Public Assessment Report

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1 Public Assessment Report Scientific discussion Cluvot 250/1250 IU Human Coagulation Factor XIII DE/H/1942/ /DC This module reflects the scientific discussion for the approval of Cluvot. The procedure was finalised at For information on changes after this date please refer to the module Update.

2 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the following Member States have granted a marketing authorisation for Cluvot 250/1250 IU, from CSL Behring GmbH: BE, BG, CZ, DE, DK, EL, ES, FI, HU, IT, MT, NL, NO, PL, PT, RO, SE and SK. Cluvot is indicated for adult and paediatric patients for prophylactic treatment of congenital FXIII deficiency and for peri operative management of surgical bleeding with congenital FXIII deficiency. A comprehensive description of the indications and posology is given in the SmPC. The marketing authorisation has been granted pursuant to Article 8(3) of Directive 2001/83/EC. As confirmed on April 20 in 2012 by the RMS Paul Ehrlich Institute (Germany), CSL Behring applies for a new marketing authorisation within a European decentralized procedure according to current effective Directive 2001/83/EC Art. 28 (3) for the plasma derived Human coagulation Factor XIII Concentrate with the intention to subsequently license the product with the proposed trade name Cluvot in Germany and further 17 European countries Congenital FXIII deficiency is a rare inherited bleeding disorder with an estimated 600 diagnosed patients worldwide and an incidence rate of one case per 1 3 million people. People of all races may be affected and history of consanguinity plays a role in certain families. The disease may be caused by a defect in the A or B subunit. The majority of mutations refer to quantitative or qualitative Subunit A deficiencies (Type 2 defects). <5% of reported cases contribute to FXIII B genes mutations (Type 1 defects). Homogenous FXIII A deficiencies are usually associated with severe and lifelong bleeding diathesis and plasma FXIII levels of <1%; heterocygote subjects can have reduced levels of FXIII A and FXIII B and will usually be clinically asymptomatic. The disease presents with umbilical bleeding of the neonate in about 80% of cases. Incidence of intracranial bleeding is about 30% accounting for high fatal threat of the concerned subjects. Delayed subcutaneous and soft tissue bruising, mucosal bleeding and other sites have been reported. Poor wound healing has been associated with the disease. Recurrent miscarriages is a common complication in FXIII deficient women. Acquired FXIII deficiency has been associated with systemic lupus erythematosus, leukaemias, severe liver disease, disseminated intravascular coagulation and inflammatory bowel disease. Normal range of FXIII activity is 53.2% 221.3%. Quantitative FXIII analysis still is challenging. Cluvot 250/1250 PAR Scientific discussion 2/14

3 Treatment options for FXIII deficiency include fresh frozen plasma (FFP) and cryoprecipitate but have subsequently changed to pasteurised plasma derived FXIII concentrates and recombinant FXIII concentrate (Subunit A homodimer). On demand treatment, prophylaxis strategy, replacement therapy in surgery, and prophylaxis in pregnancy are established therapeutic approaches. Due to the long endogenous half life of 5 to 11 days, therapeutic intervals for prophylaxis are 4 6 weeks. Prognosis of even the severe phenotype with lifelong risk of bleeding is excellent because of the good response to substitution and low incidence of severe complications as inhibitordevelopment. The current product is a purified, pasteurized, FXIII concentrate derived from human plasma. Factor XIII (FXIII) is the last enzyme in the clotting cascade. Its main function is to convert the loose fibrin polymer into a firm, highly organized, cross linked structure with increased tensible strength, firmly anchored to the site of the wound and possessing an in built resistance to fibrinolysis. FXIII is essential contributor to thrombus stabilization by catalysing the cross linking of fibrin and has therefore been named as fibrin stabilizing factor within the coagulation cascade. In addition, intracellular action contributes to tissue remodelling and repair. Furthermore, production of FXIII A2 in the placenta points to its important role in maintaining the integrity of placental attachment in the uterus. User consultation The patient leaflet for Cluvot has been user tested and achieved a satisfactory result considering the predefined success criteria. 99.6% of the information of the PIL was found and 100% of the information was understood by all participants. With regard to the results of the three testing rounds of readability testing concerning the ease or difficulty to find information, the comprehensibility of the PIL and the subjective impression, the performed readability test can be found approvable. II. QUALITY ASPECTS II.1 Introduction Cluvot is presented as a white lyophilised powder and solvent for infusion in two strengths (250 IU FXIII and 1250 IU FXIII). Both presentations consist of one vial with the lyophilised drug product and one vial with diluent (Sterilized Water for Injections) as well as a filter transfer device which allows the transfer of the diluent into the product vial. Container closure system of Cluvot consists of a glass vial and a rubber stopper sealed with a combination crimp cap. FXIII Concentrate (Human) belongs to the group of antihemorrhagics (ATC code: B02BD07). Cluvot 250/1250 PAR Scientific discussion 3/14

