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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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April 6, 2007 Approval Letter - HepaGam B

Our STN: BL 125237/0

Cangene Corporation
Attention: Mr. Christopher Fredric
3403 American Drive
Mississauga, Ontario L4V 1T4
Canada

Dear Mr. Fredric:

We have approved your biologics license application for Hepatitis B Immune Globulin Intravenous (Human) effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Hepatitis B Immune Globulin Intravenous (Human) under your existing Department of Health and Human Services U.S. License No. 1201. Hepatitis B Immune Globulin Intravenous (Human) is indicated for the prevention of Hepatitis B recurrence following liver transplantation in HBsAg-positive liver transplant patients. For this indication, Hepatitis B Immune Globulin Intravenous (Human) should be administered intravenously. Hepatitis B Immune Globulin Intravenous (Human) is also indicated for the treatment of acute exposure to blood containing HBsAg, perinatal exposure of infants born to HBsAg-positive mothers, sexual exposure to HBsAg-positive persons and household exposure to persons with acute HBV infection. For the latter indications, Hepatitis B Immune Globulin Intravenous (Human) should be administered intramuscularly.

Under this authorization, you are approved to manufacture Hepatitis B Immune Globulin Intravenous (Human) at your facility in Winnipeg, Manitoba, Canada. You may label your product with the proprietary name HepaGam BT and will market it in 1 mL and 5 mL vials.

The dating period for Hepatitis B Immune Globulin Intravenous (Human) shall be 36 months from the date of manufacture when stored at 2 - 8 oC. The date of manufacture shall be defined as the date of the --------------------------------- of the finished bulk product. Following the ----- --------------------------- of the finished bulk product, no reprocessing/reworking is allowed without prior approval from the Agency.

Please submit final container samples of the product 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 Biologic 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 patients unless this requirement is waived or deferred. We have reviewed your submission and agree that a waiver of your pediatric studies for Hepatitis B Immune Globulin Intravenous (Human) is justified because of the extremely low number of HBV related transplants in pediatric patients.

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 Hepatitis B Immune Globulin Intravenous (Human), or in the manufacturing facilities.

We acknowledge your written commitments as described in your letter of March 30, 2007 as outlined below:

Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.

  1. Cangene commits to complete the clinical study HB-005 entitled "Hepatitis B Immune Globulin (NP-002) for the Prevention of Graft Re-Infection in Hepatitis B Related Liver Transplant Patients."

     

    We request that you submit clinical protocols to your IND, with a cross-reference letter to this biologics license application (BLA), STN BL 125237. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN BL 125237. 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/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.

Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70.

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In addition, pursuant to 21 CFR 600.80(c)(2)(Periodic Adverse Experience Reports), the Agency is requiring that manufacturers report on a monthly basis any infectious disease transmission associated or possibly associated with any licensed biological product that is not reportable under 21 CFR 600.80 (c)(1)(Fifteen-day Alert Reports). The timing of this monthly periodic reporting requirement was selected, among other reasons, to permit the acquisition of patient information, including clinical evaluation, sufficient to help in the timely assessment of a causal connection between the biological product and possible or documented infectious disease transmission. This new reporting requirement was also based on the observation of inconsistent practices by some manufacturers in submitting reports of possible infectious diseases.

Please note that this monthly reporting requirement applies only to infectious disease transmission. Other periodic reports should continue to be submitted on the quarterly or annual basis that is appropriate to each licensed biological product for all other adverse experiences not reportable under 21 CFR 600.80(c)(1). You should submit these monthly reports to the Center for Biologics Evaluation and Research, Division of Epidemiology, HFM-210, 1401 Rockville Pike, Rockville, MD, 20852-1448. Please contact the Division of Epidemiology (301-827-3974) if you have any questions about these periodic adverse event reporting requirements.

You must submit adverse experience reports under the adverse experience reporting requirements for licensed biological products (21 CFR 600.80) and you must submit distribution reports under 21 CFR 600.81. You should submit postmarketing adverse experience reports and distribution reports to the Center for Biologics Evaluation and Research, HFM-210, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-1448. Prominently identify all adverse experience reports as described in 21 CFR 600.80.

You must submit reports of biological product deviations under 21 CFR 600.14. You promptly should 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 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 as well as five original paper copies of each label and the circular. For the circular only, please provide a Word-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 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.

Sincerely yours,

--- signature ---

Jay S. Epstein, M.D.
Director
Office of Blood Research and Review
Center for Biologics Evaluation and Research