Correction to: Reply: Biosimilars versus the originator of follitropin alfa in ART: eyes wide shut?

Objective: to perform a clinical and economic analysis of using drugs containing follitropin alfa as an active substance and to assess the impact of the studied drugs on the budget of the state healthcare system of the Russian Federation considering cost data for 2022 in the population of women with infertility and poor ovarian response who are undergoing treatment with the use of assisted reproductive technologies (ART).Material and methods. Clinical and economic evaluation of follitropin alfa use in patients with infertility and poor ovarian response was performed by a cost minimization method, using data from the Uniform Information System for Procurement for the period from July to December 2022 inclusive. The budget impact analysis model compared the costs required for ovarian stimulation of patients with poor ovarian response receiving only a fixed dose combination (FDC) of follitropin alfa + lutropin alfa with the expected practice of switching 25% of these patients to follitropin alfa with a modeling time horizon of 1 year.Results. A cost analysis of an ovarian stimulation course using biosimilar follitropin alfa showed cost savings of 17% compared with the cost of therapy using the original follitropin alfa. Also, cost minimization analysis per cycle of ovarian stimulation demonstrated that the use of the biosimilar follitropin alfa was characterized by cost savings of 24,420 rubles (32.37%) compared to FCD of follitropin alfa + lutropin alfa. Compared to the 2021 data, in the current study based on 2022 data and including only biosimilar follitropin alfa, there was a 103% increase in savings. Budget impact analysis determined that switching 25% of the population from FCD of follitropin alfa + lutropin alfa to follitropin alfa would reduce direct medical costs by 17.3 million rubles (8.1%) per year. Savings in direct medical costs in the current study compared to 2021 increased by 117%.Conclusion. The clinical and economic analysis, as well as the budget impact analysis of using biosimilar follitropin alfa for ovarian stimulation in a population of women with infertility and poor ovarian response, confirm the economic expediency revealed in 2021. Moreover, according to 2022 data, the use of biosimilar follitropin alfa results in additional budgetary savings.

Study question What is the effectiveness of individualised follitropin delta dosing compared to conventional follitropin alfa dosing in patients with potential poor response undergoing ovarian stimulation? Summary answer Individualised follitropin delta dosing provides a favourable efficacy and safety balance and is as good as follitropin alfa in patients with potential poor ovarian response. What is known already Poor ovarian response to controlled ovarian stimulation constitutes a challenge in in-vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) treatment. The dosing algorithm of follitropin delta incorporates the prediction of ovarian response based on anti-Müllerian hormone (AMH), an accurate marker of ovarian reserve, and body weight, for an individualised dosing. In the general IVF/ICSI population and potential high responders, individualised follitropin delta reduces the risk of ovarian hyperstimulation syndrome (OHSS) and/or preventive interventions for OHSS, with sustained efficacy compared to conventional follitropin alfa. However, the performance of follitropin delta in the subpopulation of patients with potential poor response has not been evaluated. Study design, size, duration Post hoc analysis of 332 patients with potential poor response from the ESTHER-1 trial (determined by AMH level at screening <9 pmol/L). Patients received the maximum daily dose of 12 µg follitropin delta (fixed dosing throughout stimulation) as stipulated by the dosing algorithm for patients with AMH <15 pmol/l, or follitropin alfa at a starting dose of 150 IU, with potential dose adjustments from stimulation day 6 and onwards (maximum daily dose of 450 IU). Participants/materials, setting, methods Participants were women, 18–40 years, undergoing their first IVF/ICSI cycle in a GnRH antagonist protocol, including triggering with human chorionic gonadotrophin, IVF/ICSI insemination, and single or double blastocyst transfer on Day 5. Ultrasound was performed 10–11 weeks after transfer to confirm ongoing pregnancy. All pregnancies were followed until birth. Study outcomes include number of oocytes retrieved and number of good quality blastocysts, ongoing pregnancy and live birth rates, cycle cancellation and OHSS rates. Main results and the role of chance A total of 332 patients (25.0% of the overall ESTHER-1 population) had serum AMH at screening of < 9 pmol/l and were included in the analysis: 168 were treated with follitropin delta and 164 were treated with follitropin alfa. Baseline characteristics were similar between the treatment groups, with a mean age of 34.8 years, a median AMH of 5.7 pmol/l and a mean weight of 64.5 kg. With follitropin delta, the mean daily dose was 12.0 µg and with follitropin alfa 12.4 µg, resulting in mean total doses of 104.6 µg and 112.3 µg, respectively. The mean number of oocytes retrieved was 5.8 ± 3.5 with follitropin delta and 5.5 ± 3.6 with follitropin alfa and the mean number of good-quality blastocysts was 1.2 ± 1.4 with both treatments. The ongoing pregnancy rate was 29.8% with follitropin delta and 29.3% with follitropin alfa and the live birth rates were 29.2% and 28.7%, respectively. Thirteen patients (7.7%) treated with follitropin delta and 14 (8.5%) treated with follitropin alfa had their cycles cancelled due to poor response. One case of OHSS (0.6%) was observed in the follitropin delta group, and 3 cases (1.8%) were observed in the follitropin alfa group. Limitations, reasons for caution The main limitation of the study is its post hoc nature. Furthermore, the study is based on a relatively small number of patients. Wider implications of the findings This subgroup analysis, alongside the normoresponder and the potential hyperresponder subgroup of the ESTHER-1 trial, adds evidence for the effectiveness of follitropin delta across all ovarian reserve subgroups of the infertile population. Trial registration number NCT01956110

