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An intricate landscape of bias permeates biomedical research. In this groundbreaking exploration the myriad sources of bias shaping research outcomes, from cognitive biases inherent in researchers to the selection of study subjects and data interpretation, are examined in detail. With a focus on randomized controlled trials, pharmacologic studies, genetic research, animal studies, and pandemic analyses, it illuminates how bias distorts the quest for scientific truth. Historical and contemporary examples vividly illustrate the impact of biases across research domains. Offering insights on recognizing and mitigating bias, this comprehensive work equips scientists and research teams with tools to navigate the complex terrain of biased research practices. A must-read for anyone seeking a deeper understanding of the critical role biases play in shaping the reliability and reproducibility of biomedical research.
This case report presents the case of a 25-year-old woman who developed ketamine addiction following a single sub-anaesthetic dose of intranasal ketamine in a pilot study investigating intranasal racemic ketamine for acute suicidality. She had a history of depression, obsessive–compulsive disorder, autism spectrum disorder and anorexia nervosa, and she had sporadically used alcohol and cannabis. Following the intervention, she reported a transient reduction in suicidal ideation but later sought illicit ketamine to recreate its calming effects on intrusive thoughts. Subsequently she also started abusing cocaine and 3-methylmethcathinone (3-MMC). Within weeks she had escalated to daily use, which led to financial distress, housing instability and a suicide attempt when access was cut off. Although she initially ceased use, she later relapsed into ketamine and cocaine addiction. This case highlights the addictive risk of ketamine, even in controlled settings. Given ketamine’s rising use in psychiatric treatment, careful screening, monitoring and awareness of addiction potential are essential. Future research should evaluate patient-specific risk factors and dosing strategies to minimise abuse liability.
People with intellectual disability experience substantial health inequities, including higher multimorbidity, increased healthcare utilisation and markedly reduced life expectancy. High-quality research is essential to address these disparities. The National Institute for Health and Care Research (NIHR) funded Research Delivery Network provides the infrastructure/expertise/support needed to deliver NIHR-funded studies, and supports studies funded by a non-commercial/industry partner. However, the effectiveness of NIHR-funded studies versus those supported in driving impactful intellectual disability research remains unclear.
Aims
To evaluate and compare the outcomes of NIHR-funded and supported intellectual disability research.
Method
All NIHR studies (funded/supported) relating to intellectual disability (2010–2020) were identified through systematic register searches. Primary outcomes included publication rates and impact on local, national and international clinical guidelines. Data collection was supplemented with a questionnaire to chief investigators and literature searches. Quantitative analyses examined associations between funding status, study design, publication and guideline impact, whereas qualitative responses explored implementation challenges.
Results
In total, 88 projects were identified, and 42% (37/88) were NIHR-funded. Overall, 81% of studies generated at least one publication and 28% informed clinical guidelines. NIHR funding was not significantly associated with publication or guideline impact. Randomised controlled trials (RCTs) were significantly more likely to be published and more likely to influence non-UK national and international guidelines than non-RCTs. The amount of funding showed no association with impact. Qualitative findings highlighted funding constraints, staff capacity and stakeholder engagement as key determinants of implementation.
Conclusions
NIHR-funded intellectual disability research was no more likely than NIHR-supported studies to result in publications or guideline impact.
It remains unclear whether the US clinical trial ecosystem is optimized to evaluate medical interventions efficiently. This study characterizes interventional clinical trials in the USA and examines trial progress over five years.
Methods:
Using the Aggregate Analysis of ClinicalTrials.gov (AACT) database, we conducted a cross-sectional study of interventional trials initiated in 2023 and a follow-up cohort tracking five-year completion for trials started in 2018 and registered in ClinicalTrials.gov as of 05/01/2024 by sponsor and therapeutic area. Trials with at least one US site were included. Primary outcomes were enrollment, completion status, intervention type, study arm design, and plan to share individual participant data.
Results:
Over 7,500 trials met inclusion criteria for each cohort. Most trials started in 2018 (68.4%) and 2023 (62.5%) enrolled fewer than 100 participants. Median enrollment in 2023 was higher for NIH (90) than industry-sponsored (76) trials. Within five years, 60.5% of the 2018 trials were completed, with higher completion among industry (60.9%) than NIH-sponsored (54.3%) trials. In 2023, industry predominantly funded cancer studies and trials testing drug interventions, whereas the NIH prioritized mental health studies and behavioral interventions. More than one-quarter of trials used a single-group design, 72.0% did not plan to share participant-level data, and 72.6% of drug trials were early phase.
