Wael HAYEK

Medical research constitutes an essential lever for the development of new treatments and for the continuous improvement of patient care.

In France, this research is governed by strict regulations designed to protect participants and ensure the integrity of human subjects. The Jardé Law, adopted in March 2012 and fully applied since November 2016, constitutes the legal framework for research involving human subjects (RIPH).

Relationship between the Jardé Law and the European Clinical Trials Framework

It should be noted that clinical trials involving medicinal products are primarily regulated by the EU Clinical Trials Regulation (EU) 536/2014 (CTR), which came into effect on January 31, 2022. This regulation repealed and replaced Directive 2001/20/EC. Since that date, clinical trials on drugs must be submitted via the Clinical Trials Information System (CTIS). As a reminder, any clinical trial with at least one active investigator site in France as of January 31, 2025 had to undergo a transition request to CTIS by its sponsor. The ANSM notice to sponsors provides practical guidance on the submission of applications.

The Jardé Law does not replace the CTR but complements the European framework with specific national requirements, notably regarding the protection of participants, consent and information, research classification, and procedures involving the Committees for the Protection of Persons (CPP).
Other regulatory provisions must also be integrated by sponsors, such as procedures on personal data protection (GDPR, CNIL rfefernce methodologies), procedures related to the use of medicinal products composed wholly or partially of genetically modified organisms (GMOs), and specific rules applicable to certain health products.

Indeed, depending on the nature of the research object, the applicable provisions differ. The Jardé Law thus covers: drugs, medical devices (clinical investigation) in vitro diagnostic medical devices (performance study), cell therapy products, tissues, organs, labile blood products (LBPs), or even research on dietary supplements or cosmetics.

What is the Jardé Law?

The Jardé Law, named after Deputy Olivier Jardé, is a regulation that governs the conditions under which research involving human participants can be conducted in France. It replaces the Huriet-Sérusclat Law of 1988 and aims to strengthen the protection of participants while simplifying and harmonizing procedures, taking into account the level of risk incurred.

The main reference texts include: 

– The Jardé Law, Law No. 2012-300 of March 5, 2012, relating to research involving human subjects. 

– The ordinance, known as the “modified Jardé Law,” relating to research involving human subjects. 

– Decree No. 2016-1537 of November 16, 2016, relating to research involving human subjects. 

Classification of RIPH

Research organized and conducted on human beings with the aim of developing biological or medical knowledge is referred to as “research involving human subjects” (RIPH). There are three types of RIPH:

* Research involving drugs cannot in principle fall under Category 2, except for very specific cases defined by regulation. An order sets the criteria to be met to remain within the scope of RIPH 2.

What Are the Implications for the Industry? 

Participant Information and consent

The objective of the Jardé Law is to ensure the safety of participants. Special attention is given to the notions of informed consent and clear, understandable, and fair information.

Industrials, as sponsors, must ensure that participants fully understand the stakes, procedures, risks and constraints, and potential benefits of the study. These requirements are detailed in Articles L1122-1-1 to L1122-2 of the Public Health Code (CSP).

Determination of Competent Authorities and Applicable Procedures

Sponsors must determine the category of their research during the design phase, ensure they obtain the necessary authorizations (CPP and/or ANSM), and define the applicable procedure (CTR/CTIS for drugs).

Interactions with CPPs and the ANSM 

CPPs are French ethics committees (Committees for the Protection of Persons) responsible for evaluating participant protection, the quality of information and consent, and the benefit/risk balance. Interactions with CPPs and the ANSM are essential for the validation of research projects. Good communication and submission of complete dossiers are necessary, in accordance with Articles L1123-6 and L1123-7 of the Public Health Code. For each RIPH, a CPP responsible for assessing the application is selected by random draw. The information system for research involving the human person (SI RIPH 2G) enables the submission of an application for an opinion and the random designation of a CPP. The platform also allows for the declaration of healthy volunteers participating in a study.

Procedures

Before submitting the authorization request dossier (initial authorization and substantial modification) and/or human research opinion request, or routine care research, sponsors must obtain an IDRCB registration number for the research. This number identifies each research conducted in France. For a interventional research authorization and opinion request concerning a medicinal product for human use, sponsors must instead obtain a research registration number in the European CTIS database (formerly: EudraCT).

