The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 23 September 2009

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1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 23 September 2009 CANCIDAS 50 mg, powder for concentrate for solution for infusion Vial containing 10 ml, B/1 (CIP: ) CANCIDAS 50 mg, powder for concentrate for solution for infusion Vial of 10 ml with transfer system, B/1 (CIP: ) CANCIDAS 70 mg, powder for concentrate for solution for infusion Vial containing 10 ml, B/1 (CIP: ) Applicant: MSD/CHIBRET Caspofungin ATC Code: J02AX04 List I For hospital use only Date of Marketing Authorisation: 24 October 2001 (amendment to marketing authorisation dated 26 November 2008) Reason for request: Inclusion on list of products for hospital use in the extension of indication "paediatric population". Medical, Economic and Public Health Assessment Division 1

2 1.1. Active substance caspofungin 1 PROPERTIES OF THE MEDICINAL PRODUCT 1.2. Indication "Treatment of invasive candidiasis in adult or paediatric patients. Treatment of invasive aspergillosis in adult or paediatric patients who are refractory to or intolerant to amphotericin B, lipid formulations of amphotericin B and/or itraconazole. Refractory status is defined as progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy. Empirical therapy for presumed fungal infections (such as Candida or Aspergillus) in febrile, neutropaenic adult or paediatric patients. " 1.3. Posology "CANCIDAS should be initiated by a physician experienced in the management of invasive fungal infections. After reconstitution and dilution, the solution should be administered by slow intravenous infusion over approximately 1 hour. Do not mix or co-infuse CANCIDAS with other medicines, as there are no data available on the compatibility of CANCIDAS with other intravenous substances, additives, or medicinal products. DO NOT USE DILUENTS CONTAINING GLUCOSE, as CANCIDAS is not stable in diluents containing glucose. Both 70 mg and 50 mg vials are available. CANCIDAS should be given as a single daily infusion. Dosage in adult patients A single 70 mg loading dose should be administered on Day-1, followed by 50 mg daily thereafter. In patients weighing more than 80 kg, after the initial 70 mg loading dose, CANCIDAS 70 mg daily is recommended. Dosages of more than 70 mg per day have not been sufficiently studied. No dosage adjustment is necessary based on gender or race. Dosage in paediatric patients (12 months to 17 years) In paediatric patients (12 months to 17 years of age), dosing should be based on the patient's body surface area (see Instructions for Use in Paediatric Patients, Mosteller Formula1). For all indications, a single 70 mg/m2 loading dose (not to exceed an actual dose of 70 mg) should be administered on Day 1, followed by 50 mg/m2 daily thereafter (not to exceed an actual dose of 70 mg daily). If the 50 mg/m2 daily dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg/m2 daily (not to exceed an actual daily dose of 70 mg). The efficacy and safety of CANCIDAS have not been sufficiently studied in clinical trials involving neonates and infants below 12 months of age. Caution is advised when treating this age group. Limited data suggest that CANCIDAS at 25 mg/m2 daily in neonates and infants (less than 3 months of age) and 50 mg/m2 daily in young children (3 to 11 months of age) can be considered. Duration of treatment Duration of empirical therapy should be based on the patient's clinical response. Therapy should be continued until up to 72 hours after resolution of neutropenia (ANC 500). Patients found to have a fungal infection should be treated for a minimum of 14 days and treatment should continue for at least 7 days after both neutropaenia and clinical symptoms are resolved. Duration of treatment of invasive candidiasis should be based upon the patient's clinical and microbiological response. After signs and symptoms of invasive candidiasis have improved and 1 Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct 22; 317 (17): 1098 (letter) 2

