Cost-Effectiveness Analysis of the Gonadotropin Treatments HP-hMG and rFSH for Assisted Reproductive Technology in France: A Markov Model Analysis.

OBJECTIVES: The objectives of this study were to assess (1) the expected cost of a live birth (LB) after in vitro fertilization with two different gonadotropin treatments [high purified human menopausal gonadotropin (HP-hMG) and recombinant follicle-stimulating hormone (rFSH)] as the single cost variable, and (2) the cost effectiveness of HP-hMG relative to rFSH in the context of the routine practice of assisted reproductive technology (ART) in France. METHODS: A Markov model was developed to simulate the therapeutic management, the in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) courses, and the effects of complications in hypothetical cohorts of 30,000 patients undergoing IVF/ICSI with fresh embryo transfer (up to four attempts) using data from the MERIT and MEGASET clinical trials or from French routine ART practice. RESULTS: The cost per LB was estimated at €12,145 and at €14,247 with HP-hMG and rFSH, respectively, using efficacy data from published clinical trials. The resulting incremental cost-effectiveness ratio (ICER) was - €11,616 per LB. HP-hMG was less expensive by around €15.0 million and more effective by 1289 additional LBs. Using French clinical data, the cost per LB was €16,415 and €18,7531 with HP-hMG and rFSH, respectively. The ICER for HP-hMG versus rFSH was estimated at - €7,719 per LB with a saving of about €8.54 million and 1097 additional LBs. Deterministic sensitivity analyses showed that the main ICER drivers were the LB rate, followed by the total gonadotropin doses. The probabilistic sensitivity analysis indicated that HP-hMG was the dominant strategy in 71.2% of cases using the clinical trial data and in 50.2% of cases using the French data. CONCLUSION: This analysis indicates that compared with rFSH, HP-hMG is less costly for IVF/ICSI management from the French healthcare payer's viewpoint. The results of the present Markov model analysis are consistent with previous findings in other European countries.

Cost effectiveness of letrozole and purified urinary FSH in treating women with clomiphene citrate-resistant polycystic ovarian syndrome: a randomized controlled trial.

We aimed to compare the cost effectiveness of letrozole versus purified urinary follicle stimulating hormone (FSH) in treating patients with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). This was a randomized trial conducted in Cairo University and Beni-Suef University Hospitals, Egypt. A cohort of 140 eligible women was randomized to receive either letrozole 2.5 mg twice daily for five days, or FSH using a graduated regimen starting with a dose of 75 IU. Treatment was repeated for three months if pregnancy did not occur. There were no significant differences between the two treatments in the cumulative clinical pregnancy rate (30% vs. 34%; p = 0.578), cumulative ovulation rate (47% vs. 57%; p = 0.236), miscarriage rate (9% vs. 4%, p > 0.999) or multiple pregnancy rate (0% and 8%, p = 0.491) but the FSH cycles were 4.8 times more expensive. Letrozole and FSH were both effective in treating women with CC-resistant PCOS but letrozole was more cost effective.Study registration number: NCT02304107.

Economic Evaluation of Three Frequently Used Gonadotrophins in Assisted Reproduction Techniques in the Management of Infertility in the Netherlands.

