Post-Market Surveillance - Vigilance

7/27/2019 Post-Market Surveillance - Vigilance

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Post-Market Surveillance - VigilanceComparing Medical Devices and MedicinesEric Klasen16 November 2012


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Facts and FiguresMedical Devices


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A diverse sector

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EU Medical Devices Facts and Figures

Apr 500,000 medical technologies currently available to healthcare professionals

22,500 medical technology companies in Europe

80% of these are SME

The EU medical device industry employs apr. 500,000 persons

On average, 8% of sales is spend on R&D

in 2009 the medical technology industry filed almost 16,500 patent applications

One patent every 30 minutes

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Class III - AIMD

Class IIb

Class IIa

Class I200000

150000

100000

50000


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Facts and FiguresMedical Devivces and Medicines


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Medical Devices and Medicines - EU Industry

MedicalDevices 1)

Companies

Employment

R&D as % of net sales

% of total healthexpenditure

Medicines 2)

? (1900)

660,000

15.3%

16.7%

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22,500

500,000

8%

4.2%

1) Source: Eucomed2) Source:EFPIA


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Medical Devices and Drugs Life Cycle

Medical DevicesNew Innovative product development canbe lengthy and expensive, costing tenthsof millions of Euro, but usually takes lessthan 5 yearsPatent protection relatively weakMedical devices do not benefit from anyregulatory incentive; no market exclusivitybased on regulatory data protectionSimilar devices developed by othermanufacturers come rapidly to the market

These are usually not truly generic devicesShort life cycle of the original product;thousands of patients treated

Original product is subject to continuousimprovement or iterative developmentOn average, a medical device productwil l be superseded by a new versionwithin 18-24 months

DrugsNew drugs and Biologics development is lengthyand expensive, not only costing hundreds of million Euro but also requiring up to 10 yearsOriginator products are based on uniquemolecules - New Chemical Entity (NCE)New indications can be authorized on the basisof new clinical studies (,$,Time)Line extensions are based on the samemolecule and refer to different strength andadministration routeLong life cycle of the productMillions of patients traetedPatent protection strongRegulatory incentives in the form of marketexclus ivi ty for 10-12 years; based onregulatory data protection

Additional incent ives: for new indications,pediatric indication, Rx-OTC switchGeneric products can only be marketed after regulatory exclus ivity ends

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Medical Devices Typical Life Cycle

STEP 1

Conception and development of innnovative / new device

Not previously used; e.g. new material, new indication, new therapeitic appraoch

STEP 2 TO STEP NOnce approved/CE marked, the device will usually follow a continuous or iterative life cycle

Continuous amendments and design improvements based on,

feedback from physicians / users

Product complaints : returned product analyses Adverse events trending

Changes to the labeling (IFU) additional warnings, precautions or userrecommendations

Engineering and technology developments Manufacturing improvements Bench testing

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On average, a medical device product wil l be superseded by a new version wi thin 18-24months


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Drugs Typical Life Cycle

STEP 1

Conception and development of innnovative / new drug

Not previously used; new molecule new chemical entity

STEP 2

Once approved, the drug will remain the same for its life cycle

Line extensions can be developed

New indications can be studied

Changes to the labeling (SPC) - additional warnings, precautions,contra-indications

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Medical Devices and Drugs high level comparison

Devices

Product groupsComplex systemsIterative changesDevice failureDesign errorHuman FactorsUser learning curve

Relatively low exposurecompared topharmaceuticals

Drugs

Drug classesPure moleculesNo changes (line extensions)Quality issuesN.A.N.A.Patient dosing; change of drugHigh exposure

Many patients, many scripts

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Implanted medical devices US 2010 1)Device Apr. number of Procedures 2010

Implantable Cardioverter Defibrillators - ICD 133,000

Arti ficial Hips 230,000

Heart Pacemakers 235,000

Breast Implants 366,000

Spine Screws, Rods, and Artifi cial Discs 410,000

IUDs (Intra-Uterine Devices) 425,000

Metal Screws, Pins, Plates, and Rods 453,000

Arti ficial Knees 543,000

Coronary Stents 560,000

Ear Tubes (Tympanostomy Tubes) 715,000

Arti ficial intra-ocular Eye Lenses 2,582,000

131) Source : http://247wallst.com/2011/07/18/the-eleven-most-implanted-medical-devices-in-america/#ixzz2CFHxrS3R


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Medical Devices and Drugs Clinical Studies

Drugs:Pre-market studies usually relativelylarge, phase III

Power to detect low SAE rates ishigher with increasing number of pts

NOTE: studies are large to be ableto show efficacy; statisticalsuperiority or non-inferiority towardsa marketed drug needs high power,hence large size clinical trial

