Nanotechnology in healthcare

Cécile Théard-Jallu

De Gaulle Fleurance Avocats Notaires, Paris

ctheardjallu@dgfla.com

Rozenn Carrio

De Gaulle Fleurance Avocats Notaires, Paris

rcarrio@dgfla.com

Introduction

 Nanotechnologies and nano-objects include techniques and tools from the world of the infinitely small – the millionth of a millimetre. Their development is a major innovation challenge in the area of healthcare as it opens huge perspectives for better, more efficient and affordable healthcare, with an impact on all fields of current medicine (drugs, medical devices, imaging, biomaterials, biological analysis, etc). The concept of nanotechnology is large and announces a promising tendency in the coming years in the healthcare market. The interest and relevance of using ‘nanos’ in health has even recently been reinforced with the development of messenger RNA vaccines against Covid-19.

However, the medical applications of nanotechnologies are still underdeveloped globally and prompt concern about their safety. To accompany the ongoing work on nanotechnologies and their increasingly safe implementation, the European Union and France have started to adopt regulations or guidance on their use. This article shares some insights into this evolving legal framework.

Increasing but uncertain use in healthcare

At the beginning of the 20th century, the German scientist Paul Ehrlich theorised the idea of the ‘magic bullet’, which would be specifically and actively directed against infectious agents within the body. This concept is now a reality thanks to the vectorisation of drugs made possible by nanotechnologies and also the use of nanomaterials in medical devices.

More specifically, the use of particulate nanovectors now offers answers to the difficulties encountered by conventional therapeutics. It consists of integrating an active ingredient into a vector or using mineral nanomaterials to specifically address this drug to a target tissue, without it being distributed elsewhere in the body. Vectorisation can also involve an active ingredient whose physico-chemical properties prevented it from being administered as is. Carried by the nanovector, the active ingredient is also protected from biological degradation before reaching its target tissue. Finally, it can be ‘triggered’ or released progressively over time; to do this, it is associated with a nanocompound that can be activated under the influence of a signal (laser, X-ray, etc). Nanomedicines could therefore improve the benefit–risk balance of drugs by increasing their efficacy and bioavailability in the target tissue or organ, while reducing the doses to be administered and the risk of toxicity.[1]

The use of substances in the form of nanomaterials makes it possible to improve diagnosis by identifying targets at the nanoscale that were previously unreachable, and to improve treatment by increasing the effectiveness of the therapeutic agents by enclosing them in nano-objects. An example of their application, and the oldest one, is the treatment of cancer.

Thus, a number of medicinal products and medical devices containing nanomaterials have been introduced on the market in recent years. For example, French companies such as Nanobiotix and NH TherAguiX have designed nanoparticles to significantly amplify the effectiveness of radiotherapy with the aim of reducing the necessary doses of radiation and improve radiotherapy treatment of cancer.

At the same time, studies have shown that some nanoparticles can be toxic to the human body. The degree of toxicity depends on the size and specific characteristics of the particles, some of which can cause an allergic or inflammatory response or further stimulate the immune system.

Strict supervision of the use of nanotechnologies in healthcare is therefore critical. For instance, consumer associations have revealed that nanoparticles, in particular those used as colourants such as E171 (excipient, composed of titanium dioxide nanoparticles), are present in commonly used drugs, while they are prohibited in food.[2] These nanoparticles do not have a therapeutic purpose and are therefore to be dissociated from ‘nano-drugs’, which are voluntarily designed on a nano-scale to cross physiological barriers and bring active substances more quickly and/or more precisely into the body.

AVICENN, the French association of monitoring and civic information on the stakes of nanosciences and nanotechnologies, notes that many people have called for the withdrawal of E171 from drugs in recent years and that some companies have confirmed that they are thinking of substituting titanium dioxide in their drugs.[3]

The use of nanotechnologies also lends itself to social and political debate. Some are unconditional defenders of this new industry, which they believe could make poverty disappear from the face of our planet. Others, on the other hand, call for drastic measures to counter the risks of this innovation. The imposition of a moratorium has also been demanded by various environmental organisations.

Nanotechnologies as applied to healthcare may present a range of technological, scientific and regulatory uncertainties that require appropriate methodological expertise to be solved, and the development of harmonised guidelines for the safety assessment of medicinal products and medical devices containing nanomaterials will be necessary.

Regulatory uncertainty, as far as it is concerned, is one of the main obstacles to moving from a scientific concept to an authorised health product.

