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HP-HMG versus rFSH in treatments combining fresh and frozen IVF cycles: success rates and economic evaluation
Reproductive BioMedicine Online, 2, 21, pages 166 - 178
The economic implications of the choice of gonadotrophin influence decision making but their cost-effectiveness in frozen-embryo transfer cycles has not been adequately studied. An economic evaluation was performed comparing highly purified human menopausal gonadotrophin (HP-HMG) and recombinant FSH (rFSH) using individual patient data (n = 986) from two large randomized controlled trials using a long agonist IVF protocol. The simulation model incorporated live birth data and published UK costs of IVF-related medical resources. After treatment for up-to-three cycles (one fresh and up to two subsequent fresh or frozen cycles conditional on availability of cryopreserved embryos), the cumulative live birth rate was 53.7% (95% CI 49.3–58.1%) for HP-HMG and 44.6% (40.2–49.0%) for rFSH (OR 1.44, 95% CI 1.12–1.85;P < 0.005). The mean costs per IVF treatment for HP-HMG and rFSH were £5393 (£5341–5449) and £6269 (£6210–6324), respectively (number needed to treat to fund one additional treatment was seven;P < 0.001). With maternal and neonatal costs applied, the median cost per IVF baby delivered with HP-HMG was £11,157 (£11,089–11,129) and £14,227 (£14,183–14,222) with rFSH (P < 0.001). The cost saving using HP-HMG remained after varying model parameters in a probabilistic sensitivity analysis.
Keywords: cost-effectiveness, gonadotrophins, HP-HMG, IVF, live birth, rFSH.
Assisted reproductive technologies, including IVF, have become a mainstream treatment option available to couples. Technological advances and a better understanding of human physiology and pathological processes that may lead to infertility have contributed to increased success rates (e.g., clinical pregnancies and live births) that are credited to IVF each year (Andersen et al, 2006a, Andersen et al, 2007, and Andersen et al, 2008). At the same time, they have allowed clinicians to limit the incidence of complications due to fertility treatment by decreasing the number of embryos transferred and to provide early detection and management of complications (e.g., ovarian hyperstimulation syndrome, OHSS) ( Land and Evers, 2003 ). The success of this form of medical treatment has become a routine practice with an almost guaranteed level of success, with 80–90% of couples being successful in their first year of treatment ( Brosens et al., 2004 ). This has increased the attractiveness of IVF and has been reflected in an exponential increase in fertility services usage with no contraction in sight ( Lunenfeld et al., 2004 ).
In the UK, approximately 15% of couples seek medical advice for infertility ( Cahill and Wardle, 2002 ), with a lifetime prevalence of infertility ranging between 17.3% and 26.4% (Gunnell and Ewings, 1994 and Buckett and Bentick, 1997). These projections are not expected to decline due to noted trends in lifestyle changes (e.g., increased age of marriage, sexually transmitted diseases, environmental pollution) in the general population ( Balen and Rutherford, 2007 ). In fact, the prevalence of infertility increases to over 30% in the 35–44-year-old group ( Lunenfeld et al., 2004 ) and the lower fertility of older women is becoming increasingly significant, as there is a trend over time for more women to postpone having their first child until later in life ( Commission of the European Communities, 2006 ).
Success, however, comes at a price. The average cost of a successful IVF intervention leading to a live birth is variable; it is a cumulative figure built on multiple intricate decisions taken during the IVF procedure, including the type and quantity of medications (e.g., gonadotrophins) used for ovarian stimulation, oocyte retrieval, the fertilization procedure and laboratory-related activities, staff costs and costs related to cryopreservation (e.g., freezing, storing, thawing) in addition to post-transfer care. A significant proportion of the share of the cost of IVF is attributed to medicines required for ovarian stimulation ( Al-Inany et al., 2006 ). Therefore this clinical area is often targeted for effectiveness studies and cost-effectiveness analyses. The price of recombinant FSH (rFSH) is as high as three times that of urinary FSH (Zwart van Rijkom et al, 2002 and Al-Inany et al, 2006). This has led to a fivefold increase in total FSH expenditures in a 5-year period (i.e., 1995 to 2000), while the increase in usage of gonadotrophins was considerably smaller ( Zwart van Rijkom et al., 2002 ).
Due to the rising fiscal burden that infertility treatment has placed on national health programmes, standardization of the procedures using a cost-effectiveness-based approach has been promoted by many developed countries. In contrast, in countries where reimbursement of the cost of the IVF procedure is limited or not available through governmental programmes or insurance, it is unfortunately evident that many couples are denied treatment for financial reasons (Collins, 2002, Jain et al, 2002, Al-Inany et al, 2006, and Staniec and Webb, 2007).
The National Institute for Health and Clinical Excellence (NICE), the UK National Health Service’s (NHS) health guideline authority, has noted that according to the best available efficacy and cost-effectiveness evidence, up-to-three cycles should be provided to patients ( NICE, 2004 ). The overall cost of these treatments to the NHS, and society as a whole, is expected to increase yearly in a linear fashion in parallel with the growth of the UK population. Even today. only approximately 25% of IVF cycles are being funded by the NHS ( Kennedy et al., 2006 ) and only half of the couples with infertility seek treatment ( Balen and Rutherford, 2007 ).
Since the UK, like many other developed nations, has a moral obligation both to treat infertility and at the same time to address the rising costs related to this treatment, it is important to constantly re-evaluate the available options in order to determine the most appropriate and cost-effective model for IVF treatment. The mere rationing of services and payments for infertility treatment is neither acceptable nor sensible. One alternative that has proven to be both practical and cost-effective is the use of excess, cryopreserved embryos from a fresh IVF cycle in order to increase the cumulative pregnancy and live birth rate per started cycle (Lukassen et al, 2005 and Moustafa et al, 2008).
