Global Medical Device Update
Michael Flood FIEAust CPEng (Biomed) NER APEC Engineer IntPE
Locus Consulting Pty Ltd
CANBERRA, Australia
July 2019
A little about me .............
• Biomedical Engineer
• >40 years in the medical devices sector of Healthcare Industry
• 8 years in commercial organisation – technical marketingand service engineering
• 10 years public health sector – engineering services, asset acquisition and management
• 17 years with TGA as the industry regulator
• 9 years as a consultant back to all three sectors !!
Roles within the TGA ............
Manager, Postmarket Incident Report & Investigation Scheme (IRIS)◼ Member GHTF SG 2 – Postmarket – 1996 – 1999
Manager, Device Registration and Assessment Section◼ Member GHTF SG 1 – Premarket – 2000 – 2009
Director, Application Entry & Co-ordination◼ IT systems development◼ Represent GHTF on GMDN – 2000 – 2008
Policy Advisor, Office of Devices, Blood & Tissues◼ Regulatory reform
• Re-classification• Conformity assessment activities• Health Technology Assessment Taskforce• E-health• Device & patient tracking
Other Activities
Standards Australia◼ Health & Food Sector Standards Board
◼ Medical Electrical Equipment standards
◼ Medical Gas Systems standards
◼ Conformance marking
◼ Human Exposure to EME
◼ Medical Records
Engineers Australia◼ Chairman, College of Biomedical Engineers (three terms)
◼ Board of Engineering Practice
◼ National Engineering Registration Board
◼ Appeals Board – Immigration Qualification Assessment
• Academic◼ Adjunct Lecturer – ANU – Biomedical Engineering
◼ Visiting Lecturer – several universities – regulatory affairs
◼ Visiting Lecturer – National University of Singapore
International activities
• GHTF
• SG 2 – postmarket – 1996 – 1999
• SG 1 – premarket – 2000 – 2009
• GMDN – Maintenance Agency Policy Group – 2000 –2008
• ISO – Represent Australia on TC 150 – Surgical Implants
• Liaison with EU Commission and Notified Bodies on behalf of TGA
• Conformity Assessment & market entry
• EU Australia Mutual Recognition Agreement
• AHWP, ASEAN and APEC Conferences and Workshops
• 2002 ongoing, and now ................
Harmonisation………..
……..Harmonising………..
……..are we there yet ?
Where were we……………the good old days !!
Europe
◼ Pre 1993 –
• Widely varying frameworks in the (then) 17 member states
◼ UK – Focus on quality management systems and licencing of manufacturers
◼ Germany – Focus on type testing and certification ‘marks’ issued by test houses
◼ France – Homologation rules ...........
◼ Elsewhere - ?????????????
Canada
◼ Pre 1998
• Less than 5% of medical devices required pre-market approval
◼ Contact lenses
◼ Menstrual tampons
◼ Implants > 30 days (except dental & metal orthopaedic fixation devices
◼ HIV IVD’s
Japan
◼ Pre 2005
• Licencing of manufacturers – local and overseas
• Heavy focus on premarket testing
◼ In Japan
◼ Using unique Japanese standards and requirements
United States
◼ 1976
• Medical Devices Act
◼ Expanded authority of FDA to regulate medical devices
◼ Three classes of devices
• Identified by ‘lists’ in the 21 CFR
◼ Introduced concept of ‘substantial equivalence’
• Section 510(k) of Food, Drug and Cosmetic Act –premarket notification
• PMA Premarket approval
Australia
◼ 1985
• No regulation of medical devices
• Control of small number of high risk devices using the Customs Act
◼ 1989
• Therapeutic Goods Act 1989
◼ 1991
• Therapeutic Goods Regulations
◼ Registered devices
◼ Listed devices
And then along came …….
