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New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by facilitating participation outside of traditional clinical settings and taking studies directly to participants. The Trial Innovation Network, established in 2016 by the National Center for Advancing Clinical and Translational Science to address critical roadblocks in clinical research and accelerate the translational research process, has consulted on over 400 research study proposals to date. Its recommendations for decentralized approaches have included eConsent, participant-informed study design, remote intervention, study task reminders, social media recruitment, and return of results for participants. Some clinical trial elements have worked well when decentralized, while others, including remote recruitment and patient monitoring, need further refinement and assessment to determine their value. Partially decentralized, or “hybrid” trials, offer a first step to optimizing remote methods. Decentralized processes demonstrate potential to improve urban-rural diversity, but their impact on inclusion of racially and ethnically marginalized populations requires further study. To optimize inclusive participation in decentralized clinical trials, efforts must be made to build trust among marginalized communities, and to ensure access to remote technology.
One challenge for multisite clinical trials is ensuring that the conditions of an informative trial are incorporated into all aspects of trial planning and execution. The multicenter model can provide the potential for a more informative environment, but it can also place a trial at risk of becoming uninformative due to lack of rigor, quality control, or effective recruitment, resulting in premature discontinuation and/or non-publication. Key factors that support informativeness are having the right team and resources during study planning and implementation and adequate funding to support performance activities. This communication draws on the experience of the National Center for Advancing Translational Science (NCATS) Trial Innovation Network (TIN) to develop approaches for enhancing the informativeness of clinical trials. We distilled this information into three principles: (1) assemble a diverse team, (2) leverage existing processes and systems, and (3) carefully consider budgets and contracts. The TIN, comprised of NCATS, three Trial Innovation Centers, a Recruitment Innovation Center, and 60+ CTSA Program hubs, provides resources to investigators who are proposing multicenter collaborations. In addition to sharing principles that support the informativeness of clinical trials, we highlight TIN-developed resources relevant for multicenter trial initiation and conduct.
The Trial Innovation Network has established an infrastructure for single IRB review in response to federal policies. The Network’s single IRB (sIRBs) have successfully supported over 70 multisite studies via more than 800 reliance arrangements. This has generated several lessons learned that can benefit the national clinical research enterprise, as we work to improve the conduct of clinical trials. These lessons include distinguishing the roles of the single IRB from institutional Human Research Protections programs, establishing a consistent sIRB review model, standardizing collection of local context and supplemental, study-specific information, and educating and empowering lead study teams to support their sites.
As clinical trials were rapidly initiated in response to the COVID-19 pandemic, Data and Safety Monitoring Boards (DSMBs) faced unique challenges overseeing trials of therapies never tested in a disease not yet characterized. Traditionally, individual DSMBs do not interact or have the benefit of seeing data from other accruing trials for an aggregated analysis to meaningfully interpret safety signals of similar therapeutics. In response, we developed a compliant DSMB Coordination (DSMBc) framework to allow the DSMB from one study investigating the use of SARS-CoV-2 convalescent plasma to treat COVID-19 to review data from similar ongoing studies for the purpose of safety monitoring.
The DSMBc process included engagement of DSMB chairs and board members, execution of contractual agreements, secure data acquisition, generation of harmonized reports utilizing statistical graphics, and secure report sharing with DSMB members. Detailed process maps, a secure portal for managing DSMB reports, and templates for data sharing and confidentiality agreements were developed.
Four trials participated. Data from one trial were successfully harmonized with that of an ongoing trial. Harmonized reports allowing for visualization and drill down into the data were presented to the ongoing trial’s DSMB. While DSMB deliberations are confidential, the Chair confirmed successful review of the harmonized report.
It is feasible to coordinate DSMB reviews of multiple independent studies of a similar therapeutic in similar patient cohorts. The materials presented mitigate challenges to DSMBc and will help expand these initiatives so DSMBs may make more informed decisions with all available information.
For decades, the research community called for streamlined Institutional Review Board (IRB) review processes for multisite studies. Department of Health and Human Services and National Institutes of Health (NIH) recognized this need and implemented single IRB (sIRB) of record mandates. However, announcing mandates without sufficient operational guidance and tools is insufficient to foster the desired change. Nearly 4 years into implementation of the NIH’s sIRB mandate, operational challenges remain. Fortunately, NIH supports a web-based sIRB platform, the IRB Reliance Exchange (IREx), to facilitate sIRB communication and documentation. IREx has received continuous NIH funding supporting its evolution since 2011 and is now used by over 5,000 Human Research Protection Program and research personnel, 35 sIRBs, and 415 participating sites to operationalize sIRB review and approval on over 400 studies. IREx supports over 2300 reliance relationships with an average of 7 sites per study. The platform is continually used by sIRBs and relying sites, providing a valuable centralized portal for promoting a harmonized sIRB review process. IREx can promote transparency, standardize practice, minimize workflow variation, and mitigate the need for sIRBs to implement significant technical changes to their local electronic systems. IREx has proven to be nimble and adaptable with practice and policy changes over the past decade, as evidenced by continually increasing platform utilization.
Clinical trials continue to face significant challenges in participant recruitment and retention. The Recruitment Innovation Center (RIC), part of the Trial Innovation Network (TIN), has been funded by the National Center for Advancing Translational Sciences of the National Institutes of Health to develop innovative strategies and technologies to enhance participant engagement in all stages of multicenter clinical trials. In collaboration with investigator teams and liaisons at Clinical and Translational Science Award institutions, the RIC is charged with the mission to design, field-test, and refine novel resources in the context of individual clinical trials. These innovations are disseminated via newsletters, publications, a virtual toolbox on the TIN website, and RIC-hosted collaboration webinars. The RIC has designed, implemented, and promised customized recruitment support for 173 studies across many diverse disease areas. This support has incorporated site feasibility assessments, community input sessions, recruitment materials recommendations, social media campaigns, and an array of study-specific suggestions. The RIC’s goal is to evaluate the efficacy of these resources and provide access to all investigating teams, so that more trials can be completed on time, within budget, with diverse participation, and with enough accrual to power statistical analyses and make substantive contributions to the advancement of healthcare.
