Evaluation of Proposed FDA Criteria for Evaluation of Radiolabeled Red Cell Recovery Trials Larry J....

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 (%)

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mean = 70%sd = 9%

Radiolabeled Red Cell Recovery – circa 1970

OK


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mean = 70%sd = 9%

mean = 75%sd = 9%


OK


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mean = 70%sd = 9%

mean = 75%sd = 9%

Radiolabeled Red Cell Recovery – circa late 1990s

OK min & max


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Individual recoveries < 75% are FAILURES


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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?


pdf

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


Study 345


Study 134


Study 12345


●●●

LAB 11

Study 9987


Study 7985


Study 345


Study 134


Study 12345


●●●LAB 2

●

●●

Central Database

Data verification

by Sponsors

n=12

Data review and cleaning

Methods

●

●●

Study 9987


Study 7985


Study 345


Study 134


Study 12345


●●●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)



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%


< 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




< 75%


< 70%


< 67%

Mean (%)

SD (%)

123 47.1 63.6 79.3 30.9% 18.7% 8.9% 77.9% 8.36%


< 75%


< 70%


< 67%

Mean SD

177 52.2 74.2 88.0 5.6% 2.8% 1.2% 86.6% 7.41%

BINOMIAL EXPANSION



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%

20%

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.


pdf

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

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