4 II Drug Substance Active Ingredient Active ingredient of Cluvot Factor XIII Concentrate is human coagulation factor XIII (FXIII) isolated from human plasma for fractionation and purified to receive the sterilized final bulk (drug substance). Beside the pasteurisation step, a second virus reduction step is incorporated in the production process of F XIII Concentrate (Human), to improve the virus safety profile of the product with regard to heat resistant, non enveloped viruses. The same active ingredient is contained in Fibrogammin, licensed in Germany since 1993 (plasma derived) and in four other EU states as well. Nomenclature Neither an international nonproprietary name for Factor XIII nor a monograph in a pharmacopoeia is available. Throughout the dossier, Fibrogammin is used as synonym for FXIII Concentrate (Human) due to the fact that most of the investigations, being applicable for FXIII final bulk, were performed using Fibrogammin. Manufacture Factor XIII final bulk is manufactured at CSL Behring GmbH (Emil von Behring Str. 76, Marburg, Germany), a manufacturing site for which GMP compliance has been documented. Manufacture of Factor XIII final bulk comprises four subsequent production procedures: 1) Fractionation of human plasma to cryodepleted plasma. 2) Adsorption of plasma protein components onto Ion exchange chromatography. 3) Ethanol precipitation process according to Cohn. 4) Dissolving, adsorption onto ion exchangers, elution, pasteurisation, virus filtration and purification of Factor XIII; formulation and sterilizing filtration of the final bulk solution Control of Materials Factor XIII Concentrate (Human) is produced from human plasma for fractionation which is collected, tested, stored and transported as described in the annually reviewed Plasma Master File of the MAA CSL Behring (EMA/H/PMF/000001/04/AU/012/G). Raw materials (ingredients and auxiliary materials) are of Ph Eur quality or in case a reference to a monograph is missing, an internal specification has been defined. The quality of the raw materials is considered adequate for the intended use. Control of Critical Process Steps During risk analyses, process control parameters (PCP) with a direct influence on a critical product quality attribute (PQA) have been identified and ranges or target values for these critical parameters specified, providing a basis for validation of the production process of FXIII final bulk. Cluvot 250/1250 PAR Scientific discussion 4/14

5 Control of Intermediates In process testing (IPT) is performed to control the quality of intermediates of the production process. Target ranges have been defined for the parameters tested. Analytical procedures performed for in process testing during manufacture of FXIII final bulk have been validated based on current ICH guidelines and are suitable for their intended use. Based on the data reviewed, the production process for FXIII final Bulk is considered as adequately controlled. Process validation Process evaluation encompasses risk assessments, full scale and down scale validation studies, investigation studies as well as down scale evaluation of ranges. Based on the results of validation studies, production process of Cluvot is regarded to be capable of consistently producing final drug product meeting predefined product quality attributes. II.3 Medicinal Product Description Factor XIII Concentrate (Human) is a plasma derived, purified, pasteurised, virus filtrated and lyophilised concentrate of human coagulation factor XIII provided in two strengths with the proposed trade name Cluvot (250 IU and 1250 IU). The measured factor XIII activity is not less than 50 IU/mL and not more than 80 IU/mL in the reconstituted product. Human albumin, glucose, sodium chloride and sodium hydroxide serve as excipients. The preparation is sterile and pyrogen free. The presentation consists of one vial with the lyophilised drug product, one vial with a diluent (sterile WFI) for reconstitution as well as a filter transfer device. Diluent: The diluent for the lyophilised Factor XIII Concentrate (Human) complies with the requirements in the Ph Eur monograph of Water for Injection (WFI). Transferset: A CE marked, needleless medical device allowing the transfer of diluent and filtering of the reconstituted product before withdrawal into a syringe. Compatibility of the drug product with the transfer device has been shown. An expert statement confirming the functionality of the transfer device with container closure intended for FXIII Concentrate (Human) has been provided. Manufacturer: Factor XIII Concentrate (Human) (drug product) is manufactured at CSL Behring GmbH (Emilvon Behring Str. 76, Marburg, Germany). A valid certificate of GMP compliance for the manufacturing site has been submitted. Manufacturing process of the drug product: The sterile filtrated final bulk (drug substance) is filled into final containers, lyophilised and packaged according to a filling and packaging procedure. Cluvot 250/1250 PAR Scientific discussion 5/14