Multi-center patient survey on injection pain of recombinant gonadotropin products administered for controlled ovarian stimulation (COS)

STUDY QUESTIONIs ovarian stimulation with follitropin delta in its individualised fixed-dose regimen at least as efficacious as follitropin alfa in a conventional dosing regimen in Asian population?SUMMARY ANSWEROvarian stimulation with individualised follitropin delta dosing resulted in a non-inferior ongoing pregnancy rate, a significantly higher live birth rate and a significantly lower incidence of early ovarian hyperstimulation syndrome (OHSS) and/or preventive interventions compared to conventional follitropin alfa dosing.WHAT IS KNOWN ALREADYPrevious randomised controlled trials conducted in Japan as well as in Europe, North- and South America have demonstrated that ovarian stimulation with the individualised follitropin delta dosing regimen based on serum anti-Müllerian hormone (AMH) level and body weight modulated the ovarian response and reduced the risk of OHSS without compromising pregnancy and live birth rates.STUDY DESIGN, SIZE, DURATIONRandomised, controlled, multi-centre, assessor-blind trial conducted in 1009 Asian patients from mainland China, South Korea, Vietnam and Taiwan, undergoing their first IVF/ICSI cycle. Randomisation was stratified by age (<35, 35–37, 38–40 years). The primary endpoint was ongoing pregnancy rate assessed 10–11 weeks after embryo transfer in the fresh cycle (non-inferiority limit −10.0%; analysis adjusted for age stratum).PARTICIPANTS/MATERIALS, SETTING, METHODSThe follitropin delta treatment consisted of a fixed daily dose individualised according to each patient’s initial AMH level and body weight (AMH <15 pmol/l: 12 μg; AMH ≥15 pmol/l: 0.19 to 0.10 μg/kg; min-max 6–12 μg). The follitropin alfa dose was 150 IU/day for the first 5 days with subsequent potential dose adjustments according to individual response. A GnRH antagonist protocol was applied. OHSS was classified based on Golan’s system. Women with an ongoing pregnancy were followed until live birth and 4 weeks after.MAIN RESULTS AND THE ROLE OF CHANCEThe number of oocytes retrieved was significantly (P < 0.001) lower with individualised follitropin delta versus conventional follitropin alfa (10.0 ± 6.1 versus 12.4 ± 7.3). Nevertheless, compared to the conventional dosing approach, the individualised follitropin delta dosing regimen resulted in on average 2 more oocytes (9.6 ± 5.3 versus 7.6 ± 3.5) in potential low responders as indicated by AMH <15 pmol/l, and on average 3 fewer oocytes (10.1 ± 6.3 versus 13.8 ± 7.5) in potential high responders as indicated by AMH ≥15 pmol/l. Among women with AMH ≥15 pmol/l, excessive response occurred less frequently with individualised follitropin delta than with follitropin alfa (≥15 oocytes: 20.2% versus 39.1%; ≥20 oocytes: 6.7% versus 18.5%; both P < 0.001). The incidence of early OHSS and/or preventive interventions for early OHSS was significantly (P = 0.004) reduced from 9.6% with follitropin alfa to 5.0% with individualised follitropin delta. The total gonadotropin use was significantly (P < 0.001) reduced from an average of 109.9 ± 32.9 μg (1498 ± 448 IU) follitropin alfa to 77.5 ± 24.4 μg follitropin delta. Non-inferiority of follitropin delta in its individualised dosing regimen to conventional follitropin alfa was established with respect to the primary endpoint of ongoing pregnancy rate which was 31.3% with follitropin delta compared to 25.7% with follitropin alfa (estimated mean difference 5.4% [95% CI: −0.2%; 11.0%]). The live birth rate was significantly higher at 31.3% with individualised follitropin delta compared to 24.7% with follitropin alfa (estimated mean difference 6.4% [95% CI: 0.9%; 11.9%]; P = 0.023). The live birth rate for each stratum were as follows for follitropin delta and follitropin alfa, respectively; <35 years: 31.0% versus 25.0%, 35–37 years: 35.3% versus 26.7%, 38–40 years: 20.0% versus 14.3%.LIMITATIONS, REASONS FOR CAUTIONThe trial only covered the clinical outcome of one treatment cycle with fresh cleavage-stage embryo transfers.WIDER IMPLICATIONS OF THE FINDINGSThe present trial shows that in addition to reducing the early OHSS risk, follitropin delta in its individualised fixed-dose regimen has the potential to improve the success rate in fresh cycles across all ages and with a lower gonadotropin consumption compared to conventional follitropin alfa dosing.STUDY FUNDING/COMPETING INTEREST(S)This study was funded by Ferring Pharmaceuticals. J.Q., Y.Z., X.L., T.H., H.-Y.H. and S.-H.K. have received institutional (not personal) clinical trial fees from Ferring Pharmaceuticals. M.G., B.M. and J.-C.A. are employees of Ferring Pharmaceuticals. J.-C.A. has pending and issued patent applications in the WO 2013/020996 and WO 2019/043143 patent families that comprise allowed and granted patent rights related to follitropin delta.TRIAL REGISTRATION NUMBERNCT03296527 (clinicaltrials.gov).TRIAL REGISTRATION DATE28 September 2017DATE OF FIRST PATIENT’S ENROLMENT1 December 2017

