Journal articles on the topic 'Multi-site clinical trials'
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Goodlett, Dana, Anna Hung, Ashley Feriozzi, Hien Lu, Justin E. Bekelman, and C. Daniel Mullins. "Site engagement for multi-site clinical trials." Contemporary Clinical Trials Communications 19 (September 2020): 100608. http://dx.doi.org/10.1016/j.conctc.2020.100608.
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Westphal, James, and Max W. Abbott. "Models for Multi-site Problem Gambling Clinical Trials." International Gambling Studies 6, no. 2 (November 2006): 129–45. http://dx.doi.org/10.1080/14459790600927787.
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Kurbegov, Dax, Edward S. Kim, Patricia A. Hurley, and David Michael Waterhouse. "Qualifying sites for oncology clinical trials." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 6619. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.6619.
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6619 Background: Current methods to assess trial sites for clinical trial participation are onerous, with unnecessary redundancies and “no-value” steps that impact clinical trial participation. This project assessed the impact of current sponsor and contract research organizations (CRO) methods to evaluate sites for trials. Methods: A survey was conducted with community- and academic-based trial sites. Samples of feasibility questionnaires (FQs) used by sponsors and CROs were also compiled. An ASCO sponsored multi-stakeholder meeting was held to identify strategies to more effectively assess trial sites. Results: 113 oncology practices (63 community, 50 academic) reported completing 11 FQs and 4 pre-study site visits (PSV) on average per month. On average, each FQ took 4 hours (528 hours/site and 59,664 hours for all respondents, annually) and each PSV took 10 hours (480 hours/site and 54,240 hours for all respondents, annually) to complete. Thus, the total staff hours required to complete site feasibility assessments was 113,904 annually. Respondents reported that content in both FQs (82%) and PSVs (91%) was redundant to information previously provided and FQs were redundant between different sponsors (86%). The 42 sample FQs had a median 45 questions (range 13 to 96). Respondents noted that sponsors/CROs provided insufficient study documentation to accurately complete FQs. It took 7 months on average from first contact to first patient enrolled. Respondents also provided feedback about standardizing and streamlining site qualification processes. Conclusions: The current methods of assessing site feasibility for clinical trials poses tremendous burden on site resources and is not sustainable. New methods are needed that standardize, harmonize, and streamline criteria and site assessments. Such changes will reduce burden and costs for all stakeholders, and will expedite and increase patient enrollment onto clinical trials.
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Visweswaran, Shyam, Michael J. Becich, Vincent S. D’Itri, Elaina R. Sendro, Douglas MacFadden, Nicholas R. Anderson, Karen A. Allen, et al. "Accrual to Clinical Trials (ACT): A Clinical and Translational Science Award Consortium Network." JAMIA Open 1, no. 2 (August 21, 2018): 147–52. http://dx.doi.org/10.1093/jamiaopen/ooy033.
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Abstract The Accrual to Clinical Trials (ACT) network is a federated network of sites from the National Clinical and Translational Science Award (CTSA) Consortium that has been created to significantly increase participant accrual to multi-site clinical trials. The ACT network represents an unprecedented collaboration among diverse CTSA sites. The network has created governance and regulatory frameworks and a common data model to harmonize electronic health record (EHR) data, and deployed a set of Informatics for Integrating Biology and the Bedside (i2b2) data repositories that are linked by the Shared Health Research Information Network (SHRINE) platform. It provides investigators the ability to query the network in real time and to obtain aggregate counts of patients who meet clinical trial inclusion and exclusion criteria from sites across the United States. The ACT network infrastructure provides a basis for cohort discovery and for developing new informatics tools to identify and recruit participants for multi-site clinical trials.
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Feaster, Daniel J., Susan Mikulich-Gilbertson, and Ahnalee M. Brincks. "Modeling Site Effects in the Design and Analysis of Multi-site Trials." American Journal of Drug and Alcohol Abuse 37, no. 5 (August 22, 2011): 383–91. http://dx.doi.org/10.3109/00952990.2011.600386.
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Greenwald, Ricky, and Thomas A. Schmitt. "Progressive counting: Multi-site group and individual treatment open trials." Psychological Trauma: Theory, Research, Practice, and Policy 2, no. 3 (September 2010): 239–42. http://dx.doi.org/10.1037/a0019361.
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Adams, Heather R., Sara Defendorf, Amy Vierhile, Jonathan W. Mink, Frederick J. Marshall, and Erika F. Augustine. "A novel, hybrid, single- and multi-site clinical trial design for CLN3 disease, an ultra-rare lysosomal storage disorder." Clinical Trials 16, no. 5 (June 11, 2019): 555–60. http://dx.doi.org/10.1177/1740774519855715.
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Background Travel burden often substantially limits the ability of individuals to participate in clinical trials. Wide geographic dispersion of individuals with rare diseases poses an additional key challenge in the conduct of clinical trials for rare diseases. Novel technologies and methods can improve access to research by connecting participants in their homes and local communities to a distant research site. For clinical trials, however, understanding of factors important for transition from traditional multi-center trial models to local participation models is limited. We sought to test a novel, hybrid, single- and multi-site clinical trial design in the context of a trial for Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 disease), a very rare pediatric neurodegenerative disorder. Methods We created a “hub and spoke” model for implementing a 22-week crossover clinical trial of mycophenolate compared with placebo, with two 8-week study arms. A single central site, the “hub,” conducted screening, consent, drug dispensing, and tolerability and efficacy assessments. Each participant identified a clinician to serve as a collaborating “spoke” site to perform local safety monitoring. Study participants traveled to the hub at the beginning and end of each study arm, and to their individual spoke site in the intervening weeks. Results A total of 18 spoke sites were established for 19 enrolled study participants. One potential participant was unable to identify a collaborating local site and was thus unable to participate. Study start-up required a median 6.7 months (interquartile range = 4.6–9.2 months). Only 33.3% (n = 6 of 18) of spoke site investigators had prior clinical trial experience, thus close collaboration with respect to study startup, training, and oversight was an important requirement. All but one participant completed all study visits; no study visits were missed due to travel requirements. Conclusions This study represents a step toward local trial participation for patients with rare diseases. Even in the context of close oversight, local participation models may be best suited for studies of compounds with well-understood side-effect profiles, for those with straightforward modes of administration, or for studies requiring extended follow-up periods.
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Ludmir, Ethan B., Walker Mainwaring, Austin B. Miller, Timothy Lin, Amit Jethanandani, Andres F. Espinoza, and Clifton David Fuller. "Age disparities among cancer clinical trial participants: The role of industry sponsorship." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 11527. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.11527.
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11527 Background: Randomized controlled trials (RCTs) in oncology, which often establish the standard of care for cancer patients, do not necessarily enroll trial participants representative of the broader patient population. We sought to characterize age disparities for cancer patients enrolled on RCTs, and asked whether certain trial-related factors (such as industry sponsorship) predispose trials to larger age disparities between trial enrollees and the general population. Methods: All phase 3 RCTs in clinical oncology with results available were identified through ClinicalTrials.gov. Only randomized multi-arm trials assessing a therapeutic intervention for cancer patients were included. The scope of trials was limited to breast, colorectal, lung, and prostate disease sites. Trial participant median ages were compared to national SEER data for population median ages by disease site. Results: Three-hundred and two trials met inclusion criteria. For all trials, the trial median age was an average 6.23 years younger than the population median age (95% CI: -5.55 to -6.91 years, p < 0.001). Trials with industry sponsorship had significantly younger trial patient populations compared with non-industry-sponsored trials (mean difference from population -6.57 vs -4.48 years, p = 0.02). Younger patients were enrolled on trials evaluating targeted agents (p = 0.04), superiority-design trials (p = 0.02), and trials utilizing a surrogate primary endpoint (p = 0.03). By disease site, lung cancer trials enrolled the youngest patients relative to the population median (-8.98 years), followed by breast (-7.76 years), colorectal (-6.96 years), and prostate (+2.66 years, p < 0.001). Conclusions: Industry-funded clinical trials are associated with larger age disparities among trial participants; we believe this represents a novel finding both in clinical oncology and academic medicine more broadly. Underrepresentation of older patients on RCTs has major ramifications for the generalizability of results as well as equity of access to care; future efforts to address trial participant age disparities may focus on those trials at greatest risk for disparities based on the identified risk factors, including industry sponsorship.
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Coles, Christian, Eugene V. Millar, Timothy Burgess, and Martin G. Ottolini. "The Acute Respiratory Infection Consortium: A Multi-Site, Multi-Disciplinary Clinical Research Network in the Department of Defense." Military Medicine 184, Supplement_2 (November 1, 2019): 44–50. http://dx.doi.org/10.1093/milmed/usz174.
