The regulations concerning Medical Devices (MD) and In Vitro Diagnostic Medical Devices (IVDMD) are intended to protect the patient, the user or any other person against the risks associated with their design, manufacture, packaging and use. Such regulations differ across countries, but all use a risk-based approach.
MSF purchases medical devices mainly from the European Union and from the United States.

DEFINITIONS

The following definitions are taken from the EU legislation, but the ones of the US Food and Drug Administration (US FDA) are not significantly different.

Medical Devices according to the MDR 2017/745

‘medical device’ means 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.

The following products shall also be deemed to be medical devices:

• devices for the control or support of conception;
• products specifically intended for the cleaning, disinfection or sterilisation of devices.

‘accessory for a medical device’ means an article which, whilst not being itself a medical device, is intended by its manufacturer to be used together with one or several particular medical device(s)

‘custom-made device’ means any device specifically made in accordance with a written prescription of any person authorised by national law by virtue of that person’s professional qualifications which gives, under that person’s responsibility, specific design characteristics, and is intended for the sole use of a particular patient exclusively to meet their individual conditions and needs.

‘active device’ means any device, the operation of which depends on a source of energy other than that generated by the human body for that purpose, or by gravity, and which acts by changing the density of or converting that energy. Software shall also be deemed to be an active device.
‘implantable device’ means any device, including those that are partially or wholly absorbed, by clinical intervention and which is intended to remain in place after the procedure (for at least 30 days).

‘invasive device’ means any device which, in whole or in part, penetrates inside the body, either through a body orifice or through the surface of the body.

‘single-use device’ means a device that is intended to be used on one individual during a single procedure

In Vitro Diagnostic Medical Devices according to the IVDR 2017/746

‘in vitro diagnostic medical device’ means any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, piece of 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 on one or more of the following:

• concerning a physiological or pathological process or state;
• concerning congenital physical or mental impairments;
• 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 monitoring therapeutic measures.

Specimen receptacles shall also be deemed to be in vitro diagnostic medical devices.

‘specimen receptacle’ means a device, whether of a vacuum-type or not, specifically intended by its manufacturer for the primary containment and preservation of specimens derived from the human body for the purpose of in vitro diagnostic examination.

‘accessory for an in vitro diagnostic medical device’ means an article which, whilst not being itself an in vitro diagnostic medical device, is intended by its manufacturer to be used together with one or several particular in vitro diagnostic medical device(s).

‘device for self-testing’ means any device intended by the manufacturer to be used by lay persons, including devices used for testing services offered to lay persons by means of information society services.

‘device for near-patient testing’ means any device that is not intended for self-testing but is intended to perform testing outside a laboratory environment, generally near to, or at the side of, the patient by a health professional.

Products for general laboratory use are not in vitro diagnostic medical devices, unless such products, in view of their characteristics, are specifically intended by their manufacturer to be used for in vitro diagnostic examinations.

REGULATORY PATHWAY

The market authorization systems for medical devices in the US and EU are different but the basic concept of the legislation is similar. In both systems, the effort to obtain market authorization increases with the perceived risk of a device.

Safety and performance of MDs are assessed through a balance of pre-market scrutiny, adequate manufacturer quality management systems, and the implementation of effective post-market surveillance. The assessment body typically follows rules for this evaluation (in the form of laws, regulations, guidance, standards from internationally recognized organizations, or other documents) that address the specific information that is needed for a given product, typically based on the risk that the product poses to the end-users and/or patient. It then assesses the documentation to determine if it conforms to the rule or standards it follows. This activity is sometimes referred to as conformity assessment.

A common framework for medical device regulations

LEGISLATION

In the EU

The Medical Devices Directive (MDD) 93/42/EEC and the Active Implantable Medical Devices Directive (AIMDD) 90/385/EEC were introduced in early 1992. These directives were repealed by the Medical Devices Regulation (MDR) 2017/745, formally published in May 2017.
Directive 98/79/EC constitutes the Union regulatory framework for in vitro diagnostic medical devices. However, a fundamental revision of that Directive was needed to bring EU legislation into line with technical advances, changes in medical science and progress in law-making. It was repealed in April 2017 by the IVD Regulation 2017/746.

The transition periods Directive to Regulation were 3 years for the medical devices and 5 years for the IVD, starting from May 2017, but the Covid pandemic slowed down these transitions.

