OBJECTIVES/GOALS: A new mandate for Clinical & Translational Science Award (CTSA) Programs is for pilot grant funding to support clinical and translational science (CTS) projects that study challenges in the translational research pipeline. This pivot requires new structures and supports to help investigators design and implement high-quality CTS projects. METHODS/STUDY POPULATION: The Michigan Institute for Clinical & Health Research (MICHR) at the University of Michigan (U-M) has launched two rounds of pilot funding since March 2023. Faculty and staff across U-M’s three campuses, community members, and those at collaborating institutions and hospitals were eligible to apply. New pre-award supports included a CTS project framework; a recorded webinar that educated about CTS and the funding opportunity; office hours to provide tailored project feedback; a letter of intent to screen for alignment with CTS; and reviewer training for academic and community reviewers. Funded projects operate like 'mini cooperative agreements”, with MICHR experts partnering with awardees to refine evaluation plans, prepare work products, advise on dissemination, and navigate emergent challenges. RESULTS/ANTICIPATED RESULTS: The first round of funding was launched in the absence of pre-award supports; ten applications we received from faculty proposing translational research rather than CTS. We quickly re-released the FOA, expanding eligibility to staff. We received nine applications, ultimately funding four staff and one faculty studying operational challenges in translation and helping them create robust evaluation plans. We piloted the pre-award supports in our second round, with 40 individuals viewing our webinar and 11 attending office hours. Those who watched the webinar before attending office hours better understood how to embed CTS questions within their programs of research. We recently received 19 letters of intent, addressing both operational and scientific challenges, with 16 eligible to submit applications. DISCUSSION/SIGNIFICANCE: Education and personalized feedback seem to elicit a higher yield of CTS projects. Staff are already adept at solving operational challenges, so the pre-award supports were most critical for faculty accustomed to writing traditional translational research proposals. Staff have most benefited from guidance in evaluation and dissemination.

Objectives/Goals: Identify risks in the regulatory reliance ecosystem, specifically for generic reliance pathways, using system theoretic process analysis (STPA), a proactive hazard analysis method, and create sustainable solutions to ensure global accessibility to the highest attainable standard of health. Methods/Study Population: A systematic literature review will assess the regulatory reliance ecosystem and interactions among National Regulatory Agencies (NRAs). This will involve using a hierarchical control structure (HCS) to identify operational loop failures, decision-making, and information flow. The HCS will inform an STPA to prevent adverse outcomes like patient harm or regulatory non-compliance. With IRB approval, 10 regulatory experts will also be interviewed to gather insights on risk scenarios. Their input will be used to integrate regulatory pathways into the HCS for adaptability, and a second round of interviews will be conducted to validate the scenarios and assess the effectiveness of recommendations. Results/Anticipated Results: A preliminary literature review on regulatory reliance pathways from PubMed, WHO guidelines, and the DIA global forum, revealed potential risks in NRA interactions, such as overly redacted reports obscuring critical details and discrepancies in product versions or incomplete reviews affecting evaluations. Diverging guidelines and failure to adapt to country-specific needs are potential risks that also impact patient access to essential medicines. The STPA framework, along with expert feedback, will uncover unknown risks like “secondary-reliance” and soft risks, leading to sustainable recommendations to improve and optimize the safety of regulatory reliance. Discussion/Significance of Impact: Safe regulatory reliance is crucial for global health equity and patient access to essential and innovative medicines. STPA will identify and address different layers of risk in the system, improving safety, efficiency, and innovation for timely patient access to therapeutics.

