Vaccines, Blood & Biologics

January 23, 2015 Approval Letter - BEXSERO

ACCELERATED APPROVAL

Our STN: BL 125546/0                              

January 23, 2015

Novartis Vaccines and Diagnostics, Inc.
Attention: Patricia Stoehr, Ph.D.
350 Massachusetts Avenue
Cambridge, MA 02139

Dear Dr. Stoehr:

Effective this date, we have approved your biologics license application (BLA) for Meningococcal Group B Vaccine, according to the regulations for accelerated approval, 21 CFR 601.40-46. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Meningococcal Group B Vaccine under your existing Department of Health and Human Services U.S. License No. 1751. Meningococcal Group B Vaccine is indicated for active immunization to prevent invasive disease caused by Neisseria meningitidis serogroup B. Meningococcal Group B Vaccine is approved for use in individuals 10 through 25 years of age.

Under this authorization, you are approved to manufacture Meningococcal Group B Vaccine. The Outer Membrane Vesicle drug substance will be manufactured at Novartis Vaccines and Diagnostics S.r.l. in Bellaria-Rosia, Italy. The Neisserial Heparin Binding Antigen, factor H binding protein and Neisserial adhesin A drug substances will be manufactured at ----(b)(4)-------------------------. The final formulated drug product will be manufactured, filled, labeled and packaged at Novartis Vaccines and Diagnostics in Bellaria-Rosia, Italy. You may label your product with the proprietary name BEXSERO and market it in prefilled syringes containing a single 0.5 mL dose of vaccine.

The review of this product was associated with the following National Clinical Trial (NCT) numbers: NCT00560313, NCT00661713, NCT01148524, NCT01214850, NCT01272180 and NCT01423084.

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 benefitted from an advisory committee discussion. In addition, on April 7, 2011, an advisory committee meeting was held to discuss approaches to demonstrate effectiveness of meningococcal serogroup B vaccines; advice from this committee was considered in the review of this application.

The dating period for Meningococcal Group B Vaccine shall be 24 months from the date of manufacture when stored at 2oC to 8 oC. The date of manufacture shall be defined as the date of initiation of filling into final containers.

Please submit final container samples of the drug product as well as individual concentrated bulks 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 Meningococcal Group B Vaccine, or in the manufacturing facilities.

You must submit reports of biological product deviations under 21 CFR 600.14. You should identify and investigate all manufacturing deviations promptly, 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, at the following address:

Food and Drug Administration
Center for Biologics Evaluation and Research
Document Control Center
10903 New Hampshire Ave.
WO71-G112
Silver Spring, MD 20993-0002

We are granting marketing approval of this product under the accelerated approval of biological products regulations, 21 CFR 601.40-46. Under these regulations we may grant marketing approval for a biological product on the basis of adequate and well-controlled clinical trials establishing that the biological product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. This approval requires you to study the biological product further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome.

Approval under these regulations requires, among other things, that you conduct adequate and well-controlled studies to verify and describe clinical benefit attributable to this product. For this vaccine, clinical benefit will be confirmed by demonstration of effectiveness against diverse meningococcal group B strains.

Accelerated Approval Required Studies

We remind you of your postmarketing requirements specified in your submission of January 15, 2015.

  1. To conduct the ongoing study V102_16 to assess the performance of immunologic assays for evaluating the breadth of coverage against diverse Neisseria meningitidis serogroup B strains.

    Final Protocol Submission: November 19, 2013

    Study Completion: May 28, 2015

    Final Report Submission: March 20, 2016

  2. To conduct study V72_72 of BEXSERO among persons 10 years through 25 years of age in the US to confirm effectiveness against a panel of diverse Neisseria meningitidis serogroup B strains.

    Final Protocol Submission: December 31, 2015

    Study Completion: December 31, 2017

    Final Report Submission: December 31, 2018

We expect you to complete design, initiation, accrual, completion, and reporting of these studies within the framework described in your submission of January 15, 2015.

You must conduct these studies with due diligence. If postmarketing studies fail to verify that clinical benefit is conferred by Meningococcal Group B Vaccine, or are not conducted with due diligence, we may, following a hearing in accordance with 21 CFR 601.43 (b), withdraw or modify approval if:

  • A postmarketing clinical study fails to verify clinical benefit
  • The applicant fails to perform the required postmarketing study with due diligence
  • Use after marketing demonstrates that postmarketing restrictions are inadequate to ensure safe use of the biological product
  • The applicant fails to adhere to the postmarketing restrictions agreed upon
  • The promotional materials are false or misleading
  • Other evidence demonstrates that the biological product is not shown to be safe or effective under its conditions of use.

Submit each final study report to this BLA as a supplemental application. For administrative purposes, all submissions relating to these postmarketing study requirements must be clearly designated as Subpart E Postmarketing Study Requirements.

