P H A R MA C O V IG IL A NC E/SA FETY
This paper reviews the European Union manda-
David Jefferys, BSc MD,
FFPM
FRCPSector.
Head of the Devices
Medicines and Healthcare
Products Regulatory Agency,
London. United Kingdom
Key Words
Medical devices;
Pharmacovigilance:
Vigilance;
User error;
Drug/device combinations
CorrespondenceAddress
Dr. David lefferys BSc MD,
FRCP FFPM. Head of the
Devices Sector. MHRA.
Hannibal House, Elephant
and Castle, London,
E I 6TQ. United Kingdom
(e-mail:
david.jefferys@mhra.gsi
.gov. uk) .
This paper is based on the
Device Vigilance Track at the
DlA EuroMeeting, March
10- 12.2004, Prague,
Czech Republic.
73
Adverse Incident
Reporting for Medical
Devices-A
Comparison with
Pharmacovigilance
INTRODUCTION
This paper describes and explores the differ-
ences between the adverse incident reporting
system for medical devices and the better known
pharmacovigilance system for medicines. Su-
perficially. there are considerable similarities
between the two reporting systems. However,
there are also quite profound differences.
Medical devices cover a vast range of prod-
ucts. It is estimated that there are approximately
500000 medical device products currently on
the European market. Medical devices are found
in every aspect of healthcare, as well as social
and community care. The products covered un-
der the four Medical Device Directives in Eu-
rope include implants, advanced life support
systems, imaging equipment, monitoring de-
vices, surgical instruments, in vitro diagnostics,
prosthetics, and disability equipment (1).Al-
most all the areas covered by medical devices
are undergoing rapid developments particular-
ly, for example, in the area of assistive technolo-
gies (used to alleviate disability and handicap).
Rapid changes are being fueled by a conver-
gence of advances in fields such as biomaterial
science, miniaturization, digital technology,
nanotechnology, and computing software. These
advances underscore the importance of medical
device adverse incident reporting.
Given that the statutory control of devices is
Drug hlformation Journal. Vol. 39, pp. 73-80.2005 0092-8615/2005
Printed in the USA. All rights reserved. Copyright Q 2005 Drug Information Association, Inc.
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tory Vigilance Reporting System and voluntary
user reporting gstems for medid dm’ces. Dif-
ferences between these systems and the report-
ing system for pharmaceuticals are highlighted.
Device vigilance is run a a single harmonized
system within the European Union and increus-
inglv there are international links. Recent trends
in reporting pattenzs within the United King-
dom are highlighted along with initiatives to im-
p e the number and accuracy of reports.
Drug/dmke combination products are becom-
ing increas*n& important. The handling of ad-
verse events for these and other new technology
products are described.
much more recent than that for pharmaceuti-
cals, the device sector has much to learn from
pharmacovigilance systems and drug postmar-
keting surveillance. However, pharmacogenetic
tests are in vitro diagnostics (IVDs). This is an
area which will contribute significantly to the
greater understanding of pharmaceutical ad-
verse reactions and in the better targeting and
monitoring of pharmaceutical therapy as dis-
cussed in a recent editorial (2).
The borderline between pharmaceuticals and
medical devices is becoming increasingly im-
portant (3). Under the present legislation, the
deciding factor, in both the European Union
and the United States, is the primary purpose of
the product. Increasingly sophisticated de-
vice/drug combinations are being developed,
which are likely to include complex biosensors
and feedback systems. For such products, it is
important to understand the reporting require-
ments for both components. Pharmaceutical
physicians and regulatory scientists will have to
be aware of the medical device regulations.
THE POSTMARKETIN G
SURVEILLANCE OF
MEDICAL DEVICES
The main Medical Device Directive (93/42 EC)
provides the legislative basis for two comple-
mentary reporting systems within Europe. Arti-
cle 10 of this directive established the mandato-
74 PHARMACOVIG ILANCE/SAFETY
ry Vigilance Reporting System, which requires a
manufacturer to report immediately any death
or serious adverse incident caused by a medical
device to the relevant Competent Authority.
This is the authority which has jurisdiction over
where the event occurred. Serious adverse inci-
dents are defined as those which have caused
serious injuries or have the potential to cause
serious injury or death.