Inclusion/exclusion criteria do notfully reflect the patient populationunder normal useConsidering the potentially long lifecycle, and the fact that the moleculecan not be changed, short andmedium term safety profile usuallydetermined but long term safetyprofile is part of the PMS and Post-authorization studies

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Devices:Pre-market clinical studies fornew class III/AIMD relativelysmall size and short-term (2-3years) 1)

the power to detect low SAErates is limited, especially thosethat only appear long-term

Short-term device related (S)AEare more easily identified

Long-term (S)AE e.g. late stentthrombosis with DES, are

frequently not identifiedInclusion/exclusion criteria do notfully reflect the total patientpopulation under normal useShort and Medium-term safetyprofile usually determinedLong-term safety profile part of the PMS and Post-MarketClinical Follow up (PMCF)

1) exceptions are available up to 10000 patient trials, e.g. DES Endeavor zotaromilusstent


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Medical Devices and Drugs Signal Detection

Drugs:Patient compliance is difficultto monitor (self-medication)

complications and seriousadverse events are readilyobserved but it is difficult toconfirm/reject drug related(S)AE, especially when thepatient has co-morbidities

E.g. Diabetes increases therisk for AMI attack rate,incidence, case-fatality,recurrence and mortality,

hence increased AE rate of diabetes drug is difficult toidentify (large population size)

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Devices:Patient compliance depends onwhether the patient has toactively operate the deviceDevice-related complications aremore readily identified

E.g. no pacing, pain, no painrelief, no improvement of clinicalsymptoms, inflammation,infection, malfunctioning of device

Device effectiveness is morereadily identified

DBS effect of stimulation ismeasured during implantprocedure

Where surgery is applied toimplant the device

Surgery-related complicationsare more easily monitored, e.g.infection

Implants can be monitored (CTScan, X-ray)


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Medical Devices and Drugs Recalls

DrugsDesign issues are notapplicable

When over time the benefit/riskratio changes, the followingactions are possible

Labeling change recall (withdrawal)

Manufacturing issues oftenleads to recall:FDA 2012, 37 recallsFDA 2011, 42 recalls

October 05, 2012 HospiraRecalls One Lot Of LactatedRinger's And 5-percentDextrose Injection, Usp, 1000Ml, Flexible Containers Due ToMold Contamination

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Devices:Design issues leading to SAEthat alter the benefit / risk ratioleads to field safety correctiveactions / recall

issues are recognizedfollowing increase in patientexposure and prolongedtreatment time

Root cause analyses of returned product

Manufacturing issues areidentified, usually based onreturned product analysesFDA 2012, 39 recalls

FDA 2011, 41 recallsDecember 9, 2011 MedtronicModel 8637 SynchroMed IIImplantable Infusion Pump 11


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Comparison Summary

DevicesProduct groupsOn avg moderate developmentcosts

Relatively short development timeIterative developmentShort (18-24m) life cycle per modelUser learning curveHuman factorsRelatively low exposure inpopulationDevice failuresImprovements or design

corrections can usually beimplementedClinical studies usually small sizePMS critical; PMCF tbdNo regulatory incentives

DrugsDrug classesHigh development costsRelatively long development timeNo changes to product, only lineextensions, same moleculeLong life cycleNo user learning curve - dosingNo human factorsPatient compliance riskRelatively High exposure in population

Quality IssuesSAE profile changes risk withdrawal of product if labeling changes are notadequate to reduce riskClinical studies usually large todemonstrate superiority or non-inferiority;this also provides a relatively large safetydatabasePMS and PMCF criticalRegulatory incentives significant

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Post-Market Surveillance Implications

DevicesProduct groupsOn avg moderate development costsRelatively short development timeIterative developmentShort (18-24m) life cycle per modelUser learning curveHuman factors

Relatively low exposure inpopulation for class III, AIMDDevice failure more readily identified;could lead to recallImprovements or design corrections

can usually be implementedClinical studies usually small sizePMS cri tical; PMCF tbdNo regulatory incentives

DrugsDrug classesHigh development costsRelatively long development timeNo changes to product, only lineextensions, same moleculeNo learning curveNo human factorsPatient compliance riskRelatively High exposure in population

SAE profile could lead to withdrawal of product from market if labeling changesare not adequate to reduce riskClinical studies usually large todemonstrate superiority or non-inferiority;this also provides a relatively large safetydatabasePMS and Post Author ization s tudiesRegulatory incentives significant

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Regulations and Guidelines

Medical DevicesDirective 2007/47/EC,amended the MDD, 93/42/EEC,

and the AIMDD (90/385/EEC)MDD art 10 and AnnexesAIMD art 8 and annexesIVDD art 11 and Annexes

