The legally binding text is the original French version

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1 The legally binding text is the original French version TRANSPARENCY COMMITTEE Opinion 28 March 2007 FACTANE 100 I.U. /ml, powder and solvent for solution for injection Box of ml vial (CIP: ) Box of 1 5 ml vial (CIP: ) Box of 1 10 ml vial (CIP: ) Applicant : LFB BIOMEDICAMENTS Human Coagulation Factor VIII List I Medicine for initial hospital prescription of six months (including blood transfusion organisations authorised to dispense medicinal products derived from the blood of patients treated). Issuance is restricted to pharmacies of healthcare organisations or blood transfusion organisations for patients treated therein. Date of Marketing Authorisation: 30 December, 1994 Revision (extension of indication): 4 July, 2006 Reason for request: Inclusion on the list of medicines for use by hospitals in the extension of indication: Human coagulation factor VIII is indicated for the treatment of inhibitors by immune tolerance induction (ITI). Health Technology Assessment Division 1

2 1. CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Human Coagulation Factor VIII 1.2. Indications Human coagulation factor VIII is indicated for the treatment and prevention of haemorrhagic episodes and during surgery due to factor VIII deficiency (haemophilia A) in previously treated or untreated patients, without any inhibitors against factor VIII. Treatment may be continued in patients who develop factor VIII inhibitors (neutralising antibodies) at levels less than 5 Bethesda units (BU) if clinical response persists and circulating factor VIII levels increase. Human coagulation factor VIII is indicated for the treatment of inhibitors by immune tolerance induction. FACTANE does not contain von Willebrand factor in effective quantities and is therefore not indicated in von Willebrand disease Dosage (see SPC) Treatment of inhibitors by immune tolerance induction (ITI) Immune tolerance treatment should be initiated and conducted by a centre with experience in the treatment of patients with haemophilia A. Table 1 Immune tolerance induction (ITI) Initiation Levels 0.6 to 5 BU Levels > 5 BU DOSES* 50 IU/kg/day 3 times per week to 100 IU/kg/day every day IU/kg/day 3 times per week to 100 to 300 IU/kg/day every day Administration procedures ITI should be initiated as soon as possible After disappearance of the inhibitors, resumption of normal recovery and half-life 100 IU/kg/day then 50 IU/kg/day then 50 IU/kg every other day then prophylactic treatment (* indicative treatment to be adapted according to biological controls) in monthly increments 3 times per week for at least 1 year Clinical data obtained during retrospective studies in 6 patients demonstrated that inhibitors had completely disappeared under immune tolerance induction in 5 of them after several years of follow-up and had partially disappeared in the sixth patient. 2

3 2. SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification 2006 B: BLOOD AND BLOOD FORMING ORGANS B02: ANTIHAEMORRHAGICS B02B: VITAMIN K AND OTHER HAEMOSTATICS B02BD: BLOOD COAGULATION FACTORS B02BD02: HUMAN COAGULATION FACTOR VIII 2.2. Medicines in the same therapeutic category Plasma-derived factor VIII: Recombinant Factor VIII: OCTANATE, MONOCLATE P, HEMOFIL-M (no longer marketed). HELIXATE NEXGEN KOGENATE BAYER RECOMBINATE REFACTO ADVATE None of these medicinal products has the indication treatment of inhibitors by immune tolerance induction Medicines with a similar therapeutic aim These are activated factors of prothrombin complex used in patients with anti-factor VIII inhibitors: FEIBA, NOVOSEVEN. 3. ANALYSIS OF AVAILABLE DATA The laboratory submitted 2 studies to support its request as well as a paper published by Orsini et al and a speech given at the annual convention of the French Haematology Society in Efficacy results Retrospective study LFB 1 : A retrospective, non-comparative study analysing the medical reports of children with severe haemophilia A (FVIII <1%), treated for the first time with very-high purity FVIII (FVIII-VHP) between 1988 and The files of 104 severely haemophiliac children (FVIII <1%) were studied. 1 Goudemand J, Rothschild C, Calvez T, Bridey F. A low incidence of high responder inhibitors for the treatment of severe previously untreated patients (PUPs) with haemophilia A with plasma-derived factor VIII product stabilised with von Willebrand factor. Hemophilia. 2004; 10(3): 02P023 (abstract). 3

