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BACKGROUND: The research community has historically failed to enroll diverse groups of participants in dementia clinical trials. A unique aspect of dementia care research is the requirement of a study partner, who can attest to the care recipients clinical and functional capacity. The aim of this study is to assess racial and ethnic differences and the importance of various trial considerations among dementia caregivers, in their decision to participate in clinical research as study partners. METHOD: We embedded a vignette about a hypothetical dementia clinical trial in a nationally representative survey of U.S. dementia caregivers, oversampling non-Hispanic Black and Hispanic caregivers. Dementia caregivers were asked about their willingness to participate in the trial with their care recipient and rated the importance of nine considerations in hypothetical decisions to participate. Caregiver demographic characteristics were analyzed as predictors of trial participation in a base demographic model. In a second reasons model caregiver demographic characteristics and the rated importance of the nine considerations were separately analyzed as predictors; both models used survey-weighted logistic regression. RESULT: The sample consisted of 610 dementia caregivers, including 156 non-Hispanic Black and 122 Hispanic caregiver participants. In the base demographic model, hypothetical trial participation was negatively associated with older caregiver age (OR (odds ratio) = 0.72, p =

PurposeTo evaluate functional and structural assessments as endpoints for clinical trials for USH2A-related retinal degeneration.MethodsPeople with biallelic disease-causing variants in USH2A, visual acuity ≥ 20/80, and visual field ≥ 10° diameter were enrolled in a 4-year, natural history study. Participants underwent static perimetry, microperimetry, visual acuity, fullfield stimulus testing (FST), and optical coherence tomography annually. Rates of change estimated from mixed-effects linear models and percentages of eyes with changes exceeding the coefficient of repeatability (CoR) or thresholds conforming with U.S. Food and Drug Administration (FDA) guidelines were evaluated.ResultsRates of change were generally more sensitive to change than proportions of eyes exceeding a threshold such as the CoR. Baseline ellipsoid zone area ≥ 3 mm2 was necessary to detect change. Mean sensitivity and volumetric hill of vision measures on static perimetry had similar properties and were the most sensitive to changes of the continuous measures. The highest 4-year proportions of eyes exceeding the CoR were from FST testing (47%) and microperimetry (32%). Specification of loci as functional transition points (FTPs) resulted in 45% (static perimetry) and 46% (microperimetry) at 4 years, meeting FDA guidelines for progression.ConclusionsRate of change of mean sensitivity on static perimetry was a sensitive perimetric continuous measure. Percentages of within-eye change were largest with FST testing and microperimetry. FTPs appear to be particularly sensitive to change. These results affect clinical trial design for USH2A-related retinal degeneration.Translational relevanceAnalyses of natural history data from the Rate of Progression in USH2A-Related Retinal Degeneration (RUSH2A) study can inform eligibility criteria and endpoints for clinical trials.

BackgroundMethodological limitations affect a significant number of oncology and haematology trials, raising concerns about the applicability of their results. For example, a suboptimal control arm or limited access to best care upon progression may skew the trial results toward a benefit in the experimental arm. Beyond the fact that such limitations do not prevent drugs reaching the market, other assessment tools, such as those developed by professional societies-ESMO-MCBS and ASCO Value Framework-do not integrate these important shortcomings.MethodsWe propose creating a novel framework with the scope of assessing registration cancer clinical trials in haematology and oncology (randomized or single arm)-that is trials leading to a marketing authorization. The main steps of the methods are (1) assembling a scientific board; (2) defining the scope, goal and methods through pre-specified, pre-registered and protocolized methodology; (3) preregistration of the protocol; (4) conducting a scoping review of limitations and biases affecting oncology trials and assessing existing scores or methods; (5) developing a list of features to be included and assessed within the framework; (6) assessing each feature through a questionnaire sent to highly cited haematologists and oncologists involved in clinical trials; and (7) finalizing the first version of framework.ResultsNot applicable.ConclusionsOur proposal emerged in response to the lack of consideration for key limitations in current trial assessments. The goal is to create a framework specifically designed to assess single trials leading to marketing authorization in the field of oncology and haematogy.

BACKGROUND AND OBJECTIVE: Upadacitinib is indicated for diseases affecting persons of childbearing potential including rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, atopic dermatitis, Crohns disease, and ulcerative colitis; however, teratogenicity was observed in animal studies. Given the potential for human fetal risk, pregnancy avoidance measures were required during clinical trials. This analysis describes pregnancy outcomes in patients exposed to upadacitinib during pregnancy. METHODS: Clinical trial and postmarketing cases of in utero exposure to upadacitinib were identified in AbbVies safety database through 25 April, 2023. Analysis of clinical trial cases and postmarketing reports are presented separately; prospective and retrospectively reported pregnancy outcomes are integrated for each. Descriptive rates are presented to summarize outcomes. RESULTS: There were 128 maternal upadacitinib-exposed pregnancies with known outcomes identified; 80 and 48 pregnancies were reported in clinical trials and the postmarketing setting, respectively. In clinical trials (mean in utero exposure of 5 weeks, 3 days), live births (54%), spontaneous abortions (24%), elective terminations (21%), and ectopic pregnancy (1%) were reported. There was one report of a congenital malformation: a 35-week infant with an atrial septal defect. In postmarketing cases, live births (46%), spontaneous abortions (38%), elective terminations (15%), and ectopic pregnancy (2%) were reported. CONCLUSIONS: As the data are limited for in utero exposure to upadacitinib, definitive conclusions cannot be drawn regarding the effect of upadacitinib on pregnancy outcomes. Rates of adverse pregnancy outcomes with upadacitinib exposure were comparable to rates observed in the general population or patients with autoimmune inflammatory diseases. To date, no apparent evidence of teratogenicity exists in the analyses of human pregnancies exposed to upadacitinib during the first trimester.

Clinical trials in metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis) require histologic scoring for assessment of inclusion criteria and endpoints. However, variability in interpretation has impacted clinical trial outcomes. We developed an artificial intelligence-based measurement (AIM) tool for scoring MASH histology (AIM-MASH). AIM-MASH predictions for MASH Clinical Research Network necroinflammation grades and fibrosis stages were reproducible (κ = 1) and aligned with expert pathologist consensus scores (κ = 0.62-0.74). The AIM-MASH versus consensus agreements were comparable to average pathologists for MASH Clinical Research Network scores (82% versus 81%) and fibrosis (97% versus 96%). Continuous scores produced by AIM-MASH for key histological features of MASH correlated with mean pathologist scores and noninvasive biomarkers and strongly predicted progression-free survival in patients with stage 3 (P

UNLABELLED: A common complication of chimeric antigen receptor (CAR) T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS), which presents with encephalopathy, aphasia, inattention, somnolence, seizures, weakness, or cerebral edema. Despite its significant morbidity, there are currently no effective targeted treatments. Given the clinical similarities between ICANS and the neurological manifestations of acute hypophosphatemia, we retrospectively reviewed 499 patients treated with CD19-targeted CAR T-cell therapy across multiple clinical trials between 2015 and 2020. In addition to clinical toxicities experienced by the patients, we also interrogated the impact of serum electrolyte data and repletion of corresponding electrolyte deficiencies with ICANS incidence, severity, and duration. Hypophosphatemia was a common occurrence in CAR T-cell recipients and the only electrolyte derangement associated with a significantly higher cumulative incidence of ICANS. Moreover, phosphorus repletion in patients with hypophosphatemia was associated with significantly decreased ICANS incidence and duration. Hypophosphatemia was uniquely associated with encephalopathy neurological adverse events, which also showed the strongest positive correlation with both ICANS and cytokine release syndrome severity. These findings suggest that serum phosphorus could be a reliable biomarker for ICANS, and expeditious, goal-directed phosphorus repletion in response to serum hypophosphatemia could be a safe, inexpensive, and widely available intervention for such patients. SIGNIFICANCE: Herein we show that phosphorus repletion in patients with hypophosphatemia receiving anti-CD19 chimeric antigen receptor T-cell therapeutics was associated with significantly decreased immune effector cell-associated neurotoxicity syndrome (ICANS) incidence and symptom duration. Given the significant morbidity associated with ICANS and lack of targeted interventions, hypophosphatemia may serve as both a useful biomarker and an inexpensive intervention for ICANS.