3 cultures have become negative, a switch to oral antifungal therapy may be considered. In general, antifungal therapy should continue for at least 14 days after the last positive culture. Duration of treatment of invasive aspergillosis is determined on a case by case basis and should be based upon the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response. In general, treatment should continue for at least 7 days after resolution of symptoms. Dosage in elderly patients In elderly patients (65 years of age or more), the area under the curve (AUC) is increased by approximately 30%. However, no systematic dosage adjustment is required. There is limited treatment experience in patients 65 years of age and older. Dosage in patients with renal impairment No dosage adjustment is necessary based on renal impairment. Dosage in patients with hepatic insufficiency For adult patients with mild hepatic insufficiency (Child-Pugh score 5 to 6), no dosage adjustment is needed. For adult patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), CANCIDAS 35 mg daily is recommended based upon pharmacokinetic data. An initial 70 mg loading dose should be administered on Day-1. There is no clinical experience in adult patients with severe hepatic insufficiency (Child-Pugh score greater than 9) and in paediatric patients with any degree of hepatic insufficiency. Co-administration with inducers of metabolic enzymes Limited data suggest that an increase in the daily dose of CANCIDAS to 70 mg, following the 70 mg loading dose, should be considered when co-administering CANCIDAS in adult patients with certain inducers of metabolic enzymes. When CANCIDAS is co-administered to paediatric patients (12 months to 17 years of age) with these same inducers of metabolic enzymes (see section 4.5), a CANCIDAS dose of 70 mg/m2 daily (not to exceed an actual daily dose of 70 mg) should be considered. 2 COMPARABLE MEDICINAL PRODUCTS 2.1. ATC Classification (2008) J: General anti-infectives for systemic use J02: Antimycotics for systemic use J02A: Antimycotics for systemic use J02AX: Other antimycotics for systemic use J02AX04: Caspofungin 2.2. Medicines in the same therapeutic category Antifungals in the echinocandin class. The indications of CANCIDAS are not entirely identical to those of other antifungals in the echinocandin class (ECALTA, MYCAMINE). Only CANCIDAS and MYCAMINE (micafungin) are indicated for paediatric use. CANCIDAS is the only antifungal in the echinocandin class which has marketing authorisation in paediatrics for the empirical treatment of presumed fungal infections (in particular involving Candida or Aspergillus) in children with febrile neutropenia and for the treatment of invasive aspergillosis. 3

4 Antifungals in the echinocandin class with marketing authorisation in paediatrics INN Micafungin IV form Proprietary product MYCAMINE 100 mg MYCAMINE 50 mg Indications "Adults, adolescents 16 years of age and elderly: - Treatment of invasive candidiasis. - Treatment of oesophageal candidiasis in patients for whom intravenous therapy is appropriate. - Prophylaxis of Candida infection in patients undergoing allogeneic haematopoietic stem cell transplantation or patients who are expected to have neutropenia (absolute neutrophil count < 500 cells/µl) for 10 or more days. Children (including neonates) and adolescents < 16 years of age: - Treatment of invasive candidiasis. - Prophylaxis of Candida infection in patients undergoing allogeneic haematopoietic stem cell transplantation or patients who are expected to have neutropenia (absolute neutrophil count < 500 cells/µl) for 10 or more days. The decision to use MYCAMINE should take into account a potential risk for the development of liver tumours (see section 4.4 of SPC). Mycamine should therefore only be used if other antifungals are not appropriate. " 2.3. Medicines with a similar therapeutic aim Treatment for invasive candidiasis - ABELCET (amphotericin B lipid complex) concentrate for suspension for IV infusion - AMBISOME (liposomal amphotericin B), powder for liposomal suspension for IV infusion - FUNGIZONE (amphotericin B), powder for solution for injection, capsules, oral solution - TRIFLUCAN (fluconazole), solution for infusion, capsules, powder for oral solution - VFEND (voriconazole), powder for solution for infusion, tablet, powder for oral solution (for children aged 2 and over) Treatment of invasive aspergillosis that is refractory to amphotericin B or in patients who are intolerant to this drug, to lipid formulations of amphotericin B and/or to itraconazole: - VFEND (voriconazole), powder for solution for infusion, tablet, powder for oral solution (for children aged 2 and over) Empirical therapy for presumed fungal infections (such as Candida or Aspergillus) in paediatric patients with febrile neutropenia. - AMBISOME (liposomal amphotericin B), powder for liposomal suspension for IV infusion 4