Today, nearly every fertility clinic in the UK offers embryo cryopreservation to patients undergoing IVF. Excess embryos are cryopreserved to safely and efficiently maximize the chance of conception through frozen-embryo transfers if fresh cycles fail ( Lyerly et al., 2010 ). At the same time, cryopreservation prevents the need to transfer multiple embryos at one time. This option has become even more attractive in recent years in light of the trend to decrease the number of embryos transferred in an attempt to curb the high rate of multiple gestation pregnancies associated with assisted reproduction ( Bissonnette et al., 2007 ). In a recent survey, 54% of respondents indicated that they were very likely to use cryopreserved embryos for future pregnancy attempts ( Lyerly et al., 2010 ).
In recent years, two large, prospective, randomized, multinational, non-inferiority trials were published demonstrating comparable clinical benefit of highly purified human menopausal gonadotrophin (HP-HMG, Menopur; Ferring Pharmaceuticals, St-Prex, Switzerland) versus recombinant FSH (follitropin alpha, GONAL-F; Merck Serono, Geneva, Switzerland) (European and Israeli Study Group, 2002 and Andersen et al, 2006b). Combined, the European and Israeli Study Group (EISG) and Menotrophin versus Recombinant FSH in vitro Fertilization Trial (MERiT) studies included almost 1500 women. Both were designed to compare the ongoing pregnancy rate in women undergoing down-regulation with a long gonadotrophin-releasing hormone (GnRH) agonist protocol and stimulated with either HP-HMG or rFSH. In both studies, the gonadotrophin dose was fixed at 225 IU s.c. for the first 5 days and then adjusted according to individual patient response.
Several economic evaluations partially or completely built on the results of these two large trials have been published (Lloyd et al, 2003, Wechowski et al, 2007, Connolly et al, 2008, and Wechowski et al, 2009), but only two were built on individual patient data (Wechowski et al, 2007 and Wechowski et al, 2009). The current study, supplementary to previous evaluations, sought to model the more clinically realistic scenario using available frozen-embryo transfers in addition to the fresh IVF cycles, in an attempt to determine the live birth rates per started cycle, as well as economic implication of choice of gonadotrophin. Naturally, these analyses take into consideration not only the costs of the respective medications in the UK, but also differences in live birth rates achieved from both the fresh and cryopreserved cycles, in addition to the expected availability of excess embryos for cryopreservation–thawing for future transfers. The decision to use this pooled data in addition to the follow-up of cryopreservation transfers from the randomized women was made due to the robustness and pharmacological homogeneity of the preparations and dosages in the two trials. This allowed for a precise estimate of the cost difference between the two treatment options.
Materials and methods
An evaluation comparing HP-HMG (Menopur) and rFSH (Gonal-F) in IVF treatments with cryopreserved embryos was conducted using a simulation model. The objective of the study was to determine: (i) efficacy expressed as number of patients with live births and number of babies born per patient initiating treatment; results of the simulation are an extension of the analyses presented in preceding papers (Andersen et al, 2006b and Platteau et al, 2004), which reported only outcomes from fresh IVF cycles; (ii) average IVF cost per treatment based on each of the gonadotrophin treatment options; the simulation results are reported as ‘per patient treated’, rather than ‘per cycle’, as it is the patients who were randomized in trials ( Daya, 2003 ), and each treatment consists of a number of cycles contributing to the cumulative results per patient, therefore once a patient has a live birth, no further treatment (e.g., new fresh cycle or frozen-embryo transfer) is applied; (iii) cost per patient with a live birth and per baby for each treatment option; (iv) incremental cost-effectiveness expressed as the difference in cost of the two treatment options divided by the difference in number of live births or babies born per treated patient; and (v) impact of inclusion of maternal and neonatal costs arising from successful pregnancies, considering costs of multiple pregnancies.
The modelled population was obtained by pooling patients from two prospective, randomized, multinational trials: EISG (IVF stratum,n = 255) and MERIT (all patients,n = 731) (European and Israeli Study Group, 2002, Andersen et al, 2006b, and Platteau et al, 2008). Women, aged 18–39, were recruited at 53 fertility clinics in 13 European countries and Israel. The entire modelled cohort was treated in fresh cycles with either HP-HMG (n = 491) or rFSH (n = 495) using a long GnRH agonist stimulation protocol. The primary causes of infertility in both studies were tubal and unexplained infertility and the baseline characteristics of patients, eligibility criteria, treatment protocols and primary endpoints were similar in both trials justifying the pooled analysis. Evidence on success rates following frozen cycles was obtained from a published report of follow-up of MERiT patients ( Ziebe et al., 2007 ), where the live birth rate for both HP-HMG and rFSH was equal to 9%.
For the scenario of one fresh and two frozen cycles success rates following frozen cycles were obtained both from MERiT and from the Human Fertilisation and Embryology Authority (HFEA) registry in the UK ( Human Fertilisation and Embryology Authority, 2008 ). For the latter, success rates in frozen cycles were relative to fresh cycles. The thus obtained decrement was applied to both HP-HMG and rFSH treatments. When HFEA data were used, the advantage of HP-HMG established in clinical trials for fresh cycles was perpetuated into the subsequent frozen cycles. Due to their limited applicability in the analysis and potential bias, the HFEA data were not used in the economic evaluation, but were only considered part of sensitivity analysis for efficacy results. Drop-out rates following each cycle were taken from published sources ( De Vries et al., 1999 ), as were the relative success rates for cycles within a treatment sequence ( Meldrum et al., 1998 ).
Resource use data was based on established UK treatment practices or items collected in the two randomized clinical trials. Unit costs per item were obtained from published UK sources. Treatment doses of HP-HMG and rFSH were sampled based on dosage reported in the two trials. Unit costs of £22.31 per vial of rFSH, containing 75 IU of FSH activity, and £13.65 per vial of HP-HMG, containing 75 IU of FSH activity and 75 IU of LH activity, were obtained from the British National Formulary (BNF; British Medical Association, 2008 ).
