[Current status and future perspective of clinical trials for patients with multiple myeloma].

There are two main types of clinical trials: industry-sponsored trials and investigator-initiated trials. Both of these, like the two sets of wheels on a car, are essential to development of treatments. Numerous clinical trials have been conducted in multiple myeloma, contributing to the development of new drugs and the current treatment landscape. Highly effective novel immunotherapies, such as bispecific antibodies and chimeric antigen receptor T-cell therapy, have emerged, and could be incorporated into the treatment landscape in the near future. However, given the improved performance of current standard therapies, the drawbacks (e.g., toxicity) of immunotherapy can be expected to outweigh the benefits (efficacy) in some patients. Therefore, clinical trials are designed to evaluate treatments stratified based on factors such as post-treatment efficacy and disease risk, and stratified treatment approaches are increasingly being considered as well as one-size-fits-all approaches to treatment development. In addition, the use of real-world data is being explored to make clinical trials more efficient. These approaches are expected to further improve the individualization and efficiency of multiple myeloma treatment.

Gender, racial, ethnic, and Fitzpatrick skin type representation in Acanthosis nigricans clinical trials.

Acanthosis nigricans (AN) is characterized by dark, velvety patches and thin plaques primarily in the body folds. AN is more prevalent in skin of color populations, including Black/African American, Native American, and Hispanic patients. As the U.S. population becomes increasingly diverse, the need for inclusive dermatologic research becomes more pressing. Given the increased prevalence of AN in skin of color patients, there is a need to evaluate representation in AN clinical trials. This study aims to uncover gender, race, ethnicity, and Fitzpatrick skin type (FST) representation in AN clinical trials. A systematic literature search was performed across PubMed, Embase, and Cochrane databases to identify participant characteristics in clinical trials focused on AN treatment. Our review yielded 21 clinical trials, totaling 575 participants, with an identified predominance of female participants (69.0%) and a surprising absence of race or ethnicity data. Out of the 11 studies that included FST data, 1.2% of participants were type II, 20.6% were type III, 50.0% were type IV, and 28.2% were type V. None of the participants were FST I or VI. Herein, we highlight a predominate inclusion of female and FST III-V patients in AN clinical trials, the populations most impacted by this condition. We also highlight the need for improved race and ethnicity reporting and the importance of including all FSTs in clinical studies. Addressing this gap is critical for developing safe, efficacious, patient-centered, and equitable treatments for all AN patients. Future research should prioritize comprehensive inclusion of race, ethnicity, and the full spectrum of FSTs.

Change in Patient Enrollment After Site Principal Investigator Turnover in Surgical Clinical Trials.

This cohort study examines the association of principal investigator (PI) turnover with patient enrollment in surgical clinical trials.

Advances in targeting histone deacetylase for treatment of solid tumors.

Histone deacetylase (HDAC) serves as a critical molecular regulator in the pathobiology of various malignancies and have garnered attention as a viable target for therapeutic intervention. A variety of HDAC inhibitors (HDACis) have been developed to target HDACs. Many preclinical studies have conclusively demonstrated the antitumor effects of HDACis, whether used as monotherapy or in combination treatments. On this basis, researchers have conducted various clinical studies to evaluate the potential of selective and pan-HDACis in clinical settings. In our work, we extensively summarized and organized current clinical trials, providing a comprehensive overview of the current clinical advancements in targeting HDAC therapy. Furthermore, we engaged in discussions about several clinical trials that did not yield positive outcomes, analyzing the factors that led to their lack of anticipated therapeutic effectiveness. Apart from the experimental design factors, issues such as toxicological side effects, tumor heterogeneity, and unexpected off-target effects also contributed to these less-than-expected results. These challenges have naturally become significant barriers to the application of HDACis. Despite these challenges, we believe that advancements in HDACi research and improvements in combination therapies will pave the way or lead to a broad and hopeful future in the treatment of solid tumors.

Development and deployment of a histopathology-based deep learning algorithm for patient prescreening in a clinical trial.

Accurate identification of genetic alterations in tumors, such as Fibroblast Growth Factor Receptor, is crucial for treating with targeted therapies; however, molecular testing can delay patient care due to the time and tissue required. Successful development, validation, and deployment of an AI-based, biomarker-detection algorithm could reduce screening cost and accelerate patient recruitment. Here, we develop a deep-learning algorithm using >3000 H&E-stained whole slide images from patients with advanced urothelial cancers, optimized for high sensitivity to avoid ruling out trial-eligible patients. The algorithm is validated on a dataset of 350 patients, achieving an area under the curve of 0.75, specificity of 31.8% at 88.7% sensitivity, and projected 28.7% reduction in molecular testing. We successfully deploy the system in a non-interventional study comprising 89 global study clinical sites and demonstrate its potential to prioritize/deprioritize molecular testing resources and provide substantial cost savings in the drug development and clinical settings.

