Comparing Regulation of
IVD Medical Devices
in Europe and Canada
By Ivor D. Barrett, PhD
26
May 2011
In vitro diagnostic (IVD) medical devices are
reagents and related instruments used to test
specimens derived from the human body to
obtain information regarding physiological and
pathological conditions, congenital abnormalities, compatibility of potential recipients of blood
transfusions and tissue transplants and effectiveness of therapy. As the results of these tests are
used to inform crucial clinical decisions, regulation of IVD devices is seen in many regions of
the world as an important requirement to protect
patient safety.
Major IVD markets have developed their
own regulations that, although similar in many
ways, also have fundamental differences.
Manufacturers and suppliers of IVD products
must be aware of the similarities and differences
in regional regulations to avoid contravening
local legislation when selling in these markets.
Regulatory requirements have to be considered
at an early stage of new product development
because specific performance studies may be
necessary to ensure compliance. Failure to
schedule such studies could lead to delays in
regulatory approval with consequential loss of
sales and revenue.
This article compares the IVD regulations
in two major device markets: the EU (In Vitro
Diagnostic Medical Devices Directive, IVDD1) and
Canada (Canadian Medical Device Regulations,
CMDR2). The level of intervention by European
and Canadian authorities in the premarket
approval process of IVD devices and the extent
of product validation requirements are dependent upon the risk to the patient if the test
produces false or inaccurate information. More
stringent requirements are applicable to products
where failure or misdiagnosis could result in
serious deterioration in the health or even death
of the patient.
It is important to remember that under both
EU and Canadian regulations, the legal manufacturer of a device is defined as the “manufacturer
named on the label.” The legal manufacturer
takes full responsibility for the product under the
regulations, irrespective of whether it actually
manufactured the product. For instance, an ownbrand label of an IVD product (whose name is on
the label) is fully responsible for that device even
if it is completely manufactured, packed, and
labeled by another company on its behalf. In this
article, the term “manufacturer” always refers to
the legal manufacturer of the device.
Device Classification
In both markets, the level of regulation is defined
by the classification of the product (Table 1).
In EU, higher-risk products are listed in Annex
II of the IVDD. These products are listed by
analyte and type of use (e.g., screening, blood
grouping and confirmatory test). Annex II List A
products carry the highest risk to patients. They
include screening and confirmatory tests for viral
markers such as HIV and hepatitis. Reagents for
ABO blood grouping also fall into this category.
Annex II List B products are regarded as
having an intermediate level of risk. This category includes tests for the less-important blood
phenotypes, a range of other viral markers, and
tests for the principal human leukocyte antigen
(HLA) tissue groups and hereditary disorders. It
also includes tests for prostate-specific antigen
and self-test devices for blood sugar. All other
products that are not specifically mentioned
are classified as low risk, although any self-test
products sold to the general public have more
stringent requirements than the equivalent professional tests.
The CMDR defines a much more systematic
classification process. Products fall into one of
four classes (I, II, III or IV) dependent upon the
manufacturer’s intended use of the product. The
appropriate class is obtained by applying a series
of nine rules described in the CMDR. This system is fully risk-based with highest-risk products
falling in Class IV, which is subject to the most
stringent requirements.
The EU IVDD is currently being redrafted.
It is anticipated that the revised directive
will require IVD devices to be classified by a
fully risk-based method based on the Global
Harmonization Task Force (GHTF) guidelines3
and similar to the Canadian system. However,
the publication of the new directive is still a few
years in the future.
Registration of Products,
Manufacturers and Device Licenses
Generally, in both markets, products must be
registered (Table 2) prior to making them available for sale, unless they fall into the lowest
risk category. In the EU, all products have to be
registered with the Competent Authority in the
country in which they are to be sold. In the UK,
this is the Medicines and Healthcare products
Regulatory Agency (MHRA4).
The lowest-risk products are not registered
individually but rather in terms of a group
code based on analyte and assay technology.
For higher classifications, products are assessed
individually and certified by Notified Bodies
accredited under the IVDD by the Competent
Authority in the country in which they are based.
