Page 55 - Biomedical Engineering and Design Handbook Volume 2, Applications

34 MEDICAL DEVICE DESIGN

was notified that it could now grant the CE mark. It became know as a Notified Body. Entities from
outside the EU, such as from the United States, have since become notified.
The Directive system employs the CE (Conformite Europeene) mark as the indication that a
product may be freely sold throughout the EU, without being subject to laws differing from the
Directive. In effect, it is an indication of free movement within the EU. You may have seen the CE
mark on children’s toys, which were the subject of an early Directive.
Notified Bodies have the key role in the application of the CE mark in the area of medical Devices.
A company intending to market a medical device within the EU hires one of these entities to act as
its Notified Body. So there is a vendor/customer relationship between the Notified Body and the Device
company, as well as the regulator/regulated relationship. At the same time, the Notified Body has a
responsibility to the EU and to its competent authority to properly enforce the Directives. It is a tension
that promotes both dedication to the Directive and understanding of the needs of the regulated.
The Notified Body then inspects the Device company, auditing against the standards that have been
adopted by the EU (called EN for European Norms). The Notified Body then provides a certificate of
compliance to the company. The audits are designed to test the entire quality system of the company.
First the broadest parts of the system, such as the quality manual, are inspected. As part of its work
with the company, the Notified Body regularly conducts audits. Each of these usually digs deeper into
the details of the quality system. The Notified Body is the implementer of the EU philosophy—a well-
controlled quality system will produce compliant products.
Once certified, the company may begin to use the CE mark on products. For lower-risk products,
the company just keeps records, which are then inspected by the Notified Body. For high-risk products,
such as active implantables, the company must apply to the Notified Body for permission to apply the
CE mark, much in the same manner as a company would apply to FDA for a PMA.
The use of standards in the EU are very different from the United States. One need not follow the
ENs. However, if choosing that path, the company would have to convince the EU that the product
satisfied everything required by the Directives. The more normal route is to comply with the ENs.
Then the route to the CE mark is assured.
One way to casually characterize this system is that it is more engineering-oriented than in the
United States. Notified Bodies examine devices primarily to see if they act as they are claimed to act:
if they meet specification. In comparison, the FDA system is more therapy-oriented. The main FDA
question is not: does it work as it says. Rather, the FDA asks if the device provides a medical benefit.

2.11 MARKETING CLEARANCE OF COMBINATION PRODUCTS

The path toward marketing for devices is no longer sufficient for engineers. Technology has resulted
in an increased mix of drugs and biologics with devices. These are known as combination products
(or combos in our shorthand). This is not a statutory term, but one established by FDA in order to
deal with how to regulate them.
Combos are not new. Drugs were combined with devices before the term combination products
existed. For example, steroids were applied to the tips of cardiac pacing lead electrodes to reduce
inflammation in difficult cases so the tip would achieve good electrical contact. Asthma drugs
were dispensed by metered dose inhalers, spray cans that became a part of kids’ school life.
Implantable drug dispensers were approved for specific drug delivery rather than as general tools.
Biologics were used early on devices. Some catheters had heparin coatings.
In the early days, there was uncertainty as to how to regulate combos. As discussed earlier, FDA
was divided into centers. Which center regulated a product was important, since the regulations varied
widely. Calling a product a drug, rather than a device, could result in a drastically different path to
market.
FDA established an Office of Combination Products (OCP) under the Office of the Commissioner,
so that it was not in any center. This office was to provide guidance on how to regulate combos. The
guidance employs the concept of primary mode of action. If the primary mode of action is physical,
like a device, then the combo is a device. If the primary mode of action is chemical, metabolized by