Study question To evaluate the efficacy and safety of individualised dosing with follitropin delta versus conventional dosing with follitropin alfa in an Asian population undergoing ovarian stimulation. Summary answer Individualised dosing with follitropin delta results in significantly higher live birth rate and fewer early OHSS and/or preventive interventions compared to conventional follitropin alfa dosing. What is known already Previous randomised controlled trials conducted in Europe, North- and South America mainly including Caucasian IVF/ICSI patients as well as in Japan have demonstrated that ovarian stimulation with the individualised follitropin delta dosing regimen based on serum AMH level and body weight modulated the ovarian response and reduced the risk of OHSS without compromising pregnancy and live birth rates. Study design, size, duration Randomised, controlled, assessor-blind trial conducted in 1,009 Asian patients from mainland China, South Korea, Vietnam and Taiwan, undergoing their first IVF/ICSI cycle. Randomisation was stratified by age (&amp;lt;35, 35-37, 38-40 years). The primary endpoint was ongoing pregnancy assessed 10-11 weeks after transfer (non-inferiority limit -10.0%; analysis adjusted for age strata). Patients &amp;lt;35 years underwent single embryo transfer if a good-quality embryo was available, otherwise double embryo transfer. Patients ≥35 years underwent double embryo transfer. Participants/materials, setting, methods Follitropin delta (Rekovelle, Ferring Pharmaceuticals) daily treatment consisted of a fixed dose individualised according to each patient’s initial AMH level (&amp;lt;15 pmol/L: 12 μg; ≥15 pmol/L: 0.19 to 0.10 μg/kg; min-max 6-12 μg) and body weight. Follitropin alfa (Gonal-f, Merck Serono) dose was 150 IU/day for the first five days with subsequent potential dose adjustments according to individual response. A GnRH antagonist protocol was applied. OHSS was classified based on Golan’s system. Main results and the role of chance The ongoing pregnancy rate was 31.3% with follitropin delta and 25.7% with follitropin alfa (adjusted difference 5.4% [95% CI: -0.2%; 11.0%]). The live birth rate was significantly higher at 31.3% with follitropin delta compared to 24.7% with follitropin alfa (adjusted difference 6.4% [95% CI: 0.9%; 11.9%]; p &amp;lt; 0.05). Live birth rates per age stratum were as follows for follitropin delta and follitropin alfa; &amp;lt;35 years: 31.0% versus 25.0%, 3537 years: 35.3% versus 26.7%, 38-40 years: 20.0% versus 14.3%. Early OHSS risk, evaluated as the incidence of early OHSS and/or preventive interventions, was significantly (p &amp;lt; 0.01) reduced from 9.6% with follitropin alfa to 5.0% with follitropin delta. The number of oocytes was 10.0±6.1 with follitropin delta and 12.4±7.3 with follitropin alfa. Individualised follitropin delta dosing compared to conventional follitropin alfa dosing resulted in 2 more oocytes (9.6±5.3 versus 7.6±3.5) in potential low responders (AMH &amp;lt;15 pmol/L) and 3 fewer oocytes (10.1±6.3 versus 13.8±7.5) in potential high responders (AMH ≥15 pmol/L). Among patients with AMH ≥15 pmol/L, excessive response occurred less frequently with individualised than conventional dosing (≥15 oocytes: 20.2% versus 39.1%; ≥20 oocytes: 6.7% versus 18.5%). Total gonadotropin dose was reduced from 109.9±32.9 μg with follitropin alfa to 77.5±24.4 μg with follitropin delta. Limitations, reasons for caution The trial only covered the clinical outcome of one treatment cycle with fresh cleavage-stage embryo transfers. Wider implications of the findings The present trial implies that in addition to reducing the early OHSS risk, individualised dosing has the potential to improve the take-home baby rate in fresh cycles across all ages and with a lower gonadotropin consumption. The benefits in outcomes appear to be explained by the modulation of ovarian response. Trial registration number NCT03296527