In addition to the mandatory Vigilance Re-
porting System, the directive allows Member
State Competent Authorities to introduce user
adverse reporting systems, that is, covering
those reports directly from the product user,
who may be a health professional or a patient, to
authorities. These are now established in the
majority of European Member States. Within
the pharmaceutical sector there are separate
systems for reporting defective medicines and
adverse incidents. Within the device sector
these are combined within the same reporting
arrangements.
THE VIGILANCE REPORTING SYSTEM
The Vigilance Reporting System was introduced
in Europe with the main Device Directive
(93/42EC) in 1995. A manufacturer is required
to report immediately any death or serious ad-
verse incident occurring with a device. Manu-
facturers must report the incident to the Com-
petent Authority within whose territory the
event occurred. The manufacturer does not
have to report the incident if there is no causal-
ity attributed to the medical device; the manu-
facturer assesses the causality, although this is
subject to inspection by the national agencies.
If the reported incident occurred outside the
European Union and the European Economic
Area, the manufacturer must report the inci-
dent to those European Union countries in
which the product is marketed.
It is the responsibility of the Competent Au-
thorities within Europe to circulate vigilance re-
ports received from manufacturers to all other
Competent Authorities. Currently, a paper
system is used but a new electronic distribu-
tion system and database are currently being
installed across Europe. This project, called
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Jefferys
EUDAMED (httpJ/europa.eu.int/comm/index_en
.htm). will contain both vigilance reports and
the registration data on marketed medical de-
vices. Similar manufacturer-based reporting
schemes operate in other parts of the world. The
Global Harmonisation Task Force has produced
identical reporting forms, and these are now
used across the major markets, making meeting
regulatory requirements easier for manufactur-
ers. The Global Harmonisation Task Force has
also been running a pilot National Competent
Authority reporting system. More details about
the Global Harmonisation Task Force and the
National Competent Authority reporting system
can be obtained from the task force’s Website
(www.ghtf.org)(4).
The European Union Vigilance Reporting Sys-
tem is mandatory and there are penalties for
manufacturers who do not supply the requisite
reports. Figure 1 shows that within the United
Kingdom, both the absolute number and also
the percentage of vigilance reports are increas-
ing. The increase in the number of reports is a
reflection of the phased introduction of the CE
marking evaluation system. Premarketing CE
“evaluation” became mandatory from 1998.
However, if a medical device was already in ser-
vice prior to 1998, it could remain in use. Given
that much medical equipment has a long “shelf
life,” it is not surprising that the number of re-
ports has continued to grow over the last five
years. In the United Kingdom, only about 50%
of the vigilance reports received meet the strict
criteria, which means that manufacturers often
report incidents which fall outside the strict
definition of the system. This is encouraging
and shows the highly responsible attitude that
the medical devices industry takes to its report-
ing obligations.
Within the United Kingdom, manufacturers
can now report vigilance incidents electronical-
ly to the Medicines and Healthcare Products
Regulatory Agency. This new electronic report-
ing system allows an interaction to take place
between the manufacturer and the agency. Fur-
ther details of this scheme, the Manufacturers
Online Reporting Environment (MORE), can be
found on the Medicines and Healthcare Prod-
Adverse Incident Reporting for Medical Devices
1997 1998
OCE Marked
ucts Regulatory Agency Website (www.mhra
.gov.uk). The number of electronic reports, from
healthcare professionals as well as from manu-
facturers, is rapidly rising.
In Europe the proportion of adverse incidents
submitted by manufacturers through the Vigi-
lance Reporting System is much lower than that
received through the user reporting systems.
This is very different from the picture in the Unit-
ed States, where manufacturers’ reports provide
the majority of information. Similar differences
are also seen between the United States and Eu-
rope in pharmaceutical adverse incident report-
ing. There is a strong tradition of healthcare pro-
fessionals reporting adverse incidents to the
national Competent Authorities within Europe.
USER REPORTING SYSTEMS
User reporting systems for medical device ad-
verse incidents are allowed and encouraged un-
der the Device Directive. Many of these schemes
predated the introduction of the European legis-
lation. Indeed, the United Kingdom system can
be traced back to 1964; it was introduced at the
same time as the Committee on the Safety of
Medicines’ Yellow Card Reporting System for
Medicines (3).Both systems are celebrating their
40th anniversary. The user reporting systems
capture more detailed information, are more
comprehensive, and provide more timely reports.
