# Presentation: 669257

## 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

**Blood Products Advisory Committee **
**Rockville, MD **
**May 1, 2008**

**TRANSFUSION online: 22-Feb-2008**
**doi: 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

***In vitro –***** e.g., hemolysis and ATP**
***In vivo - *****autologous 24 hour recovery**
***In vivo - *****clinical outcome (**safety trials)

## FDA - RBC Performance Criteria

***In vitro –***** e.g., hemolysis and ATP**
***In vivo - *****autologous 24 hour recovery**
***In vivo - *****clinical outcome (**safety trials)

## Background: FDA Requirements

**Mean 24h recovery ≥ 70%**
- (Ross et al. JCI 1947;26:687-703)

## 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

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**CAUTION**

**IT WILL BE OK**

## Radiolabeled Red Cell Recovery – circa 1970

**Radiolabeled Red Cell Recovery – circa 1970**

## Radiolabeled Red Cell Recovery – circa 1985

**Radiolabeled Red Cell Recovery – circa 1985**

## Radiolabeled Red Cell Recovery – circa late 1990s

**Radiolabeled Red Cell Recovery – circa late 1990s**

## Radiolabeled Red Cell Recovery – circa 2004

**Radiolabeled Red Cell Recovery – circa 2004**

## Implication

_**Implication**_

**Test RBC must have ******** 90.3% “success” for an 80% chance of passing an *****in vivo***** recovery trial**

**What is the clinical evidence?**
**What is the capability of current RBC products?**

## Our Conclusion after review of the evidence

_**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.

## Methods

**Central Database**

**Data verification by Sponsors**
**n=12**

**Data review and cleaning**

_**Methods**_

**Approved/cleared methods**
**1990-2006**

## 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 1990 - 2006 

| n=34 studies | Leukocyte-
reduced | Non-leukoctye-
reduced |  |
| --- | --- | --- | --- |
| Automated Collection |  |  |  |
| Liquid stored | 205 | 9 | 214 |
| Gamma Irradiated | 67 | 0 | 67 |
| subtotal | 272 | 9 | 281 |
| Manual Collection |  |  |  |
| Liquid stored | 291 | 136 | 427 |
| Gamma Irradiated | 24 | 32 | 56 |
| subtotal | 315 | 168 | 483 |
|  |  |  |  |
| Frozen  | 140 | 37 | 177 |
|  |  |  |  |
| TOTAL | 727 | 214 | 941 |

## Slide 18

| 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=24
Probability (Number of successes ≥ 21 ) |
| 0.693 |

## Slide 19

| BINOMIAL EXPANSION |
| --- |
| N=24
Probability (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% |

## Slide 20

| 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=24
Probability (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**

## RESAMPLING

| Number of successes (75%) ≥ 21  | = 67.3% |
| --- | --- |
| Mean ≥ 75%  | = 100% |
| SD ≤9%  | = 95.2% |

**RESAMPLING**
**n=24; N=5000**

**Failures**

## RESAMPLING

**RESAMPLING**
**n=24; N=5000**

| Number of successes (75%) ≥ 21  | = 3.5% |
| --- | --- |
| Mean ≥ 75%  | = 95.5% |
| SD ≤9%  | = 71.4% |

**Failures**

## RESAMPLING

**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

**Sensitivity to Success Threshold****n=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%)

**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

_**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
- 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. Cancelas	Mike 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