9. Subject considerations

9.1 Clinical trial subject recruitment: Are digital advertisements (including social media streams such as TikTok) allowed and, if so, what regulations govern them? 

Yes. Unless the protocol already contains this information, the procedure for including participants must be detailed in a separate document, which clearly indicates what the primary method of recruitment is, when submitting an application for clinical trial authorization.

When recruitment of participants is carried out by means of advertisements, copies of the advertising material must be presented, including any printed material as well as any sound or video recording used. Proposed procedures for handling responses to advertisements must be described. This includes but is not limited to, copies of communications used to invite participants to participate in the clinical trial and arrangements made to inform or advise individuals who come forward and are found to be ineligible to participate in the clinical trial.

9.2 Vulnerable Subjects

In France, specific provisions apply regarding the participation of certain vulnerable populations in clinical trials, such as:

• Pregnant or breastfeeding women (Art. L. 1121-5, Public Health Code):

“Pregnant women, parturients and breastfeeding mothers may only be asked to take part in the research mentioned in 1° or 2° of Article L. 1121-1 under the following conditions:

- either the size of the expected benefit for themselves or for the child is such as to justify the foreseeable risk incurred;

- or the research is justified in the light of the expected benefit for other women in the same situation or for their children and on condition that research of comparable effectiveness cannot be carried out on another category of the population. In this case, the foreseeable risks and constraints of the research must be minimal.”

• Incapacitated adults (Arts L. 1121-8, L. 1121-11, L. 1122-2, and L. 1125-10, Public Health Code).

Art. L 1121-8:

“Adults who are the subject of a legal protection measure or who are unable to express their consent may only be solicited for research referred to in 1° or 2° of Article L. 1121-1 if research of comparable effectiveness cannot be carried out on another category of the population and under the following conditions:

- either the size of the expected benefit for those persons is such as to justify the foreseeable risk incurred;

- or the research is justified in the light of the expected benefit for other persons in the same situation. In this case, the foreseeable risks and constraints of the research must be minimal.”

Art. L 1121-11:

“Research involving human beings does not give rise to any direct or indirect financial compensation for the persons who take part in it, apart from the reimbursement of the costs incurred and, where applicable, the compensation for the constraints suffered paid by the sponsor. The total amount of benefits that a person can receive in a single year is limited to a maximum set by the Minister of Health.

The payment of such compensation shall be prohibited in the case of research carried out on minors, persons who are the subject of a legal protection measure, persons of full age who are unable to express their consent, persons deprived of their liberty, persons subject to psychiatric treatment pursuant to Chapters II to IV of Title I of Book II of Part III of this Code or Article 706-135 of the Code of Criminal Procedure and persons admitted to a health and social institution for purposes other than research.

Persons likely to take part in the research referred to in 1° of Article L. 1121-1 benefit from a prior medical examination adapted to the research. The results of this examination are communicated to them directly or through the doctor of their choice.

When research involving human beings concerns the field of midwifery and meets the conditions set out in the last paragraph of Article L. 1121-5, the results of this examination shall be communicated to them directly or through the intermediary of the doctor or midwife of their choice.

When research involving human beings concerns the field of dentistry, the results of this examination shall be communicated to them directly or through the intermediary of the doctor or dental surgeon of their choice.

The social security institution has an action against the promoter for payment of the benefits paid or provided.

Art. L. 1122-2:

“I. Non-emancipated minors, protected adults or adults who are unable to express their consent and who are not subject to a legal protection measure shall receive, when their participation in research involving the human person is envisaged, the information provided for in Article L. 1122-1 adapted to their capacity to understand, both from the investigator and from the individuals, bodies or authorities responsible for assisting, representing or authorising the research, which are themselves informed by the investigator.

They are consulted to the extent that their condition allows it. Their personal support for their participation in research involving the human person is sought. In any event, their refusal or revocation of their acceptance cannot be overridden.

