# A Cost-Effectiveness Analysis of Gonadotropins Used for Ovarian Stimulation during Assisted Reproductive Technology Based on Data from the French Nationwide Claims Database (SNDS)

Isabelle Borget, Mehdi Benchaib, Philippine Poignant, Laetitia Rey, Gerard Harty, Vivek Chaudhari, Thomas D'hooghe, Juan-Enrique Schwarze, Isabelle Cedrin Durnerin, Claudia Roeder, et al.

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Isabelle Borget, Mehdi Benchaib, Philippine Poignant, Laetitia Rey, Gerard Harty, et al. A Cost-Effectiveness Analysis of Gonadotropins Used for Ovarian Stimulation during Assisted Reproductive Technology Based on Data from the French Nationwide Claims Database (SNDS). Gynecologic and Obstetric Investigation, 2024, pp.1 - 15. 10.1159/000542074. inserm-04960548

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# A Cost-Effectiveness Analysis of Gonadotropins Used for Ovarian Stimulation during Assisted Reproductive Technology Based on Data from the French Nationwide Claims Database (SNDS)

Isabelle Borget<sup>a, b</sup> Mehdi Benchaim<sup>c, d, e</sup> Philippine Poignant<sup>f</sup> Laetitia Rey<sup>f</sup>

Gerard Harty<sup>g</sup> Vivek Chaudhari<sup>h</sup> Thomas D'hooghe<sup>g, i, j</sup>

Juan-Enrique Schwarze<sup>g</sup> Isabelle Cedrin Durnerin<sup>k</sup> Claudia Roeder<sup>l</sup>

Michael Grynberg<sup>k, m</sup>

## Keywords

Recombinant human follicle stimulating hormone · Cost per live birth · Live birth · Real-world data · Incremental cost-effectiveness ratio

## Abstract

**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

<footnote><sup>a</sup>Department of Biostatistics and Epidemiology, Gustave Roussy, Paris-Saclay University, Villejuif, France;</footnote>

<footnote><sup>b</sup>Oncostat – U1018, Inserm, Paris-Saclay University, “Ligue Contre le Cancer” Labeled Team, Villejuif, France;</footnote>

<footnote><sup>c</sup>Service de médecine de la reproduction et préservation de la fertilité – CECOS, Hospices Civils de Lyon, Bron, France; <sup>d</sup>Faculté de médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France; <sup>e</sup>LBBE CNRS, Villeurbanne, France; <sup>f</sup>IQVIA, Paris, France; <sup>g</sup>Merck KGaA, Darmstadt, Germany; <sup>h</sup>EMD Serono, Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany; <sup>i</sup>Department of Development and Regeneration, Laboratory of Endometrium, Endometriosis and Reproductive Medicine, KU Leuven, Leuven, Belgium; <sup>j</sup>Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University Medical School, New Haven, CT, USA; <sup>k</sup>Jean Verdier Hospital, Bondy, France; <sup>l</sup>Pharma Value Consulting, Oberwil, Switzerland; <sup>m</sup>Hôpital Antoine-Béclère, Hôpitaux universitaires Paris-Sud, Paris, France</footnote>

<footnote>karger@karger.com
www.karger.com/goi</footnote>

<footnote>© 2024 The Author(s).</footnote>

<footnote>Published by S. Karger AG, Basel</footnote>

<footnote>This article is licensed under the Creative Commons Attribution 4.0 International License (CC BY) (http://www.karger.com/Services/OpenAccessLicense). Usage, derivative works and distribution are permitted provided that proper credit is given to the author and the original publisher.</footnote>

<footnote>Correspondence to:
Isabelle Borget, Isabelle.BORGET@gustaveroussy.fr</footnote>
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

## Introduction

Several different gonadotropin preparations are currently reimbursed in France, including those of urinary origin (e.g., highly purified human menopausal gonadotropins [HP-hMG] and highly purified urinary-human follicle stimulating hormone [u-hFSH-HP]) and recombinant human follicle stimulating hormone (r-hFSH) preparations [1, 2]. The variability in purity, isoforms, glycosylation pattern, sialic acid residue compositions, and isoelectric coefficients of different gonadotropins is based on differences in origin, production, purification, and quantification methods [2–7]. This variability could lead to differences in the therapeutic efficacies of the different gonadotropin preparations used for women who are undergoing assisted reproductive technology (ART) [2, 4, 8].

Most cost-effectiveness analyses of gonadotropin preparations used for ovarian stimulation (OS) in ART

are based on randomized clinical trials (RCTs) or their follow-up data [9–14] or on meta-analyses [15, 16]. Conversely, a smaller number of publications include clinical trial data adjusted to reflect routine practice [17], real-world data [18], or observational studies [19]. Among these, Barriere et al. [17] and Grynberg et al. [14] conducted studies in France. According to their strict eligibility criteria, only women with a normal ovarian reserve (expected normal responders) were typically included in good-quality gonadotropin registration RCTs, reflecting only 38% of the patients treated in real-world settings [20]. Utilizing large, high-quality real-world databases enables cost-effectiveness analyses based on real-world data collected from diverse treatments in large patient populations, encompassing a wider range of ages and expected ovarian responses. Real-world studies have reported the differences in clinical outcomes between r-hFSH and urinary preparations [19, 21, 22]. A real-world study in Germany demonstrated significantly higher rates of cumulative live birth (CLB), cumulative ongoing pregnancy, and cumulative clinical pregnancy with r-hFSH alfa versus urinary HP-hMG [23].

The French National Health Database (SNDS) contains individual data used for billing and reimbursement of outpatient healthcare consumption and data from the national hospital discharge database, covering 99% of the French population [1]. Thus, the SNDS provides a valuable foundation for conducting real-world studies. In France in 2018, 1 out of 30 children were estimated to be conceived with support from ART [24] and in 2017 (latest data available) a total of 108,828 ART cycles (8,528 cycles per million women aged 18–45) were carried out [25], for which thorough data are registered by the SNDS.

