Medical Device Regulation: Too Early to Assess European System's Value as
Model for FDA (Letter Report, 03/06/96, GAO/HEHS-96-65).
Pursuant to a congressional request, GAO compared the Food and Drug
Administration's (FDA) and the European Union's (EU) systems for
reviewing and approving medical devices, focusing on: (1) key
differences between the two systems; (2) the outputs of the two systems;
and (3) the feasibility of FDA adopting features of the EU system.
GAO found that: (1) U.S. and EU medical device regulatory systems share
the goal of protecting public health, but the EU system is designed to
facilitate EU-wide trade; (2) while EU reviews medical devices for
safety and performance, FDA reviews devices for safety, effectiveness,
and benefit to patients; (3) while EU gives major medical device
regulatory responsibilities to public agencies and private
organizations, FDA has sole responsibility over device regulation in the
United States; (4) both systems link the level of medical review to
device risk, but the two systems use different procedures to reach
approval or clearance decisions; (5) questions and concerns have arisen
regarding possible conflicts-of-interest in the EU medical device review
process because EU notified bodies carry out a regulatory function
within the EU medical device system and conflict-of-interest rules for
EU reviewers are less comprehensive than in the United States; (6)
sufficient data does not exist on the EU medical device review system to
permit meaningful comparison with FDA because the EU system is new and
not yet fully operational; and (7) it is too early to evaluate the
impact of new FDA streamlined review procedures.
--------------------------- Indexing Terms -----------------------------
REPORTNUM: HEHS-96-65
TITLE: Medical Device Regulation: Too Early to Assess European
System's Value as Model for FDA
DATE: 03/06/96
SUBJECT: Medical equipment
Product performance evaluation
Product safety
Safety regulation
Comparative analysis
Consumer protection
Privatization
Conflict of interest
Medical research
International relations
IDENTIFIER: United Kingdom
Germany
Medicare Program
European Union
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Cover
================================================================ COVER
Report to the Chairman, Committee on Labor and Human Resources, U.S.
Senate
March 1996
MEDICAL DEVICE REGULATION - TOO
EARLY TO ASSESS EUROPEAN SYSTEM'S
VALUE AS MODEL FOR FDA
GAO/HEHS-96-65
Medical Device Regulation
(108230)
Abbreviations
=============================================================== ABBREV
CEN - European Committee for Standardization
EU - European Union
FDA - Food and Drug Administration
FFD&C - Federal Food, Drug, and Cosmetic
GMP - good manufacturing practices
HCFA - Health Care Financing Administration
IDE - Investigational Device Exemption
IRB - institutional review board
MDD - Medical Devices Directive
NB - notified body
PMA - premarket approval
PMS - postmarketing surveillance
QA - quality assurance
SMDA 90 - Safe Medical Devices Act of 1990
UK - United Kingdom
Letter
=============================================================== LETTER
B-260738
March 6, 1996
The Honorable Nancy L. Kassebaum
Chairman, Committee on Labor
and Human Resources
United States Senate
Dear Madam Chairman:
Medical devices play a vital role in promoting public health and
diagnosing and treating illness. The Food and Drug Administration
(FDA) is the arm of the U.S. Public Health Service responsible for
ensuring that the American public has access to devices that are safe
and effective. Members of Congress, representatives of the medical
device industry, and others have expressed concern that FDA takes too
long to review and approve new medical devices, thus delaying the
public's access to useful, and possibly life-saving, medical care.\1
In 1993, the European Union (EU) began to implement a new system to
regulate medical devices--a system whose approach differs from that
of the United States.\2 Many critics of FDA have suggested that the
new EU device review system offers a model that would enable
innovative technology to reach U.S. consumers more quickly without
increasing risks to the public's health.
You asked us to examine both FDA's and the EU's device review
systems. The objectives of our review were to (1) identify key
differences between the U.S. and EU systems for reviewing medical
devices; (2) compare outputs of the two systems, such as review time,
if data were available; and (3) examine the feasibility of FDA's
adopting features of the EU system. In preparing this report, we met
with and analyzed data provided by FDA officials; EU, United Kingdom
(UK), and German government officials; and representatives of private
review bodies and the medical devices industry in the United States,
Germany, and the UK. We conducted field work in Germany and the UK
because those countries were among the most advanced in implementing
the EU system. We conducted our review from March through December
1995 in accordance with generally accepted government auditing
standards. For a complete description of our scope and methodology,
see appendix I.
--------------------
\1 See U.S. Congress, House of Representatives, Committee on
Commerce, Subcommittee on Oversight and Investigations, A Consumer's
Perspective on Medical Devices. Hearings: March 30, 1995, 104
Cong., 1st sess. (Washington, D.C.: U.S. Government Printing
Office, 1995); and The Wilkerson Group, Inc., Forces Reshaping the
Performance and Contribution of the U.S. Medical Device Industry,
prepared for the Health Industry Manufacturers Association (New York:
June 1995), p. xxvii.
\2 The 15 member states of the EU, formerly the European Economic
Community, are the United Kingdom, Ireland, Denmark, Greece, Germany,
France, Italy, Spain, Portugal, Belgium, Luxembourg, The Netherlands,
Sweden, Finland, and Austria. The medical device regulatory system
we will discuss in this report is being implemented in the European
Economic Area, which was established in January 1994 and consists of
the EU member states plus Norway, Iceland, and Liechtenstein. We
will refer to the system as the EU system throughout the report.
RESULTS IN BRIEF
------------------------------------------------------------ Letter :1
The EU system for regulating medical devices is still evolving, with
major aspects of the system not yet fully in place. Drawing a
meaningful comparison between the EU and FDA is therefore not
possible at this time. The ability of the EU system to ensure the
safety of medical devices and provide an efficient review process
will become more evident after the system accumulates several years
of experience.
However, it is possible to compare certain features of the medical
device regulatory systems in the United States and the EU. For
example, the two systems operate within different legal and policy
contexts. U.S. law gives responsibility for device regulation to
the Food and Drug Administration, an agency of the Public Health
Service. FDA's charge is a public health mandate: to ensure that
devices that reach the U.S. public are safe and effective. The EU
system's mission is twofold. It is designed not only to ensure that
devices are safe but also to facilitate EU-wide trade by creating a
single review process that permits devices to be marketed in all
member states.
Key differences between the two systems include the roles of public
and private sector bodies and the relationships among the principal
parties involved in device production and regulation. In the United
States the government alone regulates devices. Under the EU system,
both governmental and private organizations--called "notified
bodies"--review and approve medium- and high-risk devices; most
notified bodies (NB) are private. Manufacturers contract with the NB
of their choice to conduct assessments of devices they would like to
market. Reviewers in both the United States and the EU are subject
to conflict-of-interest rules, but the rules that govern FDA
reviewers are more comprehensive than those that apply to NB
employees.
The systems' criteria for device approval and clearance also differ.
In the EU, devices are generally evaluated for safety and their
ability to perform as the manufacturer intended. The criteria FDA
must use are safety and effectiveness. Effectiveness includes the
additional standard of providing benefit to patients.
Meaningful comparison of the length of review time in the United
States and the EU is not possible because there are no data
documenting review times under the new EU system comparable to data
describing FDA's experience. FDA is attempting to better manage its
review process by experimenting with different procedures. Recent
trends in FDA review time vary by type of review but generally show
improvement for applications submitted in fiscal year 1994.
BACKGROUND
------------------------------------------------------------ Letter :2
Medical devices encompass a wide array of products with myriad uses.
A medical device can be any product used to cure, prevent, diagnose,
or treat illness, provided that its principal intended purposes are
not achieved primarily by chemical or metabolic action, as would be
the case with a pharmaceutical. Devices range in complexity from
simple tongue depressors to heart pacemakers and sophisticated
imaging systems. There are more than 100,000 products in over 1,700
categories, and they cover a wide spectrum of risk. The U.S.
medical device industry grew from 5,900 firms in 1980 to 16,900 firms
in 1995. U.S. consumption of medical devices exceeded $40 billion
in 1994.
FOOD AND DRUG ADMINISTRATION
---------------------------------------------------------- Letter :2.1
The 1976 Medical Device Amendments to the Federal Food, Drug, and
Cosmetic (FFD&C) Act gave FDA expanded responsibility for regulating
medical devices in the United States. FDA's regulatory
responsibilities have three components: (1) approving new medical
devices' entry into the market; (2) monitoring device manufacturers'
compliance with FDA laws and regulations, including the good
manufacturing practices (GMP) regulation to ensure continued quality
control; and (3) operating a postmarketing surveillance (PMS) system
to gather information about problems that could necessitate
withdrawing a device from the market or taking other actions.\3
The Office of Device Evaluation within FDA's Center for Devices and
Radiological Health is responsible for the evaluation of medical
device applications. During fiscal year 1994, the Office of Device
Evaluation received 16,905 submissions for review, of which it
classified 10,293 as major submissions.
