Meeting the Requirements of the IVD Directive:
The Best Time To Start is Now
Not long ago, as the US medical device industry rushed to learn all about the CE mark and began frantically implementing ISO certification programs, the in vitro diagnostic industry just sat by, free from all anxiety.
Today, however, the shoe is on the other foot. The in vitro diagnostic manufacturers are about to learn what the device industry went though to continue selling their products in the European Community.
The CE marking requirements for in vitro diagnostic products are now being finalised in a single piece of legislation. Its name: Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical device--or the IVDD, for short. Its publication in the Official Journal on 7 December 1998 has started the countdown clock. On 7 December 1999, the transposition period will end. On 7 June 2000, manufacturers may begin applying the CE mark to their products. On 7 December 2003, the transition period will end, and CE marking for in vitro diagnostic products will be mandatory. Moreover, because of the relatively small number of in vitro diagnostic companies, there will be no additional transition period--like the one given for the MDD--for products already in the trade chain.
The Hidden Benefits of the IVDD
The IVDD completes the medical device directive series, which also governs active implantable and regular medical devices. (Only medical devices made from human tissues are not currently regulated). Still, the situation surrounding the IVDD is completely different from that of the MDD. Prior to the MDD, the market for most medical devices was more or less unregulated in most European countries. As a result, the MDD was hazy and burdensome, and most medical device manufacturers rightfully tried to avoid it as long as possible.
Most IVDs, on the other hand, are covered by national drug legislation. This means that for the EU there are 11 different drug legislation's and even more with the overall European Economic Area. All these different attempts at regulation can now be met through a single conformity assessment procedure, thus tremendously reducing the effort for launching an IVD.
So in short, for most medical device manufacturers, complying with the MDD meant a very complicated set of procedures, but for most IVD manufacturers the IVDD means simplification.
Similarities Between the IVDD and MDD
The way of regulating the IVD industry is more or less the same as with the MDD. There are essential requirements and there are conformity assessments. Member states will implement the Directive as national law, will build up a vigilance system, and will accredit and monitor notified bodies. There will be supporting regulations in MEDDEV papers and there will be forthcoming harmonized standards. There will also be a safeguard clause that allows member states to take action in the case of noncompliance with the Directive or harmonized standards. And of course, non-European manufacturers must designate an Authorized Representative within the EU--someone authorized to interact with the EC authorities on the manufacturer's behalf.
As with the MDD, the IVDD tries to rule a tremendous range of products with a single legislation. The document covers a simple test strip for glucose or a vial for blood specimens on the one hand, and an automatic multi-analyser on the other. As with the MDD, the intended purpose of a product determines whether or not it is covered by the directive. So for example, general laboratory equipment is not covered except where specifically used for diagnostic purposes. Also, general chemicals that are used for IVD purposes, like trichloric-acetic-acid for the detection of proteins in urine, are not regarded as IVDs (under the so-called home brew rule). Table 1 provides a brief synopsis of the scope of the directive.
As with the other medical device directives, all IVDs must meet the essential requirements of Annex I of the IVDD, but this would not be an increase in regulations because all these products already have to comply with national drug regulations. But, there are certain types of non regulated products that will have difficulty complying. The IVDD assumes that the risk of most products is relatively low because their use does not involve patient contact and they are normally used by qualified professionals. Table 2 provides examples of essential requirements that devices will have to meet.
New Concerns for IVD Manufacturers
In the IVD Directive, there is a reference to harmonized standards and there is a new definition of common technical specifications (CTS) that can be worked out for certain diagnostics. There is a standards and technical regulation committee procedure for changes to the harmonized standards. National authorities are allowed to insist on local languages on labelling and instructions for use (see Table 3). There is a committee on medical devices that may examine questions connected with the IVD Directive implementation. All in all, there are 11 annexes to the directive (see Table 7).
New in the regulation of the IVDD is that it is mandatory for all IVD manufacturers to keep a quality system, but in most cases it will not be mandatory to have the quality system certified. Annex II has two lists, A and B, of products that need certification. The products in list A must conform to a common technical specification (CTS) as well as have a full quality assurance system. For these products, there must be a design examination by a notified body. For some products, the notified body may control batch release. If there is no full quality assurance system, there must be an EC type examination plus the possibility for the notified body to control batch release. Additionally all products for patient use have to be reviewed by the notified body regarding the clarity of understanding in the product information (See tables 3 through 5).
For reagents, reagent products, and reference and control materials, the manufacturer shall notify Competent Authorities with all information concerning common technological characteristics and/or analytes as well as any important subsequent modification (especially market withdrawals). For all other IVDs, the manufacturer shall inform the Competent Authority on the appropriate indications. For the devices in the lists of Annex II and for self-testing products, there are additional notifying necessities in Table X of the directive. All this information will be stored in the European Regulatory Database (See Table 8).
Annex II: Notified Body Involvement
Annex II defines criteria for the involvement of notified bodies for certain products. The conformity assessment procedures are described as well as the registration requirements for manufacturers and devices--which are very similar to those outlined in the MDD. As with the MDD, a European addresses would be necessary for non-European IVD manufacturers. There is a vigilance system and a European database, and the member states can prohibit products for a limited time for health and safety reasons (See Tables 4 through 6).
