UNASSIGNED: Within-subject variability (WSV) of pain intensity reports has been shown to predict the placebo response. The focused analgesia selection test (FAST), which allows to experimentally assess WSV of pain reports, has been used as a screening tool to identify participants who are likely to have a strong placebo response in drug-development clinical trials. Yet, the reliability of FAST has not been reported.
UNASSIGNED: To assess test-retest and interrater reliability of the FAST outcomes. To mimic pharma-sponsored clinical trials, we enlisted inexperienced assessors who underwent limited training.
UNASSIGNED: Healthy volunteers performed the FAST twice within a week and were randomly assigned to either the test-retest group or the interrater group. T-tests, partial Pearson correlations, intraclass correlations (ICC), and Bland-Altman plots were generated to assess FAST outcomes\' reliability.
UNASSIGNED: Sixty-three participants completed the study and were assigned to the test-retest (N = 33) or interrater (N = 30) arms. No statistically significant differences in the FAST outcomes were detected between the 2 sessions, except for the FAST covariance (FAST CoV) in the interrater assessment (P = 0.009). Test-retest reliabilities of the FAST-main outcomes were r = 0.461, ICC = 0.385 for the FAST R 2 and r = 0.605, ICC = 0.539 for the FAST ICC and in the interrater cohort, they were FAST R 2: r = 0.321, ICC = 0.337 and FAST ICC: r = 0.355, ICC = 0.330.
UNASSIGNED: Using inexperienced assessors, the FAST outcomes test-retest ranged from moderate to strong, whereas the interrater reliability ranged from weak to poor. These results highlight the importance of adequately training study staff members before using this tool in multicentre clinical trials.

BACKGROUND: Interest in and use of electronic consent (e-consent) in the conduct of academic clinical trials has increased since the COVID-19 pandemic. E-consent offers advantages including increased efficiency and accessibility, and reduced burden on site staff, which can be appealing to academic trialists anticipating challenges in recruitment to complex trial designs or with limited funding. However, there are many options to consider when using e-consent in a study protocol. This paper presents five case studies from Norwich Clinical Trials Unit, demonstrating how e-consent models can be effectively tailored to the needs of different trials. These examples illustrate the options around and benefits of e-consent, the acceptability of e-consent by participants, and the design considerations that were made during the development of the trial protocols.
METHODS: Five randomised trials are presented, selected from a range of different trial designs, disease areas, interventions, and patient populations. E-consent was either offered as an alternative to paper consent, according to participant preference, or as the sole method of consent. E-consent was generally used to facilitate remote consent in decentralised trials but was also chosen to increase efficiency and reduce burden in an emergency department setting. The technical implementation of e-consent and detailed participant procedures were tailored to the needs of the trial settings and patient populations. For example, accompanying participant information sheets were provided in paper or electronic form, and electronic signatures could be typed or drawn. Administrative data on uptake of e-consent is presented where available.
CONCLUSIONS: This paper demonstrates that the operational and technical aspects of implementing e-consent in clinical trials can be influenced by the trial design, the needs and characteristics of the trial population, financial/efficiency considerations, and level of risk. E-consent is not a one-size-fits-all tool for trials, and its use should be carefully considered during the development of the trial protocol, in conjunction with patient and public involvement contributors, site staff and other trial stakeholders.

