Summary Basis of Decision for Berinert ®
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:
Berinert®
C1 Esterase Inhibitor, Human, 500 units/vial, Powder for solution, Intravenous
CSL Behring Canada Inc.
Submission control no: 121221
Date issued: 2011-01-06
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):
- 02352575
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On May 31, 2010, Health Canada issued a Notice of Compliance to CSL Behring Canada Inc. for the drug product Berinert®.
Berinert® is a purified, pasteurized, lyophilised concentrate of human C1 esterase inhibitor (C1-INH), derived from human plasma.
Berinert® is indicated for the treatment of acute abdominal or facial attacks of hereditary angioedema (HAE) of moderate and severe intensity. HAE is a hereditary disorder where a naturally occurring blood protein called C1-INH is present at a low level or not functioning properly. CI-INH regulates clotting and inflammatory reactions, such that a lack of functional CI-INH can lead to spontaneous episodes of oedema to various regions of the body. C1-INH has an important inhibiting potential on several of the major cascade systems of the human body, including the complement system, the intrinsic coagulation (contact) system, the fibrinolytic system, and the coagulation cascade.
An HAE attack of moderate intensity is characterized by a degree of discomfort caused by clinical HAE symptoms that result in some interference with daily activities. An HAE attack of severe intensity is characterized by a degree of discomfort caused by clinical HAE symptoms that makes it impossible to perform daily activities.
The market authorization was based on quality, non-clinical, and clinical information submitted. A pivotal Phase III prospective, multinational, randomized, parallel-group, placebo-controlled, dose-finding, three-arm, double-blind clinical study assessed the efficacy and safety of Berinert® in 124 adult and paediatric patients with C1-INH deficiency who were experiencing an acute moderate to severe attack of abdominal or facial HAE. The study objective was to show that Berinert shortens the time to onset of relief of symptoms of an abdominal or facial attack compared to placebo and to compare the efficacy of two different doses of Berinert. The study demonstrated the efficacy of a 20 U/kg body weight dose of Berinert® compared to placebo in reducing the time to onset of relief from symptoms of an HAE attack (abdominal or facial) as determined by the patient's assessment. The median time to onset of symptom relief for the Berinert® 20 U/kg body weight group was 30 minutes as compared to 90 minutes for the placebo group. In addition, both the proportion of patients with increased intensity of clinical HAE symptoms between 2 and 4 hours after start of treatment with Berinert compared to baseline and the number of vomiting episodes within 4 hours after start of study treatment were significantly reduced.
In the patients that were treated with Berinert®, the most serious adverse reaction was an increase in the severity of pain associated with HAE. The safety and efficacy of Berinert Ò for prophylactic therapy has not been established.
Berinert® (500 U/vial C1-INH) is presented as a powder for solution. The recommended dose of Berinert® for the treatment of acute abdominal and facial HAE episodes of moderate or severe intensity is 20 U/kg body weight administered by intravenous injection. Dosing guidelines are available in the Product Monograph.
Berinert® is contraindicated for individuals who have a known hypersensitivity or have had an anaphylactic or severe systemic reaction to C1-INH preparations or to any ingredient in the formulation or component of the container. Products made from human plasma may contain infectious agents such as viruses and, theoretically, the agent responsible for the Creutzfeldt-Jakob disease. The development of thrombosis has been reported in association with Berinert when used 'off-label' and at higher than labelled doses. Berinert® 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 Berinert® are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Berinert® is favourable for the treatment of acute abdominal or facial attacks of HAE of moderate and severe intensity.
3 Scientific and Regulatory Basis for Decision
Berinert® has been distributed to patients in Canada for the past five years under the Special Access Programme (SAP). The first Canadian distribution under the SAP was granted in 2002. The actual license birth date for Berinert® is 1979, where it was first approved in Germany and has since been continuously manufactured at the same site in Marburg, Germany.
Berinert® has been approved within the European Union in Germany, Hungary, Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Finland, France, Great Britain, Greece, Italy, Luxembourg, the Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, and Sweden for:
- Hereditary angioedema type I and II (HAE): Treatment of acute episodes.