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Abstract Introduction Acute respiratory infections (ARI) result in substantial annual morbidity among military personnel and decrease operational readiness. Herein, we summarize the research efforts of the Infectious Disease Clinical Research Program (IDCRP) related to ARIs. Methods The ARI Research Area of the IDCRP was established in response to the 2009 emergence of pandemic influenza A/H1N1. That year, IDCRP investigators deployed the ARI Consortium Natural History Study (ARIC NHS), a multi-centered, longitudinal observational study to assess etiology, epidemiology, and clinical characteristics of influenza-like illness (ILI) and severe acute respiratory infections (SARI) in the U.S. military. The success of this initial effort spurred implementation of several new initiatives. These include the FluPlasma trial, designed to evaluate the efficacy of hyperimmune anti-influenza plasma for the treatment of severe influenza; the self-administered live-attenuated influenza vaccine (SNIF) trial, which assessed the immunogenicity and acceptance of a self-administered live-attenuated influenza vaccine in military personnel; the Study to Address Threats of ARI in Congregate Military Populations (ATARI), a prospective study of ILI transmission, etiology and epidemiology in recruits; and the Flu Breath Test (FBT) study, a preliminary study of exhaled volatile organic compounds (VOC) in influenza patients. In addition, the InFLUenza Patient-Reported Outcome (FLU-PRO) survey, a daily diary to measure influenza symptoms during clinical trials, was developed. Lastly, the Pragmatic Assessment of Influenza Vaccine Effectiveness in the DoD (PAIVED) study, a two-year randomized trial designed to compare the effectiveness of the three types of licensed vaccines, launched in Fall 2018. Results The on-going ARIC NHS has enrolled over 2000 ILI and SARI cases since its inception, providing data on burden and clinical manifestations of ARI in military personnel and their families. The FluPlasma 2 trial concluded subject enrollment in 2018. Preliminary results from ATARI study show a high frequency of respiratory viruses circulating during the first two weeks of recruit training. Based on assessment of FLU-PRO responses, which were found to be reliable and reproducible, the survey may be a useful tool in clinical trials and epidemiological studies. The Flu Breath Study will complete enrollment in 2019. Findings from PAIVED are intended to provide evidence needed for assessing influenza vaccination policy in the military. Conclusions The ARI burden in the armed services remains significant every year and the threat is dynamic given emergent and evolving threats, such as influenzas. With strong successes to date, future initiatives of the ARI Research Area will focus on interventional studies, ARI transmission dynamics in congregate military settings, and determinants of risk of pandemic influenza and other emergent respiratory viruses.
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Tilley, Barbara C., Arch G. Mainous, Daniel W. Smith, M. Diane McKee, Rossybelle P. Amorrortu, Jennifer Alvidrez, Vanessa Diaz, et al. "Design of a cluster-randomized minority recruitment trial: RECRUIT." Clinical Trials 14, no. 3 (March 19, 2017): 286–98. http://dx.doi.org/10.1177/1740774517690146.
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Background: Racial/ethnic minority groups remain underrepresented in clinical trials. Many strategies to increase minority recruitment focus on minority communities and emphasize common diseases such as hypertension. Scant literature focuses on minority recruitment to trials of less common conditions, often conducted in specialty clinics and dependent on physician referrals. We identified trust/mistrust of specialist physician investigators and institutions conducting medical research and consequent participant reluctance to participate in clinical trials as key-shared barriers across racial/ethnic groups. We developed a trust-based continuous quality improvement intervention to build trust between specialist physician investigators and community minority-serving physicians and ultimately potential trial participants. To avoid the inherent biases of non-randomized studies, we evaluated the intervention in the national Randomized Recruitment Intervention Trial (RECRUIT). This report presents the design of RECRUIT. Specialty clinic follow-up continues through April 2017. Methods: We hypothesized that specialist physician investigators and coordinators trained in the trust-based continuous quality improvement intervention would enroll a greater proportion of minority participants in their specialty clinics than specialist physician investigators in control specialty clinics. Specialty clinic was the unit of randomization. Using continuous quality improvement, the specialist physician investigators and coordinators tailored recruitment approaches to their specialty clinic characteristics and populations. Primary analyses were adjusted for clustering by specialty clinic within parent trial and matching covariates. Results: RECRUIT was implemented in four multi-site clinical trials (parent trials) supported by three National Institutes of Health institutes and included 50 associated specialty clinics from these parent trials. Using current data, we have 88% power or greater to detect a 0.15 or greater difference from the currently observed control proportion adjusting for clustering. We detected no differences in baseline matching criteria between intervention and control specialty clinics (all p values > 0.17). Conclusion: RECRUIT was the first multi-site randomized control trial to examine the effectiveness of a trust-based continuous quality improvement intervention to increase minority recruitment into clinical trials. RECRUIT’s innovations included its focus on building trust between specialist investigators and minority-serving physicians, the use of continuous quality improvement to tailor the intervention to each specialty clinic’s specific racial/ethnic populations and barriers to minority recruitment, and the use of specialty clinics from more than one parent multi-site trial to increase generalizability. The effectiveness of the RECRUIT intervention will be determined after the completion of trial data collection and planned analyses.
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Lee, Eudocia, Ugonma Chukwueke, Shawn Hervey-Jumper, John DeGroot, Pablo Leone, Terri Armstrong, Susan Chang, et al. "INNV-33. BARRIERS TO ACCRUAL AND ENROLLMENT IN BRAIN TUMOR TRIALS." Neuro-Oncology 21, Supplement_6 (November 2019): vi137. http://dx.doi.org/10.1093/neuonc/noz175.574.
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Abstract BACKGROUND A major impediment to improving neuro-oncology outcomes is poor clinical trial accrual. METHODS We convened a multi-stakeholder group including Society for Neuro-Oncology, Response Assessment in Neuro-Oncology, patient advocacy groups, clinical trial cooperative groups, and other partners to determine how we can improve trial accrual. RESULTS We described selected factors contributing to poor trial accrual and possible solutions. We focused on patient and community factors, disparities, physician and provider factors, clinical trial factors, and site and organizational factors CONCLUSIONS We will implement strategies with the intent to double accrual to neuro-oncology trials over the next 5 years.
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Curtis, Lesley H., Laura M. Dember, Miguel A. Vazquez, David Murray, Lynn DeBar, Karen L. Staman, Edward Septimus, et al. "Addressing guideline and policy changes during pragmatic clinical trials." Clinical Trials 16, no. 4 (May 14, 2019): 431–37. http://dx.doi.org/10.1177/1740774519845682.
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While conducting a set of large-scale multi-site pragmatic clinical trials involving high-impact public health issues such as end-stage renal disease, opioid use, and colorectal cancer, there were substantial changes to both policies and guidelines relevant to the trials. These external changes gave rise to unexpected challenges for the trials, including decisions regarding how to respond to new clinical practice guidelines, increased difficulty in implementing trial interventions, achieving separation between treatment groups, and differential responses across sites. In this article, we describe these challenges and the approaches used to address them. When deliberating appropriate action in the face of external changes during a pragmatic clinical trial, we recommend considering the well-being of the participants, clinical equipoise, and the strength and quality of the evidence associated with the change; involving those charged with data and safety monitoring; and where possible, planning for potential external changes as the trial is being designed. Any solution must balance the primary obligation to protect the well-being of participants with the secondary obligation to protect the integrity of the trial in order to gain meaningful answers to important public health questions.
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Massett, Holly A., Sharon L. Hampp, Jacquelyn L. Goldberg, Margaret Mooney, Linda K. Parreco, Lori Minasian, Mike Montello, Grace E. Mishkin, Catasha Davis, and Jeffrey S. Abrams. "Meeting the Challenge: The National Cancer Institute’s Central Institutional Review Board for Multi-Site Research." Journal of Clinical Oncology 36, no. 8 (March 10, 2018): 819–24. http://dx.doi.org/10.1200/jco.2017.76.9836.
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The National Institutes of Health (NIH) issued a new policy that requires a single institutional review board (IRB) of record be used for all protocols funded by the NIH that are carried out at more than one site in the United States, effective January 2018. This policy affects several hundred clinical trials opened annually across the NIH. Limited data exist to compare the use of a single IRB to that of multiple local IRBs, so some institutions are resistant to or distrustful of single IRBs. Since 2001, the National Cancer Institute (NCI) has funded a central IRB (CIRB) that provides human patient reviews for its extensive national cancer clinical trials program. This paper presents data to show the adoption, efficiencies gained, and satisfaction of the CIRB among NCI trial networks and reviews key lessons gleaned from 16 years of experience that may be informative for others charged with implementation of the new NIH single-IRB policy.
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Perera, Nirosha, Marija Kamceva, Jolie Z. Shen, Siyou Song, Jessica Steinberg, Brandon E. Turner, Margaret Shyu, et al. "The gastrointestinal clinical trial landscape: A cross-sectional analysis of clinicaltrials.gov from 2007-2019." Journal of Clinical Oncology 39, no. 3_suppl (January 20, 2021): 468. http://dx.doi.org/10.1200/jco.2021.39.3_suppl.468.
