Product Approval Information - Licensing Action
Our STN: BL 125201/0
July 26, 2007
CSL Behring AG
Attention: Paul Hartmann, R.Ph.
1020 First Avenue
King of Prussia, PA 19406-0901
Dear Mr. Hartmann:
We have approved your biologics license application for Immune Globulin Intravenous (Human), 10% Liquid, effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce Immune Globulin Intravenous (Human), 10% Liquid, under your existing Department of Health and Human Services U.S. License No. 1766. Immune Globulin Intravenous (Human), 10% Liquid, is indicated for treatment of Primary Immunodeficiency and treatment of chronic Immune Thrombocytopenic Purpura.
Under this authorization, you are approved to manufacture Immune Globulin Intravenous (Human), 10% Liquid, at your facility in Bern, Switzerland. You may label your product with the proprietary name PrivigenTM and will market it in 50, 100, and 200 mL fill sizes.
The dating period for Immune Globulin Intravenous (Human), 10% Liquid, shall be 24 months from the date of manufacture when stored at 2 to 25 oC. 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.
Please submit final container 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).
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 Immune Globulin Intravenous (Human), 10% Liquid, for the indication of treatment of Primary Immunodeficiency in neonates and infants (up to two years of age) is justified because there are too few such subjects with this disease to study, however, for children (older than two years of age) and adolescents, we note that you have fulfilled the pediatric study requirement.
For the indication of treatment of chronic Immune Thrombocytopenic Purpura, we have reviewed your submission and agree that a waiver of your pediatric studies is justified because: 1) the indication is not applicable to neonates, 2) for infants and children, this condition is usually acute and self-limiting, and 3) chronic Immune Thrombocytopenic Purpura is rare, usually benign, and often does not require specific treatment before remission in pediatric subjects.
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 Immune Globulin Intravenous (Human), 10% Liquid, or in the manufacturing facilities.
We acknowledge your 12 written commitments as described in your letter of 23-July-2007 and as outlined below:
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70
- A protocol for a safety study under IND will be submitted to the FDA within two months of approval as agreed on July 20, 2007. The study will enroll ITP and/or PID patients to investigate the cause of the hemolysis, especially the specificity of the antibody involved and should be adequately sized to include at least 10 subjects with hemolysis. This protocol should include, but not be limited to, collection of the following information in patients with hemolysis and those who develop positive direct antiglobulin test: clinical description of event (if any), starting and finishing time of infusion, time of onset of possible hemolysis-related symptoms, event sequelae (such as transfusions, renal failure, DIC, and anemia), patient age, sex, and all diagnoses, concurrent and prior medications and transfusions, all relevant laboratory tests at baseline and after hemolysis including the date and time of testing (such as hemoglobin, hematocrit, reticulocyte count, total, direct and indirect bilirubin, LDH, haptoglobin, tests for hemoglobinemia and hemoglobinuria, microscopic urine examination, urine hemosiderin, direct antiglobulin testing, indirect antiglobulin testing with antibody identification if positive, elution of antibodies from the patient's red cells for testing on an adequate panel of human red cells), and titers of anti-RBC antibodies in the associated PrivigenTM lot. In addition, substantive details should be provided on the tests to be performed.
- CSL Behring AG commits to execution of the clinical trial regarding hemolysis as follows:
- The trial will be initiated (the first site initiated) within six months after protocol acceptance by the FDA.
- The subject enrollment rate of the trial should be similar to the enrollment rate of the previous pivotal trials
- The final clinical study report will be submitted to the FDA within six months after the 10th subject with hemolysis has completed the study
- Postmarketing Study Protocol
- Postmarketing Study Final Report
- Postmarketing Commitment Status Update
- Postmarketing Study Correspondence
- Annual Report on Postmarketing Studies
- 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).
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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 125201. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN BL 125201. Please use the following designators to label prominently all submissions, including supplements, relating to these postmarketing study commitments as appropriate:
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 (PMC Annual Report) for this product. The status report for each study should include:
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 and Word-format electronic copy as well as original paper copies (five for circulars and five for other labels).
Two copies of final printed advertising and promotional labeling should be submitted at the time of initial dissemination with a 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. 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.
Sincerely yours
--- signature ---
Jay Epstein, M.D.
Director
Office of Blood Research and Review
Center for Biologics Evaluation and Research