Potential participants seek information about clinical trials for many reasons, but the process can be challenging. We analyzed 101,249 searches in ResearchMatch Trials Today, a free interface to recruiting trials from ClinicalTrials.gov. Searches from March 2015 to November 2016 included a broad range of conditions and healthy volunteer concepts, including 12,649 unique topics. Trials Today data indicate that it is being used to identify trials on a variety of topics.
Inefficiencies in the national clinical research infrastructure have been apparent for decades. The National Center for Advancing Translational Science—sponsored Clinical and Translational Science Award (CTSA) program is able to address such inefficiencies. The Trial Innovation Network (TIN) is a collaborative initiative with the CTSA program and other National Institutes of Health (NIH) Institutes and Centers that addresses critical roadblocks to accelerate the translation of novel interventions to clinical practice. The TIN’s mission is to execute high-quality trials in a quick, cost-efficient manner. The TIN awardees are composed of 3 Trial Innovation Centers, the Recruitment Innovation Center, and the individual CTSA institutions that have identified TIN Liaison units. The TIN has launched a national scale single (central) Institutional Review Board system, master contracting agreements, quality-by-design approaches, novel recruitment support methods, and applies evidence-based strategies to recruitment and patient engagement. The TIN has received 113 submissions from 39 different CTSA institutions and 8 non-CTSA Institutions, with projects associated with 12 different NIH Institutes and Centers across a wide range of clinical/disease areas. Already more than 150 unique health systems/organizations are involved as sites in TIN-related multisite studies. The TIN will begin to capture data and metrics that quantify increased efficiency and quality improvement during operations.
Early results from the SAGE-SMC (Surveying the Agents of Galaxy Evolution in the tidally-disrupted, low-metallicity Small Magellanic Cloud) Spitzer legacy program are presented. These early results concentrate on the SAGE-SMC MIPS observations of the SMC Tail region. This region is the high H i column density portion of the Magellanic Bridge adjacent to the SMC Wing. We detect infrared dust emission and measure the gas-to-dust ratio in the SMC Tail and find it similar to that of the SMC Body. In addition, we find two embedded cluster regions that are resolved into multiple sources at all MIPS wavelengths.
We are performing a uniform and unbiased imaging survey of the Large Magellanic Cloud (LMC), using the IRAC and MIPS instruments on board the Spitzer Space Telescope (Spitzer). Meixner et al. (2006) provides an overview of the project and initial results and their Table 1 (repeated here) outlines the survey's salient characteristics. In this project, we are surveying the agents of a galaxys evolution (SAGE), i.e. the interstellar medium (ISM) and stars, and their interaction on the galaxy wide scale of the LMC. Spitzer IRAC and MIPS images provide key insights into the life cycle of matter in a galaxy because the infrared emission from dust grains is an effective tracer of the ISM, star formation, and stellar mass-loss. Three key science goals determined the coverage and depth of the survey. The detection of diffuse ISM with column densities > 1.2×1021 H cm−2 permits detailed studies of dust processes in the ISM. SAGE's point source sensitivity enables a complete census of newly formed stars with masses >3 M⊙ that will determine the current star formation rate in the LMC. SAGE's detection of evolved stars with mass loss rates > 10−8 M⊙ yr−1 will quantify the rate at which evolved stars inject mass into the ISM of the LMC (Blum et al. 2006). The SAGE data are nonproprietary. The preliminary SAGE catalog of epoch 1 photometry, prepared by the SAGE Team and released to the public on January 3, 2006, contains over 4 million IRAC sources, band merged with 2MASS photometry and over 60,000 MIPS 24 micron sources. Preliminary estimates indicate that foreground Milky Way stars and background galaxies may comprise as much as 18% and 12%, respectively, of these catalogs. To learn more about the SAGE project: http://sage.stsci.edu/.
The search for new therapeutic approaches in ARDS has multiple motivations. First, and foremost, is the persistently high mortality associated with current clinical management which ranges from 35% to 80%. Second, a plethora of mediators have been described, as discussed elsewhere in this text, that may be responsible for or significantly contribute to ARDS. Recently a wide variety of seemingly innocuous agents have been identified and purified that have been shown in vitro or in animal models to be able to block the effects of many of the putative mediators of the syndrome. What follows is a discussion of the pharmacologic agents that have received the most attention for their potential to reduce the incidence, severity, or duration of ARDS.
When washed clean of surfactant, the alveolar surface of the lung develops a marked increase in surface tension, which causes the lung to become very noncompliant and collapse at low transpulmonary pressure. Surfactant is a naturally occurring complex of phospholipids, neutral lipids, and several specific proteins that is secreted by type II pneumocytes. The clinical model of pure surfactant deficiency is infant respiratory distress syndrome, IRDS. This process is similar to ARDS, but little or no evidence indicates that surfactant abnormalities are fundamentally pathogenetic in ARDS (as they are in IRDS).
The pressure-volume behavior of the diseased lungs with ARDS has been clearly associated with surfactant depletion/dysfunction. The surfactant lavaged from ARDS patients functions poorly and is of abnormal composition. Native surfactant is impaired by inflammatory substances released by activated granulocytes and is inactivated simply by mixing with pulmonary edema fluid.
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