Berinert® has been approved in Australia for:
- Treatment for acute attacks in patients with hereditary angioedema (HAE).
Berinert® has been approved in Argentina and Switzerland for:
- Hereditary angioedema (HAE) a) treatment of acute episodes b) pre-operative prophylaxis.
Berinert® has also been approved in Japan for:
- Acute attack of hereditary angioneurotic edema.
Berinert® has also been approved in the United States for:
- The treatment of acute abdominal and facial attacks of hereditary angioedema (HAE) in adult and adolescent patients.
In this New Drug Submission (NDS) the sponsor sought approval for the following two indications:
- The treatment of acute episodes of HAE;
- Pre-operative prophylaxis to prevent HAE associated complications during or after a procedure.
In support of the second indication for short-term prophylaxis use of Berinert® pre-operatively, the sponsor provided a systematic literature review specifically for Canada using data gathered from retrospective studies. This review of literature however, could not be considered as evidence in support of this indication. In addition, deficiencies were identified in the pivotal and extension studies submitted. Consequently, on March 5, 2009 it was recommended that a Notice of Non-Compliance (NON) be issued to the sponsor. In response to the NON, the sponsor proposed approval for the first indication only in treatment of acute episodes of HAE and addressed the deficiencies identified. Sponsor's response to the NON was accepted and the submission was reviewed for the first indication only.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
C1 esterase inhibitor (C1-INH), the medicinal ingredient of Berinert®, is a naturally occurring blood protein found in human plasma. Berinert® is indicated for the treatment of acute abdominal or facial attacks of HAE of moderate and severe intensity. HAE is a hereditary disorder where functional C1-INH levels are low or not functioning properly. Given C1-INH plays a role in regulating clotting and inflammatory reactions, a lack of functional C1-INH can lead to spontaneous episodes of oedema involving various regions of the body. Although the events which induce attacks of angioedema in HAE patients are not clearly defined, it has been suggested that increased vascular permeability may be involved in bringing about an HAE attack primarily mediated through a C1-INH deficiency. Administration of Berinert® to patients with C1-INH deficiency replaces the missing protein and thereby raises the concentration of human C1-INH in human plasma back to normal levels.
Manufacturing Process and Process Controls
The current manufacturing process includes a multi-step process whereby a range of precautions have been implemented to minimize, to the greatest extent possible, the risk for potential viral transmission. In the manufacture of drug substance, C1-INH is derived from human plasma through absorption methods and then further purified through various precipitation steps. The methods employed in obtaining the drug substance have been extensively validated at full scale, down scale, and within process simulation studies. The validation studies employed are a risk based approach, identifying critical process steps, parameters, and acceptance range. The validation studies demonstrate that the drug substance can be consistently manufactured with the claimed standard and purity.
Characterization
Detailed characterization studies were performed to provide assurance that C1-INH consistently exhibits the desired biological activity.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of
C1-INH are considered acceptable. The proposed packaging components are considered acceptable.
Stability
Based on the real-time and accelerated stability data submitted, the proposed retest period, shelf-life, and storage conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Berinert® is a highly purified, pasteurized, lyophilized concentrate of human C1-INH to be reconstituted for intravenous (IV) administration. It is prepared from large pools of human plasma. Each Berinert® vial contains 500 units of C1-INH. One standard unit of C1-INH concentrate is equal to the amount of C1-INH in 1 mL of fresh citrated human plasma, which is equivalent to 270 mg/L. The product package is comprised of one carton containing a single-use vial of Berinert® and one vial containing the diluent for reconstitution, as well as a needleless medical device (Mix2VialTM) is enclosed to transfer the diluent into the vial containing the lyophilized powder. The product is sterile, free of pyrogens and does not contain preservatives.
All non-medicinal ingredients found in the drug product are well known physiological compounds and are acceptable for use in drugs according to the Food and Drug Regulations. The safety and compatibility of C1-INH with the non-medicinal ingredients has been demonstrated in pre-market and post-market clinical trials.
