Message
  • EU e-Privacy Directive

    This website uses cookies to manage authentication, navigation, and other functions. By using our website, you agree that we can place these types of cookies on your device.

    View Privacy Policy

    You have declined cookies. This decision can be reversed.

Step 1 - Getting the CE certification for a novel medical device

Definition of CE marking


 

CE Marking is the symbol as shown below. The term 'CE Mark' is also in use, but it is NOT the official term. The letters 'CE' are the abbreviation of French phrase 'Conformité Européene' which literally means 'European Conformity'.

cemark

Figure 4:Two correct and real CE conformity markings

The CE Marking is used for different legal purposes, as follows:

  • CE Marking on a product is a manufacturer's declaration that the product complies with the essential requirements of the relevant European health, safety and environmental protection legislation. In practice the Product Directives regulating medical devices are as follow:
      • The Medical Devices Regulations 2002 (SI No 618), as amended by the Medical Devices (Amendment) Regulations 2008, came into force on 13 June 2002 and implement the provisions of the Medical Devices Directive 93/42/EEC (as amended by Directive 2007/47/EC).
      • The Active Implantable Medical Devices Directive 90/385/EEC (as amended by Directive 2007/47/EC).
      • The In Vitro Diagnostic Medical Devices Directive 98/79/EEC.
  • Product directives contains the 'essential requirements' and/or 'performance levels' and 'Harmonized Standards' to which the products must conform. Harmonized Standards are the technical specifications (European Standards or Harmonization Documents) which are established by several European standards agencies.
      • CE Marking on a product indicates to governmental officials that the product may be legally placed on the market in their country.
      • CE Marking on a product ensures the free movement of the product within the EFTA and European Union (EU) single market (total 28 countries).
      • CE Marking on a product permits the withdrawal of the non-conforming products by customs and enforcement/vigilance authorities.

With more directives becoming effective, more and more products are required to bear the CE Marking for gaining access to the EFTA and European Union market. The overall CE certification process is summarised and illustrated in Figure 5.

cemark process

Figure 5 Overall CE certification process (© Health Tech and Medicines KTN, 2011).

Within this overall process, two particular steps deserve more guidance as they can prove challenging for manufacturers and these will be covered in more detail in section 1.3.1 and 1.3.2:

  • How to establish whether getting the CE-marking certification requires the realisation of a new clinical investigation or if existing prior clinical data can be re-used to demonstrate compliance to Essential Requirements?
  • How to initiate and realise a clinical investigation on patients, in UK hospitals?

 

Establishing whether a new clinical investigation is needed


 

Figure 6 summarises how manufacturers should go about to determine whether a new clinical investigation will be needed or if existing prior clinical data can be re-used to demonstrate compliance to Essential Requirements. All results from past clinical investigations are accessible free on the NHS evidence website.

new investigation required?

Figure 6 Establishing if a new clinical investigation is required (© Health Tech and Medicines KTN, 2011).

 

Standard steps to initiating a new clinical investigation


 

Medical devices manufacturers need to get a formal approval from a number of UK authoritative bodies before they can be entitled to launch a new clinical investigation involving patients in NHS hospitals. The start-up process for a new medical device clinical investigation can be explained and segmented into a three-phase route:

Phase 1 - initial contacts with and guidance from MHRA and NIHR CRN CC

Initial contacts with and guidance from MHRA: The MHRA can be contacted (see link to MHRA contact details below) for advice on whether the Medical Devices Regulations are relevant to the proposed study and whether MHRA authorisation will be required before the study can start. The MHRA are also able to advise on how to make a notification to them and the authorisation process. It is suggested that companies contact the MHRA to run through the information requirements before they submit a notification to the MHRA (ideally during study design), especially if it is their first time.

Initial contacts with and guidance from NIHR CRN: When initiating a clinical study, the medical device manufacturer is advised to contact the topic-specific NIHR CRN which therapeutic area corresponds best to the study in question. The NIHR CRN Coordinating Centre (NIHR CC) can advise on the most appropriate network (see contact details below) where this is not clear. Once contacted, the appropriate NIHR Clinical Research Network can coordinate an early, top level review of the feasibility of conducting a study in England and the likelihood of it being appropriate for the Network.

