Ganirelix, solution for injection, 250 micrograms in 0.5 mL (as acetate), single use pre-filled syringe, Orgalutran®, November 2009
Public Summary Document for Ganirelix, solution for injection, 250 micrograms in 0.5 mL (as acetate), single use pre-filled syringe, Orgalutran®, November 2009
Page last updated: 05 March 2010
Public Summary Document
Product: Ganirelix, solution for injection, 250
micrograms in 0.5 mL (as acetate), single use pre-filled syringe,
Orgalutran®
Sponsor: Schering Plough Pty Ltd
Date of PBAC Consideration: November 2009
1. Purpose of Application
The submission sought a Section 100 (IVF/GIFT PROGRAM) listing for
the prevention of premature luteinisation and ovulation in patients
undergoing controlled ovarian stimulation, followed by oocyte
pick-up and assisted reproductive techniques.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Ganirelix was TGA registered on 19 March 2001 for the prevention of
premature luteinisation and ovulation in patients undergoing
controlled ovarian stimulation, followed by oocyte pick-up and
assisted reproductive techniques.
4. Listing Requested and PBAC’s View
Section 100 (IVF/GIFT PROGRAM)
For the prevention of premature luteinisation and ovulation in
patients undergoing controlled ovarian stimulation, followed by
oocyte pick-up and assisted reproductive techniques.
NOTE:
Arrangements to prescribe this item should be made by medical
practitioners with Medicare Australia, contact telephone number
1800 700 270.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Assisted reproduction manipulates the menstrual cycle of women
receiving fertility treatments to maximise the chances of
successful ovulation and fertilisation. In women with ovulation
disorders, ovulation induction with fertility treatment may be
sufficient to achieve conception and pregnancy. For infertility due
to tubal damage, male factor infertility and ovulation disorders
where ovulation induction alone is not successful, more complex
techniques of assisted reproduction may be required. Most require
controlled ovarian hyperstimulation (COH) to induce development of
several oocytes. Oocytes may then be fertilised within the body, or
collected and fertilised outside the body and then the embryo
replaced to continue normal development in the uterus.
During controlled ovarian stimulation, follicle stimulating hormone
(FSH) is administered to stimulate oocyte development. As soon as
the follicles have reached a certain size, an injection of human
chorionic gonadotrophin (hCG) or recombinant hCG (r-hCG) is given
in place of the body’s natural luteinising hormone (LH),
which is responsible for triggering ovulation. Oocyte collection
has to be precisely timed, as the oocytes must be retrieved before
ovulation. Thus, it is important to prevent the surge in natural
LH, to prevent premature ovulation and allow the successful oocyte
collection. This is done by administration of
gonadotropin-releasing hormone (GnRH) analogues, either GnRH
agonists or GnRH antagonists.
Ganirelix is a GnRH antagonist and would provide patients with a
PBS-subsidised GnRH analogue.
6. Comparator
The submission nominated nafarelin, a GnRH agonist, as the main
comparator. The PBAC agreed that this was an appropriate
comparator, as nafarelin is the most commonly used GnRH analogue in
Australia.
7. Clinical Trials
The submission presented a comparison of GnRH analogues versus non-analogues to establish comparative efficacy and cost-effectiveness of analogues, followed by a comparison of ganirelix versus nafarelin. The submission also presented an indirect comparison of ganirelix versus nafarelin using leuprolide as the common reference
.
Analog versus non-analogue
stimulation
For the analogue versus non-analogue comparison the submission
presented a meta-analysis of 14 randomised trials comparing GnRH
analogue stimulation to non-analogue stimulation. None of these
trials included ganirelix or nafarelin. Details of the key trials
and the meta-analysis are presented in the table below
.