A recent real-world study including more than 153,000 women undergoing ART in routine clinical practice in France using data registered by the SNDS, demonstrated lower rates of live birth (LB) after fresh embryo transfer, and CLB with urinaries (mainly HP-hMG and marginally u-hFSH-HP) and biosimilars compared to r-hFSH originators (including alfa and beta) [1]. This robust dataset provided the clinical inputs for the current cost-effectiveness analysis, which estimated the incremental cost-effectiveness ratio (ICER) of using originator r-hFSH alfa and its biosimilars and urinary gonadotropin preparations (mainly HP-hMG and marginally u-hFSH-HP) in France. To the best of our knowledge, this is the first cost-effectiveness analysis of gonadotropin use for OS for ART in France using real-world data from the SNDS. More than 24 million treatment cycles (calculated from sales data and expected average use) have been performed using r-hFSH alfa originator in women. Applying a conservative live
<figure><img src="image_2.png" /><figcaption>**Fig. 1.** Model structure of the cost-effectiveness analysis. FET, frozen embryo transfer. *In case of total embryo cryopreservation without fresh embryo transfer, up to 3 further frozen transfers were included in the analysis. In cases where the first transfer was a fresh transfer, up to 4 further frozen transfers were included in the analysis.</figcaption></figure>

birth rate (LBR) of 25% for r-hFSH alfa [26] we estimate that over 6 million babies have been born because of this treatment. These outcomes underscore the significant impact of r-hFSH alfa on public health, which, when considered alongside the associated costs, highlights the importance of our health economic analysis. Such analyses are crucial in evaluating the cost-effectiveness of r-hFSH alfa originator compared to other gonadotropin preparations, ensuring that resource allocation in ART is optimized to maximize both clinical outcomes and economic efficiency. This study aimed to assess the cost-effectiveness of different gonadotropins from a real-world study based on data from SNDS and to determine the cost per LB and CLB of r-hFSH alfa originator versus its biosimilars and versus urinary gonadotropins in France [1].

## Materials and Methods

### *Study Design*

A decision-tree model was developed in Microsoft Excel®, comprising the pregnancy and LBR states for one ART cycle (up to 1 year) as it captures relevant differences in costs and outcomes between the different gonadotropins being compared. Each complete ART cycle included one fresh and up to four frozen embryo transfers following a stimulation. In the current study, cycles without freeze-all were included.

### *Model Considerations*

The key stages of ART were defined in terms of five discrete states (embryo transfer, pregnancy or no pregnancy, and delivery [LB] or no delivery). The model considers transitions starting from the first fresh or frozen-thawed embryo transfer and progressing to the following states (and the associated costs of these states): pregnancy or no pregnancy, delivery (LB) or no delivery, and up to four frozen embryo transfers. For each state in the model, a distinct cost was assigned, and the proportion of patients at the end of each treatment pathway was multiplied by the corresponding cost. The total sum of all pathways was used to generate overall costs for each intervention. The model outputs included total costs, cost per LB, and ICER, estimated as the difference in costs divided by the difference in LBR/CLBR. A representation of the decision tree of the model is presented in Figure 1.

### *Clinical Inputs*

Data from the SNDS database, including stimulation leading to oocyte pick-up (OPU) registered from January 1, 2013, to December 31, 2018, and followed up until December 31, 2019 (defined as the complete study period) was included in the analysis [1]. Women undergoing an ART cycle during the study period, where OU leading to OPU was performed with r-hFSH-alfa originator, or its biosimilars, or urinaries (mainly HP-hMG (menotropins [Menopur® Ferring Pharmaceuticals,
Saint-Prex, Switzerland; Fertistartkit® IBSA FARM-ACEUTICI SRL, Italy]), and marginally u-hFSH-HP (urofollitropin [Fostimonkit® IBSA FARMACEUTICI SRL, Italy]) were included. Patients were followed until delivery, treatment discontinuation or lost to follow up. Ovarian hyperstimulation syndrome requiring hospitalization was also documented and recorded in the SNDS. The clinical inputs included in this analysis are presented in online supplementary Table 1 (for all online suppl. material, see https://doi.org/10.1159/000542074).

## Cost Inputs

This cost analysis was performed for a health system perspective, which includes costs of all healthcare funders. Costs were applied to each individual step of ART, namely basal infertility assessment, stimulation-oocyte retrieval, fertilization method, and embryo transfer. The associated costs of a miscarriage or birth were also included but calculated separately from the ART costs. Furthermore, adverse event and drug costs (FSH and co-medication) were considered separately. During the first two phases, certain costs are modified by the proportion of ART performed either by in vitro fertilization or in-tracytoplasmic sperm injection. The proportions of in vitro fertilization and intracytoplasmic sperm injection rates reported in the French SNIIRAM study were included [1]. Similarly, the proportion of patients receiving GnRH analogs, either agonists or antagonists, was based on French SNIIRAM study data. The costs for one ART cycle were obtained from publicly available French sources.

The cost of a LB was estimated while considering the weighted average of vaginal and caesarean births and the weighted average of single and multiple pregnancies based on reported hospital stays for each scenario using data from the French ScanSanté database [27]. Hospital costs were determined using the costs of the National Scale of Costs with Common Methodology (ENCC). ENCC costs were used when the sampling rate for a given hospital were above 20%, to ensure that the costs used were representative of nationwide costs. When sampling rates were below 20%, tariffs were preferentially used as they are national health insurance costs. In addition, out-of-pocket expenses for patients were also valued. Follow-up costs were assessed based on the medical management of patients during the follow-up and determined using Nomenclature of Medical Biology Acts, Common Classification of Medical Acts (CCAM), and Ameli tariffs. Data regarding the total amount of fees and the number of consultations and

technical procedures were collected from the national health insurance (Assurance Maladie) data.