Objectives/Goals: Lung transplant is a life-saving surgery for patients with advanced lung diseases yet long-term survival remains poor. The clinical features and lung injury patterns of lung transplant recipients who die early versus those who survive longer term remain undefined. Here, we use cell-free DNA and rejection parameters to help elucidate this further. Methods/Study Population: Lung transplant candidacy prioritizes patients who have a high mortality risk within 2 years and will likely survive beyond 5 years. We stratified patients who died within 2 years of transplant as early death (n = 50) and those who survived past 5 years as long-term survivors (n = 53). Lung transplant recipients had serial blood collected as part of two prospective cohort studies. Cell-free DNA (cfDNA) was quantified using relative (% donor-derived cfDNA {%ddcfDNA}) and absolute (nuclear-derived {n-cfDNA}, mitochondrial-derived {mt-cfDNA}) measurements. As part of routine posttransplant clinical care, all patients underwent pulmonary function testing (PFT), surveillance bronchoscopy with bronchoalveolar lavage (BAL), transbronchial biopsy (TBBx), and donor-specific antibody testing (DSA). Results/Anticipated Results: Over the first 2 years after transplant, the number of episodes of antibody-mediated rejection (p) Discussion/Significance of Impact: Clinically, early-death patients perform worse on routine surveillance PFTs and experience a worse degree of CLAD. These patients also have higher levels of cfDNA as quantified by n-cfDNA and mt-cfDNA. These results provide preliminary evidence that early-death patients have worse allograft rejection, dysfunction, and molecular injury.

OBJECTIVES/GOALS: Our primary objective is to determine the demographic and linguistic characteristics of student research assistants (SRAs) in a large student-run free clinic associated with a mid-western university. Our secondary objective was to determine if the SRAs perceived any impact of those characteristics on their duties and ability to conduct research. METHODS/STUDY POPULATION: We plan to conduct a 15-question electronic survey of Student Research Assistants at the student run free clinic. There are a variety of projects that require varying levels of commitment from researchers, which will be aggregated. This survey has been modified from a previously validated survey that focused on the demographic and linguistic characteristics of pediatric research coordinators. This survey will be emailed out to student research assistants and will be done over a period of 3 months. The study population will be predominantly undergraduate students who are all interested in a career in healthcare, ages expected to range from 18-25. RESULTS/ANTICIPATED RESULTS: We anticipate that the majority of student research assistants will be older students and will be students who identify as non-white/caucasian, as the majority of students volunteering at this free clinic do not identify as white. Additionally, we anticipate that students will feel that their racial/ethnic identity will positively impact their recruitment efforts. We also anticipate that the ability of a student research assistant to speak another language is expected to positively affect their perceived recruitment efforts. We also anticipate that gender will influence the student researchers’ perceptions of their recruitment efforts. DISCUSSION/SIGNIFICANCE: An individual’s background can directly impact how they perceive their contributions towards research. Considering the paucity in research for underinsured and uninsured and the rise in undergraduate student research assistants, optimizing research efforts and SRA confidence is essential to increase the accuracy and efficiency of research.

Objectives/Goals: This research aims to modify an existing regulatory benchmarking framework, initially designed for medical products, to assess cosmetic product regulations in different countries. This tool will provide qualitative and quantitative comparisons of global regulatory approaches to cosmetics. Methods/Study Population: The World Health Organization’s global benchmarking tool (GBT) was selected as a suitable template for the adapted methodology. The GBT contains a comprehensive set of functions, indicators, and sub-indicators defining the high regulatory maturity standard. Although the 269 sub-indicators are tailored to the regulation of medical products, they can be intentionally adapted for other products. Relevant indicators specific to cosmetic regulation will be identified to construct a customized benchmarking tool. This tool will then be used to assess the regulatory maturity of selected countries and regulatory authorities, including the United States, the European Union, Japan, India, Brazil, China, Ethiopia, and Nigeria. Results/Anticipated Results: Preliminary analysis indicates a lack of harmonized standards for regulatory maturity across the global cosmetic market. The recent passage of the Modernization of Cosmetics Regulation Act of 2022 (MoCRA) has strengthened the United States’ regulatory framework, incorporating 11 of 13 adapted maturity indicators. The United States joins the European Union (10/13 indicators) and Japan (8/13 indicators) as leaders in cosmetic safety and manufacturing transparency. Common basic policies included good manufacturing practice regulations, while more advanced regulations cover adverse event reporting and premarket requirements. Discussion/Significance of Impact: Cosmetics, supplements, and homeopathic products lack transparency regarding safety and quality requirements. This project establishes a benchmark for cosmetic product regulation, addressing a historic gap in oversight. The benchmark supports regions with less developed regulatory policies to enhance cosmetic safety and quality standards.

