Corifollitropin alfa, solution for injection, 100 micrograms in 0.5 mL, 150 micrograms in 0.5 mL, pre-filled syringe, Elonva®
Page last updated: 16 March 2011
PDF printable version for Corifollitropin alfa, solution for injection, 100 micrograms
in 0.5 mL, 150 micrograms in 0.5 mL, pre-filled syringe, Elonva® (PDF 90 KB)
Product: Corifollitropin alfa, solution for
injection, 100 micrograms in 0.5 mL, 150 micrograms in 0.5 mL,
pre-filled syringe, Elonva®
Sponsor: Schering-Plough Pty Ltd (MSD)
Date of PBAC Consideration: November 2010
1. Purpose of Application
The submission sought a Section 100 IVF/GIFT Program listing for
patients who are receiving medical treatment as described in items
13200, 13201, 13202 or 13203 of the Medicare Benefits
Schedule.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
On 30 July 2010, corifollitropin was TGA registered for controlled
ovarian stimulation for the development of multiple follicles and
pregnancy in women participating in in-vitro fertilisation
techniques.
4. Listing Requested and PBAC’s View
Section 100 IVF/GIFT Program
Patients who are receiving medical treatment as described in items
13200, 13201, 13202 or 13203 of the Medicare Benefits
Schedule.
NOTE:
Supply of these items is through an accredited IVF/GIFT clinic. For
enquiries relating to the IVF/GIFT Program, medical practitioners
should contact Medicare Australia on 1800 700 270.
The PBAC did not comment on the requested restriction.
5. Clinical Place for the Proposed Therapy
Several different protocols exist for controlled ovarian
stimulation for assisted reproductive technology using different
combinations of drug treatments. During controlled ovarian
stimulation, recombinant follicle stimulating hormone (rFSH) is
administered to stimulate follicular development. rFSH
administration is initiated on stimulation day one, and on average
adequate follicular development is achieved by the ninth day of
treatment (range 6-18 days). Human chorionic gonadotrophin can then
be administered to induce final oocyte maturation.
The submission proposed that corifollitropin alfa would replace the
first seven daily doses of conventional rFSH (follitropin alfa or
beta), providing a reduced injection burden. This would be expected
to minimise patients' apprehension and anxiety, improve patient
convenience and compliance, and lessen the impact on the
patient’s lifestyle.
6. Comparator
The submission nominated conventional rFSH as the comparator,
focusing on follitropin beta. Follitropin beta
(Puregon®) and follitropin alfa
(GONAL-f®) were previously considered by the PBAC to
be equivalent on a per unit basis.
The PBAC agreed that the choice of comparator, conventional rFSH,
represented by follitropin beta (Puregon®), was
appropriate. See Recommendations and Reasons.
7. Clinical Trials
The basis of the submission was two direct randomised comparative trials, ENGAGE and
ENSURE. The ENGAGE study population consisted of 1,506 treated patients, and compared
a single injection of corifollitropin alfa 150 mcg (followed by daily injections of
150-200 IU follitropin beta 1 week later) to daily injections of follitropin beta
200 IU in women greater than 60 kg and less than 90 kg in bodyweight. The ENSURE study
population consisted of 396 treated patients, and compared a single injection of corifollitropin
alfa 100 mcg (then daily injections of 150-200 IU follitropin beta 1 week later) to
daily injections of follitropin beta 150 IU in women less than 60 kg bodyweight.
Details of the published trials presented in the submission are in the table below.
