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.

The redesigned follitropin alfa pen injector: results of the patient and nurse human factors usability testing.

OBJECTIVES: A redesigned pen injector for administration of follitropin alfa (follitropin α) has been developed for use in fertility treatment cycles. Pre-summative and summative usability testing was undertaken to assess the risk of dosing errors compared with the existing follitropin α pen. The study also assessed proper use of and dose selection with the redesigned pen. METHODS: Infertile women who were trying to conceive and specialist nurses were recruited from four cities in Germany. Usability goals relating to proper use of the pen device were defined from a risk assessment and further categorized as critical and functional operational goals. Individual, non-interventional, standardized, usability tests were performed with patients and nurses by four experienced research professionals using questionnaires that also included ease-of-use ratings. A non-standardized qualitative analysis of nurse-patient training sessions was performed in the presence of a research professional; reasons for confidence, safety, possible misunderstandings and risks when handling the pen were noted. RESULTS: The overall risk of dosing errors with the redesigned pen was not higher than with the existing pen. No unexpected operational risks and no major concerns regarding the risk of misuse or dosing errors were identified. CONCLUSIONS: The study provides useful practical information on the redesigned pen from both patient and nurse perspectives.

Factors related to successful ovulation induction in patients with WHO group II anovulatory infertility.

To identify baseline characteristics related to successful ovulation induction, data were analysed from oligo- or anovulatory patients undergoing their first cycle of human recombinant FSH (r-hFSH; follitropin alfa) in a chronic low-dose (75 IU starting dose), step-up protocol in two clinical trials (n=446). Patients were grouped according to response: group A, ovulated within 14 days (75 IU follitropin alfa); group B, ovulated after 14 days (>75 IU follitropin alfa); group C, not administered human chorionic gonadotrophin (HCG) because of poor response; group D, cycle cancelled due to over-response (HCG not administered); group E, spontaneous ovulation prior to obtaining criteria for administration of HCG. Mean body mass index (BMI) of group A (25.0 kg/m(2)) was significantly lower than groups B (27.1 kg/m(2), P<0.001) or C (28.2 kg/m(2), P<0.0001), but similar to group D (24.3 kg/m(2)). Mean antral follicle count (AFC) of group A was also significantly lower than group C (18.3 versus 22.7; P=0.018), but not significantly different from groups B (21.5) or D (19.5); group E had the highest mean AFC (35.7). Comparatively low BMI, low AFC and higher (although still within the normal range) FSH concentration at baseline were associated with successful ovulation induction in infertile women undergoing a chronic low-dose, step-up stimulation protocol.

An observational study of assisted reproductive technology outcomes in new European Union member states: an overview of protocols used for ovarian stimulation.

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.

Safety and efficacy of mixing cetrorelix with follitropin alfa: a randomized study.

OBJECTIVE: To assess the safety and efficacy of mixing cetrorelix with follitropin alfa (rFSH) in assisted reproductive technology. DESIGN: Prospective, randomized study. SETTING: An IVF center in a teaching hospital. PATIENT(S): One hundred forty patients undergoing intracytoplasmic sperm injection were randomized into mixed (M) or separate (S) injection groups. INTERVENTION(S): In the M group, rFSH and cetrorelix were mixed immediately before administration, whereas in the S group, rFSH and cetrorelix were administered separately. MAIN OUTCOME MEASURE(S): The primary efficacy end point was the incidence of premature LH surge. The secondary efficacy endpoints included estradiol levels on the day of hCG injection, numbers of oocytes obtained, implantation, and ongoing pregnancy rates. The safety endpoints included ovarian hyperstimulation syndrome, and adverse events related to injections including local tolerability. RESULT(S): Excluding eight patients who dropped out of the study, there were 66 patients in each group for analysis. Patients in the M group received significantly fewer injections than patients in the S group (9.1 vs. 13.9). Other outcome parameters, including incidences of premature LH surge, numbers of oocytes retrieved, fertilization, implantation, and ongoing pregnancy rates were similar between the two groups. CONCLUSION(S): Cetrorelix and rFSH can be mixed together without compromising their reported safety and efficacy. This observation is in line with the reported safety and efficacy profile of the products listed in their current package inserts.

A comparison of menotropin, highly-purified menotropin and follitropin alfa in cycles of intracytoplasmic sperm injection.

