The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 24 June 2009

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 24 June 2009 CLOTTAFACT 1.5 g/100 ml, powder and solvent for solution for injection B/1 (CIP code: ) Applicant: LFB-BIOMEDICAMENTS human fibrinogen ATC code (2009): B02BB01 List I Medicine for hospital prescription only Date of Marketing Authorisation: 5 May 2009 (national procedure) Reason for request: Inclusion on the list of medicines approved for hospital use. Medical, Economic and Public Health Assessment Division 1/9

2 1. CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Human fibrinogen 1.2. Background First human fibrinogen medicinal product to obtain marketing authorisation Indications 1. Constitutional hypo-, dys- or afibrinogenaemia in patients with spontaneous or posttraumatic haemorrhage. Due to the lack of data on major bleedings that are lifethreatening or functional or occuring in surgery, the use of CLOTTAFACT is not recommended in these situations. 2. Hypofibrinogenaemia acquired during: severe acute haemorrhages associated with a secondary reduction in the circulating fibrinogen level, such as severe acute postpartum haemorrhage (intrapartum haemorrhage) after the failure of uterotonic treatment and before the use of invasive treatments, haemorrhages associated with dilution coagulopathy, for example in surgical or traumatological settings. haemorrhagic syndrome associated with a reduction in hepatic fibrinogen synthesis in patients with hepatic impairment or secondary to treatment with L-asparaginase Dosage Treatment must be initiated under the supervision of a doctor specialised in haemostasis disorders. Dosage: The plasma fibrinogen concentration must be measured initially and monitored regularly to determine the dosage and frequency of administration appropriate for each individual. Constitutional deficiencies The aim of the first injection is to achieve a circulating fibrinogen level of more than 1 g/l (normal values between 1.5 and 4.5 g/l). Formula for calculating the initial dose: quantity to be injected (g) = (level to be achieved (g/l) baseline level (g/l)) body weight (kg) corresponding to 1/recovery level. The subsequent posology (doses and frequency of the injections) will be adapted to the patient s clinical condition and laboratory follow-up. Acquired deficiencies Adults: Generally, an initial dose of 1 to 2 g is administered and repeated if necessary. For severe, acute obstetric haemorrhages, higher doses of fibrinogen (4 to 8 g) may be required. In emergencies with acute haemorrhages, if the fibrinogen levels cannot be measured, an initial dose can be given and the following doses will be adapted to the concentrations measured in the meantime. Children: The dosage must be determined as a function of body weight and clinical situation (0.02 to 0.03 g/kg). 2/9

3 Method and route of administration CLOTTAFACT is a powder for extemporaneous reconstitution with water for injections by the methods described in section 6.6 Special precautions for disposal and other handling. CLOTTAFACT must always be injected intravenously as a single dose immediately after reconstitution. In clinically stable patients, the infusion rate for CLOTTAFACT must not exceed 4 ml/min. In patients with severe acute haemorrhage, the infusion rate may reach 20 ml/min. 2. SIMILAR MEDICINAL PRODUCTS 2.1. ATC classification (2009) B : Blood and blood forming organs B02 : Antihaemorrhagics B02B : Vitamin K and other haemostatics B02BB : Fibrinogen B02BB01 : Human fibrinogen 2.2. Medicines in the same therapeutic category Medicines that are strictly comparable Not applicable Medicines that are not strictly comparable Not applicable 2.3. Medicines with a similar therapeutic aim - Fresh frozen plasma (FFP), although regarded as less effective than fibrinogen, is mentioned in a document from the French Healthcare Product Safety Agency (AFSSAPS) 1 as a therapeutic alternative to fibrinogen, in the following indications: Haemorrhagic syndrome with profound hypofibrinogenaemia (< g/l) o during liver transplantation o induced by L-asparaginase if infusions of FFP are limited by the fluid intake levels acceptable for the patient. o after volume expansion with very large quantities (dilution coagulopathy) Prophylaxis of haemorrhagic risk with profound hypofibrinogenaemia (< g/l) induced by L-asparaginase. Fresh frozen plasma is not a medicinal product. - Tranexamic acid, indicated in: Haemorrhagic incidents due to a generalised primary fibrinolytic state. Haemorrhagic incidents during a treatment with a fibrinolytic effect. Haemorrhagic incidents maintained by local fibrinolysis, as is the case in: o menorrhagia and metrorrhagia: produced by hormonal dysfunction secondary to traumatic, infectious or degenerative lesions of the uterus. o o o gastrointestinal haemorrhages, haematuria originating in the lower urinary tract: prostatic adenoma, malignant neoplasms of the prostate and bladder, lithiasis, and more generally haemorrhagic urinary disorders, during surgical treatment of the prostate and surgical procedures involving the urinary tract. haemorrhages during ENT surgery (adenoidectomy and tonsillectomy). 1 Afssaps Update on fibrinogen supplies on national territory Proposed hierarchy for fibrinogen indications in a tense situation regarding supplies for the French market. 21 November /9

