Our STN: BL 102475/5002
Grifols Biologicals Inc.
Attention: Catherine L. Wong
5555 Valley Boulevard
Los Angeles, California 90032
Dear Ms. Wong:
We have approved your request to supplement your biologics license application for Antihemophilic Factor (Human). Antihemophilic Factor/von Willebrand Factor Complex (Human), Alphanate , is also indicated for surgical and/or invasive procedures in patients with von Willebrand Disease (VWD) in whom desmopressin (DDAVP ) is either ineffectiveor contraindicated. It is not indicated for patients with severe VWD (Type 3) undergoing major surgery.
We acknowledge your written commitments as described in your letter of November 21, 2006 as outlined below:
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.
Commitment 1: To conduct a Postmarketing study to further evaluate safety and efficacy of the product in type 3 vWD patients undergoing major surgeries.
Synopsis of the protocol: A total of 15 surgical procedures of which 10 are major surgeries will be evaluated in Type 3 patients. The Primary efficacy variable that will be evaluated consists of overall treatment outcome for each surgical procedure, as rated by the investigator using a 4-point verbal rating scale (VRS): "excellent," "good," "poor," or "none." The efficacy assessment period includes the entire peri-operative period. The Secondary efficacy variables: Day 0 and Day 1 treatment outcome for each treated surgical procedure, rated by the investigator using the same 4-point VRS used for the primary efficacy variable. Day 0 is the day of surgery, and Day 1 is the day following surgery. Overall treatment outcome and day 0 and day 1 treatment outcome for each treated surgical procedure rated by an independent referee committee using the same 4-point VRS used for the primary efficacy variable. The committee will be composed of 2 physicians with demonstrated clinical expertise treating subjects with similar medical characteristics to those of the study population. The committee will be blinded to the investigator ratings; and each referee will evaluate the outcomes independent of one another. Safety Variables: Clinical Safety variables will include vital signs, laboratory parameters and adverse events. The protocol will be submitted to the FDA within 2 months of approval and the Final study report by December 2009.
Please submit clinical protocols to your IND, with a cross-reference letter to this biologics license application (BLA), STN: BL 102475/5002. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to your BLA STN BL: 102475/0. 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 Protocol
- Postmarketing Study Final Report
- Postmarketing Study Correspondence
- Annual Report on Postmarketing Studies
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. 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 Internet site (http://www.fda.gov/cder/pmc/default.htm). For further information, please refer to the April 2001 Draft 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/cber/gdlns/post040401.htm).
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 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, MD 20852-1448. Please submit your final printed advertising and promotional labeling at the time of initial dissemination, accompanied by an FDA Form 2253.
We will include information contained in the above-referenced supplement in your biologics license application file.
Basil Golding, M.D.
Division of Hematology
Office of Blood Research and Review
Center for Biologics Evaluation and Research