From: Maruna, Thomas
Sent: Tuesday, June 17, 2014 12:06 PM
To: Daizadeh, Iraj (iraj_daizadeh@baxter.com)
Cc: Ananyeva, Natalya; Faulcon, Lisa
Subject: Information Requested: BLA 125512/0 Please Respond by June 23, 2014
Importance: High
Baxter Healthcare Corporation
Attention: Iraj Daizadeh, PhD
June 17, 2014
Sent by email
Dear Dr. Daizadeh:
We are reviewing your November 25, 2013 biologics license application (BLA) indicated for the treatment and prevention of bleeding episodes in patients with acquired inhibitory antibodies to human factor VIII (i.e., acquired hemophilia patients) for the following:
STN                 Name of Biological Products
BL 125512       Antihemophilic Factor (Recombinant), Porcine Sequence
We determined that the following information is necessary to continue our review:
1. On page 74/356 of the Intermediate Clinical Study Report, the reason for the early termination of Subject (b)(6) is “lack of efficacy for a secondary bleed.” However, the narrative (page 11/36 of Section 16.3.3, Subject Narratives) for this subject does not provide sufficient details about the reasons for withdrawal. Please provide additional information regarding the secondary/non-target bleeding event in this subject, including the specific location of the bleed, information about doses received including time of occurrence relative to the first dose, Factor VIII levels achieved, and the results of inhibitor testing 
 
2. For trial OBI-1-301, please clarify the following: 
a. Why subject (b)(6) was not withdrawn from the study since this subject did not meet the enrollment criteria for the diagnosis of acquired hemophilia. 
 
b. The number of non-target bleeds that were classified as subsequent bleeds, and the number of subsequent bleeds classified as severe. Page 86/356 of the Intermediate Clinical Study Report states that only one subject (b)(6)--- “suffered a serious subsequent bleeding event that was the target of OBI-1 therapy.” However, according to Appendix 16.2.6.3, subject (b)(6) also suffered a subsequent bleeding event of “left medial calf incision s/p fasciotomy” that was also considered severe. 
 
c. The number of subjects that were assessed for the initial bleeding event at 8 hours. Section 11.4.1.2.4 (page 85/356) of the Intermediate Clinical Study Report states that “Fourteen subjects were assessed 8 hours after initial infusion of OBI-1.” However, Section 11.4.1.2.2 (page 82/356) and Table 11-6 (83/356) report that 15 subjects were evaluated at 8 hours. 
 
d. The number of subjects with positive responses at 8 hours after the initial dose. Section 11.4.1.2.2 states that 14 out of 15 subjects showed a positive response; however, Section 11.4.1.2.4 states that 11 subjects had a positive response at 8 hours. 
 
e. The number of subjects with positive responses at 16 hours after the initial dose. Section 11.4.1.2.2 states that all 16 subjects showed a positive response; however, in Section 11.4.1.2.4 only 13 subjects were reported to have a positive response. 
 
f. The number of subjects with severe treatment-emergent adverse events. Table 12-2 of the study report (page 97/356) states that 3 subjects experienced severe AEs; however, Table 5 of the Summary of Clinical Safety (page 11/32) states that no severe AEs were reported. 
 
g. Whether subject (b)(6) was discontinued due to intestinal hemorrhage or inhibitor development. Section 10.1 of the Study Report (page 74/356) states intestinal hemorrhage as the reason for early termination; however, page 82/356 states that the subject was discontinued due to the development of the antibody.

 
3. For trial OBI-1-201, please: 
a. Clarify the number of TESAEs that were reported. Table 7 of the Summary of Clinical Safety (page 14/32) states that 3 SAEs were reported in 3 subjects; however, listing 16.2.7.2 of the Study Report (page 2395/3736) states that there were 4 SAEs that occurred in 3 subjects: right shoulder bleed and throat swelling in subject (b)(6), left knee hemarthrosis in subject (b)(6), and right knee hemarthrosis in subject (b)(6). 
 
b. Provide the specific reason, if known, for why subject (b)(6) withdrew consent.
The review of this submission is on-going and issues may be added, expanded upon, or modified as we continue to review this submission.
Please submit your responses as an amendment to this file by June 23, 2014 referencing the date of this request.
If it is not feasible for Baxter to provide all responses by June 23rd, please provide an alternative date to respond.
The action due date for these files is October 25, 2014.
If you have any questions, please contact me at (240) 402-8454 or thomas.maruna@fda.hhs.gov.
Very Respectfully,
Thomas J. Maruna, MSc, MLS(ASCP)CM
Lieutenant, U.S. Public Health Service
Senior Regulatory Management Officer
Food and Drug Administration
Center for Biologics Evaluation and Research
Office of Blood Research and Review
10903 New Hampshire Ave.
Bldg 71, Room 4216
Silver Spring, MD 20993
thomas.maruna@fda.hhs.gov
O: (240) 402-8454
BB: (240) 397-3419
www.usphs.gov
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