EU regulatory requirements could soon become stricter for in vitro diagnostic medical devices (IVDs), which cover a range of products that can be used for diagnosis, therapeutic drug monitoring, disease screening, assessment of medical interventions, and population screening.

Paula McCarthy

Manufacturers ofIVDs need to comply with the IVD directive 98/79/EC in order to place their products on the market in the European Union. Amidst calls for stricter regulation of medical devices within the EU, the European Commission proposed a new IVD regulation in 2012. The stated aim of the revised legislation is to ensure better consistency and safer products, and ensure that advancements in technological and scientific progress that have occurred since the IVD directive was implemented is legislated for, while maintaining fair and free trade of devices throughout the EU. Since 2012, the proposed text of the regulation has undergone rounds of negotiation and revision, with the latest amendments being made by the European Council in June 2015. The next stage in the approval process is a 'trilogue' negotiation between the European Parliament, Council and Commission, after which the final text will be adopted, possibly in Q1 or Q2 of 2016.

In this piece, I will outline seven of the key changes to the legislation proposed as it stands, and discuss the industry impact of the regulation.

1. Classification System and Conformity Assessment

The new regulation proposes a classification system that constitutes a complete overhaul of the current classification system for IVDs. A rules system based on the internationally recognized Global Harmonisation Task Force (GHTF) classification principles is proposed to replace the current list system. IVDs are classified in accordance with the risk they pose to the individual and the risk they pose to public health. IVDs will be classified in to four classes in accordance with seven rules: Class A, B, C, and D; with Class A being the lowest risk and Class D being the highest risk.

It is estimated that under the new IVD classification system, over 80% of IVDs will be classified in the medium and higher risk categories (Class B, C, and D) and will require Notified Body involvement in the conformity assessment procedure. This is in contrast with the current IVD classification system, where approximately 80% of IVDs are classified in the low risk, self-certified category. Another significant departure from the current directive is that all devices that do not fit any of the classification rules are automatically classified as Class B, whereby a notified body will be required for conformity assessment. Under the current system, such devices are self-certified.

This change to the classification system is considerable and will no doubt impact greatly on the IVD industry, with increased time, complexity, and resources required to launch new products, as well as significant investment in transitioning current products to comply with the increased regulatory requirements.

2. Clinical Evidence

It is proposed that clinical evidence will be required to support the scientific validity of the analyte, the analytical performance and where applicable, the clinical performance of the device. A performance evaluation report that includes the scientific validity report, the analytical performance report, the clinical performance report and an assessment of these reports will be required. The report will need to be updated throughout the product lifecycle, and will be part of the technical documentation. The proposed clinical evidence requirement for IVDs is one of the most debated topics in the draft regulation, and has undergone much revision since the 2012 publication of the draft regulation.

3. Traceability

The proposed regulation mandates that IVDs (other than those for performance evaluation) must have a Unique Device Identification (UDI) on the device label. The UDI will be used for reporting incidents and field safety corrective actions. Similar to FDA UDI requirements, the UDI will consist of a production identifier and device identifier. A database will be established where the UDI of each device will be input.

4. Regulatory Responsibilities within the Supply Chain

The proposed regulation outlines new responsibilities for Importers and Distributors. Before making the device available on the market, importers and distributors will have to verify that the device: is CE marked and has a declaration of conformity; is accompanied by instructions for use; and has a Unique Device Identification (UDI). Additionally, importers will have to verify that the device is labeled in accordance with the regulation and is registered in the UDI database; as well as placing their name on the product label. Importers and distributors will be obliged to ensure that while the product is under their responsibility it is stored and transported correctly, and ensure that product complaints they receive are logged and forwarded to the manufacturer for investigation where necessary. Importers and distributors will be obliged to inform the competent authority if they have reason to believe that a device presents a serious risk or is falsified.

5. Notified Bodies

The proposed regulation contains detailed requirements for monitoring of the performance of notified bodies by national competent authorities; quality management system requirements; and training, education and experience requirements for notified body assessors. This focus on notified bodies should ensure better consistency in the application of the requirements of the regulations by manufacturers, and increase the standard of competency of notified bodies.

6. Vigilance and Post-Market Surveillance

A reduction in the timeline for reporting of a serious incident to the national competent authority to no later than 15 days from when the manufacturer (or representative) has become aware of the incident is proposed. An obligation for manufacturers to produce a Periodic Safety Update Report (PSUR) on at least an annual basis is proposed in the June 2015 revision of the draft regulation. The PSUR will summarize the device's post-market surveillance data and risk-benefit information. An electronic system will be set up where incidents, field safety corrective actions, periodic summary reports, PSURs and trend reports are input. Healthcare professionals (HCPs) and members of the public will have access to the electronic system at an appropriate level. This proposal constitutes an improvement in transparency, providing the public and HCPs with information to allow them to make more informed decisions about use of an IVD. However, there will be additional burden on industry in the provision of an annual PSUR and maintaining compliance with the 15 day timeline for reporting of safety issues.

7. Companion Diagnostics

A definition for a 'companion diagnostic' is provided in the proposed regulation. Companion diagnostic tests will be classified in Class C and will require notified body involvement in the conformity assessment. Additionally, such devices, when undergoing conformity assessment by the notified body, will need to go through a consultation procedure with the European Medicines Agency (EMA) or a medicinal products competent authority. The EMA or competent authority will give its opinion regarding the suitability of the device in relation to the medicinal product concerned. The proposed change in the regulation will be very significant for manufacturers of companion diagnostic tests. Under the current regulatory system, most companion diagnostic tests are classified in the lowest risk category, and are self-certified.

Industry Perspective

In a recently published Position Paper, the European Diagnostics Manufacturers Association (EDMA) raised concerns that the European Council's general approach of June 2015 contains a 'significant amount of technical anomalies' and states that 'the regulation as proposed would put an excessive and unnecessary administrative burden on small and medium-sized enterprises. It remains to be seen whether the concerns raised by EDMA will be addressed in the trilogue negotiations, and in the adoption of the final text.

Paula McCarthy is a senior regulatory affairs advisor for Acorn Regulatory.

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