Regulatory Process For Medical Devices In Europe:
Current status and upcoming revised regulation
MEDICAL DEVICE REGULATION
IMPACT AND OUTLOOK ON THE FUTURE
Uwe H. Wallstab, Eng. Med.Tec, Overath, Germany
Jens Grothues, RegDev, Colchester, UK
Cancun, May 14th, 2015
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European Union
• 28 member states
• Everyone Else!
• The candidate countries are not part of
EU
• Iceland, Switzerland, Norway, and
Liechtenstein are EFTA
• Turkey also accepts CE Mark through
Trade Agreement
• The CE Mark is generally recognized
globally
• Some require conformity but can not
enforce
• Some have their own national laws that
include CE Mark recognition for
compliance
European Union (EU): the establishment of an inter-governmental co-operation existing
between countries in Europe for trade and “home-affairs”
Europe Free Trade Association (EFTA): is a free trade organization between four European
countries that operates parallel to, and is linked to, the EU
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– Australia / New Zealand
– India
– Colonies of the European Union countries
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Published Directives
• European Directives are published by the European
Commission http://ec.europa.eu/index_en.htm
• Encompasses the European Union – 28 countries
• Directives are published in all sectors
• Member States have a transition period to implement into
law
• Directives provide appropriate legal framework and
generally work well
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Principle of EU framework legislation
Example Medical Device in Germany
Principle of the procedure
Adoption of a directive by the European
Parliament and Council
Directive 93/42/EEC
Medical Device Directive (MDD)
Transposition of the directive
into national law
in each EU member state
Transposition of MDD
into German Law
• National Law
• Medizinproduktegesetz *1
• Additional regulations on the national law
(German Medical Device act)
• Regulations on the Medical Device Act (e.g.
MPSV)
Supportive Documents
• MEDDEV Documents
• Harmonized Standard
Member States shall not set up barriers that
impede the placing on the market if the EU
regulations are complied
(EN and ISO Standards authorized by the EC)
• NB-MED Recommendations
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Current regulatory framework on Medical Device
• 1985: Plan for the “New Approach”
– Aim: Facilitating of marketing of medical devices within Europe
• 1990: 3 Directives regarding MD were implemented (in place)
– Active implantable medical devices [AIMD] (90/385/EEC)
– In-vitro diagnostic medical device [IVDD] (98/79/EC)
– Medical device [MDD] (93/43/EEC)
• 2007: Directives were amended by directive 2007/47EC
• Medicinal product directive (2001/83/EC)
The definition determines the scope!
The directives are product driven and not system
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Definition Medical Device (EU)
MDD Article 1, §2 (a): ‘medical device’ means any instrument, apparatus, appliance,
software, material or other article, whether used alone or in combination, including the
software intended by its manufacturer to be used specifically for diagnostic and/or
therapeutic purposes and necessary for its proper application, intended by the manufacturer
to be used for human beings for the purpose of
• diagnosis, prevention, monitoring, treatment or alleviation of a disease,
• diagnosis, monitoring, treatment, alleviation of or compensation for an injury or
handicap
• investigation, replacement or modification of the anatomy or of a physiological process,
• control of conception,
and which does not achieve its principal intended action in or on the human body by
pharmacological, immunological or metabolic means, but which may be assisted in its
function by such means;
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Medical Device Risk Classes According to EU MDD
• Annex IX, 18 rules based on:
–
–
–
–
Intended use
Duration of contact
Degree of invasiveness
Special situations
The classification of the MD determines the
conformity assessment route selected by the
manufacturer
Class I
sterile
Class I
Class I
Class IIa
Class IIb
Class III
with
measurement function
Increase of potential risk
Notified Body required
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Risk classes of Apheresis products (MDD)
Examples:
• Adsorption column with material from animal origin  Class III
• Adsorption column based on sytetic materials (e.g. dextran sulfate)
 Class IIB
• Plasma separtion filter, plasma fraction filter Class IIb
• Apheresis instuments  Class IIb
• Tube line  Class IIa
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The EU medical device regulatory approval process (1)
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The EU medical device regulatory approval process (2)
Notes:
1 Annex II:
EC DECLARATION OF CONFORMITY (Full quality assurance system)
2 Annex II.4: Examination of the design of the product
3 Annex III:
EC TYPE-EXAMINATION
4 Annex IV:
EC VERIFICATION
5 Annex V:
EC DECLARATION OF CONFORMITY (Production quality assurance)
6 Annex VI:
EC DECLARATION OF CONFORMITY (Product quality assurance)
7 Annex VII: EC DECLARATION OF CONFORMITY
8 Class III devices will likely require clinical study data. Clinical evaluation by using the literature route may be acceptable. Clinical trials in Europe must be pre-approved by a European Competent Authority.