BACKGROUND AND OBJECTIVE: Subfertility represents a multidimensional problem associated with significant distress and impaired social well-being. In the Netherlands, an estimated 50,000 couples visit their general practitioner and 30,000 couples seek medical specialist care for subfertility. We conducted an economic evaluation comparing recombinant human follicle-stimulating hormone (follitropin alfa, r-hFSH, Gonal-F®) with two classes of urinary gonadotrophins-highly purified human menopausal gonadotrophin (hp-HMG, Menopur®) and urinary follicle-stimulating hormone (uFSH, Fostimon®)-for ovarian stimulation in women undergoing in vitro fertilization (IVF) treatment in the Netherlands. METHODS: A pharmacoeconomic model was developed, simulating each step in the IVF protocol from the start of therapy until either a live birth, a new IVF treatment cycle or cessation of IVF, following a long down-regulation protocol. A decision tree combined with a Markov model details progress through each health state, including ovum pickup, fresh embryo transfer, up to two subsequent cryo-preserved embryo transfers, and (ongoing) pregnancy or miscarriage. A health insurer perspective was chosen, and the time horizon was set at a maximum of three consecutive treatment cycles, in accordance with Dutch reimbursement policy. Transition probabilities and costing data were derived from a real-world observational outcomes database (from Germany) and official tariff lists (from the Netherlands). Adverse events were considered equal among the comparators and were therefore excluded from the economic analysis. A Monte Carlo simulation of 5000 iterations was undertaken for each strategy to explore uncertainty and to construct uncertainty intervals (UIs). All cost data were valued in 2013 Euros. The model's structure, parameters and assumptions were assessed and confirmed by an external clinician with experience in health economics modelling, to inform on the appropriateness of the outcomes and the applicability of the model in the chosen setting. RESULTS: The mean total treatment costs were estimated as €5664 for follitropin alfa (95 % UI €5167-6151), €5990 for hp-HMG (95 % UI €5498-6488) and €5760 for uFSH (95 % UI €5256-6246). The probability of a live birth was estimated at 36.1 % (95 % UI 27.4-44.3 %), 33.9 % (95 % UI 26.2-41.5 %) and 34.1 % (95 % UI 25.9-41.8 %) for follitropin alfa, hp-HMG and uFSH, respectively. The costs per live birth estimates were €15,674 for follitropin alfa, €17,636 for hp-HMG and €16,878 for uFSH. Probabilistic sensitivity analysis indicated a probability of 72.5 % that follitropin alfa is cost effective at a willingness to pay of €20,000 per live birth. The probabilistic results remained constant under several analyses. CONCLUSION: The present analysis shows that follitropin alfa may represent a cost-effective option in comparison with uFSH and hp-HMG for IVF treatment in the Netherlands healthcare system.

Treatment preferences and outcome in male hypogonadotropic hypogonadism: an Indian perspective.

This retrospective study assessed treatment preferences and outcome with testosterone or HCG / HCG-FSH combination in Indian male idiopathic hypogonadotropic hypogonadism (IHH) subjects (n = 31) above 18 years of age. 38.7% of IHH study subjects had no fertility plans and chose 3 monthly intramuscular testosterone undecanoate. 73.7% of subjects with fertility plans chose human chorionic gonadotropin (HCG) alone due to cost considerations. Spermatogenesis occurred in 21.4% on HCG alone and 60% of subjects on HCG with follicle-stimulating hormone (FSH) combination. Treatment failure is higher than published Western rates. FSH and HCG combination regimen is costly but superior to HCG alone. However, treatment failure still persists, suggesting unknown testicular defect in IHH.

Low dose of rFSH [100 IU] in controlled ovarian hyperstimulation response: a pilot study.

BACKGROUND: The initial dose of recombinant Follicle Stimulating Hormone [rFSH] to be used in assisted reproduction treatment depends on several factors, mainly the cause of the infertility and the patient's age. For young patients [≤35 years] usually an initial dose of around 150 IU of rFSH is recommended, but there are no studies proving that this should actually be the standard initial dose. We aimed to report the experience of a low-cost Human Reproduction Center where a dose of 100 IU of rFSH was used for controlled ovarian hyperstimulation [COH]. FINDINGS: An observational prospective study was performed on 212 women aged ≤38 years old that underwent high-complexity assisted reproduction treatments. The patients' infertility was mainly caused by tuboperitoneal, idiopathic or male factors. Controlled ovarian stimulation was performed using 100 IU of rFSH. Regarding the COH, 53.8% of the patients presented a satisfactory response, 25.9% low response, 14.2% hyper-response, and 6.1% developed ovarian hyperstimulation syndrome. Of the 55 patients with poor response, 20 started a new cycle with an initial dose of 200 IU of rFSH; 65% showed a satisfactory response, 10% a poor response, 20% a hyper-response, and 5% developed OHSS. CONCLUSION: The initial dose of 100 IU of rFSH was considered adequate for controlled ovarian hyperstimulation, meeting the aim to reduce the costs of the assisted reproduction treatment.

Cost-effectiveness comparison between pituitary down-regulation with a gonadotropin-releasing hormone agonist short regimen on alternate days and an antagonist protocol for assisted fertilization treatments.