The Biol'AM database is maintained by the national health insurance and provides information regarding the total annual amounts reimbursed and invoiced for each biological examination (until 2019). These data enable the calculation of a percentage of excess for each biological examination. The examinations were determined from Table Nationale de codage de Biologie. For technical procedures, the rates were indicated by a CCAM code. Only the mean treatment costs were obtained from the SNDS. The final average total weighted costs for the r-hFSH originator, its biosimilars, and urinary gonadotropin preparations were EUR 907, EUR 871, and EUR 855, respectively, as obtained from the SNIIRPMA database. The unit costs of this analysis were assessed in Euros for 2022. The cost considerations included in this analysis are presented in online supplementary Table 2.

All clinical and cost inputs were validated by independent clinical experts/independent KOLs who are the co-authors of the current article. In this cost-effectiveness analysis, discount rates have not been reported because this evaluation spans from the commencement of gonadotropin treatment to the attainment of a pregnancy or LB. This period is characterized by a relatively short timeframe and stable costs.

## Sensitivity Analyses

Robustness of results to parameter input variation was assessed using deterministic (one-way sensitivity analysis; OWSA) and probabilistic sensitivity analyses (PSAs). The impact of each clinical and cost input on the outcomes was analyzed by varying the parameters one at a time (by increasing and decreasing the base-case value of each parameter) using one-way analysis, which identified key drivers of model outcomes. The analysis investigated plausible upper and lower values from reported outcomes and outcomes around the confidence interval where available, or at a 20% variation.

PSA is a quantitative method to account for uncertainty in the true values of parameters. It considers random values within the distribution of each one of the inputs and calculates the ICER. This procedure is repeated 1,000 times. The results of PSA are presented as a cost-effectiveness plane and acceptability curve. Recognizing the absence of a universally accepted willingness to pay (WTP) for fertility in France, our study adopts a specific WTP threshold based on the country's gross domestic product (2020), according to the World Health Organization recommendations.
<table><caption>**Table 1.** LBR and total costs associated with r-hFSH alfa originator versus biosimilars after fresh embryo transfer</caption><thead><tr><th></th><th>r-hFSH alfa originator</th><th>Biosimilar</th><th>Difference</th></tr></thead><tbody><tr><td>LBR<sup>a</sup></td><td>16.7%</td><td>15.2%</td><td>1.5%</td></tr><tr><td>Number of LBs (a)</td><td>0.17</td><td>0.15</td><td>0.02</td></tr><tr><td>Total costs (b)</td><td>EUR 4,331</td><td>EUR 4,248</td><td>EUR 83</td></tr><tr><td>Medication costs</td><td>EUR 907</td><td>EUR 871</td><td>EUR 37</td></tr><tr><td>Adverse event (OHSS) cost</td><td>EUR 33</td><td>EUR 34</td><td>EUR -1</td></tr><tr><td>ART costs<sup>b</sup></td><td>EUR 2,852</td><td>EUR 2,841</td><td>EUR 11</td></tr><tr><td>Birth costs</td><td>EUR 539</td><td>EUR 502</td><td>EUR 37</td></tr><tr><td>Cost per LB</td><td>EUR 26,010</td><td>EUR 28,037</td><td>-2,027</td></tr><tr><td>ICER</td><td>EUR 5,538</td><td></td><td></td></tr></tbody></table>

The calculation of cost per LB is based on the total costs (b) for a one LB, given the current number of LBs (a). ART, assisted reproductive technology; ICER, incremental cost-effectiveness ratio; LBR, live birth rate; OHSS, ovarian hyperstimulation syndrome; r-hFSH, recombinant human follicle stimulating hormone; <sup>a</sup>Calculated from Grynberg et al. [1]. <sup>b</sup>Pregnancy costs were included in ART costs in this table.

## Results

A graphical representation of the main results has also been provided by the authors (Infographic abstract). A visual summary of the results of this study has been provided by the authors (online suppl. Video Summary).

### r-hFSH Alfa Originator and Its Biosimilars

In comparison to biosimilars, when considering only one fresh embryo transfer, r-hFSH alfa originator has a higher LBR and greater total costs, with an ICER of EUR 5,538 per LB. The cost per LB for r-hFSH alfa originator is lower versus biosimilars (EUR 26,010 vs. EUR 28,037). When considering cumulative embryo transfers, r-hFSH alfa originator has a higher cumulative LBR and greater costs, with an ICER of EUR 1,945 per CLB than its biosimilars. The cost per CLB for r-hFSH alfa originator was lower versus biosimilars (EUR 22,278 vs. EUR 23,807). The outcomes of a comparison between r-hFSH alfa originator and its biosimilars for LB are summarized in Table 1 and for CLB are summarized in Table 2. The cost per CLB is relatively lower than the cost per LB (fresh), due to the influence of the higher LBR resulting from the assessment of CLBs, in addition to the costs until the stimulation phase being avoided in a frozen transfer. In the cumulative setting, LBRs are higher by about 30%, and costs are also increased by about 20% – a relative difference which leads to lower costs per CLBs.

### r-hFSH Alfa Originator and Urinary Gonadotropins (Mainly HP-hMG)

In comparison to urinary gonadotropins (mainly HP-hMG), when considering only one fresh embryo transfer, r-hFSH alfa originator has a higher LBR and greater costs, with an ICER of EUR 14,090 per LB. The cost per LB for r-hFSH alfa originator was lower versus urinary gonadotropins (mainly HP-hMG) (EUR 26,010 vs. EUR 26,636). In comparison to urinary gonadotropins (mainly HP-hMG), when considering cumulative embryo transfers, r-hFSH alfa originator has a higher cumulative LBR and greater costs, with an ICER of EUR 13,742 per CLB. The cost per CLB for r-hFSH alfa originator was lower versus urinary gonadotropins (mainly HP-hMG) (EUR 22,278 vs. EUR 23,335). The outcomes of a comparison between r-hFSH alfa originator and urinary gonadotropins (mainly HP-hMG) for LB are summarized in Table 3 and for CLB are summarized in Table 4.

