Summary Basis of Decision for Tretten ®
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Tretten®
Catridecacog, 15 mg/vial, Powder, Intravenous
Novo Nordisk Canada Inc.
Submission control no: 152228
Date issued: 2012-10-19
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02389975
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
Tretten® is a registered trademark of Novo Nordisk A/S and is used under license by Novo Nordisk Canada Inc.
2 Notice of decision
On July 19, 2012, Health Canada issued a Notice of Compliance to Novo Nordisk Canada Inc., for the drug product Tretten®.
Tretten® contains the medicinal ingredient catridecacog which is a coagulation factor.
Tretten® is indicated for routine prophylaxis for bleeding in patients with congenital Factor XIII A-subunit deficiency. Tretten® is structurally identical to the human FXIII A-subunit. Activated Tretten® has been shown to increase the mechanical strength of fibrin clots, retard fibrinolysis, and enhance platelet adhesion to the site of injury.
The market authorization was based on quality, non-clinical, and clinical information submitted. A single pivotal study was conducted to establish the efficacy and safety of monthly doses of 35 IU/kg in prevention of bleeding in patients with congenital FXIII A-subunit deficiency. Forty-one patients were dosed in the study during a period of 52 weeks. The primary endpoint for the pivotal study was the rate of bleeding episodes requiring treatment with a FXIII-containing product during the treatment period with recombinant FXIII (Tretten®). During the treatment period with Tretten® (434 patient months), 5 treatment-requiring bleeds were observed, corresponding to a mean rate of 0.138 [95% confidence interval (CI): 0.058, 0.332] treatment-requiring bleeds per patient year. Based on the safety data presented, treatment with Tretten® was generally well-tolerated.
Tretten® (15 mg/vial, catridecacog) is presented as lyophilized powder to be reconstituted with solvent for injection. The recommended dose is 35 IU/kg body weight approximately once monthly, administered as an intravenous bolus injection. Dosing guidelines are available in the Product Monograph.
Tretten® is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Tretten® should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Tretten® are described in the Product Monograph.
Priority Review status was granted for the evaluation of Tretten® as it appeared to provide substantial evidence of clinical efficacy for a serious, life-threatening condition for which no drug is presently marketed in Canada.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Tretten® is favourable for routine prophylaxis for bleeding in patients with congenital Factor XIII A-subunit deficiency.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Catridecacog, the medicinal ingredient of Tretten®, is a recombinant, human coagulation factor XIII-A2 (rFXIII-A2) homodimer composed of two FXIII A-subunits. It is structurally identical to human FXIII A-subunit [A2]. The FXIII A-subunits is a 731 amino acid chain with an acetylated N-terminal serine. When FXIII is activated by thrombin, a 37 amino acid peptide is cleaved from the N-terminus of the A-subunit. Tretten® (catridecacog) is indicated for routine prophylaxis for bleeding in patients with congenital Factor XIII A-subunit deficiency.
Manufacturing Process and Process Controls
Catridecacog (rFXIII-A2) is produced intracellularly by recombinant deoxyribonucleic acid (DNA) technology in yeast Saccharomyces cerevisiae using fed-batch fermentation after which the cells are homogenized and rFXIII is released, captured, and purified.
The manufacture of rFXIII is based on a two-tiered cell line banking system (master cell bank and working cell bank) where the master and working cell banks have been thoroughly characterized and tested for identity, purity, and stability in accordance with International Conference on Harmonisation (ICH) guidelines. Results of these tests confirmed cell line identity and absence of contaminants. Genetic characterization (restriction endonuclease mapping and copy number analysis) also demonstrated genetic stability of the cell banks ranging from storage to production at the end of production cells and at the late extended culture.
The rFXIII is released from the cells by high pressure homogenization, clarified by centrifugation and filtration, and then captured using anion exchange chromatography. During the purification process another three chromatographic steps are performed. The purification process also includes two filtration steps. The bulk is then concentrated by ultrafiltration, formulated into the final formulation buffer by diafiltration and filled into suitable containers.
The batch size is supported by validation data and is considered acceptable.
The description of the fermentation, recovery, and purification processes and the in-process controls are considered adequate. Detailed information on the in-process tests (including their appropriate limits) have been provided and are considered acceptable.
