clinical trials.

Results from the long-term extension of PRIME: A randomized Phase 1b trial of aducanumab.

INTRODUCTION: Aducanumab selectively targets aggregated forms of amyloid beta (Aß), a neuropathological hallmark of Alzheimer's disease (AD). METHODS: PRIME was a Phase 1b, double-blind, randomized clinical trial of aducanumab. During the 12-month placebo-controlled period, participants with prodromal AD or mild AD dementia were randomized to receive aducanumab or placebo. At week 56, participants could enroll in a long-term extension (LTE), in which all participants received aducanumab. The primary endpoint was safety and tolerability. RESULTS: Amyloid-related imaging abnormalities-edema (ARIA-E) were the most common adverse event. Dose titration was associated with a decrease in the incidence of ARIA-E. Over 48 months, aducanumab decreased brain amyloid levels in a dose- and time-dependent manner. Exploratory endpoints suggested a continued benefit in the reduction of clinical decline over 48 months. DISCUSSION: The safety profile of aducanumab remained unchanged in the LTE of PRIME. Amyloid plaque levels continued to decrease in participants treated with aducanumab. HIGHLIGHTS: PRIME was a Phase 1b, double-blind, randomized clinical trial of aducanumab. We report cumulative safety and 48-month efficacy results from PRIME. Amyloid-related imaging abnormalities-edema (ARIA-E) were the most common adverse event (AE); 61% of participants with ARIA-E were asymptomatic. Dose titration was associated with a decrease in the incidence of ARIA-E. Aducanumab decreased levels of amyloid beta (Aß) in a dose- and time-dependent manner.

Optimising oncology drug expenditure in Ireland.

A combination of improvements in patient survival, increasing treatment duration, and the development of more expensive agents has led to a doubling of per-capita spending on cancer medicines in Ireland (2008-2018). Despite this, access to new drugs is poor in comparison to other EU countries. We examine methods to optimise oncology drug spending to facilitate access to newer anticancer agents. Key targets for spending optimisation (biosimilar use, clinical trials and expanded access programs, waste reduction, avoidance of futile treatment, and altered drug scheduling) were identified through an exploratory analysis. A structured literature search was performed, with a focus on articles relevant to the Irish Healthcare system, supplemented by reports from statutory bodies. At the present time, EMA-approved agents are available once approved by the NCPE. Optimising drug costs occurs through guideline-based practice and biosimilar integration, the latter provides €80 million in cost savings annually. Access to novel therapies can occur via over 50 clinical trials and 28 currently available expanded access programmes. Additional strategies include reversion to weight-based immunotherapy dosing, potentially saving €400,000 per year in our centre alone, vial sharing, and optimisation of treatment schedules. A variety of techniques are being employed by oncologists to optimise costs and increase access to innovation for patients. Use of biosimilars, drug wastage, and prescribing at end of life should be audited as key performance indicators, which may lead to reflective practice on treatment planning. Such measures could further optimise oncology drug expenditure nationally facilitating approval of new agents.

Clinical trial recommendations using Semantics-Based inductive inference and knowledge graph embeddings.

OBJECTIVE: Designing a new clinical trial entails many decisions, such as defining a cohort and setting the study objectives to name a few, and therefore can benefit from recommendations based on exhaustive mining of past clinical trial records. This study proposes an approach based on knowledge graph embeddings and semantics-driven inductive inference for generating such recommendations. METHOD: The proposed recommendation methodology is based on neural embeddings trained on first-of-its-kind knowledge graph constructed from clinical trials data. The methodology includes design of a knowledge graph for clinical trial data, evaluation of various knowledge graph embedding techniques for it, application of a novel inductive inference method using these embeddings, and generation of recommendations for clinical trial design. The study uses freely available data from clinicaltrials.gov and related sources. RESULTS: The proposed approach for recommendations obtained relevance scores ranging from 70% to 83%. These scores were determined by evaluating the text similarity of recommended elements to actual elements used in clinical trials that are in progress. Furthermore, the most pertinent recommendations were consistently located towards the top of the list, indicating the effectiveness of our method. CONCLUSION: Our study suggests that inductive inference using node semantics is a viable approach for generating recommendations using graphs neural embeddings, and that there is a potential for improvement in training graph embeddings using node semantics.