Direct randomised trials and associated reports presented in the submission
| Trial ID/First author | Protocol/Publication/Presentation title | Publication citation |
|
ENGAGE Devroey P, et al. Koper NP, et al. Behr B, et al. Fernandez Sanchez M, et al. Doody K, et al. Leader A, et al. Alper M, et al. |
A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol. Corifollitropin alfa demonstrates similar pregnancy rates as compared to daily recombinant FSH treatment in a controlled ovarian stimulation regimen for IVF/ICSI. Corifollitropin alfa versus recombinant FSH treatment for COS in a GnRH antagonist protocol: equal efficacy in terms of oocyte and embryo quality. Equally high ongoing pregnancy rates with corifollitropin alfa and recombinant FSH irrespective of variations in ART procedures. Success rates of a standardized rFSH/GnRH antagonist protocol are not affected by endogenous LH levels. Ongoing pregnancy rates with corifollitropin alfa/ gonadotrophin-releasing hormone (GnRH) antagonist regimen are not impacted by endogenous LH levels. Potential predictive factors of pregnancy in patients undergoing controlled ovarian stimulation (COS) in a GNRH antagonist protocol. |
Human Reproduction 2009; 24(12):3063-72. Abstract O-207. Fertility and Sterility 90(Suppl. 1):S75. ASRM 64th Annual Meeting San Francisco, CA. November 8-12, 2008 Abstract O-003 Oral. Human Reproduction 24 (Suppl 1):i1−2. ESHRE 25th Annual Meeting, Amsterdam, the Netherlands 28 June - 1 July 2009. Abstract O-005 Oral. Human Reproductio n 24 (Suppl 1):i2−3. ESHRE 25th Annual Meeting, Amsterdam, the Netherlands 28 June - 1 July 2009. Abstract O-255 Oral. Human Reproduction 24 (Suppl 1):i102. ESHRE 25th Annual Meeting, Amsterdam, the Netherlands 28 June - 1 July 2009. Fertility and Sterility 92(3):S3-S4. ASRM 65th Annual Meeting Atlanta, Georgia October 17-21, 2009. Abstract O-234 Oral. Fertility and Sterility 92(3):S68-S69. ASRM 65th Annual Meeting, Atlanta, Georgia October 17-21, 2009. |
|
ENSURE Obruca A, et al. Hillensjo T, et al. Ledger W, et al. |
Corifollitropin alfa for ovarian stimulation in IVF: a randomized trial in lower-body-weight women. A comparison of corifollitropin vs. recombinant FSH in a GnRH antagonist protocol for controlled ovarian stimulation in women weighing 60 kg or less. Two doses of corifollitropin alfa allow for similar exposure and ovarian response in patients weighing ≤ 60 kg and > 60 kg. |
Reproductive BioMedicine Online, 2010; 21(1):66−76. Abstract O-004 Oral. Human Reproduction 24(Suppl 1):i2. ESHRE 25th Annual Meeting, Amsterdam, the Netherlands 28 June - 1 July 2009. Abstract O-282 Oral. Human Reproduction 24(Suppl 1):i114. ESHRE 25th Annual Meeting, Amsterdam, the Netherlands 28 June - 1 July 2009. |
ESHRE = European Society of Human Reproduction and Embryology; ASRM = American Society
for Reproductive Medicine; BMI = body mass index; GnRH = Gonadotropin releasing hormone
COS = Controlled ovarian stimulation; LH = luteinizing hormone; ET = Embryo transfer;
ICSI = Intracytoplasmic sperm injection; IVF = In vitro fertilisation; rFSH = Recombinant follicle stimulating hormone (follitropin beta).
For PBAC’s view, see Recommendation and Reasons.
8. Results of Trials
Both ENGAGE and ENSURE studies assessed equivalence in terms of the number of oocytes
retrieved (the co-primary endpoint in ENGAGE and the primary endpoint in ENSURE).
In both studies, a lower margin of minus 3 oocytes and an upper margin of plus 5 oocytes
were applied for the difference in the number of oocytes retrieved between the treatment
groups. The rationale provided for this margin was as follows: A reduction of three
or more oocytes between the corifollitropin alfa and follitropin beta treatment arms
was considered by the submission to be clinically relevant because three oocytes are
usually required to produce one good quality embryo for transfer (or freezing). Anticipating
an average yield of 12–13 oocytes with the applied follitropin beta doses in the reference
group, an excess of more than five oocytes (giving a total of 18) would be undesirable
due to the increased risk of developing OHSS (subjects with more than 18 oocytes are
known to have an increased risk of OHSS). The rationale was considered appropriate.