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Essential Requirements
 General requirements
 Design & construction requirements
 Chemical, physical and biological properties
 Infection and microbial contamination
 Construction and environmental properties
 Information supplied by the manufacturer on the label and in the instructions
for use
 Harmonized European Standards
 “Voluntary” application of Standards
 Presumption of Conformity
 Conformity to Standard
 Conformity to Essential Requirements
http://www.newapproach.org/
http://ec.europa.eu/enterprise/newapproach/standardization/harmstds/reflist/meddevic.html
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What is Clinical Data to Support Safety/Performance?
• Clinical investigation (s) of the device concerned
• Clinical investigation (s) or other studies reported in the scientific
literature, of a similar device for which equivalence to the device in
question can be demonstrated
• Published and/or unpublished reports on other clinical experience of
either the device in question or a similar device for which equivalence
to the device in question can be demonstrated
• Compilation of information into a Clinical Evaluation Report
Note: Realization of clinical studies is not regulated by MDD and
different local regulations are in place
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High risk
Medical devices in Europe by risk class
In total: ~ 500.000
different medical
devices on the
European market
Class III
~50.000
. drug-devices, pacemake heart
valves
Class IIb ~ 90.000
e.g.
wound
dressings,
condoms, bone fixation plates,
ventilation devices
Low risk
Class IIa ~ 155.000
(eg. wound dressings, surgical clamps,
tracheotomy tubes, dental fillings)
Class I ~ 205.000
(e.g. compression bandages, stethoscopes, hospital
beds, wheel chairs)
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Regulatory Environment for Medical Devices in Europe
Current regulatory Issues
• Implementation of the directive provisions in the legislation
of every member state
• problem: Very different ways of interpreting the MDD requirements
• Accreditation of Notified Bodies by national authorities
• Approach to solve the problem: Publication of
Guidance Documents:
• MEDDEV, harmonized standards
• Introduction of the Notified Body Concept
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Initiatives of the EU commission for the restructure
of the regulatory provisions
• Continuous review of regulatory provisions by the
working groups
• Aim:
Adjustment of conformity criteria and predictable
timelines
 Necessity of restructuring identified!
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The Recast process
• Generally: Further standardization
• Critical points:
- Current provisions in respect to
uniformity, safety, quality, transparency, traceability und flow of
information
• Comparability of Notified Bodies
• Important aspects: Vigilance and Safety Reporting
• Clearer classification rules
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Initiatives of the EU commission for the restructure
of the regulatory provisions
Thougths:
• Unannounced audits by the NB
• Implementation of a system for tracking of marketed
medical devices (UDI)
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A medical device as catalyst of a process
B
B
C news
French breast implants caused a health scare across Europe and South America in year 2012.
A UK report in June 2012 found the PIP implants, made from unauthorized silicone filler, had double
the rupture rate of other implants.
The boss of the French company which distributed defective breast implants around the world has
since been sentenced to four years in prison for fraud.
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The Recast process
•
•
•
•
PIP as an example for extreme non-compliance
ca 400.000 implantations worldwide
Use of cheap industrial silicone to save money
Withdrawal of CE mark by TÜV Rheinland only one
month after the regulatory operating ban
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The Recast process
After the scandal:
Increasing discussions
• About stricter measures after infringements
• additional rules for the market surveillance
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The Recast process
• Still big inconsistencies regarding competent
authorities and ethics committees in Europe
• Wish to adopt further European harmonization
• Continuous review of the European regulatory
environment
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First concrete steps
• 2012: Draft of the Medical Device Regulation (MDR)
• Already included:
– Merge of AIMDD and MDD
– New classifications of breast implants
– New classifications of hip- knee and shoulder
replacements
• Also intended:
• IVDD  IVD Regulation
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The legislative process is in delay,
since the European parliament
was new elected in 2015, followed
by new European Commission and
obviously divagations between
Commission and Council.