Pharmaceutical Development
Changes in the manufacturing process through product development are considered acceptable. The formulation used in clinical studies is the same as the formulation to be marketed.
Manufacturing Process and Process Controls
The drug product is formulated, sterile filtered, lyophilized and aseptically filled into vials using conventional pharmaceutical equipment and facilities. All manufacturing equipment, in-process manufacturing steps and detailed operating parameters were adequately described in the documentation provided and are acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Berinert® is tested to verify that its identity, appearance after reconstitution, C1-INH activity, and protein content are within acceptance criteria. Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.
Stability
Based on the real-time and accelerated stability data submitted, the proposed 30-months shelf-life at +2°C to +25°C for Berinert® is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The facilities used for the manufacturing, processing, testing, packaging, and labelling of Berinert® at the CSL Behring facility in Marburg, Germany site is in conformance with current Good Manufacturing Practices. An OSE of the facility involved in the manufacture and testing of Berinert® was not warranted since the facility was recently evaluated.
3.1.4 Adventitious Agents Safety Evaluation
Given C1-INH is produced from pooled human plasma, a range of precautions have been implemented to eliminate, or minimize to the greatest extent possible, the risk for potential transmission of infectious and/or pathogenic viruses. In the documentation submitted, it has been demonstrated throughout the entire manufacturing process (that is [i.e.] selecting plasma centres and raw material controls to fractionation, to purification, formulation and final container filling process) that appropriate measures are taken to avoid and control viral and non-viral adventitious agents. In addition, implementation of two specific virus inactivation steps during the manufacturing process further enhances the removal/inactivation of adventitious agents.
In addition, Berinert® does not contain any animal (including bovine) derived components as raw materials nor are any used during the manufacturing process. With the stringent exclusion criteria in place for selecting plasma donors, the risk of Berinert® to convey transmissible spongiform encephalopathy (TSE) is very remote.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Berinert® 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 pharmacodynamic efficacy of Berinert® was investigated in an in-vitro study which compared the effect of Berinert® on the complement system in human and rat plasma. The primary endpoint of the study was to determine what concentration would produce a 50% inhibition of the complement activity (IC50). Results of the study showed that Berinert® inhibited the human complement system with an IC50-value of 1.053 U/mL and the rat complement system with an IC50-value of 1.011 U/mL. Consequently, inhibition of human and rat complement with Berinert® appeared to be comparable.
Also, a series of published preclinical studies in animals further supported the beneficial effects of Berinert®. In these studies, it was shown that Berinert® inhibited carrageenin-induced oedema formation, capillary leakage, and a reperfusion injury. In addition, Berinert® mitigated the occurrence of shock, reduced mortality in several sepsis cases and reduced tissue damage in a rat stroke model. It was concluded that the inhibition of different biologically active proteases leads to diminished formation of oedema and could decrease an inflammatory response.
Furthermore, Berinert® was well tolerated in a safety pharmacology study conducted in dogs. However, a reduced coagulation time in the thromboelastogram of two dogs was depicted, and one dog showed a slight decrease in thrombocyte aggregation.
3.2.2 Pharmacokinetics
The pharmacokinetics of Berinert® was assessed in rats and rabbits. In rats, a single 61.5 units per kilogram (U/kg) or 123 U/kg Berinert® IV injection was administered and plasma levels were followed for up to 96 hours post-dose. Mean baseline plasma levels of C1-INH were found to be between 15 and 29%. A dose dependent increase in Cl-INH plasma levels was observed, although there was some variation in C1-INH levels. Approximately 72 hours post-dose, plasma levels had returned to baseline values. The pharmacokinetic study conducted in rabbits following an IV injection demonstrated that the initial and terminal half-lives were 0.16 ± 0.03 or 1.41 ± 0.22 days, respectively.