Phase 2 - Completing a clinical study application on IRAS

Applications are streamlined through the Integrated Research Application System (IRAS) web Platform . Manufacturers are encouraged to use IRAS since it has been designed to simplify the initiation of clinical investigations in the NHS.

Phase 3 - Formal assessment of the clinical study application by MHRA, NREC, and NIHR CRN

  • Pre-clinical assessment by MHRA: The MHRA needs to be formally notified via a completed PCA1 or PCA2 form, setting out the reason for clinical investigations and the designed clinical protocol. This will be evaluated and will need to successfully pass a pre-clinical assessment.
  • Ethical assessment by a Research Ethics Committee (REC) : a formal approval of the ethical aspect of the clinical protocol needs to be received before a clinical investigation involving UK patients can start. Medical device manufacturers are to submit their proposed clinical study protocol to a Research Ethics Committee, for review. The mission of RECs is to protect the rights, safety, dignity and well-being of research participants.
  • Site identification, feasibility studies and permission by the National Institute for Health Research: the relevant NIHR Clinical Research Network can help companies find clinical research sites to conduct their studies and can also facilitate discussions with the local NHS R&D staff for each site, to ensure that site-specific practical issues are highlighted quickly and NHS organisations are able to give permission swiftly in due time.

For a more detailed description of this 3-phase process, the CRN CC recently produced a medtech route map available on: http://www.crncc.nihr.ac.uk/Life+sciences+industry/tools/medtech_route_map

More information follows about each of the aforementioned organisations of the clinical investigation route map.

The NIHR Clinical Research Network (NHIR CRN)

The label 'NIHR CRN' encompasses a number of organisations, as listed below and illustrated in Figure 7:

  • Six topic-specific Clinical Research Networks.
  • The Primary Care Network (PCRN).
  • The Comprehensive Clinical Research Network (CLRN).
  • The NIHR Clinical Research Network Coordinating Centre (NIHR CRN CC), advised as the point of entry for navigating the NHS clinical research network, especially for members of the life sciences industries.

clinical networks

Figure 7: Illustration of the different clinical networks encompassed under the overarching NIHR Clinical Research Networks.

The NHIR CRN CC is responsible for managing the overall performance of the networks and develops and delivers the streamlined coordinated system for NHS permissions (CSP), through which researchers can apply for permission to run a clinical study in the NHS. The NIHR CRN CC value to medical technology industries can be summarised as follows:

• A single point of national access to the NHS clinical research landscape.
• A clinical research intelligence service that provides comprehensive insight into the current research environment.
• Process simplification, so that researchers can get a clinical study up and running as quickly as possible.
• A partnership to support high quality and reliable trial delivery.
• Support for long term partnering between researchers and Industry.


Research Ethics Committees (RECs)

Research Ethics Committees (RECs) safeguard the rights, safety, dignity and well-being of people participating in research in the National Health Service. They review applications for research and give an opinion about the proposed participant involvement and whether the research is ethical.

RECs are entirely independent of research sponsors (that is, the organisations funding and hosting the research) and investigators. This enables them to put participants at the centre of their research.

Each year, RECs review around 6,000 research applications. On average, they give an opinion after 35 days: well within the maximum allowance of 60 days.

http://www.nres.nhs.uk/about-the-national-research-ethics-service/about-recs/

The Medicine and Healthcare Products Regulatory Agency (MHRA)

The MHRA is responsible for ensuring the compliance to British regulations and European directives for all medical devices placed on the market in the UK. It was established to ensure medical devices operate at acceptable safety levels. The generic steps of the approval process for a medical device are as follow:

