Identification of regulatory needs for nanomedicines

The application of nanotechnology in health care is widely accepted as a potential driver of biomedical innovation. By exploiting their unique physicochemical properties, nanomedicines can monitor, repair, and control biological systems in order to address diseases for which currently no or only insufficient diagnostic and therapeutic tools are available. Nevertheless, the opportunities of nanotechnologies in the health sector are accompanied by challenges in the regulation of these products. Sufficient knowledge on their quality, safety, and efficacy must be gained and standardised methods must be made available to support the regulatory decision making and allow a smooth translation towards clinical applications. We have conducted a survey among regulatory authorities with the aim to obtain a general overview on the status and regulatory needs of nanomedicines and to indicate some trends on future requirements. The outcome has demonstrated strong regional differences in the regulation of nanomedicines and confirmed the need for the harmonisation of information requirements on nano‐specific properties. In addition, a number of critical physicochemical properties that have already been proposed in the scientific literature were verified in the survey as relevant for regulatory decision making. Finally, the survey has demonstrated an interest of regulatory agencies in an independent nanomedicine characterisation facility that can support regulators in the evaluation of these systems and at the same time assess the performance of existing and new test methods for their application to the field of nanomedicine.


Introduction
Nanomedicines are an emerging product class in the health sector, hence, they have to comply with the high standards of the medicinal product regulation or other related legislative frameworks such as the medical devices regulation. Due to their size related physicochemical properties and the resulting biological effects, nanomaterials can require additional quality and safety testing compared with the products not using nanotechnology (Sadrieh and Tyner, 2010;Tyner et al., 2015). For the safe evaluation and supervision of nanomedicines, critical quality attributes (CQAs) and additional toxicological assessments have to be considered and translated into standardised and regulatory accepted test methods and testing strategies.
However, the wide range of structures, their physicochemical and biological properties, and the variety of therapeutic applications makes the generalisation of information requirements a challenge. Furthermore, the full exploitation of nanotechnology potential in the medical sector is ongoing, but robust datasets allowing conclusions to be drawn on information requirements are not yet available. In order to anticipate regulatory needs, competent authorities have started to publish initial reflection papers aiming to provide first guidance on the regulatory information requirements that might be requested during the different approval steps of innovative products (Committee for Medicinal Products for Human Use (EMA/CHMP, 2013a, b,c-2015US FDA CDER, 2015). In the USA, the Nanotechnology Characterization Laboratory of the National Cancer Institute (NCI-NCL) (https://nanolab.cancer. gov) has provided a thorough characterisation of the quality and safety of nanomedicines already for more than 10 years, supporting product developers and contributing to the smooth translation of such products to the market. At the same time, the NCI-NCL offers the experience and knowledge related to the assessment of nanomedicines to the regulatory agency. Since 2015, the European Nanomedicine Characterisation Laboratory (EU-NCL) (www.euncl.eu) offers a similar service for the European product developers and it can be anticipated that also European regulatory agencies and standardisation bodies will benefit from the knowledge and experiences of this platform. The EU-NCL is a cooperative arrangement between six European Laboratories and the NCI-NCL of the United States. In order to ensure that methods developed/validated in the EU-NCL are relevant for regulatory purposes and the obtained information can support the regulatory decision making, the EU-NCL is performing a series of questionnaires addressing different groups of regulatory scientists. The data presented here are the results of the first survey submitted by the scientists of regulatory bodies involved in the Nanomedicines Working Group of the International Pharmaceutical Regulators Forum (IPRF) (www. i-p-r-f.org/index.php/en). The objective of the survey was to obtain an overview on the experience of regulators with nanomedicines in the various regions, their information needs as well as the identification of future priorities to support the translation of nanomedicines towards clinical applications.

Methodological Approach
The definition of questions The questions have been defined according to recommendations of the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) (SCENIHR, 2015), members of the EU-NCL consortium and European Medicines Agency's (EMA's) reflection papers related to nanomedicine (EMA/CHMP, 2013a,b,c-2015. In addition, a similar questionnaire performed within the EU project "NANoREG" on manufactured nanoparticles has been taken into account (NANoREG, 2013). In order to avoid any bias, responders had the possibility (and were encouraged) to include additional information not covered by the predefined questions. A full description of questions and answers is available in JRC Technical Report (Bremer et al., 2016).

Information on respondents
The IPRF has established a Nanomedicines Working Group in order to discuss emerging questions and anticipate regulatory needs for nanomedicines. This working group is acting as a platform to share nonconfidential information and work related to nanomedicines/nanomaterials in drug products, borderline, and combination products. Furthermore, the group supports regulatory harmonisation and potential consensus finding on standards. Currently, the IPRF group is chaired by the EMA. Fifty-nine survey invitations to colleagues from 18 governmental Institutions regularly participating in activities of the IPRF Nanomedicines Working Group were sent out.