ENGAGE (Study 38819 – body weight greater than 60 kg and less than 90 kg):
Results for the primary outcome of ongoing pregnancy rate (presence of at least one
foetus with heart activity at least 10 weeks after embryo transfer as assessed by
ultrasound scan or Doppler) are summarised in the table below.
Primary endpoint: Results of ongoing pregnancy rate in ENGAGE (Study 38819: body weight
> 60 kg)
| Result | Corifollitropin alfa 150 mcg n/N (%) | Follitropin beta 200IU n/N (%) | Risk difference (95% CI) p-value | |
| Ongoing pregnancy rates | Per attempt a (ITT) | 294/756(38.9) | 286/750 (38.1) | 0.9 (-3.9, 5.7) p = 0.71 |
| Per embryo transfer b (Subset of the ITT pop) | 294/672 (43.8) | 286/704 (40.6) | 3.1 (-2.0, 8.2) p = 0.24 | |
| Per attempt a (PP) | 291/739 (39.4) | 733/282 (38.5) | 1.1 (-3.8, 6.0) p = 0.67 | |
| Per embryo transfer b (Subset of the PP pop) | 291/659 (44.2) | 282/687 (41.0) | 3.1 (-0.2, 8.3) p = 0.24 | |
a If a subject did not reach a certain stage in IVF treatment, zero values were imputed
(e.g. if the particular subject did not have oocyte retrieval, then the number of
oocytes, number of embryos etc. was set to zero and the pregnancy outcome was set
to not pregnant)
b ‘Per stage’ analyses were restricted to subjects who reached a specific IVF stage,
in this case only women who had embryo transfer.
Non-inferiority of corifollitropin alfa to follitropin beta, in terms of the primary
outcome of ongoing pregnancy rates (presence of at least one foetus with heart activity
at least 10 weeks after embryo transfer as assessed by ultrasound scan or Doppler),
was demonstrated in both per attempt and per stage analyses and in both intention-to-treat
(ITT) and per protocol analyses.
The per embryo transfer (or per stage) analysis of ongoing pregnancy rates favoured
corifollitropin alfa over the comparator. This was because the number of events or
the numerator did not change between the per attempt analysis and the per embryo transfer
analysis (294 events in the corifollitropin alfa arm and 286 events in the follitropin
beta arm) whilst the reduction in magnitude of the denominator (as a consequence of
exclusion from the analysis) in the corifollitropin treatment arm (756 to 672 – a
difference of 84 subjects), was larger than that in the follitropin beta arm (750
to 704 – a difference of 46 subjects).
Equivalence of corifollitropin alfa to follitropin beta, in terms of the co-primary
endpoint of number of oocytes retrieved, was demonstrated in both per attempt and
per stage analyses and in both ITT and per protocol analyses.
ENSURE (Study 107012 – body weight less than or equal to 60 kg):
Results for the primary outcome of number of oocytes retrieved are summarised in the
table below.
Primary endpoint: Number of cumulus-oocyte-complexes (per attempt and per stage) by
treatment group in ENSURE (Study 107012: body weight less than or equal to 60 kg)
| Outcome | Corifollitropin alfa 100 mcg | Follitropin beta 150 IU | RD (95% CI) P value | |
| Number of Oocytes Retrieved (ITT) Per attempt a | N (subjects) Mean (SD) Median (range) | 268 13.3 (7.3) 12.0 (0, 46) | 128 10.6 (5.9) 10.0 (0, 33) | 2.5 [1.2, 3.9] p <0.001 |
| Number of Oocytes Retrieved Per Stage b | N (subjects) Mean (SD) Median (range) | 266 13.4 (7.3) 12.0 (0, 46) | 127 10.7 (5.9) 10.0 (0, 33) | 2.6 [1.2, 3.9] p <0.001 |
a If a subject did not reach a certain stage in IVF treatment, zero values were imputed
(e.g. if the particular subject did not have oocyte retrieval, then the number of
oocytes or number of embryos etc. was set to zero and the pregnancy outcome was set
to not pregnant)
b ‘Per stage’ analyses were restricted to subjects who reached a specific IVF stage,
in this case only women with oocyte retrieval.
