August 27, 2003 Approval Letter
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
1401 Rockville Pike
Rockville MD 20852-1448
August 27, 2003
Our STN: BL 125046/0
Ms. Carol Moore
800 Dwight Way
P.O. Box 1986
Berkeley, CA 94710
Dear Ms. Moore:
We have approved your biologics license application for Immune Globulin Intravenous (Human), 10% by Chromatography Process effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce Immune Globulin Intravenous (Human), 10% by Chromatography Process, under your existing Department of Health and Human Services U.S. License No. 0008. Immune Globulin Intravenous (Human), 10% by Chromatography Process is indicated for use in primary humoral immunodeficiency and idiopathic thrombocytopenic purpura.
Under this authorization, you are approved to manufacture Immune Globulin Intravenous (Human), 10% by Chromatography Process at your facility in Clayton, North Carolina. You may label your product with the proprietary name Gamunexä and will market it in 10, 25, 50, 100, and 200 mL fill sizes.
The dating period for Immune Globulin Intravenous (Human), 10% by Chromatography Process shall be 36 months from the date of manufacture when stored at 2 to 8 °C. Immune Globulin Intravenous (Human), 10% by Chromatography Process may be stored at temperatures not to exceed 25 oC for up to 5 months during the first 18 months from the date of manufacture. The date of manufacture shall be defined as the date of final sterile filtration of the formulated drug product.
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).
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% by Chromatography Process, or in the manufacturing facilities.
We acknowledge your written commitment as described in your letter of August 21, 2003, to review the available information regarding pharmacokinetics, safety, and efficacy in pediatric patients with (1) primary humoral immune deficiency and (2) ITP and, based on your review, submit as a prior approval supplement revised draft labeling that incorporates the information in the appropriate section of the labeling in accordance with 21 CFR 201.57.
We acknowledge your written commitments as described in your letter of August 13, 2003 as outlined below:
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.
Information regarding these studies may be publicly disclosed on the agency's web site (http://cdsm11.cder.fda.gov/pmc/index.cfm), in the agency's annual Federal Register report on postmarketing studies and in the agency's special report to Congress.
In support of FDA's efforts to obtain safety data for immunoglobulin products, you have agreed to post marketing studies as outlined below.
Regarding your ongoing study #100434 - Randomized, Double-Blind, Placebo-Controlled Study to Compare the Effects of Different Dose Regimens of IGIV-Chromatography (IGIV-C), 10% Treatment on Relapses in Patients with Relapsing Remitting Multiple Sclerosis, you have agreed to amend the protocol to provide for the following additional safety testing:
LDH, GGT, plasma-free hemoglobin, serum haptoglobin, serum potassium, DAT at both pre- and post- infusion at the time of the first infusion and at the time of the infusions at weeks 12 and 24.
AST, ALT, BUN, GGT, CPK, creatinine, and urinalysis with microscopic examination of sediment at week 12.
BUN, urinalysis with microscopic examination of sediment, and serum creatinine at baseline and one time following any infusion within the first six months between days 4 and 7 post infusion. At the discretion of the investigator, subjects residing outside commuting distance from the study center may have this testing performed at a local laboratory affiliated with the subject's local primary care physician. For subjects already enrolled, day 4-7 post infusion local laboratory data may be compared to pre-treatment local laboratory data for that subject obtained within 90 days prior to the subjects' entry into the study. For subjects not yet enrolled who reside outside commuting distance of the study center, baseline testing will be conducted at the local laboratory for comparison to the later day 4-7 post infusion additional testing to be done at the local laboratory.
With regard to the timeline for inclusion of the additional safety testing to which you have agreed, you have committed to amend that clinical protocol and provide the amended protocol to each clinical investigator within one month of reaching agreement with FDA on these post approval commitments [Agreement was reached on August 12, 2003]. The additional safety testing will begin upon receipt of IRB approval of the amended protocol. You have committed to submit to the IND and BLA a study update within six months of the last patient/last visit and a final approved study report within twelve months of the last patient/last visit.
Regarding your ongoing study #100422 - Randomized, controlled, open study investigating IGIV-C 10% given at different infusion rates on intravascular hemolysis in patients with idiopathic (immune) thrombocytopenic purpura (ITP), you have committed to determining plasma free hemoglobin at both pre- and post- infusion. You have committed to submit to the IND and BLA a study update within six months of the last patient/last visit for this study and a final approved study report within twelve months of the last patient/last visit.
Regarding your planned study #100538 - Multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of IGIV-Chromatography (IGIV-C), 10% compared to placebo patients with chronic inflammatory demyelinating polyneuropathy (CIDP), you committed to add the following testing at baseline and following exposure to the product: LDH, GGT, plasma-free hemoglobin, serum haptoglobin, serum potassium, DAT, and CPK. You further agreed to add the following testing for all subjects, which may be performed, at the discretion of the investigator, for subjects residing outside commuting distance from the study center, at a local laboratory affiliated with the subject's local primary care physician: BUN, serum creatinine, and urinalysis with microscopic examination of sediment to be performed at baseline and at least once in the first placebo controlled phase of the study within days 3-5 post infusion of the dose specified in the study protocol. For these subjects, baseline testing will be conducted at the local laboratory for comparison to the day 3-5 post infusion testing to be done at the local laboratory.The additional testing will be included in a revised study protocol to be submitted as an amendment to IND -------- within one month of reaching agreement with FDA on these post approval commitments [Agreement was reached on August 12, 2003]. Bayer commits to submit to the IND and BLA a study update within six months of the last patient/last visit and the final approved study report within twelve months of the last patient/last visit.
We request that you submit clinical protocols and final study reports to your IND, with a cross-reference letter to this biologics license application (BLA), STN BL 125046. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN BL 125046. 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.
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, packaging, 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. 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 an 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.
--- signature ---
Basil Golding, M.D.
Division of Hematology
Office of Blood Research and Review
Center for Biologics Evaluation and Research