Product Approval Information

March 30, 2009

Our STN: BL 125280/0

Intercell AG
Attention: Paul J. Wilson
Campus Vienna Biocenter 2
1030 Vienna, Austria

Dear Mr. Wilson:

W e are issuing Department of Health and Human Services U.S. License No. 1790 to Intercell AG, Vienna, Austria, 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 Japanese Encephalitis Virus, Vaccine, Inactivated, Adsorbed, effective this date. Japanese Encephalitis Virus Vaccine, Inactivated, Adsorbed, is indicated for the prevention of disease caused by Japanese encephalitis virus in persons 17 years of age and older.

Under this license, you are approved to manufacture Japanese Encephalitis Virus Vaccine, Inactivated, Adsorbed, at Intercell Biomedical Ltd., Livingston, UK. The final formulated product will be manufactured, filled, labeled, and packaged at ---------------(b)(4)----------------- -------------(b)(4)----------------. You may label your product with the proprietary name, IXIARO ® and it will be supplied and marketed in 0.5 ml mono-dose pre-filled syringes.

The dating period for Japanese Encephalitis Virus Vaccine, Inactivated, Adsorbed, shall be 18 months from the date of manufacture when stored at 2-8° C. The date of manufacture shall be defined as the date of filling of the final containers of the formulated drug product. Following the final sterile filtration, no reprocessing/reworking is allowed without prior approval from the Agency. The 18 month shelf life is inclusive of the time that the final filled container is held at 2-8° C prior to packaging. Each unit dose of vaccine contains 6 mcg of the inactivated Japanese encephalitis virus.

Your biologics license application for IXIARO ® was not referred to an FDA advisory committee, because during the BLA review no safety or efficacy issues were identified that required the input of an independent expert panel in order to make an adequate risk benefit assessment.

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).

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 are deferring submission of your pediatric studies until Q3/2012 because this product is ready for approval for use in adults and the pediatric studies have not been completed. Your deferred pediatric studies are required under 505B(a) of the Federal Food, Drug, and Cosmetic Act and are therefore required postmarketing studies. The status of these postmarketing studies must be reported according to 21 CFR 601.70 and section 505B(a)(3)(B) of the Federal Food, Drug, and Cosmetic Act. These required studies will be conducted in support of the indication of active immunization for the prevention of disease caused by Japanese encephalitis virus in persons 1 year to 16 years of age. They are listed below:

IC51-322: IMMUNOGENICITY AND SAFETY OF THE JAPANESE ENCEPHALITIS VACCINE (IXIARO ®) IN A PEDIATRIC POPULATION IN NON-ENDEMIC COUNTRIES. This is an uncontrolled, open-label phase 3 study. 100 subjects aged ≥1 to < 17 years will be vaccinated with IXIARO ® to assess the immunogenicity and safety profile in a pediatric population from regions where Japanese encephalitis (JE) is not endemic.

Final Report Submission: Q3/2012
IC51-323: SAFETY OF THE JAPANESE ENCEPHALITIS VACCINE (IXIARO ®) IN A PEDIATRIC POPULATION. This is an open label, randomized, active controlled Phase 3 study in children aged ≥1 to <17 years of age. 1400 subjects will be randomized to receive IXIARO ® or U.S. licensed Hepatitis A vaccine in a 3:1 ratio. Within each treatment group, the ratio of subjects aged ≥ 1 to < 3 years and ≥ 3 to < 17 years will be approximately 1:1. Subjects randomized into the control group will be offered vaccination against Japanese encephalitis at no cost after concluding the trial.

Final Report Submission: Q3/2012

Submit final study reports to this BLA. For administrative purposes, all submissions related to these required pediatric postmarketing studies must be clearly designated “Required Pediatric Assessments”.

We are waiving the pediatric study requirement for ages 0 months to 12 months because the necessary studies would be impossible or highly impracticable. Insufficient numbers of suitable study subjects exist, because (1) maternally derived JE-neutralizing antibodies are common in infants born in endemic areas and (2) non-travelers in non-endemic regions could not be ethically enrolled in a study from which they could not expect any potential benefit.

POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS OF 21 CFR 601.70.)

Although clinical data submitted in support of your BLA do not indicate that there are specific safety issues associated with use of IXIARO â in any age group or gender, you have committed in your e-mail of February 5, 2009, to conduct the following studies according to the following schedule:

Table 1. Timelines for Postmarketing Commitments

Category

Study Code

Protocol to FDA

First Subject Enrolled

Clinical

Study Report

to FDA

Post-

Licensure

Elderly

IC51-315

November/December

2009

Q2/2010

Q2/2012

Post-licensure

surveillance

DoD Active

Surveillance

in 20,000

September/October

2009*

February/March

2010*

Q3/2012*

Post-

Licensure

surveillance

DoD

Pregnancy

Surveillance

September/October

2009*

February/March

2010*

Q4/2013**

* per initial discussions with DoD/Milvax and based on assumptions for supply of IXIARO ® to DoD
**based on follow-up durations for pregnancy cases and children

Please submit the protocols to your IND -(b)(4)-, with a cross-reference to this biologics license application (BLA), STN BLA 125280, and submit all final reports to your BLA, STN BLA 125280.

Please use the following designators to prominently label all submissions, including supplements, relating to these post-marketing study commitments as appropriate:

Postmarketing Study Commitment Protocol
Postmarketing Study Correspondence/Status Update
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),
an explanation of the status including, for clinical studies, the patient accrual rate (i.e., number enrolled to date and the total planned enrollment), and
a revised schedule if the study schedule has changed and an explanation of the basis for the revision.

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 February 2006 Guidance for Industry: Reports on the Status of Postmarketing Study Commitments – Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997 (see http://www.fda.gov/cber/gdlns/post130.htm) for further information.

You are required to report annually to FDA on the status of this study pursuant to section 506B of the Food Drug and Cosmetics Act, as well as 21 CFR 601.70 until we have notified you that the study commitment has been fulfilled, or that the study would no longer provide useful information.

CMC POSTMARKETING COMMITMENTS

---------------------------------------------(b)(4)-------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ---------------------

ADVERSE EVENT REPORTING

Adverse experience reports should be submitted 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. (Please see this CBER web site for procedures to submit the distribution reports electronically: http://www.fda.gov/cber/ldd/ldd.htm.) Under 21 CFR 600.80(c)(2) [Periodic Adverse Experience Reports], you must report each adverse experience not reported under the paragraph below 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 agree to provide expanded adverse experience reporting (in addition to complying with the requirements under 21 CFR 600.80) to the Vaccine Adverse Reporting System for one year following product licensure as follows:

As 15 day reports: All serious adverse events whether expected/labeled or unexpected/unlabeled, including seizures (including febrile seizures), shock, respiratory distress or difficulty breathing, angioedema, inspiratory stridor, anaphylaxis, and bilateral wheezing.
As 30 day (monthly) reports: All allergic events, including anaphylaxis not reported as a 15 day report; all cases of urticaria not reported as a 15 day report; neurological events not reported as 15 day reports, including Japanese encephalitis, Bell's palsy, neuritis, multiple sclerosis, CNS inflammation, convulsion, meningitis, Guillain-Barré Syndrome, serum sickness, delayed hypersensitivity, angioedema, encephalitis, encephalopathy, brachial neuritis, optic neuritis, other neuropathy, myelitis including transverse myelitis, ptosis, ataxia, multiple sclerosis, acute disseminated encephalomyelitis, and cerebrovascular accidents or transient ischemic attacks not reported as a 15 day report.

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 IXIARO ® 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.

In addition, you may wish to submit two draft copies of the proposed introductory advertising and promotional labeling with 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 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. Richard Daemer or Ms. Daryll Miller at 301-827-3070.

Sincerely yours,

Mary A. Malarkey	Norman W. Baylor, Ph.D.
Director Office of Compliance and Biologics Quality Center for Biologics Evaluation and Research	Director Office of Vaccines Research and Review Center for Biologics Evaluation and Research