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468 Background: The burden of gastrointestinal (GI) disease is high, costing over $97 billion annually in the United States (U.S.) alone. Yet the methodological rigor and characteristics of trials leading to guideline development are rarely explored. In 2007, the U.S. mandated that all interventional studies (Phase II-IV) register with ClinicalTrials.gov, the largest international clinical trial database. We characterized registered GI trials to identify features associated with early discontinuation, results reporting and increased methodological rigor. Methods: We employed a cross-sectional study design with descriptive, logistic regression, cox regression, time series and survival analyses. We downloaded data for 327 075 studies registered on the Aggregate Analysis of the ClinicalTrials.gov database from October 1, 2007 to December 31, 2019. Trials were excluded if registered prior to 2007 (n=38 111) or for non-interventional study design (n=69 233). After applying GI specific Medical Subject Heading terms to the remaining 219 731 trials, 22 339 trials were identified for manual review. 20 548 trials were found to contain true GI content, representing over seven million patients. Primary exposure variables were trial focus (disease process, anatomical location) and funding (industry, U.S. government, academic). Results: Of the 20 548 GI trials, 6.1% were funded by the U.S. government, 35.6% by industry, and 58.3% by academic institutions. The most studied disease process was neoplasia (42.6% of trials), followed by viral hepatitis (10.8%). The majority of neoplasia trials were funded by academic institutions (60.3%) and studied colorectal neoplasms (31.5%), followed by hepatic (17.9%), pancreatic (15.5%), gastric (12.8%), esophageal (10.6%) and biliary tract (4.9%) neoplasms. U.S. government funded trials had the lowest risk of early discontinuation (adjusted Hazard Ratio 0.63, 95% CI: 0.48-0.83, p<0.001) and the highest rates of results reporting (25%, X2 p<0.001). Among all trials, the majority did not report Data Monitoring Committee (DMC) oversight (58.6%). Only 12% of phase III trials employed a rigorous methodology, which we defined as being randomized, double blinded, multi-site, overseen by a DMC, and having enrolled ≥50 patients. Government sponsored trials had the highest proportion of trials meeting this definition (19%). Academic sponsored trials, constituting the majority of trials overall, had the lowest proportion (5.3%), in part due to not meeting the multi-site criteria. Conclusions: Despite constituting the minority of trials overall, U.S. government funded trials displayed the highest methodological rigor. Stakeholders can look to U.S. government funded trials as a model of improvement, but nevertheless must commit to increasing methodological rigor and results dissemination to strengthen trial findings that guide GI clinical recommendations.
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Vardeny, Orly, Adrian F. Hernandez, Lauren W. Cohen, Amy Franklin, Mina Baqai, Sarah Palmer, Barbara E. Bierer, and Nichelle Cobb. "Transitioning to the National Institutes of Health single institutional review board model: Piloting the use of the Streamlined, Multi-site, Accelerated Resources for Trials IRB Reliance." Clinical Trials 16, no. 3 (March 13, 2019): 290–96. http://dx.doi.org/10.1177/1740774519832911.
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Background/Aims Obtaining ethical approval from multiple institutional review boards is a long-standing challenge to multi-site clinical trials and often leads to significant delays in study activation and enrollment. As of 25 January 2018, the National Institutes of Health began requiring use of a single institutional review board for US multi-site trials. To learn more and further inform the research and regulatory communities around aspects of transitioning to single institutional review board review, this study evaluated the efficiency, resource use, and user perceptions of a nascent institutional review board reliance model (Streamlined, Multi-site, Accelerated Resources for Trials IRB Reliance). Methods This research was embedded within the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure trial—a multi-site trial of two influenza vaccine formulations. In the first year of the trial, a sample of sites agreed to use the developing Streamlined, Multi-site, Accelerated Resources for Trials IRB Reliance model and participated in its evaluation. In keeping with a least burdensome approach, short surveys were developed and obtained from each reporting entity (relying sites, non-relying site, lead site, and reviewing institutional review board). Data regarding time to institutional review board approval and site activation, costs, and user perceptions of reliant review were self-reported and collected via the survey form. Quantitative and qualitative analyses were performed, with costs analyzed as actual versus estimated due to the lack of established baseline cost data. Results A total of 13 sites ceded review and received institutional review board approval. Mean time to approval was substantially faster in sites that ceded review using the Streamlined, Multi-site, Accelerated Resources for Trials IRB Reliance model versus the site that did not cede review (81 vs 121 days). The mean time to approval was also faster than published averages for academic medical centers (81 vs 103 days). Time to first enrollment was faster for ceding sites versus the non-ceding site, and also faster than published averages (126 vs 149 and 169 days, respectively). Costs were higher than estimates for local institutional review board review and approval. Nearly half (47%) the stakeholders reported being very satisfied or satisfied with the reliance experience, although many noted the challenge related to institutional culture change. Conclusion Implementation of a single institutional review board represents a shift in practice and culture for many institutions. Evaluation of the reliance arrangements for this study highlights both the potential of, and challenges for, institutions as they transition to single institutional review board review. Although efficiencies were observed for study start-up, we anticipate a learning curve as institutions and research teams implement necessary process and resource changes to adapt to single institutional review board oversight. Findings may inform research teams but are, however, limited by the relatively small number of sites and lack of a control group.
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Nakada, Haruka, Suzanne Hasthorpe, Carel IJsselmuiden, Francis Kombe, Marieme Ba, Mihaela Matei, Kenichi Nakamura, Nobuko Ushirozawa, Yasuhiro Fujiwara, and Shimon Tashiro. "Recommendations for promoting international multi‐site clinical trials—from a viewpoint of ethics review." Developing World Bioethics 19, no. 4 (September 12, 2019): 192–95. http://dx.doi.org/10.1111/dewb.12245.
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Stenning, Sally P., William J. Cragg, Nicola Joffe, Carlos Diaz-Montana, Rahela Choudhury, Matthew R. Sydes, and Sarah Meredith. "Triggered or routine site monitoring visits for randomised controlled trials: results of TEMPER, a prospective, matched-pair study." Clinical Trials 15, no. 6 (August 22, 2018): 600–609. http://dx.doi.org/10.1177/1740774518793379.
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Background/aims In multi-site clinical trials, where trial data and conduct are scrutinised centrally with pre-specified triggers for visits to sites, targeted monitoring may be an efficient way to prioritise on-site monitoring. This approach is widely used in academic trials, but has never been formally evaluated. Methods TEMPER assessed the ability of targeted monitoring, as used in three ongoing phase III randomised multi-site oncology trials, to distinguish sites at which higher and lower rates of protocol and/or Good Clinical Practice violations would be found during site visits. Using a prospective, matched-pair design, sites that had been prioritised for visits after having activated ‘triggers’ were matched with a control (‘untriggered’) site, which would not usually have been visited at that time. The paired sites were visited within 4 weeks of each other, and visit findings are recorded and categorised according to the seriousness of the deviation. The primary outcome measure was the proportion of sites with ≥1 ‘Major’ or ‘Critical’ finding not previously identified centrally. The study was powered to detect an absolute difference of ≥30% between triggered and untriggered visits. A sensitivity analysis, recommended by the study’s blinded endpoint review committee, excluded findings related to re-consent. Additional analyses assessed the prognostic value of individual triggers and data from pre-visit questionnaires completed by site and trials unit staff. Results In total, 42 matched pairs of visits took place between 2013 and 2016. In the primary analysis, 88.1% of triggered visits had ≥1 new Major/Critical finding, compared to 81.0% of untriggered visits, an absolute difference of 7.1% (95% confidence interval −8.3%, +22.5%; p = 0.365). When re-consent findings were excluded, these figures reduced to 85.7% versus 59.5%, (difference = 26.2%, 95% confidence interval 8.0%, 44.4%; p = 0.007). Individual triggers had modest prognostic value but knowledge of the trial-related activities carried out by site staff may be useful. Conclusion Triggered monitoring approaches, as used in these trials, were not sufficiently discriminatory. The rate of Major and Critical findings was higher than anticipated, but the majority related to consent and re-consent with no indication of systemic problems that would impact trial-wide safety issues or integrity of the results in any of the three trials. Sensitivity analyses suggest triggered monitoring may be of potential use, but needs improvement and investigation of further central monitoring triggers is warranted. TEMPER highlights the need to question and evaluate methods in trial conduct, and should inform further developments in this area.
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McGowan, Ian, Peter A. Anton, Julie Elliott, Ross D. Cranston, Kathryn Duffill, Andrew D. Althouse, Kevin L. Hawkins, and Stephen C. De Rosa. "Exploring the Feasibility of Multi-Site Flow Cytometric Processing of Gut Associated Lymphoid Tissue with Centralized Data Analysis for Multi-Site Clinical Trials." PLOS ONE 10, no. 5 (May 26, 2015): e0126454. http://dx.doi.org/10.1371/journal.pone.0126454.
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Rhyne, Robert L., Heidi Rishel Brakey, Jacquie R. Halladay, Kathleen Mottus, K. Allen Greiner, Elizabeth Salt, Orrin Myers, Kent Sutton, Jesus Fuentes, and Kevin E. Vowles. "A non-randomized pilot study to test the feasibility of treating chronic pain and opioid prescription use in rural areas with acceptance and commitment therapy (T-PACT)." Journal of Clinical and Translational Science 4, no. 5 (March 24, 2020): 472–76. http://dx.doi.org/10.1017/cts.2020.26.
