Medical Device Link.

Originally Published IVD Technology September 2003

IVD Directive

Parallel output ports on the Picotap, an on-chip reaction-well interface. These ports house Picopins, capillary uptake devices that can extract sample from microchips.

By the time an IVD has received the CE mark and has been placed on the market in the European Economic Area (EEA), its manufacturer shall have established a systematic approach for dealing with malfunctions or adverse occurrences related to the performance of the device. 

The European Directive 98/79/EC on In Vitro Diagnostic Medical Devices (IVD Directive) stipulates that a vigilance system is to be set up and put into operation.¹ The respective regulations are more or less identical to those applied to other medical devices. The vigilance system may be seen as one component of market surveillance. 

The aim of the vigilance system is not to prosecute or even blame manufacturers for making mistakes, but rather to protect patients, users, and other parties from the risks caused by IVDs. This shall be achieved by a manufacturer’s efficient management of the risk in any particularly serious case under governmental supervision. In addition, appropriate information shall be disseminated to prevent the recurrence of similar problems with similar products from different manufacturers. Through the proper functioning of a vigilance system, general scientific knowledge regarding the safety-related issues of IVDs will be improved upon.

Requirements of the IVD Directive 

The provisions of the IVD Directive regarding the vigilance system refer to manufacturers as well as to the member states of the European Union. According to the directive, IVD manufacturers shall be obligated to systematically review the experience gained from the IVDs they have placed on the market; to implement corrective action if necessary; and to report incidents, near-incidents, and recalls to the proper competent authority.

The member states shall ensure that reported incidents, near-incidents, and recalls are centrally recorded and evaluated by a national competent authority. The member states have to establish appropriate structures and procedures to accomplish these tasks. If a national user reporting scheme has been established, manufacturers shall be informed of any user report without delay. The assessment of reports should be made together with the manufacturer, if possible. The European Commission and the other member states shall immediately be informed of cases that lead to corrective action.

The IVD Directive is addressed to the member states. Its regulations normally do not directly apply, but have to be transposed into national legislation. Some member states have further elaborated on the vigilance regulations on the national level. For instance, in Germany, an ordinance on a medical devices vigilance system has been issued, by which the reporting obligations have been extended to professional operators and users and, in order to accommodate products made available to lay users, also to pharmacies and other retail traders.² Furthermore, the ordinance regulates the risk assessment to be performed by the national competent authorities, the obligations of the parties involved, the implementation and supervision of corrective actions, as well as the exchange of information.

The vigilance requirements of the IVD Directive, as they apply to the entire EEA, are further explained and supplemented by the European Guidelines on a Medical Devices Vigilance System (MEDDEV 2.12-1).³ Although these guidelines are applicable to all medical devices and were not specifically designed for IVDs, they will contribute to a better understanding of the legal requirements according to the IVD Directive.

Postmarket Surveillance by IVD Manufacturers

According to the IVD Directive, the review of experience with IVDs that have been put on the market is to be done systematically. Manufacturers must have appropriate procedures in place ensuring that any information regarding possible product-related risks is properly collected, recorded, and evaluated, and corrective action is initiated and effectively implemented, when necessary. 

A systematic approach, as required by the directive, does not only mean to respond to reports that have been passively received, but also to actively gather data on possible problems. The information to be collected and evaluated should at least include all complaints received from customers or patients, records produced and submitted by the sales representatives, findings reported by service and maintenance staff, internal test results (e.g., stability data) or quality system records, information received from competent authorities, articles published in relevant journals, presentations delivered at relevant conferences, media reports, and safety-related improvements of competitors’ products. Depending on the type of product and the level of experience with that product, further activities may have to be considered, e.g., systematic literature reviews or additional tests, studies, or surveys.

General quality system principles that must be implemented by all manufacturers of IVDs require that the responsibilities for handling and evaluating complaints, reporting to competent authorities, and making decisions on corrective actions, as well as implementing and coordinating corrective actions, must be clearly defined and assigned to appropriately qualified personnel. 