4 3. ANALYSIS OF AVAILABLE DATA The company has submitted two clinical studies of efficacy and tolerance. One involves patients with a constitutional fibrinogen deficiency (reference: ), the other patients with postpartum haemorrhage (reference: FGT1-0505) as a model of severe acute haemorrhage responsible for acquired hypofibrinogenaemia Efficacy Study : constitutional fibrinogen deficiency The first part of this study (pharmacokinetics) was not taken into account. In the second part (clinical efficacy) detailed below, the treatment was to be administered in the following circumstances: - treatment of episodes of bleeding until they stop, - preventive treatment before a surgical procedure, - regular administration for long-term prevention. As no patient had to have to undergo a surgical procedure during the study, elements of the protocol corresponding to this indication are not detailed Method: Non-comparative phase I/II study. Inclusion criteria: Patients aged 12 to 65 years. Having constitutional afibrinogenaemia, defined as an undetectable plasma level of fibrinogen or severe hypofibrinogenaemia, defined as a plasma level of 0.5 g/l. Having already received plasma-derived medicinal products or unstable blood products Whose Serological status for HIV1, HIV2, HCV, HBV, HAV and parvovirus 19 is known. Exclusion criteria: Dysfibrinogenaemia Acquired fibrinogen deficiency History of thrombosis after fibrinogen infusion. Treatment: At each administration, the dose was calculated using the following formula to achieve a plasma fibrinogen level of between 1 and 1.5 g/l: quantity to be injected (g) = [level to be achieved (g/l) baseline level (g/l)] x 0.04 x body weight (kg). For the treatment of haemorrhagic episodes, a follow-up determination was made at 1 h and 24 h. Administrations could be repeated if necessary, with recalculation of the dose, at the appropriate frequency until the haemorrhage stopped. In patients receiving long-term prevention, the calculated dose was to be administered 2 to 4 times a month, as decided by the investigator. Endpoints: In the treatment of bleeding episodes, clinical efficacy was evaluated by the investigator on a 4-point scale: excellent (normal haemostasis), good (slight bleeding), moderate (moderate bleeding), none (severe bleeding). The evaluation also included the number of administrations required. 4/9

