Impact of financial compensation on enrollment and participation in a remote, mobile-app based research study.

Background: There is no consensus on how to determine appropriate financial compensation for research recruitment. Selecting incentive amounts that are reasonable and respectful, without undue inducement, remains challenging. Previously, we demonstrated that incentive amount significantly impacts participants' willingness to complete various hypothetical research activities. Here we further explore this relationship in a mock decentralized study. Methods: Adult ResearchMatch volunteers were invited to join a prospective study where interested individuals were given an opportunity to view details for a study along with participation requirements, then offered a randomly generated compensation amount between $0 and $50 to enroll and participate. Individuals agreeing to participate were then asked to complete tasks using a remote mobile application (MyCap), for two weeks. Tasks included a weekly survey, a daily gratitude journal and daily phone tapping task. Results: Willingness to participate was 85% across all incentive levels but not significantly impacted by amount. Task completion appeared to increase as a function of compensation until a plateau at $25. While participants described the study as low burden and reported that compensation was moderately important to their decision to join, only 31% completed all study tasks. Conclusion: While offering compensation in this study did not have a strong effect on enrollment rate, this work provides insight into participant motivation when joining and participating in studies employing mobile applications.

A viral lncRNA tethers HSV-1 genomes at the nuclear periphery to establish viral latency.

IMPORTANCE: Herpes simplex virus 1 (HSV-1) establishes lifelong latency in neuronal cells. Following a stressor, the virus reactivates from latency, virus is shed at the periphery and recurrent disease can occur. During latency, the viral lncRNA termed the latency-associated transcript (LAT) is known to accumulate to high abundance. The LAT is known to impact many aspects of latency though the molecular events involved are not well understood. Here, we utilized a human neuronal cell line model of HSV latency and reactivation (LUHMES) to identify the molecular-binding partners of the LAT during latency. We found that the LAT binds to both the cellular protein, TMEM43, and HSV-1 genomes in LUHMES cells. Additionally, we find that knockdown of TMEM43 prior to infection results in a decreased ability of HSV-1 to establish latency. This work highlights a potential mechanism for how the LAT facilitates the establishment of HSV-1 latency in human neurons.

Quantitative assessment of the impact of standard agreement templates on multisite clinical trial start up time.

Contracting delays remain a challenge to the successful initiation of multisite clinical research in the US. The Clinical and Translational Science Awards (CTSA) Contracts Processing Study showed average contract negotiation duration of > 100 days for industry-sponsored or investigator-initiated contracts. Such delays create enormous costs to sponsors and to patients waiting to use new evidence-based treatments. With support from the National Institutes of Health's National Center for Advancing Translational Sciences, the Accelerated Clinical Trial Agreement (ACTA) was developed by 25 major academic institutions and medical centers engaged in clinical research in collaboration with the University-Industry Demonstration Partnership and with input from pharmaceutical companies. The ACTA also informed the development of subsequent agreements, including the Federal Demonstration Partnership Clinical Trial Subaward Agreement (FDP-CTSA); both ACTA and the FDP-CTSA are largely non-negotiable agreements that represent pre-negotiated compromises in contract terms agreed upon by industry and/or medical center stakeholders. When the involved parties agree to use the CTSA-developed and supported standard agreement templates as a starting point for negotiations, there can be significant time savings for trials. Use of the ACTA resulted in an average savings of 48 days and use of the FDP-CTSA saved an average of 57 days of negotiation duration.

Taking AIM at serious illness: implementing an access to investigational medicines expanded access program.

When seriously ill patients have exhausted all treatment options available as part of usual care, the use of investigational agents may be warranted. Food and Drug Administration's (FDA) Expanded Access (EA) pathway provides a mechanism for these patient's physicians to pursue use of an investigational agent outside of a clinical trial when trial enrollment is not a feasible option. Though FDA has recently implemented processes to significantly streamline the regulatory portion of the process, the overall pathway has several time-consuming components including communication with the pharmaceutical company and the associated institutional requirements for EA use (contracting, Institutional Review Board [IRB], pharmacy, billing). Here, we present our experience building infrastructure at the Vanderbilt University Medical Center (VUMC) to support physicians and patients in pursuing EA, called the Access to Investigational Medicines (AIM) Platform, aligning the needs and responsibilities of institutional stakeholders and streamlining to ensure efficiency and regulatory compliance. Since its launch, the AIM team has experienced steady growth, supporting 40 EA cases for drugs/biologics, including both single patient cases and intermediate-size EA protocols in the emergent and non-emergent setting. As the EA pathway is a complex process that requires expert facilitation, we propose prioritizing EA support infrastructure at major academic medical centers as an essential regulatory knowledge function.

Leveraging the Expertise of the CTSA Program to Increase the Impact and Efficiency of Clinical Trials.

