BN5208
Biomedical Quality and Regulatory Systems
Mrinal Kanti, PhD
Department of Biomedical Engineering
National University of Singapore
What we will learn today…
• Practice MCQs to ensure you understood and retained what was taught last week
• De Novo pathway
• Going over some concepts from previous class like predicate devices, 510k and PMA
processes
• Different regulatory bodies worldwide
• About European union
• EU directives for medical devices
• Risk classification
• CE certification process
• Classification of medical devices in Singapore
• Regulatory framework of Singapore
Some additional concepts from
last lecture
De Novo pathway
For new/novel (potentially ground breaking) medical
devices, which previously have not been designated a class
(as they are new), but are ascertained to be low to medium
risk, the De Novo pathway is appropriate…
Previously (prior to DeNovo) they were being placed in Class III, requiring
significant patient data and thus enhanced time to market…which FDA
felt was not appropriate
De Novo devices are those for which general and special “controls”
provide a “reasonable assurance” of the device’s safety and effectiveness,
even though there are no legally marketed devices of the same type
EG: Specific Insulin pumps and Hearing aids
Predicate device is a legally marketed device used
for comparison to determine safety and efficacy
Substantial equivalence
• Both devices have same intended use
• New devices have same/very similar technology
Content of a 510(k) submission
CDRH submission cover A standardised cover sheet that can be used to record basic information on all pre-market
sheet submissions to the CDRH
Covering letter Identifies the device and gives a brief outline of the device
Table of contents
Statement of substantial Identifies reference device or standard and rationale for claiming equivalence/conformity
equivalence/conformity
Labelling Copies of labels, instructions for use or user manuals or other relevant information
Comparative information Data demonstrating equivalence and performance. May also include information from
predicate device to show equivalence of claims, etc.
Biocompatibility assessment Data establishing the biocompatibility of the materials
(if applicable)
Truthfulness and accuracy A signed declaration by a responsible person for the submission as to the truthfulness and
statement accuracy
Shelf life (if applicable) Data establishing the stability of the device, accelerated stress data are acceptable
Indication for use form Formal clarification of the indications for use, which will be made available to the public
510(k) Summary A summary of the submission, which will be made available to the public
Content of a PMA application
Table of contents summary Indications for use, device description, alternative practices, and procedures currently
available for the condition, marketing history (US or foreign), non-clinical laboratory
studies, clinical investigations, and overall conclusions.
Device description and Detailed drawings and description of device and methods used for manufacture and
manufacture control of the device.
Technical sections (pre- Non-clinical laboratory studies used to investigate microbiological, toxicological,
clinical and clinical data) immunological, biocompatibility, stress, wear, shelf life, and other characteristics of the
device.
Data from clinical investigations on human subjects, plus statements as regards
investigators, IRBs, and informed consent.
Device samples (on request) Provide samples of the device or a location where they may be tested by the FDA.
Copies of labelling Labels, instructions for use, user manuals, etc.
Content of a PMA application
General
requirements
Safety Devices to be designed and manufactured so as not to compromise the safety of
patients or users. Any potential risks must be acceptable when weighed against the
benefits to the patient and be compatible with a high level of protection of health and
safety.
Effectiveness The devices must be designed and manufactured in such a way that they will deliver
their intended performance under the recommended condition for use.
Risk management The design and construction of devices must adhere to the following safety principles:
– eliminate or reduce risks as far as possible (inherently safe design and
construction),
– where appropriate take adequate protection measures in relation to risks that
cannot be eliminated (eg battery powered devices),
– inform users of the residual risks due to any shortcomings of the protection
measures adopted.
Stability The devices must retain their performance characteristics over their claimed lifetime
under the normal stresses associated with their use.
The devices must be designed, manufactured and packaged so as to maintain their
performance characteristics under the intended conditions of transport and storage.
Content of a PMA application
Design and construction
/manufacturing requirements
Choice of materials Bio-compatibility data. Measures to prevent infection from devices containing
materials of biological origin.
