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December 13, 2002 Approval Letter - Pediarix

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
1401 Rockville Pike
Rockville, MD 20852-1448

December 13, 2002

Our STN: BL 103907/0

SmithKline Beecham Biologicals
Johan Van Hoof, M.D.
89, Rue de l'Institut
B-1330 Rixensart
BELGIUM

Dear Dr. Van Hoof:

Your biologics license application for Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine Combined (Pediarix), for the active immunization of infants and children against diphtheria, tetanus, pertussis, hepatitis B, and polio, is approved effective this date. SmithKline Beecham Biologicals, Rixensart, Belgium, is hereby authorized to introduce or deliver for introduction into interstate commerce, Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine Combined, under U.S. Department of Health and Human Services License No. 1090.

In accordance with approved labeling, your product will bear the proprietary name Pediarix, and will be marketed in 0.5 mL pediatric single dose glass vials and 0.5 mL pediatric single dose disposable prefilled Tip-Lok® glass syringes. Final bulk product is formulated and filled by SmithKline Beecham Biologicals, S.A., Rixensart, Belgium. SmithKline Beecham Pharmaceuticals will distribute packaged Pediarix in the United States.

The dating period for the final container for Pediarix shall be 24 months from the date of manufacture when stored continuously at 2-8°C. 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 must commence within ------- after filling. The final formulated bulk may be stored for ---------------prior to filling when maintained at ------°C. Any extension of the dating period will require the submission and approval of supporting data as a prior approval supplement to your biologics license application. Alternatively, you may submit, as a prior approval supplement to your biologics license application, a stability protocol to support the extension of dating. You are requested to submit to the Center for Biologics Evaluation and Research (CBER) samples of each future final formulated bulk lot of Pediarix together with protocols showing the results of all applicable tests. No final container lots of product shall be distributed until notification of bulk release is received from the Director, CBER.

Any changes in the manufacturing, testing, packaging or labeling of Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine Combined, or in the manufacturing facilities will require the submission of information to your biologics license application for our review and written approval consistent with 21 CFR 601.12.

We acknowledge the clinical commitments outlined in your letters of December 5, and 10, 2002, as follows:

  1. You have agreed to submit results for ongoing Study 217744/084, entitled "A phase III, open labeled, randomized, multicenter, clinical study of the safety of a primary series of GlaxoSmithKline Biologicals' (GSK Biologicals') DTaP-HepB-IPV combined candidate vaccine coadministered with HibTITER and Prevnar to healthy infants at 2, 4, and 6 months of age as compared to the separate administration of Infanrix + Engerix-B + IPOL + HibTITER + Prevnar." The protocol for Study 217744/084 was initially submitted to BB-IND ---- on ------------------, and the study was initiated on December 12, 2001. Patient accrual was completed on April 16, 2002. The study will be completed (last patient exiting) by February 16, 2003. The final clinical study report will be submitted to CBER by June 30, 2003, and revised labeling will be submitted by December 15, 2003.
  2. You have agreed to submit results for ongoing Study 217744/085, entitled "A phase III, open labeled, randomized, multicenter, clinical study of the safety and immunogenicity of a primary series of GlaxoSmithKline Biologicals' (GSK Bio) DTPa-HepB-IPV candidate vaccine co-administered with Prevnar and Hib vaccine at 2, 4, and 6 months of age as compared to the separate administration of DTPa, HepB, IPV, Hib and PrevnarT vaccines and to GSK Bio's DTPa-HepB-IPV candidate vaccine co-administered with Hib vaccine in healthy infants." The protocol for Study 217744/085 was initially submitted to BB-IND ---- on ----------------, and the study was initiated on February 8, 2002. Patient accrual was completed on August 15, 2002. The study will be completed (last patient exiting) by June 13, 2003. The final clinical study report will be submitted to CBER by October 31, 2003, and revised labeling will be submitted by December 15, 2003.
  3. You have agreed to conduct a Phase 4 post-marketing study, Study 217744/088, entitled "Phase IV, prospective, open study of the safety of GSK Biologicals' Pediarix (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine Combined) administered to a cohort of infants at a US Health Maintenance Organization (HMO) (Post-Marketing PEDIARIX Safety Surveillance)." This study is designed to evaluate as primary endpoints the risk of seizures associated with fever and the risk of medically attended fever following Pediarix administration. A draft protocol for Study 217744/088 was submitted to the biologics license application on -------------. A revised protocol will be submitted to CBER by January 31, 2003, and the study will be initiated by April 30, 2003. Completion of patient accrual and completion of the study are anticipated by April 30, 2005, and November 30, 2006, respectively. A final clinical study report will be submitted to CBER by May 31, 2007.

Maintenance of the dating period is dependent on the submission of stability data as stated in your letter of December 2, 2002.

You are required to submit reports of biological product deviations in accordance with 21 CFR 600.14. All manufacturing deviations, including those associated with processing, testing, packaging, labeling, storage, holding and distribution, should be promptly identified and investigated. 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, a report must be submitted 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.

It is required that adverse experience reports be submitted in accordance with the adverse experience reporting requirements for licensed biological products (21 CFR 600.80) and that distribution reports be submitted as described (21 CFR 600.81). According to 21 CFR 600.80(c)(2) [Periodic Adverse Experience Reports], the licensed manufacturer shall report each adverse experience not reported under paragraph (c)(1)(i) of this section at quarterly intervals for the first 3 years following approval. Since your product is characterized as a vaccine, these reports should be submitted to the Vaccine Adverse Event Reporting System (VAERS) using the pre-addressed form VAERS-1.

Please submit four copies of final printed labeling, under STN 103907/0, at the time of use and include Form FDA 2567 (09/02) with completed implementation information.

We recommend that you submit two draft copies of representative samples of your proposed introductory advertising and promotional labeling for advisory comment with a Form FDA 2253 to the Center for Biologics Evaluation and Research, Advertising and Promotional Labeling Branch, HFM-602, 1401 Rockville Pike, Rockville, MD 20852-1448. Final printed advertising and promotional labeling should be submitted at the time of initial dissemination, accompanied by a Form FDA 2253.

All promotional claims must be consistent with and not contrary to approved labeling. No comparative claims or claims of superiority over other products should be made unless data to support such claims are submitted to and approved by CBER.

Please acknowledge receipt of this letter, in writing, to the Director, Division of Vaccines and Related Products Applications, HFM-475, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research.

Sincerely yours,
--- signature ---

Karen Midthun, M.D.
Director
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research