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Main topics of the proposed changes
• Role of the notified body as a major change
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Main topics of the proposed changes
•
•
•
•
•
Review of the conformity assessment procedures
Clinical investigations
Clinical evaluation
Requirements and systems for vigilance
Requirements for market approval
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Growing Importance of
Clinical Evidence for Medical Devices
MDD 93/42 Annex X
• Clinical evaluation (1 page)
• Clinical investigation (1 page)
– MEDDEV 2.7.1 Rev.3 2009
Clinical Evaluation
– MEDDEV 2.7.4 2010 Clinical
Investigations
– MEDDEV 2.12/2 rev2 2012 PMCF
– Literature route broadly accepted for
conformity assessment
– Essential requirements based on
clinical evaluation
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MDR chapter VI
• Clinical Evaluation (Art. 49)
• Clinical investigations (Art. 50-60) Annex
XIII:
– clinical evaluation and post-market clinical
– follow-up (3 pages)
– Annex XIV: conducting clinical
investigations (6 pages)
– Class III and implantable devices (high risk
class): Literature route not acceptable
– For other risk classes: equivalence may be
difficult to demonstrate
– Enforcement of PMCF all over the life
cycle (periodic reports on risk/benefit ratio)
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Application for a Clinical investigation
According to Chapter VI, article 51
Application elements:
1. Unique ID number, generated by the application system
2. Clinical investigation in more than one member state (single
application)
3. Submission of documents listed in chapter II / confirmation on health
and safety or ethical concerns
4. Amended time frame to validate the application (14-20 d) and
approval or rejection (60 days)
5. Assessment done by a reasonable number of qualified persons, w/o
conflict of interest
6. Permission to start is depending on the risk class
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Registration of a Clinical investigation
According to Chapter VI, article 52
Before commencing
• The clinical investigation must be registered in a publicly
accessible electronic system
• Information has to be updated within one week when
changes take place
• The information on the CI will be accessible to the public
through the
• electronic system unless confidentiality of the information
(all or parts) is justified
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The Electronic system Clinical investigations
According to Chapter VI, article 52
The electronic system on clinical investigations as a tool
• Formalize the registration of clinical investigations
(in acc. with Art. 52)
• Enable sponsors to submit a single application for several member
states
• Exchange of information among the member states and the
• commission (in acc. with Art. 56)
• Convey information among MS for clinical investigations conducted in
more than one MS (in acc. with Art. 58)
• Report and convey information on SAE and device incidents (Art.
59(2))
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Provisions on equivalence
Equivalence can only be
demonstrated when
• Both devices have the same
intended purpose
• The technical and biological
characteristics of the devices
and the medical procedures
applied are similar
• There is no clinically significant
difference in the safety and
performance of the devices
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• Clinical
– Same clinical condition / purpose
– Similar population
– Similar performance
• Technical
– Same specifications/ properties
– Similar design
– Similar principle of surgery
• Biological
– Use same materials in contact with
same tissues or body fluids
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Growing Importance of Clinical Evidence for Medical
Devices
• MDR remains restricted to clinical investigations
carried out for regulatory purposes
 i.e. for obtaining or confirming regulatory
approval for market access!
• Non-commercial clinical investigations that do not
pursue a regulatory purpose are not covered by the
regulation
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“Better safe than sorry”
Samuel Lover’s Rory O’More (1837)
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Concrete changes
• Merge of AIMDD and MDD
• Integration of contents of the GHTF and the
MEDDEV guidelines as well as the EN ISO 14155
• 10 chapters with altogether 93 articles
• (in comparison: 23 articles in the current MDD)
• Extension of scope to further products
• More definitions, e.g.: Sponsor
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Concrete changes
• New assessment of classifications
• Designation of a qualified person by the
manufacturer
• Expansion of EUDAMED
• Class III devices: EUDAMED publication
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The future design of the EUDAMED European database
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Concrete changes
• Involvement of competent authorities and expert
groups in class III devices
• Annex II for technical documentation
• Implementation of EU reference laboratories
• Implementation of the UDI
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Concrete changes
• Centralized system for safety reporting and
vigilance
• Centralized submission process with multi-centric
clinical investigations
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MDR development process
Changes adopted by EUparliament
Draft MDR 26
Sep 2012
2012
Final MDR expected
MDR becomes effective
Changes
2013
Report to
ENVI
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2015
2016
2017
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Draft MDR
Scope:
• Medical devices containing biological substances are
still regulated by the MDR (9.20, 9.13)
• Discontinuation of rule 21 (Borderline devices)
 not necessarily class III products
• Classification of borderline devices
• Provisions of single use and reprocessing
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Draft MDR Content
• Unannounced inspections by the CA
• CE label:
CE mark, followed by the term “Medical Device”
• Rules for market approval for high risk devices
 SNB (Special Notified Body)
• Implants
• Device/drug combinations
• Medical devices which have been designed for the application of a
pharmaceutical (Drug – Device – Unit)
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Draft MDR Content
• Clinical data and PMCF:
 stricter assessment
• Clinical investigations:
 Stricter provisions for the informed consent of children
 Still crucial approvals by the EC
 PMCF: periodic reports to the member states
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Conclusion
• Regulatory framework will change from Directives to
Regulation
• Currently no final version of EU MDR available, still
ongoing discussions
• Final MDR document expected in the course of 2015
• Implementation of the MDR will cause changes in the
legislation of the member states
• Transition period approximately 3 year after publication
of the new regulation
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Conclusion
• Challenge for everyone involved
• Improvement of patient safety vs. obstacle to
innovations
• More effort required to reach the market clearance,
since more complex procedures
• Major efforts for adaption of the QM system +
update of product documentation
• Concrete recommendation are only possible if the
final draft is available! - Hope soon!
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Thank you for paying attention!
Any questions?
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