In the United Kingdom approximately 8500
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P HA R M A C 0V IG I L A N C E / S A F ET Y 75
n n n FIGURE 1
Adverse incident reports:
1997-2003.
1999 2Ooo 2001 2002 2003
Year
Not CE Mark/Unknm status
adverse incidents reports are received per year.
These come from a variety of healthcare profes-
sionals and more recently, have begun to be re-
ceived from patients, although the number of
patient reports seems very small. Electronic
reporting is encouraged either through the
Medicines and Healthcare Products Regulatory
Agency Website or through the National Health
Service net. Figure 2 shows a breakdown of the
sources of incident reports from 1998 to 2003,
inclusive.
Specialized report forms exist for different
types of products. Reporters are automatically
led into the specialized reports through the
electronic Website. Figure 3 shows the incident
reporting by device group. This illustrates that
many reports come from so called “low-risk”
medical devices and equipment. This is not sur-
prising given the widespread and large volume
use of such equipment.
Figure 4 shows the causes of adverse incidents
which have been reported. These are catego-
rized as: problems arising before delivery, which
include design errors, manufacturing errors
and quality control and packaging issues; prob-
lems occurring after delivery, which relate to
performance and/or maintenance failures and
service degradation; user errors in which the
device itself is not at fault: and problems for
which there is no established link to the device.
This latter category relates to situations where
76 PHA R M A C 0 V I G I 1A N C E / S A F E T Y Jefferys

FIGURE 2

Incident report sources.

1998 1999 2Ooo 2001 2002 2003

Year
N NHS W Manufacturers
H Mer Government Bodies W Overseas Reporting Organisatiom
0 Non-GovernmentOrganisatiom 0 Private Heahhwre Org~~nisotiom

Physiotherapy equipmenf
FIGURE 3 OrthOSeS
Wdkiil aids 2003
Incident reports by
device group.
lisinfection/steriliit~l 0 2002
Beds/motheaes
Hoists 2001
Droinage/Suction
Aids for ddy living
Oiinoaic imoging
IVDS
SurQical CMlwmObles
Syringes/nesdleS
jfewpport/incWnmnbators/monitors
Artificiollimbs
others
Surgical equipmi
Infusion/tmnsfusion/dmlysis
Active and non-active implants

0 200 400 600 800 1000 1200 1400 1600

Number of incidents

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Adverse Incident Reporting for Medical Devices
50
45
40
35
4 30
16 25
b
3
20
15
10
5
0
Device fauhs - before Device fa& - after d e t i i
delivery
2001
the device is found, on testing, to work as in-
tended and no cause can, therefore, be identi-
fied. Such circumstances could arise due to an
intermittent fault, tampering with the equip-
ment, or, in many instances, relates to perceived
user error which cannot be proven.
It is encouraging that device faults before de-
livery and devices faults after delivery are both
falling. The figures on user error and those
where there is no established link to the device
both show an increase over the four-year peri-
od. This reinforces the concerns over user er-
ror and the importance that this has for pa-
tient care and reducing patient morbidity and
mortality (5,6). In recent years, the Medical
Devices Agency and more recently the Medi-
cines and Healthcare Products Regulatory
Agency in collaboration with the National
Patient Safety Agency Website (www.npsa
.nhs.uk) have been focussing attention on re-
ducing user error and on improving education
and training for users of medical devices. Much
of this work is being brought together with the
“Design for Patient Safety Initiatives” (7). The
reports shown in Figure 4 add up to more than
100%because, on occasion, there may be more
than one cause of an incident, that is, both a
Drug lnformation Journal
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P H A R M A (0 V I G I L A N EE/S A FETY 77
FIGURE 4
Causes of adverse
incidents.
user error
0 2002 2003
user error and a device fault may contribute to
the incident.
