|Subject:|| BLA STN 125317|
Human Fibrinogen Concentrate, Pasteurized
OBE/DE Review for Pharmacovigilance Planning
|Date:||December 22, 2008|
|From:||Faith Barash, MD MPH|
Medical Officer, TBSB/DE/OBE/CBER
Craig Zinderman, MD MPH
Robert Wise, MD MPH
OBE/DE has completed a review of BLA STN 125317 for Human Fibrinogen concentrate, Pasteurized (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 the product be licensed.
Human fibrinogen concentrate, pasteurized (HFCP) is a concentrated form of human fibrinogen (coagulation factor I) derived from human plasma. The proposed indication for HFCP is for the treatment of patients with congenital fibrinogen deficiency, which comprises congenital afibrinogenemia, hypofibrinogenemia and dysfibrinogenemia. Determination of patients’ fibrinogen levels is recommended prior to and during treatment with HFCP, to maintain fibrinogen levels. The usual starting dose for adults is 1-2 grams, to obtain a replacement level or at or above .5-.8 g/L. Normal levels range from 200 – 450 mg/dl. If the fibrinogen level is unknown, the recommended dose is 70 mg/kg. HFCP is supplied as lyophilized powder and, after reconstitution, administered by slow, intravenous infusion. The labeled amount of HFCP is 1 g of fibrinogen with the actual potency for each lot indicated on the vial label and carton. The proposed trade name for HFCP is Riastap.
Previous clinical studies have demonstrated that HFCP is safe, effective and aims to increase fibrinogen levels to a clinically meaningful plasma level.
Congenital fibrinogen deficiency is a very rare bleeding disorder. Hereditary afibrinogenemia affects an estimated 150-300 people in the US, based on published prevalence data. The prevalence of hypofibrinogenemia and dysfibrinogenemia are unknown. Patients with any of these conditions are treated for bleeding either by substitution with a cryoprecipitate or fresh frozen plasma. There are no fibrinogen concentrate products currently approved in the US. There is arguably a medical need, as cryoprecipitate or fresh frozen plasma could carry higher risk of transmissible viral disease. Additionally, large volumes are transfused, exposing patients to unnecessary proteins and increasing the risk of anaphylaxis. FFP and cryoprecipitate must be thawed before use, and can be administered only in a hospital.
Product Marketing History
CSL Behring has marketed a fibrinogen concentrate product (Haemocomplettan P/ HS/dual) since 1986 in 7 European countries and other regions throughout the world. The drug substance production processes for both and Haemocomplettan P are equivalent, except that HFCP (Riastap) uses a US licensed -(b)(4)- human albumin, -(b)(4)-, as a stabilizing agent; Haemocomplettan uses Human Albumin ---(b)(4)----, which is not registered in the US.
When a new product is marketed, the exposed population may differ from the population studied in pre-approval trials. In this particular case, the product has been licensed and marketed previously in Europe. Thus, there has been a larger exposed population than were available in clinical trials and spontaneously reported AEs from this population are available for assessment of safety.
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 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 Postmarketing Recommendations for BLA STN 125317
These recommendations are based on the information provided from the sponsor’s assessment of the data accumulated over the time period during which the product has been licensed, as well as safety data accumulated in clinical studies presented.
CSL Behring has received a total of 48 adverse event reports for Haemocomplettan P since it began marketing in Europe (1986-2008). This corresponds to one report for every 3,414 doses distributed over this time period. CSL’s medical analyses of these reports did not reveal any relevant safety issues for the treatment of congenital fibrinogen deficiency.
There appears to be a relatively small crude number of AEs relative to the number of doses administered. However, to expedite review and assessment of potential safety risks identified in these reports, we recommend that the sponsor submit a detailed line list of all AEs, including thromboembolic events,, and any other relevant information. Also, please describe the surveillance method by which these AE reports were collected: spontaneous, passive reporting, through a registry, active surveillance, or other methods.
The sponsor indicates that two 5-year Periodic Safety Update Reports (starting in 1999) and several addendum reports covering the previous years have been compiled for Haemocomplettan P. These reports consider postmarketing safety data for the time period of 1986- 2008. We recommend that the sponsor submit these reports as addendums to the BLA for HFCP. Please also summarize the types of patients (demographics and indications) who received the marketed product in Europe, if such data is available.
Please include the safety data on acquired hypofibrinogenemia.
Safety Assessment from Clinical Studies
There were 3 studies that evaluated the safety and efficacy of HFCP in the target population. 1) the pivotal study 2001, using a surrogate endpoint for efficacy, 2) the supporting study 7MN-501FM (Phase IV), and 3) the clinical survey CE 1221_1.
