Vaccines, Blood & Biologics
January 14, 2005 Approval Letter
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
1401 Rockville Pike
Rockville, MD 20852-1448
January 14, 2005
Our STN: BL 125089 / 0
Aventis Pasteur Inc.
Attn: Luc Kuykens, M.D.
Vice President, Regulatory Affairs North America
Swiftwater, PA 18370-0187
Dear Dr. Kuykens:
We have approved your biologics license application (BLA) for Meningococcal Polysaccharide (Serogroups A, C, Y and W-135) Diphtheria Toxoid Conjugate Vaccine effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Meningococcal Polysaccharide (Serogroups A, C, Y and W-135) Diphtheria Toxoid Conjugate Vaccine under your existing Department of Health and Human Services U.S. License No. 1277. Meningococcal Polysaccharide (Serogroups A, C, Y and W-135) Diphtheria Toxoid Conjugate Vaccine is indicated for active immunization of adolescents and adults 11-55 years of age for the prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135.
Under this authorization, you are approved to manufacture Meningococcal Polysaccharide (Serogroups A, C, Y and W-135) Diphtheria Toxoid Conjugate Vaccine at your facility in Swiftwater, PA. You may label your product with the proprietary name, Menactra. The vaccine will be marketed in 0.5 mL single dose vials.
The dating period for Menactra vaccine shall be 21 months from the date of the manufacture of the final bulk when stored at 2-8°C. Of the 21 months total dating, (a) the final bulk will be held not more than -------- and (b) the final container will be held not more than -----------. The date of manufacturing of the final bulk is defined as the date of the last valid potency assay. As the final container is not to be held more than --------, the total time that elapses from the date of manufacture of the final bulk to expiry may be less than 21 months.
Please submit bulk samples of the product 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 BLA for our review and written approval under 21 CFR 601.12 for any changes in the manufacturing, testing, packaging or labeling of Menactra vaccine, or in the manufacturing facilities.
All applications for new active ingredients, new dosage forms, new indications, new routes of administration, and new dosing regimens are required to contain an assessment of the safety and effectiveness of the product in pediatric patients unless this requirement is waived or deferred. We have reviewed your submission and the data provided in the BLA is sufficient to assess the safety and effectiveness for the claimed indication in individuals 11-18 years of age. Studies demonstrating safety and effectiveness of Menactra vaccine in individuals 2 to 10 years of age are deferred until February 2005 when the BLA Supplement will be submitted. In addition, a deferral of pediatric studies with Menactra vaccine in individuals less than 2 years of age is justified as clinical development in this age range is ongoing. The status of the required post marketing commitments shall be reported annually according to 21 CFR 601.70. These commitments are listed below:
- To submit a BLA Supplement to establish the safety and effectiveness of Menactra vaccine in subjects 2-10 years of age by February 2005.
- To develop safety and effectiveness data with Menactra vaccine in subjects less than 2 years of age. Studies evaluating Menactra vaccine in this age range have been initiated. Additional data in the pediatric population less than 2 years of age will be submitted by December 2006.
In addition to these postmarketing commitments described in your letter of January 12, 2005, we acknowledge your written commitments also stated in the above letter, as outlined below:
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.
- To conduct an open label, descriptive, epidemiological, safety surveillance study that enrolls 20,000 subjects or enrolls for 1 year, whichever results in the larger enrollment. The study protocol will be submitted by May 2005. The study will be initiated by July 2005. The final study report will be submitted 1 year after the last subject has completed the study, July 2008.
- To conduct a randomized, modified double-blind, comparative study evaluating safety and immunogenicity when Menactra vaccine is given concomitantly with Tetanus and Reduced Diphtheria and Acellular Pertussis Vaccine, Adsorbed (Tdap). The study will be conducted in approximately 1400 adolescents aged 11-17 years. The study protocol will be submitted by March 2005. The study will be initiated by April 2005. The final study report will be submitted by December 2006.
- To conduct an open label study that enrolls approximately 400 participants to evaluate the duration of the antibody response in participants who had received a single dose of Menactra vaccine or Menomune vaccine 5 and 10 years earlier. Enrollees will be between 16 and 23 years of age when they are 5 years post vaccination. The study protocol will be submitted by September 2005 with study initiation for the 5 year follow up by November 2005. Study initiation for the 10 year follow up is planned by November 2010. The clinical study reports will be submitted as two reports, one report will be submitted for the 5 year follow up study and one report will be submitted for the 10 year follow up. The first report will be submitted 1 year after the last patient has completed the 5 year follow up, May 2007, and the second report will be submitted 1 year after the last patient has completed the 10 year follow up, May 2012.
- To conduct a multi-center, modified double blind, active controlled clinical study to evaluate the safety and immunogenicity of Menactra vaccine in subjects greater than 55 years of age. The study protocol will be submitted by October 2005 and the study initiated by January 2006. The final study report will be submitted by January 2008.
- To provide expanded adverse experience reporting (in addition to complying with the requirements under 21 CFR 600.80) to the Vaccine Adverse Reporting System for one year following product licensure as follows:
- As 15 day reports: All serious adverse events whether expected/labeled or unexpected/unlabeled, including seizures (including febrile seizures), shock, respiratory distress or difficulty breathing, angioedema, inspiratory stridor, and bilateral wheezing.
- As 30 day (monthly) reports: all allergic events, including anaphylaxis not reported as a 15 day report; all cases of urticaria not reported as a 15 day report; neurological events not reported as 15 day reports, including Bell's palsy, Guillain-Barré Syndrome, encephalitis, encephalopathy, brachial neuritis, optic neuritis, other neuropathy, myelitis including transverse myelitis, ptosis, ataxia, multiple sclerosis, acute disseminated encephalomyelitis, cerebrovascular accidents or transient ischemic attacks; all cases of intentional or non-intentional injury not reported as a 15 day report.
Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70.
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We request that you submit clinical protocols to your IND, with a cross-reference letter to this BLA, STN BL 125089/0. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN BL 125089/0. Please use the following designators to label prominently all submissions, including supplements, relating to these postmarketing study commitments as appropriate:
- Postmarketing Study Protocol
- Postmarketing Study Final Report
- Postmarketing Study Correspondence
- Postmarketing Study Correspondence
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. 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/cder/pmc/default.htm). Please refer to the April 2001 Draft 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/cber/gdlns/post040401.htm) for further information.
Adverse experience reports should be submitted in accordance with the adverse experience reporting requirements for licensed biological products (21 CFR 600.80) and distribution reports as described in 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. Since your product is characterized as a vaccine, submit these reports to the Vaccine Adverse Event Reporting System (VAERS) using the pre-addressed form VAERS-1.
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 a PDF-format electronic copy as well as original paper copies (ten for circulars and five for other labels). 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 had them approved.
--- signature ---
Norman W. Baylor, Ph.D.
Office of Vaccines Research and Review
Center for BiologicsEvaluation and Research