Trial Sponsors Research Articles

Regulatory and Legal Regulation of the Organization and Conduct of Clinical Trials at the International Level to Guarantee Patient Safety

Clinical trials (CT) at the international level with human participation are necessarily subject to clear and comprehensive international ethical standards in approved documents that have been in force since 1964, in order to protect the human right to health and their safety. Since then, numerous regulatory documents in the field of CT have been developed in the world, which are based on the study of previous experience in compliance, primarily with patient safety rules, and are also constantly updated to include regulatory and organizational technologies in response to the challenges of the time or requests of society. The regulatory and legal documents on the conduct of clinical trials, which are given in the review article, are directive documents for many countries, even if a country did not participate in their development, in particular for Ukraine. The participation of the World Health Organization (WHO) is highlighted in many methodological materials for the possibility of implementing directives in WHO member countries, which indicates its leading position in public health research and interest in safety control for a person participating in clinical trials and patients. WHO combines partnerships of state bodies with intergovernmental bodies and non-governmental organizations providing medical care, foundations, clinical trials sponsors, research centers and pharmaceutical companies to achieve an effective result, as well as prevent violations of ethical norms, since research is related to health and can potentially bring participants not only benefit, but also harm. The article also highlights currently unsettled issues regarding current regulatory and legal acts that do not provide detailed formalization, and the solution of many problems of clinical trials remains at the discretion of the developer. International experience in regulating clinical trials shows that none of the regulatory systems is absolutely perfect, so it is necessary to constantly monitor its effectiveness and update it. Today, information on clinical trials is available only to the Regulatory Authorities of the European Union, the European Commission and national regulatory authorities, and leading clinical trial sponsor companies publish information about their studies only on their own websites, and there is no single pan-European information resource on clinical trials. It was found that the latest approach to global clinical trial regulation works in favor of leading transnational corporations by spreading patent law, which limits the right to conduct clinical trials by medium-sized and small pharmaceutical companies. The analysis of regulatory documents on the organization and conduct of clinical trials at the international level showed that the documents need to be improved and updated taking into account the challenges of the time regarding the spread of major human diseases.

WATCH: A Workflow to Assess Treatment Effect Heterogeneity in Drug Development for Clinical Trial Sponsors.

This article proposes a Workflow for Assessing Treatment effeCt Heterogeneity (WATCH) in clinical drug development targeted at clinical trial sponsors. WATCH is designed to address the challenges of investigating treatment effect heterogeneity (TEH) in randomized clinical trials, where sample size and multiplicity limit the reliability of findings. The proposed workflow includes four steps: analysis planning, initial data analysis and analysis dataset creation, TEH exploration, and multidisciplinary assessment. The workflow offers a general overview of how treatment effects vary by baseline covariates in the observed data and guides the interpretation of the observed findings based on external evidence and the best scientific understanding. The workflow is exploratory and not inferential/confirmatory in nature but should be preplanned before database lock and analysis start. It is focused on providing a general overview rather than a single specific finding or subgroup with a differential effect.

Data Monitoring Committee Reports: Telling the Data's Story.

A Data Monitoring Committee (DMC) plays a pivotal role in monitoring participant safety and efficacy and overseeing the integrity of clinical trials. DMCs accomplish this mission by periodically reviewing accumulating data to assess benefits and harms of interventions in ongoing studies and making subsequent recommendations regarding future clinical trial conduct to the trial sponsor. Reports summarizing data from the clinical trial are prepared for the DMC by statistical and data analysis centers to inform DMC decision-making. In practice however, these reports are often disorganized, complex, and provide overwhelming detail yet insufficient information, that hinders accurate and efficient interpretation of interim data. This review paper delves into the nuances of preparing effective DMC reports, highlighting the importance of simplicity, clarity, and thoughtful relevance in data presentation. We discuss structured approaches for preparing closed reports, which deal with sensitive and sometimes messy interim data, and underscore the use of visual summaries and narrative elements that enhance comprehension and facilitate efficient assessments of trial data. The paper outlines key principles for preparing DMC reports and provides practical guidance on their structure. Ultimately, this guidance seeks to ensure that the data's story is clearly and efficiently conveyed to facilitate the DMC decision-making process.