It was partially mitigated by the publication of a recommended definition of the concept of nanomaterial by the European Commission in 2011, as follows:

• a natural, accidentally formed, or manufactured material;
• containing free particles, in aggregate form or in agglomerate form;
• at least 50 per cent of whose particles, in numerical size distribution, have one or more external dimensions between 1 nm and 100 nm.

However, local specificities may exist. For instance, the French National Agency for the Safety of Medicines and Health Products (Agence nationale de sécurité du médicament et des produits de santé or ANSM), in its report Nanomaterials in medicinal products and medical devices, defines nanomedicine as a ‘medical application of nanotechnologies both in the use of nanoparticles as therapeutic agents but also in medical imaging, diagnosis, theranostics (combined diagnosis with therapeutic effect) and the constitution of medical devices’.[4]

More globally, it has been reported that ‘strong regional differences in the regulation of nanomedicines […] confirmed the need for a harmonisation of information requirements on nano-specific properties’.[5]

Scientific, policy and practical knowledge on the quality, safety and efficacy of nanomedicines should allow the clarification of the legal definition of nanomedicines and the requirements regulating their use.

Nanotechnologies and medicinal products: collaborative work still in progress

At a European level

Directive 2001/83/EC[6] as modified defines a medicinal product as:

• ‘Any substance or combination of substances presented as having properties for treating or preventing disease in human beings’; or
• ‘Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.’

Medicinal products must in principle obtain a marketing authorisation (MA) to be marketed. An MA is issued by the competent authorities after the evaluation of the application on the quality of the product, its safety and effectiveness. An MA may be granted for the entire territory of the EU by the European Commission after receiving the opinion of the European Medicines Agency (EMA) or, at national level, by the competent authority of the country concerned (eg, the ANSM in France). Medicinal products containing nanomaterials must therefore follow this procedure to be marketed.

However, medicinal products containing nanomaterials may present specific risks as discussed and the lack of guidelines prevents this type of medicines from being appropriately processed to obtain an MA that meets the current standards.

In the current state of scientific knowledge and legislation governing nanomedicine, the Nanomedicines Regulatory Coalition recommends the following ‘to ensure patient safety and enable the EU to efficiently fully harness the potential of nanomedicines’:

• agreeing on definitions for nanomedicines at a European level, improving education and fostering awareness on the complexity and sophistication of nanomedicines among policymakers, prescribers, payors and patients;
• having all nanomedicines and nanosimilars assessed by an EMA centralised procedure, which would prevent diverging approaches between Member States; and
• clarifying and harmonising regulatory criteria in order to correctly characterise nanomedicines. The highest possible manufacturing standards must be guaranteed and included in the MA application.

Collaborative work between regulatory agencies such as the EMA and governmental or international organisations such as the World Health Organization and the Organization for Economic Cooperation and Development is under way to adapt the existing rules to assess the toxicity and compatibility of medicinal products incorporating nanomaterials.

At a French level

French law has dealt with traceability of substances in the nanoparticulate state, which is crucial to identify products at different stages of their pharmaceutical development and to anticipate the regulatory requirements for products that claim similarity to products that have already obtained an MA.

Indeed, Articles L.523-1 to L.523-5 of the French Environmental Code provide for a system of declaration of substances in the nanoparticulate state (R-Nano), whereby each manufacturer, importer and distributor of a substance in the nanoparticulate state is required to declare the quantities and uses of such substances that are produced, distributed or imported in France. Such declarations are then managed by the National Agency for Food, Environmental and Occupational Health Safety (Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail or ANSES) and incorporated in the R-Nano database.

In its current version, the R-Nano database’s objectives are to:

• gain a better understanding of these substances and their use;
• have a traceability of the use channels, a better knowledge of the market and the volumes marketed; and
• collect available information on their toxicological and ecotoxicological properties.

However, the R-Nano database is not sufficient to ensure the safety of medicinal products incorporating nanomaterials. According to a study carried out by the former ‘Non-clinical Innovation’ working group of the ANSM,[7] the existing experimental evaluation methods do not adequately assess the properties and particularities of products in nanoparticulate form. Indeed, the database[1] :

• does not include nanomaterials that are incorporated into finished products made abroad before arriving in France;
• does not clearly identify the end uses of declared nanomaterials and products containing these nanomaterials;
• does not allow the quantification, for a given use, of the weight of nano substances involved, which limits their traceability and risk assessment; and
• does not allow the location of sites where the declared nanomaterials are handled.