Importance: Multicenter clinical trials play a critical role in the translational processes that enable new treatments to reach all people and improve public health. However, conducting multicenter randomized clinical trials (mRCT) presents challenges. The Trial Innovation Network (TIN), established in 2016 to partner with the Clinical and Translational Science Award (CTSA) Consortium of academic medical institutions in the implementation of mRCTs, consists of 3 Trial Innovation Centers (TICs) and 1 Recruitment Innovation Center (RIC). This unique partnership has aimed to address critical roadblocks that impede the design and conduct of mRCTs, in expectation of accelerating the translation of novel interventions to clinical practice. The TIN's challenges and achievements are described in this article, along with examples of innovative resources and processes that may serve as useful models for other clinical trial networks providing operational and recruitment support. Observations: The TIN has successfully integrated more than 60 CTSA institution program hubs into a functional network for mRCT implementation and optimization. A unique support system for investigators has been created that includes the development and deployment of novel tools, operational and recruitment services, consultation models, and rapid communication pathways designed to reduce delays in trial start-up, enhance recruitment, improve engagement of diverse research participants and communities, and streamline processes that improve the quality, efficiency, and conduct of mRCTs. These resources and processes span the clinical trial spectrum and enable the TICs and RIC to serve as coordinating centers, data centers, and recruitment specialists to assist trials across the National Institutes of Health and other agencies. The TIN's impact has been demonstrated through its response to both historical operational challenges and emerging public health emergencies, including the national opioid public health crisis and the COVID-19 pandemic. Conclusions and Relevance: The TIN has worked to reduce barriers to implementing mRCTs and to improve mRCT processes and operations by providing needed clinical trial infrastructure and resources to CTSA investigators. These resources have been instrumental in more quickly and efficiently translating research discoveries into beneficial patient treatments.

The RIC Recruitment & Retention Materials Toolkit - a resource for developing community-informed study materials.

Clinical trials face many challenges with meeting projected enrollment and retention goals. A study's recruitment materials and messaging convey necessary key information and therefore serve as a critical first impression with potential participants. Yet study teams often lack the resources and skills needed to develop engaging, culturally tailored, and professional-looking recruitment materials. To address this gap, the Recruitment Innovation Center recently developed a Recruitment & Retention Materials Content and Design Toolkit, which offers research teams guidance, actionable tips, resources, and customizable templates for creating trial-specific study materials. This paper seeks to describe the creation and contents of this new toolkit.

Decentralized clinical trials in the trial innovation network: Value, strategies, and lessons learned.

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.

Approaches for enhancing the informativeness and quality of clinical trials: Innovations and principles for implementing multicenter trials from the Trial Innovation Network.

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.

HSV-1 LAT Promoter Deletion Viruses Exhibit Strain-Specific and LAT-Dependent Epigenetic Regulation of Latent Viral Genomes in Human Neurons.

Herpes simplex virus 1 (HSV-1) establishes latency in neurons and expresses long noncoding RNAs termed the latency-associated transcripts (LATs). Two previous studies using HSV-1 recombinants containing deletions in the LAT promoter revealed opposing effects of the promoter deletion regarding the heterochromatinization of latent viral genomes in mice ganglia. Confounding variables in these studies include viral strains utilized (17syn+ versus KOS), anatomical infection site (footpad versus eye) and infectious virus dose (500 versus 1 × 105 PFU), and to date the basis for the differences between the two studies remains unresolved. We recently reported that 17syn+ and KOS display distinct differences in heterochromatin levels during latency in human neurons. This raised the possibility that the discrepancy seen between the two previous studies could be explained by strain-specific differences within the LAT region. Here, we examine two recombinants containing orthologous 202 bp LAT promoter deletions, 17ΔPst and KOSΔPst, in a human neuronal model of latency and reactivation (LUHMES). We found that LUHMES neurons recapitulate previous observations in mice where deletion of the LAT promoter results in an increase in H3K27me3 deposition on the viral genome compared to the parental strain 17syn+ but a decrease compared to the parental strain KOS. We also found distinct strain-specific differences in the production of viral transcripts and proteins during latency. These results indicate that the function and/or regulation of the LATs differs between HSV-1 strains and may shed light on some discrepancies found in the literature when examining the function of the LATs. IMPORTANCE Herpes simplex virus 1 (HSV-1) establishes a lifelong infection in neuronal cells. Periodically, the virus reactivates from this latent state and causes recurrent disease. Mechanisms that control entry into and maintenance of latency are not well understood, though epigenetic posttranslational modification of histones associated with the viral genome are known to play an important role. During latency, the latency-associated transcript (LAT) is known to impact epigenetic marks, but the ultimate effect has been a point of controversy. Here, we utilize a human neuronal cell line model of HSV latency and reactivation (LUHMES) to characterize latency for two HSV-1 wild-type strains and their respective LAT promoter deletion viruses. We find that the LAT acts in a strain-specific manner to influence levels of chromatin marks, viral transcription, and viral protein production. This work highlights the need to account for strain-specific differences when characterizing the LAT's function and the dynamics of reactivation.

