Cost-Effectiveness of Follitropin Delta Compared with Follitropins Alfa and Beta in Controlled Ovarian Stimulation for Assisted Reproductive Technologies (ART) in France.

Across clinical trials, follitropin delta was found to be more effective than follitropins alfa and beta for women with elevated anti-Müllerian hormone (AMH) levels undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Additionally, follitropin delta provided an economically attractive treatment alternative to follitropin alfa and beta and was cost saving when excluding the cost of delivery for the additional live births.

Model results are presented in Table 4 . Treatment with follitropin delta was associated with a 4.1% higher OP rate and 5.6% higher LB rate ( p  = 0.01) than treatment with follitropins alfa and beta in women with an elevated AMH level, ≥ 15 pmol/L. Moreover, treatment with follitropin delta was associated with 1.5% fewer miscarriages and 3.3% fewer OHSS events compared with other follitropins. Table 4 Health outcomes, costs, and cost-effectiveness results in women with an elevated AMH level, ≥ 15 pmol/L—base case analysis Follitropin delta Follitropin alfa Follitropin beta Health outcomes (%) OP rate 35.7 31.6 31.6 LB rate 31.4 25.8 25.8 Miscarriage rate 4.3 5.8 5.8 OHSS rate 8.2 11.5 11.5 Costs (€) Acquisition of follitropins 366 381 432 COS and ART process 3374 3423 3423 OHSS management 186 222 222 Pregnancy until OP 173 165 165 Delivery 1380 1144 1144 Pregnancy until LB a 1553 1309 1309 Total without delivery (until OP) 4099 4191 4243 Total with delivery (until LB) 5479 5335 5387 Cost-effectiveness results Simulation until OP  OP rate 35.7 31.6 31.6  Total costs 4099 4191 4243  ICER (€/OP) Reference Dominated Dominated Simulation until LB  LB rate 31.4 25.8 25.8  Total costs 5479 5335 5387  ICER (€/LB) 2579 Reference b Dominated AMH anti-Müllerian hormone, ART assisted reproductive technologies, COS controlled ovarian stimulation, ICER incremental cost-effectiveness ratio, LB live birth, OHSS ovarian hyperstimulation syndrome, OP ongoing pregnancy a Sum of cost of pregnancy until OP and delivery cost b Comparative treatment option with the lowest total cost is used to estimate the ICER of follitropin delta (follitropin alfa is assumed similarly effective to follitropin beta, but it is less expensive in total) Health outcomes, costs, and cost-effectiveness results in women with an elevated AMH level, ≥ 15 pmol/L—base case analysis AMH anti-Müllerian hormone, ART assisted reproductive technologies, COS controlled ovarian stimulation, ICER incremental cost-effectiveness ratio, LB live birth, OHSS ovarian hyperstimulation syndrome, OP ongoing pregnancy a Sum of cost of pregnancy until OP and delivery cost b Comparative treatment option with the lowest total cost is used to estimate the ICER of follitropin delta (follitropin alfa is assumed similarly effective to follitropin beta, but it is less expensive in total) The average dose of follitropin delta (73.5 µg) was lower than the average dose of follitropins alfa and beta (105.3 µg) in women with an elevated AMH level, ≥ 15 pmol/L. This difference led to lower treatment costs with follitropin delta compared with other follitropins. The total costs associated with follitropins alfa and beta were €4191 and €4243, respectively, until achieving OP while the total cost associated with follitropin delta was €4099. The lower cost is mainly due to the reduction in total drug costs with follitropin delta compared with follitropin alfa and beta and avoided OHSS events. Hence, treatment with follitropin delta is more effective and less costly than other follitropins, leading to a dominant treatment strategy when the endpoint is additional OP. When the endpoint is additional LB, the total cost associated with follitropins alfa and beta increases to €5355 and €5387, respectively, while the total cost associated with follitropin delta rises to €5479. The added costs primarily reflect the