Medical Devices: European Union's Regulatory Process

Published by the Government Accountability Office on 1997-11-20.

Below is a raw (and likely hideous) rendition of the original report. (PDF)

      United States
GAO   General Accounting Office
      Washington, D.C. 20648
                                                                        Lx-9 53--F-%
      Health, Education and Human Services Division

      November 20, 1997

      The Honorable Edward M. Kennedy
      Ranking Minority Member
      Committee on Labor and Human Resources
      United States Senate

      Subject: Medical Devices: Euronean Union’s Regulator-v

      Dear Senator Kennedy:

      Medical devices are a heterogeneous category of products ranging in complexity
      from a simple tongue depressor to a sophisticated CT (computed tomography)
      x-ray system. The Food and Drug Administration (FDA) regulates the
      manufacture and marketing of tens of thousands of medical devices in the
      United States. Critics claim that regulatory mechanisms under the European
      Union’s (EU) system are more efficient, and thus faster, and have suggested
      that elements of the EU approach be adopted as part of a more general reform
      of FDA. In order to more fully understand the nature of the comparisons being
      made between the FDA and EU approaches, you requested that we examine the
      EU system of regulating the entry of medical devices into the marketplace, with
      a specific focus on product review time. In developing this information, we
      based our work on a comparison of U.S. and EU regulations and on previous
      GAO work.’ We did our work in accordance with generally accepted
      government auditing standards from July through October 1997.

      In summary, we found some differences between the EU and FDA systems that
      might explain why the EU system may conduct reviews more rapidly than FDA,
      but at least one difference makes it difficult to reach valid conclusions about
      the relative speed of review under the two systems?

      ‘See Medical Device Regulation: Too Early to Assess Eurouean System’s Value
      as Model for FDA (GAO/HEX%-9665, Mar. 6, 1996).
      mere are three major EU legislative provisions covering medical devices-
      Active linplantable Medical Device Directive, Medical Device Directive, and In
      Vitro Diagnostics Directive. Our work de& mainly with the Medical Device
                                  GAOLHEHS-9%19R      EU Medical   Device Regulation

A manufacturer who seeks to market a medical device in the EU has two
general types of choices that can affect the speed of the-clearance-the type of
procedure used to assess the device and the amount of resources to devote to
this assessment. Regarding the first choice, the EU requires an assessment of
both the device’s design and its manufacturing process to determine whether
the device is safe and performs as intended and whether any associated risk is
acceptable given the benefits of the device. The manufacturer may choose the
type of procedure used to make these assessments. The major decision for the
manufacturer is whether to have an evaluation of the device itself or of the
process that produces the device. Variations permitted in how the design and
the manufacturing process are assessedaffect the length of time the assessment
takes. In the United States, manufacturers have no choice. The procedure
used to clear a device for U.S. marketing depends on the kind of device it is. If
a device does not require premarket approval, FDA may clear the product if the
manufacturer can show that the new device is “substantially equivalent” in
safety and effectiveness to a similar device already on the market. Otherwise,
FDA requires that the manufacturer show, through the premarket approval
process, that the device is safe and effective.3

The second choice available to manufacturers of devices for the EU relates to
the amount of resources devoted to the assessment. Manufacturers contract
with a third party to conduct the assessment at a cost that is negotiated
between the two. For example, a manufacturer willing to devote the resources
to hire more reviewers could conceivably obtain a quicker assessment than a
manufacturer devoting less resources. In the United States, on the other hand,
FDA conducts all reviews and makes aJ.ldecisions about resources used for
product review? (FDA resources are determined by the appropriations

Directive because most devices are regulated under this. Although the Medical
Device Directive will not be fully implemented until June 14, 1998, our work
focused on the EU system of regulation and how it is expected to work once it
is fully implemented and compliance becomes mandatory.
3There is also a group of low-risk devices that are exempted from FDA
clearance for marketing.
4FDA initiated a Z-year pilot program for third-party reviews on August 1, 1996.
Under the voluntary pilot program, manufacturers negotiate with F’DA-
recognized third parties for product review. The fees for the review are
negotiated between the manufacturer and third party. Consequently,
manufacturers have a choice in resources used for product review.

 2                        GAOIHJXHS-9th19R      EU Medical   Device Regulation

&though manufacturers’ flexibility under the EU system-can contribute to more
rapid review times, we found that comparisons of review times must be made
with caution. In particular, the medical devices assessed under the EU system
are likely to be different from those entering review by FDA-that is, many of
the assessments that EU conducts are of products that have already been
cleared for marketing in the countries where they are sold. Under EU
regulation, manufacturers must show that all devices sold-including those
already introduced into national markets-conform with EU requirements.
Consequently, where the EU requirements are similar to those in countries that
are already selling the devices, the EU assessments should be relatively rapid.
For such devices, the EU assessment represents a second (and, logically,
“easier”) review than those conducted by FDA, all of which are of devices that
have never been reviewed before.

