The In Vitro Diagnostics Directive: A practical guide on how to comply

The In Vitro Diagnostics Directive: A practical guide on how to comply

Regulatory

The IVD Directive must be fully transposed into the national laws of each EU Member State by December 1999. Manufacturers producing a wide range of products may run into a regulatory bottleneck unless they are well informed, well organised and take action now.

The In Vitro Diagnostics Directive: A practical guide on how to comply provides an extensive guide to preparing to adopt the IVD Directive regulations, assessing timescales of implementation and describing the key steps that companies need to take to achieve CE marking for their products.

This authoritative guide provides indispensable advice on:

Implementing the Directive; making the right 'when' and 'how' decisions for your company
How to classify your medical diagnostics in terms of the Directive
How to prepare for compliance
The role of notified bodies in the In Vitro Diagnostics Directive
Performing clinical evaluations in line with the Directive
Implementing vigilance procedures

PUBLISHED: MAY 1999
REF: CBS813E
PAGES: 90
PRICE: £395/$830/¥95,000

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CONTENTS
LIST OF TABLES
EXECUTIVE SUMMARY
ABBREVIATIONS

CHAPTER 1 INTRODUCTION
1.1 The medical device directives
1.2 The Active Implantable Medical Device Directive
1.3 The Medical Device Directive
1.4 The In Vitro Diagnostic Device Directive
1.4.1 History
1.4.2 Structure
1.4.2.1 Recitals
1.4.2.2 Articles
1.4.2.3 Annexes
1.4.3 Timetable
1.5 'New approach' directives
1.5.1 Essential requirements
1.5.2 Harmonised standards
1.5.2.1 Product-specific standards
1.5.2.2 Horizontal standards
1.5.2.3 Semi-horizontal or group standards
1.5.3 Harmonised standards for the IVDD
1.6 Common technical specifications
1.6.1 Performance evaluation
1.6.2 Performance re-evaluation
1.6.3 Batch release testing
1.6.4 Reference methods and materials
1.6.5 Status

CHAPTER 2 ESSENTIAL REQUIREMENTS, STANDARDS AND COMMON TECHNICAL SPECIFICATIONS
2.1 Essential requirements
2.1.1 General requirements
2.1.2 Design and manufacturing requirements
2.1.3 Self-tests
2.1.4 Information supplied by the manufacturer
2.2 Standards
2.3 Common technical specifications
2.3.1 Blood grouping reagents
2.3.1.1 Key requirements
2.3.1.2 International collaboration
2.3.2 Virology testing
2.3.2.1 Need for EU system
2.3.2.2 Elements of a harmonised system

CHAPTER 3 A GUIDE TO PRODUCT DEFINITIONS
3.1 Products covered
3.1.1 Accessory
3.1.2 Devices for self-testing
3.1.3 Devices for performance evaluation
3.2 Other definitions
3.2.1 Manufacturer
3.2.2 Authorised representative
3.2.3 Intended purpose
3.2.4 Placing on the market
3.2.5 Putting into service
3.3 Products not covered by the directive
3.4 Classification of devices
3.4.1 Annex II, List A devices
3.4.2 Annex II, List B devices

CHAPTER 4 CONFORMITY ASSESSMENT PROCEDURES
4.1 Overview
4.2 Summary of Annexes III-VIII
4.2.1 Annex III - EC declaration of conformity
4.2.1.1 Technical documentation
4.2.1.2 Quality assurance
4.2.1.3 Devices for self-testing
4.2.2 Annex IV - Full quality assurance system
4.2.2.1 Quality system
4.2.2.2 Notified body responsibilities
4.2.2.3 Design
4.2.2.4 Surveillance
4.2.2.5 Verification of products in Annex II, List A
4.2.3 Annex V - EC type examination
4.2.3.1 Notified body responsibilities
4.2.4 Annex VI - EC verification
4.2.4.1 Verification by testing every product
4.2.4.2 Statistical verification
4.2.5 Annex VII - Production quality assurance
4.2.5.1 Quality system
4.2.5.2 Documentation
4.2.5.3 Notified body
4.2.5.4 Surveillance
4.2.6 Annex VIII - Statement and procedures concerning devices for performance evaluation
4.2.6.1 Manufacturer's obligations
4.3 Conformity assessment by device group