The 1976 amendments established a three-part classification system
for devices, based on the device's level of risk and the extent of
control necessary to ensure the safety and effectiveness of the
device. Most medical devices are Class I or Class II (low and medium
risk) and reach the market through FDA's premarket notification--or
510(k)--process.\4 Under its 510(k) authority, FDA may grant
clearance for the marketing of devices if it determines that they are
substantially equivalent to certain devices already on the
market--called predicate devices. Once FDA has made that
determination, a manufacturer can begin to market the new device.
High-risk, or Class III, devices enter the market through the
premarket approval (PMA) process.\5 A PMA review is more stringent
and typically longer than a 510(k) review. If a manufacturer needs
to test a new device in human subjects before applying for marketing
approval or clearance, and if the device presents a significant
health risk to subjects, the manufacturer applies to FDA for an
Investigational Device Exemption (IDE) to allow use of the device in
clinical studies. See appendix II for a more detailed discussion of
FDA's review processes.
The U.S. medical device industry values FDA's "stamp of approval"
but has leveled several criticisms against FDA. The industry
contends that FDA takes too long to review applications and that
review time increased drastically in the early 1990s. Manufacturers
maintain that FDA's review process is unpredictable and burdensome,
particularly with regard to the amount and types of data they must
submit. Additionally, the industry has stated that FDA is not always
reasonable when it requires randomized human clinical trials to
demonstrate that a device is safe and effective.\6
--------------------
\3 The GMP regulation, promulgated under section 520 of the FFD&C
Act, requires that domestic or foreign manufacturers of medical
devices intended for commercial distribution in the United States
have a quality assurance program. The regulation requires that
various specifications and controls be established for devices and
that finished devices meet these specifications. The PMS system
under the Safe Medical Devices Act of 1990 requires manufacturers,
distributors, and user facilities to submit medical device reports to
FDA whenever a device has caused or contributed to serious adverse
incidents. In addition, manufacturers are required to conduct
studies to gather data on the safety and effectiveness of certain
devices designated by FDA.
\4 Premarket notification is commonly called 510(k) in reference to
section 510(k) of the FFD&C Act.
\5 A PMA is a premarket approval application for a Class III medical
device. Another type of application is the PMA supplement, an
abbreviated application made subsequent to an approved PMA for
approval of a change or modification in a Class III medical device.
\6 The medical device industry was also critical of the Health Care
Financing Administration's (HCFA) policy of refusing to allow
Medicare coverage for certain procedures and devices undergoing
clinical trials. In September 1995, HCFA announced that it would
modify this policy and that FDA would assist in identifying
nonexperimental investigational devices for which the underlying
questions of safety and effectiveness have been resolved, and that
therefore may be eligible for Medicare reimbursement.
EUROPEAN UNION
---------------------------------------------------------- Letter :2.2
In 1990, the EU began to adopt a series of three directives to
regulate the safety and marketing of medical devices throughout the
EU. The directives specify roles in the device regulatory system for
the European Commission;\7 the governments of member states; and
review and approval organizations called notified bodies, which are
often private entities. When this system is fully in place in
several years, every medical device marketed in the EU will have to
carry a "CE" mark, indicating that it meets common standards of
performance and safety, known as essential requirements.\8 Devices
carrying the CE mark can be marketed throughout the EU.
The first EU directive, for active implantable devices, covers
powered devices that remain in the human body, such as heart
pacemakers. It first took effect on January 1, 1993. During a
2-year transitional period, member states could continue to implement
their national laws governing these devices, and manufacturers had
the choice of either seeking approval to market a device in
individual countries under each country's laws or following the
procedures that would allow the device to carry the CE mark and be
marketed throughout the EU. As of January 1, 1995, all active
implantable devices were subject to the new EU system alone.
The second directive, known as the Medical Devices Directive (MDD),
covers most other medical devices, ranging from bandages to hip
prostheses. The MDD took effect on January 1, 1995, and its
transitional period will last until June 13, 1998. The third
directive, covering in vitro diagnostic medical devices, such as
blood grouping reagents and pregnancy test kits, is under development
and will not take effect until at least 1998.
--------------------
\7 The European Commission is the executive branch of the EU and has
22 Directorates General to carry out EU legislation. Additionally,
the Commission has exclusive authority to initiate EU legislation,
which must be approved by the European Council (the principal
law-making body) and often the EU Parliament.
\8 Custom-made medical devices and devices intended for
investigational use are not required to carry the CE mark but do have
to meet the essential requirements for safety.
DEVICE REVIEW HAS DIFFERENT
GOALS IN UNITED STATES AND
EUROPEAN UNION
------------------------------------------------------------ Letter :3
The U.S. and EU medical device regulatory systems share the goal of
protecting public health, but the EU system has the additional goal
of facilitating EU-wide trade. Another distinction between the two
systems pertains to the criteria for reviewing devices. Devices
marketed in the EU are reviewed for safety and performing as the
manufacturer intended; devices marketed in the United States are
reviewed for safety and effectiveness. Effectiveness includes the
additional standard of providing benefit to patients.
EU SYSTEM INTENDED TO
PROMOTE TRADE AND PUBLIC
HEALTH
---------------------------------------------------------- Letter :3.1
One goal of the EU medical device review system is to lower trade
barriers and achieve a single market throughout the EU by harmonizing
member states' regulatory controls. At the EU level, the Directorate
General for Industry is responsible for implementing the medical
device directives. The directives specify that a member state may
not create obstacles to the marketing of a CE-marked device within
its territory.
The other goal of the EU system is to protect public health. Medical
devices that circulate in the EU must meet the medical device
directives' essential requirements, the first one being that devices
will not compromise the health and safety of patients. The
responsibility for enforcing the national regulations that implement
the directives in the member states lies with each country's
Department of Health. Before the inception of the EU system, the
level of regulation in member states varied widely, and in some
countries most medical devices were not regulated at all. Therefore,
although the system was created within the context of encouraging
trade, in many European countries the directives will increase the
level of medical device safety regulation.
The U.S. medical device regulatory system exists within a public
health context. FDA's mandate is to ensure that devices that reach
the public are safe and effective. The agency has limited statutory
responsibility to promote trade.\9
--------------------
\9 The Office of International Relations in FDA was established by
statute in 1990 to facilitate commerce by, for example, encouraging
mutual recognition of good manufacturing practices, testing
protocols, and other regulations. FDA has a Division of Small
Manufacturers Assistance, as mandated by the 1976 Medical Device
Amendments, to provide technical assistance and regulatory guidance
to manufacturers to help them comply with FDA requirements for
medical devices. Additionally, the Secretary of Health and Human
Services, in establishing effective dates for medical device
performance standards, must attempt to minimize losses to domestic
and international trade.
DEVICES MUST MEET DIFFERENT
CRITERIA IN EUROPEAN UNION
AND UNITED STATES
---------------------------------------------------------- Letter :3.2
Devices marketed in the EU under the new regulatory system must
conform to the essential requirements contained in the applicable
medical device directive.\10 Because the directives cover a wide
range of products, the essential requirements provide broad targets
for manufacturers to meet. The essential requirements are divided
into two sections. First, the general requirements state that
devices must be designed and manufactured in a way that will not
compromise patient health and safety and that devices must perform as
the manufacturer intended. Second, the design and construction
requirements cover topics such as chemical, physical, and biological
properties; labeling; radiation safety; and accuracy of measuring
functions.
The EU system relies greatly on recognized performance standards,
which can be international, European, or national.\11 Demonstrating
that a device meets such standards is voluntary, but this is an
acceptable--and often convenient--way to demonstrate that a device
complies with the essential requirements.\12
In reviewing medical device applications FDA uses the two criteria
mandated by law--safety and effectiveness. For devices entering the
market through the 510(k) route, the manufacturer must demonstrate
comparative safety and effectiveness, that is, the new device is as
safe and effective as the legally marketed predicate device. In
evaluating the safety and effectiveness of a Class III device through
the PMA route, FDA must determine that the application demonstrates a
reasonable assurance that the device is safe and effective.