5 The analysis was to include the data from patients who had received at least one administration and had no major protocol deviation. The data for all the patients included were analysed. Bleeding was defined as major if it was life-threatening, if the haemoglobin level was reduced by 2 g/dl, necessitating the transfusion of 2 or more units of packed cells, or if the bleeding was retroperitoneal or intracranial. Any other bleeding was regarded as minor. In long-term prevention, efficacy was evaluated from the number of spontaneous or posttraumatic bleeds that occurred during the study. Results: Six patients were included in the study. The follow-up period was 1 to 18 months; one patient took part in only the pharmacokinetic part of the study and did not show any bleeding during his follow-up period (1 month). The 5 other patients participated in both parts of the study. The total dose administered was between 7 and 54 g. Treatment of bleeding: Five patients took part in the 2nd part of the study; their follow-up period was 3 to 18 months. Four of them had 21 episodes of bleeding, 17 of which were haematomas. All the bleeds were regarded as minor; 19/21 were post-traumatic, the others (2/21) were spontaneous. Nineteen out of 21 episodes of bleeding were treated with a single administration. The mean dose administered per episode was g/kg (± 0.033). A total of 24 administrations of CLOTTAFACT were made. Efficacy was rated as excellent or good for 20 of the 21 episodes treated. Efficacy was rated as moderate" in one patient who presented 6 days after the onset of the bleeding. Long-term prevention Just one patient was treated in this indication for 2.4 months. He received a total of 6 injections given every 2 weeks and did not show any bleeding. These data do not allow any conclusions to be drawn about this use which does not appear in the marketing authorisation Study FGT1-0505: postpartum haemorrhages Method: Non-comparative phase IIa study. The analysis of efficacy was to include patients who had received at least one administration of CLOTTAFACT and had no major protocol deviation. Inclusion criteria: Patients more than 18 years of age, Having given birth by vaginal delivery or by caesarean section at the end of a normal or pathological pregnancy of more than 27 weeks, Haemorrhage of a volume of 100 ml in 20 min in the 2 to 6 h after a vaginal delivery or 800 ml in the case of a caesarean. Exclusion criteria: Uncontrollable haemorrhage of more than 2500 ml and/or a flow of more than 500 ml in 30 minutes, for which medicines (fibrinogen, activated factor VII) and haemostasis treatments (embolisation, ligature of the uterine artery, hysterectomy) are given at the same time, 5/9

6 Haemostasis disorder, treatment with heparin, History of venous or arterial thrombosis. Treatment: Two vials of CLOTTAFACT, i.e. 3 g of fibrinogen in a 10 min infusion. Endpoints: response to treatment. Failure: use of treatments of last resort (ligature of the uterine arteries, embolisation, hysterectomy or administration of activated factor VII) or transfusion of more than 4 units of packed cells or death after administration of CLOTTAFACT, Partial success: use of additional haemostatic treatments (fresh frozen plasma, platelet concentrates, antifibrinolytics) to stop the haemorrhage. Success: when none of the events defined above occurred. Results: Sixteen women were included in the study, 15 of whom had had a caesarean. On inclusion, the 16 women had a median haemorrhagic volume of 1667 ml [ ], a median flow of 1043 ml/30 min [ ] and a median plasma fibrinogen level of 3.8 g/l [ ] (2 missing data for this criterion). On inclusion, the 12 women in the efficacy analysis had a median haemorrhagic volume of 1617 ml [ ] and a median flow of 892 ml/30 min [ ]; their median plasma fibrinogen level was 3.6 g/l [ ] (1 missing datum for this criterion). Exposure: all the women received 2.6 g CLOTTAFACT, except one who received 1.5 g, i.e. a median dose of 30.1 mg/kg [ ]. Response to treatment: 12 women are included in the efficacy analysis for this criterion. The other 4 had another haemostasis treatment at the same time as the study treatment because of the magnitude of the bleeding. Of these 12 women, 11 received oxytocics and 7 received prostaglandins before the administration of CLOTTAFACT; 8 received oxytocics at the same time (n = 1) or after the administration of CLOTTAFACT; 4 received prostaglandins at the same time (n = 1) or after the administration of CLOTTAFACT. In these 12 women, the results in terms of the response to treatment were: Success in 8 cases Partial success in 1 case (concomitant administration of an antifibrinolytic) Failure in 3 cases Adverse effects Study Monitoring: A check for anti-fibrinogen inhibitor antibodies was made after each administration, at 1 and 6 months then every 6 months. A check of viral serology was made on inclusion and at 6 months. Results: Fifteen adverse events were noted during treatment, 1 of which was serious (arterial dissection); it occurred in the patient receiving long-term prevention but was considered as not related to the treatment. Two episodes of headaches with mild nocturnal sweating which occurred in the same patient were considered as related to the treatment. No seroconversion was found and no anti-fibrinogen inhibitor antibodies appeared. 6/9

