Archived Content

The content on this page is provided for reference purposes only. This content has not been altered or updated since it was archived.

Vaccines, Blood & Biologics

Review Memo for Pharmacovigilance Planning - Berinert, September 21, 2009

Subject:BLA STN:  125287/0/37
C1 Esterase Inhibitor, Human
CSL Behring
OBE/DE Review for Pharmacovigilance Planning
Date:September 21, 2009
From:Faith Barash, M.D., M.P.H.
Medical Officer, CBER, OBE, DE, TBSB
Through:Robert P. Wise, M.D., M.P.H.
Branch Chief and Deputy Director, CBER, OBE, DE, TBSB

Rickey Wilson, M.D., M.S., J.D.
Director, DE, OBE



OBE/DE/TBSB has completed a review of BLA STN 125287/0/37 as a resubmission of the original application for 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.

Product Background

Hereditary angioedema (HAE) is an autosomal dominant disorder of C1 inhibitor deficiency. HAE affects roughly 6,000 to 10,000 individuals in the United States.  An acute HAE attack can occur spontaneously, or during stress, surgery or infection.  It can result in 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.

Berinert [C1 Esterase Inhibitor (Human)] (C1-INH) is a plasma derived, purified, lyophilized concentrate to be reconstituted for the treatment of acute abdominal or facial attacks in patients with hereditary angioedema (HAE).     

C1-INH belongs to the group of serine protease inhibitors, which include antithrombin III, alpha1 protease inhibitor, alpha II 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 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.

Clinical Studies for this submission

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 study provides the safety and efficacy data supporting the use of C1-INH in the treatment of acute attacks in patients with HAE.  It was designed as 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 126 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.

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. 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 performed.  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 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).

Specific studies on hepatic impairment, renal impairment, and on pregnant and lactating patients were not conducted, other than a retrospective case collection study conducted in 20 pregnant patients, mentioned previously.   Safety and efficacy in children age 0-12 have not been established.  There was an insufficient number or subjects in this age group to determine whether the respond differently than older subjects.  The safety and efficacy was evaluated in 5 children (ages 3-12) and in 8 adolescents (ages 13-16).

Safety and efficacy of Berinert in the geriatric population has not been established.  Clinical studies included 4 subjects age greater than 65, and insufficient number to determine whether they respond differently from younger subjects.

Summary of Sponsor’s Pharmacovigilance Planning

Safety Assessment and Major Safety Concerns

Thrombotic Events

Berinert has not caused thrombosis when used as labeled to treat HAE. Thrombotic events have been reported in association with C1 esterase inhibitor products when used off-label and at higher than labeled doses. The Package insert used outside the US has been updated to address the potential risk of thrombosis.

Since 1985 a total of 15 spontaneous reports of thrombosis were received by the sponsor.  The outcome was fatal in 11 cases (10 off-label use), recovered in one case and unknown in three cases.  14/15 reports were in off label use in cardiac surgery (12 newborns, one 6 year old, one 72 year old).  One report was in a 52 year old, for which causality was excluded after autopsy.

Transmission of Infectious Agents

Because Berinert is made from human plasma, it may contain infectious agents.  The risk has been reduced by screening donors, by testing for the presence of current infections, and by processes demonstrated to inactivate and/or remove certain viruses during manufacturing.

Despite such measures, these products may still potentially transmit disease.

A small number of suspected cases of viral transmission have been reported.

The virus safety of Berinert 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.   No subject who underwent testing evidenced seroconversion or treatment-emergent positive polymerase chain reaction testing for the above pathogens.

The sponsor concluded that no proven cases of product-related HIV, HAV, HBV, HCV or B19 virus transmission have been reported.

Because of concerns about viral validation, the sponsor was requested to improve the viral reduction procedures and perform additional studies on viral validation.  This requirement was completed for the current submission.

Post-marketing (non study) Exposure

Patient exposure is presented as the number of estimated standard doses based on the units distributed.  This method is felt to be appropriate for the indications of C1-INH.

From 1985 until June 2009, sales amounted to --b(4)------- Units of Berinert.

Between 1 Jan 1985 and 30 Nov 2008, a total of ---b(4)-------- units of Berinert had been distributed.  During this period, a total of 54 spontaneous adverse drug reactions had been received.  The estimated standard dose was 500 U at this time.  This corresponds to

-b(4)- applications of 500 U.  Thus, approximately 1 report for every -b(4)- 500U applications had been received during this time period.

After availability of the results of clinical study CE1145_3001, dosing had been revised, and the currently labeled dose of 20 U/ kg body weight was introduced to the market.  The estimated standard dose was therefore recalculated based on the assumption of a 75 kg body weight average person, i.e. 20 U/kg body weight X 75 kg = 1500U.

