In the European Union, new drugs and biologics are regulated separately than new medical devices and in vitro diagnostics. New drugs and biologics are regulated under the European Medicine Agency (EMA).  For new medical devices and in vitro diagnostics, a declaration of conformity with the essential requirements, based on a self-assessment, are required for low risk products. For higher risk products, a Notified Body’s involvement is required.

New Drugs and Biologics – European Medicines Agency (EMA)

The European Medicines Agency (EMA) is an agency of the European Union that conducts scientific evaluation of new drugs developed by pharmaceutical companies for use in the European Union. It started in 1995 and is located in London. The requirement for EMA oversight for new drug came after EU directive 2001/83EC: Community on Medicinal Products for Human Use:

• No medicinal product (with the exception, under certain conditions, of radiopharmaceuticals prepared at the time of use) may be placed on the market of a Member State unless an authorization has been issued by the competent authorities of that Member State or by the European Medicines Agency (EMA).
• An authorization holder may submit a request for recognition of this authorization to other Member States.
• Member States must make the wholesale distribution of medicinal products subject to the possession of an authorization to engage in activity as a wholesaler of medicinal products.

EMEA or EMA?

The original organization was set up as the European Agency for the Evaluation of Medicinal Products in 1993 under EC Regulation No. 2309/93.  It was renamed in 2004 by EC Regulation No. 726/2004 to the European Medicines Agency and had the acronym EMEA until December 2009. EMA is now used. EMEA or EMA is commonly used in clinical research industry when referring to the European Medicines Agency.

How EMA works

EMA uses a centralized approach to the review and approval of new medicinal products.  Pharmaceutical companies submit one single marketing-authorization application to the EMA. An approval by the European Commission is valid in all European Union (EU) Member States and in the European Economic Area (EEA) countries: Iceland, Liechtenstein and Norway. A company can then start to market a new medicine product after it has received a marketing authorization.

EMA’s scientific evaluation is carried out mostly by its scientific committees.  Scientific committees compose of members from EEA countries and representatives of patient, consumer and healthcare-professional organizations.

Medical Devices and In Vitro Diagnostics

Medical devices and in vitro diagnostics are regulated in the European Union by three EC Directives:

1. Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical equipment (AIMDD)
2. Council Directive 93/42/EEC of 14 June 1993 concerning medical devices (MDD)
3. Council Directive 98/79/EC of 27 October 1998 on in vitro diagnostic medical devices (IVDD)

These three EC directives have been incorporated into the national laws of each EU Member State. The benefit of these directives is that products that receive regulatory approval with a CE marking can be marketed throughout the European Union (EU) without any barriers.

To get approval under any of the three EC Directive above, Essential Requirements must be met. For example, in the MDD, the list of Essential Requirements can be broken down into two groups:

1. General requirements for safety and performance
2. Technical requirements on design and manufacturing

Approval Process

For this and the remaining sections, medical device and in vitro diagnostic are referred to as devices. The responsibility for ensuring that devices meet the Essential Requirements lies with the manufacturer.

• For low risk devices (Class I) such as a tongue depressor or medical glove, the manufacturer is allowed to self-identify conformity with the Essential Requirements.
• For medium- to high-risk devices (Class IIa, IIb, III), the manufacturer must call on a third party to assess conformity. Qualified companies that may act as a third party are called Notified Bodies.

The manufacturer may choose among the above two methods above for conformity assessment, depending on the risk level of the device and/or manufacturing system. The end result is certificates of conformity that enable the manufacturer to apply a “CE marking” to the product.

Notified Bodies

One difference between new drug approval and new devices approval in Europe is the regulatory agency difference. Approval for devices is obtained through Notified Bodies, which are private companies, instead of a regulatory agency like the European Medicines Agency (EMA).

Most Notified Bodies are independent commercial organizations that are designated, monitored, and audited by the relevant Member States via the national Competent Authorities. There are more than 50 active Notified Bodies within the EU. A device manufacturer can choose any Notified Body to review and approve their new products. Post-market surveillance functions are the responsibility of a member state via the Competent Authority.

CE Marking

CE marking is an acronym for the French “Conformité Européenne.” Starting in 1993, CE marking shows that a product is compliance with EU legislation regarding safety, health and environmental protection. The CE logo ensures the free movement for products within the European Economic Area (EEA). Devices to be marketed in EEA must carry CE marking.  A product that carry a CE marking logo shows that the manufacturer has verified that the product complies with all relevant Essential Requirements of applicable EC Directives.  Therefore, to get approval for CE marking, manufacturer must meet the Essential Requirements through one of the two routes discussed under Approval Process above.

Clinical Data Requirement

Whether new drugs or devices are being considered for approval under different pathways, clinical data may be necessary to demonstrate safety and effectiveness.  The term clinical data under the EC Directives is a broad concept that may range from bench testing to clinical trials in human subjects.

For example, in the MDD, the clinical data used for CE marking may compose of one of the two forms:

1. Either a compilation of the relevant scientific literature currently available on the intended purpose of the device and the techniques employed, together with, if appropriate, a report containing a critical evaluation of the compilation
2. Results and conclusions of a specifically designed clinical investigation

In general, clinical trials (second option above) are usually needed for new drug and higher risk devices. However, literature route (first option above) may be used by manufacturers of low to medium risk devices, where safety and effectiveness can be shown through nonclinical data (bench testing and animal testing) and pre-existing data (scientific literatures).

Related pages

1. Country Specific Regulations – Global / International Trial
2. Food and Drug Administration (FDA)
3. Historical Events behind Current Regulations
4. ICH’s GCP Guideline