The ROI of Good Quality & Compliance

The ROI of Good
Quality & Compliance
April 19, 2016

2
2015
Expanded service
offering and
geographical coverage
Changing Regulations in EU & US for Medical Devices
Peter Rose, Managing Director Europe, Maetrics
Introduction to the Proposed EU Medical Device Regulations
Martin Penver, Head of Notified Body, LRQA
Integrating Quality with Corporate Compliance to Provide the Greatest Return
Seth Whitelaw, President & CEO, Whitelaw Compliance Group
The Impact of a Good Quality Management System
Carl Dover, Vice President – Quality Strategy & Process Improvement, DePuy Synthes
The Most Costly Problems and Why Continually Repeated
Adrian Toutoungi, Commercial Partner, Eversheds
Maetrics Regulatory Event in Collaboration with ABHI
The ROI of Good Quality & Compliance

3
2015
Expanded service
offering and
geographical coverageChanging Regulations in EU & US
for Medical Devices
Peter Rose
Managing Director Europe
Maetrics

Changing Regulations in
the EU and US
19th April 2016
London, UK

Introduction 3
Timelines 12
Reclassification 18
Reprocessing of Single Use Devices 20
Unique Device Identification (UDI) 22
Clinical Evidence 27
The Cost of Compliance 30
Questions 32
©2016 Maetrics. All Rights Reserved. 5
Presentation Topics

Introduction 3
Timelines 12
Reclassification 18
Questions 32
Presentation Topics

7
Introduction
 The most important change to the regulation of medical devices since CE marking was first
introduced
 Much is the same, or clarified
 Many important changes
 The new MDR is not news:
 First mooted as a Recast of the directive prior to 2007/47/EC
 Process became politicised following high profile adverse publicity for the industry
 PIP fraud using non‐medical grade silicone, over a 16 year period
 MoM hip implants, vigilance failures
 Pelvic floor mesh issues
 Inconsistencies across Notified Bodies
 Modernise the CE marking legislation
 Improve patient safety
 Assisting innovation and trade across the EU
MDR Background
©2016 Maetrics. All Rights Reserved.

8
Introduction
 The future is now
 The future has already started
 Unannounced Inspections
 Clinical Evaluation Reports
 Joint audits of Notified Bodies by DA, CAs and FVO
 Reassessment of NBs by CA
 Other key topics
 Notified Body Capacity
 EN ISO 13485:2016
 OBL (on‐site QMS audit; TF, Unannounced Inspections at OEM, no chains of OBL)
 Changes to EUAR liabilities, need for QP
 Compulsory Liability Insurance for Manufacturers
 Surveillance Fees in the UK
 Apprentice Levy (0.5% >250 employees)
 REACH / SVHC (168 substances limit to 0.1% w/w, at component level)
Not just changes within the MDR

9
Introduction
 The best companies will act early
 Notified Body capacity should be a major concern
 Wise to start planning now
 Nothing much will change, but anything can
 Learn the lessons from 2007/47/EC
Book early to avoid disappointment

10
Introduction
 2015 Data
 2082 company inspections
 Of whom, 797 companies received one or more 483s (38%)
 Totaling 1008 individual 483s
 Leading to 95 Warning Letters (4.5%)
 This is NOT probability it depends on your state of compliance
 Top 483 citations
US – Compliance Trends
Year #1 #2 #3 #4 #5
2015 CAPA Complaint
Files
Purchasing
Controls
Process Validation MDR
2014 CAPA Complaint
Files
Design
Controls
Purchasing Controls Receiving, In‐Process,
Finished Device Acceptance
2013 CAPA Complaint
Files
Design
Controls
Receiving, In‐Process,
Finished Device Acceptance
Purchasing Controls

11
Introduction
 FDA have plans to change from the current 25 district and regional offices managing
inspections to 3 offices for worldwide
 FDA have ‘Program Alignment Medical Devices and Radiological Health FY2016 Action Plan’
– see also http://www.fda.gov/AboutFDA/CentersOffices/ucm477082.htm
A. Transition to Commodity‐Based and Vertically Integrated Regulatory Program (Specialization)
B. Training and Certification
C. Medical Devices and Radiological Health Program Work Planning
D. Quality Policy and Strategy
E. Imports
F. Laboratory Optimization
G. IT
US Issues

12
Introduction
 FDA are revising
 CPGM – Compliance Program Guidance Manuals
 IOM – Investigations Operations Manual
 QSIT approach is under review with potential to be replaced by MDSAP (Medical Device Single
Audit Plan) and within that context FDA has already announced plans to retire the voluntary ISO
13485 program in favour of MDSAP. Note: this is not a commitment at this time.
US Issues – Update of inspections Approach

13
Introduction
A. Transition to Commodity‐Based and Vertically Integrated Regulatory Program (Specialization)
 More focussed approach
B. Training and Certification
 Many more highly trained resources, currently most inspectors have very general knowledge
C. Medical Devices and Radiological Health Program Work Planning
 Prioritise resources in line with the plan, and enforcement priorities
D. Quality Policy and Strategy
 FDA looking for 90% of their staff to have some connection with the public over the next 2 years to
understand the patients perspective
E. Imports
 More enforcement action on imports, especially Indian drugs hot topic
 Data integrity
 Increased foreign inspections. Proposals for increased funding, and headcount
F. Laboratory Optimization
 LDT – laboratory developed testing, validation and robustness
G. IT
 Focus on data integrity, documentation systems validation, altering of data
US Impact

14
Introduction
 No longer at an advantage during occasions where inspectors lack knowledge
 More and more Inspectors will be specialist and individually know more as a result of
extended training, e.g. electronics, software, 3D printing
 Training from Industry means specialists will be able to keep up with new manufacturing
methods and materials
 Efficiencies in filing times due to better skills set within FDA
 Conversely, will also be quicker action on compliance side, e.g. warning letters currently take
months, anticipated to be much quicker
US Impact

