Clinical investigation: which type for which need?

The application of the European regulation regarding medical devices is fast approaching, and many manufacturers will have to bring their clinical activities into compliance. Indeed, many clinical evaluations are still based on a demonstration of equivalence. As specified in MDR 2017/745 (Article 61, paragraph 5), the use of the demonstration of equivalence will only be authorized in the event of a contract authorizing the sharing of technical data between the two manufacturers. This requirement will then make the clinical investigation mandatory.

In order to define the type of clinical investigation to be implemented, it is necessary to consider the innovative nature of the device and its stage of development (before CE marking, after placing on the market, etc.).

In the case of a highly innovative medical device, it is recommended before placing it on the market to conduct a “First In Man” investigation, or feasibility study. After obtaining the necessary preclinical evidence, this first human trial allows certain adjustments to be made and the acceptability/suitability of the technique to be assessed. It is important to note that at this stage, this study does not demonstrate performance and is equivalent in value to a series of cases. However, First In Man investigations are essential if there is no data on this type of product in humans.

A feasibility study, without necessarily being a First In Man, can also make it possible to refine certain methodological points of the clinical investigation protocol, before generalizing it to a larger population (ex: reaction of the investigators to a new methodology or a new technology, draw methodology, etc.)

A “Pivot” study is a comparative study, a series of cases sufficient to allow the statistical analysis of the performance and safety criteria that the manufacturer wishes to demonstrate.

Finally, a PMCF (or Post-Market Clinical Follow-up) type investigation is carried out once the device is on the market. It can be observational in routine care, retrospective, “Pivot”, on registers, etc. For example, when the post-marketing follow-up does not claim the addition of a new indication or the extension of the device to a new population, a simple observational study covering all indications and populations claimed by the manufacturer may be sufficient.

As part of the monitoring of its device used in real life, the manufacturer must set up post-marketing clinical follow-up (SCAC/PMCF).

In France, the Jardé law (05/03/2012) distinguishes three types of Research Involving the Human Person (RIPH). Type 1 interventional RIPH involve an intervention on the person not justified by their usual care. Type 2 interventional RIPH carry only minimal risks and burdens. Finally, type 3 non-interventional RIPH correspond to observational studies, in which the products are used in the usual way, without additional or unusual diagnostic, treatment or monitoring procedures.

For its part, European regulation 2017/745 differentiates between pre- and post-CE marking investigations.

CE pre-marking clinical investigations include First In Man type studies, feasibility study, “Pivot” study or RIPH 1 studies. These investigations allow the establishment of device compliance with general performance and safety requirements. Post-CE marking clinical investigations, on the other hand, aim to further evaluate a device within the limits of its intended purpose. They include the PMCF studies, or RIPH2 and RIPH 3 according to the Jardé law.

Finally, the manufacturer can set up Research Not Involving Human Persons (RNIPH). More specifically, these are studies that do not meet the definition of research involving the human person within the scope of the Jardé law, in particular studies or evaluations relating to the reuse of existing data (medical records, medical databases, -administrative, etc.), otherwise known as retrospective studies.

To be able to begin its clinical investigation pre-marking CE or PMCF for the addition of a new indication, the sponsor (often the manufacturer) must have received a favorable opinion from the Committee for the Protection of Persons (CPP) and authorization from the National Agency for the Safety of Medicines and Health Products (ANSM).

Under the Jardé law, post-marketing investigations (RIPH 2 and RIPH 3) only require a request for an opinion from the CPP.

The RNIPH requires a prior favorable opinion from the Committee of Expertise for Research, Studies and Evaluations in the field of Health (CEREES) via the platform of the National Institute of Health Data (INDS).

It is also necessary to register any clinical investigation in the European database EUDAMED.

Finally, as part of the collection of the patient’s personal data, the promoter must request authorization from the Commission Nationale de l’Informatique et des Libertés (CNIL) and will ensure compliance with the requirements of the General Regulations on the Protection of Data (GDPR).

In the current context, where the demand for compliance with European regulations is strong and urgent, Efor brings its expertise to its MD manufacturer clients. Our experts in clinical evaluation and clinical investigation will support you, from the implementation phase of the strategy to the drafting of the report, while remaining available and open to providing tailor-made support.