Vaccines, Blood & Biologics

December 10, 2014 Approval Letter -GARDASIL 9

                                                                                                                        

Our STN: BL 125508/0                                                                                                                     

Merck Sharp & Dohme Corp.
Attention: Alison Fisher, Ph.D.                                                         
P.O. Box 1000
UG2D-68                                                       
North Wales, PA  19454-1099

Dear Dr. Fisher:

We have approved your biologics license application for Human Papillomavirus 9-valent Vaccine, Recombinant effective this date.  You are hereby authorized to introduce or deliver for introduction into interstate commerce, Human Papillomavirus 9-valent Vaccine, Recombinant under your existing Department of Health and Human Services U.S. License No. 0002.  Human Papillomavirus 9-valent Vaccine, Recombinant is indicated in girls and women 9 through 26 years of age for prevention of the following diseases:

  • Cervical, vulvar, vaginal, and anal cancer caused by Human Papillomavirus (HPV) types 16, 18, 31, 33, 45, 52, and 58.
  • Genital warts (condyloma acuminata) caused by HPV types 6 and 11.

And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58:

  • Cervical intraepithelial neoplasia (CIN) grade 2/3 and cervical adenocarcinoma in situ (AIS).  
  • Cervical intraepithelial neoplasia (CIN) grade 1. 
  • Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3.
  • Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3.
  • Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3.

Human Papillomavirus 9-valent Vaccine, Recombinant is indicated in boys 9 through 15 years of age for the prevention of the following diseases:

  • Anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58.
  • Genital warts (condyloma acuminata) caused by HPV types 6 and 11.

And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58:

  • Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3.

Under this license, you are approved to manufacture Human Papillomavirus 9-valent Vaccine, Recombinant drug substance at your ----------------(b)(4)----------------- facilities.  The final formulated product will be manufactured, filled, labeled, and packaged at your ------(b)(4)------ facility.  You may label your product with the proprietary name GARDASIL 9 and market it in vials and pre-filled 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: NCT00543543, NCT00943722, NCT00988884, NCT01047345, NCT01073293, and NCT01304498.

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 Human Papillomavirus 9-valent Vaccine, Recombinant shall be 30 months from the date of manufacture when stored at 2 to 8°C.  The date of manufacture shall be defined as the start date of filling into final containers.  Following the final sterile filtration, no reprocessing/reworking is allowed without prior approval from the Agency.  The dating period for your drug substance shall be ---(b)(4)--- when stored at ---(b)(4)---. 

Please submit final container samples of the product 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 Biologics 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 Human Papillomavirus 9-valent Vaccine, Recombinant, 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

Under 21 CFR 201.57(c)(18), patient labeling must be reprinted at the end of the package insert.  We request that the text of information distributed to patients be printed in a minimum of 10-point font.

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.

You may submit two draft copies of the proposed introductory advertising and promotional labeling with an FDA Form 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 ages 0 through 8 years because the product does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients in this age group and is not likely to be used in a substantial number of pediatric patients in this group. 

We note that you have fulfilled the pediatric study requirement for ages 9 through 17 years for this application.

AGREED UPON POSTMARKETING COMMITMENTS

We acknowledge your written commitments as described in your submission of December 8, 2014, as outlined below:

Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.

1. To complete the ongoing 10-year study extension of Protocol V503-002 to evaluate the long-term safety, immunogenicity and effectiveness of Gardasil 9 in males and females who were between 9 and 15 years of age at enrollment. 

Study Completion: September 30, 2022
Final Report Submission: March 31, 2023

2. To conduct a 10-year study extension of Protocol V503-001 to evaluate the long-term safety, immunogenicity and effectiveness of Gardasil 9 in women who were 16 to 26 years of age at enrollment.

Final Protocol Submission: January 31, 2015 
Study Completion: June 30, 2026
Final Report Submission: December 31, 2026
  
3. To conduct an observational study to further characterize the safety profile of Gardasil 9 in approximately 10,000 persons.

Final Protocol Submission: December 31, 2015
Study Completion: December 31, 2018
Final Report Submission: December 31, 2019

4. To establish a pregnancy registry as described in your final protocol submitted September 16, 2014, to continue for at least 5 years, to prospectively collect data on spontaneously reported exposures to Gardasil 9 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 five-year summary report, after which you will continue enrolling patients in the registry pending CBER review of the report and determination of whether the registry can be discontinued.

Establishment of Pregnancy Registry: January 31, 2015
Five-Year Summary Report Submission: August 10, 2020
Final Report Submission: 18 months after enrollment of the last patient

Please submit clinical protocols to your IND, with a cross-reference letter to this biologics license application (BLA), STN BL 125508.  Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA STN BL 125508.  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.

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,

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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