GHTF
◼ Preliminary meeting in 1992 – Nice, France
• EU, US, Japan and Canada
◼ First meeting 1993
• GHTF formed
• Three Study Groups formed (later to be five)
◼ Compare member jurisdictions
• Regulatory frameworks
• GMP requirements and methodologies
• Quality design systems
◼ Starting point
• An international regulatory model
• “internationalisation” of soon to be introduced EU model based on ‘new approach’ directives
GHTF
GHTF – work completed
◼ SG1 – Premarket – medical devices and IVD’s
• 12 documents published
◼ Definitions
• medical device
• Manufacturer, Authorised Representative, Importer, distributor
◼ Classification – medical devices & IVD’s
◼ Essential Principles of safety and performance
◼ Labelling
◼ Conformity Assessment procedures – medical devices & IVD’s
◼ Summary Technical Documentation (STED)
◼ Registration & Listing
GHTF – work completed
◼ SG2 – Postmarket Surveillance/Vigilance
• 6 Documents published
◼ Review of current requirements on P’mkt Surveillance
◼ Global guidance for adverse event reporting
◼ Handling of information concerning vigilance reporting
◼ National Competent Authority exchange criteria
• Application to join NCAR scheme
◼ Content of Field Safety Notices
GHTF – work completed
◼ SG3 – Quality Management Systems
• Four documents published
◼ Implementation of risk management principles within a Quality Management System
◼ Process validation guidance
◼ Guidance of corrective & preventive action and related Quality Management System processes
◼ Guidance on the control of products and services obtained by suppliers
GHTF – work completed
◼ SG4 – Auditing
• 6 Documents published
◼ Guidelines for auditing a manufacturers QMS –
• Part 1 – General requirements
• Part 2 – Regulatory auditing strategy
• Part 3 – Regulatory audit reports
• Part 4 – Multiple site auditing
• Part 5 – Audits of manufacturer control of suppliers
◼ Training requirements for auditors
• Part 1 – General requirements
GHTF – work completed
◼ SG5 – Clinical safety and performance
• 6 Documents published
◼ Clinical evidence – key definitions and concepts
◼ Clinical investigations
◼ Clinical Evaluation
◼ Post-market Clinical follow- up studies
◼ Reportable events during premarket clinical investigations
◼ IVD specific guidance on clinical evidence
....... and then there was the Steering Committee
◼ Ad hoc working groups
• Software
• Training
• Combination products
• Maintenance Mode
• Global Medical Device Nomenclature System
• Global Model
• Unique Device Identifier
• Regulatory change management
And Finally ............ The Global Model
◼ Published as a Final Document in April 2011
◼ Intended to link the work of the Study Groups into a cohesive framework
◼ Based on product life cycle
Progress since 1992 - Europe
◼ 1990
• Active Implantable Medical Device Directive – 90/385/EEC
◼ 3 year implementation
◼ 1993
• Medical Device Directive – 93/42/EEC
◼ 5 year implementation
◼ 1998
• IVD Directive – 98/79/EC
◼ 5 year implementation
◼ 2012 – Proposal to recast directives
• Announced September 2012
• More closely aligned with GHTF
◼ 2017 - Regulation (EU)2017/745 – Medical DevicesRegulation (EU)2017/745 – IVD’s
• 3 year implementation – May 2020
Progress since 1992 - Canada
◼ 1998
• Adopted GHTF in its (as then) draft form
• Introduced concept of risk based classification for IVD’s
◼ Principles, later, largely adopted by GHTFand subsequently EU in Regulation (EC)2017/746
◼ 2002 - Announced adoption of GHTF based regulatory framework
◼ 2004 – Pharmaceutical & Medical Devices Agency (PMDA) created
◼ 2005 – Framework fully implemented
• With some Japanese ‘adjustments’
Progress since 1992 - Japan
◼ 1991 – Therapeutic Goods Regulations only 1 year old
◼ 1996 – Commenced consultation with industry regarding harmonisation with EU
◼ 1998 – Language shifted to ‘international harmonisation’ ……… GHTF
◼ 2002 - GHTF based framework introduced
• 5 year transition period ….. 2007
◼ 2010 – GHTF IVD framework introduced
Progress since 1992 - Australia
◼ Language has shifted from ‘harmonisation’
to ‘convergence’
◼ ……… but still in there !
Progress since 1992 - USA
But quietly working away in the background ….