In the UK centres, GnRH agonists were used according to the trial centre standard practice and therefore the costs of down-regulation were based on buserelin (Superfact; Sanofi-Aventis) 250 g/day for an average of 14 days. Also, to reflect UK treatment practices, the costs of chorionic gonadotrophin alpha (Ovitrelle; Merck Serono) based on a single dose of 250 g at a cost of £33.31 were included in the cost calculations. Similarly, to reflect UK treatment practices, the costs of vaginal progesterone gel (Crinone; Merck Serono) were included in the costs based on treatment ranging from 13 to 42 days after embryo transfer. Since daily application is indicated for 30 days after laboratory evidence of pregnancy, three packages with 15 dosages each per successful pregnancy were assumed at £32.73 per package. Based on expert advice all moderate and severe OHSS was assumed to lead to hospitalization at an average cost of £1032 per diagnosis. Frequency of OHSS was extracted from trial data. Per cycle frequency of hospitalization due to OHSS has previously been established at 1.9% for HP-HMG and 3.2% for rFSH based on an expert panel ( Out et al., 1995 ) and used in previous economic evaluations ( Sykes et al., 2001 ). In the Out et al. (1995) study, however, the HMG preparation used was not highly purified, nor is it commercially available at present. Therefore this study did not assume cross-efficacy or lack of it and it used HP-HMG clinical trial data in the analyses instead. There was no difference in OHSS between the two treatment options, hence the actual frequencies were used: 1.83% and 1.81% for HP-HMG and rFSH, respectively. One of the authors (RK) confirmed from his clinical experience that the previously reported assumptions were applicable to this study, although to account for the fact that patients with moderate OHSS are hospitalized for shorter periods, it was assumed that average hospitalization did not exceed 5 days, a non-elective trim point (HRG Tariff 2007). Infrequent occurrence of OHSS, however, had virtually no impact on the results of the analyses.
Cost of patient visits was assumed to be included in costs of retrieval, fertilization and embryo transfer. Specialist consultation costs were added during stimulation and for pregnancy determination. Cost of delivery and neonatal care were considered separately for singletons, twins and triplets ( Ledger et al., 2006 ). Cost and outcome consequences of failed treatments and the probability of adoption were not considered. The perspective of the study was that of the NHS payer and non-medical costs and costs of time and loss of productivity were not incorporated in the analysis. Since fewer cycles would be required for HP-HMG than rFSH to achieve one delivery and one birth (baby), the exclusion of social costs had a conservative effect likely to underestimate the cost advantage of HP-HMG. Costs were indexed to 2008, with cost of drugs remaining unchanged as of 1 May 2009, and no discounting was applied due to the short time horizon employed. All input variables for costs used in the model are summarized in Table 1 .
|Cost of Gonal-F (rFSH) per IU||£0.298||£0.238–0.357||British Medical Association (2008)||Based on price of £22.31 per vial containing 75 IU of rFSH|
|Cost of Menopur (HP-HMG) per IU||£0.182||£0.146–0.218||British Medical Association (2008)||Based on price of £13.65 per vial containing 75 IU of FSH and 75 IU of LH|
|Median dose rFSH||Sample trial data||1275–6525 IU||(Lloyd et al, 2003) and (Andersen et al, 2006b)||Dose was bootstrapped from pooled MERiT and EISG trial data due to right skewness of the distribution (median 2250 IU)|
|Median dose HP-HMG||Sample trial data||1275–6825 IU||(Lloyd et al, 2003) and (Andersen et al, 2006b)|
|Cost of Buserelin||£7.54||£6.03–9.05||(Andersen et al, 2006b) and (British Medical Association, 2008)||Superfact (Sanofi-Aventis), unit cost of £11.85 per 5.5 mg vial. Dosing based on local practice, 250 μg/day for 14 days|
|Cost of chorionic gonadotrophin-alpha||£33.31||£26.65–39.97||(Andersen et al, 2006b) and (British Medical Association, 2008)||Chorionic gonadotrophin-alpha (Ovitrelle; Merck Serono) was costed as a single dose at 250 μg|
|Luteal support||£24.06||£19.25–28.87||British Medical Association (2008)||Vaginal progesterone gel (Crinone; Merck Serono) was costed after embryo transfer during 13–42 days. Since daily application is indicated for 30 days after laboratory evidence of pregnancy, three packages with 15 dosages each per successful pregnancy were assumed at £32.73 per package|
|Cost of retrieval||£795||£636–954||Lloyd et al. (2003)||UHCW cost inflated to 2008 price|
|Cost of embryo transfer||£520||£416–624||Lloyd et al. (2003)||UHCW cost inflated to 2008 price|
|Cost of fertilization||£246||£197–295||Lloyd et al. (2003)||UHCW cost inflated to 2008 price|
|Hospitalization cost for OHSS||£1079||£863–1295||Daya et al. (2001)||Inflated to 2008 price. All moderate and severe OHSS was assumed to lead to hospitalization|
|Cost of clinical pregnancy determination||£49||£39–59||Daya et al. (2001) and Curtis et al. (2005)||Inflated to 2008 price. Based on HCG test cost of £14.83 and specialist consultation at £34|
|Cost of ongoing pregnancy determination||£72||£65–79||(Daya et al, 2001) and (Curtis and Netten, 2005)||Inflated to 2008 price. Based on ultrasound cost of £38 and specialist consultation at £34|
|Cost of pregnancy loss||£281||£225–337||NICE (2004)||Inflated to 2008 price. Costs of early and late pregnancy loss were not differentiated|
EISG = European and Israeli Study Group; HCG = human chorionic gonadotrophin; HP-HMG = highly purified human menopausal gonadotrophin; MERiT = Menotrophin versus Recombinant FSH in vitro Fertilization Trial; OHSS = ovarian hyperstimulation syndrome; rFSH = recombinant FSH; UHCW = University Hospitals of Coventry and Warwickshire.
The simulation model
A discrete event simulation was designed to model clinical outcomes and-related costs and coded using Visual Basic for Applications in Microsoft Excel. Probabilities based on individual patient data from the combined trial cohort were simulated for each clinical event, using computer-generated random numbers representing chance events ( Higgins and Green, 2008 ). In such simulations, also known as Monte Carlo simulations, results from numerous runs are averaged over all patients, approximating the results that would be obtained if average probabilities, identical for each patient were used. In simulations, the events do not need to be synchronized, as in Markov models, allowing greater flexibility and more accurate representation of the patient pathway and thus reflecting clinical reality with greater accuracy. For the analyses, a total of 30,000 patients were simulated, a cohort sufficient for non-significant differences during multiple model runs.