The pivotal study for the BLA, Study No. B13023_2001, uses maximum clot firmness (MCF) as a surrogate endpoint to demonstrate hemostatic efficacy. Study 2001 is a prospective, open, uncontrolled study in 12 evaluable subjects to collect PK and safety data and to demonstrate hemostatic efficacy using MCF as a surrogate endpoint. MCF is measured using thromboelastography, which is a method for the continuous measurement of clot formation. Duration of the study is to be about 12 months.
This surrogate endpoint will be validated by showing an association between MCF and clinical efficacy in a postmarketing study (Study No. B13023_3001, see below). The postmarketing protocol for B13023_3001 has already been submitted to study sites for institutional review board approval, in order to initiate the study which has a 60 month enrollment period.
The Supporting Study 7D-501FM, “Clinical Observational Monitoring Project (COMP) on the Efficacy and Tolerance of Human Fibrinogen Concentrate (Haemocomplettan HS) in Patients with Acquired Hypofibrinogenemia”, was a prospective, open label, uncontrolled study performed between April 1991 and June 1994 in 94 subjects with acquired hypofibrinogenemia (<150 mg/dl plasma fibrinogen). This was conducted as a phase IV study after licensure in Europe.
In the pivotal study, B13023_2001, and the supporting study, 7D-501FM , safety was assessed based on reports of complications due to coagulation disorders, other AE’s and deaths. The clinical population size is in these 2 studies was very small, with Study B13023_2001 comprising only 15 patients, and 7MN-501FM comprising only 12 patients. The small size limits the ability of the studies to detect rare adverse events that could be identified once the product is marketed and exposed to a larger, more heterogenous population.
The clinical survey CE 1221_1 is a retrospective physician survey conducted in response to the FDA request for more information about congenital fibrinogen deficiency and treatments. The survey provides hemostatic efficacy data from cryoprecipitate treated patients to serve as the historical control group for the post-marketing study. Data from 100 subjects was collected by 31 physicians in 10 different countries. The survey provided descriptive analysis of bleeding frequency, treatments and fibrinogen levels. In Europe, questionnaires were sent to physicians known to treat subjects with fibrinogen deficiency. In the US, questionnaires were sent to 97 hemophilia centers or hematologists, and in Canada, they were sent to 19 centers known to use HFCP. In this survey, investigators were not explicitly asked to report on safety and the information available is based on spontaneous reports made by the participating physicians.
Study No. B13023_3001 is a prospective, open, historically controlled post-marketing commitment (Phase IV) study in 23 evaluable subjects requiring on demand treatment for acute bleeding. The purpose of this study is to validate an association between MCF, the surrogate efficacy endpoint in Study 2001, and clinical efficacy of stopping acute bleeding. A Physicians survey (CE 1221_1) on hemostatic efficacy in patients treated with cryoprecipitate will be used as the historical control. This study has an estimated duration of up to 60 months.
An Initial IND was submitted in November 2006 (/bb-ND -(b)(4)-) with the clinical study protocol and a post-marketing commitment to validate the surrogate marker for efficacy. The post-marketing protocol was submitted to CBER in July 2007 and found acceptable in March 2008. HCFP was granted Orphan Drug Designation on 13 March 2008, for the treatment of fibrinogen deficient patients.
No formal hypothesis testing was performed on safety data. AE’s and treatment emergent AE’s were summarized by treatment group, relationship to study group and by maximum intensity.
Additional Potential Post-Marketing Safety Issues
Risk of Thromboembolic Events Special safety concerns regarding increased risk of thromboembolic events in patients with acquired fibrinogen deficiency.
Does use of Riastap increase the risk further, and does the risk increase further when used in pregnant or postpartum patients?
Please consider a patient registry to capture adverse events.
What is the safety data on patients with acquired fibrinogen deficiency?
Product is plasma derived fibrinogen concentrate; indicated for congenital fibrinogen deficiency. No concentrated fibrinogen product currently available in the US.
Limited patient population in clinical studies
Extensive post-market experience in Europe, with no apparent predominant safety concerns. We will further assess safety data from this experience after more detail on these cases has been submitted.
This product does not meet the criteria that would require REMS, as it has been previously used and marketed since 1986 and no new safety data has been identified.
Potential serious safety risks identified in clinical studies include thromboembolic events
1. The sponsor should submit a summary and line listing of the 48 post-market adverse event reports collected for Haemocomplettan P. The sponsor should also describe the surveillance method by which these AE reports were collected: spontaneous, passive reporting, through a registry, active surveillance, or other methods.
2. The sponsor should submit both of the 5-year PSUR’s, along with the associated addendum reports. A summary of the types of patients (demographics and indications) who received the marketed product in Europe, if such data is available, would also be beneficial. Specifically, did the exposed population include elderly, pediatric, or other special populations?
Letter comments for communication to the sponsor from mid-cycle review:
1. The pivotal clinical studies assessing the efficacy and safety of HFCP were extremely limited in size, limiting the ability to detect unusual adverse events. Further, the population receiving a particular product after-licensure may differ from the population studied in pre-approval trials. However, in this case, the product has been licensed and marketed previously in Europe. Thus, there has been a larger exposed population than were available in clinical trials and spontaneously reported AEs from this population are available for assessment of safety.