OBJECTIVE: To compare cost-effectiveness between pituitary down-regulation with a GnRH agonist (GnRHa) short regimen on alternate days and GnRH antagonist (GnRHant) multidose protocol on in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) outcome. DESIGN: Prospective, randomized. SETTING: A private center. PATIENT(S): Patients were randomized into GnRHa (n = 48) and GnRHant (n = 48) groups. INTERVENTION(S): GnRHa stimulation protocol: administration of triptorelin on alternate days starting on the first day of the cycle, recombinant FSH (rFSH), and recombinant hCG (rhCG) microdose. GnRHant protocol: administration of a daily dose of rFSH, cetrorelix, and rhCG microdose. MAIN OUTCOME MEASURE(S): ICSI outcomes and treatment costs. RESULT(S): A significantly lower number of patients underwent embryo transfer in the GnRHa group. Clinical pregnancy rate was significantly lower and miscarriage rate was significantly higher in the GnRHa group. It was observed a significant lower cost per cycle in the GnRHa group compared with the GnRHant group ($5,327.80 ± 387.30 vs. $5,900.40 ± 472.50). However, mean cost per pregnancy in the GnRHa was higher than in the GnRHant group ($19,671.80 ± 1,430.00 vs. $11,328.70 ± 907.20). CONCLUSION(S): Although the short controlled ovarian stimulation protocol with GnRHa on alternate days, rFSH, and rhCG microdose may lower the cost of an individual IVF cycle, it requires more cycles to achieve pregnancy. CLINICAL TRIAL REGISTRATION NUMBER: NCT01468441.

The OPTIMIST study: optimisation of cost effectiveness through individualised FSH stimulation dosages for IVF treatment. A randomised controlled trial.

BACKGROUND: Costs of in vitro fertilisation (IVF) are high, which is partly due to the use of follicle stimulating hormone (FSH). FSH is usually administered in a standard dose. However, due to differences in ovarian reserve between women, ovarian response also differs with potential negative consequences on pregnancy rates. A Markov decision-analytic model showed that FSH dose individualisation according to ovarian reserve is likely to be cost-effective in women who are eligible for IVF. However, this has never been confirmed in a large randomised controlled trial (RCT). The aim of the present study is to assess whether an individualised FSH dose regime based on an ovarian reserve test (ORT) is more cost-effective than a standard dose regime. METHODS/DESIGN: Multicentre RCT in subfertile women indicated for a first IVF or intracytoplasmic sperm injection cycle, who are aged < 44 years, have a regular menstrual cycle and no major abnormalities at transvaginal sonography. Women with polycystic ovary syndrome, endocrine or metabolic abnormalities and women undergoing IVF with oocyte donation, will not be included. Ovarian reserve will be assessed by measuring the antral follicle count. Women with a predicted poor response or hyperresponse will be randomised for a standard versus an individualised FSH regime (150 IU/day, 225-450 IU/day and 100 IU/day, respectively). Participants will undergo a maximum of three stimulation cycles during maximally 18 months. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months after randomisation. Secondary outcomes are parameters for ovarian response, multiple pregnancies, number of cycles needed per live birth, total IU of FSH per stimulation cycle, and costs. All data will be analysed according to the intention-to-treat principle. Cost-effectiveness analysis will be performed to assess whether the health and associated economic benefits of individualised treatment of subfertile women outweigh the additional costs of an ORT. DISCUSSION: The results of this study will be integrated into a decision model that compares cost-effectiveness of the three dose-adjustment strategies to a standard dose strategy. The study outcomes will provide scientific foundation for national and international guidelines. TRIAL REGISTRATION: NTR2657.

The INeS study: prevention of multiple pregnancies: a randomised controlled trial comparing IUI COH versus IVF e SET versus MNC IVF in couples with unexplained or mild male subfertility.

