Note – Amended text in RED
Décret n° 2016-1537 du 16 novembre 2016: publication in the French Official Journal of a decree concerning research involving the human person
Decree No. 2016-1537 of 16 November 2016, published in the Official Gazette of 17 November 2016, is now in force.
- It specifies the modalities for research involving humans.
- This includes non-interventional research, previously excluded from the bio-medical research framework.
- It specifies in particular the definitions applicable to the various categories of research, the functioning of the Committees for the Protection of Persons (CPP) and of the National Commission for Research Involving the Human Person.
- The text became applicable on the day after its publication, on November 18, 2016.
Some Definitions under the new decree concerning research involving the human person:
The most recent legislative name, “research involving the human person”, applies to all research designed to increase scientific knowledge (and not related to medical care), whether or not involving an intervention.
If an intervention, even minimal, is not dictated by the medical care of the patient, it is considered as “interventional research”.
The law implemented by the decree of November 17, 2016 distinguishes three types of research:
Type 1 – Interventional research with risk above minimal risk (recherche interventionelle or RM) corresponds to the previous understanding of biomedical research on drugs, medical devices, other health products or research without health products. (Type 1 research / Art. L1121-1 1° CSP)
- Here an authorization of ANSM and the authorization of a research facility for phases I research remain required. Research on healthy volunteers, in which even minimal risk is not balanced by potential benefit, may fall into this category.
Type 2 – Interventional research that involves minimal risks and constraints (recherche interventionelle avec risques minimes or RIRM) is consistent with the previous research category of routine care evaluation (‘soins courants’ does not equal NIS), but also with research that is not routine care evaluation and which involves minimal constraints/risks. (Type 2 research / Art. L1121-1 2° CSP)
- These must be declared to the ANSM but do not require authorization. They benefit from a simplified procedure.
- Minimal risk research requires insurance.
- It is the importance of the risk or constraint imposed that defines the category. The acceptable threshold of risk or constraint will be defined by a list drawn up by the DGS (Direction Générale de la Santé).
- In healthy volunteers, any intervention without an expected benefit will remain a type 1-research intervention.
Type 3 – Non-interventional research does not involve any risk or constraint added by the research, or any modification of the usual care. (Type 3 research / Art. L1121-1 3° CSP)
In this context, distinguish 2 subtypes:
- Type 3a – Research with patients are involved, even without risk (may include taking a blood sample or by a questionnaires). It is the involvement of the patients that defines the research.
- Such research must have a sponsor, a favorable opinion of a CPP (EC) and requires notification to the ANSM including the CPP approval.
- Study-specific insurance is not required.
- Patient Information must be provided, but oral non-opposition may replace informed consent.
- Type 3b – Research concerns only data, already collected or to be obtained from collections or old samples. This research does not fit into the ANSM-CPP circuit, but should be sent to the CEREES (Committee for Expertise in Research, Studies and Evaluations in the field of Health) for advice (to the CCTIRS until April 2017).
The generation of a collection of elements of human origin and the change of purpose of such a collection or of a collection generated earlier must also obtain the favorable opinion of a CPP.
It is the sponsor who qualifies a research project in one of the categories above. But the CPP or the ANSM can refuse this classification and re-qualify a project. Thus, before presenting a complete file unnecessarily, the sponsor can ask the CPP for a preliminary advice on the typology of a research.
Non-interventional or observational research is subject to notification to ANSM and the approval of a CPP if they involve patients.
The only research type out of scope in this context is retrospective research on previously collected data.
Follow-up cohorts of patients whose medical care is under good practice, epidemiological research, in summary, all prospective research without intervention even in normal clinical care, fall within this framework.
It is recognized that for the purposes of research, there may be a small volume blood sample taken on the occasion of a blood test for diagnosis, or a complementary examination without risk, or questionnaires in moderate number and without any psychological impact. But the limit with type 2 research is currently blurred.
All research submission dossiers type 1, 2 or 3a must be registered with the ANSM and receive a registration number. At present it is not clear how these registrations are completed in practice, except for Eudract number (type 1).
The pilot phase for EU regulation No. 536/2014 recently initiated by ANSM does not concern non-interventional trials or research aimed at assessing routine care.
Information on the future registration of non-interventional research with ANSM was not found with available resources.
Article L1121-4 CSP as modified by ordinance no. 2016-800 of 16 June 2016 states in this context that research referred to in 2 ° of Article L. 1121-1 and non-interventional research may only be carried out after a favorable opinion has been given by the CPP referred to in Article L. 1123-1. The applicant shall send a copy of this approval and a summary of the research to the competent authority. At the latter’s request, the CPP (comité de protection de personnes) shall send all relevant information concerning the research to the competent authority without delay.
Type 3a submissions can be sent directly to a CPP.
- A set documents to submit the CCPs for the evaluation of a non-interventional or observational research project is not yet fully defined but shall contain at least the following elements:
- signed and dated request for opinion letter
- versioned, signed and dated study protocol
- protocol summary
- patient information document
- patient informed consent document or the procedure for obtaining the non-opposition statement
- investigator CVs
No study specific insurance shall be required.
Concerning type 1 and 2 research (interventional research and interventional research with minimal risks), these must be allocated to a CPP by lot. For this purpose, the sponsor must address the registration number, title and type of the project to the National Commission for Research Involving Humans.
Acknowledgements: Special thanks to Mark Heinemann who authored this article.
Mark is an expert on non-interventional study (NIS) practices and country-specific submission processes. Mark has more than 15 years of experience in phases II-IV across multiple therapeutic areas. He has provided regulatory guidance for multiple global studies. Mark works within inVentiv Health Clinical’s Late Stage Regulatory Consulting group as a Principal Regulatory Specialist.