Introduction 3
Timelines 12
Reclassification 18
Questions 32
Presentation Topics

Timelines
 In the beginning
 Final MDR expected to Enter into Force in Q2/2014
 Always moving further away, but still ever closer
 Latest expectations are Entry into Force will be around Q4/2016
 Current status
 5th October 2015 – Council agreed a full “General Approach”. Trilogues began with the Council,
Parliament and Commission
 Luxembourgish presidency (July – December 2015) – 5 Trilogues, progress slower than hoped
 Dutch presidency (January – June 2016) – 3 Trilogues planned. Great expectations, for Q2/2016
 Slovakian presidency (July – December 2016) – Q4/2016?
 Malta presidency (January – June 2017)
 United Kingdom presidency (July – December 2017)
Timelines change frequently

Timelines
MDR ‐ An early timeline
2012 2013 2014 2015 2016 2017
Draft MDR
Sept 2012
Amendments
agreed
Oct 2013
3 year transition period
Entry into
force
June 2014
Date of
Application
June 2017

Timelines
MDR ‐ Current Timeline Estimate
2012 2013 2014 2015 2016 2017
Draft MDR
Sept 2012
Amendments
agreed
Sept 2016?
3 year transition period
Entry into
force
Dec 2016?
Date of
Application
Dec 2019?
2018 2019 2020
NBs can apply
+6 months for
re‐designation

Timelines
 Entry into Force
 The date the MDR is published in the OJ
 The Date of Application
 3 years after Entry into Force
 6 months after Entry into Force, NBs may apply for Re‐designation under the MDR
 Once granted NBs may begin to issue new certificates under the MDR and products may be legally
placed on the market under the new rules
 UDAMED database – timing remains unclear
 UDI requirements – timing remains unclear
 Total of 43 delegated acts that need to be implemented before the entire MDR can be fully
implemented
MDR ‐ Entry info Force & Date of Application

Timelines
 The Date of Application is not necessarily the deadline
 No requirement that devices must be re‐certified under the MDR by the Date Of Application of the
new Regulation
 Transitional provisions
 Certificates issued before to the entry into force of MDR stay valid for the period indicated on the
certificate
‒ Except certificates under Annex 4, Directive 90/385/EEC or Annex IV, Directive 93/42/EEC, which expire at the
latest 2 years after the Date Of Application
 Certificates issued during the 3‐year transition period stay valid for the period indicated on the
certificate, BUT in any case will expire 4 years after the Date Of Application
 Devices placed on the market under the current MDD before the Date Of Application may
be made available for up to 4 years after that date
MDR ‐ Certificate Validity (– but commercial pressures may apply)

Presentation Topics
Introduction 3
Timelines 12
Reclassification 18
Questions 32

Reclassification
 Classification rules are similar to before, but some significant examples of change:
 In vitro contact with cells/embryos going back into the body to be Class III (or IIa)
 Apheresis devices to be Class III
 IVF and ART non‐invasive devices can be IIb
 Spinal implants to be Class III
 Total and partial joint replacements to be Class III
 Devices recording diagnostic images to be IIa
 Nanomaterial devices to be Class III
 AIMD accessories to be Class III
 Devices which are intended to be introduced into the human body via a body orifice, or applied on
skin and that are absorbed by or locally dispersed in the human body are to be Class III
 Reusable surgical Instruments are no longer class I
‒ (CAUTION) Rumour about Class I with NB input
Up‐Classification of Devices

Introduction 3
Timelines 12
Reclassification 18
Questions 32
Presentation Topics

Reprocessing of Single Use Devices
 A sensitive subject for some, do these proposal enhance patient safety?
 Still under debate
 Allowed products list
 Banned products list Default is that it is allowed and manufacturers must state why not (European
Parliament)
 Re‐processers become legal manufacturers
 Member States can control within their own borders
 In‐house (i.e. hospitals) can continue to operate outside of the MDR
 Re‐processers must confine activities to OEM once used product or their own re‐processed
products
 Some debate over re‐processing vs fully refurbished
Still Under Debate

Presentation Topics
Introduction 3
Timelines 12
Reclassification 18
Questions 32

26
Unique Device Identification (UDI)
UDI System (Article 24)
 Article 24: A single system for UDI shall be put in place in the Union
1. Basic requirements for the UDI system
2. Issuing agencies for UDIs in Europe
3. Assignment of UDIs
4. Placing of UDIs on device labels / how UDIs should be used
5. Recording of UDIs
6. UDI database
7. Delegated acts related to running the UDI system
8. External factors

27
Benefits of UDI
 To enhance the post‐market safety of medical devices by:
 Improving incident reporting and recall processes
 Increased visibility for competent authorities
 Reducing the likelihood of product related errors
 Better stock‐management by healthcare facilities
 Counterfeit devices

28
FDA
 UDI system – Final Rule 21 CFR Parts 16, 801 and 803
 Published September 2013
 Implements IMDRF UDI
 Timetable according to classification

29
Its not just a bar code!
 Requirements to record, and verify, UDI information on
 Complaints forms & records
 Adverse Incident / MDR forms & records
 Corrections & Removals forms & records
 DHR including QC Release forms & records
 Service forms & records
 Should have been implemented in 2013
 Unlikely to yield a 483 if UDI is not yet a requirement
 Should include a UPC (Universal Product code) if no UDI
 Includes UDI requirements as part of Design History

Presentation Topics
Introduction 3
Timelines 12
Reclassification 18
Questions 32

31
Clinical Evidence
Requirements
 Chapter 6 (12 articles)
 Clinical evaluation and clinical investigation
 Annex XIII:  Clinical evaluation and PMCF
 Annex XIV:  Clinical Investigations
 Clinical evidence
 Must justify the level of clinical evidence used (e.g. risk class, intended use, device characteristics, etc)
 Performance is not equivalence
 More data will be required, CERs already under greater scrutiny
 Greater expectation that clinical investigations will be required, especially for Class III devices
 Equivalence for Class III devices should not be from other manufacturers
 Clinical investigations
 Greater emphasis on patient safety
 Data robustness and protection of patients during clinical investigations

