From: Maruna, Thomas
Sent: Friday, April 11, 2014 11:38 AM
To: Daizadeh, Iraj (iraj_daizadeh@baxter.com)
Cc: Ananyeva, Natalya; Poole, Catherine
Subject: Sample Lots & Reagents Requested: BLA 125512 Shipment Should be Received by April 25, 2014 
Importance: High
Baxter Healthcare Corporation
Attention: Iraj Daizadeh, PhD
April 11, 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 Porcine, B-Domain Truncated Recombinant
We determined that the following necessary to continue our review: 
1. Please provide 4 vials from each of the following lots: --------------(b)(4)-----------------------. Please include the Potency values which you determined by both assays at the latest time-point.
2. If additional, recently manufactured, lots are available, please provide 4 vials from 2 different lots. Please include the testing information for these lots if they are not included in the BLA. 
3. Please provide -----(b)(4)------------ from two different lots. 
Please ship samples and reagents to the address below by April 25, 2014:
Catherine Poole
Regulatory Coordinator
Division of Biological Standards and Quality Control (DBSQC)/OCBQ/CBER/FDA
NLRC Bldg. B, Room 2411
5516 Nicholson Lane
Kensington, MD 20985
Office: 301-594-6272 
The review of this submission is on-going and issues may be added, expanded upon, or modified as we continue to review this submission.
If it is not feasible for Baxter to provide the samples and reagents requested by April 25th, please provide an alternative date. 
The action due date for these files is July 26, 2014.
If you have any questions, please contact me at (301) 827-6120.
Very Respectfully,
Thomas J. Maruna, MSc, MLS(ASCP)CM
Lieutenant, U.S. Public Health Service
Senior Regulatory Management Officer
Food and Drug Administration
CBER/OBRR/DBA/RPMB
1401 Rockville Pike
RM 562N, HFM-380 
Rockville, MD 20852
thomas.maruna@fda.hhs.gov From: Maruna, Thomas
Sent: Friday, April 04, 2014 2:41 PM
To: Daizadeh, Iraj (iraj_daizadeh@baxter.com)
Cc: Ananyeva, Natalya; Faulcon, Lisa
Subject: Information Requested: BLA 125512 Please Respond By April 18, 2014 (Clinical) and May 5, 2014 (CMC) 
Importance: High
Baxter Healthcare Corporation
Attention: Iraj Daizadeh, PhD
April 4, 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 Porcine, B-Domain Truncated (Recombinant)
We determined that the following information is necessary to continue our review: 
CMC
1. Please submit updated and detailed information in Section 3.2.S.2.4 Control of Critical Steps and Intermediates, consistent with our discussions during the inspection of the (b)(4) facility in ---(b)(4)---. Specifically, please:
a. Add in-process controls and limits for all steps of the cell culture propagation stage from ---(b)(4)-- and revise the acceptance criteria for ---(b)(4)------ at these steps according to the results of new trend analyses, if available.
b. Revise the acceptance criterion for the in-process control test ------(b)(4)-------------------------- for cell culture process in -----(b)(4)--------------------------. Please define an acceptance criterion for the number of --------------------------------------------------------------(b)(4)------------------------------------------------------------------------------------------------------------. Please support the number by historical data and calculations to show that -----------------------------------------------------------------(b)(4)---------------------------------------------------------------------------------------------------------------------------------------------.
c. Specify the temperature and time ranges for the Solvent/Detergent treatment step.
d. Include criteria for selecting fractions for each chromatographic step.
e. Verify the pressure during nanofiltration, and specify the method used for filter integrity testing.
2. Assurance of the quality and consistent performance of the ---(b)(4)----- during the (b)(4)----- relies mainly on the results of the Technical Report TCR-10-046. As discussed during the inspection, the control over (b)(4) performance in routine production should be made more stringent. Please provide a revised SOP to include descriptions of measures that were added to strengthen the control of this unit operation (e.g., addition of in-process control parameters indicative of --------------------------------------------------(b)(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------. 
3. The Accuracy (results shown in Table 9 of Document VR-12-0157) and Repeatability (results shown in Tables 10 and 11 of Document VR-12-0157) of the One-Stage Clotting Assay are not validated per ICH guidelines (ICH Q2R1, part II). Only one concentration of analyte, instead of 3 concentrations in triplicate, was used in the study. Please validate the accuracy and repeatability of the assay over the established range according to ICH guidelines and provide the validation data.
4. Your approach to validate the Intermediate Precision of the One-Stage Clotting Assay as outlined in protocol VP-12-0157 (results shown in Table 12) is deficient in that you used different size of data sets for different samples, including multiple measurements on the same day only for certain samples and days. It did not allow the establishment of the Intermediate Precision of the assay in a statistically valid manner. The investigation for discrepancy VP-12-0157-01 did not provide sufficient reasons to exclude the data of assay 2, and perform assays 4, 5, 6 as part of validation. Please validate the Intermediate Precision for the assay using a statistically sound approach.
