|Subject:||BLA STN: 125287/0 |
C1 Esterase Inhibitor, Human
OBE/DE Review for Pharmacovigilance Planning
|Date:||October 22, 2008|
|From:||Faith Barash, M.D., M.P.H. |
Medical Officer, TBSB/DE/OBE/CBER
|Through:||Craig Zinderman, M.D., M.P.H. |
Acting Branch Chief, TBSB/DE/OBE/CBER
Robert Wise, M.D., M.P.H.
Acting Division Director, DE/OBE/CBER
OBE/DE/TBSB has completed a review of BLA STN 125287/0 C1 Esterase Inhibitor, Human (CSL Behring). The purpose of this review is to identify potential safety issues that may need to be addressed through post-market safety monitoring, studies or other pharmacovigilance activities, should this product be licensed.
Hereditary angioedema is an autosomal dominant disorder of C1 inhibitor deficiency. HAE affects roughly 6,000 to 10,000 individuals in the United States. Acute HAE attacks, which can occur spontaneously or during stress, surgery or infection, produce edema of the hands, feet, face, intestinal tract, and larynx. Swelling of the larynx can lead to asphyxiation. Mortality rates are estimated at 15% - 30%, largely due to laryngeal edema. Treatment of choice in acute attacks consists of replacement with commercially available C1 Esterase Inhibitor concentrates, or, if unavailable, fresh-frozen plasma. C1 Esterase Inhibitor, Human (C1-INH) is indicated for the treatment of acute attacks in patients with hereditary angioedema (HAE).
The trade name outside the United States is “Berinert P”. The proposed trade name for CSL Behring’s C1 Esterase inhibitor product in the United States is under discussion. The product code designation is “CE 1145”.
C1-INH belongs to the group of serine protease inhibitors, which include antithrombin III, alpha1 protease inhibitor, alpha 2 antiplasmin, and heparin cofactor II. This plasma protein regulates clotting and inflammatory reactions that, when impaired, can lead to local tissue swelling. C1 esterase inhibitor is low or does not function properly in individuals with HAE.
The final product is a pasteurized concentrate of plasma derived C1-INH for intravenous administration. Each vial contains 500 U of lyophilized C1-INH, 85- 115 mg glycine, 25-35 mg sodium chloride, and 70-100 mg sodium citrate. Prior to administration, it is to be reconstituted with 10 mL of sterile water for injection.
The recommended dose is 20 units per kg body weight at an infusion rate of 4 mL per minute. Clinical studies demonstrate that 20 units per kg dose of C1-INH is effective and shortens the median time to onset of symptom relief for patients with acute HAE attacks.
When a new product is marketed, the exposed population may differ from the population studied in the pre-approval studies. The exposed population in the pre-approval trials consisted of 125 patients randomized to receive either 10 U, 20 U or placebo for treatment of acute attacks of HAE.
For most products, routine pharmacovigilance (i.e., compliance with applicable postmarket reporting requirements under FDA regulations) is sufficient for post-marketing risk assessment. As outlined in Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (http://fda.gov/CDER/guidance/63590CC.htm), FDA believes pharmacovigilance plans may be appropriate when: 1) Serious safety risks have been identified pre- or post-approval, or 2) at risk populations have not been adequately studied. The ICH E2E Pharmacovigilance Planning guidance (http://www.fda.gov/cber/gdlns/ichpvp.htm) indicates that for products with important identified risks, important potential risks, or missing information, additional actions designed to address these concerns should be considered as part of the pharmacovigilance plan. The pharmacovigilance plan is developed by a product’s sponsor and is specifically focused on detecting new safety risks and/or evaluating already identified safety risks.
Pharmacovigilance Post-marketing Recommendations for BLA STN 125287/0
These recommendations are based on the information provided from the sponsor’s assessment of the data accumulated over the time period during which a similar product has been licensed, as well as safety data accumulated in the clinical studies presented.
Postmarketing data are based on spontaneous reports from a post-marketing surveillance system received from countries/ regions where Berinert is currently licensed and marketed.
CSL and CSL Behring have established a global pharmacovigilance organization, which maintains a system to ensure that information about all individual case safety reports (ICSR) are reported to the company from any source, and is collected and collated at the designated sites. The CSL PhV sites operate in accordance with the applicable regulatory requirements, the ICH guidelines, and global company internal standards.
