IVDR: How Manufacturers Should Prepare for New EU Rules

With the Trilogue’s Completion, How Should IVD Manufacturers Prepare for New EU Rules?

Trilogue negotiations completed on the 25th of May, bringing almost four years of debate to a close.  The new rules on medical devices and in vitro diagnostics may be adopted as early as the third or fourth quarter of this year, after final provisions on single use devices and other aspects receive formal approval by the European Council’s Permanent Representatives Committee and the European Parliament’s ENVI committee.

The new provisions will be disruptive for many IVD manufacturers’ current business practices, requiring substantial operational and strategic changes for product development across almost all indications. For example, some manufacturers may need to change their Notified Bodies and conduct batch release verification testing, which require considerable advanced preparation. The proposed IVD rules provide for a five-year transition period, which is a more generous timeline than the three-year transition period granted for the new medical device rules. During this time, additional legislation can be expected that will define how the proposed framework will be implemented.

To understand how companion diagnostic developers and IVD manufacturers should respond to the rule changes, we asked ICON’s Sandra White, M.S., RAC, Director of Regulatory Affairs, and Karen Hill, Senior Manager, Regulatory Affairs, to provide their insight.

1. The new rules will profoundly affect the approval of genetic tests, companion diagnostics, and the vast majority of IVDs. What diagnostics will now require Notified Body involvement?

Karen Hill:

For the majority of manufacturers, including those of high-risk medical devices such as oncology genetic tests and companion diagnostics, the effects will be particularly pronounced on development costs and approval timelines.

The scope of EU IVDR has been widened to specifically include LDTs, genetic tests, and companion diagnostics. Importantly, about 80% of the devices covered by the new IVDR will require assessment by a Notified Body. Previously, this applied to only 20% of the devices.

2. What will Notified Body involvement now entail for those tests? What changes should manufacturers anticipate making to their development plans?

Sandra White:

The majority of manufacturers will now be required to have both their quality management systems and technical documentation audited by their Notified Body prior to marketing.  In addition, after initial certification Notified Bodies shall regularly conduct surveillance assessments in the post-market phase.  This is likely to significantly increase product development timelines and delay the availability of devices on the market.  Manufacturers will also need to employ at least one “Qualified Person” who possesses expert knowledge in the field of in vitro diagnostic medical devices and will be responsible for regulatory compliance.

Specifically for manufacturers of oncology screening or diagnostic tests, whose devices will be classified as Class C under the new classification system, they will be subject to a conformity assessment based on full quality assurance, with assessment of the design documentation held within the technical file on a representative basis.

For manufacturers of companion diagnostics intended to be used to assess patient eligibility to a treatment with a specific medicinal product, the Notified Body will be required to consult with one of the competent authorities designated by the Member States or the European Medicines Agency (EMA), adding further time to the approval process.

Notified Bodies will have to ensure that they adequately resource their activities with suitably qualified personnel.  In fact, some Notified Bodies may have to cease all activities, potentially causing an assessment backlog, and forcing some manufacturers to change their Notified Bodies. The need to change Notified Bodies can likely be foreseen based on the staff that the current Notified Body employs and the designation of all existing Notified Bodies according to the new requirements and the designation process. Changing Notified Bodies is not easy; doing so requires planning and investments in educating the new Notified Body on quality systems and other aspects of the manufacturer’s process and technology. In addition Notified Bodies will be expected to rotate review personnel at appropriate intervals, perform unannounced audits of manufacturers and their suppliers and also be continuously monitored by the national authority responsible for Notified Bodies.

3. How will manufacturers need to adapt to the post-market surveillance requirements?

Karen Hill:

More devices will require clinical evidence, which will include scientific validity of the analyte, clinical performance evaluation, and analytical performance data, which must be updated throughout the life cycle of the device. Proportionate to the risk class, manufacturers will therefore be required to produce a post-market surveillance plan detailing the process for collecting, recording and investigating complaints; keeping a register of non-compliant devices and product recalls or withdrawals; and any plans for post-market performance evaluation of the device.  Therefore, clinical performance studies to collect and evaluate information relating to the scientific validity, as well as analytical and clinical performance, based on data obtained in post-market follow-up are more likely to be required.  In addition, and as and when required, risk assessments and clinical evidence reports will have to be updated.  For manufacturers of Class C and Class D IVDs, the Notified Body is required to conduct a post-market surveillance audit at least every 12 months.  

