Medical Device Link.

The IVD Directive will come into full effect on December 8, 2003. IVD products that are marketed on or after that date must comply with the terms of the directive, and must display the CE mark to signify their compliance. Products that do not bear the CE mark may be placed on the market through December 7, 2003, but must then be put into service within two years of that date.

Although the directive provides a framework for the regulatory approval of IVD products, it is not prescriptive about the methods that manufacturers may use to achieve their CE mark. Instead, the directive provides a series of options from which manufacturers may select a procedure to demonstrate the compliance of their products. This article looks at the routes to conformity assessment established by the IVD Directive, with special reference to the documentation requirements that manufacturers must fulfill.

Depending on the classification of their devices, manufacturers have a choice among several procedures for conformity assessment to demonstrate compliance with the essential requirements of the IVD Directive. The choice of a particular procedure typically depends on the grouping of the device: the greater the risks associated with a product's category, the more stringent the conformity assessment procedures will be for that product (see Figure 1).

Figure 1. Procedures for conformity assessment of IVD medical devices under the terms of the European Union's IVD Directive. Except in the case of self-declaration, an assigned CE mark will also carry the number of the notified body that grants the mark. Source: European Diagnostic Manufacturers Association (Brussels, Belgium).

General IVD Products. For general IVD devices, manufacturers are permitted to self-declare the conformity of their products with the relevant essential requirements of the IVD Directive. This procedure sounds deceptively simple. As described in Annex III of the directive, however, the requirements involved in self-declaration are actually quite demanding. Manufacturers are required to submit technical documentation sufficient to demonstrate the conformity of their product, to implement manufacturing quality systems, and to implement a system for postmarket review and corrective action. Some key elements of these requirements are described in the following sections.

Technical Documentation. Annex III specifies 13 areas that manufacturers must address in their product's technical documentation. Some of these—such as documentation of the quality system and results of stability studies—are listed by the directive without further comment. Other areas are explained in greater detail.

In the case of design information, for instance, Annex III specifies that manufacturers should include in their technical documentation a characterization of the product's basic materials, characteristics and performance limitations of the device, and the methods of its manufacture. In the case of instruments the documentation should include design drawings and diagrams of components, subassemblies, circuits, and so on.

Similar detail is required for devices containing tissues of human origin or substances derived from such tissue, where the annex requires information about the origin of such material and the conditions in which it was collected. Finally, the annex requires manufacturers to provide "descriptions and explanations necessary to understand the abovementioned characteristics, drawings, and diagrams, and the operation of the product."

Another large category of documentation required by the annex involves the results of testing and clinical studies carried out for the device. For instance, manufacturers are required to provide the results of risk analyses, design calculations, test reports, and inspections. The same rule holds true for more specialized characteristics of certain devices. If the device is to be labeled sterile or sold in a "special microbiological state or state of cleanliness," the manufacturer must describe the processes used to make it so. Similarly, the manufacturer must document the conformity of its product when used in combination with any other devices that it is intended to be used with.

Even more complex, however, is the annex's requirement of adequate performance evaluation data to support the performance claims of the manufacturer. The annex says that such data should be supported by a reference measurement system when available. The technical file should include information on the reference methods, the reference materials, the known reference values, and the accuracy and measurement units used. According to the annex, "Such data should originate from studies in a clinical or other appropriate environment or result from relevant biographical references."

Quality Assurance Systems. Underlying all of the assessment procedures described below, the IVD Directive clearly indicates that each manufacturer must maintain quality systems adequate for their products. Such a quality system must ensure that the manufacturing process follows principles of quality assurance as appropriate for the product being manufactured. This requirement, which appears in various forms throughout the directive, is true even when the manufacturer's product can be CE marked using the simplest conformity assessment route. As described in Annex III, the manufacturer's quality system must at a minimum address the following items.

All of the elements, requirements, and provisions adopted by the manufacturer for such a quality system must be documented in a systematic and orderly manner. Such documentation typically takes the form of written policies and procedures, including a description of the quality program, quality plans, quality manuals, and quality records.

Procedures for conformity assessment can include quality system certification based on the ISO 9000 and EN 46000 series of quality systems standards, design dossier examination, type examination, batch verification, or batch record verification.²

Devices for Self-Testing. Manufacturers of most IVDs for self-testing can use the route described in Annex III to obtain a CE mark for their product, but with additional requirements that make this no longer a self-declaration method. In this case, all the requirements imposed by the annex for general IVD products still apply and must be satisfied. However, manufacturers of such self-testing devices must also satisfy the terms of Annex III, section 6, which requires examination and approval of the design of the device by a notified body.

In practice, the manufacturer must first prepare an application that includes sufficient design-related information to enable the conformity of the product to be assessed. Annex III, section 6.1 specifies the required contents of such an application.

The manufacturer then contracts with a notified body and submits its detailed device design application for examination. In turn, the notified body assesses the design of the device in terms of its suitability for nonprofessional users. Approved products receive the CE mark.

