The implementation date for the European Union’s In Vitro Diagnostic Regulation (IVDR) is a mere 16 months away, although there is widespread interest in a delayed implementation date. Nonetheless, Warren Jameson, principal regulatory consultant for North American Science Associates (NAMSA) of Toledo, Ohio, urged test makers to conduct a gap analysis of the conformity of their currently marketed tests to the new regulations because a large percentage of the underlying dossiers would not pass muster under the terms of the new regulatory regime.

The momentum for implementation of the IVDR was hardly blunted by the publication of a set of guidelines for IVD risk classification in November 2020. Perhaps predictably, industry responded with calls for delay beyond May 2022, a plea that to date has fallen on deaf ears. One of the most pressing concerns at the end of last year was that there are not enough notified bodies (NBs) that are certified to review IVD filings, but the COVID-19 pandemic has also served to distract test makers from their efforts to bring their product dossiers into compliance.

Two-year grace period for some, but no time to waste

Jameson noted that a number of IVDs will enjoy a two-year grace period beyond the 2022 deadline, adding that BSI had issued the first certificate of compliance in December 2020. According to BSI, this was the first instance of such an issuance related to a class C certificate for conformance to chapters I and III of Annex IX of the IVDR.

The new regulatory framework calls for clinical evidence for an IVD regardless of risk class, but Jameson added that some tests will be up-classified as well. There are also no grandfathering provisions for legacy tests, and the post-market surveillance requirements are substantially more demanding.

Jameson noted that up to now, roughly 80% of medium-risk IVDs have been self-declared by the sponsor, and thus there had been no inspection by any NBs. These tests also presumably have a technical dossier that might not have qualified under the existing premarket regime. He pointed out also that approximately 45,000 IVDs that currently enjoy market access in the EU will have to be recertified, a massive undertaking for the five NBs that are certified to date.

There are several reasons to delay the implementation, Jameson said. “The fact is that you’ve had a global pandemic that has put a lot of pressure on manufacturers” to keep up with test development for SARS-CoV-2 virus. “Unless there is a massive increase in NBs over the next six months, I don’t see how the [European] Commission (EC) can’t override this,” he continued. The uncertainty has not been eased by the fact that the EC has been tightlipped about its views on an extension, leaving test developers in limbo.

Jameson urged test developers to conduct a gap analysis on the dossiers for their IVDs as quickly as possible, in order to gain a clear understanding of the work they need to do to qualify those tests under the new framework. “I would advocate that people be really hard on their devices” in that gap analysis, in part because an exhaustive review would suppress the chances that an NB would kick back the application to the applicants and extend the time of return to market for that test, he said. There are hazards for any test in this premarket review, but Jameson noted that a widely used test might expose the manufacturer to additional problems with obtaining regulatory approval.

Legacy IVDs may have been reviewed via protocols that are not be up to date, and Jameson emphasized more than once that date of regulatory implementation is the deciding issue on this point, not the date of that test’s market entry. Another possible snag for legacy tests is that the diagnostic state of the art may have changed, raising questions as to whether the test is still relevant.

Off-label use a potential tripwire

The manufacturer need not have changed the label’s intended use statement to encounter drag in a regulatory filing. Jameson said that if users of a test have discovered that the test’s analyte can be used for off-label use, the developer might have a few questions to answer when filing a dossier. This is another question the developer should attempt to answer as quickly as possible to ward off any unanticipated regulatory issues.

On the question of how much clinical evidence is needed for a test, Jameson said this is largely determined by intended purpose, which is distinct from intended use. The new regulatory framework leaves it up to the manufacturer/developer to determine this because the language of the IVDR is not prescriptive about the type and volume of clinical evidence. However, the test’s risk category is somewhat of a determinant.

Jameson noted that there are some persistent concerns about the availability of class D (high-risk) tests thanks to delays in standing up the reference labs needed to validate these tests. He noted that reference labs are not being built and equipped per plans that were put together before the pandemic, a question referenced by MedTech Europe in November 2020.

Jameson advocated that test developers move toward the new IVDR framework as rapidly as possible rather than stay with the existing framework, even though the latter is less demanding. While it’s true that the developer can self-declare under the existing framework, an IVDR-compliant technical dossier will still have the bulk, if not all, of the required content needed for the existing approach. This way, the developer can avoid a do-over of the dossier development process when the IVDR finally kicks in, whenever that may be, and save some money in the process, Jameson said.