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February 6, 2009 Approval Letter - ATryn

February 6, 2009

Our STN: BL 125284/0

GTC Biotherapeutics, Inc.
Attention: Mr. Richard A Scotland
175 Crossing Boulevard
Framingham, MA 01702

Dear Mr. Scotland:

We have approved your biologics license application for Antithrombin (Recombinant) effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce Antithrombin (Recombinant) under the Department of Health and Human Services U.S. License No. 1794. Antithrombin (Recombinant) is indicated for the prevention of peri-operative and peri-partum thromboembolic events, in hereditary antithrombin deficient patients.

Under this license, you are approved to manufacture the product Antithrombin (Recombinant) drug substance at -------------b(4)-----------------------------. The final formulated product will be manufactured and filled at ---------------------------b(4)---------------------------------. The filled drug product will be labeled and packaged at --------------------------b(4)---------------------------------------------. You may label your product with the proprietary name ATryn® and will market it in 1750 IU fill size.

The dating period for Antithrombin (Recombinant) shall be 36 months from the date of manufacture when stored at 2° - 8° C. The date of manufacture shall be defined as the date of final sterile filtration of the formulated drug product. Following the final sterile filtration, no reprocessing/reworking is allowed without prior approval from the Agency. The dating period for your drug substance shall be -----------b(4)---------------------.

You currently are not required to submit samples of future lots of Antithrombin (Recombinant) to the Center for Biologics Evaluation and Research (CBER) for release by the Director, CBER, under 21 CFR 610.2. We will continue to monitor compliance with 21 CFR 610.1 requiring completion of tests for conformity with st andards applicable to each product prior to release of each lot.

You must submit information to your biologics license application for our review and written approval under 21 CFR 601.12 for any changes in the manufacturing, testing, packaging or labeling of Antithrombin (Recombinant), or in the manufacturing facilities.

You must submit reports of biological product deviations under 21 CFR 600.14. You promptly should identify and investigate all manufacturing deviations, including those associated with processing, testing, packing, labeling, storage, holding and distribution. If the deviation involves a distributed product, may affect the safety, purity, or potency of the product, and meets the other criteria in the regulation, you must submit a report on Form FDA-3486 to the Director, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville Pike, Rockville, MD 20852-1448.

Please submit all final printed labeling at the time of use and include implementation information on FDA Form 356h and FDA Form 2567 as appropriate. Please provide content of labeling in Structured Product Labeling format. Please provide a PDF-format electronic copy as well as original paper copies (three for circulars and three for other labels).

In addition, you may wish to submit two draft copies of the proposed introductory advertising and promotional labeling with an FDA Form 2253 to the Center for Biologics Evaluation and Research, Advertising and Promotional Labeling Branch, HFM-602, 1401 Rockville Pike, Rockville, MD 20852-1448.

All promotional claims must be consistent with and not contrary to approved labeling. You should not make a comparative promotional claim or claim of superiority over other products unless you have submitted data to support such claims to us and have them approved.

ADVERSE EVENT REPORTING

You must submit adverse experience reports in accordance with the adverse experience reporting requirements for licensed biological products (21 CFR 600.80) and you must submit distribution reports as described in 21 CFR 600.81. You should submit postmarketing adverse experience reports and distribution reports to the Center for Biologics Evaluation and Research, Office of Biostatistics and Epidemiology HFM-210, Food and Drug Administration, 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448. Prominently identify all adverse experience reports as described in 21 CFR 600.80. Per 21 CFR 600.2(f), please refer to http://www.fda.gov/cber/pubinquire.htm for updated mailing address information.

PEDIATRIC REQUIREMENTS

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication in pediatric patients unless this requirement is waived, deferred, or inapplicable.

Because the biological product for this indication has an orphan drug designation, you are exempt from this requirement.

POSTMARKETING REQUIREMENTS UNDER 505(o)

Title IX, Subtitle A, Section 901 of the Food and Drug Administration Amendments Act of 2007 (FDAAA) amends the Federal Food, Drug, and Cosmetic Act (FDCA) to authorize FDA to require holders of approved drug and biological product applications to conduct postmarketing studies and clinical trials for certain purposes, if FDA makes certain findings required by the statute (section 505(o)(3)(A), 21 U.S.C. 355(o)(3)(A)). This provision took effect on March 25, 2008.

We have determined that an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) of the FDCA will not be sufficient to/identify an unexpected serious risk of antibody formation to ATryn®. Formation of antibodies to ATryn® may lead to inhibition of its therapeutic effect thereby, resulting in an increased incidence of thromboembolic events following repeat exposure compared to that of untreated patients with this condition during high risk situations such as peri-operative and peri-partum periods. Furthermore, the new pharmacovigilance system that FDA is required to establish under section 505(k)(3) of the FDCA has not yet been established and is not sufficient to assess this serious risk.