costs of delivery. These results led to an incremental cost-effectiveness ratio (ICER) of €2579/LB for follitropin delta versus follitropin alfa. Sensitivity analyses confirmed the robustness of the analysis. Results of DSA expressed as the difference in net benefit per additional OP threshold and in cost per additional LB threshold showed that the most sensitive parameters were the IVF/ICSI use, transition probabilities, and the unit cost of LB (Fig. 3 ). In the PSA, for the cost per OP, follitropin delta was cost effective (dominant) in >  76% of simulations until OP versus other follitropins at a zero willingness-to-pay (WTP) threshold and had 98% probability of being cost effective at a WTP of €4500 per OP. For the cost per LB, follitropin delta had 20% probability of being cost effective at a zero WTP threshold and had 80% probability of being cost effective at a WTP threshold of €4500 per LB (Fig. 4 ). Fig. 3 DSA results until OP and LB of follitropin delta versus follitropin alfa. Comparative treatment option with the lowest total cost (follitropin alfa) is used to estimate the DSA of the ICER of follitropin delta. COS controlled ovarian stimulation, DSA deterministic sensitivity analysis, ICSI intracytoplasmic sperm injection, IVF in vitro fertilization, LB live birth, OP ongoing pregnancy Fig. 4 Incremental PSA results until OP and LB on the cost-effectiveness plane (1000 iterations). Comparative treatment option with the lowest total cost (follitropin alfa) is used to estimate the PSA of the ICER of follitropin delta. ICER incremental cost-effectiveness ratio, LB live birth, OP ongoing pregnancy, PSA probabilistic sensitivity analysis DSA results until OP and LB of follitropin delta versus follitropin alfa. Comparative treatment option with the lowest total cost (follitropin alfa) is used to estimate the DSA of the ICER of follitropin delta. COS controlled ovarian stimulation, DSA deterministic sensitivity analysis, ICSI intracytoplasmic sperm injection, IVF in vitro fertilization, LB live birth, OP ongoing pregnancy Incremental PSA results until OP and LB on the cost-effectiveness plane (1000 iterations). Comparative treatment option with the lowest total cost (follitropin alfa) is used to estimate the PSA of the ICER of follitropin delta. ICER incremental cost-effectiveness ratio, LB live birth, OP ongoing pregnancy, PSA probabilistic sensitivity analysis Alternative assumptions had moderate impact on the results and did not change the dominance of the treatment with follitropin delta. In the overall population, treatment with follitropin delta was associated with 1.3% higher OP rate and 2.7% higher LB rate than treatment with other follitropins and was associated with 1.4%-point fewer miscarriages and 2.1%-point fewer OHSS. The average dose of follitropin delta (84.7 µg) was lower than the average dose of other follitropins (106.9 µg) and led to lower treatment costs with follitropin delta compared with other follitropins. The total costs associated with follitropin alfa and follitropin beta were €4125 and €4176, respectively, until OP while the total cost associated with follitropin delta was €4084. Thus, treatment with follitropin delta is more effective and less costly than other follitropins, dominating follitropin alfa and beta treatment strategy until OP in the overall population. Extending the time frame to LB, the total cost associated with follitropin alfa and follitropin beta increases to €5310 and €5361, respectively, while the total cost associated with follitropin delta rises to €5381. These results led to an ICER of €2637/LB for follitropin delta versus follitropin alfa in the overall population. Not considering the wastage had a minor impact on the results, leading to follitropin delta dominating other follitropins until OP and to an ICER of €2495/LB for follitropin delta compared with follitropin alfa. A full list of results for the overall population is presented in Table S2 in the ESM.

