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Statistical Final Memo, June 2, 2012 - SOLX® System

 

DEPARTMENT OF HEALTH AND HUMAN SERVICES                                                                        
PUBLIC HEALTH SERVICE                                                                                                                                                                                                                                                       
FOOD AND DRUG ADMINISTRATION                                                                                                        
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH                                         
Division of Biostatistics (HFM-215)
 
Statistical Review and Evaluation
                                                                                                        
Type/Application ID/Amendment #: NDA/BN 110059
 
Subject: HEMERUS LEUKOSEP® HWB-600-XL Leukocyte Reduction Filtration System for Whole Blood with CPD Anticoagulant and SOLX® Additive
 
Applicant: Hemerus Medical, LLC
 
Indications for Use:  
• Pre-storage leukocyte reduction of CPD whole blood followed by preparation of SOLX® Red Blood Cells, Leukocytes Reduced prepared at ambient temperature and placed at 1 to 6° C within (b)(4) hours of collection. SOLX® Red Blood Cells, Leukocytes Reduced may be stored at 1 to 6° C for up to 42 days after collection.
• Preparation of Fresh Frozen Plasma (FFP), Leukocytes Reduced prepared and frozen at -18° C or below within 8 hours of collection. Fresh Frozen Plasma (FFP), Leukocytes Reduced may be stored at -18° C or below for up to one year after collection.
•---------------------------------------------------------------------------------------------------------------------------------(b)(4)-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.
 
Primary Statistical Reviewer:  Chinying Wang, Ph. D. (HFM-219)
Supervisory Concurrence:
               1st Level Review
            Supervisor Name: Tie-Hua Ng, Ph. D.
            Supervisor Title: Team Leader, OBE/DB/TEB
Concur ______________ Not Concur ______________  
Supervisory Signature
 
2nd Level Review
            Supervisor Name: Boguang Zhen, Ph.D.
            Supervisor Title: Branch Chief, OBE/DB/TEB
Concur ______________ Not Concur ______________  
Supervisory Signature
Review Project Manager: Iliana Valencia (OBRR/DBA/RPMB)
Cc:         HFM-380/Xuan Chi, M. D., Ph. D. (OBRR/DH/LCH)
HFM- 215 /Chronological File (OBE/DB)
HFM-215/Estelle Russek-Cohen, Ph. D. (OBE/DB)
HFM-215/Boguang Zhen, Ph. D. (OBE/DB/TEB)
HFM-215/John Scott, Ph. D. (OBE/DB)
 
EXECUTIVE SUMMARY
The study was conducted according to protocol PC387580, “In Vitro and In Vivo Evaluation of Hemerus LEUKOSEP® HWB-600-XL Leukocyte Reduction Filtration System for Whole Blood with CPD Anticoagulant and SOLX® Additive”. Based on the reported results, the clinical study showed that the primary endpoints of RBC mass recovery, leukorecution efficiency, hemolysis at end of storage, and 24-hour radiolabeled recovery were met for all SOLX®RBC processing groups. In addition to the assessment of the primary endpoints, this statistical reviewer performed a comparative analysis to investigate the effect of hold time at room temperature on labile coagulation factors such as Protein S, Factors V, Factor VIII and Factor XI. ------------------------------------------------------------------------  ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.
 
Background
The study was conducted according to protocol PC387580, “In Vitro and In Vivo Evaluation of Hemerus LEUKOSEP® HWB-600-XL Leukocyte Reduction Filtration System for Whole Blood with CPD Anticoagulant and SOLX® Additive”. In the United States liquid red blood cell (RBC) storage systems are currently licensed by the FDA for up to six weeks of refrigerated (1-6°C) storage. Improved systems with longer storage periods are desired to reduce the losses that occur from outdating, to enhance the quality and survival of routinely stored RBC’s, to meet the needs of remote locations and to extend the usefulness of autologous donation.
 
Clinical Study Design
The study required a total of 240 subjects completing study requirements; 180 test subjects and 60 control subjects. Fifty-six of the 180 total test subjects were evaluated for autologous, radiolabeled, in vivo red cell recovery and red cell survival. The remaining test subjects, and all control subjects, donated a unit of whole blood for in vitro evaluation only.
 
Study Processing Groups
Three processing groups of 60 whole blood units each were studied using the SOLX® System. Sixty units of control whole blood units were also tested under the processing conditions of Group 2. Processing groups are summarized below:
• Group 1: Up to two hour room temperature hold prior to whole blood filtration and processing at room temperature (60 test units). RBCs refrigerated and plasma frozen within 8 hours.
• Group 2: Greater than six hour room temperature hold prior to whole blood filtration and processing at room temperature within eight hours (60 test and 60 control units). RBCs refrigerated and plasma frozen within 8 hours.
• ----------------------------------------------------------------------------------------------------------------- ------------------------------------------(b)(4)-----------------------------------------------------------------------------------.
 
Each of three processing groups will consist of 60 test units completing the study. One control group will consist of 60 units completing the study processed according to Group 2 conditions. The allocation of sample size for each group is shown below.
 