Antibiotic Development: Lessons from the Past and Future Opportunities.

The challenge of antimicrobial resistance is broadly appreciated by the clinical and scientific communities. To assess progress in the development of medical countermeasures to combat bacterial infections, we deployed information gleaned from clinical trials conducted from 2000 to 2021. Whereas private sector interest in cancer grew dramatically over this period, activity to combat bacterial infections remained stagnant. The comparative ambivalence to antimicrobial resistance is reflected in the number of investigative drugs under clinical investigation, their stage of development and most troublingly, a declining number of organizations that are actively involved in the development of new products to treat bacterial infections. This drop reflects the exits of many companies that had previously developed antibacterial agents.

Review Deciphering the Potential of Nanotherapeutics in Lung Cancer Management.

Lung cancer remains a formidable challenge in oncology, necessitating the develop-ment of more effective prognostic and diagnostic techniques due to inefficient conventional therapeutic approaches and inadequate methods for early lung cancer diagnosis. Despite im-mense progress in the development of innovative strategies to alleviate the impact of this devas-tating disease, the outcomes, unfortunately, remain unsatisfactory, particularly in targeted drug delivery methods. Consequently, nanotechnology has emerged as a revolutionary force in cancer research to develop more effective targeted drug delivery tools due to its extraordinary capacity at the atomic and molecular levels. It has appeared as a beacon of hope in this area of unmet need, providing innovative ways for the prognosis and diagnosis of lung carcinoma. Therefore, this comprehensive review delves into the evolving field of nano-based therapeutics, shedding light on their potential to transform lung cancer treatment. This study meticulously explores the most promising nano-based strategies that have been extensively linked with the treatment of lung carcinoma and mainly emphasizes targeted drug delivery methods and therapies. Addition-ally, this review encapsulates the favorable results of clinical trials, which support the potential pathways for further development of nanotherapeutics in lung cancer management.

Complement networks in gene-edited pig xenotransplantation: enhancing transplant success and addressing organ shortage.

The shortage of organs for transplantation emphasizes the urgent need for alternative solutions. Xenotransplantation has emerged as a promising option due to the greater availability of donor organs. However, significant hurdles such as hyperacute rejection and organ ischemia-reperfusion injury pose major challenges, largely orchestrated by the complement system, and activated immune responses. The complement system, a pivotal component of innate immunity, acts as a natural barrier for xenotransplantation. To address the challenges of immune rejection, gene-edited pigs have become a focal point, aiming to shield donor organs from human immune responses and enhance the overall success of xenotransplantation. This comprehensive review aims to illuminate strategies for regulating complement networks to optimize the efficacy of gene-edited pig xenotransplantation. We begin by exploring the impact of the complement system on the effectiveness of xenotransplantation. Subsequently, we delve into the evaluation of key complement regulators specific to gene-edited pigs. To further understand the status of xenotransplantation, we discuss preclinical studies that utilize gene-edited pigs as a viable source of organs. These investigations provide valuable insights into the feasibility and potential success of xenotransplantation, offering a bridge between scientific advancements and clinical application.

A randomized comparison of recruitment messages for a weight loss clinical trial targeting men working in trade and labor occupations.

