cell therapy liaison meeting january 27, 2006 industry – outline of issues and data

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Cell Therapy Liaison MeetingCell Therapy Liaison MeetingJanuary 27, 2006January 27, 2006

Industry – Outline of Issues and DataIndustry – Outline of Issues and Data

Susan L. Stramer, PhDSusan L. Stramer, PhD

American Red CrossAmerican Red Cross

representing multiple contributing Blood and representing multiple contributing Blood and HPC CentersHPC Centers

Updated March 20, 2006

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Issue and GoalsIssue and Goals

Mini-pool (MP) NAT for HIV-1 and HCV of HPC Mini-pool (MP) NAT for HIV-1 and HCV of HPC donation samples is not currently acceptable; testing donation samples is not currently acceptable; testing must be performed by individual donation (ID) NAT must be performed by individual donation (ID) NAT (AABB/ISCT teleconference Nov 9, 2005)(AABB/ISCT teleconference Nov 9, 2005)

– Upon communication of this information from Upon communication of this information from AABB (AABB Pulse Points, Nov 29, 2005), blood AABB (AABB Pulse Points, Nov 29, 2005), blood centers converted from MP to ID NAT with the goal centers converted from MP to ID NAT with the goal of qualification of MP NAT for HPC donations in of qualification of MP NAT for HPC donations in the futurethe future

• Multiple communications within organizations to Multiple communications within organizations to ensure compliance; e.g., ARC, Dec 7, 2005; ensure compliance; e.g., ARC, Dec 7, 2005; AATB, Nov 17, 2005AATB, Nov 17, 2005

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Issues and GoalsIssues and Goals ““Specimens from other living donors (except whole Specimens from other living donors (except whole

blood, blood, blood componentsblood components or source plasma) and from or source plasma) and from cadaveric donors should be tested using the cadaveric donors should be tested using the individual donor testing method only” individual donor testing method only” – (GP insert, version IN0076-01 REV A)(GP insert, version IN0076-01 REV A)

Definition of a blood component: “product containing Definition of a blood component: “product containing a part of human blood separated by physical or a part of human blood separated by physical or mechanical means” (21 CFR 1271.3(i))mechanical means” (21 CFR 1271.3(i))

– Interpretation was that donations from HPC Interpretation was that donations from HPC donors (peripheral blood stem cells, maternal cord donors (peripheral blood stem cells, maternal cord blood, bone marrow) meet this criteriablood, bone marrow) meet this criteria

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Issues and GoalsIssues and Goals Analysis in support of MP NAT Analysis in support of MP NAT

prospectively/retrospectively by comparing prospectively/retrospectively by comparing frequency of infectious disease markers in HPC frequency of infectious disease markers in HPC donations to those of donations of whole blood donations to those of donations of whole blood (autologous and allogeneic FT/RPT donations; i.e., (autologous and allogeneic FT/RPT donations; i.e., those already approved for MP NAT)those already approved for MP NAT)

– Data to be shared with FDA but will be submitted Data to be shared with FDA but will be submitted to manufacturers so that their package inserts may to manufacturers so that their package inserts may be modified to include a claim for MP NAT of be modified to include a claim for MP NAT of HPC donations (assuming the data support such a HPC donations (assuming the data support such a modification)modification)

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Points to ConsiderPoints to Consider NAT clinical trials, and prospective use of the licensed NAT clinical trials, and prospective use of the licensed

assays, have included samples from the following assays, have included samples from the following donations in context of MP NAT: allogeneic FT/RPT, donations in context of MP NAT: allogeneic FT/RPT, autologous, pheresis, HPCsautologous, pheresis, HPCs– All samples from heart-beating donors meeting the sample All samples from heart-beating donors meeting the sample

suitability criteria of the clinical protocols/licensed inserts suitability criteria of the clinical protocols/licensed inserts were considered suitable for pooling and testingwere considered suitable for pooling and testing