II. When research involving the human person is carried out on a non-emancipated minor, consent, when required, is given by the holders of parental authority. However, this consent may be given solely by the holder of the exercise of parental authority present, subject to compliance with the following conditions:

-the research involves minimal risks and constraints;

- the minor does not lend himself to the research as a healthy volunteer;

- the other holder of parental authority may not give his or her consent within a time limit compatible with the methodological requirements specific to the conduct of the research with regard to its purposes.

When a minor taking part in research becomes an adult in the course of his or her participation, confirmation of his or her consent is required after appropriate information has been provided.

When research involving the human person is carried out on a minor, if necessary under guardianship, the authorisation shall be given by his or her legal representative and, if the committee referred to in Article L. 1123-1 considers that the research entails, by the extent of the constraints or by the specificity of the interventions to which it leads, a serious risk of invasion of privacy or the integrity of the human body, by the family council, if it has been set up, or by the guardianship judge.

When, on the date of the end of the research, the minor who has taken part in the research has acquired legal capacity, he or she becomes the personal recipient of any information provided by the investigator or sponsor.

III. A person who is the subject of a measure of safeguard of justice may not be asked to participate in research involving the human person.

When research involving the human person is carried out on an adult under curatorship, consent is given by the interested party assisted by his or her curator. However, if the adult under curatorship is asked to participate in research that the committee referred to in Article L. 1123-1 considers to entail, by the extent of the constraints or by the specificity of the interventions to which it leads, a serious risk of invasion of privacy or the integrity of the human body, the guardianship judge is seized for the purpose of ascertaining the capacity of the adult to consent. In the event of incapacity, the judge decides whether or not to authorise research involving humans.

When research involving the human person is carried out on an adult who is the subject of a future protection mandate, a family empowerment or a guardianship measure, with representation relating to the person, the authorisation is given by the person responsible for representing him/her. However, if the committee referred to in Article L. 1123-1 considers that the research entails, by the importance of the constraints or by the specificity of the interventions to which it leads, a serious risk of invasion of privacy or the integrity of the human body, the authorization shall be given by the family council if it has been set up or by the guardianship judge.

When research involving a human being that meets the conditions laid down in Article L. 1121-8 is planned on an adult who is unable to express his or her consent and who is not subject to a legal protection measure, the authorization is given by the person of trust provided for in Article L. 1111-6, failing that, by the family, or, failing that, by a person who has close and stable ties with the person concerned. The person concerned shall be informed as soon as possible and his consent shall be sought for the possible continuation of this research if he regains his capacity to consent. However, if the committee referred to in Article L. 1123-1 considers that the research entails, by reason of the importance of the constraints or the specificity of the interventions to which it leads, a serious risk of invasion of privacy or the integrity of the human body, the authorization shall be given by the guardianship judge.

IV.The consent provided for in the second paragraph of III shall be given in accordance with the forms provided for in Article L. 1122-1-1. The authorisations provided for in the first and sixth paragraphs of II and in the third and fourth paragraphs of III shall be given in writing.”

Art. L. 1125-10:

“The clinical investigation does not give rise to any direct or indirect financial compensation for the persons who take part in it, except for the reimbursement of the costs incurred and, where applicable, the compensation for the constraints suffered paid by the sponsor. The total amount of benefits that a person can receive in a single year is limited to a maximum set by the Minister of Health.

The payment of such compensation shall be prohibited in the case of clinical investigations carried out on minors, persons who are subject to a legal protection measure, persons of full age who are unable to express their consent, persons deprived of their liberty, persons subject to psychiatric treatment pursuant to Chapters II to IV of Title I of Book II of Part III of this Code or Article 706-135 of the Code of Criminal Procedure and persons admitted to a health and social institution for purposes other than clinical investigation.

Persons who are likely to undergo clinical investigations involving an intervention on the person that is not justified by his or her usual care and which expose him or her to non-minimal risks and constraints are provided with a preliminary medical examination adapted to the clinical investigation. The results of this examination are communicated to them directly or through the doctor of their choice.

When clinical investigations concern the field of midwifery, the results of this examination are communicated to them directly or through the intermediary of the doctor or midwife of their choice.

When the clinical investigations concern the field of dentistry, the results of this examination are communicated to them directly or through the intermediary of the doctor or dental surgeon of their choice.”

