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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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December 19, 2012 Approval Letter - Bivigam

Our STN: BL 125389/0

 
Biotest Pharmaceuticals Corporation
Attention: Gary Ingenito, MD., PhD
5800 Park of Commerce Blvd., N.W.
Boca Raton, FL  33487
 
Dear Dr. Ingenito:
 
We have approved your biologics license application for Immune Globulin Intravenous (Human) effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Immune Globulin Intravenous (Human) under your existing Department of Health and Human Services U.S. License No. 1792. Immune Globulin Intravenous (Human) is indicated for Primary Immune Deficiency Disorders (PIDD).
 
Under this authorization, you are approved to manufacture Immune Globulin Intravenous (Human) at your facility in Boca Raton, Florida. You may label your product with the proprietary name Bivigam™ and will market it in 10% liquid.
 
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 Immune Globulin Intravenous (Human) shall be 24 months from the date of manufacture when stored at 2-8 oC. 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.
 
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, including but not limited to, the manufacturing, testing, packaging or labeling of Immune Globulin Intravenous (Human), or in the manufacturing facilities.
 
You must submit reports of biological product deviations under 21 CFR 600.14. You should identify and investigate all manufacturing deviations promptly, 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.
 
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. 
 
Please provide your final content of labeling in Structured Product Labeling (SPL) format and include the carton and container labels. In addition, please submit three original paper copies for carton and container final printed labeling.  All final labeling should be submitted as Product Correspondence to this BLA at the time of use (prior to marketing) and include implementation information on FDA Form 356h and FDA Form 2567 as appropriate.
 
In addition, please submit the final content of labeling (21 CFR 601.14) in SPL format via the FDA automated drug registration and listing system, (eLIST), as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Information on submitting SPL files using eLIST may be found in the guidance for industry titled, “SPL Standard for Content of Labeling Technical Qs and As at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072392.pdf.
 
You may 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. You must submit copies of your final advertisement and promotional labeling at the time of initial dissemination or publication, accompanied by Form FDA 2253 [21 CFR 601.12(f)(4)].
 
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)].
 
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 ages 0 to < 2 years because:
      Necessary studies are impossible or highly impracticable. This is because of the rarity of  diagnosis in this age group.
We are deferring submission of your pediatric studies for ages 2 to 16 years for this application because:
     This product is ready for approval for use in adults and the pediatric study has not been completed.
 
Your deferred pediatric study required under 505B(a) of the Federal Food, Drug, and Cosmetic Act is a required postmarketing study. The status of this postmarketing study must be reported according to 21 CFR 601.70 and section 505B(a)(3)(B) of the Federal Food, Drug, and Cosmetic Act. This required study is listed below:
 
  1. A Phase IV, Multicentre, Open-Label Study to Evaluate the Efficacy and Safety of BIVIGAM in Primary Immune Deficiency Disorders in Children and Adolescents ages 2 to 16.
 
Final Protocol Submission: July 2013
 
Study Completion Date: July 2017
 
Final Report Submission: October 2017
 
Submit final study reports to this BLA. For administrative purposes, all submissions related to this required pediatric postmarketing study must be clearly designated “Required Pediatric Assessment.”
 
AGREED UPON POSTMARKETING COMMITMENTS
 
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.
 
We acknowledge your written commitments as described in your letter of October 24, 2011 as outlined below:
 
  1. Prospective, non-interventional, active-control, observational safety study to further assess the potential risk of hypotension, hepatic and renal impairment in Biotest-IGIV-treated patients with primary humoral immunodeficiency (PI).
 
            Final Protocol Submission: July 2013
 
            Study Completion Date: September 2017
 
            Final Report Submission: December 2017
 
Please submit clinical protocols to your IND, with a cross-reference letter to this biologics license application (BLA), STN BL 125389/0. Submit all study final reports to your BLA STN BL 125389/0.  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. 
 
We acknowledge your written commitments as described in your email of December 3, 2012 as outlined below:
 
Postmarketing 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 BL 125389/0.
 
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 601.70, 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, MD
Director
Office of Blood Research and Review
Center for Biologic Evaluation and Research