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U.S. Department of Health and Human Services

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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 U.S. 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 U.S. 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.

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 PDF-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

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

POSTMARKETING REQUIREMENTS UNDER 505(o)

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(o)(3)(A), 21 U.S.C. 355(o)(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(o)(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:
  1. 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,
  2. Procedures for establishing a baseline HAE attack frequency for each subject,
  3. 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,
  4. Scheduled monitoring of adverse events, specifically including signs and symptoms of thrombotic adverse events, and
  5. 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:

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(o)
  • Required Postmarketing Final Report under 505(o)
  • Required Postmarketing Correspondence under 505(o)
  • Annual Report on Postmarketing 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 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.

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We request that you submit information concerning nonclinical and chemistry, manufacturing, and control postmarketing commitments and final reports to your BLA, STN BL125267/0.

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

  • Postmarketing Correspondence
  • Postmarketing Commitment – Final Study Report
  • Supplement Contains Postmarketing 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 – Correspondence/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 Report or Supplement Contains Postmarketing Commitment – Final Report.

Sincerely yours,

 

Mary A. Malarkey
Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research

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