6 Filling into final containers and lyophilisation: The final bulk solution is automatically filled into depyrogenated and sterilised infusion vials. The dispensed amount of Factor XIII Concentrate (Human) 250 is 4.1 ml in a 6 ml injection vial. The filled volume for Factor XIII Concentrate (Human) 1250 is 20.5 ml into a 30 ml injection vial. After filling, sterilised stoppers are mounted onto the vials. The products are lyophilised using defined lyophilisation program sequences. After finalization of the lyophilisation process, vials are closed inside the lyophiliser by hydraulic closure of the stoppers at vacuum pressure. Subsequently, an aluminum cap is crimped around bottle neck and stopper of the closed containers. Containers are tested for the presence of vacuum in a Tesla field and subjected to visual inspection. Packaging: The dried substance vials are labelled and boxed. Stability Stability of FXIII Concentrate (Human) 250/1250 is documented for 18 months storage at long term conditions. Based on these real time data together with the supporting results, the shelf life claim for FXIII Concentrate (Human) of 36 months, when stored at +2 to +8 C, is acceptable. Shelf life claim for the reconstituted final product of 4 hours at room temperature is considered to be acceptable as well. Control of Drug Product Specification: FXIII Concentrate (Human) drug product is tested at batch release according to a quality control procedure. Parameters are listed in the table below. Parameter Practicability and organoleptic properties Dissolution time Appearance Protein Albumin Glucose Sodium chloride Physico chemical properties Osmolality ph Residual moisture Biological properties Potency Specific activity Sterility Pyrogens Specifications for the control of FXIII potency on Cluvot final drug product are considered acceptable. Cluvot 250/1250 PAR Scientific discussion 6/14

7 II.4 Adventitious safety evaluation The production process includes two steps dedicated to virus reduction i.e. pasteurization and double virus reductive filtration. These and further process steps contributing to virus reduction have been validated for their virus reduction potential. High safety margins with respect to enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV have been demonstrated. The risk assessment is considered sufficient for a safety claim with respect to HAV and B19V (see wording in SmPC section 4.4). Conclusion on Quality The chemical pharmaceutical documentation regarding Cluvot Factor XIII Concentrate (Human) is of sufficient quality in view of the present European regulatory requirements. The control tests and specifications for drug substance product are adequately drawn up. Stability studies have been performed with the drug substance. No out of specification results and no trends were observed in the parameters tested. The development of the product has been described, the choice of excipients is justified and their functions explained. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on three consecutive validation batches. The batch analysis results show that the finished products meet the specifications defined. Conditions used in the stability studies are according to the ICH stability guideline. The proposed shelf life of 36 months with when stored at +2 to +8 C for the drug product is considered acceptable. Furthermore, shelf life claim for the reconstituted final product of 4 hours at room temperature is regarded to be acceptable. The manufacturing process proposed for Factor XIII Concentrate (Human) is controlled to consistently deliver a final product meeting the defined specifications. III. NON CLINICAL ASPECTS The pharmacological profile of FXIII has been characterised in a number of non clinical studies which could demonstrate the efficacy and good tolerance of FXIII. Non clinical efficacy investigations demonstrated that intravenous FXIII could correct bleeding abnormalities and coagulation disorders. FXIII demonstrated a good tolerability in non clinical studies which showed that the dose intended for use in humans can be considered safe. Cluvot 250/1250 PAR Scientific discussion 7/14

