Periodic Reporting for period 4 - TransBioLine (Translational Safety Biomarker Pipeline (TransBioLine): Enabling development and implementation of novel safety biomarkers in clinical trials and diagnosis of disease)
Reporting period: 2022-02-01 to 2023-01-31
TransBioLine will generate exploratory and confirmatory data to support the qualification of biomarkers associated with drug-induced organ injury of five different organ systems; kidney (DIKI), liver (DILI), pancreas (DIPI), vascular (DIVI), and central nervous system (DINI); and qualifying their use for implementation in Phase I clinical trials during drug development. The regulatory qualification by the FDA and the EMA of these biomarkers will establish their useful implementation in clinical trials as highly sensitive and specific means of identifying drug-induced damage under drug therapy, minimizing potentially serious and long-term adverse outcomes on patient health and generally increasing patient safety.
TransBioLine is organized into five organ system work packages (WP) and six enabling WP that include 6-miRNA (liquid biopsy), 7-biobank and assay development, 8-data management, 10-regulatory interactions, and 11-communication packages. Each organ WP has the objective of collecting pre-clinical and clinical data that will support the utility of candidate biomarkers in the increased sensitive and specific assessment of specific organ injury. Supporting work packages aim at a) assessment of miRNAs and miRNA profiling as biomarkers for each of the five target organ systems b) developing and validating fit-for purpose assays for biomarker quantification, c) establishing and maintaining a centralized biobank, d) collecting, curating, sharing, and analyzing high-quality clinical and biomarker data, e) leading regulatory qualifications, f) effectively managing the project and g) disseminating project activities and ensuring sustainability of TransBioLine-generated assets. Overall, TransBioLine is a project dedicated to increased patient safety and streamlined drug-development processes.
TransBioLine is organized into five organ system work packages (WP) and six enabling WP that include 6-miRNA (liquid biopsy), 7-biobank and assay development, 8-data management, 10-regulatory interactions, and 11-communication packages. Each organ WP has the objective of collecting pre-clinical and clinical data that will support the utility of candidate biomarkers in the increased sensitive and specific assessment of specific organ injury. Supporting work packages aim at a) assessment of miRNAs and miRNA profiling as biomarkers for each of the five target organ systems b) developing and validating fit-for purpose assays for biomarker quantification, c) establishing and maintaining a centralized biobank, d) collecting, curating, sharing, and analyzing high-quality clinical and biomarker data, e) leading regulatory qualifications, f) effectively managing the project and g) disseminating project activities and ensuring sustainability of TransBioLine-generated assets. Overall, TransBioLine is a project dedicated to increased patient safety and streamlined drug-development processes.
The five organ WPs are running prospective observational clinical trials to recruit normal healthy volunteers and patients with respective organ-injury across >10 European academic hospitals and USA-located EFPIA partners. 47-82% of total recruitment goals have been achieved to date across the teams. A biobank (ZeBanc by Charité, Berlin, Germany) and data-sharing platform (tranSMART and OwnCloud secure transfers by ITTM, Esch-sur-Alzette, Luxembourg) have been established, as well as databases tailored to each organ WPs’ clinical trials using the FDA-validated Clindex eCRF software (managed by ABX-CRO, Dresden, Germany). >23,000 aliquots for >1100 patients and volunteers have been biobanked, with >4000 from roughly 750 patients already having been distributed to analysis partners for biomarker quantification. Analytical partners in work package 7 have validated of all bioanalytical assays for quantifying biomarkers in order to meet the high standards required by regulatory agencies (led by Signatope, Reutlingen, Germany and including MLM, TAmiRNA, and MetaHeps). Pioneering miRNA analyses are included in the liquid biopsy WP6 (led by TAmiRNA, Vienna, Austria). Dissemination of a miND data analysis pipeline for robust raw miRNA analysis using quantitative spike-in technology will impact biomarker and miRNA research fields alike and will be used to obtain high quality miRNA data. A cross-work package initiative was able to address sustainability issues as well being able to find a process to allow the use of clinical trial samples collected in the frame of our predecessor consortium SAFE-T. This difficult task quintessentially represents the complexity, importance, and power of sustainability in clinical research. Samples and data from