Nanomedicines in the European translational process

Authorised products

Currently several nanomedicines are authorised in the European Union. These nanomedicines regulated as medicinal products mainly used nanotechnology in order to overcome limitations related to physical-chemical properties of the active principle such as a lack of solubility, and/or to reduce drugs side effects by achieving a better accumulation in diseased tissues, e.g. by using the enhanced permeation and retention (EPR) effect. These so-called first generation nanomedicines have been on the European market for a long time, e.g. Caelyx – one of the first nanomedicines – was authorised in 1996 and the corresponding patents will expire soon. The results are reported in Figure 3 which shows the following results: out of the 30 products analysed, 12 nanomedicines use lipid based carrier systems aiming to optimise kinetic properties of the drug and reducing the side effects of the active principle by passive targeting; nine nanomedicines are classified as inorganic nanomaterials; four products use the nanocrystalline form of the active principles optimising the physical-chemical properties. In addition, five iron nanocomplexes that are authorised to combat anemia have been included (Figure 3). In the cases considered, nanotechnology is mainly applied to improve the physical-chemical properties of the active principle as well as to optimise the kinetics and biodistribution of the active principle (Figure 4).

Figure 3:

There is an increasing trend of using polymers and inorganic nanoparticles including nanocrystals and magnetic nanoparticles for the development of new nanomedicines. Lipid based carrier systems are less developed as new platforms in the FP 7 projects as compared to the two other types of products (authorised products n=30, clinical trials n=69, R&D n=131). (*Status of published research activities in “Cordis” in March 2015.)

Figure 4:

Authorised products use nanotechnologies mainly to optimise the physical-chemical properties of the active principle and the delivery of the active principle to the diseased tissue by passive targeting. In the recently performed research projects active targeting and controlled release of the cargo as well as the exploitation of the phys.chem. properties are more in the focus. (*Status of published research activities in “Cordis” in March 2015.)

Only eight of the investigated drugs address therapeutic gaps as identified by the WHO but 25 of the nanomedicines address diseases with a high DALY (Figures 5 and 6).

Figure 5:

The majority of authorised nanomedicines address malignant neoplasms a disease with a high DALY value. (*Status of published research activities in “Cordis” in March 2015.)

Figure 6:

Out of 131 research projects, 91 focus on therapeutic gaps as defined by the WHO and four projects are dedicated to coordination activities. Out of 69 products that are included in the EU clinical trials register 37 products are addressing priority diseases. Finally, out of 31 authorised products, only nine products address pharmaceutical gaps as defined by the WHO. (*Status of published research activities in “Cordis” in March 2015.)

Clinical trials

In order to get a better understanding on trends of nanotech based products in European clinical trials, potential nanomedicines as identified in the review articles of Hafner et al. (6), and Etheridge et al. (5) were assessed for their inclusion in the EU clinical trial data base. In total, clinical trials of 69 products were investigated and all Member States were involved in the approval process of clinical trials of different types of nanomedicines (Figure 7). The purposes of the clinical trials differed and covered aspects such as the assessment of future applicability domains of already approved formulations, e.g. different kind of neoplasms, the potential to combine nanomedicines with other therapeutic molecules in order to optimise therapeutic effects as well as safety/efficacy studies of new formulations. This non-exhaustive list of nanomedicines in clinical trials covers a wide range of diseases such as different types of solid tumours, schizophrenia, ADHD, growth disorder, hepatitis C, rheumatoid arthritis, pain relief, heart failure, HIV, etc. However, malignant neoplasms are the dominant target disease of nanomedicines (see Figure 6) and most of the nanoformulations identified are based on liposomes and polymeric nanoparticle (see Figure 3). Remarkably, at least three magnetic inorganic particle used for in vivo imaging are currently assessed in clinical trials. Nevertheless, the application of the marketing authorisation of the ironoxide “Sinerem”, an in vivo imaging diagnostic product, was withdrawn after EMA’s Committee for Medicinal Products for Human use raised concern on effectiveness of “Sinerem” in enhancing the images seen in the MRI scan. “Sinerem” is a diagnostic agent for the characterisation of lymph nodes in patients with pelvic cancer (12). Nevertheless, the data analysed in this study can only provide trends and additional clinical trials should to be included in order to complete the picture [e.g. those that are additionally reported in the “Bionest” report (13)].

Figure 7:

Sixty-nine products included in published databases have been analysed for their registration in the European clinical trial database. All European Member states were involved in the authorisation of clinical trials to a different extent. The total number of clinical trials of nanomedicines/Member State is indicated in the map. (The analysis was performed in October 2014).

