2. General Questions

2.1 Name of Regulatory Authority

The National Agency for the Safety of Medicines and Health Products/Agence nationale de sécurité du médicament et des produits de santé (“ANSM”)

2.2 Name of Ethics Committee

Comités de Protection des Personnes (“CPP”)

The Committees for the Protection of Persons (CPP) are responsible for issuing a prior opinion on the conditions for the validity of any research involving the human person, with regard to the criteria defined by Article L 1123-7 of the Public Health Code (CSP).

There are 39 CPPs in France; however, not all of them are evaluating clinical trials with medicinal products as per the EU CTR 536/2014.

2.3 Clinical Trial Application Language

English, with some documents also required to be submitted in French.

The application for authorization of a clinical trial is to be submitted in accordance with Article 5(1) of the CTR 536/2014 via the Clinical Trial Information System (CTIS) in French or English.

Documents required to be submitted via CTIS for Part I (scientific aspects) of a clinical trial authorization application may be submitted in English but the following documents must also be submitted in French:

• Summary of the protocol
• The content of the labeling of the investigational medicinal products

The details required for the application form may only be entered in CTIS in English, though fields for information that is intended to be made publicly available in France may be entered in French.

2.4 Is regulatory approval required from both regulatory authorities and/or EC?

Yes.

2.5 Can regulatory authority and EC submission be done in parallel?

Yes. A single application submission for Part I (intended for the ANSM review) and Part II (intended for the EC review) can be submitted in parallel through the EMA CTIS portal.

2.6 Requirement of any import permit/license before investigational product/study product is shipped from point of origin

Yes, not an import license but an authorization/certificate by the ANSM attesting that the imported medicinal product is intended for research.

In accordance with French regulations (Art. R. 5121-114 of the Public Health Code), a document is required to be issued by the ANSM if a medicinal product is required to be imported for use in biomedical research in France.

Once the clinical trial has been authorized in France, the ANSM issues, upon request, a certificate specifying that the imported medicinal products mentioned in the certificate are intended for the performance of an authorized clinical trial in France. This certificate may be presented by the person in charge of the import to French customs officers in the event of an inspection.

To obtain an import certificate, the sponsor must complete, in French, the specific import certificate form available on the ANSM website in the section dedicated to clinical trials of medicinal products under the Jardé Law.

And, simultaneous with a CTIS application, send it by email to the ANSM via email address: aec-essaiscliniques@ansm.sante.fr, with the subject of the email described in the format: EUCT_attestation_no _importation_ date of submission of the clinical trial application in CTIS (in year month day format).

Example: 2022-001122-26-00_attestation_importation_20220328

The ANSM will send this signed form to the sponsor by email as soon as the clinical trial is authorized.

Please access the ANSM page titled “Clinical trials: procedures for the constitution and processing of applications under the European regulation on clinical trials of medicinal product”, and within that, Part II: Application for initial authorization, notifications relating to the start of the trial and conversion procedure.

2.7 Biological Specimen Export Requirements

Yes. Authorization must be sought from the French Ministry of Research to import and export human organs, cell tissues, and their derivatives which are to be used for scientific purposes. The Ministry of Research is competent only for applications for authorization of import and/or export activities for scientific purposes of human biological samples.

Requests for import/export authorization are only made by email to the generic address: dossiers.import-export@recherche.gouv.fr.

The requestor has to submit a single authorization request by email containing the application form duly completed, accompanied by all the necessary documents depending on the type of application.

The exact documents required to be submitted in order to seek authorization are listed on the Ministry of Research website, under “Steps to follow for the application for an import/export permit”.

2.8 Are studies of GMOs permitted (e.g., GMOs used in vaccines/vaccine manufacture and other modified products)?

Yes. Procedures relating to the use of medicinal products composed in whole or in part of genetically modified organisms (GMOs), such as gene therapy medicinal products and vaccines, must be carried out with the ANSM (Decree No. 2021-1905 of 30 December 2021). This procedure is centralized in order to simplify the administrative procedures of:

Declaration of Contained Uses in Clinical Trials (Research Involving Humans - RIPH)

"Application for authorization for voluntary release" in the context of applications for authorizations for early access, compassionate access and advanced therapy medicinal products prepared on an ad hoc basis for gene therapy (ATMP-PP).

