Our STN: BL 125421/0
CSL Behring GmbH
Attention: Paula Hines, PhD
1020 First Avenue
P.O. Box 61501
King of Prussia, PA 19406-0901
Dear Dr. Hines:
We have approved your biologics license application for Prothrombin Complex Concentrate (Human) effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Prothrombin Complex Concentrate (Human) under your existing Department of Health and Human Services U.S. License No. 1765. Prothrombin Complex Concentrate (Human) is indicated for urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with acute major bleeding.
Under this authorization, you are approved to manufacture Prothrombin Complex Concentrate (Human) at your facility in Marburg, Germany. You may label your product with the proprietary name Kcentra™ and market it in 500 international units per vial size.
We did not refer your application to the Blood Products Advisory Committee because our review of information submitted in your biologics license application did not raise controversial issues which would have benefited from an advisory committee discussion.
The dating period for Prothrombin Complex Concentrate (Human) shall be 36 months from the date of manufacture when stored at 2 °C - 25 °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 samples of the product in final containers together with protocols showing results of all applicable tests. You may not distribute any lots of the 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, including but not limited to, the manufacturing, testing, packaging or labeling of Kcentra 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.
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, 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 authorized 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).
You must submit all serious and non-serious adverse experience reports for thromboembolic events as 15-day expedited reports under 21 CFR 600.80 (c)(1)(i), in the first five years after licensure.
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.
Because the biological product for this indication has an orphan drug designation, you are exempt from this requirement.
POSTMARKETING REQUIREMENTS UNDER 505(o)
Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to require holders of approved drug and biological product applications to conduct postmarketing studies and clinical trials for certain purposes, if FDA makes certain findings required by the statute [section 505(o)(3)(A), 21 U.S.C. 355(o)(3)(A)].
We have determined that an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal of a serious risk of thromboembolic events after Kcentra™ administration.
Furthermore, the new pharmacovigilance system that FDA is required to establish under section 505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
Clinical study to further assess the risk is needed as the completed studies are considered too small to reliably assess the signal of serious risk of thromboembolic events after Kcentra™ administration to patients with acute major bleeding. Therefore, based on appropriate scientific data, we have determined that you are required to conduct the following study:
- A retrospective observational cohort study to estimate the risk of thromboembolic events following Vitamin K Antagonist (VKA) reversal among patients treated with Kcentra™ or Plasma for urgent reversal of VKA therapy in the setting of acute major bleeding.
We acknowledge the timetable you submitted as part of the CSL Behring proposed PMR Study Concept dated April 19, 2013, which states that you will conduct this study according to the following schedule:
- Final Protocol Submission: 28 February 2014
- Study Completion Date: 1 June 2020
- Final Report Submission: 31 May 2021
Please submit the protocol(s) to your IND 13398, with a cross-reference letter to this BLA. Submit all final reports to this BLA and prominently identify them as appropriate:
- Required Postmarketing Protocol under 505(o)
- Required Postmarketing Final Report under 505(o)
- Required Postmarketing Correspondence under 505(o)
Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any study or clinical trial required under this section. This section also requires you to periodically report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Section 506B of the FDCA, as well as 21 CFR 601.70, requires you to report annually on the status of any postmarketing commitments or required studies or clinical trials.
We will consider the submission of your annual report under section 506B and 21 CFR 601.70 to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR 601.70. We remind you that to comply with 505(o) your annual report must also include a report on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o) on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action.
AGREED UPON POSTMARKETING COMMITMENTS
We acknowledge your written commitments as described in your letter of 11 April 2013 as outlined below:
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.
- A prospective, double-blind, randomized, multicenter study to assess the efficacy of standard and low doses of Kcentra™ in reversing effects of VKA in subjects with acute major bleeding.
- Final protocol submission date: 31 January 2014
- Study/trial completion date: 31 January 2019
- Final Report Submission date: 31 July 2019
Please submit clinical protocols to your IND 13398, with a cross-reference letter to this biologics license application (BLA), STN 125421. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA, STN 125421. 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.
Jay S. Epstein, MD
Office of Blood Research and Review
Center for Biologics
Evaluation and Research