7 3.2.2 Study FGT Monitoring: The patients were followed up for 6 weeks after delivery. Results: Fourteen adverse events were noted after the administration of CLOTTAFACT, one of which was serious (acute pulmonary oedema). No adverse event was considered as related to the treatment Conclusion The efficacy and tolerance of CLOTTAFACT were evaluated during two exploratory clinical studies: Constitutional fibrinogen deficiency: Six patients were included, 4 of whom were followed up for 6 to 18 months for the treatment of spontaneous or post-traumatic bleeding. They had 21 episodes of bleeding which were all considered as minor. The efficacy of treatment was rated by the investigators as excellent or good for 20 of the 21 episodes treated and moderate for one episode. Only 2 episodes of headaches with mild nocturnal sweating which occurred in the same patient were considered as related to the treatment. Post-partum haemorrhages: Sixteen patients were included in the study; 12 of them appear in the analysis of clinical efficacy. The other 4 required haemostasis treatment concomitantly with CLOTTAFACT because of the magnitude of the bleeding and were excluded from the analysis. The result of treatment was regarded as a success in 8 cases out of 12, as a partial success in 1 case and as a failure in 3 cases. No adverse event was considered as related to the treatment. 4. TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Constitutional hypo-, dys- and afibrinogenaemia are rare diseases characterized by bleeding that may be life-threatening. Haemorrhages with a reduction in the circulating fibrinogen level are life-threatening. Public health benefit - Constitutional deficiencies are serious but rare diseases. The public health burden is therefore small. There is an unmet therapeutic need. However, from the data available (study in 6 patients with a constitutional fibrinogen deficiency), there is no evidence that the medicinal product CLOTTAFACT can be expected to have any impact in terms of morbidity and mortality and quality of life. Consequently, the medicinal product CLOTTAFACT is not expected to offer any public health benefit in this indication. - Haemorrhages with an acquired fibrinogen deficiency are potentially life-threatening clinical situations. Their public health burden is, from the data available, hard to quantify and is at best moderate. In view of the current prognosis in these clinical situations, combined with their usual management, there is a public health need. However, from the data available, the impact on morbidity and mortality cannot be evaluated because of the very small number of patients included in the studies (only 16 patients in a clinical situation where CLOTTAFACT 7/9