The cost-effectiveness analysis was based on the pooled results of follitropin delta’s clinical trials (ESTHER, GRAPE and STORK) [ 13 – 15 ], and followed a structure similar to previously published economic evaluations assessing infertility treatments [ 17 – 19 ]. The clinical trial populations consisted of women aged 18–40 years old undergoing their first IVF/ICSI cycle with regular menstrual cycles (24–35 days) and FSH serum levels of 1–15 IU/L. The study was performed in accordance with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Good Practices for Outcomes Research consensus guidance [ 20 ] and national guidelines for health economics studies [ 21 ]. A decision-tree model was developed to assess the cost effectiveness of individualized dosed follitropin delta versus conventionally dosed follitropins alfa and beta in women initiating COS in IVF/ICSI cycles and followed until LB (Fig. 1 ). Each node of the model corresponds to a step of the COS protocol and IVF/ICSI cycles and was associated with trial-based probabilities of events, reflecting treatment efficacy according to age (< 35, 35–37, 38–40 years) and ovarian response profile of the women (AMH level < 15 pmol/L or ≥ 15 pmol/L). Women undergo a screening to determine their eligibility for treatment. Women eligible for the protocol begin COS and can continue or discontinue their IVF/ICSI cycles depending on their response to treatment. Women with successful COS pursue the process with oocyte retrieval and fertilization by IVF/ICSI. Fresh single blastocyst transfer was performed for most patients. Some patients cancelled the cycle and changed to a freeze all option, and some women did not have embryo transfer and did not have any usable blastocysts, which resulted in the end of the ART protocol. In some women, the blastocyst transfer did not lead to clinical pregnancy. Those achieving clinical pregnancy either progress to ongoing pregnancy (OP) or experience an early miscarriage (< 12 weeks). Finally, OP will either lead to LB or late miscarriage. The cost-effectiveness analysis focused on single fresh embryo transfers. Fig. 1 Model structure. COS controlled ovarian stimulation Model structure. COS controlled ovarian stimulation The time horizon of the analysis was limited to a single COS and IVF/ICSI protocol, lasting < 1 year. Hence, no discounting of health effects and costs was considered in the analysis. The analysis was carried out from a French National Health service perspective. Model outcomes were the average dose of follitropins, the rates of patients achieving each step of the IVF/ICSI cycle until OP and LB and the rates of patients with OHSS and miscarriages, in line with primary and secondary endpoints of pivotal clinical trials [ 13 – 15 ]. Model structure and endpoints are consistent with those used in previous published health economic evaluations of rFSH by Sivignon et al. (2016) and Grynberg et al. (2019) [ 18 , 19 ]. An ad-hoc individual-patient–level data analysis of pooled ESTHER, GRAPE and STORK studies was used to estimate model inputs and transitions in the decision tree, by treatment allocation, age, and the ovarian response profile of the women, corresponding to stratification criteria of the clinical trials. Probabilities associated with each node of the decision tree for patients treated with follitropin delta or other follitropins (alfa and beta) were estimated from the clinical trial data [ 13 – 15 ]. Adverse events associated with the use of gonadotropins were considered through the rates of early OHSS (≤ 9 days after triggering) and late OHSS (> 9 days after triggering), according to their severity (mild, moderate or severe) [ 7 ]. Consistently with the meta-analysis performed by Nelson et al. 2024 [ 16 ], which demonstrated high-quality evidence that the use of individualized dosing of follitropin delta is associated with improved LB rates and safety outcomes versus other follitropins for women with elevated AMH levels, the base-case analysis was focused on women with an elevated AMH level (≥ 15 pmol/L). Given that follitropin alfa and beta are commonly used in France, and despite the differences between clinical trials in terms of the populations studied and the comparators used (follitropin alfa in a Europe + rest of world population in ESTHER; follitropin alfa in a Pan-Asian population in GRAPE; follitropin beta in a Japanese population in STORK), a pooled comparator including follitropin alfa and