OBJECTIVES: Despite the significant disease burden due to cardiac arrest, there is a relative paucity of randomized controlled trials (RCTs) to inform definitive management. We aimed to evaluate the current scope of cardiac arrest RCTs published between 2015 and 2022. METHODS: We conducted a search in October 2023 of MEDLINE, Embase, and Web of Science for cardiac arrest RCTs. We included trials published between 2015 and 2022 enrolling human subjects suffering from non-traumatic cardiac arrest. Descriptive statistics were reported and the Mann Kendall test was used to evaluate for temporal trends in the number of trials published annually. RESULTS: We identified 1764 unique publications, 87 RCTs were included after title/abstract and full-text review. We found no significant increase in trials published annually (eight in 2015 and 16 in 2022, p = 1.0). Geographic analysis of study centers found 31 countries represented; Denmark (n = 13, 15%) and the United States (n = 9, 10%) conducted the majority of trials. Nearly all trials included adults (n = 84, 97%) and few included children (n = 9, 10%). The majority of trials focused on out-of-hospital cardiac arrest (n = 62, 71%). Thirty-eight (44%) trials used an intervention characterized as a process improvement; 28 (32%) interventions were characterized as a drug and 20 (23%) as a device. Interventions were implemented with similar frequency in the prehospital (33%) and intensive care unit (38%) setting, as well as similarly between the intra-arrest (53%) and post-arrest (46%) periods. Twenty (27%) trials selected a primary outcome of survival at ≥ 28 days. CONCLUSIONS: Publication of cardiac arrest RCTs remained constant between 2015 and 2022. We identified significant gaps including a lack of trials examining in-hospital cardiac arrest and pediatric patients.

This systematic review examines the landscape of extracellular vesicle (EV)-related clinical trials to elucidate the field's trends in clinical applications and EV-related methodologies, with an additional focus on the acknowledgement of EV subpopulations. By analysing data from public reporting repositories, we catalogued 471 EV-related clinical trials to date, with indications for over 200 diseases. Diagnostics and companion diagnostics represented the bulk of EV-related clinical trials with cancer being the most frequent application. EV-related therapeutics trials mainly utilized mesenchymal stromal cell (MSC) EVs and were most frequently used for treatment of respiratory illnesses. Ultracentrifugation and RNA-sequencing were the most common isolation and characterization techniques; however, methodology for each was not frequently reported in study records. Most of the reported characterization relied on bulk characterization of EV isolates, with only 11% utilizing EV subpopulations in their experimental design. While this may be connected to a lack of available techniques suitable for clinical implementation, it also highlights the opportunity for use of EV subpopulations to improve translational efforts. As academic research identifies more chemically distinct subpopulations and technologies for their enrichment, we forecast to more refined EV trials in the near future. This review emphasizes the need for meticulous methodological reporting and consideration of EV subpopulations to enhance the translational success of EV-based interventions, pointing towards a paradigm shift in personalized medicine.

BackgroundImmune checkpoint inhibitor (ICI) therapies have become increasingly popular treatment options for patients with cancer, even for patients in non-metastatic settings. Survival and responses have been reported for individual tumor types, but little is known about these outcomes, collectively. We sought to provide an overview of overall survival (OS) and progression-free survival (PFS) in ICI drugs tested in registration trials.MethodsIn a cross-sectional analysis of US FDA oncology ICI drug approvals (2011-2023), we searched for supporting ICI registration trials. We characterized these trials, regarding differences in median OS and PFS between patients in intervention and control arm participants in ICI registration trials; percentage of patients who receive ICI crossover; and whether there is correlation between the percentage of crossover and differences in OS or PFS.ResultsFifty-six (54.4 %) approvals had trials that reported median OS for both intervention and control arms (median difference was 2.8 months; IQR: 2.2 to 5.0 months). Sixty-five (63.1 %) approvals had trials that reported PFS data for both arms (median of 0.9 months; IQR: -0.2 to 3.0 months). Subsequent therapy was common (median=18.9 %) and was significantly correlated with a higher difference in median OS in all studies with reported differences (R2 =0.15; p = 0.001).ConclusionICIs are increasingly used in the treatment of cancer, yet the median OS improvement is modest, and many ICIs have not been tested for OS benefit. OS is the outcome most meaningful for patients, and drug regulation should require better testing and reporting of these data.

PURPOSE: Novel interventions for the prevention or treatment of acute kidney injury (AKI) are currently lacking. To facilitate the evaluation and adoption of new treatments, the use of the most appropriate design and endpoints for clinical trials in AKI is critical and yet there is little consensus regarding these issues. We aimed to develop recommendations on endpoints and trial design for studies of AKI prevention and treatment interventions based on existing data and expert consensus. METHODS: At the 31st Acute Disease Quality Initiative (ADQI) meeting, international experts in critical care, nephrology, involving adults and pediatrics, biostatistics and people with lived experience (PWLE) were assembled. We focused on four main areas: (1) patient enrichment strategies, (2) prevention and attenuation studies, (3) treatment studies, and (4) innovative trial designs of studies other than traditional (parallel arm or cluster) randomized controlled trials. Using a modified Delphi process, recommendations and consensus statements were developed based on existing data, with > 90% agreement among panel members required for final adoption. RESULTS: The panel developed 12 consensus statements for clinical trial endpoints, application of enrichment strategies where appropriate, and inclusion of PWLE to inform trial designs. Innovative trial designs were also considered. CONCLUSION: The current lack of specific therapy for prevention or treatment of AKI demands refinement of future clinical trial design. Here we report the consensus findings of the 31st ADQI group meeting which has attempted to address these issues including the use of predictive and prognostic enrichment strategies to enable appropriate patient selection.

BACKGROUND: Persons who speak languages other than English are underrepresented in clinical trials, likely in part because of inadequate multilevel resources. We conducted a survey of institutions affiliated with the Childrens Oncology Group (COG) to characterize current research recruitment practices and resources regarding translation and interpretation services. METHODS: In October 2022, a 20-item survey was distributed electronically to institutions affiliated with COG to assess consent practices and resources for recruiting participants who speak languages other than English to COG trials. Descriptive statistics were used to summarize responses; responses were compared by institution size and type as well as respondent role. RESULTS: The survey was sent to 230 institutions, and the response rate was 60% (n = 139). In total, 60% (n = 83) of those respondents had access to short-form consent forms. Full consent form translation was required at 50% of institutions, and 12% of institutional review boards restricted use of centrally translated consent forms. Forty-six percent (n = 64) of institutions reported insufficient funding to support translation costs; 19% (n = 26) had access to no-cost translation services. Forty-four percent (n = 61) were required to use in-person interpreters for consent discussions; the most frequently cited barrier (56%) to obtaining consent was lack of available in-person interpreters. Forty-seven percent (n = 65) reported that recruiting persons who speak languages other than English to clinical trials was somewhat or very difficult. CONCLUSIONS: Institutions affiliated with COG face resource-specific challenges that impede recruitment of participants who speak languages other than English for clinical trials. These findings indicate an urgent need to identify strategies aimed at reducing recruitment barriers to ensure equitable access to clinical trials.