32
Clinical Evidence
Data Sources
Rule 8 Clinical data
 Clinical studies
 PMCF
 Scientific literature
 Engagement with KOLs
 Clinician and patient focus groups
 Registries
 Ongoing data sources
 Active post market surveillance, routed through Risk Management process
 Use error and feedback
 Complaints, vigilance reports and MDRs
 Ongoing research by legal manufacturer
 Competitor data

Presentation Topics
Introduction 3
Timelines 12
Reclassification 18
Questions 32

34
The Cost of Compliance
Its not going to get cheaper
Rule 8 MHRA surveillance fees
 Notified Body fees, including unannounced visits
 Punitive damages – regulators
 Compensation and punitive damages – courts and patients / patient groups
 Remediation projects
 Increased requirements
 CER
 Risk
 Up‐classification
 New requirements
 UDI
 Person responsible for regulatory compliance
 Professional assistance

Presentation Topics
Introduction 3
Timelines 12
Reclassification 18
Questions 32

Maetrics
Maetrics Ltd Peter Rose
BioCity Nottingham Managing Director, Europe
Pennyfoot Street prose@maetrics.com
Nottingham +44 7811 199 346
NG1 1GF
United Kingdom
+44 115 921 6200
Contacts

37
The contents of this presentation are copyright ©2016 Maetrics. All rights reserved.
This presentation contains information in summary form and is intended for general
guidance only. It is not intended to be a substitute for detailed research or the exercise of
professional judgment. Maetrics cannot accept responsibility for loss occasioned to any
person, firm, company or corporation acting or refraining from action as a result of any
material in this publication. On any specific matter, reference should be made to the
appropriate professional advisor.

38
2015
Expanded service
offering and
geographical coverageIntroduction to the proposed EU
Medical Device Regulations
Martin Penver
Head of Notified Body
LRQA

Improving performance,
reducing risk
Introduction to the proposed EU Medical Device Regulations
Martin Penver
Head of Notified Body
LRQA

NEW Medical Device Regulation – 26/09/2012
Currently Medical Device Directives (60 pages)
Proposal are MDD & IVDD Regulations (278+)
What is the difference (apart from 218 additional pages) ?
Brussels, 26.9.2012,
COM(2012) 542 final
Proposal for a
REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL
on medical devices, and amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and
Regulation (EC) No 1223/2009
Directive is not enforceable by law across
Europe, but can be adopted by each country
Improving performance, reducing risk
A caveat: Discussions and documents are based on the
Council General Approach agreed in October 2015 – prior
to negotiations with the Parliament and the Commission. The
final text of the Medical Devices Regulation will differ from
those underlying this discussion in various respects.

The political timetable – September 2015
Jan
2014
July
2014
Jan
2015
July
2015
Jan
2016
Greek
Presidency
Italian
Presidency
Rapporteurs
appointed
Luxembourg
Presidency
New Commissioners in place
Latvian
Presidency
EP
elections
Council partial General
Approach
Trilogues
commenced
Conclude
trilogues?
Dutch
Presidency
Parliament 1st reading
full General
Approach
Entry
into
force?
July
2016
Slovak
Presidency
Started in 2012

The political timetable – March 2016
Jan
2014
July
2014
Jan
2015
July
2015
Jan
2016
Greek
Presidency
Italian
Presidency
Rapporteurs
appointed
Luxembourg
Presidency
New Commissioners in place
Latvian
Presidency
EP
elections
Council partial General
Approach
Trilogues
commenced
Conclude
trilogues?
Dutch
Presidency
Parliament 1st reading
full General
Approach
Entry
into
force?
July
2016
Slovak
Presidency
Another 6 Months
6 Month delay

Trilogues - State of the negotiations
• Council agreed a full ‘General Approach’ on 5 October 2015 – mandate for
informal trilogue negotiations with European Parliament and Commission
• 5 trilogues under the Luxembourgish Presidency – progress not as fast as
hoped
• Dutch Presidency (January-June 2016)
– 3-4 political trilogues (17 Feb, 16 March, 7 April, ? May)
– Informal political agreement by end of Dutch Presidency (June
2016?)
– Slovak Presidency (July-December 2016)
– Council formal First Reading Position (October 2016?)
– Accelerated 2nd reading by EP and adoption of final Regulations
(Autumn 2016?)

Council text
– Pre-market scrutiny
• Expert Panels
• Class III, implantable devices only
• Notified Body retains final decision
• Clinical Evaluation guidance & Common Specifications
• Exemptions if NB judges conformity with the above, and for non-
substantial modifications
– LRQA – note some panels – NB abliged to use panel – may not need if similar products,
may include renewals. This is only the council position, not yet definitive, expert panel
will be available to manufacturers, could be 100’s of devices per year.
– Panel will be a commission led process -

Council text
– In-house manufacturing exemption (IVD)
• Largely positive inclusion but some concerns
• Class C & D
• Publication of in-house practices and justification
• ‘Quality Management Systems’
• ‘Within health institutions’
– LRQA note: lists ISO15189 is stated or national provisions, some tests are not
applicable to this standard. Large discussion “on an industrial scale”
TERMINOLOGY
– Reprocessing of single-use devices
• Member State discretion
• EU minimum standard – no less than in-house manufacturing,
and reflect Common Specifications
– LRQA note: this means re-CE marking required, plus CTS’s, some question on
whether a NB is required

Council text
– Eudamed & unique device identification (UDI)
– Single Registration Number (SRN) for economic operators
– Manufacturers, Importers, Distributors required to store UDI
– Healthcare institutions not required but some system needed
Software
– Not an active device
– Classification concerns
– CE marking Laboratory Information Management Systems
(LIMS)
LRQA note: Eudamed current design does not take into account UDI, so complete
overhaul required, logic wrong.

