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Economic evaluation of a recombinant follicle-stimulating hormone (follitropin beta, Puregon) in infertile women undergoing in vitro fertilisation in Greece |
van Loon J, Liaropoulos L, Mousiama T |
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Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology Follitropin beta (Puregon (R)), a recombinant follicle-stimulating hormone (rFSH), in infertile women undergoing in vitro fertilisation (IVF).
Economic study type Cost-effectiveness analysis.
Study population Hypothetical infertile women undergoing in vitro fertilisation. Male infertility was an exclusion criterion.
Setting The setting was outpatient. The economic study was carried out in Greece.
Dates to which data relate Effectiveness and resource use data corresponded to the literature published between 1992 and 1997. The price year was 1999.
Source of effectiveness data The evidence for the final outcomes was based on a review of the literature, expert opinion, and assumptions made by the authors.
Correspondence with the authors, subsequent to this abstract being written, has indicated that the evidence was actually based on all follitropin beta studies which had been published, and which were available, at the time of the present study.
Modelling A Markov model was used to estimate the costs and effects associated with each modality incorporating clinical and resource use data from the literature and expert panel. A decision analysis software program, Data 3.5, was used to generate the Markov computer simulation. The model was based on three cycles (the chances of becoming pregnant being kept constant over the time horizon of the model), indicating that women go through the process for a maximum of three stimulation cycles, reflecting the average Greek IVF treatment practice derived from the expert panel.
Outcomes assessed in the review The review assessed the probability of becoming pregnant after fresh and frozen embryo transfer.
Study designs and other criteria for inclusion in the review The effectiveness of the first cycle was based on the ongoing pregnancy rate determined in clinical trials. Clinical data from a meta-analysis of 3 prospective, multi-centre, randomised trials (including the largest trial ever conducted in IVF) in infertile women were used: 697 women received rFSH and 463 received human menopausal gonadotrophins (hMG) or urinary FSH. Tubal disease was reported as the main cause of infertility in these trials. These studies were performed in many different IVF centres throughout Europe, including Greece. The IVF treatment was performed according to local treatment patterns.
Sources searched to identify primary studies Criteria used to ensure the validity of primary studies Methods used to judge relevance and validity, and for extracting data Number of primary studies included In total 3 studies were used as the reference for the effectiveness information, including a meta-analysis of three clinical trials.
Methods of combining primary studies A meta-analysis was used to combine primary studies; the details of which were not reported.
Investigation of differences between primary studies Results of the review The probability of becoming pregnant after fresh embryo transfer was 27.1% for follitropin beta and 21.6% for urofollitropin. The corresponding probabilities after frozen embryo transfer were 16.4% for follitropin beta and 7.6% for urofollitropin.
Methods used to derive estimates of effectiveness The chances of stopping IVF treatment (which appeared from other studies to be very locally driven) were derived from an expert opinion. Six IVF centres were included in the expert panel, two of which performed more than 1,000 IVF cycles per year.
Estimates of effectiveness and key assumptions The rates of stopping IVF treatment after the first and second attempt for non-medical reasons varied between centres, from less than 5% to greater than 20%; the rate was reported to be negligible by one-half of the members of the expert panel; the other half of the panel stated that there were 18.3% discontinuations after the first unsuccessful attempt and 28% discontinuations after the second unsuccessful attempt.
Based on the literature, it was assumed that the probability of becoming pregnant over the first three cycles of IVF treatment was constant. It was assumed that there were no spontaneous pregnancies in the model.
The percentage of patients who had no embryo transfer for various medical reasons, such as low or high ovarian response and unsuccessful fertilisation was 15.5% for follitropin beta and 16.6% for urofollitropin; there were no significant differences between the two groups. The women having 'no transfer' as a result of low ovarian response, i.e. 4.6% of the total number of women treated with follitropin beta and 7.6% of the total number of women treated with urofollitropin, were discontinued from IVF by the physician in 15% of cases; the remaining women started in the model with a consecutive cycle.
No specific Markov state was used for ovarian hyperstimulation syndrome (OHSS), because women with OHSS (leading to hospitalisation) can become pregnant. The incidence of OHSS leading to hospitalisation for follitropin beta and urofollitropin was not significantly different between the two groups (3.2 and 1.9%, respectively).
No distinction was made for parity or for the different chances of becoming pregnant per age group.
Measure of benefits used in the economic analysis The benefit measure was the cumulative ongoing pregnancy rate (defined as positive heart beat at 12 weeks) after a maximum of three subsequent IVF cycles.
Direct costs Costs were not discounted because the three cycles considered in the model generally took place within the course of a year. Some quantities were reported separately from the costs. Cost items were reported separately. The cost analysis covered the costs of hormone stimulation, fees (for gynaecologist, diagnostic procedure, puncture and laboratory phase), progesterone, hospitalisation because of OHSS, and frozen thawed embryo transfer. The perspective adopted in the cost analysis was that of society because it represented the total medical care costs of IVF treatment irrespective of the different reimbursement policies adopted by the national sickfund organisations in Greece. The cost evaluation was based upon the average patient in the clinical trials (woman with a mean age of 32 years and a mean duration of infertility of approximately 6 years). The IVF treatment and related costs in this study were based on average Greek treatment patterns derived from an expert panel of six private IVF centres. The direct medical costs of follitropin beta and urofollitropin were described and compared with no IVF treatment. The price year was 1999.
Indirect Costs Indirect costs were not included because they were considered to represent a very small proportion of the overall total costs of IVF.