It should be noted that applications for authorization for deliberate release in the context of clinical trials must be made to the Ministry of Ecological Transition.

These procedures must be carried out via the "Simplified procedures" platform.

The declaration/application for authorization must be accompanied by a technical file, the content of which is set by the decree of 25 January 2022 and must include an assessment of the risks of the use for public health and the environment.

For any declaration concerning an RIPH, the file must also include the list of sites in which the trials will be carried out.

The ANSM may refer the matter to the Expert Committee on Contained Uses of GMOs (CEUCO) attached to the Ministry of Higher Education, Research and Innovation (MESRI) so that it can issue an opinion on the contained use in question, or ANSES, for it to issue an opinion on the risk of deliberate release.

The procedure regarding the use of drugs composed in whole or part of GMOs, together with links and documents, is contained on the ANSM website.

2.9 Is in-country sponsor presence/representation required?

Only if the sponsor is not established in the EU, in which case, the Sponsor needs to establish a legal representative within the EU.

Art 74, Clinical Trial Regulation (EU) 536/2014, states:

“1. Where the sponsor of a clinical trial is not established in the Union, that sponsor shall ensure that a natural or legal person is established in the Union as its legal representative. Such legal representative shall be responsible for ensuring compliance with the sponsor's obligations pursuant to this Regulation, and shall be the addressee for all communications with the sponsor provided for in this Regulation. Any communication to that legal representative shall be deemed to be a communication to the sponsor.

2. Member States may choose not to apply paragraph 1 as regards clinical trials to be conducted solely on their territory, or on their territory and the territory of a third country, provided that they ensure that the sponsor establishes at least a contact person on their territory in respect of that clinical trial who shall be the addressee for all communications with the sponsor provided for in this Regulation.

3. As regards clinical trials to be conducted in more than one Member State, all those Member States may choose not to apply paragraph 1 provided that they ensure that the sponsor establishes at least a contact person in the Union in respect of that clinical trial who shall be the addressee for all communications with the sponsor provided for in this Regulation.”

2.10 Is there any mandatory requirement to identify a local PI or can a PI be based in a foreign country? 

According to the guidance released by the French Ministry of Health, titled “Documents expected in France for the filling of part II of the CTA (v3_17 Aug 2023)”, section 3 indicates the following:

“…Please note that the number of the Shared Directory of Health Professionals (RPPS) is the most relevant register to be entered in the CVs of the investigators in the "professional registration". Otherwise, you will need to specify the number of the directory used instead of the RPPS number.”

Therefore, it is a requirement that investigators conducting clinical trials in France are registered within the French “Shared Directory of Professionals Involved in the Health System (RPPS)”.

2.11 Is there any mandatory requirement to identify a local chief or coordinating investigator? 

No, under the EU Clinical Trial Regulation 536/2014, there is no role for a Chief or Coordinating Investigator, only Principal Investigator and Investigator.

The definitions within the EU Clinical Trials Regulation 536/2014 referred to above are as follows:

Art. 2 (2) (15): “Investigator” means an individual responsible for the conduct of a clinical trial at a clinical trial site.

Art. 2 (2) (16): “Principal Investigator” means an investigator who is the responsible leader of a team of investigators who conduct a clinical trial at a clinical trial site.

2.12 If the applicant is CRO or a third party, does regulatory authority need any authorization or transfer of obligations from the sponsor? Does the authorization letter need to be notarized and/or apostilled? 

Yes, a written contract is required between the sponsor and the CRO, delegating authority. The contract does not need to be notarized and/or apostilled, so far as we are aware, at an EMA level, now that applications are made electronically.