SiteRx AI‐Enabled Clinical Intelligence Platform Delivers Superior Amyloid PET Conversion in Early Alzheimer’s Disease (AD) Trial

AbstractBackgroundAccurate participant selection is pivotal for the success of Alzheimer’s Disease (AD) clinical trials, particularly in studies requiring confirmation of amyloid plaque presence via PET scans. SiteRx’s AI platform, InclusionAI, enabled 2.7x higher amyloid PET pass rates1 compared to other sources, delivering a significant enrollment contribution to an ongoing Phase 1 study in Early AD (the “Study”).MethodSiteRx democratizes access to clinical research via the largest neuro focused real world data network in the US. The SiteRx AI‐enabled process leverages structured and unstructured data from longitudinal health records and relevant data against trial inclusion/exclusion criteria to match candidates to trials. The SiteRx platform captures clinical insights and detailed recruitment funnel conversion across screening activities, including amyloid PET. This research compares outcomes between the SiteRx platform and all other study recruitment sources, including site databases and central advertising campaigns.ResultSiteRx patients demonstrated an amyloid PET pass rate of 64%, significantly exceeding the 23% pass rate from other sources—a testament to the predictive power of SiteRx AI‐enabled clinical intelligence. This effectiveness translated to savings of approximately $16,200 per patient in PET scan costs, amounting to over $3 million for the patients screened to date. Additionally, 85% of SiteRx’s PET‐eligible patients progressed to randomization, reflecting a higher readiness and suitability for trial participation compared to 66% from all other sources. The cumulative benefits of SiteRx have contributed more than a full Study cohort of randomizations.ConclusionSiteRx InclusionAI platform underscores a scalable and economically potent approach to AD clinical research recruitment. Access to longitudinal medical records and other relevant data such as previous brain imaging, cognitive inventory exams (e.g. MMSE, MoCA), current medications, documented ICD codes and formal AD diagnoses drive superior amyloid PET pass rates. This data showcases how targeted, data‐driven recruitment strategies can profoundly impact AD recruitment quality, efficiency and speed for clinical trial sponsors.

Evaluating multiplicity reporting in analgesic clinical trials: An analytical review.

Analgesia trials often demands multiple comparisons to assess various treatment arms, outcomes, or repeated assessments. These multiple comparisons risk inflating the false positive rate. Multiplicity correction in recent analgesic randomized controlled trials (RCTs) remains unclear despite statistical method advancements and regulatory guidelines. Our study aimed to identify reporting inadequacies in multiple analysis adjustments and explanations to understand these deficiencies. This review analysed RCTs from the European Journal of Pain, the Journal of Pain, and PAIN, published between January 2018 and December 2022. We included randomized, double-blind trials focusing on pain outcomes. Data extraction, managed by three researchers using predefined criteria, included trial characteristics, multiplicity presence, and correction methods. Descriptive statistical analyses included Fisher's exact, and Holm method for multiple comparisons. Out of 112 articles, 48 pre-specified a primary analysis plan. Multiple analyses were observed in 65 articles, with 60% adjusting for all comparisons, primarily using the Bonferroni method. Compared with previous studies, no significant changes in multiplicity correction practices were noted when stratified by trial type, size, and sponsor. The study reveals a persistent reliance on multiple comparisons in analgesic clinical trials without a corresponding increase in multiplicity corrections emphasizing a need for enhanced reporting and implementation of statistical adjustments. We acknowledge limitations in categorizing studies, the use of a surrogate for the trial stage, and sourcing data from journal webpages rather than a database. This study flags inadequate reporting on multiplicity correction in analgesic trials, stressing the risk of false positives and the urgent need for enhanced reporting to boost reproducibility.