follitropin beta was used in this analysis based on pooling the respective clinical trial data [ 13 – 15 ]. Model parameters of the base-case population are presented in Table 1 . Table 1 Model input data—women with an elevated AMH level (≥ 15 pmol/L), base-case analysis Clinical efficacy inputs Follitropin delta ( N  = 859) Follitropin alfa and Follitropin beta ( N  = 851) COS completion a 96.0% (95% CI 95.8–96.3) 98.5% (95% CI 98.4–98.6) Oocytes retrieval a 99.8% (95% CI 99.7–99.8) 99.6% (95% CI 99.6–99.7) Blastocyst transfer a 87.9% (95% CI 87.1–88.6) 83.0% (95% CI 82.0–84.0) Ongoing pregnancy (OP) a 37.9% (95% CI 36.2–39.6) 33.1% (95% CI 31.4–34.7) Early miscarriage a 4.5% (95% CI 4.2–4.9) 5.7% (95% CI 5.3–6.2) Live birth (LB) a 98.6% (95% CI 98.4–98.7) 95.7% (95% CI 95.2–96.2) Early OHSS (≤ 9 days after triggering)  Mild 1.4% (95% CI 1.3–1.5%) 3.3% (95% CI 3.1–3.5%)  Moderate 3.1% (95% CI 2.9–3.3%) 4.7% (95% CI 4.4–5.0%)  Severe 0.9% (95% CI 0.9–1.0%) 1.3% (95% CI 1.2–1.4%) Late OHSS (> 9 days after triggering)  Mild 0.2% (95% CI 0.2–0.2) 0.2% (95% CI 0.2–0.3)  Moderate 1.2% (95% CI 1.1–1.2) 0.9% (95% CI 0.9–1.0)  Severe 1.3% (95% CI 1.2–1.4) 1.1% (95% CI 1.0–1.1) rFSH mean dose (in µg) (standard deviation) 73.5 (21.6) 105.3 (30.7) Breakdown of type of fertilization procedures  ICSI 60.9% (95% CI 59.3–62.5) 59.2% (95% CI 57.6–60.8)  IVF 29.8% (95% CI 28.4–31.2) 30.0% (95% CI 28.6–31.4)  IVF + ICSI 9.3% (95% CI 8.7–9.9) 10.7% (95% CI 10.1–11.3) Source: Model input is based on ad-hoc individual-patient–level data analysis of pooled ESTHER, GRAPE and STORK clinical trials AMH anti-Müllerian hormone, CI confidence interval, COS controlled ovarian stimulation, ICSI intracytoplasmic sperm injection, IVF in vitro fertilization, OHSS ovarian hyperstimulation syndrome, rFSH recombinant follicle-stimulating hormone a Dependent probabilities applied to patients who have reached the previous step in the decision tree Model input data—women with an elevated AMH level (≥ 15 pmol/L), base-case analysis Source: Model input is based on ad-hoc individual-patient–level data analysis of pooled ESTHER, GRAPE and STORK clinical trials AMH anti-Müllerian hormone, CI confidence interval, COS controlled ovarian stimulation, ICSI intracytoplasmic sperm injection, IVF in vitro fertilization, OHSS ovarian hyperstimulation syndrome, rFSH recombinant follicle-stimulating hormone a Dependent probabilities applied to patients who have reached the previous step in the decision tree A scenario analysis was also performed to estimate the efficiency of follitropin delta versus other follitropins in the overall population. In this scenario analysis, 63.1% of women had elevated AMH levels (≥ 15 pmol/L) based on pooled patients’ characteristics and distribution in the ESTHER, GRAPE and STORK studies [ 13 – 15 ]. Model parameters of the overall population (scenario) are presented in Table S1 in the electronic supplementary material (ESM). As recommended by the French Health Authority (HAS)’s guidelines for cost-effectiveness analysis (CEA) in France, a healthcare perspective including direct treatment costs and excluding indirect costs was adopted [ 21 ]. Costs of treatment acquisition, management from COS to LB, procedures and hospitalizations, and the OHSS management costs were considered. The acquisition cost of gonadotropins was estimated, including potential wastage due to pack size availability. Treatment cost was calculated based on the average dose of rFSH (standard deviation) (Table 1 ) and considering a Gaussian distribution of mean doses (Fig. 2 ) and the French public prices (taxes included) of available packages in France (Table 2 ). Fig. 2 Gaussian distribution of rFSH mean total dose received by women considering the different available packages of follitropins delta, alfa and beta. rFSH recombinant follicle-stimulating hormone Table 2 Available packages of follitropins in France and their prices based on tariffs including VAT Follitropin delta Follitropin alfa Follitropin beta Dose (in µg) Price (€) Dose (in µg) Dose (in IU) Price (€) Dose (in µg) Dose (in IU) Price (€) 12 56.76 22 300 76.64 3.7 50 15.06 36 166.13 33 450 113.92 22 300 90.09 72 329.5 66 900 225.55 44 600 178.09 66 900 265.72 VAT value-added tax Gaussian distribution of rFSH mean total dose received by women considering the different available packages of follitropins delta, alfa and beta. rFSH recombinant follicle-stimulating hormone Available packages of