1. FDA’s Criteria for Evaluation of Red Blood Cell Products Ping He, M.D. Medical Officer Blood Products Advisory Committee 91st Meeting, May 1, 2008 Rockville Pike, Rockville, MD

2. 2 ISSUE SUMMARY FDA seeks the advice of the Committee on an industry proposal to change the current acceptance criteria for evaluation of red blood cell (RBC) studies based on in vivo radiolabeling recovery trials.

3. 3 Key Issue – Should the RBC in vivo Recovery Threshold Value be Changed? 1.Threshold value ( ≥75%) for RBC recovery study serves as a cutoff line for determining the RBC viability of a unit during the evaluation of RBC in vivo recovery studies. 2.Industry believes, based on historical data, that the overall RBC recovery studies from 1990 to 2006 would not meet the FDA’s current acceptance criteria unless the threshold value is changed from ≥75% to ≥67%. non-viable viable ≥ 75% Threshold value 3.In contrast, based on more recent data FDA believes that RBC products are improving. During the period 1998-2007, 17/19 RBC recovery studies met the current criteria. Therefore FDA maintains that the threshold value of ≥75% should not be changed. viable ≥ 67% non-viable Threshold value

4. 4 RBC Products Play an Important Role in Transfusion Medicine  RBCs are life saving products that deliver oxygen to tissues  ~14 million units of whole blood collected/year, > 38,000 units RBC product needed daily  There is no available substitute for RBC products.

5. 5 RBC Product Manufacturing Causes a “Storage Lesion” Red Blood Cells (RBCs) Anticoagulants Additive Solutions Stored at 1-6 o C Shelf life of 42 days Any preservation or manipulation can induce RBC membrane damage producing changes in the biochemical properties of RBCs and shortening their in vivo survival

6. 6 ↓ RBC viability (shortens time in circulation) reduce oxygen delivery to tissue damaged RBCs may saturate macrophage clearance mechanisms & reduce bacterial clearance ↓ ATP correlates with reduced RBC viability decrease of tissue perfusion -↓vasodilation ↓ 2,3-DPG reduce oxygen delivery to tissue Cell membrane loss makes RBCs rigid, increases spontaneous lysis, decreases microvascular flow ↑ Hemolysis harmful effects on organ function (renal toxicity) ↑ Plasma K + potential hazard to neonates (arrhythmias) Potentially Harmful Effects of the RBC Storage Lesion Mollison, 2005; Hess et al. Transf, 2001; Nishiyama et al, Can J Anesth, 2000

7. 7 42d FDA Recommended Tests on Approval/Clearance of Stored/Processed RBC Products RBC in vitro tests are used as screening tests: In vitro tests are not predictive of in vivo RBC performance non-viable New bag ~20 mL Radiolabeled RBC viable 24-hr RBC in vivo recovery

8. 8 In vivo RBC recovery at 24 hours provides a surrogate endpoint for RBC product evaluation To demonstrate the safety and effectiveness of novel RBC collection and processing systems FDA Recommended Tests on Approval/Clearance of Stored/Processed RBC Products (contd.)

9. 9 Comparison of RBC in vivo Recoveries with Different RBC Storage Periods (Mollison 1951) The longer the storage, the poorer the RBC survival and recovery. 24-h ≥ 75% RBC recovery at 24 hours is the threshold value for an individual unit viable ≥ 75% Threshold value non-viable

10. 10 FDA Acceptance Criteria for Evaluation of In vivo RBC Studies – Historical Review At least 20 volunteers, At least 2 sites Year instituted CriteriaRationale Forms of communication 1985M ≥ 75% Historical data & expert opinion FDA workshop on red cells stored in AS, Apr. 25, 1985 1998 M ≥ 75% SD ≤ 9% Industry requested Decision based on historical data 2004 (current criteria) M ≥ 75% SD ≤ 9% Proportion of units with recovery ≥75% with a one sided 95% LCL >70% Ensure the proportion successes - Decision based on Historical data - BPAC, 2004 - Pre-meetings with regulated industry - DIA meeting, 2005... 75%

11. 11 RBC Product Approvals/Clearances Since 2004 Majority of the submissions to FDA in this time period passed the current criteria. Those that did not meet the current criteria also failed the previous mean and SD criteria.