The state of individual participant data sharing for the highest-revenue medicines.

Amid growing emphasis from pharmaceutical companies, advocacy groups, and regulatory bodies for sharing of individual participant data, recent audits reveal limited sharing, particularly for high-revenue medicines. Therefore, this study aimed to assess the individual participant data-sharing eligibility of clinical trials supporting the Food and Drug Administration approval of the top 30 highest-revenue medicines for 2021. A cross-sectional analysis was conducted on 316 clinical trials supporting approval of the top 30 revenue-generating medicines of 2021. The study assessed whether these trials were eligible for individual participant data sharing, defined as being publicly listed on a data-sharing platform or confirmed by the trial sponsors as in scope for independent researcher individual participant data investigations. Information was gathered from various sources including ClinicalTrials.gov, the European Union Clinical Trials Register, and PubMed. Key factors such as the trial phase, completion dates, and the nature of the data-sharing process were also examined. Of the 316 trials, 201 (64%) were confirmed eligible for sharing, meaning they were either publicly listed on a data-sharing platform or confirmed by the trial sponsors as in scope for independent researcher individual participant data investigations. A total of 102 (32%) were confirmed ineligible, and for 13 (4%), the sponsor indicated that a full research proposal would be required to determine eligibility. The analysis also revealed a higher rate of individual participant data sharing among companies that utilized independent platforms, such as Vivli, for managing their individual participant data-sharing process. Trials not marked as completed had significantly lower eligibility for individual participant data sharing. This study highlights that a substantial portion of trials for top revenue-generating medicines are eligible for individual participant data sharing. However, challenges persist, particularly for trials that are marked as ongoing and for trials where the sharing processes are managed internally by pharmaceutical companies. Data-sharing rates could be improved by adopting open-access individual participant data-sharing models or using independent platforms. Standardizing policies to facilitate immediate individual participant data availability for approved medicines is necessary.

Diversity Action Plans in Clinical Trials

This Viewpoint discusses the US Food and Drug Administration’s upcoming mandate on diversity actions plans for trial sponsors and the importance of developing accountability mechanisms to monitor those plans.

Data quality assessment of interventional trials in public trial databases

ObjectiveHigh-quality data entry in clinical trial databases is crucial to the usefulness, validity, and replicability of research findings, as it influences evidence-based medical practice and future research. Our aim is to assess the quality of self-reported data in trial registries and present practical and systematic methods for identifying and evaluating data quality. Study Design and SettingWe searched ClinicalTrials.Gov (CTG) for interventional total knee arthroplasty (TKA) trials between 2000 and 2015. We extracted required and optional trial information elements and used the CTG's variables' definitions. We performed a literature review on data quality reporting on frameworks, checklists, and overviews of irregularities in healthcare databases. We identified and assessed data quality attributes as follows: consistency, accuracy, completeness, and timeliness. ResultsWe included 816 interventional TKA trials. Data irregularities varied widely: 0%–100%. Inconsistency ranged from 0% to 36%, and most often nonrandomized labeled allocation was combined with a “single-group” assignment trial design. Inaccuracy ranged from 0% to 100%. Incompleteness ranged from 0% to 61%; 61% of finished TKA trials did not report their outcome. With regard to irregularities in timeliness, 49% of the trials were registered more than 3 months after the start date. ConclusionWe found significant variations in the data quality of registered clinical TKA trials. Trial sponsors should be committed to ensuring that the information they provide is reliable, consistent, up-to-date, transparent, and accurate. CTG's users need to be critical when drawing conclusions based on the registered data. We believe this awareness will increase well-informed decisions about published articles and treatment protocols, including replicating and improving trial designs.

Integrating liver endpoints in clinical trials of cardiovascular and kidney disease.

