key: cord-1024337-ngvkrtik authors: Isles, Michael P. title: Nanomedicines and Nanosimilars—Why a Robust Centralised Regulatory Framework Is Essential to Enhance Patient Safety date: 2022-02-24 journal: Front Pharmacol DOI: 10.3389/fphar.2021.787239 sha: 0119200d247ea3c7687ad4525bbf7b749568b593 doc_id: 1024337 cord_uid: ngvkrtik nan There will be different manufacturers producing these similar products from different sites with differing manufacturing processes, and so the production of identical replicas of the originator product cannot ever be achieved (Ehmann et al., 2013; Marden et al., 2018) . It is for this reason that a thorough clinical valuation must be carried out before an MA can be granted. Patient harm has occurred when a nanosimilar has not had this rigorous safety and efficacy check established through a clinical trial (Rottembourg et al., 2011a) program. This article endeavors to lay out the critical success factors that will enable a centralised procedure for nanomedicines and nanosimilars to be achieved. 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 2) The evolution of many NBCD marketing authorisations (of which many are nanomedicines and nanosimilars-see Table 2 ) adapted by Klein et al. (2019) which show the diverse nature of the regulatory routes. This gives rise to different national health agencies assessing these medicines and allows for the marketing of different brand names, which in turn makes PV linkage difficult and thus compromises patient safety. 3) Interchangeability of "similar" medicines requires strong central guidelines and education programs to ensure that hospital-and community-based policies are implemented by doctors, pharmacists, and nurses in a coordinated way. 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 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 "You rightly mention that a key objective of the pharmaceutical strategy for Europe is to enable innovation and adapt the European medicines regulatory framework to cutting-edge products and scientific developments With this objective in mind, we will revise the pharmaceuticals legislation. We have already published a Roadmap/inception impact assessment, which outlines the main policy considerations to adapt the current system of authorisations and the possibility to change the scope of the centralised application procedure for innovative products. While I am not able at this moment to prejudge the result of this analysis, let me reassure you that the final policy directions will be based on a thorough impact assessment and extensive public consultations." 25. Calls on the Commission to build on the work of Europe's Beating Cancer Plan and ensure that Europe becomes the worldwide centre of excellence for R&D in emerging, innovative fields of medicine; underlines that state-of-the art technologies, such as nanomedicines, stand to provide solutions to current treatment challenges in areas such as cancer and cardiovascular diseases; highlights that these innovative fields of medicine should be authorised by the centralised approval framework for nanomedicines 101. Urges the Commission and the EMA to consider the full lifecycle of all innovative medicines and therapies, including gene and cell therapies, personalised medicine, nanotechnology and next-generation vaccines, and ensure a fit-for-purpose framework for off-patent competition at the time of loss of exclusivity; calls on the Commission to establish a regulatory framework for nanomedicines and nanosimilar medicines, and calls for these products to be approved through a compulsory centralised procedure TABLE 6 | "European stakeholders' perspectives on the therapeutic opportunities and the regulatory challenges associated with nanomedicines." Section 6: "The Future of Nanomedicines." "All interviewees saw a fairly bright future for nanomedicines. The number of MA applications is steadily increasing and the topic is more and more discussed at large conferences. Partly due to the accomplishments with the COVID-19 vaccines, it was expected that fundamental research into the size-specific properties of nanodrugs will receive a further boost and the use of already successful technologies such as encapsulation in liposomes will be extended to new indications. The question remains whether nanodrugs will mainly continue to be delivery vehicles or whether a transition to new stand-alone substances will be made. The latter would further stimulate the commercial potential of nanomedicines. In addition, it was expected that the importance of follow-on products will continue to increase in the search for more affordable medicines for a wide audience However, additional clarification of the regulatory landscape will be necessary to fully realize the potential of these drugs. Regulatory authorities must be ambitious and continue to set themselves the goal of optimizing the regulation of innovative medicines and translating an increase in knowledge into improved guidelines. What has been learned from the situation with biologicals is that this evolution is slow. The will to change European pharmaceutical legislation and include nanomedicines as a distinct concept into the legal framework is rather small. As a result, changes such as a mandatory central procedure or a specific pathway for nanomedicines' follow-on products may not be quickly realized after all." Frontiers in Pharmacology | www.frontiersin.org February 2022 | Volume 12 | Article 787239 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) "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 ( 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: "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. 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. • a harmonization of information requirements of regulators in order to correctly characterize nanomedicines • production of a scientific consensus on definitions for nanomedicines across Europe • improved education and a fostering of awareness on the complexity and sophistication of nanomedicines among policymakers, prescribers, payers, and patients. This is especially relevant when it centers on issues of interchangeability The author confirms being the sole contributor of this work and has approved it for publication. 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Free Radic Comparison of Adverse Event Profile of Intravenous Iron Sucrose and Iron Sucrose Similar in Postpartum and Gynecologic Operative Patients Entitled Enabling a Centralised Regulatory System for Nanomedicines through the Pharmaceutical Strategy for Europe Reflections on FDA Draft Guidance for Products Containing Nanomaterials: Is the Abbreviated New Drug Application (ANDA) a Suitable Pathway for Nanomedicines? AAPS 20, 92 MEP Romana Jerkovic (Croatia, Progressive Alliance of Socialists and Democrats), MEP Petar Vitanov (Bulgaria, Progressive Alliance of Socialists and Democrats), MEP Pietro Fiocchi (Italy, European Conservatives and Reformists Group), MEP Margrete Auken. Denmark: Greens/European Free Alliance Nanomedicines Regulatory Coalition Official Website of MEP Petar Vitanov Official website of MEP Maria da Graça CARVALHO The Need for a Centralised Regulatory Procedure Do two Intravenous Iron Sucrose Preparations Have the Same Efficacy? Do two Intravenous Iron Sucrose Preparations Have the Same Efficacy? Nitrosative Stress and Apoptosis in Non-Anemic Healthy Rats Induced by Intravenous Iron Sucrose Similars versus Iron Sucrose Originator Markers of Oxidative/Nitrosative Stress and Inflammation in Lung Tissue of Rats Exposed to Different Intravenous Iron Compounds Comparison of Oxidative Stress and Inflammation Induced by Different Intravenous Iron Sucrose Similar Preparations in a Rat Model Differences between the Original Iron Sucrose Complex Venofer ® and the Iron Sucrose Similar Generis ® , and Potential Implications Differences Between Original Intravenous Iron Sucrose and Iron Sucrose Similar Preparations The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.