### Sensitivity Analyses

#### One-Way Sensitivity Analysis

The results for incremental LBs with r-hFSH alfa originator versus biosimilars indicate that the outputs were most sensitive to the probability of birth for r-hFSH alfa originator and its biosimilars. The results for incremental CLBs versus biosimilars indicate that the outputs were most sensitive to the probability of pregnancy for biosimilars and the probability of birth for r-hFSH alfa originator and its biosimilars (Table 5).

The OWSA results presented below for incremental LBs versus urinary gonadotropin preparations indicate
<table><caption>**Table 2.** Cumulative LBR and total costs associated with r-hFSH alfa originator versus biosimilars</caption><thead><tr><th></th><th>r-hFSH alfa originator</th><th>Biosimilar</th><th>Difference</th></tr></thead><tbody><tr><td>Cumulative LBR<sup>a</sup></td><td>23.6%</td><td>22.0%</td><td>1.7%</td></tr><tr><td>Number of LBs (a)</td><td>0.24</td><td>0.22</td><td>0.02</td></tr><tr><td>Total costs (b)</td><td>EUR 5,258</td><td>EUR 5,226</td><td>EUR 32</td></tr><tr><td>Medication costs</td><td>EUR 907</td><td>EUR 871</td><td>EUR 36</td></tr><tr><td>Adverse event (OHSS) cost</td><td>EUR 33</td><td>EUR 34</td><td>EUR -1</td></tr><tr><td>ART costs</td><td>EUR 3,496</td><td>EUR 3,528</td><td>EUR -32</td></tr><tr><td>Birth costs</td><td>EUR 821</td><td>EUR 793</td><td>EUR 28</td></tr><tr><td>Cost per LB</td><td>EUR 22,278</td><td>EUR 23,807</td><td>-1,529</td></tr><tr><td>ICER</td><td>EUR 1,945</td><td></td><td></td></tr></tbody></table>

The calculation of cost per LB is based on the total costs (b) for a one LB, given the current number of LBs (a). ART, assisted reproductive technology; ICER, incremental cost-effectiveness ratio; LBR, live birth rate; OHSS, ovarian hyperstimulation syndrome; r-hFSH, recombinant human follicle stimulating hormone. <sup>a</sup>Calculated from Grynberg et al. [1].

<table><caption>**Table 3.** LBR and total costs associated with r-hFSH alfa originator versus urinaries (mainly HP-hMG) after fresh embryo transfer</caption><thead><tr><th></th><th>r-hFSH alfa originator</th><th>Urinaries (mainly HP-hMG)</th><th>Difference</th></tr></thead><tbody><tr><td>LBR<sup>a</sup></td><td>16.7%</td><td>15.8%</td><td>0.8%</td></tr><tr><td>Number of LBs</td><td>0.17</td><td>0.16</td><td>0.01</td></tr><tr><td>Total costs</td><td>EUR 4,331</td><td>EUR 4,214</td><td>EUR 117</td></tr><tr><td>Medication costs</td><td>EUR 907</td><td>EUR 855</td><td>EUR 52</td></tr><tr><td>Adverse event (OHSS) cost</td><td>EUR 33</td><td>EUR 17</td><td>EUR 16</td></tr><tr><td>ART costs</td><td>EUR 2,852</td><td>EUR 2,836</td><td>EUR 16</td></tr><tr><td>Birth costs</td><td>EUR 539</td><td>EUR 506</td><td>EUR 33</td></tr><tr><td>Cost per LB</td><td>EUR 26,010</td><td>EUR 26,636</td><td>EUR -626</td></tr><tr><td>ICER</td><td>EUR 14,090</td><td></td><td></td></tr></tbody></table>

The calculation of cost per LB is based on the total costs (b) for a one LB, given the current number of LBs (a). ART, assisted reproductive technology; HP-hMG, highly purified human menopausal gonadotropin; ICER, incremental cost-effectiveness ratio; LBR, live birth rate; r-hFSH, recombinant human follicle stimulating hormone; OHSS, ovarian hyperstimulation syndrome. <sup>a</sup>Calculated from Grynberg et al. [1].

that the outputs were most sensitive to the probability of pregnancy for urinary gonadotropin preparations and the probability of birth for urinary gonadotropin preparations (mainly HP-hMG) and r-hFSH alfa originators. Similarly, for CLBs, the outputs were most sensitive to the probability of birth for urinary gonadotropin preparations (mainly HP-hMG) and r-hFSH alfa originators (Table 6).

## Probabilistic Sensitivity Analysis

The PSA conducted across various scenarios consistently indicated a high probability of cost-effectiveness of r-hFSH alfa originator, specifically at a hypothetical WTP of EUR 20,000 per LB in the absence of defined thresholds in the French setting. For LBs, most iterations were clustered in the upper-right quadrant, and for CLBs, most iterations were clustered in the upper-right and lower-right
<table><caption>**Table 4.** Cumulative LBR and total costs associated with r-hFSH alfa originator versus urinaries (mainly HP-hMG)</caption><thead><tr><th></th><th>r-hFSH alfa originator</th><th>Urinaries (mainly HP-hMG)</th><th>Difference</th></tr></thead><tbody><tr><td>LBR<sup>a</sup></td><td>23.6%</td><td>21.0%</td><td>2.6%</td></tr><tr><td>Number of LBs</td><td>0.24</td><td>0.21</td><td>0.03</td></tr><tr><td>Total costs</td><td>EUR 5,258</td><td>EUR 4,900</td><td>EUR 358</td></tr><tr><td>Medication costs</td><td>EUR 907</td><td>EUR 855</td><td>EUR 53</td></tr><tr><td>Adverse event (OHSS) cost</td><td>EUR 33</td><td>EUR 17</td><td>EUR 16</td></tr><tr><td>ART costs</td><td>EUR 3,496</td><td>EUR 3,312</td><td>EUR 184</td></tr><tr><td>Birth costs</td><td>EUR 821</td><td>EUR 776</td><td>EUR 105</td></tr><tr><td>Cost per LB</td><td>EUR 22,278</td><td>EUR 23,335</td><td>EUR -1,057</td></tr><tr><td>ICER</td><td>EUR 13,742</td><td></td><td></td></tr></tbody></table>