CI = confidence interval; ITT = intention to treat; RD = risk difference
Equivalence between corifollitropin alfa and follitropin beta, in terms of the primary
outcome of number of oocytes retrieved was demonstrated.
For women with body weight less than or equal to 60 kg, the percentage of ongoing
pregnancy rates (the secondary outcome of ENSURE) did not support the non-inferiority
of 100 mcg corifollitropin alfa. The ENSURE trial lacked power to detect a difference
in this outcome measure. However, the difference of 9% and the lower margin of -19%
which favoured the comparator appeared substantial and included clinically relevant
differences. Although the submission noted that “analyses of the ongoing pregnancy
rates on a ‘per attempt’ basis showed that the estimated differences between the corifollitropin
alfa and follitropin beta treatment groups were not statistically significant”, the
analysis of the secondary outcome of ongoing pregnancy rates (presence of at least
one foetus with heart activity at least 10 weeks after embryo transfer as assessed
by ultrasound scan or Doppler) lacked power to detect a difference.
Overall, the proportion of adverse events and serious adverse events reported in ENGAGE
was higher than that reported in ENSURE. Adverse events were similar between the treatment
arms in both studies except for serious adverse events, which slightly favoured the
comparator arms in both studies. Adverse events leading to discontinuation in the
ENGAGE study also favoured the comparator arm (16 (2.1%) versus 3 (0.4%)). The risk
of discontinuing due to an adverse event in the corifollitropin treatment arm was
therefore almost 5 times the risk in the comparator arm. Although the submission commented
that these were rare events, it should be noted that the trial excluded patients with
a high risk of hyperstimulation; therefore, higher rates may be observed in the target
PBS population.
The adverse event of most concern to PBAC for corifollitropin alfa was OHSS. The table
below summarises OHSS events observed in the key trials.
Incidence and severity of ovarian hyperstimulation syndrome (OHSS) in the controlled
trials
| OHSS Categories | ENGAGE | ENSURE | ||
| Corifollitropin alfa 150 mcg (N=755) | Follitropin beta 200 IU (N=751) | Corifollitropin alfa 100 mcg (N=268) | Follitropin beta 150 IU (N=129) | |
| OHSS AE n (%) | 53 (7.0) | 47 (6.3) | 18 (6.7) | 6 (4.7) |
| Discontinuation due to OHSS AE | 12 (1.6) | 1 (0.1) | 0 (0.0) | 0 (0.0) |
| OHSS SAE n (%) | 14 (1.9) | 9 (1.2) | 7 (2.6) | 0 (0.0) |
| Discontinuation due to OHSS SAE | 4 (0.5) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| OHSS Grade | ||||
| Grade 1 (mild) | 22 (2.9 %) | 27 (3.6 %) | 9 (3.4 %) | 4 (3.1 %) |
| Grade 2 (moderate) | 17 (2.3 %) | 10 (1.3 %) | 5 (1.9 %) | 1 (0.8 %) |
| Grade 3 (severe) | 14 (1.9 %) | 10 (1.3 %) | 4 (1.5 %) | 1 (0.8 %) |
| Total | 53 (7.0 %) | 47 (6.3 %) | 18 (6.7 %) | 6 (4.7 %) |
AE = Adverse event; SAE = Serious adverse event.
Source: Extracted from the clinical study reports of ENGAGE and ENSURE
For PBAC’s view, see Recommendation and Reasons.
