5. Investigator and Investigational Product

5.1 Does local regulation require PI/CI to be approved/registered by any health authority (e.g., RA/EC)?  

No. Local Regulations do not require a PI/CI to be approved by a Health Authority, though they must meet the criteria (as indicated in Section 2.10 of this guidebook).

5.2 Does local regulation require any specific documents if PI/CI is based outside the country?

Not specified by the national regulations.

5.3 Does local authority allow electronic ICF administration, including electronic signatures?

Yes, electronic administration of ICF is permitted, including electronic signatures. Please refer to the discussion in Sections 7.7 and 7.8 of this guidebook.

5.4 Does local regulation require ICF to be administered as audio/visual and do these need to be recorded?

Yes, ICF may be administered in an Audio/Visual form and this must be recorded, as required by Article 29(1) of the EU CTR 536/2014, which reads as follows:

"Informed consent shall be written, dated and signed by the person performing the interview referred to in point (c) of paragraph 2, and by the subject or, where the subject is not able to give informed consent, his or her legally designated representative after having been duly informed in accordance with paragraph 2. Where the subject is unable to write, consent may be given and recorded through appropriate alternative means in the presence of at least one impartial witness. In that case, the witness shall sign and date the informed consent document. The subject or, where the subject is not able to give informed consent, his or her legally designated representative shall be provided with a copy of the document (or the record) by which informed consent has been given. The informed consent shall be documented. Adequate time shall be given for the subject or his or her legally designated representative to consider his or her decision to participate in the clinical trial."

5.5 Is there any specific information/requirement on data capture/management (e.g., privacy regulations, etc.)?

The EMA’s final guidance of 09 March 2023 on Computerized Systems and Electronic Data in Clinical Trials includes the following:

“6.1. Data capture and location 

The primary goal of data capture is to collect all data required by the protocol. All pertinent observations should be documented in a timely manner. The location of all source data should be specified prior to the start of the trial and updated during the conduct of the trial where applicable. 

6.1.1. Transcription 

Source data collected on paper (e.g. worksheets, paper CRFs or paper diaries or questionnaires) need to be transcribed either manually or by a validated entry tool into the EDC system or database(s). In case of manual transcription, risk-based methods should be implemented to ensure the quality of the transcribed data (e.g. double data entry and/or data monitoring).

6.1.2. Transfer 

Trial data are transferred in and between systems on a regular basis. The process for file and data transfer needs to be validated and should endure that data and file integrity are assured for all transfer. 

Data that is collected from external sources and transferred in open networks should be protected from unwarranted changes and secured/encrypted in a way which precludes disclosure of confidential information. 

All transfers that are needed during the conduct of a clinical trial need to be pre-specified. 

Validation of transfer should  include appropriate challenging test sets and ensure that the process is available and functioning at clinical trial start (e.g. to enable ongoing sponsor review of diary data, lab data or adverse events by safety committees). Data transcribed or extracted and transferred from electronic sources and their associated audit trails should be continuously accessible (according to delegated roles and corresponding access rights). 

Transfer of source data and records where the original data or file is not maintained is a critical process and appropriate considerations are expected in order to prevent loss of data and metadata. 

6.1.3. Direct capture 

Direct data capture can be done by using electronic data input devices and applications such as electronic diaries, electronic questionnaires, and eCRFs for direct data entry. Where treatment-related pertinent information is captured first in a direct data capture tool such as a trial participant diary, a PRO form or a special questionnaire, a documented procedure should exist to transfer or transcribe information into the medical record, when relevant.

Direct data capture can be done by automated devices such as wearables or laboratory or other technical equipment (e.g. medical imaging, electrocardiography equipment) that are directly linked to a data acquisition tool. Such data should be accompanied by metadata concerning the device used (e.g. device version, device identifiers, firmware version, last calibration, data originator, timestamp of events). 

6.1.4. Edit checks 

Computerized systems should validate manual and automatic data inputs to ensure a predefined set of validation criteria is adhered to. Edit checks should be relevant for the protocol and developed and revised as needed. Edits checks should be validated and implementation of the individual edit checks should be controlled and documented. If edit checks are paused at any time during the trial, this should be documented and justified. Edit checks could be either run immediately at data entry or automatically during defined intervals (e.g. daily) or manually”.