Characterization
The structural characterization and elucidation of physico-chemical properties using adequate analytical methods described in the application have confirmed that the structure and properties of the rFXIII drug substance produced by Novo Nordisk have identical features to the native FXIII-A subunit.
Control of Drug Substance
The drug substance specification includes test methods for identity, content, specific bioactivity, aggregates, purity, impurities, rFXIIIa (Non-proteolytically activated rFXIIIa) and other general tests (appearance, pH, endotoxins and microbial count). The tests for process related impurities only include host cell protein as the removal of host cell deoxyribonucleic acid (DNA) and nickel have consistently demonstrated to be below the detection limit. The drug substance specifications and analytical methods used for quality control are considered acceptable.
The validation approach and validation data are considered acceptable. Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term, real-time, and accelerated stability data submitted, the proposed shelf-life and storage conditions for the drug substance are supported and are considered satisfactory.
3.1.2 Drug Product
Description and Composition
Tretten® (medicinal ingredient, catridecacog) is supplied as a white, lyophilized powder in single-use vials. Each vial contains 15 mg (2,500 IU/vial) of catridecacog and the following non-medicinal ingredients: L-histidine; polysorbate 20; sodium chloride; and sucrose. The vials are made of Type I glass, closed with a latex-free chlorobutyl rubber stopper and sealed with an aluminium cap. The vials are equipped with a tamper-evident snap-off plastic cap.
The package includes one sterile vial adapter for reconstitution, and one vial with solvent (3.2 mL sterile water) for reconstitution.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
A comprehensive drug product process validation consisting of process design, process qualification and process confirmation was provided. The validated process is capable of consistently generating product that meets release specifications.
Control of Drug Product
The drug product (Tretten®) is tested to verify that its appearance, reconstitution time and water content are within test specifications. After reconstitution, the drug product is also controlled for its appearance, pH, identity, purity, impurities, content, aggregates, bioactivity, sterility, bacterial endotoxins, relative osmotic pressure, and particulate matter. The test specifications are considered acceptable to control the drug product. The validation process is considered to be acceptable. Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed 24-month shelf-life at 2°C to 8°C is considered acceptable when the drug product is stored in the original package, protected from light.
The compatibility of the drug product with the container closure system was demonstrated through stability studies. The container closure system met all compatibility test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Tretten® are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices.
No on-site evaluation (OSE) was conducted in support of this submission. No relevant manufacturing was planned at the fermentation plant or the drug substance purification plant during the review period. Given that the OSE process is largely dependent on the observation of ongoing manufacturing operations and based on our knowledge of Novo Nordisk quality systems through information derived from previous OSEs, an OSE was not deemed necessary. The drug product manufacturing facility had an OSE conducted by the Biologics and Genetic Therapies Directorate (BGTD), Health Canada in 2006.
3.1.4 Adventitious Agents Safety Evaluation
Tretten® is produced without the addition of human or animal derived materials. The cell banking system was also established without the use of materials of human or animal origin. The fermentation process Tretten® uses animal and human component free media. This minimizes possible contamination from adventitious viruses. The cells used for the production of Tretten® are fungi (Saccharomyces cerevisiae), therefore no virus safety testing on cell banks and unprocessed bulk are necessary and the purification process was not required to validate for its virus reducing capacity according to current guidelines. In summary, the Transmissible Spongiform Encephalopathy (TSE) safety and viral safety of Tretten® should not be a concern.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Tretten® has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
The pharmacological activity of rFXIII has been investigated in in vitro and in vivo studies. The objective was to demonstrate that rFXIII has the same pharmacodynamic properties in plasma as those described in the literature for endogenous FXIII. The study results showed that the rFXIII binds specifically to the endogenous FXIII-B, cross-links fibrin to strengthen the clot, incorporates anti-fibrinolytic proteins into the clot to enhance the clot resistance to fibrinolysis, and incorporates adhesion molecules into the clot which promotes anchoring of the clot and wound healing.
In vitro data showed that at clinically relevant concentrations (10 μg/mL or less) neither non-activated nor activated rFXIII were toxic to endothelial cells, induced up-regulation of pro-inflammatory adhesion molecules or stimulated cytokine release from whole blood. At high concentrations (100 μg/mL, 20-fold the clinical relevant concentration), activated rFXIII, but not rFXIII, may inhibit cell proliferation, and give a slight increase in expression of adhesion molecules.