Subsequently, sponsors will electronically submit the biomedical research authorization and/or opinion request dossier to the ANSM and/or CPP, in accordance with the current orders setting the dossier formats for each type of research. Various “Notices to Sponsors” guide these procedures according to the situation.

Conclusion

The Jardé Law thus ensures the safety of participants in clinical research in France.

For health manufacturers, understanding and complying with these regulations is not only a legal obligation but also a guarantee of the quality of the data generated, particularly for use in a Marketing Authorization Application (MAA) dossier.

By integrating the requirements of the Jardé Law into their processes, manufacturers contribute to the development of innovative treatments while ensuring high ethical standards, in accordance with French and European regulations on this subject.

Atessia supports you in implementing these processes with its expertise in clinical trials.

Article written by Mathilde ISRAEL 

French always do it different 

In many domains, French people like to stand out, either in a positive or negative way. 

In the Healthcare field, France has set a system that is highly effective, and very protective for the patient, but at the price of a heavy state involvement and of one of the most complex regulations. 

As a result, understanding the regulatory specificities of France is key for entering the French market. 

ATESSIA can help you in this process and provide you assistance and expertise. 

Here are a few areas where France follows its own, often complicated and restrictive, rules. 

The substances used in a medicinal product intended for the European market, including for export, are defined as raw materials for pharmaceutical use (RMP). They can be active (active substance) or inert (excipients). 

Whether the medicinal products are intended for human or veterinary use, only active substances manufactured and distributed in accordance with European Good Manufacturing Practices (GMP – Part II) and Good Distribution Practices (GDP), introduced by article L.5138-3 of the French Heath Code, can be used. 

Thus, when applying for a marketing authorization or for certain applications to modify the marketing authorization, the notice to applicants requires the submission of a signed QP declaration by the qualified person of the manufacturing site and/or of the certification of the batches of the finished product attesting that the active substance used is manufactured in accordance with good manufacturing practices. 

Concerning the excipients used in medicinal products for human or veterinary use, there is no enforceable standard in the national or European regulations and they are not subject to the QP declaration in the marketing authorization file. It is up to the manufacturer or distributor of the finished product to define its quality system the applicable standard(s) for the manufacture or distribution of the excipient, according to its/their intended use(s). This exercise will be carried out in consultation with pharmaceutical users on the basis of the results obtained during a formal quality risk assessment (GMP point 5.29). It should be noted that ANSM recommends, at a minimum, the IPEC/PQG GMP & GDP reference systems.  

However, it is recognized that for some raw materials, their pharmaceutical use may represent only a minor fraction of their other industrial uses (agri-food, cosmetics or others). Thus, their producers may not have the objective of meeting the specific requirements of pharmaceutical customers. 

The EMA’s Q&A Part 1 reaffirms that compliance with the above-mentioned standards is a legal obligation and that, in the event of difficulties in guaranteeing a supply of satisfactory quality, alternative GMP sources must be sought out, qualified and, if necessary, registered. In the case of a source identified on European territory, the establishment must apply for authorization or registration from the competent authority of the Member State in which it is established. In case of import from a third country to the European territory, the source of the identified active substance will be conditioned by the provision of a written confirmation from the competent authority of the exporting third country. This document attests that the applicable standards are at least equivalent to the GMP defined by the European Union.  

In exceptional circumstances these same EMA Q&A Part 1 introduces the possibility for manufacturing authorization holders (of the finished product) to assess and document the extent to which GMP is met, and to provide a risk-based justification for the acceptance of any deviation. At the MA level, the QP declaration should detail the rationale for stating that the standards applied provide the same level of assurance as GMP. The EMA will collect the experience gained with this approach, which can be used as a basis for discussion of possible future related changes to the guidelines. 

However, at the national level, the ANSM does not, for example, explicitly provide for derogations or for exceptional circumstances, unlike the EMA for centralized MA. When informed in advance of a particular context (such as medicinal products of major therapeutic interest or the absence of a therapeutic alternative), the competent authorities could then request additional information or carry out an inspection to ensure that the establishment complies with the standards in force in the Union. Thus, this situation can only be transitory, since these alternative sources (in the EU or in third countries) and/or their principals can request an express request for an inspection of the raw materials from a competent authority of one of the member states in order to obtain a certificate of conformity. 

