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Objective: Various gonadotropins are used for ovarian stimulation (OS). This study investigated the cost-effectiveness of different gonadotropins based on real-world data from the French National Health Database (SNDS) over a 7-year follow-up of assisted reproductive technology (ART) treatments., Design: Cost-effectiveness analysis of different gonadotropins based on real-world data from the SNDS was conducted., Participants: Women from SNDS undergoing OS leading to oocyte pick-up registered between January 31, 2013, and December 31, 2018 (N = 245,534 stimulations), and receiving either recombinant human follicle stimulating hormone (r-hFSH alfa originator; 110,439), its biosimilars (12,287), or urinaries (mainly highly purified human menopausal gonadotropin [HP-hMG; 65,654] and marginally highly purified urinary-human follicle stimulating hormone [7,821]) were included (follow-up: December 31, 2019)., Settings and Methods: Clinical inputs for this model, including live birth (LB) and cumulative LB (CLB) were calculated from data as published in [Best Pract Res Clin Obstet Gynaecol. 2023;88:102308]. A decision-tree model was developed comprising pregnancy and live birth rate (LBR) states for a complete ART cycle, including one fresh and ≤4 frozen/thawed embryo transfers and related costs. Cost inputs included those of drugs, ART procedure, pregnancy and delivery, and adverse events. Cost per LB and CLB and incremental cost-effectiveness ratio (ICER) were assessed. Robustness of results was determined by comprehensive sensitivity analyses., Results: Overall, r-hFSH alfa originator was found to be associated with a lower cost per LB and per CLB (cost per LB: EUR 26,010; CLB: EUR 22,278) versus its biosimilars (cost per LB: EUR 28,037; CLB: EUR 23,807) and versus urinaries (cost per LB: EUR 26,636; CLB: EUR 23,335). Calculated ICERs with r-hFSH alfa for LB were EUR 5,538 and EUR 14,090, whereas for CLB were EUR 1,945 and EUR 13,742 versus biosimilars and urinaries, respectively. Cost-effectiveness acceptability curve showed that in a majority of iterations, r-hFSH alfa originator had a probability of being cost-effective at a hypothetical threshold of EUR 20,000/LB. Sensitivity analyses showed that the most important variable impacting the outcome in fresh transfers was the probability of birth for biosimilars and the probability of pregnancy for urinaries, while for cumulative transfers, it was the probability of pregnancy for biosimilars and the probability of birth for urinaries., Limitations: As the clinical data were obtained from a non-interventional study and not a randomized controlled trial, the results may still be susceptible to residual confounding or other biases., Conclusions: r-hFSH alfa originator is cost-effective compared to its biosimilars and to urinaries (mainly HP-hMG) and is associated with a lower cost per LB compared to these gonadotropins, where the main driver is the higher LB efficacy rate achieved with it., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Objective: To assess the adequate ovarian follicular development and oocyte recovery between ovarian potential (antral follicle count [AFC]) before the start of ovarian stimulation (OS) and oocyte quantity and quality at oocyte retrieval. A holistic overview of the current key performance indicators (KPIs) was applied to identify the complementary strengths and identify where the current repertoire can be expanded., Design: Expert opinion., Setting: Not applicable., Patient(s): Not applicable., Intervention(s): None., Main Outcome Measure(s): To formulate a proposal for a refined and expanded repertoire of KPIs for individualized OS for assisted reproductive technology., Result(s): The performance and outcomes of OS on ovarian follicular development can be evaluated through the application of defined KPIs. Current KPIs for OS are the ovarian sensitivity index, follicular output rate (FORT), oocyte retrieval rate, and follicle-to-oocyte index (FOI). Notably, there are no specific KPIs dedicated to the assessment of follicular development (i.e., recruitment, selection, growth, and dominance). In light of this, we recommend expanding the current KPIs for OS to include "early FORT" (accounting for the number of follicles measuring ≥10 to 11 mm on day 5/6 of OS relative to AFC) and "modified FORT" (the ratio between the number of follicles measuring ≥12 mm at the time of oocyte maturation triggering and AFC); the extension of oocyte retrieval rate to include two discrete categories at oocyte retrieval-follicles measuring ≥12 mm and ≥16 mm-to ensure that all responsive follicles are accounted for; and FOI to be measured at oocyte maturation triggering and oocyte retrieval ("advanced FOI")., Conclusion(s): Once validated