March 16, 2011 Approval Letter - Adenovirus Type 4 and Type 7 Vaccine, Live, Oral

Our STN:  BL 125296/0

Teva Women’s Health, Inc.
Attention: Ms. Valerie Mulligan
Senior Director, Regulatory Affairs
424 Privet Road
P.O. Box 1005
Horsham, PA 19044-8005

Dear Ms. Mulligan:

We are issuing Department of Health and Human Services U.S. License No. 1804 to Teva Women’s Health, Inc., Horsham, PA, under the provisions of section 351(a) of the Public Health Service Act controlling the manufacture and sale of biological products. The license authorizes you to introduce or deliver for introduction into interstate commerce those products for which your company has demonstrated compliance with establishment and product standards.

Under this license, you are authorized to manufacture the product Adenovirus Type 4 and Type 7 Vaccine, Live, Oral, indicated for active immunization for the prevention of febrile acute respiratory disease caused by Adenovirus Type 4 and Type 7. Adenovirus Type 4 and Type 7 Vaccine, Live, Oral, is approved for use in military populations 17 through 50 years of age.

The review of this product is associated with the following National Clinical Trial (NCT) number: NCT00382408.

Under this license, you are approved to manufacture Adenovirus Type 4 and Type 7 Vaccine, Live, Oral, drug substance at -------------------(b)(4)---------------------------------- The final formulated product will be manufactured, filled, labeled, and packaged at Barr Labs, Inc., Forest, Virginia. You have chosen not to label your product with a proprietary name. You will distribute your product in a final package containing one bottle of 100 tablets of Adenovirus Type 4 and one bottle of 100 tablets of Adenovirus Type 7.

We did not refer your application to theVaccines and Related Biological Products Advisory Committeebecause our review of information submitted in your Biologics License Application (BLA), including the clinical study design and trial results, did not raise concerns or controversial issues which would have benefited from an advisory committee discussion.

The dating period for the product Adenovirus Type 4 and Type 7 Vaccine, Live, Oral, shall be 24 months from the date of manufacture when stored at 2-8°C.  The date of manufacture shall be defined as the date that the drug substance (Adenovirus Type 4 lyophilized intermediate or Adenovirus Type 7 lyophilized intermediate) is blended with the inner core excipients (anhydrous lactose, microcrystalline cellulose, polacrilin potassium and magnesium stearate) prior to inner core compression. The expiration date for the packaged product, Adenovirus Type 4 and Type 7 Vaccine, Live, Oral, shall be the expiration of whichever vaccine component has the earliest date of manufacture.

Please submit final container samples of each kit component in final containers 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 BLA for our review and written approval under 21 CFR 601.12 for any changes in, including but not limited to, the manufacturing, testing, packaging or labeling of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral, or changes 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.

We have received your request dated March 4, 2011, for a waiver, under 21 CFR 201.58, of the requirement in 21 CFR 201.57(c)(9)(i)(A) to describe teratogenic effects by a letter classification (i.e., A, B, C, D or X).  We grant this waiver, but note that you will continue to be required to appropriately describe the risks associated with the wild-type virus in the labeling.

Please provide your final content of labeling in Structured Product Labeling (SPL) format and include the carton and container labels. In addition, please submit three original paper copies for carton and container final printed labeling. All final labeling should be submitted as Product Correspondence to this BLA at the time of use and include implementation information on FDA Form 356h.

In addition, please submit the final content of labeling (21 CFR 601.14) in SPL format via the FDA automated drug registration and listing system, (eLIST), as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.  Information on submitting SPL files using eLIST may be found in the guidance for industry titled, “SPL Standard for Content of Labeling Technical Qs and As” at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM072392.pdf.

You may 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. You must submit copies of your final advertisement and promotional labeling at the time of initial dissemination or publication, accompanied by Form FDA 2253 (21 CFR 601.12(f)(4)).

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 substantial evidence or substantial clinical experience to support such claims
(21 CFR 202.1(e)(6)).