In terms of pharmacovigilance for marketed products, the CSL PhV sites are responsible for the ICSR processing, medical review and expedited reporting of ICSR’s from the following sources:
- Spontaneous reports from health care professionals and lay persons
- Company initiated, non-interventional post authorization studies
- Worldwide scientific literature
- Post-authorization studies not sponsored by CSLB
In worldwide post-marketing surveillance, CSL Behring received 57 adverse drug reactions (ADR) reports for the period of 1985 through December 2007. There were an estimated --b(4)-- single standard doses sold during this time period. This results in an overall ADR reporting rate of one report per --b(4)-- estimated single standard doses. CSLB indicates that 37 of the 57 ADR’s are covered by the known safety profile of CE1145.
The reported cases were as follow:
- Allergic/anaphylactic reactions 7 cases
- Chills/fever 2 cases
- Lack of effect 9 cases
- Suspected viral transmission 5 cases
- Thrombosis 14 cases
- Unexpected 20 cases
Human pasteurized C1 esterase inhibitor concentrate (CE1145) in subjects with congenital C1-INH deficiency and acute abdominal or facial HAE attack (Study no. CE1145_3001)
This is the pivotal study in this application and provides the safety and efficacy data supporting the use of C1-INH in the treatment of acute attacks in patients with HAE. It is a double-blind multinational, prospective, randomized, parallel group, placebo-controlled, dose-finding, 3-arm clinical study. In total, 125 subjects were randomized to one of the 3 arms of the study. Of the 124 subjects in the ITT population, 40 received C1-INH 10 U/kg body weight, 43 received 20 U/kg body weight, and 42 received placebo. Subjects were experiencing moderate to severe attacks of facial or abdominal HAE. Subjects ranged in age from six to 72 years old. 67.7% were female and 32.3% were male. Approximately 90% were Caucasian.
The study objectives were to show that C1-INH shortens the time to onset of relief of symptoms of an abdominal or facial attack compared to placebo, and to compare the efficacy of the two different doses.
Open-label extension study of CE1145 (human pasteurized C1 esterase inhibitor concentrate) in subjects with congenital C1-INH deficiency and acute HAE attacks
(Study no. CE1145_3003)
This clinical study is an ongoing, open-label prospective, uncontrolled, multicenter, extension study to the Study CE1145_3001. It is being conducted at 10 centers in the United States. Subjects may be enrolled in the extension study after they have received study medication in Study CE1145_3001 and the 24-hour assessment of the primary efficacy parameter in Study CE1145_3001 had been carried out. After this time, subjects who experienced HAE attacks at any body site that required treatment were eligible for treatment in Study CE1145_3003. Subjects who were screened and eligible, but not treated, and who developed laryngeal edema were also allowed to be enrolled and treated in Study CE1145_3003. As of June 29, 2007, which was the cut off date for study data in this BLA, 39 study subjects with 355 attacks have been treated.
The initial analysis of the CE1145_3001 study data was performed after the clinical database was closed on November 14, 2007. After this analysis was completed, the data base was re-opened to enter 12 week follow-up safety data. New and updated adverse event data were entered, as well as virus safety and final assessment data.
Supportive efficacy and safety data for CE1145 are also available from 2 earlier studies in subjects with HAE.
Study 7D-201CI- OB was an open label, uncontrolled study that investigated the efficacy and safety of CE1145 in 9 subjects with HAE after treatment with 20 doses of CE1145. A total of 8 subjects (16 doses) were treated for edema attacks and 1 subject (4 doses) was treated prophylactically.
Study CE1145_6001 was a retrospective case collection study conducted between 1997 and 2005 in which the efficacy and safety of CE1145 were documented for 20 women who had been treated with CE1145 during pregnancy. These women had a total of 33 deliveries involving 34 children.
Study 7A-202CH-B was a placebo-controlled, double-blind study that investigated the efficacy and safety of CE1145 in 30 subjects undergoing extracorporeal circulation.
Study 7B-201CH-C was a placebo-controlled, double-blind study that investigated the efficacy and safety of CE1145 in 30 subjects undergoing extracorporeal circulation after cardiac surgery.
Two earlier, open-label, case documentation studies conducted in 13 subjects with hereditary or acquired C1-INH deficiency were specifically designed to investigate virus safety after single administration of CE1145 (Study 7MN-402CI-OB) and multiple administration of CE1145 (Study 7MN-401CI-OB, involving long term follow-up of subjects treated in Study 7MN-402CI-OB).
