Post-Market Surveillance - Vigilance Comparing Medical Devices and Medicines

Eric Klasen 16 November 2012

Facts and Figures Medical Devices

A diverse sector

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

Class III - AIMD

50000

Class IIb
100000

Class IIa
150000

Class I
200000

Facts and Figures Medical Devivces and Medicines

Medical Devices and Medicines - EU Industry

Medical Devices 1)
Companies Employment R&D as % of net sales % of total health expenditure 22,500 500,000 8% 4.2%

Medicines 2)
? (1900) 660,000 15.3% 16.7%

1) Source:

Eucomed

2) Source:EFPIA

Medical Devices and Drugs Life Cycle

Medical Devices
New Innovative product development can be lengthy and expensive, costing tenths of millions of Euro, but usually takes less than 5 years Patent protection relatively weak Medical devices do not benefit from any regulatory incentive; no market exclusivity based on regulatory data protection Similar devices developed by other manufacturers come rapidly to the market
These are usually not truly generic devices

Drugs
New drugs and Biologics development is lengthy and expensive, not only costing hundreds of million Euro but also requiring up to 10 years Originator products are based on unique molecules - New Chemical Entity (NCE) New indications can be authorized on the basis of new clinical studies (,$,Time) Line extensions are based on the same molecule and refer to different strength and administration route Long life cycle of the product Millions of patients traeted Patent protection strong Regulatory incentives in the form of market exclusivity for 10-12 years; based on regulatory data protection Additional incentives: for new indications, pediatric indication, Rx-OTC switch Generic products can only be marketed after regulatory exclusivity ends

Short life cycle of the original product; thousands of patients treated Original product is subject to continuous improvement or iterative development On average, a medical device product will be superseded by a new version within 18-24 months

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 N
Once 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 user recommendations Engineering and technology developments Manufacturing improvements Bench testing On average, a medical device product will be superseded by a new version within 18-24 months
10

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

11

Medical Devices and Drugs high level comparison

Devices Product groups Complex systems Iterative changes Device failure Design error Human Factors User learning curve Relatively low exposure compared to pharmaceuticals Drugs Drug classes Pure molecules No changes (line extensions) Quality issues N.A. N.A. Patient dosing; change of drug High exposure
Many patients, many scripts

12

Implanted medical devices US 2010 1)

Device
Implantable Cardioverter Defibrillators - ICD

Apr. number of Procedures 2010

133,000

Artificial Hips Heart Pacemakers Breast Implants Spine Screws, Rods, and Artificial Discs IUDs (Intra-Uterine Devices) Metal Screws, Pins, Plates, and Rods Artificial Knees Coronary Stents Ear Tubes (Tympanostomy Tubes) Artificial intra-ocular Eye Lenses
1) Source

230,000 235,000 366,000 410,000 425,000 453,000 543,000 560,000 715,000 2,582,000 13

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

Medical Devices and Drugs Clinical Studies

Devices:
Pre-market clinical studies for new class III/AIMD relatively small size and short-term (2-3 years) 1)
the power to detect low SAE rates is limited, especially those that only appear long-term Short-term device related (S)AE are more easily identified Long-term (S)AE e.g. late stent thrombosis with DES, are frequently not identified

Drugs:
Pre-market studies usually relatively large, phase III
Power to detect low SAE rates is higher with increasing number of pts NOTE: studies are large to be able to show efficacy; statistical superiority or non-inferiority towards a marketed drug needs high power, hence large size clinical trial

Inclusion/exclusion criteria do not fully reflect the total patient population under normal use Short and Medium-term safety profile usually determined Long-term safety profile part of the PMS and Post-Market Clinical Follow up (PMCF)

Inclusion/exclusion criteria do not fully reflect the patient population under normal use Considering the potentially long life cycle, and the fact that the molecule can not be changed, short and medium term safety profile usually determined but long term safety profile is part of the PMS and Postauthorization studies
14

exceptions are available up to 10000 patient trials, e.g. DES Endeavor zotaromilus stent

1)

Medical Devices and Drugs Signal Detection

Devices:
Patient compliance depends on whether the patient has to actively operate the device Device-related complications are more readily identified
E.g. no pacing, pain, no pain relief, no improvement of clinical symptoms, inflammation, infection, malfunctioning of device