BACKGROUND: Solving complex research challenges requires innovative thinking and alternative approaches to traditional methods. One such example is the problem of arm and hand, or upper limb function in multiple sclerosis (MS), a neurological condition affecting approximately 2.9 million people worldwide and more than 150,000 in the United Kingdom. Historically, clinical trials and research have focused on mobility and walking ability. This excludes a large number of patients who are wheelchair users, limiting their quality of life and restricting access to possibly helpful medications. To address this issue, the ThinkHand campaign was launched in 2016, aiming to raise awareness about the importance of upper limb function in MS and develop alternative ways to measure, record, and account for hand and arm function changes.
METHODS: The campaign utilised innovative strategies at scientific conferences and online surveys to engage people affected by MS, healthcare professionals, charities, and researchers in discussing the importance of preserving upper limb function. Through co-design and interdisciplinary collaboration, the campaign developed new tools like the low-cost cardboard version of the Nine-Hole Peg Test, facilitating remote monitoring of hand function. Additionally, the campaign co-created the \"Under & Over\" rehabilitation tool, allowing individuals with advanced MS to participate in a remote rehabilitation program.The impact of the ThinkHand campaign has been significant, helping to shift the focus of both academic and industry-supported trials, including the O\'HAND and ChariotMS trials, both using upper limb function as their primary end point. The campaign\'s patient-centred approach highlighted the importance of recognising patients\' perspectives in research and challenged established assumptions and practices. It demonstrated the effectiveness of interdisciplinary collaboration, systems thinking, and co-creation with stakeholders in tackling complex problems.
CONCLUSIONS: The ThinkHand campaign provides valuable insights for health research practices. By involving patients at all stages, researchers can gain a deeper understanding of the impact of disease on their lives, identify gaps and focus research on their needs. Experimentation and iteration can lead to innovative solutions, and openness to unconventional methods can drive widespread change. The ThinkHand campaign exemplifies the potential of patient-centred approaches to address complex research challenges and revolutionise the field of MS research and management. Embracing such approaches will contribute to more inclusive and impactful research in the future.
Solving complex research challenges requires creative thinking and new ways of doing things. One such challenge is understanding the problems with arm and hand function in multiple sclerosis (MS), a neurological condition that affects more than 150,000 in the United Kingdom. In the past, research focused mainly on walking ability, leaving out many people who use wheelchairs.To tackle this issue, we created the ThinkHand campaign in 2016. Its goal was to raise awareness about the importance of hand and arm function for people with MS (pwMS) and find better ways to measure changes in these functions such that they can become outcomes in clinical trials. This could provide a pathway to better treatments for pwMS who cannot walk.The campaign used various methods, including surveys, social media posts, exhibitions and music to involve pwMS, healthcare professionals, charities, and researchers in discussions about the issues. Working together, they created tools to support pwMS, particularly those at an advanced stage of the disease (pwAMS), to take part in research and measure their hand and arm function. Through our collaborative approach focusing on patients’ perspectives, the campaign challenged old ideas and deeply embedded practices. It showed that collaboration between different areas of expertise involving pwMS at all stages of research can help solve complex problems. This campaign teaches us valuable lessons for health research. When researchers listen to patients and try new things, they can better understand how a disease affects people’s lives and develop better solutions.In conclusion, we show how embracing a patient-centred approach can address complex research challenges and improve how we study and manage MS and other conditions in the future.

The coronavirus disease-2019 pandemic resulted in a major increase in depression and anxiety disorders worldwide, which increased the demand for mental health services. However, clinical interventions for treating mental disorders are currently insufficient to meet this growing demand. There is an urgent need to conduct scientific and standardized clinical research that are consistent with the features of mental disorders in order to deliver more effective and safer therapies in the clinic. Our study aimed to expose the challenges, complexities of study design, ethical issues, sample selection, and efficacy evaluation in clinical research for mental disorders. The reliance on subjective symptom presentation and rating scales for diagnosing mental diseases was discovered, emphasizing the lack of clear biological standards, which hampers the construction of rigorous research criteria. We underlined the possibility of psychotherapy in efficacy evaluation alongside medication treatment, proposing for a multidisciplinary approach comprising psychiatrists, neuroscientists, and statisticians. To comprehend mental disorders progression, we recommend the development of artificial intelligence integrated evaluation tools, the use of precise biomarkers, and the strengthening of longitudinal designs. In addition, we advocate for international collaboration to diversity samples and increase the dependability of findings, with the goal of improving clinical research quality in mental disorders through sample representativeness, accurate medical history gathering, and adherence to ethical principles.

UNASSIGNED: The generation of structured documents for clinical trials is a promising application of large language models (LLMs). We share opportunities, insights, and challenges from a competitive challenge that used LLMs for automating clinical trial documentation.
UNASSIGNED: As part of a challenge initiated by Pfizer (organizer), several teams (participant) created a pilot for generating summaries of safety tables for clinical study reports (CSRs). Our evaluation framework used automated metrics and expert reviews to assess the quality of AI-generated documents.
UNASSIGNED: The comparative analysis revealed differences in performance across solutions, particularly in factual accuracy and lean writing. Most participants employed prompt engineering with generative pre-trained transformer (GPT) models.
UNASSIGNED: We discuss areas for improvement, including better ingestion of tables, addition of context and fine-tuning.
UNASSIGNED: The challenge results demonstrate the potential of LLMs in automating table summarization in CSRs while also revealing the importance of human involvement and continued research to optimize this technology.

