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February 24, 2010 Approval Letter - Prevnar 13

Our STN: BL 125324/0

Wyeth Pharmaceuticals, Incorporated
Attention: Jack Love, Ph.D.
Assistant Vice President, Global Regulatory Affairs
401 Middleton Road
Pearl River, NY 10965

Dear Dr. Love:

We have approved your biologics license application for Pneumococcal 13-Valent Conjugate Vaccine [Diphtheria CRM197Protein] effective this date.  You are hereby authorized to introduce or deliver for introduction into interstate commerce Pneumococcal 13-Valent Conjugate Vaccine [Diphtheria CRM197 Protein] under your existing Department of Health and Human Services U.S. License Number 0003.  Pneumococcal 13-Valent Conjugate Vaccine [Diphtheria CRM197 Protein] is indicated for active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, and for the prevention of otitis media caused by serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F when administered to children 6 weeks through 5 years of age.

Under this license, you are approved to manufacture Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM197 Protein].  Commercial manufacturing will be distributed among the following –(b)(4)- facilities:  Wyeth Pharmaceuticals, Inc., located in -------(b)(4)------------------------------------------------ -------------(b)(4)---------------------------------------------------------------------------------- ---------------------------------------------(b)(4)---------------------------------------------------  The manufacture of the pneumococcal polysaccharides will take place at the ---------(b)(4)------ ---------------------------------.  Pneumococcal polysaccharides types 1 and 5 will be manufactured at ----(b)(4)-----. Pneumococcal polysaccharides types 3, 6A, and 19A, will be manufactured ------------(b)(4)--------.  Pneumococcal polysaccharides types 4, 6B, 7F, 9V, 14, 18C, 19F, and 23F, will be manufactured -----(b)(4)----------------.  The manufacture of diphtheria CRM197 protein and pneumococcal polysaccharide- CRM197 conjugates for 3, 4, 6B, 9V, 14, 18C, 19A, and 23F, ------(b)(4)-----------------.  Pneumococcal polysaccharides-CRM197 conjugates for 1, 5, 6A, 7F, and 19F, will be manufactured --------(b)(4)-------------.  Final Pneumococcal 13-Valent Conjugate Vaccine [Diphtheria CRM197 Protein] formulation, syringe filling, labeling, and packaging will occur -----------------(b)(4)--------------------------------.  You may label your product with the proprietary name Prevnar 13™.  The vaccine will be supplied in 1.0 mL pre-filled single dose syringes, each of which will deliver a single 0.5 mL dose of vaccine.

The dating period for Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM197 Protein] (Prevnar 13™) shall be 24 months from the date of manufacture when stored at  2°C to 8°C. The date of manufacture shall be defined as the date of initiation of filling into final containers.

Please submit final container samples of the product as well as monovalent bulk conjugates 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 including, but not limited to the manufacturing, testing, packaging or labeling of  Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM197 Protein] or in the manufacturing facilities.

This approval also includes a comparability protocol for the manufacture of future working seed lots for each of the 13 pneumococcal serotypes and diphtheria CRM197 protein.  Under 21 CFR 601.12(e), approval of a comparability protocol may justify a reduced reporting category for a particular change.  In your annual report, according to 21 CFR 601.12(d), you should report information confirming that working seed changes meet the requirements specified in your approved comparability protocol and also include the information described in 21 CFR 601.12(d)(3).

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 in a timely manner.  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, 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 submitted data to support such claims to us and they are approved.

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.  Individual adverse event reports should be submitted to the Vaccine Adverse Event Reporting System (VAERS) electronically at https://vaers.hhs.gov/esub/step1 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). 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 will submit a monthly line listing of all non-15 day adverse event reports and frequency distributions of adverse event terms from each month's reports to VAERS for the first 3 years in a formatted manner as previously discussed with you on June 30, 2009.

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 birth to < 6 weeks of age for the invasive pneumococcal disease and otitis media indications because Prevnar 13™ does not represent a meaningful therapeutic benefit over initiating vaccination at 6 weeks of age, and Prevnar 13™ is not likely to be used in a substantial number of pediatric patients from birth to < 6 weeks of age.

