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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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February 15, 2011 Approval Letter - Corifact

Our STN:  BL 125385/0

CSL Behring, GmbH
Attention: Mr. Paul Hartman, R. Ph.
1020 First Avenue
King of Prussia, PA  19406-0901

Dear Mr. Hartmann:

We have approved your biologics license application for Factor XIII Concentrate (Human) effective this date.  You are hereby authorized to introduce or deliver for introduction into interstate commerce Factor XIII Concentrate (Human), under your existing Department of Health and Human Services U.S. License No. 1765.  Factor XIII Concentrate (Human) is indicated for the routine prophylactic treatment of Congenital Factor XIII deficiency.

Under this authorization, you are approved to manufacture Factor XIII Concentrate (Human) at your facility in Marburg, Germany.  You may label your product with the proprietary name Corifact™ and will market it in 1000 – 1600 IU per vial size.

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 which would have benefited from an advisory committee discussion.

The dating period for Factor XIII Concentrate (Human) shall be 24 months from the date of manufacture when stored at 2 – 8 °C (36 – 46 °F).  Within the dating period, your product may be stored at room temperature not to exceed 25 °C (77 °F) for up to six months.  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. 

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 Factor XIII Concentrate (Human), 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.

Under 21 CFR 201.57(c)(18), patient labeling must be reprinted at the end of the package insert. We request that the text of information distributed to patients be printed in a minimum of 10-point font.

Please provide your final content of labeling in Structured Product Labeling (SPL) format and include the carton and container labels.  In addition, please submit three original paper copies for carton and container final printed labeling.  All final labeling should be submitted as Product Correspondence to this BLA at the time of use (prior to marketing) and include implementation information on FDA Form 356h.

In addition, please submit the final content of labeling (21 CFR 601.14) in SPL format via the FDA automated drug registration and listing system, (eLIST), as described at: http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm1.  Information on submitting SPL files using eLIST may be found in the guidance for industry titled, “SPL Standard for Content of Labeling Technical Qs and As at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM072392.pdf
.2

You may 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.  You must submit 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)].

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)].

Please submit an amendment to all pending supplemental applications for this BLA that include revised labeling incorporating a revised content of labeling that includes this/these change(s).

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.htm3 for updated mailing address information.

In addition to the above adverse experience reporting, in a letter dated June 30, 2010, you proposed to collect detailed information about certain spontaneously reported cases (such as thromboembolic events, viral transmission, and AEs in pregnant patients) with identified risks and follow them up with a targeted questionnaire and collect general information about the patient and risk factor(s). 

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.

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

POSTMARKETING REQUIREMENTS

As requested in your letter of August 18, 2010, we are granting marketing approval of this product under the accelerated approval of biological products regulations, 21 CFR 601.40-46.  These regulations permit the use of certain surrogate endpoints or an effect on a clinical endpoint other than survival or irreversible morbidity as bases for approvals of products intended for serious or life-threatening illnesses or conditions.

Approval under these regulations requires, among other things, that you conduct adequate and well-controlled studies to verify and describe clinical benefit attributable to this product.  Clinical benefit will be evidenced by hemostatic efficacy in congenital Factor XIII deficient patients.

1.   We acknowledge your ongoing study BI71023_3001 conducted under IND 13882 will be sufficient to meet the requirement to conduct a Phase 4 study to verify the clinical benefit by showing a correlation between trough levels of FXIII (5% to 20%) and clinical efficacy and also by comparing the incidence of bleeding with treatment to historical control without treatment.  The completion dates as agreed upon are listed below:

Study is ongoing
Projected completion date: April 17, 2011
Final study report: by December 31, 2011

We expect you to complete and report this study within the framework described in your letter of January 17, 2011.

You must conduct the study with due diligence.  If postmarketing studies fail to verify that clinical benefit is conferred by Corifact™, Factor XIII Concentrate (Human), or are not conducted with due diligence, we may, following a hearing in accordance with 21 CFR 601.43(b), withdraw or modify approval of your application approved under 21 CFR 601.41.

We request that you submit the final study report (s) to this BLA. For administrative purposes, all submissions relating to this postmarketing study requirement must be clearly designated as “Subpart E Postmarketing Study Requirement.”

AGREED UPON POSTMARKETING COMMITMENTS

We acknowledge your written commitments as described in your letters of February 9, 2011 and January 19, 2011, respectively, as outlined below:

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

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We request that you submit information concerning nonclinical and chemistry, manufacturing, and controls postmarketing commitments and final reports to your BLA, STN BL 125385/0.

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

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

For each postmarketing commitment not subject to the reporting requirements of 21 CFR 601.70, 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 Study Report or Supplement Contains Postmarketing Study Commitment – Final Study Report.

If you have any questions, please contact the Regulatory Project Manager, Nannette Cagungun, at (301) 827-6174.

Sincerely yours,

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

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