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U.S. Department of Health and Human Services

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Feburary 19, 2010 Approval Letter - Menveo

Our STN:  BL 125300/0

Novartis Vaccines and Diagnostics, Inc.
Attention: Christopher Webster, Ph.D.
350 Massachusetts Avenue
Cambridge, MA 02139-4182

Dear Dr. Webster:

We have approved your biologics license application for Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine effective this date.  You are hereby authorized to introduce or deliver for introduction into interstate commerce Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine under your existing Department of Health and Human Services U.S. License No. 1751.  Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine is indicated for active immunization to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135 when administered to individuals 11 through 55 years of age.

Under this license, you are approved to manufacture Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine.  The meningococcal (Groups A, C, Y, and W-135) oligosaccharide diphtheria CRM197 conjugates are each manufactured at Novartis Vaccines and Diagnostics S.r.l., Bellaria-Rosia 53018 Sovicille (SI), Italy.  The MenCYW-135 Liquid Conjugate Component will be formulated and filled at Novartis Vaccines and Diagnostics S.r.l., Bellaria-Rosia 53018 Sovicille (SI), Italy.  The MenA Lyophilized Conjugate Component will be formulated, filled, and lyophilized at Novartis Vaccines and Diagnostics --------(b)(4)----------------(b)(4)------------.  The final formulated product will be labeled and packaged at Novartis Vaccines and Diagnostics S.r.l., Bellaria-Rosia 53018 Sovicille (SI), Italy.  You may label your product with the proprietary name MENVEO®.  The vaccine will be supplied in packages containing five single dose vials of the MenCYW-135 Liquid Conjugate Component to be used to reconstitute five single dose vials of the MenA Lyophilized Conjugate Component.

We did not refer your application to the Vaccines and Related Biological Products Advisory Committee because our review of information submitted in your BLA, including the clinical study design and trial results, did not raise concerns or controversial issues which would have benefited from an advisory committee discussion.

The dating period for the MenCYW-135 Liquid Conjugate Component shall be 36 months from the date of initiation of the final bulk formulation when stored at 2 °C to 8 °C.  The dating period for the MenA Lyophilized Conjugate Component shall be 36 months from the date of initiation of the final bulk formulation when stored at 2 °C to 8 °C. 

The dating period for the co-packaged MenCYW-135 Liquid Conjugate Component and MenA Lyophilized Conjugate Component shall be 36 months from the date of formulation of whichever vaccine final bulk component has the earliest formulation date when stored at 2 °C to 8 °C.

Please submit final container samples of the product, including each of the two vaccine components, in final containers 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 Biologic 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 in, including but not limited to, the manufacturing, testing, packaging or labeling of Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine, or in the manufacturing facilities.

You must submit reports of biological product deviations under 21 CFR 600.14.  You should identify promptly 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 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 substantial evidence or substantial clinical experience to support such claims (21 CFR 202.1(e)(6)).

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).  You should submit these reports to the Vaccine Adverse Event Reporting System (VAERS), P.O. Box 1100, Rockville, MD 20849-1100, using the pre-addressed form VAERS-1  (http://www.fda.gov/downloads/BiologicsBloodVaccines/
GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/UCM164319.pdf
).  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 agreed to provide expanded adverse experience reporting to the Vaccine Adverse Reporting System for one year following product licensure as follows:

  1. As 15 day reports: All serious adverse events whether expected/labeled or unexpected/unlabeled.
  1. As 30 day (monthly) reports if not already submitted as 15 day reports: all allergic events, including anaphylaxis; neurological events 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, and transient ischemic attacks; idiopathic thrombocytopenic purpura; Kawasaki disease; myasthenia gravis; other new onset autoimmune disease; and all cases of non-intentional injury.

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 for infants from birth to < 8 weeks of age because the product does not represent a meaningful therapeutic benefit over initiating vaccination at 8 weeks of age, and the product is not likely to be used in a substantial number of pediatric patients from birth to < 8 weeks of age.

We are deferring submission of your pediatric studies for ages 2 months through 10 years for this application because this product is ready for approval for use in adults and adolescents and the pediatric studies for younger age groups have not been completed.

Your deferred pediatric studies required under 505B(a) of the Federal Food, Drug, and Cosmetic Act are required postmarketing studies.  The status of these postmarketing studies must be reported according to 21 CFR 601.70 and section 505B(a)(3)(B) of the Federal Food, Drug, and Cosmetic Act.  These required studies are listed below:

  1. Deferred pediatric study V59P14 under PREA to evaluate the safety and immunogenicity of Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine when administered with routine infant vaccinations to healthy infants 2 through 12 months of age.  You have committed to submit the final clinical study report by March 31, 2011.
  1. Deferred pediatric study V59P23 under PREA to evaluate the safety of Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine when administered with routine infant vaccinations to healthy infants 2 through 12 months of age.  You have committed to submit the interim study report by December 31, 2011 and the final clinical study report by July 31, 2012.
  1. Deferred pediatric study V59P21 under PREA to evaluate the safety and immunogenicity of Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine when administered to healthy children 7 through 12 months of age.  You have committed to submit the final clinical study report by March 31, 2011.
  1. Deferred pediatric study V59P20 under PREA to evaluate the safety and immunogenicity of Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine when administered to healthy children 2 through 10 years of age.  You have committed to submit the final clinical study report by March 31, 2010.
  1. Deferred pediatric study V59P33 under PREA to evaluate the safety and immunogenicity of Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine when administered with routine infant vaccinations to healthy infants 2 through 12 months of age.  You have committed to submit the final clinical study report by December 31, 2011.

Please submit the interim and final clinical study reports to this BLA (BL 125300).  For administrative purposes, all submissions related to these required pediatric postmarketing studies must be clearly designated “Required Pediatric Assessments.”

We note that you have fulfilled the pediatric study requirement for ages 11 to 16 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 letter of January 15, 2010, as outlined below:

  1. To conduct a randomized, comparative trial, designed primarily to evaluate the potential for immune interference of concomitant use of MENVEO with Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine and a Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed as currently recommended by the U.S. vaccine schedule for immunization of adolescents.  You commit to provide a clinical protocol for CBER review by July 2010 and to provide complete study results by November 2012.
  1. To conduct a Phase IV self-controlled case-series study to assess the safety of Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine administered to a minimum of 50,000 HMO subjects 11 through 19 years of age to expand the understanding of the safety profile of Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine.  The final IRB approved study protocol will be submitted no later than June 20, 2010.  The study will be initiated by August 20, 2010.  The final study report will be submitted by 1 year after the last subject has completed the study and no later than August 20, 2015.
  1. To establish a U.S. pregnancy registry to collect safety data on spontaneously-reported exposures to Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine during pregnancy and lactation.  The final IRB approved pregnancy registry protocol will be submitted by August 20, 2010.  Patient accrual and data collection will begin at the time of CBER’s approval of the protocol and end no sooner than five years later. The U.S. pregnancy registry may be considered completed one month after discontinuation of patient accrual for the purpose of preparing a five-year final summary report. The five-year final summary report should be submitted to CBER five years and six months after initiation of patient accrual and data collection.  After CBER review of the five-year data, the need to continue further data collection in the U.S. pregnancy registry will be discussed with CBER.  CBER will have final approval regarding any decision to discontinue the U.S. pregnancy registry.

Please submit clinical protocols to your IND, with a cross-reference letter to this BLA,
STN 125300.  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 we think labeling changes are needed. 

Please use the following designators to label prominently 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 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 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. 

If you have any questions, please contact Dr. Cara Fiore, Regulatory Project Manager, at  301-827-3070.

Sincerely yours,

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