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October 9, 2009 Approval Letter - Berinert

October 9, 2009

Our STN:  BL 125287/0
CSL Behring GmbH
Attention:  Paul R. Hartmann, R.Ph.
1020 First Avenue, P.O. Box 61501
King of Prussia, PA  19406-0901

Dear Mr. Hartmann:

We have approved your biologics license application for C1 Esterase Inhibitor (Human) effective this date.   You are hereby authorized to introduce or deliver for introduction into interstate commerce C1 Esterase Inhibitor (Human), under your existing Department of Health and Human Services U.S. License No. 1765.  C1 Esterase Inhibitor (Human) is indicated for the treatment of acute abdominal or facial attacks of hereditary angioedema (HAE) in adult and adolescent patients.

Under this authorization, you are approved to manufacture C1 Esterase Inhibitor (Human) at your facility in Marburg, Germany.  You may label your product with the proprietary name Berinert® and market it in 500 U per vial fill 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 C1 Esterase Inhibitor (Human) shall be 30 months from the date of manufacture when stored at 2 °C to 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.  The dating period for your drug substance shall be ------------------------(b)4)--------------. 

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 Biologics 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 C1 Esterase Inhibitor (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 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 (3 for circulars and 3 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 had such claim 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/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), with the exception that all thrombotic or thrombo-embolic adverse events are to be reported as 7 or 15 day reports.

FDA expects all suspected thrombotic, thrombo-embolic, and viral transmission events to be reported 7 or 15 day reports starting from the inception of marketing.

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)

Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes 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)].

FDA has determined that you are required, pursuant to section 505(o)(3) of the Act, to conduct  three postmarketing studies.  The rationale for requiring these studies is as follows:

Immunogenicity data in your BLA were limited with respect to the numbers and percentage of hereditary angioedema subjects enrolled in clinical trials who underwent assessment of serum anti-C1-Esterase Inhibitor antibodies before and after multiple exposures to Berinert.  Despite these limitations a ~ 20% incidence of treatment-emergent anti-C1 Esterase Inhibitor antibodies has been observed thus far in your open-label extension study (IMPACT II).  Additional human immunogenicity data are required to be obtained post-marketing in order to better determine whether antibody development is associated with adverse events, i.e. acute hypersensitivity reactions and/or inadequate therapeutic response.

It was noted during review of your application that a few cases of suspected viral transmission by the product have been reported during foreign post-marketing pharmacovigilance.  The information presented in these cases was not sufficient to conclusively determine whether your product was responsible for the transmissions.  An active surveillance plan will facilitate discovery of potential viral transmissions by your product.

Use of your product at higher than recommended doses has been associated with fatal thrombotic events in a clinical trial of pediatric subjects where the product was administered for an indication other than hereditary angioedema.  The minimum dose of your product associated with thrombotic events is unknown. 

We have determined that an analysis of spontaneous post-marketing adverse events reported under subsection 505(k)(1) of the FDCA will not be sufficient to identify an unexpected serious risk when available data indicates the potential for a serious risk, i.e. (a) thrombosis, with the use of the product when administered at higher than labeled dose schedules, (b) viral transmission by the product, and (c) acute hypersensitivity reactions and/or inadequate therapeutic response that might in a larger exposed population be associated with known anti-C1 Esterase Antibody formation. 

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.

Therefore, based on appropriate scientific data, you are required to conduct the following studies:

1.   Inhibitory Antibody Study

      CSL Behring is required to conduct a study to assess inhibitory antibody formation against C1-Esterase Inhibitor.  The time points for assessing the formation of antibodies shall be determined during protocol design negotiations.  Subjects with antibodies positive by -(b)(4)- would be tested for inhibitory antibodies using a validated assay.  The study report will present aggregate immunogenicity data on a minimum of 40 subjects (for whom immunogenicity data has not already been submitted in the BLA) who have anti-C1 Esterase Inhibitor antibody testing prior to and following repeated exposures to Berinert.