It was noted that the key trials excluded women with a past history of ovarian hyper-response
(or OHSS), polycystic ovary syndrome (PCOS) or a basal antral follicle count of greater
than 20. The fact that these exclusion criteria were applied in the trial suggested
that the non-titratable dose of corifollitropin alfa may place these patients at an
increased risk of OHSS. This was supported by contraindications to its use in the
corifollitropin alfa Product Information. There was high uncertainty regarding whether
the relative adverse effect of treatment, in terms of OHSS, will remain constant across
different levels of population risk. The submission noted that in practice, clinicians
are most likely to select patients who are normal responders, similar to the populations
in the clinical trials. Nonetheless, the data should be interpreted with caution until
robust evidence indicates otherwise.
Maternal and foetal adverse events observed in Trial 38821 (follow up of ENGAGE) indicated
that there were no significant differences between the corifollitropin alfa and follitropin
beta treatment arms. Similarly, no significant differences in maternal and foetal
adverse events were observed in Trial 107014 (follow up study of ENSURE). However,
in Trial 107014, there was a trend towards an increased risk of serious adverse events
leading to a fatal outcome in the corifollitropin alfa arm compared to the follitropin
beta arm in Trial 107014 (2.3% versus 0.0%). Furthermore, in this same follow-up study,
the proportion of foetuses with serious adverse events was higher in the corifollitropin
alfa treatment arm (6.9%) compared to the follitropin beta treatment arm (5.6%). The
submission noted that live births were not specifically documented
,
however, some data have been published recently (Boostanfar, P et al (2010) (Abstract
O-119: European Society of Human Reproduction and Embryology June 2010): For 541 patients
with ongoing pregnancies from the ENGAGE trial, consistent with the ongoing pregnancy
rates after fresh embryo transfer (ET) (38.9% and 38.1% for the corifollitropin alfa
and rFSH groups, respectively), equally high live birth rates per started cycle of
35.6% and 34.4% were observed in the corifollitropin alfa and rFSH treatment groups,
respectively.
9. Clinical Claim The submission claimed corifollitropin alfa to be non-inferior in terms of comparative
effectiveness and non-inferior in terms of comparative safety over follitropin beta.
The PBAC agreed that the submission’s claim that corifollitropin alfa is non-inferior
in terms of comparative effectiveness and safety over follitropin beta appears reasonable
only in women who are most likely to respond well and least likely to “hyper-respond”.
See Recommendation and Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were as follows:
Based on the ENGAGE study of patients greater than 60 kg and less
than 90 kg, corifollitropin alfa 150 mcg as a single dose over 7
days and follitropin beta 200 IU as daily doses over 7 days are
equi-effective; and
Based on the ENSURE study of patients with a body weight less than
or equal to 60 kg, corifollitropin alfa 100 mcg as a single dose
over 7 days and follitropin beta 150 IU as daily doses over 7 days
are equi-effective.
11. Estimated PBS Usage and Financial Implications
The financial cost per year to the PBS was estimated in the
submission to be less than $10 million in Year 5. Whilst a cost
minimisation approach was taken in the economic evaluation, the
listing of corifollitropin alfa was estimated to result in an
increased cost to the PBS, primarily driven by the pricing
structure proposed in the submission. Furthermore, the submission
failed in the financial estimates to account for the fact that
patients using follitropin 150 IU daily who are dispensed 1 x 300
IU and 1 x 900 IU pens will have one day’s treatment
remaining for day 8. By assuming that the costs from day 8 onwards
are identical for corifollitropin and follitropin, the submission
favoured corifollitropin
For PBAC’s view, see Recommendation and
Reasons.
12. Recommendations and Reasons
The PBAC agreed that the choice of comparator, conventional rFSH,
represented by follitropin beta (Puregon®), is
appropriate although noting there is wide variation in the dosing
regimen of follitropin beta in fertility clinics in Australia and
that this adds some uncertainty to the submission’s clinical
and economic analyses.