Suspected virus transmission
The virus safety of CE1145 with respect to HIV-1, HIV-2, HAV, HBV, HCV and B19V was assessed by serologic markers before treatment and up to approximately 12 weeks after treatment in Study CE1145_3001, and in the same manner for the first attack in Study CE1145_3003. Overall, shifts from negative to positive were recorded in 5 subjects.
Case ---b(6)------ concerns suspected transmission of hepatitis C. The sponsor states that a causal relationship was excluded because the applied Berinert lot was produced from HCV genome negative tested source material.
Case ---b(6)------ concerns suspected transmission of hepatitis B. The last application of Berinert had taken place 2 years before the diagnosis of hepatitis B. A causal relationship was excluded by the treating physician, as the patient admitted to him a "very close" contact with a high risk population during a trip through Africa which had taken place 2-3 months prior to the diagnosis of hepatitis B.
Case ---b(6)------ concerns suspected transmission of cytomegalovirus in a 2 month old baby. A causal relationship is excluded because the incubation period of 1 day is too short, and the reporting physician assessed that a prenatal infection is the most probable cause.
Case ---b(6)------ concerns suspected hepatitis G seroconversion in an unsponsored study. The sponsor states that a causal relationship was excluded as there were no other reports of viral transmission regarding the applied lots, and the manufacturing process for Berinert has shown a high virus inactivation/elimination capacity for Bovine Viral Diarrheal Virus, which is “the model" virus for hepatitis G.
Case ---b(6)------ concerns suspected transmission of hepatitis B in a female patient who received Berinert in January 2003. Several months later, hepatitis B was diagnosed. Despite inquiries, no further information was provided. The sponsor states that a causal relationship was excluded because the respective lot was manufactured from HBV-b(4)- negative source plasma.
The sponsor concluded that no proven cases of product-related HIV, HAV, HBV, HCV or B19 virus transmission have been reported.
Thrombosis did not occur in connection with treatment of HAE. The development of thrombosis has been reported after high doses (>90 U/kg body weight) in newborns or young children with congenital heart anomalies during or after cardiac surgery under extracorporeal circulation.
5 of the 14 reports were received spontaneously, while the remaining 9 were collected by CSL Behring during active investigation. 12 reports concerned newborns, 1 report a 6 year old boy and 1 adult. All subjects had received high dose treatment with CE1145 for attempted prophylaxis or therapy of Capillary Leak Syndrome following cardiac surgery under extracorporeal circulation. This indication and dosage is not approved for use. The Package insert used outside the US has been updated to address the potential risk of thrombosis.
Overall, 20 of the 57 reported ADR’s were classified as “unexpected.” This means that they are not covered by the known safety profile of CE1145. In none of these cases could a causal relationship be established by the sponsor. Cases of special interest are discussed below.
Case -----b(6)-------concerns an interaction with acenocoumarol. Alternative explanation includes the effect of Rifampin as a concomitant medication.
Case -----b(6)------- concerns right sides pain; alternative explanation is renal colic.
Case -----b(6)------- concerns suspected Stevens Johnson Syndrome. An alternative explanation exists because the patient was suffering from graft versus host disease, and the patient was receiving numerous comcomitant medications, i.e., antibiotics, immunosuppressants.
Case -----b(6)--- concerns a 95 year old male with a history of bronchopneumopathy with asthma, myocardial infarction, hyperthyreosis, phlebitis and pulmonary embolism. Patient received Berinert for angioedema linked to treatment with angiotensin converting enzyme (ACE) inhibitors. The treatment of angioedema linked to treatment with ACE inhibitors is an unapproved indication for Berinert. The underlying disease and patient’s age provide alternative explanations for patient’s death.
Case ---b(6)----- concerns a male patient with a history of nicotine and alcohol abuse treated with Berinert 500 U for suspicion of hereditary angioedema and recurrent urticaria. Patient suffered from seizures before and during administration of Berinert. Basilar artery thrombosis was diagnosed and treated with fibrinolytic therapy. Patient died, and autopsy showed cerebral edema, cerebromalacia, subarachnoid hemorrhage, brain stem hemorrhage and sclerosis of basal cerebral arteries. Causal relationship was excluded due to the short interval (6 hours) from the time of application to the diagnosis. Cerebral hemorrhage is more likely the complication of lysis therapy.
Case -----b(6)------- concerns a four week old girl with congenital heart anomaly who underwent cardiac surgery. Intra and postoperatively, she received Berinert. Surgery required prolonged use of heart lung machine and postoperative course was complicated.