BACKGROUND: Over the last several decades, as a result of an evolution in manufacturing processes, a marked development has been made in the field of gonadotropins for ovarian stimulation. Initially, therapeutic gonadotropins were produced from a simple process of urine extraction and purification; now they are produced via a complex system involving recombinant technology, which yields gonadotropins with high levels of purity, quality, and consistency. METHODS: A retrospective analysis of 865 consecutive intracytoplasmic sperm injection (ICSI) cycles of controlled ovarian hyperstimulation (COH) compared the clinical efficacy of three gonadotropins (menotropin [hMG; n = 299], highly-purified hMG [HP-hMG; n = 330] and follitropin alfa [r-hFSH; n = 236]) for ovarian stimulation after pituitary down-regulation. The endpoints were live birth rates and total doses of gonadotropin per cycle and per pregnancy. RESULTS: Laboratory and clinical protocols remained unchanged over time, except for the type of gonadotropin used, which was introduced sequentially (hMG, then HP-hMG, and finally r-hFSH). Live birth rates were not significantly different for hMG (24.4%), HP-hMG (32.4%) and r-hFSH (30.1%; p = 0.09) groups. Total dose of gonadotropin per cycle was significantly higher in the hMG (2685 +/- 720 IU) and HP-hMG (2903 +/- 867 IU) groups compared with the r-hFSH-group (2268 +/- 747 IU; p < 0.001). Total dose of gonadotropin required to achieve clinical pregnancy was 15.7% and 11.0% higher for the hMG and HP-hMG groups, respectively, compared with the r-hFSH group, and for live births, the differences observed were 45.3% and 19.8%, respectively. CONCLUSION: Although similar live birth rates were achieved, markedly lower doses of r-hFSH were required compared with hMG or HP-hMG.

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

OBJECTIVE: To demonstrate the efficacy and safety of follitropin alfa administered with hCG on spermatogenesis in adult male hypogonadotropic hypogonadism (HH) patients. DESIGN: Phase III, multicenter, open-label, noncomparative. SETTING: Seven US medical centers. PATIENT(S): A total of 36 adult males with severe HH. INTERVENTION(S): A total of 1,000 U hCG on alternate days for 3 to 6 months, with dose adjustments after 2 months, if necessary, to normalize T levels, followed by follitropin alfa 150 U and hCG on the same alternate days for 18 months, with dose adjustments as necessary. MAIN OUTCOME MEASURE(S): Proportion of patients with sperm density > or =1.5 x 10(6)/mL. Pubertal advancement and long-term safety and tolerability were also evaluated. RESULT(S): In total, 22 of 29 patients (75.9%) who received > or =1 dose of follitropin alfa and 20 of 25 patients (80%) who completed 18 months of hCG + follitropin alfa treatments achieved a sperm concentration > or =1.5 x 10(6)/mL. A sperm concentration >20 x 10(6)/mL was achieved by 8 of 29 men (27.5%). Median sperm concentration at 18 months was 5.2 x 10(6)/mL. Pubertal development continued during the study, and testis volumes increased. Five clinical pregnancies were achieved. Acne (52% of patients) was the most common side effect, and gynecomastia was reported in 10% of patients. CONCLUSION(S): Long-term treatment of azoospermic HH men using follitropin alfa and hCG is effective for stimulating spermatogenesis and is well-tolerated.

Follitropin-alpha (Gonal-F) versus follitropin-beta (Puregon) in controlled ovarian hyperstimulation for in vitro fertilization: is there any difference?

In an attempt to examine and compare the effect of the two commercially available recombinant FSH on ovarian stimulation characteristics and IVF cycle outcome, we studied 264 IVF cycles in patients with a favorable prognosis a priori, 198 in patients using follitropin-alpha, and 68 in patients using follitropin-beta. Although both groups achieved a comparable number of retrieved oocytes, the use of follitropin-beta was associated with a tendency toward a lower clinical pregnancy rate (PR), and with significantly higher E(2) levels despite the use of significantly lower total gonadotropin dose.

Cost-saving treatment strategies in in vitro fertilization: a combined economic evaluation of two large randomized clinical trials comparing highly purified human menopausal gonadotropin and recombinant follicle-stimulating hormone alpha.

