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Regulations and Standards

EU starts five-year countdown for the IVD Directive

Maurizio Suppo

After many years of discussion and negotiation, the European Union has finally approved the long-awaited IVD Directive. Passage of this key piece of medical device legislation will change the way that IVD companies operate in Europe, bringing new opportunities to companies that learn quickly how to cope with its requirements.

Implementation of the directive could also pose certain risks for IVD manufacturers, potentially driving some companies off the market. Manufacturers that are slow to react or that choose to delay implementation could find that their products are not approved for sale when the final deadline arrives. To ensure that such consequences do not befall them, manufacturers and their distributors should begin planning for the activities that will bring them into compliance with the directive. This article will describe the key elements contained in the directive, and will offer some advice on how manufacturers can best move in the direction of compliance.

Birth of a Directive

No device manufacturer that does business in Europe should be surprised at the passage of the IVD Directive. Discussions about the need for legislative directives that would create a single European market began in the 1980s, and have been a continuous theme of the march toward European unity since that time. In fact, it was members of industry that initially identified the need for a set of directives that would regulate the European market in medical products. After some political pressure, the European Commission finally agreed to develop the directives, with a goal of setting specific rules to regulate the distribution of medical devices and diagnostic products throughout the European market and requiring only a single approval for each product.

In consultation with the health authorities of the European countries, the European Commission decided that the entire universe of medical devices should be divided into three major classes according to the perceived potential risk of the products concerned, their nature, and their intended use. These three classes are:

* Active implantable medical devices (pacemakers).

* All other medical devices (devices that may be implantable but inactive, nonimplantable, invasive, or noninvasive, including syringes, needles, medical gloves, condoms, cardiac valves, contact lenses, prostheses, etc.).

* In vitro diagnostic products.

The European Commission then proceeded to draft the directives for the first two of these classes, and the work initially proceeded rather smoothly. The Active Implantable Medical Devices Directive (90/385/EEC) was adopted in 1990, and the Medical Devices Directive (93/42/EEC) was adopted in 1993. Once the work on these directives was done, the European Commission began to work on the final remaining directive, the one for IVD products.

The commission released the first official draft of the directive in April 1995, after two years of extensive discussions with the various European national health authorities. From the very beginning it was clear that the authorities of certain countries--notably France, but other countries as well--were not satisfied with the initial draft of the directive. In their opinion, much stronger premarket controls were needed to adequately protect the health of Europe's population--especially in the case of diagnostics used in such high-risk areas as HIV, hepatitis, and blood screening and typing. Unquestionably, the very public scandals of preceding years involving the release of HIV-contaminated blood provided strong support for these authorities' insistence on having stricter controls for such products.

On the other side of the fence was another group of national health authorities and industry representatives, who believed that the April 1995 draft of the directive was more than adequate to ensure the availability of good and reliable products on the European market. In their view, stricter premarket controls were unnecessary and would only add a bureaucratic burden to the whole healthcare system (including manufacturers, health authorities, and eventually users) without significantly improving the quality or reliability of products.

This battle of opinions went on for three and a half years, bringing progress toward approval of the IVD Directive nearly to a standstill. In the meantime, other issues also intervened to slow the proceedings. During the summer of 1997 a crisis arose over the possible transmission of bovine spongiform encephalopathies to humans, where it was thought to be the cause of Creutzfeldt-Jakob disease. And there were endless discussions over a proposal to include in the IVD Directive a section that would amend the Medical Devices Directive (93/42/EEC) to make it cover medical devices containing materials of human origin.

Finally, after long and exhaustive discussions, the IVD Directive was approved by both the European Parliament and the Council of Ministers on October 5, 1998. The final text of the directive (98/79/EC) was published in the Official Journal of the European Union on December 7, 1998.

Product Classification and Premarket Activities

Like the two directives that preceded it, the IVD Directive makes a firm distinction between the parties responsible for premarket and postmarket regulatory activities. All premarket activities (whether product- or process-related) are delegated to third parties appointed by the national competent authorities and operating under their direct supervision. In European parlance, these third-party entities are called notified bodies. Any public or private organization that possesses the necessary technical, scientific, and quality systems expertise can apply for nomination as a notified body. Although many such notified bodies exist for other European Union directives (including the Active Implantable Medical Devices Directive and the Medical Devices Directive), none has yet been officially appointed for the IVD Directive.

By contrast, all postmarket activities, including direction of the medical vigilance system (the equivalent of FDA's medical device reporting system), are the exclusive responsibility of the national competent authorities.