Please provide your final content of labeling in Structured Product Labeling (SPL) format and include the carton and container labels. In addition, please submit three original paper copies for carton and container final printed labeling. All final labeling should be submitted as Product Correspondence to this BLA at the time of use (prior to marketing) and include implementation information on FDA Form 356h and FDA Form 2567 as appropriate.

In addition, please submit the final content of labeling (21 CFR 601.14) in SPL format via the FDA automated drug registration and listing system, (eLIST), as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.

Information on submitting SPL files using eLIST may be found in the guidance for industry titled, "SPL Standard for Content of Labeling Technical Qs and As" at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072392.pdf.

Please note that the accelerated approval regulation concerning promotional materials (21 CFR 601.45) stipulates that all advertising and promotional labeling items that you wish to distribute in the first 120 days following approval, must have been received by FDA prior to the approval date. After approval, promotional items intended for dissemination after the first 120 days following approval must be submitted to the FDA 30 days prior to the anticipated distribution date. Please submit draft materials with a cover letter noting that the items are for accelerated approval, and an accompanying Form FDA 2253 to the Advertising and Promotional Labeling Branch at the following address:

Food and Drug Administration
Center for Biologics Evaluation and Research
Document Control Center
10903 New Hampshire Ave.
WO71-G112
Silver Spring, MD 20993-0002

You must submit copies of your final advertisement and promotional labeling at the time of initial dissemination or publication, accompanied by Form FDA 2253 (21 CFR 601.12(f)(4)).

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
).

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 0 to less than 6 weeks of age for this application because use of the biological product in this age group does not represent a meaningful therapeutic benefit over initiating vaccination at 6 weeks of age and the product is not likely to be used in a substantial number of pediatric patients in this group.

We are deferring submission of your pediatric studies for children 6 weeks to less than 10 years of age for this application because the product is ready for approval for use in persons 10 through 25 years of age and the studies in children 6 weeks to less than 10 years of age 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. A deferred pediatric study (V72_57) under PREA to evaluate the safety and immunogenicity of BEXSERO in North American infants 6 weeks through 12 months of age for the prevention of invasive group B meningococcal disease.

    Final Protocol Submission: December 31, 2014

    Study Completion: June 30, 2017

    Final Report Submission: March 31, 2018

  2. A deferred pediatric study (V72_28) under PREA to evaluate the safety and immunogenicity of BEXSERO in infants 2.5 months through 11 months of age and in children 2 years through 10 years of age for the prevention of invasive group B meningococcal disease.

    Final Protocol Submission: December 3, 2014

    Study Completion: December 31, 2014

    Final Report Submission: December 31, 2015

Submit each final study report to this BLA. 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. For administrative purposes, all submissions related to these required pediatric postmarketing studies must be clearly designated "Required Pediatric Assessment(s)."

We note that you have fulfilled the pediatric study requirement for ages 10 years to less than 17 years for this application.

AGREED UPON POSTMARKETING COMMITMENTS

We acknowledge your written commitments as described in your submission of January 15, 2015, as outlined below:

Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.

  1. To conduct a safety and immunogenicity study (V72_79) to assess concomitant use of BEXSERO with a second dose of Meningococcal (Groups A, C, Y and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine in persons 16 years through 18 years of age.

    Final Protocol Submission: April 30, 2015

    Study Completion: March 31, 2017

    Final Report Submission: October 31, 2017

  2. To establish a pregnancy registry for BEXSERO in the US to prospectively collect data on spontaneously reported exposures to BEXSERO occurring within 30 days prior to the last menstrual period or at any time during pregnancy. You will submit annual reports as well as a three-year summary report, after which you will continue enrolling patients in the registry pending CBER review of the report and determination that the registry can be discontinued.

    Final Protocol Submission: July 31, 2015

    Study Completion: November 30, 2019

    Final Report Submission: May 31, 2020

Please submit clinical protocols to your IND, with a cross-reference letter to this BLA, STN BL 125546. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA STN BL 125546. 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.

PDUFA V APPLICANT INTERVIEW

FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim and final assessment of the Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs under PDUFA V ('the Program'). The PDUFA V Commitment Letter states that these assessments will include interviews with applicants following FDA action on applications reviewed in the Program. For this purpose, first-cycle actions include approvals, complete responses, and withdrawals after filing. The purpose of the interview is to better understand applicant experiences with the Program and its ability to improve transparency and communication during FDA review.

ERG will contact you to schedule a PDUFA V applicant interview and provide specifics about the interview process. Your responses during the interview will be confidential with respect to the FDA review team. ERG has signed a non-disclosure agreement and will not disclose any identifying information to anyone outside their project team. They will report only anonymized results and findings in the interim and final assessments.

Members of the FDA review team will be interviewed by ERG separately. While your participation in the interview is voluntary, your feedback will be helpful to these assessments.

Sincerely yours,

/s/

Marion F. Gruber, Ph.D.
Director
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research

Attachment: Approved Final Draft Labeling

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