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U.S. Department of Health and Human Services

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June 14, 2012 Approval Letter - MenHibrix

 

Our STN: BL 125363/0
 
GlaxoSmithKline Biologicals
Attention: Jody Ann Gould, Ph.D.
2301 Renaissance Boulevard
P.O. Box 61540
King of Prussia, PA 19406-2772
 
Dear Dr. Gould:
 
We have approved your biologics license application for Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine (MenHibrix) effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine under your existing Department of Health and Human Services U.S. License No. 1617. Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine is indicated for active immunization to prevent invasive disease caused by Neisseria meningitidis serogroups C and Yand Haemophilus influenzae type b. MenHibrix is approved for use in children 6 weeks of age through 18 months of age.
 
The review of this product is associated with the following National Clinical Trial (NCT) numbers:  NCT00127855, NCT00129116, NCT00129129, NCT00134719, NCT00289783, NCT00345579, NCT00345683, NCT00359983, and NCT00614614.
 
Under this license, you are approved to manufacture Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine. Commercial manufacturing will be distributed among the following facilities: GlaxoSmithKline Biologicals S.A., located in ----------(b)(4)--- GlaxoSmithKline Biologicals S.A., located in Rixensart, Belgium; GlaxoSmithKline    ---(b)(4)-----., located in ----------(b)(4)----------------------------------------------- GlaxoSmithKline  ---(b)(4)---------, located in ---------------(b)(4)---------------. Neisseria meningitidis serogroups C and Y polysaccharides and Haemophilus influenzae b polysaccharide will be manufactured at GlaxoSmithKline ---(b)(4)------., located in --------(b)(4)--------. Tetanus Toxoid (TT) will be manufactured at GlaxoSmithKline -----(b)(4)--------., located in ------(b)(4)------- and GlaxoSmithKline Biologicals S.A., located in Rixensart, Belgium. The manufacture of Neisseria meningitidis polysaccharide-TT conjugates and Haemophilus influenzae b polysaccharide-TT conjugates will occur at GlaxoSmithKline Biologicals S.A., located in Rixensart, Belgium. Final Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine formulation will occur at GlaxoSmithKline Biologicals S.A., located in Rixensart, Belgium. Final filling and lyophilization for Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine will occur at GlaxoSmithKline ------(b)(4)-----., located in ---(b)(4)-----------. Diluent (0.9% sodium chloride) manufacturing, labeling, and packaging will be conducted by ---------(b)(4)----------------, a contract facility, in ------(b)(4)-----------------------.  
 
Final labeling and packaging for Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine will occur at ----(b)(4)------------------ GlaxoSmithKline ----(b)(4)-----------, located in -----(b)(4)--------------------. Final co-packaging of the lyophilized vaccine and the 0.9% Sodium Chloride Diluent will occur at ----------(b)(4)-------------- GlaxoSmithKline        ----(b)(4)---------, located in -------(b)(4)---------------. You may label your product with the proprietary name MenHibrix. The vaccine will be supplied in packages containing 10 single dose vials of lyophilized Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine and 10 single dose vials of 0.9% Sodium Chloride Diluent for reconstitution.
 
We did not refer your application to an additional VRBPAC because our review of information submitted in your BLA, including the clinical study design and trial results, did not raise particular concerns or controversial issues which would have benefited from an advisory committee discussion. 
 
The dating period for the lyophilized Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine shall be 36 months from the date of manufacture when stored at 2 to 8°C. The date of manufacture shall be defined as the start date for filling into final containers. Following the final lyophilization, no reprocessing/reworking is allowed without prior approval from the Agency. The dating period for the 0.9% Sodium Chloride Diluent shall be 24 months from the date of manufacture when stored at 2 to 25°C. The date of manufacture for the diluent is defined as the start date for filling into final containers.  The dating period for the co-packaged product, lyophilized Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine and the 0.9% Sodium Chloride Diluent, shall be the shorter dating period of the diluent and the lyophilized vaccine.
 
Please submit final container samples of each kit component 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.
 
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 C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine, or in the manufacturing facilities.
 
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 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 biologics license application 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
.
 
You may 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. 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
). Per 21 CFR 600.2(f), please refer to http://www.fda.gov/AboutFDA/CentersOffices/CBER/ucm106001.htm for updated mailing address information.

 
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 children 0 to less than 6 weeks of age because the product fails to represent a meaningful therapeutic benefit over initiating vaccination at 6 weeks of age and is unlikely to be used in a substantial number of children 0 to less than 6 weeks of age.
 
We are waiving the pediatric study requirement for children 19 months to less than 17 years of age because MenHibrix fails to represent a meaningful therapeutic benefit over vaccination with existing vaccines and is unlikely to be used in a substantial number of children in this age group.
 
We note that you have fulfilled the pediatric study requirement for ages 6 weeks through 18 months of age for this application.
 
AGREED UPON POSTMARKETING COMMITMENTS
 
We acknowledge your written commitments as described in your letters of June 4, 2012 and June 12, 2012, as outlined below:
 
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70. 
 
1.                  To conduct a Phase IIIb open-label administration (laboratory personnel will be blinded to treatment), parallel-group, controlled, multicenter study to evaluate concomitant administration of MenHibrixwith rotavirus, 13-valent pneumococcal conjugate and hepatitis A vaccines administered according to a US recommended vaccine schedule. 
 
The study is entitled “A phase IIIb, open, randomized, controlled, multicenter study to assess the immunogenicity, safety and reactogenicity of Hib-MenCY-TT (GlaxoSmithKline Biologicals’ Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine) when administered concomitantly with Rotarix (GlaxoSmithKline Biologicals), Pediarix (GlaxoSmithKline Biologicals) and Prevnar 13 (Pfizer) as compared to Pentacel (Sanofi Pasteur) administered concomitantly with Rotarix and Prevnar 13 in healthy infants at 2 and 4 months of age. Subjects will receive a third dose of Prevnar 13, Pediarix and Hib-MenCY-TT or Pentacel at 6 months of age. The study will also assess the immunogenicity, safety and reactogenicity of a fourth dose of Hib-MenCY-TT administered concomitantly with Havrix (GlaxoSmithKline Biologicals) compared to Pentacel administered concomitantly with Havrix at 15 to 18 months of age.” The final study protocol will be submitted by December 31, 2012. The study will begin by October 31, 2013. The study will be completed by July 31, 2016. The final study report will be submitted by December 15, 2016.
 
Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70.  
 
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Please submit clinical protocols to your IND, with a cross-reference letter to this biologics license application, STN BL 125363/0. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA STN BL 125363/0. 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 regarding the above, please contact the Regulatory Project Managers, CDR David Staten or Kirk Prutzman, Ph.D., at (301) 796-2640.
 
Sincerely yours,                                              
 
 
 
                                                                        Marion Gruber, Ph.D.
                                                                        Director                                                          
                                                                        Office of Vaccines
                                                                         Research and Review                                  
                                                                        Center for Biologics 
                                                                         Evaluation and Research