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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
Rockville, MD 20852-1448
February 3, 2006
Our STN: BL 125122/0
Merck & Co., Inc.
Attn: Dr. Mark L. Bagarazzi
Director, Worldwide Regulatory Affairs, Vaccines/Biologics
Sumneytown Pike
P.O. Box 4, BLB-22
West Point, PA 19486-0004
Dear Dr. Bagarazzi:
We have approved your biologics license application (BLA) for Rotavirus Vaccine, Live, Oral, Pentavalent effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Rotavirus Vaccine, Live, Oral, Pentavalent under your existing Department of Health and Human Services U.S. License No. 0002. Rotavirus Vaccine, Live, Oral, Pentavalent is indicated for the prevention of rotavirus gastroenteritis in infants and children caused by the serotypes G1, G2, G3, and G4 when administered as a 3-dose series to infants between the ages of 6 to 32 weeks.
Under this authorization, you are approved to manufacture Rotavirus Vaccine, Live, Oral, Pentavalent at Merck and Co., Inc., West Point, PA. The final formulation, filling, labeling and packaging will be performed by Merck and Co., Inc., West Point, PA. You may label your product with the proprietary name Rotateq. Rotateq will be supplied as individually pouched single-dose tubes in packages of one or ten tubes manufactured by Merck & Co., Inc.
The dating period for Rotateq vaccine shall be 24 months from the date of manufacture when stored at 2-8 oC. The date of manufacture shall be defined as the date of final fill. The 24-month shelf life includes all of the time that the product is held at 2-8 oC prior to packaging. A single dose of vaccine shall contain no less than 2.2 x 106 infectious units for the G1 serotype, 2.8 x 106 infectious units for the G2 serotype, 2.2 x 106 infectious units for the G3 serotype, 2.0 x 106 infectious units for the G4 serotype, and 2.3 x 106 infectious units for the P1[8] serotype at end-of-expiry.
Please submit final filled 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 of September 27, 2005, for exemption from performing the General Safety Test 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 Rotateq vaccine, or in the manufacturing facilities.
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 this application.
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.
We acknowledge the postmarketing clinical commitments outlined in your submissions to the BLA as follows:
- Your submission dated January 25, 2006, included a commitment to conduct a large-scale observational post-licensure safety study to evaluate the incidence of intussusception and other safety parameters in recipients of Rotateq in approximately 44,000 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 risk of intussusception due to vaccine of 2.5 or greater with 80% probability. The final study protocol will be submitted by May 5, 2006. The study will be initiated no later than the third quarter of 2006, sooner if possible. The study will be completed by the fourth quarter of 2008.
- You have agreed to conduct an adequately powered non-inferiority study of the concomitant administration of Rotateq with acellular pertussis vaccine in which serological endpoints will be examined using a validated assay. The study will be powered sufficiently to detect a 1.5-fold difference in GMTs. This agreement was submitted to your BLA on January 31, 2006. A final concept sheet for this protocol will be submitted no later than May 3, 2006.
We request that you submit clinical protocols to your IND ----, with a cross-reference letter to this BLA, STN BL 125122. Protocols for nonclinical and chemistry, manufacturing, and controls and all study final reports should also be submitted to your BLA, STN BL 125122. 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 subject accrual rate (i.e., number enrolled to date and the total planned enrollment).
We acknowledge your written commitment stated in your letter dated October 3, 2005 and submitted to the BLA on November 2 and 18, 2005, to provide additional information regarding long-term stability studies on -------------. These studies were to be initiated by December 30, 2005 and you will submit this information to your BLA for review by CBER. Please submit this information in a separately tabbed section of the next annual report for Rotavirus Vaccine, Live, Oral, Pentavalent, Rotateq. If the studies are not completed at the time of submission of your next annual report, please include a status update on the progress towards completion of the studies and a projected timeframe for completion of the study noting your intent to report the findings in the next annual report.
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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/cder/pmc/default.htm). Please refer to the April 2001 Draft 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/cber/gdlns/post040401.htm) for further information.
Please submit adverse experience reports in accordance with the adverse experience reporting requirements for licensed biological products (21 CFR 600.80), and distribution reports as described in (21 CFR 600.81). We acknowledge your agreement submitted on January 25, 2006, to report each adverse experience not reported under paragraph 21 CFR 600.80(c)(1) (i) of this section at monthly intervals for the first 3 years following approval, and then at annual intervals. Since your product is characterized as a vaccine, submit these reports to the Vaccine Adverse Event Reporting System (VAERS) using the pre-addressed form VAERS-1.
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 at the time of use and include implementation information on FDA Form 356h. Please provide this labeling as a PDF-format electronic copy.
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.
If you have any questions, please contact Ms. Luba Vujcic 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
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