To satisfy the effectiveness requirement, a device must provide
beneficial therapeutic results in a significant portion of the target
patient population.\13 The U.S. criterion of effectiveness
encompasses more than the European criterion of performing as the
manufacturer intended; it requires the device to benefit certain
patients. For example, to market an excimer laser in the United
States, the manufacturer must demonstrate not only that the laser can
cut tissue from the patient's cornea, but also that the laser
procedure lessens or eliminates the patient's nearsightedness. In
the EU, if the manufacturer specified that the purpose of the device
was to eliminate a patient's nearsightedness, it would have to
demonstrate the validity of that claim. However, if the claim was
restricted to the device's ability to remove tissue in a particular
way, judgment of the appropriate use of the device would be left to
clinicians.
In evaluating effectiveness, FDA generally reviews an individual
device on its own merits. In certain situations, however, reviewers
consider whether a new device is potentially less effective than
available alternative therapies. FDA's position is that the agency
evaluates comparative effectiveness only when a less effective device
could present a danger to the public, that is, when a device is
designed to treat a disease that (1) is either life-threatening or
capable of causing irreversible morbidity, or (2) is a contagious
illness that poses serious consequences to the health of others.
--------------------
\10 Medical device regulation in the EU follows the approach to
harmonized regulation that the EU is applying in many different
regulatory arenas for a variety of products. The strategy is to
achieve harmonization through essential requirements that are both
general and mandatory, and that are complemented by European
standards that are both detailed and voluntary. See Linda R.
Horton, "Medical Device Regulation in the European Union," Food and
Drug Law Journal, Vol. 50 (1995), pp. 461-476.
\11 There are three levels of performance standards. Level I are
global, or horizontal, standards, which are common to all medical
devices and relate to broad dimensions like electromagnetic
compatibility and sterilization processes. Level II, or vertical,
standards apply to a family of devices, such as all implantables (for
example, pacemakers and artificial joints), and relate to subjects
like materials and toxicity. Level III standards are
product-specific (for example, for heart valves). For additional
information on standards, see Medical Technology: Quality Assurance
Systems and Global Markets (GAO/PEMD-93-15, Aug. 18, 1993), pp.
27-28.
\12 The European Commission has mandated European standards
organizations, such as the European Committee for Standardization
(CEN), to prepare harmonized European standards for medical devices
that will enable manufacturers to show that their products comply
with the essential requirements. A European Commission official told
us that the Commission expects to develop 250 standards within a few
years. Manufacturers may use national or international standards
when there is no European standard.
\13 Effectiveness means the same thing in the 510(k) and PMA
processes, but is largely presumed for 510(k)s and must be proven for
PMAs.
UNITED STATES AND EU REVIEW
SYSTEMS STRUCTURED DIFFERENTLY
------------------------------------------------------------ Letter :4
The EU gives major regulatory responsibilities to public and private
bodies; in contrast FDA has sole responsibility in the United States.
Both systems link the level of medical device review to the degree of
control needed to ensure device safety. However, the two systems use
different procedures to reach approval or clearance decisions.
PUBLIC AGENCIES AND PRIVATE
NOTIFIED BODIES HAVE ROLES
IN EU DEVICE REGULATION
---------------------------------------------------------- Letter :4.1
Governmental and private organizations both perform major functions
in the EU system for regulating medical devices. Each member state
designates a competent authority, usually in the Department of
Health, which is responsible for implementing and enforcing the
medical device directives in that country.\14 The competent authority
ensures that the directives are incorporated into national law,
approves clinical investigations of devices, and operates the
country's reporting system for adverse incidents. Additionally, the
medical device directives contain a safeguard clause. This clause
gives the competent authority the power to withdraw an unsafe device
from the market; the competent authority can be overruled by the
European Commission after consultation among all of the parties
concerned. (See app. III for a more detailed discussion of the
safeguard clause.) The competent authority also serves as the
country's liaison with the European Commission and other member
states.
One of the most important responsibilities of the competent authority
is to designate and certify the notified bodies located in that
country. NBs are the organizations that perform conformity
assessments on medical devices of medium or high risk that require
the intervention of an independent organization prior to CE marking.
The NBs determine whether a device conforms to the essential
requirements in the relevant medical device directive. If the device
is judged to be in conformance, the manufacturer may then place the
CE mark on the product and market it throughout the European Union.
NBs may be governmental or private entities, but most are private.
In making their NB designations, competent authorities consider
whether organizations meet the criteria for NBs contained in the
medical device directives. These criteria include standards of
competence, impartiality, and confidentiality. Competent authorities
may periodically audit NBs and can withdraw NB status from an
organization that does not continue to meet the criteria.
The competent authority certifies that an NB is qualified to evaluate
certain types of devices and to perform specific conformity
assessment procedures. Some NBs have a limited certification; for
example, they can evaluate only active medical devices or can perform
only certain types of quality assurance reviews. Others are
qualified to evaluate almost the full range of devices. If an NB is
not competent to perform an assessment procedure that a device
requires, it can subcontract with another NB or with another
organization, such as a testing laboratory, to perform that part of
the assessment.
A manufacturer may select an NB located in any member state to assess
its device. This is a contractual relationship, with the
manufacturer paying a fee for the NB's services. As of October 1995,
there were 40 NBs throughout the EU. Germany and the UK had the
largest number, 16 and 8, respectively. Representatives of European
industry groups and public and private officials in the UK and
Germany told us that manufacturers consider several factors when
selecting an NB. These include the NB's expertise and experience
with specific devices and assessment procedures, language, cost, and
whether the manufacturer has worked with the NB previously.
--------------------
\14 The structure of Germany's competent authority is different from
that of other countries because the central government has delegated
some medical device functions to the 16 state governments, or
Bundesl�nder. As a result, the Ministry of Health and agencies at
the state level share responsibilities that in other countries are
generally performed by only one central agency.
FDA REGULATES DEVICES IN THE
UNITED STATES
---------------------------------------------------------- Letter :4.2
In the United States, regulatory responsibilities rest with one
government body--FDA. Currently, however, FDA is creating a pilot
program to test the use of private third parties to review low- to
moderate-risk devices requiring 510(k) clearance. The agency will
individually review and accept third-party review organizations
interested in participating in the pilot. After completing a device
review, the third party will make a clearance recommendation to FDA.
In contrast with the role of European NBs, the private reviewers
participating in FDA's pilot program will not have authority to make
clearance decisions. FDA will retain that authority and will base
its decision on the third party's documented review.
Manufacturers' participation in the pilot will be voluntary; they may
continue to opt for FDA review. Applicants that must submit clinical
data on their devices will not be able to select third-party review;
FDA has prepared a preliminary list of devices that may be included
in the pilot. FDA expects that applicants that do participate will
pay a fee directly to the third party to conduct the review.\15 The
pilot is scheduled to begin in mid-1996 and will operate for 2 years;
during the second year FDA plans to evaluate the feasibility of using
third parties to conduct timely and high-quality reviews of devices.
--------------------
\15 FDA does not expect to take part in determining these fees. Fees
will be negotiated between the third party and the applicant.
BOTH SYSTEMS LINK LEVEL OF
REVIEW TO DEVICE RISK
---------------------------------------------------------- Letter :4.3
Like the United States, the EU has a risk-based device classification
system. The EU has four categories, however, instead of three. The
manufacturer determines the appropriate class for a new device, based
on classification rules in the directives. The manufacturer may also
consult with the NB reviewing the device.\16 In the United States,
the manufacturer makes a claim regarding which class a device belongs
in when it submits an application for FDA review. FDA, however, has
final authority over the classification decision. (See app. III for
a more detailed discussion of the EU classification system and app.
II for a more detailed discussion of the FDA classification system.)
Just as every device released in the United States must demonstrate
safety and effectiveness, every device in the EU, no matter what its
class, must comply with the essential requirements. In both systems,
the purpose of classifying devices is to dictate the level of control
the system exerts to ensure that devices comply with the respective
requirements.\17
The EU directives set out a complex array of assessment procedures
that manufacturers must follow to demonstrate that a device conforms
to the essential requirements. A device's class determines the type
of conformity assessment review the device must undergo, but the
manufacturer is usually permitted to choose an assessment route from
at least two options--often involving two general approaches. One
approach is a review of the full quality assurance (QA) system that
governs every phase of the manufacture of a device, from design
through shipping.\18 Officials of a German NB told us that one goal
of a full QA review is to ensure that the manufacturer has written
quality control procedures for every one of these phases and that
these procedures are followed.\19 NB reviewers conduct on-site
inspections as part of this process.
