ATryn Final Review Memorandum
BLA STN 125284/0
Antithrombin alpha (ATryn)
OBE/DE Final Review for Pharmacovigilance Planning
Date: January 16, 2009
To: Pratibha Rana, Regulatory Project Manager, Office of Blood Research and Review
Faith Barash, MD, MPH
Therapeutics and Blood Safety Branch (TBSB)
Division of Epidemiology (DE), Office of Biostatistics and Epidemiology (OBE
Craig Zinderman, MD, MPH, Acting Chief, TBSB, DE, OBE
Robert Wise, MD, MPH, Acting Director, DE, OBE
Congenital antithrombin III deficiency is an austosomal dominant disorder, characterized by either a reduction in antithrombin III or the presence of dysfunctional antithrombin III. Deficiency of antithrombin III leads to a hypercoagulable state, which can result in thromboses or pulmonary emboli. Thromboembolic events in congenital antithrombin (AT) deficient patients may increase during high risk periods, such as pregnancy, sepsis, or surgery. Up to 70% of congenital AT deficient patients develop a venous thromboembolic event during their lives. Currently, there is no approved treatment for congenital AT patients in high risk situations except plasma derived antithrombin III alone or in conjunction with heparin. The availability of plasma derived antithrombin III has been unreliable. Additionally, plasma derived antithrombin III carries a small but real risk of viral disease transmission. ATryn, manufactured by recombinant technology, can provide a continuous supply of antithrombin III, with lower risk of viral transmission than plasma derived products.
OBE/DE has completed a review of BLA STN 125284/0 for Antithrombin alpha (ATryn) from GTC Biotherapeutics, Inc. ATryn is a nanofiltered, sterile, terminally heat treated lyophilized dosage form of recombinant antithrombin III. ATryn is produced by recombinant DNA technology, using genetically engineered goats into which the gene for human antithrombin has been introduced along with a mammary gland specific promoter which directs expression of the protein in the goat’s milk.
The proposed proprietary and nonproprietary names are ATryn and Antithrombin alpha, respectively. Since ATryn is recombinant antithrombin III, it actually contains both a and b forms of antithrombin.
Atryn contains 1750 international units of antithrombin per vial and is intended for intravenous infusion following reconstitution with 10 ml of sterile water and subsequent dilution into .9% sodium chloride. ATryn is not produced from human blood, nor is it formulated with human serum or plasma proteins. The genetically engineered goats used to express ATryn are USDA certified scrapie-free and pathogen-free.
ATryn is indicated for use in hereditary antithrombin deficient patients for the prevention of peri-partum and peri-operative thromboembolic events. The dosage is individualized for each patient, with a goal of restoring and maintaining functional antithrombin activity levels between 80-120% (0.8-1.2 IU/mL) of normal, to reduce the risk of thromboembolic events, as well as for treatment of such events.
Review of Safety
The product has been licensed in Europe since August 2006 and 4 Periodic Safety Update Reports (PSUR) developed for European regulatory authorities covering the time periods including 08-01-07 to 07-31-08 have been submitted as an amendment to the BLA. There have been no actions for safety concerns, no instances of overdosage and no cases of drug interactions. No deaths or adverse events related to immunogenicity have been reported.
In a multicenter, multinational, open label Phase 2 study for safety and efficacy, one DVT was reported, likely related to treatment failure. One case of intra-abdominal hemorrhage occurred after cesarean section, in a patient who received 25,000 U of heparin instead of the recommended 5,000 U.
There is no pediatric experience, and limited data on pregnant or lactating women. There has been no new or significant safety information obtained on pregnant or lactating women, and no dosing recommendations have been made. Dosing is to be individualized, but pregnant patients were generally dosed at 2x the dose for non-pregnant patients.
Immunogenicity: Recipients of recombinant proteins such as ATryn can develop antibodies to the administered protein as a foreign substance. Further, if a patient develops antibodies against recombinant AT, those antibodies may also act against their own endogenous AT. No immunologic related adverse events were noted in clinical trials for ATryn. Assays of IgG and IgM were performed on almost all subjects, and only 1 had an IgG positive seroconversion, however, this was non-specific and may not have been clinically meaningful. Further, AT levels returned to baseline 30, 60, and 90 days after administration, suggesting that no inhibitors to endogenous AT developed.
Proposed Pharmacovigilance Plan
For most products, routine pharmacovigilance (i.e., compliance with applicable post-market reporting requirements under FDA regulations) is sufficient for post-marketing risk assessment. The ICH E2E Pharmacovigilance Planning guidance indicates that for products with important identified risks, important potential risks, or important missing information, additional actions designed to address these concerns should be considered as part of a pharmacovigilance plan (http://www.fda.gov/cber/gdlns/ichpvp.htm).
