Table 2.

Major differences in the regulation of CDx in the U.S. and in Europe (IVDR).

	U.S.—FDA	Europe—IVDR
Definition	An IVD companion diagnostic is an in vitro diagnostic device that provides essential information for the safe and effective use of a corresponding therapeutic product. The use of an IVD companion diagnostic device with a therapeutic product is stipulated in the instructions for use in the labeling of both the diagnostic device and the corresponding therapeutic product, including the labeling of any generic equivalents of the therapeutic product 30	“Companion diagnostic” means a device, which is essential for the safe and effective use of a corresponding medicinal product to: (a) identify, before, and/or during treatment, patients who are most likely to benefit from the corresponding medicinal product; or (b) identify, before, and/or during treatment, patients likely to be at increased risk of serious adverse reactions as a result of treatment. 53
Classification	In the vast majority of cases, FDA classifies CDx as Class III Medical Devices under the rationale that the risk associated with the use of the CDx is similar to the risk associated with the drug that will or will not be administered based on a CDx test. There may be cases when a Class II classification is appropriate with PMA (510(k)).	In IVDR, CDx are classified as class C IVDs under Rule 3.
Regulatory pathway for approval	Class III Medical Devices require a premarketing approval (PMA) procedure according to section 515 of the FD&C Act. Of the 44 currently FDA-approved CDx (last update: March 2021), 40 have been approved via the PMA procedure. Note: The IVD companion diagnostic device application will be reviewed and approved or cleared under the device authorities of the FD&C Act and relevant medical device regulations; the therapeutic product application will be reviewed and approved under section 505 of the FD&C Act (i.e., drug products) or section 351 of the Public Health Service Act (i.e., biological products) and relevant drug and biological product regulations, that is a PMA submission is reviewed by CDRH while a new drug application for a therapeutic is submitted and reviewed by CDER or then CBER.	According to IVDR (Annex IX, section 5.2), the conformity assessment process for CDx foresees a consultation procedure between a notified body and a medical authority. This could take place between any of the national regulatory authorities in the E.U. or the EMA, depending on who is responsible for the authorization of the corresponding medicinal product. Under the current directives, the interaction between medicines authorities, EMA, and notified bodies is limited to consultation procedures of devices that incorporate a medicinal substance. For the CDx consultation procedure itself, the notified body will seek a scientific opinion from a medical authority or EMA “on the basis of the draft summary of safety and performance and the draft instructions for use” regarding the suitability of the device to the medicinal product concerned. The timeframe for the consultation is 60 days with the possibility to extend once for another 60 days.