Additional details about our work are in the enclosure.


We provided a draft of this letter to FDA officials. They agreed with our
findings and said that our description of the EU and U.S. approaches in
regulating medical devices was “succinct and useful.” They agreed in particular
that it is diff%ult to make direct comparisons of review times under the two
systems. These officials concurred that many current EU reviews are of
products that have already been shown to conform with national requirements
in the countries where they are sold, while F’DA reviews devices that have
never been reviewed before.

FDA officials said that two other factors should be considered when comparing
FDA and EU review times. First, while the EU assessessafety and performance
for class III products, FDA looks at safety and effectiveness. For example,
while the EU would assess whether a laser performs as intended by the
manufacturer, FDA would examine whether the indicated use has clinical utility.
Thus, they noted, “U.S. clinical trial requirements are considerably more
rigorous than the EU requirements.” Second, they said that any comparison of
review times should take into account the total time required for all review
processes necessary to get a product to market. For the EU system
specifically, after a device has been found to conform with EU requirements, a
second review is required by the reimbursement authority of the country’s
health care system.

3                       GAO/HEHS-9%19R         EU Medical   Device Regulation

    &-agreed with your office, we will make copies of this correspondence
     available to interested parties. This correspondence was prepared by B&ha
     Dong and George Silberman. If you or your staff have any questions about this
    .work, please call me at (202) 512-7119or Ms. Dong at (202) 51243499.

    Sincerely yours,

    Bernice Ste6hardt
    Director, Health Services Quality
     and Public Health Issues

                             GAO/HEFfS-9%19R       EU Medical   Device Regulation
ENCLOSURE-                                                               ENCLOSURE


In 1985,in response to obstacles in creating a common market, the EU adopted what
was termed the “new approach” to medical device regulation. Obstacles included
differences in national regulations and the lengthy process for reaching agreement on
specific regulations. Under the new approach, countries zgree to broad general goals,
which are known as “Essential Requirements.” Products that conform with these
general goals are identified with a CE mar@ and are marketed throughout the
European Economic Area (EEA).6

The specific details for achieving the Essential Requirements are found in performance
standards.’ Although conformity with EU performance standards is voluntary,
devices that conform with the performance standards are assumed to also conform
with the Essential Requirements. Since it is easier to show conformity with specific
standards than with general goals, it is expected that manufacturers use the
performance standards to show conformity. To illustrate, the Essential Requirement
for a sterile product is that it must be sterilized by an appropriate and validated
method. The related performance standards specify such technical details as how
high the temperature must be and the duration of sterilization.

?‘he CE mark is a symbol used to indicate that the product complies with the relevant
Essential Requirements.
GTheEEA includes the 15 EU counu-ies and the 3 Economic Free Trade Association
(EFTA) members. The EU counties are Austria, Belgium, Denmark, Finland, Prance,
Germany, Greece, Italy, Luxembourg, the Netherlands, Portugal, Ireland, Spain,
Sweden, and the United Kingdom. The three EFTA members are Iceland, Norway, and
Liechtenstein. These 18 countries constitute a market larger than the size of the
United States, Canada, and Mexico combined.
‘The two EU-designated bodies for standard setting are CEN (European Committee for
Standardization) and CENELEC (European Committee for Electrotechnical
Standardization). These are nonprofit organizations whose members are th-e national
standards organizations of the EU and EETA countries. Generally, for medical devices
the EU adopted existing international performance standards.

5                                 GAO/HEHS-9%19R        EU Medical    Device Regulation
ENCLOSURE.                                                                         ENCLOSURE
Three major legislative provisions, in the form of EU directives,* cover medical
devices: the -Active Implantable Medical Device Directive; the Medical Device
Directive, and the In Vitro Diagnostics Directive. Each is in a different stage of
implementation (see table I. l).l”

Table 1.1: EU Medical Device Directive Imnlementation

     Directive                   Date adopted by EU     Target date for          Transition period
                                                      I implementation           ends
     Active Implantable          June 20, 1990            January 1,1993         January 1, 1995
     Medical Device
     Medical Device              June 14, 1993
     Directive               I
     In Vitro Diagnostics        Under development        Anticipated 1998
     Directive               I                        I                      I

We focused on the Medical Device Directive because most medical devices are
regulated under it. This directive also covers accessories, components, and software
associated with medical devices. It does not cover cosmetics, blood and blood
products, and animal and human tissue and their products.

