We thank the correspondents for their appraisal of and comments on our analysis of the cost-effectiveness of originator and biosimilar follitropin alfa preparations to achieve live births in Germany, Italy, and SpainCitation1. We agree that clinical trials of treatments should report on the outcome that is most important for all stakeholders, which in the case of fertility treatments is live birth, and this is the endpoint we have reported in our articleCitation2.
Biosimilars are a recent addition to the market, with the sole purpose of cost savings over the originator preparation; consequently, although in many cases there is a need to validate the cost-effectiveness of biosimilar products, there are insufficient real-world data on which to base a suitably powered cost-effectiveness analysis. The available clinical trials for fertility provide the most reliable data on pregnancy and birth outcomes to date. The clinical data, including the live-birth rates, were, therefore, taken from a phase III study that was powered to show equivalence in the number of oocytes retrieved using the originator and biosimilar preparationsCitation3, which is currently the outcome stipulated by the regulatory agencies to assess bioequivalenceCitation4, but not differences in the pregnancy or live birth rates. As this trial was designed to enable marketing approval, we can assume that it reflects clinical use and is adequately designed to calculate health economic outcomes; if we reject this notion outright, then we must also question whether these trials should enable a biosimilar product to be recommended in the treatment of infertility, or whether studies powered to evaluate live birth outcomes should be required, as oocyte retrieval rate alone is not a suitable index of efficacy to achieve a live birth.
In addition, by comparing the outcomes of the study with other available data, we can assess whether the data on pregnancy and live birth outcomes are more likely to result from chance or from an actual treatment effect. There have been three trials of GONAL-f vs biosimilarsCitation3,Citation5,Citation6, all of which showed improved pregnancy and live birth outcomes with GONAL-f. A pooled analysis of data from these trials (209 patients who received originator product and 402 patients who received a biosimilar) showed that the benefit–risk profile for live birth rate, ongoing pregnancy rate, and ovarian hyperstimulation syndrome favoured the originator preparationCitation7.
The methodological approach we have used is not novel in health economic outcomes research. For a precedent, we would refer the correspondents to the publication by Gizzo et al.Citation8, in which the cost-effectiveness of GONAL-f vs the biosimilar Bemfola was compared using the live birth rates reported by Rettenbacher et al.Citation5, obtained from similar patient numbers to those in the analysis with Ovaleap (220 and 113, respectively). This approach, using the same sources of clinical data, has also been used to show cost-effectiveness of the originator product compared with two biosimilar preparations in the context of the French healthcare systemCitation9.
Although the multiple one-way sensitivity analyses may not truly reflect the real-world scenario, where several factors will simultaneously impact on the incremental cost-effectiveness ratio (ICER), these analyses are very commonly used in health economic research to test whether the model output (i.e. ICER) is sensitive to fluctuations in any of the input parameters (i.e. efficacy, as well as mean dose and cost)Citation10. Best practice for univariate sensitivity analyses actually dictates that, for the model to truly reflect the real-world, the level of variation in the input parameters should be plausibleCitation10. This led us to choose the same level of variation as that used in Gizzo et al.Citation8 (i.e. ±5%), which is a credible and not inconsequential range that mirrors the potential real-world changeability in the input parameters and shows our model to be stable in the face of this level of fluctuation.
A full and measured reading of our article will show that we have already made great efforts to ensure that any potential limitations of our study methodology were fully acknowledged in the discussion section. Notwithstanding the potential limitations we have acknowledged, our analysis still draws attention to any potential disparity among the outcomes that could impact on cost-effectiveness, and we consider our data to be the benchmark for future discussions as more data become available.
Salvatore Gizzo (on behalf of the authors)
Transparency
Declaration of funding
This study was funded by Merck KGaA, Darmstadt, Germany.
Declaration of financial/other relationships
SG and CR have no conflicts of interest to declare. MF has previously received funding from Merck KGaA, Darmstadt, Germany. ML is an employee of Merck Serono S.p.A., an affiliate of Merck KGaA, Darmstadt, Germany. NC is an employee of Quintiles IMS, Milan, Italy. KB has received honoraria from Merck KGaA, Takeda, and Stiftung Endometriose Forschung. Medical writing support was provided by Steven Goodrick of inScience Communications, Springer Healthcare, UK, and funded by Merck KGaA, Darmstadt, Germany.
Acknowledgments
None reported.
References
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- Strowitzki T, Kuczynski W, Mueller A, et al. Randomized, active-controlled, comparative phase 3 efficacy and safety equivalence trial of Ovaleap(R) (recombinant human follicle-stimulating hormone) in infertile women using assisted reproduction technology (ART). Reprod Biol Endocrinol. 2016;14:1.
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