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AbstractChronic non-cancer pain (CNCP) involves one-third of the US population, and prescription opioids contribute to the opioid epidemic. The Centers for Disease Control and Prevention emphasizes maximizing non-opioid treatment, but many rural populations cannot access alternative therapies. Clinical and Translational Science Award hubs across four rural states performed a multi-site, single-arm intervention feasibility study testing methods and procedures of implementing a behavioral intervention, acceptance and commitment therapy, in primary care CNCP patients on chronic opioids. Using the CONSORT extension for feasibility studies, we describe lessons learned in recruiting/retaining participants, intervention implementation, data measurement, and multi-site procedures. Results inform a future definitive trial and potentially others conducting rural trials.
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Field, Craig A., Bryon Adinoff, T. Robert Harris, Samuel A. Ball, and Kathleen M. Carroll. "Construct, concurrent and predictive validity of the URICA: Data from two multi-site clinical trials." Drug and Alcohol Dependence 101, no. 1-2 (April 2009): 115–23. http://dx.doi.org/10.1016/j.drugalcdep.2008.12.003.
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Waterhouse, David Michael, Nicholas J. Robert, Edward S. Kim, Dax Kurbegov, Howard A. Burris III, Michael A. Thompson, Grzegorz S. Nowakowski, Patricia A. Hurley, Courtney Davis, and Rogerio Lilenbaum. "ASCO Research Community Forum: Impact on clinical research." Journal of Clinical Oncology 37, no. 27_suppl (September 20, 2019): 299. http://dx.doi.org/10.1200/jco.2019.37.27_suppl.299.
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299 Background: In 2011, ASCO launched a forum for the oncology research community to facilitate and promote the implementation of quality clinical research. The ASCO Research Community Forum (RCF) was created to provide a solution-oriented venue for research sites to address common challenges with conducting clinical trials. It offers in-person and virtual forums and resources to learn and share best practices with peers on a variety of topics, including site quality assessment and improvement, research site operations, and clinical trial access and accrual. Methods: An assessment was performed to measure the ASCO RCF output and to gather information on its potential impact on the cancer community. Results: The ASCO RCF has provided an in-person venue for physicians and research administrators with a steady increase in attendance, from 52 attendees in 2012 to 159 in 2018. Multi-stakeholder meetings and manuscripts have promoted best practices and solutions to address challenges with implementing quality clinical trials. Tools and resources to facilitate best practices and quality improvement at trial sites have been accessed by a range of types of research sites from across the U.S. and internationally. Its web-based library of resources was accessed over 27,000 times in 2018, alone. An online forum was launched in 2019 to provide a new opportunity to connect and impact the research community. Conclusions: The ASCO RCF is a productive and esteemed resource for the cancer research community. In-person and virtual forums, along with practical tools, promote access and accrual to clinical trials by facilitating networking, developing solutions, and providing education and resources. The ASCO RCF impact has extended from community-based oncology practices to larger research networks and academic centers across the U.S. and internationally. Its efforts to promote and facilitate access to quality clinical trials align with the vision and mission of ASCO to conquer cancer through research, education, and promotion of the highest quality patient care.
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Wong, Kit Man, Anna Capasso, and S. Gail Eckhardt. "The Changing Landscape of Phase I Trials in Oncology." American Society of Clinical Oncology Educational Book, no. 35 (May 2015): 3–8. http://dx.doi.org/10.14694/edbook_am.2015.35.3.
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KEY POINTS Several aspects of phase I trials have evolved in the current era of molecular targeted agents to adapt to the changing nature of anticancer therapy and to increase the efficiency of drug development. Current phase I designs are increasingly integrating novel dose-escalation approaches and biomarker-driven selection of patients, as well as expanding study objectives to include the evaluation of efficacy and pharmacodynamics/pharmacokinetics in addition to safety. Changes to the regulatory approval process have helped to expedite drug development, particularly for novel agents with a strong biologic rationale and proof of concept, validated predictive biomarker, and clear evidence of efficacy in early trials. As a result of the substantial changes in phase I trial goals and conduct, there is a parallel shift toward multi-institutional trials and central study management by clinical research organizations. The use of multi-institutional trials has a significant impact on the structure of phase I programs and the experience of investigators, particularly because of limited patient enrollment at each site.
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Bamford, Bryony. "Critiquing evidence-based treatments from the perspective of an RCT clinician." Clinical Psychology Forum 1, no. 201 (September 2009): 18–22. http://dx.doi.org/10.53841/bpscpf.2009.1.201.18.
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Evidence-based practice aims to improve patient healthcare by incorporating evidence from large multi-site treatment trials. This paper aims to reflect on some of the challenges resulting from combining research and clinical agenda’s from the perspective of a research therapist.
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Massett, Holly A., Jacqueline Goldberg, Sharon Hampp, Margaret M. Mooney, Brian Campbell, Suma Narasimhaswamy, Grace Mishkin, et al. "Leading the way: The National Cancer Institute’s (NCI) single IRB for multi-site research." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e18259-e18259. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e18259.
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e18259 Background: NCI instituted a Central IRB (CIRB) with voluntary participation in 2001 for its late-phase trials and demonstrated that efficiency could be improved and costs reduced (Wagner et al JCO, 2010; 28). As a forerunner to the new NIH policy for single IRBs for all NIH multi-site trials (Hudson et al. JAMA Oct 4, 2010), NCI implemented a new CIRB model in 2014 where the CIRB was the IRB of record. We report adoption data of the new model within NCI’s National Clinical Trials Network (NCTN) and lessons learned from the rollout. Methods: We reviewed: Annual CIRB participant data from 2013-2016; site/accrual data for late phase trials activated between 2013-2016 (N = 64) via CIRB or local IRBs; and data from CIRB reports to identify acceptance and lessons learned. We compared time required for CIRB protocol reviews via the new model to baseline measures in the literature. Results: Of the 2,300 U.S. NCTN sites, the percentage of participation went from 47% in 2013, to 74% (2014), 79% (2015), and 81% (2016). For activated trials, a median of 43% of sites used their local IRB in 2013, dropping to 18% in 2014, 5% in 2015, and only 1% in 2016; i.e., 99% of sites opening trials in 2016 did so using the CIRB. Annual accrual to NCTN trials remained steady through the CIRB adoption; CIRB sites represented a median of 56% of total accrual in 2013 increasing to 87% in 2016. Help-desk and survey data indicate increased acceptance and a reduction of concerns over the 3 years. Previous analyses prior to 2013 reported a median of 70-123 days required from protocol application receipt to final CIRB approval; the new model reports a median of 41 days in 2016. Conclusions: NCI has demonstrated that a single IRB for multi-site trials is not only viable but valuable. Its new CIRB model rollout over 3 years has resulted in a doubling of site adoption, high utilization rates, further efficiencies, and overall acceptance, with no noticeable effect on overall NCTN accrual. Our experiences provide important lessons learned and insights into the successful implementation of a single IRB at a national level, and support the feasibility of NIH’s recently finalized policy requiring all sites to use a single IRB for multi-site research.
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Scherer, Roberta W., Leonora D. Sensinger, Benigno Sierra-Irizarry, and Craig Formby. "Lessons learned conducting a multi-center trial with a military population: The Tinnitus Retraining Therapy Trial." Clinical Trials 15, no. 5 (May 23, 2018): 429–35. http://dx.doi.org/10.1177/1740774518777709.
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Background The Tinnitus Retraining Therapy Trial (TRTT), a randomized, placebo-controlled, multi-center trial, evaluated the efficacy of tinnitus retraining therapy and its individual components, tinnitus-specific educational counseling and sound therapy versus the standard of care, in military practice to improve study participants’ quality of life. The trial was conducted at six US military hospitals to take advantage of the greater prevalence of tinnitus in the military population. Methods During the trial, various challenges arose that were uniquely related to the military setting. To convey these challenges to investigators planning future multi-center trials in military hospitals, we itemized various challenges that arose during the trial, interviewed clinic directors and coordinators to elicit their viewpoints, and then collated and organized their responses, together with those challenges presented while conducting the Tinnitus Retraining Therapy Trial. Results We encountered challenges in site selection, the approval process, administrative issues, study personnel training and retention, participant recruitment methods and issues, adherence to protocol, reimbursement issues, and military security. Site selection involved visiting 20 military hospitals to identify six sites that enrolled and followed study participants. We found that commitment for the trial must be obtained from the full military chain of command, but with ongoing changes in staff or military priorities, initial commitments were insufficient to sustain support throughout the entire trial. More time is required to obtain necessary administrative approvals by various military authorities and institutional review boards than is typically experienced in civilian settings. Recruitment strategies must be flexible due to changing military regulations regarding display of materials. Protracted periods of inactivity were due to sequestration and delays in institutional review board approval of required study personnel or protocol amendments. While mostly adherent to the protocol, study staff had difficulties in integrating study visits into the military clinical schedule. Unexpected study expenses revolved around hiring civilian study staff and obtaining associated security clearance while maintaining a consistent flow of funds to each site. The added expense negated cost savings realized by conducting the National Institutes of Health–funded trial at federal institutions, whose personnel could not be reimbursed for their efforts. Military security concerns impacted the use of web-based data systems and led to increased time and effort required for site visits. Conclusion Overall, US military hospitals provide a unique setting to conduct multi-center trials. Challenges arise mainly due to ever-changing authority personnel and military priorities. Pre-planning and flexibility are keys in overcoming these challenges. Multi-center trials conducted in the military will likely take longer to initiate and complete than those in the civilian sector due to multiple levels of command and administrative approvals.