Conclusion:
Many clinical trials are small, lack a control group, and are incomplete within five years, with differences by sponsor. Given the urgent need to improve health through rigorous evidence generation, there are likely opportunities to improve the US clinical trial ecosystem.
Evidence suggests that partnerships between researchers and patient communities result in clinical trials that better reflect the patient experience, but there are few documented and successful models of such partnerships. Within the clinical research landscape, the Duchenne Muscular Dystrophy (DMD) community has emerged as a positive outlier in this regard, having engaged in a research partnership over multiple years and in the approval of several disease-modifying therapies where there were previously none.
Methodology:
The successful partnership factors observed in the DMD community were mapped onto the three levels of the Behavior Change Wheel framework. This mapping created an academic model of patient community readiness for research partnerships. The academic model was further translated into a user-friendly, pragmatic model and blueprint.
Results:
The FOCUS Model outlines the development of a research partnership from the ground up, where each theme represents an essential component of the partnership structure. Accompanying this model is a discussion guide that communities can use in meetings or workshops to assess and enhance their readiness for research partnerships.
Conclusions:
The FOCUS model and its blueprint offer generalizable approaches that other rare disease patient communities can leverage to foster effective and lasting partnerships with scientific, medical, and regulatory stakeholders. The approach proposed in this study has the potential to help both the clinical research community and rare disease patient communities overcome typical barriers to rare disease clinical development.
Meta-analysis synthesizes evidence from multiple randomized clinical trials and informs evidence-based practices across various medical domains. Recently, causally interpretable meta-analysis has been proposed and applied to treatment evaluations for target populations, requiring individual participant data (IPD). Standard meta-analysis assumes transportability or exchangeability of a (conditional) relative effect (such as relative risk or odds ratio), which may be violated when the relative effects are correlated with the baseline risks across clinical trials. In addition, the weighted average of some study-specific effect measures such as the (log) odds ratios or the (log) hazard ratios is non-collapsible and does not correspond to any target population. Furthermore, when the randomization ratios between treated versus untreated arms vary across trials, confounding bias may occur. To address these challenges, we propose a causal meta-analysis (CMA) framework using only aggregated data, enabling causally interpretable and accurate estimation for different target populations. The CMA adjusts its weights for treatment effect across various target populations, including the average treatment effect (ATE), the ATE on the treated (ATT) population, the ATE on the control (ATC) population, and the ATE in the overlap (ATO) population. Mathematically, we discover the connection between traditional meta-analysis estimators and CMAs. For example, the Mantel–Haenszel weighted meta-analysis is equivalent to the CMA with ATO.
Strategies to improve accrual and reduce barriers to cancer clinical trials participation are critical for the advancement and implementation of new treatments and processes to improve cancer patient outcomes. While researchers have identified several barriers to accrual from the perspective of health care providers and patients, mechanisms to address and alleviate these concerns are needed to increase participation and interest in clinical trials.
Methods:
A focus group of 9 people with lived experience of a cancer diagnosis were accrued randomly and provided with a hands-on research experience and educational resources about clinical trials, followed by a focused group discussion to capture perspectives and/or experiences with clinical trials. Focus groups were transcribed and analyzed via Braun & Clarke’s 6-phase reflexive thematic analysis.
Results:
Five key themes were identified as important to increase clinical trial accrual. These included a patient-centered approach, easily digestible educational resources, a personalized understanding of motivating factors, local outreach, and transparency on outcomes and progress of the work. Qualitative input also identified methods that could positively influence accrual rates.
Conclusions:
Providing participants with opportunities to see first-hand how research works and data are used was noted as an overwhelmingly positive experience that could improve clinical trial accrual rates. This work confirms several previous findings with respect to patient identified barriers to participation in clinical trials and provides support and a framework for development of knowledge translation strategies to increase awareness and knowledge of the importance of clinical research to improve health outcomes for cancer patients.
Young adults (19–24 years) commonly experience elevated rates of sleep disturbance, anxiety, and cognitive stress yet often underutilise formal mental-health services. Music therapy, binaural beats, and related auditory entrainment techniques offer accessible, non-pharmacological approaches that may enhance emotional regulation, cognition, and physiological stability.
Objective:
To systematically review interventional clinical trials published over the past decade evaluating music- and rhythm-based auditory interventions for mental-health and cognitive outcomes in young adults.
Methods:
A systematic search of PubMed/MEDLINE and PsycINFO (01 January 2015 – 01 January 2025) was conducted using the terms (music therapy OR binaural beats OR auditory entrainment) AND (mental health OR neurorehabilitation OR cognition OR anxiety OR depression). After screening 122 abstracts, 10 trials met inclusion criteria. Effect sizes (Cohen’s d) and 95% confidence intervals were extracted or estimated. Risk of bias was assessed using the Cochrane RoB-2 tool. The review protocol was registered in PROSPERO (CRD420251178490).
