Key Benefits:
Minister of Social Affairs and Health,
Having regard to Directive 2001/20/EC on the approximation of the legislative, regulatory and administrative provisions of the Member States relating to the application of good clinical practices in conducting clinical trials of drugs for human use;
In view of the communication from the European Commission 2011/C 172/01, detailed information on the preparation, verification and presentation of reports on adverse events/effects based on clinical trials of human drugs ("CT-3");
Vu le Public Health Codearticles L. 1123-10, R. 1123-39 to R. 1123-44, R. 1123-47 and R. 1123-52 to R. 1123-54;
On a proposal by the Director General of the National Drug and Health Products Safety Agency,
Stop it!
The safety reference information referred to in 7° of article R. 1123-39 of the Public Health Code allowing the proponent of a biomedical research on a human-use drug to determine the expected nature of an adverse reaction, are:
either in a section of the brochure for the investigator clearly defined for this purpose;
either in the summary of the characteristics of the product, in the case of an experimental drug with a marketing authorization in a Member State of the European Union and used in accordance with the conditions defined by this authorization. If the experimental drug has a marketing authorization in several Member States of the European Union concerned, the promoter chooses the summary of the characteristics of the product including the most appropriate information in terms of security of persons as a safety reference information.
The request letter provided on the occasion of the application for a search authorization from the National Drug Safety Agency and Health Products specifies whether the safety reference information for the test concerned is mentioned in the brochure for the investigator or in the summary of the product characteristics.
The expected character of a suspected adverse reaction is appreciated at the time of its appearance in the light of the last modified version of the safety reference information approved by the National Drug Safety Agency and Health Products.
The investigator assesses each adverse event with respect to its severity.
It also assesses each adverse event likely to be due to the experimental drug and, where applicable, other possible treatments and transmits the results of this evaluation to the sponsor.
The promoter evaluates the safety of each experimental drug on a continuous basis throughout the research.
It puts in place a written system and procedures to ensure the quality of the collection, documentation, evaluation, validation, archiving and reporting of cases of adverse events and effects as well as new facts mentioned in theArticle L. 1123-10 of the Public Health Code.
It assesses each adverse event reported by an investigator with regard to its severity.
For each serious adverse event suspected of being due to the experimental drug and other possible treatments, it assesses the causal link and the unexpected character of these events.
When the causal link assessments conducted by the investigator and the proponent differ, they are both referred to in the declaration provided for in the articles R. 1123-51 and R. 1123-56 Public Health Code.
The promoter of a biomedical research on a licensed human-use drug in at least one research site in France states to the National Agency for the Safety of Medicine and Health Products:
1. Suspects of unexpected serious adverse events occurring during the research.
2. Suspects of unexpected serious adverse effects related to the same active substance as that of the experimental drug of the research concerned during another research conducted exclusively in a third country to the European Union or in another Member State of the European Union, if this research is:
promoted by the same promoter; or
― promoted by another promoter who belongs to the same parent company or develops a drug jointly, on the basis of a formal agreement, with that other promoter.
The content and reporting format of unexpected serious adverse event suspicion are consistent with sections 7.7 and 7.9 of the European Commission's detailed indication of the preparation, verification and reporting of adverse events/effects based on clinical trials of human-use drugs ("CT-3").
The initial statement of suspicion of serious and unexpected adverse reaction is made as soon as possible and at the latest within the time limits provided by theArticle R. 1123-47 of the Public Health Codeas soon as the proponent is aware of at least the following:
1. The name of the experimental drug suspected of having led to the occurrence of the adverse reaction.
2. The existence of a person who has presented the adverse reaction, identifiable, in particular by its code number identifying in the research concerned.
3. A suspicion of adverse reaction considered serious and unexpected.
4. An investigator or other identifiable notifier.
5. The unique search identifier (EuraCT number, if applicable).
6. The research protocol number assigned by the proponent.
7. An assessment of causality.
The electronic transmission of this initial declaration refers to the following information:
(a) The unique identifier of the sender's security report;
(b) The date of receipt of initial information from the primary source;
(c) The date of receipt of the most recent information;
(d) The effect identification number;
(e) The sender ID.