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Voyten, Jamie, Matthew Peter Holtzman, Liron Pantanowitz, Rajiv Dhir, H. Scott Beasley, Jackie Cuda, and Sara Elizabeth Monaco. "Lessons learned from clinical trial queries on small biopsy collections from an academic cancer center." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e14016-e14016. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e14016.
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e14016 Background: Small biopsies and cytology specimens are becoming increasingly important for clinical trials and biomarker testing. Thus, institutions must ensure that there is adequate lesional material meeting specifications for a multitude of different protocols, which can involve rapid on-site evaluation (ROSE). The aim of this study is to look at the recent clinical trial biopsy characteristics and feedback on these collections at our institution. Methods: Clinical trial biopsies performed at our institution and trial feedback (so called “queries”) were analyzed from the past two years (2017-2019). The query data was reviewed in detail, in addition to protocol modifications related to biopsy requirements and study protocol changes. Results: A total of 698 biopsy collections were performed for clinical trial purposes for 95 trials, with the majority of these requiring biopsies at more than 1 time point (63.2%), for phase 1 or 2 trials (92.6%), and for specific tumor types (67.4%). Only 18 (18.9%) of the 95 trials requiring fresh tissue biopsies provided feedback. This included 90 (12.9%) cases, of which 27 (30.0%) had queries regarding insufficient (10, 37.0%) or borderline (17, 63.0%) tumor, and only 1 (3.7%) of these had ROSE by cytology. ROSE was performed due to institutional guidelines (45.3%), requirement by study (1.1%), or trial modification (5.3%).(Table). Conclusions: This investigation shows the high volume of clinical trial biopsies managed at our academic cancer center. Feedback from trials is low at 18.9%, and frequently involves suboptimal cases without ROSE at acquisition, which has led to more widespread adoption of ROSE to mitigate insufficient biopsies and repeat procedures. The high volume of clinical trial biopsies and variability in trial needs necessitates a collaborative multi-disciplinary network to facilitate these important biopsies for cancer patients. [Table: see text]
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Richardson, Lindsey, Kaitlyn Jaffe, M. Eugenia Socias, Bernard Le Foll, Ron Lim, and Didier Jutras-Aswad. "Research Participation in Substance Use Disorder Trials: Design and Methods of a Multi-Site Nested Qualitative Study." International Journal of Qualitative Methods 21 (January 2022): 160940692211311. http://dx.doi.org/10.1177/16094069221131168.
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Background Given the health and social harms of problematic substance use, randomized controlled trials (RCTs) are critical in developing and testing pharmacotherapies for substance use disorders. However, substance use RCTs can be challenging to conduct, considering the social and structural barriers to participating in research among people with substance use disorders (PSUD), including stigma, poverty, and criminalization—factors that can shape trial recruitment, enrollment, protocol adherence and study retention. Despite these barriers, adequate representation and participation of PSUD in RCT research is essential to assessing and developing treatments, and thus a deeper understanding of RCT participation dynamics among PSUD is needed to support clinical trial research. Methods We conducted a nested qualitative study within a Canadian, multisite, phase IV, open-label, pragmatic RCT that tested two approved opioid agonist treatments, methadone and buprenorphine/naloxone, among patients with prescription opioid use disorder. A subset of individuals ( n = 60) participating in this RCT were interviewed across four different regions in Canada at the beginning and end of their trial involvement, as well as study clinicians ( n = 16) and staff ( n = 16) operating the trial. Conclusion As a nested study within a real-world addiction medicine trial, this research offers an innovative approach to investigating the experiences, strategies, and challenges associated with RCTs among PSUD. While we acknowledge challenges related to the operations of multisite research and engaging marginalized populations in experimental research, this study has the potential to generate critical insights around the RCT experiences of PSUDs and trial staff to inform the conduct of future RCTs.
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McKinnon, Lyle R., Sean M. Hughes, Stephen C. De Rosa, Jeffrey A. Martinson, Jill Plants, Kirsten E. Brady, Pamela P. Gumbi, et al. "Optimizing Viable Leukocyte Sampling from the Female Genital Tract for Clinical Trials: An International Multi-Site Study." PLoS ONE 9, no. 1 (January 15, 2014): e85675. http://dx.doi.org/10.1371/journal.pone.0085675.
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Horigian, Viviana E., Renae D. Schmidt, Dikla Shmueli-Blumberg, Kathryn Hefner, Judith Feinberg, Radhika Kondapaka, Daniel J. Feaster, et al. "Suicidality as a Predictor of Overdose among Patients with Substance Use Disorders." Journal of Clinical Medicine 11, no. 21 (October 29, 2022): 6400. http://dx.doi.org/10.3390/jcm11216400.
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Increasing rates of overdose and overdose deaths are a significant public health problem. Research has examined co-occurring mental health conditions, including suicidality, as a risk factor for intentional and unintentional overdose among individuals with substance use disorder (SUD). However, this research has been limited to single site studies of self-reported outcomes. The current research evaluated suicidality as a predictor of overdose events in 2541 participants who use substances enrolled across eight multi-site clinical trials completed within the National Drug Abuse Treatment Clinical Trials Network between 2012 to 2021. The trials assessed baseline suicidality with the Concise Health Risk Tracking Self-Report (CHRT-SR). Overdose events were determined by reports of adverse events, cause of death, or hospitalization due to substance overdose, and verified through a rigorous adjudication process. Multivariate logistic regression was performed to assess continuous CHRT-SR score as a predictor of overdose, controlling for covariates. CHRT-SR score was associated with overdose events (p = 0.03) during the trial; the likelihood of overdose increased as continuous CHRT score increased (OR 1.02). Participants with lifetime heroin use were more likely to overdose (OR 3.08). Response to the marked rise in overdose deaths should integrate suicide risk reduction as part of prevention strategies.
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Lovell, A., R. Ford, T. Monninger, and E. Perlman. "Use of radionuclide bone scans in multicenter clinical trials: Opportunities for quality improvement." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e17534-e17534. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e17534.
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e17534 Background: Radionuclide bone scans are widely utilized to screen for osseous metastases given their high sensitivity for detection of metastatic disease. However, the variance in image quality can significantly impact the diagnostic interpretation. Methods: Prospective assessment of image quality on 478 digital and hard copy planar bone scans received as part of several multi-center clinical trials was completed using a two reviewer paradigm. To improve image quality, the following steps were taken: an Internal Image Quality Task Committee was formed, a comprehensive training program for all internal quality control reviewers was completed, and a site qualification process was initiated prior to site selection and/or subject enrollment with direct feedback to the sites. Results: Significant image quality issues potentially limiting the diagnostic interpretation of the radionuclide scans were initially identified in 21% of the submitted radionuclide bone scans. Quality issues were based on: technical factors, poor imaging technique, and subject factors which could not be corrected. A discordance rate of 4.3% among the two reviewers was also measured. After institution of the above steps, the net result was a 58% decrease in the quality control issues that were previously identified. The most significant improvements occurred on the basis of the site qualification process where sites changed from sending hard copy to digital images and there was direct feedback from the Imaging Core Lab to the sites to correct identified issues. Conclusions: Image quality of bone scans in multicenter clinical trials can be improved with direct communication coupled with a site qualification process prior to subject enrollment. We suspect these quality improvements will impact event driven endpoints that rely on the accurate assessment of bone lesions. We further suspect this level of quality control will continue to increase in importance as technology evolves to include hybrid scanning techniques such as SPECT/CT. This parallels our experience in the level of quality control and site qualification required for deployment of FDG-PET imaging in multicenter clinical trials. [Table: see text]
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Voynick, Irene M. "P24 Role of site and central laboratories in multi-center clinical trials: An illustration from a VA cooperative infectious disease trial." Controlled Clinical Trials 14, no. 5 (October 1993): 436. http://dx.doi.org/10.1016/0197-2456(93)90156-8.
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Holbein, Blair, Marie T. Rape, Barbara N. Hammack, Ann Melvin, Carson Reider, and Tamsin A. Knox. "Institutionally chartered Data and Safety Monitoring Boards: structured approaches to assuring participant safety in clinical research." Journal of Investigative Medicine 69, no. 5 (June 2021): 1050–55. http://dx.doi.org/10.1136/jim-2021-001779.
