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September 6, 2005 Approval Letter - ProQuad
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
Rockville, MD 20852-1448
September 6, 2005
Our STN: BL 125108 / 0
Merck & Co., Inc.
Attn: Dr. Michael Dekleva
Director, Worldwide Regulatory Affairs
P.O. Box 4, BLB-22
West Point, PA 19486-0004
Dear Dr. Dekleva:
We have approved your biologics license application (BLA) for Measles, Mumps, Rubella and Varicella Virus Vaccine Live effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Measles, Mumps, Rubella and Varicella Virus Vaccine Live under your existing Department of Health and Human Services U.S. License No. 0002. Measles, Mumps, Rubella and Varicella Virus Vaccine Live is indicated for vaccination against measles, mumps, rubella and varicella in children 12 months to 12 years of age. Measles, Mumps, Rubella and Varicella Virus Vaccine Live may be administered to children 12 months to 12 years of age if a first or second dose of measles, mumps, and rubella vaccine is to be administered.
Under this authorization, you are approved to manufacture Measles, Mumps, Rubella and Varicella Virus Vaccine Live at Merck and Co., Inc., West Point, PA. The final formulation and filling is performed by Merck and Co., Inc., West Point, PA. Labeling and packaging will be performed by Merck and Co., Inc., West Point, PA. You may label your product with the proprietary name ProQuad. ProQuad will be supplied as a single-dose vial of lyophilized vaccine or as a package of 10 single dose vials of lyophilized vaccine with a separate package of 10 vials of sterile water diluent manufactured by Merck & Co., Inc.
The dating period for ProQuad vaccine shall be 18 months from the date of manufacture of the final filled container vaccine when stored at <-15 °C. The 18-month shelf life includes all of the time that the product is held at <-20 °C prior to packaging. The date of manufacture shall be defined as the date of initiation of the last valid potency test for the component tested first.
Please submit final bulk 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).
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 ProQuad vaccine, or in the manufacturing facilities. This approval applies to the use of lyophilization ------------------ for which process validation data are available as described in the BLA. ---------------------------------------------------------------------------------------
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 submission to the BLA of July 20, 2005, as follows:
- Merck will conduct a large-scale observational post-licensure safety study to evaluate the rate of febrile seizures in recipients of ProQuad in 25,000 subjects. The final study protocol will be submitted by December 2005. The study will be initiated no later than January 2006. The study will be completed by June 2008.
In your submission you also provided a summary of the post marketing clinical study commitments following the licensure of ProQuad. We note that you plan to conduct 3 post-licensure clinical studies in order to have a safety database on 3,000 children who received ProQuad as a second dose between 15 and 23 months of age, as follows:
- V221, Protocol 019-01 - ProQuad Concomitant Use with Prevnar (Pneumococcal 7-Valent Conjugate Vaccine, Wyeth-Lederle Vaccines). The final study protocol will be submitted by September 2005. The study will be initiated by February 2006. The study will be completed by November 2007.
- V251, VAQTA + ProQuad Safety Study (Protocol 066). The final study protocol will be submitted by October 2005. The study will be initiated no later than May 2006. The study will be completed by December 2007.
- V251, Concomitant Use of VAQTA, Prevnar, and ProQuad (Protocol 067). The final study protocol will be submitted by October 2005. The study will be initiated no later than April 2006. The study will be completed by December 2007.
We acknowledge that the 1950 subjects to be enrolled in Protocols 019, 066, and 067 and the 1097 subjects in ProQuad Protocols 009 and 011 who received two doses of ProQuad with varicella doses >3.97 log10 PFU will result in a total safety database of >3,000 subjects vaccinated with ProQuad as a second dose between 15 and 23 months of age.
We request that you submit clinical protocols to your IND 7068, with a cross-reference letter to this biologics license application (BLA), STN BL 125108. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN BL 125108. 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).
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). 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. 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 and implementation information on FDA Form 356h. Please provide a PDF-format electronic copy as well as one original paper 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 Dr. Herbert Smith at 301-827-3070.
--- signature ---
Norman W. Baylor, Ph.D.
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research