. Evaluating risk, safety and efficacy of novel reproductive techniques and therapies through the EuroGTP II risk assessment tool.

Study question: Can risks associated with novelties in assisted reproduction technologies (ARTs) be assessed in a systematic and structured way? Summary answer: An ART-specific risk assessment tool has been developed to assess the risks associated with the development of novelties in ART (EuroGTP II-ART). What is known already: How to implement new technologies in ART is well-described in the literature. The successive steps should include testing in animal models, executing pre-clinical studies using supernumerary gametes or embryos, prospective clinical trials and finally, short- and long-term follow-up studies on the health of the offspring. A framework categorizing treatments from experimental through innovative to established according to the extent of the studies conducted has been devised. However, a systematic and standardized methodology to facilitate risk evaluation before innovations are performed in a clinical setting is lacking. Study design, size, duration: The EuroGTP II-ART risk assessment tool was developed on the basis of a generic risk assessment algorithm developed for tissue and cell therapies and products (TCTPs) in the context of the project 'Good Practices for demonstrating safety and quality through recipient follow-up European Good Tissue and cells Practices II (EuroGTP II)'. For this purpose, a series of four meetings was held in which eight ART experts participated. In addition, several tests and simulations were undertaken to fine-tune the final tool. Participants/materials, setting, methods: The three steps comprising the EuroGTP II methodology were evaluated against its usefulness and applicability in ART. Ways to improve and adapt the methodology into ART risk assessment were agreed and implemented. Main results and the role of chance: Assessment of the novelty (Step 1), consisting of seven questions, is the same as for other TCTPs. Practical examples were included for better understanding. Identification of potential risks and consequences (Step 2), consisting of a series of risks and risk consequences to consider during risk assessment, was adapted from the generic methodology, adding more potential risks for processes involving gonadic tissues. The algorithm to score risks was also adapted, giving a specific range of highest possible risk scores. A list of strategies for risk reduction and definition of extended studies required to ensure effectiveness and safety (Step 3) was also produced by the ART experts, based on generic EuroGTP II methodology. Several explanations and examples were provided for each of the steps for better understanding within this field. Limitations, reasons for caution: A multidisciplinary team is needed to perform risk assessment, to interpret results and to determine risk mitigation strategies and/or next steps required to ensure the safety in the clinical use of novelties. Wider implications of the findings: This is a dynamic tool whose value goes beyond assessment of risk before implementing a novel ART in clinical practice, to re-evaluate risks based on information collected during the process. Study funding / competing interest(s): This study was called EUROGTP II and was funded by the European Commission (Grant agreement number 709567). The authors declare no competing interests concerning the results of this study