If all required information cannot be provided at the time of the initial statement of suspected unexpected serious adverse reaction, the promoter searches for any relevant additional information and address in the form of a follow-up report, referenced and numbered, in the same manner as those relating to the initial declaration of suspected unexpected serious adverse reactions and within the time limits provided for in theArticle R. 1123-47 of the Public Health Code.
In the case of a suspicion of serious and unexpected adverse reaction that led to death or endangered life while it was not initially considered to be such, the promoter transmits, without delay and no later than seven days from the time it is aware of it, a combined report if this suspicion of serious and unexpected adverse reaction has not yet been the subject of an initial declaration.
The suspicions of serious and unexpected adverse reactions are transmitted electronically to the European Eudravigilance database on the adverse effects of drugs established by the European Agency for Drugs.
In addition, the proponent declares every suspicion of serious and unexpected adverse reaction to the National Drug and Health Products Safety Agency, by e-mail including the following documents in available format on the website of the National Drug Safety Agency and Health Products:
- a form for reporting a serious and unexpected adverse reaction suspicion;
- an accompanying form.
If the transmission of suspicions of unexpected serious adverse events to the National Drug Safety Agency and health products by email is made impossible, the promoter sends them by mail.
The promoter addresses suspicious reports of unexpected serious adverse reactions to articles R. 1123-42 of the Public Health Codeby mail to the protection committee of the persons concerned.
In the event of unsuspected research, where an undesirable event may be a serious and unexpected adverse event, the promoter lifts the unsuspected for the person concerned prior to reporting a suspected unexpected serious adverse event to the National Drug and Health Products Safety Agency and the Protection Committee for the persons concerned.
However, in exceptional cases, in the case of research involving a high mortality and/or morbidity pathology, where the criteria for the assessment of the research, as defined in the protocol, could also be an unexpected serious adverse effect to be the subject of an immediate declaration, the promoter may, at the time of his application for research authorization, seek the agreement of the National Agency for the Safety of Drugs and Health Products in order to provide for the purpose of These procedures for raising the knowledge and reporting suspicions of adverse effects are then defined precisely in the research protocol or in a document attached to it.
An independent monitoring committee, as mentioned in theArticle L. 1123-7 of the Public Health Code, is then set up by the promoter. Its composition and operating procedures are described in the protocol. The National Drug and Health Products Safety Agency may request access to the decisions or recommendations of the Independent Oversight Committee and the elements on which the committee relied to make any decisions or recommendations.
Anything new mentioned in theArticle L. 1123-10 of the Public Health Code, including any new safety data that may lead to a re-evaluation of the report of the benefits and risks of research or experimental drug or that may be sufficient to consider changes in the administration of the experimental drug, in the conduct of the research, or research documents are reported under the conditions set out in this section.
The proponent addresses the statement on a new fact electronically or, in the event of impossibility, by mail, to the National Drug and Health Products Safety Agency and the Protection Committee for the persons concerned.
The declaration of a new fact includes the following information:
1. The unique identifier of biomedical research.
2. The title of biomedical research.
3. The protocol code number assigned by the proponent.
4. A summary of the new fact and appropriate urgent security measures taken by the proponent.
5. Any relevant information for the assessment of the new fact.
The proponent addresses in the same manner, and in the form of a follow-up report of the fact new, within the time limit set by theArticle R. 1123-47 of the Public Health Codeany relevant additional information relating to this new fact.
The decision of May 24, 2006 establishing the form, content and terms of adverse reaction reports and developments in biomedical research involving a human drug is repealed.
The Director General of the National Agency for the Safety of Medicine and Health Products and the Director General of Health are responsible for the execution of this Order, which will be published in the Official Journal of the French Republic.
Done on 14 April 2014.
For the Minister and by delegation:
The Director General of Health,
B. Vallet