Study question Could the individualized fixed-dose algorithm with follitropin delta show a similar pregnancy rate to conventional dosing with follitropin alfa in PPOS protocol? Summary answer Individualized fixed-dose algorithm with follitropin delta showed a similar pregnancy rate to follitropin alfa In PPOS protocol. What is known already Follitropin delta (REKOVELLE, Ferring Pharmaceuticals, Switzerland) is the first human cell line driven recombinant follicle-stimulating hormone (FSH) with an individualized fixed-dose algorithm based on serum AMH level and body weight. Follitropin alfa is a Chinese hamster ovarian cell driven recombinant FSH and its dosing is adjusted according to follicular response during the stimulation period. There was no significant difference between follitropin delta and follitropin alfa in terms of pregnancy rate under GnRH antagonist protocol. Study design, size, duration A retrospective analysis of 355 patients aged under 40 years who underwent ovarian stimulation in PPOS protocol using follitropin delta or follitropin alfa and on whom frozen-thawed single blastocyst transfer was conducted between August 2021 and November 2023 was performed. Participants/materials, setting, methods 193 cycles of women who used follitropin delta were compared to 162 cycles of women who used follitropin alfa. The following clinical outcomes on each treatment group were analyzed: chemical pregnancy rate (serum β hCG), clinical pregnancy rate (gestational sac), ongoing pregnancy rate(gestational sac and fetal heartbeat), serum E2 level at trigger day, cycle proportion of ≥ 10 oocytes retrieval, blastocyst formation rate, cycle proportion of ≥ 5 blastocysts and cycle proportion of ≥ 2 good quality blastocysts. Main results and the role of chance Baseline demographics in the follitropin delta group and the follitropin alfa group were not significantly different: age, 33.9 ± 3.5 years vs 34.5 ± 3.2 years; body weight, 53.5 ± 8.3 kg vs 53.8 ± 5.9 kg; number of previous IVF cycles, 0.2 ± 0.6 vs 0.3 ± 0.7; serum AMH level, 5.5 ± 2.9 ng/mL vs 5.3 ± 3.8 ng/mL, respectively. The chemical pregnancy rate (69.9% vs. 64.8%, P = 0.308), clinical pregnancy rate (58.0% vs. 56.2%, P = 0.748) and ongoing pregnancy rate (51.8% vs. 46.3%, P = 0.338) were comparable between the follitropin delta group and the follitropin alfa group. The individualized follitropin delta treatment resulted in a smaller cycle proportion of ≥ 10 oocytes retrieval (77.7% vs. 90.8%, P &amp;lt; 0.001) with lower serum E2 level at trigger day (3273 ± 1577 pg/mL vs. 3927 ± 1732 pg/mL, p &amp;lt; 0.001). However, the blastocyst formation rate was significantly higher in the follitropin delta group (75.5% vs. 68.7%, p &amp;lt; 0.001). Moreover, the cycle proportion of ≥ 5 blastocysts (71.0% vs. 76.4%, P = 0.286) and the cycle proportion of ≥ 2 good quality blastocysts (51.8% vs. 60.3%, P = 0.115) were comparable between the groups. Limitations, reasons for caution This is a non-controlled, retrospective study. Wider implications of the findings Follitropin delta in its individualized fixed-dose regimen could have the potential to decrease the risk of OHSS by minimizing excessive ovarian response, whereas a similar pregnancy rate to conventional dosing regimen could be expected due to the number of good quality blastocysts secured. Trial registration number not applicable

