Product Approval Information

Our STN: BL 125158/0

Acambis Inc.
Attention: David Wonnacott, Ph.D.
38 Sidney Street
Cambridge, MA 02139

Dear Dr. Wonnacott:

We are issuing Department of Health and Human Services U.S. License No. 1733 to Acambis Inc., Cambridge, MA, under the provisions of section 351(a) of the Public Health Service Act (PHS 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 Smallpox (Vaccinia) Vaccine, Live. Smallpox (Vaccinia) Vaccine, Live is indicated for active immunization against smallpox disease for persons determined to be at high risk for smallpox infection.

We have completed our review of this application. At your request, it is approved with restrictions to assure safe use under the provisions of 21 CFR 601.42 (Subpart E), effective on the date of this letter, for use as recommended in the enclosed labeling text, Medication Guide, ACAM2000™ Risk Minimization Action Plan Goals and Objectives (hereinafter RiskMAP Goals and Objectives), and carton and container labels. Marketing of this product and related activities must adhere to the substance and procedures of the referenced restricted distribution approval regulations and the RiskMAP Goals and Objectives.

We have reviewed your submissions describing how you will implement education, adverse event reporting, and risk management evaluation for vaccination of persons determined to be at high risk for smallpox. Those submissions dated August 22, 2007, adequately address each of the RiskMAP Goals and Objectives. Your RiskMAP includes ongoing assessment and periodic reporting to FDA of the operation of the program and needed revisions, if any. Any change to your RiskMAP must be discussed with FDA prior to its institution and is subject to FDA's determination that the required components are still present and are sufficient to meet the RiskMAP Goals and Objectives. We expect your continued cooperation to resolve any problems regarding the RiskMAP that may be identified following approval of this application.

In the event of an actual smallpox emergency, declared by the Secretary under Section 319 of the PHS Act, the conditions for use for the vaccine would change, altering the vaccine's risk/benefit balance. Consequently, the postmarketing restrictions needed to assure safe use would change accordingly. Upon such declaration, alternative approaches that meet the RiskMAP Goals and Objectives may be immediately implemented, and as soon as possible you must notify FDA of the alternative approaches being implemented by phone, fax or email to the Division of Vaccines and Related Products Applications. For example, you may replace distribution of the Medication Guide and other details of your RiskMAP's education plan with other forms of education that would accomplish education goals i-iii of the attached RiskMAP Goals and Objectives. In addition, except for those serious and unexpected adverse experiences that 21 CFR 600.80(c)(1) requires you to include in postmarketing 15-day Alert Reports, the Center for Biologics Evaluation and Research (CBER) waives your compliance with 15-day reporting of adverse events specified under the RiskMAP Goals and Objectives, section B, such that reporting would be as soon as possible under the federally declared smallpox emergency.

Under this license, you are approved to manufacture Smallpox (Vaccinia) Vaccine, Live at your facility in --------------------. You may label this product with the proprietary name ACAM2000™ and it will be supplied in 3mL vials. The diluent will be supplied in 0.5mL vials.

The dating period for ACAM2000™ shall be 72 months from the date of manufacture when stored at -15° to -25°C (5 °F to - 13 °F). The dating period for the diluent shall be 60 months from the date of manufacture when stored at 15 °C to 30 °C (59 °F -86 °F) . The date of manufacture shall be defined as the date of final fill.

Please submit final container samples of the product together with protocols showing results of all applicable tests from lots manufactured after licensure. You may not distribute any lots of product until you receive a notification of release from the Director, CBER. For lots that Acambis, Inc. has, as of the date of this letter, already supplied under contract to the U.S. Government, the Director of CBER has determined that Acambis, Inc. is not required to submit those lots to CBER for release.

Under 21 CFR 601.27, 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 the waiver request that you submitted with this application. We have determined, however, that under 21 CFR 601.27(a) a waiver is not necessary. Specifically, based on data from adequate and well-controlled studies in adults, supplemented by historical data from use of a licensed live vaccinia virus smallpox vaccine during the smallpox eradication era, we have concluded that the course of smallpox disease and the effects of this product are similar in adults and pediatric patients, and that pediatric effectiveness can be extrapolated from those data. Consequently, ACAM2000™ is approved for pediatric use in all age groups.

You must submit information to your biologics license application for our review and written approval under 21 CFR 601.12 for any changes in the manufacturing, testing, packaging, labeling, or manufacturing facilities, including changes in your approach to satisfying the RiskMAP Goals and Objectives, of ACAM2000™.

