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U.S. Department of Health and Human Services

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July 1, 2010 Approval Letter - GLASSIA

Our STN: BL 125325/0

Kamada Ltd.

Attention: -----------(b)(4)------------
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Dear -----(b)(4)----:

We are issuing Department of Health and Human Services U.S. License No. 1826 to Kamada, Ltd., Beit Kama, Israel, under the provisions of section 351(a) of the Public Health Service Act controlling the manufacture and sale of biological products.  The license authorizes you to introduce or deliver for introduction into interstate commerce, those products for which your company has demonstrated compliance with the U.S. establishment and product standards.

Under this license, you are authorized to manufacture the product Alpha-1-Proteinase Inhibitor (Human).  Alpha-1-Proteinase Inhibitor (Human) is an intravenously administered biologic product indicated for chronic augmentation and maintenance therapy in individuals with emphysema due to congenital deficiency of alpha-1-proteinase inhibitor (Alpha1-PI), also known as alpha1-antitrypsin deficiency.

The review of this product was associated with the following National Clinical Trial (NCT) number: 00460096.

Under this license, you are approved to manufacture Alpha-1-Proteinase Inhibitor (Human) at your facility in Beit Kama, MP Negev 85325, Israel.  You may label your product with the proprietary name GLASSIA and market it in 50 mL fill size.

We did not refer your application to the Blood Product Advisory Committee because our review of information submitted in your biologics license application (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 Alpha-1-Proteinase Inhibitor (Human) shall be 24 months from the date of manufacture when stored at 2-8ºC.  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. 

For each product lot submitted for release, please submit 3 vials 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 of the Center for Biologics Evaluation and Research (CBER).

You must submit information to your BLA for our review and written approval under 21 CFR 601.12 for any changes, including but not limited to changes in the manufacturing, testing, packaging or labeling of Alpha-1-Proteinase 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 of the 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 electronic copy as well as three original paper copies for all 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 substantial evidence or substantial clinical experience to support such claims [21 CFR 202.1(e)(6)].

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).

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.

We are waiving the pediatric study requirement for this application because necessary studies are impossible or highly impracticable.  Alpha1-PI deficiency is not known to cause emphysema in pediatric subjects.

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), 21 U.S.C. 355(o)(3)(A)]. 

We have determined that an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) of the FDCA will not be sufficient to identify an unexpected serious risk from adverse events relating to the presence of visible protein aggregates in the product.

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/these serious risk(s).

A clinical trial to further assess these potential risks is needed because the presence of visible protein aggregates in the product has been a consistent finding.  The completed clinical studies, which employed filtration of the product when pooling vial contents prior to administration, are considered too small to reliably assess the potential for adverse events due to the presence of protein aggregates.

We have determined that only a clinical trial (rather than a nonclinical or observational study) will be sufficient to identify an unexpected serious risk of adverse events relating to the presence of protein aggregates in the product.

Therefore, based on appropriate scientific data, we have determined that you are required to conduct the following clinical trial:

  1. A Phase IV, double-blind, controlled multicenter study exploring potential adverse events associated with protein aggregates.  This study will evaluate the safety of the product following multiple repeat exposures over a period of at least 6 months of regular weekly administration.  It will include design features that will permit the detection of potential adverse events (AEs) due to the presence of protein aggregates in the product.  The study will also include viral nucleic acid testing (NAT) and testing for anti-Alpha1-PI antibodies using an appropriately validated assay.  We note that the planned study will also explore epithelial lining fluid analytes and potential adverse events associated with immunogenicity, and viral safety following the use of Kamada’s Intravenous, Human Alpha1-PI (GLASSIA) and another commercial Alpha1-PI, in Alpha1-Antitrypsin [Alpha1-PI] Deficient Patients.

    We acknowledge the timetable you submitted on May 27, 2010, which states that you will conduct this clinical trial according to the following schedule:
Final Protocol Submission: March 1, 2011
Trial initiation Date: September 5, 2011
Trial Completion Date: March 20, 2013
Final Report Submission: March 18, 2014

Please submit the protocol to your IND -(b)(4)-, with a cross-reference letter to this BLA.  Submit all final reports to this BLA (with a letter of cross-reference to the IND) and prominently identify them as appropriate: 

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

We 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 May 27, 2010, as outlined below:

Postmarketing Studies subject to reporting requirements of 21 CFR 601.70

  1. Submission, as a supplement to the BLA STN BL 125325, of the final report of the results of anti-Alpha1-PI antibody testing from all stored clinical samples from clinical trial API-002, including all raw data.  You have committed to submit as a supplement to the BLA the final anti-Alpha1-PI antibody assay validation report and obtain FDA’s concurrence with the assay procedure prior to running stored clinical samples from the clinical trial.
Final protocol submission date: September 18, 2007
Study/trial completion date: March 27, 2008
Submission of Assay Validation Report: November 1, 2010
Final Report Submission date: February 1, 2011
  1. A Phase IV, open-label or double-blind, multicenter study investigating Epithelial Lining Fluid of Alpha1-Antitrypsin Deficient Patients for Alpha1-PI and analytes levels following augmentation therapy with GLASSIA.

    You have elected to make this PMC clinical trial a substudy of the PMR described above.

The primary endpoint for this study will be both antigenic and functional Alpha1-PI levels in Epithelial Lining Fluid after 10-12 weeks of treatment.

Final protocol submission date: March 1, 2011
Trial initiation Date: September 5, 2011
Study/trial completion date: March 20, 2013
Final Report Submission date: March 18, 2014

  1. Conducting a post-marketing clinical program for GLASSIA which will be comprised of two clinical trials as described below:
  1. Trial 1: A Phase IV, Randomized, Placebo-Controlled, Double-Blind, Multicenter Study Investigating the Safety and Efficacy of GLASSIA vs. Placebo and another (Higher) dose of GLASSIA I.V. by Weekly Administration in Alpha1-Antitrypsin Deficient Patients with emphysema.

    This study will have a primary endpoint consisting of change in lung density assessed by serial quantitative computerized tomography of the lungs.  Additional endpoints will include incidence, duration, and severity of pulmonary exacerbations, serial pulmonary function testing, serial DLCO measurements, and mortality.
Final protocol submission date: March 1, 2011
Trial initiation Date: September 3, 2012
Study/trial completion date: March 3, 2017
Final Report Submission date: March 5, 2018
  1. Trial 2: Adequately-powered study of clinically meaningful endpoint.  Based on the results of Trial 1 above and the available scientific data, Kamada will design and conduct a fully statistically powered efficacy study for augmentation therapy with Alpha-1-Proteinase Inhibitor (Human).

    The study will be randomized and double-blind.
Final protocol submission date: January 8, 2018
Trial initiation Date: January 7, 2019
Study/trial completion date: July 8, 2024
Final Report Submission date: July 7, 2025

Please submit clinical protocols to your IND, with a cross-reference letter to this BLA, STN BL 125325/0.  Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN BL 125325.  Submit a letter of cross-reference to the IND when the final study report for a clinical trial is submitted to your BLA.  If the information in the final study report supports a change in the labeling, the final study report should be submitted as a supplement.  We may also request a supplement if we think labeling changes are needed.  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  

We acknowledge your written commitments as described in your letters of June 20, 2010 and June 22, 2010 as outlined below:

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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 BL 125325.

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, 


--signature--                                        --signature--

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