Adverse Event (AE) information collected in the clinical studies conducted for ATryn involves a limited number of exposed patients. The protein is derived from a novel source (genetically engineered animal) for a marketed therapeutic product. When a new product is marketed, the exposed population usually differs quantitatively and qualitatively from the population studied in pre-approval trials. The number of patients exposed is much larger, usage generally expands to unlabeled indications, and exposed patients have a broader array of demographic features, co-morbid conditions, and concomitant medical product use. Adverse Events may occur that were not detected in the smaller, more homogeneous study populations.
The sponsor’s pharmacovigilance plan submitted as part of the ATryn BLA identifies potential risks and planned mitigating actions associated with ATryn use. Potential safety issues for ATryn include: (1) risk of interaction with other anticoagulants, (2) risk of hemorrhage, and (3) risk of immunologic reaction.
The sponsor has instituted:
- Package insert text indicating a potential interaction with concomitant anticoagulants.
- Package insert text to inform providers of the risk of immunologic reaction with this recombinant product.
- Proposal to send letters to clinical providers informing them of the immunosurveillance program.
- A Patient registry to further examine potential immunogenicity after repeat exposures. The sponsor will provide immunosurveillance testing free of charge. Reports will be sent to physicians and to FDA via normal pharmacovigilance regulations.
The sponsor’s post-market surveillance program consists of the following pharmacovigilance process:
In the US, post-market AE reports, product complaints, and medical inquiries will be received from external parties via an affiliated private company, OvationPharmaceuticals, Inc., internal sales representatives, or medical science liaisons. Adverse event and product complaint calls will be directed to the Patient Safety department and medical inquiries will be directed to the Medical Information department. All valid adverse event and product complaint reports will be entered in Ovation’s Safety Database (AERS) with creation of electronic individual case safety records (ICSRs). The Patient Safety department will undertake follow-up with reporters to achieve complete documentation of each case report. Reports from sources outside the US will be received from -----b(4)--------- (global PSUR Safety Database) via GTC.
Case processing activities in Ovation including medical assessment and assessment for regulatory reporting will be performed on ICSRs. MedWatch reports will be produced for expedited reporting of serious unexpected reports and will be provided by Ovation to GTC for timely submission to the FDA.
On a quarterly basis for the first three years and then annually thereafter, PSURs will be produced by Ovation and provided to GTC for submission to the FDA.
The case processing activity described above also serves to identify alerts or potential signals on an ongoing basis. Cumulative and interval clinical safety data, postmarketing adverse event and product complaint data will be reviewed quarterly for signals at the Quarterly Global Pharmacovigilance Meeting. Benefit-risk assessment reports will be produced for any identified potential signals or safety concerns requiring further evaluation. These assessment reports form the basis for decisions on labeling actions by Ovation’s Central Labeling Committee. The PSUR process also serves as a periodic signaling activity with updates to labeling as indicated.
Additionally, the sponsor has instituted an immunosurveillance program to examine potential immunogenicity after repeat exposures. In this voluntary patient registry, treating physicians are encouraged to collect pre- and post-treatment serum samples from patients and to submit them to Ovation Pharmaceuticals , Inc. to be tested for the development of antibodies to recombinant human antithrombin. The program asks physicians to collect a pre-treatment serum sample within one week before initiation of treatment and samples at days 1, 7 and 28 days from initiation of treatment. Ovation Pharmaceuticals , Inc will provide instructions for the collection, processing and shipping of samples, as well as all necessary tubes and labels for the collection and processing of samples. Post-marketing immunosurveillance is planned to run for 5 years or until 50 patients have been enrolled.
All requested data has been submitted. The pharmacovigilance plan has been reviewed and is acceptable. Based on the known risks of this product, the proposed programs for post-marketing surveillance and immunosurveillance) appear adequate to monitor for adverse outcomes in this patient population. There appear to be no known risks associated with ATryn treatment that require further assessment of risk reduction strategies, beyond what has already been proposed and established by the sponsor, at this time. We have no objections to recommendation for approval.
We concur with the post-marketing studies outlined in the BLA to further assess safety and immunogenicity after repeat exposure. The patient registry for immunosurveillance, as proposed in the BLA, should be implemented and maintained, especially for the less studied populations, such as pregnant and pediatric patients. Careful monitoring of AT activity and anti Xa levels is recommended, especially when concomitant anticoagulants are used.
Letter Comments for Communication with Sponsor:
1. The safety profile is acceptable, and recombinant antithrombin III is effective in preventing thromboembolic events in surgical patients and pregnant patients in the peripartum period.
2. The proposed post-market safety monitoring and immunosurveillance program to assess safety after ATryn administration and immunogenicity after repeat exposure have been reviewed and are adequate.