EU's New In Vitro Diagnostic Regulations
Much has been written recently about the European Union’s pending new medical device regulations, encouraging medical device manufacturers to begin preparing for the broad changes that may become EU law later this year. This Medical Devices Regulation (MDR) will replace both the existing Medical Devices Directive and the Active Implantable Medical Devices Directive .
A New Definition For In Vitro Diagnostic Devices
But what about that subset of medical devices that are in vitro diagnostic devices (IVDs)? A new In Vitro Diagnostic Devices Regulation (IVDR) has been proposed to replace the existing In Vitro Diagnostic Devices Directive. Useful reading on the proposed regulation can be found at Eur-Lex, an index of European Law. In this expanded regulation, IVDRs are now defined as:
a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment, software or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information:
·concerning a physiological or pathological state;
·concerning a congenital abnormality;
·concerning the predisposition to a medical condition or a disease;
·to determine the safety and compatibility with potential recipients;
·to predict treatment response or reactions;
·to define or monitor therapeutic measures.
How IVDR Will Impact Device Classification
The IVDR will substantially change the mechanism by which IVDs may bear the CE mark. For starters, a new risk-based classification scheme will replace the "general IVD" category with four new device classes: A, B, C, and D (lowest risk to highest risk, respectively). Classes B through D will require an assessment of the technical documentation by a Notified Body. This technical documentation must include three types of clinical evidence:
1.Scientific Validity: association of an analyte to a clinical condition or physiological state
2.Analytical Performance: ability of an IVD to correctly detect and measure the analyte (LOD, LOQ, accuracy, precision and reproducibility)
3.Clinical Performance: ability of the device to yield results that relate to a particular clinical condition for the intended use and in accordance with target population, and to the intended user (if applicable)
The new regulation emphasizes additional oversight of the supply chain, which includes unannounced audits of critical suppliers and subcontractors by the Notified Bodies. Additionally, the new regulation requires regulatory roles and requirements for importers, distributors, and authorized representatives. Importers are defined as any natural or legal person, established within the EU, who places a device from a third country in the European market. A distributor is defined as any natural or legal person in the supply chain, other than the manufacturer or importer, who makes the device available on the market. In some instances, the importer may also act as the distributor.
Manufacturers must have liability insurance for their products; however, it is the responsibility of the importers to verify that the insurance is adequate, or additional insurance must be taken out by the importer. The authorized representatives, in addition to the legal manufacturer, are required to designate a person responsible for regulatory compliance within their organization. This person must have the proper education and experience within the field of IVDs. Furthermore, this individual is responsible for the technical documentation, ensuring the declaration of conformity, performance evaluations, and vigilance requirements are kept up-to-date.
Additionally, the new IVDR makes special provisions for companion diagnostics. Chief among these is the requirement for a consultation with a Competent Authority after review of the technical documentation by a Notified Body. We expect there will be specific guidance issued regarding companion diagnostics following official publication of the IVDR.
Finally, the IVDR is not limited to manufacturers of CE-marked IVD kits. If you are a US-based, CLIA-licensed laboratory intending to market your in-house developed tests in the EU, you also may have some work to do, as the same classification rules and conformity assessment routes will apply to laboratory developed tests (LDTs). This will likely require full quality system compliance with an international standard and a review of the design dossier/technical documentation file by a Notified Body.
Transitionary IVDR Regulation
The IVDR is a law proposed by the European Commission and agreed upon by the European Parliament and Council. Upon adoption, the regulation immediately enters into force in all the member states. This means there is no transposition into Member State law.
The current draft regulation provides for a five-year transitionary period and full implementation by 2021. During the transitionary period, manufacturers can choose to place products on the market under the existing directive, or to comply with the new regulation. It is unclear whether any additional guidance regarding self-declared products will be placed on the market before the full implementation date, so it is possible that manufacturers may continue to release self-declared IVDs through the day before implementation, and keep them on the market until they expire.
According to BSI, products issued a certificate from a Notified Body during the transition period may remain on the market for two years after the implementation date, or five years from issue, whichever is earlier. It currently is unclear whether there will be any additional restrictions placed on self-declared products that require a certificate issued by a Notified Body under the new regulation.
How To Prepare
In light of murky regulatory waters ahead, we recommend that manufacturers take the following steps in anticipation of this new regulation becoming law:
·Classify your IVD device according to the new classification rules.
·Perform a gap analysis of your existing technical documentation.
·Identify your crucial suppliers and critical subcontractors and augment your existing supplier quality controls.
·Evaluate your existing clinical evidence and plan for additional studies.
The IVDR will fundamentally change the way IVDs are regulated in the EU. Whereas currently only 10-20 percent of diagnostics currently require review by a Notified Body, the new IVDR will require regulatory oversight for 80-90 percent of all IVDs that are self-certified under the existing Directive. Mapping out your path ahead of time, including preparing to be flexible, will equip you to respond to this new paradigm.