. 2020 Apr 11;7(1):lsaa002. doi: 10.1093/jlb/lsaa002

Table 2.

A comparison of basic aspects between the USA and EU regulatory approach to MML in selected key domains.

Regulatory approaches to MAI/MML devices	USA	Europe
Medical device definition	‘An instrument, apparatus, implement, machine […] which is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease’ that does not achieve its ‘primary intended purposes through chemical action within or on the body of man’ and which is ‘not dependent upon being metabolized for the achievement of’ its primary intended purposes (201(h) of the FD&C Act)	‘Any instrument, apparatus, appliance, software, implant, reagent, material, or other article’ intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes: Diagnosis, prevention, monitoring, prediction, prognosis, treatment, or alleviation of disease Diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability Investigation, replacement, or modification of the anatomy or of a physiological or pathological process or state Providing information by means of in vitro examination of specimens derived from the human body, including organ, blood, and tissue donations,
		and which does not achieve its principal intended action by pharmacological, immunological, or metabolic means, in or on the human body, but which may be assisted in its function by such means. […]” (MDR, Art. 2(1))
Classification of medical devices	Three classes based on their risk profile, intended use, indications for use, technological characteristics, and the regulatory controls necessary to provide a reasonable assurance of safety and effectiveness:	Four classes of medical devices, taking into account risks associated with their manufacture and technical design:
	Class I, Class II, and Class III	Class I, Class IIa, Class IIb, and Class III
Distinctions between diagnostic, monitoring, and predictive diagnostic software	• Software in a medical device	‘Software’, which drives a device or influences the use of a device, shall fall within the same class as the device
	➔ Software used to ‘drive or control’ the medical device hardware	If the software is independent of any other device, it shall be classified in its own right” (MDR, Section 3.3. of Chapter II of Annex VIII)
	➔ Software required by a hardware medical device to perform the hardware’s medical device intended use, even if sold separately from the hardware medical device	‘Software’ intended to provide information which is used to take decisions with diagnosis or therapeutic purposes is classified as Class IIa, except if such decisions have an impact that may cause:
	• Software as a medical device	—death or an irreversible deterioration of a person’s state of health, in which case it is in Class III; or,
	➔ software intended to be used for one or more medical purposes that perform these purposes without being part of a hardware medical device	—a serious deterioration of a person’s state of health or a surgical intervention, in which case it is classified as Class IIb
	• Not all software is classified as a ‘medical device’ under the FD&C Act. Non-device software functions include:	Software intended to monitor physiological processes is classified as Class IIa, except if it is intended for monitoring of vital physiological parameters, where the nature of variations of those parameters is such that it could result in immediate danger to the patient, in which case it is classified as Class IIb
	a) Software functions that are intended ‘for administrative support of a healthcare facility’	All other software is classified as Class I” (MDR, Section 6.3 of Chapter III of Annex VIII (Rule 11))
	b) Software function that are intended ‘for maintaining or encouraging a healthy lifestyle’	• Rule 11 MDR does not explicitly mention or refer to the new terminology ‘prediction’ and ‘prognosis’ of disease in Art. 2
	c) Software functions that are intended ‘to serve as electronic patient records’	• However, the concept of ‘prediction’ and ‘prognosis’ of a disease might be embedded into the formulation: ‘Software intended to provide information […] used to take decisions with diagnosis or therapeutic purposes’
	d) Software function that are intended ‘for transferring, storing, converting formats, or displaying clinical laboratory test or other device data and results’, and	• Most MML-based medical devices will be classified as Class IIa (even if the monitoring is not intended for diagnosis or therapeutic purposes) or Class IIb if the MML SaMD monitors vital physiological parameters (eg heart rate, blood pressure respiration)
	e) Certain clinical decision support software functions (FD&C Act, Sec. 520(o))
Post-marketing surveillance (PMS)	• CGMP and QS requirements (21 CFR Part 820)	Post-market surveillance:
	• Medical device reporting requirements (21 CFR Part 803)	‘All activities carried out by manufacturers in cooperation with other economic operators to institute and keep up to date a systematic procedure to proactively collect and review experience gained from devices they place on the market, make available on the market or put into service for the purpose of identifying any need to immediately apply any necessary corrective or preventive actions’ (Art. 2 (60) MDR)
	• Recalls, corrections, and removal (21 CFR 7, 21 CFR 806, 21 CFR 810)	• Post-market surveillance system (MDR, Art. 83)
	• Medical device tracking	➔ For all devices
	➔ For certain Class II and Class III devices (21 CFR Part 821)	• Post-market surveillance plan (MDR, Art. 84)
	• Post-market surveillance studies	• Post-market surveillance report (MDR, Art. 85)
	➔ Certain Class II and Class III devices (FD&C Act, Sec. 522)	➔ For Class I devices
	• Post-approval studies	• Periodic safety update reports (PSUR) (MDR, Art. 86 MDR)
	➔ For certain devices	➔ For Class IIa, Class IIb, and Class III devices
	• Third-party inspections
Implementation of the relevant regulations and assessment of medical devices	FDA	• EMA is not the primary regulator for medical devices
		• Medical devices are regulated by the Member States and by national competent authorities appointed by the Member States
		• Member States can designate independent accredited ‘notified bodies’ to conduct the required conformity assessments
		The national competent authorities are responsible for monitoring notified bodies
MAI/MML specific initiatives and regulatory guidelines	FDA’s discussion paper on AI/ML-based SaMD⁴⁸	Lack of specific guidelines on the use of MAI/MML devices. The focus is laid on the development of enabling infrastructures. This might change in the future when the MDR becomes effective on 26 May 2020