MEDDEV 2.12-1 rev 7

March 2012, GUIDELINESON A MEDICAL DEVICESVIGILANCE SYSTEM

PharmaceuticalDirective 2001/83 as amendedby 2010/84/EURegulation 1235/2010/EU (PVRegulation)Regulation 726/2004 (EMAAgency) as amendedImplementing Regulation520/2012/EU

22 June 2012EMA/541760/2011Guideline on Good ,Pharmacovigilance practices (GVP)

Modules I XVI

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The EU pharmacovigilance system

The legal framework

The legal framework of pharmacovigilance for medicines marketed within the

EU is provided for in,Regulation (EC) No 726/2004 with respect to centrally authorised medicinal

products, and in,

Directive 2001/83/EC with respect to nationally authorised medicinal products(including those authorised through the mutual recognition and decentralised

systems).

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REGULATION (EU) No 1235/2010 OF THE EUROPEANPARLIAMENT AND OF THE COUNCIL

of 15 December 2010

Amending, as regards pharmacovigilance of medicinal products for human use ,

Regulation (EC) No 726/2004 laying down Community procedures for the

authorisation and supervision of medicinal products for human and veterinaryuse and establishing a European Medicines Agency, and

Regulation (EC) No 1394/2007 on advanced therapy medicinal products

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Commission Implementing Regulation (EU) No 520/2012 on the performance of pharmacovigilance activities stipulates operational details in relation to certainaspects of pharmacovigilance to be respected by marketing authorisation holders,national competent authorities and EMA.


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5) The main tasks of the Agency in the area of pharmacovigilance laid down in

Regulation (EC) No 726/2004 should be maintained and further developed, inparticular as regards

the management of the Union pharmacovigilance database and data-

processing network ( the Eudravigilance database ),

the coordination of safety announcements by the Member States, and

the provision to the public of information regarding safety issues .

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(7) In order to increase transparency as regards pharmacovigilance issues, a

European medicines web-portal should be created and maintained by the

Agency . .

(8) In order to ensure the availability of the necessary expertise and resources for

pharmacovigilance assessments at Union level, it is appropriate to create a new

scientif ic committee within the Agency: the Pharmacovigilance Risk

Assessment Committee. That committee should be composed of members

appointed by Member States who are competent in the safety of medicines

including the detection, assessment, minimisation and communication of risk, and in

the design of post-authorisation safety studies and pharmacovigilance audits, andof members appointed by the Commission, who are independent scientific

experts, or representatives of healthcare professionals and patients.

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6.3.2 DETERMINATION OF THE COORDINATING NATIONAL COMPETENT

AUTHORITY

The co-ordinating Competent Authority should be the one that is responsible for the

MANUFACTURER or his AUTHORISED REPRESENTATIVE, unless otherwise agreed

between Competent Authorities e.g. the National Competent Authority:

which has a particular high interest in consulting other Competent Authorities or is

already undertaking investigation on INCIDENTs and therefore initiates the coordination.

in the State where the Notified Body which made the attestation leading to CEmarking,

is situated.

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MEDDEV 2.12-1 rev 7March 2012


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(22) It is appropriate to strengthen the supervisory role for medicinal products

for human use authorised through the centralised procedure by providing that

the supervisory authori ty for pharmacovigilance should be the competent

authority of the Member State in which the pharmacovigilance system

master file of the marketing authorisation holder is located .

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Finally, the EMA has released good pharmacovigilance practice guidelines

(GVP) in order to facilitate the performance of pharmacovigilance activities.

These GVP modules replace Volume 9A of, "The rules governing medicinal

products in the European Union - Pharmacovigilance".

.

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Good pharmacovigilance practices (GVP)

The modules are a key deliverable of REGULATION (EU) No 1235/2010

Serious adverse events (SAE): expedited reporting 15 days

As of 2 July 2012:

batch report ing of non-serious adverse events (AE) 90 days

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Good pharmacovigilance practices (GVP)

The guideline on GVP is divided into 16 modules, each of which covers one major process inpharmacovigilance

The modules are a key deliverable of the 2010 PV legislation

Module I Pharmacovigilance systems and their quality systems

Module II Pharmacovigilance system master file

Module V Risk management systems

Module VI Management and reporting of adverse reactions to medicinal products

Module VII Periodic safety update report

Module VIII Post-authorisation safety studies

module VIII Post-authorisation safety studies: Member States' requirements fortransmission of information on non-interventional post-authorisation safety studies

Module IX Signal management

Etc, etc

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The full set of 16 final modules is scheduled to be availableby early 2013.


