Our STN: BL 125446/0
Baxter Healthcare Corporation
Attention: Mr. Kevin Smyth
One Baxter Way
Westlake Village, CA 91362
Dear Mr. Smyth:
We have approved your biologics license application (BLA) for Coagulation Factor IX (Recombinant) effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Coagulation Factor IX (Recombinant) under your existing Department of Health and Human Services U.S. License No. 140. Coagulation Factor IX (Recombinant) is indicated for adults with Hemophilia B for (1) control and prevention of bleeding episodes, (2) perioperative management, and (3) routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
Under this license, you are approved to manufacture Coagulation Factor IX (Recombinant) drug substance at ----b(4)--------------------------------------------------------------. The final product will be manufactured at Baxter Healthcare Corporation,----b(4)--------------------------------------------------. You may label your product with the proprietary name RIXUBIS™ and will market it in nominal dosage strengths of 250, 500, 1000, 2000 and 3000 IU per vial.
We did not refer your application to the Food and Drug Administration Blood Products Advisory Committee because our review of information submitted in your BLA, including the clinical study design and trial results, did not raise concerns or controversial issues which would have benefited from an advisory committee discussion.
The dating period for Coagulation Factor IX (Recombinant) shall be 18 months from the date of manufacture when stored at refrigerated temperature, 2 °C to 8 °C (35 °F to 46 °F). The product may be stored at room temperature not to exceed 30 °C (86 °F) for up to 6 months within the 18 month time period. The date of manufacture shall be defined as the date of final sterile filtration of the formulated drug product in accordance with 21 CFR 610.50. Following the final sterile filtration, no reprocessing/reworking is allowed without prior approval from the Agency.
You currently are not required to submit samples of future lots of Coagulation Factor IX (Recombinant) 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, including but not limited to, the manufacturing, testing, packaging or labeling of Coagulation Factor IX (Recombinant), or in the manufacturing facilities.
You must submit reports of biological product deviations under 21 CFR 600.14. You should identify and investigate all manufacturing deviations promptly, 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.
Under 21 CFR 201.57(c)(18), 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.
Please provide your final content of labeling in Structured Product Labeling (SPL) format and include the carton and container labels. In addition, please submit three original paper copies for carton and container final printed labeling. All final labeling should be submitted as Product Correspondence to this BLA at the time of use (prior to marketing) and include implementation information on FDA Form 356h.
In addition, please submit the final content of labeling (21 CFR 601.14) in SPL format via the FDA automated drug registration and listing system, (eLIST), as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Information on submitting SPL files using eLIST may be found in the guidance for industry titled, “SPL Standard for Content of Labeling Technical Qs and As at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072392.pdf.
You may 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. You must submit copies of your final advertisement and promotional labeling at the time of initial dissemination or publication, accompanied by Form FDA 2253 [21 CFR 601.12(f)(4)].
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 substantial evidence or substantial clinical experience to support such claims [21 CFR 202.1(e)(6)].
ADVERSE EVENT REPORTING
You must submit adverse experience reports in accordance with the adverse experience reporting requirements for licensed biological products (21 CFR 600.80) and you must submit distribution reports as described in 21 CFR 600.81. You should submit postmarketing adverse experience reports and distribution reports to the Center for Biologics Evaluation and Research, Office of Biostatistics and Epidemiology, HFM-210, Food and Drug Administration, 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448. Prominently identify all adverse experience reports as described in 21 CFR 600.80.
In addition, you must submit adverse event reports for any infectious disease transmission within 15 days after learning of the event. Infectious disease transmission refers to an adverse event that involves suspected or confirmed transmission of an infectious agent, whether the recipient develops the infectious disease or only has serologic or other evidence. If an infectious disease transmission event is serious and unexpected, you must submit a 15-day “alert report,” as required under 21 CFR 600.80 (c)(1)(i). Infectious disease transmission events that do not meet criteria for expedited submission require periodic reports and must be submitted as individual case reports within 15 days, as required under 21 CFR 600.80(c)(2)(i). You should submit reports for all other non-expedited adverse events under the periodic reporting requirements specified in 21 CFR 600.80(c)(2).
Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication in pediatric patients unless this requirement is waived, deferred, or inapplicable.
We are deferring submission of your pediatric study until September 30, 2013 because this product is ready for approval for use in adults and the pediatric study has not been completed.
Your deferred pediatric study is a required postmarketing study under 505B(a) of the Federal Food, Drug, and Cosmetic Act. The status of this postmarketing study must be reported according to 21 CFR 601.70 and section 505B(a)(3)(B) of the Federal Food, Drug, and Cosmetic Act. This required study is listed below:
Deferred pediatric study under PREA for the control and prevention of bleeding episodes, perioperative management and routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with Hemophilia B of all pediatric age groups
Study Completion Date: September 30, 2013
Final Report Submission: January 31, 2014
Submit final study reports to this BLA. For administrative purposes, all submissions related to this required pediatric postmarketing study must be clearly designated “Required Pediatric Assessment(s).”
AGREED UPON POSTMARKETING COMMITMENTS
We acknowledge your written commitments as described in your letters of June 5, 2013 and June 17, 2013 and as outlined below:
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.
1. Evaluation of long-term efficacy and safety of RIXUBIS™ in 100 patients of all age groups with hemophilia B, of which at least 25 will be subjects naïve to RIXUBIS™.
Final protocol submission date: July 31, 2013
Study/trial completion date: December 31, 2015
Final Report Submission date: June 30, 2016
Please submit clinical protocols to your IND, with a cross-reference letter to your BLA, STN BL 125446/0. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN BL 125446/0. If the information in the final study report supports a change in the labeling, the final study report should be submitted as a supplement. We may also request a supplement if we think labeling changes are needed. Please use the following designators to label prominently all submissions, including supplements, relating to these postmarketing study commitments as appropriate:
- Postmarketing Study Commitment Protocol
- Postmarketing Study Correspondence
- Postmarketing Study Commitment – Final Study Report
- Supplement Contains Postmarketing Study Commitments – Final Study Report
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. Label your annual report an “Annual Status Report of Postmarketing Study Commitments.” 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/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/default.htm). Please refer to the February 2006 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/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM080569.pdf) for further information.
Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70.
2. Baxter commits to provide validation data to support the Precision (Repeatability and Intermediate Precision), Linearity and Range for the test method, Method No. ---b(4)-----------------, used to determine the ----b(4)---------------------------------- in RIXUBIS™. Baxter will apply an approach similar to that used for ---b(4)-------- determination in validation report ---b(4)-------------------------, and will submit the final report to the FDA by November 30, 2013.
3. Baxter commits to place at least one RIXUBIS™ lot on the stability program annually, rotating among different dose strengths.
We request that you submit information concerning nonclinical and chemistry, manufacturing, and control postmarketing commitments and final reports to your BLA, STN BL 125446/0.
Please use the following designators to label prominently all submissions, including supplements, relating to these postmarketing study commitments as appropriate:
- Postmarketing Study Correspondence
- Postmarketing Study Commitment – Final Study Report
- Supplement Contains Postmarketing Study Commitment – Final Study Report
For each postmarketing commitment not subject to the reporting requirements of 21 CFR 601.70, you may report the status to FDA as a “PMC Submission – Status Update.” The status report for each commitment should include:
- The original schedule for the commitment, and
- The status of the commitment (i.e., pending, ongoing, delayed, terminated, or submitted).
When you have fulfilled your commitment, submit your final report as PMC Submission – Final Study Report or Supplement Contains Postmarketing Study Commitment – Final Study Report.
Jay S. Epstein, MD
Office of Blood Research and Review
Center for Biologics
Evaluation and Research