4 Primary objective: To evaluate the incidence of FVIII inhibitors during FVIII-VHP treatment, in children with severe haemophilia A, previously untreated (naive). Secondary objectives: To investigate the influence of risk factors on this incidence (individual factors, replacement therapy methods); To analyse the inhibitor s progression, and particularly the efficacy of the immune tolerance induction (ITI) treatment using FVIII-VHP in patients with inhibitors. Success criteria for ITI therapy were the following: eradication of the inhibitor validated through inhibitor level <0.6 BU with normal FVIII recovery rate ( 66%) and/or half-life ( 6 hours). Principal inclusion criteria: Children with severe haemophilia A (FVIII <1%), FVIII naive Children whose first replacement therapy was FVIII-VHP during the period from June 1988 to February Endpoints: Percentage of patients developing anti-fviii inhibitor antibodies (level > 0.6 BU) during the course of FVIII-VHP treatment and percentage of strong responder patients ( 5 BU and 10 BU). The period taken into consideration to observe the incidence of inhibitor onset was until development of an inhibitor, or for those not having developed any, until discontinuation of the FVIII-VHP therapy. Results: Principal endpoint Of the 104 children (103 of which were less than 6 years of age), 15 (14.4%) developed an inhibitor after an average of 12 cumulative days of treatment. Of these 15 children: 5 did not modify their treatment regimen (on-demand treatment) and the inhibitors (all of low level <5 BU) spontaneously resolved; 1 died due to the inefficiency of the FVIII treatment; 2 are no longer under FVIII treatment but may potentially return to the activated fractions; 7 received ITI therapy. Secondary endpoint: For one strong responder patient, tolerance induction was partial; in 6 others (3 strong responders and 3 weak responders), the inhibitor disappeared following ITI treatment. 4

5 Post-Marketing Authorisation 2 study (2005 interim report) This safety and efficacy study involved the following coagulation fractions: FACTANE (FVIII), BETAFACT (FIX), WILFACTIN / WILSTART (von Willebrand factor). It began on 20 July Only the results of the first interim analysis (May 2005) are available. The end of the study is scheduled for the 3 rd trimester of To this day, only 4 patients with a constitutional FVIII deficiency and treated with FACTANE have been analysed. ITI treatment was initiated with FACTANE either as a first-line treatment (n=2), or as second-line treatment following failure of recombinant FVIII treatment (n=2). Primary objective: Describe, in particular, the immunological safety of FACTANE based on inhibitor levels and FVIII recovery rates. One of the secondary endpoints is the clinical evaluation of efficacy of FACTANE for immune tolerance induction (ITI) therapy, based on biological evidence (inhibitor level (<0.6 BU), normal recovery rate/half-life of injected FVIII). Table 2: Results: Patients (n = 4) Strong responders (n = 4) Dosage at ITI initiation >100 IU/kg/day (strong dose) ITI Type 1 st line (n = 2) 2 nd line (n = 2) Results - 1 ITI successfully terminated - 1 ITI underway inhibitor - 2 ITI underway inhibitor In 3 out of 4 patients, a decreased inhibitor level was observed, however, these patients can not yet be evaluated as the ITI treatment is still underway. Orsini et al. 3 study This study provides additional retrospective data from 8 other strong responder patients. Seven patients were treated with non-nanofiltered FVIII and 1 patient with FACTANE. Three of these patients are included in the LFB retrospective study. Response to treatment was complete for 5 strong responder patients, obtaining a normal recovery rate ( 66% of theoretical recovery) and/or normal half-life ( 6 hours) and on undetectable inhibitor level (<0.6 BU) Adverse effects In the retrospective study, only data for serious adverse effects leading to death or onset of inhibitors were collected. Three deaths (1 due to septic shock and 2 due to cerebral haemorrhage) and 15 incidences of inhibitor onset were reported. In the post-marketing Authorisation study, no adverse effects were reported in the subpopulation of patients treated with ITI therapy (n=4). 2 Goudemand J, Calvez T, Rothschild C, Négrier C, Grevin JM, Moan AC, Bridey F, Tellier Z et le groupe d'étude FACTEUR VIII-LFB. Etude rétrospective de l'incidence des inhibiteurs "forts répondeurs" du facteur VIII dans l'hémophilie sévère traitée exclusivement par un facteur VIII d'origine plasmatique. Hématologie. 2005; 11 (n hors série): Orsini F, Rothschild C, Beurrier P, et al. Immune tolerance induction with highly purified plasma-derived factor VIII containing von Willebrand factor in haemophilia A patients with high-responding inhibitors Haematologica/J Hematol 2005; 90(9):

