Octapharma Pharmazeutika Produktionsges.m.b.H.
Attention:  Mr. Stanley Ammons
Octapharma USA, Inc.
121 River Street, 12th floor
Hoboken, NJ  07030

Dear Mr. Ammons:

We have approved your biologics license application for von Willebrand Factor/Coagulation Factor VIII Complex (Human) effective this date.  You are hereby authorized to introduce or deliver for introduction into interstate commerce von Willebrand Factor/Coagulation Factor VIII Complex (Human) under your existing Department of Health and Human Services U.S. License No. 1646.  Your product, von Willebrand Factor/Coagulation Factor VIII Complex (Human), is indicated for the treatment of spontaneous or trauma-induced bleeding episodes in patients with severe von Willebrand disease (VWD) as well as patients with mild or moderate VWD in whom the use of desmopressin is known or suspected to be ineffective or contraindicated.

Under this authorization, you are approved to manufacture von Willebrand Factor/Coagulation Factor VIII Complex (Human) at your facility in Vienna, Austria.  You may label your product with the proprietary name Wilate® and market it in 450 and 900 IU/vial fill sizes.

We did not refer your application to the 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 that would have benefited from an advisory committee discussion.

The dating period for von Willebrand Factor/Coagulation Factor VIII Complex (Human) shall be 36 months from the date of manufacture when stored at 2 to 8 °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 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, including but not limited to, the manufacturing, testing, packaging or labeling of von Willebrand Factor/Coagulation Factor VIII Complex (Human), or in the manufacturing facilities.

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 and FDA Form 2567 as appropriate.  Please provide content of labeling in Structured Product Labeling format.  Please provide three original paper copies for all 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. 

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.  Please define, capture and submit any lack of effect events, especially those related to the treatment of gastrointestinal (GI) bleeding.  These events should be reported under a separate section in the Periodic Safety Update Reports (PSURs).  You should submit postmarketing adverse experience reports and distribution reports to the Office of Biostatistics and Epidemiology/HFM-210, Center for Biologics Evaluation and Research, 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.  Per 21 CFR 600.2(f), please refer to http://www.fda.gov/AboutFDA/CentersOffices/CBER/ucm106001.htm for updated mailing address information.

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).

PEDIATRIC REQUIREMENTS

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.

If you have any questions, please contact the Regulatory Project Manager, Pauline Cottrell, at

(301) 827-3524.

Sincerely yours,

Jay S. Epstein, M.D.
Director
Office of Blood Research and Review
Center for Biologics
Evaluation and Research

全球最大的血浆制品制造商之一 Octapharma AG 今天宣布，该公司已经获得了美国食品和药物管理局 (FDA) 授予的 wilate(R) 罕见病药物独家授权。这项授权指定将 wilate(R) 用于重度血管性血友病 (VWD) 患者的自发性或创伤引起的出血治疗，以及某些已知或怀疑对去氨加压素 (desmopressin) 有禁忌或该药物对其无效的轻度和中度 VWD 患者。

    获得了 FDA 批准和 wilate(R) 罕见病药物的独家授权标志着 Octapharma USA 进入了美国凝血市场，产品预定于2010年初上市。业务发展迅猛的 Octapharma USA 是全球最大的血浆制品制造商之一 Octapharma AG 旗下的美国分部。

    Octapharma Group 副总裁 Kim Bjornstrup 表示：“FDA 授予的 wilate(R) 罕见病药物独家授权是 Octapharma 在开发这款药物中取得的重要成果。要获得罕见病药物的独家授权，需要向 FDA 提交一份关于 wilate(R) 可能较现有疗法具有哪些临床优势的说明 (1)。Wilate(R) 是专门针对血管性血友病的治疗而研发和生产的，包含了两个独特的病毒弱化步骤，拥有高纯度以及1:1生理比例的 FVIII（第八因子相关抗原）和VWF（血管性血友病因子），将为 VWD 患者提供新一代的治疗方案。”

    wilate(R) 介绍：
    Wilate(R) 是一种新开发的高纯度、双重病毒灭活的 VWF/ Coagulation Factor VIII Concentrate（第八凝血因子[人体]浓制剂），展示出了对各类 VWD 患者（包括参与了四项采用客观和主观标准衡量的前瞻性临床试验的儿童患者）的治疗效果。