12. 12 Maintenance of Quality for New RBC Products Reduction in the approval/clearance criteria would allow RBCs with a more severe storage lesion on the market which may correlate with a poorer clinical outcome

13. 13 The Association Between Duration of Storage of Transfused Red Blood Cells and Morbidity/Mortality After Reoperative Cardiac Surgery Basran et al, Anesthesia & Analgesia. 2006 There is an association between prolonged RBC storage and adverse clinical outcomes such as mortality and organ failure (retrospective analysis) In-hospital mortality Acute renal dysfunction

14. 14 Duration of Red-Cell Storage and Complications after Cardiac Surgery Koch et al, N Engl J Med 2008

15. 15 Reasons to Revise the in vivo RBC Recovery Acceptance Criteria Studyn Mean % SD % # of units with recovery < 75% One sided 95% LCL for proportion of units having recovery ≥75% Study A 2478.39.0847.9% Study B 2177.67.4556.3% Study C 2181.36.5272.9% The high failure rate of individual units in studies A and B raised concerns about the quality of RBC products and led the FDA to consider revising the criteria.

16. Study A % 24-hr RBC recovery 24-hrs after transfusion M SD 75 Study C % 24-hr RBC recovery 24-hrs after transfusion M SD 75 Study B M SD % 24-hr RBC recovery 24-hrs after transfusion 75

17. 17 Population Proportion of Successes: “95-70 Rule” To ensure that most (> 70%) products have >75% RBC recovery a new criterion was introduced:  With a one-sided 95% LCL, proportion of units with RBC recovery >75% is >70%.  To meet this “95-70 rule”, a specific number of maximum failures are allowed in a study: Sample size Number of units with recovery < 75% With a one-sided 95% LCL, proportion of units with RBC recovery ≥ 75% 20272% 24371% 28470.2% 33570.8%

18. 18 Key Issue Should the RBC in vivo recovery threshold value of >75% be changed?

19. 19 Threshold value of RBC recovery 1990~1997 (n = 140) 1998~2003 (n = 376) 2004~2007 (n = 173) Success Rate Power N = 24 Success Rate Power N = 24 Success Rate Power N = 24 ≥ 75%0.8360.430.8830.690.9310.92 ≥ 74%0.8640.580.8910.740.9420.95 ≥ 73%0.8860.710.9260.900.9480.97 # of studies meeting current criteria 4 of 89 of 118 of 8 FDA Analysis of Combined BEST & FDA Data Sets in Different Time Periods from 1990 to 2007 N = 689 (595 + 94) Note: studies 40 and 41 were not included due to lack of information of study year Power = probability of successful study

20. 20 Observations of the Combined Data Analysis  Overall the quality of RBC products approved or cleared by FDA is improving with time.  Most recent (2004-2007) RBC studies submitted to FDA passed the higher standard (“95-70 rule”) with a power of 0.92 with the threshold of ≥75%.  It is known that most clinical studies performed to satisfy FDA criteria for drugs are powered at 0.80.

21. 21 Observations of the Combined Data Analysis (continued)  Threshold value of ≥75% has provided a standard of RBC quality evaluation over the last 24 years. The current criteria assure that most of the RBC products (>70%) have a recovery ≥75%.  Based on these considerations, FDA proposes to continue applying the criteria adopted in 2004 (“95-70 rule”) to the quality evaluation of RBC products using in vivo radiolabeling studies.

22. 22 Questions to the Committee 1. Does the Committee agree with FDA's proposal to maintain the current criteria? {The current criteria are: Radiolabeling studies should be performed in at least two separate centers (laboratories) with a total of 20-24 healthy donors. The mean recovery at 24 hours for each unit should be >75% with SD 70% (successes = individual units recovery >75%)}. 2. Alternatively, does the Committee recommend that a change in the criteria is needed based on the data?

23. 23 Questions to the Committee (contd.) 3. If the answer to question 2 is yes, what changes does the Committee recommend for the threshold value of individual subject RBC in vivo recovery, with a sample size of 24? Examples to consider: a)Based on combined data from 1998-2007, with >74% as the threshold value, power = 0.82 b)Based on combined data from 1998-2007, with >73% as the threshold value, power = 0.93 c)Based on BEST data from 1990-2006, BEST recommends 67% as the threshold value, power = 0.999

24. 24 Acknowledgements FDA: Jessica Kim Tie-Hua Ng Peter Lachenbruch Ghanshyam Gupta Henry Hsu Betsy Poindexter Jaro Vostal Basil Golding BEST: Larry J. Dumont James P. AuBuchon