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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
1401 Rockville Pike
Rockville MD 20852-1448
July 25, 2003
Our STN: BL 125063/0
Ms. Arlene Vidor
Baxter Healthcare Corporation
One Baxter Way
Westlake Village, California 91362
Dear Ms. Vidor:
We have approved your Biologics License Application (BLA) for Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method under Department of Health and Human Services U.S. License No. 0140. Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method is indicated in hemophilia A (classical hemophilia) for the prevention and control of bleeding episodes. Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method is also indicated in the perioperative management of patients with hemophilia A.
Under this license, you are approved to manufacture Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method drug substance at the Baxter Healthcare Corporation facility in Neuchâtel, Switzerland. The final formulated product will be manufactured and filled at the Baxter Healthcare Corporation facility in ---------------. Final packaging/labeling will take place at the Baxter Healthcare Corporation facility in -----------------------. You may label your product with the proprietary name ADVATE, and will market it in 250 IU/vial, 500 IU/vial, 1000 IU/vial and 1500 IU/vial dosage forms.
The dating period for Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method shall be 18 months from the date of manufacture when stored at 2 - 8 oC. The date of manufacture shall be defined as the date of final sterile filtration of the formulated drug product. The dating period for your drug substance shall be ----------- when stored at -------. The expiration date for the packaged product, Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method plus Sterile Water for Injection shall be dependent on the shortest expiration date of either component.
You currently are not required to submit samples of future lots of Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method to the Center for Biologics Evaluation and Research (CBER) for release by the Director, CBER, under 21 CFR 610.2. We will continue to monitor compliance with 21 CFR 610.1 requiring completion of tests for conformity with standards applicable to each product prior to release of each lot.
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 Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method, or in the manufacturing facilities.
FDA's Pediatric Rule at 21 CFR 314.55 and 21 CFR 601.27 was challenged in court. On October 17, 2002, the court ruled that FDA did not have the authority to issue the Pediatric Rule and barred FDA from enforcing it. Although the government decided not to pursue an appeal in the courts, it will work with Congress in an effort to enact legislation requiring pharmaceutical manufacturers to conduct appropriate pediatric clinical trials. In addition, third party intervenors have decided to appeal the court's decision striking down the rule. Therefore, we encourage you to submit a pediatric plan that describes development of your product in the pediatric population where it may be used. Please be aware that whether or not this pediatric plan and subsequent submission of pediatric data will be required depends upon passage and specific requirements of legislation or the success of the third party appeal. In any event, we hope you will decide to submit a pediatric plan and conduct the appropriate pediatric studies to provide important information on the safe and effective use of this drug in the relevant pediatric populations.
We acknowledge your written commitments as described in your letters of 9 October 2002, 9 April 2003, and 15 July 2003 as outlined below:
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.
Information regarding these may be publically disclosed on the agency's web site (http://cdsml1.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.
- To submit a protocol within six (6) months of the date of product approval for the conduct of an adequately-powered randomized study of the product in routine prophylaxis which compares 2 different dosing regimens/frequencies. To initiate the study within six (6) months of the date that FDA conveys to you its agreement with the proposed study design, and, once the study has been completed, to file the final study report of the study to both the Investigational New Drug Application (IND) and BLA under 21 CFR 601.70 in a timely manner.
- To submit a protocol within 12 months of the date of product approval for the conduct of a randomized study of the product in surgery, comparing the safety and efficacy of the product administered by intermittent bolus infusion versus continuous infusion. To initiate the study within six (6) months of the date that FDA conveys to you its agreement with the proposed study design, and, once the study has been completed, to file the final study report of the study to both the IND and BLA under 21 CFR 601.70 in a timely manner. Depending on CBER's judgment of the adequacy of the data regarding the use of Antihemophilic Factor (Recombinant), Plasma/Albumin Free Methodadministered by continuous versus intermittent bolus infusion, which is to be submitted to CBER by the end of 2003 in the form of an interim report for ongoing clinical study # 069902, CBER reserves the right to consider that the submission of such data from study # 069902 may obviate the need and phase IV requirement to conduct the randomized study described in the first part of this paragraph.
- To complete and report to the IND and BLA in a timely fashion the results of the following ongoing and planned clinical studies:
- Protocol # 060102 - continuation study in PTPs (target end of Q4, 2004 to beginning of 2005)
- Protocol # 069902 - the ongoing surgery study (target end of Q4, 2004)
- Protocol # 060101 - the ongoing pediatric PTP study (target beginning to mid 2005)
- Protocol # 060103 - This pediatric study involving previously untreated patients is targeted to start in early 2004. Baxter will submit a report of this study to both the IND and BLA in a timely fashion after the study is completed.
Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70.
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- To submit to CBER a complete summary of all Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method lots produced during each quarter-year. This summary will include the lot numbers for all lots released, as well as a list of lots that were not released and the reason(s) for non-release.
To submit each quarterly report electronically or as a paper submission (in triplicate) addressed as follows:
Center for Biologics Evaluation and Research
Attention: Office of Blood Research and Review
HFM-99, Room 200N
1401 Rockville Pike
Rockville, MD 20852-1448
To submit to CBER samples and protocols for every 5th lot of each dosage strength manufactured to the following address:
Center for Biologics Evaluation and Research
Attention: Sample Custodian, HFM-672
Bldg. NLRC - B, Room 113
5516 Nicholson Lane
Kensington, MD 20895
- With reference to the distribution of Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method into the US Market: As stated in your memorandum dated September 18, 2002, "It [is] the intention of Baxter to manufacture lots of rAHF-PFM Final Drug Product (FDP) for commercial distribution beginning -
------------ (including lot --------) pending approval of the Biologics License Application (BLA)." ---------------------------------------------------------------------------------------------------
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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 125063. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN 125063. Please use the following designators to label prominently all submissions, including supplements, relating to these postmarketing 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 your annual report to the BLA;
- expected summary completion and final report submission dates, any changes in plans since the last annual report, 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.
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. 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 three 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 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,
--- signature ---
Basil Golding, M.D.
Acting Director
Division of Hematology
Office of Blood Research and Review
Center for Biologics Evaluation and Research
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