5 3 ANALYSIS OF AVAILABLE DATA Clinical development of CANCIDAS in the paediatric population has been based on: - 3 pharmacokinetic studies (protocols 033, 042 and 058) examining dosages for use in children; - 2 safety and efficacy studies (protocols 043 and 044), with similar methodology to those previously carried out in the adult population Efficacy in the paediatric population Invasive candidiasis and invasive aspergillosis (Study 043) The efficacy of caspofungin has been assessed in a prospective non-controllsed study (phase IIa) involving children aged between 6 months and 17 years, with documented candida infection or invasive aspergillosis. Forty-nine patients were included, and received CANCIDAS at a dose of 50 mg/m2 intravenously once daily, after a loading dose of 70 mg/m2 on day 1 (with maximum dose not exceeding 70 mg per day). Of the patients included, 10 had invasive aspergillosis, 38 had invasive candidiasis and 1 had oesophageal candidiasis. Efficacy results Results are broken down by type of invasive fungal infection. Invasive aspergillosis Of the 10 patients (aged between 3 to 16 years, mean age: 8.3 years) with invasive aspergillosis, there was pulmonary involvement in 6 cases. All patients had failed to respond to prior treatment. Only 3 patients were neutropenic on inclusion. The patients (9/10) were treated for a mean duration of 42.7 days (range: 8-87 days). The primary endpoint was global clinical response (complete or partial) at cessation of IV treatment: - complete response: disappearance of symptoms and signs on X-ray of aspergillosis; - partial response: clinically significant improvement in symptoms and signs on X-ray of aspergillosis. The proportion of patients experiencing a favourable clinical response at the end of caspofungin treatment is presented in Table 1. Table 1: Invasive aspergillosis - Global favourable response (ITT analysis) Caspofungin treatment (n/n) Complete response Partial response Total 3/10 2/10 5/10 Favourable response observed at the end of treatment was maintained during the post-treatment follow-up phase (14 days and 28 days after cessation of treatment). Invasive candidiasis The mean age of included patients was 7.9 years (range 6 months to 17 years). Efficacy analysis involved 37 patients with documented invasive candidiasis (1 patient was excluded, as the infection proved to be trichosporum). The majority of patients (84.2%) were nonneutropenic and had candidaemia (92.1%). Caspofungin was the first-line treatment in 81.6% of cases. The mean duration of treatment was 11.8 days (range: 2-42 days). Twenty-eight patients (73.7%) were treated for more than 14 days. 5

6 The primary endpoint was global clinical response (complete or partial) and microbiological response at cessation of IV treatment: - complete response: disappearance of symptoms and signs on X-ray of candidiasis; - partial response: clinically significant improvement in symptoms and signs on X-ray of candidiasis; - favourable microbiological response: eradication (or presumed eradication) of Candida strains. For patients with candidaemia, eradication had to be documented with negative culture over at least 48 hours. The percentage of patients experiencing a favourable clinical response at the end of treatment is presented in Table 2. Table 2: global clinical response in invasive candidiasis - (mitt analysis) Caspofungin treatment, n/n (%) [95% CI] Complete response Partial response Total 30/37 (81.1) [ ] 0/37 (0) - 30/37 (81.1) [ ] Favourable microbiological response was observed in 86.5% (95% CI: ) of patients. Of the 28 children included in the 28-day post-treatment follow-up phase (to evaluate disease recurrence), just one case of disease recurrence was observed. Empirical treatment of presumed fungal infections in febrile neutropenic children (protocol 044). Efficacy was assessed in a phase IIb study comparing the safety and efficacy of caspofungin with liposomal amphotericin B (AMBISOME) in patients aged between 2 and 17 years who were febrile and neutropenic. Population On inclusion, the patients (N=82) had received chemotherapy for a malignant condition (leukaemia, lymphoma or other condition) or had undergone transplantation of peripheral blood stem cells, were neutropenic (ANC < 500/mm3 for at least 96 hours) and feverish (> 38.0 over the 24 hours prior to randomisation) and had to have failed to respond to parenteral antibiotic