Sample Sizes by Processing Group
G 1 Group 2 Group 3Units

 
Group 1
Group 2
(b)(4)
 
Test  Units
 
Test  Units
Control Units
 
---(b)(4)----
In Vitro Only
In Vivo & In Vitro
In Vitro Only
In Vivo & In Vitro
In Vitro Only
-(b)(4)- -(b)(4)-
-(b)(4)-  -(b)(4)-
Number of Units
46
14
46
14
60
(b)(4)
(b)(4)
Total
60
60
60
(b)(4)

 
Primary Endpoints
Primary study endpoints of RBC mass recovery, leukoreduction efficiency, hemolysis at end of storage and 24-hour radiolabeled recovery were evaluated using predetermined confidence and reliability limits for binomial attribute testing. The objective performance criteria for evaluation of RBC endpoint analysis included:
• A one-sided 95% lower confidence limit for the true proportion of units with a filtration recovery of red blood cell mass of at least 85% is greater than 95%.
• A one-sided 95% lower confidence limit for the true proportion of units with residual leukocyte content of less than 5 x106 per unit is greater than 95%.
• A one-sided 95% lower confidence limit for the true proportion of units with hemolysis at end of storage of less than 1% is greater than 95%.
• Mean 24-hour, post transfusion, in vivo red cell recovery at end of storage of at least 75% with standard deviation of at most 9%, and the lower limit of a one-sided 95% confidence interval for the population proportion of successes is 70% or greater.
 
i) Filtration Recovery Results
Filtration recovery was evaluated for each whole blood processing group filtered with the SOLX® System or the control device. The filtration recovery endpoint, for purposes of this clinical study, was defined as RBC Mass Recovery
 
Table 5-15 RBC Mass Recovery Results (%)

 
Group 1
Test
Group 2
Test
Group 2
Control
 
---(b)(4)-----
Mean
94
94
93
(b)(4))94
SD
2
1
1
        (b)(4)
Min
89
91
91
(b)(4)2
Max
99
97
96
(b)(4)
n
60
60
60
(b)(4)
# Units >85% / Total
Units
 
   60/60*
 
 60/60
 
 60/60
 
 (b)(4)

 
 
 
 
 
 
 
 
 
 
 
*Two (2) Group 1 Test units had inadvertent missed samples at the post-filtration whole blood time point.
* For these two units RBC Mass Recovery was calculated from the additive RBC prepared from the WB unit
 
Each Test Group processed with the SOLX® System met endpoint criteria for RBC Mass Recovery. The Control Group also met the criteria. The results support that a one-sided 95% lower confidence limit for the true proportion of units with a filtration recovery of red blood cell mass of at least 85% was greater than 95% for each SOLX® System Test Group. The primary study endpoint for RBC Mass Recovery was met.
 
ii) Processed RBC Leukoreduction Filtration Results
 
 

 
Group 1
Test
Group 2
Test
Group 2
Control
---(b)(4)---
 
Total Units
60
60
60
(b)(4)
Number of Units < 5x106 rWBC in the Total Unites
 
60/60
 
60/60
 
59/60
 
(b)(4)

 
The results support that a one-sided 95% lower confidence limit for the true proportion of units with residual leukocyte content of less than 5 x106 per unit was greater than 95% for each SOLX® RBC processing group. The primary study endpoint for leukoreduction was met for each SOLX® group.
 
The Group 2 Control demonstrated one unit out of 60 that did not meet the criteria for residual WBC per unit and therefore did not meet the 95/95 acceptance criteria.
 
 
iii) Hemolysis at End of Storage Results
 
Table 5-23 Hemolysis (%) on Day 42 of Storage

 
SOLX®RBC Group 1
Test
SOLX®RBC Group 2
Test
 
Group 2
AS-1 RBC Control
(b)(4)
Mean
0.31
0.28
0.40
(b)(4)
SD
0.14
0.08
0.28
(b)(4)
Min
0.09
0.15
0.04
(b)(4)
Max
0.72
0.56
0.98
(b)(4)
n
60
60
60
b(4)
# Units <1.0% / Total Units
 
60/60
 
60/60
 
60/60
(b)(4)

The results support that a one-sided 95% lower confidence limit for the true proportion of units with hemolysis at end of storage of less than 1% is greater than 95% for each SOLX® RBC processing group. The primary study endpoint for hemolysis was met for each SOLX® processing group.
 
iv) In Vivo 24 Hour Red Cell Recovery Results
There were two in vivo data analysis groups in this study, one composed of Group 1 and Group 2 combined in vivo results --------(b)(4)--------------------------------------------.
 