BACKGROUND: Multiple pregnancies are high risk pregnancies with higher chances of maternal and neonatal mortality and morbidity. In the past decades the number of multiple pregnancies has increased. This trend is partly due to the fact that women start family planning at an increased age, but also due to the increased use of ART.Couples with unexplained or mild male subfertility generally receive intrauterine insemination IUI with controlled hormonal stimulation (IUI COH). The cumulative pregnancy rate is 40%, with a 10% multiple pregnancy rate.This study aims to reveal whether alternative treatments such as IVF elective Single Embryo Transfer (IVF e SET) or Modified Natural Cycle IVF (MNC IVF) can reduce the number of multiple pregnancy rates, but uphold similar pregnancy rates as IUI COH in couples with mild male or unexplained subfertility. Secondly, the aim is to perform a cost effective analyses and assess treatment preference of these couples. METHODS/DESIGN: We plan a multicentre randomised controlled clinical trial in the Netherlands comparing six cycles of intra-uterine insemination with controlled ovarian hyperstimulation or six cycles of Modified Natural Cycle (MNC) IVF or three cycles with IVF-elective Single Embryo Transfer (eSET) plus cryo-cycles within a time frame of 12 months.Couples with unexplained subfertility or mild male subfertility and a poor prognosis for treatment independent pregnancy will be included. Women with anovulatory cycles, severe endometriosis, double sided tubal pathology or serious endocrine illness will be excluded.Our primary outcome is the birth of a healthy singleton. Secondary outcomes are multiple pregnancy, treatment costs, and patient experiences in each treatment arm. The analysis will be performed according tot the intention to treat principle. We will test for non-inferiority of the three arms with respect to live birth. As we accept a 12.5% loss in pregnancy rate in one of the two IVF arms to prevent multiple pregnancies, we need 200 couples per arm (600 couples in total). DISCUSSION: Determining the safest and most cost-effective treatment will ensure optimal chances of pregnancy for subfertile couples with substantially diminished perinatal and maternal complications. Should patients find the most cost-effective treatment acceptable or even preferable, this could imply the need for a world wide shift in the primary treatment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 52843371.

Costs and outcomes associated with IVF using recombinant FSH.

Cost and outcome estimates based on clinical trial data may not reflect usual clinical practice, yet they are often used to inform service provision and budget decisions. To expand understanding of assisted reproduction treatment in clinical practice, an economic evaluation of IVF/intracytoplasmic sperm injection (ICSI) data from a single assisted conception unit (ACU) in England was performed. A total of 1418 IVF/ICSI cycles undertaken there between October 2001 and January 2006 in 1001 women were analysed. The overall live birth rate was 22% (95% CI: 19.7-24.2), with the 30- to 34-year age group achieving the highest rate (28%). The average recombinant FSH (rFSH) dose/cycle prescribed was 1855 IU. Average cost of rFSH/cycle was 646 pound(SD: 219 pound), and average total cost/cycle was 2932 pound (SD: 422 pound). Economic data based on clinical trials informing current UK guidance assumes higher doses of rFSH dose/cycle (1750-2625 IU), higher average cost of drugs/cycle (1179 pound), and higher average total cost/cycle (3266 pound). While the outcomes in this study matched UK averages, total cost/cycle was lower than those cited in UK guidelines. Utilizing the protocols and (lower) rFSH dosages reported in this study may enable other ACU to provide a greater number of IVF/ICSI cycles to patients within given budgets.

A cost per live birth comparison of HMG and rFSH randomized trials.

To help inform healthcare treatment practices and funding decisions, an economic evaluation was conducted to compare the two leading gonadotrophins used for IVF in Belgium. Based on the results of a recently published meta-analysis, a simulated decision tree model was constructed with four states: (i) fresh cycle, (ii) cryopreserved cycle, (iii) live birth and (iv) treatment withdrawal. Gonadotrophin costs were based on highly purified human menopausal gonadotrophin (HP-HMG; Menopur) and recombinant FSH (rFSH) alpha (Gonal-F). After one fresh and one cryopreserved cycle the average treatment cost with HP-HMG was lower than with rFSH (HP-HMG euro3635; rFSH euro4103). The average cost saving per person started on HP-HMG when compared with rFSH was euro468. Additionally, the average costs per live birth of HP-HMG and rFSH were found to be significantly different: HP-HMG euro9996; rFSH euro13,009 (P < 0.0001). HP-HMG remained cost-saving even after key parameters in the model were varied in the probabilistic sensitivity analysis. Treatment with HP-HMG was found to be the dominant treatment strategy in IVF because of improved live birth rates and lower costs. Within a fixed healthcare budget, the cost-savings achieved using HP-HMG would allow for the delivery of additional IVF cycles.

