Have nanomedicines progressed as much as we’d hoped for in drug discovery and development?

KEYWORDS:

• Nanomedicines
• regulatory guidelines
• standardization control
• translational drug delivery

1. Introduction

Since the early days of nanomedicine some 50 years ago, nanoparticles have been considered as promising tools that can both accelerate drug development and drug discovery exploration, allowing tailored platforms for active molecules which have failed to succeed in classical dosage forms. The concept and development of nanoparticles for drug delivery, mostly given by parenteral administration, are of particular relevance for increasing the therapeutic index of drugs by providing mechanisms of solubilization, passive targeting, active targeting, and triggered release [1].

Besides the hundreds of outstanding publications and auspicious patents, several preclinical and clinical studies have been performed which demonstrate the potential of nanoparticles to modulate the pharmacokinetics of therapeutic molecules, improving their clinical effect and reducing associated side-effects. Still, the level of excitement initially raised is not proportional to the low number of nanoformulations now approved or already on the market. Indeed, the translation of nanomedicines into clinical practice has been slow, compared to the standard path of medicines [2].

Fundamental nanoscience research has created many concepts that, though clinically interesting, are unreasonable to develop commercially. Indeed, nanomedicines are of high complexity and our understanding of their interaction with biological systems is limited [3]. The one-fits-all technological approach often assumed for classical dosage forms, which is suitable for the formulation of active pharmaceutical ingredients (APIs) with similar physiochemical properties, cannot be extrapolated to nanomedicines, where the dosage form itself is a complex entity, without the fast and total disaggregation in the body prior to its pharmacological action.

The process of getting new drugs to market involves an extensive journey from basic molecular discovery through to the construction of the dosage form, preclinical tests, clinical trials in humans, and final regulatory approval. After a timeframe of 10 to 15 years, and an investment of hundreds of millions of dollars, a new medicine may be approved. Nanoparticles, due to their size and robust integrity, must be understood beyond their simple carrier function. Still, there is no specific regulatory framework designed for the approval of nanomedicines in the main agencies, them following the same regulation procedures as all medicinal products which use common guidelines for their assessment based on the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines [4].

There are, though, basic scientific advice procedures for the product developer to adhere to in order to guide nanomedicines through the approval/authorization process [4,5]. These guidelines are not legally binding documents, with their definitive regulation missing. In a recent survey study conducted by the European Commission Joint Research Centre, this lack of regulatory standardization, and heterogenicity in marketing nanomedicines was further highlighted as being problematic across various regulatory bodies [4].

Actions for the faster translation of nanoparticles within drug development must be considered. Primarily, information regarding the selection of production methodologies and materials employed in the early stage of drug development should be considered, to facilitate the establishment of robust and reproducible industrial processes. Furthermore, more emphasis should be made about the characterization of the starting materials of nanomedicines and their quality grade. However, the unique properties regarding their size and surface composition create difficulties in their physicochemical characterization that must be overcome.

With the anticipation of standardization requirements, particular attention must be made towards regulatory information that can be triggered by the particularities of nanomedicines [6]. The most common nanomedicines in use for medicinal products are liposomes, nanocrystals, emulsions and iron-carbohydrate complexes [7], with individual and unique features, which make the uniformization of physicochemical characterization a challenge. The participation in regulatory and pharmacopoeial initiatives towards the standard quality control attributes of nanomedicines must be promoted, as there is an absence of harmonized approval processes for nanomedicines worldwide.

Also, guidance on the most relevant critical quality attributes for scale-up methodologies and translation of nanomedicines into a clinical set are often disregarded. One of the major steps is the production of large-scale batches under good manufacturing practice (GMP) conditions. There is, still, a significant gap between academic lab-scale and industrial GMP production settings [8].

Lastly, in vivo validation must be addressed; namely, the selection of animal models/species that could aid our understanding of the biodistribution and bioaccumulation of nanosystems. This selection process should not be too basic and is largely dependent on specific clinical applications, which could even justify complementary guidance. High heterogeneity between patients is often present; therefore, using selected animal models may not represent the real situation in the clinics. Preliminary imageable nanomedicines can also be used to assess in vivo fates of nanomedicines prior their therapeutic performance. In the clinical setting, imaging can play an additional role due to human and disease heterogeneity [9]. It is clear that individual/disease heterogeneity affects the translation of therapeutic nanomedicines and ultimately their performance. Also, any animal model would be of limited use if based only on phenotypical correlation rather than on physiological mechanism [10].