◼ ASEAN
• Association of South East Asian Nations
◼ ASEAN Medical Device Directive – October 2015
◼ MIDDLE EAST
• Middle East Harmonisation Working Party
◼ Eg – Saudi Arabian Regulations - decree number (1-8-1429) and dated December 2008
◼ SOUTH AMERICA
• Pan American Harmonisation Working Party
◼ EG Brazil - RESOLUTION RDC NO. 185, October 2001
◼ SOUTH AFRICA• Medicines and Related Substances Act 1965 – Amendments December
2016
◼ INDIA• Medical Device Rules, January 2017
Ref: WHO - https://www.who.int/medical_devices/safety/all_basic_levels_types_mod.jpg?ua=1
Regulation is continually moving !!
Dec 2016 / US FDA 21ST Century Cures Act
May 2017 / BRAZILNew INMETRO Rule(RDC 54) Applied
May 2017 / EUMDR & IVDR enter
force
July 2017 / UKRAINENew MD Registration
applied
August 2017 / S. AFRICANew MD Regulations
introduced
2018/2019 / PhilippinesMedical Devices Regulations
Jan 2018 / MALAYSIAMedical Device Regulations
Exemption ends
Jan 2019 / CANADA
Medical Devices Act
Jan 2018 / VIETNAMMedical Device Regulations
Introduced
Jan 2018 / INDIAMedical Devices Regulations
introduced
2018 / TAIWANMedical Devices Act
Mar 2019 / ISO 13485:2016Transition ends
May 2020 / EUMDR Transition
ends
May 2022 / EUIVDR Transition
ends
Dec 2021 / EURASIAEconomic Region
Medical Device Regulations
And that’s without factoring in -
• ASEAN – 6 economies still finalizing the
implementation of the ASEAN MD Directive
• AUSTRALIA – Amendments coming from 2016 MD
Regs review
• NEW ZEALAND – Whole new regulatory framework
• US – Amendments to QSR’s to better align With ISO
13485
• Extension of IMDRF MDSAP program
• Transition to ISO 14971:2019
• BREXIT !!
And in 2012 along came ……….
Work program…………
◼ SaMD – Software as a Medical Device• Definitions, classification, application of a QMS and clinical
assessment
◼ UDI – Unique Device Identifier• Guidance
◼ MDSAP – Medical Device Single Audit Program• Competencies
◼ Organisation◼ Assessors
• Training & Recognition• Audit report format
Work program………… cont’d
◼ Competency, Training and Conduct Requirements for Regulatory Reviewers
• Principles of Labelling (Updated)
• Essential Principles of Safety and Performance (Updated)
◼ Postmarket• NCAR – National Competent Authority Reporting
◼ CA Adverse Event information exchange• Terminologies & Coding• Adverse Event Reporting
◼ Device Registers• Essential Principles of a Register• Assessing Registry data for regulatory decision making• Principles for the use of International Registry Data
Work program………… cont’d
◼ Regulated Product Submissions – ToC• Medical Devices• IVD’s• Assembly Guide for RPS• Common Data Elements for Device ID
(this is not the same as UDI)
◼ Postmarket• NCAR – National Competent Authority Reporting
◼ CA Adverse Event information exchange• Terminologies & Coding• Adverse Event Reporting
◼ Device Registers• Essential Principles of a Register• Assessing Registry data for regulatory decision making• Principles for the use of International Registry Data
Hot Button Issues emerging……
Additive Manufacturing …….AKA 3D Printing
Why do we care about 3D printing
◼ Personalisation
• One off manufacture – prohibitive with traditional manufacturing methods
◼ Rapid prototyping
• Iterate design refinements
◼ Modelling
• Manufacturing prototype
• Surgical planning
◼ Complexity
• Intricate internal structures –sometimes impossible with traditional manufacturing methods
◼ 2000
◼ First attempt at human kidney scaffold
◼ 1999
◼ First application of 3D printing in the medical field – creating the human bladder
Replacement organs
Anatomical modelling
◼ Once only for difficult cases now becoming more mainstream
• 2003• Dr Kenneth Salyer successfully separate conjoined
Egyptian twins
◼ 2009
◼ First useable prosthetic leg
Cranioplasty
An Australian Success story……….
The ‘printer’……….!!
The implant ……….
The end result……….
The future………
◼ Customised orthopaedics…….