OBJECTIVES/SPECIFIC AIMS: To further explore the role of vWF in the pathogenesis of scleroderma by identifying its location within the tissue of sample biopsies obtained as part of routine diagnosis with the use of immuno-histochemical staining. METHODS/STUDY POPULATION: We examined 8 skin biopsies from 2 patients with systemic sclerosis (SSc), 2 with localized scleroderma (LS) and 4 with JDM. Double immunofluorescence staining was performed in each tissue with antibodies against vWF and collagens type I and III. DAPI (4′, 6-diamidino-2-phenylindole) was also used for counterstaining of inflammatory cells. Tissue staining patterns were compared between groups. RESULTS/ANTICIPATED RESULTS: Biopsies were obtained from the upper extremity of 7 females and the lower extremity of 1 male. Median age, symptom duration, and serum levels of vWF antigen around the time of biopsy was 8 years (IQR 4.5-11), 5.5 months (IQR 2.5-7), and 245% (IQR 203-302 for 7 patients), respectively. All but 1 biopsy was performed prior to initiation of immunosuppressive therapy. Immunofluorescence staining showed a superficial and deep perivascular inflammatory cell infiltrate that co-localized with vWF in all tissues. There was expression of vWF in the extravascular tissue of patients with JScl co-localizing with collagen III in the reticular dermis (Figures 1 and 2). In comparison, vWF expression was restricted to the endothelium and did not co-localize with collagen in the dermis of patients with JDM (Figure 3). Patients with SSc had higher expression of vWF as compared to patients with LS. DISCUSSION/SIGNIFICANCE OF IMPACT: vWF may participate in the pathogenesis of cutaneous inflammatory conditions. We have demonstrated that vWF co-localizes with cellular inflammatory infiltrates in the perivascular areas and in the dermis of patients with JScl and JDM. We additionally speculate that vWF may participate in the pathogenesis of fibrosing skin diseases based on evidence of increased extravascular expression in the tissue of patients with JScl (vs. JDM), and its co-localization with collagen. vWF expression intensity in the dermis of JScl patients may relate to disease extension (SSc vs. LS).

Achieving the clinical, public health, economic, and policy benefits of translational science requires the integration and application of findings across biomedical, clinical, and behavioral science and health policy, and thus, collaboration across experts in these areas. To do so, translational teams need the skills, knowledge, and attitudes to mitigate challenges and build on strengths of cross-disciplinary collaboration. Though these competencies are not innate to teams, they can be built through the implementation of effective strategies and interventions. The Science of Team Science (SciTS) has contributed robust theories and evidence of empirically-informed strategies and best practices to enhance collaboration. Yet the field lacks methodological approaches to rigorously translate those strategies into evidence-based interventions to improve collaborative translational research. Here, we apply lessons from Implementation Science and Human-Centered Design & Engineering to describe the Wisconsin Interventions in Team Science (WITS) framework, a process for translating established team science strategies into evidence-based interventions to bolster translational team effectiveness. To illustrate our use of WITS, we describe how University of Wisconsin’s Institute for Clinical and Translational Research translated the existing Collaboration Planning framework into a robust, scalable, replicable intervention. We conclude with recommendations for future SciTS research to refine and test the framework.

Objectives/Goals: This study aims to gather user feedback from clinical research professionals on the usefulness and relevance of regulatory resources found on a new regulatory web portal, OpenRegSource, to enhance its usability, thereby advancing this project from the initial to the full implementation phase of the implementation science framework. Methods/Study Population: The Regulatory Knowledge and Support core of the Southern California Clinical and Translational Science Institute developed a regulatory web portal called OpenRegSource to help researchers gain basic regulatory information prior to professional and/or paid consultation. Before publicly launching, a virtual focus group (FG) composed of 21 members of the local clinical research workforce was given two weeks to explore the web portal and answer three surveys. Two other research professionals also gave feedback outside of the focus group. The user feedback data was analyzed and discussed by the web portal project team. Updates were then made accordingly. Once the portal was launched, a plan was implemented to collect usage metrics and additional feedback for continuous improvement. Results/Anticipated Results: Of the 21 FG participants, 20 completed the feedback survey specifically for their experience with the web portal. 65% (13/20) said the number of resources was just right. 90% (18/20) found the resources to be very relevant to their respective topics. 85% (17/20) found the resources very useful and somewhat useful to their daily work activities. 75% (15/20) found the organization of the portal to be good or very good. 85% (17/20) found it very easy and somewhat easy to navigate the web portal. 90% (18/20) found the portal to be effective in providing its audience with a basic understanding of regulatory requirements. 95% (19/20) found the portal useful for novice research professionals. 85% (17/20) found the web portal useful overall. Participants were also able to provide commentary feedback for specific pages. Discussion/Significance of Impact: Obtaining stakeholder input during the development of a resource or tool is essential to ensure the final product meets user needs and is effectively utilized. In this case, involving the feedback of clinical researchers will help improve OpenRegSource to better facilitate the advancement of their work.