and adopted in clinical practice, we envisage that the proposed expanded KPIs measuring the effect of OS on follicular development (recruitment, selection, growth, and dominance) will increase the understanding of the relationship between ovarian reserve, measured by AFC, and oocyte quantity and quality at oocyte retrieval. This understanding will enable physicians to better evaluate the direct effect of different gonadotropins and doses on ovarian response, leading to a more personalized approach to OS in the context of assisted reproductive technology treatment., Competing Interests: Declaration of Interests S.K.S. reports receipt of payment or honoraria for nonpromotional educational lectures from Merck, Ferring, and MSD. J.-E.S. is an employee of Merck Healthcare KGaA, Darmstadt, Germany. R.O. reports receipt of consulting fees from Merck and Ferring and payment or honoraria for lectures from Merck and Ferring. RF has received honoraria for lectures from Merck Healthcare KGaA, Medea and Event Planet. M.H.D. has nothing to disclose. S.C.E. has received unrestricted research grants from Merck KGaA and consulting fees from Merck, Medea, and Event Planet; payment or honoraria for lecture fees from Merck, Sanitanova, Medea, and Event Planet; has a patent on the ART calculator; and is an advisory board member for Nature Reviews Urology (unpaid), Head of the Andrology Committee of the Brazilian Society of Human Reproduction (unpaid), and Co-chair of the Male Infertility Group, WHO Infertility Guidelines (unpaid). M.L. is an employee of Merck Healthcare KGaA, Darmstadt, Germany. T.D. is an employee of Merck Healthcare KGaA, Darmstadt, Germany. C.A. declares receipt of personal fees from Merck, Medea, Event Planet, IBSA, Ely Lilly, and Biogen and payment or honoraria from Merck, Medea, Event Planet, IBSA, and Ferring., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Juan-Enrique Schwarze, Susana Montenegro, and Thomas D’Hooghe are full-time employees of Merck KGaA, Darmstadt, Germany. Vivek Chaudhari is a full-time employee of EMD Serono Inc., USA. Claire Castello-Bridoux is a full-time employee of Merck Santé, France, an affiliate of Merck KGaA, Darmstadt,Germany. Cristina Masseria, and Claudia Roeder are full-time employees of AESARA Europe, Zug, Switzerland.

Research Question: According to real-world data, is recombinant human FSH (r-hFSH) combined with recombinant human LH (r-hLH) or r-hFSH alone more effective for women of advanced maternal age (AMA) in terms of live birth?, Design: Non-interventional study comparing the effectiveness of r-hFSH and recombinant r-hLH (2:1 ratio) versus r-hFSH alone for ovarian stimulation during ART treatment in women aged 35-40 years, using real-world data from the Deutsches IVF-Register., Results: Overall clinical pregnancy (29.8%, 95% CI 28.2 to 31.6 versus 27.8%, 95% CI 26.5 to 29.2) and live birth (20.3%, 95% CI 18.7 to 21.8 versus 18.0%, 95% CI 16.6 to 19.4) rates were not significantly different between the combined r-hFSH and r-hLH group and the r-hFSH alone group (P = 0.269 and P = 0.092, respectively). Treatment effect was significantly higher for combined r-hFSH and r-hLH compared with r-hFSH alone for clinical pregnancy (33.1%, 95% CI 31.0 to 35.0 versus 28.5%, 95% CI 26.6 to 30.4; P = 0.001, not adjusted for multiplicity) and live birth (22.5%, 95% CI 20.5 to 24.2 versus 19.4%, 95% CI 17.6 to 20.9; P = 0.014, not adjusted for multiplicity) in a post-hoc analysis of women with five to 14 oocytes retrieved (used as a surrogate for normal ovarian reserve), highlighting the potential benefits of combined r-hFSH and r-hLH for ovarian stimulation in women aged 35-40 years with normal ovarian reserve., Conclusions: Women of AMA with normal ovarian response benefit from treatment with combined r-hFSH and r-hLH in a 2:1 ratio versus r-hFSH alone in terms of live birth rate. The effectiveness of treatments is best assessed by RCTs; however, real-world data are valuable for examining the effectiveness of fertility treatment, especially among patient groups that are not well represented in clinical trials., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This non-interventional study compared the effectiveness of recombinant human follicle-stimulating hormone (r-hFSH) and recombinant human luteinizing hormone (r-hLH) (2:1 ratio) versus r-hFSH alone for ovarian stimulation (OS) during assisted reproductive technology treatment in women aged 35-40 years, using real-world data from the Deutsches IVF-Register (D·I·R). Numerically higher clinical pregnancy (29.8% [95% CI 28.2, 31.6] vs. 27.8% [26.5, 29.2]) and live birth (20.3% [18.7, 21.8] vs. 18.0% [16.6, 19.4]) rates were observed with r-hFSH:r-hLH versus r-hFSH alone. The treatment effect was consistently higher for r-hFSH:r-hLH compared with r-hFSH