5. The Reproducibility of ---(b)(4)------ assay was not properly established, due to inappropriate acceptance criteria (results shown in Tables 31-34 of the Document VR-12-0178). The use of p-value is not appropriate and does not allow the establishment of the Reproducibility of the assay. Please re-analyze the data and use standard deviation, relative standard deviation (coefficient of variation) and confidence interval to establish the Reproducibility as defined in ICH Q2R1, part II section 5.4.
6. Please provide the following documents related to the validation of these analytical procedures:
a. VP-12-0158 Validation Protocol for ------------(b)(4)------------------------------------
b. VP-12-0157 Validation Protocol for OSCA with (b)(4)
c. VP-126 Validation Protocol for ----(b)(4)----
d. VP-127 Validation Protocol for ---(b)(4)-----
e. VP-124 Validation Protocol for ---(b)(4)-----
f. VR-146 Validation Report for Endotoxin, including attachments 1-4 
7. The viral clearance data in Report No.113998-RPT/1.0 are summarized from the qualification reports TCR-09-087, 113172-RPT, 111477-RPT, and 111479-RPT. To complete the evaluation on the viral safety of recombinant porcine FVIII, B-domain deleted product, please provide these referenced qualification reports. 
8. In Report No. 113998-RPT/1.0, you introduced either the ---(b)(4)----------- assay or the (b)(4) assay in the viral clearance studies for the referenced viruses. Please provide the validation reports of these two assays. 
9. Please submit the final report for your additional viral clearance validation studies performed after the BLA submission, as discussed during the inspection. 
10. The proposed specification limit for -----------------(b)(4)------------------. Considering that the dose may vary depending on the severity of the bleed and patient condition, please provide a risk assessment for the maximal (b)(4) level achieved with the maximal (worst-case) doses of OBI-1 in comparison with other recombinant FVIII products. 
Clinical 
11. Regarding Study Number OBI-301/301a, Interim Phase 2/3 Study Report: for patients -------------(b)(6)---------------------, please submit in a table format the titers of anti-OBI-1 antibodies, neutralizing anti-OBI-1 antibodies, and anti-hFVIII antibodies (BU/mL) at pre-dose (screening), during time of PK blood sampling, and at the end of the study. 
12. Given the demographic differences between individuals with Acquired Hemophilia A and those with congenital hemophilia with inhibitors, please provide a rationale for the decision to comingle safety data from these two distinct populations. 
13. Please provide the narrative for the study subject enrolled in the Phase 3 study OBI-1-302. Please include underlying diagnoses, a list of adverse events including an assessment of relatedness to the study drug and details regarding the study subject’s outcome. 
14. Please comment on the availability of the anti-porcine FVIII antibody test in routine clinical practice. If the test is not commercially available or will not be made available to practitioners by the sponsor, please comment on the ability of the Treatment Registry to achieve the pre-specified safety-related endpoint of determining the incidence of these antibodies in the treated population.
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 to the Clinical comments as an amendment to this file by April 18, 2014 and your responses to the CMC comments by May 5, 2014 referencing the date of this request.
If it is not feasible for Baxter to provide all responses by the requested dates, please provide alternative dates to respond. 
The action due date for these files is July 26, 2014.
If you have any questions, please contact me at (301) 827-6120.
Very Respectfully,
Thomas J. Maruna, MSc, MLS(ASCP)CM
Lieutenant, U.S. Public Health Service
Senior Regulatory Management Officer
Food and Drug Administration
CBER/OBRR/DBA/RPMB
1401 Rockville Pike
RM 562N, HFM-380 
Rockville, MD 20852
thomas.maruna@fda.hhs.gov
O: (301) 827-6120
BB: (240) 397-3419
www.usphs.gov 
"THIS MESSAGE IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL, AND PROTECTED FROM DISCLOSURE UNDER LAW. If you are not the addressee, or a person authorized to deliver the document to the addressee, you are hereby notified that any review, disclosure, dissemination, copying, or other action based on the content of this communication is not authorized. If you have received this document in error, please immediately notify the sender immediately by e-mail or phone." 

O: (301) 827-6120
BB: (240) 397-3419
www.usphs.gov 
"THIS MESSAGE IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND MAY CONTAIN INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL, AND PROTECTED FROM DISCLOSURE UNDER LAW. If you are not the addressee, or a person authorized to deliver the document to the addressee, you are hereby notified that any review, disclosure, dissemination, copying, or other action based on the content of this communication is not authorized. If you have received this document in error, please immediately notify the sender immediately by e-mail or phone." 

