The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 25 June 2008

Size: px

Start display at page:

Download "The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 25 June 2008"

Linda O’Neal’
5 years ago
Views:

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 25 June 2008 PERGOVERIS 150 IU/75 IU, powder and solvent for solution for injection B/1 glass vial - one 1 ml vial (CIP: ) B/10 glass vials - ten 1 ml vials (CIP: ) Applicant: MERCK LIPHA SANTE Follitropin alfa or recombinant human follicle-stimulating hormone (r-hfsh) / lutropin alfa or recombinant human luteinizing hormone (r-hlh) List I Medicinal product restricted to prescription only by specialists in gynaecology and/or gynaecology-obstetrics and/or endocrinology and metabolism. Medicinal product requiring close monitoring during treatment. Date of Marketing Authorization: 25 June 2007 (centralised procedure) Reason for request: Inclusion on the list of medicines reimbursed by National Health Insurance and approved for use by hospitals. Medical, Economic and Public Health Assessment Division 1

2 1. CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Follitropin alfa or recombinant human follicle-stimulating hormone (r-hfsh) / lutropin alfa or recombinant human luteinizing hormone (r-hlh) 1.2. Indication Pergoveris is indicated for the stimulation of follicular development in women with severe luteinizing hormone (LH) and follicle-stimulating hormone (FSH) deficiency. In clinical trials, these patients were defined by an endogenous serum LH level < 1.2 IU/l Dosage Treatment with Pergoveris should be initiated under the supervision of a physician experienced in the treatment of fertility problems. Pergoveris is intended for subcutaneous. The powder should be reconstituted immediately prior to use with the solvent provided. In LH and FSH deficient women (hypogonadotrophic hypogonadism), the objective of Pergoveris therapy is to develop a single mature Graafian follicle from which the oocyte will be liberated after the of human chorionic gonadotropin (hcg). Pergoveris should be given as a course of daily injections. Since these patients are amenorrhoeic and have low endogenous oestrogen secretion, treatment can commence at any time. Treatment should be tailored to the individual patient s response as assessed by measuring follicle size by ultrasound and oestrogen response. A recommended regimen begins with one vial of Pergoveris daily. If less than one vial of Pergoveris daily is used, the follicular response may be unsatisfactory because the amount of lutropin alfa may be insufficient (see section 5.1). If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by IU increments using a licensed follitropin alfa preparation. It may be acceptable to extend the duration of stimulation in any one cycle to up to 5 weeks. When an optimal response is obtained, a single injection of 5,000 IU to 10,000 IU hcg should be administered hours after the last Pergoveris injection. The patient is recommended to have coitus on the day of, and on the day following, hcg. Alternatively, intrauterine insemination (IUI) may be performed. Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum. If an excessive response is obtained, treatment should be stopped and hcg withheld. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle. In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level <1.2 IU/l as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories. In these trials the ovulation rate per cycle was 70-75%. 2

3 2. COMPARABLE MEDICINAL PRODUCTS 2.1. ATC Classification (2008) G03GA05 (Follitropin alfa) / G03GA07 (Lutropin alfa) G : Genitourinary system and sex hormones G03 : Sex hormones and modulators of the genital system G03G : Gonadotropins and other ovulation stimulants G03GA : Gonadotropins G03GA05 : Follitropin alfa G : Genitourinary system and sex hormones G03 : Sex hormones and modulators of the genital system G03G : Gonadotropins and other ovulation stimulants G03AA : Gonadotropins G03AA07 : Lutropin alfa 2.2. Medicines in the same therapeutic category Closely comparable medicinal products Table 1: comparable medicinal products INN (hormonal activity - origin) Proprietary product Pharmaceutical form Menotropin (FSH and LH activity urinary origin) MENOPUR 75 IU / 75 IU 1 ml Powder and solvent for solution for injection, subcutaneous or intramuscular Indication - Treatment of sterility, if anovulation is the only cause of the sterility: anovulation originating in the hypothalamus/pituitary gland; ovulation disorders; - inducing ovulation in the course of Medically Assisted Procreation (IVF, GIFT, etc.); - sterility caused by insufficient production of cervical mucus. 3