Article 71, EU CTR 536/2014, provides clarification on the sponsor's role:

“Sponsor

A clinical trial may have one or several sponsors.

Any sponsor may delegate, in a written contract, any or all of its tasks to an individual, a company, an institution, or an organization. Such delegation shall be without prejudice to the responsibility of the sponsor, in particular regarding the safety of subjects and the reliability and robustness of the data generated in the clinical trial. The investigator and the sponsor may be the same person.”

2.13 Is there a requirement to register clinical trials on a local registry or database?

Yes. From the 31^st of Jan 2023, all initial clinical trial applications in the EU/EEA must be submitted through the Clinical Trials Information System (CTIS). The status and results of all trials submitted under the CTIS will be available to the public.

EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trials Regulations 536/2014 are publicly accessible through CTIS. 

2.14 What is the local requirement for clinical study documents archival; minimum of years for the archival, specific format followed (electronic/paper and/or both)?

The clinical trial master file (TMF) must be retained for 25 years after the end of the clinical trial, whilst retention of medical files of clinical trial subjects is as determined by the ANSM.

The format is unspecified, the requirements being that it be complete and legible – see Art. 58, Clinical Trial Regulation (EU) 536/2014.

“Archiving of the clinical trial master file

Unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical trial master file for at least 25 years after the end of the clinical trial. However, the medical files of subjects shall be archived in accordance with national law.

The content of the clinical trial master file shall be archived in a way that ensures that it is readily available and accessible, upon request, to the competent authorities.

Any transfer of ownership of the content of the clinical trial master file shall be documented. The new owner shall assume the responsibilities set out in this Article.

The sponsor shall appoint individuals within its organization to be responsible for archives. Access to archives shall be restricted to those individuals.

The media used to archive the content of the clinical trial master file shall be such that the content remains complete and legible throughout the period referred to in the first paragraph.

Any alteration to the content of the clinical trial master file shall be traceable.”

In France, the Data Protection Authority (CNIL) has issued guidance related to “Managing data retention periods.”

2.15 Requirements around periodic safety reporting and timelines on SAEs/AEs/ADRs/SUSARs/DSURs.

Relevant provisions on periodic safety reporting are a part of the EU CTR.

Articles 41 & 42, EU CTR 536/2014, relate to this.  

Art 41 CTR: “Reporting of adverse events and serious adverse events by the investigator to the sponsor

1. The investigator shall record and document adverse events or laboratory abnormalities identified in the protocol as critical to the safety evaluation and report them to the sponsor in accordance with the reporting requirements and within the periods specified in the protocol.

2. The investigator shall record and document all adverse events, unless the protocol provides differently. The investigator shall report to the sponsor all serious adverse events occurring to subjects treated by him or her in the clinical trial, unless the protocol provides differently.

The investigator shall report serious adverse events to the sponsor without undue delay but not later than within 24 hours of obtaining knowledge of the events, unless, for certain serious adverse events, the protocol provides that no immediate reporting is required. Where relevant, the investigator shall send a follow-up report to the sponsor to allow the sponsor to assess whether the serious adverse event has an impact on the benefit-risk balance of the clinical trial...”

Art 42 CTR: “Reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency

1. The sponsor of a clinical trial performed in at least one Member State shall report electronically and without delay to the database referred to in Article 40(1) all relevant information about the following suspected unexpected serious adverse reactions:

(a) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in that clinical trial, irrespective of whether the suspected unexpected serious adverse reaction has occurred at a clinical trial site in the Union or in a third country;

(b) all suspected unexpected serious adverse reactions related to the same active substance, regardless of pharmaceutical form and strength or indication investigated, in investigational medicinal products used in the clinical trial, occurring in a clinical trial performed exclusively in a third country, if that clinical trial is sponsored:

(i) by that sponsor, or

(ii) by another sponsor who is either part of the same parent company as the sponsor of the clinical trial, or who develops a medicinal product jointly, on the basis of a formal agreement, with the sponsor of the clinical trial. For this purpose, provision of the investigational medicinal product or information to a future potential marketing authorization holder on safety matters shall not be considered a joint development; and

(c) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in any of the subjects of the clinical trial, which are identified by or come to the attention of the sponsor after the end of the clinical trial.