– Only donations of organ and tissue donors have been tested by Only donations of organ and tissue donors have been tested by ID NAT due to sample suitability issues; testing frequently ID NAT due to sample suitability issues; testing frequently occurs in separate laboratories to segregate from samples occurs in separate laboratories to segregate from samples tested by MP NATtested by MP NAT• Hemodilution/hemolysis (not included in this presentation)Hemodilution/hemolysis (not included in this presentation)

– At request of FDA, separate analysis was performed post-At request of FDA, separate analysis was performed post-licensure to include volunteer source pheresis; insert modified licensure to include volunteer source pheresis; insert modified based on analyzed databased on analyzed data

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Points to Consider-Points to Consider-False PositivityFalse Positivity Impact of ID NAT on lost donors/productsImpact of ID NAT on lost donors/products

– MP involves two rounds of testing in contrast to ID NATMP involves two rounds of testing in contrast to ID NAT

– False positive rates since FDA licensure:False positive rates since FDA licensure:

• 1:40,000-1:100,000 (0.001-0.0025%) for MP NAT by site1:40,000-1:100,000 (0.001-0.0025%) for MP NAT by site

• 1:555-1:2150 for ID NAT by lot (0.08-0.18%; mean 1:555-1:2150 for ID NAT by lot (0.08-0.18%; mean 0.13%)0.13%)

• 32-180X (80X mean) higher reactive rate for ID NAT32-180X (80X mean) higher reactive rate for ID NAT

– Decrease in specificity of 99%Decrease in specificity of 99%

• Additional loss of 130 donors/donations for every 100,000 Additional loss of 130 donors/donations for every 100,000 testedtested

– Result is the loss of valuable, sometimes irreplaceable Result is the loss of valuable, sometimes irreplaceable donors/donationsdonors/donations

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Points to Consider-Points to Consider-CostCost

Impact of ID NAT on costImpact of ID NAT on cost

– Additional $3-5 per donation for ID vs MP Additional $3-5 per donation for ID vs MP NATNAT • Current price approx $10.00 per MP NAT; Current price approx $10.00 per MP NAT;

additional $300,000-$500,000 for every additional $300,000-$500,000 for every 100,000 donations for ID NAT100,000 donations for ID NAT

• One manufacturer (GP/Chiron) has agreed One manufacturer (GP/Chiron) has agreed not to increase pricing until March 2006; then not to increase pricing until March 2006; then price will increaseprice will increase

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Points to Consider-Points to Consider-LogisticsLogistics Impact of ID NAT on logisticsImpact of ID NAT on logistics

– Up to 8000 samples/day arrive in a consolidated Up to 8000 samples/day arrive in a consolidated testing labtesting lab

– No automated systems to sort samples; performed No automated systems to sort samples; performed manually based on visual examination of each tube manually based on visual examination of each tube and sorting based on WBN codes on tube labelsand sorting based on WBN codes on tube labels

• Procedures/processes developed to identify and test Procedures/processes developed to identify and test HPC donations by ID NATHPC donations by ID NAT

– Error prone; what is impact of an HPC inadvertently Error prone; what is impact of an HPC inadvertently tested by MP NAT?tested by MP NAT?

– Increase in staff needed for sorting/testing/QCIncrease in staff needed for sorting/testing/QC

• Cost not captured in this presentationCost not captured in this presentation

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Analysis GoalsAnalysis Goals To determine the infectious disease marker To determine the infectious disease marker

prevalence/incidence rates for donations of prevalence/incidence rates for donations of Hematopoietic Progenitor Cells (HPC) donors Hematopoietic Progenitor Cells (HPC) donors to to qualify these donations for MP NAT by qualify these donations for MP NAT by demonstrating equivalence to blood donation demonstrating equivalence to blood donation types already included in the intended use types already included in the intended use statements for licensed NAT assays, and prove statements for licensed NAT assays, and prove that the risks associated with MP NAT as that the risks associated with MP NAT as compared to ID NAT for HPC donations are no compared to ID NAT for HPC donations are no greater than the difference between MP and ID greater than the difference between MP and ID NAT for donations of whole bloodNAT for donations of whole blood