UNASSIGNED: Medical ethics guidelines require of clinical trial investigators and sponsors to inform prospective trial participants of all known and potential risks associated with investigational medical products, and to obtain their free informed consent. These guidelines also require that clinical research be so designed as to minimize harms and maximize benefits.
UNASSIGNED: To examine Merck\'s scientific rationale for using a reactogenic aluminum-containing \"placebo\" in Gardasil HPV vaccine pre-licensure clinical trials.
UNASSIGNED: We examined the informed consent form and the recruitment brochure for the FUTURE II Gardasil vaccine trial conducted in Denmark; and we interviewed several FUTURE II trial participants and their treating physicians. We also reviewed regulatory documentation related to Gardasil vaccine approval process and the guidelines on evaluation of adjuvants used in human vaccines.
UNASSIGNED: It was found that the vaccine manufacturer Merck made several inaccurate statements to trial participants that compromised their right to informed consent. First, even though the study protocol listed safety testing as one of the study\'s primary objectives, the recruitment brochure emphasized that FUTURE II was not a safety study, and that the vaccine had already been proven safe. Second, the advertising material for the trial and the informed consent forms stated that the placebo was saline or an inactive substance, when, in fact, it contained Merck\'s proprietary highly reactogenic aluminum adjuvant which does not appear to have been properly evaluated for safety. Several trial participants experienced chronic disabling symptoms, including some randomized to the adjuvant \"placebo\" group.
UNASSIGNED: In our view, the administration of a reactive placebo in Gardasil clinical trials was without any possible benefit, needlessly exposed study subjects to risks, and was therefore a violation of medical ethics. The routine use of aluminum adjuvants as \"placebos\" in vaccine clinical trials is inappropriate as it hinders the discovery of vaccine-related safety signals.

BACKGROUND: Accurately estimating the costs of clinical trials is challenging. There is currently no reference class data to allow researchers to understand the potential costs associated with database change management in clinical trials.
METHODS: We used a case-based approach, summarising post-live changes in eleven clinical trial databases managed by Sheffield Clinical Trials Research Unit. We reviewed the database specifications for each trial and summarised the number of changes, change type, change category, and timing of changes. We pooled our experiences and made observations in relation to key themes.
RESULTS: Median total number of changes across the eleven trials was 71 (range 40-155) and median number of changes per study week was 0.48 (range 0.32-1.34). The most common change type was modification (median 39, range 20-90), followed by additions (median 32, range 18-55), then deletions (median 7, range 1-12). In our sample, changes were more common in the first half of the trial\'s lifespan, regardless of its overall duration. Trials which saw continuous changes seemed more likely to be external pilots or trials in areas where the trial team was either less experienced overall or within the particular therapeutic area.
CONCLUSIONS: Researchers should plan trials with the expectation that clinical trial databases will require changes within the life of the trial, particularly in the early stages or with a less experienced trial team. More research is required to understand potential differences between clinical trial units and database types.

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Developing new drugs or generating evidence for existing drugs in new indications for ultra-rare cancers is complex and carries a high-risk of failure. This gets even harder in ultra-rare tumours, which have an annual incidence of 1 per 1,000,000 population or less. Here, we illustrate the problem of adequate evidence generation in ultra-rare tumours, using Alveolar Soft-Part Sarcomas (ASPS) - an ultra-rare sarcoma newly diagnosed in approximately 60 persons a year in the European Union - as an exemplar case showing challenges in development despite being potentially relevant for classes of agents. We discuss some possible approaches for addressing such challenges, especially focussing on constructive collaboration between academic groups, patients and advocates, drug manufacturers, and regulators to optimise drug development in ultra-rare cancers. This article, written by various European stakeholders, proposes a way forward to ultimately get better options for patients with ultra-rare cancers.

There is no satisfactory explanation for the sex-related differences in the incidence of many diseases and this is also true of Alzheimer\'s disease (AD), where females have a higher lifetime risk of developing the disease and make up about two thirds of the AD patient population. The importance of understanding the cause(s) that account for this disproportionate distribution cannot be overestimated, and is likely to be a significant factor in the search for therapeutic strategies that will combat the disease and, furthermore, potentially point to a sex-targeted approach to treatment. This review considers the literature in the context of what is known about the impact of sex on processes targeted by drugs that are in clinical trial for AD, and existing knowledge on differing responses of males and females to these drugs. Current knowledge strongly supports the view that trials should make assessing sex-related difference in responses a priority with a focus on exploring the sex-stratified treatments.