Archive: Interpreting the IVD-Directive
The In Vitro Diagnostic (IVD) Directive has a long transition period, 3.5 years, and therefore some could be tempted to believe that there is plenty of time to do everything at a leisurely pace.
They are wrong! The market, which is a much more powerful force than the regulations, will itself dramatically shorten the Directive's transition period. Medical device manufacturers already know how highly the CE mark is considered by their customers and how frequently a requirement or the strong preference for CE-marked medical devices is included in tenders.
This strong preference for CE-marked devices will be even more extreme for IVD products. It is important to remember that although the IVD Directive gives manufacturers the legal right to offer for sale non-CE marked devices until the first week of December 2003, it does not oblige their customers to buy them. This is why most of the IVD industry is planning for early compliance of products, possibly from the very first day of the transition period in June 2000, which is less than seven months away.
However, to comply with the essential requirements of the Directive, industry must know exactly, and in detail, what the requirements are. A first step in having a more complete understanding of what needs to be done is to identify those parts of the Directive that are unclear, the ones that have been termed "gray areas".
Most IVD companies, whatever their size, need to appoint a Notified Body. The problem is that now, at the time of writing, seven months away from the first day of enforcement of the IVD Directive on 7 June 2000, there are no Notified Bodies officially nominated.
In most European countries it is not technically possible to appoint a Notified Body for a specific Directive if that Directive has not yet been transposed into national law. Therefore, it is understandable that the Member States have not yet appointed any Notified Bodies. However, IVD companies should not sit and wait for them to be appointed because it may be too late by then. Companies need to actively approach those organisations that are likely to become Notified Bodies for the IVD Directive, and they must not assume that just because an organisation is a Notified Body for the Medical Device (MD) Directive (93/42/EEC), it will also be one for the IVD Directive.
There will be fewer Notified Bodies for the IVD Directive than the current 55-60 that exist for the MD Directive. The names of the five to seven most credible organisations that could qualify as Notified Bodies for the IVD Directive are known. It is the IVD manufacturer's job to seek them out and start interacting with them. It is important to do this because manufacturers will end up living with those organisations' interpretations of the grey areas of the Directive. Thus, finding a Notified Body that has a flexible and intelligent attitude and can adopt the company interpretation on how to do things (provided it is based on common sense and good scientific grounds) may be significantly more convenient than partnering with an inflexible Notified Body that imposes its own particular point of view.
It could be said that gray areas are those parts of the Directive that do not provide clear or sufficient detail for them to be unequivocally interpreted. Some of the key ones are discussed below.
Specimen containers (Art. 1, penultimate paragraph of point 2b) Here, some manufacturers may be tempted to stretch the definition of the IVD device and brand as IVDs those containers that are not purely meant for diagnostic purposes, but are closer to general laboratory products. The reason for this would be to reap the benefit of the perceived value of the CE mark for those products and to create problems for their competitors who are rightly not CE-marking those types of products.
Accessories (Art. 1, point 2c, second paragraph) Similar considerations can be made for the definition of accessories. The text of the Directive may lead some to argue that the capillaries, tubes and strips that come into contact with the human skin (normally a finger) to collect blood may be classified as medical devices and not IVDs. This hypothesis, although undesirable and substantially wrong in the opinion of the author may need an official clarification in the future.
Manufacturer (Art. 1, point 2f) The IVD business is known for its complexity of relationships between companies. This situation, although presenting no particular problems in the vastly unregulated Europe of the past, is increasingly disliked by several authorities. They are finding it practically impossible to understand exactly who has the final responsibility for the IVD systems that are made up of a combination of different parts made by different organisations. That is why, according to current trends and as demanded by the Directive, Notified Bodies and Competent Authorities are likely to be strict about requesting one (and only one) clearly identified entity that has the legal responsibility for product compliance to the applicable essential requirement of the Directive, that is "the manufacturer", as defined by the Directive.
