No abstract

Advanced therapy medicinal products, a new class of products with promising therapeutic effects, have been classified as medicinal products and as such should be developed according to a well-structured development plan, to establish their quality, safety and efficacy profile and conclude, at the time of the marketing authorisation evaluation, on a positive risk/benefit balance for patients. An important part of this development plan is achieved through clinical trials, which have also to be approved according to a well-established regulatory process, prior any initiation. This chapter is dedicated to describe the regulatory pathway to be followed in France, before initiating any clinical trial with those investigational advanced therapy medicinal products. In France, to get the final authorisation to initiate a clinical trial, the legislation imposes to run in parallel two independent but complementary authorisation procedures. The first procedure is aimed at assessing the ethical aspect of the biomedical research, while the second has to review the safety and regulatory aspects. A third procedure has to be envisaged where in case the investigational product consists or contains a genetically modified organism. The French system herein described is in line with the EU regulation on clinical trial and follows the respective deadlines for granting the final approval. The complexity of the procedure is in fact more due to the complexity of the products and protocols to be assessed than to the procedure itself which is now very close to the well-known procedure applied routinely for more conventional chemical or biological candidate medicinal products.

<b><i>Background:</i></b> Although transmission of pathogenic viruses through human tissue grafts is rare, it is still one of the most serious dreaded risks of transplantation. Therefore, in addition to the detailed medical and social history, a comprehensive serologic and molecular screening of the tissue donors for relevant viral markers for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) is necessary. In the case of reactive results in particular, clear decisions regarding follow-up testing and the criteria for tissue release must be made. <b><i>Methods:</i></b> Based on the clinical relevance of the specific virus markers, the sensitivity of the serological and molecular biological methods used and the application of inactivation methods, algorithms for tissue release are suggested. <b><i>Results:</i></b> Compliance with the preanalytical requirements and assessment of a possible hemodilution are mandatory requirements before testing the blood samples. While HIV testing follows defined algorithms, the procedures for HBV and HCV diagnostics are under discussion. Screening and decisions for HBV are often not as simple, e.g., due to cases of occult HBV infection, false-positive anti-HBc results, or early window period positive HBV NAT results. In the case of HCV diagnostics, modern therapies with direct-acting antivirals, which are often associated with successful treatment of the infection, should be included in the decision. <b><i>Conclusion:</i></b> In HBV and HCV testing, a high-sensitivity virus genome test should play a central role in diagnostics, especially in the case of equivocal serology, and it should be the basis for the decision to release the tissue. The proposed test algorithms and decisions are also based on current European recommendations and standards for safety and quality assurance in tissue and cell banking.

STUDY QUESTION What is the incidence rate of complications in women undergoing ART procedures compared to the period prior to their first oocyte retrieval? SUMMARY ANSWER The study shows a significant increase in the post-ART incidence rate of some complications but a low overall rate of occurrence relative to the total number of oocyte retrievals. WHAT IS KNOWN ALREADY ART, widely used in Europe, accounts for 3.3% of births in France. The various studies of ART complications are fairly reassuring, showing relatively low overall complication rates but only few studies have used exhaustive national registers. STUDY DESIGN, SIZE, DURATION The cohort for this study was identified from the comprehensive French national hospital-discharge database and includes women under 50 years with a first oocyte retrieval (T0) in 2012–2017, classified in three population subgroups according to the indication for oocyte retrieval: infertility (IF), oocyte donation (OD), and fertility preservation (FP). This study includes 156 916 women whose first oocyte retrieval occurred in 2012–2017 and 542 775 hospitalizations in 2010–2019 (excluding first retrieval). PARTICIPANTS/MATERIALS, SETTING, METHODS Hospitalizations for complications or others events (oocyte retrieval, delivery, pregnancy loss, and death in the hospital) during the 2 years before (control period) and after their first oocyte retrieval (post-oocyte retrieval period) were compared and expressed per 10 000 person-months (pm). MAIN RESULTS AND THE ROLE OF CHANCE In the IF subgroup, incidence rates were significantly higher after (vs before) retrieval for hospitalized ovarian hyperstimulation syndrome (OHSS) (162 vs 6/10 000 pm), adnexal torsion (14 vs 3), venous thrombosis (8 vs 1), arterial thrombosis (3 vs 1), trauma (2 vs 1), and significantly lower for infections (61 vs 87). The higher incidences of OHSS, adnexal torsion and venous thrombosis could only partially be explained by the occurrence of pregnancy. In the FP subgroup, incidence increased significantly after (vs before) retrieval for hospitalized OHSS (55 vs 0), venous thrombosis (59 vs 4), and infections (176 vs 56). For the OD subgroup, hospitalized OHSS (116 vs 0) and bleeding (24 vs 0) were significantly higher after (vs before) retrieval. LIMITATIONS, REASONS FOR CAUTION The French national health data system, despite all its advantages, present some limitations such as the risk of coding errors. The unavailability of some personal information and the absence of consideration of risk factors prevented us from adjusting the risk. Finally, only complications resulting in hospitalization were analyzed which probably leads to their underestimation. WIDER IMPLICATIONS OF THE FINDINGS The use of medico-administrative bases will be a valuable tool in public health and will furnish a better overview of the complications. Further studies are needed to complete this analysis. Adding information on drugs would help to better define T0 and less severe complications. STUDY FUNDING/COMPETING INTEREST(S) N/A. TRIAL REGISTRATION NUMBER N/A.

Diseases caused by arboviruses are on the increase worldwide. In addition to arthropod bites, most arboviruses can be transmitted via accessory routes. Products of human origin (labile blood products, solid organs, hematopoietic stem cells, tissues) present a risk of contamination for the recipient if the donation is made when the donor is viremic. This narrative review describes the risks of acquiring certain arboviral diseases from human products, mainly solid organs and hematopoietic stem cells, in the French context. Mainland France and its overseas territories are exposed to a complex array of imported and endemic arboviruses, which differ according to their respective location. The main risks considered in this study are infections by West Nile virus, dengue virus and tick-borne encephalitis virus. The ancillary risks represented by Usutu virus infection, chikungunya and Zika are also addressed more briefly. For each disease, the guidelines issued by the French High Council of Public Health, which is responsible for issuing guidelines to mitigate the risks associated with products of human origin and for supporting public health policy decisions, are briefly outlined. The aim of this review is also to contribute to the standardization of recommendations at international level in areas with the same viral epidemiology.