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Originally Published IVD Technology July/August 2005

Regulations & Standards

Examining the effects of the IVD Directive

Petra Kaars-Wiele

Petra Kaars-Wiele, PhD, is based in Germany, where she is director of regulatory affairs and affiliate compliance for Europe, the Middle East, and Africa in the diagnostics division at Abbott Laboratories (Abbott Park, IL). She can be reached at petra.kaars-wiele@abbott.com.

The European Union’s Directive 98/79/EC on In Vitro Diagnostic Medical Devices (IVD Directive) was first published on December 7, 1998. The directive applies to IVD reagents and kits, accessories, software, and instruments.

Since December 7, 2003, the IVD Directive has been implemented in the 25 European Union (EU) member states and the four European Free Trade Association (EFTA) members (Iceland, Norway, Liechtenstein, and Switzerland), which allows for free trade in this large area. During a transition period, the directive has been transposed into the individual members’ national laws.

All IVDs, including instruments, require a CE mark to demonstrate conformity with the IVD Directive. Multiple national approvals by the European countries are no longer necessary. The directive has established one single system to place IVDs on the European market.

The IVD Directive covers the following areas for obtaining a CE mark for IVDs: definitions, responsibilities, conformity assessment routes, technical documentation requirements, quality systems, product labeling, postmarket surveillance systems, and establishing a vigilance system within the member states.

Having implemented full quality systems in the late 1980s, IVD manufacturers expected to be already prepared for the IVD Directive. Such expectations of fewer requirements and regulations did not become a reality. Nonetheless, the directive is a compromise that the IVD industry has been able to live with. However, since its implementation, the IVD Directive has presented some significant challenges and cost drivers to the industry. This article will discuss such challenges and opportunities, and will evaluate the strengths and weaknesses of the IVD industry’s reactions and responses to the directive so far.

Features of the IVD Directive

The IVD Directive has facilitated the harmonization of regulations and the free movement of IVDs in Europe. The CE mark represents the passport for IVDs to be imported into the EU or EFTA countries and moved within the economic area. With the implementation of the directive, import letters that are specific to local regulations and products have become obsolete.

The IVD Directive defines the legal manufacturer as the entity that is responsible for an IVD product’s design, manufacture, packaging, and labeling. This definition applies regardless of whether an IVD manufacturer itself performs such operations or hires a third-party contract manufacturer and then places the devices on the market under its own name.

According to the IVD Directive, an IVD manufacturer from inside the EU and EFTA states may distribute its products in the area without having a representative in each country. A non-European manufacturer needs only one authorized representative located within the area, which acts on its behalf. For example, a U.S. IVD company would probably choose its European affiliate, or another responsible person or company that is located in Europe, as its authorized representative. Thus, in case an issue with an IVD product emerges, the competent authorities may contact the authorized representative. This allows the authorities to have better access to foreign manufacturers. An authorized representative must be appointed by a contract that describes its duties, responsibilities, and decision rights.

Competent authorities still have the option to work with local distributors or directly with IVD manufacturers that are located outside the EU. However, the process would improve if the communications were strictly done via the authorized representatives. A precondition is that the authorized representative is knowledgeable about the IVD products and processes, and is up-to-date with potential product issues. This may not always be the case if companies have chosen to work with an authorized representative that serves more as a mailbox.

The differences between the roles and responsibilities of notified bodies and competent authorities are well defined in the IVD Directive. A notified body works under a contract for an IVD manufacturer, and the process is transparent to the manufacturer. The terms on costs and timing are negotiable. It is an efficient, service-oriented process and clearly a benefit for IVD manufacturers. It enables the manufacturers to get faster and more-predictable access to the EU and EFTA markets. For example, in the past, HIV or hepatitis assays did not get approved in certain markets until a year after the products had been available in unregulated markets. Now, a single approval allows access to all EU and EFTA markets.

Batch verification for the highest-risk IVDs in Annex II List A has been introduced in all EU and EFTA countries. Before that, the competent authorities in Germany, Italy, and Austria conducted country-specific lot testing. While certain test kits required three lot certificates from three different countries, under the IVD Directive only one is required for all of Europe. This new procedure requires careful planning by the IVD manufacturers, since a CE mark on a test kit demonstrates that all provisions of the directive are met. Therefore, an HIV or hepatitis test kit that carries a CE mark must be batch verified by a notified body even if it is distributed outside of Europe. Since all high-risk IVD products require batch verification, the costs to the manufacturers have increased significantly.

Postmarket Surveillance

Since competent authorities are no longer involved in the premarket approval of IVDs, they concentrate instead on postmarket controls. The idea is to support IVD manufacturers’ efforts to constantly improve their products in the market. National activities for postmarket re-evaluations versus concerted EU-wide activities and shared responsibilities are being discussed.

A significant number of competent authorities have started to conduct market surveillance activities. Such activities include encouraging users to report directly to the authorities. Competent authorities also started screening the Web sites of foreign authorities for reports that have not been made available locally.

The IVD Directive mandates that IVD manufacturers and member states establish a vigilance system that improves the protection of the health and safety of patients, users, and others. Manufacturers must notify the competent authorities of incidents that directly or indirectly might lead or might have led to either the death of a patient, user, or others, or a serious deterioration in health. The same requirements apply to any systematic recall that is defined as the return of an IVD to a supplier, its modification by a supplier at the installation site, its exchange, or its destruction in accordance with instructions provided by an IVD manufacturer.