Clinical trials conducted in France must comply with GDPR and French Law No. 78-17 of the 6 of January 1978 (as amended) relating to data processing, files, and civil liberties.

5.6 If a clinical study involves the study product as OTC and this is provided via pharmacy/amazon, etc., are there any specific regulations for IP management that need to be followed?

The EU CTR 536/2014 does not mention OTC but instead, they are using the term of Auxiliary Medicinal Product (AMP), which is defined in Art 2 (8) as “a medicinal product used for the needs of a clinical trial as described in the protocol, but not as investigational medicinal product”.

Art 2. (10) goes further on the AMP clarification indicating: “a medicinal product authorized in accordance with Regulation (EC) No 726/2004, or in any Member State concerned in accordance with Directive 2001/83/EC, irrespective of changes to the labelling of the medicinal product, which is used as an auxiliary medicinal product”.

In March 2024, the EMA updated the recommendations on “Auxiliary Medicinal Products in Clinical Trials”. These recommendations can also be found in Chapter III- Quality section under the Eudralex Volume 10. This publication provides additional clarifications, such as:

“Examples are medicinal products used as rescue medication, challenge agents, to assess end-points in the clinical trial, or background treatment. Further, the medicinal product should be related to and relevant for the design of the clinical trial, which excludes ‘concomitant medications’. As outlined in preamble 54 concomitant medications is unrelated to the clinical trial and not relevant for the design of the clinical trial”. For further definition and examples, see Annex 1 of this document."

Therefore, an authorized or marketed medicinal product (i.e.: Auxiliary Medicinal Product) used in a clinical trial will need to comply with the requirements set within the EU CTR and will be labeled accordingly.

5.7 For a marketed study product/OTC, can a participant be compensated after confirmation of the purchased study product, or upfront prior to product acquisition? Does compensation in any way impact how the study is viewed (i.e., RWE vs. Interventional Study)?

National provisions do not directly address this topic.

At a European level, the purchase of study product potentially conflicts with the provisions of Annex VI of the Clinical Trial Regulation (EU) 536/2014, which provides, at C.7, in respect of authorized investigational products, that:

“the following particulars shall appear on the immediate and the outer packaging:

(a) name of the main contact;

(b) clinical trial reference code allowing identification of the clinical trial site, investigator, sponsor, and subject;

(c) 'For clinical trial use only' or similar wording”.

Investigational products should be free for participants. According to Art 92, Clinical Trial Regulation (EU) 536/2014:

“Investigational medicinal products, other products and procedures, free of charge for the subject.

Without prejudice to the Member States' competence for the definition of their health policy and for the organization and delivery of health services and medical care, the costs for investigational medicinal products, auxiliary medicinal products, medical devices used for their administration and procedures specifically required by the protocol shall not be borne by the subject, unless the law of the Member State concerned provides otherwise.” 

5.8 Is it permitted to pay participant stipends (i.e., is it permitted to pay the patients for their participation in the clinical trial)? If so, what is the average range?

Yes, but adequate compensation only.

Art. 1121-11 of the Public Health Code, states the following:

“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…”

According to the “Order of 15 Feb 2023”, the total amount of compensation payable to a clinical trial subject cannot exceed EUR6,000 over a period of 12 consecutive months. This compensation can be made in kind, in which case the sponsor must evaluate the value of the advantages in kind provided to participants and justify their use based on the specificities of the trial conducted or those of the target population.

Compensation to study participants must be detailed on the “Payment Compensation Template” and be submitted under Part II of the CTA.

The Informed Consent needs to contain language regarding reimbursement of expenses:

"Research-related costs are entirely covered by the Sponsor, participation in the study is unpaid. Reimbursement of travel expenses, accommodation, meals, and where applicable, days not worked and terms of reimbursement.”

5.9 Specific labeling requirements for clinical study product

The ANSM has published guidance for clinical drug trials in accordance with EU CTR provisions, in several volumes. Part II, entitled “Application for initial authorization, notifications relating to the start of the trial and conversion procedure”, contains guidance for the labeling of experimental and auxiliary medicine in Appendix 2 and describes criteria to be met in two different scenarios. Please note that the guidance is published in French, and this is an unofficial translation.