4 2.2.2 Medicinal products in the same therapeutic class which are not closely comparable Table 2: Medicinal products with FSH activity INN (origin) Proprietary product Pharmaceutical form Follitropin alfa (recombinant) Follitropin beta (recombinant) Urofollitropin (urinary) GONAL-f 75 IU 450 IU/0.75 ml 1,050 IU/1.75 ml GONAL-f 300 IU/0.5 ml 450 IU/0.75 ml 900 IU/1.5 ml PUREGON 50 IU/0.5 ml 75 IU/0.5 ml 150 IU/0.5 ml 300 IU/0.36 ml 600 IU/0.72 ml 900 IU/1.08 ml FOSTIMON 150 IU / ml Powder and solvent for solution for injection, subcutaneous or intramuscular Injectable solution in pre-filled pen, subcutaneous Injectable solution, intramuscular or subcutaneous Powder and solvent in injectable solution in pre-filled syringe, subcutaneous Indication - GONAL-f in association with a luteinizing hormone (LH) preparation is recommended for the stimulation of follicular development in women with severe LH and FSH deficiency. In clinical trials these patients were defined by an endogenous serum LH level <1.2 IU/l. - Anovulation (including polycystic ovarian disease, PCOD) in women who have been unresponsive to treatment with clomifene citrate. - Stimulation of multifollicular development in patients undergoing superovulation for assisted reproductive technologies (ART) such as in vitro fertilization (IVF), gamete intra-fallopian transfer (GIFT) and zygote intra-fallopian transfer (ZIFT). Puregon is indicated for the treatment of female infertility in the following clinical situations: - Anovulation (including polycystic ovarian disease, PCOD) in women who have been unresponsive to treatment with clomifene citrate. - Controlled ovarian hyperstimulation to induce the development of multiple follicles in medically assisted reproduction programs [e.g. in vitro fertilization/embryo transfer (IVF/ET), gamete intrafallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)]. - Anovulation (including polycystic ovarian disease, PCOD) in women who have been unresponsive to treatment with clomifene citrate. - Controlled ovarian hyperstimulation to induce the development of multiple follicles in medically assisted reproduction programs [e.g. in vitro fertilization/embryo transfer (IVF/ET), gamete intrafallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)]. Table 3: Medicinal product with LH activity INN (origin) Proprietary product Pharmaceutical form Lutropin alfa (recombinant) LUVERIS 75 IU Powder and solvent for solution for injection, subcutaneous Indication - Luveris in association with a follicle stimulating hormone (FSH) preparation is recommended for the stimulation of follicular development in women with severe LH and FSH deficiency (in clinical trials these patients were defined by an endogenous serum LH level <1.2 IU/l). 4

5 2.3. Medicines with a similar therapeutic aim Table 4: medicines with a similar therapeutic aim INN Proprietary product Pharmaceutical form Indication Gonadorelin acetate LUTRELEF 0.8mg LUTRELEF 3.2mg Lyophilizate and solution for parenteral use, administered subcutaneously or intravenously through a catheter Inducing ovulation for the treatment of sterility in the event of anovulation of hypothalamic origin. According to the WHO anovulation classification, only Class I and Class IIa are appropriate for the of GnRH in the case of unresponsiveness to clomifene citrate. 3. ANALYSIS OF AVAILABLE DATA The file supplied by the laboratory includes two bioequivalence studies and three efficacy studies. One of these studies (Burguès et al.) will not be included in the efficacy analysis because although the initial daily doses of r-hfsh (GONAL-F IU/day) and r-hlh (LUVERIS IU/day) correspond to those in a vial of PERGOVERIS, the dose of FSH could be adjusted during the 1st cycle from the 6th day on the basis of the response obtained. The methods of this adjustment are not described in the publication, and the results presented do not indicate how many patients needed an FSH dose adjustment Bioequivalence studies Two bioequivalence studies have compared the bioavailability of each active constituent, administered alone and in combination (with an r-hfsh/r-hlh ratio of 2:1). They were conducted on female volunteers pre-treated with a GnRH agonist. - Study IMP demonstrated the bioequivalence of r-hfsh (300 IU) administered alone and in combination with r-hlh (150 IU). - Study IMP demonstrated the bioequivalence of r-hlh (450 IU) administered alone and in combination with r-fsh (900 IU) Efficacy studies 1 The applicant submitted two multicentre, randomized, open-label dose-finding studies. The studies compared several daily doses of r-hlh combined with a fixed dose of r-hfsh These two studies included women with a severe LH and FSH deficiency. All patients received a daily dose of 150 IU of r-hfsh. Each study comprised four treatment groups, according to the daily dose of r-hlh: 0, 25, 75 and 225 IU. Each cycle was not to exceed days of treatment. Ovulation was induced by injection of hcg when a follicle 17 mm in diameter was obtained. 1 As stated in the PERGOVERIS EPAR, the efficacy studies (GF6253 and GF6905) are those already filed for registration of LUVERIS (r-hlh). No additional evidence of efficacy was requested - 5