8 IV. CLINICAL ASPECTS IV.1 Introduction The indication for Cluvot is routine prophylactic treatment of congenital factor XIII deficiency. Routinely proposed prophylaxis dosing is 40 IU/kg/BW every 28 days. The injection or infusion rate should not exceed 4 ml per minute. Overview on Clinical Studies 9 studies with Factor XIII were performed in subjects with congenital FXIII deficiency, one in healthy volunteers and 2 in other indications (ulcerative colitis). 3 Pivotal studies have been completed: BI17023_2002, a PK, Efficacy and Safety study; BI17023_3001, an Efficacy and Safety study, and BI17023_3002, an additional postmarketing Efficacy and Safety study. 9 additional supportive studies have been provided from the early beginning of product development until new therapeutic opportunities. IV.2 Pharmacokinetics No EMA guidance on clinical investigation of FXIII products is available. Due to rareness of the disease and considerable physiological differences to other factor replacement therapies guidance for such other products may be followed only in wide and general margins. Study design and methodology of the submitted pivotal PK study (BI71023_2002 are considered to be adequate. The number of evaluated subjects (n=13) as well as the repetitive administrations serve as an acceptable data base particularly in the light of the low number of affected subjects, worldwide. Standard non compartmental analysis based on the actual times of blood sampling was applied to calculate PK parameter. Descriptive statistics (n, mean, SD, median, minimum, and maximum, geometric mean, (geometric) coefficient of variation, and 95% CIs for the geometric mean) were used to summarize PK parameter and Factor XIII levels stratified for time and relevant covariates. Assay descriptions and use are well established and handled with long standing expertise. It is considered to be of specific value for reliability of the laboratory measurements that Berichrom assay has been developed in conjunction with FXIII manufacturing (Fibrogammin [P]) and control of efficacy over 3 decades. Supportive antigen evaluation is acknowledged. Results of GCP compliant pivotal study 2002 illustrate and support the dose of 40 IU/kg every 4 weeks, as a standard regimen for prophylaxis in congenital FXIII deficiency. Trough levels of 5% (standard Berichrom assay) were achieved by this regimen. Amended Berichrom assay and antigen (ELISA) assay showed lower but consistent results and are acknowledged as valuable supportive data. For summarizing the most relevant PK parameters including half life in days (in addition to hours), Table 1 has been compiled. The presented data characterize this long lasting Factor being characterised consistently by all three assays (activity and antigen). Cluvot 250/1250 PAR Scientific discussion 8/14

9 Table 1. Baseline Adjusted Pharmacokinetic Parameters After Dose 3 (Pharmacokinetic Population, N=13) Parameter(unit) Standard activity Amended acticity Antigen AUC ss, 0 inf (IU*hr/mL) Mean (SD) (65.78) (67.46) (30.0) Median Min; Max 87.9; ; ; C ss, max (IU/mL) Mean (SD) 0.88 (0.20) 0.88 (0.22) 0.83 (0.18) Median Min; Max 0.60; ; ; 1.12 Incremental Recovery 0 30min (IU/mL/IU/kg) Mean (SD) 0.02 (0.005) 0.02 (0.006) (0.004) Median Min; Max 0.01; ; ; 0.03 Half life (hr) Mean (SD) (54.97) (59.63) (41.49) Median , Min; Max 73.52; ; ; Half life (d) Mean (SD) 6.57 (2.29) 6.57 (2.48) 6.63 (1.73) Median Min; Max 3.06; ; ; 9.84 Cl (ml/hr/kg) Mean (SD) 0.25 (0.09) 0.25 (0.11) 0.27 (0.07) Median Min; Max 0.13; ; ; 0.39 In contrast to other coagulation factors, exogenously substituted FXIII has a long half life of more than 6 days with a wide range between 3 and 11 days in the target population of congenital FXIII deficiency. PK data of healthy volunteers considerably differ from the affected target group in extended half lives (2 13 days) but similar high inter individual variability. Supportive PK studies in healthy volunteers and historical data are acknowledged for comparison. Overall, the applicant presented PK data supporting the proposed treatment schedule. IV.3 Pharmacodynamics The presented pharmcodynamic data are in agreement with publications on FXIII and results of the presented studies support each other. The considerable differences between healthy volunteer data and data of deficient subjects are assumed to represent an additive effect in the healthy volunteer population. Cluvot 250/1250 PAR Scientific discussion 9/14