follitropins in France and their prices based on tariffs including VAT VAT value-added tax A scenario analysis without wastage was also performed. In this analysis, the unit cost of follitropins was estimated from the price of the lowest available pack size combination in France. The resources consumption was derived from the clinical trial data [ 13 – 15 ], gonadotropins’ summary of product characteristics (SmPC) [ 8 – 10 ], literature review and national guidelines for ART [ 22 – 26 ]. The costs of gynaecologic consultations, other medicinal products, ultrasounds, biological tests, classical IVF and ICSI, events and procedures (embryo freezing and storage, pregnancy and delivery, miscarriage, OHSS management) associated with each step of the ART process were calculated based on the French National Health Insurance tariffs and the French hospital production costs of the Agence Technique de l’Information Hospitalière (ATIH) database [ 27 , 28 ]. In the absence of relevant national data, treatment-specific distribution between IVF and/or ICSI for oocyte fertilization, based on pooled clinical trial data, was considered in the analysis (Table 1 ). All costs were updated to 2024 euros (€) using the French Consumer Price Index [ 29 ]. The costs associated with each phase of the ART process and events are presented in Table 3 . Table 3 Costs associated with each phase of the ART process and events Phase and events Cost (2024 €) Sources Screening 227.33 (95% CI 181.87–272.80) French National Health Insurance tariffs [ 27 ] French hospital production costs of the Agence Technique de l’Information Hospitalière (ATIH) database [ 28 ] COS and triggering 670.33 (95% CI 536.26–804.39) Oocyte retrieval, including IVF/ICSI 1062.05 (95% CI 849.64–1274.46) No oocyte retrieval 168.57 (95% CI 134.86–202.29) Blastocyst transfer procedure 1124.48 (95% CI 899.59–1349.38) No blastocyst transfer 168.57 (95% CI 134.86–202.29) Embryo freezing 299.00 (95% CI 239.20–358.80) No clinical pregnancy 179.62 (95% CI 143.70–215.55) Clinical pregnancy followed by early miscarriage 225.77 (95% CI 180.62–270.93) Ongoing pregnancy 241.09 (95% CI 192.87–289.31) Live birth 4370.83 (95% CI 3496.67–5245.00) Late miscarriage 1389.86 (95% CI 1111.88–1667.83) Mild OHSS 148.91 (95% CI 119.12–178.69) Moderate OHSS 2111.29 (95% CI 1689.03–2533.55) Severe OHSS 4166.31 (95% CI 3333.05–4999.57) ART assisted reproductive technologies, COS controlled ovarian stimulation, ICSI intracytoplasmic sperm injection, IVF in vitro fertilization, OHSS ovarian hyperstimulation syndrome Costs associated with each phase of the ART process and events French National Health Insurance tariffs [ 27 ] French hospital production costs of the Agence Technique de l’Information Hospitalière (ATIH) database [ 28 ] ART assisted reproductive technologies, COS controlled ovarian stimulation, ICSI intracytoplasmic sperm injection, IVF in vitro fertilization, OHSS ovarian hyperstimulation syndrome Outcomes of the cost-effectiveness analysis included costs per additional LB and costs per additional OP. Deterministic and probabilistic sensitivity analyses were performed to explore the impact of parameter uncertainty on the results of the analysis. Deterministic sensitivity analyses (DSA) assessed which parameters had the greatest impact on model outcomes by varying the parameters one by one within their 95% confidence intervals (CIs). DSA results were expressed as the difference in net benefit per additional OP or LB threshold. The net benefit per additional OP or LB threshold is estimated as the incremental cost of follitropin delta versus other follitropins divided by the incremental rate of OP or LB with follitropin delta versus other follitropins. The probabilistic sensitivity analysis (PSA) based on Monte Carlo simulations explored the impact of simultaneous variation of all input parameters by random sampling from each parameter distribution (beta for clinical inputs and gamma for costs). A thousand model iterations were performed for the PSA.

The results of this study show that follitropin delta is a cost-effective strategy given a very low WTP threshold and a dominant position when assessing only cost per OP from the perspective of French health service providers for COS in women undergoing IVF/ICSI in comparison with other follitropins. It would be relevant over time to supplement this analysis with comparative data collected on real-world practice use of follitropin delta.