Looking at the final form of the IVD Directive, it is apparent that the forces in favor of stricter premarket controls have substantially won their case--especially insofar as the so-called high-risk products are concerned. As a result of the interplay of international pressures, the final version of the directive distinguishes five separate groups of IVD products, each with its own conformity assessment procedure. Table I lists these five groups in decreasing order of the level of premarket control required by the directive. The directive does not cover home-brew products or IVDs used only for research.

Group A. The directive assigns the heaviest burden of premarket requirements to the types of products listed in Annex II List A. These are essentially the high-risk products over which so much controversy raged during the development of the directive. To bring a product in this category to market, the manufacturer must first contract with a notified body that has been appointed to certify companies according to the directive's requirements. Selection of a notified body is essential when products in Annex II List A are in question because both of the routes to premarket approval for such products rely heavily on the work of such organizations.

In the first route (specified in Annex IV), the manufacturer submits a product design dossier for approval by the notified body, which must also certify the compliance of the manufacturer's quality system with the requirements of both ISO 9001 and the IVD Directive. The second route to premarket approval (specified in Annex V) is designed for companies that do not have an ISO 9001–compliant quality system (that is, companies that do not conduct product design or development or whose quality systems have not yet been certified by a notified body). To use this route, the manufacturer must submit a complete product registration file (roughly the equivalent of FDA's premarket approval application) for approval by the notified body, which must also certify the compliance of the manufacturer's quality system with the requirements of ISO 9002. For both of the routes described above, the IVD Directive grants notified bodies the power to impose additional controls that can act as a final inspection and approval before the release of each manufactured batch of product.

Group B. Notified bodies also have a role to play in the premarket assessment of the diagnostic products specified by the IVD Directive in Annex II List B. Two assessment routes are permitted for such products, each of which requires some activity by a notified body, but both are less burdensome than the routes for products in Group A. The first route (specified in Annex IV) requires the notified body to certify the manufacturer's ISO 9001–compliant quality system. For the second route, the manufacturer must supply its notified body with a product registration file for approval (as specified in Annex V), and the notified body must provide an EC verification (as specified in Annex VI) or certify the manufacturer's ISO 9002–compliant quality system (as specified in Annex VII).

Group C. This group includes all self-testing products except blood glucose monitors. As the directive was being written, the major concern expressed by national authorities for this category was that the technology should be simple enough to be used by a layperson. The two routes to premarket approval for products in this group include correspondingly simple requirements. For the first route, the manufacturer submits the product's design dossier to a notified body for approval. For the second route, the manufacturer follows the conformity assessment procedures available for products listed in Annex II.

Groups D and E. Approval of products in these categories does not require the involvement of a notified body. Instead, the responsibility for ensuring conformity of such products with the requirements of the directive falls entirely on the manufacturer. To market products in these groups, the manufacturer simply submits an EC declaration of conformity (as specified in Annex III). Simple as this route is, manufacturers should keep in mind that they may be called upon to demonstrate the validity of their declaration. For this reason, manufacturers should generate and maintain technical and testing documentation to show how conformity was established.

Postmarket Monitoring

The national competent authorities have responsibility for monitoring the quality and reliability of diagnostic products at the postmarket level. The IVD Directive empowers them to do so by stating that

Member States shall take all necessary steps to ensure that devices may be placed on the market and/or put into service only if they comply with the requirements laid down in this Directive when duly supplied and properly installed, maintained and used in accordance with their intended purpose. This involves the obligation of Member States to monitor the security and quality of these devices. (Article 2)

The main tools that the national competent authorities will use to carry out this task will be the medical vigilance system (specified in Article 11) and periodic reevaluations of premarket product approvals. The concept of periodic reevaluations, not included in earlier drafts of the directive, is delineated in Article 5.3. It is expected that these reevaluations will be performed particularly for Annex II List A and List B products, and will be conducted either by the various national competent authorities directly or by organizations working on their behalf.

Essential Requirements and Harmonized Standards

A fundamental characteristic of the IVD Directive is the relationship between the essential requirements specified in the directive and the use of harmonized standards. The directive lists a series of essential requirements that are deemed to be the key features necessary to ensure the reliability and quality of in vitro diagnostic products. Since the directive is a law, the essential requirements that it specifies are considered mandatory.

In view of the high level of science and technology involved in IVD products, however, the European Commission recognized that it would not be possible to include all the possible technical and scientific requirements in the directive. Doing so would have virtually guaranteed that the directive would be obsolete and practically useless in a very short time.