ADVERSE EVENT REPORTING

You must submit adverse experience reports in accordance with the adverse experience reporting requirements for licensed biological products (21 CFR 600.80) and you must submit distribution reports as described in (21 CFR 600.81). You should submit these reports to the Vaccine Adverse Event Reporting System (VAERS), P.O. Box 1100, Rockville, MD 20849-1100, using the pre-addressed form VAERS-1 found in the Guidance for Industry “How to Complete the Vaccine Adverse Event Reporting System Form (VAERS-1)” at this link: (http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
Guidances/Vaccines/UCM164319.pdf).  Per 21 CFR 600.2(f), please refer to this link http://www.fda.gov/AboutFDA/CentersOffices/CBER/ucm106001.htm for updated mailing address information.

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 waiving the pediatric study requirement for this application because necessary studies are impossible or highly impracticable

AGREED UPON POSTMARKETING COMMITMENTS

We acknowledge your written commitments dated February 7, 2011, and as described in your protocol submitted on September 13, 2010, as outlined below.

Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.

1. To conduct a postmarketing surveillance study, your “Sentinel Surveillance Plan”, to detect potential safety signals and to monitor and analyze uncommon and unexpected medical events occurring within 42 days following vaccination in the first 100,000 military recruits exposed to Adenovirus Type 4 and Type 7 Vaccine, Live, Oral, during the first year post-approval through the use of the Defense Medical Surveillance System (DMSS). You commit to provide a final study report by January 31, 2013, and to the following timelines:

   Final protocol submission date:  September 13, 2010
   Study/trial completion date:  July 31, 2012
   Final Report Submission date:  January 31, 2013

2. To conduct a prospective Pregnancy Registry study of pregnant women exposed to Adenovirus Type 4 and Type 7 Vaccine, Live, Oral, and their live born offspring through the first year of life to detect potential safety signals. Approximately 340 live births are anticipated to be enrolled in an estimate of 2-4 years. The Pregnancy Registry Status Report will be submitted to CBER annually. The final study report will be submitted 6 months after the follow-up of the last subject is completed and no later than March 31, 2017. You commit to the following timelines:

   Final protocol submission date:  September 13, 2010
   Study/trial completion date:  September 30, 2016
   Final Report Submission date:  March 31, 2017

3. To conduct a surveillance study for vaccine-associated febrile respiratory illness (FRI) due to Adenovirus Type 4 and Type 7 Vaccine, Live, Oral, viral shedding. Vaccine viral shedding will be evaluated using data from the Naval Health Research Center (NHRC) Febrile Respiratory Illness Surveillance Program. The NHRC FRI data will be reviewed on a monthly basis. The proportion of FRI subjects positive for Adenovirus Type 4 and Type 7 will be evaluated on a quarterly basis and cumulatively throughout the study period to identify if there are upward trends or unusual patterns of adenovirus FRI indicating a potential signal for the transmission of the virus to the respiratory tract, thereby resulting in FRI. This surveillance study will be conducted concurrently with the Sentinel Surveillance Plan which covers the first 100,000 recruits exposed to the vaccine during the first year post-approval. The final report will be submitted with the Sentinel Surveillance study final report by January 31, 2013. You commit to the following timelines:

   Final protocol submission date:  September 13, 2010
   Study/trial completion date:  July 31, 2012
   Final Report Submission date:  January 31, 2013

Please submit clinical protocols to your IND (b)(4), with a cross-reference letter to this BLA, STN BL 125296. Submit all final study reports to your 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 determine that labeling changes are needed. Please use the following designators to label prominently all submissions, including supplements, relating to these postmarketing study commitments as appropriate:

• Postmarketing Study Commitment Protocol
• Postmarketing Study Correspondence
• Postmarketing Study Commitment – Final Study Report
• Supplement Contains Postmarketing Study Commitments – Final Study Report

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. Label your annual report “Annual Status Report of Postmarketing Study Commitments.”  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 patient 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/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/default.htm). Please refer to the February 2006 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/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM080569.pdf) for further information. 

Sincerely yours,           

      /s/                              

 

Mary A. Malarkey
Director 
Office of Compliance and
 Biologics Quality
Center for Biologics  
Evaluation and Research               

         /s/

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