In vivo data showed that there were no effects in the clot growth, blood flow, blood pressure, and platelet counts in rabbits at 2-fold the recommended clinical dose of 35 IU/kg. In the extra-corporal circulation system in monkeys, no treatment-related effects were noted in respiration, cardiovascular parameters, body temperature, clinical chemistry, haematology, coagulation or histopathology. A single dose of 2.1 and 7.1 mg/kg (10 to 34-fold the recommended clinical dose of 35 IU/kg) was well-tolerated after two hours of extra corporal circulation and with no apparent adverse effects during six hours of observation.
3.2.2 Pharmacokinetics
In rat studies, the results showed a non-linear pharmacokinetic (PK) profile between 1.5 and 15 mg/kg, and no apparent differences between males and females. The accumulation between Day 1 and Day 28 was low (<1.6 fold) and the determined half-life of 6-10 hours. In a single-dose PK study in juvenile and mature monkeys, the results demonstrated a significantly lower exposure in juvenile animals probably due to higher clearance and/or higher volume of distribution.
The binding of rFXIII to free rFXIII-B2 subunit was reported in the monkey studies. This complex had a terminal half-life of 50-225 hours; the half-life of free rFXIII was 4-7 hours. There were no apparent differences between males and females.
Tissue biodistribution was investigated in monkeys, where rFXIII was shown to be distributed to blood and highly perfused organs. No in vitro or in vivo metabolism studies were performed; this is acceptable as it is in accordance with ICH S6 guidance.
In a study where monkeys were administered radiolabelled rFXIII (total doses of either 0.5 or 5.0 mg/kg), urine was identified as the primary route of excretion. Urine and faeces accounted for average values of 51.5% and 1.93% of the administered radioactive dose, respectively, for the low dose; and 41.8 %and 2.37%, respectively, for the high dose.
Results of an activated rFVII/rFXIII combination study suggest no PK drug interaction between rFXIII and activated rFVII.
3.2.3 Toxicology
Single-Dose Toxicity
Monkeys were administered a single intravenous (IV) dose between 0-30 mg/kg rFXIII (0-143 fold the recommended clinical dose of 35 IU/kg or 0.21 mg/kg). The overall results showed that animals administered 22.5 and 30 mg/kg died or were sacrificed moribund Day 5 and Day 1, respectively. Histopathology revealed widespread thrombosis and ischaemic necrosis consistent with the diagnosis of disseminated intravascular coagulation (DIC). Evidence of a generalized occlusive coagulopathy was found with varying degrees of severity in many organs and tissues.
Repeat-Dose Toxicity
Repeat dose toxicity studies were performed in rats for up to 4 weeks and monkeys for up to 27 weeks.
Repeated doses of rFXIII were generally well-tolerated up to 5-15 mg/kg/day in rats (24 to 72-fold the recommended clinical dose of 35 IU/kg) and up to 3-8 mg/kg/2 weeks in monkeys (14 to 38-fold the recommended clinical dose of 35 IU/kg). The toxicity was considered to represent exaggerated pharmacology.
Lymphoid hyperplasia was seen in the spleen in a 4-week rat study and in one of the monkey repeat-dose studies. This finding is a reversible adaptive response to a species foreign protein but is not considered adverse. The occurrence of lymphoid hyperplasia may reflect antibody production towards yeast host-cell-proteins or product-related impurities. In view of the clinical data provided so far, there were no unusual findings which give cause for concerns in terms of immunological adverse events. However in future clinical use rFXIII should be monitored closely for occurrence of any immunological adverse events.
In one of the monkey studies, one case of glomerulopathy was noted as possibly being treatment-related, however there were no renal lesions associated with the rFXIII study drug. The glomerulopathy reported as being treatment-related was considered to be similar to those seen in other monkeys, including controls.
Genotoxicity and Carcinogenicity
Genotoxicity and carcinogenicity studies were not performed. This is in accordance with the ICH S6 guideline.
Reproductive and Developmental Toxicity
Reproductive and developmental toxicity studies were not performed with rFXIII. The toxicology programme did not identify any concerns in relation to reproductive toxicity. No dedicated fertility studies were performed, but fertility was assessed by the histopathology of reproductive organs in the repeat-dose toxicity studies which included sexually mature rats and monkeys.
