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REGULATIONS & STANDARDS

Europe's IVD Directive: More (and less) than meets the eye

Maurizio Suppo

The IVD Directive of the European Union (EU) was published in the Official Journal of the European Union last December, starting the countdown toward full implementation of the directive on December 7, 2003.¹ The next milestone will occur on June 7, 2000, when the transition period for implementing the directive formally begins and companies are permitted to market CE-marked IVD devices for the first time.

The official transition period for the directive is relatively generous, spanning 3½ years from June 7, 2000, to December 7, 2003. During this period manufacturers may continue to market existing products that comply with the old national regulatory requirements (where such requirements exist), or they may enter the market with new or newly CE-marked products by complying with the requirements imposed by the IVD Directive.

However, the real transition period—the one that will be imposed by the demands of customers—is likely to be much shorter than the period provided by the directive. To judge by the previous experience of implementing the Medical Devices Directive, manufacturers and distributors are likely to encounter strong customer preference for purchasing CE-marked products.² Although manufacturers are allowed to offer non-CE-marked IVDs up to December 7, 2003, hospitals and laboratories are under no obligation to purchase such products.

That is why companies should now look closely at the IVD Directive. They should ensure that they understand its requirements and, more important, they should convert those requirements into the tasks and objectives of their plan for complying with the directive. This article offers updated information about the progress of the IVD Directive, including insights about its requirements and about points that need special interpretation. Using this information will help IVD companies to comply with this new regulatory challenge.

The Transposition Process

EU member states have until December 7, 1999, to transpose the IVD Directive into their own legislative framework. Although states are permitted to add requirements during the transposition process, it is unlikely that any significant changes will be made to the content or structure of the IVD Directive, which was approved with the full consensus of each European country. However, member states probably will accommodate their national constituencies by adding requirements in the following areas.

• Penalties to be applied for infringement of the law. These penalties will be expressed in local currencies and will differ significantly from state to state.

• Restrictions on the use of certain IVD devices. Member states are permitted to regulate the availability of certain IVDs. A country may, for example, restrict the availability of home-use pregnancy tests by making them prescription devices. It seems probable that some member states will prohibit the distribution of self-tests for HIV or hepatitis among laypeople.The rationale for such restrictions is concern for the consequences that a test result might have for a layperson if it is delivered without appropriate medical and psychological support.

• Establishment of the documentation requirements, fees, and methods for notifying products to the attention of the national competent authorities.

• Establishment of the methods to be used for medical vigilance (adverse incident) reports. Industry, however, hopes that medical vigilance requirements will be as uniform as possible throughout Europe.

• National language requirements to be imposed on professional-use products. The IVD Directive already obliges manufacturers to label home-use products in the national languages of the country of sale; the remaining question is how broadly such requirements will be imposed on professional-use IVDs.

In theory, the period from December 7, 1999, to June 7, 2000, should be the time when manufacturers throughout Europe are preparing to meet the requirements of their new national IVD laws. With previous directives, however, member states have nearly always taken up this period to complete the transposition process. In spite of delays, there is still a reasonable hope that many of the member states will complete the work of transposing the IVD Directive into national legislation by June 7, 2000.

For manufacturers, the loss of the six months leading up to the transition period is problematic. Most European countries cannot appoint notified bodies for a specific directive until that directive has been transposed into national legislation. If a member state is late in transposing the directive, manufacturers seeking early certification of their compliance with the directive would be forced to enlist a notified body from another member state that has completed the transposition process.

The governments of countries likely to have notified bodies for the IVD Directive should therefore have a keen interest in transposing the IVD Directive and appointing their notified bodies as soon as possible. Countries in this group may include at least Denmark, France, Germany, the Netherlands, and the United Kingdom.

Notified Bodies

Except for those fortunate companies whose products fall into the "all other IVDs" category defined by the IVD Directive, all other IVD manufacturers will need to involve a notified body in the premarket evaluation of their products.

At present, the status of Europe's potential notified bodies for the IVD Directive is something like that of a boiling pot—filled with frantic activity, but difficult to see from the outside. Only a few organizations have publicly announced their interest in becoming notified bodies for the IVD Directive, and it is clear that those eventually appointed will not be so numerous as those appointed for the Medical Devices Directive (see box, below). Far from the 55 or 60 notified bodies authorized under the Medical Devices Directive, it is expected that only a dozen or so such firms may qualify as notified bodies for the IVD Directive (some believe there will be even fewer). Such a limited number could cause some problems for industry, including the potential for long delays as manufacturers queue up to have their products evaluated.

On the other hand, having such a small number of notified bodies could help to ensure that they perform their duties in a homogeneous way. It may also create an environment in which common interpretations of "gray areas" in the directive can be reached quickly—and preferably with assistance from industry.

Gray Areas

Some sections of the IVD Directive are unclear or do not provide sufficient detail for an unequivocal interpretation. Inevitably, the final interpretation of such gray areas will be formed collectively by the notified bodies, most likely through the Notified Bodies Group.

Nevertheless, it is important that industry put forward its interpretations of such areas as soon as possible. In cases where industry has proposed good, common-sense interpretations based on solid rationale, notified bodies have shown themselves willing to adopt those interpretations, often with only minor modifications. Companies should therefore consider the following areas where differences of interpretation seem likely to arise, and begin formulating rational interpretations that could be adopted for standard use.

Specimen Containers. The definition of this term is unclear (Article 1.2.b). Some manufacturers may stretch the definition of an IVD and label as such containers that are not intended purely for diagnostic purposes but are closer to being general laboratory products.

