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DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Food and Drug Administration Rockville, MD 20852-1448 May 2, 2005 Our STN: BL 125109/0 Cangene Corporation Attention: Stephen McGregor Director, Regulatory Affairs 3403 American Drive Mississauga, Ontario, Canada L4V IT4 Dear Mr. McGregor: We have approved your biologics license application for Vaccinia Immune Globulin Intravenous (Human) effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Vaccinia Immune Globulin Intravenous (Human) under your existing Department of Health and Human Services U.S. License No. 1201. Vaccinia Immune Globulin Intravenous (Human) is indicated for the treatment and/or modification of the following conditions, which are complications resulting from smallpox vaccination: Eczema vaccinatum Progressive vaccinia Severe generalized vaccinia Vaccinia infections in individuals who have skin conditions such as burns, impetigo, varicella-zoster, or poison ivy; or in individuals who have eczematous skin lesions because of either the activity or extensiveness of such lesions Aberrant infections induced by vaccinia virus that include its accidental implantation in eyes (except in cases of isolated keratitis), mouth, or other areas where vaccinia infection would constitute a special hazard. Under this authorization, you are approved to manufacture Vaccinia Immune Globulin Intravenous (Human) at your facility in Winnipeg, Manitoba, Canada. You may label your product with the proprietary name CNJ-016T and will market it in 15 mL vials. The dating period for Vaccinia Immune Globulin Intravenous (Human) 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 of final sterile filtration of the formulated drug product. Following the final sterile filtration, no reprocessing/reworking is allowed without prior approval from the Agency. The dating period for your drug substance shall be 28 days when stored at 2 - 8°C. Please submit samples of the product 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 Biologic Evaluation and Research (CBER). 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 Vaccinia Immune Globulin Intravenous (Human) (VIGIV), or in the manufacturing facilities. As requested in your letter of July 27, 2004, we are granting marketing approval of this product for the treatment of those complications resulting from smallpox vaccination stated in the first paragraph of this letter under the accelerated approval of biological products regulations, 21 CFR 601.40-46. These regulations permit the use of certain surrogate endpoints or an effect on a clinical endpoint other than survival or irreversible morbidity as basis for approvals of products intended for serious or life-threatening illnesses or conditions. Approval under these regulations requires, among other things, that you conduct adequate and well-controlled studies to verify and describe clinical benefit attributable to this product. Clinical benefit is evidenced by effects such as increased survival in progressive vaccinia and eczema vaccinatum. We expect you to complete design, initiation, accrual, completion, and reporting of these studies within the framework described in your letter of April 20, 2005. You must conduct these studies with due diligence. If postmarketing studies fail to verify that clinical benefit is conferred by Vaccinia Immune Globulin Intravenous (Human), or are not conducted with due diligence, we may, following a hearing in accordance with 21 CFR 601.43 (b), withdraw or modify approval. Submit final study reports to your BLA, STN 125109 as a supplemental application. For administrative purposes, all submissions relating to these postmarketing study commitments must be clearly designated as "21 CFR 601 Subpart E Postmarketing Study Commitments." In addition, we acknowledge your written commitments of April 27, 2005, which include the following: Postmarketing Studies subject to reporting requirements of 21 CFR 601.70. Information regarding these may be publicly disclosed on the agency's web site http://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm, in the agency's annual Federal Register report on postmarketing studies and in the agency's special report to Congress. To satisfy the requirements for Accelerated Approval: You will initiate a study that will initially include the collection of clinical data from the first 100 patients who provide informed consent for participation in the study, to describe the treatment and clinical course of patients receiving VIGIV for complications of vaccinia infection. These data will be collected according to the Case Report Forms (CRF) agreed to by FDA at the time of licensure. The data collection times are designed to determine time to resolution of vaccinia infection, morbidity and mortality. The purpose of data collection is to verify the ultimate clinical benefits of VIGIV, to further study the relationship of the surrogate endpoint (anti-vaccinia antibody levels day 5 post-infusion) to clinical benefit, and to provide information about adverse events in patients with vaccinia infection treated with VIGIV. After the first 100 subjects are enrolled, you commit to discussion of any further data collection with FDA and to implement the collection of additional information as appropriate and as defined by those discussions in a timely fashion. You will collect serum samples prior to VIGIV treatment and 5 days after treatment in the first 50 subjects, which will subsequently be analyzed to determine anti-vaccinia antibody levels at both timepoints. These data will be analyzed to assess the correlation between day 5 antibody levels and clinical improvement/outcome for each complication. At that time, FDA will determine the need for any additional collection of antibody data for certain vaccinia complications if those complications are under-represented among the first 50 patients. You will submit to the FDA within 3 months of product licensure the IND study protocol noted under item a., which shall describe the process by which clinical data and serum samples will be collected and managed, to include its planned statistical analysis of data within 3 months of product licensure, and implement it promptly upon acceptance of the protocol design by FDA. The analysis will: 1) correlate day 5 anti-vaccinia antibody levels to clinical improvement outcome for each subset of vaccinia complications, and 2) compare historical mortality rates in untreated patients to observed mortality rates in VIGIV-treated patients, for (a) eczema vaccinatum and for (b) progressive vaccinia. You will monitor the scientific literature during the postmarketing commitment period, prepare summary reports of any published use of VIGIV, and submit these to FDA. You will provide cumulative clinical information, and any statistical analyses that are undertaken, to FDA in the Annual Report on Postmarketing Studies. You agree to work with the FDA, and other public agencies as appropriate, to design and implement a clinical study protocol to include VIGIV dose ranging, when such a study is feasible, due to the actual or impending widespread use of VIGIV. We request that you submit clinical protocols to your IND, with a cross-reference letter to this biologics license application (BLA), STN BL 125109. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN BL 125109. 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 You must submit the following information in accordance with 21 CFR 601.28 and 601.70: A status summary of each reportable commitment in an Annual Report on Postmarketing Studies to the BLA; and, Expected summary completion and final report submission dates, any changes in plans since the last Annual Report on Postmarketing Studies, and, for clinical studies, number of patients entered into each study. You may refer to the "Draft" Guidance for Industry (April 2001): Reports on the Status of Postmarketing Studies - Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997. Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70. --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------ 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 original paper copies (ten for circulars and five for other labels). 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 a 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 --- Basil Golding, M.D. Director Division of Hematology Office of Blood Research and Review Center for Biologics Evaluation and Research

Updated May 9, 2005

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