3.2.4 Summary and Conclusion
The non-clinical studies for this drug submission are considered acceptable. Several in vitro and in vivo studies demonstrated that rFXIII is expected to have the same pharmacodynamic properties as endogenous FXIII. Based on the non-clinical pharmacology and toxicology studies, there are no major safety concerns that would predict unexpected adverse effects in patients treated with Tretten® at the recommended therapeutic dose.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The recombinant FXIII (rFXIII) is identical in structure to the human FXIII A-subunits. Upon injection, the rFXIII A2 dimers bind to endogenous circulating B-subunits that circulate in excess to form a stable rA2B2 heterotetramer. FXIII modifies both the mechanical strength and the physiological properties of the blood clot and is vital to normal haemostasis.
The pharmacodynamic properties of rFXIII were evaluated by testing for clot lysis in the Phase III study. In addition, clotting dynamics were exploratively assessed by thromboelastography in a Phase I study in patients with congenital FXIII deficiency. However, normalization of FXIII levels and coagulation tests cannot reflect the size of clinical benefit in the treatment of bleedings.
The immunogenicity of rFXIII was assessed throughout the development program. Tests for anti-rFXIII antibodies were performed in all of the clinical studies and tests for anti-yeast antibodies were performed in some of the studies. Furthermore, there is a theoretical risk that stabilisation of an existing thrombus might occur, resulting in increased risk of vessel occlusion.
3.3.2 Pharmacokinetics
A total of 148 healthy subjects were enrolled in the clinical pharmacology studies. In patients with congenital FXIII deficiency, one formal single-dose clinical pharmacology study was conducted in 9 patients. In addition, a total of 471 monthly doses in 41 patients of a Phase III study (F13CD-1725) contributed to the assessment, as blood sampling for the PK analyses and clot solubility was performed immediately before and one hour after each monthly dose of rFXIII as well as 14 days after the initial dose. Furthermore, preliminary results from an ongoing Phase III safety extension study (F13CD-3720) on FXIII activity and clot solubility were included (cut-off date of 11 February 2011). In this study, samples were drawn at pre-dose only.
The PK assessment was primarily based on the FXIII Berichrom® activity assay. The assay detects the activity of recombinant as well as human FXIII A-subunits irrespective of whether or not they are in complex with B-subunits. The PK properties of rFXIII were evaluated using standard PK endpoints and non-compartmental methods.
For studies in healthy subjects, the effect of baseline level FXIII activity was accounted for by subtracting the median or the mean of three pre-dose values from all post-dose values prior to calculation of the PK parameters. The primary evaluation for the PK in healthy subjects was based on the geometric mean estimates from Study NN1841-3788 in which 50 subjects were exposed to a total of 98 doses of Tretten® at the intended dose level of 35 IU/kg rFXIII (two subjects were withdrawn following the initial dose). The estimated terminal half-life was 266 hours, which is equivalent to approximately 11 days. The mean volume of distribution at steady state (Vss) was 47 mL/kg, mean residence time (MRT) was 15.5 days and mean clearance (CL) was 0.13 mL/h/kg. Comparison of arithmetic mean estimates showed no major differences in pharmacokinetics across the other studies with healthy subjects.
Study F13-1663 was a Phase I escalating dose study of the safety and pharmacokinetics of rFXIII in patients with congenital factor XIII deficiency. The terminal half-life ranged from 6 to 12 days, when excluding a very short half-life (9 hours) of a FXIII B-subunit deficient subject. The results were based on a total of 6 exposures in 6 patients.
In the pivotal Phase III study F13CD-1725 where patients received a monthly administration of rFXIII, blood sampling for pharmacokinetics was performed immediately before and one hour after each monthly dose as well as 14 days after the initial dose of rFXIII. Based on FXIII activity as measured by the Berichrom® assay for 471 monthly doses of rFXIII in the study, the crude estimate of the half-life of rFXIII in these patients with congenital FXIII deficiency was 11.5 days. This is in agreement with the elimination pharmacokinetics estimated for healthy subjects.
The shape of the mean profiles for A2B2 tetramer and total FXIII-A2 corresponded to the FXIII activity profile, reflecting that concentrations increased sharply after each rFXIII administration followed by a gradual decline during the subsequent month. The mean profile for uncomplexed B-subunit was reversed in the sense that concentrations were lowest immediately after injection of rFXIII.