We are waiving the pediatric study requirement in children from 6 to 16 years of age for the otitis media indication, because Prevnar 13™ does not represent a meaningful therapeutic benefit over existing antibiotic therapy, and Prevnar 13™ is not likely to be used in a substantial number of pediatric patients 6 to 16 years of age.

We are deferring submission of your pediatric study for ages 6 to 16 years in this application for the invasive pneumococcal disease indication, because this product is ready for approval for routine immunization in infants and children 6 weeks through 5 years of age, and the pediatric study in children 6 through 16 years of age 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. Deferred pediatric study (6096A1-3011) under PREA to evaluate the safety and immunogenicity of Prevnar 13™ in pediatric patients 6 through 16 years of age.

Final Report Submission: December 31, 2011

Submit final study reports to this biologics license application (BLA).  For administrative purposes, all submissions related to this required pediatric postmarketing study must be clearly designated “Required Pediatric Assessments.”

We note that you have fulfilled the pediatric study requirement for ages 6 weeks through 5 years for this application.

AGREED UPON POSTMARKETING COMMITMENTS

Postmarketing studies subject to reporting requirements of 21 CFR 601.70.

We acknowledge your written commitments as described in your submissions of December 9, 2009 and February 1, 2010, as outlined below:

  1. You agree to conduct study 6096A1-4002, a post-licensure observational study in a cohort of children at Northern California Kaiser Permanente who receive Prevnar 13™ as part of routine medical care, to expand the understanding of the safety profile of Prevnar 13™.  At least 43,000 subjects in the total cohort will receive all three infant series doses.  The final protocol for this study was submitted on February 15, 2010.  The study will begin in May 2010 and be completed by December 31, 2013.  The final study report will be submitted by September 30, 2014.
  2. You agree to conduct study 6096A1-4005, an observational database study to monitor the impact of Prevnar 13™ in preventing overall invasive pneumococcal disease in Northern California Kaiser Permanente members, by estimating the impact of Prevnar 13™ routine use on the annual incidence rate of invasive pneumococcal disease during the five-year surveillance period in the study population.  The final protocol for this study will be submitted by March 31, 2010.  The study will begin in May 2010 and be completed by June 30, 2015.  The final study report will be submitted by March 31, 2016.
  3. You agree to conduct study 6096A1-4010, a post-licensure observational study to evaluate the impact of Prevnar 13™ routine use in reducing acute otitis media (AOM) and nasopharyngeal colonization in young children caused by the serotypes in the vaccine.  Streptococcus pneumoniae isolates obtained from tympanocentesis, nasopharyngeal and oropharyngeal samples from subjects in this study will be serotyped.  The final protocol for this study will be submitted by April 30, 2010.  The study will be initiated by September 30, 2010, and be completed by September 30, 2015.  The final study report will be submitted by June 30, 2016.
  4. You agree to conduct a study to monitor the impact of Prevnar 13™ routine use in reducing AOM caused by serotypes in the vaccine via the United States Pediatric Multicenter Pneumococcal Surveillance Group (USPMPSG), a laboratory-based surveillance network of eight pediatric hospitals across the United States.  In this study Streptococcus pneumoniae isolates from identified AOM cases will be serotyped.  The final protocol for this study will be submitted by May 31, 2010.  The study will be initiated by December 31, 2010, and completed by December 31, 2013.  The final study report will be submitted by September 30, 2014.
  5. You agree to conduct study 6096A1-4018, an ecologic study to assess national trends in health care visits for otitis media in children younger than five years of age.  This study will utilize ambulatory health care visit data from annual national surveys conducted by the National Center for Health Statistics.  The final protocol for this study will be submitted by June 30, 2010.  The study will be initiated by December 31, 2010, and be completed by December 31, 2013.  The final study report will be submitted by September 30, 2014.

We request that you submit clinical protocols to your IND -(b)(4)- with a cross-reference letter to this BLA, STN BL 125324.  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 labeling changes are needed. 

Please use the following designators to prominently label 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 Commitment -Final Study Report

For each 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 February 10 and February 18, 2010, submissions 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 125324.

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 Mike Smith or CDR Colleen Sweeney at 301-827-3070.

Sincerely yours,                                              

--signature--

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

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