Figure 5 shows the outcome of investigations
into the reported incidents in the United King-
dom. The second column entry shows that, on
occasion, there may be only a single report of a
device failure which may result from a single
manufacturing defect. The first column refers to
those reports where the issue is being kept un-
der observation and a trend analysis is being
taken forward. This technique is increasingly
being used by authorities who seek to identify a
trend in reporting. In particular, they are look-
ing to see whether there is a sudden change in
reporting rates which may illustrate a need for
better training, new educational programs, and
so forth. A full description of the operation of
United Kingdom devices adverse incident re-
porting systems can be found in the Medicines
and Healthcare Products Regulatory Agency
Device Bulletin entitled ”Adverse Incident Re-
ports 2003 (8), which is also available on the
Medicines and Healthcare Products Regulatory
Agency Website (www.mhra.gov.uk).
In order to enhance the effectiveness of the
user reporting system, the Medical Devices
Agency in the United Kingdom introduced a
78 PHA R MA ( 0 V I G I L A N C E / S A F ETY
FIGURE 5
6o
50-
1
Investigation outcomes.
40-
i
-w
3
0
0
30-
20-
10 -
0- I I
network of device liaison officers. Such nominat-
ed individuals are now to be found in every acute
hospital trust, primary care trust, and ambu-
lance service across England. They are senior in-
dividuals with a background in bioengineering,
medical directors, or senior nurses. Increasingly,
many are the risk managers in their institutions.
The role of the device liaison officer is to en-
courage reporting of medical device adverse in-
cidents and to undertake the initial screening
and analysis of the reported problem. In the fu-
ture, they are likely to work increasingly with the
National Patient Safety Agency. Separately, they
assist the Medicines and Healthcare Products
Regulatory Agency in the distribution of Device
Alerts. Device liaison officers are seen as the eyes
and ears, and the spokesmen, for the agency.
The distributed network is supported by a focus
group of device liaison officers which meets reg-
ularly and through a United Kingdom Website.
The device liaison officers are also brought to-
gether at an annual conference.
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Jefferys
2001
0 2002
2003
I I I 1
- I
A similar system was recently adopted in
Switzerland and is being considered by other
European countries. In the future, the United
Kingdom network may also play a role in the ad-
verse incident reporting for medicines.
D R U G/D E V I CE C O M B I N A T l O N
P R O D U CTS
Druddevice combination products are becom-
ing more frequent and important. The rules gov-
erning druddevice combination products are
internationally harmonized and are relatively
simple (9). Specifically, if the primary intended
purpose is mechanical or physical, then the
product is classified as a medical device: howev-
er, if the primary intended purpose is pharma-
cological/immunological, then the product is
classified as a medicine. This means that a cyto-
toxic implant to treat a brain tumor would be
classified as a medicine, whereas a drug-eluting
coronary stent is classified as a medical device,
since the primary intended purpose is the scaf-
Adverse Incident Reporting for Medical Devices
fold of the stent to maintain the patency of the
coronary blood vessel. In this example, the drug
is present to reduce the incidence of restenosis
and hence, is extending a secondary action.
For combination products, the adverse in-
cident reporting arrangements follow the
primary classification. Thus, reports for drug-
eluting stents are made through the device sys-
tems. However, as druudevice combinations
become increasingly complex, it is important
that manufacturers and indeed users are aware
of both systems and their reporting require-
ments. This is particularly true for combination
products where the device is separately CE
marked (ie, approved as a device for indepen-
dent use). In this case, the report should be
made to both systems. Arrangements have been
made to facilitate the transfer of reports elec-
tronically between the systems and to identify
linked reports.
USER ERROR
As previously mentioned, user error is a signifi-
cant issue for both medical device and pharma-
ceutical reporting. In the devices sector, it
is more common that user error is reported
through the surveillance systems. Figure 5 shows
that user errors are frequently submitted
through the device reporting system. This may
be because causality cannot be established in
spite of a thorough root cause analysis. Alterna-
tively, the incident may have been initially re-
ported as a design failure, but user error was
subsequently identified during investigation to
have been an important factor, or indeed the
sole factor, in causing the incident.
In the United Kingdom, arrangements have
been made to electronically transfer user re-
ports in an anonymized form to the new Nation-
al Patient Safety Agency. Even when a report is
found to be solely a matter of user error, there
needs to be a careful analysis of the instructions
for use, the education program, and the design
of the device to see whether these are contribu-
tory factors in the reported user error. This ho-
listic approach is now being brought together in
the concept of "Design for Patient Safety" (6).
This important theme is being taken forward by
Drug Information Journal
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P H A R MAC 0V I GI LANCE/S A FETY 79
Europe during its presidency of the Global Har-
monisation Task Force.