The subcutaneous recombinant human follicle-stimulating hormone XM17 follitropin alfa (Ovaleap(®)) is approved in the EU as a biosimilar of follitropin alfa (Gonal-f(®)) for use in all indications for which the reference product is approved, including as a multifollicular stimulant in women undergoing superovulation for assisted reproductive technology (ART) treatment. In a nonblind, phase I study in healthy female volunteers, the pharmacokinetic profile of XM17 follitropin alfa was bioequivalent to that of reference follitropin alfa following single dosing. Moreover, in a multinational, phase III study, the efficacy of XM17 follitropin alfa as a multifollicular stimulant was equivalent to that of reference follitropin alfa in terms of the number of retrieved oocytes (primary endpoint) in women undergoing controlled ovarian stimulation for ART treatment. There were no clinically relevant differences in oocyte quality between XM17 follitropin alfa and reference follitropin alfa, with biochemical, clinical and ongoing pregnancy rates and take-home baby rates not significantly differing between the treatment groups. XM17 follitropin alfa was generally well tolerated in this patient population, with its tolerability profile generally similar to that of reference follitropin alfa and with no new unexpected tolerability concerns identified. Thus, XM17 follitropin alfa is an effective treatment option in patients requiring follitropin alfa therapy for various reproductive endocrine disorders, providing a useful alternative to reference follitropin alfa.

Stimulation of spermatogenesis with recombinant human follicle-stimulating hormone (follitropin alfa; GONAL-f®): long-term treatment in azoospermic men with hypogonadotropic hypogonadism

Study question How do ovarian responses with follitropin delta 15 µg/day compare with follitropin alfa 225 IU/day in women undergoing ovarian stimulation using conventional dosing regimens? Summary answer The ADAPT-1 trial demonstrates similar ovarian responses with follitropin delta 15 µg/day and follitropin alfa 225 IU/day as starting doses in a conventional dosing regimen. What is known already Follitropin delta, a recombinant follicle-stimulating hormone (rFSH), is currently approved for ovarian stimulation using an individualised fixed daily dose based on serum anti-Müllerian Hormone (AMH) and bodyweight (maximum 12 µg/day for first cycle and 24 µg/day in subsequent cycles). Other rFSHs, such as follitropin alfa, conventionally apply a starting dose of 150–225 IU, fixed for the initial days of stimulation, after which dose adjustments can be made. Ovarian stimulation with follitropin delta 10 µg/day provides a similar ovarian response to follitropin alfa 150 IU/day for serum oestradiol concentration and number of follicles ≥12 mm. Study design, size, duration This randomised, assessor-blinded, multicentre trial compared the efficacy and safety of follitropin delta 15 µg/day with follitropin alfa 225 IU/day in conventional dosing regimens. The primary endpoint was the number of oocytes retrieved; mean difference between treatment groups was estimated using a negative binomial regression model (treatment and serum AMH level as factors). During the follow-up period, clinical pregnancy rates from first fresh/frozen transfers within 3 months and ovarian hyperstimulation syndrome (OHSS) rates were assessed. Participants/materials, setting, methods Participants, 18–40 years, undergoing IVF/ICSI were enrolled at specialist reproductive clinics in Austria, France, Italy, Spain, and United Kingdom for ovarian stimulation if they had no contraindications for treatment with starting gonadotropin dose of 225 IU/day. Patients could enrol if they reported infertility for at least 1 year if ≤ 37 years and at least 6 months for those &amp;gt;37 years, and regular menstrual cycles (21–35 days). All cycles used a gonadotropin-releasing hormone (GnRH) antagonist protocol. Main results and the role of chance Between August 1, 2022, and April 16, 2024, 300 of 337 screened patients were randomised to, and received, follitropin delta (n = 200) or follitropin alfa (n = 100). The two treatment groups were comparable in terms of demographics, baseline characteristics, and duration of infertility. The mean duration of treatment was ∼9 days in both groups. The mean total dose of follitropin delta was 143.7±33.6 µg and 154.3±23.1 µg (2,105±315 IU) for follitropin alfa. A total of 75% (226/300) used a human choriogonadotropin trigger for final follicular maturation. A mean of 9.9 oocytes was retrieved for both groups (estimated difference: 0.0 oocytes; 95% confidence interval [CI] –1.3,1.2). The category of 8–14 oocytes retrieved was the most common ovarian response (follitropin delta: 45.5%; follitropin alfa: 50.0%). Clinical pregnancy rates were comparable (31.6% and 31.0%; estimated difference 0.6 (95% CI –10.6, 11.8). The proportion of participants who experienced adverse events was 36.5% and 40.0%. Early OHSS (≤9 days after triggering) occurred in 2.5% and 3.0%, and all cases were Grade 3 (moderate) or lower. No participant had the stimulation cycle cancelled due to excessive ovarian response. Limitations, reasons for caution Cumulative pregnancy rates after the first transfer were not followed up. All analyses are of descriptive nature and no formal hypothesis testing or multiplicity adjustment was applied. Wider implications of the findings Treatment groups had similar ovarian responses, supporting equivalence for starting doses follitropin delta 15 µg and follitropin alfa 225 IU, with low rates of early OHSS. Ovarian stimulation cycles with follitropin delta dosed in micrograms can be planned and adjusted, leveraging the established IU dose equivalence to follitropin alfa. Trial registration number Yes