Council text
– Clinical investigations
– Coherence with Clinical Trials Regulation
– Clinical evidence & equivalence
LRQA note: “clinical” taken from IVD performance has been requested to be added
back into the defined term. Has impact on ethics approval, to be brought up during
technical discussions on technical regulation.
– Post-market surveillance
– Clearer requirements
– Regular reporting for higher risk devices
Classification rules
– Further clarification during implementation
LRQA note: 19 & 21 rules out class I, all surgical instruments will become class IIa.

Council text
Non-medical medical devices – Annex XV
LIST OF PRODUCTS COVERED BY THE LAST SUBPARAGRPAH OF THE
DEFINITION OF ‘MEDICAL DEVICE’ REFERRED TO IN NUMBER (1) OF
ARTICLE 2(1)
1. Contact lenses;
2. Implants for modification or fixation of body parts;
3. Facial or other dermal or mucous membrane fillers;
4. Equipment for liposuction;
5. Invasive laser equipment intended to be used on the human body;
6. Intense pulsed light equipment.
Products can be continual added
Common specifications as a trigger – What’s the problem here? (ER6)
Cosmetic only - No medical benefit only risks

Implementation - priorities
• Pre-market scrutiny - Expert Panels
• Re-processing – national law & guidance
• In-house Manufacturing – guidance
• Genomics & companion diagnostics – guidance
• Software – guidance
• UDI & Eudamed – IT system & guidance
• Reference labs/expert panels – composition
• Notified Body Operations Groups (NBOG) codes
LRQA note:- more codes to be generated especially on IVD further discussions
3 year transition for MDD will it happen?
 it will take 2 years just to re-designate at Notified bodies,
 plus all the above.
 Plus the Implementing / delegated acts (43 in total),
 common specifications and guidance

Lets go back to the current - Trilogues
• Negotiations between
European Parliament, Council and Commission
So why since the Brussels, 26.9.2012 publication, has a final version not yet been agreed?
• Politics?
– Large differences still exist for scrutiny procedure and reprocessing of medical devices as well as the (compulsory) requirement
for all manufacturers to have liability insurance (proposed by Parliament), which was rejected by Council.
– The rapporteur for MDR - Glenis Willmott (S&D) - will be strongly bound in the coming months because of the referendum in the
UK regarding the remaining in the EU. It is therefore questionable whether the planed timeframe can be adhered.
– Maybe till June, there will be only a compromise regarding the main points of the Regulations. The details will then be regulated
later on.
• 3 versions of the MDR now exist
• Immediate Actions following Dalli Stress Test (European Commission)
The new regulation (920/2013) and recommendation (2013/473/EU which were published on
the 24 September 2013
LRQA opinion is no immediate rush, and therefore the debate will continue

Delegated and Implementing Acts MDR
I = Implementing Act D = Delegated Act
Relevance to NB : ++ very important, + important, o not so important
Act Article Content
Comm
ission
Parlia
ment
Counc
il
Relevan
ce
D 42 (11) -
Conformity
assessment
procedures
In the light of technical progress and any information which becomes available in the course of the designation
or monitoring of notified bodies set out in Articles 28 to 40, or of the vigilance and market surveillance
activities described in Articles 61 to 75, the Commission shall be empowered to adopt delegated acts in
accordance with Article 89 amending or supplementing the conformity assessment procedures set out in
Annexes VIII to XI.
X
++In the light of technical and scientific progress and any information which becomes available in the course of
the designation or monitoring of notified bodies set out in Articles 28 to 40, or of the vigilance and market
surveillance activities described in Articles 61 to 75, the Commission shall be empowered to adopt delegated
acts in accordance with Article 89 amending or supplementing the conformity assessment procedures set out
in Annexes VIII to XI.
X
D 45 (5) -
Certificates
In the light of technical progress, the Commission shall be empowered to adopt delegated acts in accordance
with Article 89 amending or supplementing the minimum content of the certificates set out in Annex XII. X X X ++
D 89 (1) - Exercise
of the delegation
The Commission shall, in drafting delegated acts, seek the advice of the MDCG.
X o
I 94 (4) -
Transitional
provisions
By way of derogation from Directives 90/385/EEC and 93/42/EEC, conformity assessment bodies which
comply with this Regulation may be designated and notified before its date of application. Notified bodies
which are designated and notified in accordance with this Regulation may apply the conformity assessment
procedures laid down in this Regulation and issue certificates in accordance with this Regulation before its
date of application if the relevant delegated acts and implementing acts have been implemented.
X ++ *

Interpretation of text – will be difficult
Lets look at one already implemented in Regulation 920 – 2013
All Nofitied Bodies shall
– (a) the necessary administrative, technical, clinical and scientific personnel with technical
and scientific knowledge and sufficient and appropriate experience relating to medical devices
and the corresponding technologies to perform the conformity assessment tasks, including
the assessment of clinical data;
The MHRA interpret this as
A GMC registered & practising clinician, employed by the Notified Body
Other Competent Authorities see this as having access to a medical person.
Some of the Commission interpret this as
Sufficient Clinicians to have specific knowledge of the full scope of devices that the Notified body
certify, including Class III & AIMD products but also for ALL Class IIa & IIb medical devices. This
includes the clinician peer reviewing all certificates already issued and re-check the clinical data.
LRQA have asked for published guidance from the Commission – nothing yet.
Published in 2013, with at least 3 interpretations, which affect the consistency of all notified bodies
completing the same assessments and therefore the same reviews on clients across the world
(Interpretation of 278 pages plus implementing and delegating acts) – not good for Manufacturers or
Notified Bodies and will it make improve product performance and safety ?