The following treatment events (stages) in the first (always fresh) treatment cycle were modelled from the combined clinical cohort: stimulation, oocyte retrieval, embryo transfer, pregnancy and live birth. Modelled treatment was consistent with the procedures performed in the clinical trials and the patient transitions between stages of the model were determined by pooled patient-level data from the two clinical trials. The number of oocytes retrieved and number of twins and triplets were also obtained from the trials data. Probabilities of fertilization and implantation success were accounted for by subsequent events and therefore were not considered explicitly in the model. The logical flow of the model is illustrated in Figure 1 ; the process is briefly described below.
Each patient entered the simulated treatment pathway in the stimulation state. Treatment with gonadotrophins was administered in this state, accounting for prior pituitary down-regulation, as described previously (European and Israeli Study Group, 2002 and Andersen et al, 2006b). Patients underwent ovulation induction and entered the oocyte retrieval state. Numbers of oocytes retrieved and fertilization rates were retrieved from the trials to allow for an accurate modelling of the effects of each gonadotrophin preparation. Following fertilization, for those patients with viable embryos available, embryo transfer was performed which led to the stage of pregnancy which resulted in either pregnancy loss or live birth, single or multiple delivery. In case of unsuccessful outcome, the patient could discontinue treatment (drop-out) or start another cycle. The second cycle could be either fresh or frozen, depending on the analysed scenario. In the base case scenario, patients were offered second fresh cycles, unless cryopreserved embryos were available. The availability of cryopreserved embryos was modelled as directly related to the number of oocytes retrieved. It was assumed that at least three oocytes had to be retrieved for a cryopreserved embryo to be available, assuming conservatively, for both treatment options, 33.9% minimum quality embryos per oocyte retrieved ( Ziebe et al., 2007 ). When the relative share of single- and double-embryo transfers, as well as fertilization rates were used from MERiT ( Andersen et al., 2006b ), the required minimum number of oocytes retrieved was also three. The number of required oocytes was tested in a sensitivity analysis in the range from three to seven, producing a trend for favouring HP-HMG with increasing requirement for the number of oocytes retrieved. This trend resulted from greater impact of drug cost with fewer frozen cycles. Acknowledging that possible variation in clinical practice with regard to single- versus multiple-embryo transfer, as well as efficiency of fertilization and cryopreservation, might necessitate considerably more oocytes to be retrieved per frozen cycle, a conservative approach favouring rFSH was selected. The number of embryos transferred was assumed to be the same for both groups and was not modelled to be associated with success rates, which were determined as described above. The transfer of cryopreserved embryos in the second cycle diminished their pool available for the third frozen cycle. The third cycle was offered following previous unsuccessful attempts, subject to drop out; frozen embryos were transferred subject to availability.
Efficacy results were simulated using available case intention-to-treat data ( Higgins and Green, 2008 ). To test robustness of the results, the last observation carried forward (LOCF) method for imputing missing values was also used; values for 57 patients were imputed in the HP-HMG and for 55 in the rFSH arm. Only the available case results are reported, as the LOCF-based results were not significantly different and did not affect the conclusions. Chi-squared test of association was used to test significance of efficacy outcomes. Odds ratios and their confidence limits were calculated using the asymptotic method ( Bland and Altman, 2000 ). Independence of babies from multiple pregnancies was assumed, which has no effect on calculated odds ratio ( Gates and Brocklehurst, 2004 ).
Simulation output cost variables were not normally distributed; hence the Wilcoxon ranks sum test was used to test the significance of mean and median results. In addition, the results were verified using a permutation test on means and medians of samples obtained by bootstrapping the cost results from the model. Also confidence intervals were produced by bootstrapping.
Bootstrapping estimates the sampling distribution of a statistic through a large number of simulations, employing sampling with replacement from the original data ( Briggs et al., 1997 ). Samples of sizes equal to the trial groups were drawn from the simulated parent population of 50,000 patients. Mean values were used for summary reporting, except for costs inclusive of maternal and neonatal costs, where means were inappropriate due to skewed irregular distribution attributed to costs associated with twins and triplets and where medians were used instead. Two-sided 95% CI were obtained based on cost distributions from bootstrap as the 2.5% and the 97.5% percentiles; binomial distributions were used to estimate confidence intervals for medians ( Conover, 1980 ). Considerable skewness of the gonadotrophin dose distribution was addressed by sampling the original trial data. Comparative cost-effectiveness of gonadotrophins was expressed using an incremental cost-effectiveness ratio (ICER). The ICER is a comparative metric used to represent the additional cost required to achieve an additional unit of clinical effectiveness between two different treatment options ( Gold et al., 1996 ). Probabilistic sensitivity analysis was performed to address uncertainty in parameters used in the model. Based on accepted practices, values for parameters were sampled 1000 times from 95% CI based on probabilities of success at each stage of simulation and from uncertainty intervals for costs, judged to conservatively approximate the 95% CI. Results from the probabilistic sensitivity analysis were summarized using cost-effectiveness acceptability curves ( Fenwick et al., 2004 ), which present the probability that a given intervention is more cost-effective than the alternative treatment as a function of ceiling ratio or willingness-to-pay for one unit of effectiveness.