CHAPTER 5 RELEVANT BODIES AND ORGANISATIONS
5.1 Competent authorities
5.1.1 General responsibilities
5.2 Notified bodies
5.2.1 Annex IX - Criteria for the designation of notified bodies
5.2.2 Activities of notified bodies
5.3 Standards organisations
5.3.1 CEN
5.3.2 CENELEC
5.4 EU Committees
5.4.1 Committee on Standards and Technical Regulations
5.4.2 Committee on Medical Devices
5.5 Trade associations
5.5.1 European Diagnostic Manufacturers' Association
5.5.1.1 IVDD Transposition Working Party
5.5.2 EUCOMED

CHAPTER 6 PREPARING FOR COMPLIANCE
6.1 Who are you?
6.1.1 Authorised representative
6.2 Does your product fit?
6.2.1 Intended purpose
6.2.2 Product classification
6.3 What are the time constraints?
6.4 Will I need to appoint a notified body?
6.5 Check the device against ERs and harmonised standards
6.6 Product documentation
6.7 Registration of manufacturer and devices
6.8 Vigilance
6.9 The CE mark
6.10 Clinical evaluation
6.10.1 Common Technical Specification developments
6.10.2 CEN Standard
6.11 Conclusion - Strategic planning
6.11.1 Product priorities
6.11.2 Conformity assessment
6.11.3 Supporting data
6.11.4 Technical documentation
6.11.5 Labelling
6.11.6 Resource allocation

CHAPTER 7 DOCUMENTATION
7.1 Types of documentation required
7.2 Technical documentation
7.2.1 Structure
7.2.2 Content
7.2.3 Language
7.2.4 Storage
7.2.5 Directive text, with comments
7.2.6 Risk analysis
7.2.6.1 Risks of IVDs
7.2.6.2 Terminology
7.2.6.3 Process and techniques
7.3 Information supplied by the manufacturer
7.3.1 Product labelling
7.3.1.1 Kit labels
7.3.1.2 New standards
7.3.1.3 Dangerous substances
7.3.1.4 The language problem
7.3.1.5 EDMA position
7.3.1.6 Present practice
7.3.1.7 Language options for Member States

CHAPTER 8 VIGILANCE
8.1 Introduction
8.2 Purpose of the vigilance system
8.3 Some underlying principles
8.4 What to report?
8.4.1 Incidents which need to be reported
8.4.2 Near incidents
8.5 Timescale for the initial report
8.5.1 Product recall
8.6 What to include in the initial report
8.7 CA actions
8.8 Actions following the initial report
8.9 Follow-up - Final report

APPENDIX I EU COMPETENT AUTHORITIES
APPENDIX II CEN, CENELEC AND EDMA
APPENDIX III EUCOMED
APPENDIX IV INCIDENT REPORT FORMAT FOR INITIAL REPORTS
APPENDIX V INCIDENT REPORT FORMAT FOR FINAL REPORTS

LIST OF TABLES
Table 4.1 Conformity assessment by device group
Table 7.1 Technical documentation required for conformity assessment of a product with the requirements of the IVDD

EXECUTIVE SUMMARY
When the European Commission began the task of drafting laws to regulate medical devices, its first consideration was (and remains) protecting the health and safety of its citizens. Thus, the first of the three planned medical directives to be drafted, later finalised and brought into force, was that applicable to active implantable medical devices, because these have a higher potential risk, as a class, than other medical products. Next came a directive embracing all other medical devices with the exception of in vitro diagnostic (IVD) devices; the latter were left until last because it was felt that they pose the least risk to patients and users.

However, many years elapsed between the time when the proposal for an IVD device directive was first discussed, and the adoption of the final text. In the interim there have been successive drafts and much heated discussion, with vigorous lobbying in the European Parliament, The troubled gestation of the directive clearly indicates that the IVD device field is not as simple and innocuous as it might first have appeared to the regulators. Part of the problem is that, although IVD devices do not come into contact with the patient and therefore have little or no risk of causing direct harm, they can, if they malfunction or are used improperly, cause harm by giving false information. This means that, for IVD devices, safety is bound inextricably, not only to the quality of the instruments and reagents, but also to the efficacy of the device in providing the information required.

