# Reply to Letter to Editor from Juan-Enrique Schwarze and colleagues – Critical appraisal on “Determining the cost-effectiveness of follitropin alfa biosimilar compared to follitropin alfa originator in women undergoing fertility treatment in France”

Matthieu Lehmann, Jean-Luc Pouly, Paul Barrière, Lauren Amy Boland, Samuel George Bean, Julian Jenkins

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Matthieu Lehmann, Jean-Luc Pouly, Paul Barrière, Lauren Amy Boland, Samuel George Bean, et al. Reply to Letter to Editor from Juan-Enrique Schwarze and colleagues – Critical appraisal on “Determining the cost-effectiveness of follitropin alfa biosimilar compared to follitropin alfa originator in women undergoing fertility treatment in France”. European Journal of Obstetrics & Gynecology and Reproductive Biology, 2024, 23, pp.100331. 10.1016/j.eurox.2024.100331. hal-04703990

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Submitted on 27 May 2025

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Reply to Letter to Editor from Juan-Enrique Schwarze and colleagues – Critical appraisal on “Determining the cost-effectiveness of follitropin alfa biosimilar compared to follitropin alfa originator in women undergoing fertility treatment in France”

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We would like to thank Schwarze et al. for raising several issues that were considered in the development of our health economic analysis, as this provides the opportunity to further clarify our manuscript, thus we will address these points in order.

When considering the dataset to study the cost effectiveness of a
follitropin alfa biosimilar (Bemfola®, Gedeon Richter Plc, Budapest,
Hungary) versus the originator (Gonal-f®, Merck KGaA, Darmstadt,
Germany) in France the published data set from a large French general
health database in France was also considered and mentioned in our
paper [1]. However, this dataset was not considered appropriate
compared to the REOLA study that was based on the specialist data
management systems of 17 Assisted Reproductive Technology (ART)
centres throughout France [2], as the French general health database
showed less granularity and lacked critical variables, the data collection
period varied between originator and biosimilars, and the multiple ad-
justments applied to the data may have led to misleading results [3]. A
dataset derived from registration trials was also considered inappro-
priate as patients included in such studies are not representative of those
in routine clinical practice [4]. Nevertheless, a previous
cost-effectiveness analysis based on the European biosimilar ART
registration studies found that, from a French perspective, the cost per
live birth with Gonal-f® pooled (including OHSS costs) was 2095.56
Euros vs 1718.15 Euros for biosimilars (Bemfola® and Ovaleap®,
Theramex Ireland Ltd, Dublin, Ireland) [5].

Regarding the comparison of cumulative live birth (CLB) of Bem-
fola® versus Gonal-f®, as Schwarze comments the REOLA study had
found no statistically significant difference across various starting doses
[2]. There is a direct relationship between higher total dose of r-hFSH
and lower chance of live birth [6] and an inverse relationship between
the starting daily dose of gonadotrophins and pregnancy rates irre-
spective of the duration of stimulation [7]. Accordingly, it is important
to ensure the groups are balanced for starting dose when comparing
efficacy of two gonadotrophins, which was the approach taken in the
REOLA study [2]. Similarly, when calculating the overall CLB across all
starting groups it is important to balance the number of patients within
each r-hFSH starting dose group as the choice of gonadotrophin is not
relevant to the r-hFSH starting dose. Table 1 shows that if the groups are
accordingly balanced, there is no difference in the weighted average CLB
between Bemfola® (21.24 %) and Gonal-f® (20.91 %), which is
consistent with the position of the European Medicines Agency (EMA)
and Heads of Medicines Agencies (HMA) that consider European
approved biosimilars are interchangeable with their originators [8]. In
contrast the large study quoted by Schwarze [1] produced results that
are inconsistent with the views of these bodies and the wider literature,
which may be a consequence of the methodological weaknesses

previously identified [2].

As part of our base case scenario, our cost-effectiveness analysis did not include wastage and showed that even without considering drug wastage Bemfola® was more cost effective than Gonal-f®. As drug wastage is an important factor in assessment of actual drug costs, a review was performed of the published literature identifying two relevant papers, which were both included in a scenario analysis of the model suggesting an even greater cost saving with Bemfola®. Although the partial dosing feature of Gonal-f® multidose pre-filled pens allows adaptation of doses and reuse of unadministered quantities, if the residual r-hFSH amount is insufficient to administer the next full dose, a patient would have to administer two injections increasing the risk of a dosing error as well as suffering the discomfort of a double injection [9]. Even if two injections were administered, a real-world study in the UK of 4078 IVF cycles with Gonal-f® suggested FSH wastage would be less if instead the single-use Bemfola® pen was used, as typical daily wastage with Bemfola® would be lower than the terminal wastage with Gonal-f® pens [10]. In Italy, the observed wastage with Gonal-f® was even greater compared to Bemfola® than estimated in the UK [11]. In France, if the residual r-hFSH in the Gonal-f® pen is inadequate to administer that days FSH dose, usually only one injection is given and the pen with the inadequate Gonal-f® dose is discarded to reduce the risk of dosing errors [2].