10 IV.4 Clinical efficacy Pivotal pharmacokinetic study BI71023_2002 (14 subjects) serves as the main study for XIII Concentrate with trough Factor XIII activity levels (5 to 20%) as the surrogate marker. Study BI71023_3001 (41 subjects) represents the link between surrogate efficacy parameter (trough levels) and efficacy in concerned subjects. Further, efficacy was demonstrated by comparing the incidence of bleeding episodes with treatment to a historical control without treatment. Supportive efficacy data were generated in studies BI71023_3002, CE1232/0 5001, and BB IND Regarding study 2002 the presented results support the assumption of the dosage of 40 IU/kg every 28 days to be effective with respect to sustaining protective FXIII levels without risk of cumulation and with no documented bleeding episode which is considered to be a most relevant support for the chosen regimen. Descriptive sub group analysis is considered to be acceptable due to the low number of available subjects. Regarding study 3001 the presented design corresponds with the pivotal PK study The overall sample size of 41 enrolled subjects is acknowledged in the light of low incidence of the disease worldwide. Bleeding episodes in correlation with the individual s condition have been described and analyzed, comprehensively. Annual bleed rate is at least within target number as recalled by the literature. Overall number and character of the documented bleeding episodes is considered to confirm clinical efficacy of the introduced prophylaxis regimen. Documentation and analysis of FXIII levels presents levels within the assumed bleedpreventing level of 5 20% FXIII with few exceptions and wide individual ranges. Clear correlation e.g. of low levels and high risk of spontaneous bleeding has not been found. However, with the exception of one FXIII level in the context of tooth extraction, no levels have been documented within the spontaneous bleeding episodes but put into context with the most recent treatment. Due to the observation of most adequate clinical effect and wide individual ranges, such general supporting result is considered to be acceptable. Dose adjustments were to be done in specific situations according to a recommendation advice. Only 8 such adjustments were required. Target dose of 40 IU/kg every 28 days is therefore supported by this additional efficacy trial. Five relevant surgeries have been documented. The documentation supports the assumption of sufficient clinical effect of FXIII replacement or prophylaxis for surgical interventions. Study design of supportive study 3002 does not allow valid efficacy conclusions based upon trough FXIII levels as for some of the 4 weeks intervals only limited individual data are available. However, overall bleeding frequency and severity, and low number of treatment adjustments support the assumption of efficient prophylaxis with the proposed regimen. Study design of post marketing study 5001 in France considerably differs from the previously described studies: Dosages, treatment regimen (on demand, prophylaxis, surgery prophylaxis) cover a wide range of therapeutic options (from 10 IU/kg every 4 weeks Cluvot 250/1250 PAR Scientific discussion 10/14

11 prophylaxis to up to 35 IU pre operative treatment). However, e.g. pharmacokinetic data (half lives) show good correlation with the interventional study results and more descriptively results from on demand versus prophylaxis add to the overall efficacy results. Dosage and conduct of study 5986 also considerably deviate from the pivotal study s approach. Therefore, the more descriptive results of that study regarding bleeding prevention are considered to be supportive, only. In addition, surgical interventions have been described: Target FXIII level under surgery is intended to be in a normal range being % for non FXIII deficient subjects. PK curves of study 2002 serve as a basis for dosagerecommendations for surgical management. The proposed intervals and adjustments are considered to be reasonably justified. Supportive study 5986 documented 15 surgical procedures with efficacy ratings; additional details regarding dosage and schedule might be supplemented. Overall the presented studies compile comprehensible data in subjects with a very rare disease. It is acknowledged that dose finding has historical background and that surrogate parameters deal with individual gaps. However, it is considered to be documented, that the proposed prophylaxis regimen of 40 IU/kg every 4 weeks and the recommendations for surgical prophylaxis have been substantiated by clinical data, adequately. IV.5 Clinical safety Nine studies with Factor XIII were performed in subjects with congenital FXIII deficiency, one in healthy volunteers and two in other indications (ulcerative colitis). Overall, 188 subjects received at least one dose of Factor XIII across these 12 clinical studies. Adverse events have been documented for all studies: Three deaths were reported which are considered to be unrelated with the application of FXIII. Other serious AEs were documented including a broad spectrum of symptoms and diseases presumably not substantially deviating from other populations. Two case reports of inhibitor development to FXIII were analysed and considered to be acceptable in the described context. Among the 188 subjects enrolled in the clinical program, 70 subjects (all with congenital Factor XIII deficiency) were <16 years of age at the time of enrolment. Among 43 subjects <16 years of age in Study 5986, nine were<2 years of age. The documented AEs reflect a broad spectrum of potential hypersensitivity reactions. Numbers, event descriptions and investigator s assessments are considered to be reasonable and reflect a spectrum as known from other coagulation products. Description of manufacturing with regard to viral safety has been provided. Reflection and interpretation of available data from clinical studies are considered to support viral safety according to current standards. Inhibitor development to FXIII in general is a rare phenomenon. From the clinical study program, one case report might reflect transient inhibitor or even laboratory error and a Cluvot 250/1250 PAR Scientific discussion 11/14