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Data and Safety Monitoring Boards (DSMBs) derived from the need to monitor large federally funded multi-center clinical trials and evolved to include commercial and other large and complex trials. Eventually, academic health centers also created institutionally focused trial monitoring mechanisms. The basic general principles that define traditional DSMBs extend to the institutional level. The primary responsibilities are assuring safety of the participants, preserving the integrity of the trial, and ensuring the reliability of the results. Institutionally chartered DSMBs meet these responsibilities but usually have fewer members, have a structure specific to the needs of the trial, are more focused and/or have different scope reviewing smaller, single site, higher risk, and investigator-initiated studies and are flexible to accommodate institution-specific requirements and approaches. Their purpose is to meet the responsibilities of oversight for safety and data integrity, ensure proper study design, rigor and conduct, as well as provide statistical support appropriate to the setting of the research. Academic health centers should recognize the importance and existence of institution level safety and data monitoring and provide support as much as possible. Investigators should have sufficient resources available to assemble DSMBs. The Clinical and Translational Science Awards Collaborative DSMB Workgroup provides an online manual to assist investigators.
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Zarei, Shadi, Sarah Colman, Aviva Rostas, Amer M. Burhan, Li Chu, Simon JC Davies, Peter Derkach, et al. "The Rationale and Design of Behavioral Interventions for Management of Agitation in Dementia in a Multi-Site Clinical Trial." Journal of Alzheimer's Disease 86, no. 2 (March 22, 2022): 827–40. http://dx.doi.org/10.3233/jad-215261.
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Background: Agitation and aggression are common in patients with Alzheimer’s disease and related dementias and pose a significant burden on patients, caregivers, and the healthcare systems. Guidelines recommend personalized behavioral interventions as the first-line treatment; however, these interventions are often underutilized. The Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) study (ClinicalTrials.gov Identifier # NCT0367220) is a multisite randomized controlled trial comparing an Integrated Care Pathway, that includes a sequential pharmacological algorithm and structured behavioral interventions, with treatment-as-usual to treat agitation in dementia in long-term care and inpatient settings. Objective: To describe the rationale and design of structured behavioral interventions in the StaN study. Methods: Structured behavioral interventions are designed and implemented based on the following considerations: 1) personalization, 2) evidence base, 3) dose and duration, 4) measurement-based care, and 5) environmental factors and feasibility. Results: The process to design behavioral interventions for each individual starts with a comprehensive assessment, followed by personalized, evidence-based interventions delivered in a standardized manner with ongoing monitoring of global clinical status. Measurement-based care is used to tailor the interventions and integrate them with pharmacotherapy. Conclusion: Individualized behavioral interventions in patients with dementia may be challenging to design and implement. Here we describe a process to design and implement individualized and structured behavioral interventions in the context of a multisite trial in long-term care and inpatient settings. This process can inform the design of behavioral interventions in future trials and in clinical settings for the treatment of agitation in dementia.
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Arora, Neeraj, Susan Enguidanos, Huong Nguyen, Richard Mularski, Corita Grudzen, Jennifer Temel, and Joseph Greer. "Optimizing the Delivery of Home-Based Palliative Care: Experiences from PCORI’s Ongoing Large Multi-Site Clinical Trials (FR472)." Journal of Pain and Symptom Management 57, no. 2 (February 2019): 430–31. http://dx.doi.org/10.1016/j.jpainsymman.2018.12.160.
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Erickson, Craig, Walter Kaufmann, Dejan Budimirovic, Ave Lachiewicz, Barbara Haas-Givler, Robert Miller, Jayne Weber, et al. "Best Practices in Fragile X Syndrome Treatment Development." Brain Sciences 8, no. 12 (December 15, 2018): 224. http://dx.doi.org/10.3390/brainsci8120224.
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Preclinical studies using animal models of fragile X syndrome have yielded several agents that rescue a wide variety of phenotypes. However, translation of these treatments to humans with the disorder has not yet been successful, shedding light on a variety of limitations with both animal models and human trial design. As members of the Clinical Trials Committee of the National Fragile X Foundation, we have discussed a variety of recommendations at the level of preclinical development, transition from preclinical to human projects, family involvement, and multi-site trial planning. Our recommendations are made with the vision that effective new treatment will lie at the intersection of innovation, rigorous and reproducible research, and stakeholder involvement.
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Gonsalvez, Irene, Roey Baror, Peter Fried, Emiliano Santarnecchi, and Alvaro Pascual-Leone. "Therapeutic Noninvasive Brain Stimulation in Alzheimer’s Disease." Current Alzheimer Research 14, no. 4 (February 16, 2017): 362–76. http://dx.doi.org/10.2174/1567205013666160930113907.
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Alzheimer’s disease (AD) is a looming public health crisis that currently lacks an effective treatment. Noninvasive Brain Stimulation (NBS), particularly transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), offers a promising alternative approach to pharmacological interventions for an increasing number of neurological and psychiatric conditions. The aim of this review is summarize data from therapeutic trials of NBS in AD and other dementing illnesses. Despite the potential of NBS, there is limited theoretical framework and a lack of guidelines for its applications to AD. Several published clinical trials failed to report key parameters of the interventions thus limiting the utility of the study to assess efficacy and safety. Our review concludes with some suggestions for future studies aimed to advance research into NBS as a potential treatment for the symptoms and disabilities caused by AD and to enable comparison of results across trials. Ultimately, appropriately powered, and controlled, multi-site randomized clinical trials will be needed to evaluate the therapeutic potential of NBS in AD.
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Rockhold, Frank W., Jessica D. Tenenbaum, Rachel Richesson, Keith A. Marsolo, and Emily C. O’Brien. "Design and analytic considerations for using patient-reported health data in pragmatic clinical trials: report from an NIH Collaboratory roundtable." Journal of the American Medical Informatics Association 27, no. 4 (February 6, 2020): 634–38. http://dx.doi.org/10.1093/jamia/ocz226.
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Abstract Pragmatic clinical trials often entail the use of electronic health record (EHR) and claims data, but bias and quality issues associated with these data can limit their fitness for research purposes particularly for study end points. Patient-reported health (PRH) data can be used to confirm or supplement EHR and claims data in pragmatic trials, but these data can bring their own biases. Moreover, PRH data can complicate analyses if they are discordant with other sources. Using experience in the design and conduct of multi-site pragmatic trials, we itemize the strengths and limitations of PRH data and identify situational criteria for determining when PRH data are appropriate or ideal to fill gaps in the evidence collected from EHRs. To provide guidance for the scientific rationale and appropriate use of patient-reported data in pragmatic clinical trials, we describe approaches for ascertaining and classifying study end points and addressing issues of incomplete data, data alignment, and concordance. We conclude by identifying areas that require more research.
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Ritchie, Christine, Amy P. Abernethy, Melissa Aldridge, R. Sean Morrison, and Jean Kutner. "Palliative care research skill development needs: Lessons from the Palliative Care Research Cooperative Group (PCRC)." Journal of Clinical Oncology 33, no. 29_suppl (October 10, 2015): 174. http://dx.doi.org/10.1200/jco.2015.33.29_suppl.174.
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174 Background: The field of palliative care (PC) has grown substantially over the past decade. PC research has not kept pace, however. One contributing factor is the paucity of clinical investigators equipped to conduct rigorous PC studies, especially multisite studies focused on interventions, dissemination and implementation. A core mission of the Palliative Care Research Cooperative (PCRC) is to enhance investigator capacity to conduct applied patient/caregiver-centered research. Methods: The PCRC Investigator Development Center (IDC) performed two needs assessments in 2015: 1) PCRC methodologic Core Directors; and 2) a subset of PCRC junior investigators. Results: Through these two assessments, PCRC identified the following knowledge/skills gaps in planning and implementing multisite clinical trials and implementation research: basic principles of clinical trials, nuts and bolts of multisite clinical trials, special considerations in behavioral and pragmatic clinical trials, testing treatment efficacy vs testing treatment effectiveness, selection of endpoints and measurement tools, recruitment and adherence issues unique to palliative care populations, data safety monitoring, budgeting and development of protocols/training for multi-site trials. These knowledge/skills gaps were identified by junior investigators as well as by senior investigators whose prior experience is primarily with single-site studies or secondary data analyses. Conclusions: Advancement of PC research requires upskilling of investigators n conduct of multisite studies. The PCRC is partnering with the National Palliative Care Research Center (NPCRC) to make available a range of investigator development resources, including one-on-one mentoring, grant review support, webinars and palliative care research boot camps.
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Potter, Barry V. L. "SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects." Journal of Molecular Endocrinology 61, no. 2 (August 2018): T233—T252. http://dx.doi.org/10.1530/jme-18-0045.