Placing on the market and putting into service (Art. 1, points 2i and 2j) What may seem an easy and obvious definition can become unexpectedly complex when certain factors begin to be considered. If a manufacturer advertises a new product in Europe that is not yet physically available in Europe, and the manufacturer states this, is he placing it on the European market? Can he advertise in Europe a product that does not yet have a CE mark just to explore the potential interest of the market? What if the advertisement is placed on the manufacturer's Website? These are examples of situations that have not been taken into account by the IVD Directive, but are currently being addressed with a lot of interest by the United States FDA for the US market.
Also the definition of "putting into service" will need, sooner or later, a clear interpretation because currently it is not clear whether an IVD product is put into service when it is delivered to the hospital or when it is used. This apparently minor issue may have some major consequences for the IVD industry.
Home-brewed products (Art. 1, point 5) Mainly as a result of strong lobbying in the United Kingdom where most culture media are still brewed by each laboratory, an exemption was granted by the Directive for home-brewed products. This exemption applies not only to culture media, but to any type of diagnostic product that will be home-brewed.
Therefore the IVD Directive contains the seeds of a potential misuse (or abuse) because some manufacturers may find it more convenient to separately offer the key components of some IVD devices (including screening tests for Annex II List A products) without making any diagnostic claims for those components, and leave the laboratory the responsibility of putting them together to obtain a functional diagnostic device. Similar considerations in the US have lead to the recent enactment of the FDA regulation for analyte specific reagents, which attempts to prevent this practice.
Another interesting aspect of this part of the Directive is the absolute lack of precision in the definition of "in the immediate vicinity", which should indicate the place(s) where these home-brewed products can be used without coming under the jurisdiction of the IVD Directive. Interesting discussions can be foreseen on this point.
Registration of manufacturers and devices (Art. 10, point 1, second paragraph) This one area alone will keep industry, the authorities, Notified Bodies and consultants busy for a long time. The required "information", "significant change" and "appropriate indications" are not defined and they need to be. It should not be forgotten that these data, whatever they are likely to be, will need to be included in the European Database for IVDs.
Medical vigilance requirements for IVDs This is another area that will need a lot of interpretation. Which adverse incidents should be reported, all products or those in Annex II only? Should every single false positive or false negative result be notified? This would inundate authorities with a huge quantity of doubtful, not to say worthless, information.
Composition of the design dossier What exactly should a design dossier contain? What is required to be submitted to the Notified Body when a company chooses the Annex IV procedure for its Annex II List A product(s)?
What is considered to be a For-Research-Use-Only (FRUO) product? Although an official definition is still lacking, it is increasingly clear that the European authorities will not tolerate the abuse that exists in the US where products with a clear clinical and analytical use are offered for research use only. For this reason the authorities are making a strict interpretation on what can be defined as a FRUO product and thus escape the requirements of the IVD Directive. They are defining FRUO products as only those products that detect analytes that have not yet been assigned a clear clinical meaning by the medical profession.
What next? It is in the interests of everyone, and primarily in the interest of the credibility of the European Union, that Member States, at least the ones that have Notified Bodies applying for the IVD Directive, will transpose as soon as possible the IVD Directive into their own national legislative framework. Once they have done this, they will be able to officially nominate their Notified Bodies. There is not much time remaining and significant delays in this area would have disastrous consequences. Industry needs to have a clear idea of which organisations are likely to be notified for the IVD Directive by the end of 1999.
Those manufacturers who rightly want to be among the first with the CE mark on their products as soon as the transition period begins in June 2000 must select the organisations that are most likely to be nominated and begin working with them.
Manufacturers should be careful when choosing their European location because their choice will determine the country and therefore the Competent Authority to which they will have to notify their products and all the national "add-ons" relating to the Directive that they must comply with. Some countries are already talking, although unofficially at the moment, about notification fees, and an attentive person may already understand what notification requirements (which data) are likely to be imposed by any specific country.
Standards, Common Technical Specifications and official position papers and guidelines. Each one of these three issues would justify an article in its own right. Manufacturers need to maintain close attention to all three if they want to successfully cope with the regulatory challenge that now, after so many years of endless discussions, is beginning to appear very concretely on their horizons.
Published on December 22, 1999