According to the applicable Directive / Regulation, a manufacturer must, prior to marketing its MD/IVD, fulfill four requirements:

• Assign the MD/IVD to a category of products (see Classification chapter below).
• Ensure that the MD/IVD meets defined “Essential Requirements”
• Follow the conformity assessment procedure corresponding to the type of device.
• Depending on the category of the device, ensure that an independent certification body, called a “Notified Body,” is involved in the conformity assessment procedure.

Notified bodies:

A Notified Body is an organization designated by an EU country to assess the conformity of certain products before they are placed on the market. These bodies perform tasks related to conformity assessment procedures defined in the applicable legislation, where a third party is required.
The MDR strengthens the rules for the surveillance of Notified Bodies.
The authorities responsible for Notified Bodies must reassess their compliance with the requirements of the new European Medical Device Regulation (MDR) at least once a year. They must carry out a full reassessment three years after the first notification and then every four years.
The MDR strengthens the position of Notified Bodies vis-à-vis manufacturers by introducing the obligation to perform unannounced on-site audits and to perform physical or laboratory testing of devices to ensure continued compliance.
Notified Bodies:

• Are free to offer their conformity assessment services to any economic operator inside or outside the EU
• Must operate in a non-discriminatory, transparent, neutral, independent, and impartial manner
• Must employ the necessary personnel, with sufficient knowledge and experience to carry out the conformity assessment in accordance with the law(s) in question
• Must make adequate arrangements to ensure the confidentiality of the information obtained in the course of conformity assessment
• Must provide information to their notifying authority, the market surveillance authorities, and other notified bodies.

Manufacturers are free to choose any notified body that has been legally designated to carry out the conformity assessment procedure.
The competence of the notified body should be subject to verification carried out at regular intervals and following the practice established by the accreditation organisations.
Lists of Notified Bodies can be found on the NANDO website (New Approach Notified and Designated Organisations). The lists include the identification number of each notified body and the tasks for which it has been notified.

CE marking

The CE marking is a certification mark that indicates conformity with health, safety, and environmental protection standards for products sold within the European Economic Area. It is mandatory to be affixed on a medical device before being placed on the European market, but this does not necessarily mean that the MD is marketed in the EU. Sometimes manufacturers get a CE marking in order to facilitate the registration of their product(s) on other non-EU markets (e.g. Africa or Middle-East).

• If the CE marking is reduced or enlarged the proportions given in the graduated drawing must be respected.
• The various components of the CE marking must have substantially the same vertical dimension, which may not be less than 5 mm;
• The C and E are not formed by perfect semi-circles, i.e. the top and bottom arms extend one square beyond the semi-circles, and the middle arm of the E stops one square short.

Registration of medical devices

The European legislation does not require registration of the medical devices with the each European authority, except for class I medical devices, custom-made and kits (procedure packs) and IVD. For this type of products, the manufacturers or their European representatives have to register the products in the countries where they have the registered offices. Few other European Authorities require class II and III medical devices be registered as well before being placed on the local market. This is the case with France, Italy, Germany, Portugal, Latvia, and Bulgaria.

Eudamed – European Databank on Medical Devices

Eudamed is the IT system developed by the European Commission to implement Regulation (EU) 2017/745 on medical devices and Regulation (EU) 2017/746 on in-vitro diagnostic medical devices.

Eudamed will include 6 interconnected modules, they will become available on a gradual basis as soon as they are functional. It is envisaged that all the modules Eudamed and the audit of the system will be completed before Q1 2023

• Actor registration (voluntary module now available)
• UDI/device registration (voluntary module now available)
• Notified bodies and certificates (voluntary module now available)
• Clinical investigations and performance studies (Q4 2022)
• Vigilance and post-market surveillance (Q4 2022)
• Market surveillance (Q4 May 2022)

In the US

The US FDA allows for two regulatory pathways that allow the marketing of medical devices.
The first and by far the most common is the so-called 510(k) process. A new medical device that can be demonstrated to be “substantially equivalent” to a previously legally marketed device can be “cleared” by the FDA for marketing as long as the general and special controls, as described below, are met. The vast majority of new medical devices (99%) enter the marketplace via this process. The 510(k) pathway rarely requires clinical trials.
The second regulatory pathway for new medical devices is the Premarket Approval process, which is similar to the pathway for a new drug approval. Typically, clinical trials are required for this premarket approval pathway.
The FDA may also issue export certificates for unapproved products in the United States, but manufactured within their territory, which have therefore no quality value.

Main differences

• In the USA, the market authorization is granted by a governmental agency, whereas in Europe this responsibility has been delegated to designated third-party companies, so called Notified Bodies.
• The large variation in time to the market in Europe and the USA, mainly for the highest risk devices, appears to be due to the stricter requirement to perform more elaborate clinical studies for medical devices going through the PreMarket Approval (PMA) procedure in the USA.
• There is no explicit requirement for post market surveillance in the USA legislation, although the FDA can require this for specific devices.
• The essential requirements for products are well described in the EU legislation, whereas this is less clear in the USA.
• The FDA makes most information on medical devices, related to market authorization and post-market activities publicly available, whereas such transparency does not exist in Europe.

Mutual recognition

The CE mark has no official status in the USA and an FDA-approved device has no official status in Europe.
Mutual Recognition Agreements are in place between Australia and the European Union, Memoranda of Understanding with both Canada and Switzerland, and other agreements with countries such as Japan, China, and Malaysia. FDA and regulatory agencies in Australia, Brazil, Canada, and Japan put in place the Medical Device Single Audit Program (MDSAP) with the goal to develop a process that allows a single audit to ensure the medical device regulatory requirements for all five countries are satisfied. The FDA will accept MDSAP audits as a substitute for routine FDA inspections, typically done every two years for all classes of medical devices and including in vitro diagnostic devices.

CLASSIFICATION OF MEDICAL DEVICES

In the EU

In Europe, medical devices are assigned to one of four regulatory classes: Class I (with subclasses sterile, and measuring function), IIa, IIb and III. The classification of a device is governed by classification rules, described in the MDD or MDR.
There are rules for medical device classification based on factors such as:

• Intended use of the device: means the use for which the device is intended according to the data supplied by the manufacturer on the labelling, in the instructions and/or in promotional materials (not the particular technical characteristics of the device, not the accidental use of the device, not the class assigned to other similar products)
• Device’s duration of contact with the patient for normal use:
• Continuous: uninterrupted
• Transient: less than 60 minutes
• Short term: not more than 30 days
• Long term: more than 30 days.
• Degree of invasiveness: Invasive device = a device which, in whole or in part, penetrates inside the body, either through a body orifice (any natural opening in the body, as well as the external surface of the eyeball, or any permanent artificial opening, such as a stoma) or through the surface of the body.
• Surgically invasive device: an invasive device which penetrates inside the body through the surface of the body, with the aid of or in the context of a surgical operation. A surgically invasive device always implies that it enters through an artificially created opening. This can be a large opening, such as a surgical incision, or it can be a pinprick opening created by a needle
• Part of body contacted by the device: higher classes are attributed to devices directly in contact with the heart or central nervous system or certain parts of the circulatory system.
• If a given device can be classified according to several rules, then the highest possible class applies
• If the device is not intended to be used solely or principally in a specific part of the body, it must be considered and classified on the basis of the most critical specified use.

Classification remains essentially the same under the MDR.

• Rule 6 keeps the reusable surgical instruments in Class I but at the same time involvement of a NB is required: Class Ir.
• Surgical meshes are Class III
• New rule for classification of software: they can fall under any risk class, Class I is the exception
• Rule 20 places devices intended for inhalation of medicinal substances in risk Classes IIa or IIb
• Rule 22 places active therapeutic devices with an integrated diagnostic function, which provides data on patient management in Class III (e.g., automated external defibrillators).

In the US

Under the Food, Drug, and Cosmetic Act, the U.S. Food and Drug Administration (USFDA) recognizes three classes of medical devices, based on the level of control necessary to assure safety and effectiveness. The classification procedures are described in the Code of Federal Regulations, Title 21, part 860 (usually known as 21 CFR 860).
In the USA legislation, no explicit rules about the classification could be identified. Device types and specific devices have been assigned by the FDA to one of these three risk classes. FDA has organized 18 medical specialty panels, in which over 1700 distinct types of devices are described. For each of these type of devices, a general description including intended use, the class to which the device belongs and information about marketing requirements are specified. For a completely new device, the risk class cannot be established from these lists and the FDA will have to be contacted to establish the risk class.

• Class I: Devices not purported to be for a use, which is of substantial importance in supporting, sustaining or preventing impairment of human life or health, and the devices do not present a potential unreasonable risk of illness or injury.
• Class II: Devices for which it is necessary to establish a performance standard, in order to provide reasonable assurance of safety and effectiveness.
• Class III: Devices for which insufficient information is available to establish a performance standard. The devices are purported to be for a use which is of substantial importance in supporting, sustaining or preventing impairment of human life or health, or the devices present a potential unreasonable risk of illness or injury.