Using a multicultural and multilingual awareness-raising strategy to enhance enrollment of racially underrepresented minoritized communities - the PassITON trial.

Racially and ethnically minoritized populations have been historically excluded and underrepresented in research. This paper will describe best practices in multicultural and multilingual awareness-raising strategies used by the Recruitment Innovation Center to increase minoritized enrollment into clinical trials. The Passive Immunity Trial for Our Nation will be used as a primary example to highlight real-world application of these methods to raise awareness, engage community partners, and recruit diverse study participants.

Treatment of infection and inflammation associated with COVID-19, multi-drug resistant pneumonia and fungal sinusitis by nebulizing a nanosilver solution.

Solutions containing Ag0 nanoclusters, Ag+1, and higher oxidation state silver, generated from nanocrystalline silver dressings, were anti-inflammatory against porcine skin inflammation. The dressings have clinically-demonstrated broad-spectrum antimicrobial activity, suggesting application of nanosilver solutions in treating pulmonary infection. Nanosilver solutions were tested for antimicrobial efficacy; against HSV-1 and SARS-CoV-2; and nebulized in rats with acute pneumonia. Patients with pneumonia (ventilated), fungal sinusitis, burns plus COVID-19, and two non-hospitalized patients with COVID-19 received nebulized nanosilver solution. Nanosilver solutions demonstrated pH-dependent antimicrobial efficacy; reduced infection and inflammation without evidence of lung toxicity in the rat model; and inactivated HSV-1 and SARS-CoV-2. Pneumonia patients had rapidly reduced pulmonary symptoms, recovering pre-illness respiratory function. Fungal sinusitis-related inflammation decreased immediately with infection clearance within 21 days. Non-hospitalized patients with COVID-19 experienced rapid symptom remission. Nanosilver solutions, due to anti-inflammatory, antiviral, and antimicrobial activity, may be effective for treating respiratory inflammation and infections caused by viruses and/or microbes.

The Trial Innovation Network Liaison Team: building a national clinical and translational community of practice.

In 2016, the National Center for Advancing Translational Science launched the Trial Innovation Network (TIN) to address barriers to efficient and informative multicenter trials. The TIN provides a national platform, working in partnership with 60+ Clinical and Translational Science Award (CTSA) hubs across the country to support the design and conduct of successful multicenter trials. A dedicated Hub Liaison Team (HLT) was established within each CTSA to facilitate connection between the hubs and the newly launched Trial and Recruitment Innovation Centers. Each HLT serves as an expert intermediary, connecting CTSA Hub investigators with TIN support, and connecting TIN research teams with potential multicenter trial site investigators. The cross-consortium Liaison Team network was developed during the first TIN funding cycle, and it is now a mature national network at the cutting edge of team science in clinical and translational research. The CTSA-based HLT structures and the external network structure have been developed in collaborative and iterative ways, with methods for shared learning and continuous process improvement. In this paper, we review the structure, function, and development of the Liaison Team network, discuss lessons learned during the first TIN funding cycle, and outline a path toward further network maturity.

Development, implementation, and dissemination of operational innovations across the trial innovation network.

Improving the quality and conduct of multi-center clinical trials is essential to the generation of generalizable knowledge about the safety and efficacy of healthcare treatments. Despite significant effort and expense, many clinical trials are unsuccessful. The National Center for Advancing Translational Science launched the Trial Innovation Network to address critical roadblocks in multi-center trials by leveraging existing infrastructure and developing operational innovations. We provide an overview of the roadblocks that led to opportunities for operational innovation, our work to develop, define, and map innovations across the network, and how we implemented and disseminated mature innovations.

The RIC COVID-19 Recruitment & Retention Toolkit: A community-informed resource of recruitment tools and strategies for clinical trial investigators.

The Recruitment Innovation Center (RIC) has created a toolkit of novel strategies to engage potential participants in response to recruitment and retention challenges associated with COVID-19 studies. The toolkit contains pragmatic, generalizable resources to help research teams increase awareness of clinical trials and opportunities to participate; produce culturally sensitive and engaging recruitment materials; improve consent and return of results processes; and enhance recruitment of individuals from populations disproportionately impacted by COVID-19. This resource, the "RIC COVID-19 Recruitment and Retention Toolkit," is available free online. We describe the toolkit and the community feedback used to author and curate this resource.

Securely sharing DSMB reports to speed decision making from multiple, concurrent, independent studies of similar treatments in COVID-19.

