The European In-Vitro Diagnostic Medical Devices Directive: Its Implications on the Clinical Marketplace and Healthcare Measurement Standards

INTRODUCTION

On December 7, 1998, the European Directive 98/79/EC on in vitro diagnostic medical devices (IIVD MD), was published in the Official Journal of the European Communities, being the starting point of a transition period of five years. The major purposes of the directive are to eliminate trade barriers within Europe by ensuring access to the entire EU market with one single product approval (CE marking), and at the same time to maintain or improve the level of health protection attained in the EU Member States. The first IVD product with a CE label may be placed on the EU market from June 7, 2000 onwards, and by December 7, 2003, all new IVD products that are placed on the market must be labeled with the CE mark. Alternatively, it remains possible to place new IVD products on the market under the old national regulations until December 7, 2003, and it remains allowed to put already existing IVD products without a CE mark into service until December 7, 2005.

CE MARKING

The definition of an IVD MD is given in the Directive as:

‘In-vitro diagnostic medical device’ means any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment, or system, whether used alone or in combination, intended by the manufacturer to be used in-vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information:

• concerning a physiologicalor pathological state, or

• concerning a congenital abnormality, or

• to determine the safety and compatibility with potential recipients, or

• to monitor therapeutic measures.

This definition implies that all instruments, reagents, calibrators, etc., used in professional laboratory medicine must be CE marked. Also specimen receptacles and manufactured devices that are used for medical analyses in a professional and commercial context, without being marketed, are subject to the Directive. However, products for general laboratory use, IVD MD's that are used for research purposes without any medical objectives, home made reagents which are not used commercially, and international certified reference materials and materials used for external quality assessment schemes, are not covered.

The total IVD MD market in Europe was about 5.6 billion US$ in 1998 and showed over the past four years a growth of about 4% per year (data from EDMA at www.edma-ivd.be). Most of the IVD market (87%) is concerned with IVD reagents, calibrators, etc., while the rest (13%) is concerned with IVD instruments. Approximately 70% of the IVD products on the European market are imported from the USA and Japan.

The global market of IVD products had a turnover of some 19 billion US$ in 1998.

In order to apply the CE mark, the manufacturer must declare that their product complies with all the “essential requirements” of the Directive. The essential requirements (Table II), are described in 43 paragraphs and compliance with all of them is mandatory.

Table II

ESSENTIAL REQUIREMENTS

A General Requirements

The IVD may not compromise in any way the clinical condition or the safety of patients or users Conformance with safety principles Analytical and diagnostic performance characteristics must be specified and guaranteed (they include sensitivity, specificity, accuracy, repeatability, reproducibility, control of known relevant interferences, detection limit) Traceability of values assigned to calibrators and control materials must be assured through available reference measurement procedures and/or available reference materials of a higher order Safety and performance characteristics must not be adversely affected during the lifetime of the device Safety and performance characteristics must not be adversely affected under storage and transport conditions

By Design and Manufacturing Requirements related to:

Chemical and physical properties Infection and microbial contamination Manufacturing and environmental properties Devices which are instruments or apparatus with a measuring function Protection against radiation Requirement for medical devices connected to or equipped with an energy source Requirements for devices for self-testing Information supplied by the manufacturer

Selected aspects of the general requirements need further explanation in order that a uniform implementation is achieved. The European Commission has mandated to the European Committee for Standardization (CEN), and the European Committee for Electro-technical Standardization (CENELEC), the development of some 22 standards, which include, for example, labeling and symbols, stability testing, colour codes for blood-specimen containers, traceability (see below), and “particular requirements for automatic and semiautomatic operating analytical equipment.” The standards are all under development and publication is expected in 2000 and later. When the European Commission judges them of significant importance, they will be published in the Official Journal of the European Communities, and from then on they will be called “harmonized” standards. Compliance with the harmonized standards is not compulsory and manufacturers may chose their own methods. However, in such cases the manufacturer must demonstrate that their methods are equivalent or better.

Compliance with the essential requirements of the IVD directive and the harmonized standards ensures end-users that the safety, reliability and quality of the IVD product is guaranteed. The application of the CE mark is for most IVD products the responsibility of the manufacturer (self-declaration), and must be underpinned by a valid “EC Declaration of Conformity.” However, before placing a product on the market, the manufacturer (or its authorized representative if the manufacturer does not have a registered place of business in the EC), shall notify the National Competent Authority in the country where it has its registered place of business. The notifications will be registered in a databank, which is accessible to the Competent Authorities in all Member States.

NOTIFIED BODIES

When the first draft of the IVD Directive was published in April 1995, discussions started about more strict requirements for IVD devices for HIV detection. Especially the events in France fueled this discussion and in the final version of the Directive, the IVD medical devices are divided in two groups:

1. IVDs for which the correct performance is essential to medical practice and the failure of which can cause a serious risk to health of patients

2. IVDs that do not constitute a direct risk to patients and are used by competently trained professionals, and for which the results obtained can often be confirmed by other means

The IVD MD's of the first category, where serious risk to health to patients is involved, have been subdivided in two further subclasses as described in Annex II of the Directive:

ANNEX II IVD MEDICAL DEVICES

1. List A products.

   Reagents and reactive products, including related calibration and control materials for:

2. List B products.

   Reagent and reagent products, including related calibrators and control materials, for:

List A products and possibly also List B products, must comply with the Common Technical Specifications which have been drawn up by a team of experts and which are a further specification of the Essential Requirements as applied to these special products. A Common Technical Specification is not mandatory and a producer is allowed to use other specifications, provided that it can be demonstrated that they are equivalent or better than the Common Technical Specifications.