therapy started at least 96 hours previously. Treatments Patients were randomised (2:1 ratio) to receive the following as double-blind, double placebo treatments: - CANCIDAS (N=56 patients): 50 mg/m2 intravenously once daily, after a loading dose of 70 mg/m2 on day 1 (with maximum dose not exceeding 70 mg per day). - or liposomal amphotericin B (N=26 patients): 3 mg/kg per day intravenously. Randomisation was stratified according to the degree of risk of fungal infection: high risk (recurrence of acute leukaemia, allogeneic transplantation of peripheral blood stem cells) or low risk, and by presence of antifungal prophylaxis. In cases of persistent fever (at least 5 days) with deterioration of the child's clinical condition, dosage could be increased to 70 mg/m2 caspofungin and 5 mg/kg liposomal amphotericin B. The treatment was continued until 72 hours after resolution of neutropenia (ANC at least 500/mm3) for a maximum duration of 28 days. In patients with documented fungal infection, treatment was continued for at least 7 days after resolution of neutropenia and symptoms (minimum 14 days, maximum 90 days). 6

7 Efficacy evaluation criterion The efficacy criterion was percentage overall favourable response, defined using a composite endpoint: - absence of a breakthrough fungal infection up to 7 days post-therapy; - survival to 7 days post-therapy; - absence of therapy discontinuation due to lack of efficacy or drug toxicity; - resolution of fever for at least 48 hours during the period of neutropenia; - successful treatment of the baseline invasive fungal infection. Results Mean age of patients included was 7.4 years (median 6 years, range 2-16 years). The most common underlying pathologies (62.1%) were acute myelogenous leukaemia (AML) and acute lymphoblastic leukaemia (ALL). The majority of patients (73.2%) were considered to have a low risk of infection. The proportion of patients who had received transplantation of peripheral blood stem cells was low (11%, n=9) and was similar in both treatment arms (6 patients in the CANCIDAS arm versus 3 in the amphotericin B arm). Around 50% of patients had received antifungal prophylaxis during the days prior to inclusion. The mean duration of treatment was 11.8 days (range: 2-87 days). The modified intention-to-treat analysis (mitt)2 involved 81 patients of the 82 who were randomised. Table 3: Proportion of patients with favourable overall response, risk-adjusted (mitt population) Favourable overall response n/n (%)* [95% CI] * analysis adjusted for risk Caspofungin 70/50 mg/m 2 26/56 (46.6) [ ] AmBisome 3.0 mg/kg 8/25 (32.2) [ ] 3.2. Adverse effects The safety data for use of caspofungin in children and adolescents are based on data from 5 clinical development studies (3 pharmacokinetic studies: 033, 042, 058; and the 2 clinical studies, 043 and 044), in which 171 patients received one or more doses of CANCIDAS: 104 patients had febrile neutropenia, 56 had invasive candidiasis, 1 had oesophageal candidiasis and 10 had invasive aspergillosis. Overall safety profile of CANCIDAS in children is comparable to that observed in adults. The incidence of adverse events was 92% (157/171). The incidence of adverse events which were considered to be linked to treatment was 26% (45/171). The most commonly reported adverse effects were fever (12%, 20/171), rash (5%, 8/171) and headache (3%, 5/171). For just one patient, a serious adverse event was reported (hypotension). This was linked to treatment, and led to premature cessation of treatment. Clinical experience (see SPC) Conclusion In children, the efficacy of caspofungin has been assessed using two phase II studies involving a limited number of patients aged between 6 months and 17 years. Favourable clinical response was observed in the following situations: refractory invasive aspergillosis (study 043): 5/10 patients, after a mean duration of treatment of 42.7 days (range 8-87 days); 2 mitt: patients who received at least one dose of the therapy 7

8 invasive candidiasis (study 043): 30/37 patients (81%), after a mean duration of treatment of 11.8 days (range 2-42 days); febrile neutropenia that had failed to respond to parenteral antibiotic therapy (study 044): 26/56 patients (46.6%) 3 treated with caspofungin (versus 8/25 patients treated with liposomal amphotericin B), after a mean duration of treatment of 11.8 days (range 2-87 days). It should be noted that the percentage of patients included who were considered to be at a high risk of fungal infection was low. Overall, these results suggest that efficacy is similar to that observed in the adult population. These limited data give no reason to suppose that the efficacy of caspofungin is higher than that of the available therapeutic alternatives. Clinical experience with caspofungin in children has not resulted in any major safety concerns regarding use of this antifungal agent. 3 Percentage response adjusted for risk 8