An economic evaluation of highly purified HMG and recombinant FSH based on a large randomized trial.

Public funding for IVF is increasingly being challenged by health authorities in an attempt to minimize health service costs. In light of treatment rationing, the need to consider costs in relation to outcomes is paramount. To assess the cost implications of gonadotrophin treatment options, an economic evaluation comparing highly purified human menopausal gonadotrophin (HP-HMG) and recombinant FSH (rFSH) has been conducted. The analysis is based on individual patient data from a large randomized controlled trial (n = 731) in a long agonist IVF protocol. The economic evaluation uses a discrete event simulation model to assess treatment costs in relation to live births for both treatments based on published UK costs. After one cycle the mean costs per IVF treatment for HP-HMG and rFSH were pound2396 (95% CI pound2383-2414) and pound2633 ( pound2615-2652), respectively. The average cost-saving of pound237 per IVF cycle using HP-HMG allows one additional cycle to be delivered for every 10 cycles. With maternal and neonatal costs applied, the median cost per IVF baby delivered with HP-HMG was pound8893 compared with pound11,741 for rFSH (P < 0.001). The cost-saving potential of HP-HMG in IVF was still apparent after varying critical cost parameters in the probabilistic sensitivity analysis.

A Markov model of the cost-effectiveness of human-derived follicle-stimulating hormone (FSH) versus recombinant FSH using comparative clinical trial data.

This study compared the cost and effectiveness of highly purified, human-derived follicle-stimulating hormone (FSH) (Bravelle) to recombinant FSH (Follistim) using Markov modeling and Monte Carlo simulation. One IVF treatment cycle resulted in costs of 11,584 dollars +/- 211 dollars for human-derived FSH and 12,762 dollars +/- 170 dollars for recombinant FSH, while three treatment cycles, holding the transition probabilities of the first cycle constant for the next two cycles, resulted in costs of 22,712 dollars +/- 1,107 dollars for human-derived FSH and 24,935 dollars +/- 1,205 dollars for recombinant FSH.

Ovulation induction with urinary FSH or recombinant FSH in polycystic ovary syndrome patients: a prospective randomized analysis of cost-effectiveness.

The aim of this prospective, randomized trial was to compare the clinical results and the cost-effectiveness of urinary FSH (uFSH) and recombinant FSH (rFSH) in ovarian stimulation for intrauterine insemination (IUI) cycles in polycystic ovary syndrome (PCOS) patients. One-hundred and seventy PCOS infertile patients undergoing IUI were enrolled, and protocols of ovarian stimulation with uFSH or rFSH were randomly assigned. The total number of cycles performed was 379 (182 and 197, respectively). The main outcome measures were the number of mature follicles, the days of stimulation, the number of ampoules and IU used per cycle, the biochemical/clinical pregnancy rates, the number of multiple pregnancies and the cost-effectiveness. No statistically significant differences were found in the follicular development, length of stimulation, pregnancy rates, delivery rates and multiple pregnancies between the two groups. In the uFSH group, the cost per cycle remained significantly lower (218.51 +/- 88.69 versus 312.22 +/- 118.12; P < 0.0001), even though a significantly higher number of IU of gonadotrophins were used (809.3 +/- 271.9 versus 589.1 +/- 244.7; P < 0.0001). The cost-effectiveness (i. e. within a group, the total cost of all cycles divided by no. of clinical pregnancies) was 1729.08 in the uFSH group and 3075.37 in the rFSH group. In conclusion, uFSH and rFSH demonstrated the same effectiveness in ovarian stimulation in IUI cycles in PCOS patients. The urinary preparation is more cost-effective due to the difference of its cost per IU.

[Pharmacoeconomic advantages of recombinant FSH vs urinary derived FSH]. / Avantages pharmaco-économiques de la FSH d'origine recombinante par rapport à la FSH d'origine urinaire.

Nowadays, the use of urinary FSH is essentially justified by a lower acquisition price compared to modern products generated by Biotechnology (recombinant FSH). However, the public price of a product is only one element of the total cost of a therapeutic regimen that must be taken into account in medical decision-making. This is the role of pharmacoeconomic studies including cost-effectiveness models, which allow proceeding to complex situational comparisons such as several attempts of Assisted Reproduction Techniques. Different models have been carried out and published in several countries and present consistently that recombinant FSH is more cost-effective that urinary derived FSH.

