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Evaluation of Proposed FDA Criteria forEvaluation of Radiolabeled Red Cell Recovery Trials
Larry J. Dumont, MBA, PhDJames P. AuBuchon, MD
for the Biomedical Excellence for Safer Transfusion (BEST) Collaborative
BESTBESTBlood Products Advisory Committee Rockville, MD May 1, 2008
TRANSFUSION online: 22-Feb-2008doi: 10.1111/j.1537-2995.2008.01642.x.
Conflicts of Interest
• Consultant– Gambro BCT– bioMérieux– BCSI– Verax Biomedical
• Research support DHMC– Cerus– Fenwal– Gambro BCT– Haemonetics– Immunetics – Navigant Biotechnologies– Verax Biomedical
• Travel Support– FDA
FDA - RBC Performance Criteria
1. In vitro – e.g., hemolysis and ATP
2. In vivo - autologous 24 hour recovery
3. In vivo - clinical outcome (safety trials)
FDA - RBC Performance Criteria
1. In vitro – e.g., hemolysis and ATP
2. In vivo - autologous 24 hour recovery
3. In vivo - clinical outcome (safety trials)
Background: FDA Requirements
Mean 24h recovery ≥ 70%(Ross et al. JCI 1947;26:687-703)
Mean 24h recovery ≥ 75% (FDA Workshop, April 25, 1985)
Mean 24h recovery ≥ 75% -and- SD 9%(FDA 1998)
FDA Requirements
Mean recovery 75% - and – SD 9% - and –
LCL95% for population proportion of successes ( 75%) > 70%
BPAC, July, 2004
“Success Threshold”
21 successes out of 24
18 successes out of 20
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CAUTION
IT WILL BE OK
40 45 50 55 60 65 70 75 80 85 90 95 10024-hour RBC Recovery (%)
mean = 70%sd = 9%
Radiolabeled Red Cell Recovery – circa 1970
OK
40 45 50 55 60 65 70 75 80 85 90 95 10024-hour RBC Recovery (%)
mean = 70%sd = 9%
mean = 75%sd = 9%
Radiolabeled Red Cell Recovery – circa 1985
OK
40 45 50 55 60 65 70 75 80 85 90 95 10024-hour RBC Recovery (%)
mean = 70%sd = 9%
mean = 75%sd = 9%
Radiolabeled Red Cell Recovery – circa late 1990s
OK min & max
40 45 50 55 60 65 70 75 80 85 90 95 10024-hour RBC Recovery (%)
Radiolabeled Red Cell Recovery – circa 2004
Individual recoveries < 75% are FAILURES
40 45 50 55 60 65 70 75 80 85 90 95 10024-hour RBC Recovery (%)
mean = 86.7%sd = 9%
ImplicationTest RBC must have 90.3% “success” for an 80% chance of passing an in vivo recovery trial
1. What is the clinical evidence?
2. What is the capability of current RBC products?
40 45 50 55 60 65 70 75 80 85 90 95 10024-hour RBC Recovery (%)
mean = 81.7%sd = 9%
Our Conclusion after review of the evidence
A success threshold of 67-70% will provide a reasonable probability of passing the FDA-proposed criteria for RBC products in current use in the United States
Objective
Define the ability of currently available Red Blood Cell (RBC) collection and storage systems to satisfy new RBC in vivo recovery criteria proposed by the FDA for approval of RBC systems.