Survey management
The survey has been performed by using the European Commission's management tool "EUSurvey" hosted at the European Commission's Department for digital services (DG DIGIT). The presentation of the results is anonymous and individual results will be kept confidential. The presented survey has been launched in October 2015 and has been finalised in November 2015. The survey has been evaluated using basic result analysis capabilities and visualization of the data in histograms and chart views as offered by the European Commission tool.

Results
The obtained information can be classified into three categories: (1) regulatory experience with nanomedicines, (2) information needs of regulators for the characterisation of nanomaterials, and (3) further steps that can support the acceptance of nanotechnology based products in health care.

Regulatory experience with nanomedicine applications
The majority of competent authorities that responded to the survey had no or only few applications of nanomedicinal products. Only two agencies reported more than 10 market authorisations for medicinal products in the last 36 months and three agencies stated that more than 10 investigational products have been approved for clinical trials (Fig. 1A).
In order to have a better understanding of whether the submitted products were innovative products or products claiming to be similar to an innovator product, the respondents were asked to quantify their applications for follow-on products ("nanosimilars"). Only one agency reported more than 10 applications for these products (Fig. 1B). An additional four agencies had one to nine applications of so called "nanosimilars." The respondents were asked how many nanotechnology involving products were regulated as medical devices. Very few products were regulated as medical devices but the decision making on their regulatory path triggered discussion in three agencies (Fig. 1B). Figure 2A is summarizing the satisfaction of agencies with the information provided by product developer. Two agencies receiving up to 10 applications for market authorisation (data not shown) responded that the information on the physicochemical characterisation was not sufficient. One of these agencies also reported insufficient data on the biological characterisation for market authorisation. Another agency with up to five clinical trial applications indicated unsatisfactory data on the biological characterisation ( Fig. 2A). It should also be noted that a considerable number of agencies (three out of nine) have not responded to the question (not shown).
Furthermore, the agencies were asked whether test methods used for the physicochemical characterisation were suitable for their decision making (Fig. 2B). One agency with more than 10 applications (data not shown) reported that the agency received applications with test methods that were not suitable for quality assessments. In particular, methods used in the applications for clinical trials were judged as not sufficiently validated by three agencies. In addition, two agencies reported insufficient information for assessing the quality of follow-on products (not shown).

Relevance of information needs for the preclinical characterisation of nanomedicines
Adequate characterisation of CQAs that may impact drug product safety and efficacy is essential for product development and quality control. In addition, also the manufacturing process and the effect of its critical steps on the CQAs should be carefully evaluated. For these reasons, a number of questions were related to the relevance of various physicochemical parameters allowing the assessment of the properties of nanomaterials for regulatory decision making. Among the most important parameters are, for example, stability, particle size (Àdistribution), surface properties, and solubility, as they may change the pharmacokinetics, biodistribution, and toxicity of the formulation (Fig. 3). Nevertheless, the relevance of each parameter is strongly dependent on the evaluated nanomedicine,  which holds true also for the functional properties including drug release data, judged as relevant by most of the respondents in another question (not shown). Agencies with no or only a few applications have not responded to this set of questions as it requires handson experience in regulating nanotechnology based products ( Fig. 3 and data not shown). Furthermore, a number of potential pitfalls affecting toxicity assessments are widely discussed in the scientific literature and a selection of questions related to major pitfalls aimed to obtain a regulatory point of view. The agencies have highlighted the need for assessing the stability, uniformity (dispersibility), endotoxin testing, and agglomeration behaviour as highly relevant before entering into clinical trials (Fig. 4A). Additional information such as the assessment of the solubilised fraction before and during the testing of metals and metal oxides seems to be more relevant at a later stage of the product development (Fig. 4B). There was also a concurrence among the authorities on the need to test the empty carrier in addition to the active pharmaceutical ingredientcontaining formulation for assessing inherent toxicities (data not shown).
Supporting the acceptance of nanotechnology based products in the health sector Some products based on nanotechnology are classified as medical devices in Europe and as medicinal product in other regions (and vice versa). The respondents were asked whether a harmonisation of testing requirements of medicinal products and medical devices for nanotechnology based products in the various regions is relevant. Six out of nine agencies confirmed the need of such a harmonisation activity (Fig. 5).
The need to harmonise also characterisation of nanomaterials used in medical devices and medicinal products might be of interest in particular for borderline products for which the regulatory path is not defined in the phase of preclinical development. A number of materials, for example, metal oxides, currently in the phase of development might fall in this category as they use mainly physical (rather than chemical) means to exert the therapeutic action. Three agencies considered such activities as relevant. However, the majority of respondents (six agencies) have not replied to the questions or had no opinion on this need (Fig. 5). An important question when characterising nanomedicines was related to additional toxicity testing requirements. Three agencies reported that they experienced further toxicity testing needs due to the involvement of nanomaterial (Fig. 6A). In addition, seven agencies felt a need to make additional ecotoxicological methods available in order to assess the impact of nanomedicines on the environment (Fig. 6B).
Finally, the agencies provided their opinion on how the EU-NCL could support their work in regulating nanomedicines (the respondents were allowed to tick several tasks) (not shown). Among them, the validation of test methods, testing facility, and providing the scientific advice were the most frequent answers.