6 Study GF Inclusion criteria: o Women aged 18 to 35 years o FSH level < 5IU/l and LH level <1.2 IU/l o With no history of ovarian hyperstimulation or systemic illness. - Primary endpoint: to obtain follicular development during the first treatment cycle as defined by the following three parameters: o follicle 17 mm diameter o preovulatory serum oestradiol level of 400 pmol/l o mid-luteal phase serum progesterone level of 25 nmol/l. - Results: Thirty-eight patients were included in the study and 34 in the primary endpoint analysis. During the first treatment cycle, 21 patients out of 38 did not receive the hcg injection, due to insufficient follicle development (14), risk of ovarian hyperstimulation syndrome (5), and withdrawal of consent (2). Of the 7 patients treated with doses of r-hlh and r-hfsh corresponding to the composition of Pergoveris, 4 had follicular development (excluding excessive follicular development). Table 5 study GF 6253 efficacy during first treatment cycle. Daily dose of r-hlh (no. of patients) 0 IU/day (n=10) 25 IU/day (n=9) 75 IU/day* (n=7) 225 IU/day (n=8) Number of patients with follicular development 0/10 1/9 6/7 8/ Number of patients with follicular development, excluding excessive follicular development 0/10 1/9 4/7 5/ * dose of r-hlh corresponding to the composition of PERGOVERIS Study GF Inclusion criteria: o Women aged 18 to 40 years o FSH level < IU/l and LH level <13.3 IU/l o Oestradiol level <60 pg/ml p - Primary endpoint: to obtain follicular development during the first treatment cycle, as defined by the following three parameters: o follicle 17 mm diameter o preovulatory serum oestradiol level of 160 pg/ml o mid-luteal phase serum progesterone level of 10 ng/ml - Results: Forty-three patients were included in the study and 40 in the primary endpoint analysis. During the first treatment cycle, 5 patients out of 40 did not receive the hcg injection due to ovarian hyperstimulation syndrome. Only 15 of the 40 patients included in the analysis had an LH level <1.2 IU/l, corresponding to the indication of PERGOVERIS. Of these 15 patients, 3 were treated with doses of r-hlh and r-hfsh corresponding to the composition of this product. 6

7 Table 6 study GF 6905 efficacy Daily dose of r-hlh IU/day IU/day IU/day* IU/day p Total number of patients n=11 n=9 n=11 n=9 Number of patients with follicular development 7/11 9/9 8/11 6/9 NS Number of patients with LH < 1.2IU** n=3 n=5 n=3 n=4 Number of patients with follicular development** 0/3 5/5 2/3 3/4 p=0.04** * dose of r-hlh corresponding to the composition of PERGOVERIS; **: a posteriori analysis 3.3. Adverse effects Two adverse events were observed in study GF 6253: a shock secondary to an injection and a miscarriage. The most frequent other adverse effects observed in the studies listed above are those cited in the SPC: - very common ( 1/10): o headache o mild to severe injection site reaction (pain, redness, bruising, swelling and/or irritation at the site of injection) o ovarian cysts - common ( 1/100, <1/10) o somnolence o abdominal pain and gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal cramps and bloating o breast pain, pelvic pain, mild to moderate ovarian hyperstimulation syndrome (OHSS) - uncommon ( 1/1,000, <1/100) o severe OHSS The PERGOVERIS SPC also states the known complications of gonadotropins used to induce ovulation: risk of OHSS, multiple pregnancy or miscarriage Conclusion Two studies (IMP et IMP 23718) concluded that r-hfsh (300 IU) was bioequivalent when administered alone and in combination with r-hlh (150 IU), and r-hlh (450 IU) was bioequivalent when administered alone and in combination with r-hfsh (900 IU). Two open-label dose-finding studies (GF 6253 and GF 6905) compared four daily doses of r- hlh (0, 25, 75 or 225 IU) associated with a fixed daily dose of 150 IU r-hfsh. Their primary endpoint was to obtain follicular development during the first treatment cycle. Study GF 6253, which included women with an LH level of under 1.2 IU/l, showed a significant difference between the four treatment groups (34 patients were included in the analysis). Follicular development (excluding excessive developments) was found in 4 of the 7 patients treated with 75 IU/day of r-hlh (dose corresponding to that of PERGOVERIS). Study GF 6905, which included women with an LH level of under 13.3 IU/l, showed no significant difference between the groups. Of the 40 patients analysed, only 15 had an LH level of under 1.2 IU/ml, 3 of whom were treated with 75 IU/day of r-hlh (dose corresponding to that of PERGOVERIS). 7