Using a decision-tree model, we evaluated the cost effectiveness of follitropin delta for COS for women undergoing IVF/ICSI compared with follitropins alfa and beta in France, based on pooled results of follitropin delta’s clinical trials (ESTHER, GRAPE and STORK). The model structure and assumptions were consistent with previously reported cost-effectiveness analyses [ 17 – 19 ]. The results highlight that follitropin delta is cost effective in comparison with other follitropins for COS in women undergoing IVF/ICSI. Follitropin delta leads to better OP and LB rates and achieves less miscarriages and OHSS in women with an elevated AMH level (≥ 15 pmol/L) and in the overall population. Follitropin delta is also an economically attractive alternative compared with other follitropins based on a lower cost per treatment cycle due to a lower average dose administrated attributed to the personalized dosing regimens with follitropin delta. Thus, follitropin delta is a dominant treatment strategy based on cost per ongoing pregnancy and leads to an ICER below €2700/LB in women with an elevated AMH level (≥15 pmol/L) and in the overall population. These results are explained by a lower total dose of follitropin delta, an improvement of OP and LB rates with follitropin delta compared with other follitropins, and lower OHSS rates. For internal validity, the results of the analysis accurately reproduce the proportion of OP and LB reported in clinical trials [ 13 – 15 ] and the modeling approach is consistent with a similar analysis assessing the cost effectiveness of human menopausal gonadotrophin (hMG) vs rFSH in France [ 30 ]. Additionally, a cost-effectiveness analysis of follitropin delta versus follitropin alfa for controlled ovarian stimulation for IVF/ICSI in China demonstrates that follitropin delta has a high probability of being a more effective and less costly treatment option in Chinese treatment practices, providing a more efficient use of limited healthcare resources [ 31 ], supporting external validity. Using pooled data from three clinical trials assuming a similar efficacy between follitropin alfa and follitropin beta in the analysis may be a limitation considering clinical trial designs and patient characteristics. However, this assumption seems reasonable regarding the comparable results reported in these clinical trials in terms of OP and LB rates in patients treated with follitropin alfa or beta [ 13 – 15 ] and the uncertainty surrounding this assumption is investigated through sensitivity analyses conducted. The focus on fresh embryo transfer cycles only may be a limitation of this analysis, as may the lack of data to support a cost-utility analysis. However, data from a prospective observational study performed among 14 French fertility centres between June 2020 and June 2021 (the DELTA study) demonstrated that > 75% of patients received a fresh transfer and that follitropin delta also performs well in real-world treatment settings with a more heterogeneous patient population [ 32 ]. This supports the relevance of the findings from this analysis in general French treatment settings. The paucity of health-related quality of life (HRQoL) data to assess the impact of treatment on quality-adjusted life years (QALYs) was extensively discussed by Skedgel et al. (2023) [ 33 ]. A fundamental disconnect between measures of HRQoL and broader measures of wellbeing associated with met and unmet parenthood goals exists. Simple concepts such as patient and carer are of limited applicability in the context of ART, where spillovers extend across a wide network of individuals, and the person receiving treatment is often not the infertile individual. Consideration of individual and societal wellbeing beyond HRQoL is crucial to understand the range of negative impacts associated with unmet parenthood goals and the corresponding positive impacts of successful ART. There is no well established WTP threshold value for cost per live birth, such as for cost per QALY in many countries. Given the challenges of using the QALY framework for economic evaluations in fertility care, it would be relevant for future research to investigate the WTP threshold for an additional live birth as a reference for assessment of the economic value of different interventions. Until such data is available, a relevant reference point may be the net present value of future societal contributions. A study of the long-term economic value of IVF-conceived singleton babies in the UK estimated the lifetime discounted net tax contributions to be approximately £110,000 (2005 values) for a baby born [ 34 ]. Adjusted for inflation, this is approximately £190,000 in 2024 values. A similar study has not been identified for France, but a study has assessed the net present value of a child born in France to be approximately €400,000 (2012 values) based on expected future gross earnings. Adjusting for inflation, this is approximately €500,000 in 2024 values. This figure does not subtract the societal transfer cost of education, health care provision, etc. [ 35 ]. With the introduction of encouraging ART policies, more patients are accessing ART services which have a positive impact on fertility rates. The proportion of babies in France that were born through IVF in 2019 was 2.9%. In comparison, the proportion was 8.2% in Spain, 7.5% in Greece and 6.3% in Denmark [ 36 ]. It will be interesting to examine how the use of ART will impact fertility rates in France in the coming years. Follitropin delta based on personalized dosing by algorithm offers an effective and economically attractive strategy to address the societal fertility challenge and the economic burden of infertility. Even though ART costs are specific to France, the positive cost-effectiveness impact of treatment with follitropin delta compared with follitropins alfa and beta in COS for ART in France is considered generalizable to other settings given the positive results of clinical trials on OP and LB rates for follitropin delta versus other follitropins [ 13 – 15 ].