    2009年12月4日，wilate(R) 获得了 FDA 注册，被批准用于治疗重度 VWD 患者的自发性和创伤引起的出血治疗，以及某些已知或怀疑对去氨加压素禁忌或该药物对其无效的轻度和中度 VWD 患者。(2) wilate(R) 是第一个双重病毒灭活的 VWF/FVIII（血管性血友病因子/ FVIII 因子）高纯度浓制剂，采用了有机溶剂／表面活性剂 (S/D) 工艺和一个特殊的终端干热 (terminal dry-heating，TDH) 系统。采取的纯化工艺在对蛋白质进行高度保护的条件下将 VWF/FVIII 复合物进行隔离，产生了1:1比例的 VWF:RCo（瑞斯托霉素辅因子）以及类似于正常血浆的 FVIII 活性。Wilate(R) 完全采自美国庞大的人类血浆库。FDA 批准建立了血浆捐赠中心，但制品中没有加入白蛋白作为稳定剂。

    四项前瞻性临床试验已经证明 wilate(R) 在各种 VWD 患者的急性出血和预防治疗中展示出了安全性、耐受性和止血功效。从客观标准来看，wilate(R) 在应用于1068例出血病例中确实取得了84%至93%的成功率，不同患者的治疗结果有所差异。(3)

    自二十世纪80年代中期以来，业界对血浆筹备工作的病毒安全性的要求越来越严格，要求证明病毒已经被清除/灭活(4) (5)。多项病毒灭活步骤的出台提高了凝血制品的安全性，但是 S/D 灭活是当前防止高传染性包膜病毒的黄金安全标准(6)。Octapharma 是全球首家将 S/D 灭活工艺应用于大规模血浆衍生物生产的制造商。wilate(R) 制造工艺提供了两项独立、有效的病毒灭活程序，即用于批量制品的 S/D 处理和对最终容器中冻干产品的 TDH 处理。此外，在 wilate(R) 制备过程中运用到的离子交换台阶色谱法也有助于提高病毒安全性。

    人血浆中含有浓度极低的 VWF 和 FVIII。该 wilate(R) 制备工艺旨在提高 VWF/FVIII 复合物的比例。同时存在的可能增加临床副作用的血浆蛋白以及可能损害凝血因子稳定性并且降低其自然结构和功能性的蛋白酶，在生产过程中被有效清除。

    血管性血友病介绍：
    血管性血友病 (VWD) 是最常见的出血性疾病，根据美国疾病预防控制中心 (Centers for Disease Control and Prevention) 的数据，该病在美国人口中的发病率约为1%至2%。(7) 该病是人体无法制造功能性血管性血友病因子导致的结果，人类蛋白可帮助血液凝结。

    Octapharma Group 简介
    总部位于瑞士 Lachen 的 Octapharma Group 是全球最大的血浆制品制造商之一，过去25年多来一直致力于病患护理和医疗创新。Octapharma 的核心业务是从人类血浆和人类细胞系中开发、生产和销售高品质的人类蛋白质疗法，其中包括免疫球蛋白静脉注射 (IGIV)。在美国，Octapharma 的 IGIV 产品 octagam(R)（5%免疫球蛋白[人体]静脉注射液）被用于治疗各种免疫系统疾病，而该公司的 Albumin（人体）则能够恢复和维持循环血量。Octapharma 拥有3000多名员工，并在包括美国在内的全球80个国家拥有生物制药经验。Octapharma USA 坐落于新泽西州霍伯肯。Octapharma 经营着两家经美国 FDA 许可的一流生产基地，最大程度地提高了生产灵活性，并将产品短缺降至最低。欲了解更多信息