Recombinant versus urinary follicle-stimulating hormone in intrauterine insemination cycles: a prospective, randomized analysis of cost effectiveness.

OBJECTIVE: To compare the clinical results and the cost effectiveness of urinary FSH and recombinant FSH in ovarian stimulation for IUI cycles. DESIGN: Prospective, randomized trial. SETTING: University Hospital, Perugia, and A.G.UN.CO. Obstetrics and Gynaecology Centre, Rome, Italy. PATIENT(S): IUI cycles were performed in 67 infertile patients. INTERVENTION(S): Protocols of ovarian stimulation with urinary FSH or recombinant FSH were randomly assigned, for a total of 138 cycles performed (67 and 71, respectively). MAIN OUTCOME MEASURE(S): Number of mature follicles, days of stimulation, number of ampules, and IU used per cycle, biochemical/clinical pregnancy rates and cost-effectiveness ratio. RESULT(S): Follicular development, length of stimulation, pregnancy and delivery rates were not statistically different. Although in the urinary FSH group a significantly higher number of IU of gonadotropins were used (815.5 +/- 284.9 vs. 596.0 +/- 253.8), the cost per cycle remained significantly lower (220.73 +/- 94.72 vs. 318.50 +/- 125.21). The cost-effectiveness ratio was 1,848.61 euro in the urinary FSH group and 2,512.61 euro in the recombinant FSH group. CONCLUSION(S): Urinary FSH and recombinant FSH are both effective in ovarian stimulation in IUI cycles. The urinary preparation is more cost effective due to the difference of its cost per IU.

[In vitro fertilization in France: economic aspects and influence of the gonadotropin choice (urinary vs. recombinant) on cost]. / La fécondation in vitro en France. Approche économique et influence du choix des gonadotrophines (urinaires ou recombinantes) sur le coût.

OBJECTIVES: The objective of the study was to make an economic evaluation of in vitro fertilization and to determine the impact of some factors on its cost, particularly the choice between recombinant follicle stimulating hormone (r-FSH) and urinary FSH (u-FSH) for ovarian stimulation. PATIENTS AND METHODS: Costs were calculated in a Public Health view, by studying two phases: the stimulation cycle (including down-regulation) and the pregnancy (including the neonatal period). The calculation has included the side effects and the frozen embryos transfers. Economic data came from various sources: the French nomenclature on medical treatments (NGAP), the French drugs dictionary (Vidal) and the French Information system medical plan (PMSI). FSH costs were computed according to the currently marketed products, i.e., Fostimon (Laboratoires Genévrier, Sophia-Antipolis, France) for urinary FSH, and Gonal-F (Laboratoires Serono, Boulogne-Billancourt, France) and Puregon (Laboratoires Organon, Puteaux, France) for recombinant FSH. Two different ways of efficacy between u-FSH and r-FSH were considered for the calculations, those reported in Daya's meta-analysis (3.7% in favour of r-FSH for the clinical pregnancy rate per initiated cycle) and in the only double-blind study (Frydman et al., no difference). RESULTS: The annual cost of ART reaches approximately 130 million Euros in France, for the cycles only, and 170 million Euros when including the pregnancy costs. Urinary FSH is much cheaper than recombinant FSH. Whereas the number of administered FSH units was higher in u-FSH, this results in a mean lower cost of 500 Euros per cycle (2422 Euros for u-FSH and 2959 Euros for r-FSH). For one complete year, in France, the potential over cost of recombinant products reaches 24 million Euros when considering only the cycles (128.4 vs. 104.0 million Euros) and 24-31 million Euros when pregnancies and babies (neonatal period) are considered (171.4 vs 140.7 and 147.0 million Euros, respectively). The IVF per baby cost can be estimated at 16 463 Euros for r-FSH and at 14 116 Euros (in case of equivalence between the two drugs) to 15 805 Euros (in case of a difference of 3.7% pregnancy per oocyte recovery) for u-FSH. CONCLUSION: This gives Public Health lighting to the choices in the matter of ovulation stimulation. It shows the economic impact of the choice in the FSH type.