2. You have reported a total of 48 adverse event reports for Haemocomplettan P since it began marketing in Europe (1986-2008), corresponding one report for every 3,414 doses distributed. We concur this seems to be a relatively small crude number of AEs relative to the number of doses administered. However, to expedite review and assessment of potential safety risks identified in these reports, please submit a detailed line list of all AEs, including thromboembolic events and viral transmission, and any other relevant information. Also, please describe the surveillance method by which these AE reports were collected: spontaneous, passive reporting, through a registry, active surveillance, or other methods.
3. Please submit both of the 5-year Periodic Safety Update Reports for Haemocomplettan P, along with the associated addendum reports. Please also summarize the types of patients (demographics and indications) who received the marketed product in Europe, if such data is available. Specifically, did the exposed population include elderly, pediatric, or other special populations?
Cumulative line listing of all adverse events from 1986-31 Oct 2008 including thromboembolic events and viral transmission as well as individual case reports is provided in Sections 220.127.116.11-8 and 18.104.22.168-9. Additional line listing sorted to medical case categories in section 22.214.171.124-10.
Information on patient gender, age, indication for treatment, dose level, number of doses, time interval from treatment to onset of AE, AE terms and description, concomitant medications and surveillance methods included in table provided in Section 126.96.36.199-11.
Complete safety reports for Haemocomplettan P European marketing period 1986-31 Oct 2008 are provided in Sections 188.8.131.52-1 to 184.108.40.206-7.
The Riastap pharmacovigilance plan per ICH E2E Pharmacovigilance Planning guidance is provided in Section 1.16. The Pharmacovigilance Plan summarizes and addresses safety concerns, includes important identified potential risks, describes routine FDA compliant pharmacovigilance practices and includes additional post-marketing actions.
Three clinical investigations were conducted in Europe that were open to patients with acquired fibrinogen deficiency. Two studies included acquired subjects and a summary description including adverse events collected are provided. For the two studies that included acquired subjects, 22 AE’s were reported from clinical investigations and 7 reported from case collections. A list of these 29 AE’s is provided in section 220.127.116.11.
Study B13.023/7D-402XX-RS was open to congentital and acquired deficiency subjects, but no acquired subjects were included and no AE’s were reported.
Study B13.023/7D-401XX-OB was a clinical observational monitoring project case collection that included congenital and acquired subjects. A final report is not available and study information was not included in the BLA submission. CSLB acknowledges that all of the information may not be available and is providing all available information, which includes seven AE’s from 37 subjects. The seven case collection AE’s are provided in section 18.104.22.168 and were not included in the cumulative line listing referenced in response to comment no. 1.
Study B13.023/7D-501FM:COMP on the efficacy and tolerance of pasteurized human fibrinogen concentrate in patients with acquired hypofibrinogenemia.
This was a prospective, open label uncontrolled clinical observational monitoring project performed between April 1991 and June 1994 in subjects with acquired hypofibrinogenemia. A total of 92 subjects received HFCP in this study. Complications due to coagulation disorders were observed in 35 subjects, with bleeding as the major complication (94%). In addition, coagulation disorder due to hemodilution and embolism of the lung were documented as complications in 1 subject each. All complications were assessed as related to the underlying coagulation disorder. Most of them had already been present before the first treatment with HFCP; in only 5 subjects (15%) did these complications occur during or after HFCP substitution.
In 92 subjects (98%) treatment with HFCP was well tolerated. AE’s (mild to moderate fever) were observed in 2 subjects.
A total of 20 subjects died during this study; however none of the 20 deaths was judged as related to substitution with HFCP, but related to the subjects’ severe undeylying diseases, e.g. disseminated intravascular coagulopathy, sepsis, immaturity, multiorgan failure, liver cirrhosis, myocardial infarction, neoplasia, and esophageal varices.
This COMP/case collection was conducted from 1984-1986 and available AE’s documented from 37 acquired and congentital patients are summarized.
Seven AE’s have been documented within this case collection. Two patients received HFCP after they developed DIC, both of whom died subsequently. One patient received HFCP for fibrinogen deficiency due to carcinoma. One patient received HFCP for bleeding tendency due to trauma. One patient had a post portal decrease in blood pressure. This was also assessed to be unrelated to the substitution with HFCP. The sixth patient developed nausea, tachycardia and elevated body temperature. One patient showed transient fever and slight decrease in platelet count.
No adverse event was assessed to be related to the infusion of HFCP. The attending physicians did not mak any assessment on causal relationships between the infusion of HFCP and these last two adverse events.
Data has been submitted and is acceptable.
Letter Comments for communication to the sponsor from Final Review:
You have submitted the requested adverse event reporting and PSUR’s.
The responses are complete and acceptable.