Introduction: 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. Methods: 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. Results: 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. Conclusion: 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.

The IRB Reliance Exchange (IREx): A national web-based platform for operationalizing single IRB review.

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.

Recruitment and retention for chronic pain clinical trials: a narrative review.

Opioid misuse is at a crisis level. In response to this epidemic, the National Institutes of Health has funded $945 million in research through the Helping to End Addiction Long-term (HEAL) Pain Management Initiative, including funding to the Vanderbilt Recruitment Innovation Center (RIC) to strategize methods to catalyze participant recruitment. The RIC, recognizing the challenges presented to clinical researchers in recruiting individuals experiencing pain, conducted a review of evidence in the literature on successful participant recruitment methods for chronic pain trials, in preparation for supporting the HEAL Pain trials. Study design as it affects recruitment was reviewed, with issues such as sufficient sample size, impact of placebo, pain symptom instability, and cohort characterization being identified as problems. Potential solutions found in the literature include targeted electronic health record phenotyping, use of alternative study designs, and greater clinician education and involvement. For retention, the literature reports successful strategies that include maintaining a supportive staff, allowing virtual study visits, and providing treatment flexibility within the trial. Community input on study design to identify potential obstacles to recruitment and retention was found to help investigators avoid pitfalls and enhance trust, especially when recruiting underrepresented minority populations. Our report concludes with a description of generalizable resources the RIC has developed or adapted to enhance recruitment and retention in the HEAL Pain studies. These resources include, among others, a Recruitment and Retention Plan Template, a Competing Trials Tool, and MyCap, a mobile research application that interfaces with Research Electronic Data Capture (REDCap).

The Recruitment Innovation Center: Developing novel, person-centered strategies for clinical trial recruitment and retention.

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.

Effects of financial incentives on volunteering for clinical trials: A randomized vignette experiment.

BACKGROUND: Financial incentives may aid recruitment to clinical trials, but evidence regarding risk/burden-driven variability in participant preferences for incentives is limited. We developed and tested a framework to support real-world decisions on recruitment budget. METHODS: We included two phases: an Anchoring Survey, to ensure we could capture perceived unpleasantness on a range of life events, and a Vignette Experiment, to explore relationships between financial incentives and participants' perceived risk/burden and willingness to participate in high- and low-risk/burden versions of five vignettes drawn from common research activities. We compared vignette ratings to identify similarly rated life events from the Anchoring Survey to contextualize ratings of study risk. RESULTS: In our Anchoring Survey (n = 643), mean ratings (scale 1 = lowest risk/burden to 5 = highest risk/burden) indicated that the questions made sense to participants, with highest risk assigned to losing house in a fire (4.72), and lowest risk assigned to having blood pressure taken (1.13). In the Vignette Experiment (n = 534), logistic regression indicated that amount of offered financial incentive and perceived risk/burden level were the top two drivers of willingness to participate in four of the five vignettes. Comparison of event ratings in the Anchoring Survey with the Vignette Experiment ratings suggested reasonable concordance on severity of risk/burden. CONCLUSIONS: We demonstrated feasibility of a framework for assessing participant perceptions of risk for study activities and discerned directionality of relationship between financial incentives and willingness to participate. Future work will explore use of this framework as an evidence-gathering approach for gauging appropriate incentives in real-world study contexts.

Engaging smokers in research: Utility of Facebook in facilitating recruitment to a smoking cessation study.

INTRODUCTION: Social media, including Facebook outreach, is increasingly being used as a participant recruitment tool, and may be particularly useful in tobacco and smoking cessation studies. The Recruitment Innovation Center at Vanderbilt University Medical Center partnered with Project LUNA, a smoking cessation study, to conduct a pilot social media campaign aimed at increasing study recruitment. METHODS: Two posts encouraging study participation were developed and promoted on Facebook to users with an interest in smoking-related topics, with a link to a study-specific webpage. Facebook and website analytics were collected, including impressions, clicks, click-through rates, website traffic, and clicks to the study screening form. Study screening and enrollment data were also collected. RESULTS: The Facebook campaign ran in June 2019 in the greater Houston area. In total, the Facebook posts logged 1,179,844 impressions, 6490 clicks, and an overall click-through rate of 0.55%. There were no differences in response to the two different promotional posts. Approximately 3812 unique individuals visited an intermediary study page, with 473 expressing interest in the study. Forty-three potential participants contacted the study team, resulting in study enrollment and randomization of 23 participants, with an estimated cost per enrolled participant of $441. CONCLUSIONS: The social media campaign was successful at increasing outreach and interest in the LUNA study. However, the price-per-participant enrolled was higher than in comparable tobacco cessation studies. These results and lessons learned may be beneficial to others considering social media as a recruitment method for their clinical research trial.