Based on the combined data from the MERiT and EISG trials, the cumulative live birth rate resulting from treatments consisting of a sequence of one fresh and up to two either fresh or frozen cycles, conditional on availability of frozen embryos, was 53.7% (95% CI 49.3–58.1%) for HP-HMG and 44.6% (95% CI 40.2–49.0%) for rFSH (OR 1.44, 95% CI 1.12 to 1.85;P = 0.004; Table 2 ). When the minimum number of oocytes required for one frozen cycle was changed to seven, the respective live birth rates were 54.7% and 45.2% and the difference remained statistically significant (P < 0.005). Using live birth rates from individual frozen cycles, in the HFEA registry data, also demonstrated an advantage of stimulation with HP-HMG (54.2% versus 44.8%, respectively,P < 0.005). When the success rate was measured by the number of babies born, accounting for multiple births, the difference in rates was also statistically significant and also in favour of HP-HMG (P < 0.001; Table 2 ). The required number of patients needed to be treated to achieve one additional live birth when using HP-HMG instead of rFSH varied in different scenarios from 11 to 24; the number of babies needed to be treated varied from 10 to 25.
|Scenarios and outcomes||HP-HMG||rFSH||P-value||Odds ratio|
|One fresh + up to two frozen cycles, conditional on availability of oocytes for cryopreservation (minimum three oocytes)|
|Live birth rate (%)||53.7 (49.3–58.1)||44.6 (40.2–49.0)||0.004||1.44 (1.12–1.85)|
|Babies per 1000 treatments||679 (639–720)||580 (536–623)||0.001||1.53 (1.18–1.99)|
|One fresh + one frozen cycle|
|Live birth rate (%)||32.6 (28.4–36.7)||27.0 (23.1–30.1)||NS||1.31 (0.99–1.72)|
|Babies per 1000 treatments||414 (370–458)||350 (308–392)||0.038||1.31 (1.01–1.70)|
|One fresh + two frozen cycles (frozen success rate from MERiT follow-up)|
|Live birth rate (%)||36.4 (32.1–40.6)||32.1 (28.0–36.2)||NS||1.21 (0.93–1.57)|
|Babies per 1000 treatments||460 (416–504)||419 (376–463)||NS||1.18 (0.92–1.52)|
|One fresh + two frozen cycles (relative frozen success rate from HFEA)|
|Live birth rate (%)||49.2 (44.7–53.6)||39.9 (35.6–44.2)||0.003||1.46 (1.13–1.87)|
|Babies per 1000 treatments||626 (584–669)||520 (476–564)||<0.001||1.55 (1.20–1.99)|
Values in parentheses are 95% CI.
EISG = European and Israeli Study Group; HFEA = Human Fertilisation and Embryology Authority; HP-HMG = highly purified human menopausal gonadotrophin; MERiT = Menotrophin versus Recombinant FSH in vitro Fertilization Trial; NS = not statistically significant; rFSH = recombinant FSH.
In the more theoretical scenario, assuming unconditional availability of frozen embryos and involving one fresh and exactly one frozen cycle, the cumulative live birth rate was 32.6% for HP-HMG and 27.0% for rFSH and the number of babies born was 414 and 350 per 1000 patients treated, respectively (P = 0.038; Table 2 ). When exactly two frozen cycles following a fresh cycle were allowed, the advantage of using HP-HMG remained, although statistical significance of the difference in success rates depended on assumptions used in the model. When the success rate for frozen cycles from the MERiT trial was used, the difference was not significant, while using the HFEA registry data resulted in a high level of significance for both live births and babies (P = 0.003 andP < 0.001, respectively; Table 2 ).
Simulations based on evidence from MERiT only reflected the trend for advantage of using HP-HMG versus rFSH established in the trial. The cumulative live birth rate varied in different scenarios: 32.4–54.0% for HP-HMG and 29.3–47.3% for rFSH.
Based on the combined data from the MERiT and EISG trials, total mean IVF costs per patient starting the treatment after one fresh and up to two fresh or frozen treatment cycles, conditional on availability of frozen embryos, for HP-HMG and rFSH were £5393 (95% CI £5341–5449) and £6269 (95% CI £6210–6324), respectively (P < 0.001; Table 3 ). The mean per treatment cost savings resulting from using HP-HMG instead of rFSH was £876. This saving would allow financing of an additional treatment for every seven HP-HMG treatments delivered. The total cost of gonadotrophin was 39.5% lower for HP-HMG than for rFSH, i.e., £990 (95% CI £963–1018) versus £1637 (95% CI £1598–1679;P < 0.001; Table 3 ). Other costs related to IVF procedures, inclusive of OHSS treatment costs, were comparable (£3283 versus £3489, respectively), as were other costs related to stimulation (£831 versus £843, respectively).
|Cost outcome||Cost (£)|
|Gonadotrophin costs per patient treatment|
|Mean||990 (963–1018) a||1637 (1598–1679) a|
|Median||988 (969–983)||1638 (1651–1673)|
|Total costs per patient treatment|
|Mean||5393 (5341–5449) a||6269 (6210–6324) a|
|Median||5369 (5144–5158)||6244 (5906–5973)|
|Cost per live birth excluding maternal and neonatal costs|
|Mean||10,046 (9238–11,002) a||14,055 (12,739–15,654) a|
|Median||9648 (9583–9608) b||13,341 (13,243–13,393) b|
|Cost per baby including maternal and neonatal costs|
|Mean||12,635 (9874–15,156) a||15,563 (13,279–19,875) a|
|Median||11,157 (11,089–11,129) b||14,227 (14,183–14,222) b|
a Significant differences between HP-HMG and rFSH (P < 0.001; Wilcoxon rank sum test), despite instances of overlap of confidence intervals. In permutation tests, confidence intervals for the difference in means and medians did not contain 0, indicating significance in all comparisons.
b Significant differences between HP-HMG and rFSH (P < 0.001; permutation test). Confidence intervals for medians provided for completeness of statistical measures; they have no clinical interpretation when the median value lies outside the interval; confidence intervals for differences obtained in permutation tests did not include zero, indicating significance.
Values in parentheses are 95% CI.
HP-HMG = highly purified human menopausal gonadotrophin; rFSH = recombinant FSH.
When maternal and neonatal costs were attributed to live birth rate data, accounting for occurrence and costs of multiple pregnancies, the median costs per patient starting the treatment with HP-HMG and rFSH were £7571 and £8278, respectively (P < 0.01).