Background: Engaging diverse populations in clinical trials is vital to research. This study evaluated the effects of varying recruitment messages for a clinical trial. Methods: The messages were evaluated in a randomly assigned, factorial design that tested enhanced trust (vs. standard) and participant endorsement (vs. standard) messaging.Four postcards were developed and randomly assigned to 4000 potential participants' addresses. Except for the messages of interest, the cards were identical, and participants were directed to four identical study websites and screening forms. Outcomes include unique website visits, visit conversion rate, screening forms completed, and participants randomized into the parent study. Results: Study websites received 74 visits (range by message type 9 to 34). There was no significant difference by message type (p = 0.79). Online screening forms were completed by 15 participants (range by message type 0-6), representing a conversion rate of 20.3% of website visits. Seven participants were randomized into the study in response to the postcards (range by message type 0 to 3; 46.7% of screenings). Overall, 0.2% of individuals who received a postcard were randomized into the study. Conclusion: Despite developing recruitment messages with participant input, the enhanced messages did not yield a greater response than standard messages. However, this method of evaluating recruitment messages shows promise.

Quantitative evaluation of the impact of relaxing eligibility criteria on the risk-benefit profile of drugs for lung cancer based on real-world data.

INTRODUCTION: Restrictive eligibility criteria in cancer drug trials result in low enrollment rates and limited population diversity. Relaxed eligibility criteria (REC) based on solid evidence is becoming necessary for stakeholders worldwide. However, the absence of high-quality, favorable evidence remains a major challenge. This study presents a protocol to quantitatively evaluate the impact of relaxing eligibility criteria in common non-small cell lung cancer (NSCLC) protocols in China, on the risk-benefit profile. This involves a detailed explanation of the rationale, framework, and design of REC. METHODS: To evaluate our REC in NSCLC drug trials, we will first construct a structured, cross-dimensional real-world NSCLC database using deep learning methods. We will then establish randomized virtual cohorts and perform benefit-risk assessment using Monte Carlo simulation and propensity matching. Shapley value will be utilized to quantitatively measure the effect of the change of each eligibility criterion on patient volume, clinical efficacy and safety. DISCUSSION: This study is one of the few that focuses on the problem of overly stringent eligibility criteria cancer drug clinical trials, providing quantitative evaluation of the effect of relaxing each NSCLC eligibility criterion. This study will not only provide scientific evidence for the rational design of population inclusion in lung cancer clinical trials, but also establish a data governance system, as well as a REC evaluation framework that can be generalized to other cancer studies.

Why are clinical trials of deep brain stimulation terminated? An analysis of clinicaltrials.gov.

Background: Although deep brain stimulation (DBS) has established uses for patients with movement disorders and epilepsy, it is under consideration for a wide range of neurologic and neuropsychiatric conditions. Objective: To review successful and unsuccessful DBS clinical trials and identify factors associated with early trial termination. Methods: The ClinicalTrials.gov database was screened for all studies related to DBS. Information regarding condition of interest, study aim, trial design, trial success, and, if applicable, reason for failure was collected. Trials were compared and logistic regression was utilized to identify independent factors associated with trial termination. Results: Of 325 identified trials, 79.7% were successful and 20.3% unsuccessful. Patient recruitment, sponsor decision, and device issues were the most cited reasons for termination. 242 trials (74.5%) were interventional with 78.1% successful. There was a statistically significant difference between successful and unsuccessful trials in number of funding sources (p = 0.0375). NIH funding was associated with successful trials while utilization of other funding sources (academic institutions and community organizations) was associated with unsuccessful trials. 83 trials (25.5%) were observational with 84.0% successful; there were no statistically significant differences between successful and unsuccessful observational trials. Conclusion: One in five clinical trials for DBS were found to be unsuccessful, most commonly due to patient recruitment difficulties. The source of funding was the only factor associated with trial success. As DBS research continues to grow, understanding the current state of clinical trials will help design successful future studies, thereby minimizing futile expenditures of time, cost, and patient engagement.

Toward Patient Centricity: Why Do Patients With Inflammatory Bowel Disease Participate in Pharmaceutical Clinical Trials? A Mixed-Methods Exploration of Study Participants.