The calculation of cost per LB is based on the total costs (b) for a one LB, given the current number of LBs (a). ART, assisted reproductive technology; HP-hMG, highly purified human menopausal gonadotropin; ICER, incremental cost effectiveness ratio; r-hFSH, recombinant human follicle stimulating hormone; OHSS, ovarian hyperstimulation syndrome. <sup>a</sup>Calculated from Grynberg et al. [1].

quadrants of the cost-effectiveness plane (Fig. 2a, b). This suggests the results obtained from the analysis are robust and that treatment with r-hFSH-alfa can be considered cost-effective, when considering a hypothetical WTP of EUR 20,000. When comparing r-hFSH alfa originator with its biosimilars, the cost-effectiveness acceptability curve demonstrated that, at a hypothetical WTP of EUR 20,000, the probability of r-hFSH alfa originator being cost-effectiveness was 70.5% and 66.3% for LB and CLBs, respectively (Fig. 2a, b lower panels).

Similarly, when comparing r-hFSH alfa originator with urinary gonadotrophins, for both live and CLBs, most iterations were clustered in the upper-right quadrant of the cost-effectiveness plane (Fig. 3a, b). Again, this suggests the results obtained from the analysis are robust and that treatment with r-hFSH-alfa can be considered cost-effective compared to urinary gonadotrophins, when considering a hypothetical WTP of EUR 20,000. The cost-effectiveness acceptability curve demonstrates a probability of cost-effectiveness of Gonaf-f of 53.5% and 60.5% for LB and CLBs, respectively, at a hypothetical WTP of EUR 20,000 (Fig. 3a, b, lower panels).

## Discussion

Overall, r-hFSH alfa originator was found to be associated with a lower cost per LB compared to biosimilars and urinary gonadotropins (mainly, HP-hMG) which

was consistent for both LBs and CLBs. The lower cost of LBs associated with r-hFSH alfa originator can be primarily attributed to the higher LBR achieved with it compared to that achieved with biosimilars and urinary gonadotropin preparations (mainly HP-hMG) for either LB or CLBs. In all the scenarios evaluated for PSA, r-hFSH alfa originator consistently exhibited a high probability of being cost-effective, specifically at a hypothetical threshold of EUR 20,000 per LB.

OWSA for the base-case comparisons indicated that the results were highly sensitive to the value of key clinical parameters, including the probability of pregnancy and LBs, for all the treatments considered. The results of the PSA revealed that for both the comparators, most simulations fell in the upper-right quadrant of the cost-effectiveness plane, indicating greater costs and more effectiveness as the use of r-hFSH alfa originator results in greater LBs compared with the use of its biosimilars and urinary gonadotropin preparations (mainly HP-hMG). The comparison of using cumulative transfers with biosimilars indicated that a portion of simulations was also positioned in the lower-right quadrant. The results of OWSA and PSA revealed that these analyses could be influenced by changes in parameters. However, these impacts are relatively small in relation to the overall magnitude of the results.

The clinical inputs used in this study were collected from Grynberg et al. [1] who reported a lower probability (adjusted odds ratio and hazard ratio) of LB and CLBs
<table><caption>**Table 5.** OWSA for LBs and CLBs with r-hFSH alfa originator and its biosimilars</caption><thead><tr><th rowspan="2">Parameter (low and high value variation)</th><th colspan="4">Low</th><th colspan="4">High</th></tr><tr><th>incremental LBs</th><th>incremental costs</th><th>ICER</th><th>% variation</th><th>incremental LBs</th><th>incremental costs</th><th>ICER</th><th>% variation</th></tr></thead><tbody><tr><td><strong>LB</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Probability of birth biosimilar (0.46, 0.68)</td><td>0.05</td><td>127</td><td>2,797</td><td>-50%</td><td>-0.02</td><td>39</td><td>-2,579</td><td>-147%</td></tr><tr><td>Probability of birth r-hFSH alfa originator (0.48, 0.71)</td><td>-0.02</td><td>35</td><td>-1,920</td><td>-135%</td><td>0.05</td><td>131</td><td>2,712</td><td>-51%</td></tr><tr><td>Probability of pregnancy biosimilar (0.25, 0.28)</td><td>0.02</td><td>121</td><td>5,252</td><td>-5%</td><td>0.01</td><td>44</td><td>6,556</td><td>18%</td></tr><tr><td>Cost of giving birth (EUR 2,006.0; EUR 3,009.0)</td><td>0.02</td><td>76</td><td>5,037</td><td>-9%</td><td>0.02</td><td>91</td><td>6,040</td><td>9%</td></tr><tr><td>Cost of pregnancy (EUR 655.0; EUR 983.0)</td><td>0.02</td><td>81</td><td>5,385</td><td>-3%</td><td>0.02</td><td>83</td><td>5,508</td><td>-1%</td></tr><tr><td>Cost of sonogram during pregnancy (EUR 640.0; EUR 960.0)</td><td>0.02</td><td>81</td><td>5,389</td><td>-3%</td><td>0.02</td><td>85</td><td>5,688</td><td>3%</td></tr><tr><td>Probability of pregnancy r-hFSH alfa originator (0.28.0.28)</td><td>0.01</td><td>74</td><td>5,682</td><td>3%</td><td>0.02</td><td>92</td><td>5,425</td><td>-2%</td></tr><tr><td>Cost of OHSS leading hospitalization (EUR 1,414.0; EUR 2,121.0)</td><td>0.02</td><td>83</td><td>5,557</td><td>0%</td><td>0.02</td><td>83</td><td>5,519</td><td>0%</td></tr><tr><td><strong>CLB</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Probability of pregnancy biosimilar (0.43, 0.46)</td><td>0.03</td><td>77</td><td>3,070</td><td>58%</td><td>0.01</td><td>-14</td><td>-1,733</td><td>-189%</td></tr><tr><td>Probability of birth biosimilar (0.39, 0.59)</td><td>0.06</td><td>95</td><td>1,578</td><td>-19%</td><td>-0.03</td><td>-31</td><td>1,135</td><td>-42%</td></tr><tr><td>Probability of birth r-hFSH alfa originator (0.42, 0.63)</td><td>-0.03</td><td>-36</td><td>1,167</td><td>-40%</td><td>0.06</td><td>100</td><td>1,570</td><td>-19%</td></tr><tr><td>Cost of giving birth (EUR 2,006.0; EUR 3,009.0)</td><td>0.02</td><td>24</td><td>1,444</td><td>-26%</td><td>0.02</td><td>40</td><td>2,447</td><td>26%</td></tr><tr><td>Probability of pregnancy r-hFSH alfa originator (0.45, 0.45)</td><td>0.01</td><td>22</td><td>1,500</td><td>-23%</td><td>0.02</td><td>43</td><td>2,298</td><td>18%</td></tr><tr><td>Cost of storage per month during frozen embryo transfer (EUR 261.0; EUR 391.0)</td><td>0.02</td><td>36</td><td>2,167</td><td>11%</td><td>0.02</td><td>28</td><td>1,724</td><td>-11%</td></tr><tr><td>Cost of miscarriage (EUR 855.0; EUR 1,282.0)</td><td>0.02</td><td>35</td><td>2,101</td><td>8%</td><td>0.02</td><td>30</td><td>1,790</td><td>-8%</td></tr><tr><td>Cost of medications during no frozen embryo transfer (EUR 134.0; EUR 201.0)</td><td>0.02</td><td>34</td><td>2,059</td><td>6%</td><td>0.02</td><td>30</td><td>1,831</td><td>-6%</td></tr></tbody></table>

