Nanomedicines and Nanosimilars—Why a Robust Centralised Regulatory Framework Is Essential to Enhance Patient Safety

Methodology

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.

FIGURE 1

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 situations¹, 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.

Results

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)

“A strong fit-for-purpose regulatory framework is needed, in order to build on all of the current knowledge and expertise. Only then will we be able to have new treatment opportunities that will benefit patients in a timely and safe way.”

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.

TABLE 3

The European Alliance for Access to Safe Medicines (EAASM) is an independent pan-European not-for-profit organization dedicated to protecting patient safety by ensuring access to safe medicines - falsified medicine awareness/safer use of off-label medicines/medication errors/nanomedicine and nanosimilar regulatory clarity

The European Cancer Patient Coalition (ECPC) ensures that the voice of cancer patients in Europe is represented in all relevant policy-making decisions in the European Union. It works to anticipate and formulate legislation taking place at the EU level and actively participates in the EU legislative health policy process

	ELPA’s aim is to promote the interests of people with liver disease: to highlight the size of the problem; to promote awareness and prevention; to address the low profile of liver disease as compared to other areas of medicine; to share experience of successful initiatives; to work with professional bodies such as The European Association for the Study of the Liver (EASL) and with the EU, to ensure that treatment and care are harmonised across Europe to the highest standards
	The European Parkinson’s Disease Association (EPDA) has been championing and working with the global Parkinson’s community for nearly 30 years, providing information and resources to all stakeholders whilst raising awareness of the disease’s complexities and impact and advocating for concrete policy change that benefits the Parkinson’s community
	The European Renal Association (ERA) objectives are the advancement of medical science by promoting fundamental and clinical advances in the field of nephrology, dialysis, renal transplantation, hypertension, and related subjects achieved by collaboration, education, research, raising public awareness, and career opportunities whilst enhancing professional networking
	ESNO promotes and represents the interests of specialist nurses in Europe. Through collaboration with stakeholder organizations and utilizing advanced science, it pursues recognition under the Directive of Professional Qualification. ESNO contributes to effective co-operation between health professionals, organizations, institutes, and agencies, thereby setting professional standards for education and continuing development

The International Alliance of Patients’ Organizations (IAPO) is a unique global alliance representing patients of all nations across all disease areas. It has 300 member organizations from 71 countries representing 50 disease areas. IAPO’s vision is to see patients placed at the center of healthcare and its mission is to help build patient-centered healthcare worldwide

Nanomedicines Regulatory Coalition.

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 4².

The lead rapporteur on the European Parliament INI report, MEP Dolors Montserrat³ (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 report⁴ 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:

“As an MEP actively involved in health care, and with the progress of the Pharmaceutical Strategy for Europe, it is the right time to set the scene for building a pan-European medical agency consensus so that regulatory weaknesses can be addressed through a robust regulatory pathway and thus provide medicines with the highest quality, safety and efficacy profiles for European patients.”

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

Conclusion

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):

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