Drug development projects

In the 7th framework programme, the European Commission funded a significant number of projects focussing on the exploitation of nanotechnology for health care, e.g. the research theme on “Nanosciences, Nanotechnologies, Materials and New Production Technologies” (NMP) has funded 86 projects with a budget of 446 M€. Additionally, 31 projects with a budget of around 150 M€ were sponsored as part of the health programme. The funding programme “Smart System Integration Challenge” of the Directorate General “Communication Networks, Content and Technology” (DG CNECT) included 35 projects for the development of Micro-Nano-Bio Systems for a total budget of 135 M€. In addition, other European funding schemes such the “European Research Council”, “People” and “ERANET” incorporated nanotechnology for medical applications into their agendas. These projects have mainly covered technology readiness levels 1–3 starting from the development of basic principles towards the experimental proof of concept. The currently ongoing European framework programme “Horizon 2020” puts a strong emphasis on the translational aspect covering further developments in a preclinical setting before demonstrating the relevance of the product in the clinical environment (also referred to as TRL 4-7) (14). The first projects addressing the translational aspects have just started. These projects belonging to the “Translation Hub” as suggested by the European Platform of Nanomedicine: i) The coordination and support action “ENATRANS” will focus on measures needed to support the networking of stakeholders; ii) The projects “Nanofacturing” and “Nanopilot” are dedicated to the scale up nanomedicines for clinical use; iii) The European Nanomedicine Characterization Laboratory “EU-NCL” will support the quality and safety assessment of nanomedicines in the preclinical phase incl. nanomedicines that have been developed within the FP7. In addition, the “EU-NCL” will develop cascades of characterisation protocols for quality and safety assessments relevant to the major nano platform and biological functionalisations that are currently used for the development of new nanomedicines (Figure 2).

131 projects have been included in the present analysis. A mapping exercise demonstrated that the majority of projects addressed diseases such as cardiovascular diseases, neuropychiatric conditions, cancer and infectious/parasitic diseases with a high DALY value (see Figure 8). A breakdown analysis of the type of products shows a slight decrease of lipid based platforms in comparison to platforms that are in clinical trials or have been already authorised (see Figure 3). However, liposomes can be multifunctionalised by decorating them with targeting moieties, cell penetration proteins including small molecules and non coding RNAs, the inclusion of different kind of active principles as well as inorganic particles for imaging. The related therapeutic actions have been investigated by several consortia as shown in Figure 4. As such, liposomes must be still considered as an important platform in particular for malignant neoplasm and infectious diseases. In contrary to the lipid based carrier systems, the use of polymer based carrier systems and inorganic nanoparticle has strongly increased for diseases with a high DALY value as can be observed in Figure 9. In order to get a better understanding on the reason why inorganic particle currently receive so much attention in research activities, a more detailed analysis of the inorganic particles used in the R&D projects has been performed and the results are presented in Figure 10. It can be seen that the magnetic properties of the particle are in the focus of the therapeutic and diagnostic concepts. This physical parameter allows the development of in vivo imaging tools and therapies based on hyperthermia. Furthermore, magnetic nanoparticle should also used for innovative concepts like theranostics allowing the direct monitoring of therapeutic effects as well as diagnosis and therapeutic intervention simultaneously (see Figure 10).

Figure 8:

The burden of a disease on the European population in 2008 was measured in disability adjusted life years (DALYs). A DALY is an integrated single measure of mortality and disability due to a particular disease. One DALY represents a lost year of healthy living. This mapping exercise shows that a majority of FP7 projects address diseases contributing to a high value of DALY such as cancer, neuropsychiatric conditions and cardiovascular diseases.

Figure 9:

In the analysis biomaterials play a major role for adressing cardiovascular diseases whereas a drastic increase of inorganic material adressing maligne neoplasms can be observed. (*Status of published research activities in “Cordis” in March 2015.)

Figure 10:

A breakdown of the inorganic material used for cancer applications demonstrated that magnetic nanoparticles such as magnetosomes produced by magnetoactic bacteria, supraparamagnetic nanoparticles, iron-platinum alloys, ferrites, magnetites and maghemites etc were the major contributor to the increase of using inorganic particle for the diagnostic/therapy of cancer. In particular, the possibility to use the magnetic property for in vivo imaging and hyperthemic applications is intensively studied within the projects. (*Status of published research activities in “Cordis” in March 2015.)