LONG-TERM SAFETY ISSUES
Implantable medical devices may present a par-
ticular problem in the monitoring of adverse
events/incidents because safety issues and im-
plant failures may only become apparent several
years after the introduction of the product.
Such problems can arise because of design fail-
ure, biocompatibility issues, and changes in
manufacturing affecting the biomaterial stabili-
ty. Recent examples have included the need to
withdraw breast implants filled with soya bean
extracts because of concerns over mutagenicity
and genotoxicity; hip implant withdrawals be-
cause of early revisions, osteolysis and migra-
tion: and the withdrawal of intraoccular lenses
because of premature clouding of the device.
Some of these failures are revealed through ad-
verse incident reports and trend analysis. In-
creasingly, they are being detected through the
use of postmarketing case control studies and
the interrogation of registries. Registries have
been set up for breast implants, joint replace-
ments, heart valves and implantable cardiac
pacemakers and are likely to be increasingly
used in the future.
FUTURE TRENDS
Medical devices and druddevice combinations
are becoming increasingly sophisticated. This is
shown by the new generation of drug-eluting
stents for coronary disease and cancer, and also
by the new closed feedback drug delivery system.
In order to adequately monitor both the long-
term effectiveness and safety of these devices, it
will be necessary to consider the use of method-
oligies currently being used in the pharmaceuti-
cal sector. Early conditional approvals could
mean that case control studies may be required.
There may also be a greater need to use product-
specific registries referred to earlier for implants
and interventional devices. Europeadinterna-
tional registries are likely to be required for hu-
man tissue engineering products, since the po-
tential concerns are likely to be longer term
safety issues and shortened duration of effect.
80 PHARMACOVIGILANCE/SAFETY
Separately, the General Practice Research
Database, which is a large scale general practice
longitudinal case record system run by the
Medicines and Healthcare Products Regulatory
Agency for pharmaceuticals, could have a role to
play for some medical device products such
as wound dressings and incontinence devices.
More details about the General Practice Re-
search Database are available on the Medicines
and Healthcare Products Regulatory Agency
Website (www.mhra.gov.uk). Similarly, the Pre-
scription Event Monitoring scheme operated in
the United Kingdom may have a part to play for
some types of medical devices. Certain drug/de-
vice combinations are likely to require prospec-
tive postmarketing studies as part of the evalua-
tion approval. These issues are currently being
considered by the the Global Harmonisation
Task Force's Vigilance Study Group.
In vitro diagnostics are covered under sepa-
rate legislation (Directive 98/79 EC). Adverse
incidents can be reported on these products
through the usual channels although the re-
port will be received in a different format. Fail-
ures of IVDs are likely to be either due to a fail-
ure of the sensitivity or specificity of the
particular device or to batch failures or vari-
abilities. There may also be problems over
"traceability" related to the different sensitivity
and specificity between particular assays. This
can arise if there is no international standard
for the particular assay. In summary, new
methodologies are likely to be required to mon-
itor the safety and effectiveness of IVDs in us-
age. These are currently undergoing considera-
tion by the regulatory authorities. Again, there
are parallels with the pharmaceutical area
which could usefully be developed.
CONCLUSION
Medical devices represent a wide range of in-
creasingly sophisticated products. Pharmaceu-
tical manufacturers will need to be more famil-
iar with device regulations and in particular, the
adverse event reporting system, especially if, as
expected, more druddevice combination prod-
ucts come to the market. This article has ex-
plored the difference in reporting regimes in
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Jefferys
Europe. Increasingly in the United Kingdom,
healthcare professionals and healthcare institu-
tions are looking to have single reporting system
as part of their risk management systems. This
will bring together the previously separate
arrangements for medicines and medical de-
vices (also possibly for other healthcare prod-
ucts). Pharmacoepidemiology has much to offer
the device sector, while user reporting and hu-
man factor engineering are probably more
widely used in the devices industry and could
help with the increasingly important concerns
over medication errors. The recent trend of
mergers between medicines and device Compe-
tent Authorities, such as the creation of the
Medicines and Healthcare Products Regulatory
Agency in the United Kingdom, should help fa-
cilitate the development of advanced systems
with significant benefits for both patients and
for healthcare professionals.
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