Between 1 Dec 2008 and 30 June 2009, a total of --b(4)-- U have been distributed.  During this time, a total of 2 spontaneous adverse drug reactions have been received.

This corresponds to approximately 1 report for every -b(4)- applications.

Routine Plans

When a new product is marketed, the exposed population may differ from the population studied in the pre-approval studies. 

In terms of pharmacovigilance for marketed products, the CSL Pharmacovigilance 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

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 (, 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 ( 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.

These recommendations are based on the information provided from the sponsor’s assessment of the data accumulated in post-market surveillance outside of the United States, as well as safety data accumulated in the clinical studies presented.

Postmarketing data are based on spontaneous reports from from countries/ regions where Berinert is currently licensed and marketed.

Routine pharmacovigilance activities include:

  1. Adverse reaction/event collection and single case processing
  • Maintenance of validated database for centralized collection, permanent retention and retrieval of post-marketing spontaneous reports
  • Real time medical review of all post-marketing adverse reaction reports
  • Follow-up of appropriate cases
  • Preparation and electronic submission of case reports to regulatory authorities
  1. Post-marketing signal detection
  • Periodic review of line listings for suspected adverse reactions
  • Signal detection methodology appropriate to the drug and number of cases
  • Surveillance of post-marketing risks based on assessment and evaluation of collected adverse reaction data
  • Routine review of the worldwide scientific literature based on safety literature searches performed on weekly basis
  1. Aggregate reports
  • Preparation of reports for health authorities, including Periodic Safety Update Reports and equivalent safety summaries
  • Ad hoc safety reports or interim reports on specific topics as requested by FDA, regulatory authorities or as dictated by signal detection activities
  1. Continuous oversight of safety
  • Continuous monitoring and management of the safety profile and benefit  risk balance of marketed products
  • Activities as a result of PV issues including labeling  updates, assessment of need for risk minimization measures and communication with FDA and other regulatory authorities as appropriate

Non-Routine Plans


Given the safety record of the product, there are few non-routine pharmacovigilance plans proposed.

Clinical studies and 24 years of documented post-marketing experience demonstrate the rarity of adverse events.

CSLB’s routine pharmacovigilance program has been shown to be effective. 

To supplement the program, additional actions as committed to FDA are presented below:

  • All thrombotic or thrombo-embolic adverse reactions or possible virus transmission will be reported to FDA as either 7- or 15- day safety reports
  • A registry of patients treated with CSLB’s C1-INH for any indication will be established in the U.S. and maintained for the first three years after licensure.  CSLB expects to enroll approximately 100 patients to the registry within three years.  A structured questionnaire will be used to obtain data on indication for C1-INH, administered doses, patient demographics, concomitant medications or plasma products, and adverse events.  The registry will permit a mechanism for enhanced detection of thrombotic or thrombo-embolic events.  Annual reporting of the overall status of the registry will be performed, and final report will be submitted to FDA 12 months after completion of the registry project.


Berinert 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 1985.  A similar human plasma-derived product from another sponsor 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 viral transmission.

Although there are no proven cases of viral transmission with C1-INH, the possibility of viral transmission remains when a product is plasma-derived.  Although the number of reported adverse events is relatively small compared to the large number of doses given, there remains concern about viral safety in any plasma derived product.  

CSL Behring has initiated improved viral reduction mechanisms and performed viral validation studies since the first submission.  The details are presented in the amended submission.

A robust pharmacovigilance plan has been submitted by the sponsor to address possible concerns about thrombotic, thrombo-embolic, and viral transmission issues.

Letter comments for communication to the sponsor:


1.  You have developed 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 the pharmacovigilance plan for C1-INH include routine pharmacovigilance (i.e., compliance with applicable post-market reporting requirements under FDA regulations) and additional post-market actions, a patient registry, and structured questionnaire to address potential safety issues, such as the possibility for viral transmission or thromboembolic events.

All thromboembolic events will be reported as expedited 7 or 15-day reports.  These will be reported whether the product is used on label or off label, and regardless of dosage or indication for use. 


2.  You will use a patient registry for HAE patients treated with C1-INH and a structured questionnaire of patients treated with C1-INH who experience thromboembolic events or viral seroconversion. Variables considered as part of the registry include administered doses, indication for C1-INH, patient demographics, concomitant medications and plasma products, adverse events, and viral testing.

Page Last Updated: 04/09/2015
Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and Players.
Language Assistance Available: Español | 繁體中文 | Tiếng Việt | 한국어 | Tagalog | Русский | العربية | Kreyòl Ayisyen | Français | Polski | Português | Italiano | Deutsch | 日本語 | فارسی | English