9 4 TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Candidiasis and invasive aspergillosis occur in children whose serious clinical condition can be life-threatening. Empirical antifungal treatment is given to patients who are neutropenic (ANC < 500/mm 3 ) and who have a serious underlying pathology. Infection in this patient group can be highly complicated and can be life-threatening. These proprietary products come within the scope of curative treatment. The efficacy/adverse effects ratio for these products is high. There are alternative products for children, but only very few. Public health benefit In children, invasive candidiasis, invasive aspergillosis and presumed fungal infection in febrile neutropenia are serious clinical situations that can be life-threatening, but they represent a minor public health burden given the limited number of children affected. Improving the treatment of these infections, and in particular those that are resistant to existing treatments and those that are very severe, is a significant therapeutic need, which for children is a public health need that falls into the category of defined public health priorities (to make suitable drugs available to paediatric practice). Although clinical trials data are very limited (phase II studies involving very limited numbers), the good safety profile of CANCIDAS and the very limited number of treatment alternatives for children mean that it can be expected to have a slight additional impact in terms of morbidity and mortality. The proprietary product CANCIDAS should therefore provide an additional response to an identified need. As a result, CANCIDAS is expected to have a public health benefit in these indications in children. This benefit is low. The actual benefit of these medicinal products is substantial Improvement in actual benefit Given the available data and the limited number of treatment alternatives that have marketing authorisation for the paediatric population, CANCIDAS provides a moderate improvement in actual benefit (IAB III) in children in terms of efficacy and safety in the therapeutic management of candidiasis, invasive candidiasis and in empirical treatment of presumed fungal infections (particularly involving Candida or Aspergillus) in children with febrile neutropenia. 9

10 4.3. Therapeutic use Systemic candidiasis The treatment of invasive candidiasis in children and newborns often requires fluconazole and amphotericin B, in the absence of specific guidelines, and these can be used in patients of any age. In newborns, fluconazole is still the first-line treatment because of its pharmacokinetic properties (oral bioavailability and excellent diffusion in tissue), its safety profile, which is better than that of amphotericin B, and its efficacy in the eradication of the most common fungi (C. albicans, parapsilosis and tropicalis). Amphotericin B or its liposomal derivatives, in combination with 5- flucytosine, are alternatives. The morbidity associated with this treatment is significant: nephrotoxicity, bone marrow suppression, hepatotoxicicy, poor digestive tolerance, fever with chills (with the latter being less common in children than in adults). In children, fluconazole is a first-line treatment for invasive infections when the isolated strain is sensitive to fluconazole. It is continued for 2 weeks following the last positive blood culture, and the switch to oral treatment is made as soon as this becomes possible. Before the Candida species is identified, fluconazole cannot be used as a first-line treatment except if the child is not neutropenic and has not previously received fluconazole. If this is not the case, amphotericin B or its liposomal derivaties remain the first-line treatment. Only liposomal amphotericin B has marketing authorisation for paediatric use, if there is renal insufficiency that is pre-existing or secondary to amphotericin B. The role of voriconazole, which is indicated in children over 2, is not clearly defined, and