The control of the supply chain is the key word. Deficiencies in the qualification and monitoring process of suppliers and/or manufacturers of raw materials are regularly the subject of injunctions issued by the ANSM against pharmaceutical establishments (2 for the year 2024 and 2 for the year 2025). For the alternative identified source, this may be a hindrance (compulsion to comply with the opposable standards) or an opportunity (to comply with them in order to enter the EU market for UPMPs). A mutualization of supplies (and on-site audits) can also be an interesting approach to encourage the source to seize this opportunity.  

This article was written by Véronique LEWIN, Senior Consultant in CMC Regulatory Affairs

Article 15 of Regulation (EU) 2017/745 on medical devices and Article 15 of Regulation (EU) 2017/746 on in vitro diagnostic medical devices formally introduce the requirement for each manufacturer (and each authorised representative) to designate a Person Responsible for Regulatory Compliance (PRRC). This requirement aims to ensure the continuous compliance of devices placed on the market, regardless of their class or medical purpose. 

This obligation applies to all types of devices: 

• Implantable or non-implantable 

• Active or non-active 

• Standard or custom-made 

• With or without a medical purpose 

Who Needs a PRRC? 

• Manufacturers  

All manufacturers placing CE-marked medical devices on the EU market are required to appoint a PRRC. 

• Authorised Representatives (ARs) 

EU-based authorised representatives acting on behalf of non-EU manufacturers are also required to designate a PRRC. 

Other economic operators such as distributors, importers, and assemblers are not required to have a PRRC. 

Roles and Responsibilities of the PRRC 

The PRRC plays a critical role throughout the regulatory lifecycle of a medical device. The main responsibilities include : 

• Verifying the conformity of devices prior to their release, relying on the manufacturer’s quality management system. 

• Preparing and updating technical documentation, including the EU declaration of conformity. 

• Post-market surveillance obligations: monitoring device performance and safety after it has been placed on the market. 

• Reporting obligations to competent authorities in the event of incidents or significant changes. 

• Submitting declarations in case of clinical investigations and performance studies, as required by the regulation. 

🔒 Independence Guarantee : The regulation ensures that the PRRC cannot be disadvantaged in carrying out their duties, whether they are an employee of the company or an external party. 

Required Qualifications to Act as a PRRC 

There are two possible routes to qualify as a PRRC, as set out in the regulation: 

1. Academic Path + Experience 

• A diploma (or certificate) in law, medicine, pharmacy, or another relevant scientific discipline. 

• ≥ 1 year of professional experience in regulatory affairs or quality management systems related to medical devices/or in vitro diagnostic medical devices. 

• For custom-made devices: ≥ 2 years of experience in a relevant manufacturing field. 

2. Professional Experience Path 

• ≥ 4 years of professional experience in regulatory affairs or quality systems applicable to medical devices /or in vitro diagnostic medical devices. 

. 

PRRC Role Based on Company Size 

The regulation acknowledges structural differences between large companies and SMEs: 

• Large enterprises: The PRRC must be a permanent part of the organization. 

• Micro and small enterprises*: The PRRC role can be outsourced, provided the person is permanently and continuously available. 

Multiple PRRCs: If more than one person is appointed, they share joint responsibility for regulatory compliance. Their respective responsibilities must be clearly defined in writing, and each individual must meet the qualification requirements. 

Registration and Compliance 

Since the Regulation came into effect on 26 May 2021, the contact details of the PRRC must be registered in EUDAMED, the European database for medical devices. 
(See our blog post on EUDAMED for more details.) 

Useful References 

• Article 15 of Regulation (EU) 2017/745 on medical devices 

• Article 15 of Regulation (EU) 2017/746 on in vitro diagnostic medical devices 

• SNITEM Guide – The Person Responsible for Regulatory Compliance 

*Commission Recommendation 2003/361/ΕC of 6 May 2003 concerning the definition of micro, small and medium-sized enterprises: 

-Within the SME category, a small enterprise is defined as an enterprise which employs fewer than 50 persons and whose annual turnover and/or annual balance sheet total does not exceed EUR 10 million. 