Additional national requirements may apply. For instance, the German medical devices act explicitly stipulates that manufacturers or their authorized European representatives located in Germany have to designate and notify the local competent authority of an appropriately qualified person who will be responsible for the collection and evaluation of any information about risks associated with the manufacturer’s products.⁴ This person shall also be responsible for coordinating corrective actions, although not necessarily for deciding whether they will be initiated, and for fulfilling legal reporting requirements related to risks. 

Reporting Obligations

Manufacturers, their authorized representatives, or their local distributors acting on their behalf have to report to the national competent authorities incidents and near-incidents as well as recalls, if these are risk related. Recalls for purely commercial reasons, which are rather rare, are not reportable. For reporting purposes, an incident is defined as a product defect (i.e., malfunction or failure, deterioration in characteristics or performance, or inadequacy of labeling or of instructions for use), that, directly or indirectly, has led or might have led to serious medical consequences, namely death or serious deterioration in the state of health of a patient, user, or another person. Such instances include cases where causality has not been established, but is possible. 

Serious medical consequences do not necessarily have to actually have occurred to qualify an event as reportable. Product shortcomings, which due to fortunate circumstances did not result in serious medical consequences, but could lead to such consequences in case of recurrence, are also reportable. These occurrences are called “near-incidents.” 

In the field of IVDs, it may be very difficult to decide whether an observed problem is reportable or not. This is mainly due to the particular nature of these devices. IVD product deficiencies may directly harm a user (e.g., by electric shocks, burns, mechanical effects, infection, or toxic effects). More often, deficiencies in IVDs lead to incorrect analytical results (e.g., false-positive or false-negative test results, falsely increased or decreased values) by which patients may indirectly be harmed through wrong medical decisions regarding diagnosis or therapy based on the laboratory findings. Another problem may be a delay in diagnosis or treatment due to the need for repeated analyses. 

Determining the possible consequences of incorrect analytical results is not an easy exercise. Ideally, manufacturers and competent authorities should agree on a common interpretation of the reporting requirements.⁵ In cases of doubt, manufacturers should submit a report rather than refrain from doing so. When a problem is reported, it does not automatically mean that there will be a need for corrective action. A disclaimer may be included in the report stating that the report is not to be understood as an acknowledgment of liability. 

In principle, the following cases are considered to be not reportable:

• The problem is not related to a product defect (e.g., user error, unless this is due to deficiencies in product design or in the instructions for use).
• The product is found to be defective after its expiration date has elapsed (provided that the failure or malfunction is related to stability).
• The problem is due to off-label use (e.g., use in a matrix for which the test is not intended according to the manufacturer’s declaration). However, this exemption would not apply in cases of foreseeable misuse or when the problem could also occur when the product is correctly used for the intended purpose as specified by its manufacturer. 
• The observed problem (e.g., an interference or analytical limitation) is already adequately addressed in the instructions for use (provided that the product still complies with the current state of the art).
• It is not possible to use the defective product or the defect is so obvious that it will definitely be detected before the product is used (unless the product is essential for use in critical situations). Similar considerations may apply to analytical results that are obviously wrong, provided that they will definitely be disregarded, and also in all cases of recurrence under different circumstances (e.g., in different laboratories or with different samples). In that context, the decisions must always be based on realistic assumptions regarding laboratory standards, not on theoretical best-practice conditions.
• There is no causal relationship, or only a very remote likelihood, that serious consequences might be caused by the defective product.

Special reporting arrangements (periodic summary reporting) or even exemptions may be established in national regulations or adopted as acceptable practice for incidents that have already been subject to an advisory notice (e.g., malfunctions that are detected in the course of recommended retesting of samples), and for well-known and sufficiently investigated problems. 

