5/25/2017
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`Fractionated Plasma Products > October 10, 2008 Approval Letter - CINRYZE
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`October 10, 2008 Approval Letter -
`CINRYZE
`
`Our STN: BL 125267/0
`
`Lev Pharmaceuticals, Inc.
`Attention: Mr. Jason Bablak
`675 Third Avenue
`Suite 2200
`New York, NY 10017
`
`Dear Mr. Bablak :
`
`We are issuing Department of Health and Human Services US. License No. 1780 to Lev Pharmaceuticals, Inc., New
`York, New York, under the provisions of section 351 (a) of the Public Health Service Act controlling the manufacture
`and sale of biological products. This license authorizes you to introduce or deliver for introduction into interstate
`commerce, those products for which your company has demonstrated compliance with establishment and product
`standards.
`
`Under this license, you are authorized to manufacture the product C1 Esterase Inhibitor (Human) from US. Source
`Plasma. C1 Esterase Inhibitor (Human) is indicated for routine prophylaxis against angioedema attacks in patients
`with Hereditary Angioedema (HAE).
`
`Under this license, you are approved to manufacture -----(b)(4)----------------------------------------------------------------------
`---------------------- and C1 Esterase Inhibitor (Human) drug substance in the Sanquin Blood Supply Foundation in
`Amsterdam, Netherlands. The final formulated product will be manufactured, filled, lyophilized, labeled, and packaged
`at Sanquin Blood Supply Foundation in Amsterdam, Netherlands. You may label your product with the proprietary
`name CINRYZE and market it in a 500 U per vial fill size.
`
`The dating period for C1 Esterase Inhibitor (Human) shall be 12 months from the date of manufacture when stored at
`2—8 °C and/or 25-27 °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. You may supplement your BLA to request extension of the shelf-life of the product by providing additional
`data from your ongoing stability studies of the recent conformance lots as they become available. The dating period
`for your early stage intermediates and drug substance shall be ----(b)(4)------------------------------ from the date of
`manufacture.
`
`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).
`
`Your request for an exemption to the general safety test (GST) on final product is granted.
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`https://www.fda.govlbiologicsbloodvacci neslb|oodbloodproducts/approvedproducts/licensedproductsblas/fractionatedplasmaproducts/ucm 093602.htm
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`CSL EXHIBIT 1034
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`CSL EXHIBIT 1034
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`5/25/2017
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`Fractionated Plasma Products > October 10, 2008 Approval Letter - CINRYZE
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`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.
`
`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 (three for circulars and three 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. Two copies of final printed advertising and
`promotional labeling should be submitted at the time of initial dissemination, accompanied by FDA Form 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 received CBER approval for such claims.
`
`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 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/cber/pubinquire.htm for
`updated mailing address information.
`
`REQUIRED PEDIATRIC ASSESSMENTS
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`5/25/2017
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`Fractionated Plasma Products > October 10, 2008 Approval Letter - CINRYZE
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`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 this biological product for this indication has an orphan drug designation, you are exempt from this
`requirement.
`
`POSTMARKETING REQUIREMENTS UNDER 505(0)
`
`Title IX, Subtitle A, Section 901 of the Food and Drug Administration Amendments Act of 2007 (FDAAA) amends the
`Federal Food, Drug, and Cosmetic Act (FDCA) to authorize 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), 21 U.S.C. 355(0)(3)(A)). This provision took effect on March 25,
`2008.
`
`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. thrombosis , with the use of the product when administered at higher than labeled dose
`schedules.
`
`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.
`
`Finally, we have determined that a clinical trial (rather than a nonclinical or observational study) will be needed to
`assess a serious risk of thrombosis, as seen with a similar product in this class, when the product is administered at
`higher than labeled doses.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required, pursuant to section
`505(0)(3) of the FDCA, to conduct the following clinical trial:
`
`1. Lev Pharmaceuticals, Inc. is required to conduct a clinical trial designed to evaluate higher than labeled dose
`schedules of CINRYZE for routine prophylaxis of angioedema attacks in patients with Hereditary Angioedema
`(HAE). The objective of the clinical trial will be to define the safety profile of intensified dose schedules that may
`be used by patients who do not obtain an acceptable clinical benefit (reduction of HAE attack frequency) from the
`labeled dose schedule of CINRYZE for routine prophylaxis of HAE attacks. The clinical trial will include the
`following features:
`
`a. Gender-balanced enrollment of subjects with HAE who are receiving CINRYZE for routine prophylaxis of HAE
`attacks at the labeled dose schedule, and who still have an unacceptable HAE attack frequency,
`
`b. Procedures for establishing a baseline HAE attack frequency for each subject,
`
`c. A dose escalation algorithm that is based on a conclusion of a lack of acceptable clinical benefit (reduction of
`HAE attack frequency) for each subject,
`
`d. Scheduled monitoring of adverse events, specifically including signs and symptoms of thrombotic adverse events,
`and
`
`e. Scheduled monitoring for immunogenicity using a validated assay that can detect antibodies to CINRYZE.
`
`The timetable you submitted on 03 October 2008 states that you will conduct this trial according to the following
`timetable:
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`5/25/2017
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`Fractionated Plasma Products > October 10, 2008 Approval Letter - CINRYZE
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`Protocol Submission: within 3 months of the date of licensure
`
`Trial/Study Start Date: within 9 months of the date of licensure
`Final Report Submission: within 48 months of the date of licensure
`
`Please submit the clinical protocols to your IND, with a cross-reference letter to this biologics license application
`(BLA), STN BL 125267/0 and submit all final reports to this BLA. Please submit a labeling supplement reflecting the
`results of the trial and use the following designators to prominently label all submissions, including supplements,
`relating to this postmarketing study requirement as appropriate:
`
`- Required Postmarketing Protocol under 505(0)
`
`. Required Postmarketing Final Report under 505(0)
`
`- Required Postmarketing Correspondence under 505(0)
`
`- Annual Report on Postmarketing under 505(0)
`
`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 5068 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 otherwise 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 also acknowledge your written commitments as described in your submission of 03 October 2008 as outlined
`below:
`
`Post marketing Studies not subject to reporting requirements of 21 CFR 601.70.
`
`We request that you submit information concerning nonclinical and chemistry, manufacturing, and control
`postmarketing commitments and final reports to your BLA, STN BL125267/0.
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