Currency Greek drachma (Dr). The conversion rate was US$1 = Dr310; 1999 values.
Sensitivity analysis A series of one-way sensitivity analyses was conducted on a wide range of critical parameters affecting the results. Furthermore, a threshold analysis was performed for the price of follitropin beta and urofollitropin.
Estimated benefits used in the economic analysis The total cumulative pregnancy rate was 0.613 for follitropin beta (0.511 for fresh and 0.102 for frozen embryo transfer) and 0.478 for urofollitropin.(0.436 for fresh and 0.042 for frozen embryo transfer).
Cost results The total medical costs per woman undergoing IVF were Dr2,070,359 (US$6,679) for follitropin beta and Dr1,711,410 (US$5,734) for urofollitropin.
Synthesis of costs and benefits The average and incremental cost ratios were calculated. The average cost per ongoing pregnancy was Dr3,373,536 (US$10,882) for follitropin beta and Dr3,585,812 (US$11,567) urofollitropin. The incremental cost per additional pregnancy achieved with follitropin beta versus urofollitropin was Dr2,630,948 ($8,487). Sensitivity analysis showed that these results were robust to variations in critical parameters.
Authors' conclusions In women undergoing IVF treatment, follitropin beta is more cost-effective than urofollitropin in the Greek healthcare settings.
CRD COMMENTARY - Selection of comparators A justification was given for the choice of the comparator, which was the older approach, used in the context in question. You, as a database user, should consider whether this is a widely used health technology in your own setting.
Validity of estimate of measure of effectiveness The internal validity of the effectiveness results can not be objectively assessed as insufficient details were provided for the meta-analysis used to derive the effectiveness evidence (for example: sources searched, quality of the primary studies, and differences in the primary studies). However, the authors reported that it was a meta-analysis of three multi-centre randomised trials. In addition, it was not clear how the other two studies, used by the authors to derive effectiveness evidence, were identified. Also, some assumptions made for the purposes of the model were based on expert opinion. However, the authors justified their reliance on the meta-analysis and expert opinion by noting that some of these data were obtained from Greece, based on the local pattern of IVF treatment; making them representative of the average situation in the country.
Validity of estimate of measure of benefit The estimation of benefits (cumulative pregnancy rates) was modelled. The instrument used to derive a measure of health benefit, a Markov model, was appropriate. The authors believed that despite the fact that quality-adjusted life years (QALYs) were not considered in this study, the fact that follitropin beta produced more pregnancies than urofollitropin would certainly have a favourable impact for the former on quality of life for the patients undergoing IVF treatment. The lack of adjustment for the different probabilities of becoming pregnant for different age groups does not appear to be justified, and may affect the validity of the benefit results. Note: correspondence with the authors after this abstract was written has indicated that an anlysis for different agre groups was not performed because ".....the clinical trial population was a hypothetical cohort. The comparison was a comparison between two gonadotrophins used for IVF and was not believed to give a difference per gonadotrophin for different age groups. On the other hand any difference in becoming pregnant for different age groups would be the same for both alternatives and would thus not reveal any relevant difference."
Validity of estimate of costs The validity of the cost analysis may have been enhanced by the following features: some quantities of the resource use were reported separately from the costs; adequate details of the methods used in the cost estimation were given; the price year and the perspectives adopted in the cost analysis were reported; sensitivity analyses were performed on the cost parameters. However, it appears that charge data were used instead of true costs; the resource use pattern was based on an expert panel rather than on actual data; the effects of indirect costs (lost opportunity) were not included in the cost analysis and the justification for this provided by the authors does not appear to be convincing; which makes the societal perspective reported to have been adopted in the study questionable.
Note: the authors have indicated that, despite the omission of indirect costs, they consider that the societal perspective is still justified as the indirect costs would have represented a very small proportion of the total costs given that women do not have to take time off work for the procedure in question.
Other issues The authors' conclusions appear to be justified given the extensive sensitivity analyses performed. The issue of generalisability was not addressed in the authors' comments, but may, in part, have been addressed in the sensitivity analysis. Adequate comparisons appear to have been made with other studies.
Implications of the study Because the costs associated with IVF are high, the better cost-effectiveness ratios achieved with follitropin beta than with urofollitropin should be considered in the context of more efficient use of increasingly scarce healthcare resources.
Source of funding Supported by grant from Organon Hellas SA, Greece and NV Organon, The Netherlands.
Bibliographic details van Loon J, Liaropoulos L, Mousiama T. Economic evaluation of a recombinant follicle-stimulating hormone (follitropin beta, Puregon) in infertile women undergoing in vitro fertilisation in Greece. Clinical Drug Investigation 2000; 19(3): 201-211 Other publications of related interest Out H J, Mannaerts B M, Driessen S G, et al. Recombinant follicle-stimulating hormone (follitropin beta, Puregon) yields higher pregnancy rates in in vitro fertilization than urinary gonadotropins. Fertility and Sterility 1997;68:138-142.
Indexing Status Subject indexing assigned by CRD MeSH Clinical Trials as Topic; Costs and Cost Analysis; Drug Costs; Female; Fertility Agents, Female /therapeutic use /economics; Fertilization in Vitro; Follicle Stimulating Hormone /economics /therapeutic use /administration & Greece; Humans; Infertility, Female /therapy /drug therapy; Menotropins /administration & Probability; Retrospective Studies; dosage /analysis; dosage /economics /therapeutic use AccessionNumber 22000000683 Date bibliographic record published 31/03/2001 Date abstract record published 31/03/2001 |
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