Results for scenarios involving one fresh plus one or two frozen cycles are presented ( Table 4 ). Across the scenarios, the cost saving resulting from using HP-HMG instead of rFSH would allow funding of an additional treatment for every 6–11 treatments delivered. Costs per patient starting the treatment were consistently lower in treatments involving stimulation with HP-HMG. The results for simulation using MERiT data only showed a similar pattern.
|Scenarios and cost outcomes||Cost (£)|
|One fresh + one frozen cycle|
|Gonadotrophin costs per patient treatment||472||734|
|Mean total costs per patient treatment||3562||3896|
|Mean cost per live birth excluding maternal and neonatal costs||10,933||14,426|
|One fresh + two frozen cycles|
|Gonadotrophin costs per patient treatment||471||737|
|Mean total costs per patient treatment||4242||4622|
|Mean cost per live birth excluding maternal and neonatal costs||11,659||14,388|
All differences between HP-HMG and rFSH are significant (P < 0.001; Wilcoxon rank sum test).
HP-HMG = highly purified human menopausal gonadotrophin; rFSH = recombinant FSH.
Based on the combined data from the MERiT and EISG trials, total mean IVF costs per live birth after one fresh and up to two frozen treatment cycles, conditional on availability of frozen embryos, for HP-HMG and rFSH were £10,046 (95% CI £9238–11,002) and £14,055 (£12,739–15,654), respectively (P < 0.001; Table 3 ). When maternal and neonatal costs were added, the respective median costs per live birth were £12,635 with HP-HMG and £15,563 with rFSH. Table 3 shows the average cost-effectiveness results expressed as mean and median cost.
The ICER was negative for both IVF cost per live birth and IVF cost per baby, indicating that HP-HMG is less costly and more effective (dominant) versus rFSH ( Table 5 ). The cost saving combined with superior effectiveness remained when maternal and neonatal costs were added to the cost of IVF. This pattern was observed in other analysed scenarios.
|Cost outcome||Incremental value (£)|
|Incremental cost per live birth||−9632|
|Incremental cost per baby||−8856|
|Incremental cost per delivery including maternity and neonatal costs||−4938|
|Incremental cost per baby including maternity and neonatal costs||−4540|
Negative values indicate a cost saving with highly purified human menopausal gonadotrophin.
Changes in drug acquisition costs
The impact of varying the acquisition costs of rFSH on comparative costs per live birth after one treatment involving one fresh and up to two frozen cycles was tested in the model. The results indicate that an equivalent cost per live birth for both gonadotrophins cannot be achieved, regardless of the cost of rFSH. To achieve an equivalent cost per live birth, the price of rFSH would have to be negative ( Figure 2 ). Even if the drug acquisition cost of rFSH was assumed to be zero, the cost per live birth when treating with rFSH would still be higher than that of treating with HP-HMG, because of other costs (e.g., procedures, tests, etc.) incurred in the treatment needed to produce one live birth with rFSH ( Figure 3 ). An equivalent total cost per IVF treatment would be achieved at the cost of rFSH £1.86 per vial (data not shown). This corresponds to a price of rFSH equal to 12% of the published BNF price for follitropin alpha.
Probabilistic sensitivity analysis
The probabilistic sensitivity analysis supported the conclusion drawn from the base case that HP-HMG was cost saving compared with rFSH. The mean and median value of ICER was negative both for cost per delivery and cost per baby. The cost-effectiveness acceptability curve showed that HP-HMG was cost saving in 100% of patients, both exclusive and inclusive of neonatal and maternal costs, when willingness-to-pay for live birth or baby (ceiling ratio) was varied from £0 to £20,000.
Health system implications
The analysis also estimated the likely budget impact of switching patients currently treated with rFSH to HP-HMG. Based on the total number of 34,855 women treated annually with IVF (HFEA 2009) and assuming 50% patients on rFSH, the total savings would be £15,266,490. This is a conservative estimate assuming all women received only one treatment in a given year. With the savings, an additional 2831 patients could be treated with IVF, leading to 1922 more babies being born. As HP-HMG also leads to higher success rates, regardless of the cost of treatment, a further 1725 babies would be born if HP-HMG is chosen, giving a combined figure of 3647 additional babies. If the figures are scaled down to actual number of IVF babies born annually, the total system savings would be £8125,255 with 1941 additional babies born. The adjusted figures, although more realistic, also reflect limited access to IVF as many patients would not be offered the recommended up-to-three cycles, which were modelled in this study.
The results of this simulation model using a sequence of one fresh and up to two fresh or frozen cycles, conditional on the availability of cryopreserved embryos, demonstrated not only a superior cumulative live birth rate for HP-HMG compared with rFSH, but also showed that the mean costs per IVF treatment were significantly less for HP-HMG. When maternal and neonatal costs were applied, the median cost per IVF baby delivered was still significantly less with HP-HMG. This cost saving from using HP-HMG depicted in this model would allow an additional treatment cycle for every seven patients treated.
The exact definition of success in assisted reproduction has been debated for years. Today, live birth has evolved to become the mainstream primary outcome of trials of effectiveness in assisted reproductive technologies. This new-found revelation is supported by the observations that previously accepted benchmarks (e.g., biochemical and clinical pregnancy rates) did not properly relate to the patients’ needs.
A new trend that is also evolving is the cost burden to individuals, organizations, governments and society as a whole as a result of infertility treatment. With budget constraints and inflation in medical costs, more weight is being placed on incorporating cost and effectiveness in any decision regarding infertility management ( Mladovsky and Sorenson, 2009 ). This also includes calls for the need to provide cost-effective treatment in medical care generally, as well as well as infertility practice.
IVF has become medically and publicly accepted as a successful option for treatment of infertile couples and patients seeking protection from the transmission of sexually transmitted diseases (e.g., HIV) and genetic disorders. Over the past decade, breakthroughs in biomedical engineering and urinary purification processes have produced purer, more consistent products for ovarian stimulation. This has led to improved clinical pregnancy rates and live birth rates that were not previously attainable. At the same time, the improved pregnancy rates have carried the burden of a higher than normal chance of a multiple gestation and rising cost of infertility treatment. This has resulted in political calls for the use of milder ovarian stimulation protocols, the transfer of fewer embryos and the use of more cost-effective medications ( Van Voorhis, 2006 ).