?lhe manufacture and marketing of medical devices are also regulated by other EU
directives. For example, all manufacturers, including medical device manufacturers,
are subject to product liability regulations.
the term “active” means having some energy source. For example, a pacemaker is an
active implantable device, while a hip replacement is inactive.
“Directives, the most common form of EU legislation, need to be transposed into
national legislation. After a directive is adopted by the EU members, countries have a
period of approximately 18 months in which to transpose the directive into national
law. This is followed by a transition period of 2 to 5 years in which both the
transposed directive and the preexisting national laws are in effect. During the
transition period, manufacturers may elect to comply with either the preexisting
national law or the directive. F’inally, a specific date is set on which the directive is
fully implemented and compliance with the directive becomes mandatory.

 6                                     GAO/HEHS-9%19R          EU Medical Device Regulation
ENCLOSURE’                                                                 ENCLOSURE

At the end of a transition period, a3l medical devices placed on the-market must
conform v&h the Essential Requirements found in the Medical Device Directive.” As
the EU hasno grandfather provision through which device types that have already
been introduced into the market can be exempted,12this situation has implications for
comparing-product review times between the EU and FDA For example, to continue
to sell ultrasonic scanners, the manufacturer needs to show that the scanners conform
with EU requirements, even though the scanners have already met the national
requirements. Where the EU system possessesfeatures similar to those found in
preexisting national requirements, like those of the United Kingdbm or Germany, the
reviews should be relatively rapid. Consequently, unless the review times of medical
devices already introduced into the market can be separated from those that have not,
product review times under the EU are not comparable with those under FDA.


To market a medical device in the EU, a manufacturer must show that the device
conforms with the Essential Requirements. There are two types of requirements-
general requirements that apply to all devices and specific requirements that apply
only to certain types of devices. For example, there are specific requirements for
devices with chemical and biological properties, devices that require sterilization, and
those that use radiation. Six Essential Requirements apply to all devices. Basically,
the device must be safe, must perform as intended, and the associated risk must be
acceptable given the benefits. These six Essential Requirements are
    -   devices must be designed and manufactured without compromising safety; any
        associated risk must be acceptable when weighed against benefits;

        design and construction of devices must conform to safety principles, in
        accordance with the state of the art;

        devices must perform as intended by the manufacturer;
    -   devices must perform safely and as intended throughout their speeised lifetime;
    -   design, manufacture, and packaging must ensure that safety and performance
        are not adversely affected by normal transport and storage; and

‘IDevices already in use need not conform with the EU requirements.
12Tbegrandfather provision for device types that are already on the market is the basis
for the premarket notification, or 510(k) process, used by FDA

7                                   GAO/HEHS-98-19R        EU Medical   Device Regulation
ENCLOSURE                                                                  ENCLOSURE
      undesirable side effects must constitute acceptable risk.     ,_ _
             .                                                    .- .
In contrast,‘FDA has two processes, each with distinct requirements, for getting a
product on the market-premarket notification, or (510(k)); and premarket approval
(?%A). For 510(k)s, manufacturers need to show that the device is “substantially
equivalent” in terms of safety and effectiveness to some predicate device already on
the market. (Over 90 percent of medical devices cleared by FDA enter the market
through the 510(k) process.“) The requirements are more stringent for PMAs:
Manufacturers need to show that the device is safe and effective.14 A group of devices
that pose little risk is exempt from both the 510(k) and PMA processes. These
devices may be subject to such controls as registering the manufa&uring site, labeling,
appropriately, and adhering to good manufacturing practices.‘5


The applicable procedure for demonstrating conformity with the EU Essential
Requirements depends on the classification of the device. The level of regulatory
control corresponds with the level of risk posed by the device. Under the EU system,
devices are grouped into four classes. The rules for determining the class of a device
are listed in the directive, such as whether the device has a therapeutic or diagnostic
function, whether it is invasive, and how long it will be in contact with the body. The
least risky devices are class I devices, classes IIa and IIb are medium risk devices, and
class III devices pose the greatest risk.

FDA also uses different regulatory controls depending on the risk associated with the
device. FDA uses three classes with increasing controls from class I to class IIl
devices. All new devices not substantially equivalent to other devices already on the
market, however, are subject to the highest level of regulatory control until enough is
known about them and their associated risk to reclassify them.