8 No difference in safety is expected between the of the fixed combination of PERGOVERIS and combined of its two constituents, at the corresponding doses and for the indication specified in the Marketing Authorization. 4. TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Infertility is not severe, but radically alters a couple s quality of life. The proprietary drug is intended to provide curative treatment. Its efficacy/adverse event ratio is high. Public health benefit Infertility associated with severe LH and FSH deficiency in women represents a low public health burden in view of the small number of patients concerned. Improving the treatment of this deficiency does not constitute a public health priority. Several hormone treatments are already available. Having regard to the available data and the conditions of use, which do not allow dose adjustment, PERGOVERIS is not expected to improve morbidity or quality of life compared with the free combination of its two constituents, LH and FSH. Consequently, PERGOVERIS is not expected to have an impact on public health. This proprietary drug is used for first-line therapy. There are alternative drugs available. The actual benefit of PERGOVERIS is substantial Improvement in actual benefit The proprietary product PERGOVERIS, a fixed combination of r-hfsh (150 IU) and r-hlh (75 IU), does not provide any improvement in actual benefit (IAB V) compared with the combined use of each of its constituents considered separately Therapeutic use Reference treatment strategy 2 Summary: The aim of the treatment is to achieve a viable single-embryo pregnancy. It is therefore essential to evaluate all the couple s infertility factors. The treatment strategy should take account of the woman s age, the duration of the infertility, associated factors and previous responses (Grade A). Handling of ovulation inducers requires specific medical training and suitable experience (expert consensus). All ovulation inducers, apart from clomifene citrate, are available only on prescription by the specialists listed in the Marketing Authorization. 2 Ovulation inducers: gonadotropins - Recommendations - Afssaps update. 8

9 An etiological assessment of infertile couples is required before a treatment strategy is decided on. This report involves at least a check on fallopian tube permeability, basic hormone assays, semen analysis and tests for thromboembolism risk factors (expert consensus). It is recommended that preventive measures should be promoted in general: prevention and treatment of sexually transmissible diseases for both partners, recommending that both partners should give up smoking, nutritional management of the female patient so that she achieves the ideal weight, and reducing the age of first pregnancy by providing information about the reduction of fertility with age (Grade C). There is no point in offering ovulation induction treatment if the basic endogenous FSH level is markedly and constantly elevated, whatever the woman s age (Grade A) Anovulation of hypothalamic origin: Diet and lifestyle measures and psychological counselling are an essential pre-requisite for the stimulation of ovulation (Grade B). Pulsatile of GnRH, or combined of FSH and LH or HMG, with careful monitoring (hormone assays, follicular ultrasonography) are recommended as firstline treatment (Grade A). The rate of pregnancies being equal, there is a lower rate of ovarian hyperstimulation and multiple pregnancies with pulsatile GnRH than with gonadotropins Therapeutic use: Pergoveris is a first-line medicine which stimulates follicular development in women with a severe LH and FSH deficiency. In clinical trials, these patients were defined by an endogenous serum LH concentration < 1.2 IU/l. The usefulness of this fixed combination for the treatment of patients compared with separate of its two ingredients has not been established. Moreover, this product is not suitable for the treatment of all patients Target population According to the available epidemiological data 3, 60,000 couples a year consult a doctor due to infertility which has lasted for more than a year. 74% of the women in those 60,000 couples are diagnosed as infertile. Hypothalamus/pituitary gland insufficiency only represents 1.2% of the causes of infertility, ie. approximately 500 women. In view of these factors, the target population of PERGOVERIS is a maximum of 500 women in France, especially as in practice, daily doses of FSH lower than the dose contained in PERGOVERIS may be suitable for some patients. Moreover, some patients treated with PERGOVERIS will require a dose adjustment. 3 Thonneau P, Patureau J, Moyse C, Marchand S, Tallec A, Ferial ML et al. L infécondité en France : résultats d une étude multicentrique dans trois départements français ( ). Contracept Fertil Sex 1992 ; 20 (1) :

10 4.5. Transparency Committee recommendations The Transparency Committee recommends inclusion on the list of medicines reimbursed by National Insurance and on the list of medicines approved for use by hospitals and various public services for the indication and at the dosage specified in the Marketing Authorization Packaging: appropriate for the prescription conditions Reimbursement rate: 100% 10

The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 22 September 2010

The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 22 September 2010 100 µg/0.5 ml, solution for injection B/1 prefilled syringe + 1 needle (CIP code: 374 590-1) 150