The working group recommends adapting the current assessment strategies on a case-by-case basis to medicinal products in nanoparticulate form to allow better traceability and risk assessment of such products.

The French General Directorate for Competition Policy, Consumer Affairs and Fraud Control (DGCCRF) has said that it remains attentive to developments in the field of nanotechnologies, although it does not currently carry out specific investigation in this field.

Nanotechnologies and medical devices: considered under the EU MD Regulation and awaiting further guidance

At European level

Subject to subsisting transitional provisions with previous European legislations, the placing of medical devices on the EU market is now governed by Regulation (EU) 2017/745 on medical devices[8] and Regulation (EU) 2017/746 on in vitro diagnostic medical devices.[9]

Let’s take the example of Regulation 2017/745, which defines a medical device as:

‘any instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes:

• diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease,
• diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability,
• investigation, replacement or modification of the anatomy or of a physiological or pathological process or state,
• providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donations’.

The specificity of medical devices incorporating nanomaterials has led the European legislator to take into account the concept of nanomaterials.

Indeed, Recital 15 of Regulation 2017/745 provides that:

‘There is scientific uncertainty about the risks and benefits of nanomaterials used for devices. In order to ensure a high level of health protection, free movement of goods and legal certainty for manufacturers, it is necessary to introduce a uniform definition for nanomaterials based on Commission Recommendation 2011/696/EU, with the necessary flexibility to adapt that definition to scientific and technical progress and subsequent regulatory development at Union and international level. In the design and manufacture of devices, manufacturers should take special care when using nanoparticles for which there is a high or medium potential for internal exposure. Such devices should be subject to the most stringent conformity assessment procedures.’

Article 2 of Regulation 2017/745 itself defines a nanomaterial as:

‘a natural, accidentally formed or manufactured material containing free particles, in the form of aggregates or agglomerates, of which at least 50% of the particles, in numerical size distribution, have one or more external dimensions between 1 nm and 100 nm’.

In addition, its Annex I on general safety and performance requirements provides that: ‘Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks linked to the size and the properties of particles […] Special attention shall be given to nanomaterials [emphasis added][2] .’[10]

Last, its Annex VIII on classification rules specifies that:

‘All devices incorporating or consisting of nanomaterial are classified as:

• class III if they present a high or medium potential for internal exposure;
• class IIb if they present a low potential for internal exposure; and
• class IIa if they present a negligible potential for internal exposure.’[11]

Players are in need of further guidance and experience sharing in the new MDR [3] landscape. In 2015, the Scientific Committee on Emerging and Newly Identified Health Risks established a guidance document at a European level, regarding, among other things, the risk assessment of nanomaterials in medical devices.[12] To date, the tools proposed in this guide are not yet practically usable by operators, but the document has the merit of identifying the risks associated with nanomaterials and the various stakeholders such as manufacturers and competent authorities.

At this stage, no specific assessment method available has been validated for nanomaterials and only a case-by-case approach can be taken in the light of current knowledge.

At a French level

At a French national level, work has been carried out to propose a framework for the safety of medical devices incorporating nanotechnologies.

Like medicinal products, the R-Nano database allows for the declaration of medical devices incorporating nanoparticulate substances.

According to the ANSM, the modalities of declaration in the R-Nano database should evolve to identify medical devices much more precisely. Indeed, this database only makes it possible to identify the reporting entity, referenced by its economic activity code (NACE code), which does not necessarily correspond to the use made of the nanoparticulate substance being reported. As a result, the field of medical devices is poorly identified.

The ANSM considers that it would be advisable to improve the reporting procedures in the R-Nano database either by adding a specific NACE code for medical devices, or by accurately identifying the categories of medical devices at stake.

Conclusion

In a nutshell, medical applications of nanotechnologies are still underdeveloped globally, the major difficulty being the assessment of the nanomaterials to go through regulatory procedures with competent authorities. Despite some initiatives in France and the EU to establish a regulatory framework for the use of nanomaterials in the health sector, some uncertainties remain. As the LEEM (Les Entreprises du Médicament), a French pharmaceutical professional organisation, pointed out:

‘France needs to structure itself in this field, to have a dedicated laboratory, similar to the American NCL, with recognized laboratories to validate nanotechnologies. We must rely on existing groups, […] and use their existing network of collaborations. In other words, we need to build an active French network.’[13]

The development of collaborative projects and initiatives, such as the European Nanomed programme, will certainly help to provide a more comprehensive framework for enhancing the high potential of nanomaterials in health for the benefit of patients.