• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

  • Print
  • Share
  • E-mail
?
-

Resources for You

March 4, 2010 Approval Letter - Hizentra

Our STN: BL 125350/0

CSL Behring AG
Attention:  Mr. Paul Hartmann
1020 First Ave
P.O. Box 61501
King of Prussia, PA  19406-0901

Dear Mr. Hartmann:

We have approved your biologics license application for Immune Globulin Subcutaneous (Human), 20% Liquid, effective this date.  You are hereby authorized to introduce or deliver for introduction into interstate commerce, Immune Globulin Subcutaneous (Human), 20% Liquid, under your existing Department of Health and Human Services U.S. License No. 1766.  Immune Globulin Subcutaneous (Human), 20% Liquid, is indicated for the treatment of Primary Immunodeficiency (PI).

Under this license, you are approved to manufacture Immune Globulin Subcutaneous (Human), 20% Liquid, drug substance prepared at your facility at CSL Behring AG, Wankdorfstrasse 10, 3000 Berne 22, Switzerland.  You must label your product with the proprietary name Hizentra™ that we have approved, and market it in 5 mL, 10 mL and 20 mL sizes.

We did not refer your application to the Blood Products Advisory Committee because our review of information submitted in your BLA, including the clinical study design and trial results, did not raise concerns or controversial issues that would have benefited from an advisory committee discussion.

The dating period for Immune Globulin Subcutaneous (Human), 20% Liquid, shall be 18 months from the date of manufacture when stored at 2-25 oC.  The date of manufacture shall be defined as the date of final sterile filtration of the formulated drug product in accordance with 21 CFR 610.50.  Following the final sterile filtration, no reprocessing/reworking is allowed without prior approval from the Agency. 

Please submit final container samples of the product in final containers together with protocols showing results of all applicable tests.  You may not distribute any lots of product until you receive a notification of release from the Director, Center for Biologic Evaluation and Research (CBER).

You must submit information to your biologics license application for our review and written approval under 21 CFR 601.12 for any changes in, including but not limited to the manufacturing, testing, packaging or labeling of Immune Globulin Subcutaneous (Human), 20% Liquid, 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 three original paper copies for all labels other than the package insert.

You must submit two copies of your final advertisement and promotional labeling at the time of initial dissemination or publication, accompanied by Form FDA 2253 (21 CFR 601.12(f)(4).  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 substantial evidence or substantial clinical experience to support such claims (21 CFR 202.1(e)(6)).

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/AboutFDA/CentersOffices/CBER/ucm106001.htm for updated mailing address information.

In addition, you must submit adverse event reports for any infectious disease transmission within 15 days after learning of the event.  Infectious disease transmission refers to an adverse event that involves suspected or confirmed transmission of an infectious agent, whether the recipient develops the infectious disease or only has serologic or other evidence.  If an infectious disease transmission event is serious and unexpected, you must submit a 15-day “alert report” as required under 21 CFR 600.80 (c)(1)(i).  Infectious disease transmission events that do not meet criteria for expedited submission require periodic reports and must be submitted as individual case reports within 15 days, as authorized under 21 CFR 600.80(c)(2)(i).  You should submit reports for all other non-expedited adverse events under the periodic reporting requirements specified in 21 CFR 600.80(c)(2).

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.

We are waiving the pediatric study requirement for ages 0 to < 2years because the necessary studies are impossible or highly impracticable.  It is rare for primary humoral immunodeficiency to present at this age group.

We are deferring submission of your pediatric study for ages 2 to < 16 years for this application because this product is ready for approval for use in adults and the pediatric study has not been completed.

Your deferred pediatric study required under 505B(a) of the Federal Food, Drug, and Cosmetic Act is a required postmarketing study.  The status of this postmarketing study must be reported according to 21 CFR 601.70 and section 505B(a)(3)(B) of the Federal Food, Drug, and Cosmetic Act.  This required study is listed below:

  1. Deferred pediatric study under PREA for the treatment of primary humoral immunodeficiency in pediatric patients ages 2 to < 16.

Final report submission date: August 31, 2010.

We request that you submit final study reports to your IND, with a cross-reference letter to this BLA, STN BL 125350/0.  For administrative purposes, all submissions related to this required pediatric postmarketing study must be clearly designated “Required Pediatric Assessments.”

AGREED UPON POSTMARKETING COMMITMENTS

Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70. 

We acknowledge your written commitments as described in your letters of February 10, 16, 18, 24, 26, and March 1, 2010, as outlined below. CSLB agrees:

 

One (1) Page Determined to be Not-Releasable:  (b)(4)


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

 

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

 

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

 

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

 

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

 

--(b)(4)--

 

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

 

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

 

We request that you submit clinical protocols and nonclinical toxicology protocols to your IND, with a cross-reference letter to this BLA, STN BL 125350/0. 

Please use the following designators to label prominently all submissions, including supplements, relating to these postmarketing study commitments as appropriate:

  • Postmarketing Study Commitment Protocol
  • Postmarketing Study Correspondence
  • Postmarketing Study Commitment – Final Study Report
  • Supplement Contains Postmarketing Study Commitments – Final Study Report

For each postmarketing study subject to the reporting requirements of 21 CFR 601.70, you must describe the status in an annual report on postmarketing studies for this product.  Label your annual report an “Annual Status Report of Postmarketing Study Commitments.”  The status report for each study should include:

information to identify and describe the postmarketing commitment,

  • the original schedule for  the commitment,
  • the status of the commitment (i.e., pending, ongoing, delayed, terminated, or submitted), and
  • an explanation of the status including, for clinical studies, the patient accrual rate (i.e., number enrolled to date and the total planned enrollment).

 

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/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/default.htm).  Please refer to the February 2006 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/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM080569.pdf) for further information. 

Sincerely yours,

/signature/

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