SAFE-T have been used by several work packages to date, and results produced by the DIKI team of SAFE-T were newly analyzed and interpreted by the TransBioLine DIKI team for dissemination during year 4. Interactions with regulatory agencies within the last 4 years have resulted in the acceptance of 4 of the 5 organ WPs’ Letters of Intent into the FDA Biomarker Qualification Program, and all 5 WPs have received supportive qualification advice from the EMA, indicating both the timely need for such studies and the appropriateness of the scientific approaches that were designed under careful consideration by each of these work packages within the first reporting year’s Study Designs. The endorsement received from both the FDA and EMA in regulatory advice meetings, organized and led by WP10, clearly demonstrates that TransBioLine is on track with the expectations and demands for successful regulatory qualification. During year 4, one work package submitted a pre-Qualification Plan briefing document to the FDA, based on learning phase study outcomes, and has received written advice towards submission of the full Qualification Plan. Communication, dissemination, project management and overall governance and guidance has been led by the remaining WPs 9 and 11, and have mitigated arising situations resulting from risks associated with the COVID-19 pandemic, Brexit, and altered EU privacy mandates resulting from CJEU rulings on the Schrem’s II case in June of 2020. Two General Assemblies were held during year 4, as the first face-to-face meetings of consortium members since the pandemic. The sustainability of the project outcomes (sample and data repository, assays) was one major focus of these meetings. Dissemination activities have increased over the last year, in both scientific publications and meeting presentations. Sustainability discussions have centered on the reassessment of timelines within the newly adjusted remaining project runtime, with the goal of accomplishing the key project outcomes of regulatory qualification of novel biomarkers across all 5 target organ systems, whether within or beyond the project, by the establishment of a robust sustainability framework to accommodate lengthy qualification timelines.
The biomarkers investigated in TransBioLine are expected to substantially improve diagnosis, management, and mechanistic understanding of drug toxicity and acute or chronic disease. A multivariate approach assessing not only individual markers in isolation, but also multifactorial panels of markers, will help connecting biomarker findings to biological pathways associated with the pathophysiology of drug side effects or disease. TransBioLine’s focus on investigating complex profiles of microRNAs will aid significantly in establishing links from a molecular to the clinical level.
During the project’s 6-year lifetime, TransBioLine will be the leading public-private partnership focusing on the clinical qualification of new safety biomarkers. TransBioLine will open new markets by introducing commercially available diagnostics products through innovative SMEs. MLM, Signatope, and TAmiRNA will substantially benefit from their involvement in the qualification process, including the validation of their assays and proprietary platforms, as an important competitive advantage. ITTM will benefit from the interaction with EFPIA and consortium partners by improving data sharing and harmonization services and technologies. The expected harmonization and improved interoperability of tranSMART with Sample Management and eCRF systems will open new opportunities and further facilitate data integration in preclinical and clinical projects. All SMEs have risen to the challenges, foreseen and unforeseen, that have occurred in TransBioLine due to its complexity and size, gaining valuable experience and advantages over competitors.
During the project’s 6-year lifetime, TransBioLine will be the leading public-private partnership focusing on the clinical qualification of new safety biomarkers. TransBioLine will open new markets by introducing commercially available diagnostics products through innovative SMEs. MLM, Signatope, and TAmiRNA will substantially benefit from their involvement in the qualification process, including the validation of their assays and proprietary platforms, as an important competitive advantage. ITTM will benefit from the interaction with EFPIA and consortium partners by improving data sharing and harmonization services and technologies. The expected harmonization and improved interoperability of tranSMART with Sample Management and eCRF systems will open new opportunities and further facilitate data integration in preclinical and clinical projects. All SMEs have risen to the challenges, foreseen and unforeseen, that have occurred in TransBioLine due to its complexity and size, gaining valuable experience and advantages over competitors.