Medical Device Link.

Originally Published IVD Technology November/December 2003

IVD DIRECTIVE

Even after the compliance deadline, the IVD Directive will continue to present regulatory challenges to IVD companies.

Sue Spencer, Doris-Ann Williams, John Andrews, and Andy Bufton

IVD companies that do business in Europe have had one target date in mind during this past year: December 7, 2003. By that date, all IVDs must comply with the IVD Directive and have a CE mark in order to be sold in the European market. In order to be compliant with the directive, companies have had to deal with a number of regulatory issues that have been discussed throughout this series on the directive.

Already, there have been several significant developments as a result of the directive. For example, some devices will be discontinued, especially certain older devices, and those in Annex II where compliance with the directive has made the product uneconomical to produce. Similarly, in some of the smaller markets that require national language labeling, individual companies may decide that the sales volume does not justify the expenditure and withdraw their devices from these markets.

Even though the December 7 deadline is fast approaching, the IVD Directive will still be here, and IVD companies will have to make sure their devices comply with it. This article examines the various issues related to the directive that IVD companies and government authorities will have to continue to address in the future, as well as other changes in the regulations themselves that may occur.

Challenges and Issues for IVD Companies

Some IVD companies have been under the impression that after December 7, they would not have to engage in any more activity once their devices were registered and CE marked. Companies need to realize that this is not the case, and that compliance is an ongoing process throughout a product's life. In the post-December 7 era, IVD companies will have a number of issues that they will have to continue to address and be concerned about in order to remain compliant with the IVD Directive.

Putting into Service. After December 7, companies will be allowed to place on the European market only those IVDs that comply with the requirements of the IVD Directive. The only non-CE marked diagnostics that can legally remain on the market are those that were already in the supply chain before the December 7 deadline and have not reached their expiration date. These devices may be used for two more years, until December 7, 2005. Despite the general agreement regarding this two-year extension, different EU member states may take different views as to what exactly "placing on the market" and "putting into service" means. This additional two-year grace period for those IVDs already put into service has caused considerable concern, and appears to be unclear. The interpretation and enforcement of these statements may vary among the member states. However, what is clear is that this extension is only applicable to existing devices on the market, and has been included specifically to reduce waste in the supply chain. Any new devices being sold for the first time in Europe must comply by December 7.

Moreover, IVD companies cannot use the additional two years to delay being in compliance by the deadline. For example, companies cannot manufacture bulk lots of a product immediately prior to the deadline to sell after December 7. Only those devices that companies have already placed in the supply chain and whose legal ownership will transfer to another entity can continue to be utilized.

Vigilance Activities. IVD companies should continue monitoring closely their current complaint systems to ensure they are recording adequate levels of information. Companies need to be sure all the technical information for their devices is easily accessible in case it needs to be reviewed. Authorized representatives also have a responsibility to make sure IVD companies can provide this information in a timely manner.

Training Needs. Sales forces at IVD companies should maintain a high level of knowledge of the requirements of the IVD Directive. Salespeople need to be able to recognize a reportable event and make sure customers are not misusing devices by either not adhering to the package insert, or by using research-use-only devices in a clinical setting.

To ensure their sales and marketing staffs are competent enough to understand and deal with the new regulations, IVD companies should consider holding short, periodic, intensive training courses on the directive. Sales staff members need to understand that being knowledgeable about the directive may affect how they do business. For example, any claims they make either verbally or in writing constitute product claims that have to be substantiated in the device technical file.

Salespeople should also understand that violating the directive carries criminal penalties, not civil, which is especially important when considering the safe-in-combination requirements. If a salesperson states that a kit that has been validated to run on systems A and B can also work on system C, this is a device claim that is subject to directive regulations. However, if the company provides software to allow the kit to be run on system C, it is endorsing the combination and therefore needs to substantiate the combination by obtaining a CE mark and updating the software to reflect the system changes.

Product Changes. IVD companies frequently underestimate the ongoing regulatory burdens they must address, particularly as a result of significant changes to their products. Companies are required to define what significant product changes they have made, especially if they work with a notified body. The company and the notified body then agree on this definition so that both parties are clear about what will be reported. In addition to reporting all significant changes to products before they are made, IVD companies should allocate sufficient time for a notified body audit in case it is required.

