
 
 
 

 

HHS 
U.S. Department of Health and Human Services
   



U.S. Food and Drug Administration 
  



  A to Z Index


  Follow FDA


  En Español

 



Search FDA  Submit search  

                

 

  Popular Content


  Home


  Food


  Drugs


  Medical Devices


  Radiation-Emitting Products


  Vaccines, Blood & Biologics


  Animal & Veterinary


  Cosmetics


  Tobacco Products

    





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.



Search Archive  Submit archive search  
       
 

Vaccines, Blood & Biologics
  
    
  
  Home
   Vaccines, Blood & Biologics
   Blood & Blood Products
   Approved Products
    Licensed Products (BLAs)
  	 Fractionated Plasma Products
    
 
  


Final Review Memorandum - Atryn




  Share


  Tweet


  Linkedin


  Pin it

  More sharing options 
    Linkedin


    Pin it



  Email


  Print

 
ATryn Final Review Memorandum

Subject: 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 

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
 Robert Wise, MD, MPH, Acting Director, DE, OBE

Background

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.

Conclusion:

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.

Recommendations:

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.
 

  


Key Resources

  Approval History, Letters, Reviews and Related Documents - ATryn	[ARCHIVED] 
   
 


More inFractionated Plasma Products
   


Resources for You

  Approval History, Letters, Reviews and Related Documents - ATryn	[ARCHIVED] 
  ATryn 
 var maincontentcss = document.getElementById("middle_js"); if(maincontentcss) {
 maincontentcss.style.width = "71%"; }       


   Page Last Updated: 08/10/2015  
 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	 




FDA


  Accessibility


  Careers


  FDA Basics


  FOIA


  No FEAR Act


  Site Map


  Nondiscrimination


  Website Policies

 




U.S. Food and Drug Administration
 10903 New Hampshire Avenue
 Silver Spring, MD 20993
 1-888-INFO-FDA (1-888-463-6332)
Contact FDA 

Subscribe to FDA RSS feeds Follow FDA on Twitter Follow FDA on Facebook View FDA 
videos on YouTube View FDA photos on Flickr 


   FDA Archive


   Combination Products


   Advisory Committees


   Regulatory Information


   Safety



   Emergency Preparedness


   International Programs


   News & Events


   Training & Continuing Education


   Inspections & Compliance



   Federal, State & Local Officials


   Consumers


   Health Professionals


   Science & Research


   Industry

 

Scroll back to top 
     


Popular Content

  Home

   
  Latest Recalls

   
  Report an Adverse Event

   
  MedWatch Safety Alerts


  News Releases


  Consumer Updates


  About FDA


  Contact FDA


  Browse by Product Area


  Product Areas

  back

    Food


    Drugs


    Medical Devices


    Radiation-Emitting Products


    Vaccines, Blood & Biologics


    Animal & Veterinary


    Cosmetics


    Tobacco Products


 