      The study report will describe in detail attempts to correlate treatment-emergent antibodies with adverse events (AEs).

       We acknowledge the timetable you submitted on August 5, 2009, which states that you will conduct this trial according to the following schedule:

Protocol Submission:              Within 180 days of licensure.

Study Start Date:                    Within 90 days of acceptance by FDA of the final protocol.

Final Report Submission:        Within 80 months of initiation of the study.

  2.   Completion of Planned Ongoing Open Label Extension Study CE1145_3003 (IMPACT II)

      The ongoing open label extension study, CE1145_3003 (IMPACT II) will provide long term safety data in subjects who have received repeated administrations of Berinert.  This will enhance our ability to detect adverse events that may be related to anti-C1-Esterase Inhibitor antibody development, and will also provide additional power to detect lower frequency adverse events, such as thrombotic events that might occur even at currently recommended doses when a monitored study population is observed following multiple repeated administrations of the study product.

        We acknowledge the timetable you submitted on August 5, 2009, which states that you will conduct this trial according to the following schedule

Protocol Submission:              August 12, 2005.

Study Start Date:                    Protocol initiated, study ongoing. 

Final Report Submission:        Within 12 months of study completion.

3.   HAE Patient Registry

      CSL Behring is required to conduct a study consisting of establishment and maintainance for 3 years of a registry of patients treated with Berinert for any indication to evaluate the safety of the product.   You should collect the following variables as part of the registry:  indication for Berinert use, administered doses, patient demographics, concomitant medications and plasma products, adverse events, including possible thrombotic or embolic events, and results of any viral testing.  The use of a structured questionnaire should be considered in the registry.  The registry should permit a mechanism for enhanced detection of thrombotic and thrombo-embolic events.  A patient registry will also facilitate discovery and reporting of potential viral transmissions by the product. CSL Behring would maintain this registry for 36 months after market application approval.

      We acknowledge the timetable you submitted on August 5, 2009, which states that you will conduct this trial according to the following schedule

Registry development plan submitted:           September 14, 2009.

Registry Implementation:                               Within 6 months of product licensure.

Duration:                                                         36 months data collection from product licensure.

Final study report:                                           Within 12 months of completion.

Please submit the protocols to your BB-IND -(b)(4)- file, with a cross-reference letter to this BLA and submit all final reports to this BLA.  Please submit a labeling supplement reflecting the results of the study and use the following designators to prominently label all submissions, including supplements, relating to these postmarketing studies requirements as appropriate:

  • Required Postmarketing Study Protocol under 505(o)
  • Required Postmarketing Study Final Report under 505(o)
  • Required Postmarketing Study 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.

AGREED UPON POSTMARKETING COMMITMENTS

We acknowledge your written commitments as described in your letter of August 5, 2009 as outlined below:

Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.

4.    CSL Behring commits to conduct a randomized masked trial that would be adequately powered to more precisely define the efficacy of Berinert for acute facial HAE attacks.  The primary endpoint is to be finalized during protocol design negotiations.  In the final study report, the use of potentially confounding medications will be compared across randomization groups.

Protocol Submission:              Within 180 days of licensure.

Study Start Date:                    Within 90 days of acceptance by FDA of the final protocol.

Final Report Submission:        Within 80 months of initiation of the study.

We request that you submit clinical protocols and nonclinical toxicology protocols to your IND, with a cross-reference letter to this BLA, STN BL 125287/0. 

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. 

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

5.  -----------------------------(b)(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

We acknowledge your submission of a pharmacovigilance plan, dated September 4, 2009, as

amendment 37 to this BLA.

We request that you submit information concerning nonclinical and chemistry, manufacturing, and control postmarketing commitments and final reports to your BLA, STN BL 125287/0.

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 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 Study Report or Supplement Contains Postmarketing Study Commitment – Final Study Report. 

Sincerely yours,

 

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