October 16, 2009 Approval Letter - Cervarix

  

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

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Food and Drug Administration Rockville, MD 20852-1448

Our STN:  BL 125259/0

GlaxoSmithKline Biologicals
Attention: Matthew Whitman
2301 Renaissance Boulevard
P.O. Box 61540
King of Prussia, PA  19406-2772

Dear Mr. Whitman:

We have approved your biologics license application for Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant, effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant under your existing Department of Health and Human Services U.S. License No. 1617. Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant is indicated for the prevention of cervical cancer, cervical intraepithelial neoplasia (CIN) grade 2 or worse and adenocarcinoma in situ, and cervical intraepithelial neoplasia (CIN) grade 1, caused by oncogenic human papillomavirus (HPV) types 16 and 18, in females 10 through 25 years of age.

Under this license, you are approved to manufacture Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant. The drug substance will be manufactured at GlaxoSmithKline Biologicals in ----b(4)-----------. The final product will be formulated at Rixensart, Belgium, filled at Rixensart and --b(4)--, and labeled and packaged at --b(4)--. You may label your product with the proprietary name CERVARIX®. The vaccine will be supplied in 0.5 mL single dose vials and 0.5 mL single dose prefilled TIP-LOK® syringes. 

The dating period for Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant (CERVARIX) shall be 36 months from the date of manufacture when stored at  2°C to 8°C.

The date of manufacture shall be defined as the start date of filling into final containers.

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Please submit final container samples of the product 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 the manufacturing, testing, packaging or labeling of CERVARIX 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, including those associated with processing, testing, packing, labeling, storage, holding and distribution in a timely manner. 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 a Form FDA 2253 to the Center for Biologics Evaluation and Research, Advertising and Promotional Labeling Branch, HFM-602, 1401 Rockville Pike, Rockville, MD 20852-1448. Please submit your final printed advertising and promotional labeling at the time of initial dissemination, accompanied by Form FDA 2253.

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 submitted data to support such claims for review and approval by CBER.

ADVERSE EVENT REPORTING

Adverse experience reports should be submitted, at minimum, in accordance with the adverse experience reporting requirements for licensed biological products (21 CFR 600.80).  Individual adverse event reports should be submitted to the Vaccine Adverse Event Reporting System (VAERS) electronically at https://secure.vaers.org/VaersDataEntryintro.htm or by mail to P.O. Box 1100, Rockville, MD 20849-1100, using the pre-addressed form VAERS-1 available at the VAERS website (http://vaers.hhs.gov). Distribution reports should be submitted on a monthly basis for the first year after market introduction and then at least every six months in accordance with 21 CFR 600.81. Under 21 CFR 600.80(c)(2) [Periodic Adverse Experience Reports], you must report each adverse experience not reported under paragraph (c)(1)(i) of this section at quarterly intervals for the first 3 years following approval, and then at annual intervals.

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 deferring submission of your pediatric study for CERVARIX, in females 9 years of age, until June 30, 2010, because the data support approval of this product for use in females 10 through 25 years of age, and this pediatric study has not been completed.

Your deferred pediatric study required under 505B(a) of the Federal Food, Drug, and Cosmetic Act (FDCA) is a required postmarketing study. The status of this postmarketing study must be reported according to 21 CFR 601.70 and Section 505B(a)(3)(B) of the FDCA. This required study is listed below:

1. A clinical study to evaluate the safety and immunogenicity of GlaxoSmithKline Biologicals’ Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant when administered to healthy females 9 through 25 years of age.

We acknowledge your September 16, 2009, commitment to submit the final clinical study report by June 30, 2010.

Please submit the final clinical study report to this BLA (STN 125259). For administrative purposes, all submissions related to this required pediatric postmarketing study must be clearly designated “Required Pediatric Assessment.”

We are waiving the pediatric study requirement for children from 0 through 8 years of age because the necessary studies are impossible or highly impracticable as there are too few children with the disease/condition to study.

We note that you have fulfilled the pediatric study requirement for children 10 through 16 years of age with this application.

POSTMARKETING REQUIREMENTS UNDER 505(o)

Section 505(o) of the FDCA authorizes FDA to require holders of approved drug and biological product applications to conduct postmarketing studies and clinical trials for certain purposes, if FDA makes certain findings required by the statute (Section 505(o)(3)(A)).

FDA has determined that you are required to conduct a postmarketing study pursuant to Section 505(o)(3)(B)(iii) of the FDCA based upon a subgroup analysis of clinical trial data suggesting a numerical imbalance in spontaneous abortions among CERVARIX recipients whose pregnancies occurred around the time of vaccination (defined as the last menstrual period occurring 30 days before until 45 days after vaccination), compared to control subjects.

We have determined that an analysis of spontaneously reported adverse events, after product licensure, pursuant to subsection 505(k)(1) of the FDCA, will not be sufficient to identify an unexpected serious risk when available data indicates such potential.