Any European Notified Body may be used
provided it has the necessary scope to assess
and certify the product type. Manufacturers
can check the scope of Notified Bodies on
the European New Approach Notified and
Designated Organisations (NANDO) website.5
The UL Notified Body6 has a comprehensive
scope covering most IVD devices. Products
approved by a Notified Body can subsequently
be legally marketed in any country in the EU
subject to the registration requirements above.
In Canada, all products in Classes II, III and
IV must be licensed by Health Canada,7 which is
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Table 1. IVD Device Classification
Europe (IVDD)
Canada (MDR)
Device Example
Non-Annex II
(Professional use)
Class I
IVD used to identify cultured
microorganism
Non-Annex II
(Self-test use)
Class II
Pregnancy test (self-test)
Annex II List B
Class III
Blood glucose monitor
Annex II List A
Class IV
HIV test kit
accredited to the Standards Council of Canada
(SCC). The requirements for Notified Body certification in Europe and product licensing in
Canada increase in stringency with risk category
and hence product classification. These requirements are summarized in the next section.
All IVD manufacturers located in the
EU have to be registered with the Competent
Authority in the country where they are based.
Manufacturers located in other parts of the
world must, by law, appoint an Authorized
Representative, resident in the EU, that is
legally responsible for communications with
the Competent Authority on behalf of the
manufacturer.
The Authorized Representative is often
a distributor of the manufacturer’s products,
but can be a specialist independent company
that represents several manufacturers. Any
entity that imports or sells a medical device
on the Canadian market requires an establishment license. However, manufacturers of Class
II, III and IV devices (along with retailers and
healthcare facilities) are exempted from this
requirement.
Manufacturers of Class I devices are not
exempt unless they import or distribute the
device solely through an organization that
holds an establishment license. Health Canada
requires manufacturers to have a regulatory correspondent. This is a named person authorized
by the manufacturer to be its official contact
with Health Canada with respect to its licensed
devices. The regulatory correspondent can simply be an employee of the manufacturer or a
local distributor.
Alternatively, an independent service
company may be used for convenience. The regulatory correspondent does not have to be based
in Canada, as there is no requirement for foreign
manufacturers to have a local authorized contact.
Product Technical Documentation
Product technical documentation for all classes
of IVD devices (Table 3) must be available for
inspection by the Competent Authority or Health
Canada at any time. The EU and Canadian
requirements for content are similar and include
comprehensive data demonstrating that the
product performs satisfactorily in meeting its
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May 2011
claims for intended use, does not cause harm to
the patient or user, and will retain its claimed
performance characteristics following transportation and storage until its expiration date.
In both the EU and Canada, the level of
scrutiny of the technical information depends
upon the classification of the product. In essence,
the higher the class, the more carefully the performance data are assessed. In Europe, technical
files for products that are not self-test or not
listed in Annex II of the IVDD do not have to
be independently assessed. The manufacturer
simply makes a legal declaration of conformity,
asserting that the product meets the requirements of the IVDD, and, following registration
of the product with the Competent Authority, is
free to sell it in the EU.
Technical data for all other products (selftest and Annex II) must be independently
assessed by a Notified Body with appropriate
IVD scope, such as UL, for compliance with the
requirements of the directive. This assessment
takes the form of a review of the technical file for
self-test and Annex II List B products, but any
List A product requires a comprehensive assessment of the full design dossier. Additionally,
Annex II List A products have to comply with
applicable Common Technical Specifications8
published in European Commission Decision
2009/886/EC.
In Canada, Class I products do not require
a product license, so no application needs to be
made to Health Canada. For Class II products,
a senior member of management has to make
a legal attestation that the product meets the
requirements of the CMDR with emphasis on
labeling, compliance with safety and effectiveness requirements and testing on human samples
representative of its intended use.
Class III products require submission of a
technical file describing the device and materials
used in its manufacture, and summarizing evidence to support safety and effectiveness claims.
To license IVDs in the highest classification,
Class IV, a full design dossier must be submitted
to support the application. Files for Class III and
IV devices are sent directly to Health Canada
for assessment. There is no third-party system
in Canada equivalent to the European Notified
Bodies.