Discussion
Previous studies evaluated that nearly 250 nanomedicines are approved or in various stages of clinical studies worldwide (D'Mello et al., 2017;Etheridge et al., 2013). In a recent review, the EMA only reported on 11 marketing authorisation applications for nanomedicines and approximately 50 nanomedicines and nanoimaging agents in the phase of clinical development (Phase I-III) in Europe (Ehmann et al., 2013;Hafner et al., 2014) (please note that the EMA is neither responsible for the authorisation of clinical trials nor for the decentralised authorisation of medicinal products). Such significant regional differences in the number of nanomedicines applications for market authorisation were confirmed in the recent survey and raised the question why the ecosystem of some regions is more suitable than others for the marketing of nanomedicines.
In order to further elaborate on the question, we investigated whether the current regulatory situation related to nanomedicines in different countries could contribute to such an observation (Table 1).
In the countries participating in the survey, there is no specific regulatory framework designed for the nanotechnology based products (Bartlett et al., 2015;Guo et al., 2014). The so-called nanomedicines follow the regulation of medicinal products and use common guidelines for their assessment based on ICH guidelines. However, the differences in the approval process can originate from regionally different legislative frameworks and classification of pharmaceuticals (Mulaje et al., 2013;Van Norman, 2016). All agencies offer early scientific advice procedures for product developer in order to guide them through the approval/authorisation process and they preconize "case-by-case" approach to address nano-specific properties of the product. Furthermore, a number of initiatives were launched within the regulatory agencies to advance the challenges linked to the regulation of nanomedicines (Bartlett et al., 2015;Yu et al., 2016). In some countries like the USA, Japan, and in the European Union, some initial guidance documents were released to help product developer in the evaluation of the nanotechnology based   products searching for the regulatory approval (Table 1). However, they are not legally binding documents and the specific regulation is missing.
In the view of the still limited number of approved nanomedicines in most countries and the heterogeneity of the product class, it is very difficult to obtain robust data sets allowing general conclusions on the information requirements related to their quality and safety (Ventola, 2012). The restricted amount of experience of most agencies might also explain the overall response rate to the questionnaire of 50% and the low response rates to those questions that require "hands on" experience in the regulation of nanomedicines. In this context, it is of particular importance to share knowledge among the regulatory bodies and seek a harmonised regulatory governance of nanotechnology products.
Another caveat for a harmonised regulation of nanomedicines is the current lack of a consistent terminology and categorization of nanomedicines that complicates the communication between agencies and eventually also explains the response rate to the survey. The establishment of a common language is often a challenge for emerging products and should be addressed at an early stage (Fischer, 2014;Sainz et al., 2015;Ventola, 2012). The need for an agreed terminology was identified as another important objective for the IPRF working group (Satalkar et al., 2016b;Tinkle et al., 2014).
According to the scientific literature, the so-called follow-on products ("nanosimilars") will pose additional challenges in the regulation of nanomedicines (Ehmann et al., 2013;Mühlebach et al., 2015). Such follow-on products are similar to an innovator product for which the patent has expired. Currently, there is no specific regulatory framework for "nanosimilars," but the regulatory bodies have provided initial guidance in the reflection papers (EMA\CHMP, 2013b in particular for the growing number of Doxil like formulations. However, the survey demonstrated that only a few so-called "nanosimilars" have requested a market authorization. But also for this question, regional differences were observed, suggesting that follow-on products might be an upcoming challenge for the European regulators. The selection of the regulatory path for certain products involving nanotechnology has triggered the attention of regulatory scientists and lawyers (Dorbeck-Jung and Chowdhury, 2011;Pachi Spyridoula, 2013). In particular, sophisticated products for which the regulatory path is blurry (borderline products) or complex products such as theranostics combining diagnostic and therapy agents (combination products) will require special regulatory awareness. The challenge of regulating borderline products is widely recognised and already flagged as a priority in the EU Medicines Agencies Network Strategy to 2020 document (EMA, 2015). Furthermore, six agencies indicated a need to harmonise the requirements related to the characterisation of nanomaterials in medicinal products and medical devices because certain products might follow different regulatory paths in the various regions (Fig. 5).
A lack of harmonisation of information needs and associated standardised testing methods was also confirmed in the survey of Satalkar et al. (2016a). The strong collaboration between the US NCI-NCL and the EU-NCL will support the harmonisation of information needs and of the corresponding testing methods. Currently, only very few standard test methods specifically addressing the application of nanotechnology in the health sector are available. Within a series of workshops, regulators currently discuss and seek for consensus on standardisation needs, for example, under the umbrella of the Global Summit on Regulatory Science (GSRS16, 2016). Several initiatives have already proposed initial lists of physicochemical and/or toxicological parameters relevant for the characterisation of nanomaterials used in the health sector. The European Commission's SCENIHR has released a guidance document on the "Determination of Potential Health Effects of Nanomaterials Used in Medical Devices" (SCENIHR, 2015). Also, the EMA published a number of reflection papers on selected categories of nanomedicines indicating physicochemical properties that should be considered when developing nanomedicines and preparing the marketing authorisation (EMA/CHMP, 2013a,b,c-2015. Finally, the EU flagship project NANoREG organised a virtual workshop to identify, formulate, and prioritise relevant issues and questions related to the safety of nanomaterials in consumer products (NANoREG, 2013). The recommendations of the various activities demonstrated a similarity of information requirements of various sectors using nanotechnology and were mostly confirmed within this survey (Fig. 3). A recently launched H2020 project REFINE will focus on the development and standardisation of methods that are most relevant for the regulatory assessment of nanotechnology based medical products and devices (REFINE, 2017).
Besides the need for careful evaluation of the physicochemical properties allowing the monitoring of the quality of nanomedicines, a number of articles have investigated the relevance of additional toxicity assessments for nanomedicines (Nyström and Fadeel, 2012;Oberdörster, 2010;Wolfram et al., 2014). Also, the present survey indicated that specific properties of nanomedicines can trigger additional testing in vitro and in vivo. The scientific literature has focussed in particular on the interaction of the nanomaterials with the blood and immune system because the latter can recognise intravenously administered materials as foreign and trigger different kind of immune responses. Furthermore, nanomaterials can be hazardous to the blood system as it is the first target organ, thus exposed to the highest concentration (David et al., 2016; 2018 | Volume 3 | Issue 1 | Page 12 Dobrovolskaia and McNeil, 2013;Dobrovolskaia, 2015;Dobrovolskaia et al., 2008;Ilinskaya and Dobrovolskaia, 2013). A better understanding of nano-specific effects on target tissues will support the identification of the hazardous potential already in the preclinical phase. Furthermore, such knowledge can inform decision makers on the need for additional toxicity assessments. Specific in vitro tests could be made available before introducing additional laborious and expensive animal experiments in biomedical research and preclinical testing. However, most of the currently available in vitro tests have been developed/validated for small molecules and the question of their suitability for nanoparticles has to be proven. Further investigations are also necessary to understand which product classes have to demonstrate the safety for the environment and what kind of environmental tests could be of interest in this context.