Infertility is a disease defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse recognized as a worldwide public health issue by the World Health Organization (WHO) [ 1 ]. Risk factors for infertility include female age, alcohol and tobacco consumption, obesity or diabetes mellitus, stress, sexually transmitted infection, or environmental factors such as exposure to pesticides or solvents [ 2 , 3 ]. The prevalence of infertility varies considerably between countries, although its estimation is not always reliable. In France, 15–25% of couples are affected by fertility disorders [ 4 ] and 3.8% of births followed an assisted reproductive treatment [ 5 ]. The most common causes of infertility are polycystic ovary syndrome (PCOS), ovarian reserve failure, uterine abnormalities, and endometriosis in women, and abnormalities of spermatogenesis in men [ 6 ]. Different treatment options are available for infertility based on medical treatments stimulating ovulation, surgical procedures and assisted reproduction technologies (ART). Recombinant follicle-stimulating hormones (rFSH) are used in controlled ovarian stimulation (COS) to stimulate the recruitment and the development of multiple follicles for in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles [ 7 ]. Follitropin delta is the newest generation of r-FSH approved by the European Medicines Agency (EMA) in 2016 [ 8 ]. It is the first gonadotropin derived from a human cell line and results in a glycosylation that is more similar to natural human FSH compared with r-FSH developed from hamster ovary (CHO) cell lines. Follitropin delta is associated with higher serum levels of FSH, and adequate ovarian response compared with other follitropins (alfa and beta) [ 9 , 10 ]. Furthermore, follitropin delta is based on personalized dosing regimens dependent on the patient’s ovarian reserve (measured through anti-Müllerian hormone [AMH] level) and body weight, achieving consistent daily dosing while maintaining efficacy in comparison with follitropin alfa and follitropin beta, which are dosed according to their license with a starting dose of 150–225 IU and potential for dose adjustment during stimulation [ 11 , 12 ]. The clinical safety and efficacy of follitropin delta was demonstrated compared with follitropins alfa and beta in three pivotal clinical trials: ESTHER (Europe + rest of world), GRAPE (Pan-Asian population) and STORK (Japanese population) [ 13 – 15 ]. ESTHER and GRAPE were designed to demonstrate non-inferiority of follitropin delta versus follitropin alfa with ongoing pregnancy (OP) as the primary endpoint defined as at least one intrauterine viable foetus 10–11 weeks after transfer and STORK was designed to demonstrate non-inferiority of follitropin delta versus follitropin beta with oocytes retrieved as the primary endpoint. Live birth (LB) rates and proportion of patients with early or late ovarian hyperstimulation syndrome (OHSS) were also assessed in all trials. Recently, a meta-analysis of the three pivotal trials demonstrated that personalized dosed follitropin delta provided a significantly higher LB rate compared with conventionally dosed follitropin alfa and beta in women with elevated AMH levels (AMH ≥ 15 pmol/L) and a numerically higher LB rate in the overall population, but with a significantly lower dose [ 16 ]. With the availability of different treatment options for COS and improved access to fertility treatments, it is timely to assess the cost effectiveness of follitropin delta (Rekovelle ® , Ferring Pharmaceuticals) versus follitropin alfa (Gonal-F ® , Merck) and follitropin beta (Puregon ® , Organon) to guide a clinically and economically rational use of rFSH for COS in adult women undergoing IVF/ICSI in France. Previously published meta-analysis data suggest that women with elevated AMH levels in particular benefit from the personalized dosing approach with follitropin delta. This analysis will therefore focus on this group of women, but also assess the cost effectiveness of the personalized dosing approach and follitropin delta in the overall population.

Below is the link to the electronic supplementary material. Supplementary file1 (DOCX 37 KB) Supplementary file1 (DOCX 37 KB)