12 second report is considered to be complicated by other immunological mechanisms interfering with FXIII response. Thus, the available data support low but potential risk of inhibitor development for this FXIII product. The presented data reflect a safety profile which is considered to be in line with other plasma derived coagulation factors. Overall, safety of the FXIII product is considered to be demonstrated, adequately. Pharmacovigilance system The RMS considers that the Pharmacovigilance system fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. Risk Management Plan Routine pharmacovigilance activities of CSL Behring include: A. Adverse event collection and single case processing Maintenance of a validated database Collection of AEs and SAEs in a validated global electronic database for centralized collection, permanent retention, and retrieval. Real time medical review of all AEs. Follow up of appropriate cases to gain additional information. Preparation and electronic submission of case reports to Competent Authorities. B. Signal detection Periodic review of line listings for all AEs and SAEs. Signal detection methodology appropriate to the age of the drug and the number of cases. Surveillance of risks. Periodic literature review. C. Aggregate reports Preparation of reports for health authorities, including PSUR, Annual Safety Reports, and equivalent safety summaries. Ad hoc safety reports or interim reports on specific topics as requested by FDA, Competent Authorities or as dictated by signal detection activities. D. Continuous oversight of safety Continuous monitoring and management of the safety profile and benefit risk balance of investigational and marketed products. Activities as a result of pharmacovigilance issues include: labeling updates, assessment of the need for risk minimization measures, and communication with FDA and Competent Authorities, as appropriate. Additional information will be collected about certain spontaneously reported cases, and will be followed up with a targeted questionnaire. Cluvot 250/1250 PAR Scientific discussion 12/14

13 Safety Concerns and Planned Pharmacovigilance Actions Safety Concern Important identified risks Hypersensitivity reactions Planned Pharmacovigilance Actions Routine pharmacovigilance Viral transmission Thrombosis Development of FXIII inhibitors Important potential risks Important missing information Pregnancy Routine pharmacovigilance Additional follow up and target questionnaire Clinical study: Study BI71023_3001 Clinical study: Study BI71023_3002 Routine pharmacovigilance Additional follow up and target questionnaire Clinical study: Study BI71023_3001 Clinical study: Study BI71023_3002 Routine pharmacovigilance Clinical study: Study BI71023_3001 Clinical study: Study BI71023_3002 None discussed. Routine pharmacovigilance Additional follow up and specialized questionnaire Cluvot 250/1250 PAR Scientific discussion 13/14

14 V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Administration of Factor XIII Concentrate aims at patients with congenital FXIII deficiency constantly being at risk of severe or even life threatening bleeding. Main objective of such treatment is prevention of bleeding under normal conditions and in case of surgical intervention. Rareness of congenital FXIII deficiency and resulting narrow database might reflect relevant source of uncertainty for both, the efficacy and safety assessment of the medicinal product. However, the presented study results (12 studies covering 188 subjects and including at least 70 paediatric patients) are considered to contribute to fundamental knowledge including PK data, repetitive administrations and long term experience on that medicinal product. The chosen treatment schedule (every 28 days) and dosage (40 IU/kg) derived from historical experience in single available patients and was adapted to clinical needs and developing treatment options. Except further analysis of the available data regarding paediatric subjects, the presented data are considered to support efficacy in the claimed indication. Risks of treatment with plasma derived coagulation factors are well known and cover nonspecific general or injection site related reactions as well as potentially life threatening events (inhibitor development, hypersensitivity, thrombosis), Whereas such events are experienced rarely, they require accurate documentation and collection for identification of signals regarding severity and incidence and adequate reflection within the SmPC which has been provided, in general. The authorized recombinant FXIII product which has received orphan designation differs with respect to its composition of two A subunits, whereas plasma derived FXIII represents functional complete FXIII. Availability of Cluvot is considered to be important for concerned FXIII deficient patients as it is indicated for all types of congenital FXIII deficiencies, including subunit B deficiencies. As a senior alternative treatment option it has a well known safetyprofile and efficacy characteristics being very close to the physiological protein. Furthermore, posology includes prophylaxis prior to surgery. Based on the available data and information the overall Benefit/Risk of Cluvot is considered positive. Cluvot 250/1250 PAR Scientific discussion 14/14