Impact of Short Term Changes to the System
Discovery of a 16 year fraud in PIP breast implants using low quality “industrial
grade” silicon oil
Stress test performed by EU Commission
Determined that changes were needed to improve early detection and prevent
this type of incident
Other high profile vigilance cases with hips, pelvic floor meshes, pacemaker
leads, etc.
Outcome: short term changes to the system – Safety & Performance
Immediate Actions
– Commission Regulation: How Competent Authorities control Notified Bodies
– Commission Recommendation: How Notified Bodies audit Manufacturers

The new regulation (920/2013) and recommendation
(2013/473/EU which were published on the 24 September 2013
MDR & IVDR
Proposal
Additional
ENVI
Proposals
920/2013
2013/473/EU
Implemented
Sept 2013

COMMISSION IMPLEMENTING REGULATION (EU) No 920/2013
of 24 September 2013 on
the designation and the supervision of notified bodies
– Re-assessment of qualifications and scope of activities of NBs
– Joint Audits of NBs by Designating Authority, Commission (FVO) plus two
other CA’s
• NBs and Designating Authorities under scrutiny
• Highlights different approaches in Member States
• More scrutiny of competency requirements, in-house clinicians,
qualifications: NBOG Codes.
• Processes and procedures clarified
IMPACT – 83 down to 61 (so far – not yet finished)

Impact of Com. Recommendation (2013/473/EU) on audits and assessments
performed by NBs – Items to be verified by NB during an audit
– Annex III: Unannounced visits to manufacturers, "critical subcontractors" or
“crucial suppliers”, in addition to planned audits
• Completely new requirement needing extra product and QMS assessors
• Significant increase in NB workload and resources
• First 3 year cycle to be completed by March 2017
LRQA on-track and demonstrated this at our re-designation audit
Sharing of UV’s for CS or CS – discussions ongoing with NB’s but 1 UV not sufficient

What is required within an unannounced visit (UV)?
– Your Notified Body must have already communicated
– Additional visit to normal LRQA assessments – not take less than one day and
should be executed by at least two auditors
– Sample devices belonging to at least three different device types
– Verifying conformity of a recently produced adequate sample (product, batch, lot)
of an approved device type
– Traceability audit (device history record and reconciliation of stock)
– Witness selected tests – sampling criteria and testing procedures should be
identified in advance
– Review two critical processes

Annex II . 2 Critical subcontractors and crucial suppliers
Critical – risk based approach by NB’s
– Key processes may not be done at the main site, and may involve subsidiaries or OEM’s
– LRQA needs to know who are the critical suppliers / subcontractors
– LRQA use the logic provided by IVD working group

Experience gained from Un-announced Visits
– Preparation is key, create a client pack for the assessment team, with an identification of what
products are on our wish list.
– Clients shock when auditors arrive – various reactions, key is to have the list of 4 or 5 contacts
(if people are on vacation)
– The team will need to categorize non-conformities into either
(a) “Product” – may affect CE certificate –immediate action required
(b) “QMS” – can be followed up at normal surveillance visit
– Robust refusal policy required, 30 day resolution timescale before CE certificate is suspended
– this is a product audit. Worst case is another PIP.
Note: visit charged to client for refusal. So lose / lose scenario.
One refusal so far by a critical subcontractor who does supply other major clients
Two clients require additional visits as key processes done at “other sites”
One certificate suspension after visiting a Critical Subcontractor
– Clients are doing what they have always told us they were doing – no real surprises (except
one).

What is in the recommendation that is different/new?
– OBL requirement for Technical files
Recommendation 2013/473/EU, was issued to facilitate consistent application of
conformity assessments contained within the Medical Directives.
Page 2 of recommendation
(9) Subcontractors or suppliers cannot fulfil in the manufacturers’ place crucial
obligations of manufacturers, such as keeping available the full technical documentation,
as this would void the concept of the manufacturer as responsible in accordance with
Directive 90/385/EEC, Directive 93/42/EEC and Directive 98/79/EC. Therefore, the
notified bodies should be advised on what they need to verify in case of outsourcing.
Page 3 of recommendation under Annex I – Product assessment
7. Notified bodies should verify all documentation related to the device’s conformity
assessment. To that end, they should verify that the technical documentation is
correct, consistent, relevant, up-to-date and complete ( 4 ) and that it covers all variants
and trade names of the device. They should furthermore verify that the manufacturer’s
device identification. ( (4) refers to a STED )

Meeting with the MHRA in February 2016
– The MHRA have provided all UK notified bodies with a guidance document
covering own Brand Labelling.
1. OBL is not a term within the Medical Directive, there are only legal
manufacturers – Clients are Virtual Manufacturers
2. Notified Bodies must complete an onsite QMS visit at an OBL company
3. Notified bodies must sample the FULL technical file.
4. MHRA are producing further Guidance in April 2016
5. OBL companies need to change their contracts with the OEM
a. To allow full access to propriety information for the OBL’s Notified Body.
b. To allow un-announced audits by the OBL notified body
c. OEM should make a declaration that they manufacture the product and not
outsource it to another OEM.

Experience gained from reviewing OBL technical file requirements
– Why are you an OBL? Why not a distributor ?
– MHRA have agreed to publish guidance on this
– No NB costs & no un-announce visits

MDR Proposals – 1
• Strengthened Designation Criteria
• Joint Audits: Three Member States and
Commission (FVO)
• Unannounced Inspections
Notified
Bodies
• Less Equivalence, More Data for High Risk
Devices
• Publish Safety and Performance Data
• Post Market Clinical Follow-up
Clinical
Evidence
• Scrutiny for High Risk Devices
• Common Technical Specifications
• Qualified Person for Manufacturers and Authorised
Representatives
Pre-
market

MDR Proposals – 2
• Central Database and Co-ordination
• Trend Reporting
• Enforcement Activities
Post-Market
Surveillance
and Vigilance
• Devices and Economic Operators Registered
Centrally
• Unique Device Identification (UDI)
• Implant Cards
Transparency
and
Traceability
• Central Committees: Scientific Advice,
Harmonised Implementation
• Expert Panels
• JRC, Reference Laboratories
Governance
and Oversight