Current initiatives have been created to boost innovation and faster translation in nanomedicines. The ETP Nanomedicine (ETPN) initiative is an initiative led by the pharmaceutical industry, to address the application of nanotechnology in healthcare. The ETPN believes that involving industry will accelerate the development of promising ideas, and provide the effective and safe health-care products that patients demand [11]. The Nanomedicine and Nanoscale Delivery Focus Group of the Controlled Release Society has also been launched by investigators from academia, industrial researchers from companies with R&D in nanosystems and experts from regulatory boards [12]. The society promotes an integrative and progressive discussion forum for all those engaged in the wide field of nanomedicine. Others like the European Foundation of Clinical Nanomedicine (CLINAM), the Nanomedicine Working group of the International Pharmaceutical Regulators Programme (IPRP) or the American Society of Nanomedicine (ASN) contribute to the establishment of complete networks of different players in the nanomedicine field, that is aiming for the regulatory harmonization or a convergence which is focused on nanomedicines, optimization of resources that can also speed up the translation of nanomedicines via outstanding pre-clinical outputs. Certainly, the congregation of all these, and other initiatives, are contributing towards the development of nanomedicine products and their push towards the clinic.

It is clear that to accelerate the transition from benchtop to clinically efficient nanomedicines, researchers need to employ suitable and standardized methods of production and characterization. The understanding of how the physicochemical properties of nanomedicines can influence the treatment’s distribution and clearance in the human body is also required at earlier stages of drug development. Indeed, the absence of adequate physicochemical characterization of nanomedicines may result in deceiving clinical impact and prove the treatment to be ultimately, worthless. Likewise, the progress of discovery and development of nanomedicines from industries requires a parallel effort from regulators to establish clear quality specifications and accurate efficacy models. Proper tools for the selection of animal models at the pre-clinical stage, and patient selection at the clinical level must also be considered. Furthermore, synergic, collaborative actions between scientific societies, pharmaceutical industries, and regulatory bodies may also play a fundamental role on the drug development process, promoting the dialogue between creators and manufacturers.

2. Expert opinion

The ability of nanoparticles to formulate drug molecules, ameliorating their biological fate, and to be actively targeted towards a receptor/transporter is highly promising. Despite this, nanomedicines represents about 15% of the total pharmaceutical market [13] and have yet to make an advanced impact in clinical practice.

It is consensual that a lack of proper and rational characterization of nanomedicines is one of the main stumbling blocks for their translation from bench to bedside. Some of the major concerns of the poor translational capacity of nanomedicines include the difficulty of scale-up production, the lack of regulatory guidelines for the full physical-chemical and biological characterization, and the pre-clinical/clinical correlation due to the proper selection of animal models. The need for the harmonized evaluation nanomedicine is already known but, so far, regulatory authorities have not been able to determine a complete list of specifications and methodologies to facilitate their commercialization.

Among the evaluation procedures, it is of upmost importance that the standardization and validation of in vitro assays for testing the safety and efficacy of nanomedicines and in vitro/ex vivo models relevant to their specific routes of administration are determined. Indeed, many promising nanomedicine products have been withdrawn during clinical trials due to the inappropriate characterization of their biological fate during the initial stages of development. The implementation of standardized methods of characterization would allow proper adjustment of formulations in due time and avoid wasted investments. To ensure clinical utility, nanomedicines must be submitted to a battery of characterization tests to demonstrate batch to batch consistency, assuring biological activity and safety. Methodologies to assess these characterizations must be robust, straightforward, implementable and universal.

The lack of specific regulation of nanomedicines has led to the commercialization of products like conventional medicines, using the existing legislation of all medical products. This author believes that it is essential that regulatory agencies, the pharmaceutical industry (particularly those with nanomedicines on their pipeline), and academic researchers which are able to establish disruptive, potentially scalable nanoparticles with tailored drug delivery properties better interact. Indeed, the experiences shared by regulatory scientists who have authorized nanomedicines, to help to close this gap as the knowledge generated in the past decades is worthwhile for potential advancements to healthcare.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This article is a result of the project NORTE-01-0145-FEDER-000012, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This work was financed by FEDER – Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 – Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through the FCT – Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior through the framework of project ‘Institute for Research and Innovation in Health Sciences’ (POCI- 01-0145-FEDER-007274).