October 16, 2009 Approval Letter - Gardasil
Our STN: BL 125126/1297
Merck & Co., Inc.
Attention: Patrick Brill-Edwards, M.D.
P.O. Box 1000, UG2D-68
North Wales, PA 19454-1099
Dear Dr. Brill-Edwards:
We have approved your request to supplement your biologics license application for Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine to include the prevention of genital warts caused by HPV 6 and 11 in boys and men 9 through 26 years of age.
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 of age because the necessary studies are impossible or highly impractical because there are too few children with the disease/condition to study.
We note that you have fulfilled the pediatric study requirement for ages 9 through 17 years of age for this application.
We acknowledge your written commitment as described in your letters of October 8, 2009, and October 9, 2009, as outlined below:
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.
- You have committed to conduct a postlicensure, observational safety study in a U.S. Managed Care Organization (MCO). As agreed, although no serious adverse conditions have been identified from clinical studies involving over 3,000 male Gardasil recipients, a postmarketing study will be initiated upon vaccine licensure to assess the general short-term safety of the vaccine as it is administered to a larger male population 9 through 26 years of age. The study population will consist of up to 44,000 male subjects completing the three-dose regimen, or 135,000 males receiving at least one dose of Gardasil. The study will estimate the incidence of medical events resulting in hospitalization or an emergency room visit in the first 60 days after vaccination, relative to a self-comparison reference period. As a secondary objective, subjects will also be followed for 6 months after each vaccination for reporting of several prespecified new onset autoimmune conditions. Incidence of events occurring on the day of vaccination will also be analyzed. The final study protocol, with study sites finalized, will be submitted to FDA no later than 6 months after product licensure and the study will commence no later than 2 months after we review and approve the final protocol, and IRB approval is obtained. The final study population size will primarily depend on vaccine uptake in the selected MCO. The study will be considered complete whenever one of three conditions is met: (a) the study sample size reaches 44,000 subjects with 3-doses, (b) sample size reaches 135,000 subjects with at least 1-dose, or (c) if 6 years have passed after the official start date of the study. Annual interim reports will be submitted to FDA within 6 months after the yearly cut-off date. The final study report will be submitted to FDA 24 months after study completion.
- To conduct a long-term evaluation of vaccine effectiveness in males by extending Protocol 020. You have agreed to actively follow study subjects for up to 10 years from day of enrollment into the base study (i.e., Day 1) for the occurrence of external genital lesions. The final study protocol will be submitted by March 31, 2010. Interim reports will be submitted by December 31, 2012 and December 31, 2015. The study will be completed and the final study report will be submitted by December 31, 2018.
Please submit clinical protocols to your IND, with a cross-reference letter to this biologics license application (BLA), STN BL 125126. 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 Protocol
- Postmarketing Study Final Report
- Postmarketing Study Correspondence
- Annual Report on Postmarketing Studies
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 Internet site (http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/default.htm). For further information, please refer to the February 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).
Under 21 CFR 201.57(c)(18), patient labeling must be reprinted at the end of the package insert and printed in a minimum of 10-point font.
Please submit all final printed labeling at the time of use and include implementation information on FDA Form 356h. 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 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, MD 20852-1448. Please submit your final printed advertising and promotional labeling at the time of initial dissemination, accompanied by an FDA Form 2253.
We will include information contained in the above-referenced supplement in your biologics license application file.
If you have any questions, please contact LCDR Elizabeth Valenti, Regulatory Project Manager, at (301) 827-3070.
Wellington Sun, M.D.
Division of Vaccines and Related Products Applications
Office of Vaccine Research and Review
Center for Biologics Evaluation and Research
Attachment: Approved Final Draft Labeling