The PBAC further agreed that the submission’s claim that
corifollitropin alfa is non-inferior in terms of comparative
effectiveness and safety over follitropin beta appears reasonable
only in women who are most likely to respond well and least likely
to “hyper-respond”. Notwithstanding that the ENSURE
trial was not powered to detect differences in pregnancy rates, but
was powered to detect differences in the number of oocytes
retrieved and that non-inferiority was demonstrated on the basis of
this outcome, the Committee considered uncertainty remains
regarding the comparative effectiveness of corifollitropin alfa
relative to follitropin beta in terms of ongoing pregnancy rates.
In the ENSURE trial corifollitropin alfa treatment was associated
with fewer ongoing pregnancy rates than follitropin beta (risk
difference -9.2%; 95% CI: -18.9 - 0.5%) with the lower margin of
the 95% confidence interval including clinically relevant
differences.
Additional clinical uncertainty arose because the women
participating in the ENSURE and ENGAGE studies may not have been
representative of the women likely to be treated under the IVF/GIFT
program, in terms of age, weight and underlying risk factors for
ovarian hyperstimulation syndrome (OHSS). The higher ages and
weights of Australian patients mean that corifollitropin alfa could
be less effective in Australian clinical practice. Additionally
patients with underlying risks for OHSS may not be as rigorously
excluded from treatment as they were from the clinical
trials.
The adverse event of most concern to PBAC for corifollitropin alfa
was OHSS, particularly as, unlike current rFSH therapies, the
clinician does not have the option to adjust the dose of
corifollitropin alfa (or even cease treatment) for baseline risk of
OHSS or on the appearance of OHSS symptoms. Although there was no
statistically significant differences in the rates of OHSS for
corifollitropin alfa vs. follitropin beta in ENGAGE (7.0% versus
6.3%, p = 0.55) or ENSURE (6.7% versus 4.7%, p = 0.42), it is
usually the case that such analyses lack adequate power. An
analysis by Tarlatzis et al (2010) of the combined incidence of
OHSS in the ENGAGE, ENSURE and TRUST studies referred to in the
pre-PBAC response also lacked adequate power and did not adjust for
early or late classification of OHSS.
Furthermore, in both ENSURE and ENGAGE there was a trend towards an
increased risk and severity of OHSS in the corifollitropin alfa
treatment arms compared with the follitropin beta treatment arms.
Overall, OHSS was reported more frequently as a serious adverse
event in the corifollitropin alfa group compared to the follitropin
beta group in both trials (2.6% versus 0.0% in ENSURE and 1.9%
versus 1.2% in ENGAGE). Additionally OHSS that led to study
discontinuation was higher in the corifollitropin alfa treatment
arm (1.6%) compared to the follitropin beta treatment arm (0.1%) of
ENGAGE. Overall PBAC remained unconvinced that corifollitropin alfa
is not associated with a higher risk of OHSS compared to
follitropin beta.
The PBAC agreed that providing the claim of comparable
(non-inferior) efficacy and safety can be supported in a future
submission, the appropriate approach to cost-minimisation is to
calculate a price for each strength of corifollitropin alfa
proposed for listing. The price of 150 mcg corifollitropin alfa
should be based on 200 IU of follitropin beta daily for 7 days; and
the price of 100 mcg corifollitropin should be based on 7 days of
150 IU of follitropin beta.
The PBAC noted that uncertainty remains with respect to the
submission’s utilisation estimates, and uncertainty about the
number of packs of the comparator which would be replaced if
corifollitropin alfa is listed, particularly as some patients using
follitropin beta would be provided with sufficient drug at the
first dispensing to last 8 rather than 7 days as assumed by the
submission.
The PBAC therefore rejected the application to list corifollitropin
on the basis of uncertainty about the claim that it is non-inferior
in terms of comparative effectiveness and safety to follitropin
beta, and the uncertainty in the cost-minimisation analysis
resulting from this clinical uncertainty and from the pricing
structure proposed by the sponsor.
Recommendation:
Reject
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
MSD is committed to working with the PBAC in order to address any
uncertainties that the Committee might have, in order to ensure
access of corifollitropin alfa for patients who are undergoing
controlled ovarian stimulation.