Study 9987
24h Recovery CONTROL TEST 78.2% 80.3% 82.1 79.4 80.7 77.3 … …
Study 7985
24h Recovery CONTROL TEST 78.2% 80.3% 82.1 79.4 80.7 77.3 … …
Study 345
24h Recovery CONTROL TEST 78.2% 80.3% 82.1 79.4 80.7 77.3 … …
Study 134
24h Recovery CONTROL TEST 78.2% 80.3% 82.1 79.4 80.7 77.3 … …
Study 12345
24h Recovery CONTROL TEST 78.2% 80.3% 82.1 79.4 80.7 77.3 … …
●●●
LAB 11
Study 9987
24h Recovery CONTROL TEST 78.2% 80.3% 82.1 79.4 80.7 77.3 … …
Study 7985
24h Recovery CONTROL TEST 78.2% 80.3% 82.1 79.4 80.7 77.3 … …
Study 345
24h Recovery CONTROL TEST 78.2% 80.3% 82.1 79.4 80.7 77.3 … …
Study 134
24h Recovery CONTROL TEST 78.2% 80.3% 82.1 79.4 80.7 77.3 … …
Study 12345
24h Recovery CONTROL TEST 78.2% 80.3% 82.1 79.4 80.7 77.3 … …
●●●LAB 2
●
●●
Central Database
Data verification
by Sponsors
n=12
Data review and cleaning
Methods
●
●●
Study 9987
24h Recovery CONTROL TEST 78.2% 80.3% 82.1 79.4 80.7 77.3 … …
Study 7985
24h Recovery CONTROL TEST 78.2% 80.3% 82.1 79.4 80.7 77.3 … …
Study 345
24h Recovery CONTROL TEST 78.2% 80.3% 82.1 79.4 80.7 77.3 … …
Study 134
24h Recovery CONTROL TEST 78.2% 80.3% 82.1 79.4 80.7 77.3 … …
Study 12345
24h Recovery CONTROL TEST 78.2% 80.3% 82.1 79.4 80.7 77.3 … …
●●●LAB 1
Approved/cleared methods
1990-2006
Liquid Stored(42 days)
Central Database
Sample with replacementn=24 N=5000
Methods
Gamma Irradiated(28 days post)
Frozen, deglycerolized(15-30 days)
Sample with replacementn=24 N=5000
Sample with replacementn=24 N=5000
FDA/CBER
Evaluable RBC Recoveries 1990 - 2006
n=34 studies Leukocyte-reduced
Non-leukoctye-reduced
Automated Collection
Liquid stored 205 9 214Gamma Irradiated 67 0 67
subtotal 272 9 281Manual Collection
Liquid stored 291 136 427Gamma Irradiated 24 32 56
subtotal 315 168 483
Frozen 140 37 177
TOTAL 727 214 941
N Min 5% Median Frequency of Recovery
< 75%
Frequency of Recovery
< 70%
Frequency of Recovery
< 67%
Mean SD
641 36 70.7 82.4 11.7% 4.5% 1.9% 82.1% 6.71%
BINOMIAL EXPANSION
N=24Probability (Number of
successes ≥ 21 )0.693
BINOMIAL EXPANSION
N=24Probability (Number of
successes ≥ 21 )0.035
N Min 5% Median Frequency of Recovery
< 75%
Frequency of Recovery
< 70%
Frequency of Recovery
< 67%
Mean (%)
SD (%)
123 47.1 63.6 79.3 30.9% 18.7% 8.9% 77.9% 8.36%
N Min 5% Median Frequency of Recovery
< 75%
Frequency of Recovery
< 70%
Frequency of Recovery
< 67%
Mean SD
177 52.2 74.2 88.0 5.6% 2.8% 1.2% 86.6% 7.41%
BINOMIAL EXPANSION
N=24Probability (Number of
successes ≥ 21 )0.957
One Sample
Replicate LAB ASC Rec <70% 257 1 1 64.20 1 257 1 1 71.60 0 257 1 1 70.20 0 257 1 1 79.30 0 257 1 1 76.70 0 257 1 1 93.50 0 257 1 1 73.40 0 257 1 1 85.53 0 257 1 1 71.14 0 257 2 1 81.04 0 257 2 1 66.85 1 257 2 1 77.13 0 257 2 1 84.04 0 257 2 1 81.85 0 257 2 1 77.68 0 257 2 1 80.49 0 257 2 1 58.09 1 257 2 1 82.71 0 257 2 3 40.32 1 257 2 3 83.42 0 257 2 3 75.44 0 257 2 5 73.69 0 257 2 5 74.95 0 257 2 5 74.26 0
Mean=74.9 X
SD=10.5 X
4/24 < 70% X
67%, 70%, 75%
Number of successes (75%) ≥ 21 = 67.3%Mean ≥ 75% = 100%SD ≤9% = 95.2%
RESAMPLING
n=24; N=5000Failures
RESAMPLING
n=24; N=5000