Study NN1841-3788 was a bioequivalence study to compare the drug substance rFXIII produced by Avecia and the rFXIII produced by Novo Nordisk. The rFXIII drug substance used for non-clinical studies and the larger part of the clinical development program was produced by Avecia. The production of the rFXIII drug substance has subsequently moved in-house to Novo Nordisk. Upon transfer of the production process from Avecia to Novo Nordisk, process modifications facilitating rFXIII production in the Novo Nordisk facilities were introduced. No changes were made to the composition of the drug substance. An analytical comparability study on rFXIII drug substance has been performed comparing rFXIIIAvecia and rFXIIINovo Nordisk and Study NN1841-3788 was conducted to demonstrate bioequivalence between rFXIIIAvecia and rFXIIINovo Nordisk Results from this study demonstrate comparability between rFXIIIAvecia and rFXIIINovo Nordisk based on the results of system exposure area under the curve (AUC) values.
3.3.3 Clinical Efficacy
A pivotal Phase III study (F13CD-1725) was conducted to investigate the haemostatic efficacy of Tretten® (catridecacog or rFXIII) in patients with congenital FXIII deficiency as reflected by the rate of bleeding episodes requiring treatment with a FXIII-containing product. An extension study to F13CD-1725 (F13CD-3720) was subsequently added, during which information on bleeding episodes was collected as for the F13CD-1725 study. The extension study is currently ongoing, and interim data as of the cut-off date of February 11, 2011 were presented.
The Phase III study was conducted as a multicentre, multinational, open-label, single-arm, multiple-dosing study evaluating the efficacy and safety of monthly replacement therapy with Tretten® in the prevention of bleeding episodes associated with congenital FXIII deficiency.
Following a 4-week run-in period, patients entered a 52-week Tretten® treatment period and could then enter into the extension period for at least 52 weeks. Patients aged ≥6 years (≥12 years in Germany) with a diagnosis of congenital FXIII A-subunit deficiency could be enrolled regardless of their previous type of treatment for their FXIII deficiency. Patients who had received regular replacement therapy prior to entering the study initiated this treatment at least 6 months prior to screening and had to have a documented history of at least one treatment-requiring bleeding episode before initiation of regular replacement therapy or a documented family history of FXIII congenital deficiency. Severe bleeders as defined by a documented history ≥2 treatment-requiring bleeds per year during regular FXIII replacement therapy were excluded. Patients who had only received on demand treatment prior to entering the study required a documented history of at least two treatment-requiring bleeding episodes within 12 months of the screening visit. Patients undergoing major surgery were excluded.
During the treatment period of 52 weeks (Visit 2 through to Visit 15), patients received 35 IU/kg Tretten® every 4th week (28 ± 2 days). Non-emergency use of FXIII-containing products other than rFXIII was not allowed during the study period. In case of acute bleeding episodes, any additional treatment as per investigator judgment was to be according to local standard practice, and additional doses of Tretten® could therefore not be used to treat such breakthrough bleedings.
The primary endpoint of rate of bleeding episodes that required treatment with a FXIII-containing product during the Tretten® treatment period was compared against a historically determined rate of 2.91 such bleedings per subject per year. This rate was based on the 16 patients of a retrospective data collection study who received on-demand treatment with FXIII-containing products and for whom sufficient data were available for the bleeding rate calculation. Monthly replacement therapy with Tretten® would be regarded as superior to on-demand treatment with FXIII containing products (defined as placebo) if the yearly bleeding rate for the Tretten® group was lower than 2.91, the fixed placebo rate.
Secondary efficacy endpoints included bleeding rates for different categories of bleeding (spontaneous, traumatic or intracranial), the percentage of patients with bleedings that did not require treatment, and the number of patient withdrawals due to lack of efficacy. In addition, FXIII activity before and one hour after Tretten® administration was measured using the Berichrom® assay, as well as the percentage of patients having a normal clot solubility one hour and 28 days after Tretten® administration.
In total, 41 patients were enrolled (mean age 26.4 years; range 7-60 years), including 39 patients previously on prophylaxis with FXIII-containing products.
Study Results
In the pivotal study F13CD-1725, the efficacy analyses were performed for both the Full analysis set (41 patients), and the Per Protocol analysis set (31 patients). Eight patients were withdrawn from the study (including 3 due to antibody development) and two patients were excluded due to protocol deviations.