Devices utilising a power source Protect against electrical shocks (device and/or connections). Avoid interference with
or by other devices (electromagnetic interference, etc.).
Ensure the reliability of power source and/or software. Protect against thermal or
mechanical risks.
Devices with a measuring function Ensure accuracy and stability of results. Use SI units.
Establish traceability to reference materials/standards.
Protection against radiation (lasers, Adopt measures to limit exposure of users or patients to radiation. Provide adequate
X-ray, etc.) control features and instructions to ensure safe administration of the intended
exposure.
Sterile devices Validate packaging and sterilisation procedures to ensure sterility.
Devices used in combination with Consider the performance of the overall system
other devices or equipment
Information supplied by the Provide mandatory information on labels and instructions for use (specified according
manufacturer to directive/type of device). Use symbols on labels.
U.S. Classification of Medical Devices
Medical devices vary widely in their complexity and their degree of risk or benefits.
They do not all need the same degree of regulation.
Thus, U.S. FDA places all medical devices into one of three regulatory classes based
on the level of control necessary to assure safety and effectiveness of the device.
These classes are:
Class I = General Controls
Class II = General Controls and Special Controls (510k)
Class III = General Controls and Premarket Approval (PMA)
Of the appx 1,700 classified devices, about 45% are Class I, 47% are Class II and 8%
are Class III.
• USA: US Food and Drug Administration
• Singapore: Health Science Authority
• Australia: Therapeutic Goods Administration
• Brazil: National Health Surveillance Agency (ANVISA)
• Canada: Health Canada
• China: China Food and Drug Administration (CFDA)
• Europe: European Commission Directorate General Health and Consumers
• Japan: Pharmaceuticals and Medical Devices Agency (PMDA) and the Ministry of Health, Labour and Welfare
List of member states of the European Union
Year of entry Member states
into the EU
1958 Belgium, France, Germany, Italy, Luxembourg, the Netherlands
1973 Denmark, Ireland, the United Kingdom
1981 Greece
1986 Portugal, Spain
1995 Austria, Finland, Sweden
2004 Czech Republic, Cyprus, Estonia, Hungary, Latvia, Lithuania, Malta, Poland,
Slovak Republic, Slovenia
2007 Bulgaria, Romania
2013 Croatia
The European Union member countries facilitate the free movement of goods (including medical devices).
Medical devices bearing the CE mark are cleared in the European Union market. The European Economic Area
(EEA) was established on 1 January 1994 following an agreement between the member states of the European
Free Trade Association (EFTA) and the European Community: Iceland, Liechtenstein and Norway are allowed to
participate in the EU’s Internal Market without a conventional EU membership. In exchange, they are obliged to
adopt all EU legislation related to the single market (including for Medical Devices). One EFTA member,
Switzerland, has not joined the EEA; CE marking of Medical Devices is, however, recognized in Switzerland by
means of a Mutual Recognition Agreement (MRA) between the EU and Switzerland.
Medical Devices Directives
The European Directives have to be transposed into national law by each member state in
order to integrate the content of these directives into laws and regulations without major
modification (Changes which conflict with EU Directive are not acceptable)
Date of Designation Scope Examples
enforcement
1990 Directive on Active Active Cardiac
Implantable Medical Implantable Pacemaker,
Devices Directive Medical defibrillator
(AIMDD) Devices
1993 Medical Device Medical Sutures,
Directive (MDD) Devices syringes
1998 Directive on In Vitro In Vitro Blood
Diagnostics Medical Diagnostics collection
Devices Directive Medical system, Petri
(IVDMDD) Devices dishes
Because the directives are harmonized, MD bearing
the CE marking may circulate freely throught EU
Transition from EU MDD (medical device
directive) to EU MDR (medical device
regulation)
• Gradual transition from MDD to MDR to be implemented by 2021.
• Not significantly different, but more emphasis on safety,
documentation, UDI (unique device identifier), PMS (post market
surveillance)
• Essentially an extension of MDD…
Active Implantable Medical Devices
The active implantable medical devices are at maximum risk: by definition
they are any active medical device which is intended to be totally or partially
introduced, into the human body and which is intended to remain after the
procedure.
