Medical Device Link.

REGULATIONS & STANDARDS

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 diagnostic division at Abbott Laboratories (Abbott Park, Il). She can be reached at petra.kaars-wiele@abbott.com

The In Vitro Diagnostic (IVD) Directive 98/79/EC, implemented seven years ago, suggests that companies do not always fully understand compliance requirements. In response, competent authorities may be required to audit such companies and take actions against noncompliances in the market. It is the responsibility of senior managers of IVD companies to ensure that their companies have sufficient resources and a corporate culture for compliance. The following is a list of the new issues that effect noncompliance reviews:

• IVD manufacturers buying in support of IVD compliance consultants in the medical device industry need to re-evaluate this practice for several significant reasons. Careful selection is necessary to find the right person for the job and to balance the investment with the output.
• First statistics of IVD vigilance reporting and noncompliances for high-risk IVD products are published. The recently published vigilance guidance will be effective December 2007.¹ IVD manufacturers may need to revise their processes or procedures to meet the authorities’ expectations.
• The new chemical framework REACH, effective since June 1, 2007, is one of the recent challenges in the European Union (EU). Careful calculations and considerations by IVD manufacturers are required.
• Last year, the Norwegian regulatory body changed the national regulations. As of October 2007, the inclusion of the Norwegian language on all labelling is mandatory.
• In early 2007, two countries joined the EU: Bulgaria and Romania. Neither member is fully integrated.
• All involved parties (manufacturers, notified bodies, competent authorities, and end-users) are continuously challenged by additional or revised regulations affecting IVDs and by the growing European Union.

Noncompliances with the IVD Directive

The IVD Directive, implemented in 2000, calls for every manufacturer to adapt to the directive and all related standards. All diagnostic products sold within the European market since December 2003 should comply with these rules. However, there are doubts within the industry that all manufacturers comply with the regulation standards.

The declaration of conformity is a good indicator of compliance. Many companies do not follow the ISO standard or the Blue Guide which states all of the elements required for a compliant product.^{2, 3} After reviewing manufacturers’ declarations, the following noncompliances were commonly found: no clear identification of the single product, no classification of the product according to Global Medical Device Nomenclature (GMDN) or European Diagnostic Manufacturer Nomenclature (EDMN), no information regarding the authorized representative in the European Union, no information on the applied standards, no change control procedure, and incorrect or misleading statements regarding compliance.

Performance evaluation is another area of potential noncompliance. The instructions for use (IFU) should inform the user of the assay performance. Several manufacturers of nucleic acid test (NAT) assays do not state the assay’s performance in their instructions for use. It can be a real challenge to find significant samples and perform studies to specific parameters, but this is not an acceptable reason for non-compliance with the directive.

Language Barriers

Additionally, specific language requirements are rarely met in all countries. Companies are overwhelmed with the translation requirements for many different countries.

Performing translations for an IVD into more than 15 languages through a change control system is a major task. The potential for misleading or wrong translations is often underestimated. This may not lead to recalls or serious injuries, but it is a burden to the customers.

Some manufacturers decide not to translate into certain languages because the cost of doing so is not in proportion to the sales within those smaller markets. Or some companies find it is too time-consuming to complete the administration (and keep it up-to-date) to ensure that users (with the users’ consent) have a suitable level of English to enable them to work with an English instructions for use; thereby leaving users and patients at a disadvantage in certain countries.

The use of harmonized symbols on labels as indicated in standard EN 980 simplifies the labelling process. Not only does it reduce the amount of text necessary for translation, but it also makes it easier for the end-user regardless of their native language. Symbols are without a doubt useful; however, they have limitations and cannot completely replace the need for translation.

Last year, the Norwegian regulatory body changed their guidance regulations. As of October 2007, all Norwegian IVD manufacturers must include the Norwegian language for all IFUs, even those products labelled “for professional use.” Manufacturers are working hard to meet these new regulations; however, the timeline is challenging as the number of pages to be translated for IFUs for tests and their systems may easily add up to several thousands.

One positive signal from Europe is the new guidance document, published in April 2007 by the European Commission, outlining the manufacturers’ requirements for providing IFUs and other information of IVDs for professional users (not for self-testing devices) in a format other than paper.⁴

Sometimes small IVD companies, which may be less aware of the IVD Directive, cause problems for compliant manufacturers if they CE mark products that do not need to be CE marked (e.g., empty Petri dishes, microscope slides, centrifuges, pipettes), which are general lab equipment, unless a specific claim makes it an IVD. The compliant manufacturer then has to explain why the company is not CE marking the product and may, as a result, be excluded from tenders, even if the company is in compliance.

The labels and declaration of conformity are items that can be seen easily by users when purchasing the product or when documentation is submitted for tenders, and yet laboratory personnel are rarely trained on these topics. Often, the CE mark on the box, the IFU, and the declaration of conformity from the manufacturer (standard included with the product) are sufficient for users to accept the product has met compliance.

Supporting Guidance Authorities

Risk analysis, risk management, complaint handling, and vigilance are also difficult areas to regulate. Are users’ complaints correctly documented? Is the risk analysis updated as needed? Do the residual risks outweigh the benefits of the product? Users have to rely on assessments carried out by the appointed authorities to answer these questions. They are the only institutions allowed to examine companies’ procedures and thus find noncompliances. Representatives of the appointed authorities require thorough training and knowledge of the standards and their use to ensure a balanced view on potential deficiencies.

Unfortunately, competent authorities do not have sufficient resources to perform all of the compliance audits required, and the majority of products, except for Annex II products and self-testing devices, are not required to verify their full compliance with the directive. However, this should not be an invitation for manufacturers to neglect their product compliance. On the contrary, manufacturers who are investing both time and money in compliance and the continuous improvement of their products should be in support of the EU authorities performing more audits and ensuring that the “black sheep” in the market are eliminated. This is also in the best interests of all stakeholders, including users and patients.