Accessory. Similar considerations can be made for the directive's definition of an accessory (Article 1.2.c). The text of the directive could lead someone to argue that capillaries, tubes, or strips that come into contact with human skin (normally a finger) in order to collect blood should be classified as medical devices rather than as IVDs. Such an interpretation would be undesirable and substantially wrong, and could make it necessary for an official clarification to be issued in the future.

Manufacturer. Because of the complexity of the IVD business, the term manufacturer could be interpreted differently according to the special interests of the parties involved (Article 1.2.f). This is an especially tricky issue when hybrid systems are considered, since it is difficult to know which corporate entity has legal responsibility for the product's compliance. For this reason, national competent authorities and notified bodies are likely to adhere strictly to the directive's requirement to have one (and only one) clearly identified entity with responsibility for the product. That entity, and no other, will be considered the manufacturer under the terms of the directive.

Placing a Product on the Market. The concept of placing a product on the market will undoubtedly create some confusion (Article 1.2.i). For instance, it is unclear whether advertising a new product in Europe, but not having it physically available, constitutes placement on the market. If it does not, does that mean that a manufacturer is permitted to advertise in Europe for a product that doesn't yet have a CE mark? What if such an advertisement is not directed specifically toward Europe but is accessible to potential European customers? And what effect does this concept have when products are promoted via the Internet? In all of these areas, practical interpretations will be required.

Putting a Product into Service. Similar difficulties exist for the concept of putting a product into service (Article 1.2.j). The directive is unclear about whether an IVD product should be considered put into service when it is delivered to the hospital or other customer, or when it is actually used. Experts are still struggling to establish a consensus on this issue with regard to medical devices, and it is certain that a similar discussion will be required for IVDs as well.

Home-Brew Products. The status of so-called home-brew products is another area likely to generate a lot of interesting discussion (Article 1.5). Home-brew products are exempt from the directive, in part because of the insistence of the United Kingdom and other countries where the majority of hospitals and laboratories still prepare their culture media in-house. However, this exemption applies equally to other types of IVDs. It is therefore possible that a laboratory could purchase the necessary raw materials and wind up creating an Annex II List A or B assay without it being subject to the IVD Directive requirements. Manufacturers could exploit this loophole in the directive by offering quasi-finished components of HIV or hepatitis assays, for instance, leaving to the laboratory the responsibility for creating the finished IVD product. Such a practice would circumvent the strict requirements of the directive, and could present a danger. At the very least, laboratories that might be tempted to create and use such home-brew tests should know that the liability for erroneous results is likely to land squarely on their shoulders.

The Immediate Vicinity. Another area of concern related to the issue of home-brew tests is the directive's lack of a precise definition for the term in the immediate vicinity. That phrase is meant to indicate the places where home-brew products can be used without falling under the requirements of the IVD Directive. It should be expected that a debate over what constitutes the immediate vicinity will take place in the not too distant future.

Sterility Assurance Level. The question of what constitutes a sterile device, so that the manufacturer should be permitted to label it as such, is still unresolved. Although this issue applies to only a few types of IVD products (notably, evacuated specimen collection tubes and plastic flasks for cell culturing), it is of high importance to the companies involved in manufacturing such products. Among manufacturers of medical devices, the current rule is that products must be terminally sterilized to a sterility assurance level (SAL) of 10^–6 if they are to be labeled sterile. The application of this rule to IVD products is still under debate.

Other Areas of Concern. In addition to the gray areas listed above, the terms of the IVD Directive have left unresolved a number of other issues of importance to manufacturers. Some of these constitute areas of considerable significance for the eventual implementation of the directive. For instance, the directive does not specify the precise composition of the design dossier that must be submitted to a notified body if a company chooses to pursue an Annex IV approval for its Annex II List A products. The directive does not define what constitutes a research-use-only product, nor does it establish the medical vigilance requirement for IVDs. More narrowly, the directive is unclear in its description of the requirements for the registration of manufacturers and devices, where the terms information, significant change, and appropriate indications are not defined (Section 10.1). Sooner or later, common European definitions and practices for these areas will need to be established.

Conclusion

This article has not touched on the many standards, common technical specifications, official position papers, and guidances that are still expected to be issued in connection with implementation of the IVD Directive. Because this body of documentation will play an important role in helping manufacturers to understand and meet the requirements of the directive, it is essential that companies stay alert and receptive to developments going on outside their walls. In the meantime, manufacturers can make some progress toward eventual compliance with the directive by considering two basic issues that they will have to confront in the coming months: selection of a notified body, and establishment of a legal place of business.

The status of notified bodies is likely to become clearer this fall, when it is probable that all or most of the potential candidates will announce their intentions. Manufacturers should then be ready to begin evaluating the available firms and selecting the notified body that they want to work with. To get ahead of the directive's implementation schedule, manufacturers should begin working with their notified body as soon as possible, even if they have not yet been formally appointed by their respective national competent authorities.

Each manufacturer will have to decide which European country to select as its legal place of business. Care should be taken in making this choice, since it will be the country where the company will notify its products to the competent authority, and where it will be subject to any national additions to the requirements of the IVD Directive. Unofficially, some countries are already talking about notification fees, so it will be in the manufacturer's best interest to stay on top of developments in all of the member states.

References

1. "Council Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on In Vitro Diagnostic Medical Devices," Official Journal of the European Union L331 (December 7, 1998).

2. "Council Directive 93/42/EEC of 14 June 1993 concerning Medical Devices," Official Journal of the European Communities L169 (July 12, 1993).

Maurizio Suppo, PhD, is a principal consultant for MTC-Quintiles (Caselle, Italy).

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