Drugs:
Patient compliance is difficult to monitor (self-medication) complications and serious adverse events are readily observed but it is difficult to confirm/reject drug related (S)AE, especially when the patient has co-morbidities
E.g. Diabetes increases the risk for AMI attack rate, incidence, case-fatality, recurrence and mortality, hence increased AE rate of diabetes drug is difficult to identify (large population size)

Device effectiveness is more readily identified

DBS effect of stimulation is measured during implant procedure

Where surgery is applied to implant the device

Surgery-related complications are more easily monitored, e.g. infection Implants can be monitored (CT Scan, X-ray)

15

Medical Devices and Drugs Recalls

Devices:
Design issues leading to SAE that alter the benefit / risk ratio leads to field safety corrective actions / recall
issues are recognized following increase in patient exposure and prolonged treatment time Root cause analyses of returned product

Drugs
Design issues are not applicable When over time the benefit/risk ratio changes, the following actions are possible
Labeling change recall (withdrawal)

Manufacturing issues are identified, usually based on returned product analyses FDA 2012, 39 recalls FDA 2011, 41 recalls December 9, 2011 Medtronic Model 8637 SynchroMed II Implantable Infusion Pump11

Manufacturing issues often leads to recall: FDA 2012, 37 recalls FDA 2011, 42 recalls
October 05, 2012 Hospira Recalls One Lot Of Lactated Ringer's And 5-percent Dextrose Injection, Usp, 1000 Ml, Flexible Containers Due To Mold Contamination
16

Comparison Summary
Devices
Product groups On avg moderate development costs Relatively short development time Iterative development Short (18-24m) life cycle per model User learning curve Human factors Relatively low exposure in population Device failures Improvements or design corrections can usually be implemented Clinical studies usually small size PMS critical; PMCF tbd No regulatory incentives

Drugs
Drug classes High development costs Relatively long development time No changes to product, only line extensions, same molecule Long life cycle No user learning curve - dosing No human factors Patient compliance risk Relatively High exposure in population Quality Issues SAE profile changes risk withdrawal of product if labeling changes are not adequate to reduce risk Clinical studies usually large to demonstrate superiority or non-inferiority; this also provides a relatively large safety database PMS and PMCF critical Regulatory incentives significant

17

Post-Market Surveillance Implications

Devices
Product groups On avg moderate development costs Relatively short development time Iterative development Short (18-24m) life cycle per model User learning curve Human factors Relatively low exposure in population for class III, AIMD Device failure more readily identified; could lead to recall Improvements or design corrections can usually be implemented Clinical studies usually small size PMS critical; PMCF tbd No regulatory incentives

Drugs
Drug classes High development costs Relatively long development time No changes to product, only line extensions, same molecule No learning curve No human factors Patient compliance risk Relatively High exposure in population SAE profile could lead to withdrawal of product from market if labeling changes are not adequate to reduce risk Clinical studies usually large to demonstrate superiority or non-inferiority; this also provides a relatively large safety database PMS and Post Authorization studies Regulatory incentives significant

18

Regulations and Guidelines

Medical Devices
Directive 2007/47/EC, amended the MDD, 93/42/EEC, and the AIMDD (90/385/EEC)
MDD art 10 and Annexes AIMD art 8 and annexes IVDD art 11 and Annexes

Pharmaceutical
Directive 2001/83 as amended by 2010/84/EU Regulation 1235/2010/EU (PV Regulation) Regulation 726/2004 (EMA Agency) as amended Implementing Regulation 520/2012/EU

MEDDEV 2.12-1 rev 7

March 2012, GUIDELINES ON A MEDICAL DEVICES VIGILANCE SYSTEM

22 June 2012 EMA/541760/2011 Guideline on Good , Pharmacovigilance practices (GVP) Modules I XVI
19

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).

20

REGULATION (EU) No 1235/2010 OF THE EUROPEAN PARLIAMENT 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 veterinary use and establishing a European Medicines Agency, and Regulation (EC) No 1394/2007 on advanced therapy medicinal products Commission Implementing Regulation (EU) No 520/2012 on the performance of pharmacovigilance activities stipulates operational details in relation to certain aspects of pharmacovigilance to be respected by marketing authorisation holders, national competent authorities and EMA.
21

REGULATION (EU) No 1235/2010 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 15 December 2010

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, in particular as regards

the management of the Union pharmacovigilance database and dataprocessing network (the Eudravigilance database),

the coordination of safety announcements by the Member States, and

the provision to the public of information regarding safety issues.

