Review for Pharmacovigilance Planning -Atryn
|Subject:||BLA STN 125284/0
Antithrombin alpha (Atryn)
OBE/DE Mid-cycle Review for Pharmacovigilance Planning
|To:||Pratibha Rana, Regulatory Project Manager, OBRR|
|From:||Faith Barash, MD, MPH
Therapeutics and Blood Safety Branch (TBSB)
Division of Epidemiology (DE),
Office of Biostatistics and Epidemiology (OBE)
|Through:||Craig Zinderman, MD , MPH Acting Chief, TBSB, DE, OBE|
OBE/DE has completed an initial 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 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.
Aytryn 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.
Safety Surveillance Data
There is no post-marketing safety surveillance data available. Section 2.7.4, Summary of Clinical Safety, details the adverse events that were observed in clinical trials for this product. No evidence for overdosage was reported in clinical studies.
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). 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. 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.
Adverse Event (AE) information collected in the clinical studies conducted for ATryn involves a limited number of exposed patients. In addition, there is a lack of post-market experience on which to base safety assessment beyond the safety database gathered in clinical studies, and 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. AEs may occur that were not detected in the smaller, more homogeneous study populations.
1. We recommend that the sponsor address potential safety issues in a pharmacovigilance plan per ICH E2E Pharmacovigilance Planning guidance to be submitted during the BLA review process so the plan can be ready for implementation if the product is licensed.
2. Please provide any adverse events reported as a result of recent post-market experience in Europe.
3. The sponsor has indicated that they (or their partners) have initiated a controlled Phase II clinical trial to examine the safety and efficacy of Atryn in patients with disseminated Intravascular Coagulation associated with severe sepsis. Please provide any adverse events reported as part of this sepsis study.