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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
Rockville, MD 20852-1448
January 9, 2006
Our STN: BL 125115 / 0
ZLB Behring, L.L.C.
Attention: Paul Hartmann
Director, Regulatory Affairs
1020 First Avenue
King of Prussia, PA 19406-0901
Dear Mr. Hartmann:
We have approved your biologics license application for Immune Globulin Subcutaneous (Human) effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce Immune Globulin Subcutaneous (Human) under your existing Department of Health and Human Services U.S. License No. 1708. Vivaglobin is indicated for the treatment of patients with primary immune deficiency (PID).
Under this authorization, you are approved to manufacture Immune Globulin Subcutaneous (Human) at your facility in Marburg, Germany. You may label your product with the proprietary name Vivaglobin and will market it in 3, 10, and 20 mL vials.
The dating period for Immune Globulin Subcutaneous shall be 24 months from the date of manufacture when stored at 2 - 8o 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.
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 Biologics Evaluation and Research (CBER).
Your pediatric assessment notes that it is rare to identify PID in a neonate. We further note that FDA’s expectation for clinical studies in PID, as articulated at a Blood Products Advisory Committee meeting, is that subjects be evaluated for serious bacterial infections over a one year period, whereas neonates are defined as being only up to 30 days of age; thus efficacy in neonates according to FDA’s expectation is moot. Since diagnosis is rare, and since maternal antibodies may mitigate the need for treatment even when a diagnosis is made within the first 30 days, we find little need for safety data in neonates for this indication.
Your pediatric assessment notes that it is difficult to study infants due to the few patients diagnosed with PID in this age group from 30 days to 2 years of age. Your assessment further notes maternal antibodies would confound assessment and that small blood volumes would preclude collecting the requisite amount of blood samples to monitor safety. We do agree that it would be impracticable to conduct even a limited study of safety in which recruitment is dependent on new diagnoses of PID in pediatric subjects. Further, we do not find sufficient public health concern regarding safety of Vivaglobin to require studies in infants.
Accordingly, a waiver for pediatric studies in neonates and infants for your application is granted under 21 CFR 601.27 at this time.
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 Subcutaneous (Human) or in the manufacturing facilities.
Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70.
We acknowledge your written commitments as described in your letter of December 12, 2005 as outlined below:
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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.
Under 21 CFR 201.57(f)(2), patient labeling must be reprinted at the end of the package insert. We request that the text of information distributed to patients be printed in a minimum of 10-point font.
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 ---
Jay Epstein, M.D.
Director
Office of Blood Research and Review
Center for Biologics Evaluation and Research
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