Number of successes (75%) ≥ 21 = 3.5%Mean ≥ 75% = 95.5%SD ≤9% = 71.4%
Failures
RESAMPLING
n=24; N=5000
Number of successes (75%) ≥ 21 = 95.4%Mean ≥ 75% = 100%SD ≤9% = 83.9%
Failures
Preliminary Conclusion
FDA-proposed success threshold of >75% for individual recovery is unacceptable
The general clinical performance for these products is adequate as proved over years of clinical practice, and certainly represents the state-of-the-art
0%
10%
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30%
40%
50%
60%
70%
80%
90%
100%
75% 70% 67% 75% 70% 67% 75% 70% 67%
Liquid Gamma FrozenSuccessful Individual Recovery
Cha
nce
of P
assi
ng
Sensitivity to Success Thresholdn=24
Chance of current, state-of-the-art RBC products passing FDA-proposed criteria
RBC Mean ≥ 75%
SD ≤9%
Success: Recovery >
75%
Success: Recovery >
70%
Success: Recovery >
67%42d Liquid Stored
100% 95.2% 69.3%
(58%)*
97.9%
(94%)*
99.9%
(99%)Gamma 95.5% 71.4% 3.5%
(3.0%)*
31.8%
(25%)*
84.0%
(74%)*Frozen 100% 83.7% 95.7%
(90%)*
99.6%
(98%)*
100%
(99%)*
* ≥ 18 successes out of 20 trials
Other Key Observations
• Current RBC components are not different than the study population
• There are differences between laboratories and/or study subjects
4 of 36 < 75% (11%)
1 of 36 < 70% (2.8%)
< 75% 11.7%
< 70% 4.5%
Current Methods are not different than the study population
There are differences between laboratories and/or study subjects
Conclusions• The FDA-proposed success threshold of >75% is
not validated against currently approved RBC products available in the US
• Based on actual in vivo recovery performance, a success threshold of 67-70% will provide a reasonable probability of passing the FDA-proposed criteria
LCL95% for population proportion of successes ( 67%) > 70%
• The mean and SD criteria may be applied as general guidance, but used with caution as distributions do not meet normality assumptions.
40 45 50 55 60 65 70 75 80 85 90 95 10024-hour RBC Recovery (%)
mean = 81.7%sd = 9%
Our Conclusion after review of the evidence1. A success threshold of 67-70% will provide a reasonable
probability of passing the FDA-proposed criteria for RBC products in current use in the United States
2. We should not make it unnecessarily burdensome for new innovations to enter the market
AcknowledgementsStudy LaboratoriesAmerican Red Cross, Louisville, KYBlood Center of Wisconsin, Milwaukee, WIDartmouth-Hitchcock Medical Center, Lebanon, NHHoxworth Blood Center, Cincinnati, OHMayo Clinic, Rochester, NYAmerican Red Cross, Norfolk, VAUniversity of North Carolina, Chapel Hill, NCUniversity of New Mexico, Albuquerque, NMUniversity of Virginia, Charlottesville, VAWalter Reed Army Institute of ResearchYale University, New Haven, CN
Study Sponsors American Red CrossBaxterBaxter/ArmyCutter / PallGambro BCT, Inc.Haemonetics / Transfusion TechnologiesHemasureMacoPharma / UnitedPharmaTerumoVitex
IndividualsLauren Clark Jaime Houghton Sherrie SawyerJose A. Cancelas Mike McAteer Yariv SivanTammy Corda Jeff Miripol Edward SnyderM. Dean Elfath Ed Nelson Tania VandenBroekeJohn Hess Leslie Rose Pamela WhitleyStein Holme Neeta Rugg