`
`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.
`
`We have approved your biologics license application for C1 Esterase Inhibitor (Human) effective this date. You are
`
`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.
`
`Page 1 of 6
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`CSL EXHIBIT 1030
`
`CSL V. Shire
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`Fractionated Plasma Products > October 9, 2009 Approval Letter - Berinert
`
`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:
`
`CSL EXHIBIT 1030
`CSL v. Shire
`
`Page 1 of 6
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`

`

`
`
`
`_ htt
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`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. 3550), 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(0)
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`Fractionated Plasma Products > October 9, 2009 Approval Letter - Berinert
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`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 PD F-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
`htt
`:Ilwww.fda. ovIAboutFDAICentersOffices/CBERlucm106001.htm
`
`
`
`:Ilwww.fda. oleboutFDA/CentersOffices/CBERlucm106001.htm _for updated mailing address information.
`
`Page 2 of 6
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`Fractionated Plasma Products > October 9, 2009 Approval Letter - Berinert
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`Section 505(0) 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(0)(3)(A)].
`
`FDA has determined that you are required, pursuant to section 505(0)(3) of the Act, to conduct three postmarketing
`studies. The rationale for requiring these studies is as follows:
`
`lmmunogenicity data in your BLA were limited with respect to the numbers and percentage of hereditary angioedema
`subjects enrolled in clinical trials who undenNent 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 ll). Additional
`human lmmunogenicity 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, Le. (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 lmmunogenicity data on a minimum of 40 subjects (for whom lmmunogenicity 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 Iicensure.
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`Fractionated Plasma Products > October 9, 2009 Approval Letter - Berinert
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`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 closes
`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
`
`indication for Berinert use, administered doses, patient demographics,
`following variables as part of the registry:
`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(0)
`
`- Required Postmarketing Study Final Report under 505(0)
`
`- Required Postmarketing Study Correspondence under 505(0)
`
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`Fractionated Plasma Products > October 9, 2009 Approval Letter - Berinert
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`Section 505(0)(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 5063 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 5068 and 21 CFR 601.70 to satisfy the periodic
`reporting requirement under section 505(0)(3)(E)(ii) provided that you include the elements listed in 505(0) and 21
`CFR 601.70. We remind you that to comply with 505(0), your annual report must also include a report on the status of
`
`any study or clinical trial othenivise undertaken to investigate a safety issue. Failure to submit an annual report for
`studies or clinical trials required under 505(0) on the date required will be considered a violation of FDCA section
`505(0)(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
`
`In the final study report, the use of potentially confounding medications will be compared across
`design negotiations.
`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).
`
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`
`
`Sincerely yours,
`
`Jay S. Epstein, MD.
`Director
`
`Office of Blood Research and Review
`
`Center for Biologics Evaluation and Research
`
`Resources for You
`
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`Fractionated Plasma Products > October 9, 2009 Approval Letter - Berinert
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`As described in 21 CFR 601 .70(e), we may publicly disclose information regarding these postmarketing studies on
`
`our Web site (htt 'Ilwww fda oleru slGuidanceCom lianceRe ulato Information/Post-
`marketin PhaselVCommitmentsldefault.htm
`
`_htt
`
`:Ilwww.fda. oleru slGuidanceCom lianceRe ulato Information/Post-
`.)- P'ease refer to the February 2006 GUidance for '“dUStryi Reports
`on the Status of Postmarketing Studies — Implementation of Section 130 of the Food and Drug Administration
`
`Modernization Act of 1997 (see
`htt
`:Ilwww.fda. ovIdownloadsIDru slGuidanceCom lianceRe ulator Information]
`
` I.
`....
`
`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:
`
`o
`
`o
`
`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.
`
`Page 6 of 6
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`