3.2.3 Toxicology
Single-Dose Toxicity
Single-dose studies with Berinert® were performed in rats and mice. Berinert® was administered intravenously at the following doses: 1500, 3000, and 6000 U/kg for mice and 1000, 2000, and 3000 U/kg for rats. Both rodent species were observed for a period of 14 days. Body weight was measured and clinical status was assessed daily. Results showed that the body weight development of mice and rats treated with C1-INH concentrate was similar to that of other control animals. All animals gained weight normally. Furthermore, there were no unscheduled deaths. Clinical investigations did not reveal any pathological signs, neither at the time of injection nor in the 14-day follow-up period. At the end of the observation period, autopsies were performed on both species. No pathological findings were observed at autopsy after 14 days in either mice or rats treated with Berinert® as compared to the controls. The compound was well tolerated at dosages of up to 6 000 U/kg and 3 000 U/kg mice and rats, respectively.
Repeat-Dose Toxicity
A repeat-dose toxicity study of Berinert® was performed in rats using doses of 20, 60 or 200 U/kg body weight (bw)/day for up to 14 days. Berinert® was administered daily as an IV bolus. A control group was treated similarly with an inert placebo (saline only). Clinical signs, food consumption, body weight and ophthalmoscopical examinations were recorded periodically during acclimatization and treatment periods. At the end of the dosing period, blood samples were withdrawn for haematology, plasma chemistry analyses and urinalysis. Results showed that IV administration of Berinert® resulted in no mortality, no clinical signs of toxicological relevance during the entire study period, no relevant changes in food consumption or body weights, no changes of toxicological relevance during the ophthalmoscopical examinations, no effects on haematology, clinical biochemistry or urine analysis parameters, no effects of toxicological relevance in the organ weights and no macroscopic or microscopic findings of toxicological relevance. However, findings of either phlebitis, periphlebitis, thrombophlebitis, and/or perivascular haemorrhage were noted at the injection sites in the majority of rats. These lesions also occurred in control rats and were attributed to the mechanical irritation caused by daily IV injections.
Measurement of C1-INH plasma levels resulted in a dose-dependency from the administered dose of Berinert®. However, the measurement of antibody response against C1-INH gave no clear results. Overall, the IV administration of Berinert® to rats appeared to be well tolerated up to the maximum dose of 200 U/kg body weight.
Genotoxicity
No studies on the genotoxic potential of Berinert® were performed as the ingredients of Berinert® are human plasma proteins and there is no evidence for mutagenic potential.
Mutagenicity/Carcinogenicity
As no oncogenic/carcinogenic effect of the product is expected in humans, no carcinogenicity studies were performed.
Neoantigenicity
A neonantigenicity study was conducted and did not indicate evidence of new antigenic determinants with use of Berinert®.
Reproductive and Developmental Toxicity
As Berinert® is manufactured from human plasma, adverse effects on fertility, postnatal development, and reproduction, as well as, teratogenic effects are not expected in humans. Furthermore, data on pregnant women treated with Berinert® did not show risks for embryotoxicity. Therefore, no studies on reproduction and developmental toxicity were performed.
Local Tolerance
A local tolerance study was conducted in rabbits administered IV and subcutaneous (SC) Berinert®. In one rabbit, a slight short-term irritation was noted after SC administration which was considered an isolated finding. Otherwise, no other pathological signs were observed.
3.2.4 Summary and Conclusion
The non-clinical program for Berinert® demonstrated that the product was generally well-tolerated in rats, mice, and rabbits. Treatment-related findings of either phlebitis, periphlebitis, thrombophlebitis, and/or perivascular haemorrhage were noted at the injection sites and were attributed to the mechanical irritation caused by daily IV injections. Overall, the non-clinical data provided supported the use of Berinert® in humans.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
No pharmacodynamic studies were performed for Berinert®. Given the physiological profile of Berinert® and the pathophysiological changes observed in patients with HAE, it is assumed that IV administered Berinert® has an identical pharmacodynamic profile to that endogenous C1-INH in the plasma of healthy individuals.
