Product Approval Information
April 3, 2008
Our STN: BL 125265/0
GlaxoSmithKline Biologicals
Attention: Donna Boyce
Senior Director
U.S. Regulatory Affairs, Vaccines
2301 Renaissance Blvd. Building-510
P.O. Box 61540
King of Prussia , PA 19406-2772
Dear Ms. Boyce:
We have approved your biologics license application (BLA) for Rotavirus Vaccine, Live, Oral effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Rotavirus Vaccine, Live, Oral under your existing Department of Health and Human Services U.S. License No. 1617. Rotavirus Vaccine, Live, Oral is indicated for the prevention of rotavirus gastroenteritis caused by G1 and non-G1 types (G3, G4, and G9) in infants and children when administered as a two-dose series between the ages of 6-24 weeks.
Under this authorization, you are approved to manufacture Rotavirus Vaccine, Live, Oral at GlaxoSmithKline Biologicals, Rixensart, Belgium, including Buildings -------- and ------(new -------filling line for vaccine filling and lyophilization) in -------------- and Building --- (Buildings -------------- for diluent formulation and Building -------- for diluent filling). Labeling and packaging will be performed by GlaxoSmithKline Biologicals, Rixensart, Belgium. You may label your product with the proprietary name ROTARIX®. The vaccine will be supplied as a vial of lyophilized vaccine, a prefilled oral applicator of 1.0 ml liquid diluent with a plunger stopper, and a transfer adapter for reconstitution in packages of 10.
The dating period for ROTARIX® vaccine shall be 24 months from the date of manufacture of the final filled container when stored at 2 to 8 °C. The 24 month shelf life includes all of the time that the final filled container is held at 2 to 8 °C prior to packaging. The date of manufacture shall be defined as the start date of filling into final containers. A single dose of vaccine shall contain no less than 1 x 106.0 mean cell culture infective dose (CCID50) at end-of-expiry.
Please submit final container samples of the product together with lot release protocols in electronic format 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). We concur with your request in the original submission for exemption from performing the General Safety Test and -------------------------------- testing on this product.
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 ROTARIX® 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 submit all final printed labeling and implementation information on FDA Form 356h. Please provide a PDF-format electronic version of the label. Your product patient labeling is FDA-approved labeling and is referenced in section 17.2 of your drug label, and must be printed immediately following this section or accompany the label.
In addition, you may wish to 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. Two copies of final printed advertising and promotional labeling should be submitted at the time of initial dissemination, accompanied by a FDA Form 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 to us and received CBER approval for such claims.
ADVERSE EVENT REPORTING
As required under 21 CFR 600.80(c)(2) you must provide Quarterly Periodic Adverse Experience Reports to the Vaccine Adverse Events Reporting System (VAERS) contractor. The Quarterly Adverse Experience Report will contain a recapitulation of all initial reports submitted for the current reporting period and will include all follow up information on VAERS forms collected during that three-month period. Pursuant to 21 CFR 600.80(c)(2), you are also required to provide the contractor for VAERS all initial postmarketing “periodic” adverse experience reports received that are subject to periodic reporting (i.e., not covered under the “15-day Alert report” requirement under 21 CFR 600.80) on a monthly basis. Initial reports received by GlaxoSmithKline in a given month will be submitted on VAERS forms to CBER and to the VAERS contractor by Working Day 10 of the following month. You have committed to providing CBER this information using the aforementioned process for the first three years after the date of licensure. Thereafter, you are required to submit these reports on an annual basis.
PEDIATRIC REQUIREMENTS
Under the Pediatric Research Equity Act of 2007 (21 U.S.C. 355c), all applications for new active ingredients, new dosage forms, new indications, new routes of administration, and new dosing regimens are required to contain an assessment of the safety and effectiveness of the product in pediatric patients unless this requirement is waived or deferred.
We note that you have fulfilled the pediatric study requirement for children from 6-24 weeks of age for this application.
We are waiving the pediatric study requirement for children from 0-5 weeks of age because it is highly impracticable to enroll subjects 0-5 weeks of age because of the potential limitations of the neonatal immune response.
We are waiving the pediatric study requirement for children from 25 weeks to 18 years of age because necessary studies are impossible or highly impracticable because it is likely that children in this age group would have already received a rotavirus vaccine or would have acquired a natural infection with rotavirus.
POSTMARKETING REQUIREMENTS UNDER 505(o)
Title IX, Subtitle A, Section 901 of the Food and Drug Administration Act of 2007 (FDAAA) amends the Federal Food, Drug, and Cosmetic Act to authorize 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), 21 U.S.C. 355(o)(3)(A)). This provision took effect on March 25, 2008.
FDA has determined that you are required, pursuant to section 505(o)(3) of the Act, to conduct a postmarketing observational study of ROTARIX® to assess the potential serious risk of intussusception; such risk was associated with another live, oral rotavirus vaccine; and to identify other unexpected serious risks. We have determined that an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) will not be sufficient to assess the potential serious risk of intussusception following vaccination or to identify unexpected serious risks that, based on available data, have the potential to occur with ROTARIX®. Furthermore, the new pharmacovigilance system that FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this signal of a serious risk.
Therefore, based on appropriate scientific data, you are required to conduct the following study:
- A large-scale observational post-licensure safety study in the U.S to assess the potential serious risk of intussusception and other serious adverse effects (specifically Kawasaki disease, hospitalizations due to acute lower respiratory tract infections, and convulsions) in recipients of ROTARIX®.
The study will include approximately 44,000 vaccinated subjects (adjustments to the sample size will be made based on the background rate of intussusception). The study will be designed to detect an increased relative risk of intussusception due to vaccine with a relative risk of 2.5 or greater and with 80% power.
We acknowledge the timetable you submitted on April 2, 2008, which states that you will conduct this trial according to the following schedule:
Protocol Submission: November 2008 Study Start Date: June 2009 Final Report Submission: March 2012
Please submit the protocol to your IND -----, with a cross-reference letter to this biologics license application (BLA), STN BL 125265, and submit all final reports to your BLA, STN BL 125265. Please submit a labeling 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)
You are required to report periodically to FDA on the status of this study pursuant to sections 505(o)(3)(E)(ii) and 506B of the FDCA, as well as 21 CFR 601.70. Under section 505(o)(3)(E)(ii), you are also required to periodically report to FDA on the status of any study or trial otherwise undertaken to investigate a safety issue associated with ROTARIX®.
If you have any questions, please contact Ms. Luba Vujcic at 301-827-3070.
Sincerely yours,
/Norman W. Baylor, Ph.D./
Norman W. Baylor, Ph.D.
Director
Office of Vaccines
Research and Review
Center for Biologics
Evaluation and Research