Manufacturers may run into difficulties in complying with the reporting requirements when, due to inherent limitations of the product performance (e.g., with regard to sensitivity or specificity), a certain number of failures or malfunctions is to be expected, most of which will normally not be communicated to the manufacturer. In such cases the concept of trending and trend reporting may be a useful approach. 

For very critical products, every relevant failure or malfunction (even if consistent with the claimed performance characteristics) should be reported. Such products include those used for safety and compatibility testing of blood donations or testing before or during pregnancy with a view to avoid embryopathy or fetopathy.

Both reports of incidents and near-incidents have to be submitted to the competent authority of the country in which the problem has occurred. Recalls are to be reported to the competent authorities of all affected countries. Addresses and contact details can be found in the appendix to the European Guidelines on a Medical Devices Vigilance System (MEDDEV 2.12-1) or on the Web pages of the respective regulatory authorities (e.g., www.bfarm.de/de/Medizinprodukte/vigilanz/index.php).³ 

Incidents and near-incidents that occur in countries outside the EEA are only reportable if they lead to corrective action that also applies to products on the European market. To which competent authority such cases have to be reported depends on where the notified body involved in the European conformity assessment procedure, or if no notified body is involved, the manufacturer or the authorized representative, has its registered place of business. Recalls, again, are to be reported to the competent authorities of all affected countries.

Risk Assessment by the Competent Authority
When evaluating the reports or other relevant information regarding risks, the task of the competent authority is to characterize the risk (in terms of probability of occurrence of harm and severity of the harm) and to assess it for acceptability. In particular, the competent authority should consider the benefit of the product in question, the availability of safer alternatives, the safety level described in relevant standards, the concept of inherent safety, the type of user (health professional or lay user), and whether the affected patient population may require special protection (e.g., fetuses, neonates, pregnant women, unconscious patients). In the case of unacceptable risks, the necessary corrective action is to be determined. If the manufacturer has already taken measures on its own initiative, the competent authority must then decide whether or not these are adequate and sufficient to remedy the problem.

Risk assessment is performed in close cooperation with the manufacturer (or, where appropriate, via the authorized representative or the local distributor). Other experts may be involved, if necessary. Manufacturers have to investigate the problem, keep the competent authority informed of the progress of the investigations, and submit a final report that includes all relevant findings and conclusions drawn. Thus, the manufacturer’s cooperation is essential. National legislation may contain an explicit obligation in that respect and mechanisms by which proper cooperation can be enforced.

Corrective Action

Once the need for corrective action has been established, it is expected that the necessary measures are “voluntarily” implemented by the respective manufacturer, its authorized representative, or its local distributors. If this is not the case, an official order will be issued or other appropriate measures will be taken by the competent authority responsible for supervising the manufacturer or the authorized representative. Competent authorities may also approach local distributors in order to enforce corrective action. Where necessary, orders may also be addressed to professional users to prohibit or restrict the operation and use of a device, or even a public warning may be issued.

When deciding upon a corrective action, a hierarchy of measures determined by the concept of inherent safety is to be followed. In principle, medical devices must be safe by design. If this is not totally possible or reasonable, appropriate technical safeguard mechanisms (e.g., alarms, error messages, or automatic stops) shall be implemented to control foreseeable risks. Only risks that remain after all reasonable technical options have been considered may then be addressed by descriptive measures (e.g., warnings in the instructions for use), provided that thus an adequate level of safety is achieved. As a practical example, software failures that have led to an incident report will normally have to be corrected by a software upgrade. A warning letter describing how to avoid manifestation of the problem may be acceptable as a temporary protective measure. 

Any necessary corrective action must be properly communicated to all customers and users. In the past, advisory notices issued by medical device manufacturers to initiate corrective action have been a matter of concern. The contents and layout of such notices did not always ensure that customers correctly understood their purpose and relevance.