Results:
Interventions included bedtime music therapy, audiovisual stimulation, and binaural-beat exposure across laboratory, clinical, and rehabilitation settings. Most studies demonstrated significant or moderate improvements in at least one domain: anxiety reduction, stress physiology, mood regulation, sleep quality, or cognitive performance (standardised mean differences 0.3–0.6).
Conclusions:
Evidence suggests that music-based and binaural-beat interventions can beneficially modulate sleep, anxiety, and cognitive processes in young adults. However, heterogeneity in design and small sample sizes limit the certainty of findings. Future adequately powered randomised controlled trials should address transdiagnostic mechanisms and long-term efficacy.
Opportunities for face-to-face interaction between sponsor-side clinical research associates (CRAs) and site-side clinical research coordinators (CRCs) have decreased with remote and risk-based monitoring, potentially impeding communication and mutual understanding – key determinants of team functioning. Accordingly, we implemented a reciprocal on-site training to enhance CRA-CRC mutual understanding and evaluated its impact.
Methods:
Seventeen sponsor staff, including 11 CRAs, joined an 8-hour hospital tour with CRC-guided process simulations and discussion; conversely, 14 hospital staff, including 11 CRCs, attended a 4-hour sponsor-office visit with system demonstrations and discussion. Self-assessed understanding of counterpart workflows and impressions of the counterpart group were rated pre- and post-training on 5-point Likert scales. Free-text feedback underwent text-mining analysis. Behavioral change was surveyed 6 months later.
Results:
CRAs improved on all 9 understanding items (e.g. “flow of daily medical practice:” median score 2.0 vs. 4.0, pre- and post-training, respectively, p < 0.0001); CRCs improved on 4 of 5. Positive impressions increased and negative impressions decreased in both groups (e.g. “bright atmosphere:” median 3.0 vs. 5.0 for CRAs, p = 0.0002; 3.0 vs. 5.0 for CRCs, p = 0.0044). Text-mining revealed the specific content participants learned, which included keywords reflecting this training’s objective of enhancing mutual understanding. At 6 months, 70% of CRAs and 88% of CRCs reported changes in their work behavior.
Conclusions:
A brief, reciprocal, on-site training improved CRA–CRC mutual understanding and perceptions, with sustained self-reported behavioral changes in work practices. From a team science perspective, such practical training may strengthen sponsor-site communication and collaboration.
Pre-approval access rights to potentially life-preserving experimental treatment is the focus of Chapter 7. The chapter considers whether people with life-threatening conditions should have a right to access possibly life-saving experimental treatments, as embodied in right to try laws. It argues that, despite their significant shortcomings, right to try laws bolster disability rights by seeking to advance the right to life and survival of people with life-threatening conditions beyond medically assisted dying.
Recruitment and retention of populations with limited prior participation in clinical trials remains a challenge. Thus, an increased understanding of the complex factors that impede or facilitate recruitment and retention is needed. Adapting the Systems Engineering Initiative for Patient Safety (SEIPS), we developed the Systems Engineering Initiative for Participant-Centric Research (SEIPR) framework that researchers can use to develop, implement, and evaluate interventions to increase trial participation.
Methods:
We performed a non-systematic literature review using the digital databases PubMed and Google Scholar to determine factors facilitating and impeding involvement of populations with limited prior participation in clinical trials. From this literature, we developed the SEIPR framework by applying it to the context of recruitment and retention.
Results:
We organized key obstacles and evidence-based solutions into five framework components: Person, Tasks and Tools, Technology, Physical Environment, and Organizational Conditions. Common obstacles included lack of awareness of active trials by participants and healthcare providers, patient’s distance from trial centers, lack of access to traditional advertising technology, and mistrust towards investigators, among others. Solutions included promotional strategies appropriate to the regional or social context, decentralizing trials, providing communication technology to participants, partnering with trusted members from the participant’s community and primary care team, using local connections and community centers, financial incentives, and transportation solutions.
Discussion:
The SEIPR framework presents a promising tool for investigators interested in increasing participant breadth in clinical trials. Future research is needed to explore real-world applications and assess its effectiveness in recruiting and retaining broad populations.
The emerging evidence for cannabis in the management of tics in Tourette syndrome has come almost exclusively from studies in adult patients. We now have two published feasibility studies of cannabis for adolescents with Tourette syndrome. Although both readily recruited adolescent participants, there was no explicit requirement for prior trials with standard evidence-based treatments. This is of concern given the known harms of regular cannabis use in adolescents, especially the association with psychosis. Investigating cannabis as an option for tics in adolescents with Tourette syndrome is worthwhile, but a high degree of caution is warranted.