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Direct randomised trials | ||
| Akman et al (2000) | Addition of GnRH antagonist in cycles of poor responders undergoing IVF | Human Reproduction 2000; 15(10): 2145-2147 |
| Akaboshi et al (1998) | The effects of gonadotrophin-releasing hormone agonist on androstenedione production and follicular development during controlled ovarian hyperstimulation. | Journal of Assisted Reproduction and Genetics 1998; 15(8): 478-484 |
| Avrech et al (2004) | Inclusion of standard and low-dose gonadotrophin releasing hormone-analogue (short protocol) in controlled ovarian hyperstimulation regimens in normogonadotropic patients aged 40-48 years who are undergoing in vitro fertilization. | Gynecological Endocrinology 2004; 19(5): 247-252 |
| Neveu et al (1987) | Ovarian stimulation by a combination of a gonadotrophin-releasing hormone agonist and gonadotrophins for in vitro fertilization. | Fertility and Sterility 1987; 47(4): 639-643 |
| Antoine et al (1990) | Ovarian stimulation using human menopausal gonadotrophins with or without LHRH analogues in a long protocol for in vitro fertilization: A prospective randomized comparison. | Human Reproduction 1990; 5(5): 565-569 |
| Kingsland et al (1992) | The routine use of gonadotrophin-releasing hormone agonists for all patients undergoing in vitro fertilization. Is there any medical advantage? A prospective randomized study. | Fertility and Sterility 1992; 57(4): 804-809 |
| Luxman et al (1995) | In vitro fertilization for women with pure tubal occlusion: The impact of short gonadotrophin-releasing hormone agonist treatment. | Fertility and Sterility 1995; 63(2): 357-360 |
| Maroulis et al (1991) | Prospective randomized study of human menotropin versus a follicular and a luteal phase gonadotrophin-releasing hormone analog-human menotropin stimulation protocols for in vitro fertilization. | Fertility and Sterility 1991; 55(6): 1157-1164 |
| Polson et al (1991) | A controlled study of gonadotrophin-releasing hormone agonist (buserelin acetate) for folliculogenesis in routine in vitro fertilization patients. | Fertility and Sterility 1991; 56(3): 509-514 |
| Ron-El et al (1991) | Gonadotrophins and combined gonadotrophin-releasing hormone agonist-gonadotrophins protocols in a randomized prospective study. | Fertility and Sterility 1991; 55(3): 574-578 |
| Van De-Helder et al (1990) | Comparison of ovarian stimulation regimens for in vitro fertilization (IVF) with and without a gonadotrophin-releasing hormone (GnRH) agonist: Results of a randomized study. | Journal of In Vitro Fertilization and Embryo Transfer 1990; 7(6): 358-362 |
| Yang et al (1995) | Comparison of human menopausal gonadotrophin and follicle-stimulating hormone with gonadotrophin-releasing hormone agonist desensitization for controlled ovarian hyperstimulation in in vitro fertilization. | Chinese Medical Journal (Taipei) 1995; 55(6): 452-456 |
| Battaglia et al (1997) | Colour Doppler changes and thromboxane production after ovarian stimulation with gonadotrophin-releasing hormone agonist. | Human Reproduction (Oxford, England) 1997; 12(11): 2477-2482 |
| Gonen et al (1991) | The use of long-acting gonadotrophin-releasing hormone agonist (GnRH-a; decapeptyl) and gonadotrophins versus short-acting GnRH-a (buserelin) and gonadotrophins before and during ovarian stimulation for in vitro fertilization (IVF). | Journal of In Vitro Fertilisation and Embryo Transfer 1991; 8(5): 254-259 |
| Meta-analyses of direct randomised trials | ||
| Hughes et al (1992) | The routine use of gonadotrophin-releasing hormone agonists prior to in vitro fertilisation and gamete intrafallopian transfer: A meta-analysis of randomised controlled trials. | Fertility and Sterility 1992; 58(5): 888-896 |
Ganirelix versus nafarelin
The comparison of ganirelix and nafarelin was based on one
head-to-head trial, with supportive evidence provided by an
indirect comparison using leuprolide as the common reference. The
key trial is presented in the table below.
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Rombauts et al (2006) | A comparative randomised trial to assess the impact of oral contraceptive pre-treatment on follicular growth and hormone profiles in GnRH antagonist-treated patients. | Human Reproduction 2006; 21(1): 95-103 |
Indirect comparison
The indirect comparison of ganirelix versus nafarelin was based on
three ganirelix versus leuprolide and three nafarelin versus
leuprolide trials. The submission also summarises the results of
four published meta-analyses which included a range of antagonists
and agonists. Details of the trials included in the indirect
comparison and the meta-analyses are presented in the table
below.