Conclusions
The recent survey confirmed that some regions are more advanced in marketing nanomedicines than others. These regional differences call for a close collaboration of various regulatory bodies in order to share experiences and to train scientists who will be confronted with more nanomedical applications in the future. Additional challenges such as the evaluation of "nanosimilars," borderline, and combination products will require special regulatory awareness and are already on the agenda of international working groups.

Major recommendations
1. Experiences in the authorisation of nanomedicines should be shared by regulatory scientists. 2. Product developer should be aware of particular requirements when developing borderline, nanosimilars, and combination products. 3. Appropriate standard test methods addressing nano-specific properties should be made available.
Regulatory scientists working for different legislative frameworks outlined a number of crucial information requirements allowing the assessment of the quality and safety of nanotechnology based products. A selection of such physicochemical parameters including in particular size, stability, and surface properties resulted from this survey. However, for most of the proposed parameters, no standards are available yet, and the reliability and relevance of the analytical methods should be assessed for their use in regulatory testing. Special emphasis should be given to the identification of in vitro tests that have the potential to identify toxic effects triggered by the nano-specific properties of the formulation. Such tests can contribute to the reduction of animal experiments in biomedical research and non-clinical testing and will support product development by an early detection of product-related hazards. The strategic partnership of the EU-NCL and the NCI-NCL will support such discussions by providing scientific/technical expertise on information needs, technology scouting, and the development and validation of new test methods. A concerted action between the NCLs will promote the marketing of nanomedicine products on both sides of the Atlantic.

Acknowledgments
Contributions to the draft survey were received from EU-NCL partners, including The final draft version of this report was reviewed by the Executive Board of the EU-NCL project.
The authors would like to thank in particular F. Ehmann from the EMA who chaired the Nanomedicines Working Group of the IPRF and supported the survey within the working group. We are grateful to the scientists of the regulatory bodies who have replied to the survey: