Medical devices containing human cells or tissues/SoHO

Medical device (MD) is the other great category of health products aside from medicinal products. Greatly diverse (from dressing to hip prosthesis, from glasses to heart valve), they mainly differ from the latter by their mode of action which must not be pharmacological, immunological or metabolical (Article 2(1) of the Regulation on medical devices). Their definition is framed in opposition to that of medicinal products. But, more than different in nature, those two types of health products are distinguished by the legal frameworks that apply to them. When medicinal products need a marketing authorisation granted whether by a national competent authority, or directly by the European Commission after the European Medicines Agency (EMA) delivered a scientific opinion within the centralised procedure, the situation is different for medical devices. Indeed, to make a medical device available on the market, they have to be certified. Such certification procedure must be carried out not before a national or supranational authority, but before a Notified Body (NB), or can be carried out by the manufacturer itself through an auto-certification for the lowest-risk medical devices.

However, the distinction between medicines and medical devices can sometimes be complex, and certain products so-called “borderline” require greater attention and consideration. This is particularly the case with medical devices manufactured from cells or tissues of human or animal origin.

This entry will focus on the commercialisation of medical devices manufactured utilising tissues or cells of human origin. It will not address the aspects related to national legislations such as reimbursement, prescription or advertising.

The first challenge regarding medical devices manufactured using tissues and cells of human or animal origin is to identify the legal framework applicable (medical device or in vitro diagnostic medical device regulation, ATMPs, SoHO). In particular, the association, whether external or integrated, between the medical device and the cells and tissues, the (non-)viability of these cells and tissues, and the ancillary or principal character of their action regarding the overall action of the medical device are crucial when determining the main legislation applicable.

Identifying the main legislation applicable is even more challenging when it comes to “borderline” products. These products even put to the test the committees or bodies responsible for assigning the legal category necessary to identify the applicable rules.

More generally, the interplay between the different applicable regulations (Regulation on medical devices, on in vitro diagnostic medical devices, on ATMPs and animal by-products or derivatives or SoHO) may be complex and source of confusion. Indeed, the identifying a product as a medical device, and thereby designating the Regulation on medical devices as the main applicable, does not prevent other regulations from applying to certain stages of the medical device development cycle. This is particularly true for medical devices manufactured using tissues and cells of human or animal origin.

Moreover, when the Regulation on medical devices is undoubtably applicable, it still may be difficult to determine which class should be assigned to the medical device, consequently which specific rules are applicable.

Medical devices using tissues of human or animal origin are generally considered as innovative medical devices and of higher risks. Then, demonstrating their conformity with the general safety and performance requirements may be more complex.

Indeed, a large part of the certification procedure is usually based on the state of the art and comparison with devices already certified; But in most cases such comparison is not possible for innovative medical devices. Those would then need a clinical investigation in order to produce new data demonstrating their safety and performance.

Finally, the medical device certificate of conformity can also be obtained through the certification procedure based on the equivalence with a medical device already available on the market (see Practical steps). In this case, the Regulation (EU) 2017/745 requires the manufacturer willing to demonstrate the equivalence with a medical device already on the market but manufactured by another company, to “have sufficient levels of access to the data relating to devices with which [it is] claiming equivalence in order to justify [its] claims of equivalence” Annex XIV Part A, 3. of the Regulation (EU) 2017/745). To this end, a contract has to be concluded between the two manufacturers: the manufacturer of the first device must give its explicit consent to the manufacturer of the second device to have full access to the technical documentation of the first device on an ongoing basis. (Article 61.5 of the Regulation (EU) 2017/745)

Use of harmonised standards

The European legislative framework allows manufacturers to rely on already existing harmonised standards to demonstrate the conformity of their medical devices with the general safety and performance requirements. Where the Regulation on medical devices sets the requirements in terms of safety and performance, the harmonised standards provide methods and technical specifications to comply with those requirements. Even if those standards are not legally binding, following them is an advantage for manufacturers as implementing them leads to a presumption of compliance with the legal requirements. In other words, the conformity assessment will mainly consist in proving the compliance with the harmonised standards instead of with each regulatory requirement.

Support for identification of applicable legal frameworks

As mentioned above, one of the difficulties of medical devices utilising substances of human or animal origin is to identify their applicable legal rules. This is why the Medical Device Coordination Group issued a series of guidance documents aiming at helping to clarify the legal status of medical devices, especially borderline medical devices. (see Borderline and Classification guidance of the MDCG)

The MDCG is also the place for Member States and the European Commission, as well as stakeholders, to cooperate on those specific qualification issues, especially through the dedicated MDCG Borderline and classification working group.

Advisory role for new expert panels

The Regulation on medical devices has established new expert panels, which members are appointed by the European Commission, in consultation with the MDCG (Article 106(1) and 106(2) of the Regulation on medical devices). The EMA also provides support to these expert panels (Article 30 of the Regulation (EU) 2022/123). 

Their role is essentially advisory at the request of the Commission and the MDCG, the Member States, the notified bodies or the manufacturers (Article 106(10) of the Regulation on medical devices). Indeed, for “High risk” medical devices (all class III and class IIb devices), the manufacturer has the possibility to consult those expert panels for opinion before proceeding to a clinical evaluation or conducting a clinical investigation (Article 61(2) of the Regulation on medical devices). Notified bodies are also required to consult the expert panels during the evaluation process of implantable class III medical devices and class IIb active devices intended to administer and/or remove a medicinal product (Article 54(1) of the Regulation on medical devices).

More information on Expert panels can be found on the European Commission Website, as well as on the EMA Website, where the panels’ opinions are made available.

EMA’s support for medical devices

In the context of the new responsibility entrusted to the  EMA by the Regulation on medical devices, two EMA activities are directly supporting medical devices’ development. 

First, the EMA launched in August 2024 a new pilot program to support the development and assessment of orphan medical devices in the EU, meaning those targeting rare diseases affecting fewer than 12,000 people annually. The program offers expert panel advice to manufacturers and notified bodies, focusing on clinical strategy and conformity assessment. It provides free guidance, particularly for small and medium-sized enterprises, and runs alongside existing initiatives to support high-risk medical devices.

The MDCG has also adopted guidance on the clinical evaluation of orphan medical devices.

Second, the EMA will launch a pilot programme for breakthrough medical devices in 2026. This programme will allow medical devices with a breakthrough designation to access enhanced regulatory support and priority scientific advice from EMA's medical device expert panels. This programme is implementing the Medical Device Coordination Group’s Guidance on Breakthrough Devices (BtX) under Regulations 2017/745 & 2017/746.

Preparing the evidence for health technology assessment and reimbursement decisions

In the context of the adoption of the Regulation (EU) 2021/2282 on health technology assessment, some high risk medical devices will be subject to a Joint clinical assessment (JCA). Those medical devices will indeed undergo a JCA under three conditions (Article 1(1)(c) of the Regulation (EU) 2021/2282):

• They are class IIb or class III
• They have been subject to scientific opinion from the expert panels mentioned above
• They have been selected by the European Commission after consulting the Member State Coordination Group on HTA (HTACG), based on the unmet medical needs they could meet, on their risk, their innovative dimension (“first in class”), their cross-border dimension and/or on their potential impact for patients or in terms of public health (Article 7(4) of the Regulation (EU) 2021/2282).

But this regulation also allows developers of medical devices likely to be the subject of JCA to seek advice from the HTACG. This procedure is called Joint Scientific Consultation (JCS). The exchange with the subgroup designated by the HTACG aims to help medical devices developers with their development plans, especially regarding their clinical evaluation and investigation to be planned (Article 16(1) and article 18(1) of the Regulation (EU) 2021/2282). See Briefing document template for HTA-only JSC of medical devices.

• The submission of a request is done through a dedicated platform (“IT platform”) set up by the article 30 of the Regulation (EU) 2021/2282 (Article 3(1) of the Commission Implementing Regulation (EU) 2025/117).
• The JSC can also be requested in parallel with the scientific advice from the expert panels mentioned above (Article 16(5) and article 17(2) of the Regulation (EU) 2021/2282). See Briefing document template for parallel HTACG/Expert Panels JSC for medical devices.

Those exchange with the HTACG may be an opportunity for manufacturers to gather information on the needed evidence for a future health technology assessment for reimbursement purpose at national level.

Combined studies for medicinal products and medical devices: the COMBINE Project

It should be mentioned that the European Commission has launched in June 2023 the COMBINE project aiming to streamline the regulation of combined studies involving medicinal products, medical devices, and IVDs in the EU. Its objectives are to identify regulatory challenges, to map the regulatory landscape, assess existing guidance, and proposes solutions to improve coordination between the Clinical Trials Regulation (CTR), Medical Devices Regulation (MDR), and In Vitro Diagnostic Regulation (IVDR). The goal is to reduce delays, simplify procedures, and make the EU more attractive for conducting combined studies while ensuring patient safety and regulatory compliance. The results and deliverables of the COMBINE project are to be particularly interesting for sponsors of clinical investigations and manufacturers. 

. Determination of the product nature
 

1 Article 2(1)(d) of the Regulation (EC) No 1394/2007 on ATMPs
2 Article 1(10) §1 of the Regulation on medical devices

2. Determination of the medical device class

The regulation on medical devices is structured around a classification of medical devices based on the risks, from devices of lesser risk, class I, to devices of higher risk, class III. The higher the class, and thus the risk, the stricter are the requirements to place them in the market.

A device’s classification is hence crucial as it will determine the applicable requirements.

3. Identification and selection of the conformity assessment procedure 

In order to put a CE marking on a medical device, as required to place it on the market (Article 20 of the Regulation on medical devices), a medical device must undergo one of the conformity assessment procedures (Article 52 of the Regulation on medical devices). This assessment is performed by a Notified body for all medical devices except for class I devices, and aims at ensuring the manufacturer complies with regulatory requirements.

As already mentioned, the class of a medical device is decisive in determining the requirements that will apply to it. The same therefore applies to the conformity assessment procedure.

For class III medical devices (all medical devices manufactured using non-viable substances of human origin):

The conformity assessment will require the involvement of a notified body. To this end, the manufacturer is free to choose and may submit its application for assessment to any notified body within the EU, designated by a national authority responsible for notified bodies (see the List of notified bodies or Actors and Network database).

There is only one condition governing the manufacturer’s choice of notified body: “provided that the chosen notified body is designated for conformity assessment activities related to the types of devices concerned”. (Article 53(1) of the Regulation on medical devices)

Before submitting an application for conformity assessment to a notified body, the manufacturer of a Class III medical device shall assign a unique device identifier (UDI-DI) to the device and register it. (Article 29(3) of the Regulation on medical devices)

Commission Implementing Regulation (EU) 2026/977 provides certain uniform quality management and procedural requirements for the conformity assessment activities carried out by a notified body (mainly quotations, timelines and re-certification).

The manufacturer then has two options regarding assessment by a Notified Body:

1. Conformity assessment based on a quality management system and assessment of the technical documentation (Annex IX of the Regulation on medical devices)
2. Conformity assessment based on type examination (Annex X) and product conformity verification (Annex XI)
    

Conformity assessment based on a quality management system and assessment of the technical documentation (Annex IX of the Regulation on medical devices)

This assessment comprises both an evaluation of the quality management system and an evaluation of the technical documentation.

Assessment of the quality management system by the chosen notified body (NB):

Following the manufacturer’s submission of an application for assessment of the quality management system, the NB assesses the manufacturer’s quality objectives, the measures taken, the organisation and the personnel qualification, the control and surveillance systems from the conception of the devices to their production. As part of this assessment, the NB conducts an on-site audit, at the manufacturer’s premises and those of its suppliers and/or subcontractors, where applicable, in order to control the Quality Management System (QMS) and its effective application.

Once this assessment has been carried out, and if the QMS is in compliance with the regulation, the NB issues an EU quality management system certificate, first step to the CE marking of conformity. (Annex IX-2 of the Regulation on medical devices)

Assessment of the technical documentation by the chosen notified body (NB):

Following the manufacturer’s submission of an application for assessment of the technical document, the NB also conducts a thorough review of the technical documentation described in the Obligations applicable to medical device manufacturers. This control consists in the assessment of the evidence provided by the manufacturer, of the risk-benefit ratio, and where applicable, of the equivalence with an already existing device, all of it taking into account the innovative character of the medical device, the risk management plan, the target population, the post-market surveillance plan and the post-market clinical follow-up (see Obligations applicable to medical device manufacturers). (Annex IX-4.1 to 4.8 of the Regulation on medical devices)

Once this assessment has been carried out, and if the device complies with the regulation, the NB issues an EU technical documentation assessment certificate. (Annex IX-4.9 of the Regulation on medical devices)

It should be noted that there are additional special procedures for certain medical devices:

• For Class III implantable medical devices, except as provided for in section 54(2) of the Regulation on medical devices, the NB must submit its clinical evaluation report to the European Commission which then forwards it to the relevant expert pane. On this occasion, the NB can also be invited by the European Commission to presents its findings directly to this expert panel. The latter will then be tasked, if it deems it appropriate, with issuing a scientific opinion on this clinical assessment report. (Annex IX-5.1 of the Regulation on medical devices)

  For more information regarding this consultation procedure of the expert panels (clinical evaluation consultation procedure or CECP), see Working instructions for Notified Bodies on the application of Article 54 of Regulation (EU) 2017/745 on medical devices and Article 48 of Regulation (EU) 2017/746 on in vitro diagnostic medical devices in the European Union Guidance section.

Conformity assessment based on type examination (Annex X) and on product conformity verification (Annex XI)

Assessment based on type examination (Annex X):

This assessment involves an examination of a representative sample of the production (i.e. a type) and a review of the technical documentation to ensure compliance with the regulation. A representative sample of the production is provided by the manufacturer to a NB. The NB evaluates it to verify that the manufactured medical device conforms to the technical documentation (Annex X-3(c) and (g) of the Regulation on medical devices)

Following this evaluation, and if the device complies with the regulation, the NB issues an EU type-examination certificate. (Annex X-4 of the Regulation on medical devices)

It should be noted that additional specific procedures applicable within the framework of conformity assessment based on a quality management system and the assessment of technical documentation (Annex X-6 by reference to Annex IX-5 of the Regulation on medical devices) mentioned above are also applicable to the following medical devices:

• Class III implantable medical devices
• Medical devices manufactured using human tissues or cells

Conformity assessment based on product conformity verification (Annex XI):

After obtaining the EU type-examination certificate, the manufacturer may choose between two options for the subsequent steps of the conformity assessment procedure for its medical device.

The first option consists in an assessment of the Quality Management System very similar to that described above (Annex IX of the Regulation on medical devices), except that it is aimed at demonstrating conformity with the type/sample assessed and certified in the preceding stage, as well as with the related documentation. Conformity allows the NB to issue an EU quality assurance certificate. (Annex XI, Part A of the Regulation on medical devices)

The second option is more burdensome and more constraining. It requires each manufactured medical device to undergo examinations and testing directly by the NB (or by a laboratory designated by it), in order to ensure each one’s compliance with the regulation and conformity with the type/sample assessed in the preceding stage. Compliance enables the notified body to issue an EU product verification certificate. (Annex XI, Part B of the Regulation on medical devices)

The certificated issued by the NB are valid for the specified period and for a maximum of 5 years. At the manufacturer’s request, the validity of the certificate may be extended by up to five years each time, following a new conformity assessment. (Article 56(2) of the Regulation on medical devices)

Last steps before placing on the market:

Regardless of the procedure chosen, once the EU certificates have been obtained, the manufacturer is still required to:

• Draw up an EU declaration of conformity (Article 10.6 of the Regulation on medical devices)
• Affix the CE marking of conformity on its medical device (Article 10.6 of the Regulation on medical devices)
• Register in the dedicated databases through the EUDAMED platform by providing the information listed in Annex VI to the MDR, or verify such information where registration has already been completed. (Article 29 of the Regulation on medical devices)
   

4. Identification and preparation of the required documentation

In order to develop a medical device that complies with regulatory requirements, the manufacturer can refer to several documents related to documentation.

On the one hand, the manufacturer must establish and continuously update the technical documentation provided for in Annex II of the Regulation on medical devices, as well as the post-market surveillance documentation set out in Annex III of the Regulation on medical devices.

On the other hand, additional standards may be applied during the design and development or manufacturing phases. They mainly consist in relevant ISO standards.

Their application is voluntary, and facilitates the demonstration of conformity.

Among ISO standards relevant for medical devices using tissues and cells of human origin, the following can be cited:

• ISO 13485:2016 Medical devices – Quality management systems - Requirements for regulatory purposes
• ISO 14971:2019 Medical devices – Application of risk management to medical devices

There is also a list of references to harmonised standards under Regulation (EU) 2017/745 on medical devices, published in the Official Journal of the European Union.