• already here to some extent
• Need to consider lead times……..post finishing is time consuming
Customised orthoses
Already here
◼ Anatomical modelling
• Emerging
• Imaging to 3D model …..familiarization and practice on difficult anatomy
◼ Replacement organs
• Still an enormous amount of work to do
◼ 3D scaffolding is easy
◼ Biology of stem cell proliferation in infancy
◼ Complex drug release profiles
Why do we care about 3D printing
◼ The technology now allows rapid production of complex one off custom made devices
• Current custom made device regulations, generally, are light touch and have focused mainly on the external orthoses market sectors
• Technology now facilitates new and emerging treatment modalities including -
◼ Custom made implants
◼ Artificial organs & biological materials
Prashant - https://www.slideshare.net/UXTrendspotting/3-d-printing-26045823
The future ……….
◼ Unlimited………………….
◼ More about cellular biology than engineering
◼ Personalised medicine will be a reality
• On-demand drug printing
◼ Printing of patients tissue to test medication effectiveness
• Simple organs today, more complex organs tomorrow
◼ Projected printable heart ~ 20 years away
◼ In situ repair of damaged tissues or organs◼ Already happening
• Skin lesion filled, in place, with keratinosytes and fibreblasts
◼ GHTF attempted to address
◼ No Consensus among members
◼ ……………….issue quietly dropped !!
◼ Result – no harmonization in the area
◼ Yet ……………..
Combination Products…….
Converging medical technologies
Medicine/Drug
Biological material
MedicalDevice
Examples ……….
Source: Google Images;
◼ Transdermal patches
Examples ………
◼ Viacyte VC-01™ - Improving Diabetes Treatment
59
cryopreserved human fibroblast-derived dermal substitute for advanced treatment of diabetic foot and leg ulcers
Dermagraft ®
Examples ………
‘Closed loop Insulin delivery
Examples ………
◼ PathVysion – breast cancer HER-2 test for Herceptin therapy
◼ Patients who are HER-2 positive, are treated with Herceptin.
Examples ………
Definition of Combination Product
AUS Not defined as a separate product. Combination Products regulated according
to main function/purpose of the Combination Product.
Canada A therapeutic product that combines a drug component and a device component
(which by themselves would be classified as a drug or a device), such that the
distinctive nature of the drug component and device component is integrated in
a singular product.
Japan No specific definition. Combination Products are regulated according to main
function/purpose of the Combination Product.
US Product comprised of 2 or more regulated components that are physically,
chemically or otherwise combined or mixed and produced as a single entity or
co-package product, or as cross-labeled products.
EU No general definition of combination product. A ‘combined advanced therapy
product’ is defined as one that incorporates as an integral part one or more
medical devices, or active implantable medical devices, and viable cells or
tissues, or non-viable cells or tissues where the action on the human body of
these cells or tissues is primary to the device.
Components of Combination Product
AUS • Medical Device
• Medicine
• Biologics (but not medicinal biologics)
Canada • Device
• Drug
Japan • Device
• Drug
US • Drug
• Biological Product
• Device
Not Combination Product if combined with:
• Cosmetics
• Foods
• Dietary Supplements
EU • Medical Device
• Medicinal Product
• Biologic
Agency Review Determinations – Who is the lead?
AUS Consider primary intended purpose and mode of action. May be referred to
an internal committee consisting of staff from relevant regulatory areas of
TGA.
Canada MDB – when classified as a Device.
Japan PMDA leads review – Offices under PMDA will lead depending on how the
Combination Product is regarded.
US Assignment by Office of Combination Product to Agency Center based on
“primary mode of action” of Combination Product. If PMOA cannot otherwise
be determined, assignment will be based on the following algorithm.
If there is an Agency Center that regulates other Combination Products
presenting similar questions of safety & efficacy with regard to the
Combination Product as a whole then the Combination Product should be
assigned to that Agency Center. If not, the Combination Product will be
assigned to the Agency Center that has the most expertise related to the
most significant safety & efficacy questions presented by the combination
product.