Historically, gonadotrophins used for ovarian stimulation were processed from the urine of menopausal women (e.g., human menopausal gonadotrophins; HMG). In the mid-1990s, rFSH was marketed but it carried a significantly higher price per IU of FSH. To offset this price difference, investigators demonstrated that due to the higher pregnancy rates and less need for gonadotrophins for stimulation, the recombinant option was more cost-effective ( Daya et al., 2001 ).
Recently, traditional HMG has been replaced by HP-HMG, which contains a higher concentration of human chorionic gonadotrophin (HCG) ( Wolfenson et al., 2005 ). Although all HMG preparations contain HCG, HP-HMG contains more HCG than traditional HMG, and lower lLH concentrations. This increased HCG component in HP-HMG provides most of the LH activity required for oocyte development ( Wolfenson et al., 2005 ). Furthermore, this new balance has been shown to induce a different follicular development profile than traditional HMG products (Filicori et al, 2005 and Platteau et al, 2006) and rFSH ( Smitz et al., 2007 ).
Today, HP-HMG and rFSH are two of the commonest medications prescribed for ovarian stimulation. Both products are proven in clinical trials to be both efficient and produce similar pregnancy and live birth rates, although pooled analyses revealed significantly higher success rates with HP-HMG (Arce and Sørensen, 2005 and Wechowski et al, 2009). A recent meta-analysis found a trend for superior efficacy of HP-HMG in IVF, concluding that the former should be preferred on grounds of efficacy ( Al-Inany et al., 2009 ). Even so, the uptake of a more cost-effective strategy will allow individuals more access to limited funds by increasing the number of cycles that an organization can afford to provide. With the non-inferior results of both these gonadotrophin preparations, the burden of deciphering this equation lies with cost-effectiveness modelling.
Lloyd et al. (2003) performed a cost-minimalization analysis to determine the cost of achieving pregnancy with HP-HMG versus rFSH. Using data from EISG (2002), they concluded that HP-HMG was less expensive per cycle, translating into a 13% increase in the number of cycles that could be offered.
Wechowski et al. (2007) performed an economic evaluation using 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 £2396 (95% CI £2383–2414) and £2633 (£2615–2652), respectively. The average cost saving of £237 per IVF cycle using HP-HMG allows one additional cycle to be delivered for every 10 cycles.
Based on the results of the recently published meta-analysis by Coomarasamy et al. (2008) comparing HMG and rFSH, Connolly et al. (2008) constructed a simulated decision tree model. Gonadotrophin costs were based on Menopur and Gonal-F prices in Belgium. After one fresh and one cryopreserved cycle, the average treatment cost with HP-HMG was lower than with rFSH (€3635 and €4103, respectively). This was the first model to take into consideration the cumulative pregnancy rate following the use of cryopreserved embryos produced from the original fresh cycle. Even so, it should be noted that the aforementioned meta-analysis included both traditional HMG and HP-HMG and both recombinant alpha- and beta-FSH preparations. These clinical heterogeneities would not be expected to completely and accurately model the effect of HP-HMG compared with recombinant alpha-FSH. Specifically, in light of the higher trend of pregnancy rates with HP-HMG compared with traditional HMG ( Al-Inany et al., 2009 ), they could have lead to an underestimation of the effectiveness of HP-HMG.
An economic evaluation was recently published that used a simulation model in order to determine the cost per IVF cycle and cost per live birth for HP-HMG and rFSH, based a pooled analysis integrating the individual follow-up data obtained from two large randomized trials that compared identical preparations and followed a similar stimulation protocol (MERiT and EISG) ( Wechowski et al., 2009 ). Using price data from the UK, HP-HMG was demonstrated to be more effective and less costly for both IVF cost per live birth and for IVF cost per baby.
The results of the current cost-effectiveness analysis demonstrate that HP-HMG is cost saving compared with recombinant alpha-FSH in terms of live births and babies born after both fresh and combined fresh- and frozen-embryo transfers, when available. This data is in line with previous work (Wechowski et al, 2007 and Wechowski et al, 2009) and that of other investigators ( Connolly et al., 2008 ).
The importance of adding frozen-embryo cycles to the current analysis provides a more robust and realistic approach to determining the cost of treatment per cycle as opposed to the use of fresh cycles only. This is in line with the ethical and political determination of curbing the iatrogenic complication of multiple gestations produced from the transfer of high numbers of embryos by using a policy of less embryos per transfer coupled with more cycles of embryo transfers (European Society of Human Reproduction and Embryology, 2000, American Society for Reproductive Medicine, 2004, and Thurin et al, 2004). The policy of multiple single-embryo transfers (Templeton and Morris, 1998 and Veleva et al, 2006) or the use of one fresh plus one frozen-embryo transfer ( Moustafa et al., 2008 ) has been demonstrated to be as effective as one double-embryo transfer. This has led to a marked decrease in the number of embryos per transfer and, in turn. a greater number of embryos being cryopreserved for future use.
One important issue to consider when choosing the type of gonadotrophin is the quality of embryos produced following stimulation. rFSH has been demonstrated to produce higher numbers of oocytes per stimulated cycle, but at the same time the embryo quality per oocyte retrieved has been proven to be higher with HP-HMG ( Ziebe et al., 2007 ). This is of great importance, since embryo quality prior to cryopreservation has been demonstrated to affect the live birth rate after a freeze–thaw transfer cycle ( Salumets et al., 2006 ). In addition, cryopreserved embryos originating from conception cycles achieve double the implantation and pregnancy rates of those obtained from unsuccessful cycles ( El-Toukhy et al., 2003 ). These points add further advantage to the use of HP-HMG.