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Steroid sulphatase is an emerging drug target for the endocrine therapy of hormone-dependent diseases, catalysing oestrogen sulphate hydrolysis to oestrogen. Drug discovery, developing the core arylO-sulphamate pharmacophore, has led to steroidal and non-steroidal drugs entering numerous clinical trials, with promising results in oncology and women’s health. Steroidal oestrogen sulphamate derivatives were the first irreversible active-site-directed inhibitors and one was developed clinically as an oral oestradiol pro-drug and for endometriosis applications. This review summarizes work leading to the therapeutic concept of sulphatase inhibition, clinical trials executed to date and new insights into the mechanism of inhibition of steroid sulphatase. To date, the non-steroidal sulphatase inhibitor Irosustat has been evaluated clinically in breast cancer, alone and in combination, in endometrial cancer and in prostate cancer. The versatile core pharmacophore both imbues attractive pharmaceutical properties and functions via three distinct mechanisms of action, as a pro-drug, an enzyme active-site-modifying motif, likely through direct sulphamoyl group transfer, and as a structural component augmenting activity, for example by enhancing interactions at the colchicine binding site of tubulin. Preliminary new structural data on thePseudomonas aeruginosaarylsulphatase enzyme suggest two possible sulphamate-based adducts with the active site formylglycine as candidates for the inhibition end product via sulphamoyl or sulphonylamine transfer, and a speculative choice is suggested. The clinical status of sulphatase inhibition is surveyed and how it might develop in the future. Also discussed are dual-targeting approaches, development of 2-substituted steroidal sulphamates and non-steroidal derivatives as multi-targeting agents for hormone-independent tumours, with other emerging directions.
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Joubert, R., U. Raeth, and T. Moehler. "Variation in enrollment of colorectal cancer patients in clinical trials." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e15094-e15094. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e15094.
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e15094 Background: Correct estimation of patient enrollment is an important success factor for planning clinical studies including studies for metastatic colorectal cancer (CRC). Methods: We reviewed all CRC studies published in the Journal of Clinical Oncology and Annals of Oncology between 01/2007 and 10/01/2008. 43 studies were found and the following data were collected from 39 studies: indication, phase, number of sites, number of patients enrolled, mean patient age, recruitment time, sponsor (Industry, NIH, Organization, University), region, line of treatment and type of drug (6 categories). 4 studies were omitted from analysis as recruitment data were largely missing. Our analysis is based on a literature review as information from unpublished trials is unavailable. This implies some limitations regarding the data interpretation. Results: An average enrollment of 0.92 Patient/Site/Month (range 0.10–7.38) was observed for these trials. The highest recruitment efficacy with a median of 4.11 Pt/S/M (range 1.81–7.38) was found in 5 single institution phase II trials. For multi-center phase II and III studies the median enrollment was 1.82 and 0.32 Pt/S/M respectively, with significant higher recruitment in phase II studies. The highest enrollment rate was observed for studies located in Europe or in USA (0.77 and 2.21 Pt/S/M respectively, p=0.03). No correlation was seen with the mechanism of action (targeted drug vs. chemotherapy), sponsor (NIH vs. Industry vs. IIT), line of treatment (first line vs. 2nd and subsequent line). For phase I recruitment analysis we retrieved 2 studies that investigated novel agents in solid tumor patients including advanced or metastatic colorectal cancer patients with a median recruitment of 0.46 Pt/S/M. For phase Ib and I/II recruitment analysis 5 studies were found with a median recruitment of 0.78 Pt/S/M. Conclusions: Single institution phase II clinical trials on novel agents with high potential to change future treatment standard demonstrate almost a tenfold higher than average recruitment rate for multi-center trials (0.45 Pt/S/M). Despite some limitations in the interpretation of results our analysis provides important information to support estimation of patient recruitment in future clinical trials for colorectal cancer. No significant financial relationships to disclose.
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Aryal, Diptesh, Abi Beane, Arjen M. Dondorp, Cameron Green, Rashan Haniffa, Madiha Hashmi, Devachandran Jayakumar, et al. "Operationalisation of the Randomized Embedded Multifactorial Adaptive Platform for COVID-19 trials in a low and lower-middle income critical care learning health system." Wellcome Open Research 6 (January 28, 2021): 14. http://dx.doi.org/10.12688/wellcomeopenres.16486.1.
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The Randomized Embedded Multifactorial Adaptive Platform (REMAP-CAP) adapted for COVID-19) trial is a global adaptive platform trial of hospitalised patients with COVID-19. We describe implementation in three countries under the umbrella of the Wellcome supported Low and Middle Income Country (LMIC) critical care network: Collaboration for Research, Implementation and Training in Asia (CCA). The collaboration sought to overcome known barriers to multi centre-clinical trials in resource-limited settings. Methods described focused on six aspects of implementation: i, Strengthening an existing community of practice; ii, Remote study site recruitment, training and support; iii, Harmonising the REMAP CAP- COVID trial with existing care processes; iv, Embedding REMAP CAP- COVID case report form into the existing CCA registry platform, v, Context specific adaptation and data management; vi, Alignment with existing pandemic and critical care research in the CCA. Methods described here may enable other LMIC sites to participate as equal partners in international critical care trials of urgent public health importance, both during this pandemic and beyond.
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Moni, J., H. T. Le-Petross, J. C. Boughey, F. Laurie, R. Hanusik, S. Howley, D. G. Logan, et al. "Quality assurance review center: Role in multi-institutional breast cancer trials." Journal of Clinical Oncology 29, no. 27_suppl (September 20, 2011): 205. http://dx.doi.org/10.1200/jco.2011.29.27_suppl.205.
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205 Background: Central review is an important trial management and validation tool. Multisite trials require data systems to accommodate diverse image acquisition and review. Breast cancer is challenging as its imaging objects are not always easily shared across departments. Quality Assurance Review Center (QARC) has a diverse portfolio of facile data acquisition and powerful informatics support that meets these needs. We report on the role of QARC in three of the current breast cancer trials from the American College of Surgeons Oncology Group. Methods: QARC data management system includes secure network infrastructure and a validated relational operating database (MAX). QARC has data acquisition/imaging re-distribution expertise for real time response reviews, response measuring tools and corresponding data archive for secondary reviews. MAX includes query ability; records link to digital information. QARC underwent systematic information systems validation process for 21 CFR Part 11. DICOM/non-DICOM files are stored in the QARC PACS. On-site/remote reviewers use MAX to retrieve, view, annotate and save images. Data extracted is securely sent to partner statistical centers. Results: In Z1031, a neoadjuvant endocrine therapy trial, all of the mammographic exams are archived at QARC. For Z1071, a sentinel lymph node trial, pre- and post-treatment ultrasound (US) images of 321 patients were remotely reviewed. For Z1072, the cryoablation US, pre and post-cryoablation MRI for 40 of 47 cases were remotely archived, retrieved and transferred to investigator workstation for post-processing and review. The other 7 patients did not have evaluable imaging studies. In all three trials, the costs of shipping hardcopies of exams and travel to QARC for central review functions were eliminated. Conclusions: QARC data management systems provide diverse informatics supports for multi-institutional trials, ranging from archives of images, provide remote access and download of data, and central review. The vibrant informatics supports meet the growing needs of clinical trials. Future directions include radiation field review for breast cancer trials and the incorporation of pathology microarray analysis as DICOM objects.
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Cuccione, Elisa, Alessandro Versace, Tae-Hee Cho, Davide Carone, Lise-Prune Berner, Elodie Ong, David Rousseau, et al. "Multi-site laser Doppler flowmetry for assessing collateral flow in experimental ischemic stroke: Validation of outcome prediction with acute MRI." Journal of Cerebral Blood Flow & Metabolism 37, no. 6 (July 28, 2016): 2159–70. http://dx.doi.org/10.1177/0271678x16661567.
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High variability in infarct size is common in experimental stroke models and affects statistical power and validity of neuroprotection trials. The aim of this study was to explore cerebral collateral flow as a stratification factor for the prediction of ischemic outcome. Transient intraluminal occlusion of the middle cerebral artery was induced for 90 min in 18 Wistar rats. Cerebral collateral flow was assessed intra-procedurally using multi-site laser Doppler flowmetry monitoring in both the lateral middle cerebral artery territory and the borderzone territory between middle cerebral artery and anterior cerebral artery. Multi-modal magnetic resonance imaging was used to assess acute ischemic lesion (diffusion-weighted imaging, DWI), acute perfusion deficit (time-to-peak, TTP), and final ischemic lesion at 24 h. Infarct volumes and typology at 24 h (large hemispheric versus basal ganglia infarcts) were predicted by both intra-ischemic collateral perfusion and acute DWI lesion volume. Collateral flow assessed by multi-site laser Doppler flowmetry correlated with the corresponding acute perfusion deficit using TTP maps. Multi-site laser Doppler flowmetry monitoring was able to predict ischemic outcome and perfusion deficit in good agreement with acute MRI. Our results support the additional value of cerebral collateral flow monitoring for outcome prediction in experimental ischemic stroke, especially when acute MRI facilities are not available.
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Pevnick, Joshua, Michelle Keller, Korey Kennelty, Michelle Ko, Logan Murry, An Nguyen, Andrew Henreid, and Jeffrey Schnipper. "Addressing COVID-19 Barriers to Clinical Trial Enrollment and Implementation in the PHARM-DC Study." Innovation in Aging 5, Supplement_1 (December 1, 2021): 103. http://dx.doi.org/10.1093/geroni/igab046.393.