Any such information reported by IVD manufacturers to member states should be disseminated among the competent authorities, especially if there is a serious risk to the safety of patients or other users in more than one European country. The coordinating competent authority is supposed to monitor the investigation and manage contacts with the manufacturer on behalf of other authorities. In practice, this principle has not been successful for one major reason. The competent authorities are primarily responsible for the protection of the health and safety of patients, users, and others in their countries. Consequently, they hesitate to rely on the judgments of other coordinating competent authorities. This puts the focus on an individual national approach rather than a true European approach. The lack of a true coordinating competent authority triggers echo reporting and forces the IVD manufacturers to report the same basic information to several authorities.

The guidelines on medical device vigilance systems are currently being revised. The new version is supposed to be aligned with Global Harmonization Task Force (GHTF) terminology and will exempt user errors from reporting. Several other changes are planned, including the requirement to get customer letters validated by competent authorities before IVD manufacturers can distribute them. Manufacturers are strongly opposed to this proposal because it would prevent an immediate notification of affected customers.

The European Data Bank

The introduction of a European data bank and a product coding system seems to be a never-ending story. The result is that IVD manufacturers are required to multiply their efforts in several countries. In most EU and EFTA member states, the manufacturer or authorized representative must provide product notifications to the local competent authority and then send copies of such notices to all of the other states. However, some countries only want to receive information regarding the IVDs that are on their markets. Doing so is almost impossible considering that Europe is an open market with free movement of products. This also presents a challenge to any competent authority in responding to any questions about whether a specific product is on the market in some country.

The IVD industry supports the implementation of the European database as soon as possible. The database may help to overcome problems related to the translation barriers and the incompleteness of the codes.

In-House Privileges

The IVD Directive addressed the in-house privilege in Article 1.5: “This Directive shall not apply to devices manufactured and used only within the same health institution and on the premises of their manufacture, or used on premises in the immediate vicinity without having been transferred to another legal entity. This does not affect the right of a Member State to subject activities to appropriate protection requirement.” This statement started a series of discussions that resulted in numerous interpretations. The UK and Irish authorities gave their opinions and provided further clarification. This topic is still unresolved and requires further discussions in the medical device expert group.

Combination of CE-Marked Products

The responsibility for combined uses of different CE-marked products is indirectly covered by the IVD Directive in Annex I B 8.7: “If the device is intended for use in combination with other devices, the whole combination must be safe.” Annex I B 8.7 also states that, “If the device must be used in combination with other medical devices or equipment in order to operate as required for its intended purpose, the instructions for use must contain sufficient details of its characteristics to identify the correct devices or equipment to use in order to obtain a safe and proper combination.”

In case an IVD manufacturer has not covered a specific combination of different CE-marked products, the user of such products has to ensure that the product combination is appropriately validated and a safe use can be expected. Due to ongoing questions from laboratories, this topic may also require an official statement from the medical device expert group to clarify the expectations of the competent authorities.

Translation into Local Languages

While national-language requirements for lay-user IVDs are accepted by the IVD industry and make sense from a safety perspective, translating into local languages for professional-use products has been questioned.

Fifteen EU countries have transposed into their national laws the requirement for translating instructions for use into their local language. These countries do not differentiate between lay products and products used by professionals. Within the past five years, IVD companies have had to increase their translation activities from 5 to 15 European languages. Depending on the market size, companies will have to decide whether it is worthwhile to translate their products’ instructions for use in order to continue serving a market in the future, especially the smaller ones. The health systems of small countries could suffer the most if this happens. Since Europe is an open market, customers may be forced to buy IVDs in neighboring countries, but at their own risk and outside the liability of the manufacturer.

In the IVD device arena, it is essential for translations to use the correct terminology. It is not acceptable if the translated instructions for use are shortened because of a decision made by a distributor or a translation company. An IVD manufacturer is fully responsible for the translations and change controls. Outsourced translation services need to be treated as subcontracting, and a manufacturer must have a system in place to audit them.

IVD products contain general descriptions on how to run an assay or a system. IVD manufacturers also provide training if their products require such training. Under the IVD Directive language requirements, companies are required to translate thousands of pages of IVD product information every year. However, it is unlikely that IVDs for professional users are safer than before, when manufacturers provided their instructions for use only in English. Some IVD manufacturers may not see any benefit of the directive’s translation requirement.

National Interpretations and Additional Requirements

The IVD Directive requires a transposition into national legislation, which therefore presents room for not only national interpretation, but also adding country-specific requirements. For example, Portugal has added a law concerning distributors that now have to comply with the local registration regulations. This law adds an extra workload, and the benefit to the safety of the products or the regulatory system is not obvious. France also recently published a new decree on the notification of products. This decree requires information in addition to what is given in the EU forms. This decree has shaken up the IVD industry, and many questions have been raised. Clarification and support is required from the EU Commission.

Since the IVD Directive was established as a directive, which requires it to be transposed into national legislation, the proliferation of individual member state regulations is allowed. On the other hand, an EU regulation would be in force in all countries without transposition or the possibility for national manipulations.

Impact on Countries outside Europe

The fundamental change under the IVD Directive that notified bodies, and not regulators, are approving an IVD before it is marketed is difficult for other authorities outside the EU and EFTA countries to follow. It may be seen as a loss of power for the regulators. Trust in this system cannot be built overnight. The support of the EU Commission to lobby for these new principles in other areas of the world would be helpful. Involvement and positioning in harmonization activities, such as GHTF, is a prerequisite to assist European IVD manufacturers and their economic success outside Europe.

Conclusion

The IVD Directive provides state-of-the-art regulation. It reflects and consolidates the regulatory intelligence and the diversified experience and expertise of the EU member states. The directive is also the first attempt to harmonize regulations and relieve IVD manufacturers and regulators from unnecessary workloads. It is a great role model for other areas of the world. Moreover, the directive may not be perfect, and the opportunity for improvement remains. It requires a shared responsibility for manufacturers and regulators to ensure the development of safe products with dependable performance at affordable prices.

Copyright ©2005 IVD Technology