LRQA Conclusion
– Where are the possible risks
To Much Focus?
– Duplication of visits on OEM’s Critical Subcontractors and Crucial subcontracts with multiple
Notified Body un-announce visits with no additional benefit – does not add value, but is a
requirement of the recommendation.
Lack of Focus?
– Mean while who is reviewing Class 1 non sterile or non Measuring? CA’s – no resource
 ALL Manufacturers still need a Declaration of Conformity as per Annex VII of the MDD
93/42/EEC
 Annex VII requires technical documentation
(Instrument sets)(incontinence pads)
 Annex VII requires conformance with Annex I (essential requirements)
( biocompatibility, state of the art, risk, clinical)
Interpretation of text?
– Clinician requirements are different
– Un-announced visits – are all NB’s doing the same level? No CA witnessing (YET)
– OBL will nearly become consistent 3 years after publication
( 1 member state still going to use OBL)

Lloyd’s Register and variants of it are trading names of Lloyd’s Register Group Limited, its subsidiaries and affiliates.
Copyright © Lloyd’s Register Quality Assurance Limited 2014. A member of the Lloyd’s Register group.
Improving performance,
reducing risk
Martin Penver
T 0800 783 2179
E enquiries@lrqa.co.uk
W www.lrqa.co.uk/medical
1 Trinity Park,
Bickenhill Lane,
Birmingham,
B37 7ES, United Kingdom
Contact Us
LRQA
T +44 (0)330 4141244
E martin.penver@lrqa.com
General Enquiries to Business
Support staff
T +44 (0)330 4141348
E medicaldirectives@lrqa.com

67
2015
Expanded service
offering and
geographical coverageIntegrating Quality with Corporate Compliance to
Provide the Greatest Return
Dr. Seth Whitelaw
President & CEO
Whitelaw Compliance Group

1 is the Loneliest Number
Integrating Quality & Corporate
Compliance To Provide the Greatest
Return Maetrics
The ROI of Good
Quality &
Compliance
London
April 19, 2016
Whitelaw Compliance Group, LLC.

Copyright © 2015 Whitelaw Compliance Group LLC. All rights reserved
The “Heart of Darkness” 69
1‐Press Release by Senator Charles Grassley (February 1, 2013)
2‐Eric Campbell et al., A National Survey of Physician‐Industry Relationships, 356 N Engl. J. Med. 1742, 1746‐47 (2007)
3‐Martin Roland, et al., Professional values and reported behaviors of doctors in the USA and UK: quantitative survey, Brit. Med. J. Quality & Safety at 3 (2011),
http://qualitysafety.bmj.com/content/early/2011/02/07/bmjqs.2010.048173.full
4‐David Grande, et al., Pharmaceutical Industry Gifts to Physicians: Patient Beliefs and Trust in Physicians and the Health Care System, J. Gen. Intern. Med. (Jun. 14, 2011), available at
http://www.ncbi.nlm.nih.gov/pubmed/21671130
NEED FOR
TRANSPARENCY
 Only 78.7% of U.S. physicians believe
in putting a patient’s interest above
their own.2
 64% of surveyed physicians said that
disclosure for doctors should be
mandatory.3
 83% supported mandatory disclosure
for researchers.3
Physician Perspective
 “We want our doctors … to rely on
evidence that is real and true and
accurate and not partial or affected
some way by a money interest behind
it.”1
 “The case has clearly been made for
requiring industry to report payments to
physicians, especially those conducting
highly influential research, often with
taxpayer support. Operating with
transparency sends a message that
there’s nothing to hide.”2
Congressional Perspective
 94% of U.S. physicians have had a
relationship with a life sciences
company2
Life Science Perspective
 55% of patients believe their doctor
receives industry gifts4
Patient Perspective

Causing Pressure for
Reform to Build
 Intractable quality issues are
dominating the global news
 Indian API debacle
 Chinese reform efforts
 Price and quality are in the forefront
of the U.S. election
 Unsupported price increases
 Value-based pricing
70

Leading to Increased
Enforcement
71
0
5000
10000
15000
20000
2008
2009
2010
2011
2012
2013
2014
2015
FDA Warning Letters
Fiscal Years 2008 – 20151
0
500
1000
1500
2010 2011 2012 2013 2014
Federal Criminal Healthcare Fraud
Prosecutions (FY10-FY14)2
1http://www.fda.gov/downloads/ICECI/EnforcementActions/UCM384647.pdf
2HHS & DOJ Annual Reports on Healthcare Fraud and Abuse Control Program

While Regulators Struggle
with Dated Frameworks
 Off-label vs. 1st Amendment
 Software as a medical device
 Genetic testing and dietary
supplements
 Drug shortages
 Opioid misuse
72

Quality & Compliance Not
Keeping Pace
73
CEO
Chief Quality
Officer
Manufacturing
Quality
R&D Quality
Chief
Compliance
Officer
Compliance
Operations

The Disconnect 74
External Regulations
Internal Audits
Quality Control
Quality Assurance
Quality
Corporate Compliance

How It Needs to Work 75
CEO
Chief Compliance
Officer
Compliance
Operations
Chief Quality
Officer
Manufacturing
Quality
R&D Quality

Achieving An Integrated
Team
 Securing commitment
 At all organizational levels
 Establishing an agreed upon framework
 Objectives of integrating
 Speaking the same language
 Defining the key terms (e.g., “risk”)
 Identifying combined
compliance/quality expertise
76

It Isn’t Just Theory
INVACARE, VALEANT AND OTHER NOTABLE STORIES
77

Invacare
 2012 Consent Decree
 Last 3 years lost money
 Latest Inspection (12/2015)
 5 months duration
 11 page FDA-483
 Consent decree non-compliance
 CEO asserting strong compliance
culture is top priority
78

Valeant
 Virazole microbial
contamination recall
 Accusations of improper
relationship with PBM Philidor
to recommend Valeant drugs
 Hedge fund loses >$1B in
single day (3/15/16)
 Former CEO subpoenaed to
testify before Senate on drug
pricing
79

OtisMed Corp.
 Distributed product after FDA
refused to approve their
application.
 Company acquired by Stryker.
 Company paid more than $80
million dollars in civil and
criminal fines.
 Its CEO pled guilty to criminal
charges, and was sentenced
this year to serve 24 months in
prison, 1 year supervised
release and a $75,000 fine.
80

