Archived Content

The content on this page is provided for reference purposes only. This content has not been altered or updated since it was archived.

Vaccines, Blood & Biologics

Letter - Filing Review - Prevnar 13

Our STN:  BLA 125324

Wyeth Pharmaceuticals, Inc.
Attention: Jack D. Love, Ph.D.
401 N. Middletown Road
Pearl River, NY 10965

Dear Dr. Love:

Please refer to your biologics license application (BLA), submitted under section 351 of the Public Health Service Act, and to our filing letter dated May 1, 2009.  While conducting our filing review we identified the following potential review issues:

With regard to Chemistry, Manufacturing and Controls (CMC) data:

  1. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)----------------------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------. 
  2. Summarized information about the testing methods for drug substance/product and validation of such methods are provided in modules 3.2.S.4 and 3.2.P.5 of your BLA.  However, the actual written procedures for these testing methods and validation documents (protocols and reports) are necessary for review of these methods and to perform product testing by CBER in support of your BLA.  On April 30, 2009, we requested a detailed list of such documents.  You have since provided these documents to us via electronic disk and e-mail, followed by official submission of these documents to your BLA on June 11, 2009.  Pending our review of these documents, deficiencies related to your product testing method procedures and validation documents, may be identified.

With regard to clinical data:

  1. Based on preliminary review of the clinical data, we have identified the following two issues, which we expect to result in requested labeling changes:
    1. According to the clinical data provided in your BLA, three serotypes (i.e., 3, 6B and 9v) failed at least one of the primary immunogenicity endpoints in study 6096A1-004, the pivotal, phase 3, non-inferiority immunogenicity study to support U.S. licensure.  We note that the Clinical Studies section in the proposed draft labeling does not convey this information.
    2. The CSR for study 6096A1-3008, titled “A Phase 3, Randomized, Active-Controlled, Double-blind Trial Evaluating the Safety, Tolerability, and Immunogenicity of a 13-valent Pneumococcal Conjugate Vaccine in Healthy Infants Given with Routine Pediatric Vaccinations in Canada,” is provided in your BLA.  The immunogenicity results from this study are presented in the proposed draft labeling in section 14.1, “Immune Responses Following a Three-Dose Primary Infant Series,” and in section 14.4, “Simultaneous Administration with Other Vaccines.”  BecauseNeisVac-C, a non-U.S. licensed vaccine, was concomitantly administered with study vaccine to subjects in this study, immunogenicity data from this study cannot be used to support U.S. licensure of 13vPnC.  Therefore, information concerning immunogenicity data from this study should be removed from the aforementioned sections of the labeling.  In addition, we have concerns about how you propose to present safety data from this study in the labeling.
  1. According to information submitted to IND -(b)(4)- on October 6, 2008, it appears that in calculating geometric mean concentrations (GMCs) for pneumococcal IgG antibody data in clinical study 6096A1-3011, assay values, which fall below the lower limit of quantitation (LLOQ), will be replaced with the antibody limit of detection (LOD).   According to the amendment submitted to IND -(b)(4)- on April 22, 2009, LOD is assigned as half of LLOQ.  Please clarify whether this approach was taken in calculating GMCs in the clinical studies submitted to your BLA.  In addition, if this approach was taken for studies 6096A1-004 and 6096A1-3005, we would like to see whether replacing those IgG antibody levels, which fall below the LLOQ with half of LOD, has an effect on GMCs for those two studies.

With regard to polio neutralization assay validation:

  1. On May 6, 2009, we requested information concerning validation of the polio neutralization assay, the report for which was provided in section, and immune response to concomitantly administered polio vaccine among subjects in study 6096A1-3005, the data for which are provided in section  You have since submitted a response to this request on May 18, 2009.  Our review of this response is pending and may result in additional requests for information.

With regard to your draft post marketing plan:

  1. We note that your draft post marketing plan, provided in section1.16, “Risk Management Plan” (i.e., Post Marketing Effectiveness Plan and Pharmacovigilance Plan), does not reflect our advice, which was conveyed to you under IND -(b)(4)- in the set of written comments dated March 9, 2009, and discussed with you in a teleconference on that day.   On June 11, 2009, you submitted a response to our March 9, 2008, comments to your BLA.  Pending our review of this response we may identify issues for further discussion with you.  Subsequent to our review of this response and any follow-up with you, a revised post marketing plan should be submitted to your BLA.

We are providing the above comments to give you preliminary notice of potential review issues.

Our filing review is only a preliminary evaluation of the application and is not indicative of deficiencies that may be identified during our complete review.  Issues may be added, deleted, expanded upon, or modified as we review the application.  If you respond to these issues during this review cycle, we may not consider your response before we take an action on your application.  Following a review of the application, we shall advise you in writing of any action we have taken and request additional information if needed.

If you have any questions, please contact either Regulatory Project Manager, LCDR Michael Smith, Ph.D., or CDR Colleen Sweeney, M.S., at (301)-827-3070.

Sincerely yours,


Wellington Sun, M.D.
Division of Vaccines and Related Products Applications
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research

Contact FDA

(800) 835-4709
(240) 402-8010
Consumer Affairs Branch (CBER)

Division of Communication and Consumer Affairs

Office of Communication, Outreach and Development

Food and Drug Administration

10903 New Hampshire Avenue

Building 71 Room 3103

Silver Spring, MD 20993-0002

Page Last Updated: 03/26/2010
Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and Players.
Language Assistance Available: Español | 繁體中文 | Tiếng Việt | 한국어 | Tagalog | Русский | العربية | Kreyòl Ayisyen | Français | Polski | Português | Italiano | Deutsch | 日本語 | فارسی | English