EU Consider primary mode of action. Opinions must be sought from relevant
expert committees for certain Combination Products
Pre-market Review of Applications for Combination
Product
AUS • None unique to Combination Product
• Prescription Medicine Applications
• Medical Device Applications
• Non-Prescription Medicine Applications
• Complementary Medicines Applications
Canada • Application for Combination Product
Japan MHLW defines primary mode of action based on rational provided by
company
US • None unique to Combination Product
• PMA
• 510(k)
• HDE
• BLA
• NDA
• ANDA
EU • None unique to Combination Product
• Medicinal product Applications (which include Advanced Therapy
Products)
• Medical Device Applications.
Agency “Non-primary” Component Consultations
AUS According to TGA algorithm
Canada Joint review with other Health Canada components.
Japan All handled within MHLW
US According to Agency SOP governing consultative/collaborative review
process.
EU Notified Body is required to consult the appropriate Drug Authority (National
or EMEA). Opinions from Expert Committees may be required.
The Digital Health Environment……
Circa ~ 1980’s ………….
Circa ~ ‘90’s – 2000 + ………….
© Locus Consulting
Today 2019 ………….
Issued raised……..Issued raised……..
◼ Connectivity• Common language for information/data exchange
◼ Data security
• Encryption
• Awareness
• Protection
◼ Patching
◼ Credentialing of users
• Levels of Access
◼ Exercising security systems
• ‘White hat’ penetration testing◼ Internal
◼ External
◼ Unauthorised loading of software, data, probes
◼ Data Backup & Restoration
◼ Network integrity
• 24/7 uptime
◼ Reliance on external suppliers
◼ Connection to a National Electronic Health Record
• Access to that NEHR
Issued to be concerned about…..
In other words …….
◼ Cybersecurity !!!
© Locus Consulting
Cybersecurity Threats…….
◼ ‘Cloud’ Security• It takes a lot more effort to defend the terrain than it does for them to
attack it !!
◼ Ransomeware• Been there…..experienced that !!
◼ IoT Exploits• Device Vulnerability (https://www.google.com/search?client=firefox-b-
d&q=dick+chaney+defibrillator )
◼ People• Lack of awareness
• Need for training
• Internal lockouts, security systems
Who is addressing it……..
◼ Is there a co-ordinated approach
• IMDRF …….silent to date
• Regulators ……not much out there
• Manufacturer’s – actively working on it
• IT vendors – aware but working in silo’s
• Integrating the Healthcare Environment
◼ www.ihe.net
◼ Collaboration of equipment vendors, IT suppliers, users attempting to bring it all together
Lots of work still to be done …….
◼ But that leads on to ……….
◼ Artificial Intelligence in Healthcare
© Locus Consulting
Immediate Areas of Application…….◼ AI Assisted robotic surgery
• Pre-op analysis of clinical records/images
• Suggest optimal surgical approach to procedure
◼ Virtual Nursing Assistants
• Facilitate better patient record keeping
• More time for patient interaction and communication
◼ Workflow & Admin Tasks
• Voice to text transcription
• Pro-actively searching/mining of ‘big data’ to suggest personalized therapies
◼ Image analysis
• Suggestions AI can analyze 3D scans > 1,000 time faster than today’s protocols
• Access to such technologies for remote areas without easy access
◼ Genetic data
• Rapid analysis and matching
Can Regulation keep up ……….??
◼ To ……
• Personal management of health
• Prevention
• Earlier diagnosis
• Milder Chronic Condition
• Shorter Rehabilitation
• Lower total cost of episode
• Containment of social cost
• Lower personal impact
• Healthcare today is a shifting approach
Why do existing Regulatory Systems struggle with innovation ……..
◼ Identification of new and emerging technologies and associated risks
• Identification of ‘novelties’
◼ Humanitarian Availability
• New modalities emerge to treat new and emerging clinical needs
• Access before broader marketing approval
◼ Lack of available ‘Standards’
◼ Challenge to find local resources to assess new modalities
◼ Lack of access or identification of ‘independent’ experts
So ……….Questions
◼ Are we there yet
◼ from a regulator’s perspective
◼ Are we there yet
◼ from an industry perspective
◼ What is missing
◼ What is yet to be done
◼ Will we ever get there ……….
© Locus Consulting
………Thank you
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