pharmacokinetic data are still limited. Micafungin is a last-resort treatment4 in children, regardless of age (see SPC). Caspofungin has a satisfactory safety/efficacy profile in this indication, for which there are few alternative treatments in paediatric practice. It is a useful alternative to amphotericin B, in particularly for treatment of strains that are resistant to fluconazole (C. glabrata or C. krusei). Invasive aspergillosis Voriconazole 5 is currently the gold-standard treatment for invasive aspergillosis. Clinical studies have shown the efficacy of voriconazole against disseminated forms of aspergillosis and its superiority versus amphotericin B in terms of favourable response and survival at 3 months. The fact that an oral form exists means that treatment can last as long as necessary (sometimes several months). Amphotericin B (or its liposomal derivatives) and itraconazole are alternatives. Caspofungin can be used to treat refractory aspergillosis after 7 days of treatment and if first-line antifungals are poorly tolerated. However, current data do not enable a comparison to be made with voriconazole. Empirical treatment of presumed fungal infections in patients with febrile neutropenia In the absence of microbiological documentation, the guidelines state that empirical antifungal treatment should be started in neutropenic patients (ANC <500/mm3) with persistent fever despite broad-spectrum antibiotic therapy, as soon as second-line treatment fails. This treatment should cover a broad spectrum of fungi and should have the lowest possible level of toxicity. Caspofungin has a satisfactory efficacy/safety profile and is a useful alternative to liposomal amphotericin B (AMBISOME). 4 Given concerns about safety (hepatic and renal toxicity), and in accordance with the wording of the marketing authorisation, micafungin must only be used if other antifungals are not appropriate. 5 Safety and efficacy have not been established in children aged under 2 years. As a result, voriconazole is not recommended in children under two (see SPC). 10

11 4.4. Target Population Treatment for invasive candidiasis: The target population for CANCIDAS corresponds to adult and paediatric patients with candidaemia or invasive candidiasis. The incidence of candidaemia can be evaluated at between 0.20 and 0.29 cases per 1000 hospital admissions 6,.7. The number of stays greater than 24 hours in medical, surgical and obstetric wards in 2006, in private and public hospitals in France, was 10,238,0008. If these two parameters are multiplied, and estimate of the annual number of cases of candidaemia is obtained, and is of the order of Proportion of children within the total target population is difficult to estimate. Considering the following hypotheses: - in children, cases of candidaemia are primarily reported in intensive care units and neonatology, and around 38% of cases occur in premature births9, - the incidence of invasive Candida infections in newborns varies from 1% in newborns weighing between 1001 and 1500 g to 4-12% in newborns weighing less than 1000 g10. - according to PMSI data from 2004, 5702 children were hospitalised with birth weight of between 1000 and 1499 g (GHM 15Z08A, 15Z08E) and 2421 with birth weight of less than 1000 g (GHM 15Z09A and 15Z09E). The target population of patients of paediatric age could be estimated to be approximately patients per year. Treatment of invasive aspergillosis in children who are refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B and/or itraconazole: The target population for CANCIDAS corresponds to adult and paediatric patients with invasive aspergillosis that is refractory to first-line treatments. The incidence of invasive aspergillosis is estimated at per 1000 hospital admissions (in France) 11, or approximately 2300 patients. Proportion of children within the total target population is difficult to estimate. Considering the following hypotheses: - invasive aspergillosis primarily occurs in patients who are immunosuppressed (on steroid therapy, with severe and prolonged neutropenia), and populations who are most often affected by aspergillosis are patients with malignant blood conditions, and in particular those requiring allogeneic haematopoietic stem cell transplantation. - in 2007, 1351 patients received 1379 transplants of allogeneic haematopoietic stem cells (bone marrow, peripheral blood or cord blood). The two main indications are still acute myelogenous leukaemia and acute lymphoblastic leukaemia. The paediatric population (aged < 18 years) receives 21.1% of these allogeneic transplantations12 (290 transplantations). 