This inevitably colours the approach to assessment with a view to regulatory approval. In fact, it is not fanciful to suggest that the evaluation of an IVD device resembles that of a pharmaceutical more than that of another type of medical device. Pharmaceuticals, like medical devices, are assessed for quality and safety but, in addition, they are judged on their efficacy, and this has a lower priority in the context of most medical devices. However, because the function of an IVD device is to provide information, its efficacy in doing this is an essential aspect of its overall safety as a factor in determining the patient's wellbeing.

The IVD Directive (IVDD; 98/79/EC) follows the same overall approach as the other two medical device directives. Like them, it is a 'new approach' directive, meaning that it lays down a set of 'essential requirements' (ERs) to which all IVD devices must conform, with an associated body of harmonised standards to be used as yardsticks against which the performance of a device may be measured.

The rigour of the validation procedure is matched to the degree of risk offered, and devices are classified in a similar manner to medical devices of other sorts. However, the details of the classification system are specific to IVD devices; the classification indicating highest risk potential includes products for determining certain blood groups and those for detecting certain viral diseases, such as human immunodeficiency virus (HIV). Next is a range of reagent-based tests for a specified list of blood types, infections, hereditary diseases, and so on. This group also includes self-tests for blood glucose levels. Finally, a third major classification includes all other devices. There are special provisions for devices that are undergoing performance evaluation.

The 'all other devices' category resembles Class 1 medical devices, in that self-certification by the manufacturer suffices to affirm conformity of the device with the relevant ERs. For all other categories, a notified body must be involved to a greater or lesser degree; for example, for all self-test devices, the design must be certified by a notified body because of the special requirements for devices to be used in a home environment by people who are not medically trained or familiar with laboratory procedures.

Because of the importance of ensuring that diagnostic tests are performed correctly, there is an emphasis on the adequacy of labelling information and instructions for use, both for devices intended for professional use and for self-tests by lay persons.
As this report was being finalised, the IVDD was being transposed into national laws among Member States of the European Union (EU). There will then be a transition period during which manufacturers will have the option of following pre-existing national regulatory processes or taking their IVD devices through the new procedures as specified in the directive. Following this, adherence to the directive provisions will become mandatory, and only devices bearing the Conformit� Europ�ene (CE) mark will be approved for sale in the EU.

This report reviews and explains, where necessary, all the major provisions of the new regulatory system as set out in the directive and in guideline documents. Chapter 1 sets the scene, describing the IVDD in the context of the medical device directives overall, and explaining briefly topics such as harmonised standards and technical specifications.

Chapter 2 discusses the ERs for IVD devices, with a brief reference to standards and a full description of 'common technical specifications', which have been introduced for certain categories of devices and which are more specific than generalised ERs.

Chapter 3 provides a guide to product definitions, and Chapter 4 links these to the range of conformity assessment procedures detailed in the annexes to the directive. Chapter 5 sets out to clarify the nature and roles of all the major bodies involved in IVD device regulation, including competent authorities, notified bodies, standards organisations and trade associations.

The remaining chapters of the report are intended to provide practical guidance. Chapter 6 suggests the decisions to be made, and processes to be undertaken, by manufacturers wishing to comply with the directive's provisions. Documentation is a vital element in the regulatory process, including both the technical documentation that supports the product and the documentation that appears as labelling and instructions for use. Chapter 7 provides a detailed survey of all the documentation issues including languages to be used.

Finally, Chapter 8 indicates what is required in order to fulfil the directive's provisions with respect to product vigilance - that is, the reporting of adverse incidents involving IVD devices, and the measures to be taken to correct any defects.

Since the IVDD has not yet come into force, there is as yet no body of experience in addressing its requirements. However, guidance is already being offered by Competent Authorities and industry associations, as well as by speakers at conferences and seminars on the directive and its implications. This report has benefited from a review of such guidance, so that it aims to be of practical value.

Although selections from the text of the directive are quoted in illustration of various topics discussed, readers are strongly urged to obtain a copy of the directive text as the ultimate, authoritative source.