Olympus Corporation of
America
 3 separate regulatory actions
 FDA
 Anti-kickback and False Claims
Act violations
 FCPA
 3 separate regulatory outcomes
 Warning Letters and Recalls
 Corporate Integrity Agreement
 Deferred Prosecution Agreement
 Total settlement - $646 million
 Chief Compliance Officer was
the whistleblower
81

Whitelaw Compliance Group, LLC.
helping companies grow sustainable integrity
www.WhitelawCompliance.com
+1.215.275.1556
82

83
2015
Expanded service
offering and
geographical coverageThe Impact of a Good
Quality Management System
Carl Dover
Vice President – Quality Strategy & Process Improvement
DePuy Synthes

The Impact of a
Good Quality Management System
Carl Dover
Vice President, Quality Strategy & Process Improvement
DePuy Synthes
Maetrics Regulatory Seminar by ABHI:
19th April 2016

Quality Management Systems Development
Quality is
COMPLIANCE
Quality is a
DISCIPLINE
Quality is an
INTEGRATED
CAPABILITY COMPETENCY
Proactive
Quality is a
CORE
COMPETENCY
Proactive Quality
is a
DIFFERENTIATOR

Quality is Compliance
• The Starting Point
• Foundational Systems
• Market Access
Opportunity Areas:
• More Reactive than Proactive
• Internal Complexity
• Higher Cost of Quality
• Internally Focused
• Sustainability Issues

Quality is a Discipline
• > Compliance Outcomes
• Enhanced Technical Capabilities
• Capability Risk Reduction Focus
• Reduced Cost of Non Conformance
Opportunity Areas:
• Goal Alignment
• Governance
• Speed to Market
• External Focus
• Customer Satisfaction

Quality is an Integrated Capability
• Reduced Complexity
• Cross Functional Engagement
• Organizational Capability
• > Design, LEAN, QE Outcomes
• Robust External Manufacturing
• Faster Cycle Times
• Reliable, Predictable Supply
• Cost Of Quality Improvement
Opportunity Areas:
• Proactive Quality
• Triple Aim
• Field Action Trend
• Quality Culture & Sustainability
Cost of
Non-Conformance
Internal
Failures
External
Failures
Cost of
Conformance
PreventionAppraisal

Proactive Quality : A Core Competency + Competitive Differentiator
• Predictive Analytics
• Reduced Complexity - Agile, Scalable, Integrated Quality Systems
• Higher Investment in Prevention
• Patient Centric Solutions – Triple Aim – Satisfaction/Outcomes/Costs
• Higher Reinvestment in Breakthrough Innovation
• Anticipating & Shaping the External Environment
• Recognized Sustainable Culture of Quality
Compliant, quality
products & services
Reliable supply of high
quality products & services
Innovative, high quality products &
services through customer insights
PROACTIVE QUALITY delivers BUSINESS GROWTH and CUSTOMER VALUE
Cost of Quality
measured
COMPLIANT
Achieve top quartile
COQ benchmark
INTEGRATED
Reinvestment of cost
savings in Innovation
PROACTIVE

Additional Benefits
Cost of Quality
Customer
Satisfaction
Consolidation
Organizational
Capability
Guaranteed
Supply
EngagementIntegration
Agility
L&A

91
2015
Expanded service
offering and
geographical coverageThe Most Costly Problems
and Why Continually Repeated
Adrian Toutoungi
Commercial Partner
Eversheds

The most costly problems (and why
continually repeated)?
Adrian Toutoungi
Partner - Eversheds LLP
19 April 2016

1. Data privacy
2. Borderline issues
3. Unharmonized issues
− advertising and promotion of medical devices
− registration requirements
− enforcement
4. Beyond regulatory compliance
On the Agenda – Traps for the unwary

Eversheds LLP | 19/04/2016 |
− An increasing problem for
medical device manufacturers
− Conventional devices
− e-health (Internet of Things)
− m-health
Data privacy

− Local, variable implementation
− Personal data
• information which on its own on when combined with other
information held, identifies or relates to a living individual
− Processing
• any use, including storing or reading
− Sensitive personal data
− Data Protection principles
• fair and lawful use
• security
• export
− Maximum fine in UK: £500,000
Data Protection Directive 95/46/EC
The existing regime

− Direct effect from 2018
− More detailed rules and obligations
− Privacy by design and default
− Tightened rules
• notice
• consent
• lawful use
− Mandatory reporting of breaches
− Enforcement
• potential fines of up to 4% of global turnover
General Data Protection Regulation
The upcoming regime

− Medical imaging technology
• MRI scanner
• Database of scanned images
• Access by device supplier
• Impact on market launch?
− m-Health software apps
Examples

− Qualification of a product can be uncertain
• medical device v medicinal product
• medicinal product v cosmetic product
• others
− Increasingly sophisticated products
• technical advances outpacing legislation and guidance
• combination products (incorporate or designed to administer a
medicinal product)
− Qualification may be vital
• commercial viability (cost, timing to market)
• to gain a competitive advantage
Borderline issues

− Article 1(2) of Directive 2001/83/EC
• Any substance or combination of substances presented as having
properties for treating or preventing disease in human beings;
• Any substance or combination of substances which may be used
in or administered to human beings either with a view to restoring,
correcting or modifying physiological functions by exerting a
pharmacological, immunological or metabolic action, or to making
a medical diagnosis’.
− Consider both presentation and function
− Definition has evolved over the years
Definition of medicinal product

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
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’
Definition of ‘Medical Device’, Article 1.2 of Directive
93/42/EEC

− Article 2(2) Directive 2001/83/EC
• in cases of doubt, where, taking into account all its characteristics, a
product may fall within the definition of a medicinal product and
within the definition of a product covered by other Community
legislation the provisions of this Directive shall apply”
− Borderline MEDDEV
− European Commission Manual on Borderline and Classification
in the Community Regulatory Framework for Medical devices,
Version 1.16 (07-2014)
− Further guidance from national regulators
• Guide to What is a Medicinal Product
• MHRA Borderline Guidance
A uniform approach?