Alcohol use disorder (AUD) is a debilitating disorder, yet currently approved pharmacotherapies to treat AUD are under-utilized. The three medications approved by the US Food and Drug Administration (FDA) for the indication of AUD are disulfiram, acamprosate, and naltrexone. The current landscape of pharmacotherapies for AUD suggests opportunities for improvement. Clinical trials investigating novel pharmacotherapies for AUD traditionally use abstinence-based drinking outcomes or no heavy drinking days as trial endpoints to determine the efficacy of pharmacotherapies. These outcomes are typically measured through patient self-report endorsements of their drinking. Apart from these traditional outcomes, there have been recent developments in novel endpoints for AUD pharmacotherapies. These novel endpoints include utilizing the World Health Organization (WHO) risk drinking level reductions to promote a harm-reduction endpoint rather than an abstinence-based endpoint. Additionally, in contrast to patient self-report measurements, biological markers of alcohol use may serve as objective endpoints in AUD pharmacotherapy trials. Lastly, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) definition of recovery from AUD and patient-oriented outcomes offer new frameworks to consider endpoints associated with more than alcohol consumption itself, such as the provider-patient experiences with novel pharmacotherapies. These recent developments in new endpoints for AUD pharmacotherapies offer promising future opportunities for pharmacotherapy development, so long as validity and reliability measures are demonstrated for the endpoints. A greater breadth of endpoint utilization may better capture the complexity of AUD symptomatology.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a progressive immune-mediated liver disease, for which no medical therapy has been shown to slow disease progression. However, the horizon for new therapies is encouraging, with several innovative clinical trials in progress. Despite these advancements, there is considerable heterogeneity in the outcomes studied, with lack of consensus as to what outcomes to measure, when to measure and how to measure. Furthermore, there has been a paradigm shift in PSC treatment targets over recent years, moving from biochemistry-based endpoints to histological assessment of liver fibrosis, imaging-based biomarkers and patient-reported outcome measures. The abundance of new interventional trials and evolving endpoints pose opportunities for all stakeholders involved in evaluating novel therapies. To this effect, there is a need to harmonise measures used in clinical trials through the development of a core outcome set (COS). METHODS AND ANALYSIS: Synthesis of a PSC-specific COS will be conducted in four stages. Initially, a systematic literature review will be performed to identify outcomes previously used in PSC trials, followed by semistructured qualitative interviews conducted with key stakeholders. The latter may include patients, clinicians, researchers, pharmaceutical industry representatives and healthcare payers and regulatory agencies, to identify additional outcomes of importance. Using the outcomes generated from the literature review and stakeholder interviews, an international two-round Delphi survey will be conducted to prioritise outcomes for inclusion in the COS. Finally, a consensus meeting will be convened to ratify the COS and disseminate findings for application in future PSC trials. ETHICS AND DISSEMINATION: Ethical approval has been granted by the East Midlands-Leicester Central Research Ethics Committee (Ref: 24/EM/0126) for this study. The COS from this study will be widely disseminated including publication in peer-reviewed journals, international conferences, promotion through patient-support groups and made available on the Core Outcomes Measurement in Effectiveness Trials (COMET) database. TRIAL REGISTRATION NUMBER: 1239.

PurposeIn 2013, afatinib was approved for non-small-cell lung cancer with subsequent indication expansion. We investigated published afatinib clinical trials to assess risk and benefit profiles for the drug in its approved indication of non-small-cell lung cancer as well as in off-label uses. Previous literature demonstrates excessive patient burden and limited benefit as afatinib has spread into more indications. A trial analysis is needed to establish efficacy and risk.MethodsIn this investigation, we screened literature databases and clinical trial registries for trials of afatinib as monotherapy or in combination interventions for cancer treatment. We extracted participant demographics, adverse event characteristics, as well as clinical and surrogate endpoints for each trial. Studies were deemed positive, negative, or indeterminate based on their achieving of primary endpoints as well as their safety.ResultsOur search yielded 2444 articles; we excluded 2352 articles for a final inclusion of 92 trials of 8859 patients. Our sample had 49 (53%) positive trials, 27 (29%) negative trials, and 16 (17%) indeterminate trials. The most common off-label indications for afatinib were breast cancer and squamous cell carcinoma of head and neck. The median OS for all trials was 8.4 months, median PFS 3.4 months, and the total ORR was 29.6%. Our study found that trials performed in disease states beyond the initial indications were largely negative with little patient benefit. The adverse events within our trial sample appear to be in line with expectations for toxicity.ImplicationsThese results are consistent with other studies that present similar findings, such as in Carlisle et al which indicate limited efficacy in nonapproved indications. Future trials should keep this potential evidence and patient burden in mind before initiation of those trials. This study contributes to the understanding of afatinib's risk-benefit profile across many clinical applications.

The articles in the June issue serve not only to inform senior care pharmacists on the importance of evidence-based approaches to reduce unnecessary aspirin use, but they also underscore the urgent need for the large and rapid increase in older adult representation in clinical trials and clinical research in general. A striking analysis performed in the United States that examined the trial populations used for Medicare coverage determinations found that while the average age of a Medicare enrollee was 70.8 years old (74.7 years old for older Medicare participants), the average age of the clinical trial population patients used in technology assessments for Medicare coverage determinations was 60.1 years. Hence, the US Medicare system, one of the largest national health care purchasers for older patients in the world, has relied on non-representative data to inform medical coverage decisions.

BACKGROUND: Older adults with multimorbidity are under-represented in clinical drug trials. Their inclusion will not increase unless they are willing and able to participate. Data on motivators and barriers to participation in trials of new medications of older adults with multimorbidity are needed. METHODS: Cross-sectional internet and telephone survey of a nationally representative sample of adults ≥65 years with ≥3 chronic conditions (NORC University of Chicago Amerispeak Panel) conducted from March-April, 2023 to determine motivators and barriers to drug trial participation, described graphically and using statistics. RESULTS: Surveyed 1318 (1142 Internet, 176 phone) with mean age 72.3 ± 6.3 (SD), 52% women; race: 83% White, 10% Black or African American, 5% Hispanic or Latino, 1.1% Asian; 4.4 ± 1.9 chronic conditions (of 16 queried), taking 7.5 ± 3.3 medications. Barriers included fear of side effects (48%), taking too many medications (44%), placebo (44%), mobility (33%), bathroom needs (25%), hearing (19%), eyesight (15%), video visits (33%; higher in women, Black or African-American respondents, and those ≥80 years). Sixty-five percent would join all in-person trials, 49% would join all-video trials. Travel >1 h was difficult for 66%, most difficult for women. Trust was a concern in 25% of Black respondents. Caregiving responsibilities or lack of time were not obstacles. Participants were most likely to consider a drug trial for a problem they have (63%) versus prevention (44%) and if invited by a physician (80%) or University healthcare system (58%). Getting better care was ranked very important (79%) followed by helping others (57%). CONCLUSIONS: Major concerns of older patients with multimorbidity about participation in drug trials are potential side effects, taking too many medicines, and video visits. Physicians have the greatest influence on decisions and in-person visits are preferred. Proposed changes in trial design to increase enrollment of under-represented older adults may not align with patient-reported preferences.

