Product Approval Information - Licensing Action

September 28, 2007

Our STN: BL 125254/0

CSL Biotherapies, Inc.
Attention: Paul R. Hartmann, R. Ph.
Senior Director, Regulatory Affairs
U.S. Agent for CSL Limited
1020 First Avenue, P.O. Box 61501
King of Prussia, PA 19406-0901

Dear Mr. Hartmann:

We are issuing Department of Health and Human Services U.S. License No. 1764 to CSL Limited, Parkville, Victoria, Australia, under the provisions of section 351(a) of the U.S. 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 approved to manufacture Influenza Virus Vaccine, at CSL Limited, 45 Poplar Rd, Parkville 3052, Victoria, Australia. The final formulated product will be filled, labeled, and packaged by CSL ---------------------------------------------------------------------------- facility. You may label your product with the proprietary name Afluria® and market it in 5 mL multi-dose vials and 0.5 mL preservative-free single dose syringes.

Afluria® is an inactivated influenza virus vaccine, indicated for active immunization of adults 18 years of age and older against influenza disease caused by influenza virus subtypes A and type B present in the vaccine. This indication is based on the immune response elicited by Afluria®; there have been no controlled clinical studies demonstrating a decrease in influenza disease after vaccination with Afluria®.

The dating period for Afluria® shall be no more than 12 months from the date of manufacture of the final container vaccine, but not to exceed June 30th of the influenza season for which it was formulated when stored at 2-8° C (36-46°F). The date of manufacture shall be defined as the date on which this vaccine is filled. Any extension of the dating period will require the submission and approval of supportive data as a prior approval supplement to your BLA; ongoing stability data may be submitted as product correspondence as it becomes available.

Please submit the first five monovalent concentrates of each strain to CBER for potency testing, along with the protocol for each submitted lot. CBER will not release monovalent lots, however, results of potency testing will be provided for your information only. For the lots to be released, please submit your final trivalent bulk samples of the product, together with lot release protocols in the proper format showing results of all applicable tests. You may not distribute any lots of the product until you receive a notification of release from the Director, Center for Biologics Evaluation and Research (CBER).

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 populations unless this requirement is waived or deferred. We have reviewed your submission and deny your request for a partial waiver for the pediatric age group birth to 6 months of age. We are deferring all of your pediatric studies for Afluria® until June 30, 2010, ---------------------------------------------------------------------------------------------. We will re-evaluate your request for a waiver for children less than 6 months of age upon submission of the data from your post marketing studies in pediatric populations.

Please note that although your pediatric studies required under section 2 of the Pediatric Research Equity Act (PREA) are deferred, the deferred status of these required postmarketing studies should be reported as such annually according to 21 CFR 314.81.

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 or labeling of Afluria®, or in the manufacturing facilities.

Postmarketing Commitments subject to reporting requirements of 21 CFR 601.70

Products approved under the accelerated approval regulations, 21 CFR 314.510, require further adequate and well-controlled confirmatory clinical studies to verify and describe clinical benefit. We remind you of your postmarketing study commitments specified in your submissions dated September 20, 2007. These commitments, along with any completion dates agreed upon, are listed below.

Clinical Endpoint Efficacy Study in a Healthy Adult Population

  1. CSL Limited agrees to conduct Study No. CSLCT-USF-06-28, a placebo-controlled clinical endpoint efficacy and six-month safety study of CSL Limited's Afluria® in healthy adults 18 to less than 65 years of age in whom vaccination is not universally recommended. The final protocol for this study will be submitted by October 12, 2007. This study will be conducted in the Southern Hemisphere during the influenza season following the accelerated approval. The study will start by March 31, 2008. If the influenza attack rate is lower than expected, participant enrollment will be extended to a second season. The final study report for the first season will be submitted by June 30, 2009; a final study report for the second season, if the study has to be extended to a second season, will be submitted by June 30, 2010.

Additional Studies to Support the Effectiveness of the Vaccine in Populations Not Included in the Clinical Efficacy Study

Non-Inferiority Study in an At Risk Adult Population 18 Years and Older

  1. CSL Limited agrees to conduct Study No. CSLCT-USF-07-41 a non-inferiority immunogenicity and safety study with CSL Limited's Afluria® and a US Licensed Trivalent Inactivated Split-Virion Influenza Vaccine in an at risk population of adults 18 years and older who have chronic medical conditions placing them at risk for complications of influenza or who otherwise fall into groups for whom yearly influenza vaccination is recommended. The final protocol for this study will be submitted by April 1, 2008. This study will start by October 1, 2008. The final study report will be submitted by June 30, 2010.

Safety and Tolerability Study in Pediatric Population

  1. CSL Limited agrees to conduct Study No. CSLCT-USF-06-29, an uncontrolled, open-label, safety and tolerability study of CSL Limited's Afluria® in a pediatric population ages 6 months to less than 18 years. The final protocol for this study will be submitted by August 1, 2008. This study, conducted in the Southern Hemisphere, will start by March 31, 2009. The final study report will be submitted by June 30, 2010.

Non-inferiority Study in Pediatric Population

  1. CSL Limited agrees to conduct Study No. CSLCT-USF-07-36, a non-inferiority innumogenicity and safety study with CSL Limited's Afluria® and a US Licensed Trivalent Inactivated Split-Virion Influenza Vaccine in a pediatric population from 6 months to less than 18 years of age. The final protocol for this study will be submitted by April 1, 2009. This study will be conducted in North America and will start by October 1, 2009. The final study report will be submitted by June 30, 2010.

Postmarketing Commitments not subject to reporting requirements of 21 CFR 601.70

We also acknowledge the postmarketing commitments outlined in your submission of September 26, 2007; CSL Limited has agreed to:

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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 125254/0. Submit non-clinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN BL 125254. 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 Web site (http://www.fda.gov/cder/pmc). 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/post130.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, you must also 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.

Please note that the accelerated approval regulation concerning promotional materials (21 CFR 601.45) stipulates that all advertising and promotional labeling items that CSL wishes to distribute in the first 120 days following approval, must have been received by FDA prior to the approval date. After approval, promotional items intended for dissemination after the first 120 days following approval should be submitted to the FDA 30 days prior to the anticipated distribution date. Please submit these materials 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 all final advertising and promotional labeling materials 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 had them approved.

If you have any questions, please contact Dr. Rakesh Pandey at 301-827-3070.

Sincerely yours,

--- signature ---

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
 
Updated: September 28, 2007