Examples of active implantable medical devices
• Implantable cardiac pacemakers
• Implantable defibrillators
• Leads, electrodes, adaptors
• Implantable nerve stimulators
• Bladder stimulators
• Implantable active drug administration device
By default, all accessories to AIMDs are covered under AIMD themselves.
In vitro and Diagnostics Medical Devices
• The classification of in vitro and diagnostics medical devices is based on
the risk of usage. If they are to be used by healthcare professionals, they
are classified with lower risk, and thus exempt from independent pre-
market approval and placed on the market based upon the manufacturer’s
self-declaration that the device comply with the requirements of the
Directive.
• When they are of higher risk and/or intended to be used by home user for
self-testing, they require a premarket design examination from a notified
body.
Examples of in vitro diagnostic (IVD’s)
medical devices per class
Class Risk Examples
List A Highest • Determining blood groups: e.g. ABO system,
including Risk • Detection, confirmation, quantification in human specimens of markers: e.g. HIV
self-test infection, hepatitis
Self-tests Interim Risk Pregnancy tests
List B Interim Reagents, calibrators, control materials for
Risk • Detection, quantification in human samples of congenital infections: e.g. rubella
• Diagnosing hereditary disease
• Determining human infections: e.g. Chlamydia
• Determining tumoral marker
Self-diagnosis device for blood sugar measurement
Self certifiable All others, Instrument, intended by the manufacturer, specifically to be used for in vitro diagnostic
lowest risk procedures;
Microbiological culture medium Reagents, calibrators, control materials for:
• Determining subfertility
• Diagnosis of rheumatoid arthritis
• Detection and differentiation of leucocytes
• Diagnosis of allergies
Specimen containers, transport media etc
EU regulations: Competent Authority
The competent authority or regulatory authority is a government agency or other
entity that exercises a legal right to control the use or sale of medical devices within
its jurisdiction. It has the ability to take enforcement action to ensure that medical
products marketed within its jurisdiction comply with legal requirements.
Its roles and responsibilities are as follows:
• indicates and inspects the notified bodies
• supervises the market
• centralizes and evaluates the vigilance data
• takes suitable medical measurements of police force
Following are the examples of competent authority:
• United Kingdom: MHRA (Medicines and Healthcare Products Regulatory Agency)
• France: AFSSAPS (Agence Francaise de Securite Sanitaire des Produits de Sante)
EU regulations
Authorized representative: Individuals or legal entities appointed by manufacturers who do
not have a registered place of business in Europe to act as regulatory contact for the
competent authorities. The AR must be established inside the EU. AR may be addressed by
authorities and NB instead of the manufacturer with regard to the latter’s obligations under
this Directive
Notified bodies: Independent entities, eg testing labs, certification organizations appointed
and accredited by CAs to conduct, conformity assessment procedures of medical device
companies to ensure compliance to MDD, IVDD, AIMDD. Most manufacturers need to be
audited by a NB unless the manufacturer only manufactures Class I (non sterile, non
measuring) devices. The manufacturer calls upon the notified body of choice: more than 76
registered notified bodies in Europe.
DOC: Declaration of conformity; is a document that a manufacturer must submit to
appropriate authorities stating that it conforms to the essential requirements of the directive
MDD or IVDD
Lets think…
If a med dev ‘X’ been approved by competent
authority in country ‘A’, will it be
automatically/legally approved for sale in
country ‘B’, within the EU
Hint: Eligible to market vis-a-vis right to market
Legal Manufacturer
• The legal manufacturer is legal person with responsibility for the design, manufacturing, packaging
and labelling of a device before it is placed on the market under his own name, regardless of
whether these operations are carried out by that person himself or on his behalf by a third party,
• The manufacturer must ensure that it is manufactured to meet or exceed the required standards
of safety and performance.