Smartphone sensors are used increasingly in the assessment of ataxias. To date, there is no specific consensus guidance regarding a priority set of smartphone sensor measurements, or standard assessment criteria that are appropriate for clinical trials. As part of the Ataxia Global Initiative Digital-Motor Biomarkers Working Group (AGI WG4), aimed at evaluating key ataxia clinical domains (gait/posture, upper limb, speech and oculomotor assessments), we provide consensus guidance for use of internal smartphone sensors to assess key domains. Guidance was developed by means of a literature review and a two stage Delphi study conducted by an Expert panel, which surveyed members of AGI WG4, representing clinical, research, industry and patient-led experts, and consensus meetings by the Expert panel to agree on standard criteria and map current literature to these criteria. Seven publications were identified that investigated ataxias using internal smartphone sensors. The Delphi 1 survey ascertained current practice, and systems in use or under development. Wide variations in smartphones sensor use for assessing ataxia were identified. The Delphi 2 survey identified seven measures that were strongly endorsed as priorities in assessing 3/4 domains, namely gait/posture, upper limb, and speech performance. The Expert panel recommended 15 standard criteria to be fulfilled in studies. Evaluation of current literature revealed that none of the studies met all criteria, with most being early-phase validation studies. Our guidance highlights the importance of consensus, identifies priority measures and standard criteria, and will encourage further research into the use of internal smartphone sensors to measure ataxia digital-motor biomarkers.

To accelerate and facilitate clinical trials, the Ataxia Global Initiative (AGI) was established as a worldwide research platform for trial readiness in ataxias. One of AGIs major goals is the harmonization and standardization of outcome assessments. Clinical outcome assessments (COAs) that describe or reflect how a patient feels or functions are indispensable for clinical trials, but similarly important for observational studies and in routine patient care. The AGI working group on COAs has defined a set of data including a graded catalog of COAs that are recommended as a standard for future assessment and sharing of clinical data and joint clinical studies. Two datasets were defined: a mandatory dataset (minimal dataset) that can ideally be obtained during a routine clinical consultation and a more demanding extended dataset that is useful for research purposes. In the future, the currently most widely used clinician-reported outcome measure (ClinRO) in ataxia, the scale for the assessment and rating of ataxia (SARA), should be developed into a generally accepted instrument that can be used in upcoming clinical trials. Furthermore, there is an urgent need (i) to obtain more data on ataxia-specific, patient-reported outcome measures (PROs), (ii) to demonstrate and optimize sensitivity to change of many COAs, and (iii) to establish methods and evidence of anchoring change in COAs in patient meaningfulness, e.g., by determining patient-derived minimally meaningful thresholds of change.

BACKGROUNDThe inclusion of adolescents in TB drug trials is essential for the development of safe, child-friendly regimens for the prevention and treatment of TB. TB Trials Consortium Study 31/AIDS Clinical Trials Group A5349 (S31/A5349) enrolled adolescents as young as 12 years old. We assessed investigator and coordinator described facilitators and barriers to adolescent recruitment, enrollment, and retention.METHODSInterviews were conducted with six investigators from sites that enrolled adolescent participants and six investigators from non-enrolling sites. Additionally, two focus groups were conducted with study coordinators from enrolling sites and two focus groups with non-enrolling sites. Discussions were transcribed, analyzed, summarized, and summaries were reviewed by Community Research Advisors Group members and research group representatives for content validity.RESULTSInvestigators and coordinators attributed the successful enrollment of adolescents to the establishment and cultivation of external partnerships, flexibility to accommodate adolescents' schedules, staff engagement, recruitment from multiple locations, dedicated recruitment staff working onsite to access potential participants, creation of youth-friendly environments, and effective communications. Non-enrolling sites were mainly hindered by regulations. Suggestions for improvement in future trials focused on study planning and site preparations.CONCLUSIONProactive partnerships and collaboration with institutions serving adolescents helped identify and reduce barriers to their inclusion in this trial..

OBJECTIVE: This study aims to evaluate published clinical trials of ramucirumab to assess the risk/benefit profile and burden over time for patients. BACKGROUND: The burden of oncologic drug development on patients paired with increasing clinical trial failure rates emphasizes the need for reform of drug development. Identifying and addressing patterns of excess burden can guide policy, ensure evidence-based protections for trial participants, and improve medical decision-making. METHODS: On May 25, 2023 a literature search was performed on Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov for clinical trials using ramucirumab as monotherapy or in combination with other interventions for cancer treatment. Authors screened titles and abstracts for potential inclusion in a masked, duplicate fashion. Following data screening, data was extracted in a masked, duplicate fashion. Trials were classified as positive when meeting their primary endpoint and safety, negative or indeterminate. RESULTS: Ramucirumab was initially approved for gastric cancer but has since been tested in 20 cancers outside of its FDA approved indications. In our analysis of ramucirumab trials, there were a total of 10,936 participants and 10,303 adverse events reported. Gains in overall survival and progression-free survival for patients were 1.5 and 1.2 months, respectively. FDA-approved indications have reported more positive outcomes in comparison to off-label indications. CONCLUSION: We found that FDA-approved indications for ramucirumab had better efficacy outcomes than non-approved indications. However, a concerning number of adverse events were observed across all trials assessed. Participants in ramucirumab randomized controlled trials saw meager gains in overall survival when evaluated against a comparison group. Clinicians should carefully weigh the risks associated with ramucirumab therapy given its toxicity burden and poor survival gains.

Drug development is complex and costly. Clinical trial participants take on risks, making it essential to maximize trial efficiency and maintain participant safety. Identifying periods of excessive burden during drug development can inform trial design, ensure patient benefit and prevent harm. This study aims to examine all published clinical trials for cabozantinib to assess patient benefit and burden over time. We conducted a retrospective cross-sectional review of interventional clinical trials of cabozantinib for solid cancer treatment. We searched PubMed/MEDLINE, Embase, Cochrane (CENTRAL) and ClinicalTrials.gov. We extracted adverse event rates, median progression-free survival (PFS), median overall survival and objective response rate (ORR) for each included trial. We calculated frequencies of trial characteristics, cumulative grade 3-5 adverse event rates and cumulative ORRs. Out of 1735 studies, 54 publications were included that involved 6372 participants and 21 cancers. Of the 54 studies in our sample, 31 (57.41%) were single-arm trials and 23 (42.60%) had negative results. Trials among and within various indications had conflicting results over time. Cumulative risk to participants increased over time, and clinical benefit decreased. The findings suggest that the risk profile of cabozantinib increased from 2011 to 2016 and has remained elevated but stable while benefit has decreased over time. The use of non-randomized and single-arm trials is concerning, and more methodologically rigorous trials are needed. The results of trials for different indications are inconsistent, and empirical administration may reduce the drug's efficacy.

Health-related social needs are prevalent among cancer patients; associated with substantial negative health consequences; and drive pervasive inequities in cancer incidence, severity, treatment choices and decisions, and outcomes. To address the lack of clinical trial evidence to guide health-related social needs interventions among cancer patients, the National Cancer Institute Cancer Care Delivery Research Steering Committee convened experts to participate in a clinical trials planning meeting with the goal of designing studies to screen for and address health-related social needs among cancer patients. In this commentary, we discuss the rationale for, and challenges of, designing and testing health-related social needs interventions in alignment with the National Academy of Sciences, Engineering, and Medicine 5As framework. Evidence for food, housing, utilities, interpersonal safety, and transportation health-related social needs interventions is analyzed. Evidence regarding health-related social needs and delivery of health-related social needs interventions differs in maturity and applicability to cancer context, with transportation problems having the most maturity and interpersonal safety the least. We offer practical recommendations for health-related social needs interventions among cancer patients and the caregivers, families, and friends who support their health-related social needs. Cross-cutting (ie, health-related social needs agnostic) recommendations include leveraging navigation (eg, people, technology) to identify, refer, and deliver health-related social needs interventions; addressing health-related social needs through multilevel interventions; and recognizing that health-related social needs are states, not traits, that fluctuate over time. Health-related social needs-specific interventions are recommended, and pros and cons of addressing more than one health-related social needs concurrently are characterized. Considerations for collaborating with community partners are highlighted. The need for careful planning, strong partners, and funding is stressed. Finally, we outline a future research agenda to address evidence gaps.