Finally, we have determined that only a clinical trial (rather than a nonclinical or observational study) will be sufficient to assess this unexpected serious risk.

Therefore, based on appropriate scientific data, FDA has determined that you are required, pursuant to section 505(o)(3) of the FDCA, to conduct a clinical trial:

1. Evaluate immunogenicity in patients with repeat exposure to ATryn® via an immunosurveillance program to detect antibodies to ATryn®, endogenous A ntithrombin, goat Antithrombin and goat milk proteins. Information on 50 patients over a period of 5 years will be collected. The timetable you submitted in your letter of November 19, 2008 states that you will conduct this trial according to the following timetable:

Final protocol Submission: August 2009
Trial start date: December 2009
Project completion date February 2014
Final Report Submission: August 2014

Submit the protocol to your BB-IND --b(4)-, with a cross-reference letter to this biologics license application, STN BL 125284/0. Submit all final report(s) to your BLA, STN BL 125284. U se the following designators to prominently label all submissions, including supplements, relating to this postmarketing clinical trial as appropriate:

  •  Required Postmarketing Protocol under 505(o)
  •  Required Postmarketing Final Report under 505(o)
  •  Required Postmarketing Correspondence under 505(o)

Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any study or clinical trial required under this section. This section also requires you to periodically report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Section 506B of the FDCA, as well as 21 CFR 601.70 requires you to report annually on the status of any postmarketing commitments or required studies or clinical trials.

FDA will consider the submission of your annual report under section 506B and 21 CFR 601.70 to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR 601.70. We remind you that to comply with 505(o), your annual report must also include a report on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o) on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action.

As described in 21 CFR 601.70(e), we may publicly disclose information regarding these postmarketing studies on our Web site ( http://www.fda.gov/cder/pmc/default.htm) . Please refer to the February 2006 Draft Guidance for Industry: Reports on the Status of Postmarketing Studies - Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997 (see http://www.fda.gov/cber/gdlns/post130.htm ) for further information.

POSTMARKETING COMMITMENTS NOT SUBJECT TO REPORTING REQUIREMENTS OF 21 CFR 601.70

We acknowledge your written commitments as described in your letter of January 28, 2009 as outlined below:

  1. -----------------------------------b(4)---------------- ------------------------------------------------------- ------------------------------------------------------- ------------------------------------------------------- ------------------------------------------------------ ------------------------------------------------------- ------------------------------------------------------- ------------------------------------------------------- ------------------------------------------------------- ------------------------------------------------------- ------------------------------------------------------- -----------------------.
  1. -----------------------------------b(4)--------------- ------------------------------------------------------ ------------------------------------------------------ ----------------------------------------------------- ------------------------------------------------------ ------------------------------------------------------ ----------------------------------------------------- ------------------------------------------------------ ---------------.

-------b(4)------------: -----b(4)---------

  1. -----------------------------------b(4)------------- ---------------------------------------------------- ---------------------------------------------------- ---------------------------------------------------- ---------------------------------------------------- ---------------------------------------------------- ---------------------------------------------------- ---------------------------------------------------- ---------------------------------------------------- ---------------------------------------------------- ---------------------------------------------------- --------------------------------------------------- ------.


  1. --------------------------------------b(4)----------- ----------------------------------------------------- ---------------------------------------------------- --------------.

-------b(4)-----------------: ----b(4)----.

  1. -------------------------------------b(4)----------- ---------------------------------------------------- ---------------------------------------------------- ---------------------------------.

----------b(4)----------------: --b(4)------

-------b(4)----------------: ---b(4)------.

We request that you submit information concerning nonclinical and chemistry, manufacturing, and control postmarketing commitments and final reports to your BLA, STN BL125145/0. Please use the following designators to label prominently all submissions, including supplements, related to these postmarketing commitments as appropriate:

  • Postmarketing Commitment Correspondence
  • Postmarketing Commitment- Final Study Report

For each postmarketing commitment not subject to the reporting requirements of 21 CFR 610.70, you may report the status to FDA as a “PMC Submission -Status Update.” The status report for each commitment should include:

  • The original schedule for the commitment, and
  • The status of the commitment (i.e., pending, ongoing, delayed, terminated, or submitted).

When you have fulfilled your commitment, submit your final report as PMC Submission - Final Report or Supplement Contains Postmarketing Commitment - Final Report.

Sincerely yours,

/signed/

Mary A. Malarkey
Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research

/signed/

Jay S. Epstein, M.D.
Director
Office of Blood Research and Review
Center for Biologics Evaluation and Research

 

Contact FDA

(800) 835-4709
(301) 827-1800
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Food and Drug Administration

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Rockville, MD 20852-1448