Study question To compare the live birth rate using frozen-thawed blastocysts obtained from ovarian stimulation with individualised follitropin delta dosing to conventional follitropin alfa dosing. Summary answer The live birth rate in cryo cycles conducted within 1 year after ovarian stimulation was comparable for individualised follitropin delta and conventional follitropin alfa treatment. What is known already It has been demonstrated that the follitropin delta (Rekovelle, Ferring Pharmaceuticals) in an individualised dosing regimen based on anti-Müllerian hormone (AMH) level and body weight is non-inferior to conventional follitropin alfa (Gonal-f, Merck Serono) dosing with respect to ongoing pregnancy and ongoing implantation rates in fresh cycles. The individualised approach also reduced the risk of ovarian hyperstimulation syndrome (OHSS) versus the conventional approach. Furthermore, treatment with follitropin delta and follitropin alfa gave comparable pregnancy rates in repeated fresh cycles. Study design, size, duration Analysis of frozen cycles using blastocysts obtained from a randomised trial comparing follitropin delta versus follitropin alfa in 1,326 IVF/ICSI patients (18–40 years) and a subsequent trial of up to two additional ovarian stimulation cycles. The clinical outcome includes women with cryopreserved blastocysts following ovarian stimulation and who underwent frozen cycles within 1 year after starting stimulation in their last cycle. Participants/materials, setting, methods A total of 917 women had at least one Day 5 blastocyst which was vitrified and stored following up to three ovarian stimulation cycles. A started cryo cycle was defined as warming of a blastocyst. After warming, 1–2 blastocysts were transferred in cryo cycles, using natural cycle or programmed regimens. Treatment differences and 95% confidence intervals (CI) were calculated with adjustment for age strata and accounting for repeated cycles within patient. Main results and the role of chance The proportion of women with frozen blastocysts was similar in the two treatment groups, with 69.5% in the follitropin delta group and 68.8% in the follitropin alfa group. Similar postwarming blastocyst survival rates were observed for the two groups, with 87.4% of the warmed blastocysts proceeding to transfer in the follitropin delta group and 88.8% in the follitropin alfa group. About half of the women (48.1% in each treatment group) with frozen blastocysts underwent at least one frozen cycle with transfer within the 1-year period, with an average of 1.5 cycles per woman in the follitropin delta group and 1.6 cycles per woman in the follitropin alfa group. The ongoing implantation rate was 27.6% in the follitropin delta group and 27.8% in the follitropin alfa group (adjusted difference 0.5% [95% CI: –7.1%; 8.2%]). The live birth rate per started cryo cycle was 32.0% in the follitropin delta group and 31.3% in the follitropin alfa group (adjusted difference 1.2% [95% CI: –6.8%; 9.3%]), while the live birth rate per cryo cycle with transfer was 33.2% and 31.9% (adjusted difference 1.9% [95% CI: –6.2%; 10.0%]), respectively. Limitations, reasons for caution The number of blastocysts to be transferred in the frozen cycles as well as the protocol for endometrial preparation was based on local centre practices. Wider implications of the findings: These findings suggest that the follitropin delta and follitropin alfa dosing regimens are equally effective in terms of live birth rate in frozen replacement cycles and add reassuring information to the clinical performance of cryopreserved blastocysts derived from ovarian stimulation with follitropin delta. Trial registration number NCT01956110, NCT01956123.