• Minors (Arts. L. 1121-7, L. 1121-11, L. 1122-2, and L. 1125- 10, Public Health Code).

Art. 1121-7

“Minors may be asked to take part in the research mentioned in 1° or 2° of Article L. 1121-1 only if research of comparable effectiveness cannot be carried out on adults and under the following conditions:

- either the size of the expected benefit for those persons is such as to justify the foreseeable risk incurred;

- or this research is justified in the light of the expected benefit for other minors. In this case, the foreseeable risks and constraints of the research must be minimal.”

• In an emergency situation (Art. L. 1122-1-3, Public Health Code).

Art L1122-1-3:

“In the case of research involving the human person to be carried out in emergency situations which do not allow the prior consent of the person to be submitted to it to be obtained, when it is required, the protocol presented for the opinion of the committee referred to in Article L. 1123-1 may provide that the consent of this person is not sought and that only that of the members of his family or that of the person concerned is sought. trust referred to in Article L. 1111-6 under the conditions set out in Article L. 1122-1-1, if present. The protocol may provide for a derogation from this obligation in the event of an immediate life-threatening emergency, which shall be assessed by that committee. The person concerned or, where applicable, the family members or the person of trust referred to in Article L. 1111-6 shall be informed as soon as possible and their consent, where required, shall be requested for the possible continuation of this search. They can also object to the use of personal data in the context of this research.”

9.3 Pediatrics (including whether consent from a single parent is sufficient vs. requiring both parents to sign)

According to the EnprEMA (Europan Network of Paediatric Research at the European Medicines Agency) and their document titled “Informed Consent for Paediatric Clinical Trials in Europe 2015 (last update 06 June 2023)”:

“Both parents of a minor (a child under 18 years of age) are generally considered to exercise parental authority. As a general rule, the joint authorization of both parents is required in order for a child to participate in a biomedical research protocol, and either parent has the right at any time to withdraw their authorization."

There are a couple of organizations in France that provide additional tools and considerations for pediatric research. Those include the Circle of Ethics in Pediatric Research as well as the Pediapic website.

9.4 Financial Disclosures

The EU CTR 536/2014 requires the following information to be submitted at the time of submission of the dossier. Please see - Annex I. P of EU CTR 536/2014: 

“69. A brief description of the financing of the clinical trial.

70. Information on financial transactions and compensation paid to subjects and investigator/site for participating in the clinical trial shall be submitted.

71. Description of any other agreement between the sponsor and the site shall be submitted.”

In addition, the European Federation of Pharmaceutical Industry Associations (EFPIA) Code provides for disclosures in relation to clinical studies, as follows (see Annex B on page 37 of the Code), in accordance with clauses 22 & 23.

Clause 23 provides that “Research and Development ToVs in each Reporting Period must be disclosed by each Member Company on an aggregate basis. Costs related to Events that are clearly related to activities covered in this section can be included in the aggregate amount under the “Research and Development Transfers of Value” category”.

Research and Development ToVs are defined in Section 15.01 of the HCP Code as: “Transfers of Value to HCPs or HCOs related to the planning or conduct of (i) non-clinical studies (as defined in OECD Principles on Good Laboratory Practice); (ii) clinical trials (as defined in Regulation 536/2014); or (iii) NIS that are prospective in nature and that involve the collection of patient data from or on behalf of individual, or groups of, HCPs specifically for the study”.

It is important to highlight that clinical trial contracts between sponsor/investigators must be submitted to the CNOM (National Council of the Order of Physicians) for approval. French investigators may also require to notify the French Ministry of Health of agreements and remunerations received from the sponsor.

9.5 ICF translations – Are Certificates Required?

The national law is silent on whether or not a translation certification is required. Under normal practice, Certificates of Translations (CoTs) are not required to be submitted. However, relevant CoTs should be filed within the Trial Master File.

9.6 Subject Compensation: Is there a need for a local sponsor to be listed on the insurance certificate, the insurance certificate to cover the duration of the study, and specific minimum amounts of coverage to be specified, both for individual events occurring and in aggregate?

Please refer to Section 2.18 of this guidebook.