3.3.2 Pharmacokinetics
The pharmacokinetic profile of Berinert® was established through one open-label, uncontrolled, single center study in subjects with mild/moderate or severe HAE who were treated with a single dose of Berinert® either as a prophylactic or as on demand for an acute attack. The patients were treated with a single bolus IV infusion of 500 to 1,500 units. Each patient's blood was then sampled for up to 72 hours after treatment to assess C1-INH activity. Results showed that the median volume of distribution for Berinert® in all subjects was approximately 45.4 mL/kg bw, which corresponds approximately to 3.2 L for a person weighing 70 kg (or 154 lbs). The median systemic clearance was 1.0 mL/kg per hour with an overall elimination half-life of approximately 36 hours. The patients with severe HAE had a lower median half-life of approximately 31 hours and a lower volume distribution of 37.5 mL/kg bw than patients with mild or moderate HAE (37 hours and 51.9 mL/kg bw, respectively).
3.3.3 Clinical Efficacy
The clinical efficacy and safety profile of Berinert® is based mainly on information obtained in a pivotal double-blind, placebo-controlled study of C1-INH subjects with congenital C1-INH deficiency and acute abdominal or facial HAE attacks (Study CE1145_3001). An open-label, uncontrolled extension study (Study CE1145_3003) was also provided as a supportive study.
The pivotal study CE1145_3001 was a prospective, multinational, randomized, parallel-group, placebo-controlled, dose-finding, three-arm, double-blind study. The primary objective of this study was to show that Berinert® shortened the time to onset of relief of symptoms of an abdominal or facial attack compared to placebo. The time to onset of relief of symptoms was determined by the subject's response to a standard question posed at appropriate intervals for as long as 24 hours after start of treatment taking into account all single HAE symptoms. A secondary objective was to compare the efficacy of two different doses of Berinert®. A total of 124 adult and paediatric patients with C1-INH deficiency who were currently experiencing an acute abdominal or facial HAE attack of moderate to severe intensity were enrolled. Patients were randomized to one of three-arms and received by slow IV infusion either a single 10 U/kg bw or 20 U/kg bw dose of Berinert®, or a single dose of placebo. For each patient, only a single abdominal or facial attack was treated and evaluated. In addition, treatment had to be started within 5 hours of onset of an acute HAE attack. At 4 hours after treatment, if needed (i.e. if no or insufficient relief of symptoms was observed), patients could receive rescue medication as follows: 20 U/kg bw of Berinert® for patients in the placebo arm, 10 U/kg bw of Berinert® for patients in the 10 U/kg bw arm, and placebo for subjects in the 20 U/kg bw group. At least 70% of the subjects in each treatment group were required to be experiencing an abdominal attack.
Results from the study showed that the primary efficacy endpoint of time between the initiation of treatment and the onset of symptom relief (patient self-assessment) was statistically significantly shorter for the Berinert® 20 U/kg bw group 30 minutes compared to placebo 90 minutes. Within one hour after study medication administration, >74% of subjects treated with Berinert® 20 U/kg bw had reported onset of symptom relief, as compared to approximately 40% of subjects treated with placebo. The m edian time to onset of symptom relief was relatively short for subjects with abdominal attacks (placebo: 75 minutes; and Berinert® 20 U/kg bw group: 30 minutes) compared to subjects with facial attacks (placebo: 24.0 hours; and Berinert® 20 U/kg bw group: 55 minutes). In addition, results from the analysis of other secondary efficacy endpoints, including increased intensity of HAE symptoms between 2 and 4 hours after start of study medication compared to baseline and number of vomiting episodes within 4 hours after start of study medication demonstrated trends in favour of Berinert® compared to placebo.
