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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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January 16, 2009 Approval Letter - RiaSTap

Our STN: BL 125317/0

CSL Behring GmbH
Attention: Mr. Paul R Hartmann
1020 First Avenue, P.O. Box 61501
King of Prussia , PA 19406

Dear Mr. Hartmann:

We have approved your biologics license application for Fibrinogen Concentrate (Human) effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Fibrinogen Concentrate (Human), under your existing Department of Health and Human Services U.S. License No. 1765. Fibrinogen Concentrate (Human) is indicated for the treatment of acute bleeding episodes in patients with congenital fibrinogen deficiency (afibrinogenemia and hypofibrinogenemia). It is not indicated for dysfibrinogenemia.

Under this license, you are authorized to manufacture Fibrinogen Concentrate (Human) at your facility in Marburg, Germany. You may label your product with the proprietary name RiaSTAP™ and will market it in a 900-1300 mg fill size with the actual potency stamped on each vial.

The dating period for Fibrinogen Concentrate (Human) shall be 30 months from the date of manufacture when stored at 2-25°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.

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 the manufacturing, testing, packaging or labeling of Fibrinogen 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. Per 21 CFR 600.2(f), please refer to http://www.fda.gov/cber/pubinquire.htm for updated mailing address information.

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).

Please note that the accelerated approval regulation concerning promotional materials (21 CFR 601.45) stipulates that all advertising and promotional labeling items that you wish to distribute in the first 120 days following approval must have been received by CBER prior to the approval date. After approval, promotional items intended for dissemination after the first 120 days following approval should be submitted to CBER 30 days prior to the anticipated distribution date. Please submit these materials using Form FDA 2253 to the Advertising and Promotional Labeling Branch, HFM-602, Center for Biologics Evaluation and Research, 1401 Rockville Pike, Rockville, MD 20852-1448. Two copies of all final advertising and promotional labeling materials should be submitted at the time of initial dissemination, accompanied by Form FDA 2253.

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 had them approved.

ADVERSE EVENT REPORTING

In addition, pursuant to 21 CFR 600.80(c)(2)(Periodic Adverse Experience Reports), the Agency is requiring that manufacturers report on a monthly basis any infectious disease transmission associated or possibly associated with any licensed biological product that is not reportable under 21 CFR 600.80 (c)(1)(Fifteen-day Alert Reports). The timing of this monthly periodic reporting requirement was selected, among other reasons, to permit the acquisition of patient information, including clinical evaluation, sufficient to help in the timely assessment of a causal connection between the biological product and possible or documented infectious disease transmission. This new reporting requirement was also based on the observation of inconsistent practices by some manufacturers in submitting reports of possible infectious diseases.

Please note that this monthly reporting requirement applies only to infectious disease transmission. Other periodic reports should continue to be submitted on the quarterly or annual basis that is appropriate to each licensed biological product for all other adverse experiences not reportable under 21 CFR 600.80(c)(1). You should submit these monthly reports to The Center for Biologics Evaluation and Research, Division of Epidemiology, HFM-210, 1401 Rockville Pike, Rockville, MD, 20852-1448. Please contact the Division of Epidemiology (301-827-3974) if you have any questions about these periodic adverse event reporting requirements.

You must submit adverse experience reports under the adverse experience reporting requirements for licensed biological products (21 CFR 600.80) and you must submit distribution reports under 21 CFR 600.81. You should submit post-marketing adverse experience reports and distribution reports to the Center for Biologics Evaluation and Research, HFM-210, Food and Drug Administration, 1401 Rockville Pike, 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.

REQUIRED 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.

POST MARKETING REQUIREMENT

As requested in your letter of July 18, 2008 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 using a predefined rating scale in congenital fibrinogen deficient patients.

1. We acknowledge your ongoing study B13023_3001, conducted under IND -- (b)(4) -- will be sufficient to meet the requirement to conduct a phase 4 study to verify the clinical benefit by comparing the hemostatic efficacy of RiaSTAP™ to historical control. This study is designed as a multinational, multicenter, prospective, open, historically controlled, non-inferiority post-marketing study. The completion dates as agreed upon are listed below:

Study ongoing
Study start date: December 2008
Projected completion date: March 2014
Final study report date: September 2014

We expect you to complete and report this study within the framework described in your letter of December 9, 2008.

You must conduct the study with due diligence. If postmarketing studies fail to verify that clinical benefit is conferred by RiaSTAP™, Human Fibrinogen Concentrate, heat treated 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.”

POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS OF 21 CFR 601.70:

We acknowledgeyour postmarketing study commitments specified in your submission dated January 13, 2009. These commitments, along with any completion dates agreed upon, are listed below.

2. You have committed to evaluate efficacy and safety in the peri-operative period in patients with congenital fibrinogen deficiency.

Protocol submitted:  within six months after approval
Study initiated:   within three months of submission of final protocol to CBER
Projected study completion:  within five years of study initiation
Final study report:  within six months of study completion

 

3. You have committed to evaluate efficacy and safety for routine prophylaxis in patients with congenital fibrinogen deficiency

Protocol submitted:  within six months after approval
Study initiated:  within three months of submission of final protocol to CBER
Projected study completion:  within five years of study initiation
Final study report:  within six months of study completion

We request that you submit clinical protocols to your IND, with a cross-reference letter to this biologics license application (BLA), STN BL 125317/0. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN BL 125317/0. Please use the following designators to label prominently all submissions, including supplements, relating to these postmarketing study commitments as appropriate:

  • Postmarketing Study Protocol
  • Postmarketing Study Final Report
  • Postmarketing Study Correspondence
  • Annual Report on Postmarketing Studies

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. 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/cder/pmc/default.htm). Please refer to the April 2001 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/post040401.htm) for further information.

Sincerely yours,

/signed/

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