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