ICER, incremental cost-effectiveness ratio; OHSS, ovarian hyperstimulation syndrome; OWSA, one-way sensitivity analysis; r-hFSH, recombinant human follicle stimulating hormone.
<table><caption>**Table 6.** OWSA for LBs and CLBs with r-hFSH alfa originator and urinaries (mainly HP-hMG)</caption><thead><tr><th rowspan="2">Parameter (low and high value variation)</th><th colspan="4">Low</th><th colspan="4">High</th></tr><tr><th>incremental LBs</th><th>incremental costs</th><th>ICER</th><th>% variation</th><th>incremental LBs</th><th>incremental costs</th><th>ICER</th><th>% variation</th></tr></thead><tbody><tr><td><strong>LB</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Probability of pregnancy urinaries (0.25, 0.27)</td><td>0.01</td><td>141</td><td>10,391</td><td>-26%</td><td>0.00</td><td>93</td><td>31,422</td><td>123%</td></tr><tr><td>Probability of birth urinaries (0.49, 0.73)</td><td>0.04</td><td>162</td><td>4,068</td><td>-71%</td><td>-0.02</td><td>71</td><td>-3,059</td><td>-122%</td></tr><tr><td>Probability of birth r-hFSH alfa originator (0.48, 0.71)</td><td>-0.03</td><td>69</td><td>-2,761</td><td>-120%</td><td>0.04</td><td>165</td><td>3,963</td><td>-72%</td></tr><tr><td>Probability of pregnancy r-hFSH alfa originator (0.28, 0.28)</td><td>0.01</td><td>108</td><td>17,035</td><td>21%</td><td>0.01</td><td>126</td><td>12,228</td><td>-13%</td></tr><tr><td>Cost of giving birth (EUR 2,006.0; EUR 3,009.0)</td><td>0.01</td><td>113</td><td>13,589</td><td>-4%</td><td>0.01</td><td>121</td><td>14,592</td><td>4%</td></tr><tr><td>Cost of pregnancy (EUR 655.0; EUR 983.0)</td><td>0.01</td><td>114</td><td>13,703</td><td>-3%</td><td>0.01</td><td>116</td><td>14,013</td><td>-1%</td></tr><tr><td>Cost of severe OHSS hospitalization (EUR 1,414.0; EUR 2,121.0)</td><td>0.01</td><td>114</td><td>13,711</td><td>-3%</td><td>0.01</td><td>120</td><td>14,469</td><td>3%</td></tr><tr><td>Cost of sonogram during pregnancy (EUR 640.0; EUR 960.0)</td><td>0.01</td><td>114</td><td>13,712</td><td>-3%</td><td>0.01</td><td>120</td><td>14,468</td><td>3%</td></tr><tr><td><strong>CLB</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Probability of birth urinaries (0.43, 0.65)</td><td>0.07</td><td>418</td><td>6,143</td><td>-55%</td><td>-0.02</td><td>297</td><td>-18,552</td><td>-235%</td></tr><tr><td>Probability of birth r-hFSH alfa originator (0.42, 0.63)</td><td>-0.02</td><td>289</td><td>-13,648</td><td>-199%</td><td>0.07</td><td>425</td><td>5,809</td><td>-58%</td></tr><tr><td>Probability of pregnancy urinaries (0.38, 0.4)</td><td>0.03</td><td>378</td><td>12,490</td><td>-9%</td><td>0.02</td><td>324</td><td>16,894</td><td>23%</td></tr><tr><td>Probability of pregnancy r-hFSH alfa originator (0.45, 0.45)</td><td>0.02</td><td>347</td><td>14,507</td><td>6%</td><td>0.03</td><td>368</td><td>13,075</td><td>-5%</td></tr><tr><td>Cost of giving birth (EUR 2,006.0; EUR 3,009.0)</td><td>0.03</td><td>344</td><td>13,240</td><td>-4%</td><td>0.03</td><td>370</td><td>14,243</td><td>4%</td></tr><tr><td>Cost of storage per month during frozen embryo transfer (EUR 261.0; EUR 391.0)</td><td>0.03</td><td>345</td><td>13,269</td><td>-3%</td><td>0.03</td><td>370</td><td>14,214</td><td>3%</td></tr><tr><td>Cost of pregnancy (EUR 655.0; EUR 983.0)</td><td>0.03</td><td>347</td><td>13,344</td><td>-3%</td><td>0.03</td><td>355</td><td>13,662</td><td>-1%</td></tr><tr><td>Cost of sonogram during pregnancy (EUR 640.0; EUR 960.0)</td><td>0.03</td><td>347</td><td>13,353</td><td>-3%</td><td>0.03</td><td>367</td><td>14,130</td><td>3%</td></tr></tbody></table>