The other approach consists of two components. The first is a
procedure called a type examination, in which the NB physically tests
a prototype of the device to determine if it meets certain standards.
The type examination component is paired with a limited QA review
focused only on the production phase of manufacture. This review is
intended to ensure the consistency of product quality. We refer to
this overall approach as the type examination route. Appendix III
contains a more detailed description of the different routes of
conformity assessment and the assessment requirements for different
device classes.
The EU system includes both of these device approval routes as a
compromise between member states that tended to rely on one approach
or the other. For example, in the UK a voluntary oversight system
had emphasized full QA system review, while the type examination
approach had prevailed in Germany's regulatory system.
Both the EU and U.S. systems minimize oversight for the devices
considered least risky. For EU Class I devices that do not involve a
measuring function or sterile products, manufacturers may simply
furnish a declaration that the device conforms to the essential
requirements and maintain technical documentation that would permit
review of the device. There is no NB review, but the manufacturer
must register such devices with the competent authority in the
country of the manufacturer's place of business. In the United
States, FDA exempts selected low-risk devices from premarket
notification requirements. Manufacturers must still register their
devices with FDA and must comply with GMP rules.
Most new U.S. devices fall into Class I or Class II and are
evaluated for substantial equivalence to devices already on the
market. FDA determines whether a device has the same intended use
and same technological characteristics as a predicate device by
reviewing a 510(k) application submission. If a new device has the
same intended use and technological characteristics, FDA deems it
substantially equivalent to a predicate device and allows the device
to be marketed. Also, if a device has new technological
characteristics and FDA determines that they do not raise different
questions of safety or effectiveness, FDA will find the device to be
substantially equivalent. If the device has new technological
characteristics and raises different questions of safety and
effectiveness, the device will be found not substantially equivalent.
The manufacturer can then seek approval for it through the premarket
approval process.
FDA requires a PMA review for most Class III devices. This is a more
rigorous review because of the device's inherent high risk or lack of
established safety and effectiveness information. A
multidisciplinary staff at FDA evaluates the PMA application.
Nonclinical studies that the team reviews may include
microbiological, toxicological, immunological, biocompatibility,
engineering (for example, stress, wear, fatigue), and other
laboratory or animal tests as appropriate. The team also reviews the
results of any clinical investigations involving human subjects.
Generally, FDA evaluates a manufacturer's tests and does not perform
its own tests on products. For a small portion of PMA reviews, FDA
reviewers seek advice from an advisory panel of clinical scientists
in specific medical specialties and representatives of industry and
consumer groups.\20
U.S. device manufacturers have expressed concern that FDA asks them
to submit an excessive amount of data during the 510(k) review
process. The director of FDA's Office of Device Evaluation told us
that FDA requires only what is necessary to establish that a device
is as safe and effective as its predicate. She also told us that FDA
has chosen to interpret the 510(k) requirements so that more devices
can go through that review process rather than the longer PMA
process. As a result, the agency needs enough data to demonstrate
that those 510(k) devices meet the standard of substantial
equivalence and do not raise new concerns regarding safety and
effectiveness.
--------------------
\16 If the NB does not agree with the manufacturer's interpretation
of the medical device directive, it will present to the competent
authority the manufacturer's reasons for believing its device belongs
in a different class. The competent authority can then make a
decision regarding the correct device classification. The competent
authority can, if necessary, ask the European Commission for a
ruling. The European Commission would act in conjunction with a
committee composed of experts from the member states.
\17 Individual devices or device categories may not be subject to the
same level of control in the U.S. and EU systems.
\18 A manufacturer choosing the full QA system route for a Class III
device is also required to submit a design dossier for the NB's
review. The dossier may include specifications and performance data
of the product as claimed; risk analysis, including risk control
methods; electrical/mechanical/chemical constructional data,
including drawings; design verification documents; and, when
relevant, clinical investigation data.
\19 The phases involved in producing a new device for the market
include a feasibility phase; the design phase, which results in a
written definition of the device; design verification, which involves
creating prototypes; mass production; and full market release. At
each of these phases the manufacturer must ensure that it has defined
the requirements for completing that phase and that the "deliverable"
for that phase--be it a product design or a packaged device--is
verified by qualified staff.
\20 FDA requests panel involvement when (1) it does not have the
knowledge or experience to properly evaluate safety and
effectiveness, (2) the specific PMA raises a new issue best addressed
by the experience of the panel, or (3) the data establishing the
clinical performance of the device reveal unanticipated safety and
effectiveness questions.
EU QUALITY ASSURANCE
APPROACH DOES NOT EXAMINE
INDIVIDUAL DEVICES
---------------------------------------------------------- Letter :4.4
When an NB certifies a manufacturer's full QA system, the
manufacturer may be able to attach the CE mark to several related
products. The philosophy behind this approach is that if a company
has a good design and manufacturing system, the devices it produces
will be safe and perform as the manufacturer claims. Therefore, the
full QA assessment route does not require the NB to conduct
individual reviews of related devices that are produced under the
same QA system, although the NB can do so when the situation warrants
it. The certification covers the related devices, allowing the
manufacturer to market all of them without going through an
additional conformity assessment. Representatives of a British
industry group told us that the QA approach makes it possible to
continually monitor a company without testing individual items that
may not be representative of the overall quality of production.
Officials who work in the EU system told us that they expect
manufacturers to choose the full QA route to conformity assessment
more frequently than the type examination route. This route can be
particularly advantageous for larger companies. The officials
believe the type examination route is more likely to appeal to
smaller companies that do not produce many product lines or a company
that wants to get a particular device to market before it has time to
put a full QA system in place.
The kinds of standards manufacturers must meet during European QA
reviews are similar to the GMP requirements in the U.S. system.
(See app. II for additional information about GMP requirements.)
However, in contrast to the ability of a full QA review to stand
alone as a conformity assessment route for some devices in the EU,
FDA never bases a 510(k) clearance or PMA approval decision solely on
a GMP inspection.
USE OF CLINICAL TRIALS MAY
EXPAND UNDER EU DIRECTIVES
---------------------------------------------------------- Letter :4.5
Some U.S. medical device manufacturers have raised concerns that FDA
sometimes asks that a new medical device be tested in a clinical
trial when the manufacturers believe that approach is inappropriate
and unwarranted. They have also asserted that clinical trials can be
performed more quickly in Europe.
European officials told us that prior to the issuance of the EU
medical device directives, Europe had very few requirements for
clinical investigations. Under the new system, manufacturers may be
required to provide clinical evidence that a device meets the
essential requirements for safety; this evidence may come from either
published scientific literature on similar devices or data from a
clinical trial on the device under consideration. Implementation of
the EU medical device directives may result in clinical trials being
required more frequently than they had been in the past.
Officials from a German NB discussed with us circumstances under
which they would be likely to need data from a clinical trial to
evaluate a new device under the EU directives. If the device uses an
accepted technology to treat a medical indication for which use of
that technology is also accepted, a clinical trial would not be
necessary. If both the technology and the application are novel,
however, they said they would require a clinical trial. In
situations where there is a mix of novel and approved device
technology and medical indication, they would need to make a judgment
call. They said that regardless of whether a clinical trial is
necessary, clinical data, based on either previous clinical trials,
scientific literature, or field experience, would have to be
provided.
Although it is unclear how frequently European reviewers will ask
manufacturers to perform clinical trials, FDA officials believe that
clinical trials are often needed to establish the safety and
effectiveness of devices undergoing PMA review. According to FDA,
fewer than 10 percent of the medical device products FDA reviews
under the 510(k) process require clinical trials. When FDA does
require a clinical trial during a 510(k) review, the agency is
looking for clinical confirmation that a device is as safe and
effective as the legally marketed predicate device.
NOTIFIED BODIES' INDEPENDENCE
COMPLICATED BY DUAL ROLES
------------------------------------------------------------ Letter :5
NBs carry out a regulatory function within the EU's medical device
system, but the manufacturers whose devices they review are also
their clients. This raises questions about the independence of the
NBs. Additionally, NB employees are subject to less comprehensive
conflict-of-interest rules than are FDA device reviewers.
