The regulatory framework

The fact that nanotechnologies are converging technologies means that it is not always clear which regulatory system applies when nanotechnologies are used in medicines and medical technology. In practice, combined products are created in which it is not always easy to establish the primary effect mechanism and the primary intended use. As a result confusion may arise about the path to be followed to gain market access. This issue is given high priority in both the pharmaceutical and the medical device industries. In March 2008, for example, this theme received extensive coverage at a conference of the Drug Information Association (DIA Euromeeting, Barcelona, 3-5 March 2008,

www.diahome.org).

There are clear differences between the legislation for medicinal products and the legislation for medical technology. The legislation on medicinal products is highly centralised: European and national government organisations handle the assessment and registration of medicines. Passage through these procedures ultimately leads either to registration or not. Nanomedicines are registered under the proviso that they only contain nanoparticles within a specified size range. It is difficult to determine whether a medicine only contains nanoparticles of the specified size range. Nanomedicines that have been registered meet the present requirements for medicines and will have been tested for efficacy and safety and quality ( http://www.rivm.nl/rvs/075_nanotechnologie/risicos_mens/geneesmiddelen/). Responsibility for the access of medical devices to the market is as far as possible decentralised. For medical devices involving little risk it is not necessary to follow an extensive route via various bodies: manufacturers themselves are responsible for a dossier which ensures quality and safety. Notified bodies, such as KEMA in the Netherlands, issue a CE-mark required for access to the market of products involving a greater risk. These bodies are subject to government supervision.

The following risk classes are applied:

• Class 1 (low risk): products such as adhesive bandages and plaster; • Class 2a and 2b: for example, surgical instruments, diagnostic equipment;

• Class 3 (high risk): for example, products which are broken down in the body, contraception, products which end up in the bloodstream and have an influence on vital organs, aids with drug components such as nanosilver and implants (with the exception of materials for dental applications.

The most important factors taken into account in this risk classification system are potential invasiveness and contact with vital body structures such as the heart, central blood circulation and brain, including the central nervous system. As a result many nanotechnological applications end up in the highest risk class.

In 2007 the working group of the European Commission for New and Emerging Technologies in Medical Devices - Nanotechnology (N&ET WG- Nanotechnology) assessed the applicability and

suitability of the present regulatory framework in relation to nanotechnology in medical technologies (N&ET Working Group, 2007). The N&ET WG – Nanotechnology came to the conclusion that the legislation on medical devices can also be applied to medical devices in which nanotechnology is used. This legislation is based on risk management and this risk management approach is also suitable for controlling the risks of nanotechnology in medical technologies. This applies both to the use of free nanoparticles as well as to fixed materials with nanostructures on the surface.

The N&ET WG – Nanotechnology recommended that a new classification rule be introduced for ‘free nanoparticles’ which will ensure that all products with free nanoparticles end up in the highest risk class:

‘All devices incorporating or consisting of particles, components or devices at the nanoscale are in the highest risk Class III unless they are encapsulated or bound in such a manner that they cannot be released to the patient's organs, tissues, cells or molecules.’

The working group also noted the following:

• In the definition of the nanoscale the working definition adopted was: at least one dimension between 1 and 100 nm;

• This rule should be reviewed after three to five years.

Because of the fact that the risks of nanotechnology are partly new and not entirely known, this working group recommended that guidance in this area be developed. A start has been made on this in 2008.

This guidance should cover:

1. The nature of the risks which need to be considered; 2. Possible solutions for risk management;

3. The organisational structure for the exchange of experience by means of a Voluntary Reporting Scheme;

4. Nessecary actions which needs to be taken in the post-marketing phase;

5. Interpretation of the legislative requirements before introducing nanoproducts onto the market; 6. Which parts of the guidance apply to in vitro diagnostics (IVDs).

The N&ET WG – Nanotechnology will also try to coordinate with groups within the EMEA (European Medicines Evaluation Agency) that are studying the issue of nanotechnology for medicines. Companies can also turn to this body for advice. EMEA also includes the following three advisory groups (Purves, 2008):

• Innovation Task Force – early consultation in the context of regulatory, scientific and other matters which may arise during the development of innovative products, for example whether the product is a medicinal product (http://www.emea.europa.eu/htms/human/mes/itf.htm); • Scientific Advice Working Party – scientific advice on preclinical and clinical research to be

carried out in relation to quality, safety and effectiveness

(http://www.emea.europa.eu/htms/human/sciadvice/Scientific.htm);

• Small and Medium Size Enterprises (SMEs) Office – procedural and scientific support for SMEs at reduced rates (http://www.emea.europa.eu/SME/SMEoverview.htm).

In 2006 EMEA also published a ‘reflection paper’ on its website (http://www.emea.europa.eu/pdfs/human/genetherapy/7976906en.pdf).

According to the N&ET WG – Nanotechnology, the present vigilance system for medical devices for reporting serious incidents to the authorities does not need to be changed. This system is sufficiently generic to also include nanotechnology matters. The working group does, however, emphasise the need for an active system of post-marketing surveillance by manufacturers. It may also be necessary to

adjust the present standards to incorporate nano aspects (e.g., EN ISO 10993: Biological evaluation of medical devices).