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Ganirelix | ||
| Barmat et al (2005) | A randomized prospective trial comparing gonadotrophin-releasing hormone (GnRH) antagonist/recombinant follicle-stimulating hormone (rFSH) versus GnRH-agonist/rFSH in women pretreated with oral contraceptives before in vitro fertilization. | Fertility and Sterility 2005; 83(2): 321-330 |
| Check et al (2004) | Effect of antagonists vs. agonists on in vitro fertilization outcome. | Clinical and Experimental Obstetrics and Gynecology 2004; 31(4):257-259 |
| Fluker et al (2001) | Efficacy and safety of ganirelix acetate versus leuprolide acetate in women undergoing controlled ovarian hyperstimulation. | Fertility and Sterility 2001; 75(1): 38-45 |
| Nafarelin | ||
| Dada et al (1999) | A comparison of three gonadotrophin-releasing hormone analogues in an in vitro fertilization programme: A prospective randomized study. | Human Reproduction 1999; 14(2): 288-293 |
| Dantas et al (1994) | Comparison between nafarelin and leuprolide acetate for in vitro fertilization: Preliminary clinical study. | Fertility and Sterility 1994; 61(4): 705-705 |
| Loh et al (1999) | Nafarelin acetate for pituitary suppressions in in vitro fertilisation cycles – A Singaporean experience. | Singapore Medical Journal 1999; 40(12): 752-755 |
| Meta-analyses | ||
| Al Inany et al (2006) | Gonadotrophin-releasing hormone antagonists for assisted contraception. | Cochrane Database of Systematic Reviews Issue 3 [Art. No.: CD001750. DOI: 10.1002/14651858.CD001750.pub2] |
| Kolibianakis et al (2006) | Among patients treated for IVF with gonadotropins and GnRH analogues, is the probability of live birth dependant on the type of analogue used? A systematic review and meta-analysis. | Human Reproduction Update 2006; 12(6): 651-671 |
| Franco Jr. et al (2006) | GnRH agonist versus GnRH antagonist in poor ovarian responders: A meta-analysis. | Reproductive BioMedicine Online 2006; 13(5): 618-627 |
| Griesinger et al (2006) | GnRH-antagonists in ovarian stimulation for IVF in patients with poor response to gonadotropins, polycystic ovary syndrome, and risk of ovarian hyperstimulation: A meta-analysis. | Reproductive BioMedicine Online 2006; 13(5): 628-638 |
8. Results of Trials
Comparative effectiveness
The meta-analysis of analogue stimulation versus non-analogue stimulation found a
statistically significant advantage for analogue stimulation in clinical pregnancy
rate (RD=7.98%; 95% CI: 3.76%, 12.20%).
The PBAC considered this advantage for analogue stimulation should be interpreted
with caution given that there was a wide range of effect across the trials, with a
number of different drugs and doses used and varying patient characteristics. The
PBAC noted some studies used human menopausal gonadotropin (hMG), FSH, FSH-hMG as
the non-analogue arm while the analogue differed in drug, doses and duration. While
these various options may have been used clinically at the time of the studies, it
made the meta-analysis highly uncertain because of a whole range of confounding factors
and thus must be treated with caution. In addition, neither ganirelix nor nafarelin
were included in any of the analogue trials.
The table below provides the results of the head-to-head trial comparing ganirelix
and nafarelin (Rombauts et al., 2006). This trial focused on the use of oral contraceptive
(OC) pre-treatment and included two ganirelix treatment arms, one with OC treatment
and one without.