OBJECTIVES/GOALS: NCATS requires that CTSA-funded pilot projects focus on translational science (TS) and evaluate the translational process. However, a consistent understanding of TS remains elusive. This gap is being addressed by a consortium of 12 CTSA hubs aimed at identifying distinctive features of TS and translational research (TR) proposals. METHODS/STUDY POPULATION: CTSA External Review Exchange Consortium (CEREC) is a reciprocal review collaboration among CTSA hubs. Reviewers were CEREC members from hubs that submitted CTSA applications (PAR-21-293); read the Notice of Funding Opportunity (NOFO) Clinical and Translations Science Pilot Module; and discussed TS with their hubs “a fair amount” or “quite a bit” and then they independently categorized proposals. Proposals were labeled TS or TR if reviewers reached a consensus on category assignment; without consensus, proposals were labeled unclassified. In addition to category assignment, reviewers commented about their classifications. R was used to evaluate the comments and create word clouds with phrases/themes that distinguished between the categories of proposals. RESULTS/ANTICIPATED RESULTS: Twelve CEREC participating hubs submitted 26 proposals, which were funded prior to the new NCATS TS requirements. Eight reviewers from distinct CEREC hubs evaluated and classified each proposal as TS or TR. Consensus (at least 87% agreement) was reached for 12 proposals, 6 TS and 6 TR. Reviewers provided comments describing the rationale for their classifications for 70% of the proposals. Qualitative analysis of the reviewers’ comments and rationale by classification (TS, TR, or unclassified) revealed common themes within and differences between groups and shed light on what defines TS and TR. The most frequent themes that distinguished TS from TR were generalizability across multiple diseases and a focus on increasing research efficiency. DISCUSSION/SIGNIFICANCE: NIH is focused on research that meets the new definition of TS. Investigators seeking to address this funding priority should explicitly state the relevance of their research to multiple diseases and to the acceleration of future research. Programs seeking to attract TS projects should instruct applicants to include this information.

OBJECTIVES/GOALS: CTSA Hubs represent complex centers where teams work to meet multiple goals of the CTSA grant. An existing challenge is to work collaboratively across teams. To address this challenge, a Translational Operations Group (TOG) was established. Results show enhanced intra-hub collaboration and communication while reducing inefficiencies. METHODS/STUDY POPULATION: The TOG is composed of all CTSA hub module program managers who are charged with operationalizing vision into reality. The TOG was formed in 2021 as a mechanism to integrate new team members, provide connection, and improve cross-core awareness and collaboration. Leveraging team science principles, a team charter was developed outlining specific TOG aims and objectives. Collectively, shared goals were identified with establishment of group norms, effective communication pathways, shared resources and knowledge and meeting cadence. Leadership of the group rotates among the TOG members annually further engaging all TOG members. Pre and Post (one year) surveys were developed and provided to TOG members to gauge TOG effectiveness and perceptions of TOG members. RESULTS/ANTICIPATED RESULTS: Survey results demonstrate the effectiveness of the TOG concept in promoting core/module awareness and goals, intra-core/module interconnectedness, and forming connections and integration into the CTSA hub ecosystem. Psycho-social questions demonstrated an increase in organizational self-esteem within the pre to post survey period in relation to the specific TOG member’s core/module and the CTSA hub as a whole. DISCUSSION/SIGNIFICANCE: Formation of a TOG has been successful within a virtual environment where connection is challenging. Integration of members to the operational activities is critical to foster a positive work environment, reduce silo effects, and provide a space for sharing resources and knowledge. Annual reflection of priorities contribute to the ongoing success.