Against a backdrop of rapidly expanding health artificial intelligence (AI) development, this paper examines how the European Union’s (EU) stringent digital regulations may incentivise the outsourcing of personal health data collection to low- and middle-income countries (LMICs), fuelling a new form of AI ethics dumping. Drawing on parallels with the historical offshoring of clinical trials, we argue that current EU instruments, such as the General Data Protection Regulation (GDPR), Artificial Intelligence Act (AI Act) and Medical Devices Regulation, impose robust internal safeguards but do not prevent the use of health data collected unethically beyond EU borders. This regulatory gap enables data colonialism, whereby commercial actors exploit weaker legal environments abroad without equitable benefit-sharing. Building on earlier EU responses to ethics dumping in clinical trials, we propose legal and policy pathways to prevent similar harms in the context of AI.
Leishmaniasis is a neglected parasitic disease responsible for significant morbidity and mortality. Currently, there is no vaccine approved for clinical use. Therefore, controlling infections in infected individuals depends on interventions to prevent infected female sand flies from biting humans, treatment of clinical infections or alternative treatment methods. This review focuses on the types of vaccine developed to control leishmaniasis and which vaccines have made it through to clinical trials. It also discusses the role CRISPR technology may play in improving vaccine candidates design.
Chronic pain research studies are important for both finding new treatments and improving existing treatments for individuals with chronic pain. For clinical trials to be effective, participants need to be engaged and willing to participate in treatment groups. Our research applies the theory of planned behavior (TPB) to understand how attitudes, perceived social norms, and perceived control over intervention engagement are associated with willingness to participate in interventions for chronic low back pain (CLBP).
Methods:
Adult Michigan Medicine patients were identified using electronic medical records and emailed a link to an online, cross-sectional survey. Participants who self-reported CLBP, ability to read and write in English, and consented to participate were able to complete the survey (N = 405).
Results:
The results showed more positive attitudes, positive social norms, and higher perceived behavioral control related to specific chronic low back pain interventions are associated with greater willingness to participate after controlling for demographic and pain-related characteristics.
Conclusion:
The findings suggest that TPB constructs may be useful in guiding recruitment efforts for chronic pain intervention trials.
Interest in psilocybin as a treatment for depression has risen over the past decade, fuelled by promising clinical trials and a rapidly evolving regulatory landscape. Media coverage plays a critical role in shaping public perceptions, yet little is known about how psilocybin is portrayed in global anglophone online news for the treatment of depression.
Methods:
This study examines the comprehensiveness and sentiment of English-language online news articles (n = 125) discussing psilocybin as a treatment for depression from January 2000 to May 2024. Articles were sourced from the top 30 global anglophone news outlets, assessed using a 13-item instrument for comprehensiveness, and analysed for sentiment across five thematic categories. A separate sub-analysis was completed for Irish media.
Results:
Findings indicate a significant increase in coverage over time, with 43.2% of articles published between 2022 and 2024, predominantly from the USA (68%). While 90.4% of articles cited researchers, fewer addressed risks (47.2%), long-term evidence (46.4%), or patient perspectives (25%). Sentiment analysis revealed a very positive sentiment across articles which was 2.27 on a scale from −5 (most negative) to + 5 (most positive) (SD 1.33), with no significant changes over the time period. Reporting on psilocybin’s onset and duration of effects increased significantly, reflecting growing clinical evidence. However, coverage remains concentrated in prominent outlets, with limited attention to patient experiences and long-term safety.
Conclusions:
These findings highlight the media’s role in shaping discourse on emerging treatments and suggest a need for more balanced reporting to align public understanding with scientific evidence. This study provides a foundation for future research on media portrayals of psilocybin and implications for public perception and policy.
There are currently no disease-modifying therapies for the frontotemporal dementias (FTD), but there are ways to enhance the lives of patients and their families by targeting the symptoms and stressors that arise. Accurate diagnosis and education are important for patients and families, and safety measures are necessary to prevent harm. Advanced care planning and caregiver support are critical for a chronic disease. Non-pharmacological treatments, such as behavioral management and a multidisciplinary approach, are recommended. The pharmacotherapy options include antidepressants, antipsychotics, and other medications, but there is limited evidence to support their use. This chapter provides information on clinical trials in FTD, including patient selection and enrollment, trial design, and potential disease-modifying treatments being explored. Further research is needed to develop effective treatments for FTD.