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Regulation (EU) No 1235/2010 and Directive 2010/84/EU introduced the

concept of the pharmacovigilance system master file . In order toaccurately reflect the pharmacovigilance system used by the marketing

authorisation holder, the pharmacovigilance system master file should

contain key information and documents covering all aspects of

pharmacovigilance activities , including information on tasks that have

been subcontracted . It should contribute to the appropriate planning and

conduct of audits by the marketing authorisation holder and the supervision

of pharmacovigilance activities by the qualified person responsible for

pharmacovigilance. At the same time it should enable national competent

authorities to verify compliance concerning all aspects of the system.

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Quality system

3.1. The manufacturer must lodge an application for assessment of his quality system with a Notifiedbody. The application must include:,

an undertaking by the manufacturer to inst itute and keep up to date asystematic procedure to review experience gained from devices in the post-

production phase , including the provisions referred to in Annex X, and to implementappropriate means to apply any necessary corrective action. This undertaking must

include an obligation for the manufacturer to notify the competent authorities of thefollowing incidents immediately on learning of them:

(i) any malfunction or deterioration in the characteristics and/or performance of a device,as well as any inadequacy in the instructions for use which might lead to or might have

led to the death of a patient or user or to a serious deterioration in his state of health; (ii) any technical or medical reason connected with the characteristics orPerformance of a device leading for the reasons referred to in subparagraph (i) to

systematic recall of devices of the same type by the manufacturer.

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MDD/AIMD/IVDD


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PSUR - periodic safety update reports

Periodic safety update reports are an important instrument to monitor the development

of the safety profile of a medicinal product after it has been placed on the Union market,including an integrated (re-) evaluation of the risk-benefit balance. In order to facilitate

their processing and evaluation, common format and content requirements should be

established

(21) It is necessary to increase the shared use of resources between competent authorities for

the assessment of periodic safety update reports . The assessment procedures provided for

in Directive 2001/83/EC should therefore apply for the single assessment of periodic safety

update reports for different medicinal products for human use containing the sameactive substance or the same combination of active substances, including joint assessments

of medicinal products for human use authorised both nationally and through the centralised

procedure.

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MEDDEV 2.12-1 rev 7

March 2012

PERIODIC SUMMARY REPORTING is an alternativereporting regime that is agreed between theMANUFACTURER and the National Competent

Authority for reporting similar INCIDENTs with the

same device or device type in a consolidated waywhere the root cause is known or an FSCA has beenimplemented


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RISK MANAGEMENT PLAN - RMP

Risk management plans are required for all new marketing authorisation

applications. They contain a detailed description of the risk managementsystem used by the marketing authorisation holder. In order to facilitate the

production of risk management plans and their evaluation by the competent

authorities, common format and content requirements should be established

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Risk Management Plan - RMPContent of the risk management plan

1. The risk management plan established by the marketing authorisation holdershall contain the following elements:

(a) an identification or characterisation of the safety profi le of the medicinalproduct(s) concerned;

(b) an indication of how to characterise further the safety profile of the medicinal

product(s) concerned;(c) a documentation of measures to prevent or minimise the risks associatedwith the medicinal product, including an assessment of the effectiveness of those

interventions;

(d) a documentation of post-authorisation obligations that have been imposedas a condition of the marketing authorisation.

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There is no RMP requirement for medical devices


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4.2 AUTHORISED REPRESENTATIVE

Any natural or legal person established in the Community who, explicitlydesignated by the MANUFACTURER, acts and may be addressed by

authorities and bodies in the Community instead of the MANUFACTURER

with regard to the latters obligations under the directive.

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MEDDEV 2.12-1 rev 7

March 2012

Commission proposal art 13: Person responsible for regulatory compliance Qualified Person, similar to QPPV for pharmaceuticals

Authorized Rep shall have available within their organization at least onequalified person


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Medical Devices - EUDAMED

Medical Devices

EUDAMED: a secure web-based portal acting as a central repository forinformation exchange between national competent authorities and the

Commission and is not publicly accessible .

Eudamed use is obligatory since May 2011

The aim of Eudamed is to strengthen market surveillance and

transparency in the field of medical devices by providing Member State competent authorities with fast access to information

on manufacturers and authorized representatives, on devices and certificates andon vigilance and clinical investigation data, as well as to contribute to a uniform

application of the Directives, in particular in relation to registration requirements.

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SummaryCurrent Medical Device PMS and Vigilance regulations are in principle

adequate for medical devices, however, compared to medicines regulations the

main differences are:

Member state and Commission resources dedicated to medical devices are

significantly less (Euro, and people) compared to medicines; there is not a

pro rata investment in regulation of the medical device sector in line with the

size of the market

Implementation / enforcement of the medical device regulations differs for

each member State, including oversight of notified bodies

Meddev rev 7 is much less detailed than the GVP modules (or earlier Vol 9A);PSUR, RMP, QP currently not applied to medical devices

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THANK YOU

Documents

Post-Market Surveillance - Vigilance