Kiose Kokkoni I, Storr Ashleigh, Kolibianakis Efstratios M, Mol Ben W, Venetis Christos A
Unit for Human Reproduction, 1st Dept of Obstetrics and Gynaecology, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Fertility Associates, Auckland, New Zealand.
Hum Reprod. 2025 Feb 1;40(2):343-359. doi: 10.1093/humrep/deae274.
Is the probability of pregnancy different between women using biosimilars versus the originator of follitropin alfa for ovarian stimulation in ART?
Meta-analysis of eight randomized clinical trials (RCTs) suggests that live birth, clinical, and ongoing pregnancy rates are significantly lower with biosimilars of follitropin alfa compared to the originator.
All biosimilars of follitropin alfa have received regulatory approval by demonstrating non-inferiority in the number of retrieved oocytes compared to the originator. Nevertheless, the most clinically relevant outcome in ART for both clinicians and patients is live birth. A meta-analysis published in 2021 suggested that biosimilars of follitropin alfa are associated with lower live birth rates compared to the originator. Since then, more relevant RCTs have been published, and thus an updated critical synthesis of the available evidence is urgently warranted.
STUDY DESIGN, SIZE, DURATION: A systematic review and meta-analysis were performed to compare biosimilars versus the originator of follitropin alfa in women undergoing ovarian stimulation for ART. A literature search was conducted until January 2024 in MEDLINE, Embase, Cochrane CENTRAL, Scopus, Web of Science, WHO, Clinicaltrials.gov, and others to identify eligible RCTs. The primary outcome was live birth. Secondary outcomes included clinical and ongoing pregnancy, duration of gonadotrophin administration and total FSH dose, number of oocytes retrieved, and ovarian hyperstimulation syndrome (OHSS).
PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were extracted independently by two reviewers. Quality was assessed using the RoB-2 Tool by Cochrane, and a sensitivity analysis was performed by excluding studies having high risk of bias. Meta-analysis was performed using the random or fixed effects model depending on the presence or not of significant (>50%) statistical heterogeneity (I2). Results were combined using the intention-to-treat principle and are reported as risk ratio (RR) or weighted-mean-difference (WMD) with 95% CIs.
Eight RCTs (n = 2987) (published between 2015 and 2023) were identified, assessing seven biosimilar products of follitropin alfa. The number of patients included in the eligible studies ranged from 100 to 1100. Three of the RCTs were deemed to be at high risk of bias. The duration of gonadotrophin administration was shorter in the biosimilars group (WMD: -0.19 days, 95% CI: -0.34 to -0.05; I2 = 0%, 5 studies, n = 2081), while no difference was observed in the total dose of FSH (WMD: -34.69 IUs, 95% CI: -74.54 to 5.16; I2 = 15.53%, 5 studies, n = 2081). No difference was observed in the number of oocytes retrieved (WMD: 0.27, 95% CI: -0.43 to 0.96; I2 = 10.7%, 6 studies, n = 1527) and OHSS rates (RR: 1.17, 95% CI: 0.90-1.52; I2 = 0%, 8 studies, n = 2986) between the two groups. A significantly lower live birth rate was observed using the biosimilars of follitropin alfa compared to the originator in women undergoing ovarian stimulation for ART (RR: 0.83, 95% CI: 0.72-0.96; I2 = 0%, 6 studies, n = 2335; moderate certainty of evidence). Similarly, clinical pregnancy (RR: 0.82, 95% CI: 0.73-0.92; I2 = 0%, 7 studies, n = 2876; low certainty of evidence) and ongoing pregnancy rates (RR: 0.81, 95% CI: 0.70-0.94; I2 = 0%, 7 studies, n = 1886; low certainty of evidence) were lower in the biosimilars group. These results were not materially altered in the sensitivity analyses performed where studies deemed at high risk of bias were excluded.
LIMITATIONS, REASONS FOR CAUTION: This meta-analysis included RCTs evaluating seven different biosimilars of follitropin alfa; however, pooled data appeared to be homogeneous. No data were available comparing biosimilars of follitropin alfa with the originator regarding cumulative live birth rate per aspiration or the probability of live birth in frozen thawed cycles. The population examined in the eligible RCTs includes mainly normal responders and no RCTs were identified focusing on poor or high responders.
Clinicians should be informed that although biosimilars of follitropin alfa produce similar number of oocytes with the originator, pregnancy rates after a fresh transfer are likely to be lower. Future research should focus on optimizing the production and use of biosimilars of follitropin alfa, so that they lead to pregnancy rates comparable to the originator.
STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. K.I.K. and A.S. have no competing interest to disclose. E.M.K. reports personal fees and non-financial support from Merck, Ferring, IBSA, and Vianex. B.W.M. has been supported by an investigator grant from NHMRC, has received consulting fees from Organon, Merck, and Norgine, research support and non-financial support from Merck KGaA, Darmstadt, Germany. B.W.M. also reports having stocks from OBsEva. C.A.V. reports grants, personal fees, and non-financial support from Merck KGaA, Darmstadt, Germany, personal fees, and non-financial support from Merck, Sharpe and Dohme, personal fees and non-financial support from Organon, grants and non-financial support from Ferring, personal fees from IBSA, and personal fees and non-financial support from Gedeon Richter and Vianex.
Protocol for the systematic review registered in The International Prospective Register of Systematic Reviews (PROSPERO; CRD42024498237).
在辅助生殖技术（ART）中，使用促卵泡素α生物类似药与原研药进行卵巢刺激的女性，其怀孕概率是否不同？
对八项随机临床试验（RCT）的荟萃分析表明，与原研药相比，促卵泡素α生物类似药的活产率、临床妊娠率和持续妊娠率显著更低。
所有促卵泡素α生物类似药均已通过证明与原研药相比回收卵母细胞数量无劣效性而获得监管批准。然而，对于临床医生和患者而言，ART中最具临床相关性的结果是活产。2021年发表的一项荟萃分析表明，促卵泡素α生物类似药与原研药相比，活产率较低。自那时以来，更多相关RCT已发表，因此迫切需要对现有证据进行更新的批判性综合分析。
研究设计、规模、持续时间：进行了一项系统评价和荟萃分析，以比较促卵泡素α生物类似药与原研药在接受ART卵巢刺激的女性中的效果。截至2024年1月，在MEDLINE、Embase、Cochrane CENTRAL、Scopus、Web of Science、WHO、Clinicaltrials.gov等数据库中进行了文献检索，以识别符合条件的RCT。主要结局是活产。次要结局包括临床妊娠和持续妊娠、促性腺激素给药持续时间和总促卵泡激素（FSH）剂量、回收的卵母细胞数量以及卵巢过度刺激综合征（OHSS）。
参与者/材料、设置、方法：由两名审阅者独立提取数据。使用Cochrane的RoB-2工具评估质量，并通过排除具有高偏倚风险的研究进行敏感性分析。根据是否存在显著（>50%）的统计异质性（I2），使用随机或固定效应模型进行荟萃分析。结果采用意向性分析原则合并，并报告为风险比（RR）或加权平均差（WMD）及9