Throughout the development of the model and our publication, care
was taken to consider and follow relevant guidelines including those of
the leading Professional Society for Health Economics and Outcomes
Research (ISPOR). As explained in the paragraphs above, the REOLA
study offers an exhaustive set of data specifically relevant to our
research question, with an appropriate level of granularity and in case of
missing data expert opinion was sought. If amendments were made
especially in the context of harmonizing the patient distribution among
starting doses between the two treatment arms, the intention was to
reduce a bias which cannot be explained other than as an artefact of a
real-world study. Whilst we agree that it is typical to use 95 % confi-
dence intervals to display uncertainty of the result in clinical studies, it is
not for cost effectiveness analysis. Instead, the impact of variance in data
from each model input is assessed through one-way sensitivity analysis
(OWSA). In the publication, we have used an OWSA which examines the
impact of each variable in the study by varying it across a plausible
range of values while holding all other variables in the analysis constant
at their baseline value. This allowed the identification of the parameters
which had the largest potential to impact the cost per cumulative live
birth in the study. This is an especially useful technique as for many of
the cost parameters taken from country databases, just one price is re-
ported with no indication of the variance. Moreover, the probability of
<caption>**Table 1**</caption>

Weighted average cumulative live birth rate of Bemfola® vs Gonal-f® balanced for equal number of patients in each r-hFSH starting dose group according to the REOLA study [2].

<table><thead><tr><th>Starting dose</th><th>Raw number of women</th><th>Raw percentage of women (%)</th><th>Raw cumulative live-birth rate (%)</th><th>Equal weighted distribution number of women</th><th>Equal weighted distribution percentage of women (%)</th><th>Equal weighted distribution cumulative live birth-rate (%)</th></tr></thead><tbody><tr><td>Bemfola®</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; 150 IU</td><td>197</td><td>8</td><td>30.46</td><td>362</td><td>16</td><td>30.46</td></tr><tr><td>150-224 IU</td><td>698</td><td>30</td><td>25.36</td><td>778</td><td>34</td><td>25.36</td></tr><tr><td>225-229 IU</td><td>527</td><td>23</td><td>21.44</td><td>441</td><td>19</td><td>21.44</td></tr><tr><td>≥ 300 IU</td><td>897</td><td>39</td><td>12.26</td><td>738</td><td>32</td><td>12.26</td></tr><tr><td>TOTAL</td><td>2319</td><td>100</td><td>19.84</td><td>2319</td><td>100</td><td>21.24</td></tr><tr><td>Gonal-f®</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; 150 IU</td><td>834</td><td>19</td><td>26.98</td><td>669</td><td>16</td><td>26.98</td></tr><tr><td>150-224 IU</td><td>1518</td><td>35</td><td>27.27</td><td>1438</td><td>34</td><td>27.27</td></tr><tr><td>225-229 IU</td><td>730</td><td>17</td><td>19.59</td><td>816</td><td>19</td><td>19.59</td></tr><tr><td>≥ 300 IU</td><td>1205</td><td>28</td><td>12.03</td><td>1364</td><td>32</td><td>12.03</td></tr><tr><td>TOTAL</td><td>4287</td><td>100</td><td>21.62</td><td>4287</td><td>100</td><td>20.91</td></tr></tbody></table>

Within each starting dose group, there was no statistically significant difference in cumulative live birth rates between Bemfola® and Gonal-f®.

progression through clinical stages was taken from absolute proportions of the 6606 cases in the dataset and therefore variance around the mean is not possible to calculate. Concerning the Probabilistic Sensitivity Analysis (PSA), while it is a robust method to determine the uncertainty, it is common for simple decision tree models to use the more simplistic sensitivity analysis; one-way sensitivity analysis. [5,12–15]. In addition, sufficient knowledge of the distribution for each factor may be not available to complete a robust PSA, making it of limited use.

We would like to thank again Schwarze and colleagues for their interest in our article and we are convinced that the clarifications provided in this letter, additionally to the discussion and limitations mentioned in the original article, should enable our readers to fairly interpret the results of our analysis.

### CRediT authorship contribution statement

**Matthieu Lehmann:** Supervision, Validation, Writing – review & editing. **Samuel George Bean:** Formal analysis, Methodology, Validation, Writing – review & editing. **Julian Jenkins:** Methodology, Validation, Writing – original draft, Writing – review & editing. **Paul Barrière:** Validation, Writing – review & editing. **Lauren Amy Boland:** Formal analysis, Methodology, Writing – review & editing. **Jean-Luc Pouly:** Validation, Writing – review & editing.

### Declaration of Competing Interest

Matthieu Lehmann is an employee of Gedeon Richter Suisse, and Julian Jenkins is a scientific advisor to Gedeon Richter Suisse. Paul Barrière received fees as a consultant and/or speaker for Merck, Gen- evrier, Ferring, Teva, MSD and Gedeon Richter. Jean-Luc Pouly received fees as a consultant and/or speaker for Gedeon Richter. Lauren Amy Boland and Samuel George Bean are employees of Remap Consulting who was commissioned to perform the initial analysis.

### References

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[2] Barrière P, et al. A real-world study of ART in France (REOLA) comparing a biosimilar rFSH against the originator according to rFSH starting dose. J Gynecol Obstet Hum Reprod 2023;52(1):102510.

[3] Barrière P, Arbo E, Jenkins J. Reply to the letter to the editor in response to 'A real-world study of ART in France (REOLA) comparing a biosimilar rFSH against the originator according to rFSH starting dose' by S. Montenegro, C. Helwig, J.-E.

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Matthieu Lehmann
Gedeon Richter Suisse, Chemin des Mines 2, 1202 Geneva, Switzerland

Jean-Luc Pouly
Université de Clermont Auvergne Faculté de médecine, 28 place Henri
Dunant, 63000 Clermont Ferrand, France

Paul Barrière
Nantes Université, CR2TI UMR 1064, CHU Nantes, 44093 Nantes Cedex,
France

Lauren Amy Boland, Samuel George Bean
Remap Consulting GmbH, Industrie Strasse 47, Postfach 7461, 6302 Zug,
Switzerland

Julian Jenkins
Gedeon Richter Suisse, Chemin des Mines 2, 1202 Geneva, Switzerland