OBJECTIVE: To assess the cost-effectiveness of two gonadotropin treatments that are available in the United Kingdom in light of limited public funding and the fundamental role of costs in IVF treatment decisions. DESIGN: An economic evaluation based on two large randomized clinical trials in IVF patients using a simulation model. SETTING: Fifty-three fertility clinics in 13 European countries and Israel. PATIENT(S): Women indicated for treatment with IVF (N = 986), aged 18-38, participating in double-blind, randomized controlled trials. INTERVENTION(S): Highly purified menotropin (HP-hMG, Menopur) or recombinant follitropin alpha (rFSH, Gonal-F). MAIN OUTCOME MEASURE(S): Cost per IVF cycle and cost per live birth for HP-hMG and rFSH alpha. RESULT(S): HP-hMG was more effective and less costly versus rFSH for both IVF cost per live birth and for IVF cost per baby (incremental cost-effectiveness ratio was negative). The mean costs per IVF treatment for HP-hMG and rFSH were 2408 pounds (95% confidence interval [CI], 2392 pounds, 2421 pounds) and 2660 pounds (95% CI 2644 pounds, 2678 pounds), respectively. The mean cost saving of 253 pounds per cycle using HP-hMG allows one additional cycle to be delivered for every 9.5 cycles. CONCLUSION(S): Treatment with HP-hMG was dominant compared with rFSH in the United Kingdom. Gonadotropin costs should be considered alongside live-birth rates to optimize outcomes using scarce health-care resources.

Lutropin alfa.

Lutropin alfa is the first and only recombinant human form of luteinizing hormone (LH) developed for use in the stimulation of follicular development. Dose-finding studies revealed a significant dose-dependent increase in the rate of optimal follicular development among women with hypogonadotropic hypogonadism and profound LH deficiency (<1.2 IU/L) who received subcutaneous lutropin alfa 0-225 IU/day plus follitropin alfa. Similarly, in a double-blind, randomized study, the rate of optimal follicular development was significantly higher in women with hypogonadotropic hypogonadism and profound LH deficiency receiving subcutaneous lutropin alfa 75 IU/day plus follitropin alfa than in those receiving placebo plus follitropin alfa. Lutropin alfa with follitropin alfa may also be of benefit in certain subgroups of normogonadotropic women (e.g. those with an inadequate response to prior follitropin alfa monotherapy, those aged >or=35 years, and those with profound LH downregulation or who required excessive exogenous follitropin alfa). However, one study in older women (>or=35 years) did not show any advantage of lutropin alfa supplementation. Once-daily subcutaneous lutropin alfa was generally well tolerated in hypogonadotropic hypogonadal women, with the majority of adverse events being of mild to moderate severity.

[Ovulation induction in high risk IVF patients: GnRH-agonist, diminished dose of urinary or recombinant chorion gonadotropin].

In high risk IVF patients the ovulation triggering was done with agonist (0.2 mg), 1.gr., Pregnyl 5000 IE, 2. and 4.gr., Ovitrelle 0.250 mg, 3.gr., and Pregnyl 10000 IE in the fifth--non-risk group. The protocol of the first and fourth group included antagonist, the second and third group was with short and the fifth group with long agonist protocol. There was no grave OHSS in the first group, one case in each second, third and fourth group and 4 cases in the fifth group, as a whole 7 patients (3.3%). In all of them an abdominal drainage lasting 4 to 30 days was performed and all pregnancies were preserved. The average success rate was 50%, 71.4% in the fourth and 43.1% in the fifth group. A protocol with antagonist and ovulation triggering with agonist or reduced dose ChG in order to diminish OHSS in high risk IVF patients is recommended.

Recombinant human luteinizing hormone, lutropin alfa, for the induction of follicular development and pregnancy in profoundly gonadotrophin-deficient women.

OBJECTIVE: To provide evidence of efficacy and safety for use of lutropin alfa in inducing follicular development and pregnancy in hypogonadotrophic hypogonadal women with profound gonadotrophin deficiency. DESIGN: An open-label, noncomparative extension of a randomized, double-blind, placebo-controlled study PATIENTS: A total of 31 hypogonadotrophic hypogonadal women with profound gonadotrophin deficiency in 23 medical centres in four countries were studied. INTERVENTIONS: Lutropin alfa 75 IU and follitropin alfa (75-225 IU), individually based on each patient's response as is consistent with usual medical practice. MEASUREMENTS: Follicular development as defined by (i) at least one follicle >or= 17 mm; (ii) preovulatory serum oestradiol level >or= 109 pg/ml on the day of hCG administration; and (iii) midluteal phase P(4) level >or= 7.9 ng/ml. Pregnancy and over-response leading to cycle cancellation were considered treatment successes. Pregnancy rates were assessed. RESULTS: In a total of 54 cycles, 27 of 31 (87.1%) profoundly gonadotrophin-deficient patients achieved follicular development within three cycles. Twenty of 27 patients (74.1%) who achieved follicular development and received hCG became pregnant; 16 (59.3%) continued to clinical pregnancy. One patient was hospitalized for severe ovarian hyperstimulation syndrome. Lutropin alfa was well tolerated. CONCLUSIONS: Coadministration of lutropin alfa 75 IU and follitropin alfa is safe and effective in inducing follicular development and pregnancy in hypogonadotrophic hypogonadal women with profound gonadotrophin deficiency in a setting consistent with established medical practice.