The intersection of cardiovascular disease, metabolic disorders and chronic kidney disease represents a complex clinical picture challenging healthcare systems worldwide. Metabolic-dysfunction-associated steatotic liver disease (MASLD) often manifests sequentially or concomitantly with these diseases, and may share underlying mechanisms and risk factors. Growing evidence suggests that new therapies could have benefits across these diseases, but trial sponsors and investigators tend to be reluctant to include patients with comorbidities-particularly liver diseases-in clinical trials. In this Perspective, we call for inclusion of patients with MASLD and measurement of liver outcomes in cardio-kidney-metabolic trials, when data suggest mechanistically plausible benefits and liver and cardiovascular safety. We discuss the implications of this new paradigm for clinical trial design and considerations for regulatory approval. Finally, we outline the challenges to implementing such an approach and provide recommendations for future clinical trial conduct.

Human papillomavirus (HPV) trials: A cross-sectional analysis of clinical trials registries

ABSTRACT Every clinical trial must be registered in a publicly accessible trial registry before enrollment of the first participant. Prospectively registering clinical trials before enrolling participants helps to prevent unethical research misconduct from occurring, duplication of research and increases transparency in research. The aim of this study was to provide cross-sectional survey analysis of planned, ongoing and completed human papillomavirus (HPV) clinical trials conducted worldwide. We searched the International Clinical Trials Registry Platform (ICTR) for registered HPV trials on 5 March 2023. Two authors independently extracted data including name of the clinical trial registry, location of the trial, recruitment status of the trial, gender of participants, phase of the trial, and type of trial sponsor. We used Microsoft Excel to perform descriptive analysis. The search yielded 1632 trials registered between 1999 and 2023. Most of the trials were registered in ClinicalTrials.gov and were registered retrospectively. We also found that most trials were conducted in North America, in recruiting stage, and indicated “not applicable” under the phase of the trial field. Finally, most trials were sponsored by hospitals. Our study found that there are many HPV clinical trials registered in different clinical trial primary registries around the world. However, many of the trials were registered retrospectively instead of the required prospectively and some had missing fields. Therefore, there is a need for registries to promote prospective trial registration and completion of all fields during the registration process.

Targeting maternal gut microbiome to improve mental health outcomes-a pilot feasibility trial.

Perinatal depression and anxiety (PDA) is prevalent in new and expectant mothers, affecting millions of women worldwide. Those with a history of mood and anxiety disorders are at the greatest risk of experiencing PDA in a subsequent pregnancy. Current safety concerns with pharmacological treatments have led to a greater need for adjunctive treatment options for PDA. Changes in the composition of the microbiome have been associated with various diseases during pregnancy, and these changes are thought to play some role in perinatal mood disorders. While the relationship between PDA and the microbiome has not been explored, evidence suggests that nutritional interventions with fiber, fish oils, and probiotics may play a favorable role in neuropsychiatric outcomes during and after pregnancy. The primary objective of the present study is to assess the feasibility and acceptability of a combination of nonpharmacological interventions to maintain stability in pregnant women who have a history of depression and/or anxiety. This study will also aim to understand ease of recruitment and protocol adherence in this cohort. This is a single-centered, partially randomized, placebo-controlled, double-blind feasibility trial. One hundred pregnant women with a history of depression and/or anxiety/PDA will be recruited and randomized into one of four arms, which could include the following: receiving a daily dose of both investigational products and dietary counseling on increasing dietary fiber, receiving a daily dose of both investigational drugs only, receiving fish oil investigational product and placebo, and a control arm with no intervention. The study involves six study visits, all of which can be conducted virtually every 3 months from the time of enrollment. At all study visits, information on diet, mental health, physical activity, and sleep quality will be collected. Additionally, all participants will provide a stool sample at each visit. It is anticipated that pregnant women with a history of depression and anxiety will be particularly interested in partaking in this trial, resulting in favorable recruitment rates. Given the positive findings of omega-3 fatty acids (O3FAs) and probiotic supplements on mental health symptoms in nonpregnant adults, we expect a similar trend in PDA symptoms, with a low likelihood of adverse events. This study will build the foundation for larger powered studies to further contribute evidence for the efficacy of this potential preventative treatment option. This trial was registered at ClinicalTrials/gov on October 6, 2023; NCT06074250. Trial Sponsor: The Canadian College of Naturopathic Medicine, 1255 Sheppard Ave E, Toronto, ON M2K 1E2, 416-498-1255.