Postmarketing Commitments subject to reporting requirements of 21 CFR 601.70

We acknowledge the postmarketing clinical commitments outlined in your submission of August 22, 2007. These commitments, along with any completion dates agreed upon, are listed below:

1. You have agreed to carry out a Phase 4 prospective cohort study in the military population receiving ACAM2000™. Study groups will include approximately 15,000 ACAM2000™ vaccinees and an appropriately sized control group. The duration of the study will be 2 years. The objectives of this study are to provide:

General safety information on expected and unexpected adverse events;
Additional information on the natural history and clinical outcome of myocarditis and pericarditis after ACAM2000™ and will include performance of EKG’s, echocardiograms, and troponin and other clinically appropriate testing at least annually on identified cases; and,
Information on the adequacy of the risk management program on reducing preventable adverse events. One specific sub-study will be to evaluate the effectiveness of screening procedures for identifying service members who should not be vaccinated.

Protocol Submission by 12/31/07
Study Start: by 12/31/08
Final Report Submission by 03/31/11

2. You have agreed to implement an enhanced surveillance program to ascertain at least 75% of symptomatic cases of myocarditis and pericarditis after ACAM2000™ vaccination. The enhanced surveillance will consist, at a minimum, of solicitation of reports using world wide web, email, telephone, and postal mail interfaces. An estimated population size of 100,000 to 200,000 military service members will be included in this program. The sample size will be expanded if a sufficient number of cases of myocarditis are not identified to meet the pharmacovigilance objectives as defined by FDA.

Protocol Submission by 12/31/07
Study Start: by 12/31/08
Interim Evaluation Report by 12/31/09
Final Report Submission by 12/31/10

3. You have agreed to implement a myocarditis registry with cases identified from routine surveillance, the Phase 4 cohort study, and the enhanced surveillance program. The goals of the myocarditis registry are to 1) further understand the natural history of myocarditis and pericarditis after ACAM2000™ vaccination, and 2) evaluate potential risk factors associated with the development of vaccine-related myocarditis and pericarditis. The submitted protocol will describe the number of cases (minimum 150 cases) to be followed, duration of follow-up (minimum of 2 years), and laboratory/clinical evaluations.

Protocol Submission by 12/31/07
Study Start: by 03/31/08
Interim Evaluation Report by 03/31/09
Final Report Submission by 12/31/11

4. You have agreed to submit a protocol describing the methods to be used to annually evaluate the risk management program for ACAM2000™ to 1) assess the presence of adverse events that may be attributable to weaknesses of elements in the risk management program, and 2) to ensure that vaccination adverse event reporting is sensitive and timely. The protocol will include methods used to monitor cases of preventable adverse events, including contact vaccinia transmission, autoinoculation, eczema vaccinatum, and inadvertent vaccination during pregnancy, including methods used during a federally declared emergency under Section 319 of the PHS Act. Submit this protocol to your IND. Submit annual evaluations of the risk management program in your IND annual report.

Protocol Submission by 12/31/07

5. You have agreed to conduct a study to examine how effectively DoD adheres to its own screening procedures to identify potential vaccinees who have risk factors for more serious adverse events after vaccination, and therefore, should not be vaccinated. This will sample a sufficiently large number of vaccinees and non-vaccinees (approximate total of 5000).

Protocol Submission by 12/31/07
Study Start: by 12/31/08
Final Report Submission by 03/31/11

Postmarketing Commitments not subject to reporting requirements of 21 CFR 601.70

We acknowledge the postmarketing quality commitments outlined in your submission of August 22 , 2007, as follows:

6. You have committed to submit results of lot release tests to CBER that you have performed for product currently stored in the Strategic National Stockpile (SNS) as per 21 CFR 610.1, which requires completion of tests for conformity with standards applicable to each product prior to release of each lot. Please submit lot release test results for 15 lots per month for the first 6 months post-licensure, or until data for all lots have been submitted.

7. ----------------------------------------------------------- ----------------------------------------------------------- ----------------------------------------------------------- ----------------------------------------------------------- -----------------------------

We acknowledge the postmarketing quality commitment outlined in your submission of August 29 , 2007, as follows:

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We request that you submit clinical protocols to your IND, with a cross-reference letter to this biologics license application (BLA), STN BL-125158/0. Submit n onclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN BL- 125158/0. 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 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 website (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.

Under 21 CFR Part 208, we have determined that this product poses a serious and significant public health concern requiring the distribution of a Medication Guide. ACAM2000™ is a product for which patient labeling could help prevent serious adverse events and inform patients of serious risks relative to benefit that could affect their decisions to be vaccinated. Therefore, a Medication Guide is necessary for safe and effective use of this product and FDA hereby approves the draft Medication Guide you submitted August 31, 2007.