Alternatives to the P value: connotations of significance.

The statistical significance of a clinical trial analysis result is determined by a mathematical calculation and probability based on null hypothesis significance testing. However, statistical significance does not always align with meaningful clinical effects; thus, assigning clinical relevance to statistical significance is unreasonable. A statistical result incorporating a clinically meaningful difference is a better approach to present statistical significance. Thus, the minimal clinically important difference (MCID), which requires integrating minimum clinically relevant changes from the early stages of research design, has been introduced. As a follow-up to the previous statistical round article on P values, confidence intervals, and effect sizes, in this article, we present hands-on examples of MCID and various effect sizes and discuss the terms statistical significance and clinical relevance, including cautions regarding their use.

Trial Participation in Neurodegenerative Diseases: Barriers and Facilitators: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Clinical trials in neurodegenerative diseases often encounter selective enrollment and under-representation of certain patient populations. This delays drug development and substantially limits the generalizability of clinical trial results. To inform recruitment and retention strategies, and to better understand the generalizability of clinical trial populations, we investigated which factors drive participation. METHODS: We reviewed the literature systematically to identify barriers to and facilitators of trial participation in 4 major neurodegenerative disease areas: Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease. Inclusion criteria included original research articles published in a peer-reviewed journal and evaluating barriers to and/or facilitators of participation in a clinical trial with a drug therapy (either symptomatic or disease-modifying). The Critical Appraisal Skills Program checklist for qualitative studies was used to assess and ensure the quality of the studies. Qualitative thematic analyses were employed to identify key enablers of trial participation. Subsequently, we pooled quantitative data of each enabler using meta-analytical models. RESULTS: Overall, we identified 36 studies, enrolling a cumulative sample size of 5,269 patients, caregivers, and health care professionals. In total, the thematic analysis resulted in 31 unique enablers of trial participation; the key factors were patient-related (own health benefit and altruism), study-related (treatment and study burden), and health care professional-related (information availability and patient-physician relationship). When meta-analyzed across studies, responders reported that the reason to participate was mainly driven by (1) the relationship with clinical staff (70% of the respondents; 95% CI 53%-83%), (2) the availability of study information (67%, 95% CI 38%-87%), and (3) the use or absence of a placebo or sham-control arm (53% 95% CI 32%-72%). There was, however, significant heterogeneity between studies (all p < 0.001). DISCUSSION: We have provided a comprehensive list of reasons why patients participate in clinical trials for neurodegenerative diseases. These results may help to increase participation rates, better inform patients, and facilitate patient-centric approaches, thereby potentially reducing selection mechanisms and improving generalizability of trial results.

Functional trajectories before and after loss of ambulation in Duchenne muscular dystrophy and implications for clinical trials.

This study examined functional trajectories of subjects during the transition phase between ambulatory and non-ambulatory Duchenne muscular dystrophy (DMD) to inform clinical trial designs for new therapeutics. Ambulatory, pulmonary, and upper limb function leading up to loss of ambulation (LoA) and non-ambulatory measures following LoA were quantified; time ordering of pulmonary and upper limb milestones relative to LoA were determined; and the 10-second time threshold for 10-meter walk/run (10MWR) as a marker of approaching LOA was explored. Included in this analysis were 51 subjects aged between 7 and 18 years who experienced LoA during follow-up in the PRO-DMD-01 natural history study. Mean age at LoA was 12.7 (7.1-18.6) years. Mean annual rates of decline in forced vital capacity (FVC) <80%-predicted and performance of upper limb (PUL) 1.2 total score were smaller before than after LoA, but not significantly (FVC %-predicted: 5.6% vs. 10.1%, p = 0.21; PUL 1.2 total score: 2.3 vs. 3.8 units, p = 0.20). More than half of patients experienced clinically significant deficits in FVC %-predicted and PUL 1.2 before experiencing LoA. Among subjects with baseline 10MWR >10 s, those with <1 year to LoA had similar mean ages but significantly worse mean ambulatory function at baseline compared to those with ≥1 year to LoA. Enriching DMD clinical trials for patients with declining pulmonary or upper limb function is achievable without restricting enrollment to non-ambulatory patients. The sequencing of LoA and initial deficits in pulmonary and upper limb function varied across patients and highlights the potential for composite outcomes or multi-outcome trial designs to assess disease-modifying therapies more comprehensively.

