May 25, 2006 Approval Letter - Zostavax
May 25, 2006
Our STN: BL 125123/0
Merck & Co., Inc.
Attn: David E. Gutsch, M.D.
Director, Worldwide Regulatory
P.O. Box 1000
North Wales, PA 19454-1099
Dear Dr. Gutsch:
We have approved your biologics license application (BLA) for Zoster Vaccine, Live, (Oka/Merck) effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Zoster Vaccine, Live, (Oka/Merck) under your existing Department of Health and Human Services U.S. License No. 0002. Zoster Vaccine, Live, (Oka/Merck) is indicated for the prevention of herpes zoster (shingles) in individuals 60 years of age and older when administered as a single-dose.
Under this authorization, you are approved to manufacture Zoster Vaccine, Live (Oka/Merck) at Merck & Co., Inc., --------------. The final formulation and filling is performed by Merck & Co., Inc., --------------. Labeling and packaging will be performed by Merck & Co., Inc., --------------. You may label your product with the proprietary name Zostavax™. Zostavax™ will be supplied as a single-dose vial of lyophilized vaccine with a package of diluent or as a package of 10 single-dose vials of lyophilized vaccine, with a separate package of 10 single dose vials of sterile diluent manufactured by Merck & Co., Inc.
The dating period for Zostavax™ vaccine shall be 18 months from the date of manufacture of the final filled container when stored at ≤-15°C. The date of manufacture shall be defined as the date of final fill. Each 0.65 ml dose of the vaccine shall contain not less than 19,400 PFU (plaque-forming units) throughout the dating period. A maximum of -------- Zostavax lots will be produced by the current manufacturing process. CBER will re-evaluate Merck's approach to the maximum release specifications prior to releasing any subsequent lots.
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 November 22, 2005, for exemption from testing for 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 Zostavax™ 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 have reviewed your submission dated May 23, 2006, and agree that a waiver of your pediatric studies for Zostavax™ for children from birth to 18 years of age is justified because Zostavax™ offers no meaningful therapeutic benefit over existing treatments and Zostavax™ is unlikely to be used in a substantial number of pediatric patients.
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.
We acknowledge the postmarketing clinical commitments outlined in your May 24, 2006, submission as follows:
- A randomized, placebo-controlled, general safety study will be conducted to assess the rates of serious adverse experiences in 6000 subjects who receive Zostavax™, compared to the rates of serious adverse experiences in 6000 subjects who receive placebo. The primary safety follow-up period for serious adverse experiences will be 42 days postvaccination. However, subjects will be followed for serious adverse experiences for 6 months postvaccination. Enrollment will be stratified by subject age, i.e., those less than 80 years of age and those 80 years of age and older. The study will target 15% enrollment in the older age cohort, and recruitment of older subjects will be re-assessed 6 to 12 months following study initiation.
- A large-scale (20,000 vaccinated subjects) observational post-licensure safety study for Zostavax™ will be conducted in a U.S. heath maintenance organization (HMO) to gain further knowledge of the safety of the vaccine in the course of ordinary clinical practice. The primary objective of this study is to assess the general safety of Zostavax™ in the general population for whom the vaccine is recommended. This post-licensure observational study is designed to detect potential safety signals following administration of Zostavax™. A time window(s) following vaccination with Zostavax™ will be considered the "risk period." All medical events resulting in an emergency room visit or a hospitalization within the risk period following vaccination with Zostavax™ will be assessed. To determine whether the rates of medical encounters during the risk period following receipt of Zostavax™ are higher than expected rates, self-comparison periods (subjects being used as their own controls in periods preceding or following the post- vaccination risk period) will be used. Details of the study protocol will be determined in consultation with CBER.
The safety of a high-potency dose of Zostavax™ will be addressed in 5000 subjects in an observational setting. If a lot with a potency of --------------------- per dose is manufactured during the 3-year period following approval of the Zostavax™ Biologics License Application, the study will be initiated and a preliminary report will be provided to CBER within 2.5 years of vaccine lot identification. Details of the study protocol will be determined in consultation with CBER.
In addition to the three studies outlined above, we agree with your commitment to completing the following study:
- A randomized, placebo-controlled, double-blind study will be conducted to assess the safety of Zostavax™ in subjects receiving low-to-moderate maintenance doses of corticosteroids (the equivalent of 5 to 20 mg per day of prednisone, with stratification by daily dose [5 to 10 mg; >10 to 20 mg]). The sample size of this study is 300 subjects, with 2:1 randomization to vaccine or placebo. Subjects will be given a Vaccination Report Card and followed for 42 days post vaccination. Blood samples for immunologic assessment will also be collected. The draft protocol concept sheet was submitted to CBER by secure e-mail on Feb 14, 2006, and to the Zostavax™ BLA on February 17, 2006. A draft protocol is undergoing internal review and will be submitted to CBER by July 2006.
Timelines for the 4 studies are shown below:
|Activity||Placebo-Controlled General Safety Study||Large-Scale Observational Study||High-Dose ZOSTAVAX™ Observational Study||Patients on Chronic Corticosteroids|
|Final Protocol Submission||Nov 2006||Nov 2006||6 mo.*||Jul 2006|
|Study Initiation||May 2007||Jan 2007||9 mo.*||Sep 2006|
|Study Completion||Nov 2010||Jun 2008||2 yr.*||Sep 2007|
|Submission of Preliminary Report||May 2011||Dec 2008||2.5 yr.*||Mar 2008|
* after high-dose ZOSTAVAX™ lot is identified
We request that you submit clinical protocols to your IND ----, with a cross-reference letter to this BLA, STN BL 125123. Protocols for nonclinical and chemistry, manufacturing, and controls and all final study reports should also be submitted to your BLA, STN BL 125123. 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). We acknowledge your agreement to report each initial adverse experience not reported under paragraph 21 CFR 600.80(c)(1) (i) of this section at monthly intervals for the first year following approval, and in addition you have agreed to submit quarterly periodic reports as described in 21 CFR 600.80 (c)(2). 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 that 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 CAPT Katherine L. Matrakas at 301-827-3070.
Norman W. Baylor, Ph.D.
Office of Vaccines
Research and Review
Center for Biologics
Evaluation and Research