Currently, there is limited data from randomized trials on the outcome of cryopreserved embryos following ovarian stimulation using HP-HMG compared with rFSH. A meticulous search of the literature (Medline, Embase and Central) revealed data on the developmental outcome of frozen embryos and frozen-embryo transfer cycles from only the MERiT (Ziebe et al, 2006 and Ziebe et al, 2007) and First IVF-ICSI Cycle Recombinant FSH vs. Menotropin (FIRM) studies ( Hompes et al., 2008 ). Data from the MERiT study was only available for a 1-year follow-up period in which 178 patients (24.35%) of the original cohort underwent thawing of cryopreserved embryos. The results demonstrated more preferable outcomes for embryos thawed in the HP-HMG group compared with the rFSH group, with a higher frequency of embryos with >50% intact blastomeres and resumed mitosis prior to transfer. However, the pregnancy rate following the first frozen cycle was the same for both groups (9%) and no information on the cumulative pregnancy rate was presented.
The FIRM trial provided similar clinical results to those in the MERiT study, with a major difference in that no data was available on the quality of the embryos post thawing and that information on the cumulative pregnancy rate was presented. The ongoing pregnancy rate following frozen-embryo transfers was non-significantly higher in the HP-HMG group (5/20, 25%) than in the rFSH group (4/35, 11.43%). This increased the 1-year cumulative ongoing pregnancy rate from 26.3% to 28.0% in the HP-HMG group and 25.2% to 26.6% in the rFSH group.
The current study’s model conservatively assumed equal success rates following frozen cycles, based on the MERiT follow-up data ( Ziebe et al., 2007 ). Use of the relative fresh/frozen success rate obtained from the HFEA registry data may incorporate the above points related to embryo quality, as it preserves the advantage of HP-HMG, as shown in the MERiT and EISG trials by applying to both drugs the same percentage decrease in frozen versus fresh cycles. Although both the approaches based on Ziebe et al. (2007) and HFEA demonstrate superior success rates on HP-HMG, only incorporating the HFEA data produce statistical significance. The current study took a conservative approach, using only clinical trial data in the economic evaluation.
The majority of assisted reproductive technologies treatments in the UK are IVF, rather than intracytoplasmic sperm injection (ICSI), with even fewer ICSI treatments funded by the NHS. This study evaluated efficacy and cost-effectiveness of IVF, as clinical trial data on live births following ICSI were unavailable. Using combined IVF and ICSI data would not be an accurate representation of either procedure, since only IVF procedures were studied in MERiT. While comparable efficacy of HP-HMG and rFSH has been demonstrated in a recent meta-analysis ( Al-Inany et al., 2009 ), the economic consequences of using either alternative would depend on unit costs of gonadotrophins. A cost-minimization analysis could be expected to show superior value for money of a less expensive drug, which is HP-HMG.
The analyses were based on evidence from clinical trials of patients whose age ranged from 18 to 39 years. While treatment effectiveness is lower in older patients, there is no evidence suggesting that the difference between gonadotrophins would be different in different age groups. The preliminary analysis of patient-level data from the combined MERiT and EISG trials showed that when younger patients were excluded (25 years old and younger), the advantage of HP-HMG was even more pronounced than on average, with 13% difference in success rates. It can also be expected that in older patients with decreasing embryo quality, more fresh cycles would have to be performed to achieve comparable results, with would further favour HP-HMG as the less costly option.
One of the limitations of this study stems from unavailability of actual market prices of gonadotrophins, which were approximated using BNF prices. BNF price is considered an established standard in economic evaluations in the UK when more accurate estimates are not available. Indeed, for illustrative purposes, the costs must be based on an objective source rather than a more subjective assessment of possible costs based on volume of purchases with short- and long-term sales targets. Incorporating discounts from non-randomly selected clinics, even if obtainable, could introduce bias, as discounts can be local and temporary, reflecting marketing strategies, and distort the true average cost of drugs. The BNF price, even if not the most accurate, offers transparency and equivalency across centres. Any provider able to purchase drugs at a discount would be able to factor in price information while interpreting these results, though sensitivity analysis clearly demonstrated that cost of gonadotrophins should have no bearing on purchasing decision, use of HP-HMG being cost saving regardless of the cost of rFSH. In addition, to account for price variation, unit costs of gonadotrophins were varied within a 20% uncertainty interval in the probabilistic sensitivity analysis. Furthermore, from the perspective of private patients, rather than private providers, costs of gonadotrophins appear to be in line with BNF, if not greater, which is a conservative assumption in favour of HP-HMG.
This evaluation was conducted from the perspective of the NHS payer, although it is believed that results are broadly applicable to the private sector payers as well. Higher success rates with HP-HMG require fewer cycles, which would lead to even greater savings than in the NHS, due to greater per procedure costs in private clinics. Higher success rate would also translate into competitive advantage of clinics using HP-HMG.
In conclusion, the results of this economic analysis demonstrate the superior cost-effectiveness of HP-HMG to produce live births over rFSH in women undergoing conventional IVF and, when available, frozen-embryo transfer cycles. Since this work more realistically models the actual situation in patients undergoing infertility management, it is believed that it will have a major implication on the decision-making process when choosing the appropriate gonadotrophin for ovarian stimulation.
JW and AA were provided an unrestricted research grant from Ferring Pharmaceuticals in support of this project.
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a PharmArchitecture, Quatro House, Lyon Way, Camberley, Surrey GU16 7ER, UK
b Ferring International Centre, St-Prex, Switzerland
c Centre for Reproductive Medicine, University Hospitals Coventry and Warwickshire NHS, UK
Jaro Wex-Wechowski is a physician with a degree in biology from Amherst College, USA. He gained his PhD in economics from Warsaw School of Economics via a study of financing of health systems from the point of view of investment in cost-effective interventions. He has worked at health technology assessment and health insurance institutions and consultancies. Currently Jaro runs an independent health outcomes consultancy. In the area of reproduction, Jaro has worked on projects related to IVF, preterm birth and contraception. His major interests are evidence-based medicine, health systems financing, pricing and reimbursement and health policy.
© 2010 Reproductive Healthcare Ltd., Published by Elsevier B.V.