6 3.3. Conclusion Data from the post-marketing Authorisation are very preliminary as only 17 patients were analysed, 4 of which corresponded to an attempt of immune tolerance induction as 1 st line treatment (2 adults) or as 2 nd line treatment (1 adult and 1 child). The LFB retrospective study, which included 104 patients with severe haemophilia A (<1%) treated with LFB FVIII (non-nanofiltered version), documents the efficacy of inhibitor treatment with the product as ITI therapy (successful in 5 of 6 patients). The results of this retrospective study are corroborated by those of the Orsini et al study, which observed the success of non-nanofiltered FVIII as ITI treatment in 4 other patients and of FACTANE in another, i.e., 5/8 strong responder patients. As FACTANE is produced following an additional stage of viral reduction through nanofiltration to the manufacturing process of FVIII-VHP, the Committee emphasizes that the slight difference between non-nanofiltered FVIII and FACTANE leads to the conclusion that the data obtained with the non-nanofiltered product could be extrapolated. Nevertheless, the studies presented have a very low level of evidence: a small number of patients included and the retrospective character of 2 of these studies. 4. TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Haemophilia A is a rare and life-threatening disease. FACTANE is intended as curative treatment. The efficacy/adverse effect ratio for this medicinal product is high. This is a first-line treatment in FACTANE induced immune tolerance. There are medicinal alternatives. Public health interest Despite the severity of haemophilia A, the burden of this rare disease is low. Improving management of haemophilia is a necessity falling within the scope of an identified public health priority (GTNDO* and National Plan for Rare Diseases). For patients developing factor VIII inhibitors, the available data do not permit estimation of the impact of FACTANE on morbidity/mortality compared to that of the other existing treatments (in particular NOVOSEVEN and FEIBA). In light of the available information, it is not possible to confidently predict that FACTANE will provide an additional benefit for the identified public health requirement. Consequently, given the current state of knowledge and the other available therapies, it is not expected that the medicinal product FACTANE will have any public health benefit. The actual benefit of FACTANE provided in this indication is substantial. * National Technical Objective Definition Group (DGS-2003) 6

7 4.2. Improvement in actual benefit This medicinal product confirms its place in therapeutic use and represents a useful therapeutic method for ITI treatment in patients developing inhibitors following FACTANE treatment Therapeutic use Haemophilia A is a sex-linked recessive inherited disease, resulting in a more or less severe factor VIII (FVIII) deficiency. Treatment is based on the intake of exogenous plasma-derived or recombinant FVIII concentrate. Onset of anti-fviii antibodies is a complication of haemophilia treatment. These antibodies, commonly known as inhibitors, are antibodies that appear in certain haemophilia A patients in response to FVIII treatment and which neutralise its coagulation action. According to the SPC, human coagulation factor VIII may remain effective in patients who develop, during the course of treatment, a factor VIII inhibitor (neutralising antibody) of low level, less than 5 Bethesda units (BU). Monitoring the factor VIII plasma level ensures that the replacement treatment undertaken is appropriate. The inhibitor level must be measured in order to verify the absence of anamnestic response. In patients with a high inhibitor level, greater than 5 BU, high doses of human coagulation factor VIII may be necessary in order to control severe haemorrhage. In certain cases, in light of the high doses necessary to maintain sufficient factor VIII plasma levels, treatment instauration may be difficult. If haemostasis cannot be obtained with human coagulation factor VIII in the presence of a high inhibitor level, the use of an activated prothrombin complex or an activated factor VIII concentrate may be considered. Such treatments must be administered by physicians with experience in treating patients with haemophilia A. Per the Afssaps recommendations of May , all types of FVIII concentrates are susceptible to successfully induce immune tolerance. However, ITI therapy should preferably be initiated with the FVIII concentrate selected to treat the patient and under which said patient developed the inhibitor (Grade 2C) Target population In France the incidence of haemophilia is approximately 1 in 10,000 births, or 1 in 5,000 male births 5. The prevalence of haemophilia is estimated at approximately 5,000 patients, of which approximately 80% present haemophilia A, i.e., approximately 4,000 patients. In France, according to the FranceCoag 6 cohort, the prevalence of inhibitors is estimated at 6%. This indicates that approximately 200 patients have inhibitors. 4 Afssaps. Développement d inhibiteurs et prise en charge chez les patients hémophiles traités par facteur VIII ou IX d origine plasmatique ou recombinante. 15 mai Sultan Y. L hémophile A et B. Encyclopédie Orphanet Accessible at 6 Institut de veille sanitaire. Réseau France Coag. Accessible at 7

8 According to specialist opinion, not all these patients would benefit from FACTANE ITI treatment, in particular: - Paediatric and adult patients with little bleeding: on-demand treatment with activated fractions - Children and families for whom observance of ITI protocol, an intensive dose or activated fraction prophylactic treatment is not envisaged. - Children who have received only recombinant factor VIII until onset of the inhibitor and in whom it is logical to initiate a recombinant ITI treatment. - Patients having developed inhibitors under a FVIII other than FACTANE, as it is recommended that ITI treatment be initiated with the same FVIII concentrate selected to treat the patient and under which the patient developed the inhibitor Transparency Committee recommendations The Transparency Committee recommends inclusion on the list of medicines approved for use by hospitals and various public services in the indication Human coagulation factor VIII is indicated for the treatment of inhibitors by immune tolerance induction (ITI). 8