The two systems are more similar than dissimilar in assigning relative risk to medical
devices. In table I.2 we provide examples of devices and their respective
classiiications under the EU and FDA systems.

i3About 5 thousand to 7 thousand 51O(k)s and 40 to 70 PMAs are submitted to FDA
14FDAinterprets effectiveness to mean having clinical utility.
15Thirty-threepercent of all FDA-regulated device types are exempted. It is unclear
how many devices on the market fall into these categories.

 8                                  GAO/HEHS-9%19R         EU Medical    Device Regulation
ENCLOSURE.                                                                        ENCLOSURE

Table 1.2: EU and FDA Medical Device Classification Examples -

    Medical device            EU classification              FDA classification
    Syringe                   Class I, reusable              Class I; class II,
                              surgical instrument;           angiography, infusion
                              class IIa, invasive and        PumP
                              intended to store liquid
                              for infusion
    Endoscope                 Class I, active-uses           Class Ii, 76 different
                              light to illuminate body,      categories for types of
                              invasive but transient         scopes, accessories
    Chemical for cleaning     Class Ila                      Class Il, ethylene-oxide
    medical devices                                          gas for sterilization
    Contact lens              Class IIa                      Class 11;class III,
                                                             extended wear soft
                                                             contact lens
    Ultra.sonic diagnostic    Class IIa, active,             Class II
    irnager                   diagnostic function
    Cleaning and wetting      Class n-b                      Class m
    agents for contact lens
    X ray diagnostic, high    Class IIb, active, emits       Class rl
    voltage generator         ionizing radiation
    Hip implant               Class In3                   Class II or class III, 27
                                                          different categories of
    Arterial or venous        Class m                        Class II, cardiovasct.ilar
    catheters                                                catheter, angiography;
                                                             class III, coronary
    Bone cement with          Class rlI                      Class m

“FDA is in the process of reclassifying these to class II.

9                                    GAOLFIEHS-9%19R           EU Medical      Device Regulation
ENCLOSURE                                                                  ENCLOSURE

In the EU, manufacturers self-certify conformity for most of the least risky, class I
devices.16 Specifically, the manufacturer holds and makes available upon request
documentation that shows conformity with the Essential Requirements. For all other
classes of device, third-party assessmentis required. The greater the potential risk of
the device, the greater the role for third-party verification of conformity.

The use of clinical data to show conformity with the Essential Requirements is
required only for class III devices.” Clinical data can come from existing scientific
literature or clinical investigation.1g That is, scienmc literature may exist for medical
devices that have been marketed for some time. Manufacturers introducing new
technology into the market may need to conduct clinical investigations to generate the
necessary clinical data.

For each class, there are different procedures to show conformity and get a CE mark
on the product. Manufacturers decide which assessment procedure to use. The major
decision is whether to use a type examination or quality system assessment. That is,
manufacturers can opt for a review that evaluates the product itself or evaluates the
process that produces the product. For a small manufacturer, it may be easier to use
the @pe examination procedure rather than to introduce design controls, process
validation, and production controls into the manufacturing process. For a
manufacturer with many different types of devices, a quality system assessment may
be more efficient. Figures I.1 through I.4 show the applicable conformity assessment
procedures by device ~lass.‘~

‘%ss I devices that have some measuring function or need to be sterilized require
third-party assessment.
17Clinicaldata are also required for active implantable devices.
‘*Clinical investigation requires the relevant ethics committee approval for the
protection of human subjects within each country. Applications to begin clinical
investigation are deemed approved after 60 days unless the government responds
otherwise. In contrast, submission for clinical investigations to F’DA are deemed
approved after 30 days.
IgThe conformity assessment procedures include the following two requirements for
manufacturers-they must institute postmarket surveillance and must report adverse
events. The EU encourages but does not require members to also institute user
reporting of adverse events. Currently, except for countries that have user reporting
systems, there is little data to assesshow well the countries are able to prevent
defective products from entering the market or take defective products off the market.

 10                                 GAO/EIEHS-9%19R        EU Medical    Device Regulation
ENCLOSURE                                                                                ENCLOSURE
Figure 1.1: Jkss I Device Conforrnitv Assessment                                 ._
                                                                               ._ .