BackgroundNatural killer (NK) cells are cytotoxic cells capable of recognizing heterogeneous cancer targets without prior sensitization, making them promising prospects for use in cellular immunotherapy. Companion dogs develop spontaneous cancers in the context of an intact immune system, representing a valid cancer immunotherapy model. Previously, CD5 depletion of peripheral blood mononuclear cells (PBMCs) was used in dogs to isolate a CD5dim-expressing NK subset prior to co-culture with an irradiated feeder line, but this can limit the yield of the final NK product. This study aimed to assess NK activation, expansion, and preliminary clinical activity in first-in-dog clinical trials using a novel system with unmanipulated PBMCs to generate our NK cell product.MethodsStarting populations of CD5-depleted cells and PBMCs from healthy beagle donors were co-cultured for 14 days, phenotype, cytotoxicity, and cytokine secretion were measured, and samples were sequenced using the 3'-Tag-RNA-Seq protocol. Co-cultured human PBMCs and NK-isolated cells were also sequenced for comparative analysis. In addition, two first-in-dog clinical trials were performed in dogs with melanoma and osteosarcoma using autologous and allogeneic NK cells, respectively, to establish safety and proof-of-concept of this manufacturing approach.ResultsCalculated cell counts, viability, killing, and cytokine secretion were equivalent or higher in expanded NK cells from canine PBMCs versus CD5-depleted cells, and immune phenotyping confirmed a CD3-NKp46+ product from PBMC-expanded cells at day 14. Transcriptomic analysis of expanded cell populations confirmed upregulation of NK activation genes and related pathways, and human NK cells using well-characterized NK markers closely mirrored canine gene expression patterns. Autologous and allogeneic PBMC-derived NK cells were successfully expanded for use in first-in-dog clinical trials, resulting in no serious adverse events and preliminary efficacy data. RNA sequencing of PBMCs from dogs receiving allogeneic NK transfer showed patient-unique gene signatures with NK gene expression trends in response to treatment.ConclusionsOverall, the use of unmanipulated PBMCs appears safe and potentially effective for canine NK immunotherapy with equivalent to superior results to CD5 depletion in NK expansion, activation, and cytotoxicity. Our preclinical and clinical data support further evaluation of this technique as a novel platform for optimizing NK immunotherapy in dogs.

ImportanceChemotherapy agents are typically initially tested in their most promising indications; however, following initial US FDA approval, new clinical trials are often initiated in less promising indications where patients experience a worse burden-benefit ratio. The current literature on the burden-benefit profile of lenvatinib in non-FDA-approved indications is lacking.ObjectiveThis study aimed to evaluate published clinical trials of lenvatinib in order to determine the burden-benefit profile for patients over time.Evidence reviewOn 25 May 2023, we searched the Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov databases for clinical trials of lenvatinib used to treat solid cancers. Eligible articles were clinical trials, containing adult participants, published in English, and involving solid tumors. Screening and data collection took place in a masked, duplicate fashion. For each eligible study, we collected adverse event data, trial characteristics, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Trials were classified as positive when meeting their primary endpoint and safety, negative (not meeting either criteria), or indeterminate (lacking prespecified primary endpoint).FindingsExpansion of clinical trial testing beyond lenvatinib's initial FDA indication demonstrated a consistent rise in cumulative adverse events, along with a decline in drug efficacy. Lenvatinib was tested in 16 cancer indications, receiving FDA approval in 4. A total of 5390 Grade 3-5 adverse events were experienced across 6225 clinical trial participants. Expanded indication testing further demonstrated widely variable ORR (11-69%), OS (6.2-32 months), and PFS (3.6-15.7 months) across all indications. After initial FDA approval, clinical trial results in expanded indications were less likely to meet their primary endpoints, particularly among non-randomized clinical trials.Conclusion and relevanceOur paper evaluated the effectiveness of lenvatinib for its FDA-approved indications; however, expansion of clinical trials into novel indications was characterized by diminished efficacy, while patients experienced a high burden of adverse events consistent with lenvatinib's established safety profile. Furthermore, clinical trials testing in novel indications was marked by repeated phase I and II clinical trials along with a failure to progress to phase III clinical trials. Future clinical trials using lenvatinib as an intervention should carefully evaluate the potential benefits and burden patients may experience.

Abstract:

The failure of the Staphylococcus aureus (SA) IsdB vaccine trial can be explained by the recall of non-protective immune imprints from prior SA exposure. Here, we investigate natural human SA humoral imprints to understand their broader impact on SA immunizations. We show that antibody responses against SA cell-wall-associated antigens (CWAs) are non-opsonic, while antibodies against SA toxins are neutralizing. Importantly, the protective characteristics of the antibody imprints accurately predict the failure of corresponding vaccines against CWAs and support vaccination against toxins. In passive immunization platforms, natural anti-SA human antibodies reduce the efficacy of the human monoclonal antibodies suvratoxumab and tefibazumab, consistent with the results of their respective clinical trials. Strikingly, in the absence of specific humoral memory responses, active immunizations are efficacious in both naive and SA-experienced mice. Overall, our study points to a practical and predictive approach to evaluate and develop SA vaccines based on pre-existing humoral imprint characteristics.

BACKGROUND: Advances in plasma biomarkers to detect Alzheimers disease (AD) biology allows researchers to improve the efficiency of participant recruitment into preclinical trials. Recently, protein levels of plasma amyloid-beta and tau proteins have been shown to be predictive of elevated amyloid in brain. Online registries, such as the Alzheimers Prevention Trials (APT) Webstudy, include and follow participants using remote assessments to facilitate efficient screening and enrollment of large numbers of individuals who may be at higher risk for AD. OBJECTIVES: The AlzMatch Pilot Study investigated the feasibility of recruiting individuals from an online registry for blood sample collection at community-based phlebotomy centers and plasma biomarker quantification to assess an individuals eligibility for AD preclinical trials. DESIGN: Pilot feasibility study with co-primary outcomes. SETTING: This pilot feasibility study included participants from the APT Webstudy, the remote assessment arm of the Trial-ready cohort for Preclinical and Prodromal AD (TRC-PAD) Platform. Novel design included collection of electronic consent, use of community laboratories for plasma collection, mass spectrometry-based biomarker assay, and telephone communication of plasma biomarker screening eligibility. PARTICIPANTS: Participants invited to the AlzMatch pilot feasibility study were active in the APT Webstudy, 50 years of age or older, resided within 50 miles of both a Quest Diagnostics Patient Services Center (a national diagnostic laboratory with convenient locations for sample collection and processing) and one of six TRC-PAD vanguard clinical trial sites, had no self-reported dementia diagnosis, were able to communicate in English and engaged with the APT Webstudy within the prior 6 months. MEASUREMENTS: Primary feasibility outcomes were completion of electronic consent (e-consent) for invited participants and collection of usable blood samples. Additional feasibility outcomes included invitation response rate, plasma biomarker eligibility status (based on amyloid beta-42/40 [Aβ42/40] concentration ratio), ApoE proteotype, and trial inclusion criterion), and completion of telephone contact to learn eligibility to screen for a study. RESULTS: 300 APT Webstudy participants were invited to consent to the AlzMatch study. The AlzMatch e-consent rate was 39% (n=117) (95% CI of 33.5%-44.5%) overall, which was higher than the expected rate of 25%. Similar consent rates were observed across participants based on self-defined sex (41% Female (n=75), 37% Male (n=42)) and race and ethnicity (37% from underrepresented groups (URG) (n=36), 40% not from URG (n=79)). Among those that consented (n=117), plasma was successfully collected from 74% (n=87) (95% CI of 66%-82%), with similar rates across sex (76% Female (n=57), 71% Male (n=30)) and race and ethnicity (75% URG (n=27) and 75% not from URG (n=59)). 60% (n=51) of participants with plasma biomarker results were eligible to screen for future preclinical AD trials. CONCLUSION: Electronic consent of participants through an online registry, blood sample collection at community-based centers, plasma biomarker quantification and reporting, and biomarker assessments for study eligibility were all feasible with similar engagement rates across demographic groups. Although this pilot was a small and selective sample, participants engaged and consented at higher than expected rates. We conclude that collecting blood at community laboratories for biomarker analyses may improve accessibility beyond research, and may facilitate broader access for clinical use of AD plasma biomarkers. Based on our results, an expanded version of the AlzMatch study is underway, which involves expanding invitations to additional APT Webstudy participants and clinical trial sites.