Background: A better understanding of motivations to participate as well as recommendations to reduce barriers to enrollment may assist in design of future clinical trials. Methods: We developed a 32-item electronic questionnaire to explore motivations, experiences, and recommendations of inflammatory bowel disease patients, who had participated in pharmaceutical clinical trials in a tertiary center in Canada over the last decade. We employed a mixed-methods approach that integrates both quantitative and qualitative research methods. Results: We distributed a total of 69 e-mails with surveys and received 46 responses (66.6% response rate). Study participants were mostly male (27/46, 58.7%), non-Hispanic White (43/46, 93.5%), with a mean age of 45.5 years (SD 10.9). Most decided to participate in a clinical trial to benefit future patients (29/46, 63.0%). Half of the participants (23/46, 50.0%) reported they were worried about the possibility of receiving placebo, although the majority (29/46, 63.0%) understood they could improve on placebo. The most challenging aspect reported was the number and length of questionnaires (15/46, 32.6%), as well as the number of colonoscopies (14/46, 30.4%). Strategies recommended to increase enrollment were reduction of the chance of receiving placebo (20/46, 43.5%), facilitating inclusion of patients who have failed multiple therapies (20/46, 43.5%), allowing virtual visits (18/46, 39.1%), including subtypes of disease traditionally excluded from trials (16/46, 34.8%) and improving outreach to underrepresented populations (13/46, 28.3%). The vast majority (37/46, 80.4%) reported their experience of participation to be better than expected. Conclusions: These results should help inform the design of future clinical trials with a focus on patient-centricity.

Promising immunotherapy targets: TIM3, LAG3, and TIGIT joined the party.

Immune checkpoint inhibitors (ICIs) have shown great promise as immunotherapy for restoring T cell function and reactivating anti-tumor immunity. The US Food and Drug Administration (FDA) approved the first immune checkpoint inhibitor, ipilimumab, in 2011 for advanced melanoma patients, leading to significant improvements in survival rates. Subsequently, other immune checkpoint-targeting antibodies were tested. Currently, seven ICIs, namely ipilimumab (anti-cytotoxic T lymphocyte-associated protein 4 [CTLA4]), pembrolizumab, nivolumab (anti-programmed cell death protein 1 [PD-1]), atezolizumab, avelumab, durvalumab, and cemiplimab (anti-PD-L1), have been approved for various cancer types. However, the efficacy of antibodies targeting CTLA4 or PD-1/programmed death-ligand 1 (PD-L1) remains suboptimal. Consequently, ongoing studies are evaluating the next generation of ICIs, such as lymphocyte activation gene-3 (LAG3), T cell immunoglobulin and mucin-domain containing 3 (TIM3), and T cell immunoglobulin and ITIM domain (TIGIT). Our review provides a summary of clinical trials evaluating these novel immune checkpoints in cancer treatment.

ECLIM-SEHOP: how to develop a platform to conduct academic trials for childhood cancer.

INTRODUCTION: ECLIM-SEHOP platform was created in 2017. Its main objective is to establish the infrastructure to allow Spanish participation into international academic collaborative clinical trials, observational studies, and registries in pediatric oncology. The aim of this manuscript is to describe the activity conducted by ECLIM-SEHOP since its creation. METHODS: The platform's database was queried to provide an overview of the studies integrally and partially supported by the organization. Data on trial recruitment and set-up/conduct metrics since its creation until November 2023 were extracted. RESULTS: ECLIM-SEHOP has supported 47 studies: 29 clinical trials and 18 observational studies/registries that have recruited a total of 5250 patients. Integral support has been given to 25 studies: 16 trials recruiting 584 patients and nine observational studies/registries recruiting 278 patients. The trials include front-line studies for leukemia, lymphoma, brain and solid extracranial tumors, and other key transversal topics such as off-label use of targeted therapies and survivorship. The mean time from regulatory authority submission to first patient recruited was 12.2 months and from first international site open to first Spanish site open was 31.3 months. DISCUSSION: ECLIM-SEHOP platform has remarkably improved the availability and accessibility of international academic clinical trials and has facilitated the centralization of resources in childhood cancer treatment. Despite the progressive improvement on clinical trial set-up metrics, timings should still be improved. The program has contributed to leveling survival rates in Spain with those of other European countries that presented major differences in the past.