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Analysis MethodsAnalysis Methods Prevalence of HIV, HCV and HBV determined by Prevalence of HIV, HCV and HBV determined by

antibody or antigen confirmed positive rates (using antibody or antigen confirmed positive rates (using specific confirmatory tests or NATspecific confirmatory tests or NAT, or repeat reactivity , or repeat reactivity if none of the above exist, such as anti-HBc)if none of the above exist, such as anti-HBc)

IncidenceIncidence of each agent (including WNV) will be of each agent (including WNV) will be determined determined by NAT yieldby NAT yield (antibody/antigen negative) (antibody/antigen negative)

Included in the analysis are the test results for samples Included in the analysis are the test results for samples of donations of of donations of HPC donors collected from HPC donors collected from geographically distinct US collection facilities from the geographically distinct US collection facilities from the time of NAT licensure to the end of 2005time of NAT licensure to the end of 2005

Results from screening ARC whole blood donations Results from screening ARC whole blood donations from a similar period of time serve as the controlfrom a similar period of time serve as the control

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Analysis MethodsAnalysis Methods Spreadsheet distributed through AABB and ABC to Spreadsheet distributed through AABB and ABC to

collecting and testing sites (Nov 30, 2005)collecting and testing sites (Nov 30, 2005) Requested results for all infectious disease testing Requested results for all infectious disease testing

including: anti-HIV-1/2, HIV-1 NAT, anti-HCV, including: anti-HIV-1/2, HIV-1 NAT, anti-HCV, HCV NAT, HBsAg, anti-HBc, HBV NAT and HCV NAT, HBsAg, anti-HBc, HBV NAT and WNV, as availableWNV, as available– FDA licensed tests or testing using approved FDA licensed tests or testing using approved

investigational protocols/reagentsinvestigational protocols/reagents Break out requested by HPC typeBreak out requested by HPC type

– Peripheral blood stem cells (PS)Peripheral blood stem cells (PS)– Bone marrow (B)Bone marrow (B)– Maternal cord blood (C)Maternal cord blood (C)

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Analysis MethodsAnalysis Methods Data submitted to ARC to prepare a consolidated Data submitted to ARC to prepare a consolidated

line listing and to perform analysis vs a control line listing and to perform analysis vs a control population already approved for MP NATpopulation already approved for MP NAT– ARC donor population: autologous and allogeneic ARC donor population: autologous and allogeneic

donations from 4/1/04-3/31/05donations from 4/1/04-3/31/05

• 6.55 million allogeneic and 1.066 million 6.55 million allogeneic and 1.066 million autologous donationsautologous donations

Data included in the analysis represent all Data included in the analysis represent all donations that meet the donations that meet the licensed/investigational package insert sample licensed/investigational package insert sample suitability requirementssuitability requirements

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Data Collection from HPC SitesData Collection from HPC Sites Data received from Data received from 10 organizations10 organizations, ,

many with multiple organizations many with multiple organizations representedrepresented– e.g., NMDP has 72 submitting centers with e.g., NMDP has 72 submitting centers with

34 different testing sites34 different testing sites

171,619 HPC submitted data points 171,619 HPC submitted data points having both NAT and serology results having both NAT and serology results (next slide)(next slide)– 139,654 HPC samples associated with a 139,654 HPC samples associated with a

donation (removal of 31,965 “unknown donation (removal of 31,965 “unknown types” not associated with a donation)types” not associated with a donation)

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Donations Analyzed-Donations Analyzed-updateupdate 3/20/063/20/06SiteSite Samples Samples