INTRODUCTION: Metrics of a participants socioeconomic status (SES) are not routinely collected or standardized in clinical trials. This omission limits the ability to evaluate the generalizability of trial results and restricts clinicians from confidently interpreting the efficacy of new treatments across important sub-populations. METHODS: We adapted an SES measure of social disparity; the Hollingshead Two Factor Index of Social Position, which combines education and occupation into a single metric. We modernized the 1965 occupations to reflect the 2017 careers tabulated by the US Bureau of Labor Statistics. We currently use this adapted measure in Alzheimers Clinical Trials Consortium studies. RESULTS: We present the revised table of occupations. We found that the collection of SES data using the modified Hollingshead was feasible in a multi-site clinical trial and scores were distributed across all SES strata. DISCUSSION: The modified Hollingshead provides a standardized method for collecting SES information, enabling data aggregation, monitoring, and reporting.

BackgroundSince September 2005 the International Committee of Medical Journal Editors has required that trials be registered in accordance with the World Health Organization (WHO) minimum dataset, in order to be considered for publication. The objective is to evaluate registries' and individual trial records' compliance with the 2006 version of the WHO minimum data set.MethodsA retrospective evaluation of 21 online clinical trial registries (international, national, specialty, pharmaceutical industry and local) from April 2005 to February 2007 and a cross-sectional evaluation of a stratified random sample of 610 trial records from the 21 registries.ResultsAmong 11 registries that provided guidelines for registration, the median compliance with the WHO criteria were 14 out of 20 items (range 6 to 20). In the period April 2005-February 2007, six registries increased their compliance by six data items, on average. None of the local registry websites published guidelines on the trial data items required for registration. Slightly more than half (330/610; 54.1%, 95% CI 50.1% - 58.1%) of trial records completed the contact details criteria while 29.7% (181/610, 95% CI 26.1% - 33.5%) completed the key clinical and methodological data fields.ConclusionWhile the launch of the WHO minimum data set seemed to positively influence registries with better standardisation of approaches, individual registry entries are largely incomplete. Initiatives to ensure quality assurance of registries and trial data should be encouraged. Peer reviewers and editors should scrutinise clinical trial registration records to ensure consistency with WHO's core content requirements when considering trial-related publications.

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) 10 s, those with

In 2011, the UK medical research charity Cure Parkinsons set up the international Linked Clinical Trials (iLCT) committee to help expedite the clinical testing of potentially disease modifying therapies for Parkinsons disease (PD). The first committee meeting was held at the Van Andel Institute in Grand Rapids, Michigan in 2012. This group of PD experts has subsequently met annually to assess and prioritize agents that may slow the progression of this neurodegenerative condition, using a systematic approach based on preclinical, epidemiological and, where possible, clinical data. Over the last 12 years, 171 unique agents have been evaluated by the iLCT committee, and there have been 21 completed clinical studies and 20 ongoing trials associated with the initiative. In this review, we briefly outline the iLCT process as well as the clinical development and outcomes of some of the top prioritized agents. We also discuss a few of the lessons that have been learnt, and we conclude with a perspective on what the next decade may bring, including the introduction of multi-arm, multi-stage clinical trial platforms and the possibility of combination therapies for PD.

BackgroundAccording to the new AASLD Practice Guidance, all patients with primary sclerosing cholangitis (PSC) should be considered for participation in clinical trials. However, PSC's rarity has posed challenges to characterizing patient interest in trial participation and identifying predictors of patient willingness to participate in drug trials.MethodsPSC Partners Seeking a Cure developed the "Our Voices" survey to inform the development of the Externally-Led Patient-Focused Drug Development Forum, an FDA initiative to capture patient experiences and perspectives on drug development.ResultsOf 797 survey respondents from over 30 countries, 536 (67%) identified slowing disease progression as the most important outcome. Eighty-nine percent identified their hepatologist/gastroenterologist as someone they would approach for advice about trials. Although 61% reported being willing to participate in drug trials, only 26% had ever been asked to participate. Notable barriers to trial involvement included unknown long-term risks (71%), long travel times to the study center (32%), and a liver biopsy requirement (27%). On multivariable logistic regression, pruritus (OR 1.62, 95% CI: 1.09-2.40, p = 0.017) was positively associated with willingness to participate in disease-modifying therapy trials, while jaundice (OR 0.34, 95% CI: 0.19-0.61, p < 0.001) and inflammatory bowel disease (OR 0.64, 95% CI: 0.42-0.98, p = 0.038) were negatively associated. Pruritus (OR 2.25, 95% CI: 1.50-3.39, p < 0.001) was also independently associated with willingness to participate in symptom treatment trials.ConclusionsMost patients with PSC report interest in participating in clinical trials, but few have been asked to participate. Referral of patients with PSC by their hepatologist/gastroenterologist to clinical trials and patient education on trial participation are vital to closing the gap between trial interest and participation. Pruritus may serve as a key indicator of patient interest in trial participation.

OBJECTIVE: The natural history of Friedreich ataxia is being investigated in a multi-center longitudinal study designated the Friedreich ataxia Clinical Outcome Measures Study (FACOMS). To understand the utility of this study in analysis of clinical trials, we performed a propensity-matched comparison of data from the open-label MOXIe extension (omaveloxolone) to that from FACOMS. METHODS: MOXIe extension patients were matched to FACOMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline modified Friedreich Ataxia Rating scale (mFARS) score, and baseline gait score. The change from baseline in mFARS at Year 3 for the MOXIe extension patients compared to the matched FACOMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis. RESULTS: Data from the MOXIe extension show that omaveloxolone provided persistent benefit over 3 years when compared to an untreated, matched cohort from FACOMS. At each year, in all analysis populations, patients in the MOXIe extension experienced a smaller change from baseline in mFARS score than matched FACOMS patients. In the primary pooled population (136 patients in each group) by Year 3, patients in the FACOMS matched set progressed 6.6 points whereas patients treated with omaveloxolone in MOXIe extension progressed 3 points (difference = -3.6; nominal p value = 0.0001). INTERPRETATION: These results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity-matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations.