CLASSIFICATION OF IVDs

In regards to the classification of in-vitro medical devices, the Directive 98/79/EC groups IVDs into four categories according to the perceived risk associated with the relative danger to public health and/or patient treatment by an IVD failing to perform as intended.

1. List A: for determining the blood groups: ABO system, rhesus (C, c, D, E, e) anti-Kell or for the detection, confirmation and quantification in human specimens of markers of HIV infection (HIV 1 and 2), HTLV I and II, and hepatitis B, C and D
2. List B: device for self-diagnosis: for the measurement of blood sugar
3. IVDs for self-testing: Pregnancy RDT
4. General IVDs: (Non A / non B): any IVD not identified in Annex II List A or List B or for self-testing

• Tropical diseases: Malaria RDT, Cholera RDT, Cryptococcus RDT, Leishmaniasis RDT, Dengue RDT, Meningitis RDT, Trypanosoma RDT
• Non tropical disease: Syphilis RDT, Rotavirus test, Adenovirus test, Biochemistry Urine strips

In the new classification system, IVDs will be divided into four classes of risk: A (lowest risk), B, C and D (highest risk).

Class Risk level Examples

Under the current IVD directive 10-15% IVD’s require Notified Body assessment but under the new Regulation 85-90% will require Notified Body assessment.
FDA classifies IVD products into Class I, II, or III according to the level of regulatory control that is necessary to assure safety and effectiveness. The classification of an IVD (or other medical device) determines the appropriate premarket process.

QUALITY MANAGEMENT SYSTEM (QMS) FOR MEDICAL MATERIAL

Harmonized standard

European Directives & Regulations related to medical devices set out the “essential requirements” which must be met by the manufacturers in order to have the authorization to affix the CE marking.

The technical specifications to be complied with in order to meet the essential requirements of a directive are referred to as “harmonised standards”. Compliance with harmonised standards applicable to medical devices will provide a presumption of conformity with the essential requirements of the above-mentioned Directives.

US FDA published guidance for industry on the recognition and use of national and international consensus standards
Some standards are transversal or horizontal and cover many categories of medical devices such as EN ISO 10993 series on Biological evaluation of medical devices or EN ISO 11607 series on Packaging for terminally sterilized medical devices. Others are specific to a type of product called vertical standards such as EN ISO 4074 on Natural latex rubber condoms - Requirements and test methods or EN 455-1 on Medical gloves for single use.

ISO standards

ISO, the International Organization for Standardization develops and publishes International Standards: documents that provide requirements, specifications, guidelines or characteristics that can be used consistently to ensure that materials, products, processes and services are fit for their purpose. Regulators and governments count on ISO standards to help develop better regulation, knowing they have a sound basis.

ISO 13485 – Medical devices Quality management systems: is an internationally agreed standard that sets out the requirements for a quality management system specific to the medical devices industry. It is designed to be used by organizations throughout the life cycle of a medical device, from initial conception to production and post-production, including final decommission and disposal. It also covers aspects such as storage, distribution, installation and servicing, and the provision of associated services.

ISO 13485:2016 responds to the latest QMS practices, reflecting the evolution in medical device technology and changes in regulatory requirements and expectations. This ensures that the standard remains compatible with other management system standards, including the new edition of ISO 9001.

Standards used in the US

All medical device manufacturers supplying medical devices to the U.S. are required to maintain a quality management system in compliance with the Code of Federal Regulations (CFR) Title 21, otherwise known as 21 CFR 820. The quality management system requirements cover a broad range of areas, including production and process controls, corrective and preventive actions, product development and management.

ASTM International, formerly known as American Society for Testing and Materials, is an international standards organization that develops and publishes voluntary consensus technical standards for a wide range of materials, products, systems, and services. ASTM International has no role in requiring or enforcing compliance with its standards. In the United States, ASTM standards have been adopted, by incorporation or by reference, in many federal, state, and municipal government regulations. The National Technology Transfer and Advancement Act, passed in 1995, requires the federal government to use privately developed consensus standards whenever possible. The Act reflects what had long been recommended as best practice within the federal government.

The U.S. Pharmacopeial Convention (USP) is a scientific, nonprofit organization that sets standards for the identity, strength, purity, and quality of food ingredients, medicines, medical materials and dietary supplements manufactured, distributed and consumed worldwide. Their standards are enforceable in the United States by the Food and Drug Administration (FDA), and they are also used in more than 140 countries.