Chimeric antigen receptor T-cell therapy in childhood acute myeloid leukemia: how far are we from a clinical application?

Recurrent and/or refractory (R/R) pediatric acute myeloid leukemia (AML) remains a recalcitrant disease with poor outcomes. Cell therapy with genetically modified immune effector cells holds the promise to improve outcomes for R/R AML since it relies on cytotoxic mechanisms that are distinct from chemotherapeutic agents. While T cells expressing chimeric antigen receptors (CAR T cells) showed significant anti-AML activity in preclinical models, early phase clinical studies have demonstrated limited activity, irrespective of the targeted AML antigen. Lack of efficacy is most likely multifactorial, including: (i) a limited array of AML-specific targets and target antigen heterogeneity; (ii) the aggressive nature of R/R AML and heavy pretreatment of patients; (iii) T-cell product manufacturing, and (iv) limited expansion and persistence of the CAR T cells, which is in part driven by the immunosuppressive AML microenvironment. Here we review the results of early phase clinical studies with AML-specific CAR T cells, and avenues investigators are exploring to improve their effector function.

Bispecific T-cell engagers in childhood B-acute lymphoblastic leukemia.

Immunotherapy has revolutionized treatment for a wide variety of cancers yet its use has been relatively limited in childhood malignancies. With the introduction of bispecific T-cell engagers (BiTE®) and chimeric antigen T-cell receptor technologies, previously refractory patients have attained remission, including molecularly negative states of disease, thus providing the possibility of long-term cure. Blinatumomab is a widely available CD3-CD19 BiTE that has dramatically changed the landscape of therapy for some children with precursor-B acute lymphoblastic leukemias (B-ALL) and lymphoblastic lymphomas. Challenges remain with using BiTE in a broader population although the appeal of now-confirmed reduced toxicity and deeper molecular remissions suggests that this approach will be an essential part of future treatment of childhood B-ALL. Herein, we review some of the pertinent literature covering clinical trials with blinatumomab and address future approaches and combination trials including BiTE.

Mapping Strategies for Reaching Socioeconomically Disadvantaged Populations in Clinical Trials.

Importance: Socioeconomically disadvantaged patients, such as persons with low income and those with low educational attainment, are less likely to participate in clinical trials than those with higher earnings and higher educational attainment, despite the former being more likely to have chronic medical conditions. Ways to improve the representation of socioeconomically disadvantaged patients in clinical trials deserve attention. Objective: To examine whether current recruitment and enrollment strategies used by US clinical research sites appropriately include patients from socioeconomically disadvantaged backgrounds. Design, Setting, and Participants: This survey study was conducted between April and July 2023. An online survey was distributed among US clinical research sites to explore their use of these strategies and the types of patient sociodemographic and socioeconomic data they collect. The survey was distributed by 13 pharmaceutical companies and 1 clinical research organization. Eight targeted strategies known to increase the recruitment and retention of socioeconomically disadvantaged participants as well as 6 general strategies to recruit and retain clinical trial participants were identified. Data analysis was performed between August and September 2023. Main Outcomes and Measures: Proportions of for-profit vs nonprofit or governmental sites that use recruitment and retention strategies, proportions that have partnerships with community organizations that target socioeconomically disadvantaged groups, and the distribution of sociodemographic and socioeconomic data collected by sites about their patients. A χ2 test of independence was performed to assess the association between research site ownership type and levels of adoption of strategies. Results: A total of 492 responses were collected from 381 clinical research sites in the US (219 for-profit sites [57.5%] and 162 nonprofit or governmental sites [42.5%]). Overall, compared with nonprofit or governmental sites, for-profit sites reported higher use of strategies shown to increase the recruitment and retention of socioeconomically disadvantaged populations, including always or often providing after-hours visits (84 of 173 for-profit sites [48.6%]; 22 of 123 nonprofit or governmental sites [17.9%]) and offering financial compensation (135 of 162 for-profit sites [83.3%]; 60 of 123 nonprofit or governmental sites [48.8%]). Additionally, there was an association between research site ownership type and levels of adoption of these strategies; for example, for-profit sites were more likely to provide after-hours visits (χ2 = 30.33; P < .001) and offer financial compensation (χ2 = 49.35; P < .001). Only 7.2% of for-profit sites (12 of 167) and 13.0% of nonprofit or governmental sites (16 of 123) collected information on the patient's annual income. Conclusions and Relevance: In this survey study, we found an association between a clinical research site's ownership type (for-profit vs nonprofit or governmental) and how often it used strategies to engage socioeconomically diverse populations in clinical research. Regardless of ownership type, most clinical research sites did not collect socioeconomic information from patients. Adoption of strategies to engage socioeconomically diverse populations, particularly by nonprofit or governmental sites, may help minimize barriers to participation for socioeconomically disadvantaged patients.

