A national evaluation analysis and expert interview study of real-world data sources for research and healthcare decision-making.

Real-world data (RWD) can provide intel (real-world evidence, RWE) for research and development, as well as policy and regulatory decision-making along the full spectrum of health care. Despite calls from global regulators for international collaborations to integrate RWE into regulatory decision-making and to bridge knowledge gaps, some challenges remain. In this work, we performed an evaluation of Austrian RWD sources using a multilateral query approach, crosschecked against previously published RWD criteria and conducted direct interviews with representative RWD source samples. This article provides an overview of 73 out of 104 RWD sources in a national legislative setting where major attempts are made to enable secondary use of RWD (e.g. law on the organisation of research, "Forschungsorganisationsgesetz"). We were able to detect omnipresent challenges associated with data silos, variable standardisation efforts and governance issues. Our findings suggest a strong need for a national health data strategy and data governance framework, which should inform researchers, as well as policy- and decision-makers, to improve RWD-based research in the healthcare sector to ultimately support actual regulatory decision-making and provide strategic information for governmental health data policies.

Quality Criteria for Real-world Data in Pharmaceutical Research and Health Care Decision-making: Austrian Expert Consensus.

Real-world data (RWD) collected in routine health care processes and transformed to real-world evidence have become increasingly interesting within the research and medical communities to enhance medical research and support regulatory decision-making. Despite numerous European initiatives, there is still no cross-border consensus or guideline determining which qualities RWD must meet in order to be acceptable for decision-making within regulatory or routine clinical decision support. In the absence of guidelines defining the quality standards for RWD, an overview and first recommendations for quality criteria for RWD in pharmaceutical research and health care decision-making is needed in Austria. An Austrian multistakeholder expert group led by Gesellschaft für Pharmazeutische Medizin (Austrian Society for Pharmaceutical Medicine) met regularly; reviewed and discussed guidelines, frameworks, use cases, or viewpoints; and agreed unanimously on a set of quality criteria for RWD. This consensus statement was derived from the quality criteria for RWD to be used more effectively for medical research purposes beyond the registry-based studies discussed in the European Medicines Agency guideline for registry-based studies. This paper summarizes the recommendations for the quality criteria of RWD, which represents a minimum set of requirements. In order to future-proof registry-based studies, RWD should follow high-quality standards and be subjected to the quality assurance measures needed to underpin data quality. Furthermore, specific RWD quality aspects for individual use cases (eg, medical or pharmacoeconomic research), market authorization processes, or postmarket authorization phases have yet to be elaborated.

Safety and clinical efficacy of the secretome of stressed peripheral blood mononuclear cells in patients with diabetic foot ulcer-study protocol of the randomized, placebo-controlled, double-blind, multicenter, international phase II clinical trial MARSYAS II.

BACKGROUND: Diabetes and its sequelae such as diabetic foot ulcer are rising health hazards not only in western countries but all over the world. Effective, yet safe treatments are desperately sought for by physicians, healthcare providers, and of course patients. METHODS/DESIGN: APOSEC, a novel, innovative drug, is tested in the phase I/II study MARSYAS II, where its efficacy to promote healing of diabetic foot ulcers will be determined. To this end, the cell-free secretome of peripheral blood mononuclear cells (APOSEC) blended with a hydrogel will be applied topically three times weekly for 4 weeks. APOSEC is predominantly effective in hypoxia-induced tissue damages by modulating the immune system and enhancing angiogenesis, whereby its anti-microbial ability and neuro-regenerative capacity will exert further positive effects. In total, 132 patients will be enrolled in the multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-ranging phase I/II study and treated with APOSEC at three dose levels or placebo for 4 weeks, followed by an 8-week follow-up period to evaluate safety and efficacy of the drug. Wound area reduction after 4 weeks of treatment will serve as the primary endpoint. CONCLUSION: We consider our study protocol to be suitable to test topically administered APOSEC in patients suffering from diabetic foot ulcers in a clinical phase I/II trial. TRIAL REGISTRATION: EudraCT 2018-001653-27 . Registered on 30 July 2019. ClinicalTrials.gov NCT04277598 . Registered on 20 February 2020. TITLE: "A randomized, placebo-controlled, double-blind study to evaluate safety and dose-dependent clinical efficacy of APO-2 at three different doses in patients with diabetic foot ulcer (MARSYAS II)".

Reproducibility of GMP-compliant production of therapeutic stressed peripheral blood mononuclear cell-derived secretomes, a novel class of biological medicinal products.

BACKGROUND: The recent concept of secretome-based tissue regeneration has profoundly altered the field of regenerative medicine and offers promising novel therapeutic options. In contrast to medicinal products with a single active substance, cell-derived secretomes comprise pleiotropic bioactive ingredients, representing a major obstacle for reproducible drug product efficacy and warranting patient safety. Good manufacturing practice (GMP)-compliant production guarantees high batch-to-batch consistency and reproducible efficacy of biological medicinal products, but different batches of cellular secretomes produced under GMP have not been compared yet, and suitable quality control parameters have not been established. To this end, we analyzed diverse biological and functional parameters of different batches produced under GMP of the secretome obtained from γ-irradiated peripheral blood mononuclear cells with proven tissue regenerative properties in infarcted myocardium, stroke, spinal cord injury, and skin wounds. METHODS: We quantified key secretome ingredients, including cytokines, lipids, and extracellular vesicles, and functionally assessed potency in tube formation assay, ex vivo aortic ring sprouting assay, and cell-based protein and reporter gene assays. Furthermore, we determined secretome stability in different batches after 6 months of storage at various ambient temperatures. RESULTS: We observed that inter-batch differences in the bioactive components and secretome properties were small despite considerable differences in protein concentrations and potencies between individual donor secretomes. Stability tests showed that the analytical and functional properties of the secretomes remained stable when lyophilisates were stored at temperatures up to + 5 °C for 6 months. CONCLUSIONS: We are the first to demonstrate the consistent production of cell-derived, yet cell-free secretome as a biological medicinal product. The results from this study provide the basis for selecting appropriate quality control parameters for GMP-compliant production of therapeutic cell secretomes and pave the way for future clinical trials employing secretomes in tissue regenerative medicine.