The IVDs that do not constitute a direct risk to patients have been subdivided into subclasses, which require different conformity assessment procedures:

1. IVDs for self-testing except those listed in Annex II

2. IVDs for performance evaluation

3. All other IVDs

A Notified Body plays an essential role in the conformity assessment procedure in all the above-mentioned categories, except for the groups “IVDs for performance evaluation” and “all other IVDs.” The role of the Notified Body may include approval of design dossiers and registration files, certification of the manufacturers ISO 9001 or 9002 quality system, and batch-release controls or EC verification. A Notified Body must be appointed by a National Competent Authority and must operate under their direct supervision. Any public or private organization that possesses the necessary technical, scientific and quality systems expertise can apply for nomination as a Notified Body. The different conformity assessment routes are summarized in Table III.

Table III.

Conformity Assessment Routes for IVD Medical Devices

IVDs on List A of Annex II

Notified Body approves design dossier and ISO 9001 quality system, and can impose batch-release controls, or Notified Body approves registration file and ISO 9002 quality system, and can impose batch-release controls

IVDs on List B of Annex II

Notified Body certifies ISO 9001 quality system Notified Body approves registration file and certifies ISO 9002 quality system Notified Body approves registration file and provides EC verification

IVDs for self-testing except those listed in Annex II

Notified Body approves design dossier

IVDs for performance evaluation

Manufacturer submits statement regarding devices for performance evaluation

All other IVDs

Self declaration by manufacturer by submitting an EC Declaration of Conformity

THE TRACEABILITY REQUIREMENT

The Directive requires that the values assigned to calibrators and/or control materials of IVD devices are traceable to available measurement standards and/or available measurement procedures of a higher order.

Annex I.A.3

The traceability of values assigned to calibrators and/or control materials must be assured through available reference measurement procedures and/or available reference materials of a higher order

How to achieve this traceability is the subject of the work in the technical committee CEN/TC 140 “In vitro diagnostic medical devices” of the European Committee for Standardization. In this committee a European Standard is developed in parallel with the technical committee ISO/TC 212 “Clinical laboratory testing and in vitro diagnostic test systems” of the International Standardization Organization. This European and International Standard is at present in the stage of the pre draft prEN ISO 17511.

The usual end point of a traceability chain is a national or international measurement standard, which ideally has a value traceable to the SI system of units. In order to make a measurement traceable to the SI, the measurable quantity must be clearly defined. For those measurements for which traceability to the SI is not (yet), possible, it is also necessary for the manufacturer to precisely (exactly), define the intended use of the product e.g., in relation to medical needs.

Traceability to the SI requires a complete knowledge of the molecular structure of the analyte, and a definition of the quantity and the unit. For example, the amount of substance concentration of cortisol in human serum, with a unit of mol.m³ or mol.l^-1.

CGPM = Conference Generale des Poids et Mesures, NMI = National Metrology Institute, ARML = Accredited Reference Medical Laboratory, ML = Medical Laboratory.

In order to assign values to measurement standards for quantities of which measurement results can be made traceable to SI, a primary measurement procedure must be available, which is a measurement method specific for the analyte and whose measurement result can be obtained without reference to a standard of the same kind. Isotope ratio mass spectrometry, coulometry, and gravimetric and volumetric analysis have the potential to be primary, depending on the specificity of the measurement procedure and quantitative knowledge of all influence factors. A reference material which is used as a calibrator and whose value is assigned by a primary method is called a primary reference material. Primary reference measurement procedures and one or more primary reference materials (used as calibrators) are available for approximately 25–30 types of well defined compounds such as some electrolytes, metabolites, steroid hormones, and some thyroid hormones.

A complete traceability chain for such well-defined analytes, being the inverse of the calibration hierarchy, starts with the measurement result as obtained with the IVD device up to the SI. Figure I illustrates such a traceability chain together with an indication of the organizations which normally are responsible for the correct assignment of values to (primary), reference materials and/or calibrators using (internationally), accepted (reference), measurements procedures. In general, the measurement uncertainty will increase from the top level of the traceability chain down to the IVD measurement result.

For other quantities the traceability chain will stop before the SI level and the measurement result will become traceable to, for example, an arbitrary unit. The prEN ISO 17511 distinguishes four cases for which traceability can be achieved up to:

1. An international conventional reference measurement procedure (RMP), and one or more international conventional calibration materials with values assigned by that procedure (e.g., Haemoglobin A1_c).

2. An international conventional RMP but no international conventional calibration materials are available. This category comprises ∼30 types of quantity with components such as haemostatic factors.

3. One or more international conventional calibration materials, but no international conventional RMPs are available. This category comprises ∼250 types of quantity, including quantities for which WHO international standards are available, such as e.g., (glyco), protein hormones.

4. An in-house measurement procedure and/or a calibrator of the manufacturer. Neither international conventional RMPs or calibration materials are available. This category comprises ∼300 types of quantity such as tumor markers and antibodies.

CONCLUSION

In the future, it will be necessary to improve traceability for results of all quantities for which traceability to SI is not possible and for which RMPs and/or reference materials are missing. This can be achieved only, by working together on an international level between National Metrology Institutes (NIST, NMi, PTB, etc.), accredited reference laboratories for laboratory medicine (ARMLs), and international scientific organizations to determine priorities and to start development of new primary or international conventional RMPs and calibrators. □