• The legal manufacturer is responsible of all the operations necessary to design, manufacture, label
and package the product throughout its lifecycle from design to distribution to the final customer.
The legal manufacturer is responsible to choose the notified body and affixing the CE mark on the
product once it is obtained.
• The manufacturer has an obligation to ensure that a product intended to be placed on the
Community market is designed and manufactured, and its conformity assessed, to the essential
requirements in accordance with the provisions of the applicable New Approach directives.
• The manufacturer may use finished products, ready-made parts or components, or may
subcontract these tasks. However, he must always retain the overall control and have the
necessary competence to take the responsibility for the product
Risk base EU classification of
Medical Devices
Medical devices are divided into four classes — Class I, Class IIa, Class IIb,
and Class III — according to the level of risk the device as based on the
following criteria:
• duration of use (transient, short term, long term)
• active/non-active
• implantable
• specific hazards (e.g. contact with the central nervous system, animal
tissues, absorbable material, ionizing radiation etc)
Steps to conformity and CE marking
Device classification
Examples of medical devices per class
Class Risk Examples
Class I Low risk • Surgical instruments
• Non-invasive tubing to evacuate body liquids
• Examination gloves/masks
• Hospital beds
Class Is Low risk (sterile) • Sterile body liquid collection devices
• Sterile absorbent pads
Class Im Low risk (with a • Syringe without needle (graduated barrel)
measuring function) • Device for measuring body temperature
• Device for measuring intra-ocular pressure
Class IIa Medium low risk • Syringe with needle
• Tubing intended for use with an infusion pump
• Non-medicated impregnated gauze dressings
• Short term corrective contact lenses
Class IIb Medium high risk • Hemodialysers
• Long term corrective contact lenses
• Urinary catheters intended for long term use
• Insulin pens
Class III High risk • Neurological catheters
• Prosthetic heart valves
• Pre-filled syringe for vascular access device
• Spinal needle
• Absorbable/resorbable sutures
CE Mark… the eventual goal
• The CE mark is the proof from the manufacturer that the product is in
conformity with the regulations.
• CE marking attests that the products are in conformity with the
essential requirements of the applicable directives and that the
products were subjected to the procedure of conformity evaluation
envisioned in the directives.
• CE marking is affixed before marketing the product.
• CE marking allows freedom of movement of the medical device in the
territory of the European Union.
Conformite Europeenee
Not to say that the product is ready for marketing but rather the
product conforms to established directives MDD, IVDD and AIMDD
Medical Device Classification By the Legal Manufacturer
MDD: Class Is, Im, IIa, IIb, III
AIMD: High Risk MDD: Class I
IVD: List A and B IVD: Self-tests, Self
Notified Body identification certifiable
Self certification by legal
manufacturer
Conformity assessment procedure
selection by legal manufacturer
Technical documentation
review by notified body
Batch verification
by notified body
Quality management system
Steps to CE
verification by notified body marking
CE mark certificate delivered
by notified body
Class I
Class Is, Im, IIa, IIb, III
Plus identification number of
the Notified Body
Continued batch verification CE declaration of conformity issued by legal manufacturer
by notified body
Implications on Manufacturer (most affected;
MDD to MDR)
Manufacturers bear the biggest burden in ensuring compliance to the
regulations. Article 10 lists manufacturers’ general obligations, explaining
what they need to do, and the Annexes explain how they need to do it. Here
is a summary of the responsibilities:
• Conduct clinical evaluations, including post-market clinical follow-ups
• Declaration of Conformity written and affixed to CE marking of conformity
• UDI compliance
• Establish a system for risk management
• Ensure incidents and field safety corrective actions are recorded and reported
• Cooperate with competent authority to provide information or product samples as needed
• Ensure processes are in place to manage compensation claims for damages caused by a
defective device
• Implement a postmarket surveillance program and ensure it is up to date
• Ensure devices are accompanied by all relevant information in the languages determined
by the member states where each device is available. The label shall be indelible, easily
legible, and clearly comprehensible to the intended user or patient.