In addition, in terms of vigilance, manufacturers will now be required to report incidents and field safety corrective actions through a new electronic system, no later than 15 days after they become aware of the event.

4. For companion diagnostic developers, how may these reforms affect the synchronisation of test and therapeutic development timelines?

Karen Hill:

For companion diagnostics intended to be used to assess the patient eligibility for treatment with a specific medicinal product, the Notified Body will be required to consult one of the designated competent authorities or the EMA with regards the medicinal product component, which will involve additional time.  Also, Notified Bodies assessing high risk Class D devices will be required to notify the Commission of applications for conformity assessment, in order to determine whether or not an additional review by the MDCG will be required.  If required, this could add an additional 60 days to the certification process.

5. How should manufacturers weigh pursuing a companion diagnostic via the in vitro diagnostic pathway versus developing it as a laboratory developed test?

Sandra White:

Currently, the IVD Directive exempts from compliance “devices manufactured and used only within the same health institution and on the premises of their manufacture or used on premises in the immediate vicinity without having been transferred to another legal entity” (i.e., a laboratory developed test). 

Under the new IVD Regulation, however, devices that are manufactured and used within a single health institution will be included in the scope.  Therefore, manufacturers of these types of devices will now be subject to increased scrutiny.

6. EU IVDR has also modified the definitions of IVDs, companion diagnostics, accessories, and kits. What should manufacturers be alert to in those changes?

Karen Hill:

The definitions section of the IVDR has been significantly expanded with the definition of “in vitro diagnostic medical device” having been updated to specifically include devices providing information concerning the predisposition to a medical condition or a disease and those used to predict treatment of responses to reactions. In addition, software has been included in the IVD definition. 

7. Each IVD presently on the market must be transitioned to the new system as their certificates expire. When and how do you advise manufacturers to prepare to begin this process?

Karen Hill:

Although the transition period for the new IVDR will be 5 years, manufacturers should begin preparing now.  Initially they will be required to determine the new classification for their device(s) and whether or not this will change their need to involve a Notified Body in the certification process.  In addition they will be required to determine whether the clinical evidence they currently have is sufficient for re-certification purposes or whether new clinical evidence will have to be produced.  Both the conduct of new performance evaluation studies and the appointment and audit by a Notified Body could take considerable time.  In addition manufacturers will have to assess, and possibly update and have audited, their quality management system.

8. To offset budget and timeline challenges posed by the new rules, how should IVD manufacturers prepare to alter clinical operations and development strategy?

Sandra White:

More devices will require clinical evidence, which includes scientific validity, performance evaluation, and analytical performance. Therefore, clinical performance studies (i.e., clinical trials) will need to be factored into development timelines and budgets.

To be efficient, however, US clinical data that is already available can move a product toward a speedier Notified Body approval in Europe. It is critical that the data is collected by investigators who are accustomed to doing clinical studies for IVD devices, and that the CRO is familiar with EU medical device regulations.  The EU regulators’ most common objection to US data is related to how representative the American subjects are of the EU patient population. Some illnesses may be reported differently, drugs and herbal medications may be reported under a different name, and even personal hygiene may differ.  Manufacturers should be prepared to justify to the Notified Bodies and regulators why the US clinical data are applicable to EU medical practice.  Manufacturers must also perform post-market follow-up that is more extensive and proactive.

In addition, ISO 13485:2016 was published on 25 February 2016 giving manufacturers up to 3 years to transition their current certification to the updated requirements. We have written up a short brief on how manufacturers should prepare.

The Medical Device and Diagnostics Research Group at ICON is available to answer questions, solve problems, and develop winning strategies from prototyping through to ensuring market penetration.

9. How will new rules for traceability and transparency affect manufacturers?

Karen Hill:

In terms of traceability, manufacturers will be required to fit their devices with a Unique Identification Number (UDI), the system for which will be implemented gradually with highest risk devices taking priority. This will involve additional updates to the manufacturer’s quality manufacturing system and internal procedures (e.g., labelling, packaging, etc.).

In terms of transparency, manufacturers of high risk devices will be required to make publicly available a safety and performance summary that will include key elements of the supporting clinical data. 

Furthermore, the European medical device database, EUDAMED, will be further developed to contain additional information, with large parts becoming publicly available.

For More Information:

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