22

REGULATION (EU) No 1235/2010 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 15 December 2010
(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 scientific 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, and of members appointed by the Commission, who are independent scientific experts, or representatives of healthcare professionals and patients.

23

REGULATION (EU) No 1235/2010 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 15 December 2010
Pharmacovigilance Risk Assessment Committee T(14) To ensure the highest levels of expertise and the functioning of the Pharmacovigilance Risk Assessment Committee, rapporteurs providing assessments for Union pharmacovigilance procedures, periodic safety update reports, post-authorisation safety study protocols and risk management systems should receive payment through the Agency. Meddev rev 7: 6.3.1 Competent Authorities should determine a single coordinating National Competent Authority under the following circumstances: INCIDENTs of similar types occurring in more than one country within the EEA, Switzerland and Turkey; FSCA conducted in more than one country within the EEA, Switzerland and Turkey
24

MEDDEV 2.12-1 rev 7 March 2012

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.
25

REGULATION (EU) No 1235/2010 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 15 December 2010
(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 authority 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.

26

REGULATION (EU) No 1235/2010 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 15 December 2010

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". .

27

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 reporting of non-serious adverse events (AE) 90 days

28

Good pharmacovigilance practices (GVP)

The guideline on GVP is divided into 16 modules, each of which covers one major process in pharmacovigilance 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 for transmission of information on non-interventional post-authorisation safety studies Module IX Signal management Etc, etc

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

29

REGULATION (EU) No 1235/2010 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 15 December 2010

Regulation (EU) No 1235/2010 and Directive 2010/84/EU introduced the concept of the pharmacovigilance system master file. In order to accurately 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.

30

MDD/AIMD/IVDD
Quality system 3.1. The manufacturer must lodge an application for assessment of his quality system with a Notified body. The application must include:
,

an undertaking by the manufacturer to institute and keep up to date a systematic procedure to review experience gained from devices in the postproduction phase, including the provisions referred to in Annex X, and to implement appropriate means to apply any necessary corrective action. This undertaking must include an obligation for the manufacturer to notify the competent authorities of the following 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 or Performance of a device leading for the reasons referred to in subparagraph (i) to systematic recall of devices of the same type by the manufacturer.
31

REGULATION (EU) No 1235/2010 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 15 December 2010 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 same active 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.
32

MEDDEV 2.12-1 rev 7 March 2012

PERIODIC SUMMARY REPORTING is an alternative reporting regime that is agreed between the MANUFACTURER and the National Competent Authority for reporting similar INCIDENTs with the same device or device type in a consolidated way where the root cause is known or an FSCA has been implemented

33

REGULATION (EU) No 1235/2010 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 15 December 2010

RISK MANAGEMENT PLAN - RMP

Risk management plans are required for all new marketing authorisation applications. They contain a detailed description of the risk management system 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

34

Risk Management Plan - RMP

Content of the risk management plan 1. The risk management plan established by the marketing authorisation holder shall contain the following elements: (a) an identification or characterisation of the safety profile of the medicinal product(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 associated with the medicinal product, including an assessment of the effectiveness of those interventions; (d) a documentation of post-authorisation obligations that have been imposed as a condition of the marketing authorisation.

There is no RMP requirement for medical devices

35

MEDDEV 2.12-1 rev 7 March 2012

4.2 AUTHORISED REPRESENTATIVE Any natural or legal person established in the Community who, explicitly designated 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.

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 one qualified person
36

Medicinal products - EudraVigilance

EudraVigilance is a data processing network and management system for reporting and evaluating suspected adverse reactions during the development and following the marketing authorisation of medicinal products in the European Economic Area (EEA). The first operating version was launched in December 2001 The EudraVigilance Clinical Trial Module (EVCTM) The EudraVigilance Post-Authorisation Module (EVPM)

EudraVigilance is also one of the main pillars of the European Risk Management Strategy, a joint effort between the EMA and national Competent Authorities to strengthen the conduct of pharmacovigilance in the EEA

37

Medical Devices - EUDAMED

Medical Devices EUDAMED: a secure web-based portal acting as a central repository for information 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 and on vigilance and clinical investigation data, as well as to contribute to a uniform application of the Directives, in particular in relation to registration requirements.

38

Summary
Current 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

39

THANK YOU