Table 5-26 In vivo 24-Hour Recovery for SOLX®RBCs on Day 42

 
Day 42
 
®
SOLX  RBC
Group 1 + 2
 
--(b)(4)--
 
Parameter
 
Criteria
Single Label n=27
Double Label n=26
(b)(4)
(b)(4)
Mean
Recovery (%)
 
≥ 75%
 
88.1
 
86.5
(b)(4)
(b)(4)
 
SD (%)
 
≤ 9%
 
5.8
 
6.5
(b)(4)
(b)(4)
% LCL for Population Proportion of Successes
(# Pass/Total)
 
≥ 70%
 
89.5 (27/27)
 
83.0 (25/26)
(b)(4)
(b)(4)
 
Study Outcome
 
Pass
 
Pass
(b)(4)
(b)(4)

Each SOLX® RBC analysis group (Groups 1+2 ---(b)(4)----) met study acceptance criteria for 24-hour in vivo red cell recovery when assessed for mean recovery, standard deviation and 95% lower confidence limit for the population proportion of successes.
 
v) In Vivo Red Cell Survival Results
Survival studies were conducted with SOLX® RBC and were not performed with the concurrent control group. There are no recognized criteria for survival of stored red blood cells; therefore the RBC survival studies conducted for this NDA were performed for reference purposes.
 
 Table 5-27 In vivo RBC Survival Studies for SOLX®RBC Stored for 42 Days
 

 
Day of
Reinfusion
 
Parameter
Mean ± SD
®
SOLX RBC
Group n=14
®
SOLX  RBC
Group n=13
 
-(b)(4)-
 
Day 42
Linear RBC
Survival T50 (Days)
 
32 ± 9
 
35 ± 12
(b)(4)
Linear RBC
Survival Lifespan (Days)
 
70 ± 20
 
80 ± 27
(b)(4)

SOLX® RBC demonstrated similar survival parameters for each analysis group. There were no statistically significant differences when comparing SOLX® RBC Groups for survival.
 
Statistical Review
Based on the reported results, the clinical study showed that the primary endpoints of RBC mass recovery, leukorecution efficiency, hemolysis at end of storage, and 24-hour radiolabeled recovery were met the objective performance criteria for all SOLX®RBC processing groups.
 
In addition to the assessment of primary endpoints of the clinical study, this statistical reviewer conducted the comparative analysis that the sponsor did not perform to investigate the effect of temperature and time of storage on labile coagulation factors. The review committee of this submission suggested analyzing the results of Factors V, VIII, XI, and Protein S for groups with different process on freezing rate and temperatures:  
(1)   -------------------------------------------------------------------------------------------------------------------------------------------(b)(4)--------------------------------------------------------------------------------------;
(2)   Test FFP was the plasma unit derived from Hemerus collection system that was held at room temperature for up to 8 hours post collection before freezing (Group 2);
(3)   Control FFP was derived from FDA approved (Hemerus) collection system (Group 2).
 
Due to the fact that the clinical study of this submission was not designed as paired-sample study, two-sample t-test was performed to compare the coagulation factors between ------------------------------------------(b)(4)------------------------------------ (c) Test FFP and Control FFP.
 
The results of Coagulation inhibitors (Protein S) and Coagulation factors of Factor V (FV), Factor VIII (FVIII) and Factor XI (FXI) for the comparisons are shown in Table 1 below. The table indicates that the Protein S level and Factor VIII ------(b)(4)------------ are significantly less than those of Control FFP and Test FFP. Especially, the results of Factor VIII in Table 1 showed highly significant difference as compared to Test FFP. The descriptive statistics of these Coagulation factors are presented in Table 2.
 
---------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)-------------------------------------------------------------------------------------------------
 
Table 1. The mean difference of the Hemerus Coagulation Factors: Test - Control (95%CI)
Coagulation Factors for the Test FFP, Test -----(b)(4)-----, and Control FFP
 
Protein S
FV
FVIII
FXI
-----------(b)(4)------
-----
-------------
-----------(b)(4)------
 
-----(b)(4)--------
(b)(4)
 
--(b)(4)----
-----------(b)(4)------
 
-----------(b)(4)------
(b)(4)
 
---(b)(4)-------
-----------(b)(4)------
-----
------(b)(4)----
-----------(b)(4)------
 
-----(b)(4)--------
(b)(4)
 
--(b)(4)----
    -----------(b)(4)------
 
-----------(b)(4)------   
(b)(4)
 
---(b)(4)-------
Test FFP
vs.
Control FFP
-0.067
 
(-6.16 , 6.02)
-3.58
 
(-9.58 , 2.42)
4.62
 
(-8.5 , 17.73)
0.1
 
(-8.16 , 8.36)
 
Control FFP (n=60): FFP derived from FDA approved collection system.
Test FFP (n=60): FFP derived from Hemerus collection system.
--------------------------------------(b)(4)-------------------------------------------------------------------------------------------------
* Statistical significance using 2-sided t-test for the mean difference of two independent samples.
 
[(b)(4)]
 
 
 
Conclusions
Based on the reported results, the clinical study showed that the primary endpoints of RBC mass recovery, leukorecution efficiency, hemolysis at end of storage, and 24-hour radiolabeled recovery were met for all SOLX® RBC processing groups.
 
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
 
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------