Annex II also defines certain rules for the designation and surveillance of notified bodies. The section delineates the proper methods of CE marking and the steps that must be taken when a CE mark is wrongly applied. The Annex also discusses notifications in the case of restriction of products. Member states have to observe confidentiality, and they have to cooperate.
IVD manufacturers should take a hard look at the lessons learned by their counterparts, the medical device manufacturers, as they tried to comply with the MDD requirements to assure continued uninterrupted access to the European market.
As we have seen, there is no reason to delay CE marking for IVD products; on the contrary, there are many good reasons to start CE marking from the first possible day. The best time to comply is now--not later. Waiting will only cause competitive problems that may not be easy to erase.
About the Author:
Hans Haindl, MD, MSc., is medical device consultant and officially appointed expert for medical devices in Germany. After several years of clinical experience, he became head of R&D at B. Braun. Since 1990, he has been providing consultancy as well as R&D in regulatory affairs for German and international companies. Dr. Haindl is chairman of the scientific board of MDSS, a company serving as Authorised European Representative for non-European companies.
Table 1 IVD Directive Explanatory Scope
Professional use majority Self test some products Specimen receptacles included Accessories included Controls & calibrators included Home brew products excluded General lab. Products excluded, not medical devices
Table 2 Annex I: Examples of essential requirements for all products
Must be safe. Any risk must relate to patient benefit Traceability must be assured via reference measurement procedures and/or reference materials Design, manufacture and packaging to allow correct transport and storage, to reduce infection risk and leakage, to allow safe disposal Protection against radiation emissions and interference's, mechanical risk, noise, heat Special design requirements for self-testing: ease of use and understandable instructions
Table 3 Essential requirements apply to all products Label requirements and Instructions for use
Instructions for use must accompany the product and must contain where appropriate:
most of what is on the label; composition of the reagent, concentration or amount of active ingredients; storage conditions and shelf life; analytical and diagnostic sensitivity and specificity; accuracy, repeatability, reproducibility, interference data, limits of detection; assured traceability; any special equipment requirement; type of specimen to use; detailed description of procedure to follow; the measurement procedure; limitations of the method; information on use of available reference measurements; the mathematical approach; measures to take if analytical performance changes; internal quality control and validation procedures; reference intervals and population used; information and instalment of equipment, its verification; maintenance and calibration needs of equipment.
Label must have manufacturer name or trade name and address; product identity; lot or serial number; and where applicable: - name and address of Authorized Representative; - date of expiry; - special storage or handling conditions; - warnings; - self test or sterility label; ....etc.
Table 4 Composition of Annex II
Reagents & reagent products including related calibrator & control material
List A - HIV 1 and 2, HTL V I/II, Hepatitis B, C, D - ABO System, Rhesus (C, c, D, E, e) - Anti-Kell
List B - Anti-Duffy, Anti-Kidd, Irregular anti-erythrocytic antibodies - Rubella, Toxoplasmosis, CMV - Chlamydia - Hereditary disease: PKU - HLA tissue groups: DR, A, B - PSA - Self-tests for blood glucose
Table 5 Annex II List A conformity assessment
Common Technical Specifications (CTS)* plus EITHER Annex IV (Full Quality Assurance) - Design examination by notified body: sect. 4 - Possibility for notified body to control batch release: sect. 6 OR Annex V (EC type examination) plus Annex VII (Production Quality Assurance) - Possibility for notified body to control batch release: sect. 5 * CTS are sets of analyte-specific performance requirements agreed among all Competent Authorities (CA) establishing performance (re)evaluation criteria, batch release criteria, reference methods and materials.
Table 6 Annex II List B conformity assessment
CTS where necessary plus EITHER Annex IV - Design examination by notified body: sect. 4 - Possibility for notified body to control batch release: sect. 6 OR Annex V plus Annex VI (EC verification) OR Annex V plus Annex VII
Table 7 Annexes - about 45 pages
Annex I Essential requirements 16 pages Annex II List A & B products 2 pages Annex III Conformity Declaration 4 pages Annex IV Full QA declaration 7 pages Annex V EC Type examination 3 pages Annex VI EC verification 3 pages Annex VII Production QA declaration 4 pages Annex IX Evaluation products 2 pages Annex X Criteria for notified bodies 3 pages Annex XI CE mark 1 page
Table 8 Registration of manufacturers and devices, Art. 10.1
For reagents, reagent products, reference and control materials: manufacturers or their Authorized Representative shall notify Competent Authorities ( information concerning common technological characteristics and/or analytes ( any important/subsequent modification (market withdrawals)
For other IVD medical devices: manufacturers or their Authorized Representative shall notify Competent Authorities ( appropriate indications e. g.: categories of devices for instruments or systems
For devices of Annex II and self testing products: all data allowing device identification ( analytical parameters ( if appropriate, diagnostic parameters (Annex 1.3) ( results of performance evaluation (Annex 8) ( conformity assessment certificates (Notified Bodies) ( any significant change (placing on the market discontinued ( member states may request label & instructions for use Page 7 of 8)
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