Therefore, you are required to conduct a post-licensure analytic epidemiologic study to assess the risk of spontaneous abortion following CERVARIX vaccination as outlined below:

2. To conduct a post-licensure analytic epidemiologic study to assess the risk of spontaneous abortion following administration of CERVARIX to women who become pregnant shortly after vaccination and in women who inadvertently received CERVARIX prior to knowledge of their pregnancy.

We acknowledge the timetable you submitted on September 24, 2009, which states that you will conduct this trial according to the following schedule: The draft protocol will be submitted by December 31, 2009, and the final protocol by April 30, 2010. Study initiation will occur 6 to 12 months after final protocol submission. The anticipated study completion date will be when subject enrollment is sufficient to detect an increased relative risk of approximately 2.0 for spontaneous abortions if it exists. The final clinical study report will be submitted within 6 months after study completion. Interim reports will be submitted to the FDA every 6 months for the duration of the study.

Please submit the study protocol to your IND -b(4)-, with a cross-reference letter to this BLA, and submit all final reports to this BLA. Please submit a supplement, reflecting the results of the study, and use the following designators to prominently label all submissions, including supplements, relating to this postmarketing study requirement as appropriate:

• Required Postmarketing Study Protocol under 505(o)
• Required Postmarketing Study Final Report under 505(o)
• Required Postmarketing Study Correspondence under 505(o)
• Required Postmarketing Study 6-Month Interim Report under 505(o)

Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any study or clinical trial required under this section. This section also requires you to periodically report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Section 506B of the FDCA, as well as 21 CFR 601.70, requires you to report annually on the status of any postmarketing commitments or required studies or clinical trials.

FDA will consider the submission of your annual report, under Section 506B and

21 CFR 601.70, to satisfy the periodic reporting requirement under Section 505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR 601.70. We remind you that to comply with 505(o), your annual report must also include a report on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o) on the date required will be considered a violation of FDCA Section 505(o)(3)(E)(ii) and could result in enforcement action.

AGREED UPON POSTMARKETING COMMITMENTS

Postmarketing study subject to reporting requirements of 21 CFR 601.70

We acknowledge your written commitments as described in your correspondence and submissions of July 31, August 14, September 21, and October 2, October 7, and

October 9, 2009, as outlined below:

3. To conduct an observational study in a U.S. managed care organization to evaluate the incidence of new onset autoimmune disease among at least 50,000 CERVARIX recipients. The final protocol will be submitted by March 2010. Projected completion of patient accrual, subject to vaccine uptake, will be completed by March 2013. Projected study completion, subject to vaccine uptake, will be completed by September 2014. The final study report is projected to be submitted by March 2015 (6 months after study completion).
4. To establish a U.S. pregnancy registry. The registry will be initiated immediately after vaccine licensure and continue for at least 5 years. Supplemental data from an ongoing pregnancy registry in the United Kingdom, operated by the Health Protection Agency, will be included in all GSK analyses submitted to FDA.
5. To submit final study reports for the following on-going long term efficacy studies:
   1. Study HPV-008: This study will be completed by October 30, 2009. The final clinical study report will be submitted by December 31, 2010.
   2. Study HPV-009: This study will be completed by October 30, 2010. The final clinical study report will be submitted by January 31, 2012.
   3. Study HPV-015: This study will be completed by October 30, 2010. The final clinical study report will be submitted by December 31, 2011.
   4. Study HPV-023: This study will be completed by September 30, 2010. The final clinical study report will be submitted by September 30, 2011.
   5. Study HPV-024: This study has been completed. The final clinical study report will be submitted by December 31, 2009.
   6. Study HPV-040: The final protocol will be submitted by December 1, 2009. Subject accrual will be completed on December 31, 2009. This study will be completed by June 30, 2014. The final clinical study report will be submitted by December 31, 2015.

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)
• an explanation of the status including, for clinical studies, the patient accrual rate (i.e. number enrolled to date and the total planned enrollment)

Please submit clinical protocols to your IND -b(4)-, with a cross-reference letter to this BLA. Submit chemistry, manufacturing, and controls protocols and final study reports 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. Please use the following designators to prominently label 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  

When you have fulfilled your commitment, submit your final report as “PMC Submission – Final Study Report” or “Supplement Contains Postmarketing Study Commitment – Final Study Report.”

As described in 21 CFR 601.70(e), we may publicly disclose information regarding these postmarketing studies on our Web site http://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm.

Please refer to FDA’s Guidance for Industry: Reports on the Status of Postmarketing Commitments - Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997 for further information.

Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70.  

We acknowledge your written commitments as described in your correspondence of

October 2 and October 8, 2009, as outlined below:

6. --------b(4)-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

7. -------------------b(4)-------------------------------------------------------------------------------------------------------------------------------------.

For each postmarketing commitment not subject to the reporting requirements of 21 CFR 601.70, you may report the status to FDA as a “PMC Submission – Status Update.” The status report for each commitment 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),
• An explanation of the status including, for clinical studies, the subject accrual rate      (i.e., number enrolled to data and the total planned enrollment).

If you have any questions, please contact Ms. Helen S. Gemignani, Regulatory Project Manager, at 301-827-3070.

Sincerely yours,

--signature--

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