Results of efficacy outcomes across the direct randomised trial
| Outcomes | Ganirelix + OC mean ± SD | Ganirelix mean ± SD | Nafarelin mean ± SD | p-value |
| Rombauts et al (2006) | N=111 | N=110 | N=111 | |
| Primary outcomes | ||||
| No. of oocytes recovered per attempt | 13.1 ± 7.8 | 11.5 ± 7.6 | 12.9 ± 8.7 | NS a |
| No. of good quality embryos obtained | 5.1 ± 3.8 | 5.0 ± 4.5 | 5.7 ± 4.3 | NS a |
| Key secondary outcomes | ||||
| Duration of rFSH (treatment days±SD) | 11.7 ± 1.9 | 9.4 ± 1.6 | 10.3 ± 1.7 | ≤0.001 a |
| Total rFSH dose (IU) | 2667.0 ± 880.7 | 1965.7 ± 515.5 | 2221.8 ± 655.3 | ≤0.001 a |
| No. of GnRH analogue treatment days | 4.6 ± 1.6 | 4.5 ± 1.3 | 27.0 ± 3.7 | - |
| Fertilisation rate % (SD) | 61.2% (25.7) | 66.7% (24.7) | 64.7% (23.7) | - |
| Number of LH rises n (%) | 2 (1.7%) | 17 (14.5%) | 1 (0.8%) | ≤0.001 b |
| Implantation rate per transfer % (SD) | 12.3% ± 27.3 | 17.4% ± 30.8 | 21.6% ± 33.4 | 0.03 c |
| Ongoing pregnancy rate per attempt n (%) | 18 (16.2%) | 23 (20.9%) | 26 (23.9%) | NS a |
SD = standard deviation; NS = not significant p>0.05
a All pairwise comparisons.
b Ganirelix alone compared with ganirelix + OC and nafarelin groups.
c Ganirelix + OC compared with nafarelin group.
The PBAC noted that there were no statistically significant differences between the
ganirelix groups and nafarelin in the patient-relevant outcome of ongoing pregnancies.
There were statistically significant differences between all groups in duration and
total rFSH use. The ganirelix group with the scheduled oral contraceptive required
significantly more rFSH than the other groups while the group administered ganirelix
alone required significantly less than others. The PBAC noted that it is not known
what percentage of patients would use the combination of ganirelix with oral contraceptive
in practice. Compared with other groups, the participants administered ganirelix without
the OC experienced significantly more LH rises. This was a concern for the PBAC as
the prevention of LH rises is a key reason for the use of a GnRH analogue.
The results of the supportive indirect comparison using leuprolide as the common reference
found no statistically significant difference between ganirelix and nafarelin in clinical
pregnancy rate (RR=1.06; 95% CI: 0.58, 1.95). However, the wide confidence interval,
potentially stemming from the small population size in the trials, indicated that
the relative risk was somewhat imprecise and should be interpreted with caution. The
PBAC noted that the ganirelix trials were conducted after the year 2000 whereas all
the nafarelin trials were conducted before the year 2000. The success rates for leuprolide
in the ganirelix trials were generally higher than in the nafarelin trials which may
indicate improvement in technique over the five year period between the two groups
of studies.
The PBAC noted that the results of the meta-analyses summarised by the submission,
which included a range of antagonists (including ganirelix) and a range of agonists
(including nafarelin) were conflicting, with one reporting equi-efficacy between antagonists
and agonists for live birth rate (Kolibianakis et al 2006) while a Cochrane review
(Al Inany et al 2006) reports that antagonists had statistically significantly lower
rates of clinical pregnancy and ongoing pregnancy/live birth rate compared to agonists.
Comparative toxicity
In the comparison of ganirelix with nafarelin, the Rombauts et al (2006) trial reported
numerically higher numbers of adverse events including ovarian hyperstimulation syndrome
(OHSS) in the nafarelin group, with the exception of serious adverse events, which
occurred with greater frequency in the OC and ganirelix group. No statistical comparison
of adverse events was provided and the trial was not powered to detect statistically
significant differences between groups in rates of OHSS. Only three of the trials
included in the indirect comparison provided safety information. The extended assessment
of comparative harms in the submission did not enable conclusions as to comparative
adverse event rates to be made.
9. Clinical Claim
The submission described GnRH analogue use in COS as superior in
terms of comparative effectiveness (clinical pregnancies) and made
no statement about comparative safety over non-analogue treatment
in COS.