Instead, the European Commission removed such scientific and technical details from the text of the directive, incorporating them only by reference to the use of relevant harmonized standards. These standards are documents that contain the technical and scientific requirements necessary to support the essential requirements of the directive. They are developed by the European Committee for Standardization (CEN) and the European Committee for Electrotechnical Standardization (CENELEC) under a specific mandate from the European Commission. The sidebar on page 22 lists all the harmonized standards mandated by the IVD Directive.

Despite the large number of standards related to the IVD Directive, however, compliance with such harmonized standards is not compulsory. A company may chose its own scientific and technical methods to demonstrate the compliance of its products with the essential requirements of the directive. In such a case, however, the company must be prepared to demonstrate to notified bodies or national competent authorities that its method of ensuring product quality is at least equivalent to, if not better than, the one provided in the relevant harmonized standards.

Implementation of the IVD Directive

The December 1998 publication of the IVD Directive marks the beginning of a five-year phase-in period for the directive. The first 18 months are called the transposition period, during which each of the member states of the European Union will be required to write and pass the laws necessary to transpose the directive into its own national legislative framework. During this period no company will be permitted to affix to its products the CE mark that indicates compliance with the requirements of the directive.

The end of the transposition period in June 2000 will usher in a transition period that will last 31/2 years. During this period, each manufacturer will have a choice of routes to bring its products to market. The company may continue to register its IVD products according to the traditional national regulatory requirements, but will then have to do so for every country in which there is a relevant national regulation. The company may instead choose to follow the new registration provisions of the IVD Directive. The firm would then register its product only once, and when the product has been approved to carry the CE mark the company would be permitted to market the product in all member states of the European Union.

The transition period will end in December 2003. From that time onward, the only IVDs that will be allowed to enter the European market will be those CE marked to indicate their conformity with the requirements of the IVD Directive.

Notably, the directive includes no grandfathering clause for existing products. All IVD products, regardless of how long they may have been on the market, will be required to bear the CE mark if they are introduced into commerce after December 2003.

Practical Suggestions

Implementing the terms of the directive will be a major undertaking for all IVD companies. Manufacturers can help to ease their own burdens, however, by following the suggestions outlined below.

Understand the Directive. Manufacturers should be certain that they understand which products are covered by the IVD Directive and which are not. In this regard, the most important problem is the distinction between research-use and investigational-use products. IVD companies should be aware that European authorities are becoming increasingly strict in their interpretation of what constitutes a real research product and what is simply an investigational-use product.

Another important area to be understood involves the legal responsibilities that are assumed by IVD product manufacturers according to the terms of the directive. Notably, companies that do not have a legal place of business located in Europe will be required to appoint an authorized representative that is located in Europe.

Assess Notified Bodies. Not every IVD manufacturer will require the services of a notified body, but many will. It is therefore a good idea to begin assessing those companies that are most likely to be appointed as notified bodies for the IVD Directive. These may or may not be firms that are also notified for the other medical device directives.

It is anticipated that there will be fewer notified bodies appointed for the IVD Directive than have been appointed for the previous two medical device directives. As the transition period approaches, the calendars of many such firms are likely to become clogged with business, and this could result in long delays in the registration of both new and existing products. It is therefore important for every IVD company to begin assessing potential notified bodies as early as possible.

Watch Out for Standards. Manufacturers should closely monitor the development of the many harmonized standards mandated by the IVD Directive. Standards-writing activities are already being carried out by CEN technical committee (TC) 140 as well as by CENELEC (for electrical and electronics-related standards). Both of these organizations are European standards-writing bodies whose mandate does not extend beyond the boundaries of the European Union.

However, a significant part of the standards-writing process is also being shared with TC 212 of the International Organization for Standardization (ISO), which is a worldwide standards-writing body. Insofar as ISO chooses to adopt the standards developed in conjunction with the IVD Directive, those documents could come to have an important influence even on companies that do no business in Europe. It is therefore important for IVD manufacturers to maintain a global perspective as far as standards for IVDs are concerned.

In addition, manufacturers whose products fall into Annex II List A have a vital interest in monitoring the development of the common technical specifications (CTSs) mandated by the directive. CTSs are a set of analyte-specific performance standards that will be drafted by a working group of experts appointed from each European member state and reporting directly to the European Commission.

Strategize. As early as possible, manufacturers should begin to develop a strategy for bringing their products and processes into compliance with the IVD Directive. As part of this process, the company should assess the completeness, accuracy, and reliability of the data it has in support of its products. Further on, a key decision will be to determine when during the transition period the company will submit its products for CE marking to indicate compliance with the requirements of the directive. Finally, manufacturers should quantify the necessary work ahead and prepare a detailed compliance plan.

Maurizio Suppo, PhD, is a principal consultant with Medical Technology Consultants (Caselle, Italy).