NOTIFIED BODIES HAVE CLIENT
RELATIONSHIP WITH SUBJECTS
OF REVIEW
---------------------------------------------------------- Letter :5.1
Unlike FDA, an NB is in the complicated position of both performing a
public health function--and in that capacity having to answer to a
governmental competent authority--and having a client relationship
with the manufacturer that has hired it to review a device. NBs have
a duty to ensure that medical devices that carry the CE mark conform
to the EU medical device directives' essential requirements regarding
safety and performance. At the same time, however, they are in
competition with each other to secure the business of manufacturers
seeking assessment services.
The businesses of some NBs include consulting work as well as product
reviews, which can further complicate their independence. The
director of the UK competent authority told us that if an
organization has a consulting arm, his agency checks to see if the
consulting function is kept separate from the conformity assessment
function. Only then can it be designated as an NB. An EU official
told us that he believes the European Commission needs to address
this problem of potential conflict of interest for NBs.
EU REVIEWERS SUBJECT TO LESS
COMPREHENSIVE
CONFLICT-OF-INTEREST RULES
THAN FDA REVIEWERS
---------------------------------------------------------- Letter :5.2
The EU medical device directives require the staff of NBs to be free
of all pressures and inducements, particularly financial, that might
influence their judgment or the results of their reviews, especially
from anyone with an interest in the outcome of the review. To meet
this requirement, NBs and their personnel must comply with European
standards governing potential conflicts of interest.\21 These
standards are very general. Essentially, they (1) prohibit anyone
involved in product testing or accreditation from having a
commercial, financial, or other interest that could affect their
judgment; and (2) attempt to shield laboratory and certification
personnel from control by anyone with a direct financial interest in
the outcomes of testing and accreditation. Key terms in the
standards, such as control, direct, commercial interest, and
financial interest, are not defined.
Officials of NBs we visited told us that their employees are bound by
international standards and that they must disclose potential
conflicts of interest in connection with their assignments. One
official told us that as an internal control, the staff who conduct
the periodic follow-up surveillance reviews of manufacturers after
the initial certification of a product or QA system are different
from those who conducted the initial review.
FDA employees are subject to a more comprehensive set of rules than
are NB personnel. FDA rules include a substantial list of general
rules that encompass all the goals and prohibitions included in the
EU rules. In addition, they include supplemental guidance on
specific matters that could present conflicts of interest, for
example, outside employment, stock ownership, gifts, entertainment,
filing responsibilities, and political activity. The EU rules are
silent on how the general rules might apply in these situations.
--------------------
\21 Criteria governing these personnel are in the EN 45000 series of
European standards.
INFORMATION NOT AVAILABLE TO
COMPARE OUTCOMES OF NEW EU
SYSTEM AND A CHANGING FDA
------------------------------------------------------------ Letter :6
The EU medical device system is new and not yet fully operational.
Although FDA's system has been in place for almost 2 decades, the
agency's process is in flux as managers try to respond to criticism
by experimenting with streamlined procedures. It is too early to
evaluate the impact of those efforts on the length of FDA's review
process. At this time there are no data on the experience of the EU
device review system that permit meaningful comparison with FDA.
EU DEVICE REVIEW SYSTEM NEW
AND STILL EVOLVING
---------------------------------------------------------- Letter :6.1
In contrast to FDA's almost 20 years of experience in carrying out
the U.S. device review program, implementation of the EU system is
quite new. The only medical device directive that is fully in effect
is the one for active implantable devices. The transition period for
the directive that covers most devices began just 1 year ago.
The system is not yet fully in operation. For example, each
competent authority is supposed to establish a system for
manufacturers to report adverse incidents with devices; eventually
all of these national systems will be electronically linked. The UK
already had an extensive voluntary system in place that it can build
on, but most countries have barely begun to develop their systems. A
UK official told us it will probably be a few years before an EU-wide
system is in place. In the meantime officials are communicating by
fax and letter when they identify problems.
It is too early to know how some aspects of the EU system will
translate from the directives into a practical working system. For
example, the various competent authorities are bound by the same
criteria when designating NBs, and the various NBs--both within and
across individual member states--are all supposed to use the same
criteria to perform conformity assessments. At present there is no
way to measure whether that consistency is occurring in practice.
European officials told us that experience levels among the competent
authorities and NBs vary. For example, in countries that previously
had a regulatory program in place, such as the UK and Germany, the
competent authorities already had experience carrying out some of the
functions the EU system requires of them. Similarly, some NBs have
long histories of evaluating medical devices or QA systems, while
others have considerably less experience. Even well-established NBs
may have greater experience with particular conformity assessment
routes or device categories. For example, NBs in the UK tend to have
extensive experience performing full QA system reviews and some
German NBs have extensive experience with product testing.
RESULTS OF FDA INITIATIVES
TO REDUCE REVIEW TIME NOT
YET CLEAR
---------------------------------------------------------- Letter :6.2
Medical device manufacturers in the United States have charged that
FDA takes too long to approve new medical devices and have asserted
that the review process in Europe is faster. In response to
criticism about the length of its device review process, FDA is
attempting to better manage and streamline its system by
experimenting with different review procedures. Agency officials
believe these initiatives have reduced review time, but it is too
early to evaluate their impact.
FDA's management actions include the May 1994 implementation of a
three-tier system of review to improve management of its workload and
better link the rigor of review with a device's level of risk. In
addition, since December 1994, FDA has exempted close to 300
additional medical devices from premarket notification requirements
and moved other devices into lower classification categories in an
effort to concentrate on riskier products and reduce the regulatory
burden on manufacturers.
FDA is also experimenting with an expedited review process for
life-sustaining and life-saving devices under which selected
applications move to the front of the review queue. At least 40
devices had been reviewed under this process as of July 1995.
Additionally, FDA is refusing to accept deficient or poorly prepared
applications until manufacturers provide the information needed for
review.
We recently analyzed patterns in review time for FDA device
applications submitted from October 1988 to May 1995.\22 Review times
for 510(k) applications and PMA supplements submitted in 1994 were
still higher than they were in 1990 but had decreased from 1993
levels. The trend for original PMAs was less clear, in part because
FDA has not yet completed the review of a large portion of those
applications.
--------------------
\22 See Medical Devices: FDA Review Time (GAO/PEMD-96-2, Oct. 30,
1995).
NO COMPARABLE DATA ON LENGTH
OF EU REVIEW PROCESS
---------------------------------------------------------- Letter :6.3
The EU does not have data on the length of its review process that
can be compared with the data available about FDA's experience. The
EU system has been in effect for only a short time. Anecdotal
information suggests review time may be shorter in the EU, but
differences between the systems make it difficult to find comparable
benchmarks. For example, NBs may have extensive interaction with
manufacturers before the review process formally begins, and they
sometimes perform preliminary reviews before beginning the official
conformity assessment. This could make it difficult to identify the
date on which the NB's review begins. For similar reasons of lack of
comparable data, it is also difficult to compare FDA's record with
the experience of individual European countries prior to initiation
of the EU-wide system.
CONCLUSIONS
------------------------------------------------------------ Letter :7
The EU system for regulating medical devices is not only new--it is
not yet fully in place. Therefore, it is too early to evaluate its
success in ensuring the safety of medical devices and bringing them
to market in an efficient manner. Because the major actors in the EU
system have not had sufficient time to establish a record on how they
will carry out their duties, it will be some time before information
is available to answer the following questions:
How strictly will competent authorities oversee NBs, for example,
will competent authorities rescind certifications of NBs if
warranted?
Will the performance of all competent authorities and NBs be of
equal quality, and therefore, will public health authorities and
consumers be able to have the same level of confidence in
devices no matter where they are reviewed?
Will the full QA system and type examination conformity assessment
routes both prove to be appropriate ways to regulate devices?
Will NBs maintain the necessary degree of independence from
manufacturers who are their clients?
How will NBs implement requirements for clinical evidence on new
devices?
Will an adequate postmarket surveillance system be developed?
U.S. government officials who want to consider integrating features
of the EU approach into the U.S. device review system will be better
able to assess the value of the EU system after it accumulates
several years of experience. The U.S. medical device industry has
advocated giving private third parties a role in the review of
medical devices, and FDA is exploring this possibility in a pilot
project. Ensuring that private reviewers have the necessary
independence, requisite expertise, and sufficient resources would
enhance the confidence of the Congress and the American public in the
integrity of the device review process. The importance of this
assurance would increase if private review organizations were given
the added authority of clearing new devices for marketing.
AGENCY COMMENTS
------------------------------------------------------------ Letter :8
FDA and European officials reviewed a draft of this report. FDA's
written comments are reproduced in appendix IV. FDA generally found
the report to be accurate and complete and made a number of technical
comments clarifying aspects of the agency's review processes. We
incorporated these as appropriate, basing the changes in some
instances on further discussions with FDA officials. We also
incorporated technical clarifications on the EU system received from
European officials.