Comparison of different gonadotrophin preparations in intrauterine insemination cycles for the treatment of unexplained infertility: a prospective, randomized study.

BACKGROUND: A comparison of the effectiveness of different gonadotrophin preparations in intrauterine insemination (IUI) cycles for patients with unexplained infertility was performed. METHODS: Two hundred and forty-one patients were prospectively randomized using computer-generated random numbers into three groups: 81 in the Follitropin alpha (Group I), 80 in the urinary FSH (uFSH) (Group II) and 80 in the hMG (Group III). The primary outcome was clinical pregnancy rate with duration of stimulation, total gonadotrophin dose, number of dominant follicles, clinical pregnancy rate, multiple pregnancy, miscarriage rate and ovarian hyperstimulation syndrome (OHSS) rate being secondary outcomes. RESULTS: Clinical pregnancy rate was significantly higher in the rFSH group (25.9% in Follitropin alpha, 13.8% in uFSH and 12.5% in HMG groups; P = 0.04). There was no significant difference in terms of duration of stimulation, but mean FSH dose consumed per cycle was significantly lower in the recombinant FSH (rFSH) group compared with others (825 IU in Follitropin alpha, 1107 IU in uFSH and 1197 IU in HMG groups; P = 0.001). The number of follicles > or =16 mm diameter was significantly higher in the rFSH group compared with the uFSH and HMG groups (2.6 in Follitropin alpha, 1.3 in uFSH and 1.4 in HMG groups; P = 0.001). CONCLUSION: rFSH may result in a better outcome in IUI cycles for unexplained infertility.

Further improvement in IVF outcome may need more than consistency in ovarian stimulation.

It is agreed that reliability of hormonal products, starting with recombinant technology, has improved uniformity of ovarian response to a specified dosage, and that this has resulted in better pregnancy rates. Nevertheless, IVF cycle cancellation rate has not experienced a substantial decline in the last 5-10 years. We feel that further improvement will be more likely to be achieved once we gain better understanding of factors intrinsic to oocyte biology, such as oocyte ageing and oocyte depletion.

Improving the consistency of ovarian stimulation: follitropin alfa filled-by-mass.

In their quest for a child, infertile couples embark on a journey that is full of expectations and hopes. Over recent years, treatment procedures for assisted conception have become safer and more efficient. However, couples undergoing treatment can still experience some degree of emotional stress due to disappointment if pregnancy is not achieved, or if treatment cycles may have to be cancelled due to a low- or hyper-response. Strategies aimed at minimizing the variability of ovarian response or overall treatment outcome can be expected to significantly reduce this emotional stress. New developments have led to the production of follitropin alfa filled by mass. This is a highly consistent FSH preparation improving the consistency of ovarian response and reducing the risk of cycle cancellation. The impact of this new FSH preparation for assisted reproduction treatments is discussed in this review.

Predictive factors and a corresponding treatment algorithm for controlled ovarian stimulation in patients treated with recombinant human follicle stimulating hormone (follitropin alfa) during assisted reproduction technology (ART) procedures. An analysis of 1378 patients.

BACKGROUND: Identifying parameters that can accurately predict the response to controlled ovarian stimulation (COS) would be of great benefit in assisted reproductive technology (ART) procedures. An analysis was undertaken with the objective of determining whether specific factors could optimally predict a response to stimulation in ART, and to then develop a corresponding treatment algorithm that could be used to calculate the optimal starting dose of recombinant human follicle stimulating hormone (r-hFSH; follitropin alfa) for selected patients. METHODS: The overall population consisted of 2280 normo-ovulatory ART patients from 11 randomised clinical trials. However, for the final analysis population, only patients less than 35 years of age who received r-hFSH monotherapy (N = 1378) were included. RESULTS: Backwards stepwise regression modelling indicated that predictive factors for ovarian response included basal FSH, BMI, age and number of follicles < 11 mm at baseline screening. The concordance probability index was 59.5% for this model. CONCLUSIONS: In the largest data series so far analysed to determine predictive factors of ovarian response, basal FSH, BMI, age and number of follicles < 11 mm at screening were the most important variables in ART patients less than 35 years of age who were treated with r-hFSH monotherapy. Using these four predictive factors, a follitropin alfa starting dose calculator was developed that can be used to select the FSH starting dose required for an optimal response. The relevance of this dose calculator will be evaluated in a prospective clinical trial.