Objectives/Goals: The informed consent (IC) process is similar between clinical trials and expanded access (EA), which allows clinical use of investigational products outside studies. Physicians face unique barriers to IC in clinical environments. This project assesses IC documentation, identifies potential barriers, and evaluates efforts to improve compliance. Methods/Study Population: This is a continuous quality improvement project. To assess the compliance of IC processes for EA patients, informed consent documents signed by EA patients in 2023 were collected and reviewed against institutional standards. Five components of each form were evaluated, and the number and type of noncompliant documentation were tracked. Five physicians who provided EA treatments in 2023 were interviewed and the transcripts were analyzed to identify barriers to physician’s and teams’ IC processes. Efforts made to address these barriers and improve the compliance of informed consent documentation are being tracked and trends in compliance are being evaluated. Results/Anticipated Results: Sixty seven (67) signed informed consent documents for EA treatments were systematically reviewed and 34% were found to be compliant in all key aspects assessed. Analyses of interview notes, transcripts, and memos identified barriers to informed consent processes for expanded access treatments, including the infrequent or irregular occurrence of EA treatments making it difficult for care teams to develop and maintain their understanding of IC process and resources. Efforts made to improve compliance by pre-populating available information into informed consent documentation and removing unnecessary boxes in these forms may have driven improvement in compliance with further efforts underway. Discussion/Significance of Impact: This project evaluated the compliance of IC documentation for EA treatments and identified drivers affecting physicians’ IC processes for these patients. Different strategies to improve the compliance of IC documentation were evaluated and potential best practices for EA support were identified.

Objectives/Goals: Diffusion of innovations (DoI) posits that new health-related ideas spread through communities over time and across stages of adoption. We will apply DoI to understand a paradigm shift toward seeing participants as partners in clinical research, specifically through delivery of plain language summaries of results. Methods/Study Population: The return of results in lay language (plain language) to clinical trial participants represents a paradigm shift in the EU and now the USA. We will conduct a systematic review of the implementation of “lay summaries” or “plain language summaries” in different jurisdictions to understand current regulatory influence. We will then review PLS samples and published studies to determine the rate of adoption by industry and non-pharmaceutical company sponsors. Using the DoI framework, groups will be placed in an adopter category. Finally, we will employ an implementation science approach to understand the diffusion process and the translation to participants, laying the groundwork for a culture of change in medical product development. Results/Anticipated Results: Our search on PubMed using key terms “Diffusion of Innovation” and “Plain Language Summary” did not produce any relevant results in the context of clinical trials in the USA, which illustrates a gap in the literature and application of this theory in this context. In the future analyses, we will examine factors influencing the adoption stage and outcomes, such as regulatory action, what best practices have been defined/implemented (if any), culture shifts in the context of clinical research, health communications, and inclusion of patient voices in clinical research. Our analysis will include a network analysis to evaluate characteristics that influence adoption of PLS in clinical research. We hope to identify who is at the forefront of innovation and why. Discussion/Significance of Impact: Novel application of DoI theory will help lay the groundwork for a culture of change in patient-focused drug development, specifically for the dissemination of results to patients. In future studies, we plan to develop a tailored framework for the inclusion of PLS as part of a paradigm shift in the patient-focused drug development process.

Routine, nonmedical and ancillary medical costs associated with participation in clinical research create barriers to enrollment for economically disadvantaged individuals. To the extent that race, ethnicity, and gender are linked to SES, such barriers impact efforts to diversify clinical research enrollment. But payment policies and practices often reflect the longstanding and singular concern that payment to participants will bias decision-making and compromise informed consent. We argue that this concern must be viewed in a larger ethical context in which the untoward consequences for the individual participant and for the broader research enterprise are considerable when either inadequate or no payment is provided for expenses incurred (“reimbursement”) and time committed (“compensation”). Fairness in payment and protection from undue influence of payment on the informed consent process are important but distinct ethical considerations. Fundamentally, approaches to payment that leave participants financially worse off as a consequence of taking part in research are inherently unjust as they have a differential impact on recruitment and retention based on socioeconomic status. Sponsors, funders, investigators, and IRBs must be cognizant of the impact of inadequate payment on clinical trial inclusion of historically understudied groups. We address practical and fair payment strategies to advance inclusion, the additional barrier of ancillary medical costs, and potential unintended consequences of payment.