6 Tortorano A.M, Peman J, Bernhardt H, Klingspor L, Kibbler C.C, Faure O, Biraghi E, Canton E, Zimmermann K, Seaton S, Grillot R. The ECMM Working Group on Candidaemia, Epidemiology of candidaemia in Europe: results of 28-Month European Confederation of Medical Mycology (ECMM) Hospital-Based Surveillance Study, Eur J Microbiol Infect Dis, 2004, 23: Richet H, Roux P, Des Champs C, Esnault Y. Candidemia in French Hospitals : incidence rates and characteristics, Clin Microbiol Infect, 2002, 8: DREES. L activité des établissements de santé en 2006 en hospitalisation complète et partielle [Activity of healthcare establishments in 2004: full and partial admissions]. No. 618, December Available at (consulted on 03/11/2008). 9 Dardé M.L., Infections fongiques: épidémiologie et problématique [Fungal infections: epidemiology and issues]. Communication available at: (in French - consulted on 27 July 2009) 10 Brian Smith P., Steinbach WJ, Benjamin DK. Neonatal candidiasis. Infec Dis Clin N Am 2005; 19: Pouteil-Noble C.: Infections fongiques en transplantation rénale [Fungal infection in renal transplantation]. Communication available at: (in French - consulted 27 July 2009) 12 Agence de la biomédecine [Biomedicines Agency]: Bilan des activités de prélèvement et de greffe en France en 2007 [Summary of harvesting and transplantation activities in France in 2007]. Available at (In French - consulted 27 July 2009) 11

12 - the incidence of invasive aspergillosis in patients who have undergone allogeneic transplantation of haematopoietic stem cells is estimated to be between 11-15%, or patients per year; - Allografts are the underlying condition in 25% of patients with aspergillosis13. The target population of patients of paediatric age could be estimated to be approximately patients per year. It should be noted that CANCIDAS, in this indication, is a last-resort treatment for patients in whom there are no other options. The target population for CANCIDAS in this indication in children is therefore likely to be very small. Empirical therapy for presumed fungal infections (such as Candida or Aspergillus) in febrile, neutropaenic children: Epidemiological data concerning the number of cases of presumed fungal infections in neutropenic children requiring "empirical" treatment are not available. It is estimated that children 14 are treated each year in Franceh for a solid tumour or for leukaemia, and that a large number of these present at least one episode of febrile aplasia requiring presumptive treatment for infection (Expert opinion). Initiation of empirical antifungal treatment is only justified in neutropenic patients (ANC < 500/mm3) with persistent fever despite treatment with broad-spectrum antibiotics. We do not have access to data that enable us to estimate the number of such patients. This number is probably very limited. According to a study concerning systemic treatment for fungal infection involving yeasts or filamentous fungi 15, antifungals are prescribed empirically in 36% of cases and as curative treatment in 42% of cases. Overall, the target population for CANCIDAS of patients of paediatric age will be very limited, in the context of the overall target population Transparency Committee recommendations The Transparency Committee recommends inclusion on the list of medicines approved for use by hospitals and various public services in the extension of indication. 13 Lortholary O. Infection fongiques systémiques et immunodépression [Systemic fungal infections and immunosuppression]. Communication available at: DESCMIT0504.pdf. (in French - consulted 27 July 2009) 14 Poirée M., Sirvent N. Cancers de l enfant : particularités épidémiologiques, diagnostiques et thérapeutiques [Childhood cancers: epidemiological, diagnostic and therapeutic features] (144)) In POLYCOPIE NATIONAL DE CANCEROLOGIE. February 2006 (updated February 2006) : (consulted on 27/07/2009) 15 Challier S., Corriol O, Segard D., Singlas E., Berche P., Poisson-Salomon A.-S. et al. Traitement par voie systémique des infections fongiques à l'hôpital Necker-Enfants Malades [Systemic treatment of fungal infections at Necker Children's Hospital]. Journal de Mycologie Médicale [Journal of Medical Mycology] Vol 13, N 1 - March 2003 pp Avail able at (consulted on 27 July 2009). 12