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Abstract Recent hospitalization puts older adults at higher risk of experiencing adverse drug events (ADEs) that are a common cause of hospital readmission. Yet, most ADEs are preventable. The PHARMacist Discharge Care (PHARM-DC) study is a multi-site randomized controlled trial that seeks to evaluate the effect of pharmacist-led peri- and post-discharge interventions on 30-day hospital readmissions among older adults taking ≥10 medications or ≥3 high-risk medications. The PHARM-DC intervention includes pharmacist-led patient counseling, medication reconciliation at discharge, and a follow-up phone call post-discharge. We will highlight study protocol adaptations undertaken during the COVID-19 pandemic to address challenges to enrollment and to minimize risk of COVID-19 exposure for study participants and research personnel. Additionally, we will share insights from focus groups and semi-structured interviews with pharmacist interventionists and pharmacy leaders on barriers and facilitators to implementation due to the pandemic and strategies for future clinical trials to overcome barriers.
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Hill, Marcus. "Grassroots Approaches To Community-Based Representative Recruitment In Multidomain Trials." Innovation in Aging 5, Supplement_1 (December 1, 2021): 67–68. http://dx.doi.org/10.1093/geroni/igab046.260.
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Abstract U.S. POINTER is a randomized, controlled, multi-domain clinical trial to slow the progression of cognitive decline within the American population via tailored and culturally-appropriate healthy lifestyle interventions. For findings to be broadly relevant across the American population, incorporating an inclusive and robust recruitment effort has been essential to form a diverse and properly representative participant cohort. As such, the trial’s inclusive enrollment goal is 30% from traditionally underrepresented communities that include those at elevated risk for Alzheimer’s disease and related disorders. To accomplish this goal, U.S. POINTER developed and deployed a grassroots recruitment strategy in partnership with outreach specialists at each site that includes a mix of evidence-based and innovative community engagement approaches. While the COVID-19 pandemic continues to present unique challenges for recruitment, our team has been able to strategize ways to continue working within the community to support trial recruitment. An overview of these methods will be presented.
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Frances Ndyetukira, Jane, Richard Kwizera, Florence Kugonza, Cynthia Ahimbisibwe, Carol Namujju, Alisat Sadiq, Alice Namudde, et al. "The conundrum of clinical trials and standard of care in sub-Saharan Africa – the research nurse perspective." Journal of Research in Nursing 24, no. 8 (March 26, 2019): 649–60. http://dx.doi.org/10.1177/1744987118824625.
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Background Nurses form a very important part of the health workforce in sub-Saharan Africa. Research nurses are critical to the implementation of clinical trials. The duties and responsibilities of a research nurse are complex and continue to evolve as new practices and guidelines are formulated. Aims In this paper, we have highlighted the major contributions of research nurses in HIV clinical trials in sub-Saharan Africa from the unique perspective of Ugandan nurses. Methods The requirements and challenges of two multi-site, randomised cryptococcal meningitis clinical trials in Uganda were assessed from the perspective of research nurses conducting complex research in resource-limited settings. Results Over the course of 8 years, approximately 1739 participants were screened and 934 people were enrolled into the two trials. The nurses found that patient education and engagement were among the most important predictors of success in minimising loss to follow-up. Conclusions Research nurses played a key role in communicating clinical research goals to patients, obtaining informed consent, minimising loss to follow-up, and ensuring that research practices are translated and implemented into standard of care. However, there remains a need to integrate the same level of care provided in clinical research studies to non-study patients.
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Veeraraghavan, Harini, Herbert Alberto Vargas, Alejandro-Jiménez Sánchez, Maura Micco, Eralda Mema, Yulia Lakhman, Mireia Crispin-Ortuzar, et al. "Integrated Multi-Tumor Radio-Genomic Marker of Outcomes in Patients with High Serous Ovarian Carcinoma." Cancers 12, no. 11 (November 17, 2020): 3403. http://dx.doi.org/10.3390/cancers12113403.
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Purpose: Develop an integrated intra-site and inter-site radiomics-clinical-genomic marker of high grade serous ovarian cancer (HGSOC) outcomes and explore the biological basis of radiomics with respect to molecular signaling pathways and the tumor microenvironment (TME). Method: Seventy-five stage III-IV HGSOC patients from internal (N = 40) and external factors via the Cancer Imaging Archive (TCGA) (N = 35) with pre-operative contrast enhanced CT, attempted primary cytoreduction, at least two disease sites, and molecular analysis performed within TCGA were retrospectively analyzed. An intra-site and inter-site radiomics (cluDiss) measure was combined with clinical-genomic variables (iRCG) and compared against conventional (volume and number of sites) and average radiomics (N = 75) for prognosticating progression-free survival (PFS) and platinum resistance. Correlation with molecular signaling and TME derived using a single sample gene set enrichment that was measured. Results: The iRCG model had the best platinum resistance classification accuracy (AUROC of 0.78 [95% CI 0.77 to 0.80]). CluDiss was associated with PFS (HR 1.03 [95% CI: 1.01 to 1.05], p = 0.002), negatively correlated with Wnt signaling, and positively to immune TME. Conclusions: CluDiss and the iRCG prognosticated HGSOC outcomes better than conventional and average radiomic measures and could better stratify patient outcomes if validated on larger multi-center trials.
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Shahid, Shahira, Shiyam Sunder Tikmani, Nick Brown, Anita K. M. Zaidi, Fyezah Jehan, and Muhammad Imran Nisar. "Young infant clinical signs study, Pakistan: a data note." Gates Open Research 5 (August 12, 2021): 122. http://dx.doi.org/10.12688/gatesopenres.13317.1.
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Neonatal sepsis is the leading cause of child death globally with most of these deaths occurring in the first week of life. It is of utmost public health importance that clinical signs predictive of severe illness and need for referral are identified early in the course of illness. From 2002-2005, a multi country trial called the Young Infant Clinical Signs Study (YICSS) was conducted in seven sites across three South-Asian (Bangladesh, India, and Pakistan), two African (Ghana, and South Africa), and one South American (Bolivia) country. The study aimed to develop a simplified algorithm to be used by primary healthcare workers for the identification of sick young infants needing prompt referral and treatment. The main study enrolled 8,889 young infants between the ages of 0-59 days old. This dataset contains observations on 2950 young infants aged 0-59 days from the Pakistan site. The data was collected between 2003-2004 with information on the most prevalent signs and symptoms. The data from this study was used to update the Integrated Management of Childhood Illness guidelines. The World Health Organisation (WHO) seven-sign algorithm has been used in other major community-based trials to study possible serious bacterial infection and its treatment regimens.
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Currow, David Christopher, Tania M. Shelby-James, Meera Agar, John Plummer, Deborah Rowett, Paul Glare, Odette Spruyt, and Janet Hardy. "Planning phase III multi-site clinical trials in palliative care: the role of consecutive cohort audits to identify potential participant populations." Supportive Care in Cancer 18, no. 12 (November 29, 2009): 1571–79. http://dx.doi.org/10.1007/s00520-009-0780-6.
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Winter, Helen, Joanna Willis, Stephen Lang, Kay Drury, Jonathan Heywood, Jeremy Bewley, Natalie Blencowe, et al. "Building capacity and ensuring equity in clinical trials during the COVID-19 pandemic." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e13598-e13598. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e13598.
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e13598 Background: The impact on cancer outcomes from the Covid-19 pandemic has yet to be determined. Concerns persist on screening, delays in diagnosis, treatment interruptions and outcomes of infection in the immunosuppressed. The need for agile working has been exemplified by establishment of Nightingale Hospitals, staff redeployment and sudden integration of virtual consultations into clinical working. With most cancer clinical trials halted, recruitment into COVID-19 research became essential and embedded into the everyday. Here we present how rapid implementation of COVID-19 randomised clinical trials within an NHS organisation during the pandemic was achieved. Methods: A COVID-19 senior facilitation committee was set up to provide oversight, maximise staff capacity and resource and prioritise studies. Specific strategies to maximise access and clinical trials recruitment for patients including children and those with solid tumours were designed. These included presence of a research nurse at clinical ward rounds and team meetings, the promotion of protocol and informed consent training to all including doctors in the acute settings and weekly research meetings to share-best practice. Reflecting on learnings from this time provide an opportunity to consider how we adjust working for our patients in the future. Results: The integration of research into the everyday working of clinical teams looking after patients with COVID-19 has become the norm. The provision of protocol and informed consent training for all levels of staff and the consideration of all patients for trials during clinical ward rounds and multi-disciplinary meetings, have ensured access to trials has become embedded. The integration of research nurses working, upskilling and prompting clinical colleagues has ensured equity of access and provided a research presence and focus during the busy clinical day. The adoption of cross-disciplinary working, sharing best practice and a culture of commitment and support to the trials ensures no patient is denied the opportunity to participate. Three RTCs opened over 7 weeks. At one site 1904 patients were screened for one of the randomised-controlled trials and over 18% of these patients (351) were recruited and 175 patients declined. Conclusions: The pandemic has had a devastating impact across the UK. However, a coordinated and collaborative multi-disciplinary approach has supported high recruitment and equity of access for patients into COVID-19 trials. Learnings from this work may lead to embedding clinical trials and access to translational research for cancer patients in the future as we recover from the full impact of the pandemic. COVID-19 research has demonstrated how increased recruitment accelerates access and implementation of new innovations and novel drug combinations.The full impact of improved access to cancer research in the future during COVID recovery is worthy of more research.