SubmittedSubmittedResults with Results with

NATNATResults with NAT Results with NAT

and Serologyand Serology

BSLBSL 71,00671,006 57,69757,697 57,68257,682

ARCARC 31,78131,781 29,18429,184 14,91714,917

BergenBergen 181181 181181 181181

PSBCPSBC 22912291 21132113 21132113

BonfilsBonfils 27892789 804804 803803

NMDPNMDP 54,25754,257 45,86545,865 45,80645,806

StemCyteStemCyte 15,44115,441 15,44115,441 15,44115,441

CHOCCHOC 20302030 20302030 20302030

FBSFBS 10,28310,283 10,28310,283 10,26910,269

CIRBCCIRBC 23,25823,258 22,37722,377 22,37722,377

TOTALTOTAL 213,268213,268 185,975185,975 171,619171,619

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Submissions from All Submitting Sites Combined Submissions from All Submitting Sites Combined by HPC Donation Type; Complete Data for by HPC Donation Type; Complete Data for

N=139,654 N=139,654 (3/20/06)(3/20/06)

HPC TypeHPC Type FrequencyFrequency PercentPercent

UnknownUnknown 43544354 3.13.1

Bone marrowBone marrow 71447144 5.15.1

Bone Bone marrow/PSmarrow/PS

676676 0.50.5

Cord bloodCord blood 114,070114,070 81.781.7

PSPS 13,41013,410 9.69.6

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Frequencies of Marker Positives in Whole Blood DonationsFrequencies of Marker Positives in Whole Blood DonationsARC; 4/1/04-3/31/05ARC; 4/1/04-3/31/05

6.55 million Allogeneic and 1.066 million Autologous Donations6.55 million Allogeneic and 1.066 million Autologous Donations

Combined Combined Donations per Donations per

10,00010,000

Allogeneic Allogeneic Donations per Donations per

10,00010,000

Autologous Autologous Donations per Donations per

10,00010,000

Anti-HIVAnti-HIV TotalTotal 0.3050.305 0.2630.263 2.9082.908

FTFT 1.1421.142 1.0251.025 3.9573.957

RPTRPT 0.1210.121 0.1000.100 2.0482.048

RangeRange 0.100-3.9570.100-3.957

HIV NATHIV NAT TotalTotal 0.00750.0075 0.00760.0076 00

FTFT 0.01670.0167 0.01740.0174 00

RPTRPT 0.00550.0055 0.00560.0056 00

RangeRange 0-0.01740-0.0174

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10,00010,000


10,00010,000


10,00010,000

Anti-HCVAnti-HCV TotalTotal 5.1035.103 3.4833.483 104.67104.67

FTFT 22.3322.33 18.3118.31 118.71118.71

RPTRPT 1.3201.320 0.3240.324 93.1793.17

RangeRange 0.324-118.710.324-118.71

HCV NATHCV NAT TotalTotal 0.0420.042 0.0400.040 0.1880.188

FTFT 0.1170.117 0.1040.104 0.4170.417

RPTRPT 0.0260.026 0.0260.026 00

RangeRange 0-0.4170-0.417

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10,00010,000


10,00010,000


10,00010,000

Anti-HBcAnti-HBc TotalTotal 35.6135.61 29.6629.66 401.34401.34

FTFT 121.32121.32 107.96107.96 441.74441.74

RPTRPT 16.7916.79 12.9812.98 368.25368.25

RangeRange 12.98-441.7412.98-441.74

HBsAgHBsAg TotalTotal 1.4921.492 1.2871.287 14.1614.16

FTFT 6.9546.954 6.4976.497 17.9117.91

RPTRPT 0.3040.304 0.1760.176 12.1212.12

RangeRange 0.176-17.910.176-17.91

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10,00010,000


10,00010,000


10,00010,000

WNVWNV TotalTotal 0.1220.122 0.1170.117 0.3750.375

FTFT 0.1330.133 0.1130.113 0.6240.624

RPTRPT 0.1190.119 0.1180.118 0.1710.171

RangeRange 0.113-0.6240.113-0.624

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Frequencies of Marker Positives in HPC DonationsFrequencies of Marker Positives in HPC DonationsAll Submitting Sites; Date of Licensure-12/31/05All Submitting Sites; Date of Licensure-12/31/05139,654139,654 HPC Donations vs Control Donations HPC Donations vs Control Donations

