The new law on research in France introduces changes for the medical device industry by facilitating the conduct of postmarketing studies. Devices will no longer have to be provided free of charge for low-risk interventional studies making France a possible location for such trials in the future.
A new French law on clinical research (No. 2012-300 of March 5, 2012 and Decree 2016-1537 dated November 16, 2016) came into force late last year. Known as the “Jardé Law,” it introduces major changes to a regulatory system which has been relatively stable for the last 30 years. On the other hand, it has the advantage of being better adapted in some respects to clinical research of medical devices and may facilitate the conduct of certain postmarketing studies that were difficult to perform under the previous law. Furthermore, it will bring the French requirements for such studies more into line with those for medical device trials in some of the other major European Union (EU) countries. More importantly, France is the second-largest market for medical devices in Europe and the new rules should facilitate market access by enabling postmarketing trials for clinical evidence development that can also be used to meet increasing EU regulatory requirements for clinical data (MEDDEV 2.7/1 rev.4 and Medical Devices Regulation 2017).
For historical reasons, the previous law governing medical device trials in France, known as the “Huriet Law,” dated 2004, presented a number of disadvantages compared to other EU member states. The original biomedical research law that bears the name of Senator Huriet dates back to 1988, and was developed primarily to regulate clinical research of medicinal products. However, as it had a broad scope (all interventional clinical trials in human subjects), it also applied to medical device trials. One of the limiting factors of the law, and which subsisted in the 2004 version, was the requirement that investigational devices be provided free of charge. As the law did not differentiate between CE marked and non-CE marked devices, this created a deterrent for manufacturers wishing to conduct postmarketing clinical trials, especially those involving expensive devices, e.g., implantables.
Another issue with the previous law was the lack of regulatory framework for non-interventional studies. Registries play an important role in medical device development and regulation, especially of long-term implantable devices such as orthopedic joint replacements. As a general rule, most clinical data on medical devices is generated in the postmarketing phase, rather than pre-market due to the much shorter life cycle of medical technology as compared to medicines. Furthermore, clinical investigations of medical devices under the medical device directives are subject to the harmonized standard ISO 14155, which requires ethics committee (EC) review of clinical investigation protocols. The fact that non-interventional trials conducted in France did not require CPP (Comité de Protection des Personnes) review was an issue for compliance with EU medical device regulation. Furthermore, it created difficulties for acceptance of data for publication in peer reviewed journals.
The new regulatory framework under the Jardé Law resolves the above issues, at the cost of some additional regulatory burden and uncertainty. The key changes with their impact on medical device trials are as follows:
Reclassification of clinical research studies
A key aspect of the new French law is to introduce a new risk-based classification for clinical research, including three different categories: “interventional studies,” “interventional studies with minimal risk or burden,” and “non-interventional studies.” The table below shows how the new classification compares to that of the previous regulation. The new classification brings clinical studies in France in line with the definitions of clinical trials in Directive 2001/20/EC and the new Clinical Trial Regulation (EU) No. 536/2014 (the CTR).
Under the new rules, Category 1 “interventional studies” are subject to the highest regulatory control, requiring full EC (CPP) and competent authority (ANSM) approval. This includes:
Medical devices used in Category 1 trials are provided free of charge as per the new law. Therefore, the cost issue remains for postmarketing highly interventional trials. An example would be a randomized trial with a crossover.
Category 2, “interventional studies with minimal risk or burden,” is new and will now make it easier to conduct certain post-CE marketing trials in France that were previously classified in Category 1, even if the risk of intervention was minimal. As these trials only involve CE marked devices, they are subject to less controls than Category 1 (EC approval and competent authority notification). For the avoidance of doubt when determining whether a trial falls in Category 1 or 2, a decree (Placeholder5) has been published listing specific diagnostic and monitoring procedures that are considered to be non-interventional. Category 2 trials will, however, require specific insurance as for Category 1, but the cost for requisite coverage should be less.
Another major change involves Category 3 studies, which are “non-interventional.” Under the previous law, such studies, also known as registry or observational studies, were not subject to EC approval but rather to approval from the French data protection authorities (CCITRS and CNIL). In addition to longer approval timelines (six to eight months on average), the lack of EC approval led to difficulties for investigators to have their data accepted for publication. The new law establishes the requirement for EC approval but also adds a CA notification procedure. These are studies of CE marked devices used in accordance with their marketing authorization and within standard clinical practice. They require EC approval and competent authority notification, but mandatory clinical research insurance is not required as for the other two categories of research.
The advantage of the new classification system is to make it easier for sponsors to determine which category a study falls into and requirements apply. Furthermore, under the new law, all studies benefit from EC review. Although this may be seen as an impediment for non-interventional studies, it should be noted that this is common practice for non-interventional medical device trials in the majority of other EU member states.
Randomized allocation of ethics committees
This particular change is the most unsettling from a medical device perspective, where an understanding of the medical device technology may be important in making a judgement concerning the research. Under the previous law, EC approval was required for clinical trials in Categories 1 and 2 and the EC was selected according to the geographical location of the coordinating investigator. As a consequence, CPPs in the region of centers of excellence were able to gain a lot of experience in a center’s particular area of specialization by reviewing multiple research projects over a period of time in the same area. This was particularly useful for quickly evolving technologies such as transcatheter heart valves.
Under the new law, CPP approval is required for all three categories of research and the EC is allocated at random via a web-based platform. The purpose is to spread the workload more evenly across all CPPs in France. The disadvantage is that CPPs can no longer be selected based on competency and area of expertise. This will definitely introduce a great degree of uncertainty in the CPP approval process, especially for innovative medical technologies that require specific expertise. On the other hand, under the new law, CPPs are no longer responsible for the review of study methodology. This has been transferred to the competent authority (ANSM) and may mitigate to some extent this uncertainty. Finally, all ECs will come under the oversight of a central body known as the CNRIHP. The law includes the right to appeal.
Category 1 research requires approval from the French CA (ANSM). Approvals are now valid for two years instead of one. Another change is that the role of ANSM has been extended for Category 1 trials to cover methodological review of the research protocol.
Categories 2 and 3 require notification only.
The timelines appear to be approximately the same for research categories 1 and 2. However, the law does not stipulate how long the CA can take to acknowledge that the file is complete and ready to start the 60-day waiting period. On the other hand, for Category 3 trials, the timelines should be shorter than under the current data protection regulations as stated above.
Adverse event reporting
Adverse event reporting requirements under the new French law are in conformity with EU regulatory requirements applicable to medical devices.
Reporting for ‘new information’
The law introduces a specific reporting requirement related to sponsor awareness of “new information” that could have an impact on study safety. “New information” in the French law is defined as any new data that could lead to:
As a consequence, double reporting is required if the “new information” is a serious adverse event.
The new law on clinical research in France introduces long awaited changes for the medical device industry by facilitating the conduct of postmarketing studies. Under the new rules, devices will no longer have to be provided free of charge for low-risk interventional studies as is currently the case in other EU member states, making France a possible location for such trials in the future. Given the importance of the French market within Europe, this is a significant development.
Victor Bony is Assistant, New Business Development, Medpass