2. The period for the reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency shall take account of the seriousness of the reaction and shall be as follows:

(a) in the case of fatal or life-threatening suspected unexpected serious adverse reactions, as soon as possible and in any event not later than seven days after the sponsor became aware of the reaction;

(b) in the case of non-fatal or non-life-threatening suspected unexpected serious adverse reactions, not later than 15 days after the sponsor became aware of the reaction;

(c) in the case of a suspected unexpected serious adverse reaction which was initially considered to be non-fatal or non-life threatening but which turns out to be fatal or life-threatening, as soon as possible and in any event not later than seven days after the sponsor became aware of the reaction being fatal or life-threatening….”.

The ANSM has published guidance within their “Clinical Trials: Procedures for the Constitution and Processing of Application under the European Clinical Trial Regulation on Medicinal Products” section that covers reporting of SAEs/SUSARs and ASR; see below:

•  “Part V: Reporting of Serious and Unexpected Adverse Reactions (SAEs/SUSARs) and Annual Safety Report (RAS/ASR)”

2.16 Requirement on any periodic clinical study update, specific template, and its frequency (e.g., interim or annual progress report and final report, etc.)? 

Annual reports of clinical trials falling within the scope of the EU CTR 536/2014 shall be submitted to the EMA Clinical Trials Information System (CTIS).

Article 43, EU CTR 536/2014:

“1. Regarding investigational medicinal products other than placebo, the sponsor shall submit annually through the database referred to in Article 40(1) to the Agency a report on the safety of each investigational medicinal product used in a clinical trial for which it is the sponsor.

2. In the case of a clinical trial involving the use of more than one investigational medicinal product, the sponsor may, if provided for in the protocol, submit a single safety report on all investigational medicinal products used in that clinical trial.

3. The annual report referred to in paragraph 1 shall only contain aggregate and anonymized data.

4. The obligation referred to in paragraph 1 starts with the first authorization of a clinical trial in accordance with this Regulation. It ends with the end of the last clinical trial conducted by the sponsor with the investigational medicinal product…”.

There are also other reporting/notification requirements, that will be required to be performed within the CTIS, those are:

2.17 Does the local regulation require notification of “serious breaches” of GCP or the trial protocol? 

Yes, notification is required within seven days of becoming aware of the breach (see details below).    

Notification of a Serious Breach allows the sponsor to inform about a breach likely to affect to a significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the clinical trial. These notifications must be made without undue delay but no later than 7 days from the date on which the sponsor became aware of the breach (article 52 of the CT Regulation). 

For more information, refer to the following EMA guidance on notification of serious breaches: 

1. Guideline for the notification of serious breaches of Regulation (EU) No 536/2014 or the clinical trial protocol 
2. Appendix III b – Information to be submitted with a notification of a serious breach

The ANSM has published guidance within their “Clinical Trials: Procedures for the Constitution and Processing of Application under the European Clinical Trial Regulation on Medicinal Products” section that covers notification of serious breaches and other urgent safety measures, see below:

• Part VI: Notification of Unexpected Events Other Than IMETs, Urgent Security Measures, Serious Breaches

2.18 Does RA/CA require insurance and indemnity to cover the sponsor and investigator’s potential liability?

Yes. Articles R1121-4 to R1121-9 of the Public Health Code specify the French insurance requirements to be met by trial sponsors. The full trial name and trial duration are to be specified on the policy and require cover in the amount of €1,000,000 euros per participant claim, €6,000,000 per research protocol, and €10,000,000 for all claims submitted during an insurance year under several research protocols.

The clinical trial insurer must be established within the European Union (see Arts. L310-2 and L 310-10 of the Insurance Code).