Ten of the 20 ADR’s were received from an investigator initiated study, and included septic shock. In all cases, the reporting physician stated that the underlying disease was an alternative and more probable cause for the adverse event.
The most frequently observed AE’s and ADR’s in the post marketing experience, with approved usage ,were anaphylactic/allergic reactions similar to the AE profile of the clinical studies.
The most serious adverse reaction reported in subjects in clinical studies was an increase in the severity of pain associated with HAE.
Overall, 12 serious adverse events (SAE’s) occurred in 6 subjects (5 unique individuals) in Studies CE1145_3001 and CE1145_3003. 11 of these serious AE’s were cases of HAE ( new attack or exacerbation), while the remaining SAE was a case of staphylococcal infection occurring approximately 6 weeks after treatment. Only one was considered by the investigator to be at least possibly related to the study medication. All resolved without sequelae.
There were no deaths in Studies CE1145_3001 and CE1145_3003.
Two deaths occurred in the supporting studies, in subjects undergoing extracorporeal circulation in the context of cardiac surgery. Both events leading to death (Staphylococcal septicemia in Study 7A-202CH-B and aortic rupture in Study 7B-201CH-C) were assessed as unrelated to study medication and were attributed to the underlying disease.
Seven deaths occurred in earlier studies that are not included in the current submission. One death each due to aspergillosis and pneumothorax/sepsis, one death due to multiorgan failure, 2 deaths due to sepsis. The investigators considered all 7 deaths as unrelated to the treatment with CE1145.
Of the 399 attacks treated with CE1145 20 U/kg body weight, 19 (4.8%) were associated with adverse events. AE’s were most frequently reported in the system organ classes of gastrointestinal disorders, general disorders and administration site conditions, and musculoskeletal/connective tissue disorders.
In worldwide post marketing surveillance, CSL Behring has received 57 suspected adverse reactions reports for the period of 1985 through December 2007. There were an estimated --b(4)-- single standard doses sold during this time period. This results in an overall ADR reporting rate of one report per every -b(4)- estimated single standard doses. Overall, 37 of the 57 ADR’s are covered by the known safety profile of CE1145.
CE1145, known as “Berinert” in other countries/regions, is a plasma derived C1 Esterase inhibitor concentrate for the treatment of acute attacks of hereditary angioedema. The product has been licensed and used in Europe since 1987,
A similar product has been recently licensed for the prophylactic treatment of attacks of HAE. The alternative treatment is fresh-frozen plasma, which carries with it the increased risk of sensitization and viral transmission.
Although there are no proven cases of viral transmission with C1-INH, the possibility of viral transmission remains when the product is plasma-derived. Although the number of adverse events is relatively small as compared to the large number of doses given, there remains some concern about viral safety. There are alternative explanations for the 5 seroconversions observed in clinical trials and the source plasma of the lots involved in these cases screened negative for viral markers. However, viral transmission due to the product cannot completely be excluded in at least three of the cases
1. The sponsor should develop and implementing a pharmacovigilance plan, per the ICH E2E Pharmacovigilance Planning guidance, to monitor long-term safety with the use of C1-INH. The major components of a pharmacovigilance plan for C1-INH should include routine pharmacovigilance (i.e., compliance with applicable post-market reporting requirements under FDA regulations) and possibly additional post-market actions (e.g., a patient registry) to address any potential safety issues, such as the possibility for viral transmission.
2. The sponsor should maintain a patient registry of patients treated with C1-INH. HAE is a very rare disease, and increased reporting of associated safety problems may be achieved by use of a patient registry. Variables to consider recording as part of the registry include administered doses, indication for C1-INH, patient demographics, concomitant medications and plasma products, adverse events, and viral testing.
Letter comments for communication to the sponsor:
1. You should develop and implement a post-licensure pharmacovigilance plan, per the ICH E2E Pharmacovigilance Planning guidance, to monitor long-term safety with the use of C1-INH. The major components of a pharmacovigilance plan for C1-INH should include routine pharmacovigilance (i.e., compliance with applicable post-market reporting requirements under FDA regulations) and possibly additional post-market actions (e.g., a patient registry) to address any potential safety issues, such as the possibility for viral transmission.
2. You should maintain a patient registry of patients treated with C1-INH. HAE is a very rare disease, and increased reporting of associated safety problems may be achieved by use of a patient registry. Variables to consider recording as part of the registry include administered doses, indication for C1-INH, patient demographics, concomitant medications and plasma products, adverse events, and viral testing.