Overcoming Delays in the Progress against Cancer: Identifying Tobacco Use among Cancer Patients Enrolled in Clinical Trials.

Though smoking causes adverse cancer treatment outcomes and smoking cessation can improve survival, prior literature demonstrates deficits in collecting tobacco use information in clinical trials. Results by Streck and colleagues represent a thorough structured assessment of tobacco use and alternative tobacco product use in patients enrolled in cooperative group trials. Among patients with predominantly non-tobacco related cancers, observations demonstrate that approximately 27% of patients reported using one or more forms of tobacco use after diagnosis. Alternative tobacco use was reported by many patients, including patterns of dual use. Results demonstrate the feasibility of collecting comprehensive structured tobacco use information, and further support the need to address tobacco and cessation even among patients with non-tobacco related cancers. See related article by Streck and colleagues, Cancer Epidemiol Biomarkers Prev 2023;32:1552-57.

Approaches and experiences implementing remote, electronic consent at the Leeds Clinical Trials Research Unit.

BACKGROUND: Use of electronic methods to support informed consent ('eConsent') is increasingly popular in clinical research. This commentary reports the approach taken to implement electronic consent methods and subsequent experiences from a range of studies at the Leeds Clinical Trials Research Unit (CTRU), a large clinical trials unit in the UK. MAIN TEXT: We implemented a remote eConsent process using the REDCap platform. The process can be used in trials of investigational medicinal products and other intervention types or research designs. Our standard eConsent system focuses on documenting informed consent, with other aspects of consent (e.g. providing information to potential participants and a recruiter discussing the study with each potential participant) occurring outside the system, though trial teams can use electronic methods for these activities where they have ethical approval. Our overall process includes a verbal consent step prior to confidential information being entered onto REDCap and an identity verification step in line with regulator guidance. We considered the regulatory requirements around the system's generation of source documents, how to ensure data protection standards were upheld and how to monitor informed consent within the system. We present four eConsent case studies from the CTRU: two randomised clinical trials and two other health research studies. These illustrate the ways eConsent can be implemented, and lessons learned, including about differences in uptake. CONCLUSIONS: We successfully implemented a remote eConsent process at the CTRU across multiple studies. Our case studies highlight benefits of study participants being able to give consent without having to be present at the study site. This may better align with patient preferences and trial site needs and therefore improve recruitment and resilience against external shocks (such as pandemics). Variation in uptake of eConsent may be influenced more by site-level factors than patient preferences, which may not align well with the aspiration towards patient-centred research. Our current process has some limitations, including the provision of all consent-related text in more than one language, and scalability of implementing more than one consent form version at a time. We consider how enhancements in CTRU processes, or external developments, might affect our approach.

Clinical trial capacity building in a pandemic-outcome of a rapid site readiness project in Latin America.

Background: Latin America (Latam) has a tradition of large-scale vaccine trials. Because of fluctuating demand, many sites have downsized their infrastructure. Therefore, BMGF launched a clinical trial site-readiness initiative early in the coronavirus-2019 (COVID-19) pandemic including Latam countries between August and September 2020. This survey evaluated clinical development performance measures pre/post initiative (September 2022). Results: 20/21 prequalified sites participated in COVID-19 vaccine/drug development trials. 156 clinical trials (140 COVID-19 vaccine/drug trials) were initiated in the 2 years since prequalification, compared to 176 in the 5 years before. 33,428/37,810 participants were included in COVID-19 programs. The number of enrolled subjects/day across sites quadrupled from 15 (1-35) to 63 (5-300). The dropout rate was 6.8%. Study approval timelines were reduced from 60 (12-120) to 35 (5-90) days. Mean qualified staff was increased from 24 (6-80) to 88 (22-180). Conclusion: Clinical trial sites across Latam were successfully prequalified to participate in COVID-19 developments. For the 100 days mission of vaccine availability in a new pandemic sufficient and well-trained clinical trial sites readily available are essential. This is only achievable if sites-especially in low/middle-income countries-are maintained active through a constant flow of vaccine studies.