ICER, incremental cost-effectiveness ratio; OHSS, ovarian hyperstimulation syndrome; OWSA, one-way sensitivity analysis; r-hFSH, recombinant human follicle stimulating hormone.
<figure><img src="image_3.png" /><figcaption>**Fig. 2.** Incremental costs versus incremental LBs with r-hFSH alfa originator versus biosimilars and cost-effectiveness acceptability curve for LB (a) and CLB (b) (PSA). r-hFSH, recombinant human follicle stimulating hormone.</figcaption></figure>

with biosimilars and urinary gonadotropin preparations (mainly HP-hMG) compared with that obtained with r-hFSH alfa originator [1], consistent with the corresponding adjusted LBRs reported in the current study, which were 16.7%, 15.8%, and 15.2% for r-hFSH alfa originator, urinary gonadotropin preparations (mainly HP-hMG), and biosimilars, respectively. Owing to the higher live and cumulative LBRs, r-hFSH alfa exhibited a lower cost per LB in the current study for both fresh and cumulative transfers than biosimilars and urinaries.

The data on the comparison between the r-hFSH originator with urinaries and biosimilars from the current study agree with those published in previous literature from other European countries [11, 16, 18, 28-35]. There was a lack of data from France regarding cost-

effectiveness comparison of r-hFSH alfa originator with urinary preparations, which has been addressed by data from the current study. Grynberg et al. [14] reported that r-hFSH alfa originator is more cost-effective than its biosimilars in the French population. In ovarian hyper-stimulation syndrome cases, ICER for r-hFSH alfa originator ranged from EUR 3,274.80 to EUR 4,877.76 compared with that of the pooled biosimilars. This analysis drew data from the French Programme de Médicalisation des Systèmes d'Information (PMSI) hospital database, literature reviews, and French clinical experts using 2017 Euro tariffs [14].

Our results are in disagreement with those of previously published cost-effectiveness analyses where HP-hMG was compared with r-hFSH alfa, in France. The
<figure><img src="image_4.png" /><figcaption>**Fig. 3.** Incremental costs versus incremental LBs with r-hFSH alfa originator versus urinary gonadotropins (mainly, HP-hMG) and cost-effectiveness acceptability curve for LB (a) and CLB (b) (PSA). HP-hMG, highly purified human menopausal gonadotropin; r-hFSH, recombinant human follicle stimulating hormone.</figcaption></figure>

study by Barriere et al. [18], only considered the cost-effectiveness for one fresh ART cycle based on efficiency data obtained from only two RCTs (the MERIT trial [36, 37] and the MEGASET trial [38]), which also supplemented the data of patients collected from routine clinical practice in France. However, converse to the data obtained from the nationwide SNDS in the current study, Barrière et al. [18] reported data based on a hypothetical cohort of 30,000 patients. The cohort of 30,000 patients extrapolates the sample of the RCTs and parameters were applied to construct a hypothetical cohort with the aim to closely reflect the outcomes observed in French medical practice. Notably, certain parameters which were applied to the sample population were completely based on KOL inputs owing to the lack of relevant data in the French

national databases. Thus, the hypothetical cohort was an extrapolation of the selected sample of the two RCTs, which may not fully reflect real-world clinical practice. Additionally, the data inputs were derived from the outcomes of the MERIT and MEGASET trials, which demonstrated the non-inferiority of HP-hMG compared with r-hFSH alfa. Thus, cost-effectiveness analysis relied on statistically non-significant differences reported in these RCTs. Thus, the analysis outcomes may have been limited in their applicability to real-world settings. Compared with the two studies mentioned above [11, 18], our results may be more relevant from a payer/stakeholder perspective as they are based on patients treated in real-life practice (instead of typically good prognosis patients included in RCTs). Due to the highly
selected sample of patients included in RCTs based on inclusion criteria for expected normal ovarian response, economic analyses based on them may have limited generalizability. In contrast, the more comprehensive cost-effectiveness analysis presented here addresses a broader payer perspective, going beyond the narrow focus of a smaller datasets or direct costs, and incorporates the effectiveness component of the products being evaluated. The SNDS covers most of the French population, and the clinical outcomes in Grynberg et al. [1] reported the LB and cumulative LBR.