Table 2. Registration of IVD Products, Manufacturers and Device Licenses
Europe (IVDD)
Classification
Non-Annex II
(Professional
use)
Non-Annex II
(Self-test use)
Annex II List B
Product
Registration of
product group
with Competent
Authority (CA)
Assessment by
Notified Body
Registration with
CA
Canada (MDR)
Manufacturer
Registration
with Competent
Authority
If not based
in Europe,
Authorized
Representative
in Europe
required
Annex II List A
Classification
Class I
Product
Manufacturer
No device
license required
Establishment
license
required unless
importing/
distributing
product solely
through
company with
establishment
license
Device license
required
Establishment
license not
required
Class II
Class III
Class IV
Quality Management System (QMS)
Requirements
The majority of manufacturers of IVDs probably
have an approved quality system certified to
ISO9001:2008 and/or ISO13485:2003 (Table 4).
However, manufacturers of Class I products destined for sale in Canada are not obliged to have
a certified quality system. Class II devices must
be manufactured under an ISO13485:2003 quality
system, although the requirements of Clause 7.3
(Design and Development) can be excluded.
Manufacturers of Class III and IV devices
must have full quality system certification to
ISO13485:2003, including design and development. The registrar certifying that the
quality system conforms to the requirements of
ISO13485:2003 must be recognized by Health
Canada under the Canadian Medical Devices
Conformity Assessment System (CMDCAS)
and the auditors used must be qualified under
the CMDCAS program, as the auditing process
includes the elements of the CMDR.
The QMS requirements for manufacturers
of IVDs for sale in the EU are noticeably different. Manufacturers of devices that are not listed
in Annex II of the IVDD do not have to have an
approved quality system. Devices that are listed
Table 3. IVD Device Technical Submissions
Europe (IVDD)
Classification
Product Submission
Non-Annex II
(Professional use)
Technical file must be available
No submission
Self-declaration that
requirements of IVDD met
Non-Annex II
(Self-test use)
Technical file assessed by
Notified Body
Design examination certificate
issued; alternatively, full quality
assurance route (like Annex II
products) may be used
Annex II List B
Technical file and quality system
assessed by Notified Body
Full quality assurance certificate
issued
Annex II List A
Design dossier and quality
system assessed by Notified
Body
Design examination and full
quality assurance certificates
issued
Canada (MDR)
Classification
Product Submission
Class I
Technical file must be
available
No submission to Health
Canada required
No product license required.
Class II
Attestation of compliance
to MDR submitted to Health
Canada
Technical file must be
available
Product license issued
Class III
Summary technical file
submitted to Health Canada
supporting compliance with
MDR
Product license issued
Class IV
Full design dossier submitted
to Health Canada supporting
compliance with MDR Product
license issued
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Table 4. Quality System Requirements for IVD Manufacture
Europe (IVDD)
Product Submission
Classification
Product Submission
Non-Annex II
(Professional use)
No certified QMS requirement
Class I
No certified QMS requirement
Non-Annex II
(Self-test use)
No certified QMS requirement
Class II
ISO13485:2003 certification under
CMDCAS required (design and
development can be excluded)
Annex II List B
Quality system assessed
by Notified Body. EC full
quality assurance certificate
issued. No requirement for
ISO13485:2003 certification
Class III
ISO13485:2003 certification under
CMDCAS required (design and
development must be included)
Annex II List A
Quality system assessed
by Notified Body. EC full
quality assurance certificate
issued. No requirement for
ISO13485:2003 certification.
All batches of product must be
verified by Notified Body prior
to release
Class IV
ISO13485:2003 certification under
CMDCAS required (design and
development must be included)
No requirements under MDR for
batch verification.
in Annex II are normally manufactured under
a full quality assurance system that must be
audited and approved by a Notified Body.
The requirements for this full quality
assurance system are based upon those in
ISO13485:2003 but also include quality elements
of the IVDD. Certification by a Notified Body
alone, however, does not permit automatic certification to ISO13485:2003. Conversely, ISO13485
certification alone is not sufficient to show compliance with the IVDD.
For convenience and to minimize costs,
many manufacturers have their quality system
certified to ISO13485 and IVDD requirements
by a combined registrar and Notified Body.
However, the quality system may be certified to
ISO13485 by one registrar and to IVDD requirements by a completely separate Notified Body.