Gene therapy clinical trials worldwide to 2023-an update.

To date, 3,900 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. Our database brings together global information on gene therapy clinical activity from trial databases, official agency sources, published literature, conference presentations and posters kindly provided to us by individual investigators or trial sponsors. This review presents our analysis of clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of our March 2023 update, we have entries on 3,900 trials undertaken in 46 countries. We have analyzed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and which genes have been transferred. Details of the analyses presented, and our searchable database are on The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at https://a873679.fmphost.com/fmi/webd/GTCT. We also provide an overview of the progress being made around the world, and discuss key trends since the previous review, namely the unprecedented increase in gene therapy clinical trial activity, including the implementation of genome editing technology with the potential to transform the field moving forward.

FOUND Trial: randomised controlled trial study protocol for case finding of obstructive sleep apnoea in primary care using a novel device

IntroductionObstructive sleep apnoea (OSA) is a common, but underdiagnosed, sleep disorder. If untreated, it leads to poor health outcomes, including Alzheimer’s disease, cancer, cardiovascular disease and all-cause mortality. Our aim...

Pooling Alzheimer's disease clinical trial data to develop personalized medicine approaches is easier said than done: A proof-of-principle study and call to action.

Pooling data from past Alzheimer's disease clinical trials may help identify subgroups most likely to benefit from specific treatments and may help inform future trial design.Accessing past trial datasets is complicated, frustrating the field's communal effort to find the best treatments for the right individuals.We urge trial sponsors and the academic research community to remove data access barriers and improve collaboration through practicing open science and harmonizing outcome measures.

Determining the extent and frequency of on-site monitoring: a bayesian risk-based approach

BackgroundOn-site monitoring is a crucial component of quality control in clinical trials. However, many cast doubt on its cost-effectiveness due to various issues, such as a lack of monitoring focus that could assist in prioritizing limited resources during a site visit. Consequently, an increasing number of trial sponsors are implementing a hybrid monitoring strategy that combines on-site monitoring with centralised monitoring. One of the primary objectives of centralised monitoring, as stated in the clinical trial guidelines, is to guide and adjust the extent and frequency of on-site monitoring. Quality tolerance limits (QTLs) introduced in ICH E6(R2) and thresholds proposed by TransCelerate Biopharma are two existing approaches for achieving this objective at the trial- and site-levels, respectively. The funnel plot, as another threshold-based site-level method, overcomes the limitation of TransCelerate’s method by adjusting thresholds flexibly based on site sizes. Nonetheless, both methods do not transparently explain the reason for choosing the thresholds that they used or whether their choices are optimal in any certain sense. Additionally, related Bayesian monitoring methods are also lacking.MethodsWe propose a simple, transparent, and user-friendly Bayesian-based risk boundary for determining the extent and frequency of on-site monitoring both at the trial- and site-levels. We developed a four-step approach, including: 1) establishing risk levels for key risk indicators (KRIs) along with their corresponding monitoring actions and estimates; 2) calculating the optimal risk boundaries; 3) comparing the outcomes of KRIs against the optimal risk boundaries; and 4) providing recommendations based on the comparison results. Our method can be used to identify the optimal risk boundaries within an established risk level range and is applicable to continuous, discrete, and time-to-event endpoints.ResultsWe evaluate the performance of the proposed risk boundaries via simulations that mimic various realistic clinical trial scenarios. The performance of the proposed risk boundaries is compared against the funnel plot using real clinical trial data. The results demonstrate the applicability and flexibility of the proposed method for clinical trial monitoring. Moreover, we identify key factors that affect the optimality and performance of the proposed risk boundaries, respectively.ConclusionGiven the aforementioned advantages of the proposed risk boundaries, we expect that they will benefit the clinical trial community at large, in particular in the realm of risk-based monitoring.