The usual challenges of conducting primary care research, including randomized trials, have been exacerbated, and new ones identified, during the COVID-19 pandemic. HOMER (Home versus Office for Medication Enhanced Recovery; subsequently, Comparing Home, Office, and Telehealth Induction for Medication Enhanced Recovery) is a pragmatic, comparative-effectiveness research trial that aims to answer a key question from patients and clinicians: What is the best setting in which to start treatment with buprenorphine for opioid use disorder for this patient at this time? In this article, we describe the difficult journey to find the answer. The HOMER study began as a randomized trial comparing treatment outcomes in patients starting treatment with buprenorphine via induction at home (unobserved) vs in the office (observed, synchronous). The study aimed to enroll 1,000 participants from 100 diverse primary care practices associated with the State Networks of Colorado Ambulatory Practices and Partners and the American Academy of Family Physicians National Research Network. The research team faced unexpected challenges related to the COVID-19 pandemic and dramatic changes in the opioid epidemic. These challenges required changes to the study design, protocol, recruitment intensity, and funding conversations, as well as patience. As this is a participatory research study, we sought, documented, and responded to practice and patient requests for adaptations. Changes included adding a third study arm using telehealth induction (observed via telephone or video, synchronous) and switching to a comprehensive cohort design to answer meaningful patient-centered research questions. Using a narrative approach based on the Greek myth of Homer, we describe here the challenges and adaptations that have provided the opportunity for HOMER to thrive and find the way home. These clinical trial strategies may apply to other studies faced with similar cultural and extreme circumstances. [ABSTRACT FROM AUTHOR]

Interest in incorporating historical data in the clinical trial has increased with the rising cost of conducting clinical trials. The intervention arm for the current trial often requires prospective data to assess a novel treatment, and thus borrowing historical control data commensurate in distribution to current control data is motivated in order to increase the allocation ratio to the current intervention arm. Existing historical control borrowing adaptive designs adjust allocation ratios based on the commensurability assessed through study-level summary statistics of the response agnostic of the distributions of the trial subject characteristics in the current and historical trials. This can lead to distributional imbalance of the current trial subject characteristics across the treatment arms as well as between current control data and borrowed historical control data. Such covariate imbalance may threaten the internal validity of the current trial by introducing confounding factors that affect study endpoints. In this article, we propose a Bayesian design which borrows and updates the treatment allocation ratios both covariate-adaptively and commensurate to covariate dependently assessed similarity between the current and historical control data. We employ covariate-dependent discrepancy parameters which are allowed to grow with the sample size and propose a regularized local regression procedure for the estimation of the parameters. The proposed design also permits the current and the historical controls to be similar to varying degree, depending on the subject level characteristics. We evaluate the proposed design extensively under the settings derived from two placebo-controlled randomized trials on vertebral fracture risk in post-menopausal women.

The 2022 mpox outbreak presented a familiar challenge to clinical laboratories. Accordingly, our institution was able to swiftly implement in-house mpox testing to meet the imminent diagnostic needs of the public health emergency. While the FDA authorized laboratory-developed tests (LDTs) for lesion specimens, however, it restricted the testing of rectal swabs despite mounting evidence of its clinical utility. Notably, within the short timeframe when rectal testing was available, we identified a high-risk patient without apparent lesions who tested monkeypox-positive only by our in-house rectal swab assay. In order for our institution to continue testing non-lesion samples, The FDA required a separate Emergency Use Authorization (EUA) application that demanded additional resource-costly validation studies despite utilizing the same testing platform as lesion samples. Here, we provide a brief review of the history, current status, and legal scope surrounding LDT validations, with an in-depth comparison of the technical requirements by CLIA, CAP and the FDA. Importantly, we provide our experience with the mpox EUA submission process to serve as context for the challenges that may be imposed by the new FDA regulations. We hope that our experience will offer a valuable perspective that promotes constructive discourse towards addressing the imperative to offer high-quality laboratory diagnostics without compromising on the need of the medical laboratory community to provide effective patient care.

BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.

Randomized trials offer a powerful strategy for estimating the effect of a treatment on an outcome. However, interpretation of trial results can be complicated when study subjects do not take the treatment to which they were assigned; this is referred to as nonadherence. Prior authors have described instrumental variable approaches to analyze trial data with nonadherence; under their approaches, the initial assignment to treatment is used as an instrument. However, their approaches require the assumption that initial assignment to treatment has no direct effect on the outcome except via the actual treatment received (i.e., the exclusion restriction), which may be implausible. We propose an approach to identification of a causal effect of treatment in a trial with 1-sided nonadherence without assuming exclusion restriction. The proposed approach leverages the study subjects initially assigned to control status as an unexposed reference population; we then employ a bespoke instrumental variable analysis, where the key assumption is partial exchangeability of the association between a covariate and an outcome in the treatment and control arms. We provide a formal description of the conditions for identification of causal effects, illustrate the method using simulations, and provide an empirical application.

BACKGROUND: A feature of HIV cure trials is the need to interrupt treatment to test the efficacy of experimental interventions-a process known as analytical treatment interruptions (ATIs). OBJECTIVES: We report the experiences of participants after they completed an extended ATI. METHODS: From April to November 2022, we conducted post-ATI in-depth interviews with BEAT2 clinical trial (NCT03588715) participants who stopped ART while receiving an immunotherapy regimen. We used conventional content analysis to code the data. RESULTS: We conducted interviews with 11 Black/African American and three White/Caucasian participants (11 males, two females, and one transgender woman). The mean ATI was 38 weeks. Participants noted several significant experiences surrounding the interventions side effects, ATI, and returning to medication. Some participants had positive experiences with their ATI. Other participants were nervous during the ATI. Rising viral loads led some to feel a sense of failure. Although trial experiences were heterogeneous, participants unanimously had positive interactions with the clinical trial staff which facilitated their retention in the trial. Participants shared their experiences with the trial, including changes in expectations, experiences with experimental interventions and procedures, compensation as a measure of respect, effort, transportation, and effects of COVID-19 during the trial. Based on these results, we provide considerations for the conduct of future HIV cure-directed clinical trials involving ATIs. CONCLUSIONS: Managing expectations, focusing on participants contributions, and providing support to reduce feelings of having failed the research team and/or the HIV community following viral rebound should be part of HIV cure trial design. Discussing the mental health impact of rebound during consent, distinct from risk, is needed. Continued efforts to understand how people with HIV experience ATIs will improve future designs of HIV cure clinical trials.

Alzheimer's disease (AD) research has entered a new era with the recent positive phase 3 clinical trials of the anti-Aβ antibodies lecanemab and donanemab. Why did it take 30 years to achieve these successes? Developing potent therapies for reducing fibrillar amyloid was key, as was selection of patients at relatively early stages of disease. Biomarkers of the target pathologies, including amyloid and tau PET, and insights from past trials were also critical to the recent successes. Moving forward, the challenge will be to develop more efficacious therapies with greater efficiency. Novel trial designs, including combination therapies and umbrella and basket protocols, will accelerate clinical development. Better diversity and inclusivity of trial participants are needed, and blood-based biomarkers may help to improve access for medically underserved groups. Incentivizing innovation in both academia and industry through public-private partnerships, collaborative mechanisms, and the creation of new career paths will be critical to build momentum in these exciting times.

Background: Little is known about the patient-reported quality of and satisfaction with advance care planning (ACP) conversations with surrogates and clinicians among English- and Spanish-speaking older adults, or the potential disparities associated with ACP communication satisfaction. Objectives: To determine patients perceived quality of and satisfaction with ACP surrogate/clinician conversations and associated patient characteristics. Design: Cross-sectional baseline data were used from two ACP trials, 2013-2017. Outcomes included self-reported ACP conversation quality (general vs. detailed) and communication satisfaction (5-point Likert scale). Associations were determined by chi-squared and t-tests. Setting/Subjects: Subjects were primary care patients ≥55 years with chronic/serious illness in the United States. Results: Of 1398 patients, mean age was 65.6 years (±7.7), 46% women, 32% Spanish speaking, 34% had limited health literacy, and 589 (42%) reported conversations with surrogates and 216 (15%) with clinicians. Of these, less than half rated the conversations as detailed high quality (clinician: 43%; surrogate: 37%). Five-point communication satisfaction scores were higher with detailed versus general conversations (e.g., surrogates: 4.4 vs. 4.1, p = 0.001; clinicians: 4.4 vs. 4.2, p = 0.18) and more often reported by men versus women [(4.4 (0.8) vs. 4.0 (1.0), p = 0.003]; those with adequate versus limited health literacy [4.4 (0.8) vs. 4.0 (0.9), p = 0.002]; and English versus Spanish speakers [4.5 (0.7) vs. 3.5 (0.9), p

CRISPR-Cas9 genome editing has enabled advanced T cell therapies, but occasional loss of the targeted chromosome remains a safety concern. To investigate whether Cas9-induced chromosome loss is a universal phenomenon and evaluate its clinical significance, we conducted a systematic analysis in primary human T cells. Arrayed and pooled CRISPR screens revealed that chromosome loss was generalizable across the genome and resulted in partial and entire loss of the targeted chromosome, including in preclinical chimeric antigen receptor T cells. T cells with chromosome loss persisted for weeks in culture, implying the potential to interfere with clinical use. A modified cell manufacturing process, employed in our first-in-human clinical trial of Cas9-engineered T cells (NCT03399448), reduced chromosome loss while largely preserving genome editing efficacy. Expression of p53 correlated with protection from chromosome loss observed in this protocol, suggesting both a mechanism and strategy for T cell engineering that mitigates this genotoxicity in the clinic.

