Evaluation of Proposed FDA Criteria for Evaluation of Radiolabeled Red Cell Recovery Trials Larry J. Dumont, MBA, PhD James P. AuBuchon, MD for the Biomedical Excellence for Safer Transfusion (BEST) Collaborative BESTBEST Blood Products Advisory Committee Rockville, MD May 1, 2008 TRANSFUSION online: 22-Feb-2008 doi: /j 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: ) 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 – LCL 95% for population proportion of successes (  75%) > 70% BPAC, July, 2004 “Success Threshold”  21 successes out of 24  18 successes out of 20

% % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % CAUTION IT WILL BE OK

Radiolabeled Red Cell Recovery – circa 1970 OK

Radiolabeled Red Cell Recovery – circa 1985 OK

Radiolabeled Red Cell Recovery – circa late 1990s OK min & max

Radiolabeled Red Cell Recovery – circa 2004 Individual recoveries < 75% are FAILURES

Implication Test 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?

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 h Recovery CONTROL TEST 78.2% 80.3% … … Study h Recovery CONTROL TEST 78.2% 80.3% … … Study h Recovery CONTROL TEST 78.2% 80.3% … … Study h Recovery CONTROL TEST 78.2% 80.3% … … Study h Recovery CONTROL TEST 78.2% 80.3% … … ● ● ● LAB 11 Study h Recovery CONTROL TEST 78.2% 80.3% … … Study h Recovery CONTROL TEST 78.2% 80.3% … … Study h Recovery CONTROL TEST 78.2% 80.3% … … Study h Recovery CONTROL TEST 78.2% 80.3% … … Study h Recovery CONTROL TEST 78.2% 80.3% … … ● ● ● LAB 2 ● ● ● Central Database Data verification by Sponsors n=12 Data review and cleaning Methods ● ● ● Study h Recovery CONTROL TEST 78.2% 80.3% … … Study h Recovery CONTROL TEST 78.2% 80.3% … … Study h Recovery CONTROL TEST 78.2% 80.3% … … Study h Recovery CONTROL TEST 78.2% 80.3% … … Study h Recovery CONTROL TEST 78.2% 80.3% … … ● ● ● LAB 1 Approved/cleared methods

Liquid Stored (42 days) Central Database Sample with replacement n=24 N=5000 Methods Gamma Irradiated (28 days post) Frozen, deglycerolized (15-30 days) Sample with replacement n=24 N=5000 Sample with replacement n=24 N=5000 FDA/CBER

Evaluable RBC Recoveries n=34 studiesLeukocyte- reduced Non-leukoctye- reduced Automated Collection Liquid stored Gamma Irradiated670 subtotal Manual Collection Liquid stored Gamma Irradiated subtotal Frozen TOTAL

NMin5%MedianFrequency of Recovery < 75% Frequency of Recovery < 70% Frequency of Recovery < 67% MeanSD %4.5%1.9%82.1%6.71% BINOMIAL EXPANSION N=24 Probability (Number of successes ≥ 21 ) 0.693

BINOMIAL EXPANSION N=24 Probability (Number of successes ≥ 21 ) NMin5%MedianFrequency of Recovery < 75% Frequency of Recovery < 70% Frequency of Recovery < 67% Mean (%) SD (%) %18.7%8.9%77.9%8.36%

NMin5%MedianFrequency of Recovery < 75% Frequency of Recovery < 70% Frequency of Recovery < 67% MeanSD %2.8%1.2%86.6%7.41% BINOMIAL EXPANSION N=24 Probability (Number of successes ≥ 21 ) 0.957

One Sample Replicate LAB ASC Rec <70% 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=5000 Failures

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

Sensitivity to Success Threshold n=24

Chance of current, state-of-the-art RBC products passing FDA-proposed criteria RBCMean ≥ 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%) Gamma95.5%71.4%3.5% (3.0%)* 31.8% (25%)* 84.0% (74%)* Frozen100%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 LCL 95% 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.

Our Conclusion after review of the evidence 1.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

Acknowledgements Study Laboratories American Red Cross, Louisville, KY Blood Center of Wisconsin, Milwaukee, WI Dartmouth-Hitchcock Medical Center, Lebanon, NH Hoxworth Blood Center, Cincinnati, OH Mayo Clinic, Rochester, NY American Red Cross, Norfolk, VA University of North Carolina, Chapel Hill, NC University of New Mexico, Albuquerque, NM University of Virginia, Charlottesville, VA Walter Reed Army Institute of Research Yale University, New Haven, CN Study Sponsors American Red Cross Baxter Baxter/Army Cutter / Pall Gambro BCT, Inc. Haemonetics / Transfusion Technologies Hemasure MacoPharma / UnitedPharma Terumo Vitex Individuals Lauren Clark Jaime Houghton Sherrie Sawyer Jose A. CancelasMike McAteer Yariv Sivan Tammy Corda Jeff Miripol Edward Snyder M. Dean Elfath Ed Nelson Tania VandenBroeke John Hess Leslie Rose Pamela Whitley Stein Holme Neeta Rugg