Scenario 1: Investigational medicinal product and auxiliary medicinal product without marketing authorization

The following information must appear on the outer packaging and primary packaging:

1. information to identify contact persons or persons participating in the clinical trial;
2. information to identify the clinical trial;
3. information enabling the drug to be identified;
4. information relating to the use of the drug.

Detail required on the label of unauthorized IMP:

1. the name, address, and telephone number of the person to be contacted in priority for any information on the IMP, on the clinical trial, and on the emergency unblinding;
2. the name of the substance and its dosage or activity, and in the case of blinded clinical trials, the name of the substance must appear, together with the name of the placebo, both on the packaging of the unauthorized IMP and on that of the placebo;
3. the pharmaceutical form, the route of administration, and the quantity of dose units;
4. lot number or code identifying the contents and operation of the package;
5. a clinical trial reference code;
6. participant identification number and/or processing number and, if applicable,
7. the visit number;
8. the name of the investigator (if it is not already indicated in a) or e);
9. the instructions for use;
10. the mention “reserved for clinical trials”, or a formula equivalent;
11. storage conditions;
12. duration of use expressed in months and years;
13. the statement “keep out of reach of children”, unless the drug is intended for clinical trials in which participants do not take it home.

Symbols or pictograms may appear to explain some of the information mentioned above, as well as additional information, warnings, or handling instructions.

Reduced labeling for primary packaging:

The EU CTR provides for restricted labeling for primary packaging when the primary packaging and the outer packaging are supplied together and the outer packaging contains all the data listed above, or the primary packaging takes the form of blisters or small units such as ampoules, on which it is not possible to include the information indicated above, in which case these particulars must appear on a label affixed to the outer packaging.

The primary packaging then comprises the following elements:

1. the name of the main contact;
2. the pharmaceutical form, the route of administration, the quantity of dose units, and, in the case of a clinical trial without a blinding procedure, the name/identifier of the product and its strength/activity;
3. the batch number and/or the code identifying the contents and the operation of the packaging;
4. a clinical trial reference code;
5. the participant’s identification number and/or treatment number and, if applicable, the visit number;
6. duration of use expressed in months and years.

Detail of the content of the labeling of unauthorized experimental medicine:

The primary packaging and outer packaging of unauthorized IMP must include the following information:

1. the name of the main contact;
2. the name of the medicinal product, its strength, and its pharmaceutical form;
3. the qualitative and quantitative composition of active substances per unit dose;
4. the batch number or the code making it possible to identify the content and operation of the packaging;
5. an EC reference code;
6. instructions for use (or a reference to a leaflet or other explanatory document intended for the participant or the person responsible for administering the MA);
7. the statement “reserved for clinical trials”, or an equivalent formula;
8. the storage conditions;
9. the period of use in months and years.

Scenario 2: Experimental and auxiliary medicine which is authorized (MA granted)

When IMP is authorized, two types of labeling are possible:

1. the content of the complete “clinical trials” labeling as detailed above for each;
2. or their commercial labeling.

If the specific circumstances of a clinical trial, as provided for in the protocol, require the guarantee of safety of a participant or the reliability and robustness of data obtained during the clinical trial, the authorized IMP must be labeled with commercial drug labeling and additional labeling on the primary packaging and outer packaging containing the following information:

1. the name of the main contact;
2. a clinical trial reference code;
3. the statement “reserved for clinical trials”, or equivalent wording.

5.10 What documents need to be submitted (including relevant fee if any), and to whom, if a permit is needed for an investigational/study product being shipped from outside the country? Are there any specific requirements for biologics?

Please refer to Sections 2.6 and 2.7 of this guidebook.

5.11 What is the turn-around time to get an import permit?

From the research conducted, a timeline was not evident. Please refer to Section 2.6 for procedural details.

5.12 Does local authority allow the destruction of clinical supplies at an off-site location (e.g. third-party vendor in or outside the country) after study completion? Are certificates of destruction required?

From the research conducted, this was not evident, but it is expected that the ANSM would permit the destruction of clinical supplies at an off-site location as described.