alone in terms of clinical pregnancy (relative risk [RR] 1.16 [1.05, 1.26]) and live birth (RR 1.16 [1.02, 1.31]) in a post-hoc analysis of women with 5-14 oocytes retrieved (used as a surrogate for normal ovarian reserve), highlighting the potential benefits of r-hFSH:r-hLH for OS in women aged 35-40 years with normal ovarian reserve., Competing Interests: Declaration of competing interest APB has received honoraria for lectures from Merck Healthcare KGaA, Darmstadt, Germany, and affiliates. JES, DC, ML, and TDH are employees of Merck Healthcare, Darmstadt, Germany. PV was an employee of Merck Healthcare KGaA, Darmstadt, Germany at the time of the study. RF has received honoraria for lectures and an advisory board on the role of LH from Merck Healthcare KGaA, Darmstadt, Germany, and affiliates. BH was an employee of EMD Serono, Rockland, Massachusetts, USA, an affiliate of Merck KGaA, at the time of the study. JK has received honoraria for lectures from Merck Healthcare KGaA, Darmstadt, Germany, and affiliates., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Considerable costs are associated with infertility treatment, but little evidence is available on the main drivers of treatment costs. This cost analysis investigated key costs for treatment with assisted reproductive technology (ART) and the proportion of costs attributed to the acquisition of recombinant human follicle-stimulating hormone (r-hFSH) alfa originator for one fresh embryo transfer (ET) leading to a live birth in Spain, Norway, the UK, Germany, Denmark, South Korea, Australia, and New Zealand. The total costs for one ART cycle with a fresh ET leading to a live birth varied between countries (€4108-€12,314). Costs for pregnancy and live birth were the major contributors in European countries, and the costs of oocyte retrieval, monitoring during ovarian stimulation, pregnancy, and live birth were the top contributors in the Asia-Pacific countries, included in this analysis. Acquisition costs for r-hFSH alfa originator contributed to only 5%-17% of the total costs of one ART cycle with one fresh ET leading to a live birth., Competing Interests: Declaration of Competing Interest RM has received lecture fees and grants from Merck and Ferring; support for attending scientific conferences from Gedeon Richter, Hungary, Merck Healthcare KGaA, Darmstadt, Germany, Angelini, Italy, and Ferring, Switzerland. KFB has received honoraria or consultation fees from Merck Healthcare KGaA, Darmstadt, Germany, Ferring, Switzerland, Bayer, Germany, Stiftung Endometriose Forschung, Germany, and Takeda, Japan and is a member of an advisory board for Merck Healthcare KGaA, Darmstadt, Germany. HK and C-WC declare no relevant conflicts of interest. SI has received personal fees and non-financial support from Merck Healthcare KGaA, Darmstadt, Germany, Ferring, Switzerland, and Gedeon-Richter, Hungary. VC, JES, and TDH are employees of Merck Healthcare KGaA, Darmstadt Germany. CR is an employee of Pharma Value Consulting, Switzerland, and at the time of the study was a consultant for Merck, KGaA Darmstadt, Germany. RM has received a lecture fee from Merck Healthcare KGaA, Darmstadt, Germany; support for attending scientific conferences from Gedeon Richter, Hungary, and Merck Healthcare KGaA, Darmstadt, Germany; and is the Chair of the British Fertility Society., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This comparative non-interventional study using data from the French National Health Database (Système National des Données de Santé) investigated real-world (cumulative) live birth outcomes following ovarian stimulation, leading to oocyte pickup with either originator recombinant human follicle-stimulating hormone (r-hFSH) products (alfa or beta), r-hFSH alfa biosimilars, or urinaries including mainly HP-hMG (menotropins), and marginally u-hFSH-HP (urofollitropin). Using data from 245,534 stimulations (153,600 women), biosimilars resulted in a 19% lower live birth (adjusted odds ratio (OR) 0.81, 95% confidence interval (CI) 0.76-0.86) and a 14% lower cumulative live birth (adjusted hazard ratio (HR) 0.86, 95% CI 0.82-0.89); and urinaries resulted in a 7% lower live birth (adjusted OR 0.93, 95% CI 0.90-0.96) and an 11% lower cumulative live birth (adjusted HR 0.89, 95% CI 0.87-0.91) versus originator r-hFSH alfa. Results were consistent across strata (age and ART strategy), sensitivity analysis using propensity score matching, and with r-hFSH alfa and beta as the reference group., Competing Interests: Declaration of competing interest MG has received fees from Merck Healthcare KGaA, Darmstadt, Germany, as a medical expert for this study, and lecture fees from Merck KGaA, Darmstadt, Germany, MSD, Ferring, IBSA, Gedeon Richter, Theramex, General Electric, Novartis, Besins Healthcare. I-CD has