Trends in phase 1 oncology clinical trials across Australia; Analysis of ClinicalTrials.gov 2012-2022.

Phase 1 oncology trials provide access to new therapies and may improve cancer outcomes. Phase 1 trials conducted in the Asian-Pacific region are increasing at a faster rate than the global trend. This study aimed to describe the changing landscape of phase 1 oncology trials in Australia in the last decade. This cross-sectional study reviewed phase 1 oncology trials registered on ClinicalTrials.gov conducted in Australia. Phase 1 trials were included for analysis if they enrolled adults with solid organ malignancies, used at least one systemic agent, and were first registered between January 1, 2012, and December 31, 2022. The number of trials, site locations, sponsor type, and drug class were analyzed using descriptive statistics. Over the 10-year period, ClinicalTrials.gov included 493 phase 1 clinical trials across 71 Australian sites. Most sites were in metropolitan locations; in Melbourne, trials were concentrated within selected sites, while in Sydney, trials were spread across a larger number of sites. The number of phase 1 trials per annum increased from 18 in 2012 to 75 in 2022. Since 2020, emerging biopharmaceutical companies have become the predominant sponsor type, a trend that is also seen globally. While most trial sponsors were North American (42%), there was increasing representation from Asian sponsors over the 10-year period (6% in 2012 to 39% in 2022). Immunomodulatory (45%) and targeted approaches (44%) accounted for most drug classes used alone or in combination. There are an increasing number of phase 1 trials conducted within Australia. Sponsors of phase 1 trials are increasingly from Asian countries and are more likely to be emerging biopharmaceutical companies.

Évaluation des dépenses du circuit des produits de santé dans le cadre d’études institutionnelles – Étude de cas au CHU de Toulouse

Clinical research faces complex and unpredictable budgetary challenges, despite its central role in the development of healthcare products. This retrospective study examines the estimated and actual costs of 13 trials managed by the Clinical Trials Coordinating Pharmacy at the University Hospital of Toulouse. It aims to assess the accuracy of estimates, identify trial-influencing events and identify budget adjustment variables. The results show that only two of the 13 studies stay within their initial estimates, with most exceeding their projected margins. Costs vary by area, with shipping and packaging in particular exceeding the initial budget, while distribution costs are more accurately estimated. Several factors influence costs, including study duration, centre locations, number of enrolments, product stability and protocol amendments. Extending the study duration leads to increased costs in all areas, while reducing the number of inclusions tends to be in line with the original budget. In conclusion, budget management in clinical trials is complex due to numerous influencing variables. Careful planning and consideration of the specifics of each trial are crucial for more accurate estimates and budget adherence. This study enhances the understanding of the financial challenges faced by institutional sponsors of clinical trials and contributes to the refinement of budgeting methods for future clinical trials.

Evaluating speaker gender in scientific sessions at ASCO and ASCO GI (2019-2023).

