Please review the language below related to EU Drug Device Combinations in the EU and U.S. Combination Products. Please present your observations and comments regarding the differences and similarities (as well as potential advantages/disadvantages)

Article117

Amendment to Directive2001/83/EC

In AnnexI to Directive2001/83/EC, point 12 of Section3.2. is replaced by the following:

'(12)

Where, in accordance with the second subparagraphof Article1(8) or the second subparagraphof Article1(9) of Regulation(EU)2017/745 of the European Parliament and of the Council(*1)Links to an external site., a product is governed by this Directive, the marketing authorisation dossier shall include, where available, the results of the assessment of the conformity of the device part with the relevant general safety and performance requirements set out in AnnexI to that Regulation contained in the manufacturer's EU declaration of conformity or the relevant certificate issued by a notified body allowing the manufacturer to affix a CEmarking to the medical device. If the dossier does not include the results of the conformity assessment referred to in the first subparagraphand where for the conformity assessment of the device, if used separately, the involvement of a notified body is required in accordance with Regulation(EU)2017/745, the authority shall require the applicant to provide an opinion on the conformity of the device part with the relevant general safety and performance requirements set out in AnnexI to that Regulation issued by a notified body designated in accordance with that Regulation for the type of device in question.

U.S. Combination Products

Combination products are defined in 21 CFR 3.2(e). The term combination product includes:

(1) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity;

(2) Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;

(3) A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or

(4) Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.

Primary Mode of Action (U.S.)

Combination products are assigned to a FDA center that will have primary jurisdiction for its premarket review and regulation. Consistent with section 503(g)(1) of the Act, assignment to a center with primary jurisdiction for premarket review and post-market regulation, or a lead center, is based on a determination of the "primary mode of action" (PMOA) of the combination product. For example, if the PMOA of a device-biological combination product is attributable to the biological product, the Agency component responsible for premarket review of that biological product would have primary jurisdiction for the combination product.

Section 503(g) defines primary mode of action as "the single mode of action of a combination product that provides the most important therapeutic action of the combination product" (see also definitions at 21 CFR 3.2Links to an external site.. In some cases, the most important therapeutic action cannot be determined. For example, a combination product may have two independent modes of action, neither of which is subordinate to the other. To resolve these types of questions, FDA's regulations at 21 CFR Part 3Links to an external site.include an algorithm for determining center assignment. The algorithm directs center assignment based on which center regulates combination products raising similar types of safety and effectiveness questions, or, if there is no such center, based on which center has the most expertise to evaluate the most significant safety and effectiveness questions raised by the combination product. References:

https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32017R0745&from=EN#ntr*1-L_2017117EN.01000101-E0038

https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-3/subpart-A/section-3.2

https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-3