received fees from Merck Healthcare KGaA, Darmstadt, Germany, as a medical expert for this study, and lecture fees from Merck KGaA, Darmstadt, Germany, MSD, Ferring, IBSA, Gedeon Richter, and Theramex. FR and EH are employees of HEVA, Lyon, France. LL, FP, SP, and CC-B are employees of Merck Santé, Lyon, France, an affiliate of Merck KGaA, Darmstadt, Germany. PV, JES, and TDH are employees of Merck Healthcare KGaA, Darmstadt Germany. CH is an employee of Merck KGaA, Darmstadt Germany. MB has received fees from Merck Healthcare KGaA, Darmstadt, Germany, as a medical expert for this study, and lecture fees from Merck KGaA, Darmstadt, Germany., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This was a retrospective real-world evidence analysis of the costs per live birth for reference recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa) versus highly purified urinary human menopausal gonadotropin (hMG-HP), based on data from a German in vitro fertilization registry (RecDate). Pregnancy and live birth rates from the RecDate real-world evidence study over three complete assisted reproductive technology (ART) cycles using the same gonadotropin drug were used as clinical inputs. Costs related to ART treatment and to drugs were obtained from public sources. Treatment with r-hFSH-alfa resulted in higher adjusted cumulative live birth rates versus hMG-HP after one (25.3% vs. 22.3%), two (30.9% vs. 27.5%), and three (31.9% vs. 28.6%) ART cycles. Costs per live birth were lower with r-hFSH-alfa versus hMG-HP after one (€17,938 vs. €20,054), two (€18,251 vs. €20,437), and three (€18,473 vs. €20,680) ART cycles. r-hFSH-alfa was found to be a cost-effective strategy compared with hMG-HP over three cycles., Competing Interests: Declaration of competing interest KFB has received honoraria or consultation fees from Merck Healthcare KGaA, Darmstadt, Germany, Ferring, Bayer, Stiftung Endometriose Forschung, and Takeda and is a member of an advisory board for Merck. CR is an employee of Pharma Value Consulting, Switzerland. JES, ML, and TDH are employees of Merck Healthcare KGaA, Darmstadt, Germany. AA was an employee of Merck Healthcare KGaA, Darmstadt, Germany, at the time of the analysis. EF is an employee of IQVIA, Real World Solutions, London, UK. VL is an employee of IQVIA, Real World Solutions, Amsterdam, NL. RF has received honoraria for lectures from Merck Healthcare KGaA, Darmstadt, Germany, and affiliates., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study compared the cost per live birth and cost-effectiveness of the originator recombinant human follicle-stimulating hormone follitropin alfa (r-hFSH-alfa) and r-hFSH-alfa biosimilars for ovarian stimulation prior to assisted reproductive technology treatment in Spain. A decision tree model was developed, comprising pregnancy and live birth for one treatment cycle with fresh embryo transfer. Clinical inputs were based on a recent meta-analysis by Chua et al. [4]. Cost inputs were extracted from publicly available Spanish sources. The costs per live birth were lower with originator r-hFSH-alfa (€18,138) versus r-hFSH-alfa biosimilars (€20,377). The incremental cost-effectiveness ratio was €7208 for originator r-hFSH-alfa versus biosimilars. Drug acquisition costs for originator r-hFSH-alfa represented 10.5% of total costs in the base case analysis, and 6.2% in a treatment cycle resulting in live birth with one fresh embryo transfer. Results from the sensitivity analyses confirmed the robustness of the findings., Competing Interests: Declaration of competing interest SI has received personal fees and non-financial support from Merck Healthcare KGaA, Darmstadt, Germany, Ferring and Gedeon-Richter. EF is an employee of IQVIA Ltd., London, UK. VL was an employee of IQVIA Solutions B.V., Amsterdam, The Netherlands, at the time of the study. CR is an employee of Pharma Value Consulting, Switzerland, and is a consultant for Merck, KGaA Darmstadt Germany. CAV has received personal fees from Merck Healthcare KGaA, Darmstadt, Germany, personal fees, grant, and non-financial support from Merck Healthcare KGaA, Darmstadt, Germany, personal fees and non-financial support from Merck Sharp & Dohme, grant and non-financial support from Ferring, personal fees from Besins, personal fees and non-financial support from Gedeon-Richter, and research funding and non-financial support from Abbott. EAC is an employee of Merck, S.L.U., Madrid, Spain, an affiliate of Merck KGaA. TDH and JES are employees of Merck Healthcare KGaA, Darmstadt, Germany. RM has received personal fees, research funding, grants and non-financial support from Merck Healthcare KGaA, Darmstadt, Germany, and personal fees, grants and non-financial support from Ferring and Gedeon-Richter., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)