During the Tretten® treatment period (mean treatment period of 322 days), five bleeding episodes that required treatment with a FXIII-containing product were observed in four patients. All five events were traumatic bleeding episodes. The mean rate of treatment-requiring bleeds was determined to be 0.138 per patient year. In the primary endpoint analysis, the age-adjusted rate (number per patient year) of treatment-requiring bleeds during the Tretten® treatment period was 0.048/year. When compared with retrospectively collected data from patients with congenital FXIII deficiency, the bleeding frequency observed in the present study was significantly lower than the rate of 2.91 treatment-requiring bleeds per year in patients receiving on-demand treatment. The occurrence of treatment-requiring bleedings did not appear to be associated with low FXIII activity levels as measured by the Berichrom® assay. There were no patient withdrawals due to lack of efficacy of Tretten® treatment.
Thirty-three patients who completed study F13CD-1725 entered into study F13CD-3720. In the extension study F13CD-3720 (mean observation period 359 days), five bleeding episodes that required treatment with a FXIII-containing product were recorded in three patients during the extension period. Of these, two bleeds in two patients occurred spontaneously. Bleeding frequencies associated with exposure to drug substance produced by Avecia and Novo Nordisk were similar. The age-adjusted rate (number per patient year) of treatment-requiring bleeds during the extension period was 0.038 per year which is similar to the corresponding rate for the main study period. No patients were withdrawn due to lack of efficacy of rFXIII treatment.
3.3.4 Clinical Safety
The clinical safety of Tretten® was evaluated in the pivotal Phase III study F13CD-1725 and from the preliminary report obtained from the ongoing extension study, F13CD-3720. The studies are described in section 3.3.3 Clinical Efficacy.
No clinically significant safety issues were identified. A total of 14 adverse events (AEs) were evaluated by the investigator to be possibly or probably related to the study drug in studies F13CD-1725 and F13CD-3720. These comprised of:
- Positive antibody test (4 events in 4 patients). These cases were reported in young patients below the age of 18. The antibodies were seen at the start of the treatment with Tretten®. In three cases, patients discontinued the study and returned to their previous treatment. One patient continued to be treated with Tretten® and recovered approximately three months later.
- Incorrectly administered dose (3 events in 2 patients).
- Injection site pain (1 event).
- Increase in fibrin D-dimer (1 event) and pain in extremity (1 event). In addition, one case of phlebitis was reported in study F13CD-1725. Otherwise, 3 events of myocardial infarction possibly or probably related to the administration of rFXIII were reported in study NN1810-3540. Cases of increased D-dimer were also reported in a healthy subject in a PK study.
- Headache (1 event).
- Overdose (1 event).
- Coinciding events of neutropaenia and leucopaenia in one patient (worsening of mild neutropaenia initially diagnosed before first drug administration.
Overall, no thromboembolic or fatal adverse events were reported. Four patients developed transient, low-titre anti-rFXIII antibodies that had no neutralising effect and were not found to be clinically significant.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Priority Review status was granted for the evaluation of Tretten® as it appeared to provide substantial evidence of clinical efficacy for a serious, life-threatening condition for which no drug is presently marketed in Canada.
Congenital factor XIII deficiency is characterized by haemorrhagic diathesis frequently associated with spontaneous abortions and defective wound healing. Current treatment options in FXIII deficiency include cryoprecipitate, fresh frozen plasma, and plasma-derived FXIII concentrate. The choice of using Tretten®, a recombinant FXIII, presents an advantage especially regarding viral safety. Prophylactic therapy with FXIII concentrate should be indicated to prevent recurrent bleedings such as intracranial haemorrhage. Intracranial haemorrhage can be life threatening, but prognosis is favourable if adequate treatment is provided.
The beneficial effect of treatment with Tretten® is the prevention of bleeding episodes in patients with severe congenital FXIII deficiency, which is regarded very important for patients with this rare disease. Overall, the pivotal study appears to provide satisfactory results with respect to efficacy and safety. There was no occurrence of intracranial or life-threatening bleedings. No safety signals were raised by the data provided. However, it should be noted that there was very limited data from patients with congenital FXIII deficiency who received only rFXIIINovo Nordisk (7 patients - 80 doses).