Anti-HIV per 10,000 Anti-HIV per 10,000 donationsdonations

HIV-1 NAT per HIV-1 NAT per 10,000 donations10,000 donations

HPC TotalHPC Total 0.360.36 00

Bone Marrow/PSBone Marrow/PS 0.000.00 00

Cord Blood onlyCord Blood only 0.180.18 00

PS onlyPS only 2.242.24 00

UnknownUnknown 00 00

HPC RangeHPC Range 0-2.240-2.24 NANA

Control RangeControl Range 0.10-3.960.10-3.96 0-0.0170-0.017

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Frequencies of Marker Positives in HPC DonationsFrequencies of Marker Positives in HPC DonationsAll Submitting Sites; Date of Licensure-12/31/05All Submitting Sites; Date of Licensure-12/31/05139,654 139,654 HPC Donations vs Control DonationsHPC Donations vs Control Donations

Anti-HCV per Anti-HCV per 10,000 donations10,000 donations

HCV NAT per HCV NAT per 10,000 donations10,000 donations

HPC TotalHPC Total 15.4015.40 0.930.93

Bone Marrow/PSBone Marrow/PS 33.2433.24 1.281.28

Cord Blood onlyCord Blood only 14.1114.11 0.960.96

PS onlyPS only 20.8920.89 00

UnknownUnknown 00 2.302.30

HPC RangeHPC Range 0-33.240-33.24 0-2.300-2.30

Control RangeControl Range 0.32-118.710.32-118.71 0-0.4170-0.417

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Frequencies of Marker Positives in HPC DonationsFrequencies of Marker Positives in HPC DonationsAll Submitting Sites; Date of Licensure-12/31/05All Submitting Sites; Date of Licensure-12/31/05109,286 109,286 HPC Donations vs Control DonationsHPC Donations vs Control Donations

Anti-HBc per Anti-HBc per 10,000 donations10,000 donations

HBsAg per HBsAg per 10,000 10,000

donationsdonations

HBV NAT per HBV NAT per 10,000 10,000

donationsdonations

HPC TotalHPC Total 274.42274.42 25.4425.44 00

Bone Bone Marrow/PSMarrow/PS

132.97132.97 9.019.01 00

Cord Blood Cord Blood onlyonly

301.44301.44 28.8828.88 00

PS onlyPS only 100.0100.0 1.591.59 00

UnknownUnknown 87.3087.30 2.302.30 00

HPC RangeHPC Range 87.30-301.4487.30-301.44 1.59-28.881.59-28.88 00

Control Control RangeRange

12.98-441.7412.98-441.74 0.176-17.910.176-17.91 nana

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Frequencies of Marker Positives in HPC DonationsFrequencies of Marker Positives in HPC DonationsAll Submitting Sites; Date of Licensure-12/31/05All Submitting Sites; Date of Licensure-12/31/05

38,05238,052 HPC Donations vs Control Donations HPC Donations vs Control Donations

WNV NAT per 10,000 donationsWNV NAT per 10,000 donations

HPC TotalHPC Total 0.790.79

Bone Bone Marrow /PSMarrow /PS

00

Cord Blood Cord Blood onlyonly

00

PS onlyPS only 1.891.89

UnknownUnknown 5.515.51

HPC RangeHPC Range 0-5.510-5.51

Control RangeControl Range 0.113-0.6240.113-0.624

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Comparisons by MarkerComparisons by MarkerHPC vs Control Sample Sets Analyzing Controls as: HPC vs Control Sample Sets Analyzing Controls as:

Combined, Allogeneic and AutologousCombined, Allogeneic and Autologous HIVHIV

– Antibody => only significant difference observed was Antibody => only significant difference observed was autologous > HPCsautologous > HPCs• 2.91 autologous vs 0.36 HPCs/10,000 donations2.91 autologous vs 0.36 HPCs/10,000 donations