It is a bit more complex but I have tried to put it in simpler terms to facilitate your understanding
Some fundamental points for
comparing EU/US Medical Device
Legislation
30
Purpose
• EU • USA
• European Treaty • To promote inter-state trade
• Requirements to allow medical • Requirements to allow medical
devices to be traded across the devices to be traded across
Member States without trade individual States
barriers
Authorities
• Legal authority: 28 Competent • Legal authority: FDA
Authorities
• Approval (PMA): FDA
• Vetting compliance with ER: 60
• Notification (510k): FDA
Notified Bodies
• Authority which can prosecute
• Authority which can prosecute
you: FDA
you: Competent Authorities
31
Content
EU USA
• Sets out Essential Requirements • Sets out Pre-Market Approval
(ER) which all devices must meet (PMA) requirements and confers
• Lists procedures through which Pre-Market Approval
manufacturers can demonstrate • Sets out Substantial Equivalent
compliance with ER (SE) process and issues SE
• Manufacturer makes Declaration Notification
of Conformity
Routes to market
• EU: seven different routes • PMA (Pre market approval)
covering • 510(k) Notification
– Active implantables
– Medical devices
– In vitro diagnostic medical
devices 32
Process
EU USA
• Manufacturer (M) classifies • FDA specifies classification
device (four classes) • FDA specifies route - PMA or 510(k)
• M chooses route • PMA: FDA specifies tests etc to be
• M does work to demonstrate carried out
compliance with ER • 510(k): M demonstrates this device
like another already on the market
• Notified Body assesses
• FDA writes Approval (PMA) or
compliance Notification (510k)
• M writes DoC
33
Compliance (simplified!)
EU USA (510 k)
• Notified Body carries out on-site • FDA examines technical
audit submission
• Checks QMS & Tech File • Issues ‘notification letter’
• Issues certificate • Marketing product
• Declaration of Conformation by M • At sometime later (2-4 years) on
• Marketing product site inspection of QMS
• Post market surveillance required
34
Singapore: Medical Device
Regulatory System
HSA (Health Science Authority)
Formed April, 2001 and comprises of:
• Health product regulation group
• Blood services group
• Applied science group
HSA passed Health products act (HPA) in
2007. The objectives are:
• Mandatory registration of all med devices
• Any dealer in med dev (manufacturer, importers etc) has
to be registered
• Post market responsibilities
Singapore Health Sciences Authority (HSA), Medical Device Branch, is entrusted
with regulating medical devices in Singapore. HSA has adopted the new regulatory
system based on the principles endorsed by the Global Harmonization Task Force
(GHTF) with modification to suit the Singapore context.
HSA has also studied the medical device regulatory system in developed country
counter parts, including the US Food and Drug Administration (FDA), European
Union, Canada’s Medical Devices Bureau (MDB), Japan’s Ministry of Health,
Labour and Welfare (MHLW), and Australia’s Therapeutic Goods Administration
(TGA).
In general, the regulatory framework for medical devices in Singapore is mapped
in order to safeguard public health but without unduly restricting consumer
choices and their access to new technologies.
In 2002, HSA introduced the Voluntary Product Registration Scheme and post-
market monitoring and surveillance program for medical devices in the Singapore
market. With the passage of the Health Products Act 2007 in February 2007, HSA
implemented the Health Products (Medical Devices) Regulations to further
strengthen the control of medical devices in local market.
Implementation phases of the regulatory control
November 1, November August 10, January 1, 2012
2007, onward 1, 2008, 2010
onward
Phase 1 Phase 2 Phase 3A Phase 3B
Imposition of duties Acceptance of license Only licensed dealers Unless authorized by HSA,
and obligations on application of parties shall manufacture, all classes of MDs are
dealers: dealing with MD import and supply MDs prohibited from supply
• Report product Acceptance of unless authorized by (Class A, B, C, D) MDs
defects and AEs Registration of Class HSA or listed on the licensed under Radiation
• Recall product upon C, D MDs (Transition Transition list, all Protection Act, NEA —
HSA instructions list/registered) Unregistered Class C, D August 1, 2011
• Keep distribution MDs are prohibited
Records from supply
Classification of Medical Devices (Classes A,
B, C, and D)
Principle
Regulatory control is proportional to the level of risk associated with a medical
device, which increases with higher degree of risk involved. Therefore, medical
devices are classified on the basis of their risk to patients and users substantially
on its intended purpose and effectiveness of the risk management techniques
applied during design, manufacture and use.