The current results are also in disagreement with those of a recent cost-effectiveness analysis publication from France [39], which reported a cost per CLB of EUR 18,147 for an r-hFSH alfa biosimilar (Bemfola®) compared to EUR 18,834 for the r-hFSH alfa originator. The analysis was based on clinical inputs from the REOLA study [40] which was conducted as a descriptive analysis of 6,606 OSs, including 2,319 ART OS cycles with Bemfola® and 4,287 cycles with r-hFSH alfa originator [40]. The REOLA clinical study clearly stated its descriptive nature; however, the authors drew comparative conclusions between both cohorts. Furthermore, the analysis did not adjust for confounding factors, rendering the populations incomparable. Biological and clinical data were not utilized in the analysis to adjust the results despite such data being available. The REOLA clinical study had a limited sample size compared to other recent real-world publications [40], e.g., as the SNDS publication by Grynberg et al. [1], on which the clinical inputs of the current analysis are based. Moreover, the REOLA clinical study emphasized the analyses based on the starting dose of r-hFSH to achieve population homogeneity and explore the relationship between FSH dose, usage conditions and outcomes. However, it is important to recognize that the decision regarding the starting dose is made by a healthcare practitioner, based on his/her own experience on evaluation of patient's baseline characteristics, and is not according to specific inclusion criteria. The REOLA cost-effectiveness analysis by Lehmann et al. also mentions in their abstract that their model assumed equal distribution of the biosimilar compared to r-hFSH alfa originator across the starting dose categories [39]. Thus, the cost-effectiveness data are based on a clinical analysis with several limitations and may affect the generalizability of the REOLA cost-effectiveness results.

To the best of our knowledge, this is the first study to assess the cost-effectiveness of gonadotropins in France using data obtained from a comprehensive nationwide database (SNDS) that reflects routine clinical practice. As

the SNDS covers almost the entire population of France, it provides an interesting opportunity for conducting a real-world study investigating the cost-effectiveness of various gonadotropins in the country. The main strength of this analysis is the large number of patients included and the robustness of the underlying data obtained using the propensity score method to adjust for known confounders at baseline and provide confidence in the interpretation of the data.

SNDS data are routinely collected for reimbursement purposes and not specifically for this study; thus, the events used as outcomes for assessing cost-effectiveness are not influenced by the study objective but rather reflective of real-world clinical practice. The robustness of the model was assessed using PSA, which is the standard approach mandated by Health Technology Assessment agencies globally to quantify the impact of uncertainty within health economic evaluations [41].

The results of this study should be interpreted alongside its limitations. As the clinical data were obtained from an NIS and not an RCT, the results may still be susceptible to residual confounding or other biases. As the inclusion of women in the study was limited to the stage of OPU, the costs associated with cycle cancelation were not considered. An algorithm was employed to identify stimulation in the claims database; hence, it was not possible to include the canceled cycles. However, it is important to note that a previous metanalysis has reported similar cancelation rates between rhFSH alfa originator and urinary preparations [42] and previous publications have reported similar or lower cancelation rates with rhFSH originator compared to biosimilars [43, 44]. Similarly, an algorithm was used to identify the freeze-all population. Although the SNIIRAM database encompasses almost the entire French population and contains exhaustive data regarding all reimbursements for health-related expenditures, it cannot provide information if no reimbursement is associated with the event. In addition, the PMSI analysis is limited to capturing information within the scope of hospital settings. Thus, some patients or events might have not been considered in the model, although the obtained results were assumed to represent the French population. In the current study, cycles without freeze-all were included. As freeze-all cycles account for around 10% of cycles [45], it should be noted that excluding them, would still result in a majority of the cycles being included. It will be interesting to assess cost-effectiveness outcomes in such a patient population in further studies. While this analysis considered up to four frozen embryo transfers, it is important to note that couples may choose to proceed
with additional embryo transfers depending on the number of frozen eggs produced during the initial controlled OS.

## Conclusions

Thus, the findings of this study reveal that r-hFSH alfa originator is cost-effective at a hypothetical WTP of EUR 20,000 compared to urinary gonadotropins and biosimilars. Additionally, r-hFSH alfa originator had a lower cost per LB due to a higher LB and CLBR compared with that of its biosimilars and urinary gonadotropin preparations. To the best of our knowledge, this is the first study to report the cost per LB of gonadotropin preparations used for OS in France derived from a large national claims database (SNDS) that covers most of the French population.

## Acknowledgments

Medical writing support was provided by Ashwini Kumar K M, M.Sc. (Merck Specialties Pvt. Ltd., Bangalore, India, an affiliate of Merck). This support was funded by Merck KgaA, Darmstadt, Germany.

## Statement of Ethics

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors; it does not require the approval of the Independent Ethics Committee.

## Conflict of Interest Statement

Mehdi Benchaib has worked on the Scientific Committee of Merck. Gerard Harty, Thomas D'Hooghe, and Juan-Enrique Schwarze are full-time employees of Merck KGaA, Darmstadt,

Germany. Vivek Chaudhari is a full-time employee of EMD Serono Research & Development Institute, Inc., Billerica, USA, an affiliate of Merck KGaA, Darmstadt, Germany. Other authors declare no conflicts of interest to disclose regarding this publication.

## Funding Sources

This study was funded by Merck. Merck KgaA (Darmstadt, Germany) designed and approved the study, participated in data collection and data analysis, and contributed to the data interpretation and final draft of the manuscript.

## Author Contributions

Isabelle Borget, Mehdi Benchaib, Philippine Poignant, Laetitia Rey, Gerard Harty, Vivek Chaudhari, Thomas D'hooghe, Juan-Enrique Schwarze, Isabelle Cedrin Durnerin, Claudia Roeder, and Michael Grynberg contributed to the conception and design of the analysis, including the interpretation of data and writing, editing, and proofreading the manuscript, and took part in discussions regarding the results. All authors read and approved the manuscript for submission to the journal.

## Data Availability Statement

All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. Any requests for data by qualified scientific and medical researchers for legitimate research purposes will be subject to Merck KgaA's Data Sharing Policy. All requests should be submitted in writing to Merck KgaA's data sharing portal (https://www.merckgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html). When Merck KgaA has a co-research, co-development, co-marketing, or co-promotion agreement, or when the product has been out-licensed, the responsibility for disclosure might be dependent on the agreement between parties. Under these circumstances, Merck KgaA will endeavor to gain agreement to share data in response to requests.

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