During the clinical development program (at the cut-off date of 11 February 2011), 41 patients with congenital FXIII deficiency received Tretten® at the dose 35 IU/kg which is the selected dose. A total of 317 doses of rFXIIINovo Nordisk have been administered to 31 of the 33 patients who continued into the extension study F13CD-3720 which is ongoing. Among these 31 patients receiving only rFXIIINovo Nordisk in the F13CD-3720 study, 21 (67.7%) experienced 82 treatment emergent adverse events. Only two patients experienced a serious treatment-emergent adverse event (one otitis media chronic and one laceration) and no patients experienced an adverse event leading to withdrawal. Only one patient experienced a treatment-emergent adverse event possibly related to the study drug (rFXIIIAvecia). This was a case of overdose/dosing error in an 8-year old patient who recovered. The risk of medication errors under real-life conditions, particularly in the home-treatment setting, is included in the Risk Management Plan as an important potential risk.
The most frequent adverse drug reactions in the 41 patients treated with rFXIII were non-neutralizing antibodies. Transient antibody development was observed in four patients after being treated with rFXIIIAvecia but there were no apparent signs of inhibitor activity. The prevention of life-threatening bleedings outweighs the risk of antibody development.
No investigation is available for the use of Tretten® in the on-demand treatment setting. The indication is restricted to prophylactic treatment and taking into account the current practice (patients treated at home), a risk of inappropriate use of Tretten® in the treatment of breakthrough bleedings should be considered.
Studies in paediatric patients from 1 to <6 years old are ongoing, and very limited data were provided. No conclusions could be drawn concerning this population. Tretten is not indicated in this population and information concerning this population is not included in the Tretten® Product Monograph.
Due to the mechanism of action of rFXIII, there is a theoretical risk that stabilization of an existing thrombus might occur resulting in an increased risk of vessel occlusions.
Incorrect storage of the product after reconstitution must be avoided as it may result in loss of sterility and increased levels of non-proteolytical activated rFXIII. Increased levels of non-proteolytical activated rFXIII may increase the risk of thrombosis. Cases of increased D-dimer have been reported in the clinical studies. Because of these cases and because there is a risk of clotting and fibrinolysis during sampling due to incorrect storage, the risk of thromboembolic events remains a concern.
Two studies have been initiated to evaluate the safety and efficacy of Tretten® in patients undergoing cardiac surgery requiring cardiopulmonary bypass. Safety data from these cardiac surgery studies provide supportive evidence of the overall safety profile of Tretten®.
A Phase IV, post-marketing observational study is planned as part of the pharmacovigilance plan to substantiate the safety profile of Tretten® after marketing authorization.
An RMP for Tretten® was prepared in accordance with the current guideline from the Committee for Medicinal Products for Human Use and the European Medicines Agency, the ICH E2E Guideline for Pharmacovigilance Planning and the Food and Drug Administration (FDA) Guidance for Industry. The sponsor submitted the RMP and Health Canada reviewed it and proposed several post-market actions that adequately manage the risks associated with the proposed use of Tretten® in Canada.
Overall, the benefit/risk assessment is favourable for the use of Tretten® for the approved indication. Current treatment options for patients with a congenital FXIII deficiency include cryoprecipitate, fresh frozen plasma, and plasma-derived FXIII concentrate. Tretten® represents an additional choice with an advantage over the other products of no potential virus safety risk. In addition, the beneficial effect of treatment with Tretten® in the prevention of bleeding episodes in patients with severe congenital FXIII deficiency is regarded as an important aspect for patients with this rare disease.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Tretten® is favourable for routine prophylaxis for bleeding in patients with congenital Factor XIII A-subunit deficiency. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Tretten®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2010-09-21 - 2011-06-27 |
| Request for priority status | |
| Filed: | 2011-01-11 |
| Approval issued by Director, Centre for Blood and Tissue Evaluation: | 2011-12-08 |
| Submission filed: | 2011-12-20 |
| Screening | |
| Screening Acceptance Letter issued: | 2012-01-23 |
| Review | |
| Quality Evaluation complete: | 2012-07-19 |
| Clinical Evaluation complete: | 2012-07-17 |
| Biostatistics Evaluation complete: | 2012-07-17 |
| Labelling Review complete: | 2012-05-15 |
| Notice of Compliance (NOC) issued by Director General: | 2012-07-19 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| TRETTEN | 02389975 | NOVO NORDISK CANADA INC | CATRIDECACOG 2500 UNIT / VIAL |