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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - REFINE (Regulatory Science Framework for Nano(bio)material-based Medical Products and Devices)

Teaser

REFINE proposes a Regulatory Science Framework for the risk-benefit assessment of medicinal products and medical devices that are based on nanomedicines and biomaterials. Our goal is to demonstrate the relevance of the framework for the most pressing regulatory challenges in...

Summary

REFINE proposes a Regulatory Science Framework for the risk-benefit assessment of medicinal products and medical devices that are based on nanomedicines and biomaterials. Our goal is to demonstrate the relevance of the framework for the most pressing regulatory challenges in nanomedicine, which are: borderline products, nanosimilars, and products combining several functionalities. We will study/predict physiological distribution of nanomedicines and biomaterials, as well as develop and validate new analytical or experimental methods and assays requested by the regulators. These latter developments are performed in a quality management system, enabling the possible standardisation of our assays. REFINE gathers a wide community of stakeholders in regulation, industry, science, technology development, patients, and end-users, into an envisioned Consortium for the Advancement of Regulatory Science in Biomaterials and Nanomedicine. Our aim is to contribute to a faster and more robust assessment of new nanomedical products, to speed up their regulatory validation prior to accessing the market and the patients, ultimately. We want to achieve various objectives including: 1) the liaison with regulators, identify regulatory concerns. Since our aim is to provide answers to the unmet regulatory needs of regulators in the field of nanomedicines and nanobiomaterials (NBM), REFINE wants to initiate a dialog with regulators in order to identify needs and gaps seen by regulators. 2) Match regulatory concerns with intelligent testing strategies. The huge novelty of REFINE is its capacity to transform regulatory concerns into development of new assays that will provide the missing data in the regulatory dossiers prepared by nanomedicine developers. 3) Rationalise testing. However, due to the novelty of the nanomedicine space, the list of assays required for best characterising a given nanomedicine, is not uniform and might be different depending on the regulatory agency involved. Therefore, REFINE develops methods to rationalise the selection process of characterization assays. 4) Refine testing methods to answer to the current most pressing regulatory concerns. We want to establish a first set of characterisation assays which covers physico-chemistry as well as in biological testing. This assay set is revised regarding the protocol design by test runs in individual labs and round robin tests. 5) Assure quality standards for development & testing. The development of new assays implies that quality standards high enough for being accepted by regulators are respected. REFINE has the ambition to develop assays that fulfil the high-quality standards demanded by regulators. 6) Bridge communities. Developing new characterisation assays and having them recognised as reference assays by regulators requires not only a technical work but also an intense communication with all stakeholders in the field. REFINE wants to take measurements to build bridges among other communities assessing nanomaterials, with regulators, developers and analysts to jointly define routes for development of new assays, using the existing shared expertise.

Work performed

A deep analysis of the regulatory concerns reported in publications, conferences and reports have been conducted by the REFINE consortium. Mapping the unmet regulatory needs and concerns together with the rationalisation of testing strategies resulted in the extraction and categorization of regulatory challenges. These results are explained and presented in a first draft of a White Paper. In addition, it is planned to publish the major findings of this work in a peer-reviewed journal. The regulatory challenges will guide further experimental work in REFINE on the and identification of new methods. The experimental work started with a set of assays for in silico, biodistribution and biological response which were performed in the partner labs with three representative nanomaterials (Lipidots, PACA and Gold particles). 18 out of 20 assays of this Starter Set were selected to be validated in an interlaboratory round robin trial. The laboratory protocols of the selected assays were translated into a standardised SOP template, which was developed to meet regulatory validation requirements. Currently the SOPs are validated in the interlaboratory round robin. The regulatory challenges were particularly interesting for the first Knowledge Exchange Conference which bridged different communities beside the medical field such as Food, Cosmetic, and Chemicals. As a result, the different stakeholder communities started to connect and interact. Additionally, they started to initiate a shared glossary of terminology between the communities and a knowledge-sharing platform (Knowledge-HUB) to collect and structure experience (case reports, DSS and round-robin communities), expertise (position papers), and knowledge produced in REFINE. Based on the compiled information, we are developing a user-friendly web-based Decision Support System (DSS), which facilitates the implementation of intelligent testing strategies (ITSs) for stakeholders from industry and regulatory bodies. A first prototype will serve as a scaffold for further expansion in the second iteration and will be available at the end of 2019. In addition, the need to agree on and align nomenclature used, and correspondingly, the need for standardisation of method and measurement descriptions as well as the necessity to compress the scope of the DSS to mainly concern only physicochemical parameters and only for a limited number of model nanomedicines were identified as challenges during the process. The DSS is intended to inform on pre-clinical safety testing for the market approval of medicinal products and medical devices.

Final results

First, mapping the unmet regulatory needs in relation to the regulatory evaluation of nanopharmaceuticals and nanobiomaterials enabled devices is one of the first milestones in REFINE which will have major impact on the nanomedicine community including research, industry and regulation. To our knowledge such a systematic analysis and extraction of information needs has been done for the first time resulting in the identification of major regulatory challenges and will certainly be very useful for the whole community. This inventory sets the basis for all the experimental work carried out on the development of new analytical methods and collection of data on immunotoxicity and pharmacokinetics. As a result, the elaborated White Paper is expected to be a key document for the nanomedicine community by its novelty and will most likely have an impact on the different communities in the field of NBM. Second, the DSS with its rationalisation of the selection process to identify characterisation assays for NBM will support developers in preparing their NBM-based product for the market. Third, a set of characterisation assays for biodistribution, biological testing and in silico testing of different NBM is currently under development with respect to strict quality and standardisation criteria. A full set of characterisation assays, available at the end of the project, covering all fields necessary to respond to regulatory needs will be seen as a milestone and pillar for refining the Regulatory Science Framework for pre-clinical characterisation of nanomedicines and nanobiomaterials for medical devices.

Website & more info

More info: http://refine-nanomed.com.