Even with the additional requirement for design assessment, the requirements of Annex III offer the simplest route available for the approval of self-testing products. Nevertheless, manufacturers of such products can opt to follow the conformity assessment routes for higher risk products, as described in the sections below.

Annex II Products. The IVDs having the highest risk—and therefore the most stringent requirements for conformity assessment—are those listed in Annex II. As discussed in the first installment of this series, Annex II divides these products into two groups (List A and List B), and offers a different set of conformity assessment routes for the products on each list. In no case, however, can a manufacturer self-declare the conformity of such products. Each of the routes provided by the IVD Directive for the assessment of Annex II products requires the involvement of a notified body.

The elements of the routes that may be used for Annex II products are described in Annexes IV–VII. The fullest of the routes is described in Annex IV, which requires that a notified body inspect and verify the manufacturer's full quality assurance system. Annex V describes the procedures for a notified body to conduct type examination of the manufacturer's products; that is, an examination of the product using only representative samples. Annex VI describes the procedures for a notified body to verify the conformity of products directly, either by examination and testing of every product or on a statistical basis (batch testing). Annex VII describes the procedures for a notified body to inspect and verify the manufacturer's production quality assurance system.

By combining the requirements described in these annexes as permitted by Article 9 of the directive, the manufacturer can devise a conformity assessment route appropriate to its products. The routes permitted under the directive for each of the two Annex II lists are described below.

Annex II, List B Products. The directive offers three routes for the conformity assessment of List B products. In the first case, described in Annex IV, the manufacturer would contract with a notified body to verify its full quality assurance system. Although Annex IV describes the procedures for examination of the design dossier and for batch verification (Annex IV, sections 4 and 6), these activities are not required for List B products.

Alternatively, the manufacturer can contract with a notified body to carry out an assessment using the procedures described in Annex V (EC type examination) coupled with those described in Annex VI (EC verification). The underlying logic of this combination of requirements is that type examination is used to demonstrate that the manufactured product conforms with the essential requirements of the directive, while verification ensures that the products produced by the manufacturer are the same as the samples used in the type examination.

In the third alternative, the notified body again carries out an assessment using the procedures described in Annex V (EC type examination), but couples this with the procedures described in Annex VII (production quality assurance). The logic of this combination is that type examination confirms conformity with the essential requirements, while assessment of the production quality systems ensures that the manufacturer can reproducibly make products that are the same as the samples.

Annex II, List A Products. The directive offers two routes for the conformity assessment of List A products. Once again, the manufacturer can contract with a notified body to verify its full quality assurance system, as described in Annex IV. In this case, such an assessment must include examination of the design dossier and batch verification, as described in Annex IV, sections 4 and 6. Batch verification and release is typically carried out by the notified body in cooperation with a subcontracted reference laboratory.

Alternatively, the notified body can combine the procedures of Annex V (EC type examination) with those of Annex VII (production quality assurance) to perform its assessment. The logic of this route for List A products is the same as when it is applied to List B products.

Common Technical Specifications. Because Annex II products represent the highest-risk group of IVDs, the IVD Directive made special accommodation for additional requirements to be imposed on such products. Although these requirements do not appear within the text of the directive or its annexes, they are incorporated by reference in Article 5 of the directive.

These so-called common technical specifications (CTS) mandate "performance evaluation and reevaluation criteria, batch release criteria, reference methods, and reference materials," beyond the essential requirements that apply to other IVD products. They represent the basis for evaluating the performance of IVD products that appear in Annex II, List A and, where necessary, List B.

In practice, the CTS have the same status as harmonized standards, as discussed below. They establish the required performance characteristics of the IVD products they apply to, and they must be addressed in any evaluation of those products.

Devices for Performance Evaluation. Products that are being released only for use in studies to evaluate their performance receive special consideration under the IVD Directive. The procedures to be followed for such devices are described in Annex VIII of the directive, which requires the manufacturer to prepare a statement containing the following information.

Other documentary requirements apply to devices for performance evaluation, and the manufacturer is instructed to "take all the measures necessary for the manufacturing process to ensure that the products manufactured conform to the documentation."

As in the case of other EU directives, manufacturers can achieve compliance with the IVD Directive by applying harmonized standards whose preparation has been mandated by the European Commission (e.g., EN 1441, EN 980, EN 61010). The use of such standards will assist manufacturers by providing practical evidence of the compliance and conformity of their products with the relevant essential requirements.^2–8

A key challenge related to the standardized evaluation of antibody and antigen assays (especially immunoassays) will be for appropriate authorities to make available reference materials, seroconversion panels, and critical samples (e.g., isoforms of proteins or subtypes and rare variants of viruses).⁹ Such reference panels with defined areas of application and performance criteria could be established by experts of the member states designated by competent authorities and other interested parties.

The individual members of reference seroconversion panels should be native specimens from single individuals, stored frozen in aliquots, and defined in terms of geographical origin, clinical status of the patient or donor, nature of the specimen (e.g., serum, plasma), positivity criteria, and method of preservation. A specific organization should be responsible for developing such reference materials and panels, including the collection, preparation, storage, and distribution of the materials. As they become available, the reference materials should be made available to all interested parties.