DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
1401 Rockville Pike
Rockville MD 20852-1448
July 8, 2003
Our STN: BL 125078/0
Leonard M. Baum, R.Ph.
Aventis Behring L.L.C.
1020 First Avenue
P.O. Box 61501
King of Prussia, Pennsylvania 19406-0901
Dear Mr. Baum:
We have approved your biologics license application for Alpha1-Proteinase Inhibitor (Human) effective this date. Aventis Behring L.L.C. is hereby authorized to introduce or deliver for introduction into interstate commerce Alpha1-Proteinase Inhibitor (Human) [Zemaira], under Department of Health and Human Services License No. 1281.
Alpha1-Proteinase Inhibitor (Human) [Zemaira] is indicated for use as chronic augmentation and maintenance therapy in individuals with alpha1-proteinase inhibitor deficiency and evidence of emphysema. Under this authorization, you are approved to manufacture Alpha1-Proteinase Inhibitor (Human) at your facility in ------------------. You must label your product with the proprietary name Zemaira that we have approved and will market it in a 1.0 gram fill size.
The dating period for Zemaira shall be 24 months from the date of manufacture when stored at 2 to 25 °C. The date of manufacture shall be defined as the date of first sterile filtration of the formulated drug product.
Changes to the product, production processes, location of production processes, equipment, facilities, or responsible personnel are required to be reported to FDA as specified in Title 21 Code of Federal Regulations (CFR) Section 601.12.
Please submit final container samples of the product together with protocols showing results of all applicable tests. No lots of product shall be distributed until notification of release is received from the Director, CBER.
All adverse experience reports should be submitted according to 21 CFR 600.80 to the Center for Biologics Evaluation and Research (CBER), HFM-210, Food and Drug Administration, 1401 Rockville Pike, Rockville, Maryland 20852-1448. In addition, safety related information obtained in the course of ongoing clinical studies should be reported to BB-IND ----- in accordance with 21 CFR 312.32. It is also requested that distribution reports be submitted according to 21 CFR 600.81.
As agreed upon in your letter, dated July 3, 2003, the following post-marketing commitments must be fulfilled:
- Aventis Behring commits to conduct a clinical trial, which shall be comprised of two stages as described below. The conduct of the second stage will be contingent on the outcome and results of the first stage.
Pilot trial of clinically meaningful endpoint(s). Examples of acceptable endpoints include pulmonary exacerbations, serial pulmonary functions, and serial quantitative computerized axial tomographic (CT) lung scans.
- A randomized, controlled, parallel, masked design.
- A minimum enrollment of 60 subjects (30 subjects per treatment group) in the pilot study.
- The control group may be a different dose of the test product (i.e., higher, such as 120 mg/kg/week or 240 mg/kg/2 weeks) in comparison to the labeled dosing regimen of the test product or placebo.
- The trial will be a minimum of one-year's duration to avoid seasonal bias in pulmonary exacerbations.
- The trial design will include measurement of baseline and steady state antigenic and functional alpha1-proteinase inhibitor blood levels.
- The trial may include a post-trial follow-up assessment.
- A final protocol will be filed to the IND and BLA 6-12 months after product approval.
- The trial will be initiated within 6-12 months after protocol acceptance by the FDA.
- Alternate study designs and features may be discussed with the Agency following feedback from experts.
- The final study report will be submitted in a timely fashion to the IND and BLA.
Adequately-powered study of clinically meaningful endpoints(s).
- Based on the results of the pilot study and the available scientific data at the time that this study is being designed, Aventis Behring will work with entities maintaining registries of alpha1-proteinase inhibitor deficient patients and with the National Institutes of Health (NIH) to design and conduct an adequately-powered study of a clinically meaningful endpoint(s). The study design could involve a single product or could potentially involve a cooperative simultaneous study of multiple products in parallel arms, using a factorial design. In the event that the study involves more than one product, Aventis Behring commits to provide sufficient product to administer to an equal proportion of subjects as are being provided any of the other products. The design/conduct of the study may be contingent upon:
- The amount of product available.
- The number of available subjects.
- The number of subject-years necessary to attain an adequately powered study based on the results of the previous study and current scientific data.
- The participation of other manufacturer(s) of this product class.
- The results of the pilot study will be taken into account in the design of the follow-up study. A strong positive outcome in the pilot study may obviate the need for a follow-up study.
- The trial may include one or more post-trial follow-up assessment(s).
- The final protocol for this study will be filed to the IND and BLA within one year of the filing of the final report of the pilot study.
- The final study report will be submitted in a timely fashion to the IND and BLA.
- Validation studies will be performed to demonstrate the capacity of the Zemaira manufacturing process to inactivate and remove West Nile Virus. These studies will be complete within six months after product approval.
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- The first three lots of Zemaira manufactured post-licensure will be placed into the long-term stability program at --- °C. Every year thereafter during which Zemaira is manufactured, one lot will be placed on long term stability. Data will be provided in the product Annual Report.
You are required to submit reports of biological product deviations in accordance with 21 CFR 600.14. All manufacturing deviations, including those associated with processing, testing, packaging, labeling, storage, holding, and distribution, should be promptly identified and investigated. If the deviation involves a distributed product and may affect the safety, purity, or potency of the product, which meets the other criteria in the regulation, a report must be submitted 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 choose 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. 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. No comparative promotional claim or claim of superiority over other products should be made unless data to support such claims are submitted to and approved by the Center for Biologics Evaluation and Research.
Aventis Behring L.L.C. will have a third party consultant(s) review the batch record deviations for Alpha1-Proteniase Inhibitor (Human). The third party consultant(s) will generate a written report of deviation review. This report will include issues that Quality Assurance (QA) failed to note or to address during QA review of batch record deviations for release of product. These reports will be available for review upon inspection. The FDA reminds Aventis Behring L.L.C. that manufacture of Alpha1-Proteniase Inhibitor (Human) [Zemaira] is subject to the terms of the Consent Decree of Permanent Injunction entered against Aventis Behring L.L.C. on January 28, 1997 and FDA's letters issued there under.
It is recommended that a copy of this letter be available for review at the time of FDA inspections.
--- signature ---
Basil Golding, M.D.
Division of Hematology
Office of Blood Research and Review
Center for Biologics Evaluation and Research