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Regulatory Science Framework for Nano(bio)material-based Medical Products and Devices

Periodic Reporting for period 2 - REFINE (Regulatory Science Framework for Nano(bio)material-based Medical Products and Devices)

Reporting period: 2019-06-01 to 2020-11-30

REFINE proposes a Regulatory Science Framework for the risk-benefit assessment of medical 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, ensuring the possible standardisation of our assays. REFINE gathers a wide community of stakeholders in regulation, industry, science, and technology development. Our aim is to contribute to a faster and more robust assessment of new nanomedicines, 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 challenges. Since our aim is to provide answers to the unmet regulatory needs of regulators in the field of nanomedicines and nanobiomaterials (NBM), REFINE want 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 challenges into development of new assays that aim to 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 implicated. 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 cover physico-chemistry as well as in biological testing. This assay set is revised regarding the protocol design, interlaboratory test runs and round robin tests. 5) Assure quality standards for development & testing. The development of new assays implicates that quality standards high enough for being accepted by regulators are respected. REFINE wants to develop assays that fulfil the high-quality standards demanded by regulators. 6) Bridge communities. 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.
In compliment to direct contact initiation with regulatory agencies, a deep analysis of the regulatory concerns reported in publications, conferences and reports have been conducted by the REFINE consortium. Identifying, mapping, and matching of the open regulatory challenges and needs together with the rationalisation of testing strategies resulted in the extraction and categorization of regulatory demands. These results are explained and presented in the White Paper. To initiate the dialogue with regulators, REFINE developed a survey to collect feedback to the identified gaps from the communities which will be integrated in the White Paper. . In addition, the major findings of this work were published in a peer-reviewed journal to provide the context of the regulatory challenges. The identified regulatory gaps will guide further work in REFINE on the methods identification and experimental work. Based on these compiled information, the regulatory validation requirements were elaborated as a base for assay development and a pathfinder to standardisation. To harmonise this process, the SOP for in silico, biodistribution and biological response assays were refined and standardised. The biological response assays were tested in interlaboratory comparison to evaluate their liability, transferability, and stability. The identified regulatory challenges and gaps were discussed and shared with other communities in the second Knowledge Exchange Conference (KEC) which bridged different communities beside medical field such as Food, Cosmetic, Chemicals, Medicinal product, Medical Devices. The second KEC aimed for the confirmation to create a dedicated knowledge sharing space, 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 stakeholders from industry, and regulatory bodies the implementation of intelligent testing strategies (ITSs). A first prototype was presented. 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.
First, mapping the open regulatory challenges in relation to the regulatory evaluation of nanopharmaceuticals and nanobiomaterials enabled devices was one of the first milestones in REFINE which have major impact on the nanomedicine community including research, industry, and regulation. 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, second, the White Paper was elaborated and 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. Moreover, a gap analysis identified information needs, and gaps in available methods to answer these needs fully or partially. 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. Third, 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. Fourth, a set of characterisation assays for biodistribution, biological testing and in silico testing of different NBM was developed with respect to strict quality and standardisation criteria. A full set of characterisation assays, covering all fields and addressing (open)regulatory challenges will be a milestone and pillar of REFINE.
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REFINE Regulatory Science Framework