8 is indicated: post-partum haemorrhage). Consequently, taking into account the available data, the public health benefit of the medicinal product CLOTTAFACT cannot be evaluated. The medicinal product is a replacement treatment. The efficacy/adverse effect ratio is high. In constitutional fibrinogen deficiencies, this medicinal product is a first-line therapy for the treatment of spontaneous or post-traumatic haemorrhages. There is no therapeutic alternative. In hypofibrinogenaemia acquired during haemorrhages, this medicinal product is a secondline treatment. There are therapeutic alternatives: fresh frozen plasma, surgical haemostasis. In constitutional fibrinogen deficiencies, the actual benefit of this medicinal product is substantial. In profound hypofibrinogenaemia acquired during haemorrhages, the actual benefit of this medicinal product is substantial Improvement in actual benefit (IAB) In constitutional hypo-, dys- or afibrinogenaemia, in the absence of any therapeutic alternative validated by a marketing authorisation, CLOTTAFACT provides a major improvement in actual benefit (level I) in patient management. In hypofibrinogenaemia acquired during haemorrhages, the data presented in the dossier concern only post-partum haemorrhages. In addition, the number of patients included and analysed is limited and most of the patients that appear in the analysis of efficacy had a fibrinogen level of more than 1 g/l on inclusion. Under these circumstances, and given the limited nature of the data produced, the Committee believes that CLOTTAFACT contributes only a minor improvement in actual benefit (level IV) in the management of patients presenting with hypofibrinogenaemia acquired during haemorrhages Therapeutic use Constitutional fibrinogen deficiencies In haemorrhagic episodes, fibrinogen infusions are the treatment of choice. 2,3 - Therapeutic use of the medicinal product CLOTTAFACT is a first-line treatment for spontaneous or post-traumatic haemorrhages apart from major haemorrhages that are life-threatening or incapacitating or occur in surgery Hypofibrinogenaemia acquired during haemorrhages - According to a recommendation by the National Board of French Gynaecologists and Obstetricians 4, the initial management of an immediate post-partum haemorrhage entails uterine revision or artificial delivery under anaesthesia and the administration of oxytocin and 2 ORPHANET congenital fibrinogen deficiency April Bolton-Maggs PHB, Perry DJ et al. The rare coagulation disorders review with guidelines for management from the United Kingdom Haemophilia Centre Doctor s Organisation. Haemophilia 2004; 10: Recommendations for clinical practice Immediate post-partum haemorrhages November April /9

9 uterine massage. If the haemorrhage persists, the administration of prostaglandins is recommended. If there is no response to these uterotonic treatments, invasive treatments are used (embolisation or arterial ligature, hysterectomy). - A European recommendation 5 advocates the administration of fibrinogen in the event of a major bleed accompanied by a fibrinogen level of less than 1 g/l, even though there is no randomised study of efficacy in this indication. - In another, British recommendation 6, the administration of fibrinogen is advocated if the administration of fresh frozen plasma fails to keep the fibrinogen level above 1 g/l. - Therapeutic use of the medicinal product: In post-partum haemorrhages, CLOTTAFACT is a second-line treatment, after uterotonic treatments have failed and before invasive treatments are used (embolisation, surgery). Use of this medicinal product must not however delay the use of necessary invasive treatments Target population According to data from ORPHANET 7, the prevalence of congenital fibrinogen deficiency is 0.15/100,000 which, on the basis of the provisional evaluation of the population by the French National Institute of Statistics and Economic Studies (INSEE) in 2008, would correspond to 95 people. According to data from the French Technical Hospitalisation Information Agency (ATIH), 1563 procedures for post-partum haemorrhage (ligature, embolisation and hysterectomy) were performed in The target population in post-partum haemorrhages would therefore be of the order of 1600 patients. The company supplied the results of a market study (June 2007). It contains an evaluation of the distribution by indication of patients treated with fibrinogen injections (whatever the medicinal product used). This part of the survey is based on a sample of 1146 patients. In this study, haemorrhages during delivery account for 28.1% of the patients treated with fibrinogen. The other indications mentioned are massive haemorrhages (multiple injuries, transplantation, cardiac surgery, other types of surgery), treatment with L-asparaginase, constitutional deficiency. It should be noted that the study did not identify the prescription of fibrinogen in patients with hepatic impairment; however, it is thought that this underestimation is offset by an overestimation of the number of patients exhibiting congenital fibrinogen deficiency (3% in the market study). On this basis, the total target population for CLOTTAFACT would be 5700 patients (including 95 patients with congenital fibrinogen deficiency) Transparency Committee recommendations The transparency Committee recommends inclusion on the list of medicines approved for hospital use and various public services in the indications and dosages of the Marketing Authorisation. 5 SPAHN RD et al. Management of bleeding following major trauma: a European guideline. Critical care 2007; avril Stainsby D, Mac lennan S, Thomas D et al. Guidelines on the management of massive blood loss. Br J Haematol 2006; 135: recommendation by the British Society of Haematology. 7 ORPHANET Reports Prevalence of rare diseases: bibliographical data November /9