Some IVD companies have not budgeted enough resources to deal with product changes. Those companies that hired external consultants to prepare their files for the December 7 deadline may struggle to maintain an efficient system without in-house trained resources. Standards and guidance documents are constantly changing, so IVD companies need to have a system to keep up-to-date with the changes. An auditor can easily identify a system that is not well maintained because the required references are incorrect.

Challenges and Issues for Competent Authorities and Notified Bodies

Postmarket Surveillance. Postmarket surveillance is both proactive and reactive. Competent authorities have realized that this surveillance is one of the most powerful tools in protecting public health. While in the past auditors may have looked for just a procedure, today they are actively looking for evidence that postmarket surveillance data are being gathered and the appropriate corrective and preventive actions are being taken. This is an area where it appears that notified bodies have raised an increased number of noncompliances.

Notified Body Consistency. The notified bodies are the organizations that will audit the higher risk devices. Maintaining consistency among all the notified bodies will be a challenge for the competent authorities that appoint and monitor them. The competent authorities have to manage consistency both within each member state and among the member states. If a consistent standard is not applied among the notified bodies, the whole system will be ineffective.

The European Commission and the competent authorities recognized this problem and created two groups that operate at the competent authority level: the Notified Body Oversight Group (NBOG) and the Market Surveillance Operations Group (MSOG). NBOG realized that the biggest threat to notified body consistency was each member state having different criteria and rules for appointing and monitoring notified bodies. This group has therefore taken a document originally written by the UK competent authority and expanded it so that it can be adopted by all competent authorities.

The competent authorities have also started a program of observing each other's audits of notified bodies. For example, the Finnish competent authority recently observed the audits of notified bodies in the UK. It is hoped that this sharing of best practices will contribute to building up consistency among notified bodies. In addition, there have been some concerns that IVD companies will deliberately choose to work with weak notified bodies. However, in practice, many companies want a strong notified body that will identify problems before they become a potential vigilance case. Companies want to be reassured that they have been properly audited and have a good notified body in their corner in case anything does go wrong.

Finally, the notified bodies have formed a trade association that will not only represent the interests of its members, but also provide a platform for cross notified body communication.

Batch Testing. There are many questions concerning batch testing, especially as to whether the relatively small number of notified bodies will be able to keep up with the demand for lot testing once the IVD Directive becomes mandatory. It remains to be seen how this sort of testing could work. The testing organizations have consistency issues that are exactly the same as those of the notified bodies. In addition, several different batch testing approaches are allowed: physically sending kits to an external lab, a manufacturer sending independent patient samples for testing and subsequent data approval, or data and witnessed testing at a manufacturer's site. However, some member states do not allow all of these testing options, and there is no evidence that these methods are equivalent.

Many IVD companies had hoped that batch testing would initially be done on every batch, and that notified bodies would reduce the amount of testing over time. So far, this has not happened. If it does happen, a number of issues will need to be resolved, such as to what extent batch testing will be allowed, whether there will be a consistent approach among the notified bodies, and, since batch testing is an ongoing cost, whether the costs remain the same.

Enforcement. The IVD industry has seen many cases in which companies report to the competent authories other companies that are not conforming to the legal requirements. In many ways, the IVD Directive is a directive written for, and policed by, trade. While this route of enforcement relies on competent authorities investigating complaints, it is yet another area where there is huge variation among the member states.

For example, in the UK, all complaints are investigated. MSOG coordinates these investigations in an effort to enhance the consistency of market surveillance by the competent authorities. Meanwhile, other member states such as France have continued their tradition of testing all kits for a designated analyte. In the past, some of these kits could have been taken off the French market. Some member states are concerned that if investigations in the future were conducted under the auspices of MSOG, these kits could be removed throughout Europe.

Developments in the Regulations

Common Technical Specifications (CTS). The current CTS do not meet the scope described in the IVD Directive. Article 5 of the directive says, "These specifications shall establish appropriate performance evaluation and re-evaluation criteria, batch release criteria, reference methods, and reference materials." While the current CTS address performance evaluation, they do not address re-evaluation criteria, batch release criteria, reference methods, or reference materials. A subgroup of the Competent Authorities Expert Group is currently reviewing the CTS.

In addition, the directive stipulates that additional CTS may be prepared for Annex II list B devices. While there are some people in the IVD industry who would like to see other CTS prepared, at present, there is no will to write any new CTS.