  • Firstly the manufacturer needs to confirm that the product falls within the scope of the Directive.
  • The manufacturer's products must meet all of the relevant Essential Requirements contained in Annex 1 of the Directive. This will include amongst others, as relevant:
    • A device does not compromise the clinical condition or safety of the patient, the safety and health of users or, where applicable, any third party (eg biological safety, electrical safety. electromagnetic compatibility).
    • A device achieves its intended purpose as designated by the manufacturer (ie 'fit for purpose').
    • Any risks associated with the use of the device are acceptable when weighed against the benefits to the patient and compatible with a high level of protection of health and safety.
    • And also additional matters such as: handling of clinical data, sterilization, labelling and instructions and others.
  • Manufacturers will also need to determine the classification of their products.
  • Once this has been determined they will need to follow the appropriate conformity assessment procedure. This may require them to have their quality systems and technical documentation reviewed by a Notified Body before they can place their products on the market. Furthermore, in most cases new clinical data will be required to demonstrate that the Essential Requirements are met and manufacturers will have to initiate and realise clinical investigations on patients, in UK hospitals. Sometimes, manufacturers are allowed to re-use existing clinical data from equivalent medical devices.
  • The Notified Body will review clinical data and/or quality systems and technical documentation. If the Notified Body is assured that Essential Requirements have been met the relevant CE-marking certification can be issued. In the UK, medical devices are regulated by the Medicines and Healthcare products Regulatory Agency (MHRA).
  • Manufacturers can then place the CE-marking on their products to communicate and demonstrate their compliance with the requirements and are allowed to launch the product commercialisation in the UK and/or the EFTA and European Union market.
  • Manufacturers have to manage post-marketing vigilance and an appropriate monitoring of the device in use. Post-marketing vigilance is out of the scope of this report.

Additional organisations and initiatives supporting the initiation and management of clinical investigations in the NHS


 

The National Institute for Health Research (NIHR) is developing improved services and support for device clinical studies. A summary of recent NIHR initiatives aiming to improve the environment for industry research is available at the following web page: http://www.nihr.ac.uk/industry/Pages/default.aspx

This section now expands on some of those initiatives and shows how they are relevant to the industry.

NIHR Office for Clinical Research Infrastructure (NOCRI)

This organisation is set up to help businesses wishing to undertake studies in the UK (England), and will create links and explain systems to support clinical investigations. It is a relatively new body (established 2010), but is open for business so direct contact can be made. Over time, guides on how to undertake clinical research as effectively as possible will become available. http://www.nihr.ac.uk/infrastructure/Pages/nocri.aspx


Model Clinical Investigation Agreement (mCIA) - UK wide

A model Clinical Investigation Agreement (mCIA) developed in consultation with industry and designed for use for medical technology industry-sponsored research conducted in the NHS was launched in 2008. The agreement is designed to simplify and therefore speed up the process for signing off and initiating clinical investigations involving NHS patients or clients in NHS hospitals. It removes any need for either sponsors or hospitals to undertake further legal review of contracts in response to another party proposing modifications.

It is intended that the mCIA is used routinely without modification by all medical technology industry sponsors of contract clinical research in HSC trusts. Versions were prepared that reflect the special governance and legal arrangements of Scotland, Northern Ireland and Wales. http://www.nihr.ac.uk/industry/Pages/model_clinical_trials_agreement.aspx

 

Summary of initiatives facilitating the initiation of clinical investigations


 

Figure 8 illustrates with two distinct examples how those initiatives can fit together to support the initiation clinical investigations: the blue example represents a case of University-led research while the red example is a case of industry-led research.

scenarios

Figure 8 Two fictional scenarios illustrating how UK initiatives fit to facilitate the initiation of clinical investigations
(UK CRC , 2010).

 

Further guidelines for the management of clinical investigations in the UK


 

Beyond the initiation of the clinical investigations, manufacturers will also have to successfully manage the actual realisation. For guidelines in this area, an insightful report by Warwick University was published in December 2009 and presents the findings from a two-year project.

The scope of this report encompasses the whole clinical research community; hence it covers a broad range of clinical investigations (eg investigations led by NHS researchers, drug manufacturers or medical device manufacturers). The report defines a common set of competences that were found to generally support the successful management of clinical investigations (ie within planned timeline and costs):

  • Understanding of regulation and governance to successfully design and set-up clinical investigations.
  • Retaining knowledge and expertise of the project team that manages clinical investigations.
  • Developing an effective network of relationships with all key stakeholders of the UK clinical investigations landscape.
  • Developing appropriate engagement mechanisms and incentives for the different partners of the clinical investigations (eg NHS staff, patients, manufacturers).