- Gynocaps capsule
• for correcting bacterial imbalances in
the vagina
• lactobacillus, lactose and magnesium
stearate in a gelatine capsule
• Marketed as a Class III device since
2006 in AU, DE, ES, FIN, FR
• reclassified in FIN as a medicinal
product in November 2008
- CJEU confirmed that MS are not
bound by decisions of other MS
- Major adverse commercial impact
Laboratoires Lyocentre case (Case C-109/12,

Overview of different MS
Member State Legal Framework Borderline Products
Belgium Assessment of border products is carried out by a
specific body in the Federal Agency for Medicines and
Health Products (FAFMP) – the joint committee
France Classification is carried out by French Agency of
Sanitary Security of Health Products (AFSSaPS). Case
law prefers a broad view of the term “medicinal
product”
Germany Extensive civil and administrative case law on
classification of borderline products
Italy The Italian Ministry of Health is the Competent
Authority on borderline issues. It follows the borderline
MEDDEV and Guidance
The Netherlands Assessment is carried out by the CIBG
Sweden There is some civil case law on classification of
borderline products
UK MHRA’s Borderline section offers advice. The MHRA also
publishes its own guidance

− Review the applicable legislation and guidance
− Check precedent cases and competent authority
decisions
− Consider the method by which the principal action is
achieved
− Consider the intended purpose of the product, taking
into account the presentation
• careful positioning of the product may be required
• ensure consistency of labelling, claims and advertising
− Consider limiting marketing of the product to selected
MS
− Don’t assume that the US classification will apply, or
even be persuasive
Practical tips on dealing with borderline questions

−Mouthwash
• purpose of the product was to reduce bacterially-caused dental
plaque and to protect from gingivitis
• “pharmacological means” = interaction between molecules of the
substance and a cellular constituent (usually referred to as a
receptor) which either results in a direct response or blocks the
response to another agent (borderline MEDDEV)
• CJEU clarified that the cellular constituent must be present in the
user’s body, but does not need to be a cellular constituent of the
user’s body.
−Hyaluronic acid and sodium pre-filled syringe
• natural compound of joint fluid, which provides the viscosity and
elasticity required for protection of joints
• principal means of action was physical
−Stand-alone software
• a different type of borderline issue
Examples

− Do not overestimate the degree of EU harmonization
• take local law advice
− Aim of New Approach
• No further conformity assessments should be required
• But Article 14 allows MS to require notification by manufacturer of marketing
of Class IIa, IIb and III devices;
• other issues are unharmonized (e.g. enforcement, transfers of value to HCP)
− Advertising/promotion is not harmonized
• Directive 2006/114/EC, concerning misleading and comparative advertising
• Directive 2005/29/EC concerning unfair business-to-consumer commercial
practices
• Eucomed Code of Ethical Business Practice
• National laws and guidance may be more stringent
• Careful clearance of advertising campaigns is required
Lack of regulatory harmonization across the EU

Member State Provisions relating to medical device marketing
Belgium No advertising of non-CE marked devices (Royal Decree). Limited
exemption for trade fairs, exhibitions and demonstrations
France No specific regulation. French Consumer Code prohibits false or
misleading advertising. Enforced by DGCCRF
Germany Strict provisions on advertising medical devices can be found in the Law
on Advertising of Medicinal Products. Also Code of Conduct of trade
bodies
Italy Advertising to general public of prescription devices or devices only
used with the assistance of an HCP is prohibited; other advertising
requires prior consent of Ministry of Health. Some regional regulations
too, and provisions in the Assobiomedica Code of Conduct
The Netherlands Few specific provisions. The self-regulatory Code on Public Advertising
of Medical Devices 2009 applies. Medical device advertising is however
subject to pre-approval by the council of Inspection of Public
Advertising of Medicinal Products (KOAG)
Spain FENIN Code of Conduct (Association of manufacturers of medical
devices) regulates advertising of medical devices
UK No specific regulation. ABHI Code of Conduct.
Advertising medical devices in the EU
regulation

4. Beyond regulatory compliance

−Procurement
• failing to challenge tender processes and unfavourable awards
−Product liability
• intended use, device description, instructions for the user
−Pricing and reimbursement
• failing to challenge unfavourable Health Technology Assessments
− Patent infringement issues
• Unified Patent Court and Unitary Patent
A wider perspective on costly problems in the sector
Beyond regulatory compliance

Europe
01 London 24 Turku
02 Ipswich 25 Helsinki
03 Cambridge 26 Tallinn
04 Cardiff 27 Riga
05 Birmingham 28 Vilnius
06 Nottingham 29 Warsaw
07 Manchester 30 Budapest
08 Leeds 31 Vienna
09 Newcastle 32 Munich
10 Edinburgh 33 Zurich
11 Dublin 34 Berne
12 Belfast 35 Geneva
13 Paris 36 Madrid
14 Brussels 37 Milan
15 Rotterdam 38 Rome
16 Amsterdam 39 Bucharest
17 Hamburg
Africa18 Berlin
19 Stockholm 40 Tunis
20 Pori 41 Durban
21 Tampere 42 Johannesburg (Bryanston)
22 Jyvaskyla 43 Johannesburg (Sandton)
23 Hameenlinna 44 Port Louis
Middle East
45 Amman
46 Erbil
47 Baghdad
48 Riyadh
49 Doha
50 Abu Dhabi
51 Dubai
Asia
52 Beijing
53 Shanghai
54 Hong Kong
55 Singapore
LDS_002-#4206473CAR_LIB1-#11019113CAM_1B-#4930708

eversheds.com
©2016 Eversheds LLP
Eversheds LLP is a limited liability partnership
Adrian Toutoungi
Partner - Eversheds LLP
+44 788 775 4482
adriantoutoungi@eversheds.
com

The ROI of Good Quality & Compliance

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