The majority of R&D projects address pharmaceutical gaps such as cancer, cardiovascular diseases including Ischemic heart disease and – to a lesser extent – the antibacterial resistance. Other priority diseases such as depression, tuberculosis, neglected tropical diseases, post haemorrhage, maternal mortality, acute stroke and rare diseases have not received so much attention in the FP7 projects on nanomedicines. However, a significant amount of projects addresses basic concepts that – once progressing in the technological development – might lead to a variety of therapeutic indications including the above mentioned priority diseases.

Selection of the regulatory pathway

As already indicated a challenge for regulating nanomedicines is related to the selection of the regulatory pathway. Therapeutic and diagnostic agents can be either classified as medicinal products (15) or as medical devices (16) and this distinction is mostly based on the principal mode of action of the product. The principal intended action is achieved by physical means for medical devices and by pharmacological, immunological or metabolic means for medicinal products (see Table 2). However, sometimes the principal mode of action is blurry and nanomedicines can exhibit complex mechanisms involving mechanical, chemical, pharmacological and immunological mode of actions as seen for examples in the research activities of the projects such as “Nanother”, “NAD”, “Namdiatream” etc. Such borderline products are often subject of discussion in the Medical Devices Expert Group on Borderline and Classification (17). The uncertainty that is related to the regulation of such products has been addressed previously (18, 19) and the European Medicines Agency acknowledged the fact in its reflection paper on Nanotechnology based medicinal products for human use, that … many novel applications of nanotechnology will span the regulatory boundaries…. (20). The proposal of the European Commission on the medical device regulation is referring to nanomaterials and is requesting that …the manufacturer should take special care when using nanoparticles that can be released to the human body and those devices should be subject to the most severe conformity assessment procedure…. (21). As such the regulation of nanomedicines requires a close collaboration between the regulatory bodies and a harmonisation of information requirements and associated methods characterising the nanospecific properties of the product.

Assessment tools

The requested assessment procedures are directly linked to another challenge concering the evaluation of the nanospecific properties of the nanomedicine. As demonstrated by this study there is a trend towards sophisticated products using, e.g. chemical and biological functionalisations such as targeting moieties and proteins optimising drug release mechanisms. Other active nanostructures are designed to modify the behaviour depending on changes in their environment or a set of received signals (upon exposure to mechanical forces, electromagnetic radiation, pH and temperature changes, etc.). All these approaches can also be combined in complex multi-component nanomedicines. For such “next generation” nanotechnology-based products, the nanoscale size is still important, but above all the functional design of the nanomaterial matters and might pose new challenges, as risks may change as the material changes during therapeutic action. The regulation of such drugs therefore require the optimisation of existing tools for safety, efficacy and quality assessments or even the development and validation of new methods and testing strategies. Flexible validation strategies are needed as each product is unique and standard operation procedures for testing might need to be adapted to the various physical-chemical properties of the product and its functionalizations. Since no specific regulation in relation to nanomedicines exists, additional information with regard to the nanomaterial is requested on a case-by-case basis and creates an uncertainty for the product developer. Nevertheless, the regulatory community is well aware of that challenge and has started to provide guidances such as EMA’s reflection paper on the nanotechnology-based medicinal products for human use.

The European Commission’s Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) released recently an opinion on the determination of potential health effects of nanomaterials used in medical devices (22). Furthermore, new initiatives such as the project EU-NCL financed within the European Commissions framework programme “Horizon 2020” will provide scientific/technical solutions and will develop new strategies for characterisation of advanced nanomedicine products.

Nanosimilars

The expiry of patents of the first nanomedicines will pose additional challenges since company will apply for marketing authorization of generic drugs (23). The first liposomal nanoformulations received their marketing authorisation in the late 1990s beginning or the beginning of the new century; e.g. Caelyx, one of the first nanomedicines, was authorised in 1996. A prominent example illustrating the regulatory challenge of so-called “nanosimilars” is the evaluation of doxorubicin SUN/Lipodox that is manufactured in India by SUN Pharma Global FZE. The product was authorised by the FDA but received a “not approvable” opinion from EMA’s Committee for Medicinal Products for Human use (CMPH). The CMPH had objections related to the clinical and preclinical evaluation (24). The US Nanocharacterisation Laboratory of the National Cancer Institute and the EU-NCL initiative might contribute to this harmonisation needs by developing cascades of advanced characterisation protocols to identify the possible difference between the nanosimilars and the original products.