9009 Background: Gender disparities exist in medicine, including academic and medical society leadership, journal editorial boards, and research teams. Women are also underrepresented in clinical trial leadership and authorship, with one study reporting fewer than 10% female corresponding authors for randomized clinical trials in GI Oncology, GU oncology, and Hematology. Clinical trial leadership, subsequent podium presentations and authorship have downstream effects on promotion, reputation, and funding opportunities. We examined the gender of speakers in scientific sessions at the ASCO Annual Meeting (AM) and Gastrointestinal Symposium (ASCO GI) from 2019-2023. Methods: We examined speaker gender, role (session chair, abstract presenter, abstract discussant), speaker region (Asia, Europe, N. America), and presentation topic (colorectal cancer or non-colorectal cancer) for the ASCO AM GI scientific sessions and ASCO GI from 2019-2023. For the ASCO AM, we included GI oral abstracts and plenary sessions; for ASCO GI we included oral and rapid abstracts. Self-identified gender was not available; therefore, gender was assigned by physical appearance via ASCO video or institutional websites. Statistical analyses were performed using the two-proportions z-test with a p value <0.05 considered statistically significant. Results: 208 scientific abstracts were reviewed across both meetings over 5 years. There was a statistically significant difference in the % of men vs. women as abstract presenters (77% vs 23%, p <0.001). This did not differ when looking at ASCO and ASCO GI separately (ASCO 76% vs 24%, ASCO GI 78% vs 22%, p <0.001 for both) and was observed across all 5 years. Similarly, there was a predominance of men as abstract presenters regardless of speaker region (Asia 93%, Europe 74%, N. America 67%, p<0.001 for all) and presentation topic (CRC 76% vs 24%, non-CRC 78% vs. 22%; p <0.001 for both). The percent of men as repeat presenters for scientific abstracts was statistically higher than women (84% vs 16%, p <0.001). Importantly, there was no difference in men vs. women in the invited chair/discussant roles (51% vs 49%, p = 0.89). Conclusions: Our analysis of 5 years of scientific sessions for ASCO and ASCO GI shows a stark difference in the proportion of men vs women as abstract presenters regardless of presentation topic, region of presenter, and meeting year. Our data highlight the need for all trial sponsors to be more intentional in the selection of principal investigators and lead authors as these opportunities are critical to the promotion of women in GI Oncology and to diversifying approaches to clinical trial design and access. Our data is limited by how gender was assigned (i.e., not self-reported). Lastly, we commend ASCO on their efforts to ensure gender equity among the roles that are within their control, and we advocate for them to consider opportunities for self-identification of gender in their membership directory.

A reactogenic "placebo" and the ethics of informed consent in Gardasil HPV vaccine clinical trials: A case study from Denmark.

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. To examine Merck's scientific rationale for using a reactogenic aluminum-containing "placebo" in Gardasil HPV vaccine pre-licensure clinical trials. 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. 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. 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.

MASLD and MASH at the crossroads of hepatology trials and cardiorenal metabolic trials.

Steatotic liver disease (SLD) is a worldwide public health problem, causing considerable morbidity and mortality. Patients with SLD are at increased risk for major adverse cardiovascular (CV) events, type 2 diabetes mellitus and chronic kidney disease. Conversely, patients with cardiometabolic conditions have a high prevalence of SLD. In addition to epidemiological evidence linking many of these conditions, there is evidence of shared pathophysiological processes. In December 2022, a unique multi-stakeholder, multi-specialty meeting, called MOSAIC (Metabolic multi Organ Science Accelerating Innovation in Clinical Trials) was convened to foster collaboration across metabolic, hepatology, nephrology and CV disorders. One of the goals of the meeting was to consider approaches to drug development that would speed regulatory approval of treatments for multiple disorders by combining liver and cardiorenal endpoints within a single study. Non-invasive tests, including biomarkers and imaging, are needed in hepatic and cardiorenal trials. They can be used as trial endpoints, to enrich trial populations, to diagnose and risk stratify patients and to assess treatment efficacy and safety. Although they are used in proof of concept and phase 2 trials, they are often not acceptable for regulatory approval of therapies. The challenge is defining the optimal combination of biomarkers, imaging and morbidity/mortality outcomes and ensuring that they are included in future trials while minimizing the burden on patients, trialists and trial sponsors. This paper provides an overview of some of the wide array of CV, liver and kidney measurements that were discussed at the MOSAIC meeting.