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August 19, 2009 Approval Letter - Hiberix

Our STN:  BL 125347/0

GlaxoSmithKline Biologicals, S.A.
Attention: Elisa Harkins
Associate Director
North American Regulatory Affairs - Vaccines
2301 Renaissance Blvd.
P.O. Box 61540
King of Prussia, PA 19406

Dear Ms. Harkins:

We have approved your biologics license application for Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) according to the regulations for accelerated approval effective this date.  You are hereby authorized to introduce or deliver for introduction into interstate commerce, Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) under your existing Department of Health and Human Services U.S. License No. 1671.  Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) is indicated for active immunization for the prevention of invasive disease caused by Haemophilus influenzae type b when administered as a booster dose in children 15 months through 4 years of age (prior to fifth birthday).

Under this license, you are approved to manufacture Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate).  The Haemophilus b polysaccharide is manufactured at your facility in          -b(4)-, Belgium.  The tetanus toxoid is manufactured at ------------b(4)--------------------------

---------------b(4)----------------------------------------------------.  The saline diluent is manufactured at -----------------------------b(4)----------------------------------------.  The final product will be formulated at your Rixensart, Belgium facility and manufactured, filled, labeled, and packaged at your facility in --b(4)--, Belgium.  You may label your product with the proprietary name Hiberix® and market it in packages of 10 single-dose vials of lyophilized vaccine to be reconstituted with the accompanying saline diluent in prefilled TIP‑LOK® syringes.

We are granting marketing approval of this product for booster immunization against invasive disease caused by Haemophilus influenzae type b under the accelerated approval of biological products regulations, 21 CFR 601.40-46.  The evaluation of effectiveness of booster immunization with Hiberix® was based on serological endpoints that are accepted as predicting protection from invasive disease caused by Haemophilus influenzae type b.  These endpoints have not been evaluated in controlled clinical studies comparing booster immunization with Hiberix® and a U.S.-licensed Haemophilus b Conjugate Vaccine.

We did not refer your application to the Vaccines and Related Biological 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 Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) (Hiberix®) shall be 36 months from the date of manufacture when stored at 2-8° C (36-46° F).  The date of manufacture shall be defined as the start date for filling into final containers.  The maximum storage time for the bulk product (Hib-TT) 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).  We have approved your request for exemption from the General Safety Test.

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 Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) (Hiberix®), or in the manufacturing facilities.

You must submit reports of biological product deviations under 21 CFR 600.14.  You should promptly 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.

In addition, as specified in 21 CFR 601.45, you must submit promotional items intended for dissemination after the first 120 days following approval to the FDA at least 30 days prior to the initial publication of any advertisement or to the initial dissemination of any promotional labeling.  Please submit these materials with 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 they are approved.

ADVERSE EVENT REPORTING

Adverse experience reports should be submitted, at minimum, in accordance with the adverse experience reporting requirements for licensed biological products (21 CFR 600.80).  Individual adverse event reports should be submitted to the Vaccine Adverse Event Reporting System (VAERS) electronically at https://secure.vaers.org/VaersDataEntryintro.htm or by mail to P.O. Box 1100, Rockville, MD 20849-1100, using the pre-addressed form VAERS-1 available at the VAERS website (http://vaers.hhs.gov).  Distribution reports should be submitted on a monthly basis for the first year after market introduction and then at least every six months in accordance with 21 CFR 600.81.  Under 21 CFR 600.80(c)(2) [Periodic Adverse Experience Reports], you must report each adverse experience not reported under paragraph (c)(1)(i) of this section at quarterly intervals for the first 3 years following approval, and then at annual intervals.  In addition, in your June 17, 2009 submission to the BLA, you agreed to provide monthly periodic reports of all U.S. serious adverse events for the first year following market introduction of Hiberix®. 

ACCELERATED APPROVAL REQUIRED STUDY

Under the accelerated approval of biological products regulations, 21 CFR 601.40-46, we require that you study Hiberix® further to verify and describe its clinical benefit.  We acknowledge your written commitment as described in your letter of July 24, 2009, as outlined below:

  1.  To conduct Study Hib-097, a comparative safety and immunogenicity clinical trial of primary and booster immunization with Hiberix® relative to U.S. licensed control vaccines.

Protocol Submission: Third Quarter of 2009

Study Initiation: First Quarter of 2010

Final Report Submission: Fourth Quarter of 2013

The status of this required postmarketing study must be reported annually according to

21 CFR 601.70. We expect that your study will be designed, initiated, and reported on within the framework described in your letter of July 24, 2009.

You must conduct this study with due diligence.  If postmarketing studies fail to verify that clinical benefit is conferred by Hiberix® or are not conducted with due diligence, we may, following a hearing in accordance with 21 CFR 601.43(b), withdraw or modify approval.

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 in infants from 0 to <6 weeks of age because Hiberix® does not represent a meaningful therapeutic benefit over initiating vaccination at 6 weeks of age and Hiberix® is not likely to be used in a substantial number of pediatric patients 0 to <6 weeks of age.

We are waiving the pediatric study requirement in children 5 to 17 years of age because Hiberix® does not represent a meaningful therapeutic benefit over vaccination at younger ages and Hiberix® is not likely to be used in a substantial number of patients as the risk of invasive disease due to Haemophilus influenzae type b is generally negligible in this age group.  In addition, necessary studies are impossible or highly impracticable because the number of unimmunized children 5 to 17 years of age who have underlying medical conditions that may predispose them to invasive disease due to Haemophilus influenzae type b is limited, and such children would be geographically dispersed.

We are deferring submission of your study for ages 6 weeks to 14 months for this application because this product is ready for approval for use as a booster vaccination in children 15 months through 4 years of age and the study in patients ages 6 weeks to 14 months has not been completed.

Your deferred study required by section 505B(a) of the Federal Food, Drug, and Cosmetic Act is a required postmarketing study.  The status of this postmarketing study must be reported annually 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.  Deferred pediatric study (Study Hib-097) under PREA for the prevention of invasive disease caused by H. influenzae type b in pediatric patients ages 6 weeks to 14 months.

Protocol Submission: Third Quarter of 2009

Study Initiation: First Quarter of 2010

Final Report Submission: Fourth Quarter of 2013

We note that you have fulfilled the pediatric study requirement for ages 15 months through 4 years for this application.

As noted above (Accelerated Approval Required Study and Pediatric Requirements), we acknowledge your written commitment to conduct Study Hib-097 as described in your July 24, 2009 submission to the BLA.

We request that you submit clinical protocols to your IND, with a cross-reference letter to this BLA, STN BL 125347. 

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 Commitment – Final Study Report
  •  Supplement Contains Postmarketing Study Commitments – Final Study Report

In addition for Study Hib-097, we request that you also use the following designations on all submissions:

  • Subpart E Postmarketing Study Commitment
  •  Required Pediatric Assessment

For this postmarketing study, which is 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 non-clinical commitments as described in your July 31, 2009 submission to the BLA.

We request that you submit information concerning nonclinical and chemistry, manufacturing, and control postmarketing commitments and final reports to your BLA, STN BL 125347.

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.

If you have any questions, please contact LCDR Jason Humbert at 301-827-3070.

Sincerely yours,                                              

Norman W. Baylor, Ph.D.
Director 
Office of Vaccines Research and Review 
Research and Review
Center for Biologics Evaluation and Research