June 24, 2008
Our STN: BL 125260/0
Attention: Ms. Donna Boyce
U.S. Regulatory Affairs, Vaccines
2301 Renaissance Blvd. Building- 510
P.O. Box 61540
King of Prussia , PA 19406-2772
Dear Ms. Boyce:
We have approved your biologics license application for Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine, effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine under your existing Department of Health and Human Services U.S. License No. 1617. Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine is indicated for active immunization against diphtheria, tetanus, pertussis, and poliomyelitis as the fifth dose in the diphtheria, tetanus, and acellular pertussis (DTaP) vaccine series and the fourth dose in the inactivated poliovirus vaccine ( IPV) series in children 4 through 6 years of age whose previous DTaP vaccine doses have been with INFANRIX ® and/or PEDIARIX ® for the first three doses and INFANRIX ® for the fourth dose.
Your application for KINRIX™ was not referred to an FDA advisory committee because the DTaP component is the same as that in INFANRIX® and PEDIARIX® and the IPV component is the same as that in PEDIARIX®, and KINRIX™ did not pose unique concerns.
Under this license, you are approved to manufacture Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine. The Diphtheria and Tetanus Toxoids Adsorbed Combined Bulk (For Further Manufacturing Use) is manufactured at Novartis Vaccines and Diagnostics GmbH & Co. KG (U.S. License 1754), Marburg, Germany. The diphtheria and tetanus toxoids, acellular pertussis and inactivated poliovirus components are combined, and the final formulated product is filled, labeled, and packaged at your facility in Rixensart, Belgium. You may label your product with the proprietary name KINRIX™. The vaccine will be supplied in 0.5 mL mono-dose pre-filled syringes and vials.
The dating period for KINRIX™ shall be 36 months from the date of manufacture of the final bulk when stored at 2-8° C (36-46°F). The date of manufacture shall be defined as the date of initiation of the earliest valid potency test conducted on the final formulated bulk vaccine or final container vaccine, regardless of which component is tested first. All potency testing, whether performed on material from the final bulk or final container will commence within ------ after filling. The final bulk may be stored for up to ------ prior to filling when maintained at -----.
Please submit final container samples of the product in final containers together with lot release protocols in electronic format 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 BLA for our review and written approval under 21 CFR 601.12 for any changes in the manufacturing, testing, packaging or labeling of KINRIX™, 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 and implementation information on FDA Form 356h. Please provide a PDF-format electronic version of the label.
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 a 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
As required under 21 CFR 600.80(c)(2) you must provide Quarterly Periodic Adverse Experience Reports to the Vaccine Adverse Events Reporting System (VAERS) contractor. The Quarterly Adverse Experience Report will contain a recapitulation of all initial reports submitted for the current reporting period and will include all follow up information on VAERS forms collected during that three-month period. Pursuant to 21 CFR 600.80(c)(2), you are also required to provide the contractor for VAERS all initial post-marketing “periodic” adverse experience reports received that are subject to periodic reporting (i.e., not covered under the “15-day Alert report” requirement under 21 CFR 600.80) on a monthly basis.
Initial reports received by GlaxoSmithKline in a given month will be submitted on VAERS forms to CBER and to the VAERS contractor by Working Day 10 of the following month. You have committed to providing CBER this information using the aforementioned process for the first three years after the date of licensure. Thereafter, you are required to submit these reports on an annual basis.
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(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable. We note that you have fulfilled the pediatric study requirement for ages 4 to 6 years for this application.
We are waiving the pediatric study requirement for KINRIX™ in infants from 0-5 weeks of age because necessary studies are impossible or highly impracticable due to the potential for suppression of immune responses to subsequent vaccines and since neither diphtheria, tetanus, nor poliomyelitis occur in U.S. infants too young to be protected from vaccination beginning at 6 weeks of age. For the pediatric population 0-5 weeks of age, KINRIX™ does not represent a meaningful therapeutic benefit over initiating vaccination against diphtheria, tetanus, and poliomyelitis at 6 weeks of age and is not likely to be used by a substantial number of patients.
We are waiving the pediatric study requirement for children from 6 weeks – 3 years of age because KINRIX™ does not represent a meaningful therapeutic benefit over existing DTaP and IPV containing vaccines and is not likely to be used by a substantial number of pediatric patients in this age group.
We are waiving the pediatric study requirement for children from 7-18 years of age because necessary studies are impossible or highly impracticable since the recommended DTaP and IPV series is completed by age 4-6 years, and a dose of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap) is recommended at 11-12 years of age. In addition, KINRIX™ does not represent a meaningful therapeutic benefit over Tdap for patients 10-18 years of age or over IPV for patients 7-18 years of age, and is not likely to be used by a substantial number of pediatric patients in these age groups.
Postmarketing Commitments subject to reporting requirements of 21 CFR 601.70.
1. You have committed to conduct a randomized, open label, comparative trial, designed primarily to evaluate the immunogenicity of KINRIX™ when given concomitantly with varicella vaccine. The trial will be conducted in approximately 400 children 4-6 years of age who previously received three doses of DTaP using INFANRIX® and/or PEDIARIX® and a fourth dose of DTaP using INFANRIX ®.
Based on the timetable you submitted on January 15, 2008, you have committed to conduct this trial according to the following schedule:
Protocol Submission: by August 30, 2008
Study Start Date: by January 30, 2009
Final Report Submission: by July 31, 2011
Please submit the protocol to your IND -------, with a cross-reference letter to this biologics license application (BLA), STN BL 125260, and submit all final reports to your BLA, STN BL 125260.
Please use the following designators to prominently label all submissions, including supplements, relating to this post-marketing study commitment as appropriate:
- Postmarketing Study Commitment Protocol
- Postmarketing Study Correspondence/Status Update
- 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 “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),
- an explanation of the status including, for clinical studies, the patient accrual rate (i.e., number enrolled to date and the total planned enrollment), and
- a revised schedule if the study schedule has changed and an explanation of the basis for the revision.
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/cder/pmc/default.htm). Please refer to the February 2006 Guidance for Industry: Reports on the Status of Postmarketing Study Commitments – Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997 (see http://www.fda.gov/cber/gdlns/post130.htm) for further information.
You are required to report annually to FDA on the status of this study pursuant to section 506B of the FDCA, as well as 21 CFR 601.70 until we have notified you that the study commitment has been met.
If you have any questions, please contact Dr. Joseph Temenak at 301-827-3070.
/Norman W. Baylor, Ph.D./
Norman W. Baylor, Ph.D.
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research