– NAT => no HIV yield samplesNAT => no HIV yield samples HCVHCV

– Antibody => significant differences observed where Antibody => significant differences observed where autologous > all othersautologous > all others• 105 autologous vs 15.40 HPCs/10,000 donations105 autologous vs 15.40 HPCs/10,000 donations

– NAT => no significant differences between autologous NAT => no significant differences between autologous and HPC donationsand HPC donations• Confirmatory data lacking for five of thirteen HCV Confirmatory data lacking for five of thirteen HCV

NAT yield HPC donationsNAT yield HPC donations

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Comparisons by MarkerComparisons by MarkerHPC vs Control Sample Sets Analyzing Controls as: HPC vs Control Sample Sets Analyzing Controls as:

Combined, Allogeneic and AutologousCombined, Allogeneic and Autologous HBVHBV

– Antibody => significant differences where autologous highestAntibody => significant differences where autologous highest• 30 allogeneic, 36 combined, 274 HPCs vs 401 30 allogeneic, 36 combined, 274 HPCs vs 401

autologous/10,000 donationsautologous/10,000 donations– HBsAg => significant differences where HPC highestHBsAg => significant differences where HPC highest

• 1.29 allogeneic, 1.49 combined, 14.16 autologous vs 1.29 allogeneic, 1.49 combined, 14.16 autologous vs 25.44 HPCs/10,000 donations25.44 HPCs/10,000 donations

• Impact of Ortho 3 false positivity unknownImpact of Ortho 3 false positivity unknown– 70% (196/278) of HPC positives Ortho 3 confirmed70% (196/278) of HPC positives Ortho 3 confirmed

– NAT => no yield samplesNAT => no yield samples

WNVWNV– NAT => no significant differences between any groupsNAT => no significant differences between any groups

• Confirmatory data lacking for two of three WNV NAT Confirmatory data lacking for two of three WNV NAT yield HPC donationsyield HPC donations

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Comparison of Prevalence Rates/10,000 donationsComparison of Prevalence Rates/10,000 donations

Combined Combined Whole Whole BloodBlood

Autologous Autologous Whole Whole BloodBlood

Combined Combined HPCsHPCs

Anti-HIVAnti-HIV 0.300.30 2.91*2.91* 0.360.36

Anti-HCVAnti-HCV 5.105.10 104.7*104.7* 15.4015.40

Anti-HBcAnti-HBc 35.6135.61 401.3*401.3* 274.4274.4

HBsAgHBsAg 1.491.49 14.1614.16 25.44*,**25.44*,**

*p<0.05 for one or multiple comparisons; ** Ortho System 3

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Summary and ConclusionsSummary and Conclusions Overall comparison of prevalence rates shows no Overall comparison of prevalence rates shows no

difference between control groups and HPC difference between control groups and HPC donationsdonations– 3 of 4 cases autologous higher, 1 case of 4, HPC higher 3 of 4 cases autologous higher, 1 case of 4, HPC higher

where Ortho 3 used only for HPC groupwhere Ortho 3 used only for HPC group

No significant differences in incidence (as No significant differences in incidence (as determined by NAT yield) observed between control determined by NAT yield) observed between control groups and HPC donationsgroups and HPC donations– With HPC NAT-reactives mostly unconfirmed With HPC NAT-reactives mostly unconfirmed

No additional risk of MP NAT for HPC donations as No additional risk of MP NAT for HPC donations as compared to the control groups for which MP NAT compared to the control groups for which MP NAT occursoccurs

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Next StepsNext Steps

Share presentation with test kit Share presentation with test kit manufacturersmanufacturers

Prepare line listings by submitting Prepare line listings by submitting site/donation type, including analysis versus site/donation type, including analysis versus control population and provide to the NAT control population and provide to the NAT test kit manufacturers for labeling test kit manufacturers for labeling modifications to allow MP NAT of HPC modifications to allow MP NAT of HPC donations donations

Next series of slides highlight the Next series of slides highlight the individual manufacturers’ data (3/20/06)individual manufacturers’ data (3/20/06)

cell therapy liaison meeting january 27, 2006 industry – outline of issues and data

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