In its comments, FDA stated that the EU system does not evaluate
individual devices, but instead evaluates a manufacturer's quality
assurance system. As we noted in the draft report, in some
situations the EU system does evaluate individual devices, such as
when a manufacturer chooses the type examination route of conformity
assessment or when a Class III device's design dossier is reviewed.
---------------------------------------------------------- Letter :8.1
We will distribute this report to the Secretary of Health and Human
Services, the Commissioner of the Food and Drug Administration, and
other interested parties.
This report was prepared under the direction of Mark V. Nadel,
Associate Director for National and Public Health Issues. If you or
your staff have any questions, please call me at (202) 512-7119 or
Bruce D. Layton, Assistant Director, at (202) 512-6837. Other major
contributors to this report include Helene F. Toiv, Claude B.
Hayeck, Mary W. Freeman, Michele Grgich, and Liv Gorla.
Sincerely yours,
Sarah F. Jaggar
Director, Health Financing and
Public Health Issues
SCOPE AND METHODOLOGY
=========================================================== Appendix I
For our review of the European Union's medical device approval
process, we conducted field work in Germany and the United Kingdom.
These countries were ahead of most other member states in adopting
the EU regulatory system into their national laws and had greater
experience with implementing the new system. Additionally, over half
of the notified bodies, which review and approve medical devices
under the EU system, were located in these two countries.
In Germany and the UK we interviewed government health officials
responsible for medical device regulation; officials from two NBs,
T�V Product Service and the British Standards Institution; and
representatives of medical device industry groups. We also
interviewed EU officials and a representative of an EU-wide industry
association. We reviewed EU documents governing the EU regulatory
process. Several officials we interviewed reviewed a draft of this
report.
We reviewed Food and Drug Administration documents and policies as
well as laws and regulations governing FDA. In addition, we
interviewed officials from FDA's Center for Devices and Radiological
Health.
We talked with representatives of the U.S. medical device industry,
including the Health Industry Manufacturers Association, the National
Electrical Manufacturers Association, and the Medical Device
Manufacturers Association, as well as representatives of individual
device companies. We also reviewed position papers of several
industry groups. We interviewed representatives of organizations
with expertise on product review and certification, including
officials from the U.S. Department of Commerce; Underwriters
Laboratories Inc.; the American National Standards Institute; and the
Emergency Care Research Institute.
We conducted our review from March through December 1995 in
accordance with generally accepted government auditing standards.
DESCRIPTION OF SELECTED ASPECTS OF
FDA PROCESSES FOR REGULATING
MEDICAL DEVICES
========================================================== Appendix II
This appendix provides additional information about several features
of the U.S. system for regulating medical devices and FDA review
procedures.
The process of bringing a new medical device to market takes one of
two routes--premarket notification or premarket approval. Most new
devices are variations of already marketed devices, are classified as
low to moderate risk, and reach the market through FDA's premarket
notification--or 510(k)--review process. During the 510(k) review,
FDA judges whether a device is substantially equivalent to one
already on the market. The premarket approval (PMA) process is
reserved for high-risk devices. PMAs and PMA supplements require a
more stringent FDA review, which may include the analysis of clinical
data to provide a reasonable assurance of safety and effectiveness.
In addition, manufacturers must comply with certain postmarket
requirements such as reporting of certain device-related adverse
events. In fiscal year 1994, FDA's Office of Device Evaluation
received 6,434 510(k) applications and 415 PMAs and PMA
supplements.\23
--------------------
\23 In addition, this office received about 10,000 other submissions
for review. They include Investigational Device Exemption
applications, PMA amendments, and 510(k) and IDE supplements.
DEVICE CLASSES
-------------------------------------------------------- Appendix II:1
Medical devices are grouped into three classes according to (1) the
degree of potential risk and (2) the types of regulatory control
needed to reasonably ensure their safety and effectiveness. Class I
devices (for example, bedpans and tongue depressors) are those for
which general controls provide reasonable assurances of safety and
effectiveness. Class II devices (for example, syringes and hearing
aids) require special controls in addition to general controls.
Class III devices (for example, heart valves and pacemakers) are
subject to general controls and must undergo more rigorous scientific
review and approval by FDA as well.
General controls include registering device manufacturing facilities,
providing FDA with regularly updated lists of marketed devices,
complying with good manufacturing practices, and maintaining records
and filing reports of device-related injuries and malfunctions. The
Safe Medical Devices Act of 1990 (SMDA 90) revised the requirements
for Class II devices, subjecting them to both general and special
controls.\24 Special controls include performance standards,
postmarketing surveillance, patient registries, and other controls as
deemed necessary. Class III devices are subject to the PMA process,
which requires the manufacturer to present evidence, often including
extensive clinical data, that there is a reasonable assurance that a
device is safe and effective before placing it on the market.
--------------------
\24 Prior to SMDA 90, Class II devices were to be regulated by
performance standards encompassed by FDA regulations. FDA has not
implemented performance standards for these devices, with the
exception of a number of devices that are radiation-emitting
electronic products under the radiological health provisions of the
Federal Food, Drug, and Cosmetic Act.
TRIAGE
-------------------------------------------------------- Appendix II:2
To help assess the appropriate level of review for devices, the
Center for Devices and Radiological Health in May 1994 introduced a
three-level "triage" system that, within the existing classification
system, assigns priorities for application review based upon the
complexity and risk of the device. A tier I review is essentially a
labeling review to ensure that the label correctly identifies the
intended use of the device. Most Class I devices fall within tier I
because a less rigorous scientific evaluation of these low-risk
devices does not adversely affect the public health. A tier II
review is a scientific and labeling review. This tier encompasses
the majority of 510(k)s and select PMA supplements. A tier III
review is an intensive scientific and labeling review, using a team
review approach for devices utilizing new technology or having new
intended uses. FDA convenes an advisory panel when it lacks the
expertise to address questions of safety and effectiveness for
devices placed in tier III or when it is otherwise appropriate to
obtain advice on scientific matters.
PREMARKET NOTIFICATION--510(K)S
-------------------------------------------------------- Appendix II:3
Most new medical devices incorporate incremental changes to devices
already on the market. To clear these devices for marketing, FDA
determines whether they are substantially equivalent to (that is, as
safe and effective as) legally marketed predicate devices.\25
Substantial equivalence means that a device has (1) the same intended
use and same technological characteristics as the marketed device or
(2) the same intended use and different technological
characteristics--but is as safe and effective as the marketed device
and does not raise different questions of safety and effectiveness.
FDA initially determines whether a 510(k) submission is sufficiently
complete before undertaking a substantive review.\26
During the review, FDA determines the intended use of a device by
examining the manufacturer's proposed label statements, including
statements in promotional materials that describe the device and its
use. To evaluate technological characteristics, FDA reviews the
physical and performance characteristics of the device, such as
device design, materials used, and power source. For example, in
reviewing a new pacemaker lead made of polyurethane, FDA would assess
performance testing information to confirm that the new lead is
substantially equivalent to the predicate (or previously approved)
lead. This is necessary because differences in chemical formulations
of polyurethane or differences in design and assembly can affect
safety and effectiveness.
In arriving at a determination, FDA reviewers may use voluntary
standards and guidance about a particular device.\27 Reviewers also
commonly used earlier agency decisions on 510(k)s for similar
devices. Another resource is the files of the Center for Devices and
Radiological Health, such as establishment inspection and
postmarketing surveillance files. These files allow reviewers to
examine the reviews of similar device types and to determine what
questions, if any, were raised by FDA inspectors about a particular
type of device.
During the review of a 510(k) application, the reviewer may determine
that additional information about the device is necessary to complete
the review. This additional information may be descriptive
information and/or performance testing information. Descriptive
information includes the intended use, physical composition, method
of operation, specifications, and performance claims of the device.
Performance testing information can be data from bench testing or
from animal or clinical testing.
Upon completion of the review, the Office of Device Evaluation issues
a decision letter, which is then sent to the manufacturer. The
letter may contain one of the following:
a substantially equivalent decision,
a not substantially equivalent decision,
a request for additional information, or
a determination that the device is exempt from a 510(k) submission.