The extension study CE1145_3003, is a prospective, uncontrolled, multicenter, open-label study undertaken in subjects who had participated in the pivotal study. The primary objective of this study is to document the multiple uses of C1-INH in the treatment of all types of HAE attacks, including laryngeal and peripheral attacks that were not eligible in the pivotal study. The s ubjects received study medication at a dosage of 20 U/kg bw by IV infusion, and were observed at the study site until the onset of relief of HAE symptoms. The primary efficacy endpoint was considered by the sponsor to be identical to that of the pivotal study CE1145_3001 (i.e. the time between the start of study medication administration and onset of relief of symptoms from an HAE attack as determined by the subject's assessment). However, the use of concomitant medication prior to the onset of symptoms relief was not taken into account. In this study, a total of 56 subjects (19 males and 37 females with 559 HAE attacks treated with 20 unit/kg bw dose of Berinert® per attack were observed at the study site until onset of relief of HAE symptoms and were followed up for AEs for 7 to 9 days following treatment of each HAE attack. There were 49 subjects with abdominal attacks, 11 subjects with facial attacks, 28 subjects with peripheral attacks and 12 subjects with laryngeal attack.
In conclusion, from the data submitted, it was demonstrated that Berinert® was effective in hastening the start of relief of abdominal and facial HAE attack symptoms in the overall population.
3.3.4 Clinical Safety
The clinical safety of Berinert® was assessed using data from the pivotal double-blind, placebo-controlled study CE1145_3001 and its ongoing, open-label, uncontrolled extension study CE1145_3003. In addition, further safety data was also provided from studies outside of the scope of HAE attack treatment.
The most serious adverse reactions reported in subjects included in the clinical studies and who received Berinert® was an increase in the severity of pain associated with HAE.
The most common adverse reactions that have been reported in greater than 4% of the subjects who received Berinert® are headache, abdominal pain, nausea, muscle spasms, pain, diarrhea, and vomiting. The other common adverse reactions that have been reported in 1% to 4 % of the subjects who received Berinert® are back pain, dysgeusia, edema peripheral, abdominal distension and upper respiratory tract infection.
In the pivotal study during the first 4 hours after the product administration, (4 hours safety population) 20 % of subjects in the Berinert® 20 U/kg experienced AEs compared to 44% of placebo subjects. Adverse events considered at least possibly related to study medication were also lower in the Berinert® 20 U/kg bw group (11%) compared to the placebo group (20%).
Only one subject within the Berinert® 20 U/kg bw group reported severe AEs, in comparison to eleven subjects in the placebo group. One serious adverse event (SAE) leading to discontinuation of the study medication (infusion related reaction) occurred within 4 hours after start of the study medication in one 20 U/kg Berinert® subject.
No deaths occurred in either study. The deaths which occurred in the earlier supportive studies were all considered to be caused by pre-existing underlying conditions other than HAE. In all cases, these deaths were not attributed to the administration of Berinert®.
However, the use of Berinert® at higher than recommended doses has been associated with the development of thrombosis in another clinical trial in paediatric subjects where the product was administered for an indication other than HAE.
Overall, clinical studies have demonstrated that Berinert® is safe, effective and shortens the median time to onset of symptom relief for patients with acute HAE attacks.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Therapeutic options for HAE are limited. The data in this application demonstrated that when Berinert® is given within 5 hours of onset of acute abdominal or facial HAE attacks, it was effective in hastening the start of relief of HAE attack symptoms in the overall study population. Berinert®, when used as per the recommendations in the Product Monograph was demonstrated to have an acceptable safety profile. The benefit risk ratio for Berinert® is favourable.
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 Berinert® is favourable in the treatment of acute abdominal or facial attacks of hereditary angioedema (HAE) of moderate and severe intensity. 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: Berinert®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2008-03-17 |
| Submission filed: | 2008-04-07 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2008-05-29 |
| Review 1 | |
| Quality Evaluation complete : | 2009-03-11 |
| Clinical Evaluation complete: | 2009-03-25 |
| Notice of Non-Compliance (NON) issued by Director General (efficacy issues): | 2009-03-25 |
| Response filed: | 2009-06-19 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2009-07-29 |
| Review 2 | |
| Quality Evaluation complete: | 2010-03-10 |
| Clinical Evaluation complete: | 2010-05-28 |
| Labelling Review complete: | 2010-05-28 |
| Notice of Compliance issued by Director General: | 2010-05-31 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| BERINERT 500 | 02352575 | CSL BEHRING CANADA INC | C1 ESTERASE INHIBITOR (HUMAN) 500 UNIT / VIAL |