Under the IVDD, Annex II List B products can
alternatively be certified by a combination of
EC Type Examination and EC Verification by a
Notified Body. EC Type Examination requires
assessment of product technical documentation
and physical examination/testing of initial samples of the device to confirm that they have been
manufactured in accordance with that documentation and meet the essential requirements of the
IVDD.
EC Verification requires examination and
testing of all batches of product to ensure continued compliance with the IVDD. Similarly, Annex
II List A products can also be initially certified by
EC Type Examination, but this certification has to
be supplemented by assessment and continuing
surveillance of the manufacturer’s production
quality assurance system. These certification
routes have not been described in detail as they
are complex and few manufacturers of Annex II
products opt for them.
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Canada (MDR)
Classification
May 2011
Additionally, it must be emphasized that,
to comply with IVDD requirements, all Annex II
List A products are subject to batch verification
prior to QC release for sale. Each batch has to
be certified by the Notified Body as compliant
with its quality control release specifications by a
process of independent testing or witness testing
arranged by the Notified Body. There is no similar requirement in the Canadian regulations for
verification and release of each batch of high-risk
products prior to sale.
Conclusion
I have pointed out the principal similarities and
differences between the current European and
Canadian regulations on in vitro diagnostic
medical devices.
Although differences exist, there are
opportunities to simplify the process a little if
manufacturers intend to sell in both markets. As
the technical documentation requirements for
Notified Body certification and Canadian device
licensing are similar, there is considerable scope
for manufacturers to present the data in a format
suitable for their regulatory applications in both
regions.
Additionally, the manufacturer’s quality
system can be audited for both Canadian and
European IVD regulatory compliance in the
most efficient and economical way by using
a CMDCAS-recognized ISO13485 registrar
that is also a European IVD Notified Body.
Nevertheless, regulatory professionals at companies that are planning to sell IVD products
on these markets should study the details of the
IVDD and the CMDR to ensure full compliance
with the legislation.
These documents are available on
the European Commission and Canadian
Department of Justice websites. Further help and
information can be obtained from any European
Competent Authority or Health Canada directly.
References
1. Directive 98/79/EC of the European Parliament and of the
Council of 27 October 1998 on in vitro diagnostic medical
devices. European Commission website. http://ec.europa.
eu/consumers/sectors/medical-devices/documents/.
Accessed 19 March 2011.
2. Medical Devices Regulations (SOR/98-282). Department
of Justice, Canada website. http://laws.justice.gc.ca/eng/
SOR-98-282/. Accessed 19 March 2011.
3. Global Harmonization Task Force (GHTF): Principles of
In Vitro Diagnostic (IVD) Medical Devices Classification
(2008). GHTF website. www.ghtf.org/documents/sg1/
sg1final_n045.pdf. Accessed 19 March 2011.
4. Medicines and Healthcare products Regulatory Agency,
London, United Kingdom. MHRA website. http://www.
mhra.gov.uk/. Accessed 19 March 2011.
5. European Commission Nando (New Approach Notified
and Designated Organisations) Information System.
European Commission website. http://ec.europa.eu/
enterprise/newapproach/nando/index.cfm. Accessed 19
March 2011.
6. Underwriters Laboratories. UL website. http://www.
ul.com/. Accessed 19 March 2011.
7. Medical devices – Legislation and guidelines. Health
Canada website. http://www.hc-sc.gc.ca/dhp-mps/
md-im/legislation/index-eng.php. Accessed 19 March 2011.
8. Commission Decision of 27 November 2009 amending
Decision 2002/364/EC on common technical specifications
for in vitro diagnostic medical devices (2009/886/EC).
European Commission website. http://ec.europa.eu/consumers/sectors/medical-devices/documents/. Accessed
19 March 2011.
Author
Ivor Barrett has 27 years of experience in design and development, manufacturing, quality control and quality assurance
within the IVD medical device industry. He is currently an
IVD certification manager in the UL Notified Body with additional responsibilities as a quality system lead auditor for the
European IVD Directive, ISO13485, ISO9001 and CMDCAS. He
holds a postgraduate doctorate from the University of London
(Institute of Cancer Research).
Disclaimer
This article is intended for general information purposes only
and is not intended to provide specific legal or other advice
with respect to its subject matter and UL disclaims any responsibility or liability therefor.
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