Under 21 CFR 208, you are responsible for ensuring that the Medication Guide is available for every person who is to be vaccinated with.ACAM2000™. Therefore, you must format the proposed Medication Guide in a manner that will assure its appropriate distribution to vaccinees and distribute the Medication Guide according to your plans for the RiskMap submitted on August 22 , 2007. The labels must state that the Medication Guide is provided to each vaccinee.

You must 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 thereafter. Since your product is a vaccine, you must submit these reports to the Vaccine Adverse Event Reporting System (VAERS) using the pre-addressed form VAERS-1. In addition, you must submit the following to FDA as 15-day reports, and a summary and discussion of the clinical significance of these events should also be provided in the periodic adverse experience report: autoinoculation, cardiomyopathy, central nervous system disease, contact transmission of vaccinia, death, eczema vaccinatum, fetal vaccinia, generalized vaccinia, ischemic heart disease, ocular vaccinia, potential myocarditis and pericarditis, progressive vaccinia, Stevens-Johnson Syndrome, and superinfection of vaccination site.

You must submit reports of biological product deviations under 21 CFR 600.14. You should identify and investigate all manufacturing deviations, including those associated with processing, testing, packing, labeling, storage, holding and distribution promptly. 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.

In response to your August 14, 2006, submission, w e waive, under 21 CFR 201.58, the requirements of 21 CFR 201.57(d)(8) regarding the length of highlights of prescribing information. This waiver applies to all future supplements containing revised labeling unless we notify you otherwise. Please submit all final printed labeling at the time of use and include implementation information on FDA Form 356h and FDA Form 2567 as appropriate. Please provide a PDF-format electronic copy.

The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert, Medication Guide, immediate container and carton labels). Marketing the product with FPL that is not identical to the approved labeling text may render the product misbranded and an unapproved new drug.

As required by 21 CFR 601.45, after the initial 120 day period following this approval, you must submit all promotional materials, including promotional labeling as well as advertisements, at least 30 days prior to the intended time of initial distribution of labeling or initial publication of the advertisement. Send two copies of all promotional materials, accompanied by FDA Form 2253, directly to:

Food and Drug Administration
Center for Biologics Evaluation and Research
Advertising and Promotional Labeling Branch, HFM-602
1401 Rockville Pike
Rockville, MD 20852-1448

Sincerely yours,

/signed

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

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

ACAM2000 RISK MINIMIZATION ACTION PLAN GOALS AND OBJECTIVES

Education

Acambis will implement education of vaccinees and vaccine providers for the administration of ACAM2000 to achieve the following goals:

The vaccine is administered safely and effectively,
Vaccinees are informed of the risks (including the risk of myocarditis and pericarditis, vaccinia transmission and vaccinia autoinoculation) and benefits of the vaccine,
The risks of vaccinia transmission and autoinoculation are minimized.

To help meet these three goals, the FDA-approved Medication Guide will be distributed to each vaccinee.

Adverse Event Reporting

Acambis will implement a reporting and collection system for the expedited reporting of adverse events associated with the use of ACAM2000 that complies with reporting requirements for an approved BLA (21 CFR 600.80). The following adverse experiences, which include both those required under 21 CFR 600.80 and others that are sometimes associated with smallpox vaccines, will be submitted to FDA as 15 day reports, and a summary and discussion of the clinical significance of these events will be provided in the periodic adverse experience report:

Autoinoculation
Cardiomyopathy
Central nervous system disease
Contact transmission of vaccinia
Death
Eczema vaccinatum
Fetal vaccinia
Generalized vaccinia
Ischemic heart disease
Ocular vaccinia
Potential myocarditis and pericarditis
Progressive vaccinia
Stevens-Johnson Syndrome
Superinfection of vaccination site

Risk Management Evaluation

Acambis will implement a program to evaluate the effectiveness of the overall risk management program in assuring that ACAM2000 is used safely and that Acambis achieves Education goals listed in i - iii above. This evaluation program will include:

An annual adverse event report that will analyze data from VAERS and other sources to assess the presence of adverse events that may be attributable to weaknesses of elements in the risk management program and summarize corrective actions taken in response. This report will be submitted as part of the annual report required under 21 CFR 601.70.
Annual surveillance evaluations to ensure that vaccination adverse event reporting is sensitive and timely and a listing of correction actions taken in response. Such evaluations and listing will be summarized in a report to be submitted as part of the annual report required under 21 CFR 601.70.

Protocols for the risk management evaluation program will be submitted as Phase 4 studies.