We aimed to compare the efficacy and safety of recombinant human follicle-stimulating hormone (follitropin alfa) and purified urinary human follicle-stimulating hormone (urofollitropin) for ovulation induction in Japanese women with anovulatory infertility;also to verify the noninferiority (in terms of ovulation rate) of follitropin alfa versus urofollitropin. In a Phase III, multicenter, single-blind, parallel-group study, we enrolled 265 Japanese women aged 20-39 years. The patients were menstruating without apparent ovulation or were amenorrheic (with a positive progestin challenge test), and had failed to conceive with anti-estrogen ovulation-induction therapy. The patients underwent a low-dose step-up regimen using follitropin alfa or urofollitropin with a starting dose of 75 IU. The primary endpoint was the proportion of patients who ovulated (mid-luteal serum progesterone ≥5 ng/mL and/or confirmed clinical pregnancy). Secondary endpoints included the proportion of patients with a dominant follicle (≥18 mm) and the duration of stimulation. Ovulation occurred in 79.1% and 82.6% of the patients who received follitropin alfa and urofollitropin, respectively, in the full-analysis set (n = 261), and in 79.2% and 82.5% of the per-protocol set (n = 251). The predefined noninferiority criteria for the primary endpoint were achieved. No significant differences were observed in any secondary endpoint. Treatment-emergent adverse events were reported by a similar proportion of patients in each group (follitropin alfa, 53.5%; urofollitropin, 50.0%). No significant difference in the primary efficacy endpoint (rate of ovulation) was observed between follitropin alfa and purified urofollitropin in women with anovulatory infertility who were menstruating or had progestin-positive amenorrhea. The use of treatment holidays in this study prevents comparison of the data with previous trials that utilized consecutive daily doses.

Establishing the follitropin delta dose that provides a comparable ovarian response to 150 IU/day follitropin alfa

Study question Is there a difference in a clinical outcome between using follitropin delta and follitropin alfa undergoing a progestin primed ovarian stimulation (PPOS) protocol? Summary answer There was no difference between follitropin delta and follitropin alfa in terms of pregnancy rates. What is known already Follitropin delta (REKOVELLE, Ferring Pharmaceuticals, Switzerland) is the first recombinant human follicle-stimulating hormone (FSH) using the algorithm-based individualized dosing regimen while reducing the risk of ovarian hyperstimulation syndrome (OHSS) as compared with conventional dosing strategies. The efficacy and safety of follitropin delta has been demonstrated in randomized controlled trials (RCTs). Study design, size, duration We performed a retrospective analysis of 645 patients who underwent ovarian stimulation by a PPOS protocol using follitropin delta or follitropin alfa between April 2022 and August 2022. (325 patients using follitropin delta and 320 patients using follitropin alfa, respectively.) Participants/materials, setting, methods 325 cycles of women who used follitropin delta were compared to 320 cycles of women who used follitropin alfa. The following outcomes were analysed; fertilized rate, 2 pronuclear embryo rate, good quality embryo rate, blastocyst rate, good quality blastocyst rate. A total of 499 women who underwent embryo transfer in cryo cycles using natural cycle or hormone replacement cycle were analysed about biochemical pregnancy rate, clinical pregnancy rate. Main results and the role of chance Baseline demographics for 325 women in follitropin delta group and 320 women in follitropin alfa were: age, 35.1±4.3 years and 35.2±4.3 years; number of previous IVF cycles, 1.6±1.6 and 1.7±1.7, respectively. The laboratory data were: fertilization rate, 81.4% and 80.1%, 2 pronuclear embryo rate, 73.9% and 71.5%, good quality cleavage stage embryo rate, 59.4% and 55.9%, blastocyst rate, 58.9% and 55.7%, good quality blastocyst rate, 41.3% and 38.7%, respectively. Only good quality cleavage stage embryo rate and good quality blastocyst rate were significantly higher (P &amp;lt; 0.05) in follitropin delta group. A vitrified-warmed embryo transfer was performed for 257/325 women (79.1%) and 242/320 women (75.6%) and subsequent positive β-human chorionic gonadotropin (βhCG) reported for 218/621 cycles (35.1%) and 194/570 cycles (34.0%), respectively. Ongoing pregnancy rate after embryo transfer were 19.2% (n = 119) and 19.6% (n = 112) and cumulative ongoing pregnancy rate were both 46.3%. Mild OHSS was reported for 131 women (40.3%) and 170 women (53.1%), respectively (P = 0.07). Limitations, reasons for caution This is a non-controlled, retrospective study. Wider implications of the findings The present study shows that in addition to reducing the OHSS risk, follitropin delta in its individualised fixed-dose regimen has the potential to improve the quality of embryos although there was no significant difference in clinical outcomes. Trial registration number not applicable