--------------------
\25 A legally marketed predicate device is (a) a device that was
legally marketed before May 28, 1976 (date of the Medical Device
Amendments of 1976, which expanded FDA's authority to regulate
medical devices); (b) a Class III device that has been reclassified
into Class I or II; or (c) a device that is substantially equivalent
to a device placed in (a) or (b).
\26 For example, the FDA reviewer determines whether the application
contains the information required under the Federal Food, Drug, and
Cosmetic Act. Also, the application should have photographs of the
device as well as engineering drawings of it.
\27 FDA uses a variety of voluntary standards and draft guidance
against which to judge the design and performance of medical devices.
Some of these voluntary standards were developed and endorsed by
groups such as the Association for the Advancement of Medical
Instrumentation, often with FDA assistance. In addition, FDA staff
develop FDA guidance documents for their own internal use.
Manufacturers use many of these FDA internal guidance documents to
help ensure that they submit a complete medical device application to
FDA.
PREMARKET APPROVAL
-------------------------------------------------------- Appendix II:4
As it does for 510(k)s, FDA first decides whether to accept the PMA
or refuse to file it because it does not meet minimum requirements.
If FDA accepts the application, a multidisciplinary staff evaluates
the filed PMA. The team reviews nonclinical studies such as
microbiological, toxicological, immunological, biocompatibility,
animal, and engineering tests. The team also reviews the results of
clinical investigations involving human subjects. During this stage,
FDA prepares a critique of the scientific evidence of the safety and
effectiveness of the device.
During the review, FDA may, on its own initiative or if requested by
the applicant, refer the PMA to an advisory committee representing
the appropriate medical field for a "panel" review. FDA will request
such a review when it lacks the knowledge or experience to evaluate
the safety and effectiveness questions posed by the device or when it
is otherwise appropriate to obtain advice on scientific matters.
Problems identified in FDA's critique of the scientific evidence can
be discussed further during advisory panel meetings. The committee
submits a final report to FDA, but the agency is not bound by the
committee's recommendations.
The review team also checks the manufacturer's compliance with the
GMP regulation and makes a judgment about the quality controls used
in the manufacture of a device. The purpose of the review is to
ensure that the manufacturer is capable of producing devices of high
quality.
At the end of the approval review stage, FDA may take one of the
following actions:
Issue an order approving the PMA.
Issue an order denying approval.
Send the applicant an approvable letter indicating that the FDA
intends to approve the device if certain problems (for example,
labeling deficiencies) are resolved.
Send the applicant a not-approvable letter describing significant
deficiencies in the application. Eventual approval is not
precluded if the manufacturer provides an adequate response.
INVESTIGATIONAL DEVICE
EXEMPTIONS
-------------------------------------------------------- Appendix II:5
Almost all PMAs and a small subset of PMA supplements and 510(k)s
require clinical trials to obtain answers to questions on safety and
effectiveness. A researcher wishing to conduct a study involving
human subjects to develop safety and effectiveness data for a medical
device can apply to FDA for an IDE. An approved IDE application
permits the use in a clinical study of a device that would ordinarily
be subject to market clearance procedures. An IDE approval is needed
for a significant risk device. For a nonsignificant-risk device (for
example, daily wear contact lenses) investigation, the sponsor
presents the proposed study to an institutional review board (IRB)
along with a report of prior investigations and the investigational
plan.\28 If the IRB approves the investigation as a
nonsignificant-risk study, the investigation is considered to have an
approved IDE and can begin immediately. FDA is not involved in the
approval process of the clinical study. If the IRB or FDA
determines, however, that the proposed investigation involves a
significant-risk device (for example, a heart valve), the sponsor
must submit an IDE application to FDA.\29
The application must contain an investigational plan that includes
such information as the purpose of the study, a written protocol, a
risk analysis and description of patient selection, a description of
the device, monitoring procedures, labeling, and consent materials.
An IDE application may also include data on the design of the device
and data from bench and animal tests.
FDA determines whether the study should be approved, considering such
factors as whether the benefits of the investigation outweigh the
risks and whether the proposed study is scientifically sound. The
investigation can begin after the sponsor obtains both FDA and IRB
approval for a significant-risk investigation. FDA conducts
bioresearch monitoring inspections to help ensure that clinical
investigations are conducted in accordance with study protocols and
that the rights and safety of study participants are protected.
--------------------
\28 An IRB is any board, committee, or other group formally
designated by an institution to review, to approve the initiation of,
and to conduct periodic review of biomedical research involving human
subjects. The purpose of such review is to ensure the protection of
the rights and welfare of human subjects, the appropriateness of the
method for securing the subjects' informed consent to participate,
and the balance of risks and benefits. The board must be composed of
a minimum of five members sufficiently qualified to foster a complete
and adequate review of research activities commonly conducted by the
institution.
\29 FDA is the final arbiter of whether an investigation is a
significant- or nonsignificant-risk study. FDA learns of IRB
nonsignificant-risk decisions through various means, including
bioresearch monitoring and communications from IRBs and other
sources, and can overrule an IRB's decision.
GMP INSPECTIONS
-------------------------------------------------------- Appendix II:6
FDA determines compliance with the GMP regulation primarily through
factory inspections conducted by its field staff. Section 704(a) of
the FFD&C Act gives FDA authority to conduct GMP inspections of
medical device manufacturers.\30 During these inspections, FDA
investigators examine facilities, records of manufacturing processes,
and corrective action programs. The results provide information
necessary to evaluate a firm's compliance with the medical device GMP
regulation.
FDA may initiate a GMP inspection for any of several reasons. These
include routine scheduling, the need to obtain data on an industry
new to FDA, investigation of a consumer or trade complaint, a product
defect report, an adverse reaction to a device, or a device-related
death. FDA also conducts GMP inspections in conjunction with
approval of products.
--------------------
\30 Anyone who manufactures, labels, packages, imports, or stores a
medical device can be inspected. A manufacturer is any person,
including a repackager or relabeler, who writes specifications for,
manufactures, fabricates, assembles, or processes a medical device.
POSTMARKETING SURVEILLANCE
-------------------------------------------------------- Appendix II:7
One key provision of the Safe Medical Devices Act of 1990 requires
that manufacturers conduct postmarketing surveillance, such as
studies to gather data on the safety and effectiveness of certain
devices. This requirement applies to devices that (1) are permanent
implants, the failure of which may cause serious adverse health
consequences or death; (2) are intended for use in supporting or
sustaining human life; or (3) present a potential serious risk to
human health. FDA also has discretion to require postmarketing
surveillance for other devices under certain circumstances.
Another provision of SMDA 90 requires manufacturers and distributors
to submit medical device reports of certain adverse events related to
a device they manufacture or distribute. Specifically, manufacturers
and distributors must report to FDA whenever they become aware of
information that suggests that a device (1) caused or contributed to
a death, serious illness, or serious injury; or (2) malfunctioned,
and there is a probability that if the malfunction were to recur, the
device would cause or contribute to a death, serious injury, or
serious illness. Medical device user facilities such as hospitals,
nursing homes, and outpatient treatment facilities are also required
to report to FDA serious adverse incidents involving device problems.
DESCRIPTION OF SELECTED ASPECTS OF
EUROPEAN UNION SYSTEM FOR
REGULATING MEDICAL DEVICES
========================================================= Appendix III
This appendix expands on information provided in the report about
several features of the EU system for regulating medical devices.
DEVICE CLASSES
------------------------------------------------------- Appendix III:1
The EU Medical Devices Directive, which covers most devices,
established a four-part classification system for medical devices.
The rules for classification take into account the riskiness of the
device, the device's degree of invasiveness, and the length of time
the device is in contact with the body.
Class I devices are generally regarded as low risk and include most
noninvasive products, certain invasive products, and reusable
surgical instruments.
Class IIa devices are generally regarded as medium risk and include
both invasive and noninvasive products, generally for short-term
use. This class includes some wound dressings; certain products
that channel and store blood for administration into the body;
surgically invasive devices for transient or short-term use;
most active therapeutic devices that administer or exchange
energy; and active diagnostic devices that supply energy (other
than for illumination) absorbed by the body, such as ultrasonic
imagers.
Class IIb devices are also regarded as medium risk, but this class
covers active products therapeutically delivering energy or
substances at potentially hazardous levels. Devices placed in
this class include blood bags, chemicals that clean or disinfect
contact lenses, surgically invasive devices for long-term use,
radiological equipment, and condoms and other contraceptive
devices (except for intrauterine devices, which are in Class
III).
