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

Periodic Reporting for period 3 - REFINE (Regulatory Science Framework for Nano(bio)material-based Medical Products and Devices)

Reporting period: 2020-12-01 to 2022-02-28

REFINE proposes a Regulatory Science Framework for the risk-benefit assessment of medical products and medical devices that are based on nanomedicines and nanobiomaterials (NMBs). Our goal is to demonstrate the relevance of the framework for the most pressing regulatory challenges in nanomedicine. We studied physiological distribution of NMBs, as well as developed and validated new analytical or experimental methods and assays requested by the regulators. These latter developments were performed in a quality management system, approaching the assays to a possible standardisation. REFINE gathered a wide community of stakeholders in regulation, industry, science, and technology development. Our aim was 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. The result we achieved during the project based on our objectives are: 1) the liaison with regulators, identification of regulatory challenges. The identification of regulatory needs based on regulatory documents, guidelines etc. was reflected with stakeholders and their feedback was included into the REFINE White Paper. The analysis was further used to map regulatory needs against available methods to identify methodological gaps. Both analyses were used to guide the experimental work in REFINE. 2) Match regulatory concerns with intelligent testing strategies. The huge novelty of REFINE is its capacity to transform regulatory needs into the development of new assays providing the missing data in the regulatory process during the development of NBMs. The methodological gaps analysis guided the experimental work packages that addressed some of the identified gaps by developing new or improving existing methods. In addition, these data helped also to develop the Decision Support System (DSS). 3) Rationalise testing. However, due to the novelty of the nanomedicine space, the list of assays required for best characterisation of a given nanomedicine is not uniform and might be different depending on the regulatory agency implicated. Therefore, the DSS was built to support developers to rationalise the selection process of characterization assays for their products. In REFINE, the DSS was completed in two modules (physico-chemical and immunotoxcicity characterisation) ready to support users. 4) Refine testing methods to answer to the current most pressing regulatory concerns. A set of characterisation assays which cover physico-chemical as well as in biological testing was developed and chosen assays were tested internally to develop high quality SOPs preparing these assays towards standardisation. 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 developed assays that fulfil the high-quality standards demanded by regulators. 6) Bridge communities. REFINE built bridges with other communities assessing nanomaterials, with regulators, developers and analysts to jointly define routes for development of trans regulatory exchange, using the existing shared expertise. A lively interaction and common organisation of a joint event with the H2020 Gov4Nano project took place to discuss and to raise awareness for trans regulatory challenges.
Complementary to direct contact initiation with regulatory agencies, a deep analysis of the regulatory challenges reported in publications, conferences and reports have been conducted. Identifying, mapping, and matching of open regulatory challenges / needs together with the rationalisation of testing strategies resulted in the extraction and categorization of regulatory requirements. These results are explained and presented in the White Paper and updated with collected feedback from the communities to be additionally published in a peer-reviewed journal. To identify methodological gaps, the regulatory information needs were mapped against available methods resulting in the identification of five areas where an insufficient number of methods are available to respond to these regulatory needs. Further work in REFINE on the methods identification and experimental work was performed based on these results. In line, 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. They are stored on the open access repository Zenodo for optimised accessibility. The biological response assays were tested in interlaboratory comparison to evaluate their liability, transferability, and stability. Results were published and peer-reviewed in the REFINE special issue in DDTR to be accessible for different stakeholders. Results of REFINE were discussed and shared with other communities in the three Knowledge Exchange Conference (KEC) which bridged different communities beside medical field such as Food, Cosmetic, Chemicals, Medicinal product, Medical Devices. All three KECs aimed for the dissemination of achieved knowledge in REFINE, in collected feedback from the invited communities on trans regulatory challenges and of knowledge sharing, e.g. by a knowledge sharing platform (Research Gate for REFINE), joint events (Joint session between REFINE and Gov4Nano) to overcome regulatory silos. Based on the compiled information with the goal to support developers in the identification of the best fitting testing strategy for their respective material, we developed a user-friendly web-based Decision Support System (DSS). The DSS is intended to inform on pre-clinical safety testing for the market approval of medicinal products and medical devices. The scope of the DSS was mainly focussed on physicochemical characterisation of NBMs with the elaboration of an additional immunotoxicology characterisation module.
First, mapping, identification and analysis of open regulatory challenges and methodological gaps in relation to the regulatory evaluation of nanotechnology-based health products was one of the first milestones in REFINE. This work has key importance with major impact on communities dealing with nanotechnology-based products including research, industry, and regulation. It set the basis for all the experimental work on the development of new analytical methods and collection of data on immunotoxicity and pharmacokinetics. To our knowledge such a systematic analysis and extraction of information needs has been done for the first time with certainly high importance for the whole community. The DSS will support developers in preparing their nanotechnology-based health products for the market. Additionally, a set of characterisation assays for biodistribution, biological responses and in silico testing of different NBMs was developed with respect to strict quality and standardisation criteria addressing the identified methodological gaps. A full set of characterisation assays, covering all fields and addressing (open) regulatory challenges will be a milestone and in REFINE some of the most pressing regulatory requirements and fields were addressed. The REFINE results are collected and published in a Special Issue illustrating the achievements and impact of the project in an integrated way.
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REFINE Regulatory Science Framework