Classification
Various factors contribute to the risk classification of medical devices, which
includes:
• duration of medical device contact with the body
• degree of invasiveness
• delivery of medicinal products or energy to the user
• intended to have biological effect on the user
Risk classification system for medical
devices In Singapore
Risk class Risk level Medical device examples
A Low risk Surgical retractors/tongue depressors
B Low-moderate risk Hypodermic needles/suction equipment
C Moderate-high risk Lung ventilator/bone fixation plate
D High risk Heart valves/implantable defibrillator
Product Registration for Higher Risk Medical
Devices (Class B, C, and D)
Assoc. of Southeast Asian Nations (ASEAN), Common Submission Dossier Template
(CSDT) template is to be used for submission to HSA. All product registration
applications are to be submitted via the online Medical Device Information and
Communication System (MEDICS). Upon successful submission, the application will
be screened before it can be accepted for evaluation to ensure that there are no
major deficiencies that would hinder the evaluation.
Along the screening and evaluation processes, the registrant may be requested to
provide additional information if any major deficiencies are identified. The input
request will be made to the registrant and the registrant will be required to submit
the requested material and information within 14 calendar days from the date of
request.
The evaluation decision will be made on the basis of the evaluation outcome of the
submitted information, i.e., registrable, rejection. For medical devices that receive a
“Registrable” evaluation decision, the registrant may submit an application to list
the medical device on the SMDR (Singapore Med Dev Register).
Product Registration for Lower Risk Medical
Devices (Class A)
Submission in Common Submission Dossier Template (CSDT) is not required for
Class A medical devices.
The data requirement for Class A medical devices
• Letter of Authorization
• Singapore Declaration of Conformity
• Copies of product labeling, i.e., instructions for use, brochure, label, etc.
• Name, address, and contact information for all authorized importers
• Quality management system certificate for the manufacturing site and
sterilization site (if applicable)
• Sterilization method and sterilization validation standard(s) used (if applicable)
Additional requirement for Class A, in vitro Diagnostic (IVD)
• List of all materials and source of animal, human, microbial, and recombinant
origin used in the IVD medical device.
Routes to registration for Class B,
C and D classes
• Full Evaluation Route:
• Letter of authorization
• CSDT should include:
• Summary
• Declaration of conformity
• Device description
• Design verification and validation
• Labelling
• Risk management
• Manufacturing facility
• Abridged method:
• If it is approved in either; USA, EU, Australia, Japan, Canada
Country Regulatory agency/body National healthcare
policies/laws/regulations
US FDA Food, drug and cosmetics act and its
• Center for devices and radiological amendments
health (CDRH)
EU European commission MDD
• National competent authorities IVDMDD
• Notified bodies
AIMDD
Singapore HSA Health products act and its amendments
AIMDD: active implantable medical device directive
IVDMDD: in vitro diagnostics medical device
MDD: medical device directive
The level of complexity and burden on medical device market clearance
process is defined by the controls established in the country of interest
Some take home massages…
• Device classification for EU and Singapore is also risk based like
FDA; only that the nomenclature is little different
• Of the appx 1,700 FDA classified devices, about 45% are Class I,
47% are Class II and 8% are Class III
• EU has three directives to classify Med Devices
• The CE marked product conforms to established EU med dev
directives MDD, IVDD and AIMDD
• HPA was enacted by HSA in 2007
References
• Tobin JJ, Global marketing authorisation of biomaterials and medical devices
• Raps.org
• Wong et al. Med Dev RA in Asia
• https://www.hsa.gov.sg/