Analytical treatment interruptions (ATIs) have become a key methodological approach to evaluate the effects of experimental HIV cure-related research interventions. During ATIs, sex partners of trial participants might be at risk of acquiring HIV. This risk raises both ethical and feasibility concerns about ATI trials. We propose a partner protection package (P3) approach to address these concerns. A P3 approach would provide guidance to investigators, sponsors, and those who are designing and implementing context-specific partner protections in HIV cure-related trials involving ATIs. The approach would also help assure institutional review boards, trial participants, and communities that ATI trials with a P3 would provide appropriate partner protections. We offer a prototype P3 framework that delineates three basic considerations for protecting participants' sex partners during ATI trials: (1) ensuring the scientific and social value of the ATI and the trial, (2) reducing the likelihood of unintended HIV transmission, and (3) ensuring prompt management of any acquired HIV infection. We outline possible ways of implementing these basic considerations.

Important progress has been made over the last decade in the classification, imaging, and treatment of neuroendocrine neoplasm (NENs), with several new agents approved for use. Although the treatment options available for patients with well-differentiated neuroendocrine tumors (NETs) have greatly expanded, the rapidly changing landscape has presented several unanswered questions about how best to optimize, sequence, and individualize therapy. Perhaps the most important development over the last decade has been the approval of 177Lu-DOTATATE for treatment of gastroenteropancreatic-NETs, raising questions around optimal sequencing of peptide receptor radionuclide therapy (PRRT) relative to other therapeutic options, the role of re-treatment with PRRT, and whether PRRT can be further optimized through use of dosimetry among other approaches. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trial planning meeting in 2021 with multidisciplinary experts from academia, the federal government, industry, and patient advocates to develop NET clinical trials in the era of PRRT. Key clinical trial recommendations for development included 1) PRRT re-treatment, 2) PRRT and immunotherapy combinations, 3) PRRT and DNA damage repair inhibitor combinations, 4) treatment for liver-dominant disease, 5) treatment for PRRT-resistant disease, and 6) dosimetry-modified PRRT.

An increasing number of clinical trials are enrolling patients with myasthenia gravis (MG). A lack of standardization in the performance of outcome measures leads to confusion among site research teams and is a source of variability in clinical trial data. MGNet, the NIH-supported Rare Disease Clinical Research Network for MG, views standardization of MG outcome measures as a critical need. To address this issue, a group of experts summarized key outcome measures used in MG clinical trials and a symposium was convened to address issues contributing to outcome measure variability. Consensus recommendations resulted in changes to outcome measure instructions and, in some cases, modifications to specific instruments. Recommended changes were posted for public commentary before finalization. Changes to the MG-Activities of Daily Living, MG-Quality of Life-15r, and MG-Impairment Index were limited to adding details to the administration instructions. Recommendations for proper positioning of participants and how to score items that could not be performed because of non-MG reasons were provided for the MG Composite. The Quantitative MG (QMG) score required the most attention, and changes were made both to the instructions and the performance of certain items resulting in the QMG-Revised. The Postintervention Status was believed to have a limited role in clinical trials, except for the concept of minimal manifestation status. As a next step, training materials and revised source documents, which will be freely available to study teams, will be created and posted on the MGNet website. Further studies are needed to validate changes made to the QMG-Revised.

IntroductionThe development of biomarkers for Alzheimer's disease (AD) has allowed researchers to increase sample homogeneity and test candidate treatments earlier in the disease. The integration of biomarker "screening" criteria should be met with a parallel implementation of standardized methods to disclose biomarker testing results to research participants; however, the extent to which protocolized disclosure occurs in trials is unknown.MethodsWe reviewed the literature to identify prodromal AD trials published in the past 10 years. From these, we quantified the frequency of biomarker disclosure reporting and the depth of descriptions provided.ResultsOf 30 published trials using positron emission tomography or cerebrospinal fluid-based amyloid positivity as an eligibility criterion, only one mentioned disclosure, with no details on methods.DiscussionPossible reasons for and implications of this information gap are discussed. Recommendations are provided for trialists considering biomarker screening as part of intervention trials focused on prodromal AD.HighlightsFew prodromal Alzheimer's disease (AD) trial papers discuss biomarker disclosure. Disclosure has implications for participants, family members, and trial success. Disclosure must be consistently integrated and reported in prodromal AD trials. Best practice guidelines and training resources for disclosure are needed.

An increasing number of clinical trials are enrolling patients with myasthenia gravis (MG). A lack of standardization in the performance of outcome measures leads to confusion among site research teams and is a source of variability in clinical trial data. MGNet, the NIH-supported Rare Disease Clinical Research Network for MG, views standardization of MG outcome measures as a critical need. To address this issue, a group of experts summarized key outcome measures used in MG clinical trials and a symposium was convened to address issues contributing to outcome measure variability. Consensus recommendations resulted in changes to outcome measure instructions and, in some cases, modifications to specific instruments. Recommended changes were posted for public commentary before finalization. Changes to the MG-Activities of Daily Living, MG-Quality of Life-15r, and MG-Impairment Index were limited to adding details to the administration instructions. Recommendations for proper positioning of participants and how to score items that could not be performed because of non-MG reasons were provided for the MG Composite. The Quantitative MG (QMG) score required the most attention, and changes were made both to the instructions and the performance of certain items resulting in the QMG-Revised. The Postintervention Status was believed to have a limited role in clinical trials, except for the concept of minimal manifestation status. As a next step, training materials and revised source documents, which will be freely available to study teams, will be created and posted on the MGNet website. Further studies are needed to validate changes made to the QMG-Revised.

Background: Public involvement enhances the relevance, quality, and impact of research. There is some evidence that public involvement in Australian research lags other countries, such as the United Kingdom. The purpose of the systematic review was to establish the rates and describe the characteristics of public involvement in Australian clinical trials. Methods: We reviewed evidence of public involvement in all Australian randomised controlled trials published in the first 6 months of 2021. To determine the quality of public involvement, we used the five-item short-form version of the Guidance of Reporting Involvement Patients and the Public, version 2. Results: In total, 325 randomised controlled trials were included, of which 17 (5%) reported any public involvement. Six trials reported public involvement in setting the research aim and seven in developing study methods. The authors of one study reflected on the overall role and influence of public involvement in the research. Conclusion: Rate of public involvement in Australian clinical trials is seemingly substantially lower than those reported in countries with similar advanced public health care systems, notably the United Kingdom. Our observations may be explained by a lack of researcher skills in how to involve the public and the failure by major funding agencies in Australia to mandate public involvement when deciding on how to award grant funding. [ABSTRACT FROM AUTHOR]