Classifying IVDs. It is likely that additional analytes will be added to Annex II in the future. The IVD Directive includes a provision for this to occur. For example, more tumor markers and genetic tests could be added to Annex II. It is also anticipated that once kits for screening blood and tissue donations for variant CJD (the human form of mad cow disease) have been developed, they too will ultimately be included in Annex II. Device reclassification has always occurred as part of the life cycle of the medical device directives. Notified bodies are normally given a transition period of 6–12 months to allow the necessary documentation to be prepared and additional audits to be conducted.

Challenges and Issues Outside Europe

Export Activities. Other countries outside of EU jurisdiction may also require that IVDs obtain a CE mark in order to be placed in their markets, in the same way that some countries demand FDA approval. At the same time, CE marking may affect export activities from EU countries. Some non-EU countries already require IVD companies to secure from their home governments a certificate of free sale that states the device can legally be sold in their own country, thus facilitating export to the foreign country. Unfortunately, some companies produce devices that are only intended for export beyond Europe, e.g., Asia or Africa. Clearly, these devices will not receive a CE mark if they are not sold in Europe, which makes it difficult for a certificate of free sale to be issued. The UK government is currently working on the wording of another certificate that will allow companies to continue with their export activities beyond Europe without requiring them to go through the process of obtaining a CE mark. The costs involved to get a CE mark can be substantial if the devices are Annex II list A devices.

EU Expansion. Adding new member states to the European Community will present a host of regulatory and logistical issues and will increase the compliance challenges for IVD companies. For starters, EU expansion will obviously bring additional language requirements. EU expansion will also bring other complications, such as the lack of a transition phase in some candidate states. For example, CE marking will be required in some countries as soon as they join the EU. In addition, some candidate countries have included their own requirements in the directive that they introduced in their national laws during transposition. For example, Poland requires an authorized representative to be designated in Poland. Such actions are contrary to the principles of new approach directives and are very frustrating for the industry.

Global Harmonization. There has been some discussion as to what effect global harmonization efforts will have in Europe and on the IVD Directive. Some analysts believe that while global harmonization would certainly help to improve the industry, it will take many years to do so because none of the authorities involved will want to relinquish their own regulatory structures. However, some effects of the global harmonization task force (GHTF) can already be seen. Many member states and notified bodies now write guidances to be in compliance with GHTF. Some GHTF members have also been sharing vigilance information, which means that a vigilance case could someday become a global issue.

Conclusion

It cannot be denied that CE marking is about to change the world in which it functions. For example, as discussed above, EU enlargement will require IVDs to add many more languages to their package inserts. Market reactions to discontinued devices, non-CE marking of analytical platforms under the claim of being general-purpose laboratory equipment, and using devices in combination are all issues that management teams at IVD companies have largely left to their regulatory colleagues to wrestle with within their own narrow sphere. In addition, training of sales and marketing divisions on the impact of the IVD Directive is overdue and must be embraced, as customers line up to request help and assistance with the complexities of in-house manufacturing, safe use of devices in combination, device discontinuations, and off-label use of devices.

Following the earlier medical device directives, the majority of complaints made to the competent authorities came from the competitors of those companies that exhibited noncompliance. Should this be the case in the IVD industry, the added feature of noncompliance is an issue that the management at IVD companies should contemplate. This is not just a regulatory issue, any more than any of the other issues concerning the directive has been purely regulatory in nature. This is also a marketing issue, which concerns the market environment, and the directive is the biggest climate change in the IVD market during the past few decades. The challenges for the industry post-December 7 are ones relating to what, how, and where it sells its products. Senior management, particularly those responsible for sales and marketing, needs to engage with how the directive is changing the face of the diagnostics business in Europe, since it has serious commercial implications both now and in the future.

ILLUSTRATION BY MARCO AGUILERA

Sue Spencer is director of Cascade Consulting Ltd. (Aldershot, Hampshire, UK). She can be reached at sue@cascade-consulting.com. Doris-Ann Williams is the director-general of the British In Vitro Diagnostics Association (London). She can be reached at doris-ann@bivda.co.uk. John Andrews is technical manager at Lloyds Register Quality Assurance (Coventry, UK). He can be reached at john.andrews@lrqa.com. Andy Bufton is director of external and regulatory affairs at Abbott Diagnostics (Abbott Park, IL). He can be reached at andy.bufton@abbott.com.

Copyright ©2003 IVD Technology