The submission described ganirelix as similar in terms of
comparative effectiveness (pregnancy outcomes) and superior in
terms of comparative safety over nafarelin.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
A stepped economic evaluation was presented. The type of analysis
was a cost-effectiveness analysis and the submission presented a
comparison of analogue versus non-analogue stimulation and a
comparison of ganirelix versus nafarelin.
Step 1 of the evaluation was a trial-based analysis and step 2 was
an extrapolation of this over six cycles.
The model was driven by rates of clinical pregnancies (efficacy)
and drop-outs. The model was sensitive to changes in efficacy and
to increased FSH use.
The base case incremental cost per clinical pregnancy of the
analogue versus non-analogue comparison was dominant for analogue
stimulation. The base case incremental cost per clinical pregnancy
of the ganirelix versus nafarelin comparison was estimated to be
less than $15,000.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of packs dispensed per
year to be between 10,000 and 50,000 in Year 5. The financial cost
per year to the PBS was estimated to be <$10 million in Year
5.
12. Recommendation and Reasons
The PBAC recommended the listing of ganirelix on the PBS in the Section 100 IVF/GIFT
Program for the prevention of premature luteinisation and ovulation in patients undergoing
controlled ovarian stimulation, followed by oocyte pick-up and assisted reproductive techniques, at the same price
as nafarelin acetate for the treatment of endometriosis, which equates to a cost of
DPMQ $95.51 x 2 per patient per fresh cycle of assisted reproduction technique (ART).
The PBAC considered this is a pragmatic way forward in the context of a clinical need,
considering that gonadotrophin releasing hormone (GnRH) analogues are commonly used
in current clinical practice, and considering the evidence as a whole presented in
the submission suggests that GnRH analogues are effective agents in ART and that ganirelix
and nafarelin are of similar efficacy and safety. The PBAC also noted that the cost
effectiveness of nafarelin in ART is unknown as nafarelin is not listed on the PBS
for ART. The PBAC considered insufficient evidence was provided to substantiate the
claim that ganirelix is of superior comparative safety to nafarelin.
The PBAC considered the economic evaluation presented in the submission was highly
uncertain. The submission’s claim that patients treated with ganirelix would use less
follicle stimulating hormone (FSH) than patients being treated with nafarelin was
highly uncertain and FSH use may be dependant on whether oral contraceptives are used.
The PBAC considered it was inappropriate to use the metric of an incremental cost
per discounted “life year created” considering the lack of reference to this metric
in the published literature. The Committee also considered it was not appropriate
to include incremental differences in dropout rates between ganirelix and nafarelin
in the economic evaluation based on a better adverse event profile for ganirelix,
as the evidence did not provide a sufficient base to support the claim of superior
safety of ganirelix over nafarelin. Furthermore, although ganirelix may appear to
be superior to nafarelin in terms of incidence of ovarian hyper-stimulation syndrome
(OHSS), OHSS is a very rare event and there were insufficient data to draw any conclusions
in this regard.
The assumption that the clinical pregnancy rate is 7.98 % higher with analogues compared
to non-analogues adds to the uncertainty in the economic model. Further, the meta-analysis
performed in the submission comparing analogues to non-analogues is highly uncertain
as the source data do not include nafarelin or ganirelix-treated patients. Additionally,
there was a potential for considerable heterogeneity between the trials.
The PBAC considered listing in the Section 100 IVF/GIFT program of nafarelin and cetrorelix
for ART on the same basis as ganirelix may be appropriate and would be willing to
consider submissions from the respective sponsors of nafarelin and cetrorelix to this
effect.
Recommendation:
GANIRELIX, solution for injection, 250 micrograms in 0.5 mL (as acetate), single use
pre-filled syringe and 5 pre-filled syringes
Restriction:
NOTE:
Arrangements to prescribe this item should be made by medical practitioners with Medicare
Australia, contact telephone number 1800 700 270.
Section 100 (IVF/GIFT PROGRAM)
For the prevention of premature luteinisation and ovulation in patients undergoing controlled ovarian stimulation, followed by oocyte pick-up and assisted reproductive techniques as described in item 13200 of the Medicare Benefits Schedule.
Pack size: 1 (250 micrograms in 0.5 mL)
Pack size: ‡1 (250 micrograms in 0.5 mL (5))
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor has no comment.