This list is regularly updated on the European Commission’s website here.

5. Requirements for placing a medical device on the market 

Requirements applicable to all medical devices (Annex I of the Regulation on medical devices)

To be placed on the market or put into service, a medical device must comply with general safety and performance requirements. (Annex I of the Regulation on medical devices)

They include:

• General requirements (Chapter I of the Annex I of the Regulation on medical devices),
• Requirements regarding design and manufacture (Chapter II of the Annex I of the Regulation on medical devices) and
• Requirements regarding the information supplied with the device (Chapter III of the Annex I of the Regulation on medical devices).

The general requirements concern the safety and effectiveness of medical devices with regard to the performance and intended purpose specified by the manufacturer: medical devices must be designed and manufactured in such a way as to be suitable for their intended purpose under normal conditions of use; risks must be reduced as far as possible, and the benefit-risk balance must be favourable.

These requirements include the implementation of a risk management system and its systematic and periodic updating throughout the entire life cycle of medical devices. They must be complied with throughout the entire life cycle of medical devices, including during storage and transport, so as to prevent any alteration of their performance and characteristics. (Chapter I of the Annex I of the Regulation on medical devices)

Requirements regarding design and manufacture concern the reduction of the risks associated with chemical (toxic, carcinogenic, mutagenic, endocrine disruptors) or biological substances (microbial infections), physical factors (risk of injury, radiation, etc.), and with electronic systems and software (active and software-based medical devices). (Chapter II of the Annex I of the Regulation on medical devices)

Requirements regarding the information supplied with the device concern labelling and the instructions for use. (Chapter III of the Annex I of the Regulation on medical devices)

6. Registration obligations applicable to all economic operators

Before the marketing of medical devices, and even prior to the conformity assessment procedure, economic operators (manufacturers, authorised representatives and importers) are required to register. To do so, they may choose to register once on the EUDAMED platform by providing the information listed in Annex VI, Part A-1 of the Regulation on medical devices, registration that will be effective throughout the EU. (Article 30 and 31 of the Regulation on medical devices)

However, since the platform is not yet fully operational (Article 123(3)(d) of the Regulation on medical devices), direct registration with national competent authorities remains possible, although such registration is valid only in the territory of the Member State where the relevant formalities were carried out.

From 28 May 2026, the registration on EUDAMED will be mandatory for all economic operators. (Commission Decision (EU) 2025/2371 and Regulation (EU) 2024/1860)

In addition to registration, the obligations of each economic operator are specified in the chapter II of the Regulation on medical devices.

Only the manufacturer’s obligations will be detailed in the dedicated subsection.

Interactions with expert groups (Article 61(2) of the Regulation on medical devices)

With regard to the clinical development strategies envisaged by manufacturers and proposed clinical investigations, manufacturers of Class III medical devices (manufactured from animal or human cells or tissues) may request the opinion of an expert group (Article 106 of the Regulation on medical devices). This opinion must be taken into account by the manufacturer and documented in the clinical evaluation report.

See the consultation procedures regarding the high-risk medical devices on the EMA website. 
 

Interactions with Notified bodies

Notified bodies are key interlocutors for manufacturers. Before and during certification procedures, manufacturers may engage with notified bodies in order to gain a better understanding of the applicable regulatory requirements. 

Interactions with national authorities

The conduct of a clinical investigation requires the submission by its sponsor of an application to the competent national authorities, which are responsible for its validation or authorisation (see Clinical investigation in Obligations applicable to medical device manufacturers). The procedure set out in Article 70 of the Regulation on medical devices shall be carried out directly in the Member State(s) concerned, pending the deployment of the Clinical investigations & performance studies module of the EUDAMED platform. Prior to submission, it is possible to engage with the competent national authority or authorities, depending on the options they offer. (See Support from National medicines Agencies for the development of innovative medicines at the National levels)

Published: 29/05/2026

Authors:

Valentin Roby, EuroGCT information officer on Ethical, Legal and Societal Issues 

Aurélie Mahalatchimy, EuroGCT WP4 Convenor, UMR 7318 DICE CERIC, Aix-Marseille University, CNRS, Aix-en-Provence, France