As a consequence, competent authorities expect these notices to meet certain basic requirements. For example, the German ordinance on medical devices vigilance systems specifically requires advisory notices to contain:

• The name and contact details of a person to whom further questions about the problem can be addressed.
• A clear identification of the affected product or product batch(es).
• A sufficiently detailed description of the problem and a detailed description of its root cause (if known).
• A comprehensive discussion of the risks associated with the problem, including all relevant facts and data on which the assessment has been based.
• An unambiguous specification of the required action.²
Additional information may be included, e.g., recommendations on retesting of specimens, if appropriate. Playing down the risk and incorporating promotional statements are explicitly forbidden.

Exchange of Information

In principle, CE marked devices enjoy free movement in the entire EEA. Thus, there is a need for information to be exchanged between competent authorities, in particular when corrective action is to be taken. The IVD Directive therefore requires that the European competent authorities inform each other and the European Commission of all cases that lead to corrective action by means of a vigilance report. The competent authorities shall not rely on the assumption that the manufacturers, their authorized representatives, or their distributors will correctly inform them and reliably and effectively implement adequate corrective action in all countries concerned. 

Having been informed through a vigilance report, all competent authorities can then monitor the corrective action in their area of responsibility and also consider whether similar products made by other manufacturers may also be affected by the observed problem.

The experience gained so far reveals that the European competent authorities in different member states have implemented different policies regarding the exchange of vigilance reports related to IVDs and other medical devices. Whereas Germany strictly follows the provisions as laid down in the relevant directives and only refrains from sending a vigilance report when the information to be communicated would really not be relevant for the recipients, other countries apparently do apply additional criteria to reduce the number of reports to be sent. Several European countries participate in the Global Harmonization Task Force (GHTF) vigilance report exchange scheme, based on the criteria as defined by GHTF.⁶

Conclusion

Hans-Georg Will, director and professor, is head of the Medical Devices Division will@bfarm.de

The vigilance system is a key element of the European legislation. It will ensure that all serious problems caused by products already on the market are properly dealt with under governmental supervision and that appropriate information is disseminated to avoid recurrence of similar problems. Thus the vigilance system significantly contributes to the aim of safeguarding public health by achieving and maintaining an appropriate level of quality, suitability, and safety of IVDs. It requires active cooperation between all parties concerned, in particular between competent authorities, manufacturers, and users. In light of the quite-liberal market-access requirements of the IVD Directive, proper functioning of the vigilance system will be an essential prerequisite for credibility and for public confidence in the European regulatory system.

Rüdiger Siekmeier, MD, is head of the Department of In Vitro Diagnostics in the Medical Devices Division of the Federal Institute for Drugs and Medical Devices (Bonn, Germany).  r.siekmeier@bfarm.de

References

1. “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 Communities L 331 (1998): 1–37.

2. “Medizinprodukte-Sicherheitsplanverordnung,” Bundesgesetzblatt Teil 1, 24 (2002) 2131 [cited 19 August 2003]; available from Internet: www.bfarm.de/de/Medizinprodukte/mp_recht/index.php.  

3. European Commission, Guidelines on a Medical Devices Vigilance System MEDDEV 2.12-1 rev. 4 (2001) [cited 12 August 2003]; available from Internet: http://europa.eu.int/comm/enterprise/medical_devices/meddev/index.htm). 

4. “Medizinproduktegesetz in der Fassung der Bekanntmachung,” Bundesgesetzblatt Teil 1, 7 (2002) 3146 [cited 19 August 2003]; available from Internet: www.bfarm.de/de/Medizinprodukte/mp_recht/index.php. 

5. German Association of the Diagnostics Industry (VDGH), Die Anforderungen der Medizinprodukte-Sicherheitsplanverordnung für in-vitro-Diagnostika im Rahmen des Medizin- produktegesetzes (2002) [cited 11 August 2003]; available from Internet: www.vdgh.de. 

6. Global Harmonization Task Force, Medical Devices Post Market Surveillance: National Competent Authority Report Exchange Criteria GHTF/SG2/N20R10 (2002) [cited 12 August 2003]; available from Internet: www.ghtf.org.  

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