Companies with consistent training schedules create products that reflect the manufacturer’s knowledge and compliance with the IVD Directive. It is management’s responsibility to not only ensure that the appropriate resources are in place, but also that there is an attitude and support for compliance within the company.

Medical Device Consultants

When employing consultants in the IVD Directive field, there are several issues that deserve close attention. Not every medical device consultant is a qualified IVD medical device consultant. The person you hire should have a good technical background in IVDs and ideally some previous experience in the IVD business. Often consultants working in their professions for many years are sometimes distant from the daily business of the IVD industry. This is particularly important since the IVD business has evolved and technology has changed dramatically over recent years.

A careful study of the consultant’s career history and reference list is key. Although a background in European legislation is important, lawyers are not necessarily good IVD consultants. A former regulatory affairs professional from an IVD or medical device company is preferable to a lawyer.

It is also beneficial to check whether the consultant has published articles on IVD regulations or regularly gives presentations at conferences on IVD issues and concerns. Although consultants who meet these specific requirements may be expensive and difficult to find, it is money well spent. Consultants may only be necessary in a critical situation, such as preparing a product for compliance or verifying all activities and documentation are completed correctly when entering the EU market for the first time. Expertise must be built within a company to ensure a continuous improvement and compliance of all areas of the product—from design to market.

Vigilance Update

Recently the German competent authorities, ZLG (the German designating and notifying authority in the field of medical devices including IVD medical devices) and the IVD vigilance group of PEI (Paul-Ehrlich-Institute) published their experiences with high-risk IVDs in Europe.⁵ From 2002 until 2005, PEI received 130 incident notifications. The number increased from 22 reports in 2002 to 52 reports in 2005. The majority of the notifications came from manufacturers, and less than 20% came from users. Other authorities within European member states and proficiency-testing organizations did submit any reports.

A close look revealed that stability and sensitivity issues with the device were often the cause of the incidents. Most manufacturers (80%) did not or could not provide performance evaluation data when requested by the competent authority. Only 1% of the cases were the result of user errors. Also, 10% of all cases were not reported within the recommended 30-day time frame, including those with a potential serious risk to public health.

PEI detected one case where the common technical specifications (CTS) were not met and lacked the necessary notified body’s surveillance activity. Although this statistic is only related to a limited number of IVDs, these data make it clear that there is room for improvement. Performance evaluations in accordance with the CTS requirements throughout the shelf life of the product, cooperation with the competent authorities, timely reporting of incidents or near-incidents are all areas that need particular attention from the manufacturer’s side. A responsible manufacturer should also ensure that he contracts a challenging notified body. Regular product reviews are essential as part of the manufacturer’s postmarket surveillance.

Communication between manufacturers and competent authorities has increased. Competent authorities also review Internet updates on postmarket surveillance from fellow regulatory authorities throughout the world. IVD manufacturers may wish to review Internet updates as well. A list of all EU competent authorities, with links to the national Web pages, is located at the following Web site: http://ec.europa.eu/enterprise/medical_devices/ca/list_ca.htm.

MedDev 2.12 revision 5, the recently published guidance document, will be effective December 2007. Two significant changes in the document include:

• Manufacturers are required to define threshold values to establish trend reports of events, which are not required to be reported, but may become necessary when passing the threshold.
• Manufacturers are required to issue field safety corrective actions to authorities for documented incidents, where customers then will be informed by field safety notices. This guidance change implies that more corrective actions are due to safety reasons. Non-safety-related field actions are therefore not required to be reported. However, this new corrective guidance is contrary to the current transposition between Germany and France, which dictates that any systematic recall is reportable, even if the recall is non-safety-related.

Manufacturers should carefully study this revised guidance and adapt their processes and procedures accordingly.

Regulating Chemicals

REACH, which stands for Registration, Evaluation, and Authorization of Chemicals, has been effective since June 1, 2007.⁶ Many IVD manufacturers may think that their products are not subject to this regulation. Although it is true that weights of less than 1 t per year do not fall under this new framework, manufacturers, importers, and downstream users are required to comply with the regulation. Sulphates, phosphates, sodium chloride, sucrose or Triton are some of the common chemicals used in IVDs. These materials may add up throughout the year, and a careful calculation is required if the limit of 1 t is exceeded.

Companies have until June 1, 2008, to complete a pre-registration to fall under the 11-year transition period that ends in 2018. Chemicals that may contain carcinogenic compounds, alter genetic material, or compromise reproduction (i.e., CMR chemicals) must receive a complete authorization, which may require that the chemicals’ use be limited or stopped. Hazardous materials like CMR chemicals will be evaluated until 2014. Seven years is sufficient time to change the product design and switch to more biologically safe ingredients. IVD manufacturers may also consider buying their chemicals in Europe to benefit from the possibility that the chemical producer completes the product registration, evaluation, and authorization in-house.

Future Harmonization

Bulgaria and Romania joined the EU at the beginning of 2007; however, neither country is fully integrated. Both nations have not fully adapted the IVD Directive into their national laws and still require local processes to be completed. Unfortunately, they are not alone as there are other EU members (e.g., Poland, Italy) that are still performing their own activities and are not fully aligned.

As long as the EU community continues to grow, it is unlikely that the authorities will have the opportunity to harmonize their processes. Until this harmonization is successful, the discussion of a centralized European regulatory body will continue.

The European IVD regulatory system is a qualified guidance organization, but it requires a lot of discipline by competent authorities, notified bodies, and manufacturers. It is unclear if it will take another seven years for the system to achieve its goals, but it is certain that all involved parties are continuously challenged by additional or revised regulations affecting IVDs.

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