                       Class I Devices

                   -T-       I

                  Hold Technical Documents
                         (Annex VII)

                                      Verification of     Production Quality System    Product Qualii System
                                 SteriliitioniMeasuring      Audii of Sterilkation/     Audit of Steriiiition/
                                        Features by          Measuring Features         Measuring Features
                                                                                          by Notified Body

11                                         GAOLHEHS-9%19R             EU Medical      Device Regtilation
    ENCLOSURti                                                                       ENCLOSURE

                                                                           .- -
    Figure 1.2: Class IIa Device Conformitv Assessment

                            Classila Devices

                                                                    I      -
Full Quality System                                           Manufacturer’s
      Auditby                                                   Declaration:
   Notified Body                                         Hold Technical Documents
     (Annex II)                                                 (Annex VII)

                                  Product Verification     Production Quality           Product Quali
                                                            System Audi by              System Audi by

      12                                 GAWEIEHS-9%19R            EU Medid         Device Regulation
          ENCLOSURE                                                             ENCLOSURE

          ??ime 1.3: ‘Class IIb Device Conformitv Assessment

                                Class lib Devices

    Full Quality System                                    Type Examination
          Audit by                                                 4’
       Notified Body                                         Notified Body
         (Annex ti)                                           (Annex Ill)

                                                                                 Product Quality
                                                                                 System Audit by
                                                                                  Notified Body
                                                                                   (Annex Vi)

           13                                 GAOIEIEHS-9%19R     EU Medicd   Device Regulation
     ENCLOSURE                                                                             ENCLOSURE

     Figure 1.4: Ciass III Device Conformitv Assessment

                          u  Class Ill Devices

          I                                                                 I
Full Quality System                                                Type Examination
      Audit by                                                             by
   Notified Body                                                     Notified Body
     (Annex II)                                                       (Annex 111)

  Design Dossier                            Product Verification                      Production Quality
  Examination by                                     by                                System Audit by
   Notified Body                               Notified Body                            Notified Body
    (Annex II)                                  (Annex IV)                                (Annex V)

       CE                                          CE                                       CE
       Mark                                        Mark                                     Mark

      14                                   GAOIHEHS-9%19R                EU Medical     Device Regulation
ENCLOSURE                                                                   ENCLOSURE
The quality system assessment is similar to FDA’s Good Manufacturing Practice (GMP)
regulations: -To harmonize regulations with the EU and other co%&ies, FDA revised
its GMP regulations to include preproduction design controls and other features inits
harmonized quality system approach.”


The Medical Device Directive specties who is responsible for particular functions-
government regulators, their “notified bodies” (designated third parties), or
manufacturers. The government organization responsible for implementing the
directive within each country is called the Competent Authority.’ Generally, these are
the ministries of health or some organization under the ministry. The Competent
Authorities also have the power to take appropriate interim measures to withdraw or
restrict the marketing of medical devices they deem unsafe; approve clinical
investigations and maintain a register of class I device manufacturers; and designate
notified bodies and report their identities to the EU.21

Notified bodies are the third parties responsible for conducting conformity
assessment. Notified bodies can be either private or public organizatiorx? and must
meet certain minimum requirements listed in the directive.= These requirements
include independence, professional integrity, professional and technical competence,
trained staff, impartiality, liability insurance, and confidentiality. As part of the
conformity assessment, notified bodies conduct periodic audits of the manufacturer,
including at least one on-site inspection. Notilied bodies may also conduct
unannounced inspections.

2”These revised reb@ations, renamed Quality Systems Regulations, were effective June
1, 1997.
21TheEU Commission assigns the notified body a unique identification number, which
appears along with the CE mark that manufacturers Z&X to the medical devices.
%Some public notified bodies were government agencies responsible for similar
functions prior to the directive-this was the case in Prance, Italy, Spain, and Portugal.
This does not, however, preclude the Competent Authority from designating other
private sector notified bodies.
?I’he Competent Authority is responsible for oversight of notified bodies and is
responsible for withdrawing the designation if a notified body no longer satisfies the
minimum requirements. In addition to the criteria set out in the directive, the EU has
performance standards for accrediting and certifying notiiied bodies.

15                                 GAO/HEHS-9%19R         EU Medical    Device Regulation
ENCLOSURE                                                              ENCLOSURE
The manufacturer may contract with any notified body to conduct the conformity
assessment.. For example, a German manufacturer can select an ftalian notified body.
Manufacturers negotiate with the notified body on the type of conformance procedure
to use and the amount of time to complete the assessment. Once the notied body
issues a ceticate of conformity, the manufacturer can put a CE mark on the device
and market it within the EEA-‘* The manufacturer is responsible for informing the
notified body of any changes in the device design or manufacturing process.
Depending on the nature of the changes, recertification of the device may be
necessary. Manufacturers are also responsible for implementing ~ostmarketing
surveillance and reporting adverse events to the relevant Competent Authority.


%e notied body is required, upon request, to inform other notified bodies of
conformity certificates issued, refused, or withdrawn.

 16                               GAOLESEHS-9%19R       EU Medical   Device Regulation
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