Class III devices are generally regarded as high risk and include
products that are used to diagnose or monitor or that come in
contact with the circulatory or central nervous system, such as
vascular grafts. This category also includes devices that
incorporate medicinal products, such as bone-cement containing
an antibiotic.\31
--------------------
\31 The EU directive covering active implantable devices does not
contain a classification scheme, but the devices governed by that
directive are subject to the same review requirements as MDD Class
III devices.
CONFORMITY ASSESSMENT ROUTES
------------------------------------------------------- Appendix III:2
Under the EU system, the classification of a medical device governs
the type of assessment procedure the manufacturer must undertake to
demonstrate that the device conforms to the essential requirements in
the relevant medical device directive. Generally, when an NB must
perform aspects of conformity assessment, the manufacturer may choose
the assessment route from two or more options.\32
--------------------
\32 Annex numbers following the names of the assessment routes refer
to the sections of the EU medical device directives that describe the
various conformity assessment routes.
FULL QUALITY ASSURANCE
SYSTEM REVIEW (ANNEX II)
----------------------------------------------------- Appendix III:2.1
This type of review examines every aspect of the manufacturer's
quality assurance system, covering every phase of the manufacture of
a device, from design through shipping. The phases involved in
producing a new device for the market include a feasibility phase;
design phase, which results in a written definition of the device;
design verification, which involves creating prototypes of the
device; mass production; and full market release. At each of these
phases the manufacturer must ensure that it has defined the
requirements for completing that phase and that the "deliverable" for
that phase, such as a product design or a packaged device, is
verified by qualified staff.
A manufacturer choosing the full QA system route for a Class III
device is also required to submit a design dossier for the NB's
review. The dossier may include specifications and performance data
of the product as claimed; an explanation of how the product meets
the essential requirements for safety; risk analysis, including risk
control methods; electrical/mechanical/chemical constructional data,
including drawings; design verification documents; and, when
relevant, clinical investigation data.
After certifying a manufacturer's QA system, the NB must carry out
periodic inspections to ensure that the manufacturer is continuing to
implement the QA system. Additionally, the NB may pay unannounced
visits to the manufacturer to check that the quality system is
working properly.
Under the full QA assessment route, the NB does not need to conduct
individual reviews of related devices that are produced under the
same QA system. If the NB certifies the manufacturer's QA system,
that certification covers the related devices. This practice allows
the manufacturer to place a CE mark on and market all of the related
devices without going through an additional conformity assessment
review.
TYPE EXAMINATION (ANNEX III)
----------------------------------------------------- Appendix III:2.2
Type examination is a procedure in which the NB ascertains and
certifies that a representative sample of the device being reviewed
conforms to the essential requirements. The NB reviews documentation
on the device that the manufacturer provides and conducts a product
test of the device. The NB physically tests a prototype of the
device to determine whether it meets certain standards. The
documentation reviewed might include documentation of other product
tests. Type examination is always linked with a QA review limited to
the production phase of manufacture. The QA review is intended to
ensure the consistency of product quality. There are three types of
limited QA reviews, as follows.
PRODUCT VERIFICATION
(ANNEX IV)
--------------------------------------------------- Appendix III:2.2.1
In this type of review, the NB must individually test every device
produced or test a random sample from every production batch. (This
option is also referred to as batch verification.) Few companies
choose this approach because it is very expensive.
PRODUCTION QUALITY
ASSURANCE (ANNEX V)
--------------------------------------------------- Appendix III:2.2.2
Under this type of review, the NB reviews the manufacturer's QA
system for the production stage of manufacturing devices, including
inspection and QA techniques. The NB must carry out periodic
inspections after certifying the production QA system and can pay
unannounced visits to the manufacturer. Officials who work with the
EU system reported to us that this is the type of production phase
quality review that manufacturers select most often to complement
type examination.
PRODUCT QUALITY ASSURANCE
(ANNEX VI)
--------------------------------------------------- Appendix III:2.2.3
The NB reviews and certifies the manufacturer's system for inspecting
and testing final products in an Annex VI review. The NB must carry
out periodic inspections and can pay unannounced visits to the
manufacturer.
DECLARATION OF CONFORMITY
(ANNEX VII)
----------------------------------------------------- Appendix III:2.3
Under this procedure, which is available only for devices in Classes
I and IIa, a manufacturer furnishes a declaration that a device
conforms to the essential requirements and maintains technical
documentation that would permit review of the device.
ASSESSMENT REQUIREMENTS FOR
DEVICE CLASSES
------------------------------------------------------- Appendix III:3
The EU's MDD specifies which conformity assessment routes each class
of devices may use to demonstrate conformity with the essential
requirements. Figure III.1 illustrates the assessment routes
available to each device class.
Figure III.1: Conformity
Assessment Routes in European
Union Medical Devices Directive
(See figure in printed
edition.)
Source: Medical Devices Agency, Department of Health, UK.
CLASS I
----------------------------------------------------- Appendix III:3.1
For Class I products that do not involve measuring devices or
sterilization, manufacturers may simply furnish the declaration of
conformity (Annex VII) and maintain sufficient technical
documentation to permit review of the device. There is no NB review,
but the manufacturer must register such devices with the competent
authority in the country of the manufacturer's registered place of
business. If the device has a measuring function or must be placed
on the market in a sterile condition, the manufacturer is also
subject to one of the assessment routes covering production quality
(Annexes IV, V, or VI). The NB's review focuses only on the
measurement or sterilization aspect of the device.
CLASS IIA
----------------------------------------------------- Appendix III:3.2
The manufacturer itself may declare conformity with the essential
requirements covering the design phase and choose one of the
assessment routes covering production quality (Annexes IV, V, or VI).
Alternatively, the manufacturer may undergo the full QA system review
(Annex II).
CLASS IIB
----------------------------------------------------- Appendix III:3.3
The manufacturer may choose either the full QA system review (Annex
II), or type examination (Annex III) plus one of the production
quality reviews (Annexes IV, V, or VI).
CLASS III
----------------------------------------------------- Appendix III:3.4
The requirements are the same as for Class IIb, with two exceptions.
If the manufacturer chooses the full QA system review (Annex II), it
must also submit a design dossier to the NB. If the manufacturer
chooses type examination (Annex III), it must choose either product
verification (Annex IV) or production quality assurance (Annex V) for
the production phase assessment. Product quality assurance (Annex
VI) is not an option for Class III devices.
THE SAFEGUARD CLAUSE
------------------------------------------------------- Appendix III:4
The EU's medical device directives have a safeguard clause that
requires each member state's competent authority to withdraw from the
market CE-marked devices that the competent authority finds may
compromise patients' health or safety. The competent authority must
immediately inform the European Commission both that it has taken
this action and of its reasons for withdrawing the device. If the
Commission agrees that the action was justified, it will inform the
other member states that the device has been withdrawn. If the
Commission believes the withdrawal was unjustified, it informs the
competent authority that made the decision and the device
manufacturer of that decision. If a competent authority persists in
banning a CE-marked product from its country's market, despite the
European Commission's decision that the device belongs on the market,
the Commission can bring a legal proceeding in the European Court of
Justice. European officials view the safeguard clause as a last
resort, not something to be invoked routinely. If member states
could routinely block the sale of CE-marked devices in their
countries, the EU system's goal of facilitating EU-wide trade would
be undermined.
(See figure in printed edition.)Appendix IV
COMMENTS FROM THE FOOD AND DRUG
ADMINISTRATION
========================================================= Appendix III
(See figure in printed edition.)
(See figure in printed edition.)
(See figure in printed edition.)
(See figure in printed edition.)
(See figure in printed edition.)
(See figure in printed edition.)
(See figure in printed edition.)
(See figure in printed edition.)
RELATED GAO PRODUCTS
=========================================================== Appendix 0
Medical Devices: FDA Review Time (GAO/PEMD-96-2, Oct. 30, 1995).
FDA Drug Approval: Review Time Has Decreased in Recent Years
(GAO/PEMD-96-1, Oct. 20, 1995).
Medical Technology: Quality Assurance Systems and Global Markets
(GAO/PEMD-93-15, Aug. 18, 1993).
Medical Technology: Implementing the Good Manufacturing Practices
Regulation (GAO/T-PEMD-92-6, Mar. 25, 1992).
Medical Technology: Quality Assurance Needs Stronger Management
Emphasis and Higher Priority (GAO/PEMD-92-10, Feb. 13, 1992).
Medical Devices: FDA's 510(k) Operations Could Be Improved
(GAO/PEMD-88-14, Aug. 17, 1988).
*** End of document. ***