The recommendations of this article have been developed due to extensive desk research (Patient Safety and Nanomedicines, 2020) and in consultation with field experts in one-on-one interviews and through two round-tables which took place in the European Parliament in April 2019 (Event summary, 2019) and November 2020 and which were fully reported.

This has enabled the EAASM to adopt a robust strategy of a continuous extensive advocacy program with all influential stakeholders and the EU Institutions (Nanomedicines Regulatory Coalition, 2021).

This strategy aims to raise the political temperature (Letter to Commissioner for Health and Food Safety Ms. Stella Kyriakides, 2021) so that even more focus can be placed on the regulatory institutions to ensure that a fit-for-purpose regulatory pan-European procedure is adopted as quickly as possible.

The need for a harmonised centralised regulatory procedure is highlighted by three key factors:

1) The plethora of nanomedicines in the pipeline (see Figure 1; Table 1; Van Trier, 2021) which indicates the diversity and complexity of these medicines

Nanocolloidal solutions of iron carbohydrates for intravenous applications are another example of frequently used nanomedicines. The first nanotechnology-based intravenous iron product was introduced in the 1950s and is now known as Venofer^®. To overcome the high toxicity of iron (II) salts, iron in the form of polynuclear Fe(III)-oxyhydroxide core stabilized by a carbohydrate shell was developed. Intravenously applied Venofer^® nanoparticles have been shown to be tolerated at more than 20-fold higher 50% lethal dose (LD 50) levels, compared to iron sulphate solutions in mice (Geisser et al., 1992).

After administration, the iron carbohydrate particles interact with the innate immune system for uptake and release of bioavailable iron (Geisser and Burckhardt, 2011; Koskenkorva-Frank et al., 2013). It is assumed that the characteristics of the nanoparticles affect the fate and disposition in the body (Toblli et al., 2009a; Toblli et al., 2009b; Toblli et al., 2012; Toblli et al., 2015; Toblli et al., 2017). There is a plethora of evidence showing that iron sucrose follow-on products from different manufacturers have different efficacy and safety profiles despite most of them complying with the USP monograph quality requirements (Rottembourg et al., 2011b; Lee et al., 2013; Agüera et al., 2015). Since the structural and functional relationships are not fully understood and, hence, the clinically meaningful critical quality attributes (CQAs) are not fully identified, the manufacturing process defines the product and is crucial for the consistency and quality of the end product and its clinical performance. A robust manufacturing procedure needs to be in place and thoroughly sustained in order to ensure batch-to-batch consistency. Hence, the call for a harmonised centralised regulatory process to ensure the highest safeguards against patient safety issues.

It should be noted that whilst the centralised procedure is already compulsory in a number of situations ¹ , including all those products containing new active substances in, for example, the field of oncology and viral diseases, it does not cover all nanomedicines and nanosimilars. This means that a large number of innovative nanomedicines (including the COVID mRNA) go through the centralised procedure by default. The gap in the system is that for many nanomedicines (i.e., for other indications), it is not yet compulsory for all follow-on/nanosimilars.

As described, for example, by Klein et al., current different routes obtained for marketing approval allows the same nanosimilar to be registered under a variety of brandnames in different countries. This means that when adverse event cases are reported, it is hard to link these patient safety incidences.

As such, nanosimilars would benefit from a mandatory centralised procedure, as this will guarantee consistency in the scientific evaluation of such follow-on products. Another benefit of the centralised procedure is the guarantee of centralised safety monitoring and the obligation for the use of a single brand name throughout the EU. This will facilitate better traceability and adequate identification of product-specific safety issues for nanosimilars.

In 2020, a comprehensive scientific report (Patient Safety and Nanomedicines, 2020) was produced by the EAASM, and a leading politician who sits on the ENVI Committee, namely, MEP Maria da Graca Carvalho (Official website of MEP Petar Vitanov, 2021) (EPP, Portugal), stated in the foreword that (Patient Safety and Nanomedicines, 2021)

An outreach petition encouraging interested parties to join have resulted in the following organizations (Table 3) becoming part of the Nanomedicines Regulatory Coalition, namely, European Alliance for Access to Safe Medicines, European Cancer Patient Coalition, European Liver Patients’ Association, European Parkinson’s Disease Association, European Renal Association, European Specialist Nurses Organization, International Alliance of Patients’ Organizations.

In addition, the EAASM has held focused interviews with leading MEPs (MEP Cyrus Engerer, 2021) whose major interest is health related and who were co-signatories to a letter sent to the EU Commissioner for Health and Food Safety, Ms. Stella Kyriakides, on 30 June 2021, to which a positive reply was received, and the Commissioner’s statement can be seen in Table 4 ² .

The lead rapporteur on the European Parliament INI report, MEP Dolors Montserrat ³ (EPP, Spain), charged with challenging the Commission’s legislative proposal, was receptive to the recommendations that nanomedicines should be specifically mentioned in the INI report. The amendments will be voted in the EU Parliament plenary session in Q4 2021, and there is confidence that the inclusion of nanomedicines and nanosimilars will remain and thus be transposed into the EU Pharmaceutical Strategy master policy document that will ultimately result in new legislation.

For the current amendments that are in the Environment, Public Health, and Food Safety (ENVI) Committees’ INI report ⁴ 2021/2013/INI 08/11/2021, see Table 5.

MEP Petar Vitanov (Official website, 2021) (S&D, Bulgaria) was interviewed by the Parliament Magazine (Parliament Magazine Nanomedicines and Nanosimilars, 2021) and clearly stated the following:

Following on from two Parliament round-table events, a third follow-up event is tabled for Q3 2021.

In the comprehensive Master Research protocol (Van Trier, 2021) thesis entitled “European stakeholders’ perspectives on the therapeutic opportunities and the regulatory challenges associated with nanomedicines,” the main conclusions under Section 6.3, “The Future of Nanomedicines,” were as follows (see Table 6):

This last sentence is a significant cause for concern and so the Nanomedicines Regulatory Coalition under the umbrella of the EAASM intends to continue its strong advocacy program to ensure the following:

• all nanomedicines and nanosimilars be assessed by the EMA Centralised Regulatory Procedure.