-Within the SME category, a microenterprise is defined as an enterprise which employs fewer than 10 persons and whose annual turnover and/or annual balance sheet total does not exceed EUR 2 million. 

Article written by Camille NEERMUL, Senior Consultant in Quality and Regulatory Affairs for medical devices 

Legal basis: 

When marketing authorization holders wish to register a medicine in Europe, they submit a marketing authorisation (MA) application to the health authorities.  

Once marketing authorisation has been obtained, it is the responsibility of the marketing authorisation holder to keep the dossier up to date and to report any changes that affect the marketing authorisation. These changes may be of various types (administrative, quality, safety).  To do this, the marketing authorisation holder must submit a notification or a variation application to the competent health authorities.  

A variation is a modification to the marketing authorisation.  

There are also other types of MA modifications, known as MA extensions. 

Changes to the terms of a European marketing authorisation are provided for in Directive 2001/83/EC and Regulation (EC) No 726/2004, and detailed in Regulation (EC) No 1234/2008 on the examination of variations to the terms of marketing authorisations for medicinal products for human use (hereinafter referred to as the ‘Variations’ Regulation). New guidelines to facilitate the interpretation and application of the Variations Regulation were published in the Official Journal on 22 September 2025 and are applicable on 15 January 2026. The Annex to these guidelines provides details of the classification of variations. These guidelines cover the following categories of variations, defined in Article 2 of the Variations Regulation: 

— Minor variations of Type IA, 

— Minor variations of Type IB, 

— Major variations of Type II, 

— Extensions, 

— Urgent safety restrictions. 

Any modification must be classified in one of the above categories. However, in some cases, the distinction between a Type II (major) variation or an extension is complex. 

Definitions: 

1. Type II variations 

Type II variations are considered as major variations. These are variations which are not extensions of marketing authorisations and may have a significant impact on the quality, safety or efficacy of the medicinal product concerned. This type of variation is generally assessed within 60 days, but shorter assessment periods (30 days for safety-related variations) or longer periods (90 days for indication extensions) may be necessary. 

2. Extensions 

Certain changes to a marketing authorisation must be considered as fundamentally altering the terms of that authorisation and therefore cannot be granted through a variation procedure. Annex I of the Variations Regulation sets out a list of changes to be considered as extensions; the two main changes requiring an extension are:  

– Changes to the active substance(s): 

– Changes to strength, pharmaceutical form and route of administration 

According to Article 19 of the « modification » Regulation, an application for an extension shall be evaluated and granted in accordance with the same procedure as for the initial marketing authorisation to which it relates.  

The extension may either be granted as a new marketing authorisation (national procedures, MRP and DCP) or included in the initial marketing authorisation to which it refers (centralised procedure). 

In all cases, the new MA obtained is part of the global marketing authorisation and is not eligible to additional data protection (except in cases of ‘significant’ indication extensions based on comparative data). 

The assessment timetable for an extension is the same as that for an initial marketing authorisation application. 

In practice 

Experience has shown problems in the classification of extension applications versus variations particularly regarding the items pharmaceutical form and strength. The « GUIDELINE ON THE CATEGORISATION OF EXTENSION APPLICATIONS (EA) versus VARIATIONS APPLICATIONS (V) » (Revision 4 – July 2019), proposes a harmonised and agreed interpretation of the Standard terms, with the aim of facilitating the application of the Regulation on variations throughout the EU and helping in the classification of requests.   

The main principles of classification of extensions versus type II variations are as follows: 

^*: unless the modification results in a change to the strength, pharmaceutical form or route of administration. 

The guideline also provides examples presented as table for more complex cases. 

It is important to note that variation requests may be grouped together with a marketing authorisation extension request. The assessment period applied to variations will be that of the marketing authorisation extension. 

In summary 

Apart from the question of the regulatory classification of the application (variation or extension), numerous practical questions may arise when compiling the application: 

– Will my brand name be affected? 

– How should I submit my extension request? 

– What data should I generate? 

– Can I group extension submissions with other types of variations? 

– Do I need to meet pediatric requirements in my extension application? 

– How should I integrate this extension into the eCTD? 

ATESSIA can assist you in developing your regulatory strategy and drafting your variation or extension application dossiers, regardless of the registration procedure. 

This article was written by Anne-Valérie Angérard, senior regulatory affairs consultant.