Background:The development of new fertility treatment options has facilitated individualized assisted reproductive technology (ART) protocols to improve outcomes. Manufacturing improvements to recombinant human follitropin alfa have allowed precise dosing based on mass (filled-by-mass; FbM) rather than bioactivity (filled-by-bioassay; FbIU). Continued monitoring and reporting of follitropin alfa treatment outcomes in routine clinical practice is essential.Objective:To provide an overview of the frequency of different controlled ovarian-stimulation protocols used in in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles in new European Union member states, and to provide post-registration efficacy and safety data on follitropin alfa.Research design and methods:A 2-year, prospective, observational, multicentre, Phase IV study conducted at ART clinics in the Czech Republic, Estonia, Latvia, Lithuania, Poland, Slovakia and Slovenia. Women aged 18–47 years undergoing ovarian stimulation with follitropin alfa for conventional IVF or ICSI were eligible for inclusion. The main treatment outcome was cumulative clinical pregnancy rate. Data were analysed descriptively.Results:Clinical pregnancy outcomes were available for 4055 of 4085 (99.3%) patients. In total, 1897 (46.8%) patients used follitropin alfa FbIU; 2133 (52.6%) used follitropin alfa FbM. Clinical pregnancy was achieved by 39.5% (1603/4055) of patients. A greater proportion of patients with polycystic ovary syndrome achieved a clinical pregnancy than those with endometriosis (41.8% vs 37.8%, respectively). A higher cumulative pregnancy rate was observed with the use of follitropin alfa FbM than follitropin alfa FbIU (41.3% vs 37.8%, respectively; p = 0.02).Conclusions:This study represents the most comprehensive audit of individualized ART in clinical practice in Central and Eastern Europe. Overall, clinical pregnancy was achieved by 39.5% of patients after stimulation with follitropin alfa. The use of follitropin alfa FbM resulted in a higher cumulative pregnancy rate than did the FbIU formulation. However, limitations of the study include the observational and non-comparative study design, and descriptive nature of statistical analyses; furthermore, the study was not designed to make direct comparisons between the success rates of different ovarian-stimulation protocols.

BackgroundGonadotropins are used in ovulation induction (OI) for patients with anovulatory infertility. Pharmacologic OI is associated with risks of ovarian hyperstimulation syndrome and multiple pregnancy. Treatment protocols that minimize these risks by promoting monofollicular development are required. A starting dose of 37.5 IU/day follitropin alfa has been used in OI, particularly among women at high risk of multifollicular development and multiple pregnancy. A retrospective case series study was performed to evaluate rates of monofollicular development and singleton pregnancy following standard treatment with 37.5 IU/day follitropin alfa.MethodsSpanish centers that had performed at least five OI cycles during 2008 using 37.5 IU/day follitropin alfa as a starting dose were invited to participate. Data could be provided from any cycle performed in 2008 (up to a maximum of 12 consecutive cycles per site). Case report forms were collected during April-November 2009 and reviewed centrally. Descriptive statistics were obtained from all cases, and follicular development and clinical pregnancy rates assessed. Potential associations of age and body mass index with follicular development and clinical pregnancy were assessed using univariate correlation analyses.ResultsThirty centers provided data on 316 cycles of OI using a starting dose of 37.5 IU/day follitropin alfa. Polycystic ovary syndrome was the cause of anovulatory infertility in 217 (68.7%) cases. Follitropin alfa at 37.5 IU/day was sufficient to achieve ovarian stimulation in 230 (72.8%) cycles. A single follicle ≥16 mm in diameter developed in 193 cycles (61.1%; 95% confidence interval [CI] 55.7-66.4%). Seventy-eight women (24.7%; 95% CI 19.9-29.5%) became pregnant: 94.9% singleton and 5.1% twin pregnancies. Fourteen started cycles (4.4%) were cancelled, mainly due to poor response. Univariate correlation analyses detected weak associations.ConclusionsMonofollicular growth rate was comparable with optimal rates reported elsewhere and the pregnancy rate exceeded that in other studies of OI using gonadotropins. A starting dose of 37.5 IU/day follitropin alfa is an effective option in selected cases to prevent ovarian hyper-response without loss of efficacy. The analysis could not identify a single selection criterion for individuals who would benefit from this treatment approach; this merits further investigation in prospective studies.